Clinical Immunology_ Principles and Practice ( PDFDrive )

53









Juvenile Idiopathic Arthritis



Randy Q. Cron, Peter Weiser, Timothy Beukelman








Juvenile idiopathic arthritis (JIA) is a collection of conditions Distinctions based on the types and location of joints manifesting
that manifest with chronic arthritis in childhood. By definition, arthritis may prove useful in identifying more homogeneous
JIA occurs prior to the 16th birthday (juvenile), has no known subtypes. Thus the criteria will likely continue to evolve and
causes (idiopathic), and has evident chronic (>6 weeks’ duration) benefit from more precise clinical, laboratory, and genetic distinc-
1
swelling/inflammation of a joint or joints (arthritis). The tions. One such suggested reclassification of JIA categories is
nomenclature and subcategorization of JIA have been published, based on shared similarities among children with JIA who are
3
with a second revision in 2004, partly in an attempt to unify the positive for antinuclear antibody (ANA) regardless of total joint
American (juvenile rheumatoid arthritis [JRA]) and European count, and a recent proposal used probabilistic principal com-
1
(juvenile chronic arthritis [JCA]) classification schemes. Removal ponent analysis of a large set of biological and clinical data to
4
of the word “rheumatoid” was also important to distinguish subdivide patients with JIA. Moreover, there have been several
these unique disorders from adult rheumatoid arthritis (RA) attempts to characterize the genetics of the JIA categories by
(Chapter 52). The new classification of JIA also includes the using a variety of approaches. 5
human leukocyte antigen (HLA)-B27–associated spondyloar-
thropathies (Chapter 57), which occur frequently during child- Polygenic Disorder
hood (Table 53.1). Like most autoimmune conditions, JIA is a polygenic disorder
Because JIA is a diagnosis of exclusion, other causes of child- with ≥20 potential genes contributing to the phenotypes of
hood chronic arthritis need to be ruled out. For example, sar- chronic arthritis presenting during childhood. An exception is
coidosis (Chapter 73), Sjögren disease (Chapter 54), systemic the systemic JIA (sJIA) category, which resembles an autoinflam-
6
lupus erythematosus (SLE) (Chapter 51), Lyme disease (Chapter matory disorder rather than a solely autoimmune process. Unlike
28), dermatomyositis (Chapter 56), and a variety of vasculitides autoimmunity, which is believed to be the result of an imperfect
(Chapters 58 and 59) may all present as chronic arthritis in adaptive immune system, autoinflammatory conditions are
childhood. JIA, by definition, is idiopathic; however, chronic thought to result from genetic perturbations in the innate immune
arthritis as part of inflammatory bowel disease (IBD) (Chapter response. Many autoinflammatory recurrent fever syndromes
75) or associated with psoriasis (Chapter 64) is categorized under have been identified as resulting from single gene defects, such
the JIA umbrella. When considering the seven categories of JIA as pyrin in familial Mediterranean fever (FMF), and tumor
together, the estimated prevalence of JIA is roughly 1 in 1000 necrosis factor (TNF) receptor in TNFR1-associated periodic
6
children, with rates varying in different regions of the world, syndrome (TRAPS) (Chapter 60). Whether sJIA is the result
likely because of genetic risk factors and/or environmental triggers. of a single gene defect or is one of many potential single gene
Moreover, the relative rates of JIA categories vary in different defects in the same immune pathway is currently unknown.
regions of the world (e.g., oligoarticular JIA is very common in However, a common complication of sJIA is the life-threatening
Scandinavia, and enthesitis-related JIA is more typical in Latin condition of macrophage activation syndrome (MAS), which
America). resembles familial hemophagocytic lymphohistiocytosis (fHLH)
(Fig. 53.1). MAS may be present in ≈50% of children with sJIA
ETIOLOGY AND PATHOGENESIS in either an overt or occult/subclinical fashion. Recently, genetic
7
polymorphisms and heterozygous (single copy) mutations in
Genetic Contribution genes associated with fHLH when present as homozygous defects
7
Because JIA is an eclectic group of disorders with joint inflam- have been identified in children with sJIA and overt MAS. Protein
mation, is far less common than RA, and is classified into unique products of these genes, including perforin 1 and MUNC 13-4,
categories based largely on subjective clinical phenotypes, are critical in the pathway mediating cytolysis by CD8 T cells
understanding its genetic causes is extremely difficult. Indeed, and natural killer (NK) cells (Chapter 17). This cytolysis is crucial
the relatively arbitrary distinction of having ≤4clinically arthritic to the ability to shut down an immune response following control
joints to be considered as oligoarticular JIA is influenced by of infection. Defects in this pathway can result in a hyperinflam-
whether temporomandibular joint (TMJ) arthritis (or in essence matory state (cytokine storm) leading to pancytopenia, coagu-
7
any other suspected joint involvement) is screened for with lopathy, and multisystem organ failure. The most common
magnetic resonance imaging (MRI) because clinical examination condition resulting in MAS during childhood is sJIA. Therefore
2
is neither sensitive nor specific for diagnosing TMJ arthritis. sJIA may be genetically related to fHLH but associated with
723

724 Part six Systemic Immune Diseases



TABLE 53.1 Clinical and Laboratory Features of the Juvenile idiopathic arthritis
(Jia) Categories

Jia
Classifications Former Juvenile rheumatoid arthritis (Jra) spondyloarthropathy
+
−
JIA categories/ Systemic RF polyarticular RF polyarticular Oligoarticular Psoriatic (early Enthesitis-related arthritis (ERA)
features (persistent & and late onset) (including ankylosing spondylitis (AS)
extended) and inflammatory bowel disease [IBD])
Human leukocyte DRB1*11 DRB1*08 DRB1*04 A2 DRB1*01 B27
antigen (HLA)
Gender Equal F≫M F≫M F≫M F>M M≫F
Age at onset Peak 2 years Dual peaks Teenage 1–3 years Dual peaks Teenage
Antinuclear antibody Rare Yes Yes Yes Yes Rare
(ANA)
Uveitis Rare Yes Yes Yes Yes Non-silent
Temporomandibular Yes Yes Yes Yes Yes Yes
joint (TMJ)
Enthesitis No No No No Older age Yes
Arthritis Erosive Symmetric Erosive Mixed Dactylitis Axial



in the development of sJIA are additional arguments to consider
sJIA as autoinflammatory rather than autoimmune.
In contrast, enthesitis-related arthritis (ERA) and psoriatic
JIA share one of the strongest known MHC associations, HLA-B27,
for any described autoimmune disorder. HLA-B27 is present in
70–90% of Caucasian children with ERA. Inheritance of ERA
follows an autosomal dominant pattern and is the only JIA
category likely to have similarly afflicted first-degree relatives.
The pathophysiological explanation for the association of
HLA-B27 remains unknown, but hypotheses vary from molecular
mimicry of pathogens presented by HLA-B27 (Chapter 50) to
8
the unfolded protein response. The remaining JIA categories
have all been linked to various other MHC proteins to lesser
degrees (see Table 53.1).
Non-HLA Associations
Genes outside of the MHC have also been linked to developing
FiG 53.1 Hemophagocytosis as Part of Macrophage Activation JIA. Genetic approaches have highlighted the importance of
Syndrome (MAS). A centrally located, vacuolated histiocyte is genetic differences in the development of JIA, but at most, 11%
5
pictured engulfing numerous nucleated immune cells and non- of the contribution can be linked to the MHC. Recent develop-
nucleated mature red blood cells. Wright stain at ×198 magnifica- ments in high-throughput genetic sequencing combined with
tion. (Courtesy of Dr. David Kelly.) the identification of densely present restriction fragment length
polymorphisms (RFLPs) throughout the human genome have
allowed for powerful new genetic approaches. These include
genome-wide association studies (GWAS) designed to identify
genes associated with a variety of disorders, including autoimmune
9
heterozygous, rather than homozygous, mutations in genes critical diseases, such as JIA. To date, several genes have been reported
for cytolysis. 7 to be associated with JIA. 5
Strong evidence that genetic factors contribute to JIA sus-
HLA Associations ceptibility include twin and family studies. Data from a JIA
For all other JIA categories, polygenic influences, including national registry revealed that monozygotic twin pairs have a
the major histocompatibility complex (MHC), contribute to higher-than-expected proportion of twins with JIA. Moreover,
disease pathology. The MHC is complex and densely packed siblings of children with JIA have as high as a 30-fold increased
(>200 genes) with immune-associated genes (Chapter 5). The risk of JIA compared with the general population. Interestingly,
MHC is also the most polymorphic region of the human genome siblings with JIA typically share the same JIA category, age of
5
and gives rise to MHC class I and class II genes, complement onset, and disease course. Polymorphisms in MHC class II genes
proteins, TNF, and others. The critical role of MHC proteins have been estimated to account for <20% of the recurrence risk
in preventing autoimmunity by shaping the T-cell repertoire of JIA in siblings and thus support the concept that JIA is a
(Chapter 8) likely explains why the MHC is the most consistently complex genetic trait. JIA likely shares general or common
and strongly associated genetic locus for most JIA categories. autoimmunity gene risk factors with many autoimmune disorders
However, weak MHC associations and lack of gender predilection but may also be influenced by specific JIA risk-associated genes. 9

CHaPtEr 53 Juvenile Idiopathic Arthritis 725


+
Using linkage and association studies, researchers have identi- found in a partially overlapping subset of children with RF
15
fied a variety of potentially JIA-associated genes. However, outside poly-JIA. Thus a variety of autoantibodies are associated with
of the HLA genes, only a small percentage of these genes have JIA.
been independently confirmed by other investigators. A few of
the independently confirmed JIA-associated genes/gene products T-Helper Cells
include PTPN22 (a phosphatase involved in inhibition of T-cell T lymphocytes are also thought to play a major role in the
activation), WISP3 (a signaling protein), interleukin-1α (a development of JIA as evidenced by their relative predominance
proinflammatory cytokine), TNF (another proinflammatory among mononuclear cells in synovial fluid of chronically inflamed
cytokine), macrophage migratory inhibitory factor (MIF), and joints in children with JIA. CD4 T-helper (Th) cells have been
SLC11A1 (a resistance factor to intracellular pathogens in categorized into a variety of cytokine-producing subsets (Chapter
5
macrophages). Thus gene products linked to both innate and 16). CD4 Th1 cells characterized by the production of interferon-γ
adaptive immune responses likely contribute to JIA disease (IFN-γ) have been identified in chronically inflamed joints in
susceptibility. Ongoing GWAS may help validate the importance children with JIA, whereas IL-4–producing Th2 CD4 T cells are
of these genes and may identify other candidate gene risk factors more commonly involved in the joints in oligoarticular JIA
for JIA in the near future. Recently, epigenetic (modifications (generally less aggressive arthritis) than in polyarticular JIA. More
to DNA nucleotides rather than changes in the DNA sequence) recently, two relatively newly described CD4 Th subsets, regulatory
risk factors that confer susceptibility to JIA are beginning to be T cells (Tregs) and Th17 cells, are being examined as potential
explored. 10 players in JIA pathology.
+
CD4 , CD25 high Tregs are characterized by the transcription
ENVIRONMENTAL FACTORS factor, FoxP3, and by the ability to suppress immune activation
16
(Chapter 18). The ability of Tregs to suppress other T cells
In addition to genetic factors, there are likely a variety of envi- likely occurs by both cell-contact dependent (through the surface
ronmental triggers for developing JIA in genetically susceptible protein cytotoxic T lymphocyte antigen-4 [CTLA-4]) and
16
hosts. A number of infectious agents have been explored as risk independent (via suppressive cytokines) mechanisms. Tregs
factors for development of JIA. Perhaps two of the best studied secrete the antiinflammatory cytokines, IL-10 and transforming
have been parvovirus and rubella virus infections. However, growth factor-β (TGF-β). Th17 cells, characterized by the
replication of these associations has been difficult. In addition, transcription factor, retinoid orphan receptor (ROR)γT, produce
17
some scientists have suggested that heat shock proteins, resulting the proinflammatory cytokine, IL-17. IL-17 is thought to
from cells undergoing environmental stress, may contribute to contribute to a variety of autoimmune disorders, including JIA.
11
the development of JIA. There is also a clear link between gut The balance between these two juxtaposed Th subsets may
pathogens and potentially commensal organisms (gut microbi- determine whether autoimmunity develops (Th17-dominant)
ome) and the development of HLA-B27–associated spondylo- or a state of immune tolerance to self (Chapter 12) persists
12
arthropathies. Last, prior to the identification of Borrelia as a (Treg-dominant). Indeed, recent studies have identified a pre-
cause of childhood arthritis, Lyme disease associated arthritis dominance of Th17 cells and associated proinflammatory
17
13
was difficult to distinguish from oligoarticular JIA. Perhaps cytokines in the inflamed joints of children with JIA. Thus a
because there a variety of potential environmental triggers for balance of proinflammatory cytokines and suppressive cytokines
JIA, combined with the number of different JIA categories, no may dictate the expression of autoimmunity in the form of JIA.
single environmental trigger has been conclusively identified as
contributing to the development of JIA. Cytokines
Cytokines (Chapter 9), and particularly their inhibition, have
IMMUNE ABNORMALITIES taken a prominent status in the pathology and treatment of
chronic arthritis, including JIA. The bench-to-bedside translation
Autoantibodies of anti-TNF therapy to the treatment of chronic arthritis has
As JIA is considered an autoimmune disease, except for sJIA as revolutionized the care of adults with chronic arthritis, as well as
discussed earlier, there have been a variety of explorations into children with JIA. Inhibition of this proinflammatory cytokine
the role of various components of the immune system involved in the circulation (via specific monoclonal antibodies [mAb]
in JIA pathogenesis. The importance of the immune system in or receptor fusion proteins) rapidly and effectively treats most
1
JIA pathology is highlighted by the increased incidence of child- forms of JIA. The one exception is sJIA, which may or may not
hood chronic arthritis among children with various immuno- respond to anti-TNF treatment. However, other proinflammatory
deficiencies. For example, children with immunoglobulin A (IgA) cytokines, including IL-1, -6, and -18, are thought to be central to
1
deficiency are at increased risk of developing chronic arthritis. sJIA pathogenesis. Indeed, serum from sJIA patients was shown
In contrast, the presence of specific autoantibodies is associated to induce transcription of a variety of innate immunity genes,
with various forms of JIA. ANAs are present in up to 40% of including IL-1, in normal peripheral blood mononuclear cells.
patients with JIA, particularly those with oligoarticular JIA and Fortunately, novel therapies that target either IL-1 or IL-6 have
14
are associated with silent uveitis (Chapter 74). Similarly, antibod- proven highly successful in treating even the most severe forms
ies to the nuclear oncoprotein DEK have been associated with of sJIA, including associated macrophage activation syndrome
uveitis as well as joint inflammation in children with JIA. IgM (MAS). 1,7
rheumatoid factor (RF) is present in a smaller subset of children
with polyarticular JIA and is associated with a more aggressive/ Macrophage Activation Syndrome
erosive form of arthritis as in adults with rheumatoid factor– The sometimes fatal complication MAS is most commonly seen
+
1
positive (RF ) RA (Chapter 52). More recently, identification in sJIA among rheumatic diseases. Clinically, MAS resembles
of anti–cyclic citrullinated peptide (CCP) antibodies have been many features of a sJIA disease flare-up, and it has been suggested

726 Part six Systemic Immune Diseases



KEY CONCEPts JIA category affecting boys more than girls—ERA, with inflam-
Macrophage Activation Syndrome (MAS) mation of the entheses, attachments of the tendons, and ligaments
8
to bone (see Table 53.1). An important finding of recent years
• MAS is present in up to 50% of children with systemic juvenile idiopathic is that imaging (MRI and, in certain cases, ultrasonography) can
arthritis (sJIA) in a subclinical or overt (10%) form. identify ongoing inflammation in clinically asymptomatic joints.
• MAS manifests as fever, liver dysfunction, pancytopenia, central nervous This has led to screening for TMJ inflammation primarily with
system disturbance, hyperferritinemia, hemophagocytosis, and MRI, as arthritis of this joint is frequently clinically silent but
coagulopathy. capable of resulting in facial dysmorphism from micrognathia
• MAS resembles hemophagocytic lymphohistiocytosis (HLH) and is in all JIA categories, including oligoarticular JIA. 2
thought to result from defects in perforin-mediated cytolysis by CD8
T cells and natural killer (NK) cells.
• Patients with sJIA and MAS have been noted to have NK-cell defects Oligoarticular JIA
and mutations in perforin-1 and MUNC13-4 cytolytic pathway genes. Oligoarticular JIA is likely the most common category of JIA,
• MAS can be fatal if not recognized and treated early. Mainstays of affecting children who have 1–4 joints inflamed, most commonly
therapy include high-dose corticosteroids and cyclosporine. knees, ankles, the TMJ, and fingers. The archetype of this group
1
• Recently, interleukin-1 (IL-1) blockade with biological therapies has is a preschool-aged, blonde-haired, blue-eyed girl who limps
been found to be quickly and dramatically beneficial in treating MAS
associated with sJIA. and has swollen knees. The diagnosis of arthritis may be delayed,
as it is often painless. Because of this, by the time she is seen in
the medical office, she may already have developed bony hyper-
trophy and limb length discrepancy, as chronic articular inflam-
that MAS may be inherent to sJIA disease pathology in up to mation stimulates the osteoblasts of the nearby growth plates.
7
half of all patients with sJIA. MAS is likely part of the spectrum In addition, there is often notable muscle wasting around the
of HLH disorders. Primary HLH, or fHLH, typically presents arthritic joint that can last into adulthood. The oligoarticular
in infancy following infection and results from homozygous JIA category has the highest percentage of positive ANA blood
14
mutations in genes involved in the cytolytic pathway employed tests and associated potentially damaging silent uveitis. Mono-
by NK cells and CD8 T cells. Recent evidence suggests that patients articular involvement calls for a careful differential diagnosis.
with sJIA who have MAS have heterozygous defects in these JIA rarely presents with isolated hip involvement; toxic synovitis,
18
same cytolytic pathway genes. MAS can be triggered by a variety septic hip, and malignancy all need to be considered. Oligoar-
of infectious organisms, particularly members of the herpes virus ticular JIA is also quite uncommon in middle and high school
family, but the precise role of infectious triggers of MAS in aged children, where the diagnosis of reactive arthritis, IBD-related
children with sJIA remains unknown. Nevertheless, the inability arthritis, and Lyme disease should be entertained. The ILAR
to effectively shut down an immune response via cytolytic classification has a separate sub-category for children who develop
mechanisms results in a “storm” of proinflammatory cytokines, additional joint involvement after the first 6 months based on
1
such as IL-1, IL-6, IL-18, TNF, and IFN-γ. Mouse models of clinical presentation, extended oligoarticular JIA, which might
MAS/HLH have suggested that IFN-γ is the pivotal cytokine in be a variant of the RF-negative polyarticular category. Wrist
MAS. In practical terms, inhibition of IL-1, and potentially of involvement is considered to be a bad prognostic factor, as is
IL-6, has proven rather effective at treating MAS in children the extended oligoarticular phenotype, and elevated laboratory
with sJIA. 1,7,18 It is quite remarkable how dampening of one indicators of inflammation.
critical cytokine can help restore the immune imbalance of
multiple proinflammatory cytokines and rapidly reverse the Polyarticular JIA
life-threatening clinical scenario of MAS. Arthritis of ≥5 joints includes two main JIA categories (see Table
53.1) based on the presence of serum RF, an IgM antibody against
JIA CLINICAL SUBTYPES the IgG Fc receptor.
RF-positive serum on two occasions at least 3 months apart
+
As already mentioned, JIA is a group of chronic inflammatory is required for a child to be diagnosed with RF polyarticular
joint diseases, which last for at least 6 weeks and commence JIA. Joint involvement is typically bilateral and symmetrical,
1
prior to the age of 16 years with no identifiable cause. There is involving the small joints of hands and feet. However, large
+
heterogeneity of clinical presentation and progression of the joints and cervical involvement are often present. RF polyarticular
various subtypes, which is largely addressed by the International JIA usually presents in adolescent girls and is considered a form
1
League Against Rheumatism (ILAR) classification schema (see of early-onset adult RA. It is a relatively infrequent category of
Table 53.1). Nevertheless, as more information about genetic JIA with <5 % of all patients with JIA classified in this category.
factors, response to medication, and subsequent outcomes Antibodies to CCP are much less common in children with
15
becomes available from multicenter studies, revisiting the clas- polyarticular JIA than in adults, but affected children usually
sification in the near future seems inevitable. A recent elegant have active arthritis for many years. The presence of RF predicts
report has suggested five distinct groups of patients categorized more destructive/erosive disease calling for early aggressive
on the basis of clinical disease trajectories, all with subsets different therapy. As in adult RA, arthritis of the wrists and fingers can
from those defined by the ILAR classification. 4 lead to ulnar deviation and boutonniere and swan neck deformi-
2
The current classification of JIA relies heavily on the number ties. Destructive TMJ involvement is also common. Similar to
+
of the joints involved (≤4in oligoarticular JIA; ≥5 in polyarticular adult RA, RF polyarticular JIA in children commonly has
1
JIA, with or without the presence of RF). Other categories of JIA extraarticular manifestations, such as low-grade fever and
are also classified on the basis of associated symptoms and signs, occasionally rheumatoid nodules over bony surfaces.
including fever, rash, and laboratory indicators of inflammation in RF-negative polyarticular JIA usually presents as asymmetrical
sJIA, or associated diseases, such as psoriasis. There is a separate involvement of the large joints, mostly knees, wrists, and ankles.

CHaPtEr 53 Juvenile Idiopathic Arthritis 727


As in psoriatic JIA, small joint involvement tends to occur later in typical at onset and may subside later in the disease. Arthritis
−
life. Another similarity between psoriatic JIA and RF polyarticular is often very aggressive and frequently involves wrists, ankles,
JIA is the bimodal distribution in preschool children and early and knees but also causes ankylosis of the hip and neck leading
1
adolescent patients. There is more frequent silent uveitis in the to long-term damage and gait abnormalities. Occasionally, joint
former group, and this form of JIA is often difficult to distinguish involvement begins months after fever onset, making sJIA
from ERA in the latter. TMJ inflammation occurs frequently, diagnosis more difficult. The initial presentation mimics those
leading to condylar damage and facial dysmorphism. 2 of infections and malignancies, and this has to be taken into
consideration, as sJIA is a diagnosis of exclusion. Fifty percent
Psoriatic Arthritis of children may develop (only 10% clinically overt) MAS,
Arthritis with concurrent psoriasis, or arthritis with two of three described previously. 7
factors—dactylitis, psoriatic nail changes, or family history of a
first-degree relative with psoriasis—comprises a separate category Laboratory Evaluation
of JIA. There seems to be a bimodal distribution of age at onset There is no one laboratory indicator that will establish or rule
19
for psoriatic JIA. Preschool-aged children have mostly large out chronic arthritis per se. The complete blood count (CBC)
joint involvement like those in the oligoarticular category but is largely normal in oligoarticular involvement, as is the eryth-
may also have dactylitis, whereas middle school–aged patients rocyte sedimentation rate (ESR). White blood cells (WBCs) are
have JIA that resembles ERA with enthesitis, sacroiliac joint highly elevated in sJIA but are mostly within normal limits in
8
involvement (albeit milder), and even spondylitis. In general, other groups. Anemia of chronic disease presents as normocytic
there is asymmetrical involvement of the joints, and if untreated, and normochromic and is often found in polyarticular involve-
it will progress to polyarticular joint disease. Since up to 50% ment. In those cases, the ESR can also be elevated. Intermittent
of the patients develop psoriatic skin findings several years after joint effusion of a single large joint with an elevated ESR neces-
arthritis presentation, it is often difficult to diagnose this condition sitates further evaluation, and IBD should be considered, especially
at onset. It is important to carefully examine children with JIA if there is a low serum albumin level and/or growth delay. Of
for dactylitis (tenosynovitis causing swelling of the digit beyond note, elevated ESR on presentation predicts a worse outcome
the joint capsule) and nail pits and onycholysis. Psoriatic JIA for those with the oligoarticular subtype. The platelet count, as
seems to be more resistant to therapy, and approximately 40% a marker of inflammation, can be elevated in polyarticular disease
of children have active disease into adulthood while on medica- and substantially so in sJIA.
tions. Insidious onset of anterior uveitis is more typical for the Liver function tests are used for monitoring certain disease
younger age group, whereas those with enthesitis have JIA that modifying antirheumatic drugs (DMARDs), such as methotrexate
resembles the adult type of psoriatic arthritis with an associated and leflunomide. They can be elevated as a result of prolonged,
HLA-B27 genotype and chronic symptomatic, often painful, eye and frequently concomitant, use of nonsteroidal antiinflammatory
disease (see Table 53.1). drugs (NSAIDs).
As mentioned above, in 10% of patients, sJIA can progress
Enthesitis-Related Arthritis to overt MAS. Ferritin, an acute-phase reactant, is a very sensitive
1
ERA affects boys more than girls and may sometimes be a indicator of this condition. A sudden drop of at least two cell
manifestation of IBD. Entheses are the attachments of the tendons, lines in the CBC, a rising cross-reactive protein (CRP) level with
ligaments, or joint capsules to bone. These can be tender even in decreasing ESR, elevated liver transaminases, prolonged pro-
healthy children, but usually ≥3 tender entheses are associated thrombin or partial thromboplastin times, high D-dimer levels,
with disease (see Table 53.1). ERA often occurs in boys 8 years elevated triglycerides, and low fibrinogen should all alert caregivers
1,8
of age and older. They typically complain of joint pain related about the likelihood of MAS in a child with sJIA. 7
to playing sports, but there is also morning stiffness and pain Although 75–85% of adult patients with RA have either a RF
that gets better during the day and worsens toward the end of or CCP antibodies, <5% of patients with JIA have the RF, and
the day or after engaging in a lot of activities. Many consider those are mostly patients with early-onset RA, often teenage girls
ERA a potential prelude to ankylosing spondylitis (Chapter 57), with symmetrical small joint involvement. Another rather fre-
a HLA-B27–associated inflammatory condition resulting in quently ordered test is the serum ANA titer. Similar to the RF,
irreversible fusion of the vertebrae. Recent therapeutic efforts are ANA is not suitable for screening, as it is of no diagnostic utility
20
focusing on preventing the calcifying hypercorrection of inflamed in either making or excluding a diagnosis of JIA. ANA serves
vertebral edges using TNF blockade. Outcomes are still under as a prognostic factor by identifying patients already diagnosed
investigation but appear promising with early treatment. with JIA who have the highest risk for developing uveitis. 3,14 In
addition, ANA levels may alert the clinician to the possibility of
Systemic JIA juvenile Sjögren disease or SLE being the etiology for the chronic
Approximately 10% of children with chronic arthritis belong to arthritis.
the sJIA category, also known as Still disease. The peak incidence The prevalence of the HLA-B27 antigen is 8% in the general
of sJIA is ages 1–5 years, but it can present in adulthood. The Caucasian population but nearly 90% in the ankylosing spondylitis
8
ILAR criteria to classify sJIA require fever for 2 weeks, with at group. HLA-B27 is useful to predict axial involvement in ERA,
least three episodes of daily spiking (quotidian) fever, with at psoriatic JIA, and IBD-related arthritis but should be evaluated
least one of the following: fleeting pink macular rash, arthritis, in patients with clinically established arthritis and/or enthesitis,
1
lymphadenopathy, and hepatosplenomegaly. When febrile, rather than as a routine screening test during a workup for
children appear rather ill, and the rash is more prominent and back pain.
can be evoked by contact (Koebner phenomenon). Typically, the Additional laboratory indicators may be helpful. Elevated
fever subsides, and children are visibly better in the morning serum lactate dehydrogenase and uric acid levels may indicate
hours. High levels of indicators of systemic inflammation are malignancy. Elevated angiotensin converting enzyme (ACE) and

728 Part six Systemic Immune Diseases


lysozyme levels are useful when considering sarcoidosis as the
etiology of childhood arthritis and uveitis in early-onset sar-
coidosis cases, but noncaseating granulomas seen on biopsy are
much more revealing. As for imaging techniques, radiography
can be helpful in ruling out structural changes resulting from
disease processes other than arthritic disease. Nevertheless,
periarticular osteopenia is commonly seen around an inflamed
joint. The clinical presentation usually precedes the development
of bony erosions, but sclerosis of the sacroiliac joint may indicate
axial involvement in patients with ERA. The role of ultrasonog-
raphy for diagnosis and monitoring of disease progression in
pediatric patients is promising, but further establishment of
normative data is still required. MRI, with and without intra-
venous contrast, may help identify synovitis, but even this imaging
modality can sometimes yield false-positive results in certain
joints in otherwise healthy children. 8,21,22

