Clinical Immunology_ Principles and Practice ( PDFDrive )

772 Part six Systemic Immune Diseases



TABLE 57.3 Genetic Factors implicated in spondyloarthritis
HLA-B27 AS = 90%, reactive arthritis = 70%; psoriatic spondylitis = 70%; peripheral psoriatic arthritis = 24%; IBD-associated arthritis =
60%. No association with psoriasis, Crohn disease, ulcerative colitis, or peripheral enteropathic arthritis
Other MHC genes AS=B*40, B*51, A*02, MICA*007, *019
IBD—None for Crohn disease per se; HLA-DRB1*01:03 for peripheral arthritis with IBD;HLA-DRA locus with UC; HLA-C*06:02
with psoriasis, HLA-B*38, B*39 with psoriatic arthritis
AS, CD, UC, and PS IL23R, IL10, ADCY3, IL12B, CDKAL1, CCL21, ZMIZ1, ETS1, SH2B3, FOS, TNP2, RPS6KB1, RAVER1, TYK2, DNMT3B, UBE2L3
AS, PS, and CD SP140, FUT2
AS, PS, and UC CD28, IRF5
AS, CD, and UC RORC, HMGN2P18, ITLN1, FCGR2A, DNMT3A, IL1R2, CXCR2, GPR35, MST1, ANTXR2, PTGER4, ERAP2, C5orf56, IRGM,
BACH2, C7orf72, JAK2, TLR4, ZNF365, NKX2-3, OR5B21, SMAD3, NOD2, IL27, ZPBP2, PTPN2
AS and CD alone IL6R, ANKRD55, FGFR1OP, TNFSF8, NOTCH1, TFRSF1A/LTBR, RIC8B, LSM14
AS and UC alone ASAP2, ITGAL, FAM118A
AS and PS alone ERAP1, TNFAIP3, ZC3H12C, PPP2R3C, NOS2
CD, UC, and PS PARK7, OSMR, RN7SKP226, IL2RA, PLAU, TSPAN14, NFKBIA, STAT3
CD and PS FIBP, TAGAP
UC and PS GNA-12, HDAC7A
CD and UC SDF4, PTPN22, DENND1B, GCKR, FOSL2, THADA, PUS10, IL18R1, BANK1, IL21, DAP, NDFIP1, PRDM1, SKAP2, TNFSF15,
CREM, GLYAT, CD6, IFNG-AS1, LINC00284, FNDC3A, UBAC2, CLEC16A, PRKCB, ORMDL3, CD226, KEAP1, PKIG, CD40,
ZNF831, TNFRSF6B, UQCR10
AS alone IL1R1, CMC1, NPM1P17, ACTA2, NPEPPS, ERN1
CD alone HIPK1, GBAP1, TEX41, TG16L1, GAL3ST2, CPEB4, CCR6, JAZF1, MYRF, LRRK2, SR1, C17orf67, NFATC1, SBNO2, STK11,
PPP5C, IFNGR2
UC alone TNFRSF14, RNF186, HSPA6, NR5A2, IL8RA; LSP1, NXPE1, SLC39A11, HNF4A, UBASH3A
PS/PsA alone IFNLR1, LCE3B, IL36RN, STAT4, IL17RD, FBXL1, IL4/IL13, TNIP1, TRAF3IP2, DEFB4, IL23A, IL22, GJB2, SETD1A, CARD14,
SOCS3, STARD6, ILF3, CARM1, SLC9A8, RNF114
HLA, human leukocyte antigen; MHC, major histocompatibility complex; IL23R, interleukin-23 receptor; ADCY3, adenylate cyclase 3; CDKAL1, CDK5 regulatory subunit-associated
protein 1-like 1; CCL21, chemokine; CC motif, ligand 21; IL12B, The Interleukin-12 p40 subunit; ZMIZ1, zinc finger MIZ-domain containing 1; ETS1, V-ETS avian erythroblastosis
virus E26 oncogene homologue 1; SH2B3, SH2B adaptor protein 3; FOS, V-FOS FBJ murine osteosarcoma viral oncogene homologue; TNP2, transition protein 2; RPS6KB1,
ribosomal protein S6 kinase, 70-kDa, 1; TYK2, tyrosine kinase 2; DNMT3B, DNA methyltransferase 3b; UBE2L3, ubiquitin-conjugating enzyme E2L; SP140, nuclear body protein
140; FUT2, fucosyl transferase 2; CD28, CD28 antigen; IRF5, interferon regulatory factor 5; RORC, RAR-related orphan receptor C-3; HMGN2P18, high mobility group nucleosomal
binding domain 2 pseudogene 18; ITLN, intelectin 1; FCGR2A, Fcγreceptor 2A; DNMT3A, DNA methyltransferase 3b; IL1R2, interleukin-1 receptor, type II; CXCR2, chemokine, CXC
motif, receptor 2; GPR35, G protein–coupled receptor 35; MST1, macrophage stimulating 1; ANTXR2, anthraxin receptor receptor 2; PTGER4, Prostaglandin E receptor 4, EP4
subtype; ERAP2, endoplasmic reticulum–associated aminopeptidase 2; C5orf56, chromosome 5 open reading frame 56; IRGM, immunity-related GTPase family, M; BACH2, basic
leucine zipper transcription factor 2; C7orf72, chromosome 7 open reading frame 72; JAK2, Janus kinase 2; TLR4, Toll-like receptor 4; ZNF365, Zinc finger protein 365; NKX2-3,
NK2 homeobox 3; OR5B21, olfactory receptor family 5 subfamily B member 21; SMAD3, Mothers against decapentaplegic, Drosophila, homologue of, 3; NOD2, Nucleotide-binding
oligomerization domain protein 2; IL27, interleukin-27; ZPBP2, zona pellucida–binding protein 2; PTPN2, protein tyrosine phosphatase, non–receptor type, 2; IL6R, interleukin-6
receptor; ANKRD55, ankyrin repeat domain–containing protein 55; FGFR1OP, fibroblast growth factor receptor 1 oncogene partner; TNFSF8, tumor necrosis factor ligand
superfamily, member 8; NOTCH1, NOTCH, Drosophila, homologue of, 1; TFRSF1A/LTBR, tumor necrosis factor receptor superfamily, member 1A/ lymphotoxin B receptor; RIC8B,
RIC8, C. elegans, homologue of, b; LSM14, LSM Protein A; ASAP2, development-and differentiation-enhancing factor 2; ITGAL, integrin, alpha-L; FAM118A, family with sequence
similarity 118 member A; ERAP1, endoplasmic reticulum aminopeptidase I; TNFAIP3, tumor necrosis factor-α-induced protein 3; ZC3H12C, zinc finger CCCH domain-containing
protein 12C; PPP2R3C, protein phosphatase 2, regulatory subunit B-double prime, γ; NOS2, nitric oxide synthase 2A; PARK7, Parkinson disease 7, autosomal recessive early-onset;
OSMR, oncostatin M receptor; RN7SKP226, RNA, 7SK small nuclear pseudogene 226; IL2RA, interleukin-2, receptor alpha; PLAU, plasminogen activator, urinary; TSPAN14,
tetraspanin 14; NFKBIA, nuclear factor of κ light chain gene enhancer in B-cell inhibitor, α; STAT3, signal transducer and activator of transcription 3; FIBP, fibroblast growth factor,
acidic, intracellular binding protein; TAGAP, T-cell activation GTPase-activating protein; GNA-12, guanine nucleotide-binding protein, α-12; HDAC7A, histone deacetylase 7A; SDF4,
stromal cell-derived factor 4; PTPN22, protein tyrosine phosphatase, non–receptor type, 22; DENND1B, DENN/MADD domain-containing protein 1B; GCKR, glucokinase regulatory
protein; FOSL2, FOS-like antigen 2; THADA, thyroid adenoma-associated gene; PUS10, pseudouridylate synthase 10; IL18R1, Interleukin-18 receptor; BANK1, B-cell scaffold protein
with ankyrin repeats 1; IL21, interleukin-21; DAP, death-associated protein; NDFIP1, NEDD4 family-interacting protein 1; PRDM1, PR domain-containing protein 1;SKAP2, SRC
kinase associated phosphoprotein 2; TNFSF15, tumor necrosis factor ligand superfamily, member 15; CREM, cAMP response element modulator; GLYAT, glycine N-acyltransferase;
CD6, CD6 molecule; IFNG-AS1, interferon gamma antisense RNA 1; LINC00284, long intergenic non–protein coding RNA 284; FNDC3A, fibronectin type III domain containing 3A;
UBAC2, UBA domain containing 2; CLEC16A, C-type lectin domain family 16, member A; PRKCB, protein kinase C, subunit B; ORMDL3, ORM1-like protein 3;CD226, CD226
antigen; KEAP, KELCH-like ECH-associated protein 1; PKIG, protein kinase, cAMP-dependent catalytic, inhibitor gamma; CD40, CD40 antigen; ZNF831, zinc finger protein 831;
TNFRSF6B, tumor necrosis factor receptor superfamily, member 6B; UQCR10, ubiquinol-cytochrome c reductase complex, 7.2-kDa subunit; IL1R1, interleukin-1 receptor, type I;
CMC1, COX assembly mitochondrial protein 1, S. cerevisiae, homologue of; NPM1P17, nucleophosmin 1 (nucleolar phosphoprotein B23, numatrin) pseudogene 17; ACTA2, actin,
α 2, smooth muscle, aorta; NPEPPS, aminopeptidase, puromycin-sensitive; ERN1, endoplasmic reticulum-to-nucleus signaling 1; HIPK1, homeodomain-interacting protein kinase 1;
GBAP1, glucosylceramidase β pseudogene 1; TEX41, testis expressed 41 (non–protein coding); ATG16L1, autophagy 16-like1; GAL3ST2, galactose-3-O-sulfotransferase 2; CPEB4,
cytoplasmic polyadenylation element-binding protein 4; CCR6, chemokine, cc motif, receptor 6; JAZF1, juxtaposed with another zinc finger gene 1; MYRF, chromosome 11 open
reading frame 9; LRRK2, leucine-rich repeat kinase 2; KSR1, kinase suppressor of RAS 1; C17orf67, chromosome 17 open reading frame 67; NFATC1, nuclear factor of activated
T-cells 1; SBNO2, strawberry notch, Drosophila, homologue of, 2; STK11, serine/threonine protein kinase 11; PPP5C, protein phosphatase 5, catalytic subunit; IFNGR, interferon-
γreceptor 1; TNFRSF14, tumor necrosis factor receptor superfamily, member 14; RNF186, Ring finger protein186; HSPA6, heat-shock 70-kDa protein 6; NR5A2, nuclear receptor
subfamily 5, group A, member 2; IL8RA, interleukin-8 receptor A; LSP1, lymphocyte specific protein 1; NXPE1, neurexophilin and PC-esterase domain family member 1; SLC39A11,
solute carrier family 39 (zinc transporter), member 11; HNF4A, hepatocyte nuclear factor 4-α; UBASH3A, ubiquitin-associated and SH3 domain-containing protein A; IFNLR1,
interferon-λ receptor 1; LCE3B, late cornified envelope protein 3b; IL36RN, Interleukin-36 receptor antagonist; STAT4, signal transducer and activator of transcription 4; IL17RD,
interleukin-17 receptor D FBXL1, S-phase kinase-associated protein 2; IL4/IL13, Interleukin-4/interleukin-13; TNIP1, TNFAIP3-interacting protein 1; TRAF3IP2, TRAF3-interacting
protein 2; DEFB4, Defensin β, 4A; IL23A, interleukin-23; IL22, interleukin-22; GJB2, gap junction protein, β 2 ; SETD1A, SET domain-containing protein 1A; CARD14, caspase
recruitment domain-containing protein 14; SOCS3, suppressor of cytokine signaling 3; STARD6, START domain-containing protein 6; ILF3, interleukin enhancer–binding factor 3;
CARM1, coactivator-associated arginine methyltransferase 1; SLC9A8, Solute carrier family 9 (sodium/hydrogen exchanger), member 8; RNF114, ring finger 114 protein.

CHaPtEr 57 Spondyloarthritis 773



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FiG 57.1 The six major families of human leukocyte antigen (HLA)-B27 subtypes (HLA- B*27:59,
B*27:64, B*27:65 and B*27:94 represent truncated genes with deletions of most of exons 2
and 3 and are not included above) are denoted in relationship to the “parent” subtype HLA-B*27:05.
The ethnic or geographic origin of the subtypes is indicated in parentheses next to the allele:
EU, European; NA, North American; SA, South American; EA, East Asian; SEA, Southeast Asian;
NEA, Northeast Asian; ME, Middle East; Afr, African; UK, British Isles; Tur, Turkish; Mex, Mexican
mestizo. Where no parentheses are given, the origin of the cell line from which the sequence
came is unknown. Most B27 subtypes have evolved through five patterns of evolution along
geographic lines. The first group, with HLA-B*27:02-B*27:23 (and B*27:30), appears to have
evolved in Europe and the Middle East, entails anywhere from one to seven amino acid substitu-
tions in the first (α 1 ) domain, and has the second (α 2 ) domain identical to B*27:05. The second
group, including HLA-B*27:04 as the most common allele, evolved in Eastern Asia and includes
a uniform amino acid substitution in the α 1 domain and anywhere from one to seven substitutions
in the α 2 domain. The third and fourth groups seem to have evolved directly from HLA-B*27:05,
from mutations in either exon 2 or 3, respectively. The fifth group, including HLA-B*27:07 as its
leading member, evolved in southern and eastern Asia, the Middle East, and Sardinia with patterned
amino acid substitutions in the α 2 domain. Finally, the sixth group, with HLA-B*27:08 as its
common member evolved largely in East Europe, has different characteristic pattern of amino
acid substitutions in the α 2 domain. Notable exceptions include HLA-B*27:13, B*27:109 and
B*27:112-27:115, which have amino acid substitution outside α 1 and α 2 in the membrane proximal
(α 3 ) domain. (Data are derived from http://www.ebi.ac.uk/cgi-bin/imgt/hla/allele.cgi.)





proinflammatory target or receptor for humoral or cell-mediated whereas SpA will develop in up to 20% of HLA-B27–positive
autoimmune responses. However, it is not yet known whether relatives of patients with AS. Family studies have suggested that
HLA-B27 homodimer formation is specific for, or even correlates HLA-B27 contributes less than 40% of the overall genetic risk
12
with, the presence of SpA; in fact, disease does not develop in for SpA, whereas the entire effect of the MHC is about 50%. 11,13
most HLA-B27–positive individuals. HLA-B60, a serologically defined HLA specificity that cor-
relates with HLA-B*40:01 on DNA analysis, has been described
Other MHC Genes and SpA Susceptibility as augmenting the risk for AS in both HLA-B27–positive and
HLA-B27 is not the only genetic factor involved in AS and SpA HLA-B27–negative individuals from Europe and Taiwan. 11,13
susceptibility (see Table 57.3). Fewer than 5% of HLA-B27–posi- Other MHC genes have also been implicated in AS in addition
tive individuals in the general population become affected, 11,13 to B27, although their identification is complicated by the tight

774 Part six Systemic Immune Diseases



CD4 positive
T lymphocyte
Natural killer
CD8 positive (NK) cell
T lymphocyte
αβ KIR receptor
T cell B2
receptor
Free B27 HLA-class II
heavy chain (DR, DQ, DP) HLA-B27 homodimers
A2 presenting at cell surface A2
HLA-B27:B2microglobulin:peptide HLA-B27 peptide
trimolecular complex
Endoplasmic reticulum BiP BiP ERAD
BiP BiP
B B27 misfolding,
homodimerization UPR
Golgi
B1 A1
B27 folding, assembly and HLA-B27:B2M:peptide trimolecular
loading of peptide Tapasin
B27 heavy chain (HC) complex transported to the cell
B2 microglobulin surface via the golgi apparatus
B27 HC folding (B2m) loading peptide loading
Calnexin Calreticulum
A BiP B2m Macrophage
Ribosome
TAP 1,2
proteolytic degradation
within proteasome peptide fragments
Viral, bacterial or
tumor protein



FiG 57.2 After transcription of the human leukocyte antigen (HLA)-B27 heavy chain on ribosomes,
it is inserted into the endoplasmic reticulum (ER), glycosylated, and two pathways ensue. (A)
The B27 heavy chain is retained through binding with calnexin and ERp57, folded into its tertiary
structure, and bound to β 2 microglobulin. After that calnexin releases the complex and it is
associated with calreticulum, which, in turn, chaperones the formation of the peptide loading on
to the complex of heavy chain, β 2 microglobulin and antigenic peptide, via the TAP proteins and
tapasin. The antigenic peptide is derived from intracellular proteins from viruses, bacteria, tumors,
and so on, that have been degraded in proteasomes, and then the peptides are trimmed for
optimal length for peptide loading by endoplasmic reticulum-associated aminopeptidases (ERAP1
and ERAP2). Then the trimolecular peptide complex (HLA-B27 heavy chain, β 2 microglobulin and
peptide) travels through the Golgi apparatus (A1) to the cell surface, where the antigenic peptide
is presented either to the α: β T-cell receptor on CD8 T lymphocytes or to the killer immunoglobulin
(KIR) receptor on natural killer (NK) cells (A2); or (B) the HLA-B27 heavy chain misfolds in the
ER, forming B27 homodimers and other misfoldings which are bound to the ER chaperone BiP.
Then, they either (B1) accumulate there, causing either ER-associated degradation (ERAD) or a
proinflammatory ER unfolded protein response (UPR); or (B2) the B27 homodimers migrate to
the cell surface, where they either become antigenic themselves or present peptide to receptors
on T cells and NK cells.


linkage disequilibrium found within the MHC, and many of HLA-DRB1*01:03 has been associated with enteropathic peripheral
the associations may reflect linkage to B27. These include the arthritis. 13
epithelial “stress” marker MICA, located adjacent to HLA-B27,
which acts as a ligand for cells expressing a common activator NK Non-MHC Genes in Susceptibility to Spondyloarthritis
receptor (NKG2D), as well as the tumor necrosis factor (TNF), Recent genome-wide association studies (GWAS) in AS from
heat shock protein (HSP)-70, LMP-2 and LMP-7, HLA-DRB1*01, the United Kingdom and North America 15,17 have implicated up
13
and DRB1*04 alleles. In addition, HLA-DRB1*08 has been to 70 genes in AS susceptibility (see Table 57.3). These genes fall
implicated both in susceptibility to uveitis in the setting of into the following functional networks:
AS and to juvenile-onset AS. 1,13 In psoriasis, the primary 1. Genes involved in IL-17–mediated immunity (IL23R,
MHC association is with HLA-Cw6 (HLA-C*06:02). Both TYK2, IL6R, IL7R?, IL27, IL1R2/IL1R1, IL12B, JAK2, RORC,
HLA-DRB1*04 and *07 alleles have been implicated in PsA. There PTGER4) (Note: Gene symbols are explained in the legend to
is not a significant MHC association with IBD per se, although Table 57.3.)

CHaPtEr 57 Spondyloarthritis 775


2. Genes involved in CD8 T-cell function (RUNX3, EOMES, the other for the receptor activator of NF-κB (RANK). No
IL7R, ITGAL) evidence was found for an MHC contribution to radiographic
3. Genes involved in peptide processing and presentation (HLA-B, severity.
ERAP1, UBE2L3, NPEPPS, ERN1, ASAP2)
4. Genes involved in microbial sensing (CARD9, NOS2, NOD2,
IRGM) Infection
5. Genes involved in nuclear factor (NF)-κB (NF-κB) activation A role for triggering infections has been better documented
(TLR4, NOD2, NOTCH1, TNFAIP3) in SpA than in most other rheumatic diseases. In developed
6. Others (ZMIZ1, FCGR2A, KIF21B, SH2B3, TNFRSF1A, GPR65, countries, the most frequent type of ReA occurs following
SULT1A1, GPR35, BACH2, ICOSLG, NKX2-3) urogenital infections with Chlamydia trachomatis (endemic
The most consistent (and best replicated) association is ReA). Postdysenteric ReA, more commonly encountered in
with ERAP1, which acts as a molecular ruler in the ER in “less technologically advanced countries,” occurs after various
trimming peptides processed in proteasomes to optimal Shigella and Salmonella (especially S. typhimurium and S.
length of nine amino acids for MHC class I binding and enteriditis), Campylobacter jejuni and C. fetus, and, in Europe,
presentation. HLA-B27–negative patients with AS lack an Yersinia enterocolitica species. Microorganisms implicated in
15
association with ERAP1, although an association with ERAP2 ReA share common biological features: (i) They can invade
is seen. mucosal surfaces and replicate intracellularly; and (ii) they
A number of genes whose products are operative in the Th17 contain lipopolysaccharide (LPS) in their outer membrane.
pathway have also been associated with AS susceptibility: the Of particular note, antigens from Salmonella, Yersinia, and
IL-23 receptor (IL23R), which pairs with the IL12RB1 gene Chlamydia have been found in the synovial tissues and fluids
product to confer IL-23 (but not IL-12) responsiveness on cells of patients with ReA, often many years after the initial infec-
expressing both subunits; prostaglandin E receptor 4 (PTGER4), tion. Although only bacterial fragments of the enteric pathogens
which stimulates dendritic cell (DC) production of IL-23 and, have been found, evidence for viable C. trachomatis and perhaps
in turn, Th17 expansion and is overexpressed in SpA synovium; C. pneumoniae have been demonstrated in several studies.
signal transducer and activator of transcription 3 (STAT3), a key Chlamydia and other organisms have also been reported in the
regulatory factor in Th17 responses; and IL-12β (IL12B), which joints of healthy individuals, and this has led to questioning
encodes the IL12p40 protein, a component of both IL-12 and of the pathogenic significance of these findings. Other data,
IL-23. however, support the likelihood that bacterial persistence plays
GWAS in psoriasis and PsA have identified over 60 genes an important role in ReA, including the finding of specific IgA
18
implicated in disease susceptibility outside the MHC. These antibodies and synovial T-cell proliferation to the initiating
include genes in common with those for AS (IL23R, IL12B, infectious agent.
CDKAL1, and ERAP1, the last showing interaction with
HLA-Cw6 similar to that seen with HLA-B27). Detailing all
the non-MHC genes associated with psoriasis is outside the The Gut and Spondyloarthritis
scope of this chapter. Non-MHC genes implicated in PsA In studies from Belgium and from Scandinavia, up to 50% of
susceptibility include IL-1A, as well as the IL-2/IL-21 and the patients with AS have microscopic ileal inflammation seen on
IL-4/IL-13 gene complexes (both important in Th2-associated ileocolonoscopy. Moreover, two-thirds of patients with undif-
autoimmunity). ferentiated SpA have histological gut inflammation. Gut inflam-
The first gene to be implicated in IBD susceptibility was NOD2/ mation in AS appears to be immunologically related to that seen
CARD15, which accounts for about 20% of CD susceptibility in CD. These observations have raised the speculation that the
and whose protein product serves as a receptor for bacterial inciting event in the SpA may be a breakdown of the gut–blood
products in monocytes that transduces signals leading to NF-κB barrier to intestinal bacteria, although such has yet to be proven.
activation. A number of GWAS conducted since then have It has been established that patients with AS and their relatives
17
implicated over 130 genes in IBD susceptibility, including 113 have increased intestinal permeability compared with healthy
for CD and 100 for UC, and at least 83 shared genes between controls.
CD and UC. The autophagy 16-like 1 gene (ATG16L1), which The bacterial population inhabiting human intestines,
is highly expressed in intestinal cell lines, is linked to CD sus- referred to as the gut microbiota (Chapter 14), is a vast
ceptibility. DCs from patients with CD with susceptibility variants microbial community. The number of bacteria in the human
in NOD2 or ATG16L1 are deficient in autophagy induction, gut outnumbers the cells in the body 10-fold, and they contain
20
suggesting that these genes influence bacterial degradation and 100 times more genes than in the entire body. In fact, there
interact with the MHC class II antigen-presenting machinery. is a beneficial relationship between the gut microbiome and
What is especially striking is the number of genes shared in the human system. The human gut provides nutrients and the
common with the various types of SpA, suggesting a common microbiome provides metabolic and physiological capacities,
pathogenesis. which possibly affect the education of the adaptive immune
system. Many studies, from early antibody and fecal carriage
studies suggesting a role for gut Klebsiella pneumonia in the
Genes and Severity of SpA pathogenesis of SpA (which has not been confirmed by modern
20
Disease severity in AS also has a hereditary component. By sequencing studies) to more recent findings showing an
defining severity on the basis of radiographic involvement, interplay between host genetics (e.g., HLA-B27) and intestinal
two genes have been identified in a large candidate gene bacterial composition and others suggesting a link between
19
study. One was the gene for cyclooxygenase I (COX-I), the intestinal dysbiosis and SpA, are suggesting that upsetting the
target of nonsteroidal antiinflammatory drugs (NSAIDs), homeostasis between the gut microbiome and the host immune

776 Part six Systemic Immune Diseases


20
systems. This is clearly an area where more work needs to CLINICAL FEATURES
be done.
Ankylosing Spondylitis
PATHOLOGY OF SPA Musculoskeletal Symptoms
One of the biggest problems with studies of the synovium KEY CONCEPts
in SpA and PsA is that most lesions are examined late in Clinical Features of Inflammatory Back Pain
the course of disease (i.e., in the hips), and this only at joint
replacement. Few data exist from early disease, and the dif- • Low-back pain that is present every day for at least 3 months
ficulty with tissue access further complicates this. 21,22 For the • Age of onset <45 years
most part, the synovium in SpA resembles that of rheumatoid • Morning stiffness in the back lasting at least 30 minutes
arthritis (RA), with some notable differences. The synovium in • Pain that is relieved by exercise and worsened by rest
SpA displays a tortuous vascular morphology compared with • Alternating buttock pain
• Relief with nonsteroidal antiinflammatory agents
the rheumatoid synovium, which is linear and has diminished
lymphoid aggregates. This may be caused by vascular endothelial
growth factor (VEGF) and the angiogenic growth factor Ang2,
the messenger RNA (mRNA) of which have been observed at The first symptoms of AS usually appear in adolescence or early
higher levels in the synovium in PsA compared with RA. VEGF adulthood and usually start before the age of 45 years. The
5
is particularly interesting because it can synergize with RANK hallmark of AS is the presence of inflammatory back pain, a
ligand (RANKL) to induce bone resorption and also synergize dull, persistent ache, usually in the buttocks or hips, that is worst
with bone morphogenetic proteins to trigger bone formation, in the early-morning hours (between 2 and 5 a.m.) and is associ-
both processes typical of the altered bone remodeling seen in PsA ated with morning stiffness lasting >30 minutes (and sometimes
and SpA. 21,22 several hours to all day). The pain is classically worsened by rest
Increased production of the scavenger receptor CD163 by or recumbency and improves with activity. One important
macrophages in both the lining and sublining layers is seen in component of inflammatory back pain is the striking improve-
20
SpA compared with RA. Local production of soluble CD163 ment that results from the use of NSAIDs (usually in high doses).
inhibits synovial T-cell activation, and levels of synovial CD163 Although the pain may be unilateral or intermittent at first (in
5
fall with effective treatment. Increased expression of Toll-like fact, alternating buttock pain is a cardinal feature of the disease),
receptors 2 and 4 (TLR2, TLR4) has been shown in SpA on within a few months it usually becomes persistent and bilateral,
+
4,5
CD163 peripheral blood mononuclear cells in patients with and the lower lumbar area becomes stiff and painful. Occasion-
synovitis, which decreases with TNF-α blockade. This leads to ally, the first symptom of AS comes from extraspinal sources,
the speculation that SpA represents an exaggerated inflammatory such as AAU, peripheral arthritis, or enthesitis, especially in
response of the innate immune system in genetically susceptible patients with disease onset in childhood.
patients. 22 In patients with AS, the most commonly affected joints outside
22
Osteoclasts also appear to have a role and have also been the spine are the hips (in up to 50% of patients), with rapidly
+
observed at the bone–pannus junction in PsA. In addition, CD14 progressive destructive arthritis that necessitates joint arthroplasty
monocytes that are committed to becoming osteoclasts or at an early age. A characteristic radiographic finding is a fairly
osteoclast precursors are increased in the circulation of patients characteristic osteophytic collar that forms at the junction of
23
with PsA compared with healthy controls and decline rapidly the femoral head and the neck. Peripheral arthritis other than
following treatment with TNF antagonists. The clinical improve- in the hips and shoulders is uncommonly seen in patients with
ment is accompanied by an MRI-defined reduction of bone AS but, when present, is typical of that seen in other types of
marrow edema. SpA, with an asymmetric oligoarthritis presenting predominantly
Even fewer data exist on enthesitis (the enthesium being the in the lower extremities.
insertion of tendons, ligaments, joint capsules, or fascia into Chest pain, often pleuritic, can be seen in patients with AS
bone). Pathological examination of enthesitis in AS demonstrates as a result of involvement of the costovertebral and manubri-
local inflammation, fibrosis, erosion, and ossification. Immu- osternal joints. This and progressive thoracic spinal involvement
nohistochemical staining for phosphorylated SMAD1/5 in may result in fusion of the costovertebral joints, with loss of
entheseal biopsies of patients with SpA reveals active bone chest expansion and a mechanical restrictive ventilatory defect.
morphogenetic protein signaling. 21 Enthesitis is a classic feature of AS and other SpA (Fig. 57.3).
The pathology of psoriasis consists of an inflammatory cell The most common (and most disabling) sites for enthesitis are
infiltration in the dermis, with localized increased cytokine in the foot, at the insertion of the Achilles tendon, and of the
production and hyperproliferation of keratinocytes (Chapter plantar fascia on to the calcaneus. 24
64). CD4 cells are prominent in the dermis, CD8 in the epi- Three physical measurements have been validated and rec-
dermis; Langerhans cells function as antigen-presenting cells ommended by an ASAS Working Group as useful for evaluating
(APCs). The synovium is infiltrated with CD8 T cells but patients with AS specifically and with inflammatory back pain
demonstrates less pronounced intimal lining layer hyperplasia in general. The Schober test is measured as the increase with
and fewer synovial T cells. It is more vascular than the synovium maximal forward spinal flexion with locked knees of a 10-cm
in RA, contains numerous B cells and macrophages, and has segment marked on the patient’s back with the inferior mark
upregulation of adhesion molecules, such as intercellular adhe- at the level of the posterosuperior iliac spines. The measured
sion molecule (ICAM)-1 and E-selectin, and overexpression distance should increase from 10 cm to at least 13.5 cm in an
of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, adult. Chest wall expansion with inspiration is measured with
and IL-18. 22 a tape measure placed circumferentially around the chest wall

CHaPtEr 57 Spondyloarthritis 777






















A B
FiG 57.3 (A) Achilles tendinitis/enthesitis in a patient with reactive arthritis. (B) Schematic drawing
of enthesitis, showing periosteal new bone formation, and subchondral bone inflammation and
resorption.


