674 ParT fivE Allergic Diseases
Please check your eBook at https://expertconsult.inkling.com/ 11. Boldogh I, Bacsi A, Choudhury BK, et al. ROS generated by pollen
for self-assessment questions. See inside cover for registration NADPH oxidase provide a signal that augments antigen-induced allergic
details. airway inflammation. J Clin Invest 2005;115:2169–79.
12. Hur GY, Park HS. Biological and genetic markers in occupational asthma.
Curr Allergy Asthma Rep 2015;15:488.
REFERENCES 13. Carlsten C, Blomberg A, Pui M, et al. Diesel exhaust augments
allergen-induced lower airway inflammation in allergic individuals: a
1. Tarlo SM, Lemiere C. Occupational asthma. N Engl J Med controlled human exposure study. Thorax 2016;71:35–44.
2014;370:640–9. 14. Caceres AI, Brackmann M, Elia MD, et al. A sensory neuronal ion
2. Lemiere C, Vandenplas O. Asthma in the workplace. In: Broaddus VC, channel essential for airway inflammation and hyperreactivity in asthma.
editor. Murray & Nadel’s textbook of respiratory medicine. 6th ed. St. Proc Natl Acad Sci USA 2009;106:9099–104.
Louis, MO: Elsevier; 2016. p. 1295–306. 15. Larbanois A, Jamart J, Delwiche J, et al. Socioeconomic outcome of
3. Lambrecht BN, Hammad H. Biology of lung dendritic cells at the origin subjects experiencing asthma symptoms at work. Eur Respir J
of asthma. Immunity 2009;31:412–24. 2002;19:1107–13.
4. Miller MJ, Hejazi AS, Wei SH, et al. T cell repertoire scanning is 16. Lemiere C, Boulet LP, Chaboillez S, et al. Work-exacerbated asthma and
promoted by dynamic dendritic cell behavior and random T cell motility occupational asthma: do they really differ? J Allergy Clin Immunol
in the lymph node. Proc Natl Acad Sci USA 2004;101:998–1003. 2013;131:704–10.
5. Huh JC, Strickland DH, Jahnsen FL, et al. Bidirectional interactions 17. Lougheed MD, Lemiere C, Ducharme FM, et al. Canadian Thoracic
between antigen-bearing respiratory tract dendritic cells (DCs) and T Society 2012 guideline update: diagnosis and management of asthma in
cells precede the late phase reaction in experimental asthma: DC preschoolers, children and adults. Can Respir J 2012;19:127–64.
activation occurs in the airway mucosa but not in the lung parenchyma. 18. Pralong JA, Lemiere C, Rochat T, et al. Predictive value of nonspecific
J Exp Med 2003;198:19–30. bronchial responsiveness in occupational asthma. J Allergy Clin Immunol
6. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med 2016;137:412–16.
2012;18:693–704. 19. Vandenplas O, Suojalehto H, Aasen TB, et al. Specific inhalation challenge
7. Moscato G, Pala G, Boillat MA, et al. EAACI position paper: prevention in the diagnosis of occupational asthma: consensus statement. Eur Respir
of work-related respiratory allergies among pre-apprentices or J 2014;43:1573–87.
apprentices and young workers. Allergy 2011;66:1164–73. 20. Vandenplas O, D’Alpaos V, Heymans J, et al. Sputum eosinophilia: an
8. Gautrin D, Ghezzo H, Infante-Rivard C, et al. Natural history of early marker of bronchial response to occupational agents. Allergy
sensitization, symptoms and diseases in apprentices exposed to laboratory 2009;64:754–61.
animals. Eur Respir J 2001;17:904–8. 21. Lemiere C, D’Alpaos V, Chaboillez S, et al. Investigation of occupational
9. Remen T, Acouetey DS, Paris C, et al. Early incidence of occupational asthma: sputum cell counts or exhaled nitric oxide? Chest
asthma is not accelerated by atopy in the bakery/pastry and hairdressing 2010;137:617–22.
sectors. Int J Tuberc Lung Dis 2013;17:973–81.
10. Romberger DJ, Heires AJ, Nordgren TM, et al. Proteases in agricultural
dust induce lung inflammation through PAR-1 and PAR-2 activation.
Am J Physiol Lung Cell Mol Physiol 2015;309:L388–99.
CHaPTEr 49 Occupational Respiratory Allergies 674.e1
MULT i PLE-CHO i CE QUEST i ONS
1. Which characteristics have been identified as risk factors for A. Childhood asthma
developing occupational asthma (OA)? B. Absence of airway hyperresponsiveness (AHR)
A. Atopy C. Normal spirometry
B. Obesity D. Absence of eosinophilic inflammation
C. Smoking E. None of the above
D. Genetic markers 3. In a subject with diagnosed sensitizer-induced occupational
E. None of the above
asthma (OA) what is the most effective intervention?
2. In a subject with a history of childhood asthma who A. Complete removal from exposure
decided to quit his work because of recurrence of asthma, B. Reduction of exposure
which factors can exclude the diagnosis of occupational asthma C. Treatment with anti–immunoglobulin E (IgE) therapy
(OA)? D. Immunotherapy to the occupational agent.
50
Mechanisms of Autoimmunity
Brendan Antiochos, Antony Rosen
Human autoimmune diseases occur frequently (affecting in KEY CONCEPTS
aggregate >5% of the population worldwide) and impose a
significant burden of morbidity and mortality on the human Autoantibodies in Autoimmune Diseases
1
population. Autoimmune diseases are defined as diseases in • Some autoantibodies precede the development of any symptoms by
which immune responses to specific self antigens contribute to years (e.g., antinuclear antibodies and antiphospholipid antibodies in
the ongoing tissue damage occurring in the disease. Both the systemic lupus erythematosus [SLE], anti– cyclic citrullinated peptide
specificity of the immune response and its role in tissue damage [CCP] in rheumatoid arthritis [RA]).
are central components of the definition. Autoimmune diseases • Some autoantibodies only occur at around the time of onset of disease
manifestations (e.g., anti-Sm and anti-ribonucleic protein [RNP] in SLE).
can be either tissue specific (e.g., thyroid, β-cells of the pancreas), • There is a striking association of specific autoantibodies with distinct
where unique tissue-specific antigens are targeted, or can be more clinical phenotypes (e.g., antitopoisomerase-1 with diffuse scleroderma
systemic, in which multiple tissues are affected and a variety of and interstitial lung disease).
2
apparently ubiquitously expressed autoantigens are targeted.
Although the definition appears relatively simple in concept,
the complexity of this spectrum of disorders is enormous and
has greatly challenged elucidation of simple shared mechanisms. THE DISTINCT PHASES IN THE DEVELOPMENT
This complexity affects almost every domain, including genetics, OF AUTOIMMUNITY
phenotypic expression, and kinetics. In the last case, there is
frequently a prolonged period (weeks to months) between initial A major barrier to understanding mechanisms of autoimmunity
onset of symptoms and development of the diagnostic phenotype, comes from difficulty in defining early events in these diseases.
and the expression of disease may vary within the same individual Since diseases are only recognizable after development of the
over time. However, despite this enormous complexity, there is a diagnostic phenotype, there has been a tendency to interpret
striking association of the clinical phenotype with the targets of findings at the time of disease diagnosis with events present
the autoimmune response. This association is, in fact, so strong at disease initiation. Significant recent data from studies of
that autoantibodies have been used for diagnosis and prognosis the development of autoantibodies over time in patients who
2
in the human autoimmune diseases. For example, autoantibod- subsequently manifest an autoimmune disease have demonstrated
ies recognizing thyroid peroxidase are found in patients with that the onset of an autoimmune response and the development
autoimmune thyroiditis, autoantibodies to the Sm splicing of clinical symptoms are generally separated in time. In the case of
ribonucleoprotein (RNP) complex are diagnostic of systemic type I diabetes, development of islet cell autoantibodies frequently
lupus erythematosus (SLE), and autoantibodies recognizing precedes diabetes, and additional islet cell autoantibodies accrue
3
topoisomerase-1 are found in patients with the diffuse form over time. Similarly, autoantibodies recognizing citrullinated
of scleroderma. The immune response in autoimmune diseases proteins (rheumatoid arthritis [RA]–specific autoantibodies;
4
has features of an adaptive immune response (usually directed see below) frequently precede the development of RA. These
against exogenous antigens), but its targets are autoantigens. Since findings indicate that either a threshold needs to be exceeded
the adaptive immune response is initiated when suprathreshold in terms of tissue damage before symptoms manifest, or that
concentrations of molecules with structures not previously there are two distinct phases in disease development, one marked
tolerized by the host are encountered in a proimmune context, by production of a group of autoantibodies and the second
the association of specific autoantibodies with distinct clinical by autoamplifying tissue damage. In a landmark study in SLE,
5
phenotypes provides critical clues to understanding the initiation Arbuckle et al. have provided important insights into this issue.
and propagation of autoimmune diseases. They analyzed sera collected from patients from the US military,
This chapter highlights some of the mechanistic principles who subsequently developed SLE. Strikingly, autoantibodies in
that underlie autoimmune diseases. The extraordinary breadth SLE could be divided into two groups: (i) those that precede the
and complexity of this disease spectrum means that the areas diagnosis of SLE by several years—these included antinuclear
included cannot nearly encompass everything relevant. and antiphospholipid antibodies; and (ii) those that occurred
677
678 ParT Six Systemic Immune Diseases
around the time of onset of symptoms—these included anti-Sm, Susceptibility Initiation Propagation (Resolution)
anti-RNP, and to a lesser extent anti-DNA. The observation that B D
one group of autoantibodies precedes symptoms in SLE and that
another group appears coincident with the phenotype strongly A
suggests that the groups mark distinct events in the development Normal host
of autoimmune disease. Members of the first group are likely
markers of disease initiation; members of the second group are
likely markers of disease propagation. The antigens targeted by
the immune system in this latter phase (i.e., associated with
clinical disease) are more likely to have some function in disease
‘Free energy’
propagation, possibly through their possession of proinflamma-
tory or adjuvant functions (see below). 6 Autoimmune host
KEY CONCEPTS
Barriers to Defining Mechanisms of Human
Autoimmune Disease
• Genetic and phenotypic complexity
• Interval between initiating events and development of diagnostic
phenotype
• Challenges in quantifying human immune responses
C
It is therefore useful to examine the development of auto-
immune diseases in four phases (Fig. 50.1): Time
1. Susceptibility phase—before disease, but where one or several A Susceptibility
preconditions for later initiation are satisfied. This would
include impaired tolerance induction or altered immune • Impaired tolerance induction
• Impaired production of regulatory T cells
signaling thresholds. The susceptibility phase could either be • Altered immune signaling thresholds
inherited or acquired and permanent or transient.
2. Initiation phase—before onset of clinical disease, but marked B Initiation
by the presence of an autoimmune response (e.g., in the case • Suprathreshold concentration of autoantigens
of SLE—antiphospholipid antibodies). • Non-tolerized structure
3. Propagation phase—this corresponds with the onset of clinical • Pro-immune context – infection, malignancy, exposure to adjuvants
disease, marked by propagation-specific immune responses C Propagation
(e.g., in the case of SLE—anti-Sm antibodies). • Acquisition of adjuvant properties by disease specific autoantigens
4. Regulation/resolution phase—it should also be noted that in • Increased autoantigen expression in the target tissue
many cases during disease propagation, immunoregulatory • Immune effector pathways generate/expose autoantigen, which further
pathways are also activated, which may result in natural drives the immune response
inhibition of clinical disease over time. In rare cases, these FiG 50.1 Mechanisms of Autoimmunity. Autoimmune diseases
inhibitory pathways can lead to permanent resolution. This result from a complex interplay of pathways and events that
resolution phase will not be discussed further here, but its allow autoreactivity to manifest, and cause self-sustaining tissue
existence provides important evidence that homeostasis damage. Mechanistically, it is useful to divide the process into
can be reestablished even after the amplified phenotype three phases: (1) susceptibility phase—this is present before
develops. disease and is the phase in which one or several preconditions
for later initiation are satisfied; (2) initiation phase—this is marked
PHASE I: SUSCEPTIBILITY by the presence of autoimmunity, but precedes the diagnostic
clinical phenotype; (3) propagation phase—this is marked by
Although autoimmune diseases in humans are genetically autoimmunity and tissue damage, in which immune effector
complex, significant advances in understanding have occurred pathways cause damage and provide antigen to drive the ongoing
over the past several years. In some cases, advances have come immune response.
from the study of autoimmunity with mendelian patterns of
inheritance (e.g., autoimmune polyendocrinopathy with candi-
diasis and ectodermal dysplasia [APECED], immune dysfunction/
polyendocrinopathy/enteropathy/X-linked [IPEX] syndrome,
C1q deficiency). Advances have also come from genetic association Incomplete Thymic Tolerance Induction Predisposes
studies of various autoimmune phenotypes (e.g., SLE, type I to Autoimmunity
diabetes mellitus [DM]). There have also been important advances Significant insights into basic mechanisms can derive from
in the genetics of autoimmunity in several mouse models. These the study of rare human phenotypes. This has been true for
studies highlight a critical role for pathways of tolerance induction, autoimmunity, where several monogenic disorders have defined
immunoregulation, and setpoints/thresholds for immune signaling important pathogenic principles. Autoimmune polyendocri-
in avoiding emergence of autoimmunity. nopathy syndrome type 1 (APS-1;also called APECED) is a
CHaPTEr 50 Mechanisms of Autoimmunity 679
KEY CONCEPTS Impaired Clearance and Tolerance Induction by
Mechanisms Underlying Susceptibility Apoptotic Cells: Susceptibility Defect in
to Autoimmunity Systemic Autoimmunity
• Incomplete induction of tolerance in the thymus to peripherally Although little is known in humans about the thymic pathways
expressed autoantigens (autoimmune regulator [AIRE] deficiency of tolerance induction to ubiquitously expressed autoantigens,
causing autoimmune polyendocrinopathy with candidiasis and ecto- there is accumulating evidence to suggest that in the periphery,
dermal dysplasia [APECED]) apoptotic cells play an important role in providing a source of
• Impaired clearance and tolerance induction by apoptotic cells (e.g., autoantigens against which the organism becomes tolerant.