DIFFERENTIAL DIAGNOSIS

A wide variety of conditions can mimic the symptoms and signs FiG 53.2 Posterior synechia, a complication of chronic anterior
of JIA. Although both acute and chronic arthritis may present uveitis, is associated with several categories of juvenile idiopathic
with joint pain, tenderness, swelling, and warmth, a single acutely arthritis (JIA). The irregularities of the inner margins of the iris
involved joint at onset should be considered septic until proven reflect fibrous adhesions between the iris and lens capsule.
otherwise. Septic arthritis frequently has an erythematous dis- (Courtesy of Dr. Scott Olitsky.)
coloration of skin, whereas JIA does not. Prompt evaluation
with arthrocentesis is necessary, especially in indeterminate cases.
Infection of the joint may lead not only to rapid destruction of knee pain without improvement in teenagers could be caused
the joint but also to systemic dissemination of infection. Specifi- by osteochondritis dissecans. Other common causes of teenage
cally, Kingella species should be considered in painful monoar- knee pain include Osgood-Schlatter disease and patellofemoral
ticular cases of young children when symptoms have sudden syndrome.
onset without prolonged morning stiffness.
Parainfectious arthritis, often resulting from viral disease, is Clinically Silent Complications
usually short-lived and typically requires only NSAID treatment. There are two common findings that present insidiously during
In contrast, Lyme disease is characterized by a chronic extensively the course of JIA and yet can cause major damage/morbidity—
13
swollen joint(s), commonly the knee. It appears several weeks uveitis and TMJ arthritis. Uveitis is a relatively common complica-
to months after the usually unnoticed tick bite and should be tion of JIA with potentially long-term morbidity. Risk factors
considered in areas of high incidence (e.g., northeastern United for uveitis among patients with JIA include young age of onset,
14
States). There are a few diseases associated with migratory arthritis, positivity for ANA, oligoarticular disease, and female sex. It
including malignancy, gonococcal arthritis, and rheumatic fever usually presents as iridocyclitis, but the choroid may also be
arthritis, the last having a typically very tender, red, hot joint affected. Although extremely rare in sJIA, approximately 20%
persisting in each location for a couple of hours before moving of patients with oligoarticular JIA and 5% of patients with
14
to another. polyarticular JIA develop eye inflammation. Some children
As sJIA is a diagnosis by exclusion, multiple other etiologies with psoriatic JIA are also at risk of developing silent uveitis,
19
of systemic inflammation should be considered. Fever and elevated especially in the ANA-positive subgroup. Uveitis may lead to
WBCs, platelets, and ESR may accompany polyarteritis nodosa, a great deal of morbidity, including cataracts, increased intraocular
Kawasaki disease, Henoch-Schönlein purpura, and other vascu- pressure, band keratopathy, and posterior synechiae (Fig. 53.2),
14
litides. Ehrlichiosis and recurrent fever syndromes (e.g., familial with decreased vision developing in up to 40%. The danger of
Mediterranean fever, TNF receptor–associated periodic fever most JIA-associated uveitis is its asymptomatic presentation, with
syndrome) may also manifest as systemic inflammation, arthral- the exception of symptomatic uveitis in children with ERA.
gias, and rashes. A typically nonerosive symmetric arthritis may Considering that the highest prevalence is in patients with oli-
occur in SLE, often with cytopenias. Arthritis is also seen in goarticular JIA, which is most common in preschool and younger
related diseases (e.g., Sjögren syndrome, mixed connective tissue children, it is not surprising that many of the cases go unnoticed.
disease [MCTD]), and evidence of antibodies to extractable A routine ophthalmological examination may fail to detect uveitis,
nuclear antigens are common in SLE (anti-Smith, anti–double- and children need to have a formal slit-lamp examination to
14
stranded DNA) and MCTD (anti–ribonuclear protein [RNP]). identify inflammatory cells. The most common presenting signs
Patients presenting with joint pain only, without associated are synechiae (an irregular iris border resulting from adhesions
swelling or morning stiffness, most commonly have overuse to the lens), hypopyon, and band keratopathy (see Fig. 53.2).
23
syndromes or benign hypermobility syndrome. Little league Uveitis may develop many months or years after joint symptoms,
shoulder and elbow are rather common in middle school–aged and therefore close follow-up is warranted. ANA positivity and
baseball players; wrist pain occurs in gymnasts frequently. Pain young age are associated with increased incidence; thus ANA-
in the hip, without morning stiffness, may indicate Legg-Calve- positive children with oligoarticular JIA need to be screened the
Perthes disease or slipped capital femoral epiphysis. Relentless most often, but those in other categories should be followed up

CHaPtEr 53 Juvenile Idiopathic Arthritis 729


14
on a set schedule as well. Failure to do so and missed eye TREATMENT
involvement may lead to the occurrence of cataracts, glaucoma,
impaired vision, and even blindness. Overview
Despite significant advances in the understanding of the patho-
KEY CONCEPts genesis of JIA, there are currently no curative treatments. JIA
Temporomandibular Joint (TMJ) Arthritis frequently persists into adulthood and may result in significant
morbidity, including physical disability. The objective of treatment
• TMJ arthritis is extremely common, present in up to 80% of children is to prevent disability and preserve normal growth and develop-
with juvenile idiopathic arthritis (JIA). It is typically asymptomatic and ment while providing relief of symptoms and improved quality
thus requires early screening with magnetic resonance imaging (MRI) of life by controlling the inflammatory process. 1
with contrast. Over the past 15 years, remarkable advances have been made
• TMJ arthritis is often active despite therapy with disease-modifying 1
antirheumatic drugs (DMARDs) and biologicals (e.g., methotrexate in the treatment of JIA. Chief among these advances was the
plus tumor necrosis factor [TNF] inhibitors) and thus treatment with advent of targeted biological therapeutic agents (Table 53.2)
intraarticular long-acting corticosteroids or TNF inhibitors may help (Chapter 89). These agents have been shown to be quite beneficial
prevent mandibular growth damage and associated micrognathia and against active disease and are generally well tolerated. The early
1
facial dysmorphology. initiation of biological therapeutic agents may, in fact, alter and
1
improve the subsequent disease course. These new breakthroughs
Another frequently asymptomatic complication of JIA is TMJ have prompted pediatric rheumatologists to “invert the treatment
arthritis. TMJ arthritis in children with JIA has been recognized pyramid,” that is, to rapidly incorporate more effective therapeutic
increasingly in recent years as a joint inflammation leading to agents instead of slowly progressing to them in a stepwise fashion. 1
2
silent destruction and facial deformity despite systemic therapy.
TMJ arthritis is quite common, with 40–80% of all patients with tHEraPEUtiC PriNCiPLEs
2
JIA patients affected. The overall true prevalence is likely closer Early Aggressive Therapy
to the higher range, since not all children with JIA receive TMJ
MRI screening, which frequently reveals synovial thickening (Fig. • Accumulating evidence suggests that early aggressive therapy that
53.3) at disease onset, and premicrognathic arthritis may be includes targeted biological agents near the time of clinical diagnosis
missed. 2,22 The highest rates of TMJ arthritis have been found (during the “window of opportunity”) may improve the future disease
in the extended oligoarticular JIA and RF-negative polyarticular course.
JIA groups, as well as in children with upper extremity and neck
2
involvement, as well as an elevated ESR. Currently, intraarticular In response to the growing number of treatment options for
corticosteroid injection seems to be beneficial in certain cases, JIA and the advent of the biological therapeutics, the American
whereas TMJ arthritis often develops despite systemic use of College of Rheumatology (ACR) issued Recommendations for
24
2
methotrexate and TNF inhibitors. TMJ arthritis needs to be the Treatment of JIA in 2011. These recommendations were
recognized early in children with JIA so that it can be treated developed by using a rigorous methodology to produce evidence-
prior to growth disturbance. based and consensus-based guidance that reflected the current
state of the field. The guidelines were updated in 2013 to include
advances in the treatment of sJIA. 25
With new and effective therapies continuing to be introduced
to the therapeutic armamentarium, treatment goals have become
elevated and more stringent. The current goal is to achieve a
26
status of clinically inactive disease, that is, the absence of any
significant signs or symptoms of active arthritis. Although cur-
rently this is not possible for all children, until that becomes a
reality, curative therapy for JIA (achievement of inactive disease
status) for as many children as possible remains the goal.
Recent advances in the treatment of adults with inflammatory
arthritis have elucidated some differences in the effectiveness of
specific biological agents for specific forms of arthritis. For
example, many non-TNF inhibitor biologicals, such as abatacept,
rituximab, and tocilizumab, are highly effective in the treatment
of RA but are far less effective in the treatment of ankylosing
spondylitis. In contrast, some of the more recently introduced
biological agents, such as the IL-17 inhibitor secukinumab, appear
effective against ankylosing spondylitis but are likely less effective
for RA. 27
FiG 53.3 Acute and Chronic Temporomandibular Jaw (TMJ) Despite these recent advances, the treatment of JIA is not
Arthritis in a Child With Juvenile Idiopathic Arthritis (JIA). currently strongly influenced by the distinct categories of JIA, with
Synovial thickening and enhancement (long dashed arrow) and the exception of sJIA. For example, there are no specific therapies
mandibular condyle (“C”) flattening with contour irregularity/ currently approved for the treatment of children with psoriatic
erosion (short arrow) are noted in this parasagittal postcontrast arthritis as opposed to RF-negative polyarthritis. Accordingly, the
T1-weighted magnetic resonance imaging (MRI) image. (Courtesy discussion of treatment in this chapter will not detail all categories
of Dr. Dan Young.) of JIA but will focus rather on the “treatment groups” as defined

730 Part six Systemic Immune Diseases



TABLE 53.2 Biological therapeutic agents Used in the treatment of Juvenile idiopathic
arthritis (Jia)
Frequency of
Biological target Name structure administration route of administration
Tumor necrosis Etanercept TNF receptor-immunoglobulin G Twice weekly to weekly Subcutaneous (SQ) injection
factor (TNF) (IgG) fusion protein
Infliximab Monoclonal antibody (chimeric) Every 4–8 weeks Intravenous (IV) infusion
Adalimumab Monoclonal antibody (humanized) Every 1–2 weeks SQ injection
Golimumab Monoclonal antibody (humanized) Every 4 weeks SQ injection
Every 8 weeks IV infusion
Certolizumab pegol Monoclonal antibody (humanized Every 2 weeks SQ injection
and PEGylated)
CD80/86 Abatacept Cytotoxic T lymphocyte antigen-4 Every 4 weeks IV infusion SQ injection
(CTLA-4–IgG fusion protein Weekly
Interleukin-1 (IL-1) Anakinra Receptor antagonist Daily SQ injection
Canakinumab Monoclonal antibody (humanized) Every 8 weeks SQ injection
Rilonacept Receptor-fusion protein Weekly SQ injection
IL-6 receptor Tocilizumab Monoclonal antibody (humanized) Every 2–4 weeks IV infusion SQ injection
Every 1–2 weeks
+
CD20 B cells Rituximab Monoclonal antibody 2 infusions 2 weeks apart, IV infusion
repeat every 6 months
IL-12 and IL-23 Ustekinumab Monoclonal antibody Every 12 weeks SQ injection
IL-17A Secukinumab Monoclonal antibody Every 4 weeks SQ injection





24
by the 2011 ACR Recommendations for JIA treatment. As our form the foundation of therapy for children with mild or limited
knowledge about pathophysiology and response to treatment oligoarthritis. In addition, intraarticular injections may be effective
continues to expand, differential therapeutic approaches for the in children with more extensive arthritis and in those who are
disparate JIA phenotypes are eagerly anticipated. receiving concurrent systemic therapy. Randomized trials have
shown unequivocally that injected triamcinolone hexacetonide
Nonsteroidal Antiinflammatory Drugs has the longest duration of effect. 26
NSAIDs formed the foundation of the treatment of JIA for JIA also may be effectively treated with systemic glucocorti-
decades, and numerous NSAIDs have been shown to have coids. They are frequently used in the treatment of systemic
beneficial effects. In the absence of significant numbers of head- features of JIA and may form the foundation of the treatment
to-head trials, it is believed that in general all NSAIDs are similarly for the sJIA category, although biological therapies may signifi-
26
1
effective, although indomethacin is considered by some to be cantly lessen the need for this practice. The use of systemic
the most effective NSAID (especially in sJIA). One NSAID may glucocorticoids for the treatment of synovitis in children with
be found to be more effective than another for a particular JIA is not an uncommon practice. However, the risks, benefits,
individual child. and appropriate use of this approach are less clear. The recent
In general, NSAIDs are not considered to be disease-modifying 2011 ACR Recommendations for JIA treatment do not include
agents, that is, they are not felt to slow the progression of disease this use of systemic glucocorticoids because of the near-complete
24
or prevent the appearance of radiographic damage. For this absence of any published evidence. In general, most pediatric
reason, monotherapy with NSAIDs initially began to decline rheumatologists would agree that the use of DMARDs is preferable
with the advent of agents, such as methotrexate, that have been to the use of moderate-dose or high-dose systemic glucocorticoids
shown to modify the disease process. NSAIDs are frequently for the treatment of synovitis in JIA. The anticipated adverse
used for symptomatic relief, but most children who require daily effects of long-term use of moderate doses of glucocorticoids
chronic use of NSAIDs would likely benefit from the addition includes growth failure, osteoporosis, cataract formation, glau-
of systemic immunosuppression, such as from DMARDs. coma, hyperglycemia, hypertension, avascular necrosis of bone,
Gastrointestinal (GI) discomfort is a frequent adverse effect of striae, and others. 26
NSAID therapy, although frank GI bleeding appears to occur at
a lower incidence than in adults. Scarring pseudoporphyria of Nonbiological DMARDs
sun-exposed skin is another risk associated with NSAID use. The use of DMARDs was introduced in the 1980s (Chapter 87).
The long-term cardiovascular effects of NSAIDs in children have The most widely used and studied is methotrexate, which has
not been studied. been shown in randomized clinical trials to be efficacious in
1
treatment of JIA. Following these studies, methotrexate became
Glucocorticoids the cornerstone of therapy for many children with JIA. Methotrex-
Similar to many rheumatological diseases, JIA has been shown ate is typically administered weekly through either the oral or
to respond to treatment with glucocorticoids (Chapter 86). the subcutaneous route, although studies have shown subcutane-
Intraarticular glucocorticoid injections typically result in a ous methotrexate to be better absorbed and more effective. 1
near-immediate decrease in inflammation that is maintained Methotrexate may be associated with several typically
28
for many months. Accordingly, intraarticular injections may minor adverse effects, such as nausea and fatigue. Occasionally,

CHaPtEr 53 Juvenile Idiopathic Arthritis 731


methotrexate may cause liver toxicity, necessitating periodic
measurement of serum aminotransferase levels for routine Treatment of Oligoarthritis (Arthritis of ≤4 Joints)
monitoring. Because of fewer involved joints, oligoarthritis may generally be
Leflunomide has been shown to be slightly less efficacious viewed as a milder form of JIA. However, significant disability
1
than methotrexate in the treatment of JIA. It may serve as an can still occur, and children with this condition should not be
alternative therapy for children who are intolerant of methotrex- assumed to have had good clinical outcomes without proper
ate. Sulfasalazine is used, to varying degrees, by pediatric evaluation and therapy. The foundation of treatment for this
rheumatologists and may be of particular benefit to children JIA phenotype is intraarticular glucocorticoid injections. These
1
with JIA of the ERA category. Hydroxychloroquine monotherapy injections may be administered in multiple joints concurrently
28
has been demonstrated inefficacious in treating JIA. 1 and may be repeated, as needed. A good response typically
results in resolution of clinical signs and symptoms of arthritis
Biological DMARDs for 4–12 months. DMARD therapy should be initiated in children
The use of biological DMARDs for the treatment of JIA began who do not respond as desired to injections or who have more
24
in the late 1990s (Chapter 89). Etanercept, a TNF inhibitor, was significant arthritis. Methotrexate is typically the agent of first
the first studied and was shown to be efficacious in a randomized choice. Significant arthritis that does not respond adequately to
1
clinical trial. Additional TNF inhibitors have been introduced methotrexate can be treated with TNF inhibitors. 24
and used in the treatment of JIA; adalimumab was also shown
1
to be efficacious in a randomized clinical trial. Notable dif- Treatment of Polyarthritis (Arthritis of ≥5 Joints)
ferences have been discovered regarding the effectiveness of Methotrexate is currently recommended for nearly all children
24
the TNF receptor fusion protein (etanercept) and the mAbs with polyarthritis. If a brief trial of methotrexate proves
(adalimumab, infliximab, and others). mAb TNF inhibitors have inadequate to control the arthritis, then TNF inhibitors are
24
been shown to be effective against two important JIA-associated frequently recommended. If an adequate response to the initial
conditions—anterior uveitis and IBD. Receptor fusion proteins TNF inhibitor is not seen, then switching to another of the TNF
24
have been shown to be far less effective in treating these condi- inhibitors or switching to abatacept is currently recommended.
tions. The precise mechanism for these differences in treatment The most appropriate role of other effective biological DMARDs,
effectiveness is not clear but may be related to the ability of such as tocilizumab (see Table 53.2), in the treatment of poly-
etanercept to bind lymphotoxin or the ability to bind surface articular JIA has yet to be clearly defined.
membrane-bound TNF. 29
Because the TNF inhibitors are large proteins, they must be Treatment of Arthritis Involving Specific Joints
administered parenterally, either by subcutaneous injection or Arthritis involving the TMJ, hip, and sacroiliac joints may deserve
intravenous infusion (see Table 53.2). TNF inhibitors are not special therapy. Destructive arthritis of the TMJ among children
generally associated with common medication adverse effects, with JIA has been noted for decades. Clinical evaluation of this
such as headache or nausea, although they may result in injection joint is particularly challenging, as symptoms are often absent
site or infusion reactions. There appears to be a modest increase initially, and physical examination findings may be normal.
in the incidence of bacterial infections associated with TNF Accordingly, the optimal treatment for TMJ arthritis is unclear.
30
inhibitor use and a significant risk of reactivation of latent Many authors recommend targeted therapy with intraarticular
29
tuberculosis. Therefore individuals should be screened for glucocorticoid injections, similar to the treatment of arthritis
2
tuberculosis infection prior to initiating treatment with TNF in other joints. Increased systemic therapy is likely also appropri-
24
inhibitors. The possible association between TNF inhibitors ate, although TMJ arthritis has been known to demonstrate
and an increased rate of malignancy in JIA remains an open radiographic progression despite treatment with systemic TNF
question; however, currently, there is no convincing evidence of inhibitors and in the absence of signs of active synovitis of other
a strong increased risk of overall malignancy. 31 joints. 2,22
In addition to TNF inhibitors, the T-cell costimulation The presence of hip arthritis in JIA has been shown in
24
modulator abatacept has been shown in a randomized clinical several studies to portend a poor prognosis. Accordingly, many
1
trial to be efficacious in the treatment of JIA. Presumably, because authors advocate early intraarticular glucocorticoid injections
of the effectiveness of TNF inhibitors, the use of abatacept has and increased systemic therapy when active hip arthritis is
remained relatively limited in clinical practice. identified.
The B-cell–depleting agent rituximab has been minimally Sacroiliac arthritis is strongly associated with the development
1
studied in the treatment of JIA. However, it appears effective in of ankylosing spondylitis. Because axial arthritis has been shown
some instances, particularly in children who appear to have early- to be less responsive to methotrexate therapy, current recom-
+
onset RA (teenagers with RF and CCP-positive polyarthritis). mendations suggest a lower threshold for the initiation of TNF
24
The IL-1 inhibitor anakinra has been shown in both inhibitors when sacroiliac arthritis is present. However, early
uncontrolled and controlled studies to be particularly effective treatment with TNF inhibitors, or perhaps even newer biological
in the treatment of sJIA. 1,25 Similar to the experience in adults agents that inhibit IL-17 or IL-12/IL-23, may be optimal for the
with RA, anakinra appears less effective in treating synovitis treatment of spondyloarthritis to help prevent progression of
among children with the other categories of JIA. Additional ankylosis in children. 27
IL-1 inhibitors (rilonacept, canakinumab) are also now com-
mercially available and have been shown beneficial in clinical trials Treatment of Erosive Arthritis
treating sJIA. 1 It appears that not all children with JIA have the propensity to
Unlike other biological agents, the IL-6 inhibitor tocilizumab develop an erosive arthritis that is similar to that frequently seen
has been shown in randomized clinical trials to be efficacious in adults with RA. Children who develop erosions visualized on
in the treatment of both sJIA and polyarticular JIA. 1 plain radiographs are considered to have a worse prognosis, and

732 Part six Systemic Immune Diseases


the current recommendation is to increase the intensity of their management of children who attain prolonged inactive disease
treatment accordingly. 24 status will be an important future focus. 32
Treatment of Systemic Features of Systemic Arthritis TRANSLATIONAL RESEARCH
For decades, the mainstay of therapy for sJIA has been systemic
glucocorticoids and NSAIDs. Nearly all children with sJIA will
respond favorably to systemic glucocorticoids, if given in sufficient ON tHE HOriZON
doses. However, often children become “steroid dependent,” and
efforts to decrease the glucocorticoid burden to minimize adverse • Novel criteria for identifying macrophage activation syndrome (MAS)
effects have been unsuccessful. Presumably because of its different among children with systemic juvenile idiopathic arthritis (sJIA) have
been generated using real patient data that are diagnostically highly
pathogenesis, sJIA has not been shown to respond to TNF sensitive and specific.
inhibitors as favorably as the other categories of JIA. Instead, • Genetic screening for mutations in cytolytic pathway genes will help
IL-1 and IL-6 appear to be key cytokines in the disease process. identify those individuals at risk for developing MAS.
Accordingly, IL-1 (anakinra, canakinumab) and IL-6 (tocilizumab) • Murine models are paving the way for a better understanding of MAS
inhibitors are recommended as the first-line nonglucocorticoid immunopathology and potential pathways for clinical intervention.
treatments for sJIA. 25 • Clinical trials involving treatment of MAS with inhibitors of proinflam-
matory cytokines are just underway.
The appearance of clinically significant MAS generally requires
directed therapy. The typical treatment approach involves increased
systemic glucocorticoids. The calcineurin inhibitor cyclosporine The explosion in advances in immunology and genetics are
1,7
is frequently added, and some authors advocate IL-1 and IL-6 leading to major breakthroughs in therapy for rheumatic diseases,
1,7
inhibitors for treatment of MAS. In severe refractory cases, including JIA. Challenges remain, however, in diagnosing and
cytotoxic chemotherapeutic agents, such as cyclophosphamide treating MAS complicating sJIA. To distinguish a sJIA disease
or etoposide, may be warranted. flare-up from MAS, expert opinion and Delphi techniques are
currently being used to explore novel criteria for diagnosing
Treatment of Arthritis of Systemic Arthritis MAS in children with sJIA. Data collection regarding clinical,
Some children with sJIA will develop a chronic course of poly- laboratory, and pathological features of children with sJIA, with
arthritis with a relative absence of concurrent systemic features. and without MAS, have been used to develop new classification
33
In general, it is recommended that these children be treated as criteria. Furthermore, genetic mutations and polymorphisms
those with polyarthritis who did not have systemic features at in genes linked to the defective cytolytic pathway in lymphocytes
24
onset. Based on clinical trial results, the IL-6 inhibitor tocili- from patients with MAS are being explored to identify patients
18
zumab may be the most effective treatment for these patients. with sJIA with a propensity to develop MAS. Mouse models
of MAS are helping to better understand MAS immunopathology
Treatment of Uveitis and the role of pro-inflammatory cytokines in the process.
34
JIA-associated anterior uveitis frequently requires directed therapy. Early recognition of MAS and a better understanding of the role
Topical glucocorticoid eye drops, such as prednisolone acetate of various cytokines in the pathogenesis of MAS will allow for
1%, are frequently initiated at the time of diagnosis by the treating improved targeted therapy for this often fatal condition.
14
ophthalmologist. Although effective in decreasing the inflam-
mation of uveitis, glucocorticoid eye drops cannot be tolerated Please check your eBook at https://expertconsult.inkling.com/
in high doses for extended periods because of the risk of cataracts for self-assessment questions. See inside cover for registration
14
and glaucoma. For this reason, systemic medications are fre- details.
quently employed in the treatment of JIA-associated uveitis.
Methotrexate has been shown to be effective for uveitis and is REFERENCES
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CHaPtEr 53 Juvenile Idiopathic Arthritis 733.e1


MUL ti PLE-CHO i CE QUE sti ON s

1. Which of the following is NOT associated with increased risk C. Hyperferritinemia
of uveitis in children with juvenile idiopathic arthritis (JIA)? D. Rising cross-reactive protein (CRP) level
A. Female gender E. Rising erythrocyte sedimentation rate (ESR)
B. Antinuclear antibody (ANA) positivity 3. What is the most reliable finding denoting onset of temporo-
C. Rheumatoid factor (RF) positivity mandibular joint (TMJ) arthritis in a child with JIA?
D. Oligoarticular disease A. TMJ pain
E. Young age at disease onset
B. Maximal incisal opening <5 cm
2. Which of the following is NOT consistent with the diag- C. Elevated ESR
nosis of macrophage activation syndrome in a child with D. Synovial thickening on magnetic resonance imaging (MRI)
systemic JIA? E. TMJ popping
A. Thrombocytopenia
B. Coagulopathy

54









Sjögren Syndrome



Sarfaraz A. Hasni, Leyla Y. Teos, Ilias Alevizos






Sjögren syndrome (SS) is a chronic systemic autoimmune disease viral infections, may lead to epithelial cell activation that triggers
characterized by lachrymal and salivary gland dysfunction. It a protracted inflammatory response with features of autoim-
was named after the Swedish ophthalmologist Henrik Sjögren munity. Autoreactive lymphocytes and autoantibodies are
after he published a report of 19 cases of keratoconjunctivitis considered important in this process, although the pathogenic
1
in 1933. The hallmark feature of SS is deficient tear and saliva role of any particular autoantibody is still undefined. 4
production as a result of lymphocytic infiltration of the salivary
and lachrymal glands leading to xerostomia (dry mouth) and Immunogenetic Factors
xerophthalmia (dry eyes). In addition, SS can involve any organ SS is associated with certain human leukocyte antigen (HLA)
system and present with a wide spectrum of clinical features. class II haplotypes. Initial reports of HLA class II associations
The autoimmune process seems to primarily affect the lining described enrichment of DR3 and DR2 in European populations
epithelium of various organs; in fact, some experts have proposed of patients with primary SS. This genetic association predomi-
the term “autoimmune epithelitis” to be used instead of SS. 2 nantly involves antibody-positive but not antibody-negative
patients with SS. Several genetic polymorphisms previously linked
to other autoimmune diseases are also associated with SS. Among
KEY CONCEPTS these, two transcription factors, STAT4 (signal transducer and
activator of transcription 4) and IRF5 (interferon [IFN] regulatory
• Sjögren syndrome (SS) is one of the most common autoimmune factor 5), which were both independently associated with SS,
diseases, mainly affecting females. It targets the salivary and lachrymal showed an additive effect, increasing the risk of SS from around
glands, causing xerostomia and xerophthalmia. 1.6–1.9 for one risk allele to 6.7 when both risk alleles were
• The diagnosis of SS is complex and requires a multidisciplinary team present. 5
for the assessment of oral, ocular, and systemic manifestations.
• Anti-Ro/SSA and Anti-La/SSB autoantibodies are encountered in Although the individual gene approach has successfully
approximately 70% of patients with SS. Significantly increased incidence identified genes associated with SS, two large-scale genome-wide
of congenital heart block is present in the offspring of Anti-Ro/Anti-La association studies have increased the number of genetic loci
6
7
positive mothers. that function as potential risk factors. A study by Lessard et al.
• The risk of lymphoma is significantly higher in patients with SS, and genotyped more than 10 000 patients with SS and control subjects
this risk increases over time. of European descent and found seven genetic loci to be signifi-
• Currently, there is only palliative treatment for alleviation of the cantly associated with SS. These loci included the following genes:
symptoms of SS.
MHC-II, IRF5, STAT4, IL-12A, BLK, CXCR5, and TNIP1. A second
large-scale study examined DNA variations from approximately
1700 patients with SS and controls subjects from Han, China,
EPIDEMIOLOGY and identified a new gene associated with SS, the transcription
factor GTF2I located in 7q21. However, the odds ratio for GTF2I
SS predominantly affects females (female-to-male ratio 9 : 1) in was a moderate 2.2. 8
their fourth and fifth decades of life. However, symptoms can
be present for a much longer time, and there is usually a 5- to Environmental Factors
10-year delay in the diagnosis of SS. The reported prevalence of The inciting etiopathogenic event in SS is not known, and it
3
SS varies widely from 0.1% to 4.8%. This variation may result may not be a single event. The strong predominance of females
from the use of different classification criteria, geographical and suggests gender-specific predisposing factors. Although sex
environmental influences, and varying study sizes and target hormones are of obvious interest, there is no conclusive proof
populations. When a more strict definition is applied to the that the difference in the pathogenesis between males and females
available data, the true prevalence of SS is estimated to be around can be attributed to sex hormones alone. Overall, estrogens are
1
1%, making it the second most common systemic rheumatic considered contributors to autoimmunity, whereas androgens
disease after rheumatoid arthritis (RA). are thought to be protective.
Viral infections have also been proposed as inciting events. This
IMMUNOPATHOGENESIS theory is supported by the observation that chronic inflammation
of the salivary glands occurs with chronic hepatitis C, human
The pathogenesis of SS is largely unknown. In a genetically T-lymphotropic virus 1 (HTLV-1), and human immunodeficiency
predisposed individual, various environmental factors, such as virus (HIV) infections, and such infections cause a disease with a