1
1
at the fourth intercostal space. Normal chest expansion in an cystoid macular edema. Rarely, increased ocular pressure is seen.
adult is >5 cm, although this may vary with age and gender. An Macular edema has been shown to be the main factor that
1
occiput-to-wall distance of >2.5 cm is definitely abnormal. To determines visual outcome in cases of uveitis. Although AAU
measure the occiput-to-wall distance, the patient stands with the is the most common uveitis associated with AS, posterior uveitis
heels and buttocks touching the wall behind and with the knees has been reported and tends to be more severe, especially in
straight. The patient is asked how far back he or she can move those with coexistent IBD. 1
the head, still keeping the chin in the normal position. In the Cardiac manifestations. The characteristic cardiac abnormali-
straight position, the distance between the posterior convexity of ties in AS are aortitis, aortic regurgitation, and conduction
the occiput and the wall is measured to the nearest 0.1 cm. The abnormalities. Less commonly associated cardiac conditions
better of two attempts is recorded. Anything >0 is regarded as include pericarditis, cardiomyopathy, and mitral valve disease.
abnormal. HLA-B27 is an important genetic risk factor for these cardiac
Another commonly employed measurement is lateral bending. conditions. Aortic regurgitation is well characterized and dis-
Here, the patient stands with the heels and back against the wall. tinguished from aortic valvular dysfunction in other disorders.
There is no flexion of the knees or bending forward. The distance Three factors contribute to the development of incompetent
between the patient’s middle fingertip and the floor is measured. aortic valves: dilatation of the aortic root, fibrotic thickening
The patient then bends sideways without bending the knees or and downward retraction of the bases of the cusps, and inward
lifting the heels. A second reading is taken, and the difference rolling of the edges or margins of the cusps. Aortic regurgitation
between the two is recorded. The best of two tries is recorded is present in 2–10% of patients with AS and increases in likelihood
for the left and right sides. The mean of left and right gives the with greater disease duration.
final result (in centimeters to the nearest 0.1 cm). Normal is Cardiac conduction abnormalities, including atrioventricular
>10 cm. and intraventricular blocks, have been regarded as the most
common cardiac complication in patients with AS. Complete
Extraarticular Manifestations heart block has been found in 1–9% of patients with AS.
Uveitis. The anterior portion of the uvea consists of the iris Electrophysiological studies show that the preferential level of
and ciliary body, and the posterior portion is known as the choroid. block is in the atrioventricular node itself, which is in contrast
Inflammation of the anterior uveal tract is known as anterior to most cases of acquired complete heart block, where 80%
uveitis or iritis (Chapter 74). When the adjacent ciliary body is are within or below the bundle of His. Rare complications
also inflamed, the process is known as iridocyclitis. AAU represents include myocardial involvement, mitral regurgitation, and
the typical uveitis found in SpA, occurring in up to 40% of pericarditis.
1
patients with AS, of whom approximately 90% are HLA-B27 Pulmonary manifestations. The incidence of pleuropulmonary
1
positive (see Table 57.2). Typically, AAU presents unilaterally involvement in AS is estimated to be 1%. The most frequently
with sudden onset, is self-limiting, and tends to be recurrent. recognized manifestations are upper-lobe fibrosis, mycetoma
Symptoms may include redness, pain, blurred vision, increased formation, and pleural thickening. Fusion of the costovertebral
lacrimation, photophobia, and miosis. The diagnosis is charac- joints caused by inflammation and ankylosis of the thoracic
teristically confirmed by slit-lamp examination, which is also spine may lead to restrictive ventilatory impairment on pulmonary
useful in monitoring response to treatment. function testing. The upper-lobe fibrosis tends to be progressive.
Prognosis is favorable in AAU, with resolution of symptoms Another common finding is the presence of bilateral symmetric
within a few weeks. However, if treatment is delayed or inadequate, apical pleural thickening. Several recent studies have demonstrated
complications may occur; these include anterior synechiae that high-resolution computed tomography (HRCT) is more
(adherence of the iris to the cornea), posterior synechiae (adher- sensitive than chest radiography in detecting the presence of
ence of the iris to the lens), which can lead to cataracts, and pulmonary abnormalities in AS, suggesting that pulmonary

778 Part six Systemic Immune Diseases


involvement in AS is more common than once thought. The symptoms has been reported in approximately one-third of
clinical implications of these observations remain unclear as patients with AS, with women reporting more depression than
lung involvement in AS is usually asymptomatic. men. Pain was found to be a major determinant of depression
Renal manifestations. Renal involvement in AS, although for women but was of lesser importance for men.
uncommon, can include secondary renal amyloidosis (AA type), AS in women. AS in women may not be as severe as it is in
NSAID nephropathy, and glomerulonephritis. men and may present with isolated neck pain in the absence of
26
Osteoporosis. Measuring bone mineral density in patients typical back pain. There tends to be a greater delay in the
with spondylitis is complicated by false increases in spinal density diagnosis of AS in women compared with that in men. Women
from dense syndesmophyte formation, leading some to recom- tend to have less severe involvement of the spine, with peripheral
mend quantitative CT over standard dual-energy X-ray absorp- joint involvement. A large review of the impact of AS on reproduc-
tiometry (DEXA) for bone mineral density measurements. tive events on women concluded that AS did not adversely affect
Nevertheless, up to half the patients with long-standing AS have the ability to conceive, pregnancy outcome, or neonatal health. 27
25
been reported as having osteopenia or osteoporosis, which has
been attributed to the impact of inflammation on bone remodel- Reactive Arthritis
ing as a result of aberrant activation of bone morphogenic protein The classic triad of arthritis, urethritis, and conjunctivitis,
and Wnt signaling. This may be further worsened by treatment representing what was formerly known as Reiter syndrome, is a
factors and decreased mobility or physical activity, in addition presenting feature of only a minority of patients with ReA
to osteoclast/osteoblast imbalance. 25 (comprising only a third of the cases in some series). In ReA,
Spondylodiscitis and spinal fractures. An uncommon but the clinical features are nowadays viewed more as a spectrum
well-recognized complication of AS is spondylodiscitis, a destruc- ranging from the classic triad to undifferentiated SpA. In fact,
26
tive discovertebral lesion also called Andersson lesion. Typically, the manifestations vary among patients, depending on the genetic
these lesions are confined to the thoracolumbar spine, sometimes makeup, the triggering event, and the sequential immunological
with multiple-level involvement. Pain and tenderness localized reaction.
to the affected disk are the most common presenting features Typically, the features start 1–4 weeks after a triggering event,
of spondylodiscitis, although it can be asymptomatic and only frequently identified as an enteric or urogenital infection, but
detected on routine radiographic examination many years later. often the event passes unnoticed without any specific symptoms.
Spondylodiscitis usually occurs at an advanced stage of AS under The syndrome starts with constitutional symptoms, such as
the form of an erosive condition related to both mechanical fatigue, malaise, and fever, and then is typically manifested by
factors and osteoporosis. However, early spondylodiscitis may asymmetrical, additive lower-extremity oligoarticular inflam-
occur as a result of the inflammatory process. Patients may or matory arthritis along with an array of different extraarticular
may not have a history of preceding trauma. features, including a sterile oligoarticular or monoarticular and
Even trivial falls can be catastrophic for AS patients, who are asymmetrical arthritis of the lower extremities, especially knees,
at risk for spinal fractures because of their spinal rigidity and ankles, and, occasionally, hips. Upper-extremity involvement is
osteoporosis. The estimated prevalence of vertebral fractures in encountered less commonly. Dactylitis occurs in the toes or
AS varies from 4% to 18%. Fractures through the disk space, fingers, resulting in the “sausage digits,” which represent inflam-
the weakest point in the ankylosed spine, are most common, mation not only of the interphalangeal joints of the hands and
with the cervical spine being the most frequently affected region, feet but also of the surrounding soft tissue structures, including
followed by the thoracolumbar junction, and may or may not tendons and subcutaneous tissue.
be complicated by injury to the spinal cord, ranging from mild Sacroiliitis and spondylitis are less common than peripheral
sensory loss to quadriplegia. Spontaneous atlantoaxial subluxation arthritis, although inflammatory back pain does occur. Unilateral
is also rarely seen. and bilateral sacroiliac involvement and even spondylitis occur,
Neurological manifestations. Neurological involvement in AS especially in those with chronic or long-standing disease. The
is most often related to spinal fracture, atlantoaxial subluxation, most common sites for enthesitis are the Achilles tendon and
or cauda equina syndrome. The cauda equina syndrome in AS plantar fascia insertions, although tenderness over the symphysis
is characterized by a slow insidious progression and a high pubis, iliac crest, ischial tuberosity, greater trochanters, and
incidence of dural ectasia, although a rapid onset secondary to thoracic cage ribs may also occur.
a traumatic event has been reported. It tends to be a late manifesta- Mucocutaneous lesions may be difficult to distinguish from
tion of AS, often when the disease is no longer active. The PsA, especially circinate balanitis and keratoderma blennorrhagica.
prevalence of neurological findings in cauda equina syndrome Circinate balanitis is an ulcerative mucosal lesion over the glans
in AS is very high, presenting with a prodrome of sensory, motor, or shaft of the penis that is demarcated by a serpiginous
or reflex loss before the progression to sphincter disturbance. erythematous border. The lesion is usually painless and sterile
About half the patients have pain in the rectum or lower limbs unless a superimposed infection occurs. Keratoderma blennor-
that is presumably neurogenic in origin. Case reports have also rhagica is a painless desquamative psoriatic-like papulosquamous
been published about the occurrence of AS with a multiple eruption and is sometimes referred to as pustulosis palmoplantaris
sclerosis (MS)–like syndrome and transverse myelitis, although and occurs on the palms and soles of the feet. Oral lesions have
the association is not conclusive. been described as shallow, painless ulcers or patches on the palate
Fatigue and psychosocial manifestations. Fatigue is a common and tongue, or mucositis of the soft palate and uvula. Conjunc-
problem in AS and seems to be associated with more severe tivitis and AAU also occur, as described in AS. Conjunctivitis
disease. Sleep disturbance has been reported to be as high as may be unilateral or bilateral and is usually an early feature
nearly 81% of female patients with AS and 50% of male patients. manifesting with irritation, erythema, and lacrimation. It is
The disturbance is closely related to pain during the night usually associated with a sterile discharge unless a superimposed
characteristic of active disease. A high level of depressive infection occurs because of eye rubbing. It can be severe and

CHaPtEr 57 Spondyloarthritis 779


occasionally progresses to episcleritis, scleritis, or keratitis. Other Finally, pustular psoriasis is the type most closely associated
findings seen in AS, such as cardiac involvement, rarely occur. with HLA-B27. Usually, the disease appears coincident with or
Although renal involvement is mainly described in the context after the onset of skin manifestations, although approximately
of the urogenital triggering infectious process, sterile pyuria in 15–20% of patients will have preexisting arthritis. The joint
conjunction with proteinuria and microscopic hematuria are disease likewise occurs in different subtypes, as defined by the
sometimes encountered. Documented glomerulonephritis is Moll and Wright classification (Fig. 57.4), including oligoarticular,
rarely described. asymmetrical, polyarticular, symmetrical, distal interphalangeal
(DIP)-predominant, spondylitis (sacroiliitis), arthritis mutilans,
Juvenile Spondyloarthritis inflammation of DIP joints (often with nail involvement (≈80%)),
26
There are two clinical subsets of JSpA: (i) undifferentiated JSpA, dactylitis (“sausage digits”), and enthesitis. Extraarticular features
which includes peripheral arthritis and enthesitis, primarily affects include nail pitting (which correlates best with DIP involvement)
the lower limbs, may also present with sacroiliac tenderness and/ and uveitis (which occurs in some series as high as 33% but in
or inflammatory spinal pain, and also includes isolated episodes most far less). Radiographically, large eccentric erosions are
of arthritis, enthesitis, tendinitis, dactylitis, and seronegative encountered.
28
enthesopathy and arthropathy (SEA) syndrome ; (ii) differenti-
ated JSpA (juvenile AS, PsA, IBD-related arthropathy) includes Enteropathic Arthritis
peripheral arthritis and enthesitis plus evidence of structural The arthritis associated with IBD (enteropathic arthritis) is most
changes in juvenile AS (radiographic sacroiliitis, spinal disease, commonly nondestructive and reversible. Two patterns have been
or tarsal ankylosis) and/or specific extraarticular symptoms (e.g., recognized (Table 57.4). Type 1 is oligoarticular, involving the
psoriasis or IBD). SEA syndrome was originally referred to the knees and ankles more than the upper extremities. It tends to
combination of enthesitis and arthritis or arthralgia as an resolve in <6 weeks. The second type has a polyarticular presenta-
idiopathic disease or as part of a well-defined SpA. 27 tion, is more likely to involve the metacarpophalangeal (MCP)
and proximal interphalangeal (PIP) joints than the lower extremi-
Psoriatic Arthritis ties, and is more likely to have a chronic course. The symptoms
29
Skin involvement exhibits four clinical patterns. The most of peripheral arthritis tend to coincide with activity of the bowel
common type is psoriasis vulgaris. Nearly as common is guttate disease in UC but not in CD. Total colectomy is associated with
psoriasis. The most severe type is the erythrodermic variety. remission of arthritis in half the patients. In contrast, axial






















$ %



















& '
FiG 57.4 Patterns of psoriatic arthritis, showing (A) rheumatoid-like distribution; (B) sausage
digits; (C) distal interphalangeal involvement; and (D) psoriatic arthritis mutilans.

780 Part six Systemic Immune Diseases



TABLE 57.4 Extraintestinal Manifestations TABLE 57.5 Frequencies of Different
of inflammatory Bowel Disease symptoms and signs in Patients With
Undifferentiated spondyloarthritis
Crohn Disease Ulcerative Colitis
Feature (%) (%) Feature Percent (%)
Peripheral arthritis 15 10 Demographic
Axial arthritis 15–20 10–15 Males 62–88
Septic arthritis Rare No association Mean age at onset (years) 16–23
Skin <9 <1
Aphthous ulcers Rare 8 Clinical
Nephrolithiasis <15 No association Low-back pain 52–80
Liver disease 3–5 7
Uveitis 13 4 Peripheral arthritis 60–100
Polyarthritis
40
Vasculitis Takayasu arteritis <5
Clubbing of fingers 4–13 1–5 Enthesopathy 56
Heel pain 20–28
Mucocutaneous involvement 16
Conjunctivitis 33
Genitourinary disease 28
involvement may precede the development of IBD, has no gender Inflammatory bowel disease 4
predilection, and resembles the development of AS. The axial Cardiac abnormalities 8
symptoms do not parallel activity of IBD. In addition to spon-
dylitis, an isolated sacroiliitis occurs that is often asymmetric Laboratory
and not associated with HLA-B27. Elevated erythrocyte sedimentation rate 19–30
Mucocutaneous complications of IBD include erythema Human leukocyte antigen (HLA)-B27 positive 80–84
nodosum, which occurs in fewer than 10% of those with CD radiographic
and is rare in UC; pyoderma gangrenosum, seen in slightly over Sacroiliitis 16–30
1% of those with CD and rarely occurring in those with UC; Spinal radiographic changes 20
and, rarely, erythema multiforme. Painful aphthous ulcers occur
in about 8% of those with UC and are rare in CD. Adapted from Chen CH, Lin KC, Yu DT, et al. Serum matrix metalloproteinases and
The uveitis with IBD that is bilateral, posterior, insidious in tissue inhibitors of metalloproteinases in ankylosing spondylitis: MMP-3 is a
reproducibly sensitive and specific biomarker of disease activity. Rheumatol (Oxf)
onset, and/or chronic in duration contrasts with the uveitis 2006; 45: 414–420.Table 56.6 Measurements of disease outcome in spondyloarthritis.
associated with other types of SpA, which is predominantly
anterior, unilateral, sudden in onset, and limited in duration.
Only 46% of patients with uveitis associated with IBD are
HLA-B27 positive, as opposed to 89% of the patients with SpA. AS is not excluded by normal ESR and/or CRP levels. Synovial
Episcleritis, scleritis, and glaucoma are more common among fluid does not differ in appearance or cytology from that of any
patients with IBD than in those with SpA. inflammatory joint disease.
Undifferentiated Spondyloarthritis
Patients who do not meet criteria or clinical features of the DIAGNOSIS
“classic” spondyloarthritides are regarded as having undifferenti-
ated SpA. Generally, at presentation, about 40% of patients will In most cases, SpA is largely diagnosed, or at least initially
30
be classified as having undifferentiated SpA, and the frequency suspected, on clinical grounds. Current criteria for AS demand
of HLA-B27 reaches around 80% in Caucasians (Table 57.5). that the patient have radiographic sacroiliitis (at least grade II
Follow-up studies suggest that over time about one-third will bilaterally or grade III unilaterally) in conjunction with clinical
go into remission and more than half will develop a “classic” signs of inflammatory back pain and limitation of spinal mobility.
SpA, usually AS. 30 However, given that up to 10 years can pass from the onset of
inflammatory back pain and the development of radiographic
sacroiliitis, many of those with inflammatory back pain might
LABORATORY INVESTIGATIONS not have radiographic evidence of sacroiliitis. With the develop-
ment of effective treatments (i.e., anti-TNF blockers), criteria
The most useful investigations in SpA come from musculoskeletal have been developed for earlier diagnosis of axial SpA that take
imaging, but some laboratory tests are informative. into account recent advances in MRI scanning as well as the
Data on the correlation of erythrocyte sedimentation rate added benefit provided in HLA-B27 testing. 5,6
(ESR) and cross-reactive protein (CRP) in the assessment of
disease activity in SpA show ambiguous results, although most Measures of SpA Activity and Severity
studies suggest that CRP performs better. A recent literature In the past few years, outcome measures have been developed
review on the validity of ESR and CRP in AS concluded that and validated to quantitate disease activity and severity; these
ESR and CRP do not comprehensively represent the disease are summarized in Table 57.6. These instruments are extensively
process and thus do not have the same validity as in RA. 13,30 validated and easy to administer in clinical practice and have
Generally, it is felt that patients with peripheral joint involvement been shown to perform well in clinical trials. The Ankylosing
or with IBD more often have elevated ESR and CRP than patients Spondylitis Disease Activity Scale (ASDAS) has recently been
13
with axial disease. However, the presence of clinically active developed to gauge disease activity.

CHaPtEr 57 Spondyloarthritis 781



TABLE 57.6 Measurements of Disease Radiographic Imaging of Spondyloarthritis
Outcome in spondyloarthritis Axial Spondyloarthritis
The bottom line in the diagnosis of AS is the demonstration of
ankylosing spondylitis radiographic sacroiliitis (Fig. 57.5). Two outcome instruments
4
1) Disease activity have been introduced in the assessment of disease damage and
(a) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) progression in AS: the Bath Ankylosing Spondylitis Radiographic
(b) Ankylosing Spondylitis Disease Activity Score (ASDAS) Index (BASRI) and the modified Stokes Ankylosing Spondylitis
(c) Patient and Physician Global Assessments 31
2) Function Scoring System (mSASSS). As a rule, these instruments have
(a) Bath Ankylosing Spondylitis Functional Index (BASFI) a low sensitivity to change (7.5% over 2 years), have been validated
(b) Dougados Functional Index in long-duration disease only, and their predictive effect for
3) Quality of Life disease activity is not yet ascertained.
(a) SF-36 One problem with radiographic imaging is the average decade-
(b) Ankylosing Spondylitis Quality of Life Index (ASQOL) long interval from the onset of inflammatory back pain to the
(c) ASAS Health Index 5
4) Metrometry appearance of radiographic sacroiliitis. The introduction of MRI
(a) Schober test (lumbar flexion) imaging of the spine and entheses has allowed not only correct
(b) Chest expansion anatomical description of spinal structures but also differentiation
(c) Occiput-to-wall distance of AS-related and unrelated inflammatory spinal lesions earlier
(d) Lateral bending than is possible with standard radiography. MRI of the sacroiliac
32
(e) Bath Ankylosing Spondylitis Metrology Index (BASMI) lateral joints and spine is currently the only imaging tool to localize
ending
5) Imaging and quantify spinal inflammation accurately (Fig. 57.6) and is
(a) Standard radiography being developed as a measure of disease activity and treatment
(b) Computed tomography response.
(c) Magnetic resonance imaging
6) Assessment in Ankylosing Spondylitis (ASAS) 20 Psoriatic Arthritis
(a) An improvement of 20% and absolute improvement of 10 units PsA has some characteristic radiographic manifestations, including
on a 0–100 scale in three of the following four domains:
i. Patient global assessment (by visual analogue scale [VAS] asymmetrical involvement, involvement of the DIP joints, and
global assessment) the classic “pencil-in-cup” deformities. Also seen are periostitis,
ii. Pain assessment (the average of VAS total and nocturnal pain bony ankylosis, and bony erosions with new bone formation.
scores) Radiographic severity is quantitated by the modified Sharp scoring
iii. Function (represented by BASFI) method used in RA.
iv. Inflammation (the average of the BASDAI’s last two VAS The measures used in PsA to assess disease severity include
concerning morning stiffness, intensity, and duration) the ACR response criteria, the Psoriatic Arthritis Response Criteria
v. Absence of deterioration in the potential remaining domain
(deterioration is defined as 20% worsening) (PsARC), which entail improvement in at least two of the fol-
lowing four criteria: (i) physician; and (ii) patient global assess-
Psoriatic arthritis ments (on 0–5 visual analogue scales); (iii) tender and swollen
1) Arthritis joint scores (>30% improvement), with improvement in at least
(a) ACR response criteria one of these two joint scales; and (iv) no worsening in any criteria.
(b) Psoriatic Arthritis Response Criteria (PsARC) The Ritchie Articular Index is also used. The Psoriasis Area and
(c) Ritchie Articular Index Severity Index (PASI) is used to assess the extent of skin involve-
2) Skin response ment, as well as general measures, such as the target lesion score,
(a) Psoriasis Area and Severity Index (PASI)
(b) Target lesion score and the static global assessment. The PASI is a composite index
(c) Static global assessment of skin disease severity, including an overall evaluation and
3) Quality of life (HAQ, SF-36, DLQI) quantitation of the extent of scaling, erythema, and induration
4) Radiographic weighted: (i) by severity; and (ii) by body surface area. A target
lesion is a single lesion >2 cm in diameter that is evaluated over
time by a dermatologist and is graded for size, elevation, erythema,
CLiNiCaL rELEVaNCE and scaling.
Utility of Human Leukocyte Antigen (HLA)-B27 DISEASE COURSE AND PROGNOSIS
Testing in the Evaluation of Inflammatory Back
Pain and Spondyloarthritis Ankylosing Spondylitis
AS significantly impacts the lives of those affected. Recent data
• Not indicated where the diagnosis is unquestionable, as it has little suggest that patients with AS are more likely to be work disabled or
value in prognosis. even not participate in the labor force compared with population
• Although patients with spondyloarthritis of African and Middle Eastern
ancestry are more likely to be HLA-B27 negative, the finding of HLA-B27 controls, especially in older patients and in those with longer
in these patients has higher predictive value. disease duration. Moreover, in the same study, patients with AS
• Most useful in patients with either inflammatory back pain without were more likely to have never married or to be divorced. Women
radiographic changes or with other features of spondyloarthritis with AS were less likely than expected to have had children. 32
(unexplained lower extremity arthritis in a young adult, uveitis, etc.). Although AS is a chronic condition that can frequently have
• If serological testing is used to ascertain HLA-B27, it must be ensured an unpredictable course, some studies suggest that those with
that the blood sample arrives in the laboratory within 24 hours of
being drawn (false negatives will be caused by cell death). higher levels of disease activity early in the course of the disease
33
are more likely to have active disease in the future (Fig 57.7).

782 Part six Systemic Immune Diseases

























A B


















C D
FiG 57.5 Grading of radiographic sacroiliitis, including (A) grade 0–1 (normal); (B) grade 2–3, with
sclerosis and small erosions; (C) advanced grade 3, with joint space narrowing and large erosions;
and (D) grade 4 (total sacroiliac fusion).

36
32
Hip involvement is a predictive factor for severe disease. Other general, the prognosis of ReA is fairly good. Most cases appear
factors that may suggest severe disease and severe outcome include to remit within 6 months of onset. Given the introduction of
ESR >30 mm/hr; unresponsiveness to NSAIDs; limitation of highly effective biological agents, such as anti-TNF blockers, it
lumbar spine; “sausage” digits; oligoarthritis; or onset at <16 is likely that the long-term prognosis in ReA will improve even
33
years. Longitudinal studies in patients with AS revealed that further.
deformities and disability occurred during the first 10 years of
disease and correlated significantly with the occurrence of Psoriatic Arthritis
peripheral arthritis, radiographic changes of AS in the spine, Recent studies—although before the introduction of biological
and the development of “bamboo” spine. 33 treatments—showed that the prognosis of PsA is worse than
Significant risk factors for work disability from several studies previously suggested. 29,37 In one large cohort, 40–57% of patients
3
include older age, longer disease duration, lower level of education, had deforming arthritis, 17% had five deformed joints, and up
reduced physical functioning, pain, and more physically demand- to 19% of patients had disability. Overall, more rapidly progressive
ing jobs. Patients with AS have an overall frequency of disability disease was associated with a greater number of actively inflamed
and economic costs similar to that of RA, with a threefold greater joints, the early use of disease-modifying agents, and the presence
rate of disability than the general population, a higher rate of of HLA-B27 and -B39. Patients with PsA have also been shown
sick leave episodes (up to 50% more), and an overall 8% loss of to have increased mortality, which is associated with a high ESR,
34
productivity. Moreover, a growing body of data has shown that high “advanced” medication use, and early radiographic damage.
patients with AS are at risk for early mortality as a result of
35
cardiovascular disease. However, the impact of newer agents, Juvenile Spondyloarthritis
such as anti-TNF and anti–IL-17 drugs, on the natural history Although not extensively studied, the prognosis in JSpA is
28
of this disease remains to be seen. guarded. Available data suggest that children with disease activity
for >5 years are more likely to be disabled. In fact, the probability
Reactive Arthritis of remission was only 17% after 5 years of disease. Nearly 60%
Early studies of outcome in ReA suggested a relatively poor of children with JSpA have moderate to severe limitation after
prognosis. More recent studies, however, have found that, in 10 years of disease. What is not clear is the extent to which the

CHaPtEr 57 Spondyloarthritis 783






























A






























B C
FiG 57.6 (A) Magnetic resonance imaging (MRI) of the sacroiliac joints, showing areas of marrow
edema (indicated by arrows) on STIR sequences. (B) Lateral spine, showing enhancement of
the insertion of the annulus fibrosis on the disk (arrowheads) and subchondral bone (arrows).
(C) Involvement of the subchondral bone of the apophyseal joints.





Patient Education and Physiotherapy
outcome in juvenile-onset AS is different from that in adult-onset
disease. A great deal of educational information is available for patients
(http://www.spondylitis.org and http://www.arthritis.org). Unsu-
TREATMENT pervised recreational exercise improves pain and stiffness, and
back exercise improves pain and function in patients with AS and
Recent guidelines for treatment of SpA have been put forth by other types of SpA, but these effects differ with disease duration.
the American College of Rheumatology and the European League Health status is improved when patients perform recreational
against Rheumatism based on current literature and clinical trials exercise at least 30 minutes per day and back exercises at least
(Table 57.7). 38,39 5 days per week.

784 Part six Systemic Immune Diseases























FiG 57.7 The “classic” course of ankylosing spondylitis, showing disease progression from shortly
after disease onset in 1947 until just before the patient’s death in 1973. The slight improvement
between 1972 and 1973 was as a result of his having undergone total hip arthroplasties.