9
deficiency of C1q, C4, milk fat globule–epidermal growth factor (EGF) Apoptotic cells are generally very efficiently cleared by phagocytic
8 [MFG-E8], Mer)
• Defective production of regulatory T cells (FOXP3 deficiency causing cells; these events are normally associated with the production
9
immune dysfunction/polyendocrinopathy/enteropathy/X-linked [IPEX] of antiinflammatory cytokines and result in tolerance induction.
syndrome) Interestingly, early components of the classical complement
• Altered immune signaling thresholds (e.g., cytotoxic T lymphocyte pathway (e.g., C1q and C4) and cross-reactive protein (CRP)
antigen-4 [CTLA-4] polymorphisms, protein tyrosine phosphatase, are required for efficient apoptotic cell clearance, with production
non–receptor type 22 [PTPN22] polymorphisms) of interleukin-10 (IL-10) and transforming growth factor-β
(TGF-β). Therefore it is of particular note that homozygous C1q
deficiency is associated with a striking susceptibility to SLE in
humans, and this suggests that rapid, efficient, tolerance-inducing
clearance of apoptotic cells may play a role similar to AIRE
rare disease in which patients develop multiple autoimmune expression in the thymus in preventing subsequent emergence
10
7
diseases, often beginning in childhood. Although candidiasis of autoimmunity to ubiquitously expressed autoantigens.
and ectodermal dystrophy (including involvement of enamel Additional support for this model comes from recent studies of
and nails, as well as keratopathy) are features of the disease, milk fat globule–epidermal growth factor (EGF) 8 (MFG-E8),
the syndrome is characterized by striking autoimmunity a glycoprotein secreted from macrophages that is required for
directed against multiple different target tissues. Autoimmune the efficient attachment and clearance of apoptotic cells by
processes include autoimmune hypoparathyroidism, Addison macrophages and immature dendritic cells (DCs). MFG-E8 is
disease, autoimmune gastritis with pernicious anemia, type I also expressed in tingible-body macrophages in the germinal
DM, thyroid disease, autoimmune hepatitis, celiac disease, and centers of secondary lymphoid tissues. Interestingly, many
gonadal failure. Numerous autoantigens have been defined as unengulfed apoptotic cells are present in the germinal centers
targets of autoimmunity in APS-1 and include enzymes specifically of the spleen in MFG-E8–deficient mice, which develop a striking
11
expressed in various endocrine tissues (e.g., steroid 21-hydroxylase, lupus-like phenotype (reviewed in Rai and Wakeland ). Together,
specific for adrenal cortex; steroid 17α-hydroxylase, found in the data strongly suggest that efficient, antiinflammatory clearance
adrenal cortex and gonads; GAD65, found in pancreatic islets; of apoptotic cells plays a central role in tolerance induction and
and thyroid peroxidase). The genetic basis of APS-1 was mapped prevention of autoimmunity.
to a gene on chromosome 21q22.3, subsequently termed AIRE
(for autoimmune regulator). AIRE expression is highest in the Defective Production of Regulatory T Cells
thymus, where it is expressed in medullary thymic epithelial Although there are pathways that (i) regulate autoantigen expres-
cells. Several predicted structural features of the AIRE protein sion at sites of tolerance induction and (ii) guide autoantigens
and its localization in nuclear dots suggested that the protein toward tolerance-inducing outcomes, these pathways alone are
might be a transcriptional regulator, and significant evidence clearly insufficient to prevent the emergence of autoimmune
for this proposal was obtained in vitro. Several AIRE-deficient disease. This fact is highlighted by the emergence of autoimmunity
mouse models were subsequently generated, which allowed for when regulatory T-cell (Treg) differentiation is abnormal in
the definition of important pathogenic pathways in APS-1 that humans with IPEX syndrome, the human equivalent of the scurfy
may be broadly relevant to the mechanisms of autoimmunity mouse. IPEX is a rare, X-linked recessive disorder characterized
in general. Thus mice deficient in AIRE developed various by type I DM, thyroiditis, atopic dermatitis, and inflammatory
autoimmune phenotypes, resembling those found in human bowel disease (IBD) and is caused by mutations in the FOXP3
12
APS-1. These included multiorgan lymphocytic infiltration gene. FOXP3 is a member of the forkhead family of transcription
+
and autoantibodies, as well as autoimmune eye disease. In an factors and is essential for the development of CD4 Tregs, which
elegant series of experiments, Anderson et al. demonstrated that have been shown to regulate the activation and differentiation
AIRE regulates expression in thymic epithelial cells of various of effector T cells at many different levels (Chapter 18).
peripheral autoantigens normally expressed exclusively in endo- Preliminary investigations into the role of Tregs in human
8
crine target tissues. Thus AIRE appears to regulate the ectopic autoimmune diseases have produced mixed results, but these
expression in the thymus of tissue-restricted autoantigens and cells likely play important roles in regulating disease onset and
to provide an antigen source against which to establish central amplitude. As additional cell subsets and details about function
tolerance. 8 emerge, this area will be clarified significantly.
These data demonstrate that expression of peripheral autoan-
tigens in the thymus constitutes a major barrier to the subsequent Signaling Thresholds and Susceptibility
development of autoimmunity against these peripheral sites. to Autoimmunity
Although it is possible that similar principles apply to ubiquitously Several modulators of T-cell signaling have been defined as impor-
11
expressed autoantigens targeted in systemic autoimmune diseases, tant susceptibility determinants in autoimmunity. For example,
there are currently few data directly addressing this issue. cytotoxic T lymphocyte antigen-4 (CTLA-4) polymorphisms
680 ParT Six Systemic Immune Diseases
are associated with increased risk of a variety of autoimmune
diseases, including type I DM, Graves disease, and RA. Similarly, Dominance and Crypticity
14
a functional polymorphism in protein tyrosine phosphatase, Studies by Sercarz et al. have stressed that although antigens
non–receptor type 22 (PTPN22), has been identified as a major contain numerous potential determinants that could be presented
risk factor for several human autoimmune diseases, including SLE, on major histocompatibility complex (MHC) class II molecules
RA, and type I DM. Although the exact mechanisms underlying during antigen processing, not all determinants in a particular
susceptibility to autoimmunity remain unclear, in both cases, the molecule are equally likely to be efficiently presented. Those
polymorphisms appear to regulate the balance of stimulatory determinants that are most efficiently presented are termed
and inhibitory signaling in effector and Tregs, favoring effector “dominant”; those that are not loaded onto MHC class II to a
T-cell activation. significant degree are termed “cryptic.” For self antigens, it is
Recent genetic studies have also suggested a potential role for likely that a constant set of dominant determinants are generated
innate immune sensors in autoimmunity, focusing attention on during antigen processing under most circumstances, with similar
the critical balance between activation of the immune response outcomes in the thymus and the periphery. Antigens processed
to mitigate infectious damage and limiting the magnitude of by the “standard” pathway are, therefore, fully tolerized, with
the response to avoid immunopathology. Gain-of-function (GOF) the T-cell repertoire purged of reactivity to the dominant self.
variants of IFIH1 (encoding melanoma differentiation-associated However, the balance of dominant and cryptic epitopes presented
13
protein 5 [MDA5]) are associated with susceptibility to SLE. during antigen processing is influenced significantly by changes
This RNA helicase is essential for the detection of cytoplasmic of protein structure, which occur during various relevant physi-
15
viral RNA and activation of type I interferon (IFN) secretion ological states (Chapter 6). Several potential mechanisms that
by infected cells. The increased susceptibility to SLE with increased may alter antigen processing to reveal potentially cryptic epitopes
function of this antiviral pathway suggests that excessive IFN are summarized below.
signaling may facilitate the development of autoimmunity. Key
immune signaling pathways that protect the host from deleterious High-Affinity Binding of Antigen to Ligands or Antibodies
infectious and malignant challenges but potentially also enhance Several studies have demonstrated that antigen processing can
damage of self tissues in the process may, therefore, be important be dramatically altered when the antigen binds with high affinity
susceptibility factors in autoimmune diseases. to a ligand or antibody. The study by Simitsek and colleagues
15
Thus there are many barriers to the development of autoim- (reviewed in Lanzavecchia ) demonstrated that presentation of
munity, including effective tolerance induction in the thymus T-cell determinants in tetanus toxin can be either enhanced or
and the periphery, tightly regulated immune signaling, and suppressed as a direct consequence of antibody modulation of
homeostatic pathways of immunoregulation to limit anti-self antigen processing in human B-lymphoblastoid cells. Remark-
responses should they occur. It is likely that the genetic susceptibil- ably, a single bound antibody can simultaneously enhance the
ity to autoimmunity in outbred humans represents an integrated presentation of one T-cell determinant by more than 10-fold
threshold involving genes that regulate these various pathways— while strongly suppressing the presentation of a different T-cell
upon which environmental and stochastic events act to accomplish determinant. Biochemical analyses have shown that both the
disease initiation and propagation. suppressed and boosted determinants fall within an extended
domain of antigen stabilized by this antibody during proteolysis.
PHASE 2: INITIATION Thus ligand-induced changes in processing can destroy dominant
determinants or reveal cryptic self determinants. Similar observa-
Initiation of an adaptive immune response requires presentation tions have also been made with numerous other antigen–antibody
to T cells of suprathreshold concentrations of molecules with partners. 15
structure not previously tolerized by the host. One of the more
persuasive models proposed to explain the persistence of poten- Tissue-Specific Protease Expression
tially autoreactive T cells within the repertoire of the host is that The study by Watts and associates (reviewed in Darrah and
16
of immunodominance of T-cell epitopes. This model provides Rosen ) showed that a principal human leukocyte antigen–D
major insights into the pathogenesis of autoimmunity. 11,14 related type 2 (HLA-DR2)–restricted epitope in myelin basic
protein amino acids 85–99 (MBP85–99) contains a processing
site for asparagine endopeptidase (AEP), with cleavage by AEP
abolishing the epitope. AEP activity is, therefore, a critical factor
KEY CONCEPTS in presentation of this epitope. In human antigen-presenting
16
Potential Mechanisms That Can Alter Antigen cells (APCs), presentation of MBP85–99 is inversely proportional
Processing to Reveal Potentially Cryptic Epitopes to the amount of cellular AEP activity, and inhibition of AEP
greatly enhances presentation of the MBP85–99 epitope. Interest-
• Modification of autoantigen processing through high-affinity binding ingly, both MBP and AEP are expressed in the thymus, AEP at
to ligands or antibodies abundant levels. These data suggest that this major epitope in
• Distinct proteolytic machinery in the thymus and periphery—or dif-
ferential modification of proteolytic activity neurological autoimmunity may not be presented under normal
• Modification of autoantigen structure that modifies its processing by circumstances in the thymus as a result of destruction by AEP,
endogenous antigen-presenting cell (APC) machinery, generally through therefore raising the potential for later presentation in the
posttranslational modifications periphery in the setting of decreased AEP activity.