735

736 ParT Six Systemic Immune Diseases


are targeted against ribonucleoprotein antigens. Anti-Ro/SSA
recognizes two RNA binding proteins (the 52-kilodalton [kDa]
or the 60-kDa protein), whereas anti-La/SSB antibodies recognize
RNA polymerase III. Anti-Ro/SSA antibodies are found in over
70% of patients with SS but are also frequently encountered
in systemic lupus erythematosus (SLE) and other autoimmune
diseases, even in the absence of oral or ocular dryness. Anti-La/
SSB is more specific; it is present in 50% of patients with primary
SS or SS/SLE but is rarely seen in other diseases. The patho-
genic role of these antibodies has not yet been defined, except
in infants born to women with anti-Ro/SSA and/or anti-La/
SSB antibodies. These antibodies can cross the placenta and
bind to Ro and La antigens located on the cell surface of fetal
myocardial tissue, leading to fetal heart block. Other autoanti-
bodies, such as antinuclear antibodies (ANAs) and rheumatoid
factor, are frequently present in patients with both primary and
FiG 54.1 Minor salivary gland biopsy with characteristic periductal secondary SS. Although these antibodies lack specificity, they are
inflammation. markers of a systemic autoimmune response and thus can help
distinguish SS from other causes of salivary or lachrymal gland
dysfunction.
clinical spectrum similar to that of SS. The fact that some viruses,
such as Epstein-Barr virus (EBV), replicate in oropharyngeal and AUTONOMIC NERVOUS SYSTEM ABNORMALITIES
lachrymal glands has led to the hypothesis that these viruses
might contribute to the pathogenesis of SS. Other viruses, such Autonomic nervous system (ANS) abnormalities are common
as coxsackievirus or endogenous retroviruses, have also been in SS and may play a critical role in its pathogenesis. Xerostomia
proposed as agents of interest. However, to date, there is no and xerophthalmia, the cardinal manifestations of SS, are fea-
proof that any of these viruses plays a pathogenic role in SS. tures of cholinergic parasympathetic ANS dysfunction, whereas
sympathetic cholinergic failure results in xerosis and decreased
Epithelial Cell Activation and Chronic Inflammation sweating, which are frequently reported by patients with SS.
The histological hallmark of SS is a periductal mononuclear The complexity of the ANS, along with differences in meth-
infiltrate in salivary and lachrymal glands (Fig. 54.1). The majority odology and studied populations, has resulted in variable results,
of the infiltrating cells are CD4 T lymphocytes, whereas CD8 but abnormalities in SS have been reported in both sympathetic
cytotoxic T cells are found in smaller numbers. Activated B and parasympathetic ANS domains.
lymphocytes are also present, including autoantibody-secreting
plasma cells. CLINICAL MANIFESTATIONS
Epithelial cell activation, signified by the expression of HLA
class II molecules, is key to initiating recruitment of the inflam- Clinical manifestations resulting from dysfunction of salivary
matory infiltrate. The expression of these molecules, along with and lachrymal glands are the dominant features of SS. Symptoms
upregulation of adhesion molecules and chemokines, contributes secondary to other exocrine gland dysfunction, such as skin and
to the recruitment of inflammatory cells, such as T and B lympho- vaginal dryness, and chronic cough caused by tracheal dryness
cytes, macrophages, and dendritic cells (DCs), and suggests that are frequently reported. Multiple extraglandular manifestations
epithelial cells may act as antigen-presenting cells (APCs), actively can also be present, reflecting the systemic nature of the auto-
9
participating in lymphocyte activation. The ensuing chronic immune process. 4
inflammatory process is characterized by a complex interaction
between activated epithelial cells and the innate and adaptive Constitutional Symptoms
immune systems. In the most severe forms of inflammation, the One of the most common extraglandular manifestations of
characteristic periductal infiltrates can progress to the formation SS is excessive fatigue. Approximately 70% of patients with SS
of germinal centers, which is associated with a higher risk of complain about disabling fatigue leading to reduced quality of
11
lymphoma development. Extraglandular manifestations occur as life. Attempts to identify a biological basis for fatigue have
a result of similar lymphocytic infiltrations in other organs. This failed to reveal any correlations with levels of inflammatory
is described by some as autoimmune epithelitis to better reflect markers, cytokines, or autoantibodies. This fatigue is commonly
9
the systemic nature of the disease. In most patients, only partial associated with arthralgia, malaise, and mental cloudiness (brain
destruction of the glands is noted. Local production of cytokines, fog), resulting in a diagnosis of fibromyalgia or chronic fatigue
autoantibodies, metalloproteinases, and other inflammatory syndrome. Less commonly, patients also experience low-grade
mediators may contribute to the dysfunction of the remaining fever and weight loss.
epithelial cells. It is increasingly recognized that the innate immune
system plays a crucial rule in the immunopathogenesis of SS. Ocular Involvement
Lachrymal gland dysfunction leads to dry, sandy eyes and sensa-
Autoantibodies tion of foreign body in the eyes. Frequently, there is a history of
Autoantibodies are the hallmark of systemic autoimmune dis- intolerance to contact lenses. Patients often complain of sticky
eases, including SS. The best-defined autoantibodies in SS are eyes and accumulation of thickened mucus as a result of loss of
10
anti-Ro/SSA and anti-La/SSB antibodies. Both autoantibodies aqueous tear components.

CHaPTEr 54 Sjögren Syndrome 737



CLiNiCaL PEarLS
• Chronic fatigue is a prominent presenting feature of Sjögren syndrome
(SS).
• Autonomic nervous system involvement and peripheral nervous system
involvement are often underrecognized.
• Mimics of SS include immunoglobulin G4 (IgG4)–related disease
(Mikulicz disease), hepatitis C infection, sarcoidosis, and human
T-lymphotropic virus (HTLV) infection.
• Presence of joint erosions and complement control protein (CCP)
antibody is indicative of secondary SS caused by rheumatoid
arthritis.
• Prolonged use of topical ophthalmic nonsteroidal antiinflammatory
drugs (NSAIDs) and steroid preparations should be avoided to reduce
the risk for local complications.
• Sudden normalization of previously elevated rheumatoid factor should
prompt evaluation for development of lymphoma.
• Oral candidiasis should be identified and treated. Patients with SS FiG 54.3 Enlargement of the parotid gland.
are at a high risk for oral candidiasis, which can present as oral erythema
and/or pain.
• Pediatric primary SS is rare and presents with variable, atypical features,
most commonly recurrent tender parotid gland swelling.



















FiG 54.4 Papillary atrophy and candidiasis of the tongue. The
loss of filiform papillae results in a smooth surface of the tongue.
Oral candidiasis is common in Sjögren syndrome (SS) and can
FiG 54.2 Punctate keratitis. Lissamine green stains dead or present as erythema only with minimal or no exudate (arrow).
degenerated corneal epithelial cells green. (Courtesy of Manuel
Datiles, MD.)



Enlarged lachrymal glands can be noted at the onset of disease.
In the initial stages, injected conjunctivae with strands of
thickened mucus at the inner canthus can be found. In more
advanced stages, conjunctivae may lose their normal luster and
become edematous. Corneal involvement results in punctuate
keratitis as a result of epithelial cell death (Fig. 54.2). During
early stages, the keratitis may be limited to the lower quadrants
of the cornea to eventually involve the entire cornea. If left
untreated, corneal ulcers can develop and result in rapid corneal
thinning. In addition to reduced tear production, there is also
evidence of inflammation of the ocular surface epithelium, as FiG 54.5 Root caries on anterior teeth caused by loss of the
indicated by the presence of inflammatory cell infiltrate and protective functions of saliva is a common finding. The cusp
elevated levels of inflammatory cytokines. tips of the posterior teeth are also commonly affected.
Oral Involvement
Saliva plays a critical role in maintaining oral health and comfort. 99% water, electrolytes, and proteins, the initial saliva is secreted
It has antibacterial, lubricating, remineralizing, digestive, buffering, by acinar cell clusters, which are innervated by both sympathetic
and cleansing properties. Therefore decreased salivary production and parasympathetic nerves. The sympathetic nerve activates
or altered salivary composition can result in numerous conditions alpha- and beta-adrenergic receptors at the plasma membrane,
affecting oral health, comfort, and quality of life. Composed of initializing a process that eventually catalyzes exocytosis of

738 ParT Six Systemic Immune Diseases


Parasympathetic nerve Chronic xerostomia necessitates the use of fluids throughout
the day and night. It is not uncommon for patients with SS to
wake up at night to drink fluids to relieve dryness and also to
DAG require the use of fluids to be able to speak, chew, and swallow.
PIP2
M3R A burning sensation along with taste alterations and decreased
ACh
tolerance to spicy foods is described by a significant percentage
Na + PLC + Interstitium of patients.
Head and neck examination often reveals dry and chapped
K + lips, angular cheilitis, and swollen major salivary glands (Fig.
54.3), which may be recurrent or chronic. Intraoral findings
G g /G 11 include decreased salivary pooling under the tongue and a
IP 3 depapillated tongue surface often associated with erythematous
STIM1 candidiasis (Fig. 54.4). Vasculitis can also manifest in the oral
IP3R cavity and lead to tissue breakdown. Teeth often exhibit an
Ca 2+ increased rate of caries with characteristic decay affecting the
Ca 2+ roots and cusp tips (Fig. 54.5).
ER A description of the water secretion molecular mechanism
IP3R in salivary epithelial cells in shown in Fig. 54.6.
Orais/
TRPCS
channels Musculoskeletal Involvement
Musculoskeletal complaints are present in the majority of patients
with SS. The rate of incidence of arthralgias has been reported
AQP5
as 50–75% in various studies and precedes sicca symptoms in
up to 30% of patients. Arthralgias are symmetrical and usually
K + Cl – without evidence of synovitis or erosions. Large-joint and small-
− Lumen joint involvement is equally reported, and 10–20 % of patients
have recurrent monoarthritis or oligoarthritis. From a clinical
FiG 54.6 Acinar cells fluid and electrolyte regulation signaling perspective, it is often difficult to differentiate between patients
pathway. M3 receptors coupled to G proteins activate phospho- with primary SS and symmetrical joint involvement and those
lipase C (PLC); this results in hydrolysis of phosphatidylinositol with RA presenting with sicca symptoms.
1,4 bisphosphate (PIP2) to yield diacylglycerol (DAG) and inositol
1,4,5-trisphosphate (IP3). IP3 diffuses in the cytosol and binds and Neuropsychiatric Manifestations
activates the IP3 receptors positioned on the plasma membrane Primary SS can result in multiple neurological manifestations
of the endoplasmic reticulum (ER). This causes opening of the involving both the central nervous system (CNS) and the periph-
19
IP3 receptors releasing calcium from the stores. The decrease in eral nervous system (PNS). PNS manifestations are more common
calcium within the ER is sensed by the calcium sensing protein, and are present in 5–20% of patients with SS. PNS involvement
stromal interaction molecule 1(STIM1). STIM1 translocates to the can present as sensory neuropathy, small-fiber neuropathy, cranial
plasma membrane and activates the Calcium Release-Activated neuropathy, inflammatory myopathy, and autonomic neuropathy.
Calcium Modulator (ORAI) and Tansient Receptor Potential, Small-fiber neuropathy is increasingly being recognized as the
Canonical (TRPCs) calcium channels. These channels are called most common PNS manifestation of SS. It presents as a subacute
store-operated channels (SOCs), which upon activation cause to chronic development of excruciating burning pain. There is
−
calcium influx. The calcium (Cl ) entering the cells originating at selective impairment of pinprick and temperature sensation,
+
the apical pole as a result of polarity activate potassium (K ) and with preserved vibratory sense and proprioception. Diagnosis
−
+
−
Cl channels releasing K and Cl into the lumen. Subsequently, is made with skin biopsy. Symptoms suggestive of autonomic
calcium propagates to the basolateral side of the cell where it dysfunction, such as orthostatic hypotension, temperature intoler-
+
+
activates K channels releasing K into the interstitium. This ance, constipation, urinary frequency or hesitancy, and delayed
+
creates an electrochemical gradient that drives sodium (Na ) gastric emptying, are present in up to half the patients with
20
across the paracellular pathway. The ion accumulation in the SS. CNS involvement is rare and can present as white matter
15
lumen drives water out through the aquaporin 5 (AQP5) channels, lesions, difficult to distinguish from multiple sclerosis, myelopathy,
causing cell shrinkage.
and optic neuritis, as well as cognitive dysfunction, seizures,
15
and encephalopathy. Neuromyelitis optica spectrum disorders
(NMOSDs), with the hallmark features of acute optic neuritis or
transverse myelitis with a relapsing course, have been linked to
proteins. Meanwhile, the parasympathetic nerve activates mus- the presence of antiaquaporin-4(AQP4) serum autoantibody. In
carinic receptors (M3) by releasing acetylcholine, which induces 213 patients diagnosed with NMOSD, 78 (37%) were found to
a calcium-dependent cascade of acinar cell volume change fulfill criteria for SS. 16-18 Anxiety and depression are commonly
(majority of salivary fluid) and secretion of electrolytes. 12-14 seen in patients with SS, perhaps because of the severe impact
Symptoms and signs of salivary gland dysfunction include of the manifestations of disease on the patients’ quality of life.
oral dryness (xerostomia); oral pain and sensitivity; difficulty
chewing, swallowing, and speaking; diminished taste; inflamed, Dermatological Involvement
19
morphologically altered, or infected mucosal tissues; and increased Skin is involved in about 50% of SS patients ; lesions can be
tooth decay. vasculitic or nonvasculitic. The most common nonvasculitic

CHaPTEr 54 Sjögren Syndrome 739


involvement is dry, itchy skin (xerosis) and angular cheilitis.
Other less common nonvasculitic lesions include alopecia, vitiligo, Genitourinary and Renal Involvement
eyelid dermatitis, and erythema nodosum–like lesions. Annular Renal involvement is frequently caused by tubulointerstitial
erythema, a rash similar to subacute cutaneous lupus, has been nephritis often presenting as distal (type1) renal tubular acidosis,
reported in about 10% of patients with SS and is closely associated renal calculi, and hypokalemia. Glomerular disease has been
with the presence of anti-SSA and/or anti-SSB autoantibod- rarely reported and, in most cases, is linked to cryoglobulinemic
ies. However, the rash is less photosensitive and histologically vasculitis. Inflammation of the urinary bladder epithelium can
has deeper perivascular and periappendageal lymphocytic cause interstitial cystitis. Vaginal dryness leading to dyspareunia
infiltrates. has been reported in 40% of women.
Vasculitic lesions include nonpalpable purpura caused by
hypergammaglobulinemia, palpable purpura, and urticarial vas- Clinical Manifestations in Children
19
culitis. Patients with vasculitis have higher prevalence of positive Primary SS is rarely diagnosed in children, but many adult patients
ANA, anti-Ro/SSA antibodies, and rheumatoid factor compared with SS recall the presence of symptoms since childhood. Clinical
with those with nonvasculitic skin involvement. Palpable purpura presentation in children is more insidious with predominant
is histologically characterized by leukocytoclastic vasculitis and recurrent parotitis and, less commonly, sicca symptoms. 26
may indicate presence of underlying cryoglobulinemia. Raynaud
phenomenon (RP) is seen in 30–50% of SS patients and frequently Associated Autoimmune Conditions
precedes the development of sicca symptoms. Autoimmune thyroiditis is seen in more than one-third of patients
with SS. Celiac disease is also increasingly recognized in these
Gastrointestinal Involvement patients, with a prevalence 10 times higher than in the general
Dysphagia is common as a result of dryness of the pharynx and population.
esophageal dysmotility. Nausea, epigastric pain, and constipation
are frequently encountered. Gastrointestinal (GI) tract dysmotility Lymphoma Associated With SS
can be seen as a result of ANS involvement. Pancreatic dysfunction, SS is associated with increased risk of lymphoma, with about
with reduced production of amylase and lipase, is present in 5% of patients developing lymphoma. In a meta-analysis of 20
25% of patients with SS. studies the standardized incidence rate of lymphoma was 18.9%
27
(confidence interval [CI] 9.4–37.9). Most of these are low-grade
Pulmonary Involvement marginal zone lymphomas of the mucosa-associated lympho-
Cough is a common complaint in patients with SS and results reticular tissue (MALT) type. Only 10% of lymphomas in patients
from tracheobronchitis sicca (tracheal and bronchial dryness). with SS evolve into a less differentiated cell (more aggressive)
Clinically significant pulmonary involvement is reported in variety. Risk factors for development of lymphoma include
20
9–12% of SS patients. Pulmonary manifestations include persistent enlargement of the parotid glands, palpable purpura,
large airway disease and small airway disease, bronchial hyper- leg ulcers secondary to vasculitis, mixed cryoglobulinemia, and
responsiveness, recurrent respiratory infections, interstitial lung low C4 levels.
disease, pulmonary hypertension, pleuritis, and pulmonary
amyloidosis. Interstitial lung disease is increasingly recognized DIAGNOSIS AND CLASSIFICATION CRITERIA
as an extraglandular manifestation of SS and can precede the
diagnosis of SS. Patients with SS can present with heterogeneous combinations
Patients with primary SS presenting with unexplained dyspnea of sicca symptoms and extraglandular manifestations. Moreover,
should be evaluated for pulmonary arterial hypertension (PAH); various clinical syndromes and medications can lead to similar
an unexpectedly high prevalence (14%) of pulmonary hyperten- symptoms and mimic SS. The diagnosis of SS is based on the
sion was found in a cohort of 1158 patients. The majority of combination of subjective symptoms of dryness (sicca symptoms),
patients with SS and PAH manifest symptoms early in the disease objective evidence of lachrymal or salivary gland hypofunction,
course. 21,22 and evidence of autoimmunity or salivary gland inflammation.
Classification criteria were proposed by an American–European
Cardiac Involvement consensus group (AECG) in 2002, primarily for classification
28
Clinically significant cardiac involvement is uncommon in primary of patients in clinical studies. These criteria are widely accepted
SS. Patients may develop pericarditis, thickened pericardium, and are frequently used as a guide for clinical diagnosis. Applica-
or left ventricle diastolic dysfunction. Rhythm abnormalities tion of these criteria to classify patients with primary SS has a
resulting from autonomic dysfunction may be encountered. sensitivity of 89.5% and specificity of 95.2%, whereas for second-
28
Placental transfer of anti-SSA/Ro and anti-SSB/La antibodies ary SS, it has a sensitivity of 97.2% and specificity of 90.2%.
from pregnant patients with SS can cause lesions in the cardiac The AECG classification scheme is based on a set of two subjective
conducting system of the fetus. Pregnant women with positive criteria and four objective criteria.
anti-SSA/Ro and anti-SSB/La antibodies have a 2.5% risk of Patients are classified as having primary SS in the absence of
delivering a baby with congenital heart block. any other systemic autoimmune disease, whereas in secondary
Like patients with other chronic inflammatory conditions, SS, sicca manifestations are present in conjunction with other
patients with SS are at an increased risk of premature atheroscle- underlying autoimmune diseases, such as SLE, RA, polymyositis/
rosis and cardiovascular events. Some traditional cardiovascular dermatomyositis, or systemic sclerosis. SS is excluded if patients
risk factors, such as hypertension and hypercholesterolemia, are use anticholinergic medications or have other conditions that
more prevalent in patients with SS. However, disease-specific can mimic SS, such as chronic viral infections, graft-versus-host
factors also contribute to the pathogenesis of premature disease (GvHD), or status post irradiation of the head and neck
atherosclerosis. 23-25 region.

740 ParT Six Systemic Immune Diseases


Patients presenting with sicca symptoms suggestive of SS The reasons for this increased interest mainly stems from recogni-
should undergo specialized testing to confirm the diagnosis. tion of the master regulatory roles they play in normal and
Lachrymal function can be assessed by using the Schirmer test altered physiological states and also their stability compared with
to quantify the amount of tear production, whereas corneal and mRNAs, a characteristic that allows them to be readily isolated
conjunctival damage caused by dryness can be measured by from archived samples, such as formalin-fixed paraffin-embedded
fluorescein and lissamine green staining. Salivary gland evaluation (FFPE) tissues or frozen saliva. 32-34
is done by collection of unstimulated saliva or by performing The role of miRNAs in primary SS is being investigated by
salivary scintigraphy. Laboratory workup should include testing several groups worldwide not only for their effects on immune
for autoantibodies to SSA/Ro and SSB/La antigens, which are cells but also on the target organs, such as the salivary glands. 35-37
detected in sera of 45–70% and 20–50%, respectively, in patients Rheumatoid factor is commonly positive in patients with SS
with SS. However, the AECG criteria have been criticized for and is part of the new ACR criteria for the diagnosis of SS.
including subjective symptoms and physiological tests lacking Recently, anticentromere antibodies were found to be present
specificity and for using alternative tests that are diagnostically in up to 13% of patients with SS.
nonequivalent. In addition, with the potential use of biological
agents to treat SS, more standardized, clear, and highly specific TREATMENT
criteria are needed.
To address these concerns, in 2012 the American College of
Rheumatology (ACR) proposed new classification criteria for THEraPEUTiC PriNCiPLES
SS, which required the presence of two out of three objective Management of Sjögren Syndrome (SS)
criteria in individuals suspected of having SS based on their
signs and symptoms (Table 54.1). These new criteria include no Ocular Manifestations
subjective ocular and oral symptoms and no functional tests for • Symptomatic relief with artificial tear drops and lubricating ointments
the salivary glands. • Topical cyclosporine eye drops
In subsequent studies comparing the AECG and ACR criteria, • Blockage of nasolacrimal duct by punctual plug placement or surgical
the degree of concordance ranged from modest (κ = 0.53) to cautery
high (κ = 0.81), but neither set of criteria has been shown to be
clearly superior to the other. At present, it appears that the stricter Oral Manifestations
ACR criteria are more suitable for high-risk clinical trials, such • Symptomatic relief with water and artificial saliva preparations
• Physical measures to increase saliva production: sugar-free candies
as those using biologicals, and the AECG criteria may have broader and gum
applicability in clinical research. 29-31 • Maintaining meticulous oral hygiene; use of fluoride toothpaste
• Sialogogues: pilocarpine or cevimeline
Novel Biomarkers for Diagnosis and Management of
Sjӧgren Syndrome Systemic Manifestations
MicroRNAs (miRNAs) are small regulatory noncoding RNAs • Hydroxychloroquine most commonly used to alleviate fatigue and
of 18–25 nucleotides in length. Over the last few years, interest arthralgias
in miRNAs as clinical biomarkers has been increasing steadily. • Other immunosuppressive medications may be considered in more
severe internal organ involvement
• Anti–tumor necrosis factor (TNF) blocking agents are not recommended
• Role of rituximab needs clarification
TABLE 54.1 Proposed american College of Patient Education
rheumatology (aCr) Classification Criteria • Patients should receive the following instructions:
for Sjögren Syndrome • Avoid extreme dry environments, such as proximity to open fire
places.
The classification of Sjögren syndrome (SS), which applies to • Wear protective eye glasses or goggles.
individuals with signs/symptoms that may be suggestive of SS, will • Use sugar-free sour candies or gum.
be met in patients who have at least two of the following three • Maintain good ocular and oral hygiene.
objective features: • Avoid use of medications and substances causing sicca symptoms.
1. Positive serum anti-SSA (Ro) and/or anti-SSB (La) or (positive • Women of child-bearing age with positive anti-SSA or anti-SSB antibod-
rheumatoid factor and antinuclear antibody [ANA] ≥ 1 : 320) ies should be counseled about the risk of congenital heart block.
2. Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis • Educate patients about increased risk of lymphoma associated with
with a focus score ≥1 focus/4 mm 2 SS.
3. Keratoconjunctivitis sicca with ocular staining score ≥3 (assuming • Safety precautions should be taken with regard to smoke and gas
that the patient is not currently using daily eye drops for glaucoma, leakage in the environment of patients with loss of smell.
and has not had corneal surgery or cosmetic eyelid surgery in the • Information regarding focus groups, such as Sjögren’s Syndrome
last 5 years) 3 Foundation (http://www.sjogrens.com/) and the British Sjögren’s
Prior diagnosis of any of the following conditions would exclude Syndrome Association, should be provided to patients.
participation in SS studies or therapeutic trials because of
overlapping clinical features or interference with criteria tests:
History of head and neck radiation treatment
Hepatitis C infection Symptomatic Treatment of Sicca Symptoms
Acquired immunodeficiency syndrome The mainstay of treatment in SS is providing symptomatic relief.
Sarcoidosis Use of artificial tears is often helpful. In patients with sticky
Amyloidosis mucus or strands over the eyes, use of mucolytic agents is
Graft-versus-host disease
Immunoglobulin G4 (IgG4)–related disease indicated. Blockage of lachrymal ducts with punctual plugs or
surgically can be beneficial.