TABLE 57.7 treatment of tHEraPEUtiC PriNCiPLEs
spondyloarthritis Treatment Principles for Medical Management of
• Patient education Spondyloarthritis
• Physiotherapy
• Medications • Patient education, regular exercise, smoking cessation, and physio-
• Nonsteroidal antiinflammatory drugs therapy should be initiated early in the disease course.
• Disease-modifying antirheumatic drugs • Nonsteroidal antiinflammatory drugs (NSAIDs) remain the “first-line”
• Sulfasalazine (especially for peripheral arthritis) treatment.
• Methotrexate (especially for psoriatic arthritis, psoriasis) • Disease-modifying antirheumatic drugs (DMARDs: sulfasalazine,
• Leflunomide methotrexate) are used for peripheral arthritis.
• Corticosteroids • Intraarticular/intralesional corticosteroid injections are administered.
• Systemic • Biological (anti–tumor necrosis factor [TNF], anti–interleukin-17 [IL-17]
• Intraarticular, intralesional agents) for axial disease refractory to NSAIDs, peripheral arthritis
• Biological agents refractory to DMARDs, and entheseal lesions refractory to NSAIDs.
• Tumor necrosis factor blockers • It is important to remember to treat coexistent/complicating conditions
• Interleukin (IL)-17/-IL-23 blockers (inflammatory bowel disease [IBD], psoriasis, osteoporosis, premature
• Treatment of osteoporosis atherosclerosis).
• Surgery
• Hip replacement
• Corrective spinal surgery
Other DMARDs. Although less well studied than sulfasalazine,
methotrexate has been shown to be effective in some but not all
studies of peripheral arthritis and psoriasis in patients with AS
Medical Treatment and other SpA. Its efficacy in treating axial SpA has not been
established.
Nonsteroidal Antiinflammatory Drugs The use of leflunomide in patients with SpA has not been
NSAIDs remain the starting point of treatment, and many well examined. Limited data suggest that it may be useful in the
patients will attain satisfactory symptom control with these agents treatment of peripheral joint involvement in SpA as well as PsA,
alone. There are no strong data to suggest the superiority of although not for axial involvement. Apremilast, an oral phos-
any specific NSAID in patients with SpA. NSAIDs when taken phodiesterase 4 inhibitor, has been shown to be effective in
regularly (not on an as-needed basis) and at full antiinflam- psoriatic arthritis but not in AS. 43
40
matory doses retard the radiographic progression of AS, an Corticosteroids. Although not well studied in patients with
41
observation that has recently been replicated. COX-2 antagonists AS, many clinicians add low-dose glucocorticoids to the manage-
are recommended mainly for patients with proven peptic ulcer ment of active SpA where NSAIDs or DMARDs fail to achieve
disease. Of concern is the association of the use of NSAIDs with a satisfactory response. On occasion, pulse steroids have also
flares of colitis, suggesting they should be used with care in been utilized. Given the lack of controlled data as to their
this setting. effectiveness, the side effects of long-term glucocorticoid therapy
(including osteoporosis, a major cause of morbidity in AS patients,
Disease-Modifying Antiinflammatory Drugs and possible worsening of psoriasis), and the emergence of more
Sulfasalazine. The efficacy of sulfasalazine in the treatment effective treatments, their use is not recommended unless more
of peripheral joint involvement in AS and other SpA has been effective treatments are not available.
shown in several controlled trials, including two large multicenter
42
studies in the United States and France. It is not efficacious in Intraarticular/Intralesional Corticosteroids
axial disease. Coincident with improvement in peripheral arthritis Intraarticular and peritendinous injections of depot steroid prepa-
is a fall in acute-phase reactants, such as the ESR and CRP. rations are frequently employed by clinicians for symptomatic

CHaPtEr 57 Spondyloarthritis 785


relief of local flare-ups, although they have not been extensively infusion of a chimeric mAb to TNF-α (infliximab) at 5 mg/kg
studied in controlled trials. Injecting around the Achilles of infliximab every 6–8 weeks; etanercept, given 50 mg subcutane-
tendon is generally not recommended because of the risk of ously weekly; adalimumab, which is used at a dose of 40 mg
tendon rupture. administered subcutaneously every other week; golimumab, at
a dose of 50 mg administered subcutaneously monthly; and
Antibiotics certolizumab, at either 200 mg administered subcutaneously
45
Early data suggested that a 3-month course of antibiotics in the every other week or 400 mg once a month. The onset of action
acute phase after disease onset may have a beneficial effect on is quite rapid, usually following the first infusion or injection.
46
the course of ReA, specifically in those with Chlamydia These agents are effective also in PsA and axial SpA. 45,47 Improve-
trachomatis–triggered ReA, but not in other patients. Recent ment was seen not only clinically but also radiographically, with
long-term follow-up data, however, suggest that tetracycline clearing of lesions suggestive of disease activity on MRI, and, in
treatment did not change the natural history of the disease. In studies extending >4 years, radiographically. Although earlier
another recent study, however, a 6-month course of azithromycin studies following up patients for 2 years did not demonstrate
and rifampin in the acute phase was found to have a beneficial that anti-TNF agents affect radiographic severity in AS, data
effect on the long-term prognosis, although this has not been from observational cohorts from North America and Europe
44
reproduced in all studies. It is clear that early antibiotic therapy spanning longer periods have shown they do, indeed, slow
for chlamydial genital infections can prevent ReA, although the radiographic progression, especially in those with shorter disease
same is not true for enteric pathogens. For patients at risk for duration treated for an extended period. 48
enteric infections and ReA, prophylactic antibiotics should be
considered. There is no evidence that antibiotics have any place Interleukin-17 Blockers (Secukinumab)
in the management of other SpA. Secukinumab is an anti–IL-17A mAb that has been shown to
control the symptoms of active AS in one phase II trial and two
TNF-α Blockers phase III clinical trials and has been approved by the FDA. The
49
This category of medications has been shown to be effective in impact of this medication on other disease features, such as
controlling inflammation and improving function in patients radiographic progression, remains to be determined.
with AS (Table 57.8). The use of TNF blockers in the treatment
of AAU is less clear, however. Recent data suggest they are useful, Surgical Treatment of AS Complications
1
at least those comprising monoclonal antibodies (mAbs). Cur- Because the hip is the joint most commonly involved in patients
rently five agents that have been approved for use by the Food with AS, total hip arthroplasty is the most common surgical
24
and Drug Administration (FDA) are in clinical use for the procedure. Heterotopic new bone formation may be a potential
treatment of AS in the United States, including infliximab, an problem.
Limited prevalence data suggest that patients with AS, even
those with mild disease, are at increased risk for vertebral fracture,
25
often resulting in neurological compromise. In general, halo
TABLE 57.8 international assessment in vest immobilization is recommended. Surgical intervention may
ankylosing spondylitis (asas) Consensus be necessary when neurological impairment is seen. The fixed
statement for the Use of anti–tumor kyphotic deformities seen in patients with advanced AS are of
Necrosis Factor (tNF) agents in Patients considerable distress to patients and may result in substantial
With ankylosing spondylitis (as) and axial functional impairment. A small minority of patients with AS
spondyloarthritis (aspa)* will seek surgical correction of their spinal deformities. In
general, open, polysegmental, and closing wedge osteotomies are
1. For the initiation of anti–TNF-α therapy: employed. Loss of correction is seen least commonly in closing
(a) A diagnosis of definitive AS by modified NY criteria or axial SpA
by ASAS criteria wedge osteotomy. In a meta-analysis of the literature between
(b) Presence of active disease for at least 4 weeks as defined by 1945 and 1998, an average correction of 37°–40° was seen, with
both a sustained Bath AS Disease Activity Index (BASDAI) of at perioperative mortality of 4% as a result of pulmonary, cardiac,
least 4 and an expert opinion based on clinical features, and intestinal problems. 50
acute-phase reactants, and imaging modalities
(c) Presence of refractory disease defined by failure of at least two
nonsteroidal antiinflammatory drugs during a single 4-week
period, failure of intraarticular steroids if indicated, and failure of CONCLUSIONS AND RESEARCH OPPORTUNITIES
a disease-modifying antirheumatic drug, preferably sulfasalazine,
in patients with peripheral arthritis
(d) Application and implementation of the usual precautions and ON tHE HOriZON
contraindications for biological therapy
2. For the monitoring of anti–TNF-α therapy: both the BASDAI and the Research Opportunities in
ASAS core set for clinical practice should be followed regularly Spondyloarthritis (SpA)
3. For the discontinuation of anti-TNF-α therapy: in nonresponders,
consideration should be made after 12 weeks’ treatment. Response • Improved understanding of pathogenetic mechanisms of SpA
is defined as improvement of: • Elucidation of the roles of non–major histocompatibility complex (MHC)
(a) At least 50% or 2 units (on a 0–10 scale) of the BASDAI genes in SpA
(b) Expert opinion that treatment should be continued • Definition of the link between gut inflammation and ankylosing
spondylitis (AS) triggering
*van der Heijde D, Sieper J, Maksymowych WP, et al. 2010 Update of the • Improved measures of treatment outcomes
international ASAS recommendations for the use of anti-TNF agents in patients with • Advances in biological therapies of SpA
axial spondyloarthritis. Ann Rheum Dis 2011; 70 :905–8.

786 Part six Systemic Immune Diseases


Progress has been made in the classification and epidemiology observed with ankylosing spondylitis. Arthritis Rheumatol
of SpA, particularly in the elucidation of the factors involved 2015;67:140–51.
in SpA pathogenesis in recent years. It has become clear that 13. Reveille JD. The MHC and Ankylosing Spondylitis. Clin Rheum
HLA-B27, the primary genetic factor, functions in a variety 2014;33:749–57.
of roles, including “classic” antigen presentation. GWAS have 14. Reveille JD, Hirsch R, Dillon CF, et al. The prevalence of HLA-B27 in the
United States: data from the U.S. National Health and Nutrition
identified a vast number of susceptibility genes for SpA, including Examination Survey, 2009. Arthritis Rheum 2012;64:1407–11.
those in the antigen processing and Th17 pathways, some of 15. International Genetics of Ankylosing Spondylitis Consortium (IGAS),
which are shared by some or all SpA and others that are specific Cortes A, Hadler J, et al. Identification of multiple risk variants for
for a given disease. Their specific roles and how they interact ankylosing spondylitis through high-density genotyping of
are currently being elucidated, and with larger-scale studies and immune-related loci. Nat Genet 2013;45:730–8.
whole-genome sequencing, new candidates are being identified. 16. Delay ML, Turner MJ, Klenk EI, et al. HLA-B27 misfolding and the
However, less progress has been made with regard to nonge- unfolded protein response augment interleukin-23 production and are
netic factors. Despite what has been learned in ReA, no infectious associated with Th17 activation in transgenic rats. Arthritis Rheum
trigger has been identified in AS (and, in fact, there might be 2009;60:2633–43.
no specific trigger). The link of gut inflammation to the triggering 17. Ellinghaus D, Jostins L, Spain SL, et al. Analysis of five chronic
inflammatory diseases identifies 27 new associations and highlights
of AS is strongly suggested by data thus far, especially its possible disease-specific patterns at shared loci. Nat Genet 2016;48:510–18.
link to the gut microbiome. This is clearly an area of further 18. Genetic Analysis of Psoriasis Consortium and The Wellcome Trust Case
investigation. Control Consortium 2. A genomewide association study identifies new
Novel outcome measures have been developed that will help psoriasis susceptibility loci and an interaction between HLA-C and
provide better care to patients, especially in the area of imaging. ERAP1. Nat Genet 2010;42:985–90.
The advances in treatment have been most exciting, particularly 19. Cortes A, Maksymowych WP, Wordsworth BP, et al. Association study of
the development of biological treatments, which hold promise genes related to bone formation and resorption and the extent of
for a better future for patients with these diseases. radiographic change in ankylosing spondylitis. Ann Rheum Dis
2015;74:1387–93.
20. Costello ME, Robinson PC, Benham H, et al. The intestinal microbiome
in human disease and how it relates to arthritis and spondyloarthritis.
REFERENCES Best Pract Res Clin Rheumatol 2015;29:202–12.
21. Melis L, Elewaut D. Progress in spondylarthritis. Immunopathogenesis of
1. Monnet D, Breban M, Hudry C, et al. Ophthalmic findings and frequency spondyloarthritis: which cells drive disease? Arthritis Res Ther
of extraocular manifestations in patients with HLA-B27 uveitis: a study of 2009;11:233.
175 cases. Ophthalmology 2004;111:802–9. 22. van Kuijk AWR, Tak PP. Synovitis in psoriatic arthritis:
2. Nurmohamed MT, van der Horst-Bruinsma I, Maksymowych WP. immunohistochemistry, comparisons with rheumatoid arthritis, and
Cardiovascular and cerebrovascular diseases in ankylosing spondylitis: effects of therapy. Curr Rheumatol Rep 2011;13:353–9.
current insights. Curr Rheumatol Rep 2012;14:415–21. 23. Sweeney S, Gupta R, Taylor G, et al. Total hip arthroplasty in ankylosing
3. Dougados M, van der Linden S, Juhlin R, et al. The European spondylitis: outcome in 340 patients. J Rheumatol 2001;28:1862–6.
Spondylarthropathy Study Group preliminary criteria for the 24. McGonagle D, Gibbon W, Emery P. Classification of inflammatory
classification of spondylarthropathy. Arthritis Rheum 1991;34: arthritis by enthesitis. Lancet 1998;352:1137–40.
1218–27. 25. Carter S, Lories RJ. Osteoporosis: a paradox in ankylosing spondylitis.
4. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic Curr Osteoporos Rep 2011;9:112–15.
criteria for ankylosing spondylitis. A proposal for modification of the 26. Mitra D, Elvins DM, Speden DJ, et al. The prevalence of vertebral
New York criteria. Arthritis Rheum 1984;27:361–8. fractures in mild ankylosing spondylitis and their relationship to bone
5. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic mineral density. Rheumatology (Oxford) 2000;39:85–9.
arthritis: development of new criteria from a large international study. 27. Lee W, Reveille JD, Davis JC, et al. Are there gender differences in the
Arthritis Rheum 2006;54:2665–73. severity of ankylosing spondylitis: results from the PSOAS cohort. Ann
6. Rudwaleit M, van der Heijde D, Landewe R, et al. The development of Rheum Dis 2007;66:633–8.
Assessment of SpondyloArthritis International Society classification 28. Colbert R. Classification of juvenile spondyloarthritis: Enthesitis-related
criteria for axial spondyloarthritis (part II): validation and final selection. arthritis and beyond. Nat Rev Rheumatol 2010;6:477–85.
Ann Rheum Dis 2009;68:777–83. 29. Ritchlin C. Psoriatic disease—from skin to bone. Nat Clin Pract
7. Rudwaleit M, van der Heijde D, Landewe R, et al. The Assessment of Rheumatol 2007;3:698–706.
SpondyloArthritis International Society classification criteria for 30. Zeidler H, Brandt J, Schnarr S. Undifferentiated spondyloarthritis. In:
peripheral spondyloarthritis and for spondyloarthritis in general. Ann Weisman MH, Reveille JD, van der Heijde D, editors. Ankylosing
Rheum Dis 2011;70:25–31. spondylitis and the spondyloarthropathies. Philadelphia: Elsevier; 2006. p.
8. Stolwijk C, van Onna M, Boonen A, et al. The global prevalence of 75–93.
spondyloarthritis: a systematic review and meta-regression analysis. 31. van der Heijde D, Landewe S, van der Linden S. How should treatment
Arthritis Care Res (Hoboken) 2016;68:1320–31. effect on spinal radiographic progression be measured? Arthritis Rheum
9. Thom N, Ritchlin CT, Zhang X, et al. Prevalence of chronic axial pain, 2005;52:1979–85.
inflammatory back pain and spondyloarthritis in diagnosed psoriasis. 32. Maksymowych WP, Inman RD, Salonen D, et al. Spondyloarthritis
Arthritis Care Res (Hoboken) 2015;67:829–35. Research Consortium of Canada magnetic resonance imaging index for
10. Loftus EV. Clinical epidemiology of inflammatory bowel disease: assessment of sacroiliac joint inflammation in ankylosing spondylitis.
incidence, prevalence, and environmental influences. Gastroenterology Arthritis Rheum 2005;53:703–9.
2004;126:1504–17. 33. Ward MM, Reveille JD, Learch TJ, et al. Impact of ankylosing spondylitis
11. Brown MA, Kennedy LG, MacGregor AJ, et al. Susceptibility to ankylosing on work and family life: comparisons with the US population. Arthritis
spondylitis in twins: the role of genes, HLA, and the environment. Rheum 2008;59:497–503.
Arthritis Rheum 1997;40:1823–8. 34. Boonen A, Brinkhuizen T, Landewe R, et al. Impact of ankylosing
12. Robinson PC, Claushuis TA, Cortes A, et al. Genetic dissection of acute spondylitis on sick leave, presenteeism and unpaid productivity, and
anterior uveitis reveals similarities and differences in associations estimation of the societal cost. Ann Rheum Dis 2010;69:1123–8.

CHaPtEr 57 Spondyloarthritis 787


35. Szabo SM, Levy AR, Rao SR, et al. Increased risk of cardiovascular and 43. Edwards CJ, Blanco FJ, Crowley J, et al. Apremilast, an oral
cerebrovascular diseases in individuals with ankylosing spondylitis: a phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and
population-based study. Arthritis Rheum 2011;63:3294–304. current skin involvement: a phase III, randomised, controlled trial
36. Sairanen E, Paronen I, Mahonen H. Reiter’s syndrome: a follow-up study. (PALACE 3). Ann Rheum Dis 2016;75:1065–73.
Acta Med Scand 1969;185:57–63. 44. Barber CE, Kim J, Inman RD, et al. Antibiotics for treatment of reactive
37. Gladman DD, Chandran V. Review of clinical registries of psoriatic arthritis: a systematic review and meta-analysis. J Rheumatol
arthritis: lessons learned?: value for the future? Curr Rheumatol Rep 2013;40:916–28.
2011;13:346–52. 45. Coates LC, Helliwell PS. Treating to target in psoriatic arthritis: how to
38. Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/ implement in clinical practice. Ann Rheum Dis 2016;75:640–3.
Spondylitis Association of America/Spondyloarthritis Research and 46. Haibel H, Rudwaleit M, Listing J, et al. Efficacy of adalimumab in the
Treatment Network 2015 Recommendations for the Treatment of treatment of axial spondylarthritis without radiographically defined
Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. sacroiliitis: results of a twelve-week randomized, double-blind,
Arthritis Rheumatol 2016;68:282–98. placebo-controlled trial followed by an open-label extension up to week
39. van den Berg R, Baraliakos X, Braun J, et al. First update of the current fifty two. Arthritis Rheum 2008;58:1981–91.
evidence for the management of ankylosing spondylitis with 47. Landewé R, Braun J, Deodhar A, et al. Efficacy of certolizumab pegol on
non-pharmacological treatment and non-biologic drugs: a systematic signs and symptoms of axial spondyloarthritis including ankylosing
literature review for the ASAS/EULAR management recommendations in spondylitis: 24-week results of a double-blind randomised
ankylosing spondylitis. Rheumatology (Oxford) 2012;51:1388–96. placebo-controlled Phase 3 study. Ann Rheum Dis 2014;73:
40. Wanders A, van der Heijde D, Landewe R, et al. Nonsteroidal 39–47.
anti-inflammatory drugs reduce radiographic progression in patients 48. Haroon N, Inman RD, Learch TJ, et al. The Impact of TNF-inhibitors on
with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum radiographic progression in Ankylosing Spondylitis. Arthritis Rheum
2005;52:1756–61. 2013;65:2645–54.
41. Poddubnyy D, Rudwaleit M, Haibel H, et al. Effect of non-steroidal 49. Baeten D, Sieper J, Braun J, et al. Secukinumab, an Interleukin-17A
anti-inflammatory drugs on radiographic spinal progression in patients Inhibitor, in Ankylosing Spondylitis. N Engl J Med 2015;373:
with axial spondyloarthritis: results from the German Spondyloarthritis 2534–48.
Inception Cohort. Ann Rheum Dis 2012;71:1616–22. 50. Van Royen BJ, De Gast A. Lumbar osteotomy for correction of
42. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and thoracolumbar kyphotic deformity in ankylosing spondylitis. A
placebo for the treatment of axial and peripheral articular manifestations structured review of three methods of treatment. Ann Rheum Dis
of the seronegative spondylarthropathies: a Department of Veterans 1999;58:399–406.
Affairs cooperative study. Arthritis Rheum 1999;42:2325–9.

58









Small- and Medium-Vessel Primary Vasculitis



Raashid Ahmed Luqmani, Ana Águeda, Lorraine O’Neill











Small- and medium-vessel vasculitides are characterized by EPIDEMIOLOGY
inflammation of the blood vessel wall resulting in end organ
failure or irreversible tissue damage and necrosis. In some cases, Despite improvement in our understanding of the epidemiology
this is relatively trivial and may lead to minor inconvenience for of the systemic vasculitides, patients are often not diagnosed as
the patient. However, in many forms of vasculitis, the conse- having vasculitis for extended periods. The discovery of antibodies
quences of rapid onset of ischemia and occlusion of blood vessels to neutrophil cytoplasm (ANCA) and their association with
12
are devastating, leading to organ failure and death. small-vessel vasculitis has improved recognition. Greater aware-
The distinction between small- and medium-vessel vasculitis ness of vasculitis may be a factor that explains an apparent increase
2
entities is arbitrary, with three main patterns of vasculitis: small, in incidence from 1.5/million/year to 6.1/million per year. The
medium, and large. Although there is merit in this classification, incidence of ANCA-associated vasculitides (AAV) is 10–20 new
3
there are different patterns of involvement for patients with cases per million per annum. In southern Europe, the number
predominantly small-vessel involvement (characterized by capil- of cases of MPA is greater than those of GPA.
laritis) compared with, but overlapping with, patients with MPA is also more common than GPA in Japan. ANCA directed
medium-vessel involvement typified by small arteriolar inflam- against myeloperoxidase is the predominant antibody detected
mation. For example, in the kidney, small-vessel involvement in patients with AAV in Japan, whereas autoantibodies directed
leads to inflammation of glomeruli (glomerulonephritis); by against proteinase 3 (PR3) are rarely seen in Japanese patients
contrast, medium-vessel inflammation of renal arterioles results but are the most frequent ANCA antibody in patients in northern
in infarction of the kidney with tissue loss. Therefore patterns Europe.
of disease are well recognized, with typical dominance of kidney, The epidemiology of EPGA is less well understood compared
lung, and upper airway involvement in patients with granulo- with other forms of AAV. EGPA is characterized by an elevated
matosis with polyangiitis (GPA), previously termed Wegener’s eosinophil count in patients with late-onset asthma. Around
granulomatosis. In microscopic polyangiitis (MPA), there is lack 50% of cases have ANCA, usually directed against myeloperoxi-
of upper airway involvement but significant renal and lung dase. EGPA is less common than either GPA or MPA, with an
involvement. Finally, in eosinophilic glomerulonephritis with incidence of around 0.6/million per annum. There is a potential
polyangiitis (EGPA), previously termed Churg-Strauss syndrome, overlap condition called hypereosinophilic syndrome (HES), and
the pattern of clinical involvement is dominated by upper and it is not clear whether some cases of HES are really cases of
lower airway disease combined with neurological (peripheral EGPA, or vice versa. Indeed, if patients are ANCA negative,
4
nerve) features. These three entities are grouped together by distinguishing the two conditions can be challenging. Further-
their association with the presence of antineutrophil cytoplasmic more, because bronchospasm is a key feature of EGPA, it is
antibody (ANCA) in most, but not all, cases. possible that some cases of asthma, an extremely common
In patients with polyarteritis nodosa (PAN), one of the main condition, may, in fact, represent mild forms of EGPA. This has
forms of medium-vessel vasculitis, the most characteristic findings been brought more to light in cases of drug-induced EGPA,
are bowel ischemia or infarction and peripheral neuropathy. In specifically in the setting of the use of montelukast, a leukotriene
a childhood onset form of medium-vessel vasculitis (Kawasaki inhibitor, as a treatment for moderate to severe asthma. It has
disease [KD]), the clinical features are diverse and include been suggested that these patients probably had underlying EGPA,
mucocutaneous inflammation and systemic upset with fever, which had previously been suppressed with systemic glucocor-
and in 2–4% of cases, there is coronary artery dilatation and/or ticoids, but when these were withdrawn, features of EGPA became
aneurysm development, which can potentially rupture, leading more apparent.
to fatal consequences. 1 AAV typically affects older individuals in their 60s or 70s but
The diversity of different forms of vasculitis with overlapping can occur at any age. Most patients survive their initial illness
features suggests that the underlying mechanisms are varied, as a result of effective immunotherapy, and therefore the preva-
but some pathways are likely to be shared. This is reflected in lence of these diseases is growing. In southern Sweden, estimates
treatment approaches, which, with some exceptions, are often of prevalence are 160 per million (95% confidence interval [CI]
very similar across diseases. 114–206) for GPA, 94 (58–129) for MPA, 31 (11–52) for PAN,

789

790 Part SIX Systemic Immune Diseases



TABLE 58.1 Diagnosis, Incidence and Prevalence in KD, PaN, aaV and
Leukocytoclastic Vasculitis
Diagnosis Incidence Prevalence references/ reviews
KD For children <5 years old: Not applicable
2431/million (Japan) Makino N, et al., 2015 96
1131 per million (Korea)
690 per million (Taiwan)
36–185/million (Italy)
PAN 3.6/million adults 2.6–14/million adults Nesher G, et al., 2016 5
Mohammad AJ, et al., 2007 4
ANCA-associated vasculitides 9.5–16/million/year (Germany) 149/million Reinhold-Keller E, et al., 2005 10
22.6/million (Japan) Herlyn K, et al., 2014 11
21.8/million (UK) Fujimoto S, et al., 2011 94
Leukocytoclastic vasculitis 45/million (equal male and female; increased No data Arora A, et al., 2014 7
incidence with age)
AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; KD, Kawasaki disease; PAN, polyarteritis nodosa.





6
and 14 (0.3-27) for EGPA. However, these are based on a relatively 210.5/100 000 children, in contrast to the rate for Caucasian
small population size and are higher than those reported from children in Hawaii of 13.7/100 000, similar to the rate of 12.0/100
a Spanish series, where the prevalence of all forms of AAV was 000 among Caucasian children in continental United States. 6
under 45/million. Leukocytoclastic skin vasculitis is one of the more common
The two main forms of medium-vessel vasculitis are PAN forms of small vessel vasculitis occurring with an annual incidence
7
and KD. PAN is extremely rare. There is very wide misconception of about 45/million (Table 58.1). Less than a third is found in
among many physicians that PAN is the most common form of association with immunoglobulin A (Henoch-Schönlein purpura
vasculitis, and this is partly encouraged by the older literature, [HSP], or IgA vasculitis). IgA vasculitis is very common in children
which refers to all forms of vasculitis as PAN (initially called and is usually self-limiting; annual incidence is 100–200/million
8
periarteritis nodosa and subsequently polyarteritis nodosa). In children ≤17 years of age. By contrast, this is a much less common
fact, the majority of patients with so-called PAN probably did disease in adults (around 13/million/year).
not have this disease but were more likely suffering from one of Cryoglobulinemic vasculitis is strongly associated with hepatitis
the forms of small-vessel vasculitis, particularly MPA and GPA. C, and its epidemiology is likely to mirror the prevalence of the
PAN has been associated with infection, especially hepatitis B hepatitis C virus (HCV). However, there are no published incidence
and hepatitis C. The epidemiology of hepatitis B has been and prevalence figures for cryoglobulinemic vasculitis itself.
transformed by effective immunization; as a result of this, hepatitis
B associated with PAN is now an extremely rare disease. Recent PATHOGENESIS OF AAV
figures suggest an incidence of PAN of 0.6–3.6/million adults. 5
KD is most common in children under the age of 5 years but The Pathogenic Role of ANCA in GPA and MPA
can occur in older children and young adults, in which case it There is some evidence that ANCA play a significant role in the
is more difficult to diagnose because it is not suspected. In a pathogenesis of GPA, MPA, and EGPA. Based on the immuno-
recent Italian study of children under the age of 14 years, the fluorescence pattern, different forms of ANCA can be distin-
incidence rate was 17.6/100 000 children under the age of 5 guished, but only two are of direct clinical relevance: cytoplasmic
years, with a slight increase in reported cases during spring and c-ANCA (corresponding to antibodies directed against PR3)
winter compared with other times of the year. This is a slightly and perinuclear p-ANCA (predominantly corresponding to
higher incidence rate than previously reported by other studies antibodies directed against myeloperoxidase [MPO]). p-ANCA
in Europe with a range of 3.6–15.2/100 000 children under the can also be directed against other antigens, including bactericidal/
age of 5 years. Earlier figures from a large-scale study from the permeability-increasing (BPI) protein, lactoferrin, human
United States of over 6000 children admitted to hospital because neutrophil elastase (HNE), cathepsin G, and azurocidin, but
of KD suggested that the peak age of onset was 1 year, and their clinical significance is not well characterized. Although
children under the age of 2 years accounted for over a third of ANCAs are associated with vasculitis, titers are not reliable for
all cases. The under-5-year incidence was reported as 8.1 per monitoring disease status because there is no clear relationship
100 000 children in 1988, rising to 18.5 per 100 000 children in with remission or relapse.
1997, similar to the recent Italian experience. Males were more Transfer of MPO-ANCA in humans (maternal–fetal route)
commonly affected than females (approximately 60% males); and animal models (necrotizing pauciimmune glomerulonephritis
there was no obvious seasonal variation. In a recent nationwide after passive transfer of purified antibody or splenocytes from
hospital survey in Japan, however, the incidence rates for KD MPO-deficient mice immunized with purified murine MPO)
13
during 2011 and 2012 were over 2400 cases per million children has resulted in features typical of MPA. By contrast, the
under the age of 5 years. The higher incidence of KD in patients pathogenicity of antiPR3 antibodies is less well established. In
of Japanese ethnicity appears to be independent of their geo- one animal model of autoimmune-prone nonobese diabetic
graphical location. In fact, during 1996–2006, the average annual (NOD) mice, immunization with recombinant mouse PR3
incidence of KD in Japanese American children in Hawaii was (rmPR3) in complete Freund’s adjuvant (CFA) had no clinical