• Novel proteolytic events not present in the normal APC pathways
(e.g., novel cleavage during cell death or damage or inflammation) Posttranslational Modification of Autoantigen Structure
• Novel forms of autoantigens generated by mutation, truncation, or
splicing Autoantigens undergo a variety of posttranslational modifications,
including phosphorylation, proteolytic cleavage, ubiquitination,
CHaPTEr 50 Mechanisms of Autoimmunity 681
17
transglutamination, citrullination, and isoaspartyl modification. mechanism may play an important role in generating immune
18
In several cases, autoantibodies recognize exclusively the modified responses to self and tumor antigens. In this study, Engelhorn
form of the antigen (e.g., RNA polymerase-II large subunit, serine/ et al. examined whether mutated self gene products are more
arginine-rich [SR] proteins, citrullinated vimentin, and other likely to initiate immunity and used a systematic approach to
RA autoantigens), indicating that the modified forms of the define some of the principles that determine this. They generated
molecules are important in driving the immune response. In complementary DNA (cDNA) libraries encoding large numbers of
17
addition, Doyle and Mamula have demonstrated that post- random mutations in syngeneic TRPs. They then used an approach
translational modification of autoantigen structure may be more of DNA immunization of black mice to test the immunogenicity
broadly relevant than can be appreciated by studying autoantibody of the altered proteins encoded by the pools of mutated cDNA.
specificity alone. They showed that although mouse immunization Immunization with nonmutated proteins induced no detectable
with a murine cytochrome c peptide (amino acids 90–104) immune responses, consistent with establishment of tolerance to
resulted in no T- or B-cell response, immunization with the the full-length molecules. In contrast, the mutated cDNA pools
isoaspartyl form of this peptide resulted in strong T- and B-cell elicited both autoimmune depigmentation and the ability to reject
responses. The autoantibodies that were elicited recognized both melanoma tumors. Additional analysis showed that autoimmunity
the modified and the native forms of the antigen, but T cells resulted from mutations that altered autoantigen cell biology,
only recognized the isoaspartyl form. Similar observations have particularly degradation rates and pathways. Mutations also
also been made for several SLE autoantigens. The difficulty created new T-helper (Th) cell epitopes and induced recognition
detecting and quantifying antigen-specific T cells in various of nonmutated but previously cryptic epitopes. Interestingly,
autoimmune diseases may reflect their preferential recognition mutations themselves did not form part of CD8 epitopes that drive
of subtly modified forms of autoantigen. This is an important the anti-self and antitumor immune responses. Mutated molecules
area for future study—currently there is no systematic way to that were immunogenic were frequently truncated, leading the
generate the relevant autoantigen forms. authors to propose that inappropriately truncated self proteins
can provoke autoimmunity when present in a proinflammatory
Novel Antigen Cleavage During Cell Damage, Cell Death, environment. This study has provided an important mechanistic
or Inflammation underpinning for the proposal that accumulated mutations have
Recent studies have provided evidence that single proteolytic a role in the initiation of autoimmunity and that “autoimmunity”
events early in antigen processing can play critical roles in defin- might target the cancer mutanome.
ing the epitopes generated. For example, Watts and colleagues Recent work in the autoimmune rheumatic diseases (sclero-
16
(reviewed in Darrah and Rosen ) have conclusively demonstrated derma and dermatomyositis) highlights the relationship between
that early cleavage by AEP determines subsequent proteolytic cancer and the autoimmune process. In these diseases, patients
events. Modifications of the antigen that affect this early cleav- demonstrate an increased risk of cancer compared with controls.
age dramatically change the epitopes loaded onto MHC class They also show a temporal clustering of cancer diagnosis around
II molecules. 16 the time of dermatomyositis or scleroderma onset (reviewed in
19
Inflammatory microenvironments can create significant Shah ). Similarly, there is evidence for an association between
potential to load distinct epitopes because unique proteolytic SLE and cancer, particularly lymphoma, clustered within the first
20
activities are present. Activated inflammatory cells constitute a 2 years of SLE diagnosis. These associations, both with timing
major source of proteases, including various cytotoxic lymphocyte of diagnosis and preferentially with specific tumor types, are
granule proteases (granzymes), as well as numerous neutrophil strongly indicative of a nonrandom clustering of autoimmune
and monocyte granule proteases. It is of interest that numerous processes and cancer, which is likely of mechanistic significance.
autoantigens targeted in systemic autoimmune diseases are The mechanistic link between scleroderma and cancer was
substrates for these inflammatory proteases and that unique confirmed in a study that tested the hypothesis that an anticancer
autoantigen fragments are generated through the activity of immune response may target a mutated autoantigen in the
16
granzyme B and potentially other similar proteases. Such patient’s cancer, which spreads to the wild-type version of the
autoantigen forms are not generated during other forms of cell antigen to trigger a self-sustaining autoimmune disease (reviewed
19
damage or death, and similar activity is not observed against in Shah ). In this study of patients with scleroderma and cancer,
nonautoantigens. Thus novel proteolytic cleavage of intracellular genetic changes (either mutations or loss of heterozygosity) were
autoantigens during activity of cytotoxic immune effector identified in POLR3A (encoding RNA polymerase III large
pathways may provide a source of cryptic epitopes not generated subunit) in the tumors of six of eight patients with anti-RNA
during homeostatic “tolerance-inducing” tissue turnover. Direct polymerase III antibodies, whereas no such changes were identified
evidence that inflammatory protease-mediated revelation of in eight patients who lacked these antibodies. Anti-RNA poly-
cryptic epitopes is relevant to initiation of autoimmunity in vivo merase III autoantibodies in patients with cancer demonstrated
is still needed. no specificity for the mutant form of the protein over the wild-
type version, and analyses of peripheral blood lymphocytes
Autoantigen Alteration Caused by Mutation, Truncation, identified T-cell reactivity against the mutant protein. These data
or Splicing suggest that somatic mutations arising in the context of cancer
Since the final epitopes generated and loaded onto MHC class II may prompt immune responses that mediate immunoediting
molecules can be profoundly influenced by single, early cleavage as well as damage to nontumor host tissues.
events during antigen processing, relatively minor but critically It is, therefore, likely that somatic mutations acquired with
placed changes in the primary structure of autoantigens can age and their association with malignancy are important in the
have the capacity to influence peptide selection. A study of the genesis of some forms of human autoimmunity. Additional studies
melanoma and vitiligo-associated autoantigens, tyrosinase-related to confirm this and elucidate the underlying mechanisms remain
proteins (TRPs) 1 and 2 has strikingly demonstrated that this a high priority. However, the barriers to such studies in humans
682 ParT Six Systemic Immune Diseases
are very significant, as effective anticancer immunity may be antigens, and to spread the response to additional antigens in
phenotypically silent, and convenient technologies to quantify that tissue, greatly reduces the stringency that must be met to
somatic mutation and specific immune responses in normal keep the process going.
individuals will be needed to draw conclusions of causality.
PHASE III: PROPAGATION
Antigen Mimicry
The process of antigen mimicry (see below) has frequently been Principles of Amplification
21
proposed as a potential initiator of autoimmune diseases. This One of the central features of human autoimmunity is the
mechanism, particularly when isolated, is only likely relevant to tendency of the process to amplify progressively with the accu-
those autoimmune processes clearly associated with antecedent mulation of significant immune-mediated tissue damage. Fur-
infections, particularly infections that resolve spontaneously and thermore, in the vast majority of cases, once such amplification
subsequently recur upon reexposure to the offending agent. The begins, the process is very unlikely to resolve spontaneously.
mechanism may, however, also play a role in initiation of the Autoantigens themselves can be very important in this phase,
autoimmune response in self-sustaining autoimmune processes in terms of both acquisition of adjuvant properties and regulation
but, in this case, requires that T-cell responses to the cross-reacting of levels of expression. The essential features of amplification
self antigen are initiated. are a substrate cycle, in which antigen expression and adjuvant
Foreign antigens, which often differ from their homologous properties induce an immune response, which, in turn, induces
self antigens in some areas, may, nevertheless, bear significant increased antigen expression and tissue damage—and further
structural similarity to self antigens in other regions. Initiation drives the immune response. The importance of tissue-specific
of an immune response to the foreign antigen may generate a autoantigen expression in focusing such immune responses is
cross-reactive antibody response that also recognizes the self only beginning to be recognized.
protein (antigen mimicry). When the antigen is a cell surface
molecule, antibody-mediated effector pathways can lead to host Acquisition of Adjuvant Properties by
tissue damage. Although the antibody response is cross-reactive Disease-Specific Autoantigens
with self molecules, the T cells that drive this response are gener- In spite of the fact that tens of thousands of molecules could be
ally directed at the foreign antigen, at least initially (see below). targeted by the immune system in autoimmunity, the number
Diseases involving this sort of “antigen mimicry,” therefore, tend of molecules that are frequently targeted in the different phe-
to be self-limiting, although they can recur upon reexposure to the notypes are markedly restricted—limited perhaps to 100 or so.
offending antigen. It is important to realize that antigen mimicry This has led to the proposal that frequently targeted autoantigens
alone cannot explain self-sustaining autoimmune diseases, which may themselves have properties that make them proimmune.
22
are driven by self antigens and autoreactive T cells. In these Work by Howard and associates (reviewed in Plotz ) provided
cases, there is a requirement for overcoming T-cell tolerance important initial support for this proposal. They observed that
to the self protein. The central issues in this regard are (i) how the autoantigenic histidyl aminoacyl tRNA synthetase (HRS),
T-cell tolerance to self antigens might initially be broken, and which is targeted in autoimmune myositis (but not non–
(ii) once this has occurred, why these antigens continue to drive autoantigenic lysyl- and aspartyl-aminoacyl transfer RNA [tRNA]
the immune response to self. The simultaneous liberation of self synthetases), is a chemoattractant to immature DCs and other
antigen in the presence of the cross-reactive antibody response has leukocytes. The authors suggested that the selection of a self
been proposed to play critical roles in this regard. For example, molecule as a target for an autoantibody response may be a
several studies have suggested that when a humoral response consequence of proinflammatory properties of the molecule
to a foreign protein is induced that cross-reacts with the self itself. They further suggested that modification of autoantigen
antigen, a strong Th-cell response specific for the self antigen structure during processes of cell damage or death may be critical
can occur. The simultaneous liberation of significant amounts of in recruiting these additional functions of autoantigens.
self antigen in the setting of a cross-reactive antibody response
may allow for effective presentation of cryptic epitopes in the self Role of Innate Immune Receptors in Amplification
antigen to autoreactive T cells by activated cross-reactive B cells. Several innate immune receptor systems that sense and transduce
If continued release of self antigen occurs, a specific, adaptive the signals from pathogen-associated molecular patterns (PAMPs)
immune response to self will be sustained. Antigen release from (e.g., receptors of the Toll-like receptor [TLR] and retinoic acid-
tissues likely plays a critical role in driving this autoimmune inducible gene I [RIG-I]–like receptor [RLR] families) may also
process. Understanding the mechanisms of ongoing antigen play roles in transducing the proinflammatory properties of
6
release at sites of tissue damage in autoimmune disease (e.g., autoantigens. Ligands for TLRs include both microbial and
unique pathways of cell injury and death) is a high priority for endogenous molecules, the latter group being particularly relevant
future work, as it provides a novel target for therapy (see below). to autoimmunity (see below). Microbial ligands include com-
It is clear from the above discussion that extraordinary ponents of gram-positive bacteria, gram-negative bacteria, yeasts,
complexity is operative in initiation of the human autoimmune and protozoans. For example, lipoteichoic acid and fungal
diseases. The patient population is genetically heterogeneous, products (e.g., zymosan) signal through TLR2, lipopolysaccharide
the human immune system is complex and extremely plastic, activates TLR4 signaling, dsRNA signals through TLR3, flagellin
and it interacts with a plethora of environmental stimuli and through TLR5, single-strand RNA (ssRNA) through TLR7 and
stochastic events. The simultaneous confluence of susceptibility TLR8, bacterial or viral DNA through TLR9, and Toxoplasma
23
factors and initiation forces to set off the self-sustained and profilin through TLR11. Although viral and bacterial nucleic
autoamplifying process is, therefore, a rare occurrence. In contrast, acids are the most likely ligands for TLRs, accumulating data
once activation of autoreactive T cells has occurred, the ability demonstrate that complexes containing endogenous nucleic acids
of the immune system to vigorously respond to low concentrations are able to signal through TLRs. The exact nature and source of
of antigen, to amplify the specific effector response to those endogenous ligands for TLRs in vivo remains unclear; however,
CHaPTEr 50 Mechanisms of Autoimmunity 683
recent studies have demonstrated that components from stressed, autoimmunity, IFN-α–inducing activity is abrogated by chlo-
injured, and dying cells may play critical roles in this regard. 6 roquine or bafilomycin, agents that interfere with endosome
Working in several models, numerous investigators have now acidification and TLR7 and TLR9 signaling. In addition, Rön-
25
provided evidence that the frequent targeting of nucleoprotein nblom and colleagues (reviewed in Hall and Rosen ) demon-
autoantigens (which contain DNA or RNA) results from the ability strated that when added to material from apoptotic or necrotic
of these nucleic acid components to ligate TLRs (reviewed in cells, autoantibodies from patients with SLE and Sjögren syndrome
6
Kawasaki et al. ). For example, antichromatin immune complexes with specificity for DNA or RNA autoantigens induce striking
can activate DCs and B cells through ligation of both FcγR and IFN secretion. Type I IFNs have a broad set of functions that
TLR9. B-cell activation via TLR7 ligation by RNA-containing likely contribute to the feed forward, propagation phase of
6
immune complexes has also been demonstrated. In vivo studies systemic autoimmune diseases. For example, they (i) promote
have linked these in vitro findings to the development of autoim- the differentiation of monocytes into mature DCs, which drive
munity. For example, when TLR9 deficiency is bred onto MRL-lpr autoreactive T- and B-cell responses; (ii) increase target cell
mice—which are an excellent model of SLE—animals no longer sensitivity to killing pathways; (iii) upregulate cytotoxic effector
develop autoantibody responses to chromatin. Interestingly, these pathways; and (iv) upregulate expression of autoantigens, such
animals, nevertheless, manifest the SLE phenotype—in some cases, as Ro52.
more severely than the TLR9-sufficient animals. Similarly, when This general ability of autoantigens, particularly in the context
mice are rendered TLR7 deficient, the autoantibody response to of immune complexes, to stimulate secretion of IFN and other
Sm is markedly inhibited, and severity of the SLE phenotype is cytokines is likely an important principle in the initiation and
reduced. Reciprocally, overexpression of TLR7 is sufficient to propagation of autoimmunity.