CHaPTEr 54 Sjögren Syndrome 741


Artificial saliva available as spray or lozenges provides only LYMPHOMa iN SJÖGrEN SYNDrOME
limited relief. Local activation of salivary glands (in patients
with preserved function) with sugar-free sour candies or gums risk Factors
provides some relief of symptoms. • Increase in risk with time: cumulative risk 3.4% at 5 years and 9.8%
Cholinergic agonists, such as pilocarpine and cevimeline, at 15 years after diagnosis of Sjögren syndrome (SS)
provide effective symptom relief in selected patients. Cevimeline • Persistent enlargement of parotid glands
• Splenomegaly and lymphadenopathy
is a more selective muscarinic agonist predominantly affecting • Palpable purpura
M1 and M3 receptors and hence is associated with fewer side • Leg ulcers secondary to vasculitis
effects compared with pilocarpine. 4 • Mixed cryoglobulinemia
The Sjögren’s Syndrome Foundation’s Clinical Practice • Low complement levels
Guidelines Committee recently recommended the use of topical • CD4 lymphocytopenia
fluoride to reduce dental caries in patients with SS who suffer
from dry mouth. 38 Staging and Management (in Collaboration With an Oncologist)
• Computed tomography (CT) of neck, thorax, and abdomen
Immune-Modulating Medications • Laboratory tests: Lactate dehydrogenase (LDH), serum and urine
electrophoresis and immunofixation, human immunodeficiency virus
Cyclosporine eye drops are frequently prescribed to reduce the (HIV), and hepatitis C serology
local immune response involving the conjunctiva and the cornea. • Bone marrow biopsy
Use of topical nonsteroidal antiinflammatory and steroid-based • Localized low-grade mucosa-associated lymphoreticular tissue (MALT)
eye drops provide short-term benefits and should be used lymphoma (most common): careful monitoring required
cautiously. • Multiple extranodal site involvement: single agent chemotherapy
• High-grade transformation or aggressive lymphoma at presentation:
Hydroxychloroquine is commonly prescribed for patients with rituximab and CHOP (cyclophosphamide, hydroxy doxorubicin, Oncovin,
SS, even though some trials have shown significant laboratory and prednisone)
improvement but no beneficial effects on symptoms.
Other immune-modulating agents, such as azathioprine,
cyclosporine, methotrexate, and mycophenolate mofetil, have
shown only limited benefits in treating sicca symptoms and are
used primarily for extraglandular manifestations. 39 their sicca symptoms. Women of child-bearing age with positive
Trials using biological agents, such as infliximab and etanercept, anti-SSA/Ro and anti-SSB/La antibodies should be counseled
failed to show any significant improvement in the primary regarding the risk of congenital heart block in the fetus. Patients
outcomes of treatment for oral and ocular dryness. 39 with loss of smell associated with SS are at an increased risk of
Data on the use of rituximab are controversial, with some injury in the event of gas leakage. Alternative methods should
studies showing only modest benefit. 39 be employed to detect gas leakage in the patient’s environment.
An open-label trial using the anti–B cell–activating factor
(BAFF) monoclonal antibody (mAb) belimumab revealed no TRANSLATIONAL RESEARCH AND
major safety concerns. There were minor improvements in parotid FUTURE DIRECTIONS
gland swelling and lymphadenopathy but no significant improve-
ment in salivary and lacrimal gland function or patient-reported
outcomes. Despite the central role of autoantibodies in the ON THE HOriZON
pathogenesis of SS, targeting of B-cell function has been surpris-
ingly unsuccessful in managing SS. • Whole transcriptome and exome studies will lead to better understand-
ing of genetic risk factors.
Treatment for Lymphoma Associated With SS • Further studies are needed to better understand the interaction between
immune and nonimmune abnormalities leading to Sjögren
As discussed above, lymphoma associated with SS is usually low syndrome.
grade with 5-year survival rates of 86–100%. In a study of patients • Pilot clinical studies are needed to identify potential therapeutic
with SS, overall survival rates of patients with MALT lymphoma candidates for larger efficacy trials.
24
was similar in both the treated and the untreated groups. • There is a pressing need to identify and to validate clinically relevant
biomarkers.
However, patients with disseminated and more aggressive
lymphoma have reduced overall survival. Recently, high levels
of BAFF and Flt3 were shown to be highly predictive of lymphoma SS is the clinical manifestation of a complex interplay between
development in patients with SS. 40 genetic factors and environmental and stochastic events that
involve innate and adaptive immunity, hormonal mechanisms,
PATIENT EDUCATION and the ANS. A better understanding of these elements is necessary
to develop more effective treatments. Two large genome-wide
Because of its significant impact on quality of life, educating patients association studies are currently underway to better delineate
and their families is of utmost importance. Excellent resources the genetic risk factors of SS. Pilot treatment trials targeting key
for patient education are available through focus groups, such as cells (B and T lymphocytes) and mediators (Blyss, lymphotoxin,
the Sjögren’s Syndrome Foundation (http://www.sjogrens.com/) IFN) of autoimmune/inflammatory pathways are expected to
and the British Sjögren’s Syndrome Association. identify the most promising molecule(s) that can be tested in
In general, patients are advised to avoid dry environments, larger efficacy studies. There is a clear and present need to identify
protect the eyes from bright sunlight, maintain good dental and validate biomarkers that can be used in clinical trials as well
hygiene, and be aware of symptoms suggestive of lymphoma. as everyday clinical practice to improve the management of
They should avoid medications and substances that may worsen patients with SS.

742 ParT Six Systemic Immune Diseases


As no effective treatment is currently available to treat patients 21. Vassiliou VA, Moyssakis I, Boki KA, Moutsopoulos HM. Is the heart
with SS, several medications and other non–drug-based modalities affected in primary Sjogren’s syndrome? An echocardiographic study.
are being studied. Currently, several clinical trials using agents Clin Exp Rheumatol 2008;26:109–12.
targeting IFN, interleukin-6 (IL-6), Toll-like receptors (TLRs), 22. Lin DF, Yan SM, Zhao Y, et al. Clinical and prognostic characteristics of
573 cases of primary Sjogren’s syndrome. Chin Med J 2010;123:3252–7.
and inhibition of T-cell stimulation are underway. Use of steroids 23. Atzeni F, Sarsi-Puttini P, Signorelllo MC, et al. New parameters for
locally in the salivary glands showed some promising initial identifying subclinical atherosclerosis in patients with primary Sjogren’s
results, which should be confirmed in independent studies. syndrome: a pilot study. Clin Exp Rheumatol 2014;32:361–8.
24. Sezis Demirci M, Karabulut G, Gungor O, et al. Is There an Increased
Please check your eBook at https://expertconsult.inkling.com/ Arterial Stiffness in Patients with Primary Sjogren’s Syndrome? Intern
for self-assessment questions. See inside cover for registration Med 2016;55:455–9.
details. 25. Valim V, Gerdts E, Jonsson R, et al. Atherosclerosis in Sjogren’s syndrome:
evidence, possible mechanisms and knowledge gaps. Clin Exp Rheumatol
2016;34:133–42.
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Sjogren syndrome with neuromyelitis optica]. Zhonghua Nei Ke Za Zhi 40. Papageorgiou A, Voulgarelis M, Tzioufas AG. Clinical picture, outcome
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20. Hatron PY, et al. Pulmonary manifestations of Sjogren’s syndrome. Presse
Med 2011;40:e49–64.

CHaPTEr 54 Sjögren Syndrome 742.e1


MULT i PLE-CHO i CE QUEST i ONS

1. What is the typical salivary gland histological feature in Sjögren C. Acquired immunodeficiency syndrome (AIDS)
syndrome (SS)? D. Mucosa-associated lymphoreticular tissue (MALT)
A. Diffuse inflammation throughout the salivary gland lymphoma
parenchyma 3. Which of the following is NOT a risk factor for the develop-
B. Clusters of tightly packed lymphocytes surrounding ducts ment of lymphoma in SS?
C. Increased proliferation of acinar cells A. Increased CD4 counts
D. Increased proliferation of ductal cells
B. Persistent enlargement of parotid glands
2. Which of the following is NOT an exclusion criterion for the C. Mixed cryoglobulinemia
classification/diagnosis of SS? D. Low complement levels
A. History of head and neck radiation treatment
B. Hepatitis C infection

55









Scleroderma–Systemic Sclerosis



John Varga, Fredrick M. Wigley







Systemic sclerosis (SSc) is a chronic multisystem connective tissue with other autoimmune diseases, particularly systemic lupus
disease characterized by autoimmunity and inflammation, erythematosus (SLE), and are involved in immune regulation
widespread functional and structural abnormalities in small and innate immune responses, highlighting the potential impor-
blood vessels, and progressive fibrosis of the skin and visceral tance of immune dysregulation in the pathogenesis of SSc. 3
organs. Multiple cell types and their products interact to mediate
the pathogenetic processes that underlie the diverse clinical Environmental Factors
manifestations of SSc. Although the etiology if SSc is unknown, microbial exposures
and exposure to environmental and occupational agents, dietary
PREVALENCE AND EPIDEMIOLOGY factors, and drugs have been implicated as potential triggering
factors. Patients with SSc have increased serum levels of antibodies
SSc is a sporadic disease with worldwide distribution. Incidence directed against the human cytomegalovirus (hCMV). Evidence
estimates in the United States range from 9 to 19 cases per million for a potentially pathogenic role for CMV, Epstein-Barr virus
per year, and prevalence rates range from 28 to 253 cases per (EBV), and parvovirus B19 infection or reactivation, as well as
million. According to the revised American College of Rheumatol- Helicobacter pylori infection, has also been presented. These studies
ogy classification criteria, which are more sensitive for identifying need confirmation, and the etiological role of microbial patho-
early stage of disease, the prevalence estimates are expected to gens in SSc remains a conjecture. Although reports of apparent
1
be considerably higher. Age, gender, and ethnicity are important geographical clustering of SSc cases suggest shared environmental
2
factors that determine disease susceptibility. Like other connective exposures, careful investigations have generally not been able to
tissue diseases, SSc is more prevalent in women, with the most substantiate these clusters. Epidemic outbreaks of apparently
common age of onset in the range of 40–60 years. Disease onset novel multisystemic illnesses with SSc-like features have been
tends to occur at an earlier age among patients of African descent linked to environmental exposures, such as contaminated rapeseed
than among whites. Furthermore, black patients are more likely cooking oils in Spain (the toxic oil syndrome) and l-tryptophan
to have diffuse skin involvement, digital ulcers, pulmonary dietary supplements (eosinophilia–myalgia syndrome) in the
4
hypertension (PH), and pulmonary fibrosis, and have a worse United States. The incidence of SSc is increased among miners
prognosis. and others with occupational exposure to silica. Additional
occupational exposures linked to increased risk of SSc include
ETIOLOGY AND PATHOGENESIS polyvinyl chloride, trichloroethylene, and organic solvents. Drugs
potentially implicated in SSc-like illnesses include bleomycin,
The pathogenesis of SSc involves dynamic interplay among taxane, pentazocine, cocaine, and anorexigens associated with
inherited genetic risk factors, environmentally induced stable pulmonary artery hypertension. The apparent association of
epigenetic modifications, and acute or subacute environmental SSc with silicone breast implants originally raised concern,
exposures. but epidemiological investigations have not substantiated the
hypothesis of an increased risk. 5
Genetic Factors
Systemic sclerosis is not inherited in a mendelian fashion, and Pathology
disease concordance rates among both monozygotic and dizygotic The hallmark pathological features of SSc are a noninflammatory
twins are relatively low (<5%). Nonetheless, 1.6% of patients obliterative microangiopathy in multiple vascular beds and fibrosis
with SSc have a first-degree relative with the disease (relative of the skin and internal organs. In early-stage disease, cellular
risk of 13), indicating an important role for genetic background infiltrates may be prominent in many organs. In skin, inflam-
in SSc disease susceptibility. Specific human leukocyte antigen matory cells are located predominantly around blood vessels.
(HLA) haplotypes show strong association with distinct SSc- With disease progression, these infiltrates become sparse.
specific autoantibody responses. Genetic investigations in SSc Vascular injury is the earliest and possibly primary event in
have focused on candidate genes and genome-wide association the pathogenesis of SSc. Patients with established SSc show
studies (GWAS). Candidate genes shown to be associated with widespread vascular lesions characterized by bland intimal
SSc include those implicated in interferon (IFN) signaling, T- and proliferation in the small- and medium-sized arteries (Fig. 55.1).
B-cell activation, DNA clearance, and innate immunity (Table In late stages, perivascular adventitial fibrosis and generalized
55.1). It is remarkable that a majority of these genes are shared capillary rarefaction are prominent.

743

744 Part SIX Systemic Immune Diseases



TABLE 55.1 Genetic associations With adipocytes. Lungs show patchy infiltration of the alveolar walls
Systemic Sclerosis (SSc) with lymphocytes, plasma cells, macrophages, and eosinophils
in early disease. In later stages, fibrosis and vascular damage
Genetic predominate in the lungs, often coexisting in the same lesions.
Polymorphisms However, in patients with limited cutaneous SSc, the vascular
Gene Locus Gene Function associated With SSc lesions typically predominate. Intimal thickening of the pulmo-
IRF5 Activation of interferon rs2004640, others nary arteries, best seen with elastin stain, is a pathological hallmark
IRF8 Monocyte differentiation rs11642837 of PH and at autopsy is often associated with multiple pulmonary
IRF7 Activation of interferon rs4963128 emboli. Progressive fibrous thickening of the alveolar septae
IL12R Interleukin-12/T-cell rs3790567 results in obliteration of the air spaces with a characteristic
signaling nonspecific interstitial pneumonia (NSIP) pattern and, less
STAT4 T-cell signaling rs7574865, others commonly, honeycombing, as well as loss of the pulmonary
DNASE1L3 DNA clearance rs35677470
ATG Autophagosome rs9373839 blood vessels. This process impairs gas exchange and contributes
biogenesis to worsening of PH. In the GI tract, pathological changes can
PPARG Adipogenesis rs310746 occur at any level, from the mouth to the rectum. The esophagus
CD247 T-cell receptor signaling rs2056626 shows atrophy of the lamina propria, submucosa, and muscular
CSK Src family tyrosine kinase rs1378942 layers, with variable fibrosis. Replacement of the normal intestinal
PTPN22 T-cell signaling rs2476601 architecture leads to disordered peristaltic activity, resulting in
phosphatase
BANK1 B-cell receptor signaling rs10516487, others gastroesophageal reflux, small bowel dysmotility, and bacterial
BLK B-cell receptor signaling rs2736340 overgrowth. Chronic gastroesophageal reflux leads to esophageal
TNFAIP3/A20 Negative regulation of rs5029939, others inflammation, ulcerations and stricture formation, and, in some
nuclear factor (NF)-κB cases, premalignant Barrett metaplasia.
inflammation The heart is frequently affected, with prominent myocardial
TNIP1 Negative regulation of rs2233287, others contraction band necrosis, which reflects ischemia–reperfusion
NF-κB inflammation
TNFSF4 T cell–antigen-presenting rs1234314, others injury, and patchy areas of myocardial fibrosis. In the kidneys,
cell interaction vascular lesions predominate, and glomerulonephritis is rare.
Chronic renal ischemia is associated with shrunken glomeruli
and interstitial fibrosis. Scleroderma renal crisis (SRC) is associated
with reduplication of elastic lamina, marked intimal proliferation,
and narrowing of the lumen (onion skinning), often accompanied
by microangiopathic hemolysis.
Pathogenesis
A comprehensive view of SSc pathogenesis must be capable of
integrating the vasculopathy, immune dysregulation, and fibrosis
of multiple organs, which are the hallmarks of the disease. As
illustrated in Fig. 55.2, complex and dynamic interplay among
these distinct pathomechanistic processes initiates, amplifies, and
6
sustains tissue damage in SSc. Animal models of disease (see
Table 55.2) can be informative for identifying cell types, molecular
mechanisms, and pathways contributing to SSc pathogenesis.
Microangiopathy
Evidence of vascular involvement is an early and widespread
feature of SSc, and vascular damage has major impact on the
course of the disease. Vascular endothelial cell injury is initially
FIG 55.1 Pulmonary Arterial Involvement. Significant intimal associated with largely functional and potentially reversible altera-
layer hyperplasia is seen, leading to narrowing of the vascular tions. There is abnormal blood flow response to vasomotor or
lumen. (Courtesy of Dr. Anjana Yeldandi.) cold challenge and altered production of and responsiveness to
factors mediating vasodilatation (nitric oxide and prostacyclins)
and vasoconstriction (endothelins). Microvessels show loss of
Fibrotic changes are most prominent in skin, lungs, gastro- pericyte coverage, increased permeability, enhanced transendo-
intestinal (GI) tract, heart, tendon sheath, and perifascicular thelial leukocyte migration, activation of fibrinolytic cascades,
tissue surrounding skeletal muscle. Accumulation of collagen-rich and platelet aggregation culminating in thrombosis. Activated
connective tissue composed of fibulins; elastin; proteoglycans; endothelial cells express elevated surface adhesion molecules and
matricellular proteins, such as tenascin-C and alternatively spliced release endothelin-1, which further promotes leukocyte adhe-
fibronectin (EDA isoform), and other structural macromolecules sion and smooth muscle cell proliferation, and might also drive
in these organs leads to distortion of tissue architecture, resulting endothelial–mesenchymal transition. Ensuing intimal and medial
in progressive functional impairment. In skin, fibrosis causes hypertrophy and fibrosis of the adventitial layers lead to vessel
massive dermal expansion with obliteration of hair follicles and stiffening and luminal narrowing. Combined with endothelial
sweat and sebaceous glands. Collagen deposition invades the cell apoptosis, the process culminates in the characteristically
subjacent adipose layer with entrapment and obliteration of striking absence of blood vessels seen on angiograms of the

CHaPtEr 55 Scleroderma–Systemic Sclerosis 745



Vascular injury
• Endothelial dysfunction
• Endothelial cell activation
• Platelet activation, coagulation


Leukocyte recruitment Endothelin-1
+
+
• Activated Th2 cells (CD4 CD8 )
Autoantibodies • Dendritic cells, interferon
• Monocytes/macrophages
• Activated B cells


• TGF-β, CTGF, PDGF
• Th2 cytokines
• Lysophosphatidic acid 1
• Chemokines Obliterative
microangiopathy thy


Fibroblast activation ROS, Tissue hypoxia
• Myofibroblast differentiation
• Adhesion, contraction, ROS


Collagen deposition
Matric remodeling, matrix stiffness
Impaired matrix degradation



Fibrosis
FIG 55.2 Pathogenesis of Systemic Sclerosis. Interactions of cellular and molecular events
triggered by injury that underlie the pathogenesis of vascular and immune dysfunction, culminating
in fibrosis. TGF-β,transforming growth factor-β; CTGF, connective tissue growth factor; PDGF,
platelet-derived growth factor; ROS, reactive oxygen species.


TABLE 55.2 Selected animal Models of SSc
animal Model Fibrosis Inflammation Vascular affected Organ Comment
Bleomycin (subcutaneous) + + ± Skin, lungs Fibrosis self-limited; localized
Graft-versus-host disease (GvHD) + + − Skin, lung, kidney Complex procedure; radiation
Ang2-induced + + + Skin, lung Skin localized
Fra2 tg + + + Skin, lung Pulmonary hypertension (PH); early mortality
PDGFR tg + − − Multiorgan
Wnt10b tg + − − Skin Loss of dermal white adipose tissue (dWAT)
TSK1 + − − Hypodermal Fibrillin-1 mutation
lungs—emphysema
TSK2 + + − Skin Collagen III mutation
Stiff skin syndrome + + − Skin Fibrillin-1 mutation
Fli1-deleted + − RVH Skin, heart
ROS + + + Skin, lung, kidney Not widely used
Topo 1 immunization + + − Skin Not well established
Chronic GvHD + + ± Skin Immune-driven



hands and kidneys in late-stage disease. Paradoxically, despite kidneys of patients with SRC, with evidence of complement
elevated levels of angiogenic signals, including vascular endothelial activation and endothelin-1 deposition in the damaged small
growth factor (VEGF), reflecting pervasive tissue hypoxia, the vessels.
process of revascularization appears to be defective in SSc,
possibly as a result of defects in the generation and matura- Cellular and Humoral Immune Responses
+
tion of bone marrow–derived CD34 endothelial progenitor In the early stages of SSc, activated T cells and monocytes/
7
cells. Vascular injury in SSc is particularly prominent in the macrophages accumulate within lesional skin and the lungs,

746 Part SIX Systemic Immune Diseases


where they secrete proinflammatory and profibrotic mediators, is a fundamental pathogenetic alteration underlying fibrosis
including transforming growth factor-β (TGF-β), cytokines, and in SSc.
chemokines. These molecules can activate fibroblasts as well as Fibroblasts explanted from lesional SSc tissues continue to
endothelial cells, recruit further inflammatory cells, and initiate display an abnormal phenotype when propagated ex vivo, with
the fibrotic response. Because TGF-β, in particular, can induce enhanced rate of synthesis of collagen and other ECM molecules,
its own production as well as that of other profibrotic growth expression of α smooth muscle actin and cell surface adhesion
factors, such as connective tissue growth factor (CTGF) and molecules, and spontaneous generation of ROS through the
platelet-derived growth factor (PDGF), an initial cytokine burst nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
could result in amplified cytokine production and sustained complex pathway as well as from mitochondrial respiration.
autocrine and paracrine signaling. Additionally, as the extracellular Additionally, explanted SSc fibroblasts show hallmarks of
matrix (ECM) undergoes remodeling, it loses compliance and senescence. The persistent activated scleroderma phenotype is
increases its stiffness, which, in itself, triggers biomechanical likely to reflect epigenetic modifications caused by chromatin
activation of resident stromal cells, in part by liberating and remodeling, DNA methylation, or altered expression of noncoding
activating latent matrix-bound latent TGF-β. Alterations in regulatory RNAs, including microRNA and long noncoding
the relative proportions and function of regulatory T cells RNAs.
(Tregs) and T-helper 17 (Th17) cells, and innate lymphoid cells TGF-β is a pleiotropic cytokine and a pivotal regulator of
(ILCs), have been documented and may play important roles tissue repair and fibrosis (Chapter 9). Multiple abnormalities in
in pathogenesis. TGF-β pathways have been identified in SSc, indicating a key
Virtually all patients with SSc have antinuclear and other role in pathogenesis. Lesional fibroblasts secrete TGF-β and
autoantibodies in serum. These autoantibodies are generally exhibit TGF-β hyperresponsiveness caused by elevated expression
highly specific for SSc and tend to be mutually exclusive (see of TGF-β surface receptors, and integrin-mediated activation of
below). Moreover, SSc-specific autoantibodies show strong latent TGF-β. Furthermore, SSc fibroblasts show evidence of
association with individual disease subphenotypes, and their constitutive phosphorylation of Smad transcription factors and
titers can fluctuate with disease activity. Multiple mechanisms other key intracellular signaling pathways that, together with
have been proposed to account for autoantibody generation in deficiencies in endogenous antifibrotic mechanisms, might
10
SSc. In patients with SSc, B cells overexpress the surface receptor contribute to the persistence and progression of fibrosis.
8
CD19, resulting in hyperresponsives. Additionally, specific Therapies that selectively or nonselectively block growth factor
self antigens undergo posttranslational modifications, such as signaling and abrogate fibrogenic pathways triggered by growth
proteolytic cleavage, increased expression or misdirected subcel- factors, chemokines, PDGF, Wnt, and CTGF are currently under
lular localization that create neoepitopes recognized as nonself development.
by the immune system. Although SSc-associated autoantibodies
have well-established clinical utility as diagnostic and prognostic CLINICAL FEATURES
markers, their direct role in SSc-associated tissue damage remains
9
uncertain. Recent studies have indicated that patients with SSc Overview
also commonly have functional antibodies that are directed against The term “scleroderma” is used to describe both systemic scle-
fibroblasts and endothelial cells; the PDGF receptor; vascular rosis and localized scleroderma, a disorder generally limited to
receptors, such as endothelin-1 and angiotensin II receptors; skin. SSc is highly variable in its clinical expression and thus
and matrix metalloproteinases (MMPs). represents a broad spectrum of disease. The disease process
can target skin, blood vessels, and the lungs, heart, GI tract,
Fibrosis: Cellular and Molecular Components kidneys, and musculoskeletal system, subsets of patients exist
Interstitial and vascular fibrosis, the hallmarks of SSc, is character- with unique clinical features and distinct clinical outcomes.
ized by replacement of normal tissue architecture with dense Raynaud phenomenon is virtually universal in SSc, suggesting
and noncompliant connective tissue. Although isolated organ that perturbation of the terminal arteries of the circulation is
fibrosis is a generalized and frequent sequel to any form of chronic a fundamental process that links the different subsets of the
or recurrent tissue injury, fibrosis concurrently affecting multiple disease. Thickening of the skin distinguishes SSc from other
organs is unique to SSc. Fibroblasts and related stromal cells of rheumatic diseases (Table 55.3); scleroderma (hard skin) is the
mesenchymal origin are key effector cells responsible for the most specific and prominent physical finding. Patients vary in
development of fibrosis. In response to extracellular signals, such the expression of the skin changes and are classified into two
as TGF-β, CTGF, PDGF, Wnt, chemokines, endothelin-1, lyso- major subsets defined by the degree of clinically involved skin.
phosphatidic acid (LPA1), reactive oxygen species (ROS), and In the diffuse skin variant called diffuse cutaneous SSc (dcSSc),
hypoxia, as well as integrin-mediated biomechanical signals from fibrosis of skin is widespread, and the illness is more violent
a stiff ECM, these cells proliferate; migrate; produce a broad in expression, with rapid onset and increased risk of serious
array of matrix macromolecules; adhere to and remodel con- and internal organ disease. In contrast, the limited skin variant
nective tissue; secrete growth factors, cytokines, and chemokines called limited cutaneous SSc (lcSSc) presents with long-standing
and express surface receptors for them; and undergo transdif- Raynaud phenomenon, skin fibrosis limited to the fingers or
ferentiation into apoptosis-resistant contractile myofibroblasts. distal limbs, and a generally indolent disease course. Limited SSc
Under physiological conditions, the fibroblast repair program is less likely to be associated with organ failure or shortened life
is tightly regulated and self-limiting to enable tissue regeneration, expectancy. Predictors of elevated mortality rates among patients
whereas under pathological conditions, fibroblast activation is with SSc include diffuse skin disease with a rapid rate of skin
sustained and amplified, resulting in exaggerated matrix deposi- progression and internal organ involvement (especially the lungs
tion and disruption of tissue architecture. Uncontrolled activation or the kidneys, resulting in an SRC), male gender, black race,
of fibroblasts, combined with their relative resistance to apoptosis, and later age of disease onset. 11,12

CHaPtEr 55 Scleroderma–Systemic Sclerosis 747



KEY CONCEPtS Although classification of SSc as diffuse and limited cutaneous
Clinical Patterns of Systemic Sclerosis has utility, disease expression is far more complex, and several
distinct phenotypes are recognized within each of the two subsets.
Limited Cutaneous Scleroderma For example, 10–15% of patients with lcSSc develop severe
• Distal skin sclerosis (sclerodactyly) pulmonary arterial hypertension without significant lung fibrosis.
• Severe Raynaud phenomenon with digital ischemia Other patients develop systemic features of SSc without appre-
• Numerous telangiectasia ciable skin involvement, a phenotype that is termed systemic
• Isolated pulmonary arterial hypertension sclerosis sine scleroderma. Unique clinical phenotypes of SSc are
associated with specific autoantibodies (Table 55.4). For example,
Diffuse Cutaneous Scleroderma anticentromere antibodies are associated with lcSSc, whereas
• Rapidly progressing widespread skin involvement antitopoisomerase-I antibodies are associated with the presence
• Scleroderma renal crisis of interstitial lung disease. The presence of anti-RNA polymerase
• Interstitial lung disease
• Severe gastrointestinal dysmotility antibodies is associated with rapid and widespread skin disease
• Cardiomyopathy and an increased risk of an SRC. In some patients with SSc who
have “overlap” features, SSc coexists with clinical and laboratory
evidence of another autoimmune disease, such as polymyositis,
autoimmune thyroid disease, Sjögren syndrome, polyarthritis,
autoimmune liver disease, or SLE (see Table 55.4).
TABLE 55.3 Classification of Systemic Instead of SSc, the term “ localized scleroderma” is now
Sclerosis (SSc) properly used to describe a group of patients with disease generally
limited to fibrosing skin disorders that occurs with similar
Diffuse cutaneous scleroderma—skin thickening on the trunk in
addition to the face, proximal and distal extremities frequency in both children and adults (Table 55.5). Localized
Limited cutaneous scleroderma—skin thickening limited distal to scleroderma is infrequently associated with significant systemic
the elbow and knee; may also involve the face and neck involvement. Morphea, a form of localized scleroderma, can
CrESt syndrome—subcutaneous calcinosis; Raynaud phenomenon; occur as solitary or multiple lesions (generalized morphea) of
esophageal dysmotility; sclerodactyly; telangiectasia expanding circular patches of thickened skin. The most common
Sine scleroderma—no apparent skin thickening but characteristic form of localized scleroderma in children is linear scleroderma.
visceral organ involvement, vascular and serological features
Overlap syndrome—criteria for SSc, coexisting with features of It presents as a streak of thickened skin, generally in one or both
systemic lupus erythematosus, rheumatoid arthritis, or inflammatory lower extremities. Linear scleroderma often involves the subcu-
muscle disease taneous tissues with fibrosis and atrophy of supporting structures,
Mixed connective tissue disease—overlap syndrome with anti-U1 muscle, and bone, and radiographs may show melorheostosis
ribonucleoprotein (RNP) antibodies of long bones. In children with linear scleroderma, the growth
Early disease—Raynaud phenomenon (RP) with clinical and/or of affected tissues, muscles, and long bones can be retarded.
laboratory features of SSc; specific autoantibodies, abnormal nailfold
capillaroscopy, finger edema, and ischemic injury When the lesions cross joints, significant contractures of the
affected joint can develop. Linear scleroderma can occur on the


TABLE 55.4 Frequency and Clinical Correlations of Systemic Sclerosis (SSc) autoantibodies
% Frequency in SSc Disease Subtype Clinical associations Prognosis
Anticentromere 20–38 lcSSc Pulmonary arterial hypertension Better prognosis
Antitopoisomerase I 15–42 dcSSc Pulmonary fibrosis Worse prognosis
Heart involvement
Anti-RNA polymerase III 5–31 dcSSc Renal crisis Increased mortality
Tendon friction rubs, synovitis,
myositis, Joint contractures.
Increased risk of malignancy
Anti-U3 RNP (fibrillarin) 4–10 dcSSc Renal crisis and cardiac involvement Poor prognosis especially
in African Americans
Anti-Th/To 1–13 lcSSc Pulmonary fibrosis and renal crisis Poor prognosis
Anti-U11/U12 RNP 3.2 — RP Increased mortality
Gastrointestinal involvement
Lung fibrosis
Anti-U1 RNP 2–14 lcSSc RP, puffy fingers, arthritis, myositis, Better prognosis
overlap syndrome (i.e., MCTD)
Anti-PM-Scl 4–11 Overlap with polymyositis RP, arthritis, myositis pulmonary Better prognosis
lcSSc involvement, calcinosis, and sicca
symptoms
Anti-Ku 2–4 — Myositis, arthritis, and joint —
contractures
Anti-hUBF (NOR 90) <5 lcSSc Mild internal organ involvement Better prognosis
Anti-Ro52/TRIM21 15–20 Association with other Older age onset, pulmonary fibrosis —
autoimmune diseases
dcSSc, diffuse cutaneous SSc; lcSSc, limited cutaneous SSc; MCTD, mixed connective tissue disease; RNP; ribonucleoprotein; RP, Raynaud phenomenon; TRIM, tripartite motif.
From Kayser C, Fritzler MJ. Autoantibodies in systemic sclerosis: unanswered questions. Frontiers Immunol 2015;6:167.