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 791



KEY CONCEPtS
Pathogenic Mechanisms in ANCA-Associated Vasculitides

• The recognition of an association between some forms of vasculitis • Environmental factors
and the presence of antibodies to neutrophil cytoplasm (ANCA) has • Silica exposure
transformed understanding of the group of diseases considered to be • Specific strains of Staphylococcus aureus
associated with ANCA and in which ANCAs are suspected to have a • Inflammatory processes
pathogenic role. • Ineffective T-cell regulation
• Granulomatosis with polyangiitis (GPA) • Neutrophil generation of extracellular traps (NETs) containing proteinase
• Microscopic polyangiitis (MPA) 3 and myeloperoxidase
• Eosinophilic granulomatosis with polyangiitis (EGPA) • Activation of alternative complement pathway by ANCA-activated
• A genome-wide association study (GWAS) has demonstrated strong neutrophils
associations with specific alleles.
• Anti-proteinase 3 ANCA with specific HLA-DP alleles and alleles
encoded by genes for α 1 -antitrypsin and proteinase 3
• Anti-myeloperoxidase ANCA with specific HLA-DQ alleles






effect but resulted in high levels of circulating c-ANCA; transfer GENETICS
of splenocytes from these immunized animals into mice with
severe combined immunodeficiency (SCID) resulted in vasculitis There has been significant progress in the understanding of AAV
14
and severe segmental and necrotizing glomerulonephritis. genetics following the publication of two genome-wide association
17
Transfer of splenocytes from the CFA-alone-immunized mice studies (GWAS). The strongest human leukocyte antigen (HLA)
(controls) resulted in no disease, further suggesting that disease association is with the HLA-DPB1 haplotype, initially described
development depends on PR3-specific immune responses. In a in German cohorts and confirmed in both GWAS, especially
second model of PR3ANCA vasculitis, based on animals with a for the PR3-ANCA–positive subgroup, regardless of the clinical
14
15
human–mouse chimeric immune system, >70% of mice treated diagnosis. Further analysis has revealed an association between
with IgG from patients with antiPR3 AAV (as compared with MPO-ANCA and a single nucleotide polymorphism (SNP) in
IgG from patients with nonvasculitic renal disease; or healthy the HLA-DQ region, which had probably been masked previ-
controls) developed mild kidney disease with glomerular hyper- ously as a result of the small number of MPO-ANCA–positive
cellularity and focal pulmonary hemorrhage. Fifteen (83%) mice patients included in initial analyses. Other HLA associations are
treated with antiPR3 IgG later showed mild kidney disease with reported, such as HLA-DRB1*09:01 and HLA-DQB1*03:03 in
glomerular hypercellularity, and three (17%) had severe glo- Japanese patients with MPA. Less robust findings, not replicated
merular injury. In the lungs, 13 (72%) showed areas of focal in other studies, include a protective effect of HLA-DR13(6)
pulmonary hemorrhage, whereas lungs of the control group (n and HLA-DR1, but an increased proportion of HLA-DR4 in
18
= 8) appeared normal (p < 0.01). There were no granulomatous Dutch patients with GPA compared with controls ; HLA-DRB1
17
lesions, but because granulomatous lesions are dependent on a in PR3-ANCA-positive (but not MPO-ANCA) patients ;
robust T cell–mediated response, the authors argued that a HLA-B50, HLA-DR1, HLA-DR9, HLA-DQw7, and HLA-DR3
refinement of the model to include greater levels of chimerism in GPA. 19-21 In EGPA, the most robust association is with
and administration of interleukin-7 (IL-7)–Fc protein to augment HLA-DRB4. Overall, there is evidence for genetic susceptibility
T-cell development would be required to study this. 15 to AAV, related to specific SNPs in the HLA region. Other genetic
Even though these studies strongly support a pathogenic role associations with GPA include PRTN3, SERPINA 1, PTPN22, and
for ANCA, conventional serological assays fail to detect ANCA CTLA4.
in some patients with classic clinical and pathological features PR3 is either stored in neutrophil azurophilic granules or
of AAV, and titers do not correlate well with disease activity. exposed on the cell membrane (where it can interact directly
16
Roth et al. examined MPO epitopes specificities, reporting 25 with ANCA). Although the proportion of neutrophils displaying
+
different epitopes bound by anti-MPO antibodies; although some membrane PR3 (mPR3 ) is stable over time, surface expression
+
epitopes were associated with active disease, others were either of PR3 may be enhanced. The percentage of mPR3 neutrophils
not specific to active disease or not associated with disease at is genetically determined. Schreiber et al. showed that among
all. Igs purified from patients with ANCA-negative vasculitis 125 healthy controls, 35 patients with GPA, 15 patients with
could bind to a specific MPO epitope. Furthermore, the absence other inflammatory diseases, and 27 pairs of monozygotic (MZ)
+
of ANCA in some patients could be explained by competitive and dizygotic (DZ) twins, the percentage of mPR3 neutrophils
binding to a fragment of ceruloplasmin (CP), the natural inhibi- correlated significantly in MZ twins (but not in DZ twins) and
tor of MPO. This CP fragment decreased anti-MPO 447–459 the heritability percentage was estimated as 99%. Furthermore,
autoantibody reactivity by 30–50%, whereas full-length CP did the absolute number of PR3 molecules expressed on the cell
16
not have any effect. ANCAs are reported in small numbers membrane was correlated among MZ (but not DZ) twins, with
22
of healthy individuals. How the pathogenic transformation of a heritability estimate of 96.7%. Patients with GPA have a higher
+
ANCA occurs is still unclear, but it is probably a multifactorial percentage of mPR3 neutrophils compared with healthy controls
+
process requiring a complex interaction among genetics, the or patients with other inflammatory diseases (mPR3 percentage
22
environment, and the immune system facilitating a break in of 76.8% vs 56.1% vs 59.4%, respectively). Following neutrophil
immune tolerance. activation and enzyme release, PR3 can mediate direct tissue

792 Part SIX Systemic Immune Diseases


damage. α 1 -antitrypsin, encoded by the gene SERPINA1 (found trigger. Several triggers have been associated with AAV, including
on chromosome 14), is the major inhibitor. Two α 1 -antitrypsin toxins, viral and bacterial infections, and some licit and illicit
alleles, Z and S, are associated with low enzymatic activity. A drugs.
significant correlation with the Z allele (odds ratio [OR] 0.3; p Silica dust exposure has been associated with the development
= 1.25 × 10−5), but not the S allele, is reported in PR3-ANCA– of AAV and other autoimmune diseases, such as SLE, RA, and
28
17
positive patients with GPA. PRTN3 (the gene encoding PR3) scleroderma. Silica is an abundant earth material found in
is associated with GPA, especially among patients who are sand, grain, grass, and wool. Processing these materials may
PR3-ANCA-positive. 17 expose workers to respirable crystalline silica. Silica-induced
The 620WPTPN22 variant of PTPN22 (encoding lymphoid ANCA-positive disease is often associated with p-ANCA, targeting
tyrosine phosphatase) correlates with abnormal regulatory CD4 MPO, and the clinical presentation is usually MPA rather than
29
T regulatory cell (Treg) function, increased humoral activity, and GPA. Case-control studies show that a high percentage (22–46%)
23
enhanced neutrophil function in patients with GPA. CTLA-4 of patients with AAV were previously exposed to silica. 25,29 A
(encoding cytotoxic T lymphocyte antigen-4) polymorphisms systematic review and meta-analysis of 332 cases and 516 controls
14
are associated with GPA, especially the G allele of CT60 (p = found that prior silica exposure was associated with development
0.001) and +49 (p = 0.03). By contrast, only borderline significance of AAV, with a summary odds ratio (OR) of 2.56 (95% CI
24
was noted between CT60 SNP and MPA (p = 0.05). CTLA-4 is 1.51–4.36). Pooled ORs were similar for GPA and MPA, 3.56
a negative regulator of T-cell activation, which competes with (95% CI 1.85–6.82) and 3.95 (95% CI 1.89–8.24), respectively.
the costimulatory molecule CD28 for binding of CD80 or CD86 Other confounders, such as other occupational exposures or
on antigen-presenting cells (APCs). Abatacept, a monoclonal tobacco use, were not analyzed, which could have resulted in an
25
antibody (mAb), containing the binding domain of CTLA-4 overestimation of the risk attributed to silica. The mechanism
reduces CD28–CD80/CD86 interaction and therefore T-cell by which silica exposure triggers the development of AAV is not
stimulation, which could explain its potential benefit in a fully understood. In vitro, silica can activate monocytes and
25
small trial of non–life-threatening GPA. Haplotypes of IL-10 macrophages, releasing cytokines, such as IL-1 and tumor necrosis
(a pleiotropic cytokine with complex and multiple effects in factor-α (TNF-α), as well as releasing oxygen radicals and
30
immune modulation) are associated with several immuno- lysosomal enzymes, including proteinase 3 and myeloperoxidase.
logical disorders, including systemic lupus erythematosus Furthermore, silica can inactivate α 1 -antitrypsin. Asbestos, another
(SLE), rheumatoid arthritis (RA), and giant cell arteritis. IL-10 silicon-containing mineral, has been suggested as a trigger for
production is largely (50–70%) determined by genetic factors, and AAV in a small case-control study of 31 patients (22 GPA, 8
26
elevated plasma levels are reported in EGPA, but not in GPA. MPA, 1 EGPA) and 30 healthy controls; three patients had prior
31
Wieczorek et al. evaluated the impact of functionally relevant exposure to asbestos versus none of the controls. There are few
IL-10 polymorphisms in 403 patients with GPA, 103 with EGPA published studies investigating the potential pathogenic role of
26
(compared with 507 controls). There was a significant association asbestos in the development of AAV.
with the 3575/1082/592 TAC haplotype, part of the extended It is estimated that 63% of patients with GPA are chronic
ancient haplotype of IL-10.2, in ANCA-negative EGPA, but not nasal carriers of Staphylococcus aureus, resulting in an increased
in GPA. 26 risk of relapse. Maintenance treatment with trimethoprim-
sulfamethoxazole (cotrimoxazole) has been shown to reduce the
EPIGENETICS incidence of relapse in a double-blind, placebo-controlled study
in patients with GPA, where a maintenance dose of 960 mg two
Genetic factors alone are not enough to explain the range of times daily of trimethoprim-sulfamethoxazole resulted in a 60%
phenotypic presentations in AAV. Epigenetic dysregulation is reduction in relapse. However, this has not been replicated in
increasingly recognized as a contributor to immune-mediated other studies. The mechanism for the pathogenic role of S. aureus
diseases. Epigenetics relates to heritable changes in the function is still unclear. Potential pathways include stimulation of B and/
of genes, without altering the DNA sequence. It includes DNA or T cells by S. aureus superantigens; polyclonal activation of B
methylation, histone, and microRNAs (miRNAs). Epigenetic cells by cell wall components of the bacterium, resulting in
modifications can be stable over time or can respond to devel- persistence of ANCA; and neutrophil priming leading to surface
opmental and environmental triggers, leading to phenotypic expression of PR3. 28
aberrances. Central to the pathogenesis of AAV is a dysregulated Although parvovirus B19 has been proposed as a trigger for
immune response resulting in ANCA production and aberrant AAV in a few case reports, a case-control study failed to dem-
expression of their target autoantigens, MPO and PR3. The onstrate any association because IgG antibodies to parvovirus
expression of MPO and PR3 occurs primarily during early B19 were detected equally in the sera of patients with AAV and
neutrophil development to produce intragranular constituents control subjects, and all 13 patients with AAV and 39 controls
32
and is silenced in mature cells. However, in AAV, expression were negative for IgM antibodies and viral DNA. Hepatitis B
28
remains active. One epigenetic change that helps explain this is virus (HBV) is implicated in the pathogenesis of PAN, but
the reduced levels of the H3K27me3 histone modification at there is no evidence to support a role for HBV or HCV in AAV.
both the MPO and PR3 gene loci. H3K27me3 histone is associated The presence of circulating c-ANCA and PR3-ANCA has been
with transcriptional silencing in patients with AAV compared reported to be higher in patients with chronic hepatitis B and
with healthy individuals. 27 C compared with controls. In a study of patients with liver disease
(11 patients with primary biliary cirrhosis, 216 with chronic
ENVIRONMENTAL AND INFECTIOUS TRIGGERS hepatitis B, 516 with chronic hepatitis C, and 44 healthy controls),
ANCAs were detected in 55.6% of patients with hepatitis C (all
Genetic and epigenetic modifications may render a patient had a c-ANCA pattern with PR3 specificity and 4.8% had concur-
33
susceptible to developing disease in the presence of an appropriate rent MPO specificity). ANCA-positive patients had a higher

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 793


prevalence of skin involvement, anemia, abnormal liver functions, with PTU-induced AAV (usually MPO-positive) are younger,
33
and elevated α-fetoprotein (FP) levels ; however, the findings more commonly female compared with those with primary AAV,
were not replicated in other studies. 34 and usually have significantly higher anti-MPO ANCA titers
Lysosomal-associated membrane protein 2 (LAMP-2) is a compared with patients without vasculitis. Other ANCA subtypes
heavily glycosylated type 1 membrane protein, abundant on may be found, including HNE-ANCA and lactoferrin (LF)-ANCA;
neutrophil and endothelial cell surfaces, which shuttles between however, when PTU-induced AAV develops, MPO-ANCA is
lysosomes and the cell membrane. LAMP-2 cross-reacts with usually present, regardless of the existence of other forms of
FimH, a gram-negative adhesin, which facilitates bacterial entry ANCA. The pathogenesis of AAV related to antithyroid drugs
to host tissues. Preliminary studies have suggested a role for is unclear. PTU is predominantly metabolized in the liver, but
38
LAMP-2 in small-vessel vasculitis. The LAMP-2 epitope P41–49 a proportion is modified by MPO in neutrophils. Neutrophils
has been reported to have a 100% homology with amino acids are responsible for neutrophil extracellular trap (NET) formation,
35
72–80 of mature FimH. Antibodies to human LAMP-2 have and PTU can induce abnormal configured NETs in vitro; these
been shown to injure human microvascular endothelium in abnormal NETs cannot easily be released into liquid phase and
vitro and induce focal necrotizing glomerulonephritis (FNGN) are not effectively digested by DNase I, therefore remaining in
39
in rats; immunization with FimH-induced pauciimmune FNGN the tissue. Immunization of rats with abnormal NETs results
associated with antibodies that bound human and rat LAMP-2; in production of MPO-ANCA. 39
furthermore, patients with pauciimmune FNGN were found to
have an increased likelihood of infections with FimH-expressing Hydralazine
35
bacteria shortly before presentation of their FNGN. LAMP-2 Hydralazine is widely used to treat hypertension, acting as a
antibodies were found in patients with active disease or relapse smooth muscle relaxant and causing arterial and arteriolar
35
but not in those in remission. Although this a promising vasodilation. It has been implicated in the development of drug-
new explanation for some cases of small-vessel vasculitis, induced SLE and AAV. High titers of MPO-ANCA, ANA,
the lack of replication of these findings makes them hard to anti–double-stranded DNA (dsDNA), and antihistone antibodies
substantiate. are found; hypocomplementemia is also frequent. The underlying
CpG-oligodeoxynucleotides (ODN) is a short synthetic DNA mechanism of action for hydralazine-induced AAV is not clear.
containing unmethylated CpG motifs, highly prevalent in bacterial One potential pathway by which hydralazine acts is through
DNA, and recognized by Toll-like receptor 9 (TLR9), which is reverse epigenetic silencing of tumor suppressors, but also
expressed by a variety of cells in the immune system. TLR9 potentially of MPO and PR3.
triggering results in proinflammatory IL production. It has been
reported that CpG motifs and IL-2 exposure can induce B Levamisole-Contaminated Cocaine
lymphocytes to proliferate, increase antigen presentation, produce It is commonplace for illicit drugs, such as cocaine, to be combined
a range of cytokines, and differentiate into Ig-producing cells, with adulterants, such as levamisole, in an effort to increase
ultimately leading to ANCA production. 36 profits. Levamisole is similar in physical appearance and has
possible potentiating effects on levels of dopamine in the central
DRUG INDUCED AAV nervous system. It is estimated that >75% of cocaine users in
the United States are exposed to levamisole.
The most commonly implicated drugs that can induce an Clinical manifestations of AAV induced by levamisole-
AAV-like syndrome are propylthiouracil (PTU), hydralazine, contaminated cocaine include constitutional features; arthralgia;
levamisole-adulterated cocaine, TNF-α inhibitors, sulfasalazine, retiform purpura involving the ears, face, and extremities; and,
D-penicillamine, and minocycline (Fig. 58.1). less commonly, renal and lung diseases. Laboratory abnormalities
include leukopenia, neutropenia, and high-titer p-ANCA, directed
Propylthiouracil against MPO-ANCA or against atypical p-ANCA–associated
The most commonly described drug associated with the presence antigens, such as HNE, lactoferrin, and cathepsin G. PR3-ANCA,
of ANCA is propylthiouracil (PTU). PTU is used to treat hyper- ANA, and antiphospholipid autoantibodies have also been
thyroidism and was the first drug described to induce a condition described in these patients. This multiplicity of antibodies helps
mimicking AAV in the 1990s. Even though its use has declined distinguish AAV induced by levamisole-contaminated cocaine
over time, reports of PTU-induced AAV still emerge. Clinically, from primary AAV, which usually targets just one antigen.
PTU-induced AAV may manifest as acute kidney injury caused Levamisole has an estimated mean half-life of 5.6 hours;
by pauciimmune necrotizing and crescentic glomerulonephritis therefore serum testing is likely to be negative if the most recent
in addition to respiratory tract, joint, and skin diseases. exposure occurred >24 hours prior to sample collection. Urinary
Reports of the proportion of patients who develop ANCA as detection of levamisole is highly suggestive of drug-induced
a result of exposure to antithyroid medications varies widely disease and is useful if exposure occurred <48 hours prior to
from 4% to 46%; by contrast, the prevalence of antithyroid testing.
drug-induced AAV is much lower (0–1.4%). Although PTU is The mechanism by which levamisole-contaminated cocaine
the most commonly reported antithyroid drug, methimazole induces AAV is unclear. Levamisole, like PTU, could serve as
and carbimazole have also been implicated. In a study by Noh a substrate for MPO to form reactive metabolites that might
37
et al., the estimated annual incidence of antithyroid drug- induce autoimmunity. Levamisole can enhance NETosis through
induced vasculitis was 0.53–0.79 patients per 10 000 patients engagement of muscarinic (subtype 3) receptors; furthermore,
with Graves disease, especially for patients receiving propylthio- neutrophil extracellular traps (NETs) generated by levamisole
uracil; the ratio of the estimated incidence for methimazole and can induce endothelial cell death and vascular dysfunction by
propylthiouracil was 1 : 39. Most patients with PTU-induced disrupting normal endothelium-dependent vasorelaxation.
ANCA will not develop clinical features of vasculitis. Patients Abusing cocaine without levamisole can also trigger a syndrome

794 Part SIX Systemic Immune Diseases









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FIG 58.1 Proposed pathogenic mechanisms in antineutrophil cytoplasmic antibody (ANCA)
associated vasculitis. The interaction between activated neutrophils and ANCA is depicted in the
figure, with resting neutrophils becoming activated (A), interacting with ANCA in the intravascular
space (B), triggering a series of cascading events leading to vascular invasion (C) by inflammatory
cells and the formation of neutrophil extracellular traps (NETs) and eventually chronic inflammation
in the extravascular space (D).


mimicking AAV. The clinical presentation can be identical to glomerulonephritis. The autoantibody profile usually includes
that of patients with GPA, although cerebral angiitis, urticarial c-ANCA with PR3 specificity, although there are reports of
vasculitis, and EGPA-like syndromes have also been described. cases with negative ANCA or p-ANCA with PR3 specificity.
In GPA-like vasculitis, patients typically present with cutaneous In these cases, the target of p-ANCA may be atypical, such as
vasculitis, nasal septal destruction, and pauciimmune crescentic HNE.

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 795


Cocaine-induced midline destructive lesions (CIMDLs) in the stimulator (BLyS) levels are significantly increased, thereby
45
40
upper respiratory tract mimic limited forms of GPA. Patients promoting B-cell differentiation, proliferation, and survival.
with CIMDLs may present with or without ANCA, and when B cells may play a number of roles in AAV: as precursors to
ANCA-positive, the pattern often varies. Some patients are positive antibody-producing plasma cells; as APCs; producing proinflam-
for c-ANCA with PR3 specificity, but more often, patients with matory mediators; or in costimulation of T cells.
CIMDLs present p-ANCA with specificity for atypical ANCA,
such as HNE. Wiesner et al. reported that 76% of the patients ROLE OF NEUTROPHILS
with CIMDLs were ANCA-positive (mostly p-ANCA): 57% had
PR3-ANCA and 86% had HNE-ANCA; this compares with the In addition to containing the antigens for ANCA, activated
absence of HNE-ANCA in GPA and MPA, suggesting that the neutrophils release many mediators that modulate the inflam-
presence of HNE-ANCAs may be helpful in distinguishing CIMDL matory response and can directly contribute to tissue inflam-
from GPA. 41 mation, vascular injury, and damage in AAV via phagocytosis,
Table 58.2 provides a summary of the most significant associa- degranulation, and cytokine production. Neutrophils release B
tions between drugs and ANCA or AAV. The management of cell–activating factors (BAFFs) that enhance B-cell proliferation
all forms of drug-induced AAV is withdrawal of the offending and retard apoptosis. Neutrophils from patients with AAV are
46
agent, supportive measures, and, in severe cases, immunosup- more prone to spontaneous release of NETs. In the normal
pression, dialysis, and plasma exchange. immune system, NETs consist of chromatin fibers released from
dying neutrophils and are designed to trap and kill extracellular
LOSS OF B- AND T-CELL TOLERANCE IN pathogens. NETs not only contain proinflammatory proteins
ANCA-ASSOCIATED VASCULITIS that directly cause endothelial cell damage and complement
activation but also form a link between innate and adaptive
The imbalance of effector and Tregs underpins the autoimmune immunity via providing access to MPO and PR3.
dysregulation seen in AAV with multiple alterations in the circulat-
ing T-cell population. Patients with AVV have a reduced number ROLE OF COMPLEMENT
42
of circulating Tregs, which are functionally impaired, and an
expanded population of CD4 effector memory T cells with an Despite the apparent paucity of immune complexes in AAV,
43
increased number of activated T cells. Persistence of CD4 T-cell complement (and in particular activation of the alternative
44
activation in peripheral blood correlates with disease severity. complement pathway) plays a crucial role in the pathogenesis
Aberrant T helper (Th) polarization, with an increase in proin- of AAV. When primed neutrophils are activated by ANCA, they
flammatory Th17 responses, further contributes to vascular produce C5a, which, in addition to recruitment, primes addi-
47
43
injury. It has been suggested that these alterations to the tional neutrophils for further activation by ANCA. C3a, C5a,
peripheral T-cell compartment could be influenced by environ- and soluble C5b-9 levels are elevated in active disease; plasma
mental factors, such as infection. levels of complement factor H, a regulator of the alternative
The discovery of B cells in the inflammatory lesions in AAV complement pathway, are significantly lower in patients with
48
together with the success of B-cell depletion therapies suggests that active AAV. Low serum levels of C3 at diagnosis are associated
49
B cells play a significant role in the pathogenesis of AAV; however, with a worse prognosis. There is also a suggestion that C5a
the exact mechanism of this involvement is still not known. may play a role in the hypercoagulability associated with active
Regulatory B cells are reduced in AAV, whereas B-lymphocyte AAV.
TABLE 58.2 Drug-Induced Vasculitis associated With aNCa Positivity—Implicated Drugs,
Proposed Mechanisms of action and Laboratory Findings

Other aNCa
Drug/Class Proposed Mechanism of action IF Pattern aNCa Serotype autoantigens Other antibodies ref.
allopurinol Limited data p-ANCA MPO-ANCA - ANA 50
anti–tNF-α TNF-α may induce the formation of p-ANCA MPO-ANCA - ANA 51
(aDa, EtN, immune complexes, activation of c-ANCA PR3-ANCA
IFX) complement and mediate
inflammation by switching from a
cytokine response of T-helper type 1
to type 2, upregulating antibody
production
Benzylthiouracil Limited data p-ANCA MPO-ANCA HNE - 52
Lactoferrin
Carbimazole Limited data p-ANCA MPO-ANCA - -
c-ANCA PR3-ANCA

Cocaine Enhanced formation of NETs enriched c-ANCA PR3-ANCA HNE 40, 41
in neutrophil elastase and p-ANCA
inflammatory mitochondrial DNA with
enhanced release of B cell–activating
factor belonging to the TNF family (B
cell–activating factor [BAFF])
Continued

796 Part SIX Systemic Immune Diseases



TABLE 58.2 Drug-Induced Vasculitis associated With aNCa Positivity—Implicated Drugs,
Proposed Mechanisms of action and Laboratory Findings—cont’d
Other aNCa
Drug/Class Proposed Mechanism of action IF Pattern aNCa Serotype autoantigens Other antibodies ref.
D-penicillamine Limited data p-ANCA MPO-ANCA HNE ANA 53
Lactoferrin Anti-dsDNA abs
Hydralazine Hydralazine mediated reversal of P-ANCA MPO-ANCA HNE ANA
epigenetic silencing of MPO and PR3-ANCA Lactoferrin Anti-dsDNA abs
PR3, with subsequent increased Antihistone abs
expression of both autoantigens. Anticardiolipin abs
Induction of cytotoxic products and
neutrophil apoptosis mediated by
hydralazine binding MPO

Levamisole Enhanced NETosis through p-ANCA MPO-ANCA HNE ANA 54, 40
contaminated engagement of muscarinic subtype 3 c-ANCA PR3-ANCA (double Cathepsin G Anticardiolipin abs
cocaine receptor + is very Lactoferrin
Metabolism of levamisole by MPO common)
with formation of reactive
metabolites
Genetic susceptibility to
agranulocytosis in HLA B27+ patients
Methimazole Limited data p-ANCA MPO-ANCA HNE ANA 55, 56

c-ANCA PR3-ANCA
Atypical
ANCA
Minocycline Minocycline oxidation by MPO, with p-ANCA MPO-ANCA HNE ANA 57
abnormal production of reactive Atypical PR3-ANCA Cathepsin G Anti-dsDNA abs
metabolites and modification of ANCA BPI
enzymatic activity, triggering the
induction of ANCA
Cytotoxicity leading to premature
apoptosis of neutrophils, with
abnormal release of nucleosomes
and drug-modified proteins (including
myeloperoxidase, elastase, LL37, and
HMGB1), which can be bound to
neutrophil extracellular traps (NETs)
triggering lupus/vasculitis via type I
IFN production
Propylthiouracil Cross-reactivity between anti- p-ANCA MPO-ANCA HNE ANA 27, 55, 95, 58

(PtU) thyroperoxidase (anti-TPO) antibody atypical PR3- ANCA Lactoferrin Antihistone abs
and MPO ANCA BPI Anticardiolipin abs
Alteration of NET configuration Azurocidin
PTU-induced structural change in MPO, Cathepsin G
which serves as a neoantigen
Metabolism of PTU by MPO (in the
−
presence of H 2 O 2 and Cl ) into strong
toxic metabolites. Subsequent
binding to neutrophils proteins and
recognition by T cells with B cells
activation resulting in autoantibody
production
Competitive inhibition of MPO
oxidation activity by PTU, in a dose
dependent manner

Sulfasalazine Sulfasalazine-induced neutrophil p-ANCA MPO-ANCA Lactoferrin ANA 50, 59
apoptosis, with subsequent c-ANCA PR3-ANCA Anti-dsDNA abs
membrane expression of PR3 and
MPO
abs, antibodies; ADA, adalimumab; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibody; BPI, bactericidal permeability increasing protein; dsDNA, double-
stranded DNA; ETN, etanercept; HLA, human leukocyte antigen; HNE, human neutrophil elastase; IF, immunofluorescence; IFN, interferon; IFX, infliximab; MPO, myeloperoxidase;
NET, neutrophil extracellular trap; PR3, proteinase 3; Ref, references; TNF, tumor necrosis factor.

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 797



PATHOGENESIS OF KAWASAKI DISEASE such as intercellular adhesion molecule-1, vascular cell adhesion
molecule-1, and E-selectin, suggesting that endothelial cell
The incidence of KD is highest in East Asian countries, such as activation could perpetuate and potentiate the inflammatory
Japan, Korea, and Taiwan. The incidence in Japanese children milieu. IFN-γ and TNF-α increase the expression of class I major
is 10-fold higher compared with that in the United States. histocompatibility complex (MHC) antigens and induce MHC
Japanese data show a seasonal variation in incidence, with an class II expression, resulting in antigen presentation to T cells.
increase seen in the winter; furthermore, siblings of patients with In one study of 24 patients with idiopathic PAN, macrophages
KD are at increased risk of disease compared with the general and CD4 T lymphocytes were the predominant cell types found
60
population, and the risk of sibling patients is increased among in lesions. T lymphocytes were more abundant in nerve biopsy
60
patients whose parents previously had the disease. KD shows specimens compared with muscle biopsy specimens (52% vs
geographical clustering, with shared clinical features between 35%; p < 0.001), whilst macrophages were predominant in muscle
clusters of disease. These findings suggest a role for an infectious specimens (45% vs 33%; p = 0.005). Histologically, T lympho-
environmental trigger, together with genetic susceptibility. Several cytes were distributed throughout the vessel wall, whereas
disease susceptibility genes have been identified, including genes macrophages predominated in the periphery. 70
that affect the function of molecules involved in the calcineurin- In HBV-induced PAN, there is direct injury to the vessel wall
59
nuclear factor of activated T cells (NFATs) pathway; transforming as a result of viral replication and deposition or in situ formation
growth factor-β (TGF-β) lipopolysaccharide-induced endothelial of immune complexes, which activate complement, thereby
cell inflammation pathways; and genes encoding Fcγ receptors, recruiting and activating neutrophils. The immunological process
such as ITPKC, FAM167-BLK, CD40, FCGR2A, HLA, CASP3, usually occurs within 6 months of HBV infection. During the
61
TGFB2, TGFBR2, SMAD3, and PLCB4/PLCB1. CD40 and active phase of disease, complement levels are low, consistent
FCGR2A have been associated with disease susceptibility in with complement consumption resulting from immune complex
Europeans. deposition.
SNPs identified within the ITPKC and PLCB4/PLCB1 genes Alterations in the MEFV gene (encoding pyrin) may represent
61
are associated with the risk of coronary artery aneurysms. ITPKC an important susceptibility factor for PAN. Pyrin is critically
and CASP3 SNPs are associated with lack of response to intra- important in regulating IL-1β production; mutations of pyrin
62
venous immunoglobulin (IVIG) treatment. ITPKC is a negative may be associated with loss of regulation of inflammatory
2+
regulator of T-cell activation via downregulation of the Ca / pathways via apoptosis and IL-1β release, resulting in augmented
NFAT signaling pathway. The SNP located in the intron of ITPKC inflammation, similar to patients with familial Mediterranean
regulates splicing, decreasing negative regulation of T cells and fever, who can be carriers of MEFV mutations. 71
leading to increased T-cell activation and IL-2 production. 63
TNF-α, nuclear factor-κB (NF-κB), IL-17, TGF-β, interferon-γ PATHOGENESIS OF CRYOGLOBULINEMIC
(IFN-γ), granulocyte–colony-stimulating factor (G-CSF), IL-1β, VASCULITIS
IL-6, follistatin-like protein 1, and TLR2 are reported to be
elevated in patients with KD. 64,65 In the acute phase of disease, The pathological hallmark of cryoglobulinemic vasculitis is
circulating IL-17 levels and IL-17–induced cytokinesis are deposition of cold-precipitating Igs in small vessels, resulting in
increased, suggesting an imbalance between Th17 and Tregs. vascular inflammation and damage. In most patients, chronic
66
Th17 levels are higher in children with coronary lesions. There HCV infection is the trigger, but cryoglobulinemic vasculitis
is evidence for marked activation of cytotoxic and Th lymphocytes can also occur in the context of other chronic infections and in
and dendritic cells, with upregulation of type I IFN responses, some autoimmune rheumatic diseases and lymphoproliferative
supporting a possible viral etiology of KD, based on a transcrip- disorders.
tomic study of patients who died or who were undergoing heart HCV plays several important roles in the pathogenesis of
transplantation. 67 cryoglobulinemic vasculitis. HCV glycoproteins interact directly
KD has been suspected to be triggered by bacterial or viral with B-cell surface receptors, lowering the activation threshold
72
infections, but no single causative agent has been identified. It and resulting in polyclonal activation and expansion of B cells.
has been suggested that superantigens (SAgs) are implicated. Circulating, clonally expanded B cells produce monoclonal
Several microorganisms can produce SAgs, including bacteria IgM rheumatoid factor (RF). Mixed cryoglobulins contain a
(e.g., staphylococci, streptococci, mycobacteria, Mycoplasma, monoclonal IgM RF directed against the Fc segment of IgG and
Yersinia, Lactobacillus) and viruses (e.g., Epstein-Barr virus). polyclonal IgG. When IgM RF is exposed to cold conditions, it
SAg-producing bacteria have been isolated from children with undergoes conformational changes resulting in cryoprecipitation.
acute KD, including TSST-1 producing S. aureus and pyrogenic Cold-insoluble immune complexes are formed predominantly
68
exotoxin–producing Streptococcus. In a mouse model involving by IgM RF linked to IgG (which, in turn, is bound to HCV
injections of intraperitoneal Lactobacillus casei, disease could core protein). Cryoglobulinemic vasculitis should be considered
not be induced in recombinase activating gene-1–deficient mice, an antigen-driven disease, because HCV persistence ensures
implicating T cells as critical drivers of the disease process. 69 sustained lymphoid proliferation and continued cryoglobulin
production.
PATHOGENESIS OF POLYARTERITIS NODOSA C1q protein levels and C1q binding are significantly increased
in cryoglobulinemic vasculitis. C1q is required for binding of
The pathogenesis of idiopathic PAN is unknown; clinical immune complexes to endothelial cells. Although mixed cryo-
responses to immunosuppressive therapy strongly support an globulins can be detected in up to 60% of patients with chronic
underlying immunological mechanism. Elevated levels of IL-2, hepatitis C, cryoglobulinemic vasculitis occurs only in a minority,
IL-8, IFN-γ, TNF-α, and IL-1β have been reported in PAN, as suggesting that host factors must be equally important in the
well as elevated levels of circulating soluble adhesion molecules, pathogenesis of the disease.