6
induce an SLE-like disease (reviewed in Kawasaki et al. ). These
data confirm that autoantigens frequently selected in different Enhanced Autoantigen Expression in the Target Tissue
autoimmune phenotypes likely have the dual property of being The striking association of specific autoantibody responses
able to simultaneously activate the innate and adaptive immune with distinct phenotypes suggests that autoantigen expression
systems. The source, form, and uptake of nucleic acids clearly or form in specific target tissues may play an important role in
influence adjuvant activity. For example, bacterial and viral DNA both focusing the immune response and generating tissue damage.
and oligonucleotides with CpG motifs have significant adjuvant Unfortunately, very little is currently known about such param-
activity, whereas mammalian genomic DNA, in which CpG is eters in vivo in relevant target tissues, both in normal and
usually methylated, has very poor adjuvant activity. In contrast, pathological circumstances.
human DNA present within immune complexes in SLE serum Recent studies on human autoimmune myopathies have begun
activates plasmacytoid DCs effectively in a DNA-dependent way. to provide important insights into this problem. Myositis-specific
Several potential explanations have been advanced to explain these autoantigens are expressed at very low levels in control muscle
6
observations. First, FcγR-mediated uptake effectively captures but at high levels in myositis tissue, where antigen expression is
29
self DNA bound by anti-DNA antibodies and directs it to the at highest levels in regenerating muscle cells. Interestingly,
correct endosomal compartment for TLR signaling. Second, histidyl tRNA synthetase (HRS) expression is also found at high
coligation of TLR9 and either B-cell receptor or FcγR alters the levels in lungs, and anti-HRS antibodies are associated with
signaling threshold of immune complexes. Last, the difference autoimmune myopathies with interstitial lung disease. Recently,
lies in the nucleic acid itself, with additional modifications of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)
DNA and RNA structure occurring in cells under different physi- was identified as an autoantigen in patients with statin-associated
30
ological circumstances (e.g., cell death) and regulating nucleic autoimmune myopathy. In addition to the induction of HMGCR
24
acid binding to TLRs. Recent studies have suggested that other protein expression by statin treatment of cultured cells, this group
sensors of PAMPs (e.g., nucleotide-binding oligomerization also demonstrated increased expression of this protein in
domain [NOD]–like receptors [NLRs], RIG-like receptors) may regenerating muscle fibers of anti–HMGCR-positive patients.
play similar roles to TLRs in amplifying adaptive responses to These data suggest that enhanced autoantigen expression in the
specific intracellular autoantigens (e.g., MDA5, interferon-γ– target tissue may be a feature of disease propagation and that
inducible protein 16 [IFI16]), but definitive evidence is not yet antigen expression during tissue repair may provide an ongoing
available. antigen source to sustain and amplify tissue damage.
The TLR–IFN interface has been recognized as critical in the Defining whether similar principles are operating in other
propagation phase of systemic autoimmune diseases (reviewed autoimmune diseases and elucidating the pathways of antigen
26
25
in Hall and Rosen, and Swiecki and Colonna ). Much attention expression and modification in relevant target tissues are an
has been focused on plasmacytoid dendritic cells (pDCs), a important areas of focus in future studies and may have important
relatively rare class of immature DCs that can secrete large therapeutic potential.
amounts of type I IFNs upon TLR ligation and that express
26
TLR7 and TLR9 at high levels. Recent studies in mouse models
have demonstrated the ability of pDCs to alternately promote ON THE HOriZON
wound healing or chronic inflammation, depending on the • Precise clinical and molecular phenotyping of patients at various disease
predisposing genetic background. For example, nonspecific skin stages is critical for improving diagnosis, monitoring, and treatment
injury in wild-type mice (by tape stripping) leads to pDC recruit- of autoimmune diseases.
ment, TLR7 and TLR9 recognition of nucleic acids, and transient • Understanding mechanisms of disease amplification, propagation, and
27
expression of type I IFNs with subsequent wound healing. In regulation will enable the development of effective targeted
contrast, the same skin damage in a lupus-prone mouse strain therapies.
results in chronic inflammation mediated by sustained type I • Understanding the mechanisms of human autoimmunity will likely
IFN expression, which can be ameliorated with pDC depletion provide important insights into the normal functioning of the immune
system, particularly with regard to natural cancer immunity.
28
or TLR7/9 inhibition. Extending these observations to human
684 ParT Six Systemic Immune Diseases
TRANSLATIONAL RESEARCH 9. Elliott MR, Ravichandran KS. Clearance of apoptotic cells: implications
in health and disease. J Cell Biol 2010;189(7):1059–70.
The challenge in the next decade is to continue elucidating the 10. Macedo AC, Isaac L. Systemic Lupus Erythematosus and Deficiencies of
underlying mechanisms of autoimmunity to improve diagnosis Early Components of the Complement Classical Pathway. Front Immunol
2016;7:55.
and treatment and enable more precise monitoring of these 11. Rai E, Wakeland EK. Genetic predisposition to autoimmunity–what have
diseases. The existence of distinct phases in the development of we learned? Semin Immunol 2011;23(2):67–83.
autoimmune disease provides an opportunity to identify patients 12. Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation,
at risk of developing tissue damage before this occurs and polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by
potentially to interdict the process before the amplification cycle mutations of FOXP3. Nat Genet 2001;27(1):20–1.
is established. Understanding natural mechanisms of regulation 13. Oliveira L, Sinicato NA, Postal M, et al. Dysregulation of antiviral
of disease amplitude, or in some circumstances, even disease helicase pathways in systemic lupus erythematosus. Front Genet
resolution, will provide important opportunities for therapy. 2014;5:418.
The role of the target tissue as an active participant, rather than 14. Sercarz EE, Lehmann PV, Ametani A, et al. Dominance and
a passive bystander, in the ongoing destruction will likely be crypticity of T cell antigenic determinants. Annu Rev Immunol
1993;11:729–66.
understood in molecular detail and provide novel approaches 15. Lanzavecchia A. How can cryptic epitopes trigger autoimmunity? J Exp
to decreasing the amplitude of amplifying cycles. The identifica- Med 1995;181(6):1945–8.
tion of the precise biomarkers of all these events requires 16. Darrah E, Rosen A. Granzyme B cleavage of autoantigens in
exceptional clinical phenotyping of patients early in the disease autoimmunity. Cell Death Differ 2010;17(4):624–32.
course, longitudinal analysis by centers of excellence that follow 17. Doyle HA, Mamula MJ. Posttranslational modifications of self-antigens.
up large numbers of patients with similar phenotypes over time, Ann N Y Acad Sci 2005;1050:1–9.
and effective coupling to basic laboratory enterprise. Critical 18. Engelhorn ME, Guevara-Patino JA, Noffz G, et al. Autoimmunity and
areas of future investigation relevant to diagnosis and therapy tumor immunity induced by immune responses to mutations in self. Nat
include clarification of the roles of genetic and epigenetic factors, Med 2006;12(2):198–206.
interactions between the innate and adaptive immune responses, 19. Shah AA, Casciola-Rosen L, Rosen A. Review: cancer-induced
Tregs, and focus on the target tissue and antigen contributions autoimmunity in the rheumatic diseases. Arthritis Rheumatol
2015;67(2):317–26.
to ongoing amplification. 20. Bernatsky S, Boivin JF, Joseph L, et al. An international cohort study of
cancer in systemic lupus erythematosus. Arthritis Rheum
Please check your eBook at https://expertconsult.inkling.com/ 2005;52(5):1481–90.
for self-assessment questions. See inside cover for registration 21. Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism
details. of autoimmune disease. Clin Rev Allergy Immunol 2012;42(1):102–11.
22. Plotz PH. The autoantibody repertoire: searching for order. Nat Rev
Immunol 2003;3(1):73–8.
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2. Bizzaro N. Autoantibodies as predictors of disease: the clinical and 2011;23(2):106–12.
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diabetes: a scientific statement of JDRF, the Endocrine Society, and the 26. Swiecki M, Colonna M. Unraveling the functions of plasmacytoid
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4. Dekkers J, Toes RE, Huizinga TW, et al. The role of anticitrullinated Immunol Rev 2010;234(1):142–62.
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autoantibodies before the clinical onset of systemic lupus erythematosus. 28. Guiducci C, Tripodo C, Gong M, et al. Autoimmune skin inflammation is
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6. Kawasaki T, Kawai T, Akira S. Recognition of nucleic acids by TLR7 and TLR9. J Exp Med 2010;207(13):2931–42.
pattern-recognition receptors and its relevance in autoimmunity. 29. Casciola-Rosen L, Nagaraju K, Plotz P, et al. Enhanced autoantigen
Immunol Rev 2011;243(1):61–73. expression in regenerating muscle cells in idiopathic inflammatory
7. Cutolo M. Autoimmune polyendocrine syndromes. Autoimmun Rev myopathy. J Exp Med 2005;201(4):591–601.
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CHaPTEr 50 Mechanisms of Autoimmunity 684.e1
MULT i PLE-CHO i CE QUEST i ONS
1. Antibodies directed against which of the following antigens 2. Which of the following autoantibodies is likely associated
has been shown to be associated with an increased risk of with systemic lupus erythematosus (SLE) propagation, based
cancer in scleroderma? on the observation that it arises closest to the time of symptoms
A. Topoisomerase onset?
B. RNA polymerase III A. Antinuclear
C. Centromere B. Anti-La
D. Fibrillarin C. Antiphospholipid
E. NXP-2 D. Anti-Sm
51
Systemic Lupus Erythematosus
Cynthia Aranow, Betty Diamond, Meggan Mackay
Systemic lupus erythematosus (SLE) is a systemic autoimmune mortality, and response to therapy are also modulated by ethnicity,
disease characterized by the production of autoantibodies and and all studies support observations of increased disease activity,
a broad spectrum of clinical manifestations. It most commonly damage, and mortality in nonwhite populations (Table 51.2). 4
presents in women during their childbearing years. Although
the etiology of SLE is unknown, both genetic and environmental Mortality
factors contribute to loss of self-tolerance. Current therapeutic Increased awareness leading to earlier diagnoses, availability and
modalities are antiinflammatory and immunosuppressive. use of immunosuppressive agents, and improved treatment for
comorbid diseases have contributed to a dramatic decrease in
EPIDEMIOLOGY mortality over the last half-century, with a 5-year survival rate
5
of 50% in the 1950s to 96–99% in the past 5 years. Despite this
The American College of Rheumatology (ACR) classification increase in survival, lupus patients continue to suffer significant
(Table 51.1), created initially to classify this disease with multiple morbidity and mortality related to disease and medication effects.
diverse manifestations, has undergone several revisions in efforts Compared with the general population, risk of death is reported
1
to improve sensitivity and specificity of the criteria. The revised as 2–5 times higher in lupus patients, with standardized mortality
1997 classification scheme is the most widely accepted instrument rates as high as 6.7 and 7.8 in SLE cohorts with lupus nephritis.
for “diagnosing” lupus; however, these criteria do not represent Overall, mortality is modulated by gender, ethnicity, race, geo-
the full spectrum of disease. Patients fulfilling 4 out of the 11 graphical location, disease comorbidity, age at diagnosis, and
criteria are classified with SLE with approximately 95% certainty, the presence of lupus nephritis or end-stage renal disease.