748 Part SIX Systemic Immune Diseases



TABLE 55.5 Classification of
Localized Scleroderma
• Plaque types of morphea
• Circumscribed plaques
• Guttate
• Keloid/nodular
• Bullous
• Generalized morphea
• Three or more locations
• Pansclerotic morphea
• Linear scleroderma
• Frontoparietal linear morphea (en coup de sabre)
• Parry-Romberg syndrome (progressive hemifacial atrophy)
• Linear streaks on limbs or trunk
• Deep morphea

FIG 55.3 Skin Fibrosis in Systemic Sclerosis. Severe fibrosis
of the skin of the hands and forearms causing joint contractures
head leaving severe facial deformity. When this occurs, it is called and skin ulcerations in a woman with diffuse cutaneous systemic
en coupe de sabre. This should be distinguished from Perry- sclerosis.
Rhomberg syndrome, or facial hemiatrophy, which also affects
the face, usually unilaterally, with atrophy of skin rather than
fibrosis. Both en coupe de sabre and Perry-Rhomberg syndrome
can be associated with central nervous system (CNS) involvement,
presenting as headaches, visual disturbance, or a seizure disorder.
Uncommon forms of localized scleroderma include pansclerotic
morphea, keloid morphea, deep morphea presenting as a fasciitis,
and bullous morphea with blistering. Morphea lesions can be
seen in patients with SSc, and often lichen sclerosus is seen in
association with morphea.
Symptoms
Characteristically, the earliest symptoms of SSc are nonspecific
and include fatigue, musculoskeletal distress (stiffness or pain),
and feeling ill. Cold sensitivity and Raynaud phenomenon occur
early in the disease and may be the only clinical clue to the
presence of active disease. Symptoms of esophageal dysfunc-
tion with dysphagia, heartburn, and periodic GI reflux are FIG 55.4 Pigmentation Changes in the Skin. Vitiligo (salt-and-
common problems, which, along with Raynaud phenomenon, pepper) appearance of the involved skin in a patient of African
can precede other manifestations of SSc by years. Visible capillary descent with diffuse cutaneous systemic sclerosis.
abnormalities easily seen at the nailfold (dilatation and loss or
dropout of capillaries) are almost a universal finding in SSc.
These nailfold capillary changes provide a clinical clue to presence Soft tissue swelling, intense pruritus and burning, and nonpitting
of the underlying vascular disease in that changes occur early edema are signs of the early inflammatory or “edematous” phase
in the disease course and progress in association with other of the diffuse cutaneous form of the disease. The skin of the
systemic involvement. An individual presenting with Raynaud fingers, hands, distal limbs, and face are usually affected first
phenomenon, abnormal nailfold capillaries, and the presence and more severely compared with other body areas (Fig. 55.3).
of an SSc-specific autoantibody can be suspected of having SSc Carpal tunnel syndrome can be present as a consequence of soft
even before other more obvious manifestations are noted. 13 tissue inflammation around hands and wrists. Patients may note
skin hyperpigmentation (patches or generalized tanning). Other
CLINICaL PEarLS early skin changes include vitiligo-like hypopigmentation (“salt
Clinical Features of Early Systemic Sclerosis and pepper” appearance), often on the chest or the back (Fig.
55.4). Escalating musculoskeletal symptoms are common and
• Definite Raynaud phenomenon are associated with muscle weakness and decreased joint mobility.
• Gastroesophageal reflux with heartburn Significant finger and hand/wrist disease limits the patient from
• Swelling of the fingers and hands doing simple chores or performing self-care.
• Musculoskeletal pain and stiffness The early edematous phase of dcSSc has prominent inflam-
• Dilated nailfold capillaries
• Hyper- or hypopigmentary changes of skin matory features, with significant skin edema and erythema, and
is associated with inflammatory cell infiltration in the dermis.
After a period of weeks to months, the inflammatory phase evolves
Diffuse SSc into the “fibrotic” phase as increased collagen and extracellular
In general, patients with dcSSc have a short interval between material is deposited in skin, causing thickening and loss of
the onset of Raynaud phenomenon and other signs and symptoms. flexibility. The fibrotic process starts in the dermis and is associated

CHaPtEr 55 Scleroderma–Systemic Sclerosis 749


with loss of body hair, reduced production of skin oils, and a disease, severe GI dysfunction, SRC, progressive heart disease,
decline in sweating capacity as these cutaneous structures atrophy. and recurrent digital ulcers during the initial active inflammatory
Gradually, the subcutaneous tissue becomes affected, with atrophy and fibrotic phases of the skin disease. In practical terms, this
of subcutaneous fat and fibrosis extending to the underlying means that in dcSSc, the initial 3–4 years is the period that the
fascia, muscle, and other soft tissue structures. During the fibrotic systemic process is most active; if organ failure does not occur
phase, patients note pain, progressive loss of flexibility, distressing during this period, the systemic process may stabilize without
disfigurement, and profound weight loss. Progressive flexion further progression.
contractures of the finger joints ensue. Other joints, including
wrist, elbow, shoulder, hip girdle, knees, and ankle, can also be Limited Cutaneous SSc
affected as a result of fibrosis of the supporting joint structures The disease course in the limited cutaneous variant of SSc is
(see Fig. 55.3). Thick ridges at the neck caused by firm adherence more indolent and often relatively benign. After the onset of
of skin to the underlying platysma muscle interfere with neck Raynaud phenomenon, several years may pass before additional
extension. Tendon friction rub is a prominent crepitation that symptoms or signs are recognized. The most common non-
can be felt or even heard over tendons of the lower and upper Raynaud symptoms in patients with lcSSc are those of upper
extremities. Tendon friction rubs are caused by fibrosis in the GI disease with dysphagia and gastroesophageal reflux. Dilated
tissues surrounding the affected joints; they are associated with capillaries form visible erythematous vascular lesions (telangi-
rapidly progressive skin disease and are linked to an overall poor ectasia), seen most commonly on the fingertips, nailfold areas
prognosis. Fibrosis of the skin of the face yields a characteristic of the digits, palms, face, lips, and inside the oral cavity (Fig.
facial appearance with diminished oral aperture, loss of facial 55.6). CREST (subcutaneous calcinosis, Raynaud phenomenon,
expression, vertical lines around the lips, loss of lip thickness, esophageal dysfunction, sclerodactyly, and telangiectasia) syn-
and protrusion of teeth. drome is a subtype of lcSSc, with distinctive features, an overall
The natural history of skin disease in dcSSc tends to be good prognosis, and an association with the presence of anti-
monophasic, and relapse is uncommon after the edematous and centromere antibodies. Subcutaneous calcinosis caused by
active fibrotic phase. The duration of active skin disease from deposition of calcium hydroxyapatite crystals occurs commonly
the first signs of skin involvement to its maximal extent is at sites of tissue ischemia and recurrent trauma, such as the
characteristically less than 3 years; cutaneous inflammation and fingertips, forearm, or elbow.
progressive fibrosis gradually subside, and regression of skin Although significant internal organ disease occurs with lower
involvement begins. However, this time frame is highly variable frequency in patients with lcSSc, isolated pulmonary arterial
from one patient to another, with many patients demonstrating hypertension (PAH) develops in 10–15% of patients and may
14
rapid skin regression and others showing chronically active disease be life-threatening. Significant interstitial lung disease can
over years. In the late stages of dcSSc, skin remodeling can be occur in about 20% of patients with lcSSc. Severe Raynaud
dramatic, with return to normal-appearing skin in those areas phenomenon with macrovascular occlusive involvement occurs
spared from severe end-stage fibrosis. In more severely affected more frequently in lcSSc than in dcSSc and can be associated
areas, the skin becomes thin or atrophic and can be bound down with critical digital ischemia, ischemic ulcerations, gangrene,
to underlying structures. Skin ulcerations or dystrophic calcifica- and amputation. Overlap with other autoimmune syndromes,
tion often complicate the fibrotic, atrophic, and avascular skin including the sicca complex, polyarthritis, cutaneous vasculitis,
(Fig. 55.5). and autoimmune liver disease, such as biliary cirrhosis, is seen
Although the skin involvement is generally the most dramatic primarily in the lcSSc subset of SSc.
and visible manifestation of dcSSc, internal organ involvement
occurs during the early active stage of advancing skin disease. Raynaud Phenomenon
Patients with dcSSc have a significant risk for interstitial lung The skin has a unique vascular architecture that is designed to
maintain a stable central body temperature. This system has
superficial and deep vascular plexuses that allow shunting of























FIG 55.5 Traumatic Digital Ulcer. Ulceration of atrophic skin FIG 55.6 Telangiectasia. Characteristic telangiectasia on the
over the metacarpal joint of patient with diffuse scleroderma. lip in a woman with limited cutaneous systemic sclerosis.

750 Part SIX Systemic Immune Diseases


blood away from the skin surface during cold exposure and Digital sympathectomy is used when medical therapy has failed
increases surface blood flow during hot ambient temperatures. to reverse critical digital ischemia. In a few cases, macrovascular
Arteriovenous anastomoses (AVAs) connecting arterioles and occlusive disease (particularly in the ulnar artery) can be surgically
venules allow blood to bypass capillaries, thus allowing rapid and bypassed to improve distal blood flow.
marked increases in cutaneous blood flow. Increased activity of
the sympathetic nervous system via both the CNS (body chilling) Gastrointestinal Involvement
and the peripheral nervous system (local cooling of skin) initiates GI disease is a major cause of morbidity and mortality and
vasoconstriction and heat conservation. Selective responses to accounts for one of the most frequent initial symptoms of
cold by AVAs allow preservation of nutritional blood flow through scleroderma. Every part of the GI tract can be involved, including
skin capillaries. Raynaud phenomenon–associated increase in the oral pharynx, esophagus, stomach, and the small and large
vascular tone results, in part, from a defect in the vascular response bowels. A reduced oral aperture (microstomia) is not only
to normal sympathetic signals. Studies find that α 2 adrenergic cosmetically unpleasant, but it also impairs daily hygiene and
receptors on the smooth muscle cells of cutaneous vessels mediate normal mastication. Periodontal disease is a consequence of
vasoconstriction in AVAs during a response to cold temperature. several factors, including decrease salvia, difficulty in dental care,
This response to sympathetic input is abnormally increased in GI efflux disease, gum recession, and bone resorption. Caries
patients with Raynaud phenomenon. 15 and tooth loss can result. Initial symptoms are difficulty chewing
Raynaud phenomenon is clinically defined as well-demarcated and difficulty swallowing dry or a larger bolus of food.
color changes of the digits induced by cold or emotional stress. Almost all patients with SSc demonstrate evidence of distal
Vascular constriction of AVSs, arterioles, and small arteries in esophageal dysfunction. Clinically, this presents with dysphagia,
the skin and tissues of the digits causes the pallor of the digits, heartburn, and regurgitation typical of gastroesophageal reflux
the phase of complete loss of blood flow. The initial vasospasm disease (GERD). These symptoms are caused by peristaltic dysfunc-
and pallor is followed by cyanosis of the skin caused by venous tion of the distal esophagus, decreased lower esophageal sphincter
pooling and low flow with deoxygenated blood. Finally, after (LES) pressure, and delayed gastric emptying, which is thought
rewarming, the recovery phase occurs with vasodilation manifested to be secondary to autonomic dysfunction. Pathological studies
by hyperemia with blushed reddened skin as blood flow rebounds. of the esophagus show that the smooth muscle (circular greater
Raynaud phenomenon affects as much as 3–5% of the general than longitudinal) of the bowel atrophies without significant
18
population. Raynaud phenomenon is considered to be primary fibrosis, vascular injury, or obvious inflammation. Functional
when there is no other associated disease state. In these cases, it and pharmacological studies have shown that a neurogenic
is thought to represent a genetic trait with cold sensitivity as a process precedes smooth muscle dysfunction. Autoantibodies
result of abnormal cutaneous vessel reactivity to environmental directed against enteric neurons and antimuscarinic antibodies
temperatures. In SSc, the disease process targets the peripheral are found, suggesting that an immune process is involved in
vasculature, including AVAs or thermoregulatory blood vessels. the pathogenesis of bowel dysmotility. Esophageal manometric
This leads to not only the abnormal reactivity to ambient evaluation reveals the characteristic triad of low or absent primary
temperatures typical of Raynaud phenomenon but also significant and secondary peristaltic activity in the distal esophagus, normal
structural disease of blood vessels, which causes tissue ischemia proximal esophageal (striated muscle) motility, and the loss of the
as a result of compromise to blood flow within capillaries or LES tone. Complications include reflux esophagitis, esophageal
nutritional vessels. As a consequence of both an exaggerated strictures, mucosal erosions, and bleeding; Barrett metaplasia
response to cold and structural vascular disease, patients with or, very rarely, adenocarcinoma may also develop.
SSc have severe Raynaud phenomenon with multiple, and often Early satiety, bloating, nausea, periodic vomiting, and decreased
prolonged, daily episodes. The severe vascular disease can lead appetite with weight loss are seen secondary to poor gastric
to critical ischemia with digital ulcerations or deep tissue infarc- emptying and retention of food and liquids in the stomach.
tion and gangrene. The vascular disease in SSc is not limited to Gastroparesis is commonly associated with esophageal dysfunction
skin but is systemic. There is evidence that abnormal vascular and aggravates GERD. Dilatation of mucosal capillaries in the
reactivity resulting in tissue injury occurs in the pulmonary, GI tract is common, particularly in the gastric antrum. Gastric
renal, GI, and coronary circulations. antral vascular ectasia (GAVE), also known as “watermelon
Treatment of Raynaud phenomenon must be individualized stomach,” is the major gastric manifestation, which may lead to
and adjusted according to its severity. Initial therapy should occult bleeding and significant anemia. Intestinal dysmotility
include avoidance of cold exposure and use of methods of stress can involve the small and large bowels. Patients may note a
reduction. The best studied medications to treat Raynaud change in bowel habits or present with episodes of pseudoobstruc-
phenomenon are the calcium channel blockers (e.g., nifedipine), tion with severe abdominal pain, bloating, abdominal distension,
which remain the recommended first choice of therapy. Other and vomiting. Persistent diarrhea may be a manifestation of
vasoactive drugs reported to be helpful include the phosphodi- malabsorption of fats as a result of bacterial overgrowth in the
esterase inhibitors, such as sildenafil; serotonin reuptake inhibitors, atonic small bowel and can be associated with dramatic weight
such as fluoxetine; nitrates, such as topical nitroglycerine; and loss and malnutrition. In the late stages, the bowel wall thins
16
intravenous prostaglandins. Bosentan, an endothelin-1 receptor out and traps air (pneumatosis cystoides intestinalis). Wide-mouth
inhibitor, was recently shown to reduce the incidence of new diverticuli develop in the colon or the bowel and may rupture.
digital ulcers in patients with SSc but not to alter the frequency Incontinence of stool can occur as a result of dysfunction of
17
of Raynaud events. Statins may also protect peripheral blood anal sphincters.
vessels and prevent ischemic digital ulcers, and antioxidants have
the potential to reduce oxidative stress to tissues. Botulinum Pulmonary Involvement
toxin injected locally at the base of the fingers is reported to be Lung disease is now the leading cause of death in patients
helpful, but a controlled clinical trial is needed to define its role. with SSc and accounts for significant lifetime morbidity. Lung

CHaPtEr 55 Scleroderma–Systemic Sclerosis 751


involvement is often asymptomatic and nonprogressive, yet idiopathic pulmonary fibrosis), and nintedanib (a tyrosine kinase
significant lung abnormalities can be detected in over 40% of inhibitor). 23,24
patients with sensitive lung function testing or special imaging.
In a subgroup of patients (10–20%), the disease process can Pulmonary Arterial Hypertension
lead to major pulmonary vascular disease or inflammation with PAH is detected in 8–15% of patients with SSc and may occur
progressive fibrosis and subsequent respiratory failure and death. as the sole pulmonary manifestation of the disease or in
25
A recent survey reported that 35% of all SSc-related deaths were association with ILD. The natural history of PAH is highly
directly attributable to pulmonary fibrosis or interstitial lung variable. In many patients, it is clinically silent for years before
19
disease (ILD), and 26% of deaths resulted from PAH. Additional it presents with exertional dyspnea and hypoxia secondary to
pulmonary manifestations of SSc include aspiration pneumo- altered gas exchange and right heart failure. It is most often
nitis, pulmonary hemorrhage, bronchiectasis, bronchiolitis a late (9–12 years after onset of Raynaud phenomenon [RP])
obliterans with organizing pneumonia, pleural reactions, and complication in patients with limited scleroderma; but PAH
pneumothorax. The risk of lung cancer is increased in patients can occur within 5 years from the disease onset, particularly
with SSc. in patients older at the time of SSc diagnosis. Risk factors for
PAH in SSc include disease onset at a later age, history of severe
Interstitial Lung Disease RP, numerous skin telangiectasias, abnormal nailfold capillar-
Nonspecific interstitial pneumonia (NSIP) is the most common ies, the presence of anticentromere, anti-U1 ribonucleoprotein
histopathological pattern in patients with SSc-related ILD (RNP), anti–U3 RNP (fibrillarin), or anti-B23 antibodies.
(SSc-ILD). The prevalence of SSc-ILD is found in 50% of Untreated, the estimated 3-year survival is approximately
those with dcSSc compared with 35% in those with lcSSc. The 50%. Although responses to current therapy are not as good
presence of topoisomerase-I autoantibodies is strongly linked among patients with SSc and PAH compared with patients
to the development of ILD, and the worst outcome is often with idiopathic PAH, there is evidence of improved survival on
seen in African Americans and Native Americans. Inflamma- modern therapy compared with historical controls. Prognosis
tory alveolitis and subsequent tissue fibrosis causes restrictive is poor among patients with PAH associated with ILD, and an
ventilatory defect and an abnormal gas exchange. Patients with even worse prognosis is associated with increased blood brain
ILD usually experience rapid initial decline in lung function natriuretic protein (BNP), echocardiographic signs of right heart
during the early period of active disease. About 20% of patients disease, and decreased diffusion capacity of the lungs for carbon
who eventually developed severe ILD (FVC ≤50%) have a fall monoxide (DLCO) on lung testing. PH can occur in SSc in the
in forced vital capacity (FVC) within 4 years of the onset of absence of PAH as a result of left heart disease or secondary
symptoms. If there is only minor impairment in FVC on lung to chronic hypoxia from severe ILD. Therefore patients need
function after more than 5 years of disease duration, then is it to undergo a right heart cauterization to confirm the presence
unlikely that the patient will ever develop severe lung fibrosis. of PAH or PH and characterize its severity. Current therapy
In early disease, most patients have no respiratory symptoms. for SSc-associated PAH is focused on supportive care, reduc-
26
The most sensitive methods to detect early lung disease are tion of cardiac work load, and vasoactive drugs. Short-acting
pulmonary function testing and imaging with high-resolution prostacyclin analogues, including intravenous (epoprostenol or
computed tomography (HRCT). The presence of fibrosis and treprostinil) or inhaled (iloprost) prostaglandins, are used for
ground-glass opacities on HRCT is an indication of the activity treating severe disease. Selective and nonselective endothelin-1
of the disease process and correlates with subsequent decline in receptor inhibitors (bosentan, ambrisentan, and macitentan),
FVC. When the extent of disease defined by HRCT is <20%, the a phosphodiesterase type 5 inhibitor (sildenafil, tadalafil, and
10-year survival is reported to be 67%, whereas in the group vardenafil), and a soluble guanylate–cyclase stimulator (riociguat)
with HRCT-defined disease extent of >20%, 10-year survival is are helpful for treating milder disease. Early intervention and
20
considerably poorer at 43%. Likewise, FVC of <70% is associated combination therapy may help achieve improved outcomes. In
with a poor prognosis. Biological biomarkers that can detect active relatively short-term clinical trials, each of these treatments has
alveolitis and predict disease progression are needed. The presence been shown to improve exercise tolerance and hemodynamics,
of neutrophilia in fluid obtained from bronchoalveolar lavage with variable benefit on disease progression. Early detection
(BAL) was thought to predict outcome, but neutrophilia does of PAH is important as it provides an opportunity for timely
not clearly define prognosis or response to therapy. Both Krebs intervention. A systematic detection program in which periodic
von den Lungen-6 (KL-6), a lung glycoprotein, and surfactant screening was performed in every patient with SSc detected less
protein-D (SP-D) levels are elevated in patients with SSc compared severe pulmonary vascular disease and showed better survival
with controls and higher in patients with alveolitis compared on therapy compared with that in patients managed by usual
27
with those without alveolitis; thus SP-D levels are thought to clinical practice. Because of the complexity of life-threatening
be useful biomarkers of disease progression. Two multicenter PAH, it is recommended that patients be referred to experts in
clinical trials have been completed; one compared cyclophos- pulmonary medicine, especially in PAH, to manage these cases.
phamide to placebo, and the other compared cyclophosphamide Lung transplantation remains an option for carefully selected
to mycophenolate. 21,22 Both studies demonstrated statistically patients with SSc, with survival following lung transplanta-
significant stabilization or improvement of lung function along tion being similar to that of non-SSc patients with other lung
with improvement in scleroderma skin score and a variety of diseases.
clinical measures. These studies suggest that immunosuppres-
sive therapy can control active lung disease. A variety of other Cardiac Involvement
agents are now being tested in SSc-ILD, including rituximab Cardiac involvement is common, but often there are no signs
(monoclonal antibody [mAb] to CD20 on B lymphocytes), or symptoms until the heart has been severely affected. The
pirfenidone (an antifibrotic/antiinflammatory agent used in reported prevalence of heart disease varies, depending on method

752 Part SIX Systemic Immune Diseases


of detection. Clinical criteria are insensitive, but modern sensitive process, which leads to glomerular hypoperfusion and a high
tools, such as echocardiography, tissue Doppler imaging, speckle- renin state.
tracking echocardiography, cardiac magnetic resonance imaging, Patients with SRC who present with a creatinine >3 mg/dL have
or thallium scanning, can detect disease early and suggest that a poor outcome, with increased likelihood of permanent hemo-
40–60% of patients have heart disease. When heart disease is dialysis, need for renal transplantation, and/or high mortality.
symptomatic, the prognosis is poor. SSc can affect virtually any Prompt and aggressive intervention with angiotensin-converting
cardiac structure, including the myocardium with fibrosis or enzyme (ACE) inhibitors to achieve blood pressure control before
inflammatory myocarditis, the myocardial microvasculature, or evidence of renal dysfunction is seen significantly improves the
the pericardium with asymptomatic small effusions or large prognosis. Introduction of ACE inhibitors dramatically improved
effusions leading to cardiac tamponade. As a consequence of survival from a 1-year survival rate of 10% to a 5-year survival
cardiac tissue injury, left ventricular (LV) systolic dysfunction rate of 60%. All patients with SRC should be treated with an
and/or LV diastolic dysfunction and/or right ventricular (RV) ACE inhibitor, but other vasodilators, including calcium channel
failure and/or conduction abnormalities with complex arrhyth- blockers, endothelin receptor inhibitors, and prostaglandins,
mias can occur, but valvular heart disease is unusual. Cardiac can be helpful. About 45% of patients whose blood pressure is
dysfunction can be primary to the disease process or secondary normalized do not require dialysis. Reasonable kidney function
to other organ diseases, including PAH, ILD, or SRC. Cardiac can resume months after renal failure and the need for dialysis
disease occurs in both the limited and the diffuse subtypes but support. Despite ideal therapy, approximately 40% of patients
is more common in the patients with rapidly progressive diffuse still need long-term kidney support or have a poor survival.
skin disease, in those with anti-U3 RNP antibodies, and in Overall survival on chronic dialysis is worse in patients with SSc
28
association with peripheral muscle disease. Heart disease is compared with those without SSc, but renal transplantation is
reported to be a cause of death in 20–30% of patients and is an still an option with a long-term outcome similar to that of other
independent risk factor for death. Optimal screening for heart causes of renal failure.
disease is not well defined, but periodic clinical assessment coupled
with echocardiography and blood levels of BNP is recommended.
Modern techniques for detecting occult heart disease provide CLINICaL PEarLS
opportunities for early intervention and should be used for Recommended Approach to Systemic Sclerosis
thorough evaluation of the patient when cardiac involvement
is suspected. The ideal therapy is defined by the underlying situ- • Determine scleroderma skin score to define clinical subtype
• Frequent clinical reassessment to define disease activity
ation (e.g., vasodilator therapy to improve heart perfusion or • Careful clinical history to evaluate for gastrointestinal dysmotility
antiarrhythmia therapy for a complex arrhythmia). A disease- • Monitor for new onset hypertension: prevent renal crisis
modifying drug that specifically targets scleroderma heart disease • Pulmonary function test: early detection of interstitial lung disease
has not yet been discovered. • Doppler echocardiography: screen for pulmonary arterial hypertension
• Obtain serology profile to help predict clinical outcome
Renal Involvement
Renal disease is an important clinical problem with both direct
involvement and kidney compromise secondary to other organ Musculoskeletal Complications
dysfunction. The most dreaded renal complication is an SRC, Musculoskeletal impairment is a leading cause of disability and
which is defined as the new onset of accelerated arterial hyper- poor quality of life among patients with SSc. It is seen in the
tension and/or rapidly progressive oliguric renal failure during majority of patients, occurs early in the disease, and commonly
the course of the disease. It is recognized that other causes of has a dominant effect on hand function. There is a variety of
renal disease, including interstitial nephritis, glomerulonephritis, associated clinical symptoms, including arthralgias, myalgias,
and antineutrophil cytoplasmic antibody (ANCA)–associated stiffness, pain and loss of function as a result of joint contractures,
vasculitis, can occur. SRC develops in 10–15% of patients with inflammatory arthritis, myopathy, nerve entrapment (e.g., carpal
dcSSc, but in less than 5% of patients with lcSSc. It is gener- tunnel syndrome), fibrosis of tendons, and deconditioning from
ally a relatively early (<3–4 years) complication of the disease disuse. Loss of joint function is less likely to be secondary to
29
and is more likely to occur in males. The presence of rapid synovitis but is usually caused by fibrosis of the overlying skin,
progression of diffuse skin disease; tendon friction rubs; cardiac the supporting joint structures, and the joint capsule itself. Flexion
disease with clinically silent pericardial effusion, arrhythmias, contractures associated with “friction rubs” most prominently
or congestive heart failure; new unexplained anemia; or the felt over the ankles, knees, shoulders, and wrist are typical of
use of corticosteroids are all associated with an increased risk advanced dcSSc. Muscle weakness is a common comorbid condi-
of SRC. The autoantibody status is also helpful in identifying tion caused by deconditioning, muscle disuse, or malnutrition
patients at risk for SRC. In approximately 30% of patients with associated with weight loss. A scleroderma-related myopathy
anti-RNA polymerase III, seen almost exclusively in dcSSc, SRC defined by weakness with elevated serum creatine kinase (CK)
develops; however, SRC occurs in only 10% of patients with level; myopathic features on electromyography (EMG); and/or
antitopoisomerase antibodies and only rarely in patients with muscle biopsy is reported to occur in about 20% of patients. Most
anticentromere antibody. SRC characteristically presents as sudden patients with skeletal myopathy have proximal muscle weakness
onset of malignant hypertension with rapidly progressive oliguric on examination, and about 40% have one of the scleroderma/
renal failure. Proteinuria, microhematuria, and evidence of a myopathy–associated autoantibodies (i.e., anti-PM/Scl-75,
microangiopathic hemolytic process with thrombocytopenia anti-PM/Scl-100, or anti-CD1). The histopathological findings
are present. The exact mechanism triggering acute SRC is are highly variable, with fibrosis alone seen only in a small subset.
not known, but an autoimmune insult to the underlying SSc When inflammation and/or necrosis are seen, immunosuppressive
microvascular disease is thought to initiate a self-perpetuating therapy has the potential to control the muscle disease.