798 Part SIX Systemic Immune Diseases



PATHOGENESIS OF EGPA define disease entities. They are not true classification or diagnostic
criteria because they are not evidence based (they are consensus
Despite the established role of ANCA in GPA and MPA, the of opinion from several experts); but they have advantages over
pathogenic role of ANCA in EGPA is less clear. In EGPA, only the 1990 ACR criteria. They were developed after recognition
30–40% of patients are ANCA positive; the presence or absence of ANCAs, which are an important part of the 2013 definitions.
of ANCA in EGPA defines distinct clinical phenotypes. The One of the major flaws of the ACR criteria is the failure to
74
pathological hallmark of EGPA is prominent tissue and peripheral recognize MPA as an entity separate from PAN. This failure to
blood eosinophilia, suggesting a central pathogenic role for the separate PAN and MPA has probably prevented proper diagnosis,
eosinophil. EGPA is considered to be Th2 mediated, given the and it is a historical legacy from an assumption that almost all
striking early allergic manifestations, together with the marked forms of vasculitis are, in fact, variations of PAN.
increase in circulating Th2 cytokines, including IL-5, which plays
a crucial role in eosinophil differentiation in bone marrow as DIAGNOSIS
well as recruitment and activation of eosinophils at sites of
inflammation. IL-5 could delay apoptosis of eosinophils and Individual Diseases
73
modulate the function of mast cells and basophils. Elevated AAV are a group of three main entities: GPA, MPA, and EGPA.
levels of IFN-γ (a potent Th1 cytokine involved in granuloma These three conditions overlap with many shared clinical features.
formation) provide evidence for the involvement of other Th Figs. 58.2 and 58.3 describe clinical patterns in patients with
responses. Th17 responses are upregulated, and B lymphocytes MPA and GPA and show that there are many similarities, with
and humoral responses are likely to be important, given that a dominance of kidney and lung involvement in both conditions.
B-cell depletion can induce remission and reduce circulating EGPA is characterized by eosinophilia, late-onset asthma, and
IL-5 and eosinophils. neuropathic involvement, but cardiac involvement may develop
The precise mechanisms of eosinophil-mediated inflammation in a subset of patients with EGPA, particularly in association
in EPGA remains unclear. Eosinophils are granulocytic cells with hypereosinophilia. Systemic features, such as malaise, fever,
capable of releasing multiple proinflammatory cytokines, che- weight loss, or myalgia, could be mistaken for a variety of other
mokines, and reactive oxygen species, which have direct effects conditions, and it may delay recognition of disease. Patients with
on the vessel and perivascular tissues, including tissue fibrosis, MPA can present just with isolated microscopic hematuria and
thrombosis, and allergic inflammation; indirect effects include hypertension, with nonspecific systemic features. In contrast,
recruitment and activation of other inflammatory cells to perpetu- patients with GPA typically suffer from upper airway problems,
ate the inflammatory response. with nasal crusting, blood-stained discharge, sinusitis, or hearing
loss. In anti–glomerular basement membrane (anti-GBM)
CLASSIFICATION antibody disease, clinical features sometimes overlap with those
of AAV, but the dominant features are pulmonary hemorrhage
Several sets of classification criteria have been published, the most leading to hemoptysis and rapid deterioration in renal function.
recent being one by the American College of Rheumatology (ACR) It is not entirely clear whether the anti-GBM disease should be
in 1990. These are primarily for the purposes of epidemiological regarded vasculitis or vasculopathy, but it has been included in
studies or for defining patients for inclusion in clinical studies, the current Chapel Hill Consensus definitions of a small-vessel
rather than being used in clinical practice. However, as is often the vasculitis. Confusingly, some patients with anti-GBM antibodies
case with classification criteria, they are misapplied as diagnostic also have ANCA.
criteria in daily practice and may fail to provide a clear-cut distinc- The clinical course in MPA is typically acute, whereas GPA
74
tion between vasculitis and other conditions. An international may remain undiagnosed for several months or even years before
effort is currently underway to develop improved classification the upper airway and or lower airway symptoms are recognized
criteria as well as diagnostic criteria for patients with vasculitis as being related to vasculitis. For almost all forms of acute AAV,
or suspected vasculitis, and it is likely to lead to a new set of the differential diagnosis is infection, cancer, or drug toxicity.
75a
evidence-based criteria to improve diagnosis and classification of One of the drugs recently recognized to mimic AAV is cocaine,
74
vasculitis in the future. There is considerable overlap between which can cause local tissue necrosis, especially in the palate,
different forms of vasculitis. The group of patients with diseases leading to palatal and nasal septal perforation. Interestingly
clustered around the presence of ANCA share many features cocaine can induce ANCA production and therefore can be a
in common, particularly the presence of glomerulonephritis true mimic of AAV. Typically the ANCA is directed against elastase
and pulmonary infiltrates. In the case of EGPA, patients also or is nonspecific. Careful history taking, sometimes with sensitive,
experience rhinitis, nasal polyps, asthma, and rashes and may confidential, repeated questioning, may be required to eventually
develop mononeuritis multiplex or sensory peripheral neuropathy. identify this as a cause of a patient’s condition. Contamination
In addition to renal and lung inflammation, patients with GPA of cocaine with levamisole is becoming a growing problem.
typically suffer from upper respiratory problems, such as nasal Presumably, levamisole (a veterinary anthelmintic agent) is a
crusting or discharge; subglottic stenosis; or hearing loss. Patients cheap white powder that can be mixed readily with cocaine but
with MPA do not usually develop significant upper airway disease; can cause an acute necrotizing vasculitis of skin and the extremi-
their disease tends to be more limited to the kidneys and/or lungs. ties. Discontinuation of levamisole and cocaine usually stops
All of these conditions can also affect any other organs, such as further progression of disease, but once palatal or nasal perforation
skin. Skin is the most commonly affected site in most forms of has developed, patients may require local surgical repair.
vasculitis. This can vary from small infarcts around nail edges Cryoglobulinemic vasculitis typically presents with purpuric
to purpura, ulcers, nodules, and even gangrene. lesions on the legs, and the lesions may ulcerate. Patients often
The development of consensus criteria for diagnosis by the complain of joint pains and malaise. Neuropathies can occur
Chapel Hill group has provided a more rational approach to with either mononeuritis multiplex or sensory neuropathy;

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 799


ORGAN INVOLVEMENT IN GPA systemic inflammatory syndrome. The child typically has mucosal
100 inflammation with strawberry tongue; approximately 10 days
90 after the onset, skin desquamation is a very typical feature. The
most worrying feature of KD is the development of coronary
80 artery aneurysms, which occur in around 2–4% of children
70 and can be fatal, if untreated. This can be detected by using
echocardiography.
60
Laboratory Investigations
50
The investigation of patients with suspected small- or medium-
40
vessel vasculitis should follow a careful history and examination
30 to determine the likely diagnosis and underlying illness. The
20 differential diagnosis is very wide. It is important to be vigilant
in looking for positive signs of vasculitis, but it is equally
10 important not to forget to look for more common causes of the
0 clinical presentation. Many of the studies performed can result
ENT Lung Kidney Heart GI Skin CNS PNS in nonspecific findings, such as an elevated white blood cell
FIG 58.2 Organ involvement in patients with granulomatosis count, platelet count, or the erythrocyte sedimentation rate. The
with polyangiitis (GPA). (Data compared across seven cohorts— C-reactive protein (CRP) level is typically raised. Patients may
reviewed by Luqmani R, Ponte C. ANCA associated vasculitides be anemic. Liver or, more importantly, renal function may be
and polyarteritis nodosa. In: Bijlsma JWJ, Hachulla E, eds. EULAR abnormal. The presence of hypereosinophilia can be suggestive
Textbook on Rheumatic Diseases. London, UK: BMJ Publishing of a diagnosis of EGPA, but there are other causes of hypereo-
Group Ltd; 2015. Chapter 27, p.717-753) 75 sinophilia, particularly drug reactions. It is important to test
renal function in patients with suspected vasculitis in case there
is nephritis, and it is always important to perform urinalysis for
microscopic hematuria or proteinuria. Although these might be
ORGAN INVOLVEMENT IN MPA explained by the presence of a kidney infection or other causes,
120 they raise a strong suspicion of glomerular inflammation. An
abnormal urinary sediment in combination with hypertension
100 should alert the physician to the possibility of kidney involvement
12
by small-vessel vasculitis. Since the 1980s, the discovery of ANCA
80 has transformed the recognition of renal vasculitis, so that these
60 patients can be managed more effectively.
Histology remains a very important diagnostic test, not only
40 to make a positive diagnosis but also to exclude other causes.
20 Although histology from the airways can be nondiagnostic, this
may still assist in ensuring that the patient does not have cancer,
0 sarcoidosis, o tuberculosis, or IgG4-related disease, all of which
ENT Lung Kidney Heart GI Skin CNS PNS could present in a similar way with inflammation of the upper
FIG 58.3 Organ involvement in patients with microscopic or lower airway. Renal histology is still the gold standard to
polyangiitis (MPA). (Data compared across seven cohorts— diagnose suspected glomerulonephritis and may be useful in
reviewed by Luqmani R, Ponte C. ANCA Associated Vasculitides predicting the prognosis. Four categories of renal lesion have
76
and Polyarteritis Nodosa. In: Bijlsma JWJ, Hachulla E, eds. EULAR been proposed: focal, crescentic, mixed, and sclerotic. Follow-up
TEXTBOOK ON RHEUMATIC DISEASES. London, UK: BMJ of patients with different patterns has shown outcomes: progres-
Publishing Group Ltd; 2015. Chapter 27, p.717-753) 75 sively worse renal outcome from focal (the best) through to
sclerotic (the worst) over the subsequent 5 years.

ASSESSMENT
membranous glomerulonephritis is a recognized complication.
Most cases appear to be associated with hepatitis C (>90% in The outcome of small- and medium-vessel vasculitis has been
some series), and eradication of hepatitis C appears to be effective completely transformed by immunosuppressive therapy. With
in reducing the manifestations of disease. treatment almost all patients with KD recover from their initial
True PAN typically presents with neuropathies, systemic illness. In AAV, >70% survive at least 5 years from starting treat-
inflammation, and ischemic abdominal pain (difficulty eating ment. The majority of patients with PAN respond to initial
because of medium-vessel supply to the gut and nerves). If it is therapy. However, the risk of recurrence of disease is high in
associated with hepatitis B, the patient may or may not have small-vessel vasculitides. Relapse rates are likely to exceed 50%
46
obvious signs of liver disease. over time. Patients experience comorbidities as a consequence
Isolated cutaneous vasculitis typically presents as purpuric of the disease or its treatment and can suffer from infections or
lesions, skin ulceration, or broken livedo, and biopsy of the skin other complications that contribute to their overall poor health.
will show typical changes of a necrotizing vasculitis. In the long term, small-vessel vasculitides and their treatment
KD usually presents in childhood as an acute illness, with can be associated with effects on the cardiovascular system with
relapsing high fevers, significant lymphadenopathy, and a increased risk of hypertension, coronary heart disease, and stroke.

800 Part SIX Systemic Immune Diseases


Immunosuppressants given to patients can significantly improve point each); with 15–19 major items and 19–23 minor items,
disease control but may increase the risk of malignancy. The the range of sores is 0–76. The PVAS was developed as a pediatric
continued use of high doses of glucocorticoid therapy contrib- version of the BVAS, but validated in children with vasculitis
utes to hypertension, diabetes, heart diseases, osteoporosis, and and demonstrated to be effective at discriminating different
infection. disease states and is increasingly used as a research tool in pediatric
It is therefore obvious that careful evaluation of a patient’s vasculitis.
status is required throughout the course of disease. Constant
vigilance is required to detect and manage any flare-up of disease
because the consequences of untreated inflammation of vessels
to vital organs can be severe. Although for most patients, initial KEY CONCEPtS
therapy is very successful and improvements in disease status is
obvious to the patient, the subsequent disease course can be Assessment of Disease Activity in Vasculitis
much more complicated because of comorbidities, the evolution
of disease-related damage, and morbidity caused by treatment • For small- and medium-vessel vasculitis in adults, version 3 and a
specific version of the BVAS for granulomatosis with polyangiitis (GPA)
as well as disease flare-ups. There are no suitable biomarkers are used.
that can be universally applied in small- and medium-vessel • BVAS version 3 is the most generic and applicable across different
vasculitides to determine the patient’s disease state to provide forms of vasculitis; BVAS for GPA has been specifically designed for
an evidence-based rationale for adjustment of therapy. ANCA use in GPA and contains very specific items related to that
titers fluctuate during the course of disease, and although ANCA condition.
remains a very useful diagnostic test, its value in managing • During sequential monitoring, a time frame of 3 months is recommended
so that disease activity is considered to be of most relevance during
variations in disease activity is very limited. Up to 40% of patients this time. The time frame is based on pragmatic clinical experience
have an elevation of ANCA without any new deterioration in that this is the usual time taken during which immunosuppressive
clinical state, but a recent study has shown that patients with therapy is likely to have a significant effect on active disease
renal involvement as part of their presentation are likely to have manifestations.
77
relapses associated with ANCA rises. Among 166 patients with
AAV, all were positive for ANCA and 104 had renal involvement
(a mixture of PR3-ANCA and MPO-ANCA). The hazard ratio
for ANCA rises predicting subsequent relapse was 11.09 (CI
5.01–24.55), suggesting that this test may be of value in detection Damage Assessment in Vasculitis
of future relapse in this subset of patients. However, for the The concept of damage in patients with vasculitis is about the
majority of patients with systemic vasculitis, careful clinical permanent consequences of having vasculitis. It is an attempt
evaluation remains a cornerstone of effective disease management to measure disease burden regardless of cause. The Vasculitis
as recommended by the EULAR guidelines on management of Damage Index (VDI) is the most widely used and validated
systemic vasculitis. 78 measure for assessment of damage in vasculitis (reviewed in
79
In simple terms, at the onset of the condition, disease activity Ponte et al., 2014). The VDI captures the long-term consequences
is the dominant problem, and treatment should be directed of a diagnosis of vasculitis and its treatment and associated
toward it; but over the course of time, with the development of comorbidities. Damage is defined as lasting at least 3 months
consequences of vasculitis or its treatment, there is an increasing or occurring at least 3 months ago for single time point events
component of damage or scarring and also side effects of drug (e.g., stroke or myocardial infarction) and should be recorded
therapy. Similarly, different patients function at different levels as a permanent change to the patient’s damage status. A VDI of
with the same amount of disease, or damage, and therefore the >5 points recorded within 6 months of disease carries a significant
ability to perform normal tasks is an important component of increased risk of subsequent mortality compared with a lower
79
their overall condition to consider (Table 58.3). damage index at 6 months (reviewed in Ponte et al., 2014).
The primary tool used is the Birmingham Vasculitis Activity VDI is a useful index of future harm. A further development of
Score (BVAS) in adults and the Paediatric Vasculitis Activity the damage index has been the combined damage assessment
79
Score (PVAS) in children (reviewed in Ponte et al., 2014). (CDA). In a comparative study with the VDI, CDA was shown
Training is recommended for assessment in the Birmingham to be inferior to it (reviewed in Ponte et al., 2014). 79
Vasculitis Activity Score (BVAS). BVAS provides a quantitative
score based on individual items, providing an effective means TREATMENT
to define the patient’s status with regards to response to therapy.
Many recent studies of different immunosuppressive agents have Once a diagnosis of small- and medium-vessel vasculitis has
made use of the BVAS either to define improvement in terms been established, treatment should be focused on patients and
of a fall in BVAS score or to define a cut-off representing active their problems rather than the specific diagnosis. Treatment for
disease, or inactive disease, or flare-up, depending on the number different forms of vasculitis may look very different, but many
of items present. Although it is subject to observer variability, aspects of different forms of vasculitis require the same therapeutic
it provides an effective means by which groups of patients can approach. Without a clear understanding of the underlying
be compared against each other and allows individual patients pathogenesis of disease, we are inevitably led by the need to
to be followed up over the course of their condition. The score suppress inflammation and reduce damage to prevent mortality
is weighted according to the organ system and the individual and improve survival. However, as well as modifying immune
manifestation, to reflect the severity of the disease. The range dysregulation, it is important to consider other aspects of the
of scores for BVAS and PVAS are 0–63. For BVAS GPA, items patient’s condition, such as comorbidities and the prevention
are divided into major (scoring 3 points) and minor (scoring 1 of future comorbidities.

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 801



TABLE 58.3 assessing Disease activity in Vasculitis
System
assessed BVaS BVaS WG PVaS Comments
General Myalgia, arthralgia/ arthritis, Arthritis, fever Myalgia, arthralgia/ arthritis, These are typical features in many forms
fever, weight loss fever, weight loss of systemic vasculitis.
Skin Infarct, purpura, skin ulcer, Purpura, skin ulcer, Polymorphous exanthema, Skin is a common organ involved in most
gangrene gangrene livedo, panniculitis, forms of small and medium vessel
purpura, skin nodules, vasculitis. Skin manifestations in
infarct, ulcer, gangrene, ANCA-associated vasculitides tend to be
other skin vasculitis less serious compared with
manifestations in kidneys, lungs, and
upper airways.
For skin vasculitis in children the
manifestations are more diverse.
Mucous Mouth ulcers, genital Mouth ulcer, conjunctivitis/ Mouth ulcers, genital Eye involvement is most common in GPA
Membrane/ ulcers, adnexal episcleritis, retro-orbital ulcers, adnexal and less often seen in MPA or EGPA.
eyes inflammation, proptosis, mass, uveitis, scleritis, inflammation, proptosis,
red eye, (epi)scleritis, retinal exudates red eye (epi)scleritis,
conjunctivitis, blepharitis, conjunctivitis, blepharitis,
keratitis, blurred vision, keratitis, blurred vision,
visual loss, uveitis, retinal visual loss, uveitis, retinal
vasculitis vasculitis
Ear, nose, Bloody nasal discharge, Blood nasal discharge, Blood nasal discharge, ENT manifestations are most common in
and throat paranasal sinus paranasal sinus paranasal sinus GPA and rarely seen in MPA or EGPA.
involvement, subglottic involvement, swollen involvement, subglottic However, EGPA is often characterized
stenosis, conductive salivary glands, subglottic stenosis, conductive by the presence of nasal polyps, which
hearing loss, inflammation, conductive hearing loss, are inflammatory in nature.
sensorineural hearing hearing loss, sensorineural sensorineural hearing
loss hearing loss loss
Chest Wheezing, nodules or Nodules or cavities, Wheezing, nodules or The chest is commonly affected in all
cavities, pleural effusion, pleurisy, infiltrates, cavities, pleural effusion, three forms of ANCA vasculitis.
infiltrates, endobronchial endobronchial changes, infiltrates, endobronchial Wheezing is a common feature of EGPA
changes, massive alveolar hemorrhage changes, massive as are infiltrates. In contrast, infiltrates,
hemoptysis, respiratory hemoptysis, respiratory hemoptysis, respiratory nodules, and endobronchial disease
failure failure failure dominate in GPA. Massive hemoptysis
can occur in patients with GPA or MPA
and less frequently in patients with
EGPA, but may also be a typical feature
with GBM (glomerular basement
membrane) disease.
Cardiovascular Loss of pulses, ischemic Pericarditis Loss of pulses, bruits, Cardiovascular manifestations are most
system cardiac pain, blood pressure widely recognized in KD, which is not
cardiomyopathy, discrepancy, claudication, particularly well covered by PVAS.
congestive cardiac failure, ischemic cardiac pain, Although CVD manifestations do occur
valvular heart disease, cardiomyopathy, in small- and medium-vessel vasculitis,
pericarditis congestive cardiac failure, they are more typically seen in large
valvular heart disease, vessel diseases, such as Takayasu
pericarditis arteritis.
Abdominal Ischemic abdominal pain, Mesenteric ischemia Abdominal pain, peritonitis, Gut involvement is more typical in
system peritonitis, bloody bloody diarrhea, bowel medium-vessel vasculitis, especially
diarrhea ischemia polyarteritis nodosa, but is well
recognized in patients with GPA
especially with colitis giving rise to
bloody diarrhea.
Renal system Hypertension, proteinuria, Hematuria, red cell casts, or Hypertension, proteinuria, Renal involvement in small-vessel
hematuria, impaired renal glomerulonephritis, hematuria, impaired renal vasculitis is one of the major
function, deterioration in deterioration in renal function, deterioration in manifestations leading to organ failure
renal function function renal function and death and should be carefully
assessed. Renal involvement in
medium-vessel vasculitis is much less
common and takes the form of infarction
of segments of the kidney leading to
hematuria and hypertension with
consequent impairment of renal function.
Nervous Headache, meningitis, Meningitis, stroke, cord Headache, meningitis, Neurological involvement is a common
system organic confusion, involvement, cranial nerve organic confusion, feature in small- and medium-vessel
seizures, stroke, cord lesion, sensory or motor seizures, stroke, cord vasculitis; often it does not lead to
involvement, cranial neuropathies involvement, cranial immediate loss of life. Strokes are less
nerve, lesion, sensory or nerve, lesion, sensory or common, whereas peripheral
motor neuropathies motor neuropathies neuropathies are more common and can
cause long-term disability.

802 Part SIX Systemic Immune Diseases


study demonstrated the superiority of plasmapheresis over IV
No Treatment/Symptom Relief prednisolone, both used as adjunct therapies (in combination with
Small-vessel vasculitis, such as isolated cutaneous vasculitis cyclophosphamide and high doses of oral prednisolone) for treat-
resulting from infection or use of pharmaceutical agents, may ment of severe AAV (mainly MPA plus some cases of GPA) with
respond to simple withdrawal of the offending agent or resolution significant renal impairment (creatinine levels above 500 µmol/ L
of the infection without the need for specific treatment. However, [5.66 mg/dL]).
for more recalcitrant disease, symptom relief may be required The role of glucocorticoid therapy is been increasingly chal-
and occasionally systemic steroids. Symptom relief could be lenged by more recent trials using smaller doses for shorter
provided in the form of antipruritic agents or topical cream to periods or even eliminating steroid use completely in some
reduce skin inflammation and/or topical steroids. NSAIDs can instances. Glucocorticoid side effects are well known: weight
be helpful in relieving symptoms of joint pain or swelling. As loss, increased appetite, mood swings, hypertension, risk of
monotherapy they are unlikely to resolve skin manifestations diabetes, risk of infection, risk of cataract, and skin striae. The
but could be tried in combination with other therapies. Colchicine risk of osteoporosis is largely preventable with concurrent use
has been used for skin vasculitis and occasionally can be effective, of bisphosphonate therapy (unless there is significant renal
although the doses required should remain below 2 mg/day to dysfunction) with supplementary calcium and vitamin D
avoid the predictable side effects of abdominal cramps and replacement.
diarrhea.
Other Immunosuppressive Therapies
Target-Directed Therapies Cyclophosphamide (Chapter 87) has been available since the
In diseases where there is a clearly defined provoking agent, as 1950s but was first used for the management of systemic vasculitis
in hepatitis B–related PAN or hepatitis C–related cryoglobulinemic in the 1970s and remains the most effective agent we have for
vasculitis, eradication of the virus is a key part of treatment of managing multiorgan systemic vasculitis. Initially it was used as
the disease. Effective antiviral agents play a vital role in the a daily oral agent at 2–3 mg/day, and it transformed the outcome
management of virus, associated with the need for immunosup- of patients with AAV from inevitable mortality to a high likelihood
pression. Hepatitis B–related PAN is treated with a combination of survival. It is a cytotoxic agent and carries with it the risk
of antiviral therapy plus plasma exchange to remove immune- associated with chemotherapy, including increased risk of
complexes and other inflammatory mediators combined with a malignancy, especially in the bladder because it is predominantly
course of glucocorticoid therapy. For hepatitis C–related cryo- excreted through the kidneys and accumulates in the bladder.
globulinemic vasculitis, recent reports of virus eradication may Initial protocols were associated with excessive risks of bladder
also be transforming the outcome of this disease. Unfortunately, cancer (approximately 33-fold), but despite this, the daily oral
the toxicity of these regimens can be considerable, with >40% cyclophosphamide dosing regimen was not effective in maintain-
requiring erythropoietin, red blood cell transfusions, and or ing control of disease. Therefore over the past 20 years or so,
G-CSF. there have been a number of trials comparing reduced doses of
81
cyclophosphamide, high-dose intermittent pulse therapy, or
Specific Therapies with combination strategies of induction with short courses of
In KD, although the etiological factors have not yet been defined, cyclophosphamide followed by a switch to another drug for
81
it seems likely that this is related to some kind of infectious maintenance, or by replacing cyclophosphamide with another
81
agent (see earlier section on pathogenesis). The most effective agent, such as methotrexate. All these studies have demonstrated
therapy is use of high doses of IVIG (0.4 g/kg/day for 5 days) the equivalence of using shorter courses of daily oral cyclophos-
combined with high doses of aspirin, which is usually curative. phamide and, more recently, of using of high-dose intermittent
Whether or not this will prevent long-term harm to the cardio- pulses of cyclophosphamide to reduce the total dose even further.
vascular system, particularly the coronary arteries, remains to The total cumulative dose from six cycles of cyclophosphamide
be explored. over a period of 3 months would be 6 g (based on 15 mg/kg/
treatment on six occasions). This compares with 9–12 g of
Glucocorticoids cyclophosphamide given as daily oral therapy over 4–6 months. 81
Glucocorticoids (Chapter 86) remain a cornerstone in the Although the relapse rate for patients given high-dose intermit-
management of most forms of multisystem vasculitis. They are tent cyclophosphamide was higher during the subsequent 5 years
relatively contraindicated in KD because they may potentially compared with that for patients who were not given daily oral
worsen the development of coronary artery aneurysm, but cyclophosphamide, relapse was always effectively managed with
78
they have been used in combination with IVIG and aspirin reintroduction of therapy and never led to mortality. The
with beneficial outcomes. However, they are an integral part of consequences of exposure to cyclophosphamide are likely to be
almost all therapeutic regimens for management of vasculitis. risk of cancer (more recent studies suggest that this risk is relatively
In some instances, such as isolated skin vasculitis, they are the modest now that the regimens include much lower total doses),
only treatment required, but more often they are insufficient infertility, hair loss, nausea, vomiting, diarrhea, cytopenia, and
on their own without causing significant morbidity from side increased risk of infection. Less common complications of
effects. Typical doses of glucocorticoid therapy are 1 mg/kg/ cyclophosphamide include hyponatremia. The introduction of
day over a period of 2–4 weeks, reducing to around 10–15 mg/ rituximab for AAV has had a significant impact on the use
day within 6 months, and then slowly withdrawing steroids of cyclophosphamide, with increasing numbers of patients being
in the next 6–12 months. The use of high-dose intravenous managed with rituximab in place of cyclophosphamide, especially
methylprednisolone is popular but lacks evidence. The only if patients are of child-bearing years, or if there is a potential
randomized trial of intravenous methylprednisolone compared contraindication to using cyclophosphamide, such as a previous
80
it against plasma exchange in patients with severe AAV. This history of bladder cancer.