although many individuals who meet only two or three criteria Generally, highest mortality rates are associated with male sex,
may also be considered as having SLE. More recently, the Systemic black race, and active lupus nephritis. The leading causes of
Lupus International Collaborating Clinics (SLICCs) have proposed death include cardiovascular disease, infection, and active SLE;
and validated a revised classification scheme that seeks to improve the order of frequency depends on the population reported. A
sensitivity and specificity by inclusion of a broader range of bimodal distribution of death has been well recognized; early
immunological and clinical criteria. A patient will satisfy the deaths often result from infections or active disease, whereas
SLICCs classification of SLE if there is biopsy-proven lupus deaths occurring later in the course of disease are frequently
nephritis with an autoantibody (antinuclear antibody [ANA] or attributed to end-stage organ damage and cardiovascular disease,
anti-dsDNA) or if a minimum of 4 predefined criteria are met usually in the setting of inactive disease. Both cardiovascular
(1 of these 4 criteria must be clinical, and one must be immu- disease and organ failure are associated with damage accrued
2
nological). During the childbearing years, the ratio of women from recurrent SLE disease activity and medication effects.
to men with lupus is approximately 9 : 1. This ratio is less in
younger and older populations, supporting a role for hormonal DAMAGE
factors in disease induction. The majority of lupus presents during
adulthood; approximately 20% of cases are in the pediatric With improved survival, the impact of comorbid conditions has
population. Recent studies suggest that age at diagnosis may be become increasingly important. Patients may accrue irreversible
increasing in some populations; mean ages at diagnosis reported damage over time resulting from active disease and/or toxicities
since 2002 range from 31 years in Martinique and Brazil to 51.7 of medications. The SLICCs/ACR Damage Index (SDI) is a validated
years in Wisconsin (United States) and 47 years in Sweden. instrument to measure damage. Damage accumulates over time
Lupus occurs throughout the world; susceptibility is linked and is associated with poorer quality of life as well as increased
to race and ethnicity as well as environmental exposures. World- morbidity and mortality. Renal, musculoskeletal, and cardiac
wide incidence rates vary from 1.9–8.7/100 000, and prevalence domains are important contributors to damage. There is increased
3
rates vary from 19.3–207/100 000; however, incidence rates in awareness of cardiovascular disease in SLE. As discussed below
African Americans, African Caribbeans, Hispanics, and Asians (cardiac involvement: coronary artery disease), events attributable
are approximately three times greater than in Caucasians. to atherosclerotic disease occur significantly more frequently in
Although epidemiological data are scant, it appears that the lupus cohorts compared with their age-matched controls. Tradi-
incidence of SLE in Africa is lower. Data from animal models tional risk factors, e.g., hypertension, hyperlipidemia, physical
suggest this may be a consequence of a protective effect of malaria inactivity, and impaired glucose control, are enriched in lupus
infection. Clinical manifestations, disease activity, damage accrual, patients. However, the risk of cardiovascular events continues to
685
686 Part SIX Systemic Immune Diseases
TABLE 51.1 american College of rheumatology Criteria for Systemic Lupus Erythematosus
Criteria Description
Malar rash Fixed malar erythema, flat or raised
Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
Photosensitivity Skin rash as an unusual reaction to sunlight, by patient history or physician observation
Oral ulcers Oral and nasopharyngeal ulcers, usually painless, observed by physician
Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion
Serositis Pleuritis (convincing history of pleuritic pain or rub heard by physician or evidence of pleural effusion)
or
Pericarditis (documented by electrocardiogram or rub or evidence of pericardial effusion)
Renal disorder Persistent proteinuria > 0.5 grams per day or > than 3+ if quantification not performed
or
Cellular casts may be red cell, hemoglobin, granular, tubular, or mixed
Neurological Seizures—in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance
disorder or
Psychosis—in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte
imbalance
Hematological Hemolytic anemia—with reticulocytosis
disorder or
Leukopenia (<4000/mm total on two or more occasions)
3
or
Lymphopenia (<1500/mm on two or more occasions)
3
or
Thrombocytopenia (<100 000/mm in the absence of offending drugs)
3
Immunological Anti-ds DNA: antibody to native DNA in abnormal titer
disorder or
Anti-Sm: presence of antibody to Sm nuclear antigen
or
Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of immunoglobulin G (IgG) or IgM
anticardiolipin antibodies; (2) a positive test for lupus coagulant using a standard method; or (3) a false-positive serological test for
syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent
treponemal antibody absorption test
Antinuclear An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of
antibodies drugs known to be associated with “drug-induced lupus” syndrome
be greater in lupus patients compared with their healthy peers increasing with age. Common ANA specificities found in lupus
even after controlling for traditional risk factors, suggesting that patients include double-stranded (ds) DNA, single-stranded (ss)
lupus per se confers a risk for atherosclerotic events. DNA, extractable nuclear antigens (Sm, RNP, Ro, and La), histones,
and chromatin. Specific ANAs are associated with disease subsets
IMMUNOPATHOGENESIS such as anti-Ro antibodies with subacute cutaneous and neonatal
6
SLE, anti-dsDNA, and anti-C1q antibodies with renal disease.
The immune system is designed to protect the host against foreign Most autoantibody titers do not correlate with disease activity;
pathogens and to remove cellular debris without damaging self. anti-ds DNA antibodies are a notable exception. Their fluctuation
With their universal production of autoantibodies and charac- with disease activity suggests a pathogenic role for this autoan-
teristic pathological findings of inflammation, vasculitis, vascu- tibody, and monitoring their titer helps to predict impending
lopathy, and immune complex deposition, SLE patients display disease flare in some patients.
a failure to maintain immune tolerance and immune homeostasis.
The heterogeneity of disease manifestations reflects the multiplic- The Predisposed Host: Genetic Contributions
ity of genetic, hormonal, and immune abnormalities and the SLE is a multigenic disease. Most disease-associated alleles are
diversity of environmental triggers or modifiers contributing to present in healthy individuals. Only when multiple alleles are
clinical disease (Table 51.3). Progression from initial autoreactivity present, along with an appropriate environmental trigger, will
to clinical disease occurs over time (Fig. 51.1), with the first a lupus-like phenotype arise. Familial disease clustering and a
detectable immune abnormalities of either the presence of serum higher disease concordance in monozygotic than dizygotic twins
autoantibodies or the increased expression of interferon (IFN)- suggest both an underlying genetic susceptibility and the impor-
inducible gene in blood cells (the IFN signature). tance of environmental or epigenetic factors. Cell types with
highest expression of genes for which there are SLE susceptibility
Autoantibodies alleles are B cells and dendritic cells (DCs), suggesting that these
ANAs are present in over 98% of patients diagnosed with SLE. cell lineages may be drivers of disease. This is an intriguing
Their presence is not specific to SLE, as they are observed in hypothesis, as it suggests that alterations in B-cell tolerance
patients with other autoimmune diseases, malignancies, and viral mechanisms and alterations in antigen presentation to T- effector
(hepatitis) and parasitic (malaria) infections as well as in response and T-regulatory cells and altered cytokine production are central
to environmental triggers such as therapeutic agents (see section to disease pathogenesis.
on drug-induced lupus, below). Furthermore, ANAs are found Presumed susceptibility genes identified in humans include
in low titer in 5% of the general population, with prevalence those affecting lymphocyte activation, proliferation and apoptosis,
CHaPtEr 51 Systemic Lupus Erythematosus 687
‡ Chinese d (n = 175) 58 6 31 15 54 9 29 11 58 95 81
† african american PrOFILE cohort a (n = 216) 45 33 46 46 89 16 54 60 82 97 79
Prevalence (%) of american College of rheumatology Criteria in Different Ethnic Cohorts
† Caucasian Danish f (n = 513) 48 14 43 11 67 13 45 39 67 98 98
† Caucasian Norwegian e (n = 346) 40 13 41 1 83 8 17 34 36 99 57
† Caucasian PrOFILE cohort a (n = 260) 67 12 72 57 87 9 23 42 62 97 65
‡ Caucasian USa d (n = 46) 24 24 46 7 54 4 54 26 83 83 57 c Buján S, Ordi-Ros J, et al. Contribution of the initial features of systemic lupus erythematosus to the clinical evolution and survival of a cohort of Mediterranean patients. Ann Rheum Dis 2003;62(9):859–65. d Thumboo J, Uramoto K, et al. A comparative study of the clinical manifestations of systemic lupus erythematosus in Caucasians in Rochester, Minnesota, and Ch
‡ Caucasian Spain c (n = 239) NA 27 29 18 71 6 23 33 55 100 NA b Vilá LM, Mayor AM, et al. Clinical and immunological manifestations in 134 Puerto Rican patients with systemic lupus erythematosus. Lupus 1999;8(4):279–86.
† Hispanic Puerto rican b (n = 134) 72 10 77 30 67 9 30 28 77 93 NA a Alarcón GS, McGwin Jr G, et al. Baseline characteristics of a multiethnic lupus cohort: PROFILE. Lupus 2002;11(2):95–101.
† Hispanic PrOFILE cohort a (n = 78) 64 6 59 58 91 12 59 64 85 97 83
TABLE 51.2 Malar rash Discoid rash Photosensitivity Oral/nasal ulcers Arthritis Seizure/psychosis Renal Serositis Cytopenias Antinuclear antibody Immunological † Cumulative data. ‡ Inception data. 2001;45(6):494–500.
688 Part SIX Systemic Immune Diseases
Progression of autoimmunity may dictate autospecificity (as above) but is less important in
determining risk of disease.
Benign
autoreactivity
Genes Associated With Impaired Clearance
Susceptible + Environmental of Apoptotic Debris
host triggers
Patients with severe deficiencies of C2, C4, and C1q display disease
11
Pathogenic autoantibodies risks of 10%, 75%, and 90%, respectively, for SLE. Reduced
epitope spreading, uptake of apoptotic cells has been implicated in disease initiation
heavy chain class switching in murine models of SLE and is seen histopathologically in lymph
12
nodes of lupus patients. Though rare, individuals homozygous
for null alleles of C2, C4, and C1q are at significantly increased
Antibody/immune complex risk. Polymorphisms of mannose-binding lectin (MBL) and
deposition in tissue
C-reactive protein (CRP)—acute-phase reactants that facilitate
opsonization and phagocytosis of immune complexes, apoptotic
debris, and microbes—also associate with SLE susceptibility;
Clinical disease Cellular infiltration and MBL haplotypes appear to be more important in Chinese and
inflammatory response
Spanish populations than in Caucasians. TREX1 encodes a 3′
repair exonuclease that monitors DNA synthesis; TREX1 defi-
Tissue destruction, ciency leads to accumulation of endogenous DNA and is associated
fibrosis with increased expression of IFN and autoimmunity. ITGAM
FIG 51.1 Spectrum of Autoimmunity. encodes the α-chain of an integrin adhesion molecule that binds
C3b fragments and other proinflammatory molecules. GWASs
have identified associations of TREX1 and ITGAM variants with
and SLE susceptibility in European populations. ITGAM has
TABLE 51.3 Factors Contributing to also been reported as a susceptibility gene in African American
9
autoimmunity and Hispanic populations but not in Asian populations.
The Fcγ receptors—FcγR1 (CD 64), FcγRII (CD32), and
• Genetic factors FcγRIII (CD16)—have different binding affinities for immuno-
• Loss of peripheral tolerance
• B-cell abnormalities globulin (IgG) and immune complexes as well as different
• T-cell abnormalities cell-specific expression and function. FcγRI, FcγRIIa, and FcγRIIIa
• Dendritic cell abnormalities and IIIb are all activating receptors. Cross-linking these receptors
• Cytokine milieu by immune complexes results in degranulation, phagocytosis,
• Hormonal influences antibody-dependent cellular cytotoxicity, cytokine gene transcrip-
• Environmental triggers tion, and release of inflammatory mediators by myeloid cells.