CHaPtEr 55 Scleroderma–Systemic Sclerosis 753


31
Evidence-based management of SSc is helpful while innova-
Emotional Aspects tive therapies are being further studied in clinical trials.
32
SSc impacts every aspect of a patient’s life and is a disfiguring Scleroderma is a multifaceted disease that includes active autoim-
disease; therefore, it is not surprising that significant depression munity, vascular injury, and fibrosis and/or epithelial damage.
30
is common among patients with SSc. Patients are frequently Thus the major targets for therapy include regulating the immune
distressed by their appearance and avoid social interaction. system, controlling tissue fibrosis, and protection or prevention
Chronic pain and lack of social support are major causes of of progressive vascular disease. The majority of therapeutic
depression; therefore, family education, emotional support, pain interventions for scleroderma attempt to modify the disease
control, and management of depressive symptoms are most process by immunomodulation in early active dcSSc because of
important. the evidence that the SSc is an autoimmune disease initiated
and/or propagated by an immune process. Drugs currently used
Treatment for dcSSc include methotrexate, cyclophosphamide, and myco-
phenolate mofetil. Targeting specific immune cells is now a novel
tHEraPEUtIC PrINCIPLES strategy that includes eliminating B cells with rituximab and
Treatment of Systemic Sclerosis suppressing activation of T cells with abatacept. In cases of severe
life-threatening disease in highly selected cases not responding
Organ-Specific therapy to low-dose immunosuppression, immunoablative therapy with
• Vasodilator therapy for Raynaud phenomenon high-dose cyclophosphamide alone or with radiation, followed
• Proton pump inhibitor for gastroesophageal reflux by stem cell rescue, may be considered. Studies to evaluate the
33
• Angiotensin-converting enzyme (ACE) inhibitor for scleroderma renal safety and efficacy of stem cell therapies are in progress. Inhibit-
crisis ing proinflammatory and/or profibrotic cytokines or signaling
• Vasodilator therapy for pulmonary arterial hypertension pathways that may block tissue injury and fibrosis are being
• Antiinflammatory therapy for arthritis explored. These include antichemokines (CCR2) or inhibitors
• Immunosuppressive therapy for interstitial lung disease
of CTGFs, recombinant humanized mAb to block TGF-β1 activity,
Disease-Modifying agents modulation of interleukin-6 (IL-6) signaling, antagonists of the
• No ideal treatment available; immunomodulatory, antiinflammatory, bioactive phospholipid LPA, and small-molecule inhibitors, such
vasoactive, and antifibrotic agents are used and/or under study. as tyrosine kinase inhibitors or pirfenidone. It is recognized that
vascular disease also plays a fundamental role in the morbidity
and mortality seen in scleroderma. Novel drugs targeting vascular
To date, no drug or intervention has been proven to be effective disease, including endothelin receptor antagonists, agents that
and safe for modifying the overall disease course. Most successful enhance nitric oxide production, prostacyclin analogs, antiplatelet
SSc treatments are directed to the specific organ(s) involved. agents, and statins, are currently being used.
Therapy is focused on an organ-specific disease process (e.g.,
ACE inhibitor in SRC) or to aid a failing organ (e.g., proton ON tHE HOrIZON
pump inhibitors for GERD). Therefore it is important to carefully Novel Therapeutic Approaches to Systemic
characterize the patient’s clinical phenotype, specific organ Sclerosis (SSc) Management in Clinical Trials
involvement, and level of disease activity before deciding on
therapy. For example, a patient who has lcSSc but no evidence • Targeted therapies to block transforming growth factor-β (TGF-β)
of visceral organ involvement is likely to have a benign course • Development of antifibrotic agents, including new approaches to
that requires only symptomatic therapy (e.g., treatment of GERD blocking of fibrogenic pathways
and RP); use of systemic disease-modifying drugs would not be • Use of biological agents, including anticytokines, antichemokines, and
growth factor inhibitors
indicated. It is also important to distinguish disease activity from
severity or advanced cumulative organ damage. For example, a
patient with late-stage dcSSc with irreversible organ damage is Other Fibrosing Diseases
34
unlikely to benefit from aggressive immunosuppressive or Several disorders can cause skin fibrosis and mimic SSc. SSc
antiinflammatory therapy. Intervention with currently available can be distinguished from these SSc-like fibrosing conditions
drugs should be initiated early, ideally during the edematous by its characteristic clinical, pathological, and laboratory features.
active inflammatory phase of the disease. It is during the early The most distinguishing clinical features of SSc include the
stage of the disease that immunosuppression and antiinflam- presence of RP, nailfold capillary changes, the characteristic
matory and antifibrotic agents have the greatest potential to distribution, and characteristic skin changes. The skin pattern
control disease progression. Clinical experience teaches that once in SSc is noted for severe finger, hand, and distal limb involvement
the edematous phase of the disease shifts to the more indolent and sparing of the skin of the back of the trunk. SSc-specific
fibrotic phase, current treatments are less likely to control the serum autoantibodies also help define the presence of the SSc
progression of disease and tissue damage. The primary outcome disease process.
measure in clinical trials that focused on aggressive skin disease Conditions that mimic SSC include localized forms of
has been the modified Rodnan skin score; in current studies, scleroderma (see Table 55.5), eosinophilic fasciitis, nephrogenic
however, composite scores that tally the burden of disease (activity systemic fibrosis, scleromyxedema (papular mucinosis), scler-
and severity) as well as patient reported distress are included. edema, graft-versus-host disease (GvHD), toxic oil syndrome,
Few well-designed controlled studies have been carried out for and eosinophilia–myalgia syndrome (Table 55.6). Eosinophilic
the treatment of early active disease; most reports are of anecdotal, fasciitis presents with induration of subcutaneous tissues, par-
uncontrolled experiences, complicated by investigator bias and ticularly in the proximal limbs, without RP or systemic organ
the highly variable natural course of SSc. involvement. A peripheral eosinophilia with radiological and

754 Part SIX Systemic Immune Diseases



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• Nephrogenic fibrosing dermatopathy systemic sclerosis. Lancet 2004;364:603–10.
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• Eosinophilia–myalgia syndrome homeostasis in systemic sclerosis: expanded naive B cells and diminished
• Generalized morphea but activated memory B cells. Arthritis Rheum 2004;50:1918–27.
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• Diabetic digital sclerosis 2003;48:1964–78.
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• Bleomycin exposure involvement in diffuse scleroderma. Ann Rheum Dis 2011;70:104–9.
• Werner syndrome 12. Mendoza F, Derk CT. Systemic sclerosis mortality in the United States:
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• Vibration white finger syndrome 13. LeRoy EC, Medsger TA Jr. Criteria for the classification of early systemic
• Chronic reflex sympathetic dystrophy sclerosis. J Rheumatol 2001;28:1573–6.
14. Chung L, Domsic RT, Lingala B, et al. Survival and predictors of
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and recognition of outcomes in scleroderma registry. Arthritis Care Res
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histological evidence of an inflammatory process in the fasciae 15. Flavahan NA. A vascular mechanistic approach to understanding
is present. Nephrogenic systemic fibrosis is described in patients Raynaud phenomenon. Nature 2015;11:146–58.
with end-stage renal disease who were exposed to gadolinium- 16. Cappelli L, Wigley FM. Management of Raynaud phenomenon and
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based contrast agents. Scleromyxedema, a condition of mucinous digital ulcers in scleroderma. Rheum Dis Clin North Am 2015;41:
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gammopathy that is characterized by a diffuse, papular skin 17. Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic
eruption. Scleredema occurs with deposition of collagen and sclerosis: prevention by treatment with bosentan, an oral endothelin
receptor antagonist. Arthritis Rheum 2004;50:3985–93.
mucin in the dermis and primarily involves the upper back, 18. Roberts CG, Hummers LK, Ravich WJ, et al. A case-controlled study of
neck, and face. It occurs in association with diabetes, a monoclonal the pathology of oesophageal disease in systemic sclerosis (scleroderma).
gammopathy, or postinfection pharyngitis, particularly streptococ- Gut 2006;55:1697–703.
cal pharyngitis. GvHD occurs after bone marrow or stem cell 19. Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in
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matory and thickened skin with liver and GI involvement. Toxin Research (EUSTAR) database. Ann Rheum Dis 2010;69:1809–15.
exposure was linked to the toxic oil syndrome (adulterated 20. Goh NS, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in
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by banning the agents involved, but sporadic cases of eosinophilia– Research Group. Cyclophosphamide versus placebo in scleroderma lung
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(SLS II) shows that both oral cyclophosphamide (CYC) and
Please check your eBook at https://expertconsult.inkling.com/ mycophenolate mofetil (MMF) are efficacious in treating progressive
for self-assessment questions. See inside cover for registration interstitial lung disease (ILD) in patients with systemic sclerosis (SSc).
details. Arthritis Rheumatol 2015;67(Suppl. 10). http://acrabstracts.org/abstract/

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the-scleroderma-lung-study-ii-sls-ii-shows-that-bothoral-cyclophospha 29. Denton CP, Lapadula G, Mouthon L, et al. Renal complications and
mide-cyc-and-mycophenolate-mofitil-mmf-are-efficacious-in-treatingpro scleroderma renal crisis. Rheumatology (Oxford) 2009;48(Suppl.iii):32–5.
gressive-interstitial-lung-disease-ild-in-patients-w/. 30. Haythornthwaite JA, Heinberg LJ, McGuire L. Psychologic factors in
23. Silver KC, Silver RM. Management of systemic-sclerosis-associated scleroderma. Rheum Dis Clin North Am 2003;29:427–39.
interstitial lung disease. Rheum Dis Clin North Am 2015;41:439–57. 31. Khanna D, Denton CP. Evidence-based management of rapidly
24. Lota HK, Wells AU. The evolving pharmacotherapy of pulmonary progressing systemic sclerosis. Best Pract Res Clin Rheum
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25. Le Pavec JL, Humbert M, Mouthon L, et al. Systemic sclerosis-associated 32. Denton CP. Advances in pathogenesis and treatment of systemic sclerosis.
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2010;181:1285–93. 33. Van Laar JM, Naraghi K, Tyndall A. Haematopoietic stem cell
26. Mathai SC, Hassoun PM. Therapy for pulmonary arterial hypertension transplantation for poor-prognosis systemic sclerosis. Rheumatology
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CHaPtEr 55 Scleroderma–Systemic Sclerosis 755.e1


MUL t IPLE-CHOICE QUES t IONS

1. Which of the following complications is MOST frequent in 3. Which of the scleroderma related autoantibodies are associated
systemic sclerosis (SSc)? with the highest risk for developing a scleroderma renal crisis
A. Glomerulonephritis (SRC)?
B. Scleritis A. Anticentromere
C. Renal crisis B. Antitopoisomerase
D. Tendon rupture C. Anti-RNA polymerase III
E. Pulmonary arterial hypertension D. Anti-U1 ribonucleoprotein (RNP)
E. Anti-U3 RNP
2. Characteristic thoracic involvement in SSc include all of the
following EXCEPT: F. Anti-U11/U12 RNP
A. Pulmonary fibrosis 4. What is the major cause of mortality in scleroderma in the
B. Apical nodules modern era?
C. Peripheral reticulations A. Scleroderma renal crisis
D. Enlarged pulmonary artery B. Severe skin disease
E. Patulous esophagus C. Scleroderma lung disease
D. Gastrointestinal failure
E. Complications of medications

56









Inflammatory Muscle Diseases



Arash H. Lahouti, Lisa Christopher-Stine







The idiopathic inflammatory myopathies (IIMs) are a group of can help to better estimate the burden of disease and differentiate
rare systemic diseases. They consist of polymyositis (PM), acute changes (edema) from chronic changes (atrophy). The role
dermatomyositis (DM), inclusion body myositis (IBM), and more of new imaging modalities such as whole-body MRI needs to
recently described immune-mediated necrotizing myopathy be further investigated.
(IMNM). Traditionally, they are believed to be autoimmune Interstitial lung disease, gastrointestinal involvement, and
diseases, although recent studies suggest that there is a close arthritis are among the most common extramuscular manifesta-
resemblance between IBM and other neurodegenerative diseases. tions of the IIM. Interstitial lung disease commonly occurs as
Similar to patients with other autoimmune diseases, those with part of the antisynthetase syndrome in a subset of patients who
IIM often have serum autoantibodies. Some of these antibodies have antisynthetase autoantibodies. Gastrointestinal manifesta-
are specific for myositis and are not seen in other rheumatic tions include dysphagia and aspiration pneumonia. Dysphagia
disorders. Our knowledge of the myositis-specific antibodies is particularly common and can be seen in all forms of the IIMs.
(MSAs) is incomplete. There has been considerable effort to Certain forms of IIM, particularly DM, can be a paraneoplastic
better characterize antibodies associated with myositis and to phenomenon. The most common cancers associated with myositis
discover new antibodies. Many MSAs are closely linked to a include gynecological (ovarian), pulmonary, gastrointestinal
unique clinical phenotype. Thus they are useful in classifying (pancreatic, stomach, and colorectal), and non-Hodgkin lym-
the IIM. They can forewarn of particular extramuscular manifesta- phoma. Also, the IIMs may be associated with other autoimmune
tions and guide appropriate treatment strategies. diseases such as systemic lupus erythematosus (SLE), Sjögren
IIM patients present with muscle weakness and elevated muscle syndrome, and systemic sclerosis.
enzymes. In patients with DM, skin manifestations may be the Muscle biopsy is critical for the diagnosis of the IIMs. The
initial presentation. The differential diagnosis of muscle disease presence of perifascicular atrophy is strongly suggestive of DM,
is broad and includes drug-induced myopathies, neuromuscular whereas the finding of rimmed vacuoles in the appropriate context
disorders, muscular dystrophies, and metabolic and endocrine suggests IBM. Muscle biopsy also differentiates between the IIMs
myopathies. To add to the complexity, some DM patients do not and other forms of myopathy such as drug-induced myopathies
develop muscle weakness, referred to as clinically amyopathic DM. and muscular dystrophies.
The patient’s age and gender, the pattern of the weakness, the Treatment of the IIMs is based largely on experience.
severity of manifestations, and associated symptoms are commonly Corticosteroids remain the mainstay of therapy. Steroid-sparing
helpful in leading to the correct diagnosis. For example, IBM is agents such as azathioprine, methotrexate, mycophenolate mofetil,
distinguished from other IIMs by a characteristic involvement and hydroxychloroquine are frequently initiated at presentation
of the finger flexor and knee extensor muscles, which is often while a steroid taper is attempted. In patients with refractory
asymmetrical. IBM is more common in older men, whereas PM disease, rituximab, intravenous immunoglobulin, and biological
and DM are commonly seen in young to middle-aged women antirheumatic medications may be tried. IBM is the most resistant
and children. DM is often associated with characteristic skin subset of the IIMs.
findings, which are not a feature of PM and IBM. However, in DM, PM, IBM, and IMNM constitute the largest subgroup
many patients differentiation between the IIMs cannot be made of the acquired myopathies. They are a heterogeneous group
on clinical grounds, and further diagnostic testing is required. and are rare among immunological illnesses. However, the IIMs
For example, both PM and IMNM present in the same fashion share many clinical features and laboratory abnormalities,
with a predominantly symmetrical proximal muscle weakness including related autoantibodies, and are closely related to
and elevated muscle enzymes. They can be distinguished only by major autoimmune diseases. Because their presentation and
pathological examination. On muscle biopsy, IMNM is associated major clinical manifestations are weakness and/or rash, the
with necrosis and regeneration of muscle fibers and a characteristic differential diagnosis includes many more common diseases
sparse inflammatory infiltrate. In contrast, PM is associated with familiar to neurologists and dermatologists.
the presence of cytotoxic inflammatory cells surrounding and
invading muscle fibers. Electromyography is a valuable tool for CLINICAL FEATURES
differentiating between weakness originating from muscle rather
than peripheral nerves. Magnetic resonance imaging (MRI) can The clinical hallmark of PM, DM, and IMNM is the gradual
be extremely helpful in identifying inflammatory changes in onset of symmetrical proximal muscle weakness over weeks to
patients with subtle clinical muscle involvement. Moreover, MRI months. In some cases, myalgia may be the presenting or most

757

758 Part SIX Systemic Immune Diseases


bothersome symptom, but more often the patient is evaluated known as Gottron papules. In some cases, the metatarsophalangeal
for the physical limitations imposed by weakness: difficulty arising joints, elbows, knees, and malleoli show a similar rash. Both
from a low chair or bed, or combing and brushing hair. Rash is heliotrope and Gottron rashes can occur rarely in cases of frank
the first feature in a considerable proportion of patients who SLE without muscle involvement. Other common rashes include
have DM, but muscle weakness usually follows within a few a flat, red blanching eruption of the upper chest (often in a V
months. A subset of patients with DM, clinically amyopathic distribution), the upper back (where a shawl would touch), and
dermatomyositis (C-ADM), may present only with rash in the sometimes the extensor surfaces of the upper arms and thighs.
absence of muscle weakness throughout the course of their illness. Another rash that mimics the malar rash of lupus on the face
These patients are also at risk for pulmonary involvement, as may be present; however, in contrast to lupus, it does not spare
are those with classic DM. The prevalence of interstitial pneu- the nasolabial folds. Although found on sun-exposed parts of
monitis in C-ADM can approach 5–10%, compared with 40% the body, these rashes are often not photosensitive in nature. As
1
of patients with classic DM. Arthritis, Raynaud phenomenon, in other connective tissue diseases, nailfold capillary dilatation,
fever, or lung disease presenting as cough or dyspnea may infarcts, and cuticular overgrowth occur. Mechanic’s hands, a
dominate the clinical picture. Cardiac and gastrointestinal roughening and cracking of the radial sides of the fingers and
symptoms, other than dysphagia in severe cases, are rarely early the palm, resembling a condition found in people who labor
manifestations. Renal and central nervous system (CNS) involve- with their hands, is characteristic of a subset of myositis patients
ment are almost never a part of the IIMs. with the “antisynthetase syndrome” and can also be seen in
patients with PM-Scl and U1-RNP autoantibodies.
KEY CONCEPtS CLASSIFICATION
Definition and Incidence of Idiopathic
Inflammatory Myopathies (IIMs) In the past 40 years, several investigators have proposed diag-
nostic classification criteria for IIM. The criteria proposed by
• Polymyositis (PM), dermatomyositis (DM), and related inflammatory Bohan and Peter four decades ago remain the most familiar
muscle diseases are called IIM. and accepted definitions of PM and DM (Table 56.1). They
2,3
• Indistinguishable muscle inflammation may accompany other auto- combine clinical, laboratory, electrodiagnostic, and pathological
immune connective tissue diseases or limb-girdle muscular
dystrophies. features. These criteria currently serve as the gold standard for
• The annual incidence in the US is 5–10 cases per million. DM and clinical diagnosis and for inclusion in clinical trials. However,
PM are more common in women than in men in all age groups; they are limited by their poor specificity in distinguishing PM
inclusion body myositis (IBM) is more common in men. from other entities, including late-onset muscular dystrophies.
The resultant misclassification limits the homogeneity of the
patients included in previous observational and interventional
Some of the rashes of DM are virtually pathognomonic; others studies. Additionally, the Bohan and Peter criteria completely
are not disease-specific (Fig. 56.1). The heliotrope rash, a vio- omit the diagnosis of IBM, the most frequent type of IIM in
laceous discoloration of the eyelids, is sometimes no more than patients over 50 years of age.
a line along the margin of the upper lid, but it may also affect In 2004, more comprehensive criteria of IIM were proposed
both upper and lower lids completely and can be associated with and approved by a group of international experts (Table 56.2).
edema mimicking thyroid disease. A reddish, sometimes raised Unlike the previous criteria, these new criteria offer the advantage
and/or scaly, eruption over the metacarpophalangeal joints is of classifying two rare forms of autoimmune myositis, i.e., IMNM























A B
FIG 56.1 Dermatomyositis Rash. (A) In addition to the heliotrope rash on the eyelids of this
patient with dermatomyositis, there is a flat, red rash on the nose and cheeks. (B) A raised,
shiny-red rash—Gottron papules—is apparent on the interphalangeal and the second and third
metacarpophalangeal joints of this man with dermatomyositis.

CHaPtEr 56 Inflammatory Muscle Diseases 759



TABLE 56.1 Idiopathic Inflammatory to the aminoacyl-tRNA (transfer RNA) synthetases, of which
Myopathy: Diagnostic Criteria Jo-1 is the best known, have a characteristic syndrome called
antisynthetase syndrome, which usually includes interstitial lung
Bohan and Peter disease, nondeforming inflammatory arthritis, fevers, mechanic’s
Criteria hands, and Raynaud phenomenon, in addition to myositis. Those
1. Symmetrical proximal with antibodies to the signal recognition particle (anti-SRP)
muscle weakness
2. Skeletal muscle have an IMNM manifested by severe disease of abrupt onset,
enzyme elevation often in the autumn. According to some studies, cardiac involve-
3. Abnormal EMG a ment is less common and survival is better in patients with
4. Muscle biopsy anti-SRP than has previously been reported. Those with antibod-
6
abnormalities ies to the nuclear antigen Mi-2 almost always have the V and
5. Typical skin rash shawl rashes and cuticular overgrowth in addition to myositis.
of DM b
A recently discovered antibody, anti-3-hydroxy-3-methylglutaryl-
coenzyme A reductase (anti-HMGCR), is tightly linked to
7,8
IMNM. Interestingly, the HMGCR is the pharmacological target
of statin drugs, such as atorvastatin, and a subset of patients
with anti-HMGCR antibodies develop this antibody in the context
a Polyphasic, short, small motor-unit potentials; fibrillation, positive sharp waves,
increased insertional irritability; bizarre, high-frequency, repetitive discharges. of previous statin exposure, although it is also seen in statin-naïve
b Gottron sign, heliotrope rash. individuals, albeit to a lesser extent. Patients with anti-HMGCR
Possible PM = any two of the first four criteria; possible DM = criterion 5 (rash) + any antibodies present with profound proximal muscle weakness
two criteria. Probable PM = any three of the first four criteria; probable DM = criterion
5 (rash) + any three criteria. Definite PM = all four of the first four criteria; definite and a marked creatine kinase (CK) elevation. Further, compared
DM = criterion 5 (rash) + all four other criteria. with statin-exposed individuals, statin-naïve anti-HMGCR
DM, dermatomyositis; EMG, electromyography; PM, polymyositis.
positive patients tend to be younger, have higher CK levels, and
have a blunted response to immunosuppressive medications
(Table 56.5). 2,8
4
and DM sine dermatitis, as separate categories (Table 56.2). IBM is different from other inflammatory myopathies. Patients
Separate classification criteria systems for IBM have been devised. with IBM rarely improve in strength with immunosuppressive
According to most of the previous IBM criteria, characteristic therapy. They tend to be older, and in contrast to patients with
muscle biopsy changes were necessary for a definite diagnosis PM and DM, who are predominantly women, patients with IBM
of IBM. However, because selective involvement of finger flexors are more commonly men. They have gradual, painless, asym-
and knee extensors is almost exclusive to IBM among other metrical, progressive weakness and focal atrophy that develop
forms of myopathy, the newly proposed ENMC IBM Research over years, and they may complain of frequent falls. Two decades
Diagnostic Criteria 2011 entails a separate category for clinically after onset, they are frequently wheelchair-bound. The forearms
defined IBM (Table 56.3). 5 of these patients exhibit a scalloped appearance, attributed to
It has been useful for some purposes to divide cases into muscle atrophy. Difficulty with swallowing can occur with any
groups: PM, DM, juvenile myositis, myositis associated with inflammatory myopathy and is frequently a major problem in
another connective tissue disease (usually systemic sclerosis, SLE, patients with IBM. The CK and other skeletal muscle–associated
or Sjögren syndrome), cancer-associated myositis (usually cases serum enzymes are normal in about one-quarter of patients
in which the diagnoses are made within 6–12 months of one with IBM and only moderately elevated in the remainder. The
another), IBM, and a miscellaneous group that includes such electromyogram in IBM frequently demonstrates both myogenic
rare entities as eosinophilic myositis (Table 56.4). This classifica- and neurogenic features secondary to the effective denervation
tion has allowed recognition of unique clinical and pathogenetic of some muscle cells by inflammation and necrosis.
features and response to therapy. In the case of cancer-associated Proposed criteria for the diagnosis of IBM rely on both
myositis, a more rational approach to workup based on recogni- pathological and clinical features. In the clinical setting of an
tion of groups at risk is now possible. inflammatory myopathy, the presence of the characteristic inclu-
sions or rimmed vacuoles is diagnostic. Among the inflammatory
KEY CONCEPtS myopathies, IBM is distinguished by substantial numbers of
Characteristic Hallmarks of rimmed cytoplasmic vacuoles with tubulofilamentous material
within myofibers. A variety of proteins have been found by
Inflammatory Myositis immunohistochemistry in the muscle cells in IBM, including
ubiquitin, β-amyloid precursor protein, and the transcription
• The clinical hallmark is proximal limb and neck weakness, rarely
associated with muscle pain. factor nuclear factor (NF)-κB. Many of the proteins accumulating
• The laboratory hallmarks are elevated serum levels of creatine kinase in the IBM muscle are also involved in other neurodegenerative
(CK), aldolase, lactic dehydrogenase, and the transaminases; a char- diseases. For example, aggregation of p62, an autophagy-related
acteristic pattern (“irritable myopathy”) is seen on electromyography protein, has been shown in IBM muscle, in Lewy bodies in
(EMG). Elevated serum levels of autoantibodies are common. Parkinson disease, and in neurofibrillary tangles in Alzheimer
• The pathological hallmarks are focal muscle necrosis, degeneration, disease, suggesting the possibility of a degenerative process in
regeneration, and inflammation.
IBM. More recently, an autoantibody to cytosolic 5′-nucleotidase
1a (c5N1A) was discovered. Although this antibody has a good
Several autoantibodies, called “myositis-specific autoantibod- specificity to distinguish IBM against other forms of autoimmune
9
ies,” are unique to myositis. These have allowed a useful alternative myopathy, it is roughly positive in 60% of IBM patients. In
classification (Table 56.5). For example, patients with antibodies addition, anti-c5N1A can be detected in other connective tissue

760 Part SIX Systemic Immune Diseases



TABLE 56.2 Proposed Diagnostic Criteria for Inclusion Body Myositis
The European Neuromuscular Centre (ENMC) criteria for the idiopathic inflammatory myopathies 4
1. Clinical criteria
a. Subacute onset
b. Age >18 years (onset may be in childhood in DM and nonspecific myositis)
c. Symmetrical proximal weakness
d. Typical DM rash (including heliotrope, Gottron papules, Gottron sign, V sign, and shawl sign)
e. Lack of features suggestive of IBM (asymmetry, finger flexor ≥ deltoid weakness, and knee extensors/ankle dorsiflexors ≥ hip flexors weakness),
toxic myopathies, endocrine myopathies, amyloidosis, family history of muscular dystrophy or proximal motor neuropathies (e.g., SMA)
2. Elevated serum creatine kinase level
3. Other laboratory criteria
a. Abnormal electromyography
Inclusion criteria
I. Increased insertional and spontaneous activity in the form of fibrillation potentials, positive sharp waves, or complex repetitive discharges
II. Morphometric analysis reveals the presence of short duration, small amplitude, polyphasic motor-unit action potentials (MUAPs)
Exclusion criteria
I. Myotonic discharges that would suggest proximal myotonic dystrophy or other channelopathy
II. Morphometric analysis reveals predominantly long duration, large-amplitude MUAPs
III. Decreased recruitment pattern of MUAPs
b. MRI: diffuse or patchy increased signal (edema) within muscle tissue on Short T1 Inversion Recovery (STIR) images
c. Myositis-specific antibodies detected in serum
4. Abnormal muscle biopsy
a. Endomysial inflammatory cell infiltrate surrounding and invading nonnecrotic muscle fibers
b. Endomysial CD8 T cells surrounding, but not definitely invading, nonnecrotic muscle fibers; or ubiquitous MHC-1 expression
c. Perifascicular atrophy
d. Membrane attack complex (MAC) depositions on small blood vessels, or reduced capillary density, or tubuloreticular inclusions in endothelial cells
on EM, or MHC-1 expression of perifascicular fibers
e. Perivascular, perimysial inflammatory cell infiltrate
f. Scattered endomysial CD8 T-cell infiltrate that does not clearly surround or invade muscle fibers
g. Many necrotic muscle fibers as the predominant abnormal histological feature. Inflammatory cells are sparse or only slight perivascular; perimysial
infiltrate is not evident
h. Rimmed vacuoles, ragged red fibers, cytochrome oxidase–negative fibers that would suggest IBM
i. MAC deposition on the sarcolemma of nonnecrotic fibers and other indications of muscular dystrophies with immunopathology

Polymyositis–Definite polymyositis: 1. All clinical criteria with the exception of rash, 2. Elevated serum creatine kinase (CK), 3. Muscle biopsy criteria include a and exclude c, d, h,
i; Probable polymyositis: 1. All clinical criteria with the exception of rash, 2. Elevated serum CK, 3. Other laboratory criteria (1 of 3), 4. Muscle biopsy criteria include b and exclude
c, d, g, h, i. Dermatomyositis–Definite dermatomyositis: 1. All clinical criteria, 2. Muscle biopsy criteria include c; Probable dermatomyositis: 1. All clinical criteria, 2. Muscle biopsy
criteria include d or e, or elevated serum CK, or other laboratory criteria (1 of 3). amyopathic dermatomyositis–1. Rash typical of DM: heliotrope, periorbital edema, Gottron
papules/sign, V sign, shawl sign, holster sign, 2. Skin biopsy demonstrates a reduced capillary density, deposition of MAC on small blood vessels along the dermal-epidermal
junction, and variable keratinocyte decoration for MAC, 3. No objective weakness, 4. Normal serum CK, 5. Normal electromyogram, 6. Muscle biopsy, if done, does not reveal
features compatible with definite or probable DM. Possible dermatomyositis sine dermatitis–1. All clinical criteria with the exception of rash, 2. Elevated serum CK, 3. Other
laboratory criteria (1 of 3), 4. Muscle biopsy criteria include c or d. Nonspecific myositis–1. All clinical criteria with the exception of rash, 2. Elevated serum CK, 3. Other laboratory
criteria (1 of 3), 4. Muscle biopsy criteria include e or f and exclude all others. Immune-mediated necrotizing myopathy–1. All clinical criteria with the exception of rash, 2.
Elevated serum CK, 3. Other laboratory criteria (1 of 3), 4. Muscle biopsy criteria include g and exclude all others.