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 803


Because of the nature of AAV, relapse is common. Therefore Mycophenolate mofetil is a widely used transplantation drug
a single course of therapy rarely achieves long-lasting remission. that has been tested in AAV but is less effective than azathioprine
Repeat cycles of treatment are likely to be required, which accounts as maintenance agent for patients who have achieved remission.
for the accumulation of higher doses of cyclophosphamide, It is currently being tested against cyclophosphamide as an
especially in the pre-rituximab era. Therefore although each induction agent in AAV. Is typically given as 2–3 g/day as an oral
individual course of therapy may only contain 6–9 g, during a dose, along with reducing courses steroids. It is contraindicated
patient’s life time, they may require treatment for several relapses, in pregnancy.
which would then start building up the total exposure to cyclo- Cyclosporine is a well-established immunosuppressive drug
phosphamide. Nevertheless, even though it is being slowly that has been used for transplantation for many decades. Cyclo-
replaced, it remains an important aspect in the therapy of sporine has been given to limited numbers of patients with
82
vasculitis even in the present time. systemic vasculitis, with one small well-conducted trial in 32
Azathioprine is an immunomodulator with cytostatic proper- patients with GPA. In combination with plasmapheresis, it was as
ties. It inhibits cell division; it has been an effective immunosup- effective as continuous oral cyclophosphamide as a maintenance
pressant agent for decades. It was first used in combination with agent. It is generally limited by its toxicity and is not routinely
steroids and found to reduce mortality in systemic vasculitis in used.
82
an open-label retrospective study of 64 patients. The 5-year Leflunomide, an antilymphocyte agent used extensively for
survival of patients given no therapy was 12%, and those given the management of inflammatory arthritis, has been tested in
steroids alone had a 53% survival rate, whereas those treated patients with AAV in limited trials demonstrating its ability to
with steroids plus another agent (mainly azathioprine but a few maintain remission. Indeed, in a recent meta-analysis, it was
had cyclophosphamide) had a survival rate of 80%. It is an oral reported to be superior to azathioprine, MTX, and mycophenolate
medication given at 2–2.5 mg/kg/day, and it has largely been as a maintenance agent for AAV, but more trial data are needed.
superseded as an induction agent by cyclophosphamide. Aza- It is an oral agent that is characterized by a very long half-life,
thioprine is usually now used as maintenance therapy once the and it is not suitable for use in pregnancy.
disease has been controlled with another agent. It has been shown The role of hydroxychloroquine in mild forms of vasculitis
76
to be equivalent to methotrexate and superior to mycophenolate is uncertain. There is anecdotal evidence that it is beneficial in
as maintenance therapy. It is a relatively safe immunosuppressant patients with skin manifestations with small-vessel vasculitis. Its
and can be used safely throughout pregnancy. use probably stems from its known effects in the treatment of
Methotrexate (MTX) is popular among rheumatologists connective tissue diseases with skin and joint manifestations,
but less so among renal physicians who regard it with some such as SLE. Other similar agents, such as mepacrine and dapsone,
suspicion because of its potential for nephrotoxicity. The latter have also been used for skin vasculitis with occasional reported
is only the case for patients who have well-established renal positive outcomes. However, the potential toxicity for each of
disease (typically with a creatinine level >300 µmol/L). MTX is these agents should be considered alongside the relatively limited
an effective immunosuppressant agent used very widely in the evidence for benefit.
management of inflammatory arthritis and has found its place
in the management of GPA, where studies have demonstrated Specific Immunotherapy
78
its efficacy in comparison to oral cyclophosphamide. However, Better understanding of the pathogenesis of vasculitis (see section
it needs to be given continuously, rather than as induction on pathogenesis) has led to the development of targeted immu-
regimen over the short period of time. Although MTX is as notherapy for some of these diseases. Rituximab is an mAb against
effective as cyclophosphamide in inducing remission in GPA, B cells (Chapter 89) and has been in widespread use for treatment
stopping the drug inevitably leads to relapse. MTX is recom- of RA. Its role as an effective agent in AAV is well established
mended for non–life-threating AAV, usually in combination with with two randomized trials demonstrating efficacy comparable
78
steroid treatment. MTX is available either as oral, intramus- with cyclophosphamide. Rituximab induction therapy is just
cular, or subcutaneous administration. The dose is 20–25 mg/ as effective as cyclophosphamide for moderate and moderate-
week in most studies of vasculitis. It is contraindicated in to-severe AAV. Maintenance therapy with rituximab is a real
pregnancy. possibility with the potential to provide long-term control and
Cotrimoxazole, an antibiotic containing sulfonamide and trim- reduce relapse risk. The long-term consequences of repeat cycles
ethoprim, was fortuitously discovered to have beneficial effects in of rituximab, however, are unexplored. The risks are hypogam-
patients with GPA who had been treated coincidentally for infec- maglobulinemia, which occurs in most cases, and the potential
tions. There has been a significant advance in our understanding increase in incidence of infections. The most feared complication
of GPA, partly as a result of this historical experiment and partly is the risk of reactivation of the JC virus leading to the complica-
based on suggestions that S. aureus plays a role in initiating disease tion of progressive multifocal leukoencephalopathy (PML), which
by its effect on the nasal mucosa. Eradication of the organism has has a very high mortality rate.
been suggested as one mechanism by which it works, although
the drug is not particularly effective against this organism. It is Other Therapies
more likely that the drug has an immunosuppressive effect in Belimumab is currently undergoing clinical trials as a maintenance
itself; it has been demonstrated to be effective in combination agent for AAV. The drug is a BAFF inhibitor and may be an
with low-dose steroids in a randomized trial of localized forms of effective means to control the disease over the long term.
78
GPA. It is also commonly used as a prophylactic agent against Mepolizumab is an mAb directed against IL-5, which controls
Pneumocystis jiroveci infection; it is given 3 times per week for eosinophil production. Mepolizumab has been successfully used
patients receiving other more potent immunosuppressant therapy, in the treatment of hypereosinophilic syndrome and is undergoing
such as cyclophosphamide or even MTX (despite the potential a trial in EGPA. IVIG (Chapter 84) has been available as a
for drug interactions leading to anemia). replacement therapy for patients with hypogammaglobulinemia

804 Part SIX Systemic Immune Diseases


for several years, and it is the standard of care for KD, but its steroid doses remain high after 6 months. Interstitial lung disease
use in AAV has been limited. An initial study suggested benefit, (nonspecific interstitial pneumonia) is reported in around 20%
82
but the likelihood is relatively short-term control. Plasmapheresis of Japanese patients, especially those with MPA. This is a higher
has been available for several decades. It is not entirely clear how prevalence than that seen in other populations and may reflect
it works; there are many theories suggesting the removal of genetic and environmental differences unique to Japan. Chronic
87
circulating immune mediators is effective in reducing inflam- neuropathy occurs in 15% of patients with AAV and can be
mation. It has been successful for rescue therapy in patients with very distressing for patients. Upper airway disease generally
very aggressive AAV or anti-GBM disease. The MEPEX trial continues to cause long-term problems in 65% of patients with
demonstrated that it was able to reduce renal dysfunction in GPA because of chronic mucosal damage causing symptoms of
88
78
patients with severe AAV. However, the long-term follow-up chronic nasal congestion, discharge, and discomfort. Symptom
of the MEPEX trial demonstrated that the difference between relief is only partially successful in alleviating these problems.
patients treated with plasma exchange and those given methyl- The risk of cardiovascular disease among patients with small-
prednisolone pulses (both as adjunct treatment alongside vessel vasculitis is probably around four times greater in patients
83
cyclophosphamide and steroid) did not last. It has been suggested with AAV compared with the general population. The risk of
this is accounted for by the fact that many patients with severe cardiovascular events is around 14% within 5 years of diagnosis,
renal disease had already developed irreversible changes to their especially in older patients who have baseline hypertension and
89
kidneys and that renal dysfunction would have been secondary MPO antibodies. Cancer is associated with the presence of
to damage rather than active disease. A new study is underway small-vessel vasculitis. It may predate as well as occur at the same
to test the role of plasma exchange in patients with less severe time as diagnosis or develop subsequently, but it is recognized
renal disease, but results are not yet available. Plasmapheresis is as a risk among patients treated with immunosuppressive and
effective in conjunction with antiviral therapy and steroids in cytotoxic agents. Cancer of the bladder particularly has been an
the management of hepatitis B–related PAN. established risk arising from treatment with cyclophosphamide
for many years; the original data from the 1970s suggested up to
OUTCOMES 33-fold increased risk of bladder cancer among patients treated
with cyclophosphamide for vasculitis compared with background
The majority of patients have a successful initial outcome. Either controls. However, this risk has been reduced with the use of more
the condition is self-limiting in the case of more isolated forms limited courses of cyclophosphamide (typically 3–6 months dura-
of skin vasculitis or the initial immunosuppressive therapy is tion) and particularly with use of intermittent cyclophosphamide
successful. Over 94% of patients with generalized AAV would delivery. In a recent large series from the European Vasculitis
78
expect to survive the first 18 months, whereas patients with Study Group (EUVAS), the only increased risk of cancer was for
more severe disease, especially with significant renal impairment, nonmelanoma skin cancer, and this may also have reflected the
55
82
have a mortality of around 25% after 2 years. This contrasts use of azathioprine as well as use of cyclophosphamide. Shang
90
with >80% likelihood of dying without adequate treatment. et al. showed that in a meta-analysis of over 2500 patients,
However, with current therapy, 5-year survival figures suggest the standardized incidence rate of late-occurring malignancies,
around 25–30% mortality among AAV-affected patients. 84 particularly nonmelanoma skin cancer, leukemia, and bladder
The bigger problem, however, is morbidity. The quality of cancer, was 1.74 (95% CI = 1.37–2.21). We advise all of our
survival for most patients with multiorgan disease is compli- patients to wear sun protection.
cated by episodes of relapse in 50–70% of cases and low-grade The ability to work is significantly affected by AAV; among
grumbling disease, which never quite goes into full remission 410 patients interviewed, 26% of those of working age were
85
91
in up to a third of cases. This is added to the comorbidity classified as work disabled. The strongest influences on this
experienced by older patients, usually a combination of vasculitis- outcome were fatigue, depression, high levels of damage (measured
related damage, steroid-induced side effects, and the long-term using the VDI), and being overweight. Patients’ functional
consequences of immunosuppressive agents. In the first year of outcome can be variably affected by vasculitis and its treatment.
diagnosis, the most likely cause of mortality is active vasculitis Patients report impairment of function as measured by using
62
92
or infection, the latter being a surrogate measure of the severity generic tools, such as EQ-5D or the short form 36. The impair-
in immunosuppressant therapy required to control the disease. ment is similar to that found in other chronic diseases. Physical
Long-term adverse outcomes in vasculitis can be measured functions tend to be more affected than mental functions,
using a structured VDI (see Assessment section above). One of especially in older patients with evidence of neurological involve-
the most important outcomes is the development of end-stage ment, usually peripheral neuropathy. Functional outcome is not
renal failure and the requirement for dialysis. It is likely that this directly correlated to disease activity, although in a Japanese
is significantly reduced as a result of effective therapy given within cohort, 18 months after initiation of therapy, many aspects of
93
the first 4 months of diagnosis. Transplantation is successful function had started to improve. One of the problems of
in patients with AAV, and these patients should be offered this determining long-term outcomes in patients with vasculitis is
treatment. Ten-year survival rates (32.5%) are similar to those the compounding effect of the very intensive immunosuppressive
reported for other patients without diabetes receiving a kidney therapy required to control disease. Over the last 3 decades, we
86
transplant. The immunosuppressive regimens used for maintain- have seen dramatic shift away from long course cyclophosphamide
ing the transplant (Chapter 81) are often sufficient to keep the toward short courses of intermittent dose therapy, but we are
vasculitis in remission, but there is a need for ongoing review. now witnessing an era when targeted biological therapies are
Infection is a significant concern, especially in the early course able to take the place of cyclophosphamide. Therefore eliminating
of disease when potent treatment being commenced, especially the use of cyclophosphamide altogether in some patients may
high doses of steroids. The risk of serious infection requiring reset potential future outcomes. If this is coupled with a reduced
62
hospitalization is very high in the first year, especially if the use of glucocorticoid therapies and maintaining better disease

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 805


control with less frequent relapses, the outcome may well be 9. Nakamura Y, et al. Epidemiologic Features of Kawasaki Disease in Japan:
improved considerably for patients in the future. Results of the 2009-2010 Nationwide Survey. J Epidemiol
2012;22(3):216–21.
10. Reinhold-Keller E, et al. Stable incidence of primary systemic vasculitides
over five years: Results from the German vasculitis register. Arthritis
ON tHE HOrIZON Rheum 2005;53(1):93–9.
11. Herlyn K, et al. Doubled prevalence rates of ANCA-associated vasculitides
• Improved understanding of the underlying pathogenic mechanisms and giant cell arteritis between 1994 and 2006 in northern Germany.
in different forms of vasculitis is starting to lead to more logical, Rheumatology 2014;53(5):882–9.
rational therapies, some of which have become established as standard 12. van der Woude FJ, et al. Autoantibodies against neutrophils and
of care or should be available in the near future. monocytes: tool for diagnosis and marker of disease activity in Wegener’s
• Rituximab is available and is being increasingly used in place of granulomatosis. Lancet 1985;1(8426):425–9.
cyclophosphamide in the management of ANCA-associated vasculitis 13. Xiao H, et al. Antineutrophil cytoplasmic autoantibodies specific for
(AAV). Rituximab therapy is also effective in patients with cryoglobu- myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin
linemic vasculitis, even when associated with the presence of hepatitis
C. There is a concern that this might lead to reactivation of the virus Invest 2002;110(7):955–63.
and increase the risk of hepatoma or induce the development of the 14. Primo VC, et al. Anti-PR3 immune responses induce segmental and
B-cell clone. However, better control of hepatitis C with effective necrotizing glomerulonephritis. Clin Exp Immunol 2010;159(3):327–37.
antiviral agent is now possible. 15. Little MA, et al. Anti-proteinase 3 anti-neutrophil cytoplasm
• Multiple proinflammatory cytokines are being explored as therapeutic autoantibodies recapitulate systemic vasculitis in mice with a humanized
targets, although this will only allow for the suppression of common immune system. PLoS ONE 2012;7(1):e28626.
pathways in the end stage of inflammation. 16. Roth AJ, et al. Epitope specificity determines pathogenicity and
• Mepolizumab has recently been shown to be effective in the treatment detectability in ANCA-associated vasculitis. J Clin Invest
of eosinophilic granulomatous polyangiitis (EGPA) in a large randomised 2013;123(4):1773–83.
controlled trial. 17. Lyons PA, et al. Genetically distinct subsets within ANCA-associated
• Blocking interleukin (IL)-6 may be of benefit for some patients. vasculitis. N Engl J Med 2012;367(3):214–23.
• The discovery of the involvement of the complement pathway (C5) 18. Stassen PM, et al. HLA-DR4, DR13(6) and the ancestral haplotype
in AAV has led to the testing of therapies directed against C5a in A1B8DR3 are associated with ANCA-associated vasculitis and Wegener’s
humans. granulomatosis. Rheumatology (Oxford) 2009;48(6):622–5.
• The ultimate goal remains to identify upstream pathologies leading 19. Cao Y, et al. DRB1*15 allele is a risk factor for PR3-ANCA disease in
to vasculitis, which promises to fundamentally change the management African Americans. J Am Soc Nephrol 2011;22(6):1161–7.
of these devastating diseases, as it may permit the induction and 20. Papiha SS, et al. Association of Wegener’s granulomatosis with HLA
maintenance of drug-free remission.
antigens and other genetic markers. Ann Rheum Dis 1992;51(2):246–8.
21. Spencer SJ, et al. HLA class II specificities in vasculitis with antibodies to
neutrophil cytoplasmic antigens. Kidney Int 1992;41(4):1059–63.
ACKNOWLEDGEMENTS 22. Schreiber A, et al. Membrane expression of proteinase 3 is genetically
determined. J Am Soc Nephrol 2003;14(1):68–75.
The authors thank Jana Vaskova for administrative and secretarial 23. Alberici F, Martorana D, Vaglio A. Genetic aspects of anti-neutrophil
support. cytoplasmic antibody-associated vasculitis. Nephrol Dial Transplant
2015;30(Suppl. 1):i37–45.
24. Kamesh L, et al. CT60 and +49 polymorphisms of CTLA 4 are associated
Please check your eBook at https://expertconsult.inkling.com/ with ANCA-positive small vessel vasculitis. Rheumatology (Oxford)
for self-assessment questions. See inside cover for registration 2009;48(12):1502–5.
details. 25. Langford CA, et al. An open-label trial of abatacept (CTLA4-IG) in
non-severe relapsing granulomatosis with polyangiitis (Wegener’s). Ann
REFERENCES Rheum Dis 2014;73(7):1376–9.
26. Wieczorek S, et al. Functionally relevant variations of the interleukin-10
1. Kawasaki T, et al. A new infantile acute febrile mucocutaneous lymph gene associated with antineutrophil cytoplasmic antibody-negative
node syndrome (MLNS) prevailing in Japan. Pediatrics 1974;54(3):271–6. Churg-Strauss syndrome, but not with Wegener’s granulomatosis.
2. Andrews M, Edmunds M, Campbell A, et al. Systemic vasculitis in the Arthritis Rheum 2008;58(6):1839–48.
1980s-is there an increasing incidence of Wegener’s granulomatosis and 27. Ciavatta DJ, et al. Epigenetic basis for aberrant upregulation of
microscopic polyarteritis? J R Coll Physicians 1990;24(4):284–8. autoantigen genes in humans with ANCA vasculitis. J Clin Invest
3. Watts RA, Mooney J, Skinner J, et al. The contrasting epidemiology of 2010;120(9):3209–19.
granulomatosis with polyangiitis (Wegener’s) and microscopic 28. Chen M, Kallenberg CG. The environment, geoepidemiology and
polyangiitis. Rheumatology (Oxford) 2012;51(5):926–31. ANCA-associated vasculitides. Autoimmun Rev 2010;9(5):A293–8.
4. Mohammad AJ, et al. Prevalence of Wegener’s granulomatosis, 29. Gomez-Puerta JA, Gedmintas L, Costenbader KH. The association
microscopic polyangiitis, polyarteritis nodosa and Churg-Strauss between silica exposure and development of ANCA-associated vasculitis:
syndrome within a defined population in southern Sweden. systematic review and meta-analysis. Autoimmun Rev
Rheumatology 2007;46(8):1329–37. 2013;12(12):1129–35.
5. Nesher G, et al. The Incidence of Primary Systemic Vasculitis in 30. Tervaert JW, Stegeman CA, Kallenberg CG. Silicon exposure and
Jerusalem: A 20-year Hospital-based Retrospective Study. J Rheumatol vasculitis. Curr Opin Rheumatol 1998;10(1):12–17.
2016;43(6):1072–7. 31. Rihova Z, et al. Silica and asbestos exposure in ANCA-associated
6. Holman RC, et al. Racial/ethnic differences in the incidence of Kawasaki vasculitis with pulmonary involvement. Ren Fail 2005;27(5):605–8.
syndrome among children in Hawaii. Hawaii Med J 2010;69(8):194–7. 32. Eden A, et al. Lack of association between B19 or V9 erythrovirus
7. Arora A, et al. Incidence of Leukocytoclastic Vasculitis, 1996 to 2010: A infection and ANCA-positive vasculitides: a case-control study.
Population-Based Study in Olmsted County, Minnesota. Mayo Clinic Rheumatology (Oxford) 2003;42(5):660–4.
Proceedings 2014;89(11):1515–24. 33. Wu YY, et al. Proteinase 3 and dihydrolipoamide dehydrogenase (E3) are
8. Watts RA, Scott DGI. Epidemiology of the vasculitides. Semin Respir Crit major autoantigens in hepatitis C virus (HCV) infection. Clin Exp
Care Med 2004;25(5):455–64. Immunol 2002;128(2):347–52.

806 Part SIX Systemic Immune Diseases


34. Calhan T, et al. Antineutrophil cytoplasmic antibody frequency in chronic vasculitis: follow-up data from European Vasculitis Study Group clinical
hepatitis B patients. Dis Markers 2014;2014:982150. trials. Ann Rheum Dis 2011;70(8):1415–21.
35. Kain R, et al. Molecular mimicry in pauci-immune focal necrotizing 56. Guma M, et al. Frequency of antineutrophil cytoplasmic antibody in
glomerulonephritis. Nat Med 2008;14(10):1088–96. Graves’ disease patients treated with methimazole. J Clin Endocrinol
36. Hurtado PR, et al. CpG oligodeoxynucleotide stimulates production of Metab 2003;88(5):2141–6.
anti-neutrophil cytoplasmic antibodies in ANCA associated vasculitis. 57. Lenert P, Icardi M, Dahmoush L. ANA (+) ANCA (+) systemic vasculitis
BMC Immunol 2008;9:34. associated with the use of minocycline: case-based review. Clin
37. Noh JY, Yasuda S, Sato S, et al. Clinical characteristics of myeloperoxidase Rheumatol 2013;32(7):1099–106.
antineutrophil cytoplasmic antibody-associated vasculitis caused by 58. Zhang AH, et al. Inhibition of oxidation activity of myeloperoxidase
antithyroid drugs. J Clin Endocrinol Metab 2009;94(8):2806–11. (MPO) by propylthiouracil (PTU) and anti-MPO antibodies from
38. Waldhauser L, Uetrecht J. Oxidation of propylthiouracil to reactive patients with PTU-induced vasculitis. Clin Immunol 2007;122(2):
metabolites by activated neutrophils. Implications for agranulocytosis. 187–93.
Drug Metab Dispos 1991;19(2):354–9. 59. Denissen NH, et al. Can sulfasalazine therapy induce or exacerbate
39. Nakazawa D, et al. Abnormal conformation and impaired degradation of Wegener’s granulomatosis? Scand J Rheumatol 2008;37(1):72–4.
propylthiouracil-induced neutrophil extracellular traps: implications of 60. Takahashi K, Oharaseki T, Yokouchi Y. Update on etio and
disordered neutrophil extracellular traps in a rat model of immunopathogenesis of Kawasaki disease. Curr Opin Rheumatol
myeloperoxidase antineutrophil cytoplasmic antibody-associated 2014;26(1):31–6.
vasculitis. Arthritis Rheum 2012;64(11):3779–87. 61. Lin YJ, et al. Genetic variants in PLCB4/PLCB1 as susceptibility loci for
40. Berman M, Paran D, Elkayam O. Cocaine-Induced Vasculitis. Rambam coronary artery aneurysm formation in Kawasaki disease in Han Chinese
Maimonides Med J 2016;7(4). in Taiwan. Sci Rep 2015;5:14762.
41. Wiesner O, et al. Antineutrophil cytoplasmic antibodies reacting with 62. Onouchi Y, et al. ITPKC and CASP3 polymorphisms and risks for IVIG
human neutrophil elastase as a diagnostic marker for cocaine-induced unresponsiveness and coronary artery lesion formation in Kawasaki
midline destructive lesions but not autoimmune vasculitis. Arthritis disease. Pharmacogenomics J 2013;13(1):52–9.
Rheum 2004;50(9):2954–65. 63. Yeung RS. Kawasaki disease: update on pathogenesis. Curr Opin
42. Tsurikisawa N, et al. Decreases in the numbers of peripheral blood Rheumatol 2010;22(5):551–60.
regulatory T cells, and increases in the levels of memory and activated B 64. Gorelik M, et al. Plasma follistatin-like protein 1 is elevated in Kawasaki
cells, in patients with active eosinophilic granulomatosis and polyangiitis. disease and may predict coronary artery aneurysm formation. J Pediatr
J Clin Immunol 2013;33(5):965–76. 2012;161(1):116–19.
43. Abdulahad WH, Boots AMH, Kallenberg CGM. FoxP3(+) CD4(+) T cells 65. Lin IC, et al. Augmented TLR2 expression on monocytes in both human
in systemic autoimmune diseases: the delicate balance between true Kawasaki disease and a mouse model of coronary arteritis. PLoS ONE
regulatory T cells and effector Th-17 cells. Rheumatology 2012;7(6):e38635.
2011;50(4):646–56. 66. Jia S, et al. The T helper type 17/regulatory T cell imbalance in
44. Marinaki S, et al. Persistent T-cell activation and clinical correlations in patients with acute Kawasaki disease. Clin Exp Immunol
patients with ANCA-associated systemic vasculitis. Nephrol Dial 2010;162(1):131–7.
Transplant 2006;21(7):1825–32. 67. Rowley AH, et al. The transcriptional profile of coronary arteritis in
45. Holden NJ, et al. ANCA-stimulated neutrophils release BLyS and promote Kawasaki disease. BMC Genomics 2015;16:1076.
B cell survival: a clinically relevant cellular process. Ann Rheum Dis 68. Leung DY, et al. Prevalence of superantigen-secreting bacteria in patients
2011;70(12):2229–33. with Kawasaki disease. J Pediatr 2002;140(6):742–6.
46. Nakazawa D, et al. Enhanced Formation and Disordered Regulation of 69. Schulte DJ, et al. Involvement of innate and adaptive immunity in a
NETs in Myeloperoxidase-ANCA-Associated Microscopic Polyangiitis. J murine model of coronary arteritis mimicking Kawasaki disease. J
Am Soc Nephrol 2014;25(5):990–7. Immunol 2009;183(8):5311–18.
47. Yuan J, et al. C5a and its receptors in human anti-neutrophil cytoplasmic 70. Cid MC, et al. Immunohistochemical characterization of inflammatory
antibody (ANCA)-associated vasculitis. Arthritis Res Ther 2012;14(3). cells and immunologic activation markers in muscle and nerve biopsy
48. Chen SF, et al. Plasma complement factor H is associated with disease specimens from patients with systemic polyarteritis nodosa. Arthritis
activity of patients with ANCA-associated vasculitis. Arthritis Res Ther Rheum 1994;37(7):1055–61.
2015;17. 71. Yalcinkaya F, et al. Prevalence of the MEFV gene mutations in childhood
49. Fukui S, et al. Antineutrophilic cytoplasmic antibody-associated vasculitis polyarteritis nodosa. J Pediatr 2007;151(6):675–8.
with hypocomplementemia has a higher incidence of 72. Sansonno D, et al. Hepatitis C virus infection, cryoglobulinaemia, and
serious organ damage and a poor prognosis. Medicine (Baltimore) beyond. Rheumatology 2007;46(4):572–8.
2016;95(37). 73. Varricchi G, et al. Interleukin-5 pathway inhibition in the treatment of
50. Choi HK, Merkel PA, Niles JL. ANCA-positive vasculitis associated with eosinophilic respiratory disorders: evidence and unmet needs. Curr Opin
allopurinol therapy. Clin Exp Rheumatol 1998;16(6):743–4. Allergy Clin Immunol 2016;16(2):186–200.
51. Hirohama D, et al. Development of myeloperoxidase-antineutrophil 74. Craven A, et al. ACR/EULAR-endorsed study to develop Diagnostic and
cytoplasmic antibody-associated renal vasculitis in a patient receiving Classification Criteria for Vasculitis (DCVAS). Clin Exp Nephrol
treatment with anti-tumor necrosis factor-alpha. Mod Rheumatol 2013;17(5):619–21.
2010;20(6):602–5. 75. Luqmani R, Ponte C. ANCA associated vasculitides and polyarteritis
52. Jarraya F, et al. Myeloperoxidase-antineutrophil cytoplasmic nodosa. In: Hachulla E, Bijlsma JWJ, editors. EULAR Textbook on
antibody-positive crescentic glomerulonephritis associated with rheumatic diseases. BMJ Publishing Group Ltd; 2015. p. 717–53.
benzylthiouracil therapy: report of the first case. Nephrol Dial Transplant 75a. Stahelin L, et al. Cocaine-induced midline destruction lesions with
2003;18(11):2421–3. positive ANCA test mimicking Wegener’s granulomatosis. Rev Bras
53. Bienaime F, et al. D-Penicillamine-induced ANCA-associated crescentic Reumatol 2012;52(3):431–7.
glomerulonephritis in Wilson disease. Am J Kidney Dis 2007;50(5): 76. Flossmann O, Berden A, de Groot K, et al. Long-term patient survival in
821–5. ANCA-associated vasculitis. Ann Rheum Dis 2011;70(3):488–94.
54. Carmona-Rivera C, Purmalek MM, Moore E, et al. A role for muscarinic 77. Kemna MJ, Damoiseaux J, Austen J, et al. ANCA as a predictor of relapse:
receptors in neutrophil extracellular trap formation and levamisole- useful in patients with renal involvement but not in patients with
induced autoimmunity. JCI Insight 2017;2(3):e89780. nonrenal disease. J Am Soc Nephrol 2015;26(3):537–42.
55. Heijl C, Harper L, Flossmann O, et al. Incidence of malignancy in 78. Ntatsaki E, Carruthers D, Chakravarty K, et al. BSR and BHPR Standards,
patients treated for antineutrophil cytoplasm antibody-associated Guidelines and Audit Working Group BSR and BHPR guideline for the

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 807


management of adults with ANCA-associated vasculitis. Rheumatology 88. Martinez Del Pero M, Walsh M, Luqmani R, et al. Long-term damage to
(Oxford) 2014;53(12):2306–9. the ENT system in Wegener’s granulomatosis. Eur Arch Otorhinolaryngol
79. Ponte C, et al. Optimisation of vasculitis disease assessments in clinical 2011;268(5):733–9.
trials, clinical care and long-term databases. Clin Exp Rheumatol 89. Suppiah R, Judge A, Batra R, et al. A model to predict cardiovascular
2014;32(5 Suppl. 85):S-118-25. events in patients with newly diagnosed Wegener’s granulomatosis and
80. Mukhtyar C, G L, Cid MC, et al. BSR and BHPR Standards, Guidelines microscopic polyangiitis. Arthritis Care Res (Hoboken)
and Audit Working Group BSR and BHPR guideline for the management. 2011b;63(4):588–96.
Ann Rheum Dis 2009;68:310–17. 90. Shang W, Ning Y, Xu X, et al. Incidence of Cancer in ANCA-Associated
81. Szpirt WM, Heaf JG, Petersen J. Plasma exchange for induction and Vasculitis: A Meta-Analysis of Observational Studies. PLoS ONE
cyclosporine A for maintenance of remission in Wegener’s 2015;10(5):e0126016.
granulomatosis-a clinical randomized controlled trial. Nephrol Dial 91. Basu N, McClean A, Harper L, et al. Markers for work disability in
Transplant 2011;26(1):206–13. anti-neutrophil cytoplasmic antibody-associated vasculitis. Rheumatology
82. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for (Oxford) 2014;53(5):953–6.
the management of primary small and medium vessel vasculitis. Ann 92. Walsh M, Mukhtyar C, Mahr A, et al. Health-related quality of life in
Rheum Dis 2009;68(3):310–17. patients with newly diagnosed antineutrophil cytoplasmic
83. Walsh M, Casian A, Flossmann O, Westman K, et al. Long-term follow-up antibody-associated vasculitis. Arthritis Care Res (Hoboken)
of patients with severe ANCA-associated vasculitis comparing plasma 2011;63(7):1055–61.
exchange to intravenous methylprednisolone treatment is unclear. Kidney 93. Suka M, Hayashi T, Kobayashi S, et al. Improvement in health-related
Int 2013;84(2):397–402. quality of life in MPO-ANCA-associated vasculitis patients treated with
84. Flossmann O, Berden A, de Groot K, Hagen C, et al. Long-term patient cyclophosphamide plus prednisolone: an analysis of 18 months of
survival in ANCA-associated vasculitis. Ann Rheum Dis follow-up data from the JMAAV study. Mod Rheumatol
2011;70(3):488–94. 2012;22(6):877–84.
85. Hoffman GS, Kerr G, Leavitt RY, et al. Wegener granulomatosis: an 94. Fujimoto SWR, Kobayashi S, Suzuki K, et al. Comparison of the
analysis of 158 patients. Ann Intern Med 1992;116:488–98. epidemiology of anti-neutrophil cytoplasmic antibody-associated
86. Hruskova Z, Stel V, Jayne D, et al. Characteristics and Outcomes of vasculitis between Japan and the U.K. Rheumatology (Oxford)
Granulomatosis With Polyangiitis (Wegener) and Microscopic 2011;50(10):1916–20.
Polyangiitis Requiring Renal Replacement Therapy: Results From the 95. Chen M, et al. Propylthiouracil-induced antineutrophil cytoplasmic
European Renal Association-European Dialysis and Transplant antibody-associated vasculitis. Nat Rev Nephrol 2012;8(8):476–83.
Association Registry. Am J Kidney Dis 2015;66(4):613–20. 96. Makino N, Nakamura Y, Yashiro M, et al. Descriptive epidemiology of
87. Suppiah R, Hadden R, Batra R, et al. Peripheral neuropathy in Kawasaki disease in Japan, 2011-2012: from the results of the 22nd
ANCA-associated vasculitis: outcomes from the European Vasculitis Study nationwide survey. J Epidemiol 2015;25(3):239–45.
Group trials. Rheumatology (Oxford) 2011;50(12):2214–22.