Substitutions of one or more amino acids in the activating FcγR
genes—arginine (R) for histidine (H) at position 131 in γFcγRIIa
and phenylalanine (F) for valine (V) at position 158 in γFcγRIIIa—
cytokine production, antigen presentation, and clearance of results in decreased affinity for IgG immune complexes. Because
apoptotic debris. Many of these genes are also implicated in apoptotic debris is opsonized by antibody to promote clearance,
susceptibility to other autoimmune diseases (e.g., CTLA4 such deficiencies may lead to immune activation by apoptotic
in Graves disease and type 1 diabetes, PTPN22 polymorphisms debris. Associations between the γFcγRIIa R131H allele and disease
7,8
in rheumatoid arthritis and type 1 diabetes). Genome-wide susceptibility or nephritis occur in Brazilian, Thai, Korean,
association studies (GWASs) and genome-wide linkage analyses German, and African American populations, and FcR polymor-
have utilized high-throughput techniques to study hundreds of phisms may also predict a therapeutic response to immunobiologi-
13
thousands of single nucleotide polymorphisms (SNPs) in cal agents such as rituximab. γFcγRIIIa F158V and γFcγRIIIb
individual patients with SLE and have yielded approximately 50 NA2/NA2 polymorphisms are reported to associate with disease
9
SLE-associated susceptibility loci, some of which are of particular susceptibility in Dutch, Korean, Thai, and Caucasian populations
14
relevance in ethnic and racial groups (Chapter 33). (reviewed in Mackay et al., 2006). In contrast, FcγRIIb is an
inhibitory receptor. Engagement of FcγRIIb on DCs delivers an
Genes Associated With Antigen Presentation inhibitory signal. Cross-linking of FcγRIIb and the B-cell receptor
Polymorphisms of major histocompatibility complex (MHC) (BCR) results in decreased intracellular calcium flux with
genes determine the peptides of self and foreign antigens presented decreased B-cell activation and proliferation. The FcγRIIb I232T
within MHC molecules that select the naïve T-cell repertoire. allele leads to the inability of the receptor to enter lipid rafts
Human leukocyte antigen (HLA)-DR2 haplotypes in African and perform its inhibitory function. This allele is associated with
15
American, African, Taiwanese, and Korean populations and SLE in Asian populations, and dysregulation of FcγRIIB expres-
HLA-DR3 haplotypes in Caucasian populations have been sion on activated memory B cells has been reported in SLE
associated with a two- to threefold increased risk for developing patients. 14
10
SLE. Associations between anti-Ro antibodies and HLA-DR3
and anti-La antibodies and HLA-DR25 are consistent with the Genes Associated With Lymphocyte Activation,
concept of antigen-driven processes involving T-cell recognition. Proliferation, and Function
The association of HLA with SLE is not as dominant as with Several SLE risk genes have been implicated in the regulation
other autoimmune disease, suggesting that the T-cell response and activation of lymphocytes. BLK, LYN, and BANK1 encode
CHaPtEr 51 Systemic Lupus Erythematosus 689
the tyrosine-kinase proteins Blk and Lyn and B-cell scaffold adaptive immune responses and suggesting that the effect of
protein with ankarin repeats; all are associated with intracellular IFN-α on autoimmunity is complex.
signaling pathways. ETS1 and IKZF1 encode transcription factors Multiple polymorphisms in the IL10 gene have been reported,
and are believed to play a role in B-cell differentiation and self- with conflicting results with respect to SLE susceptibility. A
tolerance. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is meta-analysis of 15 studies concluded that some IL10 polymor-
upregulated on T cells after activation and dampens inflammatory phisms do associate with SLE, but their importance is modulated
responses. It has a higher affinity than CD28 for B7.1 (CD80) by ethnic background. 19
and B7.2 (CD86), thereby competitively inhibiting engagement In the NZB/W murine model, a tumor necrosis factor (TNF)
of CD28 and blocking the costimulatory signal required for T-cell allele associated with low production is linked with disease, and
activation. CTLA-4 ligation of B7 also activates indoleamine treatment with TNF decreases autoantibody production. Con-
dioxygenase (IDO) expression, an enzyme involved in tryptophan sistent with this observation, TNF blockade for rheumatoid
metabolism, and diminishes T-cell proliferation. Finally, CTLA-4 arthritis or inflammatory bowel disease can lead to autoantibody
−/−
is critical for activation of regulatory T cells. In CTLA-4 mice, production and infrequently to frank lupus. Several polymor-
an uncontrolled, lethal inflammatory response occurs. CTLA-4 phisms for genes encoding TNF-α and -β (lymphotoxin-α) have
alleles with decreased production of soluble CTLA-4 are impli- been associated with SLE; these associations are also influenced
cated in the pathogenesis of several autoimmune diseases, by ethnicity. 20
including Sjögren disease, ulcerative colitis, psoriasis, type 1
diabetes, and multiple sclerosis as well as SLE. 16 Genes Associated With Cell Survival
The PTPN22 gene encodes a tyrosine phosphatase that has Fas ligand (expressed on activated T cells) binding to Fas (CD95)
been suggested to downregulate T-cell and B-cell receptor (BCR) stimulates a signaling pathway resulting in apoptotic death of
activation, although the precise role of polymorphic PTPN22 I the Fas-expressing cell. Fas-induced apoptosis of activated cells
disease pathogenesis remains unresolved. A PTPN22 polymor- contributes to the elimination of autoreactive B and T lympho-
phism resulting in diminished ability to control T-cell antigen cytes. Lymphopenia in SLE has been associated with increased
receptor activation has been reported in SLE and other auto- Fas expression on lymphocytes, and Fas and Fas ligand alleles
21
immune diseases, suggesting a common mechanism of immune have been linked to disease susceptibility. Whereas lack of Fas
dysregulation. The PTPN22 risk allele has also been associated expression in mice leads to an SLE-like phenotype, lack of Fas
with reduced type I IFN production by myeloid cells after activa- expression in humans is associated with a lymphoproliferative
tion of Toll-like receptor (TLR) 7. disease that does not share autoantigen specificities and target
organs with SLE.
Genes Encoding Cytokines and Chemokines Bcl-2 family genes encode intracellular proteins that are either
IFN regulatory factor 5 gene (IRF5) encodes a critical transcription pro- or antiapoptotic. Increased expression of Bcl-2, an anti-
factor in the type I IFN pathway; the IRF5 locus has the strongest apoptotic molecule, leads to a lupus-like serology and nephritis
association with SLE outside of the MHC region. Four allelic in mice with certain genetic backgrounds. Increased intracellular
variants have been identified in multiple ethnically diverse levels of Bcl-2 have been reported in SLE, particularly in Chinese
populations. Variants of the signal transducer and activator of and Mexican populations. The combination of a Bcl-2 susceptibil-
transcription factor 4 protein (STAT4) gene have also been ity allele and interleukin-10 (IL-10) susceptibility allele confers
associated with SLE susceptibility in GWASs of Caucasian and a 40-fold increased risk of SLE, demonstrating that infelicitous
Asian populations. There are data suggesting interaction between combinations of risk alleles potentiate risk. 22
IRF5 and STAT4, and the presence of one or more risk alleles
of the two genes may confer increased susceptibility. IL-1 receptor- Genes Regulating Target Organ Damage
associated kinase 1 (IRAK1) and methyl-CPG-binding protein Only a few genes are known to regulate the vulnerability of
2 (MECP2) genes are both found on the X chromosome. IRAK1 target organs, the kidney in particular, to autoimmune attack.
regulates multiple pathways in innate and adaptive immune In mice, genes encoding kallikreins, which upregulate bradykinins,
responses, including the link between immune complexes, TLR have SLE susceptibility alleles. In human studies a risk allele for
signaling, T-cell receptor (TCR) signaling, and IFN production. ABIN1, which regulates nuclear factor (NF)-κB activation, can
Monocyte chemoattractant protein (MCP-1) is a potent chemoat- lead to greater kidney disease. Two risk alleles of APDOL1 are
tractant for monocytes, memory T cells, and natural killer T particularly common in the African American population and
cells. MCP-1 expression is upregulated in renal tubular cells, and are thought to contribute to the increased severity of renal disease
glomeruli in lupus nephritis and urine levels of MCP-1 are in this population.
increased in patients with active lupus nephritis. An MCP-1
polymorphism resulting in increased MCP-1 production has Epigenetic Contributions
17
been associated with SLE nephritis. Polymorphisms in the Epigenetic regulation plays a determining role in gene activation.
tyrosine kinase-2 (TYK2) gene are associated with increased Major epigenetic influences in SLE involve DNA methylation at
expression of type I IFNs (IFN-α, IFN-β) in SLE. IFN-α-regulated cytosine-guanine nucleotides (CpG methylation) and histone
genes are highly expressed in peripheral blood cells from SLE posttranslational modifications (lysine acetylation or methylation,
18
23
patients compared with healthy controls (the IFN signature). phosphorylation of serine or threonine, arginine methylation).
IFN-α mediates maturation of DCs and monocytes, increasing SLE susceptibility and autoantibody production is associated
24
the capacity for T-cell activation, and promotes B-cell differentia- with DNA hypomethylation. Several drugs known to induce
tion and Ig class switching. However, in two murine models of a lupus-like disease (procainamide, hydralazine) also cause
lupus, decreases in type I IFNs unexpectedly led to worsening decreased DNA methylation. A landmark study of high-throughput
disease, consistent with numerous studies showing that type I analysis of DNA methylation in discordant twins demonstrated
25
IFNs have both pro- and antiinflammatory effects on innate and greater DNA hypomethylation in the affected siblings. It is not
690 Part SIX Systemic Immune Diseases
surprising that genes encoding integrins, NGAL, CD40 ligand, healthy donors shows that the frequency of germinal centers
+
IFN-γ receptor, and IL-6 are among the hypomethylated genes with 9G4 cells is less than 1%, implying that negative selection
in SLE. Mechanisms for hypomethylation remain unclear; of autoreactive cells occurs at the transition of naïve to germinal
decreased efficacy of DNA methyltransferases (DNMTs) and center B cells. In contrast, tonsillar biopsies from SLE patients
overexpression of microRNAs (miRNA) that interfere with DNMT demonstrate that 15–20% of germinal centers are positive for
activity have been proposed. 26 autoreactive 9G4 B cells. This study, as well as others, suggests
Vitamin D has been shown to contribute to the regulation that checkpoints exist for entry into and exodus from the germinal
of the epigenome. Vitamin D levels are low in many lupus patients, center response and that these may be altered in SLE.
but the relationship of vitamin D levels to disease risk or disease For example, it is clear that some pathogenic autoantibodies
severity remains controversial. 27 are not derived from natural autoantibodies. Back mutation of
Inflammation itself may alter the epigenome; some studies suggest several anti-DNA antibodies to their germline-encoded precursors
that the metabolic modulator metformin can reverse some of has identified nonautoreactive precursors. The failure of censoring
the inflammation-induced alterations. Recent studies show that mechanisms in germinal centers to prevent the maturation of
metformin can reduce murine lupus, although the mechanism autoreactive cells may reflect intrinsic B-cell abnormalities or
for this therapeutic effect is not completely clear. abnormalities in costimulatory molecules, cytokines (such as B
cell–activating factor [BAFF]; see below), follicular DCs, or T-cell,
B Cells B-cell interactions.
B-Cell Selection
The process of immunoglobulin variable region gene rearrange- B-Cell Signaling
ment produces large numbers of self-reactive B cells. Most B Hyperactive B-cell responses to immunological stimulation are
cells displaying self-reactive immunoglobulin are deleted centrally implicated in the production of pathogenic antibodies. SLE B
2+
in the bone marrow and at subsequent checkpoints in the cells have increased intracellular Ca flux in response to BCR
29
periphery (Fig. 51.2), so the frequency of autoreactive cells signaling, partially due to FcγRIIb dysfunction (Ile 232 Thr). 15
decreases from ~75% in immature B cells in the bone marrow The intracellular protein tyrosine kinase Lyn has both positive
to ~20% in the mature naïve B-cell population in healthy and negative effects on BCR signaling. Decreased expression of
2+
individuals. Many of the autoreactive B cells in the naïve popula- Lyn results in increased intracellular Ca flux and B-cell hyper-
tion are normally suppressed by anergy induction. Several of activity. Correspondingly, Lyn expression is decreased in resting
these checkpoints appear deficient in SLE. The IgM cross-reactive and activated B cells in one-half to two-thirds of SLE patients,
autoantibodies made by these remaining autoreactive mature suggesting that Lyn may modulate negative regulation of BCR
naïve B cells are thought to facilitate clearance of apoptotic cells, signaling in human disease. In contrast, a Lyn mutation in mice
decreasing the development of potentially pathogenic T- and leading to increased expression results in autoantibody production
B-cell responses to self-antigens. When IgM autoreactive antibod- and severe glomerulonephritis, suggesting that balanced Lyn
ies are missing in mice, a lupus-like phenotype develops. expression is critical to tolerance pathways.