TABLE 56.3 ENMC IBM research TABLE 56.4 traditional Classification of
Diagnostic Criteria 2011 5 Idiopathic Inflammatory Myopathies

Clinical and Laboratory Type I Primary idiopathic polymyositis
Features Pathological Features Type II Primary idiopathic dermatomyositis
Type III Dermatomyositis or polymyositis associated with
a. Duration >12 months I. Endomysial inflammatory malignancy
b. Age at onset >45 years infiltrate Type IV Childhood dermatomyositis or polymyositis
c. CK no greater than 15 × ULN II. Rimmed vacuoles Type V Myositis associated with another connective tissue
d1. Knee extension weakness > III. Protein accumulation* or disease
hip flexion weakness 15–18-nm filaments Type VI Inclusion body myositis
d2. Finger flexion weakness > IV. Upregulation of MHC class I Type VII Miscellaneous: eosinophilic myositis, localized nodular
shoulder abduction weakness myositis, etc.
*Demonstration of amyloid or other protein accumulation by established methods
(e.g., for amyloid Congo red, crystal violet, thioflavin T/S, for other proteins p62,
SMI-31, TDP-43). Current evidence favors p62 in terms of sensitivity and specificity,
but the literature is limited, and further work is required.
Clinicopathologically defined IBM: clinical criteria include a–c and at least one of
the d criteria plus the first three pathological features. Clinically defined IBM: All
clinical criteria plus one or more pathological features. Probable IBM: clinical criteria
include a–c and at least one of the d criteria plus one or more pathological features.
CK, creatine kinase; IBM, inclusion body myositis; ULN, upper limit of normal.

CHaPtEr 56 Inflammatory Muscle Diseases 761



TABLE 56.5 Clinical Features associated With Myositis-Specific autoantibodies
autoantibodies association Characteristic Clinical Features
Anti-Jo-1 and other PM, DM, IMNM Relatively acute onset of myositis, frequent interstitial lung disease, fever, Raynaud
antisynthetases phenomenon, arthritis, mechanic’s hands, moderate response to therapy, persistent
disease. Patients sometimes meet criteria for SLE or RA, but muscle disease or lung
disease dominate the clinical picture and prognosis.
Anti-SRP IMNM Very acute onset of myositis, often in autumn, severe weakness, no rash, palpitations,
females predominate, poor response to therapy
Anti-Mi-2 DM Relatively acute onset of myositis, classic dermatomyositis rashes with V sign and shawl
sign, cuticular overgrowth, good response to therapy
Anti-HMGCR IMNM Necrotizing myopathy, may be preceded by statin therapy, very high CK levels, minimal
muscle wasting
Anti-MDA5 DM, Clinically Clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease;
amyopathic DM characteristic skin findings include cutaneous ulcers and palmar papules
Anti-TIF1-γ (p155/140) DM Juvenile dermatomyositis and cancer-associated dermatomyositis
Anti-SAE DM Severe skin manifestations and dysphagia
Anti-NXP-2 DM Associated with calcinosis and muscle contractures in children

DM, dermatomyositis; IMNM, immune-mediated necrotizing myopathy; MDA5, melanoma differentiation–associated protein 5; NXP-2, nuclear matrix protein; PM, polymyositis; RA,
rheumatoid arthritis; SAE, small ubiquitin-like modifier activating enzyme; SLE, systemic lupus erythematosus; SRP, signal recognition particle; TIF1-γ, transcription intermediary
factor 1-γ.



diseases (such as lupus, DM, and Sjögren syndrome) as well as
in healthy subjects. 10 Drugs and Toxins
IBM must be distinguished from other chronic myopathies. A large number of environmental agents have been associated
These include acquired myopathies, such as those caused by with myopathies. Drug-induced myopathy should be considered
toxins, and genetically determined myopathies, such as some particularly in cases where no other cause has been identified.
muscular dystrophies and the metabolic myopathies. There are Sometimes the illness strikingly resembles the spontaneous disease.
several important differences between IBM and these other D-penicillamine, for example, can induce a variety of autoimmune
myopathies. The distinction, however, is not as well defined as phenomena, including an inflammatory myopathy that closely
might be expected. Although some of the familial forms of IBM resembles PM. A number of drugs can also produce myopathies
have a distinctive clinical presentation, often early in life, there that can be clinically confused with IIM but are histologically
have been several families with the typical late onset and inflam- distinct. This large group includes 3-hydroxy-3-methylglutaryl-
matory picture of the presumed sporadic cases. Several genetic coenzyme A (HMG-coA) reductase inhibitors, corticosteroids,
loci have been identified in familial IBM, so it will be important colchicine, and zidovudine (AZT).
to assess any identified mutations in familial IBM–associated In corticosteroid-induced myopathy, type II muscle fiber
genes in sporadic cases. 11 atrophy is prominent on muscle biopsy, and weakness improves
when the dose is lowered. Colchicine can cause myopathy and
ETIOLOGY painful neuromyopathy. The CYP3A4 system metabolizes col-
chicine, and taking another drug metabolized by the same pathway
Immunological Clues to Origin can result in myopathy. Muscle biopsy shows autophagic vacuoles
14
The implications of myositis-specific autoantibodies that bind that stain for acid phosphatase. Discontinuation of colchicine
to and inhibit the function of native human enzymes involved usually results in improvement. AZT produces a characteristic
in the formation of new proteins are tantalizing and probably mitochondrial myopathy. The myopathy associated with HIV
significant. These autoantibodies appear to develop before infection can be distinguished from that caused by AZT by muscle
symptomatic weakness or serum CK elevation, suggesting a close biopsy, as characteristic mitochondrial abnormalities are found
link to an initiating factor. Some of the clinical features, such as in the latter. Amiodarone rarely causes proximal and distal muscle
fever, arthritis, and lung disease, and the apparent seasonality weakness, or the accompanying tremor or distal sensory loss.
in onset of disease in patients with anti-SRP, are reminiscent of Muscle biopsy reveals autophagic vacuoles with myeloid inclusions
some viral infections. In patients with autoantibodies against and debris. This is seen more commonly in patients with chronic
one of the aminoacyl-tRNA synthetases, such as Jo-1 (histidyl- kidney disease. The antimalarial drugs chloroquine and hydroxy-
tRNA synthetase), the possible connection to a viral inciting chloroquine produce a vacuolar myopathy, possibly by raising
agent appeared compelling, as certain picornaviruses, which are the intralysosomal pH so that the acid cathepsins that digest
closely related to viruses long suspected of causing myositis, waste products in the lysosome are inoperable, so waste products
such as coxsackie viruses, can mimic tRNA in acting as a substrate accumulate in vacuoles.
12
for an aminoacyl-tRNA synthetase. Direct proof connecting
picornaviruses to human myositis, however, has not been obtained. Bacterial and Parasitic Diseases
In individuals infected with HIV or human T-cell lymphotropic Certain parasitic diseases can produce an illness by direct invasion
virus (HTLV)-1, the development of IBM has been noted. of muscle. Weakness, fever, and eosinophilia are usually present.
However, it is not always the first manifestation in these cases. Bacterial pyomyositis is uncommon in North America but occurs
There is no evidence of viral replication within the muscles, but more commonly in other parts of the world. It is attended by
instead the chronic infection triggers an inflammatory response. 13 the signs of local infection and is often asymmetrical. A recent

762 Part SIX Systemic Immune Diseases


report, however, details two cases of pyomyositis initially diag- highly related glycoproteins, including IFN-α and IFN-β, that
nosed as PM. Patients presenting with disseminated pyomyositis act on the type 1 IFN receptor. In DM muscle, the IFN-Is likely
17
may be difficult to distinguish clinically from those with IIM, are produced by plasmacytoid dendritic cells (pDCs). After
especially in immunosuppressed individuals, who may not mount activation of the IFN receptor, a cluster of IFN-I–inducible genes
a systemic response. 15 is transcribed, resulting in upregulation of several proteins, also
known as the IFN signature, in the muscle and peripheral blood
PATHOGENESIS of patients with DM. Well known is the myxovirus resistance
protein A (MxA), which, similar to other IFN-I–inducible proteins,
The precise mechanisms of cell damage and death in the IIMs has antiviral properties. This protein is overexpressed in both
are still unknown. T lymphocytes invading muscle fibers are the muscle and skin in DM but not in PM or IBM. Further,
predominantly lacking the costimulatory receptor CD28, indicative decreased expression of MxA mRNA in peripheral blood mono-
that they are chronically stimulated and end-differentiated. nuclear cells may correlate with decreasing muscle symptoms
null
CD28 lymphocytes are found in both muscle tissue and in juvenile DM patients. Indeed, some of the IFN-induced proteins
peripheral blood. They produce proinflammatory cytokines and may sustain autoimmunity in DM. For example, retinoic acid-
release perforin and granzyme into targeted muscle cells. B cells inducible gene 1 (RIG-I) and melanoma differentiation-associated
and plasma cells are also present in myositis muscle infiltrates. gene 5 (MDA-5) are IFN-I–induced proteins that induce IFN-I
The differentiation of B cells into antibody-producing plasma production in a positive feedback fashion. Both proteins con-
18
cells occurs within myositis muscle and is regulated by B cell– tribute to IFN induction in response to measles virus infection,
activating factor (BAFF). These antibodies are likely directed nurturing the suspicion for a role of viral infections in myositis.
19
against autoantigens or cross-reacting viral antigens. Engel and colleagues have demonstrated several important
In addition to adaptive immune mechanisms, innate and pathological distinctions between DM and PM and have suggested
nonimmune mechanisms also may be responsible for muscle that in DM, the capillaries are the initial point of injury. A model
cell damage and death. For example, Toll-like receptor (TLR)-3 of disease has been proposed in which primarily capillaries are
and TLR-7 are expressed by infiltrating inflammatory cells and damaged and myocytes are secondarily involved. Complement
immature myoblasts in myositis muscle. TLR activation leads and immunoglobulins may be found in the capillary walls even
to production of inflammatory cytokines such as interleukin where the remainder of the muscle is normal. The membrane
(IL)-6, thereby triggering or perpetuating inflammatory responses. attack complex of complement deposits there, and endothelial
Classic apoptosis is absent in IIM biopsies, but growing evidence cells are swollen and pale. Even in unaffected regions of muscle,
suggests that autophagy could be responsible for myofiber death. special staining reveals a marked decrease in capillary numbers.
After damage, a muscle fiber, which is a syncytium, can More advanced changes include microtubular endothelial inclu-
regenerate. Initially, on light microscopy one can appreciate sions and microvacuoles. Evaluation of lymphocyte populations
loss of striations leading to a homogeneous appearance, fiber in DM shows a high percentage of B cells and macrophages in
size variation, atrophy, and centralization of the nuclei. In the the perivascular regions and an increasing frequency of CD4 T
inflammatory myopathies, cell-mediated cytotoxicity is a primary cells and pDCs toward the perimysium and endomysium. In
method of destruction. Macrophages and cytotoxic T cells invade DM, especially the juvenile-onset form, inflammation and necrosis
the myofibers. The myocyte cytoplasm close to the invaginated followed by atrophy appear in a perifascicular pattern. Perivascular
cells appears vacuolated and swollen. Other regions of the same lymphocytic infiltrates, typical of later disease, have not been
cell may show intense regeneration, as seen histologically by described as an early change. Consistent with the importance
aggregates of nuclei with prominent nucleoli and fiber splitting. of immune complexes, histological abnormalities in the DM
Thus degeneration and regeneration can coexist in the same fiber. skin are indistinguishable from the changes in lupus.
Cytokines and chemokines (Chapters 9 and 10) , which form In contrast to DM, PM and IBM do not demonstrate marked
an integrated network regulating inflammation, are produced capillary changes, the perivascular infiltrates are less pronounced,
by muscle fibers, immune cells, and endothelial cells. As an and T-cell infiltrates in the perimysial and endomysial regions
example, IL-1 is consistently found in myositis muscle. IL-1 are more pronounced. Nonnecrotic fibers may be surrounded
facilitates transmigration of leukocytes by increasing the expres- by T cells and macrophages. T cells are enriched for the CD8
sion of adhesion molecules on endothelial cells. Further, IL-1 subset. There is negligible evidence of natural killer (NK) cell
can decrease the proliferation of myoblasts. In some myositis presence. Should cytotoxic T cells prove to be the major effector
patients, treatment with anakinra, an IL-1 receptor antagonist, cells, cloned T cells could lead to relevant antigenic targets. CD8
results in improvement. This finding further supports a pathogenic T cells recognize their antigenic peptide in association with major
role of IL-1. IL-1 acts in synergy with the other proinflammatory histocompatibility complex (MHC) class I molecules. Although
cytokines, tumor necrosis factor (TNF)-α and IL-17, to induce resting normal muscle has very low class I expression, it is
the production of IL-6 and CCL20 by myoblasts. The chemokine upregulated in regenerating and degenerating fibers found in
CCL20 recruits Th17 lymphocytes and immature dendritic cells both inflammatory and noninflammatory myopathies. Interest-
into the muscle. IL-6 perpetuates inflammation by suppressing ingly, in DM, class I expression is upregulated predominantly
+
FOXP3 regulatory T cells. More recently, IL-15 has been reported in the perifascicular regions, around sites of atrophy, and near
to have a pathogenic role. IL-15 is expressed in muscle cells and sites of cellular invasion. In contrast, in PM, class I expression
myoblasts derived from PM and DM patients. IL-15 regulates may be diffusely upregulated even where there is no cellular
T-cell activation and proliferation, and a higher expression of infiltrate. IBM shows a more focal class I distribution in regions
this cytokine at baseline may be associated with a poor response of T-cell invasion. The presence of focal regions of MHC class
to immunosuppressive therapy. 16 I expression in nonnecrotic fibers at the site of activated CD8
The role of type I interferons (IFN-Is) in the pathogenesis T cells is compatible with cytotoxicity as a prime mechanism of
of DM has been extensively studied. The IFN-Is are a family of myocyte necrosis in IBM and PM. A pivotal study using transgenic

CHaPtEr 56 Inflammatory Muscle Diseases 763


mice demonstrated that abnormal accumulation of MHC class GENETICS
I molecules in the endoplasmic reticulum (ER) of muscle may
initiate the ER stress response. 20 The IIMs do not exhibit a simple mode of inheritance, and the
rare familial cases mostly reflect IBM of early onset. As noted
KEY CONCEPtS above, there are HLA associations for particular MSAs. Specifically,
Differential Histological Features of Myositis HLA-DR52 has a strong association (90%) with antisynthetase-
positive myositis in people of both European and African
22
• In dermatomyositis the earliest changes involve vessel walls, and B descent. HLA DRB1*11:01 was recently shown to be associated
cells and CD4 T cells predominate in the muscle biopsy. with an increased risk of anti-HMGCR myopathy. 23
• In polymyositis and inclusion body myositis, the dominant pathological
feature is targeting and invasion of muscle cells by CD8 cytotoxic T
cells. NATURAL HISTORY
The prognosis for patients with IIM varies greatly with clinical
Proposed pathogenic mechanisms for the development of type, autoantibodies, extraskeletal muscle involvement, and the
the sporadic forms of IBM are complex and include both autoim- interval between diagnosis and the start of treatment.
munity and degeneration. Many proteins also found in other Patients with DM or myositis accompanying another con-
neurodegenerative diseases have been shown to accumulate in nective tissue disease are likely to recover most of their strength
IBM muscle. In addition, IBM patients typically do not respond with prompt and adequate therapy. Although recurrences
to immunosuppressive medications. These findings likely suggest are common, persistent profound weakness does not usually
that IBM is a degenerative disease. However, IBM is sometimes occur. Most patients with anti-Mi-2 autoantibodies also usually
associated with other autoimmune diseases. In IBM biopsy respond well to therapy. Strength usually recovers well in patients
specimens, inflammatory cells are predominantly composed of whose myositis is cancer related, but overall mortality due to
CD8 T cells, and a majority of patients express a circulating the tumor is high. Indeed, an accompanying tumor remains
antibody to cytosolic 5′-nucleotidase 1A, supporting the role of one of the most frequent causes of death in patients with an
autoimmunity in the pathogenesis of IBM. IIM. Among the MSAs, anti-TIF-1γ and anti–NXP-2 antibodies
In necrotizing autoimmune myositis (also known as IMNM), are found with increased frequency in patients with cancer-
there is necrosis of muscle fibers with myophagocytosis and associated DM. 24
regeneration and paucity of T-cell infiltration. Complement Patients with PM fare less well, even when those with IBM are
deposition on blood vessels has been reported. In muscle biopsies rigorously excluded. A return to normal strength is very unusual,
from patients with statin-associated necrotizing autoimmune and each recurrence is likely to be followed by greater residual
myositis, MHC class-I upregulation is frequently seen. 13 weakness, even if inflammation is fully controlled. IBM has a
The pathogenic role of autoantibodies found in IIM patients poorer prognosis, but it is possible that the gradual decline in
remains uncertain. MSAs are found in 60–80% of patients and strength can be halted for long periods by corticosteroid and/
appear to delineate specific clinical entities; each group has a or cytotoxic therapy if continuing inflammation is present.
strong but not absolute human leukocyte antigen (HLA) associa- Severe muscle weakness and atrophy and very high CK levels
tion. In a patient with myositis and antihistidyl-tRNA synthetase are prominent features in patients with anti-SRP autoantibod-
(Jo-1) autoantibodies, sera available from long before the onset ies. Patients with anti-MDA5 antibodies are at increased risk
of symptoms or biochemical damage to muscle tissue contained for developing progressive interstitial lung disease. Those with
the autoantibodies, suggesting that the autoantibodies were not anti-Jo-1 autoantibodies or antibodies to another synthetase are
merely a response to release of tissue antigens. The extraordinary likely to respond to therapy initially, but they typically require
specificity of MSAs for IIM and the lack of evidence for strong continuing immunosuppression to treat frequent recurrences.
polyclonal stimulation in these diseases suggest that MSAs are In this group morbidity and mortality are heavily influenced
related to the fundamental causative process in IIM. by the progression of lung involvement. Longitudinal outcome
The structures bound by MSAs are mostly intracellular studies in DM and PM are few. Cardiac involvement, respira-
ribonucleoproteins involved in protein synthesis, such as the tory involvement, and cancer were the main causes of death
aminoacyl-tRNA synthetases and the SRP. These autoantigens in several cohort analyses. Disease course is monocyclic in
are found in every nucleated cell. In general, the antibodies bind approximately 20% of patients, polycyclic in 20%, and chronic
to conformational epitopes and, at least in the case of the in the remainder. Relapses have been noted in the initial years
antisynthetases, block enzymatic activity. It is possible that a of therapy and after prolonged disease-free intervals; therefore
structural property of muscle allows these particular proteins periodic surveillance is warranted for at least 2 years after
to be presented to the immune system when the cells are damaged; remission.
alternatively, the capacity of muscle fibers to degenerate alongside
intense regeneration within the same fiber may allow these PATIENT MANAGEMENT
21
proteins to be efficiently displayed. Experiments have suggested
that some aminoacyl-tRNA synthetases have a direct proinflam- The treatment of myositis is based on controlling skeletal muscle
matory role through a subsidiary chemokine-like action. inflammation and damage. Immunosuppressive therapy is used
A landmark study determined that cultured myoblasts express in the initial stages of the disease to reduce inflammation and
high levels of autoantigens, which are strikingly downregulated muscle damage. There are very few randomized controlled trials
as cells differentiate into myotubes in vitro. These data strongly of any of the immunosuppressive agents used; thus therapeutic
associate regenerating rather than mature muscle cells as the regimens and responses have remained largely anecdotal. After
source of continuous autoantigen supply in autoimmune the initial inflammation is controlled, strengthening exercises
myositis. 21 are useful in improving functional capabilities.

764 Part SIX Systemic Immune Diseases


with immunosuppressive agents. 34,35 Patients with limb-girdle
Corticosteroids muscular dystrophies may mimic PM clinically. They may have
Corticosteroids are the main immunosuppressive agents used inflammation on muscle biopsy and may occasionally have
in myositis treatment. An initial course of pulses of methyl- associated autoantibodies. Thus patients with a suspected IIM
prednisolone may be helpful, particularly in disease of acute who do not respond to immunosuppressive therapy should
onset, and may also be helpful in managing disease flares. If undergo further evaluation, including genetic testing, to search
active muscle inflammation persists or the side effects of for a limb-girdle muscular dystrophy.
corticosteroids are severe, other immunosuppressive treatments
are employed. Nonskeletal Muscle Involvement
Other organs frequently involved in myositis include the skin,
Second-Line and Third-Line lungs, and joints. Such organ involvement and the systemic
Immunosuppressive Therapies features of myositis (fever and weight loss) usually improve with
The most frequently used second-line agents in the treatment immunosuppressive therapy that controls inflammation in the
of myositis are azathioprine and methotrexate. Azathioprine skeletal muscle. Hydroxychloroquine and other antimalarials are
reduces long-term disability. Methotrexate is useful in patients useful in controlling the rashes associated with myositis.
with little or no response to corticosteroid therapy. Combination
therapies, such as methotrexate with azathioprine, are useful DIAGNOSTIC TOOLS, EVALUATION, AND
even if patients have failed to respond to one of the agents alone. DIFFERENTIAL DIAGNOSIS
High-dose intravenous immunoglobulin (IVIG) is of proven
25
benefit in DM. Whereas patients with statin-associated anti-
26
HMGCR myopathy may be particularly responsive to IVIG, CLINICaL PEarLS
its usefulness in PM is less predictable. Apheresis proved ineffective
27
in a controlled blinded study. Both cyclosporine and tacrolimus Clinical Features That Suggest a Non-Idiopathic
have been effective in some cases, as have cyclophosphamide Inflammatory Myopathy Diagnosis
and chlorambucil. The most recent therapeutic options include
mycophenolate and rituximab. Recently a large randomized • Family history of a similar illness
• Weakness related to exercise, eating, or fasting
placebo-phase clinical trial was conducted to elucidate the role • Sensory, reflex, or other neurological signs
of a 44-week course of rituximab therapy in adults and children • Cranial nerve involvement
with refractory PM and DM. In general, 83% of refractory myositis • Fasciculations
patients met the Definition of Improvement (DOI), and the • Muscle cramping (severe)
presence of antisynthetase and anti–Mi-2 autoantibodies was • Myasthenia (increasing weakness with repeated contractions)
associated with a shorter time to improvement. 28,29 In refractory • Myotonia (difficulty relaxing a contracted muscle)
• Significant atrophy or hypertrophy early in the illness
patients who have not responded to the above-mentioned treat- • Marked asymmetry
ments, biological agents such as etanercept, adalimumab, anakinra, • Dyspnea due to diaphragmatic weakness with normal chest x-ray
abatacept, and high-dose cyclophosphamide have been tried with
variable success. 16,30–33 Thus far, there has been no effective
therapeutic regimen for IBM. However, IVIG has been reported Clinical, laboratory, pathological, and electrodiagnostic findings
to provide a transient response. 13 contribute to the proper diagnosis of IIM. Even in individuals
with typical clinical features, it is essential to exclude other diseases
Monitoring Disease Activity that may have similar symptoms and signs (Table 56.6). Certain
Improvement in strength and normalization of serum CK activity clinical features should suggest a different diagnosis. These include
are the best indirect measures of disease activity. A decrease in a family history of a similar illness; sensory, reflex, or other
serum CK activity may herald clinical improvement, but cortico- neurological changes; fasciculations; a relationship of the weakness
steroid treatment alone can reduce CK activity without associated to exercise, food intake, or fasting; major muscle cramping,
clinical improvement. A lack of improvement in strength in a myotonia (difficulty relaxing a contracted muscle), or myasthenia
corticosteroid-treated patient may be due to the resistance of the (increasing weakness with repeated contractions); significant
inflammatory process, the presence of a corticosteroid-induced early muscle atrophy or hypertrophy; marked asymmetry; weak-
myopathy, muscle atrophy, and/or misdiagnosis. A diagnostic and ness in the distribution of the cranial nerves; and dyspnea due
therapeutic taper of the corticosteroids may then be warranted. If to diaphragmatic weakness rather than lung fibrosis.
inflammation is present concurrently, other immunosuppressive The single most useful laboratory feature of muscle destruction
agents are useful as the dosage of corticosteroids is lowered. If is elevation of the serum CK, although this is nonspecific, and
the CK value begins to rise, even if it is still within the normal a small proportion of patients—probably <5%—have a bonafide
range, and the symptoms of myositis are worsening in a patient inflammatory muscle disease without ever having an elevated
whose disease has previously been controlled with corticosteroids, CK. Elevations of the serum levels of aldolase, serum glutamic-
an increase in the dose may be warranted. oxaloacetic transaminase (SGOT), serum glutamate pyruvate
transaminase (SGPT), and lactate dehydrogenase (LDH) are as
Treatment-Resistant Myositis frequent but less specific for muscle disease. Unlike inflammatory
Some treatment-resistant PM patients have another disease. In markers for other autoimmune inflammatory diseases, those
such cases IBM or a liED-girdle muscular dystrophy should be such as the erythrocyte sedimentation rate (ESR) and C-reactive
suspected. Unlike other myositis patients, those with IBM rarely, protein are often not elevated. Although some studies have shown
if ever, improve in strength with immunosuppressive therapy, ESR to be elevated in 50% of patients, most experts find a
but stabilization of strength can be achieved in some IBM patients substantially lower proportion of IIM patients to have an elevated