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 807.e1


MUL t IPLE-CHOICE QUES t IONS

1. Which of the following types of vasculitis are usually associated 3. Which of the following treatments are not effective for use
with the presence of antineutrophil cytoplasmic antibody in patients with newly presenting generalized ANCA-associated
(ANCA)? vasculitis?
A. Microscopic polyangiitis A. Colchicine
B. Polyarteritis nodosa B. Glucocorticoid therapy alone
C. Goodpasture syndrome C. Glucocorticoids and methotrexate
D. Cryoglobulinemic vasculitis D. Rituximab and glucocorticoid therapy
E. Granulomatosis with polyangiitis E. Plasmapheresis with cyclophosphamide and glucocorticoid
therapy
2. Which of the following is the least common form of vasculitis
in Europe?
A. Kawasaki disease
B. Polyarteritis nodosa
C. Granulomatosis with polyangiitis
D. Microscopic polyangiitis
E. Leukocytoclastic cutaneous vasculitis

59









Large-Vessel Vasculitides



Cornelia M. Weyand








Most tissues have compensatory mechanisms that allow them monitoring. Excellent progress has been made in unraveling the
to sustain the damaging effects of acute and chronic inflammation, pathogenesis of GCA, and this will inevitably lead to improve-
but medium and large arteries are organs without redundancy ments in diagnosis, long-term management, and broadening of
and limited regenerative capacity. Life is unsustainable unless the therapeutic armamentarium.
the major arteries have uncompromised function. Accordingly,
inflammatory damage to such arterial vessels leads to severe EPIDEMIOLOGY
clinical consequences, immediately posing a threat for the loss
of function of vital organs. When affected by inflammation, the GCA may be a very old disease, as suggested by historic evidence
aorta and its branches have two possible response patterns: (i) that more than 1000 years ago removal of the temporal artery
Inflammatory destruction of the vessel wall leads to dilatation, was recommended by a physician in Baghdad. In 1932, Horton
aneurysm formation, and rupture. Alternatively, the wall layers et al. at the Mayo Clinic in Minnesota recognized that GCA was
dissect. (ii) The inflammation initiates a maladaptive response an inflammatory vasculopathy when they found dense inflam-
to injury, resulting in luminal occlusion, disruption of blood mation in the temporal arteries of two patients who were systemi-
supply, and ischemic damage of dependent organ structures. cally ill and had severe headaches. The first reports of TA, or
In contrast to other vasculopathies, especially those related “pulseless disease,” in young women surfaced in Japan in the
to atherosclerosis, vasculitides of the larger blood vessels are nineteenth century. The syndrome was named after Dr. Takayasu,
almost always associated with a syndrome of intense systemic an ophthalmologist, who, in 1905, described peculiar optic fundus
1
inflammation. Recent evidence has challenged the traditional abnormalities caused by ischemia-driven collateral formation.
3,4
view that systemic inflammation represents a spillover of inflam- The strongest risk factor for GCA, TA, and PMR is age.
matory mediators from the vasculitic lesions. Instead, systemic GCA and PMR are essentially absent in individuals <50 years
activation of the innate immune system appears to be a pinnacle of age, and their incidence climbs continuously during the seventh
event that initiates the processes leading to vessel wall inflam- and eighth decades of life. TA is almost exclusively diagnosed
mation. The coincidence of malaise, fever, wasting, and myalgias, in individuals <40 years of age, with peak incidence during the
with signs of ischemia caused by vascular failure, remains a critical second and third decades of life. Women are affected more often
clue for the physician when diagnosing and treating large-vessel by all three syndromes compared with men, with a 2 : 1 ratio in
vasculitides (LVVs). PMR and GCA and a 9 : 1 ratio in TA. 3,5
The two major forms of LVVs are giant-cell arteritis (GCA) Marked geographical variations in the incidence and prevalence
and Takayasu arteritis (TA). In addition, aortitis can infrequently of GCA, TA, and PMR have given rise to speculations about
be seen in other diseases, such as infections, connective tissue environmental exposures as key factors in disease pathogenesis.
diseases, sarcoidosis, and inflammatory bowel disease (IBD), and GCA is the most frequent vasculitis in the Western world, with
occasionally is diagnosed as an idiopathic syndrome. Polymyalgia yearly incidence rates reaching 10–20 cases per 100 000 persons
3
rheumatica (PMR) is a condition closely related to GCA; it occurs >50 years of age. In general, PMR is diagnosed three- to fourfold
in the same patient population and often precedes or follows more frequently, with a prevalence of up to 1 case per 133
2
2
the clinical diagnosis of GCA. Patients with PMR do not have individuals >50 of age. Iceland, Norway, Sweden, and Denmark
typical vascular lesions; consequently, PMR is not classified as are high-risk areas; higher incidence rates are also seen in
a vasculitis. However, patients with PMR do have a systemic Scandinavian immigrant populations in the United States. The
inflammatory syndrome indistinguishable from GCA, and about risk is significantly lower in Hispanics and African Americans.
10% of patients with PMR eventually progress to full-blown Although TA can afflict all races, a predilection exists for individu-
vasculitis. Similarities in the vascular lesions of GCA and TA als of Asian and Central and South American origins. Japan,
have been interpreted as revealing parallels in immunopatho- Thailand, India, Turkey, and nations in Central and South
genesis. Whether similarities in histomorphology and tissue Americas are considered high-incidence regions. TA is a rare
targeting reflect similarities in underlying molecular defects disease with an annual incidence of 1–2 cases/million. The typical
remains unclear. Whether the systemic inflammatory reactions patient is a female in her 20s to 30s. In middle-aged men and
accompanying GCA, TA, and PMR have disease-specific elements women, it can be challenging to differentiate TA from rapidly
also remains unanswered, but this has opened the possibility of progressing atherosclerotic disease, especially as both disease
developing biomarkers that are urgently needed for clinical processes may coexist. 6

809

810 Part SIX Systemic Immune Diseases





Vascular component Extravascular component
Granulomatous, transmural intense acute phase response
inflammation (IL-6, SAA, CRP, ESR, etc)
dendritic cells, CD4 T cells, myalgias
macrophages, giant cells, etc malaise, anorexia, fever



Giant cell
arteritis
Vessel wall remodeling
Aorta: dissection, wall damage,
aneurysm, rupture Age of the host
Branches: intimal hyperplasia,
luminal occlusion GCA/PMR: >50 yrs
TA: <40 yrs


Tissue tropism
th
GCA: Aorta + 3-5 branches
axillary, temporal, ophthalmic, etc
st
nd
TA: Aorta + 1 and 2 branches
subclavian, carotid, mesenteric, renal, etc
FIG 59.1 Key Pathogenic Traits in Giant-Cell Arteritis (GCA). In the emerging pathogenic
model, five hallmarks of disease have been identified that represent fundamental pathogenic
traits and distinguish GCA from other immune-mediated disorders. Vascular GCA (granulomatous
vasculitis) is now separated from extravascular GCA (systemic inflammation and intense hepatic
acute phase response). Age remains the strongest risk factor with evidence for a signature
immunosenescence program in patients with GCA. The stringent tissue tropism for selected
vascular beds is suspected to reflect heterogeneity of vascular cells. Clinical complications are
related to the patterning of vascular damage, spanning from wall destruction to luminal occlusion.




ETIOLOGY AND PATHOGENESIS fruste of GCA, in which inflammatory attack to the vessel wall
remains below a threshold, and standard histology describes
Abnormal innate and adaptive immune responses are essential noninflamed arteries.
pathogenic elements in medium-vessel vasculitides and LVVs. Distinctive features—hallmarks of disease—provide clues to
The end result is a disease process that separates GCA, PMR, the fundamental pathogenic mechanisms (see Fig. 59.1), including
and TA from other vasculitides and from other autoinflammatory a stringent age cutoff, a stringent tissue tropism for selected
and autoimmune syndromes. Progress has been made in identify- vascular territories (aorta and major branches), an extravascular
ing and characterizing the cellular and molecular elements that disease module defined by an abrupt and intense acute phase
define LVVs. Recent work has delineated disease-specific signa- response, a granulomatous transmural vasculitis, and two oppos-
tures, with the goal to mark the pinnacle abnormality triggering ing patterns of vessel wall remodeling causing aortic wall
the disease and to discover intersection points that lend themselves destruction versus luminal occlusion in the branch vessels.
for diagnostic and therapeutic purposes.
Pathogenic studies and careful clinical observation have INNATE IMMUNE SYSTEM DEFECTS
prompted a substantial shift in the pathogenic model (Fig. 59.1):
LVVs are now understood to be chronic conditions that target Innate immune cells make critical contributions to the patho-
restricted vascular beds and have two major disease compo- genesis of LVVs, but where circulating monocytes and neutrophils
nents: (i) granulomatous, intramural inflammation inducing encounter their activating stimuli remains unknown (Fig. 59.2).
7
vascular wall remodeling; and (ii) extravascular inflammation Circulating monocytes and macrophages are highly activated
manifesting with an intense acute phase response, myalgias, and and contribute to the array of proinflammatory cytokines
8
constitutional symptoms. Emerging data suggest at least partial measurably elevated in the serum of affected patients. Altered
9
autonomy in the pathogenic cascades of both disease components, neutrophil functionality has also been described. Early in the
predicting separate biomarkers, separate pathogenic mechanisms, disease process, circulating neutrophils resemble those induced
and separate responses to immunosuppression. Similarities in by a lipopolysaccharide stimulus, displaying T-cell suppressive
tissue tropisms and histological lesions of GCA and TA suggest functions. Interleukin-8 (IL-8) and IL-6 are associated with
overlapping disease pathways, and many aspects of immune neutrophil activation. IL-6, first described in the early 1990s, is
10
pathogenesis may be transferrable from one syndrome to the highly elevated in GCA and PMR and is explicitly steroid
11
other. The etiopathogenesis of PMR is less well understood, sensitive. IL-6 acts as an inducer of the acute phase response
but experimental evidence suggests that it represents a forme in the liver, triggering production of C-reactive protein (CRP),

CHaPtEr 59 Large-Vessel Vasculitides 811



Triggering of innate immune cells (monocytes,
neutrophils, etc) Clinical consequences 7 0
? Site 7 '& 7
? Identity of stimuli Elevated CRP, ESR 7
7 0
Elevation of innate pro-inflammatory cytokines Muscle pain (PMR) 7 0 7 7 '&
-IL-6, IL-8, IL-12p70, MCP-1, MIP-1β, eotaxin, Malaise '& 7 0
Failure-to-thrive
pentraxin 3, etc Fever 0 0 7
Anemia 0 7 7
Thrombocytosis 7
Induction of hepatic acute phase proteins 7 7 7 '& 7
- C-reactive protein, mannose-binding protein, ?? priming of 0 0
ferritin, serum amyloid A, haptoglobin, selected vascular $'9(17,7,$ 0(',$ 7
fibrinogen, von willebrand factor, hepcidin, etc beds 7
'& '& 7
&' &' &KHPRNLQHV ,17,0$
Induction of inflammatory amplification loops 3' / 7 0
- Activation of neutrophils, monocytes, endothelial 3' / &'
cells, fibroblasts, etc 7 FHOOV 7 FHOOV 7 FHOOV 7
,)1 \ ,/ ,)1 \ ,/ ,)1 \ ""
,/ ,/
FIG 59.2 Extravascular Giant-Cell Arteritis (GCA). Circulating ,/ ,/
innate cells (monocytes, neutrophils, etc.) are highly activated 0DF 0DF 0DF
and elicit a hepatic acute-phase response. Several of the acute 7*)% ,/ % 9(*) 3'*) L126
phase proteins serve as biomarkers (C-reactive protein [CRP], ,/ )*)
$OGRVH UHGXFWDVH
erythrocyte sedimentation rate [ESR]) of disease. Extravascular
GCA is explicitly sensitive to corticosteroid therapy and to cytokine FIG 59.3 Vascular Giant-Cell Arteritis (GCA). Adaptive
blockade. Whether the extravascular competent has a direct or immune responses in vascular GCA are supported by trans-
indirect involvement in driving/sustaining granulomatous vasculitis mural granulomatous infiltrates. Dendritic cells (DCs), present
remains unknown. Polymyalgia rheumatic (PMR) may represent in healthy arteries at the adventitia–media border, serve as
an isolated form of extravascular GCA. antigen-presenting cells (APCs) and provide costimulatory signals
but are deficient in the coinhibitory ligand programmed death
ligand 1 (PD-L1). Wall-infiltrating T cells are multifunctional,
producing a broad spectrum of effector cytokines, including
serum amyloid A (SAA), and several other acute-phase proteins. interferon (IFN)-γ, interleukin (IL)-17, IL-9, and IL-21. Macro-
Accordingly, treatment with an IL-6 receptor–blocking antibody, phages, some of which transform into multinucleated giant cells,
effectively reduces the laboratory abnormalities measured in supply a multitude of cytokines, metalloproteinases, reactive
12
patients with GCA. Whether IL-6 has additional functions in oxygen species (ROS), growth factors, angiogenesis factors
the disease process, particularly in the inflamed vessel wall, is and inducible nitric oxide synthase (iNOS). Their functional
uncertain. Some acute-phase proteins (e.g., SAA) have proinflam- commitment depends on their geographical location in the
matory functions by themselves, functioning as proinflammatory vessel wall.
13
amplifiers. Although abnormal innate immunity dominates
the extravascular component of LVVs, underlying mechanisms composition of the intramural granulomatous infiltrates. Con-
(e.g., what the original triggers are, where the activation occurs, sidering that vital arteries (e.g., the aorta) are protected by immune
how the systemic inflammation interfaces with vascular inflam- privilege, malfunction of endogenous vasDCs may, indeed, be
mation) are essentially unexplored. the pinnacle defect–initiating vasculitis.
Defects in innate immunity contributing to the early and late Other innate immune cells captured in the vasculitic lesions,
14
events in the vasculitic lesions are much better understood specifically macrophages, are particularly important as inflam-
18
(Fig. 59.3). A population of vessel wall–residing dendritic cells matory effector cells. Multiple functional domains of macro-
15
(vasDCs) have been identified in normal human arteries, phages have pathogenic relevance. Intriguingly, the functional
localized at the adventitial–medial junction, close to the adventitial commitment of lesional macrophages is closely linked to their
19
microvascular network. Given their strategic positioning, they geographical location in the tissue site. Intima-positioned
are believed to guard the artery’s “backdoor.” vasDCs serve a macrophages produce inducible nitric oxide synthase, participat-
gatekeeper function in vasculitis, and stimulation of such vasDCs ing in regulating vascular tone. Adventitial macrophages secrete
is a prerequisite to break the natural immunotolerance (immune cytokines (IL-1β, IL-6, transforming growth factor-β [TGF-β]),
privilege) of the arterial wall. Their activation presages vasculitis, conditioning the local inflammatory environment. Granuloma
as indicated by their transition from the resting state to the formation and giant cells dominate in the media and at the
activated state in PMR arteries, where no vessel wall infiltrates media–intima border. Functional profiling of media-residing
16
are as yet detectable. In frank vasculitis, vasDCs undergo macrophages has connected them to tissue damage; they produce
expansion, penetrate deep into the wall, produce chemokines metalloproteinases and reactive oxygen species (ROS), provide
17
and cytokines, and express costimulatory ligands. They have antioxidant regulation, and supply growth factors for myofibro-
been implicated in presenting local antigen to induce T-cell clonal blasts and newly formed microvessels. Essentially they drive the
expansion and, through their chemokine production, shape the hyperplasia of the intimal layer that leads to luminal obstruction

812 Part SIX Systemic Immune Diseases



$257$ $257,& %5$1&+(6 Analysis of clonal CD4 populations has yielded identical T-cell
receptors (TCRs) in independent temporal artery biopsies from
the same patient, strongly supportive for antigen driving T-cell
20
behavior in the tissue microenvironment. Wall-embedded
vasDCs serve as antigen-presenting cells (APCs); the nature of
the antigen remains unknown. Reports about infectious agents
isolated from temporal arteries have notoriously not been
confirmed in independent studies. The older adult host is expected
to accumulate viral and bacterial microorganisms, and locally
deposited pathogens may not indicate causal involvement but,
rather, represent the vascular microbiota. Carefully designed
experiments need to probe for a specific role of pathogens isolated
from temporal artery tissue.
T helper 1 (Th1) cells are a key pathogenic element in GCA.
Interferon-γ (IFN-γ), the Th1 marker cytokine, has multiple
disease-relevant functions: activating endothelial cells and
macrophages, regulating wall remodeling, inducing microvascular
14
neoangiogenesis, and driving intimal-layer expansion. IFN-γ
production is predominantly produced in the adventitia, where
T cells are instructed by vasDCs. Th1 cells are present in lesions
from untreated patients and persist despite prolonged cortico-
21
steroid therapy, suggesting independence of vasculitogenic
Th1 cells from the steroid-sensitive acute-phase response and
$GYHQWLWDO WKLFNHQLQJ $GYHQWLWDO QHRDQJLRJHQHVLV
emphasizing their role as stabilizers of chronic-persistent lesions.
0HGLDO WKLQQLQJ ZDOO GHVWUXFWLRQ 0\RILEUREODVW PRELOL]DWLRQ During early vasculitis, Th1 cells are accompanied by Th17 cells.
$QHXU\VP IRUPDWLRQ DQG SUROLIHUDWLRQ However, Th17 cells are highly sensitive to steroid therapy and
21
'LVVHFWLRQ ,QWLPDO K\SHUSODVLD chronic lesions are Th17 depleted. Comparative analysis of
/XPLQDO RFFOXVLRQ
sequential temporal artery biopsy tissues harvested from patients
before and after treatment has demonstrated that adaptive
FIG 59.4 Patterns of Vessel Wall Damage in Giant-Cell Arteritis immune responses evolve over the course of the disease and that
(GCA). Transmural granulomatous vasculitis results in two distinct different subpopulations of lesion-residing T cells are differentially
damage patterns. In the aorta, the inflammatory infiltrates destroy responsive to immunosuppression.
the wall, inducing dissection and aneurysm formation. As a result Recent data have emphasized that the T-cell infiltrate in
of neoangiogenesis and fibrosis, the adventitia expands. In the GCA-affected arteries is typically multifunctional and composed
aortic branches, transmural granulomatous infiltrates predomi- of a broad spectrum of functional lineages. Besides Th1 and
22
nantly elicit a maladaptive healing response, characterized by Th17 cells, Th9, and IL-21–producing T follicular helper (Tfh)
the mobilization, migration, and proliferation of myofibroblasts cells are part of the infiltrate. Little is known about precise effector
forming hyperplastic and lumen-obstructive neointima. Formation functions of these T cells. However, overall the T-cell population
of neotissue is associated with microvascular neoangiogenesis recruited to and retained in the vessel wall is functionally highly
in the intima, media, and adventitia. New research indicates that diverse, raising the possibility that a mixed set of antigens with
intimal hyperplasia and neoangiogenesis are ultimately regulated vasculitogenic potential. Alternatively, the defect leading to
through the intensity of the T-cell response in the vasculitic granulomatous wall inflammation is the sequel of antigen-
lesions. nonspecific defects. 22
T cells have now been placed at the top of the artery’s mal-
adaptive response to injury, but precise effector pathways are
and tissue ischemia. Whether macrophage effector functions are not understood (see Fig. 59.4). Chronic aortitis leads to wall
fundamentally different in aortitis, compared with branch destruction and aneurysm formation. Dissection is increasingly
vasculitis, requires further exploration. Differences of tissue recognized as a sequel of aortic wall inflammation. In rare cases,
damage patterns (wall destruction versus luminal occlusion) LVV results in the fatal complication of aortic rupture. In TA,
suggest at least substantial variances (Fig. 59.4). direct cytotoxic function of CD8 T cells, natural killer (NK)
23
cells, and γδ T cells has been implicated in local tissue injury.
ADAPTIVE IMMUNE SYSTEM DEFECTS Conversely, in the aortic branches, LVV typically causes luminal
stenosis/occlusion as a result of formation of lumen-obstructive
The hallmark lesions in the vessel wall are granulomatous neotissue. Proliferating myofibroblasts lay down matrix and
infiltrates, in essence a mixture of highly activated macrophages, build hyperplastic intima. Newly formed microvessels appear
giant cells, and surrounding lymphocytes (see Fig. 59.3). The in the adventitia and intima to supply oxygen and nutrients to
overwhelming majority of these lymphocytes are memory CD4 the thickening wall. How T cells instruct vascular cells to this
T cells. CD8 T cells are infrequent, and B cells are rare. Multinucle- maladaptive wound healing response and whether heterogeneity
ated giant cells are present in about 50% of patients, often localized of such vascular cell populations imposes the disease’s tissue
close to the intima–media border adjacent to the lamina elastica tropism are the subjects of ongoing research. So far, the few
interna. Fragmentation of that elastic membrane is a hallmark wall-infiltrating B cells have not been assigned to a specific
of GCA. pathogenic mechanism.

CHaPtEr 59 Large-Vessel Vasculitides 813



KEY CONCEPtS impact on the density of newly formed microvessels and the
25
Large Vessel Vasculitis thickness of the hyperplastic intimal layer. Hyperactive check-
points are now targeted therapeutically to unleash T-cell immunity
• Medium and large arteries in humans have multiple wall layers and in patients with cancer. A role for PD-1–derived negative signaling
a wall structure substantial enough to be the target of transmural in vasculitis predicts that such patients are at risk to develop
inflammation. drug-induced vasculitis.
• Vasculitis causes the rapid and concentric growth of hyperplastic intima,
leading to luminal occlusion and ischemia of dependent tissues.
Intramural inflammation of the aorta can result in wall damage followed CLINICAL FEATURES IN GIANT CELL ARTERITIS
by aneurysm formation and rupture.
• Because of the vital function and nonregenerative nature of large
human arteries, the threshold for the induction and persistence of
innate and adaptive immune responses in the wall structures of such CLINICaL PEarLS
arteries must be explicitly high. Clinical and Epidemiological Clues in
• Inflammatory infiltrates typical for granulomatous vasculitis enter the Giant-Cell Arteritis
vessel from the “back door,” the adventitia, and not from the lumen.
• Besides their critical role in securing blood flow, medium and large • Patient older than 50 years of age
blood vessels also possess immunoregulatory functions mediated by • Female
dendritic cells (DCs) indigenous to the vascular wall. DCs in each • Northern European heritage
vascular territory express a distinctive pattern of Toll-like receptors • Laboratory findings of a highly activated acute-phase response
(TLRs), giving each vessel its own immunological identity. • Insidious onset of nonspecific symptoms (weight loss, night sweats,
malaise, fever)
• Ischemia of ocular structures, cranial muscles, scalp, or upper
extremities
Defective T Regulatory Cells and Insufficient Immune
Checkpoints in Giant Cell Arteritis
Recent data have brought to the forefront that antigen-nonspecific Clinical manifestations of GCA reflect the combination of a
immunoregulatory pathways may have disease relevance in LVVs, systemic inflammatory syndrome with vascular insufficiency
2,26
specifically in enabling unopposed and lasting adaptive immune (Table 59.1). Increased sensitivity of vascular imaging methods
responses to induce and sustain vessel wall inflammation. and longer survival of affected individuals have made it clear
Like in many chronic inflammatory lesions, GCA’s arterial that in most patients medium and large arteries are involved.
wall infiltrates lack sufficient antiinflammatory T regulatory cells In some patients, the disease preferentially targets more peripheral
(Tregs). This may be a consequence of the proinflammatory branches of the aorta (e.g., cranial arteries, such as the temporal
milieu, but recent studies have identified a novel mechanism of artery). In others, the aorta and its proximal branches (e.g.,
Treg-dependent immunosuppression that is nonfunctional in subclavian, axillary arteries) are involved to a major extent. In
GCA. In healthy individuals, secondary lymphoid tissue are a subpopulation of patients, the clinical consequences of arterial
occupied by a population of CD8 Tregs that effectively control inflammation are minimal, and these consequences come to
clonal expansion of CD4 T cells, and thus the overall size of the clinical attention because of failure to thrive.
24
CD4 T-cell compartment. Such CD8 Tregs suppress activation In cranial GCA, symptoms result from vascular stenosis of
and expansion of neighboring CD4 T cells by the directed transfer the neck and head arteries, most prominently in the branches
of nicotinamide adenine dinucleotide phosphate (NADPH) of the external carotid artery. Arteritis of the scalp arteries leads
oxidase 2 (Nox2)–containing membrane particles. The population to the typical presentations of headaches and scalp tenderness.
+
+
of Nox2 CD8 Tregs is distinctly low in patients with GCA and Patients report difficulties with wearing glasses or combing their
remains low with antiinflammatory therapy, suggesting a preexist- hair. The headaches are often intense and unresponsive to standard
ing abnormality in the patients’ immune system. Implicating analgesics. Headaches are a nonspecific clinical symptom, yet in
Nox2 expressed on CD8 T cells in the threshold setting of CD4 an older individual with other findings of an inflammatory
T-cell immunity opens an entirely new perspective in vasculitis syndrome, physicians need to rule out GCA. Insufficient blood
research and redirects the focus away from antigenic triggers flow to the masseter muscles and the tongue causes jaw or tongue
that induce protracted macrophage activity. claudication, elicited by prolonged chewing and talking. Although
A second immunoregulatory defect weakening proper control this type of claudication is present in <30% of patients, it is
of CD4 T-cell immunity has been localized to the programmed clinically helpful because it rarely occurs outside of GCA. Similarly,
25
death 1 (PD-1) immunoinhibitory checkpoint. Inhibitory painful dysphagia can be a useful clinical clue.
checkpoints are designed to protect tissue from excessive immune The orbits and the optic nerve are strictly dependent on blood
reactivity. PD-1 is expressed on activated T cells, the ligand PD-L1 supply from the external carotid system, particularly the oph-
is expressed on APCs. Triggering of PD-1 sends negative signals thalmic artery. GCA in branches of the ophthalmic artery, specifi-
into T cells and stops their proliferation and polarization. DCs cally the posterior ciliary arteries, leads to anterior ischemic optic
in patients with GCA, both lesional vasDCs and circulating DCs, neuropathy, presenting as sudden and painless vision loss.
low
are PD-L1 . GCA T cells thus lack negative signaling and fail Typically, patients lose vision in the early-morning hours or
to undergo clonal contraction. Indeed, in inflamed temporal wake up blind. Involvement of one eye may be followed by visual
+
arteries PD-1 T cells are strongly enriched. In human artery– loss in the partner eye if the disease is not diagnosed and treated
chimeric mice, blocking PD-1 with antibody treatment exacerbates promptly. Besides anterior optic neuropathy, GCA can cause a
+
vasculitis, and wall-infiltrating PD-1 T cells produce a spectrum number of ischemic complications in the orbits and along the
18
of effector cytokines (IFN-γ, IL-17, IL-9, IL-21, etc.). Most visual axis, which may present as diplopia or partial vision loss.
importantly, PD-1–PD-L1 interactions in the artery have direct If recognized and treated immediately, vasculitis-associated sight