Another important peripheral checkpoint is entry into the
T-cell-dependent, long-lived memory compartment. B cells with B-Cell Rescue
the 9G4 idiotype express antibodies encoded by the VH4-34 B lymphocyte stimulator (BAFF; also known as BLyS) is a member
gene, reactive with N-acetyllactosamine (NAL) determinants of of the TNF family and participates in B-cell maturation and
glycoproteins on blood group antigens targeted by cold agglu- survival. BAFF enhances survival of B cells through engagement
tinins, gangliosides, gastrointestinal (GI) mucins, glycolipids, of several receptors–BCMA, BAFF-R, and TACI. High levels of
28
and CD45 on B lymphocytes. 9G4 B cells are reported to be this cytokine allow survival of autoreactive B cells in mice,
30
present in 5–10% of the naïve B-cell population in healthy donors resulting in a lupus-like disease (reviewed in Liu and Davidson).
as well as in the IgM memory compartment. However, 9G4 B Evidence supporting a role for BAFF in autoreactive B-cell rescue
cells are excluded from the T-cell–dependent IgG memory and and human SLE includes the elevated levels seen in lupus patients,
plasma cell populations, suggesting that these autoreactive cells associations of BAFF levels with autoantibody titers, and, in
fail to cross a developmental checkpoint after activation in normal some reports, correlations with disease activity. Recently belim-
individuals. Evaluation of tonsillar biopsies and spleens from umab, a monoclonal antibody directed against soluble BAFF,
Immature Transitional 1 B cells Bone marrow
Transitional 1 Transitional 2 B cells Spleen
Transitional 2 Mature/naïve B cells Spleen
Mature/naïve Germinal center/long-lived plasma cells Spleen/lymph nodes
Short-lived plasma cells
? Pathogenic autoantibodies
FIG 51.2 Autoreactive B-Cell Checkpoints. There are tolerance checkpoints at every stage of
B-cell activation and maturation. How many checkpoints need to be breached to achieve a
pathogenic state and clinical disease is not known.
CHaPtEr 51 Systemic Lupus Erythematosus 691
has been shown to increase the percentage of ANA-positive B IFN-α in SLE pathogenesis is now well described; the primary
cells that are anergic in SLE patients. cells responsible for IFN-α production are pDC. TLR7 or TLR9
Interactions between CD40 (B cell) and CD40 ligand (CD40L, activation with RNA and DNA, respectively, induces immature
T cell) are essential for B-cell proliferation, differentiation of DC to differentiate to immunocompetent, IFN-α-producing DC
memory cells into plasma cells, and germinal center formation. that have wide-reaching effects on T cells, B cells, neutrophils, and
Immature autoreactive B cells can be rescued from antigen- monocytes. Of note, type I IFN increases plasmablast differentiation
31
induced apoptosis by engagement of CD40 or by IL-4. SLE T favoring short-lived plasma cells over germinal center matured
and B cells have upregulated CD40L, providing a critical molecule long-lived plasma cells. Plasmacytoid dendritic cells (pDC) have
to mediate B-cell rescue. The combination of IL-17 and BAFF been demonstrated in skin and renal lesions, and upregulation of
facilitates B-lymphocyte proliferation and maturation. This the “IFN signature” is observed in many, but not all, SLE patients
combination can serve as an alternative stimulatory signal for and has been associated with disease activity. A number of sus-
B-cell activation and can replace CD40/CD40L interactions. ceptibility genes identified through GWASs are associated with
Therefore in a permissible and proinflammatory cytokine milieu, IFN pathways in SLE including IRF5, IRF7, and STAT4.
B-cell activation and autoantibody production may occur in the
32
absence of cognate T-cell help. These studies are consistent T Cells
with the increased numbers of plasmablasts present in blood of T cells are critical in the abrogation of self-tolerance by providing
lupus patients with active diseases and with the increased numbers help to autoreactive B cells and facilitating the production of
of class-switched CD27-negative B cells in blood of lupus patients. somatically mutated, high-affinity, pathogenic autoantibodies.
Lupus patients can exhibit T-cell phenotypes consisting of
B-Cell Pathogenicity Unrelated to Antibody Production increased numbers of CD3 CD4 CD8 T cells, increased Th17
+
−
−
An essential role for B cells in SLE that is independent of antibody cells, T-follicular helper (Tfh) cells, and decreased numbers or
37
production is demonstrated by the T-cell activation, kidney function of T regulatory cells (Tregs). Additionally, lupus T
inflammation, and increased mortality in MRL/lpr lupus-prone cells display increased expression of activation markers and
mice that lack the ability to secrete antibody and the absence of abnormal TCR signaling responses. A substitution of TCR ζ-chain
such cells in mice that lack B cells. B cells are efficient antigen- by the γ-chain of the Fc receptor results in increased intracellular
2+
presenting cells; B cells with self-reactive specificity that have influx of Ca after TCR stimulation and a concomitant decrease
escaped tolerance are likely to present self-antigen to autoreactive in IL-2 production, disfavoring the induction of Tregs.
T cells. This may explain, in part, the beneficial effects of treatment Self-tolerance is maintained in part by the suppressive actions
with rituximab, a B-cell–depleting drug, in SLE as autoantibody of Treg. “Natural” Tregs arise de novo in the thymus, whereas
levels remain unaffected. “induced” Tregs evolve from naïve T cells exposed to IL-2 and
transforming growth factor (TGF)-β in the periphery. These
Neutrophils cells are characterized by high surface expression of the IL-2
An important link exists between neutrophils and autoimmunity. receptor α-chain, CD25, and high levels of FOXP3 intracellularly.
Neutrophil extracellular traps (NETS) are chromatin filaments Tregs act together with tolerogenic DC to maintain a steady state
released from neutrophils to trap microbes. In addition to of immature DC. In contrast, effector T cells can secrete IFN-γ
microbial peptides, NETS also contain neutrophil peptides, and IL-17 that promote immature DC differentiation to immu-
including neutrophil-encoded antimicrobial peptide LL37 nogenic DC capable of secreting IL-1, IL-6, IL-12, and TNF-α
(cathelicidin). Circulating DNA-containing immune complexes and can activate autoreactive T cells, thereby establishing a
from lupus patients have been shown to contain peptide LL37. feedback loop with impaired Tregs and activation of autoreactive
38
These combined DNA/LL37 immune complexes are potent TLR9 T cells. Studies demonstrate alterations in Tregs in patients
stimulants, resulting in production of IFN-α by plasmacytoid with SLE. Some have demonstrated reduced numbers and altered
+
+
+
33
DC (pDC). Moreover, anti-RNP antibodies also induce “NETosis” function of peripheral CD4 CD25 FOXP3 cells in patients with
34
in a process that is dependent on TLR7 and FcγRIIa signaling. active disease, whereas others fail to identify a defect. 39
Thus it is possible that autoantibodies accelerate NET formation
and increase formation of DNA/LL37 immune complexes and HORMONAL INFLUENCES
pDC production of IFN-α. These studies confirm earlier work
that described a “granulocyte signature” with significant upregula- The most compelling evidence for the role of sex hormones in
tion of granulocyte-specific transcripts within peripheral blood SLE is the observation that lupus preferentially affects women
mononuclear cells in pediatric SLE patients. 35 of childbearing age. The female-to-male ratio is 2 : 1 before
menarche, 8–9 : 1 in the fourth decade, and 2 : 1 after menopause.
Dendritic Cells Numerous case reports and studies of disease flares correlating
DCs recognize pathogens through membrane pattern recognition with pregnancy, menstruation, and use of oral contraceptives
receptors (PRRs) and are a critical component of the immune containing high doses of estrogen suggest a role for estrogen in
36
system connecting innate and adaptive immune responses. They disease activity. A significant correlation between plasma levels
can be tolerogenic or highly inflammatory due to their high of estradiol and clinical disease activity and increased
expression of costimulatory molecules. DCs function normally α-hydroxylation of estrogen in SLE yielding the more active
40
as surveillance cells, phagocytizing cellular debris and determining metabolite 16α-hydroxyestrone are also reported. No significant
whether there is cause for alarm. PRRs on DCs bind pathogen- differences in levels of sex hormones (including estrogen, tes-
associated molecular patterns (PAMPs) and damage-associated tosterone, prolactin) are noted in male SLE patients, suggesting
molecular patterns (DAMPs) that are present in sterile inflam- that the development of SLE in females may be more closely
mation. After internalization of the PAMPs or DAMPs, endosomal related to sex hormones than in men. Randomized controlled
TLRs are activated by nucleic acids and other ligands. Enhanced studies of estrogen in SLE suggest that the use of exogenous
692 Part SIX Systemic Immune Diseases
estrogen in patients with stable disease may be safe; however, a including inception versus long-standing lupus cohorts, com-
subset of patients appears to have an estrogen-sensitive disease. munity versus academic settings, socioeconomic factors, and
Mild to moderate flare rates were significantly increased in ascertainment differences are also likely to contribute to observed
postmenopausal women treated with hormone replacement differences in the prevalence of clinical manifestations. Over
therapy. time, the course of lupus is characterized by flares and remissions
Most of what we understand about hormonal modulation of disease activity.
31
of B-cell development comes from mouse studies. Estrogen
treatment of NZB/W and MRL/lpr mice or castration of male
lupus-prone mice exacerbates disease, whereas oophorectomy KEY CONCEPtS
of female mice ameliorates disease. Treatment of lupus-prone • Continued heightened awareness of systemic lupus erythematosus
mice with the selective estrogen receptor modulator tamoxifen to shorten the time between onset of symptoms and diagnosis will
also ameliorates disease. improve outcomes.
Estrogen and prolactin promote the loss of B-cell tolerance • Lupus is a disease characterized by recurrent flares.
in nonautoimmune mice. Estrogen results in diminished B-cell • Attentive monitoring even during periods of disease remission leads
responsiveness to BCR cross-linking and in less stringent negative to early recognition of impending flare, better control, and better
prognosis.
selection. Additionally, estrogen has also been reported to inhibit • Lupus is a chronic disease; the importance of a therapeutic partnership
activation-induced T-cell death by downregulation of Fas ligand between physicians and patients, emotional/social support, and patient
expression, thereby permitting increased numbers of autoreactive education cannot be overemphasized.
41
T cells. Emerging data suggest that estrogen receptor signaling • Advances in understanding mechanisms of disease pathogenesis
promotes differentiation of DC into immune-competent DC correspond to advances in treatment strategies and development of
through increased expression of the transcription factor IRF4. 42 therapies with improved efficacy and safety profiles.
Elevated prolactin levels are reported in 20% of patients with
SLE, and increased prolactin exposure in lupus-prone mice
exacerbates disease activity. Whereas treatment of patients with The most common features of lupus are constitutional and
bromocriptine yielded equivocal results, treatment of NZB/W include fatigue, malaise, low-grade fever, anorexia, and lymph-
lupus mice with bromocriptine results in improved survival. adenopathy. These symptoms are believed to result from elevated
Transmembrane prolactin receptors are present on a variety of serum levels of inflammatory cytokines and may accompany
cells, including T and B cells. Upregulation of both Bcl-2 and other organ system manifestations of active disease, or they may
CD40 on B cells and CD40L on T cells occurs in response to occur in isolation. Although frequent, these symptoms are
prolactin, identifying pathways that may be involved in the nonspecific and do not aid in making the diagnosis of SLE.
prolactin-mediated rescue of autoreactive B cells. Symptoms of fatigue and malaise may also represent fibromyalgia,
Data on the microbiome demonstrate that sex hormones can which can co-occur with SLE or confound the diagnosis. 44
modulate its composition. Studies in murine lupus suggest that
androgens generate a microbiome that prevents the development Musculoskeletal Involvement
of lupus, whereas estrogen maintains a disease-permissive The musculoskeletal system is the most common organ system
microbiome. Studies of the microbiome in human disease are affected in SLE; joint pain is the presenting symptom in approxi-
just beginning. 43 mately 60–70% of patients, and 85% have joint involvement
after 5 years. 45
CLINICAL MANIFESTATIONS Arthritis and Arthralgia
CLINICaL PEarLS The pattern of joint involvement is usually symmetrical, affecting
the small joints of the hands, wrists, and knees. Pain in the
• Systemic lupus erythematosus (SLE) is a systemic disease with the ankles, elbows, shoulders, or hips or monoarticular involvement
potential to affect any organ system.
• Not all symptoms experienced by a patient with SLE are from SLE is less typical. In contrast to rheumatoid arthritis, morning
disease activity. Attribution is critical to determine before initiation of stiffness is typically limited to several minutes. Frequently, the
treatment. The differential diagnosis of a lupus flare mandates con- subjective complaints of pain are greater than the objective
sideration of infection, drug toxicities, or other etiologies. findings of warmth, swelling, and erythema. Lupus arthritis is
• Corticosteroid exposure should be minimized. characteristically nonerosive on X-ray and nondeforming.