CHaPtEr 56 Inflammatory Muscle Diseases 765



TABLE 56.6 Differential Diagnosis of
Idiopathic Inflammatory Myopathy

Neuromuscular Disorders
Genetic muscular dystrophies
Metabolic myopathies
Disorders of carbohydrate metabolism: McArdle disease,
phosphofructokinase deficiency, adult acid maltase deficiency, and
others
Disorders of lipid metabolism: carnitine deficiency, carnitine palmitoyl
transferase deficiency
Disorders of purine metabolism: myoadenylate deaminase deficiency
Mitochondrial myopathies
Spinal muscular atrophies
Neuropathies: Guillain–Barré and other autoimmune polyneuropathies,
diabetes mellitus, porphyria
Myasthenia gravis and Eaton–Lambert syndrome
Amyotrophic lateral sclerosis
Myotonic dystrophy and other myotonias
Familial periodic paralysis
Endocrine and Electrolyte Disorders
Hypokalemia, hypercalcemia, hypocalcemia, hypomagnesemia
Hypothyroidism, hyperthyroidism
Cushing syndrome, Addison disease
FIG 56.2 Magnetic Resonance Images of the Upper and Lower
toxic Myopathies (Partial List) Thighs of a Patient With Dermatomyositis Using the Fat-
Alcohol Suppressed T2 (STIR) Technique. With this technique inflam-
Amiodarone mation appears as a bright signal; normal muscle is gray; bone,
Chloroquine and hydroxychloroquine fat, fascia, and normal skin are dark. Blood vessels may appear
Cocaine as bright spots. Note the remarkable symmetry of the inflam-
Colchicine mation. In this patient most of the involvement is in the quadriceps
Corticosteroids in the upper thighs and around the periphery of the hamstring
D-penicillamine muscle group.
Ipecac
Statins and other lipid-lowering agents
Zidovudine (AZT)
37
Infections fascial tissue that was undetectable on clinical examination.
Viral: HIV, human T-lymphotropic virus 1 (HTLV-1), influenza MRI can also help differentiate active disease from chronic disease,
Bacterial: Staphylococcus, Streptococcus, Clostridia with active myositis being notable for changes consistent with
Parasitic: toxoplasmosis, trichinosis, schistosomiasis, cysticercosis muscle edema on T2-weighted images, and chronic myositis
revealing a decrease in muscle bulk and replacement by adipose
Miscellaneous on T1-weighted images. Although not specific, the changes of
38
Polymyalgia rheumatica inflammatory myopathy on imaging can provide considerable
Vasculitis
Eosinophilia myalgia syndrome assistance in confusing cases, as well as help in choosing a site
Paraneoplastic syndromes to biopsy.
A muscle biopsy should be performed in every suspected case
of myositis (Fig. 56.3). Although the patchy involvement means
that the biopsy can occasionally miss inflammation, certain
36
ESR, even with active disease. Likewise, hematological abnormali- confounding diagnoses—for example amyloidosis, eosinophilic
ties, including anemia, are uncommon and rarely related to the myositis, dystrophy, or some metabolic myopathies as well as
underlying myopathy. If a significant abnormality is found, the the important variant IBM—can be diagnosed definitively only
physician should be alert to another cause for it. by biopsy. The identification of autoantibodies, particularly the
Electromyographic (EMG) abnormalities are frequently myositis-specific autoantibodies, has distinct clinical and prog-
present. Although the test is useful for excluding some neurological nostic use.
diseases that resemble IIM, it is painful for many patients and
not useful for following the course of the illness.
MRI, especially a combination of the T1 and the fat-suppressed ON tHE HOrIZON
T2 (STIR) sequences, is remarkably useful in defining the extent • Development of revised and updated classification criteria for inflam-
of involvement and in planning a biopsy (Fig. 56.2). Whole-body matory myopathies is needed.
MRI has been shown to facilitate the characterization of inflam- • Improved diagnostic classification of cases through novel autoantibodies
matory myopathy, as certain patterns of muscle and subcutaneous as well as immunohistochemistry.
tissue inflammation were predictive of the IIM subset (DM, PM, • Long-term studies are needed to better characterize the prognosis of
or IBM). In a recent study in juvenile DM, whole-body MRI idiopathic inflammatory myopathies, particularly in relation to recently
discovered autoantibodies.
was able to reveal inflammatory changes of subcutaneous and

766 Part SIX Systemic Immune Diseases






















A B
FIG 56.3 Biopsy in Dermatomyositis. (A) Low-power (original magnification ×100) view of a
muscle biopsy from a patient with dermatomyositis. Note the marked variation in fiber size and
the large number of atrophic myocytes, particularly at the periphery of the fascicles. (B) High-power
(original magnification ×200) view of inflammation around the vessels in the muscle biopsy of a
patient with dermatomyositis. There are nearby atrophic cells and cells whose nuclei have moved
away from the periphery of the cell (centralized nuclei).


5. Rose MR. 188th ENMC International Workshop: Inclusion Body
PITFALLS Myositis, 2–4 December 2011, Naarden, The Netherlands. Neuromuscul
Disord 2013;23:1044–55.
It is increasingly apparent that the boundary between IIM and 6. Kao AH, Lacomis D, Lucas M, et al. Anti-signal recognition particle
some genetically determined myopathies cannot be cleanly drawn. autoantibody in patients with and patients without idiopathic
Recently dystrophies with an extraordinary variety of clinical inflammatory myopathy. Arthritis Rheum 2004;50:209–15.
manifestations (with regard to age and distribution of weakness) 7. Christopher-Stine L, Casciola-Rosen LA, Hong G, et al. A novel
39
have also been described. Not only can inflammation be seen autoantibody recognizing 200-kd and 100-kd proteins is associated with
on biopsy in some patients, but a partial clinical response to an immune-mediated necrotizing myopathy. Arthritis Rheum
corticosteroids also can occur. Furthermore, it is increasingly 2010;62:2757–66.
recognized that mitochondrial abnormalities can be limited to 8. Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against
groups of skeletal muscles, leading to confusion with IIM. Toxic 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with
myopathies, of course, will continue to occur with the release statin-associated autoimmune myopathy. Arthritis Rheum
2011;63:713–21.
of new drugs and thus will continue to be a possible source of 9. Lahouti AH, Amato AA, Christopher-Stine L. Inclusion body myositis:
diagnostic confusion. update. Curr Opin Rheumatol 2014;26:690–6.
Thus not only must the history, physical examination, and 10. Lloyd TE, Christopher-Stine L, Pinal-Fernandez I, et al. Cytosolic
biopsy be performed and interpreted with compulsiveness and 5’-nucleotidase 1A as a target of circulating autoantibodies in
care, but molecular diagnostic techniques also must be employed autoimmune diseases. Arthritis Care Res (Hoboken) 2016;68:
by clinicians in pursuit of an accurate diagnosis and appropriate 66–71.
therapy. The correct response to disease that persists in the face 11. Argov Z, Eisenberg I, Mitrani-Rosenbaum S. Genetics of inclusion body
of powerful immunosuppressive therapy is a careful rethinking myopathies. Curr Opin Rheumatol 1998;10:543–7.
of the diagnosis, including, on occasion, rebiopsy and molecular 12. Mathews MB, Bernstein RM. Myositis autoantibody inhibits
consultation. histidyl-tRNA synthetase: a model for autoimmunity. Nature
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13. Dalakas MC. Pathophysiology of inflammatory and autoimmune
Please check your eBook at https://expertconsult.inkling.com/ myopathies. Presse Med 2011;40:e237–47.
for self-assessment questions. See inside cover for registration 14. Mor A, Wortmann RL, Mitnick HJ, et al. Drugs causing muscle disease.
details. Rheum Dis Clin North Am 2011;37:219–31, vi.
15. Walji S, Rubenstein J, Shannon P, et al. Disseminated pyomyositis
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emphasis on dermatologic aspects. Dermatol Clin 2002;20:387–408. treatment on interleukin-15 and interleukin-15 receptor alpha expression
2. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). in muscle tissue of patients with polymyositis or dermatomyositis. Ann
N Engl J Med 1975;292:344–7. Rheum Dis 2012;71:1055–63.
3. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two 17. Greenberg SA, Pinkus JL, Pinkus GS, et al. Interferon-alpha/
parts). N Engl J Med 1975;292:403–7. beta-mediated innate immune mechanisms in dermatomyositis. Ann
4. Hoogendijk JE, Amato AA, Lecky BR, et al. 119th ENMC international Neurol 2005;57:664–78.
workshop: trial design in adult idiopathic inflammatory myopathies, with 18. Ikegame S, Takeda M, Ohno S, et al. Both RIG-I and MDA5 RNA
the exception of inclusion body myositis, 10–12 October 2003, Naarden, helicases contribute to the induction of alpha/beta interferon in measles
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19. Engel AG, Arahata K, Emslie-Smith A. Immune effector mechanisms in 28. Oddis CV, Reed AM, Aggarwal R, et al. Rituximab in the treatment of
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1990;68:141–57. randomized, placebo-phase trial. Arthritis Rheum 2013;65:314–24.
20. Nagaraju K, Casciola-Rosen L, Lundberg I, et al. Activation of the 29. Aggarwal R, Bandos A, Reed AM, et al. Predictors of clinical improvement
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2005;52:1824–35. 30. The Muscle Study Group. A randomized, pilot trial of etanercept in
21. Casciola-Rosen L, Nagaraju K, Plotz P, et al. Enhanced autoantigen dermatomyositis. Ann Neurol 2011;70:427–36.
expression in regenerating muscle cells in idiopathic inflammatory 31. Park J-K, Yoo H-G, Ahn D-S, et al. Successful treatment for conventional
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22. Goldstein R, Duvic M, Targoff IN, et al. HLA-D region genes associated with adalimumab. Rheumatol Int 2012;32:3587–90.
with autoantibody responses to histidyl-transfer RNA synthetase (Jo-1) 32. Lahouti AH, Brodsky RA, Christopher-Stine L. Idiopathic inflammatory
and other translation-related factors in myositis. Arthritis Rheum myopathy treated with high-dose immunoablative cyclophosphamide—A
1990;33:1240–8. long-term follow-up study. JAMA Neurol 2015;72:1205–6.
23. Mammen AL, Gaudet D, Brisson D, et al. Increased frequency of 33. Kerola AM, Kauppi MJ. Abatacept as a successful therapy for myositis—a
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24. Fiorentino DF, Chung LS, Christopher-Stine L, et al. Most patients with immunosuppressive therapy. Medicine (Baltimore) 1993;72:225–35.
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CHaPtEr 56 Inflammatory Muscle Diseases 767.e1


MUL t IPLE-CHOICE QUES t IONS

1. A 42-year-old Asian woman comes to your office complaining about 1 year later. He also began having difficulties walking
of a rash on her face and upper back that started 2 months on uneven ground. He has not had any difficulty swallowing.
ago. Around the same time, she developed joint pain and His past medical history is significant for elevated serum CK
swelling in both hands. Approximately a week ago, she noticed levels of 1400 (normal range: 24–170 U/L) 5 years ago and
mouth sores as well as weakness, with difficulties walking hypercholesterolemia. His family history includes breast cancer
upstairs. Other medical problems include an episode of in his mother. He has a 33-pack-year smoking history,
pulmonary collapse resulting in intensive care unit admission but he quit 2 years ago. He has no other medical problems.
and requiring intubation and treatment with antibiotics and Neurological examination reveals reduced triceps strength
steroids 3 years ago, but she had full recovery after this. (right: 4+/5, left: 4/5), finger flexion (2/5 bilaterally), knee
Otherwise, she has been healthy. She has never smoked and extension (4+/5 bilaterally), and left wrist flexion (4+/5) muscle
does not drink alcohol. Her mother has rheumatoid arthritis. strength. The patient’s laboratory tests show an elevated CK
She takes no medications. Physical examination reveals level of 1030 U/L. Electromyography reveals positive waves,
heliotrope rash, Gottron sign, shawl sign, nail bed erythema, fibrillations, and mixed neurogenic and myopathic motor
dilated capillary loops, and swelling of the hands. There is units in the involved muscles. A quadriceps muscle biopsy is
extensive ulceration and necrosis of the fourth digit. Neurologi- performed. Which of the following findings is most likely
cal examination demonstrates symmetrically reduced hip present on biopsy?
flexion (4/5) muscle strength. Further evaluation reveals a A. Many necrotic muscle fibers and sparse inflammatory cells
serum CK level of 100 U/L (normal range: 24–170 U/L) and B. Perifascicular atrophy
an aldolase level of 15.6 U/L (normal = <8.1 U/L). Which of C. Endomysial inflammatory infiltrate and rimmed vacuoles
the following antibodies is most likely to be detected in this D. MAC depositions on small blood vessels
patient’s serum? 3. Which of the following antibodies is associated with the disease
A. Anti-Jo-1 presented in question 2?
B. Anti-SRP A. Anti-HMGCR
C. Anti-RNP B. Anti-SAE
D. Anti-MDA5 C. Anti-c5N1A
E. Anti-La
D. Anti-Mi-2
2. A 58-year-old Caucasian man began noticing progressive E. Anti-SRP
weakness with bilateral foot slapping 3 years ago. He began F. No recognized antibodies are associated with this
struggling with stairs and progressive weakness in his handgrip condition.

57









Spondyloarthritis



John D. Reveille







The term spondyloarthritis (SpA) (otherwise known as spondylo- for peripheral spondyloarthritis based on the presence of
arthropathy) encompasses a heterogeneous group of inflammatory peripheral arthritis, enthesitis, or dactylitis have also been
7
diseases characterized by spinal and peripheral joint arthritis, developed utilizing these innovations. The result of this is a
inflammation of the attachments of ligaments and tendons to reclassification of all the various spondyloarthritides under the
bones (enthesitis), and, at times, mucocutaneous, ocular, and/or diagnoses of axial and peripheral SpA.
cardiac manifestations. These disorders show familial aggregation
and are typically associated with genes of the major histocompat- EPIDEMIOLOGY
ibility complex (MHC), particularly human leukocyte antigen
(HLA)-B27 (Chapter 5). The SpA spectrum includes (i) axial The frequency of SpA in general and AS in particular varies in
spondyloarthritis (AxSpA), including ankylosing spondylitis different populations and parallels the frequency of HLA-B27.
(AS); (ii) reactive arthritis (ReA), known previously as Reiter The prevalence of AS varies from 0.2% to 0.7% among
syndrome; (iii) psoriatic arthritis (PsA) and/or spondylitis; (iv) people of European ancestry 8-10 and has been reported in
enteropathic arthritis and/or spondylitis associated with the similar frequencies in eastern Asia (Table 57.2). Higher rates
inflammatory bowel diseases (IBD), ulcerative colitis (UC), of prevalence have been reported in Eskimo groups from
or Crohn disease (CD); and (v) undifferentiated SpA, which Siberia and Alaska as well as in groups from Scandinavia and
encompasses patients expressing elements of, but failing to as high as 4.3% in male Haida Native Canadian groups, where
8
fulfill, accepted criteria for one of the above diseases. In addition, the frequency of HLA-B27 is 50%. AS is much less frequent
1
isolated acute anterior uveitis (AAU) and spondylitic heart disease in persons of African and Japanese descents, in whom HLA-B27
2
(complete heart block and/or lone aortic regurgitation) associ- is rare.
ated with HLA-B27 may also be classified within the spectrum The prevalence of ReA is unknown and probably varies
of SpA. over time, depending on endemic rates of the sexually acquired
(Chlamydia) and enteric (Shigella, Salmonella, Campylobacter)
CLASSIFICATION OF SPONDYLOARTHRITIS infections that trigger it. It appears that the frequency of ReA
has dramatically declined following the adoption of safer sexual
There are no diagnostic criteria for any of the SpA types. Clas- practices and better sanitation, at least in Western countries, in
sification criteria have been developed to provide greater specificity the wake of the human immunodeficiency virus (HIV) epidemic.
9
in clinical studies. The European Spondyloarthropathy Study Psoriasis affects 1–3% of the general population. The fre-
Group (ESSG) criteria for SpA were developed in 1991, have quency of PsA is less clear and is higher in those with more
been validated in numerous population groups, and remain the severe disease; population studies among Caucasians estimate a
3
basis of many clinical and epidemiological studies (Table 57.1). frequency of approximately 0.1%. 8
The modified New York criteria, developed in 1966 and modified The prevalence of IBD is 100–200 per 100 000 among Cau-
4
8,10
in 1984, remain the “gold standard” for AS. However, this depends casians, with an equal male-to-female ratio. It is rare in people
on the presence of radiographic sacroiliitis, which takes up to of African and Asian descents. The risk of spondylitis and
10 years to develop after the onset of inflammatory back pain. peripheral arthritis varies in different reports, perhaps reflecting
For PsA, the classification criteria for psoriatic arthritis (CASPAR) the subspecialty of the observer. Spondylitis occurs in as many
5
(see Table 57.1) have stemmed from the perception that the as 15–20% of those with IBD. In general, peripheral arthritis
ESSG criteria were not “sensitive” enough. occurs less frequently in those with UC (up to 10%) than
The International League Against Rheumatism (ILAR) juvenile in those with CD (up to 20%), although its frequency tends to
idiopathic arthritis (JIA) classification criteria for enthesitis-related be higher in series where the assessor was a rheumatologist. 8,10
arthritis (ERA) have been proposed for juvenile SpA (JSpA; see
Table 57.1). No criteria have been validated for enteropathic
arthritis. PATHOGENESIS
New criteria have been developed by the Assessment of
SpondyloArthritis International Society (ASAS) for axial SpA Genetics of Spondyloarthritis
based on the presence of inflammatory back pain that take Familial Aggregation
advantage of imaging innovations, such as magnetic resonance Susceptibility to AS is clearly attributable to genetic factors, with
6
imaging (MRI) and HLA-B27 typing. More recently, criteria a sibling recurrence risk ratio as high as 82 and twin-based studies
769

770 Part six Systemic Immune Diseases



TABLE 57.1 Current Classification Criteria for spondyloarthritis
a. European spondyloarthropathy study Group (EssG) (a) Inflammatory low back pain
Criteria for spondyloarthritis (b) Arthritis
1. Inflammatory back pain or synovitis (asymmetrical, lower extremity) (c) Enthesitis
plus one of the following: (d) Dactylitis
(a) Alternating buttock pain (e) Psoriasis
(b) Sacroiliitis (f) Crohn disease or ulcerative colitis
(c) Heel pain (enthesitis) (g) Good response to nonsteroidal antiinflammatory agents
(d) Positive family history (h) Positive family history of SpA
(e) Psoriasis (i) Presence of human leukocyte antigen (HLA)-B27
(f) Crohn disease, ulcerative colitis (j) Elevated cross-reactive protein
(g) Urethritis or cervicitis or acute diarrhea in the preceding 4 weeks
E. asas Criteria for Peripheral spondyloarthritis—arthritis or
B. the Modified New York Criteria for Enthesitis or Dactylitis With at Least One of:
ankylosing spondylitis 4 a. Uveitis
1. Clinical criteria: b. Psoriasis
(a) Low-back pain and stiffness for more than 3 months which c. Crohn disease or ulcerative colitis
improves with exercise, but is not relieved by rest d. Previous infection
(b) Limitation of motion of the lumbar spine in both the sagittal and e. Presence of HLA-B27
frontal planes f. Sacroiliitis on imaging
(c) Limitation of chest expansion relative to normal values correlated OR
for age and gender with at least two of:
2. Radiological criterion: a. Inflammatory low back pain
(a) Sacroiliitis grade 2 bilaterally or grade 3–4 unilaterally b. Arthritis
(b) Definite ankylosing spondylitis if the radiological criterion is c. Enthesitis
associated with at least one clinical criterion d. Dactylitis
e. Positive family history of SpA
C. the Classification Criteria for Psoriatic arthritis (CasPar)
Criteria for Psoriatic arthritis F. the international League against rheumatism (iLar)
1. Inflammatory joint disease plus at least three points from the following Juvenile idiopathic arthritis Classification Criteria for
Enthesitis-related arthritis (Era)
features:
(a) Current psoriasis (assigned a score of 2; all others assigned a score Arthritis and enthesitis
of 1) OR
(b) History of psoriasis Arthritis or enthesitis with at least two of:
(c) Family history of psoriasis 1. Sacroiliac joint tenderness and/or inflammatory spinal pain
(d) Dactylitis 2. Presence of HLA-B27
(e) Juxtaarticular new bone formation 3. Family history in at least one first- or second-degree relative of
(f) Rheumatoid factor seronegativity medically confirmed HLA-B27-associated disease
(g) Nail dystrophy 4. Anterior uveitis that is usually associated with pain, redness, or
photophobia
D. asas Criteria for axial spondyloarthritis in Patients With 5. Onset of arthritis in a boy after 8 years of age
Chronic Low Back Pain for at Least 3 Months Exclusions
1. Sacroiliitis on imaging (either MRI findings of inflammatory disease in • Psoriasis confirmed by a dermatologist in at least one first- or
the sacroiliac joints or sacroiliitis on standard pelvic X-rays by New York second-degree relative
criteria) plus ONE of the following OR HLA-B27 positivity plus TWO of • Presence of systemic arthritis
the following:





KEY CONCEPts estimating disease heritability to exceed 90%. The concordance
11
The Genetic Basis of Spondyloarthritis rate for AS in identical twins has been reported to be as high as
11
63% compared with 23% in nonidentical twins. The concurrence
• Human leukocyte antigen (HLA)-B27 comprises nearly 80% of the
overall genetic susceptibility to ankylosing spondylitis (AS) and con- rate for psoriasis in monozygotic twins is 70 versus 15–30% in
tributes heavily to susceptibility to reactive arthritis, psoriatic arthritis, dizygotic twins. Recurrence risk for parents and sibs of patients
and enteropathic spondylitis. with CD is 4.8% and 7%, respectively, and for UC 0.9 and 1.2%,
• Additional influences seem to come from other major histocompatibility respectively. 11
complex (MHC) genes, including HLA-A*02, B*40 for AS and C*0602
for psoriasis, whose identification has been confounded by linkage HLA-B27 and Spondyloarthritis
to HLA-B27.
• Genome-wide association studies (GWAS) utilizing dense single HLA-B27, which is encoded in the MHC class I region (Chapter
nucleotide polymorphism (SNP) mapping have located at least 70 5), confers the greatest known risk for AS and is found in up to
genes or genetic regions in AS susceptibility. 90% of AS patients of European ancestry 11-13 (Table 57.3), as
• Over 60 genes have been identified thus far in psoriasis opposed to 6–8% of healthy Caucasians. 12,14 The estimated
pathogenesis. prevalence of HLA-B27 in the United States is 6.1% overall, is
• GWAS utilizing dense SNP mapping will likely locate many of the highest in younger individuals (7.5% before age 50 years), and
remaining genes in AS susceptibility. 14
falls rapidly over age 50 years (3.3%).

CHaPtEr 57 Spondyloarthritis 771



TABLE 57.2 the Epidemiology of spondyloarthritis
HLa-B27 Prevalence of as Prevalence of Prevalence of
Ethnic Group Frequency (%) %(Criterion) Psa % (Criterion) spa % (Criterion)
Europe
Azores n.a. n.a. 1.6 (ESSG)
Czech Republic 0.09 (mNY) 0.05 (Vasey) n.a.
France 0.08 (questionnaire) 0.19 (questionnaire) 0.3 (questionnaire)
Germany 0.86 (mNY) 0.29 (ESSG) 1.9 (ESSG
Greece 0.24 (mNY) 0.17 (ESSG) 0.49 (ESSG)
Iceland 0.13 (mNY) 0.14 (other) 0.49 (ESSG)
Italy 0.37 (mNY) 0.42 (mNY) n.a.
Netherlands 0.24 (questionnaire plus Xray) n.a. n.a.
N. Norway(Sami) 24 1.8 (NY) n.a. n.a.
Norway-general 24 1.1-1.4(mNY) 0.23 (ICD) n.a.
South Sweden 0.25 (ICD10) 0.25 (ICD10) 0.45 (ICD10)

america
United States 6.1 0.52 (questionnaire plus X-ray) 0.16 1.4 (ESSG)
Mexico 4.6 0.02 (mNY) 0.02 n.a.
Alaska (Eskimo) 0.4 (NY) <0.1 2.5 (ESSG)
Argentina n.a. 0.07 (CASPAR) n.a.
asia
China 0.25 (mNY) 0.02 0.78 (ESSG)
Iran 0.12 (unclear) n.a. 0.23 (COPCORD)
Japan 0.0065 (NY) 0.001 0.0095
Pakistan n.a. n.a. 0.1 (COPCORD)
Siberia 37 1.1 (NY) 0.3 2.5 (ESSG)
Taiwan 0.19–0.54 (mNY) n.a. n.a.
Turkey 0.49 (mNY) n.a. 1.05 (ESSG)
Vietnam n.a. n.a. 0.28 (COPCORD)
AS, ankylosing spondylitis; HLA, human leukocyte antigen; n.a., not available; PsA, psoriatic arthritis; SpA, spondyloarthritis; NY (New York) and mNY (modified New York criteria for
AS); ESSG (European Spondyloarthropathy Study Group Criteria)



Approximately 70% of patients with ReA have HLA-B27, class I molecules) to CD8 T cells, resulting in an HLA-B27–
except in Africa, where no association of HLA-B27 is seen in restricted cytotoxic T-cell response found only in joints and
those with HIV-associated SpA. 13 other affected tissues (the so-called arthritogenic peptide
HLA-B27 is found in 60–70% of patients with psoriatic hypothesis). However, such peptides have not been reproducibly
spondylitis and in 25% of those with peripheral PsA. 12,13 Up to identified to date. In fact, gene association data showing interac-
70% of those with IBD-associated spondylitis have HLA-B27, tion between HLA-B27 and a gain-of-function (GOF) variant
although no HLA-B27 association is seen with asymptomatic of endoplasmic reticulum (ER)–associated aminopeptidase I
sacroiliitis. Approximately 50% of patients with AAU alone are (ERAP1) suggest that aberrant antigen processing may play a
15
HLA-B27 positive. 12 central role in AS susceptibility. The same has been described
16
Over 146 molecular subtypes of HLA-B27 have been described for HLA-C*06:02 and psoriasis. An alternative concept focuses
this far (http://www.ebi.ac.uk/ipd/imgt/hla/nomenclature/ on self-association as a unique property of the HLA-B27 molecule.
index.html). The most common subtypes (HLA-B*27:05, B*27:02, HLA-B27 heavy chains can form homodimers in vitro that are
B*27:04, B*27:07, B*27:14) are clearly associated with SpA. Two dependent on disulfide binding through their cysteine-67 residues
subtypes of HLA-B27—HLA-B*27:06 and B*27:09—found in in the extracellular α 1 domain (as well as other cysteine residues
Southeast Asia and Sardinia, respectively, appear not to be in other domains) (Fig. 57.2). 13,16 This occurs as a result of B27
13
associated with AS, possibly in part as a result of amino acid misfolding within the ER. The accumulation of misfolded protein
differences in the “B” pocket of the HLA antigen-binding cleft results in a proinflammatory intracellular stress response through
at positions 114 and 116 that could alter the composition and the stimulation of secretion of type 1 interferon (IFN). Also,
anchoring of peptides presented by these HLA-B27 subtypes. HLA-B27 homodimers are detectable at the cell surface in patients
The other subtypes of HLA-B27 are too rare to have had disease with SpA, are capable of peptide binding, and are more abundantly
associations established. These subtypes evolved from the parent expressed when the cell’s antigen-presenting function is impaired.
allele HLA-B*27:05 along three lines (Fig. 57.1) in three distinct They are ligands for a number of natural killer (NK) and related
geographical regions. cell surface receptors. Populations of synovial and peripheral
The exact mechanism underlying the effect of HLA-B27 on blood monocytes, NK cells, and B and T lymphocytes from
disease susceptibility has still not been determined. One theory patients with SpA and controls carry receptors for HLA-B27
suggests that SpA results from a unique set of antigenic peptides, homodimers, including killer immunoglobulin-like receptor
either bacterial or self, that are bound and presented by all (KIR)3DL1 and KIR3DL2 and immunoglobulin (Ig)–like
disease-associated HLA-B27 subtypes (but not by other HLA transcript 4 (ILT4). 13,15 These homodimers may act as a