814 Part SIX Systemic Immune Diseases



TABLE 59.1 Clinical Features of Giant-Cell Disability can be significant, as patients have difficulties with
arteritis (GCa), Polymyalgia rheumatica activities of daily living. With stenotic lesions of the subclavian
(PMr), and takayasu arteritis (ta) arteries, blood pressure readings can be unreliable or not possible,
requiring alternative strategies for blood pressure monitoring.
Organ FrEQUENCIES Although carotid involvement is considered infrequent, it can
System Clinical Features GCa PMr ta be challenging to distinguish atherosclerotic disease and vasculitic
disease. Patients with carotid GCA are at high risk for cerebral
Vascular Headaches +++ * ischemic events. Aortic involvement preferentially targets the
Limb claudication + *** thoracic aorta and infrequently the abdominal aorta (Fig. 59.6).
Scalp tenderness **
Jaw claudication ** Dilation of the aortic root can lead to aortic insufficiency. Aortic
Absent or asymmetrical * *** aneurysms are often clinically silent. The diagnosis may first be
pulses made from tissue obtained surgically during aortic aneurysm
Asymmetrical blood * *** repair. In extreme cases, the aortic wall ruptures.
pressure readings The response pattern of arteries to inflammation may not
Bruit * *** include intimal hyperplasia, thus eluding luminal compromise
Tongue claudication * and vascular failure. In such patients, the systemic inflammatory
Tissue gangrene *
Abdominal angina * component dominates the clinical presentation. Fever, fatigue,
Cough (dry, nonproductive) * * malaise, weight loss, and depression are often intense enough
Constitutional Malaise ** ** *** to prompt a workup for a malignancy. GCA needs to be a
Failure to thrive * ** * differential diagnosis in all cases of fever of unknown origin,
Weight loss ** ** ** particularly in older individuals. Patients with cranial GCA have
Fever * * * abnormally thick and tender temporal arteries exhibiting nodular-
Central Ocular symptoms ** * ity and loss of pulses, whereas clinical findings in nonstenosing
nervous
Stroke/transient ischemic * * GCA can be unremarkable. Temporal artery biopsy should
attack be pursued even if clinical examination does not suggest the
Peripheral Peripheral neuropathy * diagnosis.
nervous
Cardiac Aortic dilatation and * * CLINICAL FEATURES IN
regurgitation
Myocardial infarction * * POLYMYALGIA RHEUMATICA
Congestive heart failure *
Musculoskeletal Proximal stiffness/muscle ** *** PMR is diagnosed in patients presenting with pronounced
pain stiffness and pain in the shoulder and pelvic girdle muscles
2
Synovitis of peripheral joints * (see Table 59.1). Laboratory testing reveals a systemic inflam-
Others Intense acute-phase *** *** *** matory syndrome; arterial biopsy is negative for arteritis. It is
response estimated that about 10% of patients with PMR without any
Normochromic or ** * ** signs of vascular inflammation will eventually develop full-blown
hypochromic anemia
vasculitis. Notably, PMR often occurs in patients with GCA and
*** = high frequency (>70%); ** = moderate frequency (20–70%); * = low frequency is present in about 40% of patients with GCA at disease onset.
(<20%). Tapering of immunosuppressive therapy in GCA is frequently
26
associated with new or remittent PMR symptoms. Complaints
are focused on muscle pain and stiffness, classically affecting the
loss is preventable, which indicates that GCA should be considered neck, shoulders, and pelvic girdle. The muscles of the torso may
an ophthalmological emergency. be involved. Peripheral areas of the arms and legs are spared.
Chronic nonproductive cough can be related to arteritis in Muscle pain is most intense in the early morning and improves
bronchial artery branches. If the vertebral and basilar arteries during the day. Inability to get out of bed, stand up from a chair,
develop vasculitic stenosis, ischemia of the central nervous system or get off the toilet seat should alert the physician to consider
manifests with transient ischemic attacks or frank stroke. PMR. Some patients with PMR have synovitis or bursitis in their
2,28
In patients with large-vessel GCA, cranial symptoms may be shoulder and hip joints, making it difficult to distinguish these
27
minimal, and temporal artery biopsy can be negative. Instead, patients from those with seronegative polyarthritis. No diagnostic
vascular insufficiency is focused on the upper-extremity vessels procedure that allows for the diagnosis of PMR is available; the
and the aorta. In rare cases, lower extremities are affected. Typi- syndrome remains an exclusion diagnosis in cases of myalgia
cally, patients have asymmetrical blood pressure readings or combined with laboratory signs of systemic inflammation. On
experience total loss of upper-extremity blood pressure and pulse. clinical examination, passive motion of shoulder and hip joints
The underlying lesions are occlusions in the distal subclavian is seen to be maintained, but active motion is restricted because
arteries, often extending into the axillary sections (Fig. 59.5). of pain. Muscle strength is often normal. Careful evaluation
Patients with subclavian GCA are on average about 10 years of the temporal arteries is warranted to avoid missing fully
younger at disease onset compared with those with dominant developed GCA.
cranial manifestations. Diagnosis of large-vessel GCA can be
delayed as symptoms are nonspecific and the systemic inflam- CLINICAL FEATURES IN TAKAYASU ARTERITIS
matory component is less pronounced. Ischemic pain in the
hands when using the arms is often combined with coolness The clinical manifestations of TA are diverse and depend on the
29
and bluish discoloration. Gangrene of the fingertips is rare. affected vascular territory (see Table 59.1; Table 59.2). Initial

CHaPtEr 59 Large-Vessel Vasculitides 815

































$ %




























& '
FIG 59.5 Diagnostic Imaging in Giant-Cell Arteritis (GCA): Computed Tomographic Angiography
(CTA). Contrast-enhanced CTA in a 74-year-old female with a temporal artery biopsy positive for
GCA. CTA imaging shows diffuse, circumferential mural thickening along the entire descending
aorta and the abdominal aorta (A). Arrows mark the thickened aortic wall. Axial images (B, C,
and D) reveal the circumferential distribution (arrows) of the wall thickening from the distal arch
to the intrarenal portion of the aorta. Thickness measurements can be used to monitor disease
burden over time. The aortic diameter is within normal limits, indicating that the aortitis has not
yet resulted in aneurysm formation. [Images were generated by Dr. D. Fleischmann, Department
of Radiology, Stanford University.]



symptoms are usually nonspecific and include fever, cough, between host risk genes and dysfunctional immunity. In North
malaise, weight loss, night sweats, myalgias, and arthralgias. Signs American, Japanese, and Korean patients, the aortic arch and
of vascular deficiency develop later in the disease course and its primary cervical and upper extremity branches are preferen-
generally are ischemic in nature. Geographical variations in tially targeted, giving rise to aortic insufficiency, cerebral ischemia,
disease pattern have been reported, likely reflecting the interplay face and neck pain, ocular ischemia, and the typical presentation

816 Part SIX Systemic Immune Diseases






























A B





























C D
FIG 59.6 Diagnostic Imaging in Giant-Cell Arteritis (GCA): Magnetic Resonance Angiography
(MRA). Contrast-enhanced MRA of the chest and abdomen in the patient whose computed
tomographic angiography (CTA) images are presented in Fig. 59.5. Double-inversion recovery
magnetic resonance imaging (MRI) scans in the axial plane demonstrate diffuse, contiguous
mural thickening of the great vessels (A, brachiocephalic trunk) and the aorta (B–D). Arrows are
placed to mark the circumferential distribution of the mural thickening and compare luminal
diameter and wall thickness at different levels of the vessels. [Images courtesy of Dr. D. Fleischmann,
Department of Radiology, Stanford University.]




of “pulseless disease” (Fig. 59.7). In patients in India, the abdomi- particularly in young women. Consequently, the diagnosis can
nal aorta and renal arteries are more commonly affected, causing be missed for months. Only a few patients come to clinical
renovascular hypertension and the long-term risk of cardiac attention because of catastrophic neurological symptoms related
failure (Fig. 59.8). 30 to brain ischemia. Helpful clues are differences in blood pressure,
Nonspecific complaints of headaches, syncope, and face and loss of pulses, and vascular bruits heard on clinical examination.
neck pain are often misinterpreted as stress-related problems, Retinal neoangiogenesis, induced by hypoperfusion of the eye,

CHaPtEr 59 Large-Vessel Vasculitides 817



TABLE 59.2 takayasu arteritis: majority of patients. 2,26,34 Generally this is captured by measuring
relationship Between Clinical Symptoms ESR or CRP. It is important to note, however, that a subset of
and affected Vascular territories patients with GCA has normal ESR readings, even before initiation
of immunosuppressive therapy. A normal ESR or CRP reading
Vascular Bed approximate Predominant Clinical is not sufficient to exclude the diagnosis, and further diagnostic
Involvement Frequency (%) Symptoms workup is required if clinical presentation is suspicious for
Subclavian 90 Arm claudication, vasculitis. Other acute-phase proteins, such as fibrinogen and
pulselessness SAA, have been reported to be elevated as well. IL-6 is a potent
Common carotid 60 Visual defects, stroke, inducer of acute-phase proteins in the liver and has been found
transient ischemic to be a sensitive marker of continuous systemic inflammation. 10,11 .
attack, syncope Other laboratory abnormalities, such as elevation of alkaline
Abdominal aorta 45 Claudication, hypertension, phosphatase, thrombocytosis, and anemia, are in line with a
abdominal angina
Renal 35 Hypertension robust acute-phase response.
Aortic arch/root 35 Aortic insufficiency, Autoantibody measurements are not helpful beyond
congestive heart failure excluding differential diagnoses, such as rheumatoid arthritis
Vertebral 35 Dizziness, visual (RA), systemic lupus erythematosus (SLE), or antineutrophil
impairment cytoplasmic antibody (ANCA)–related vasculitides. No disease-
Celiac axis 20 Abdominal angina specific autoantibodies for GCA and TA have been discovered,
Superior mesenteric 20 Abdominal angina emphasizing that B-cell immunity may not contribute to vascular
Iliac 20 Claudication
Pulmonary 10 Dyspnea, chest pain inflammation.
Coronary 10 Myocardial infarction,
angina Tissue Biopsy
In patients with TA, tissue biopsies are rarely available unless
the patient had to undergo vascular reconstructive surgery. In
most patients, the diagnosis is made on the basis of imaging
is now relatively rare, but fleeting visual abnormalities may procedures revealing luminal and wall abnormalities in affected
indicate transient ischemic attacks. Signs of aortic insufficiency blood vessels.
are unlikely to be encountered in early disease, but continuous In contrast, arterial biopsy remains a critical diagnostic
monitoring for aortic dilation is an essential part of follow-up approach in managing patients with GCA. Temporal arteries are
care. Coronary artery stenosis in a young patient must prompt easily accessible, and a segment of these arteries can be removed
the physician to rule out TA. In a subset of patients, the origins in an outpatient setting. Recommendations include harvesting
of mesenteric arteries are involved by stenosing vasculitis. Clinical 2–3 cm of the temporal artery, starting at the most symptomatic
consequences include weight loss, nausea, vomiting, diarrhea, side. Frozen tissue sections can lead to a quick diagnosis of
and abdominal claudication, typically elicited by the increased granulomatous vasculitis. Whether the second side should be
intestinal blood demand following a meal. biopsied during the same surgical procedure remains a matter
Renal artery stenosis may be clinically silent and is often of debate. In cohorts that included several hundred patients,
noticed in routine screening. Correct measurement of blood vasculitis was detected in 2–3% of tissue samples from the second
pressure can represent a pressing clinical problem if the upper- side if the first side was negative. If the clinical suspicion is
extremity arteries are affected. Involvement of the infrarenal strong, biopsy confirmation can be sought from a second-side
aorta can lead to lower-extremity claudication. Musculoskeletal biopsy immediately after the first biopsy or after careful monitor-
examinations are usually unrevealing, although joint and muscle ing of the patient for several weeks. Negative findings on temporal
pains are common complaints. artery biopsy do not exclude the diagnosis of GCA. In a retrospec-
tive cohort study, about half of all patients with subclavian GCA
DIAGNOSIS had no evidence of vasculitis in the temporal arteries, emphasizing
that the disease may display clear preference for certain vascular
35
Classification criteria have been developed for GCA and TA to territories. There has been a recent trend toward considering
differentiate patients with LVV from those with other vasculitic negative biopsies as “false negative” and classifying patients with
entities (Tables 59.3 through 59.5). 31-33 Age at disease onset and a negative biopsy as having GCA. This may lead to unnecessary
the pattern of arteritis are clearly important for establishing the immunosuppressive therapy, and the patient may not thus obtain
diagnosis and distinguishing between these two related vascu- a proper diagnosis. Findings that prompt biopsies (headaches,
lopathies. Diagnostic criteria for PMR remain a challenge (see elevated acute-phase reactants) are notoriously nonspecific, and
Table 59.3) as they rely on nonspecific symptoms, such as muscle both physicians and patients are anxious to avoid treatable
pain and stiffness and elevated erythrocyte sedimentation rate blindness, biasing toward overtreatment. The temporal artery
2
(ESR), all of which can occur in many other diseases. No specific biopsy remains a powerful diagnostic tool and the major tool
laboratory test is currently available to diagnose PMR. Therapeutic that allows unequivocal classification of the disease process. A
responsiveness of patients with PMR to low-dose corticosteroids technically proper temporal artery biopsy will detect vasculitis
is clinically helpful but stresses the need for objective diagnostic in the vast majority of patients.
criteria. Corticosteroid therapy does not eradicate pathological findings
of vascular wall infiltrates, and biopsy can still be valuable in
Laboratory Tests making the diagnosis in patients on steroids. Nevertheless it
21
In all three conditions—GCA, PMR, and TA—the laboratory is possible that treatment with steroids leads to a false-negative
findings indicate an intense acute-phase response in a vast biopsy result in some patients.

818 Part SIX Systemic Immune Diseases



























A B


























C D






FIG 59.7 Diagnostic Imaging in Takayasu Arteritis (TA):
Computed Tomographic Angiography (CTA). Contrast-
enhanced CTA shows markedly increased wall thickness
of the scanned arteries in a 28-year-old woman. A, Coronal
images demonstrate wall thickening (arrows) of the ascend-
ing aorta, the aortic arch and the proximal aortic branches
(brachiocephalic, left common carotid, and left subclavian).
B and C, Axial images allow for precise measurements of
wall thickness in the ascending aorta (B) and in the aortic
arch (C). D shows marked thickening of the circumferential
wall of both common carotid arteries (arrows). E and F,
Vessel wall inflammation has resulted in moderate stenosis
of both carotid arteries (arrows), with wall irregularities more
pronounces on the right side. [Images were provided by
E F Dr. D. Fleischmann, Department of Radiology, Stanford
University.]

CHaPtEr 59 Large-Vessel Vasculitides 819



























$ %












FIG 59.8 Diagnostic Imaging in Takayasu Arteritis (TA):
Magnetic Resonance Angiography (MRA). Contrast-
enhanced MRA in a 28-year-old patient with TA taken
after 6 months of corticosteroid treatment. Pretreatment
CTA images are presented in Fig. 59.7. T1-weighted
double-inversion recovery magnetic resonance imaging
(MRI) scans of the ascending aorta (A), the aortic arch
(B), and the descending aorta (C) show residual mural
thickening. Thickened vascular walls are marked with
& arrows. [Images courtesy of Dr. D. Fleischmann, Depart-
ment of Radiology, Stanford University.]





TABLE 59.3 american College of TABLE 59.4 Provisional Classification
rheumatology 1990 Classification Criteria for Polymyalgia rheumatica
Criteria for Giant-Cell arteritis and Age ≥50 years required
a
Polymyalgia rheumatica Bilateral shoulder ache required
Abnormal C-reactive protein (CRP) and/or erythrocyte required
Age at disease onset ≥50 years sedimentation rate (ESR)
New-onset or new type of headache Morning stiffness >45 minutes 2
Temporal artery tenderness or decreased artery pulse Hip pain or limited range of motion 1
Elevated erythrocyte sedimentation rate (≥50 mm/hr) Absence of rheumatoid factor (RF) or anti-citrullinated 2
Histological incidence of arteritis (characterized by a predominance of protein antibody (ACPA)
mononuclear cell infiltrates or a granulomatous process with Absence of other joint involvement 1
multinucleated giant cells)
A score of ≥4 is categorized as polymyalgia rheumatica.
a A patient is classified as having giant-cell arteritis if at least three of the five criteria
are present. Reprinted from Dasgupta B, et al. Provisional classification criteria for polymyalgia
Reprinted from Hunder GG, Bloch DA, Michel BA, et al. The American College of rheumatica: A European League Against Rheumatism/American College of
Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum Rheumatology collaborative initiative. Arthritis Rheum 2012; 64: 943–954.
1990; 33: 1122–1128, with permission of Wiley-Liss, Inc., a subsidiary of John Wiley
& Sons, Inc. ©1990.

820 Part SIX Systemic Immune Diseases


Histomorphological reports describe mononuclear cell infiltrates. Marked wall thickening with inflammatory tissue
infiltrates penetrating through all layers of the vessel wall (Fig. extending into perivascular structures is typical for TA (Fig.
1
59.9). Recent discussions have focused on the diagnostic relevance 59.10). Destruction of elastic membranes is often extensive and
of isolated inflammatory cell clusters in the adventitia or peri- combined with patchy areas of media necrosis. Weakening of
36
vascular lymphocytes limited to small blood vessels. These the vessel wall can lead to aneurysm formation. Inflammatory
findings may not be sufficient to indicate arteritis. Multinucleated lesions may be arranged in a “skipped” pattern, with normal
giant cells may or may not be found. They tend to lie along the vessel wall segments alternating with stretches of intense destruc-
internal elastic lamina, at the junction between the media and tive inflammation.
the intima. Media destruction is not unusual, but findings of Physicians may encounter morphological findings of granu-
fibrinoid necrosis should prompt a search for a different vasculitic lomatous aortitis in patients undergoing aortic aneurysm repair
entity. The vessel lumen is more or less compromised by hyper- without any prior diagnosis of vasculitis. Detailed workup of
plastic intima formed from proliferating fibroblasts, smooth- these patients is necessary to identify those with undiagnosed
muscle cells, and deposition of acid mucopolysaccharides. PMR, GCA, or TA. Rare causes of aortitis, including inflammatory
The histology of TA is similar to that of GCA, making it bowel disease, sarcoidosis, syphilis, relapsing polychondritis, and
difficult to dissect both syndromes in tissue samples derived connective tissue disease, should be ruled out. Isolated granu-
from the aorta or its primary branches. Lymphocytes and plasma lomatous aortitis is diagnosed as idiopathic aortitis. The
cells accumulate around vasa vasorum and form transmural pathogenesis and prognosis of this condition are essentially
unknown.
Diagnostic Imaging
TABLE 59.5 american College of Modern imaging modalities have fundamentally changed the
26
a
rheumatology 1990 Criteria for the diagnostic approach to LVV. Indeed, diagnosing TA mostly
Classification of takayasu arteritis depends on identifying vascular lesions in typical distribution
by imaging. 37
Disease onset at ≤40 years Conventional angiography still has its place in preoperative
Claudication of an extremity planning and can be combined with intravascular interventions.
Decreased brachial artery pulse
>10 mm Hg difference in systolic blood pressure between arms It provides ideal visualization of the vascular lumen not only
Bruit over the subclavian arteries or the aorta for large but also for medium-sized arteries, such as the axillary
Arteriographic evidence of narrowing or occlusion of the entire aorta, and brachial arteries (see Fig. 59.5). Ultrasound (US)–based
its primary branches, or large arteries in the proximal upper or lower methods are extremely useful for screening carotid arteries, but
extremities they have also emerged as the method of choice for initial assess-
ment of the distal subclavian arteries, vertebral arteries, renal
a For purposes of classification, a patient is classified as having Takayasu arteritis if
more than three of the six criteria are fulfilled. arteries, and femoral arteries. US examination is also the optimal
Reprinted from Arend WP, Michel BA, Bloch DA, et al. The American College of method for long-term monitoring of vessel bypasses in patients
Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum who have undergone revascularization surgical procedures. Magnetic
1990; 33: 1129–1134, with permission of Wiley-Liss, Inc., a subsidiary of John Wiley
& Sons, Inc. ©1990. resonance imaging (MRI), magnetic resonance angiography (MRA),

























$ %

FIG 59.9 Histomorphology of Giant-Cell Arteritis (GCA). (A) Temporal artery cross-section
with mononuclear infiltrates throughout all wall layers. The adventitia is infiltrated by round cells
with cuffing of vasa vasorum by lymphocytes. The vessel lumen is occluded by intimal hyperplasia.
(B) Higher magnification showing intense granulomatous inflammation with multinucleated giant
cells in the proximal media and at the media–intima junction.

CHaPtEr 59 Large-Vessel Vasculitides 821


been disappointing, cautioning one that edema-weighted MR
should not be used as a sole means of measuring disease activity
38
and therapeutic responsiveness. Both, CT angiography and
MRA are now used routinely to monitor progression or regression
of vascular involvement and have an important place in managing
the chronic phase of GCA and TA.


THERAPEUTIC MANAGEMENT

tHEraPEUtIC PrINCIPLES
Treatment of Large Vessel Vasculitides

• To prevent vision loss, patients with giant-cell arteritis (GCA) require
immediate treatment. Similarly, with the threat of catastrophic cerebral
ischemia in Takayasu arteritis (TA), prompt initiation of therapy is
$ imperative.
• Corticosteroids are the immunosuppressive drug of choice for large-
vessel vasculitides (LVVs). Often, the drugs must be given over a
period of several years but may be clinically effective at very low
doses.
• Clinical trials have failed to show convincing steroid-sparing effects
for either methotrexate or tumor necrosis factor (TNF)-α blockade in
GCA.
• A phase 3 clinical trial has demonstrated steroid-sparing effect of
treatment with tocilizumab.
• Molecular studies of the inflammatory infiltrate in GCA have shown
that early and untreated disease is characterized by two functional
T-cell lineages; T helper (Th)1 and Th17 cells. Th17 cells are rapidly
responsive to corticosteroids, whereas Th1 cells persist and promote
chronic, smoldering vasculitis.
• It is not known whether the smoldering activity persisting beyond the
acute phase of the disease requires immunosuppressive therapy or
whether the benefits of chronic immunosuppressive therapy outweigh
the potential risks.
• Clinical experience (not evidence-based therapeutic trials) suggests
that a combination of methotrexate, mycophenolate mofetil, or
TNF-α–blocking agents with corticosteroids may be beneficial in
controlling disease in some patients with TA.
• Close monitoring for diabetes, hypertension, and hyperlipidemia
% combined with bone-saving therapy should be part of the treatment
regime in patients with LVVs on long-term corticosteroids.
FIG 59.10 Histopathology of Takayasu Arteritis (TA). (A) Full-
thickness section of the aortic wall shows dense mononuclear
infiltrates in the adventitia and media. The intima is thickened With increasing knowledge of the disease process and refine-
and wavy; hematoxylin and eosin (H&E). (B) Florid granulomatous ment of diagnosis and long-term treatment, the prognosis for
inflammation along the media–intima junction with numerous patients with LVVs has significantly improved. Life expectancy
giant cells; H&E. of patients with GCA is preserved. Follow-up studies of Japanese
patients with TA have suggested good control of disease activity
in about 75% of patients, with only 25% experiencing serious
and computed tomography (CT) are now widely used for evaluat- complications and cardiac manifestations dominating long-term
ing the vascular tree. These methods provide excellent information outcome. Whether vasculitis predisposes patients to acceler-
on abnormalities of the vascular lumen and wall, with increasing ated atherosclerotic disease, given the combination of chronic
resolution, now capturing abnormalities in the more peripheral inflammation and injury to vessel wall structures, is still being
arterial branches. CT imaging is fast, well tolerated by patients discussed. It is not known whether progression of atherosclerosis
with claustrophobia, and allows excellent assessment of the aorta and its complications require a different management approach
and its wall (see Fig. 59.7). However, it has the disadvantages of or whether standard vasoprotective measures (treating hyperten-
contrast loading and radiation exposure. With its inherent sion and hyperlipidemia, smoking cessation, etc.) are sufficient. 6
multiplanar imaging capabilities, magnetic resonance is used to Pathogenic studies have pointed out that the traditional view
11
examine neck vessels, the aorta, and its primary branches (see of GCA as a self-limiting disease is incorrect. To the contrary,
Figs. 59.6 and 59.8). Great hope was placed on its potential to granulomatous vasculitis has shown surprising resistance to
measure wall edema and intramural vascularity, which would immunosuppression, with vessel wall infiltrates persisting for
make MR useful for estimating disease burden and responses >12 months in almost 50% of patients despite appropriate
to therapy. However, a carefully conducted study comparing immunosuppressive therapy. Based on examination of serial
imaging results with laboratory parameters of inflammation to temporal artery biopsy specimens from patients before and after
results from surgically harvested vessel biopsy specimens has treatment, it is now clear that arteritis persists, albeit sustained

822 Part SIX Systemic Immune Diseases



ON tHE HOrIZON consecutive days, therapy was continued with oral prednisone,
and daily doses were swiftly tapered. Compared with the control
• Medium and large arteries in humans sense danger signals through arm, patients who received three initial steroid pulses had lower
wall-embedded cells; changing the understanding of how the immune likelihoods of disease flare-ups. Particularly, once they reached
system interacts with the vascular system.
• The multilineage nature of vasculitic T cells, which display differential prednisone doses close to 10 mg/day, these patients could tolerate
therapeutic responsiveness, almost certainly will require more complex steroid withdrawal significantly better, and most were taking 5 mg/
40
therapies, adapted to disease stage and immune status of the host. day prednisone at 36 weeks. The benefit from initial pulse therapy
• The immune system changes profoundly with age. Age-appropriate continued over subsequent months, suggesting the potential benefit
management of each patient and avoidance of overtreatment of older of intense immunosuppression during early disease.
adults are important. Several biological agents have been explored or are currently
• Current therapies in large-vessel vasculitis induce partial remission. undergoing testing in clinical trials. Tumor necrosis factor-α
41
Appropriately designed studies are required to explore whether partial
remission is sufficient and whether the risk/benefit ratio is maintained (TNF-α) inhibitors may have a role in TA but had no steroid-
42
if complete remission is attempted. sparing effect in GCA. Preliminary study results suggest that
targeting T-cell costimulation with abatacept may prevent disease
relapses in GCA. Ustekinumab, a monoclonal antibody (mAb)
21
by an immune network distinct from that in untreated patients. targeting IL-12 and IL-23, was reported to have potential efficiency
It is currently not known whether this persistent smoldering in refractory GCA in a small open-label study. The IL-6 receptor
process needs to be treated and what the risk/benefit ratio is for blocker tocilizumab has been explicitly effective in reducing acute
the older patient population affected by GCA. Unchanged life phase reactants (CRP, ESR) and is being explored in GCA and
expectancy in GCA suggests adequacy of current management. TA and a phase 3 double-blind trial of tocilizumab given weekly
Whether intensification of immunosuppressive therapy or chronic or every other week demonstrated substantial steroid-sparing
maintenance therapy can prevent long-term complications, such effect over a one-year period. 12
as aortic aneurysm/dissection from GCA aortitis, and improve
the overall prognosis is unknown. The ultimate decision depends Maintenance Therapy
on the cost/benefit analysis comparing the risk from smoldering With a major shift in the pathogenic concept about LVVs,
disease with the risks imposed by long-standing immunosup- especially the realization that the disease process has two, partly
pression. In that context, it is important to remember the independent components (extravascular, vascular) and that
profound impact of the immune aging process, which leaves the vessel wall infiltrates persist chronically, the therapeutic needs
patient with an impaired immune system and amplifies the risk for maintenance therapy have become the dominant issue for
of immunosuppression. 39 the treating physician. Patients with PMR are often managed
successfully with low-dose corticosteroids (prednisone 5 mg daily)
Induction Therapy and typically are highly responsive to transient and very small
In newly diagnosed patients with GCA, TA, and PMR, the dose increases (1–2 mg prednisone/day). Long-term management
immunosuppressants of choice are corticosteroids. Patients with of patients with GCA and TA relies on low-dose corticosteroids
GCA are started on a daily prednisone dose of 40–60 mg (about as well unless there is objective evidence for progressive vascular
1 mg/kg body weight). In patients with PMR, a daily dose of wall inflammation. Unfortunately no reliable biomarkers can
20 mg prednisone is sufficient in almost all patients. The response separate the extravascular and vascular disease components, and
is usually dramatic, with improvements within 24–48 hours. no evidence that suppressing acute phase response in the periphery
The promptness of clinical improvement is so exceptional that will ultimately restrict transmural vasculitis has been presented.
it has been suggested as a diagnostic criterion for PMR. However, Methotrexate is considered to have mild-to-moderate steroid-
43
the promptness of response may be limited to extravascular LVVs. sparing potential in GCA and PMR but is more frequently
44
Myalgias, fever, malaise, and headaches improve swiftly, in parallel used in TA. When given to human artery–severe combined
with a fast reduction of acute-phase reactants (CRP, IL-6, ESR). immunodeficiency (SCID) chimeras, acetylsalicylic acid (aspirin)
Emerging data suggest that the vascular component is much has marked antiinflammatory activities, with suppression of IFN-γ
more resistant to immunosuppression and may require entirely in vascular lesions. Clinical trials are needed to test whether this
new therapeutic strategies. immunosuppressive action can translate into corticosteroid
Once the condition is stabilized, steroid tapering is guided sparing. Because arteries are the primary targets of LVVs, the use of
by close monitoring of the clinical presentation as well as labora- aspirin as an antiplatelet agent should be routinely recommended.
tory markers of inflammation. In general, steroids should be There is no evidence that immunosuppressants, such as
reduced by 10–20% every 2 weeks. Monthly monitoring of ESR azathioprine and cyclophosphamide, lower steroid needs, prevent
and CRP is mandatory to adjust therapy. Patients frequently vascular complications, or shorten the duration of steroid use.
return with signs or symptoms of recurrent disease as immu- Whether any of the biological agents described above has a place
nosuppression is lowered. Fortunately, disease exacerbations to effectively suppress vessel wall inflammation and change the
causing vision loss are infrequent. Disease flare-ups typically course of chronic disease is currently unknown.
present with PMR symptoms or nonspecific manifestations of An integral part of chronic immunosuppression with pred-
malaise and failure to thrive. In most patients, a transient small nisone is regular monitoring for diabetes and hypertension.
increase in the steroid dose reinstates disease control. Patients should be encouraged to increase physical activity, as
Much effort has been invested in identifying steroid-sparing steroid-induced myopathy occurs frequently. A major issue of
agents. In a small study, treatment with pulse corticosteroids chronic steroid treatment, particularly in older individuals, is
appeared to have long-term beneficial effects, reducing the overall the risk of excessive bone loss, possibly resulting from increased
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steroid requirement and the rate of disease flare-ups. After bone resorption and impaired bone formation. Several effective
pulses of 1000 mg methylprednisolone were administered for 3 and safe therapies for osteopenia/osteoporosis are available.