• In the absence of data from randomized trials, use of aggressive Anticyclic citrullinated peptide antibodies occur frequently in
treatment must be balanced against associated toxicity. the rare patients with erosive arthritis. Some lupus patients
• SLE patients accumulate damage from both repeated episodes of
inflammatory disease and medication toxicities. Prompt recognition develop a nonerosive hand deformity with hypermobile joints
and appropriate treatment of disease flares should result in reduced secondary to tendon and ligamentous laxity (Jaccoud arthritis)
exposure to corticosteroids and immunosuppressive agents. (Fig. 51.3). Proliferative tenosynovitis, synovitis, small erosions
• SLE patients are at increased risk of developing atherosclerotic disease, not detectable on plain radiographs, and capsular swelling are
osteoporosis, malignancy, diabetes mellitus, and hypertension. It is features of joint and soft-tissue involvement that may be seen
essential to screen for and reduce modifiable risk factors. on MRI. The role of ultrasound and MRI in the evaluation of
musculoskeletal symptoms is not established.
Joint effusions, when they occur, are usually small. The fluid
The prevalence of the diverse clinical and laboratory features of is clear yellow with normal viscosity and forms a mucin clot. It
lupus varies in published reports (Table 51.2). Both genetic and is typically noninflammatory with a normal glucose level and a
environmental factors are likely to account for much of the white blood cell (WBC) count of less than 2000 cells/mL that
variability between cohorts. Characteristics of published cohorts, is predominantly lymphocytic. ANA performed on the synovial
CHaPtEr 51 Systemic Lupus Erythematosus 693
wrists. The majority of AVN is associated with previous administra-
tion of high doses of corticosteroids (>30 mg/day); associations
with vitamin D deficiency, minority ethnicity, hypertension, and
renal disease have also been reported. Bone biopsy in lupus patients
affected by AVN does not reveal unique findings.
Mucocutaneous Manifestations
Skin
The skin is commonly affected in SLE, with a wide variety of
lesions from malar erythema to severe bullous lupus and scarring
discoid lesions (DLE). SLE-associated cutaneous lesions are
generally categorized as acute cutaneous lupus erythematosus,
subacute cutaneous lupus erythematosus (SCLE), and chronic
cutaneous lupus erythematosus (CCLE). Known triggers for
cutaneous SLE include ultraviolet (UV) light, infections, and
drug reactions. Many lupus rashes arise in sun-exposed areas,
and sun exposure can precipitate flares of systemic disease.
FIG 51.3 Jaccoud Arthritis in Systemic Lupus Erythematosus. Typically, a photosensitive rash erupts within hours of sun
exposure and consists of tiny pruritic plaques and vesicles lasting
several days. UV light induces DNA strand breaks in keratinocytes,
resulting in apoptotic cell death and providing a rich source of
fluid may be positive, and lupus erythematosus (LE) cells may autoantigen (e.g., Ro52 antigen). SLE patients have increased
48
be present. Synovial fluid complement levels can be normal or numbers of apoptotic keratinocytes after exposure to UV light,
depressed. Synovial histology in lupus is not specific and shows and these apoptotic cells have been identified in the basal layer
synovial hyperplasia with fibrin deposition and microvascular of CCLE lesions. Particularly in a setting of impaired ability to
changes that include perivascular infiltrates in the majority of clear apoptotic debris, the abundance of autoantigen provides
cases. stimuli for autoreactive T and B cells and recruitment of pDC
with ensuing production of proinflammatory cytokines (IL-1,
Tendinitis IFN-α, TNF-α, IL-6, IFN-γ). UV-oxidized DNA is resistant to
Tendinitis is not usually attributed to SLE unless associated with cytosolic enzymatic degradation, thereby potentiating pDC
tendon rupture. When present, it is usually located in the Achilles expression of IFN-α. In addition to the proinflammatory
tendon or the tendons around the knee. Tendon ruptures are cytokines, cutaneous lupus lesions demonstrate increased expres-
more common in males and have been associated with trauma, sion of IFN-α-inducible chemokines CXCL9, CXCL10, and
46
49
steroid use, long disease duration, and Jaccoud arthropathy. CXCL11, which attract lymphocytes. Transcript analysis of
Biopsy shows a mononuclear infiltrate with tendon degeneration lesional skin in CCLE demonstrates a paucity of Tregs with
and neovascularization. The diagnosis can be easily demonstrated increased numbers of T-helper 1 (Th1), IFN-γ producing cells.
on ultrasound or MRI. Increased NETS extruded from dying neutrophils are also seen
in cutaneous lupus lesions. The DNA in NETS is resistant to
Myositis/Myalgia degradation and may contribute to ongoing pDC activation
Generalized myalgia is extremely common in lupus. It frequently through TLRs and IFN-α expression characteristic of cutaneous
affects the deltoids and quadriceps and occurs during flares of lesions.
active disease. Muscle disease secondary to treatment with
corticosteroids, statins, and antimalarials or in association with Acute Cutaneous SLE
hypothyroidism is also frequent and must be considered in the The malar rash typically occurs across the cheeks and nose but
evaluation of a lupus patient with myalgia. Inflammatory muscle can include the forehead and chin, sparing the nasolabial folds
disease with weakness and an elevated creatine phosphokinase (unlike seborrheic dermatitis) (Fig. 51.4). It usually begins as
is less common, occurring in approximately 10% of lupus small discrete erythematous macules or papules that coalesce,
44
patients. Electromyography can be normal or can be charac- is frequently associated with sun exposure, and heals without
teristic of the myositis observed in polymyositis or dermato- scarring. Some patients additionally have facial swelling. The
myositis. Muscle biopsy can also be normal or can show changes differential diagnosis includes acne rosacea, seborrheic dermatitis,
associated with dermatomyositis such as a perivascular or peri- erysipelas, dermatomyositis, and contact dermatitis. Microscopical
fascicular infiltrate and immunoglobulin and complement analysis reveals a sparse inflammatory lymphocytic dermatitis
deposition. Muscle atrophy, fiber necrosis, microtubular inclu- with occasional histiocytes engulfing nuclear debris resembling
sions, and/or a mononuclear infiltrate have been documented. LE cells found close to the dermoepidermal junction. Immuno-
MRI findings are nonspecific. fluorescent staining for complement components and immu-
noglobulin at the dermoepidermal junction is positive in 70–80%
Avascular Necrosis of patients.
Avascular necrosis (AVN) has been reported in up to 30% of lupus
47
patients, is frequently asymptomatic, and is detected by MRI. Subacute Cutaneous SLE
The most commonly affected site is the femoral head. Groin pain SCLE is characterized by recurrent, nonscarring skin lesions.
exacerbated with weight bearing is a common complaint. In This distinctive rash consists of erythematous papules and plaques,
addition to the hip, AVN can involve the knees, shoulders, and with or without adherent pityriasiform scale, that erupt on the
694 Part SIX Systemic Immune Diseases
FIG 51.4 Malar Rash in a Systemic Lupus Erythematosus
Patient.
FIG 51.6 Cutaneous Vasculitis Affecting the Hands in a Patient
With Active Systemic Lupus Erythematosus.
follicles and epidermis. There is vacuolar degeneration of the
basal layer of epidermal keratinocytes and prominent keratotic
follicular plugging. Dermal mucin deposition is also present,
and there is usually dense granular deposition of immunoglobulin
(predominantly IgG) and C3 at the dermal–epidermal junction.
Patients with C2, C4, and C1q deficiencies may be predisposed
to DLE, and promoter region polymorphisms leading to high
IL-10 and low TNF-α are risk factors for DLE.
Lupus profundus typically presents as firm, tender, deep
FIG 51.5 Discoid Lesion in Systemic Lupus Erythematosus.
subcutaneous nodules that may atrophy over time. Overlaying
epidermal changes include DLE, ulcerations, and dystrophic
calcification. Biopsy reveals a lobular panniculitis with patchy
extremities and trunk, usually sparing the head and neck. These lymphoplasmacytic infiltrate in subcutaneous fat lobules. Pan-
lesions may assume an annular polycyclic form with central niculitis occurs in 10–20% of patients and must be differentiated
pallor and tiny vesicles at the active margins and can be mistaken from a subcutaneous T-cell lymphoma, erythema nodosum,
for erythema multiforme. The differential diagnosis also includes pancreatic panniculitis, and morphea.
psoriasis, polymorphic light eruption, and tinea corporis. SCLE Nonspecific skin lesions reported in SLE are typically seen
is exacerbated by UV light and a growing list of medications, during disease flares and are associated with greater disease
including thiazides and calcium channel blockers. Biopsy reveals severity. These lesions include, but are not limited to, entities
a lymphocytic dermatitis confined to the superficial and mid such as cutaneous vasculitis (Fig. 51.6), urticaria, Raynaud
dermis, frequently with associated dermal edema, mucinosis, phenomenon, livedo reticularis, alopecia, sclerodactyly, calcinosis
and degenerating keratinocytes. Both TNF-α and IL-6 have been cutis, atrophie blanche, bullous lesions, erythema multiforme,
demonstrated in active SCLE lesions. SCLE is most commonly lupus tumidus, and leg ulcers. Nonspecific cutaneous lesions
seen in Caucasian populations. Genetic analyses have revealed such as cutaneous vasculitis or ulcers are associated with a more
associations with HLA-A1, HLA-B8, and HLA-DR3 haplotypes aggressive disease course than most of the SLE-specific lesions.
as well as with deficiencies of C2, C4, and C1q. From 60–90% The lupus band test (LBT) refers to the deposition of immu-
of SCLE patients have circulating anti-Ro antibodies; however, noglobulin (IgG, IgM, and/or IgA) and/or C3 along the dermo-
they are also deposited in nonlesional skin. epidermal junction. Approximately 25% of normal individuals
display weak IgM staining at the dermoepidermal junction,
Chronic Cutaneous SLE whereas 70–80% of SLE patients have a positive LBT in sun-
DLE are usually localized to the head and neck in photo-exposed exposed, nonlesional skin. Half of SLE patients have a positive
areas, with a predilection for the ears and periorbital areas LBT in non-sun-exposed, nonlesional skin. It is unclear whether
(Fig. 51.5). The lesions vary in size and result in scar tissue with the LBT is a consequence of circulating ANA targeting denatured
significant disfigurement. Early lesions appear as erythematous DNA from UV light–damaged keratinocytes, or a result of
plaques with or without follicular hyperkeratosis, plugging, and immune complex deposition or antibasement membrane antibod-
scale and progress to scarring annular lesions with an erythe- ies. The test may be useful diagnostically and prognostically, as
matous, indurated border, adherent scale, and a central area with it correlates with increased systemic disease severity.
atrophy and telangiectasias. There are no autoantibody associa-
tions with DLE, and only 5% of patients with DLE develop Hair and Nail
systemic lupus. High-titer ANA, Raynaud phenomenon, and the Hair involvement in SLE includes scarring alopecia resulting in
presence of arthralgias may identify patients at risk for systemic permanent hair loss, induced by DLE. This can be differentiated
evolution. Histopathology characteristically reveals a lymphocytic from other common forms of scarring alopecia by immuno-
interface dermatitis with CD4 lymphocytes and pDCs involving fluorescent studies. Patchy or diffuse nonscarring alopecia is
CHaPtEr 51 Systemic Lupus Erythematosus 695
frequently associated with disease activity. Histologically, there vasculitis preferentially affects the superior mesenteric artery,
is a peribulbar lymphocytic infiltrate surrounding shrunken involving the small intestine more commonly than the large
anagen hair bulbs similar to findings in alopecia areata. Nonscar- bowel. Vasculitis can also occur in the esophagus, stomach,
ring alopecia resolves with complete hair regrowth with control peritoneum, rectum, gallbladder, pancreas, and liver. Computed
of disease activity. tomography (CT) and/or magnetic resonance with or without
A wide spectrum of nail abnormalities, including pitting, angiography are the preferred imaging tests for evaluation of
ridging, onycholysis, and dyschromia with blue or black hyper- abdominal pathology; the radiographic signs of intestinal ischemia
pigmentation, are reported in up to 30% of SLE patients, but do not differ based on pathogenesis.
none are lupus-specific. Nail fold erythema with ragged cuticles In cases with an insidious clinical course, endoscopy and
and splinter hemorrhages resembling the changes of dermato- colonoscopy may provide evidence of ischemia demonstrating
myositis are common. ulcerating or heaped-up lesions with overt vasculitis on biopsy.
The lesions are segmental and focal. Histologically, there is a
Oral Lesions small-vessel arteritis and venulitis with neutrophilic, lymphocytic,
The spectrum of oral lesions reported in SLE includes cheilitis, and macrophage infiltrates and fibrinoid necrosis of the vessel
ulcerations, erythematous patches, lichen planus–type plaques walls, associated thrombosis, and mononuclear infiltrate in the
50
on the buccal mucosa and palate, and DLE. Most oral lesions lamina propria. There may be immunoglobulin, C3, and fibrin
are asymptomatic and must be looked for on examination. Positive deposition in the adventitia and media.
immunofluorescent staining on biopsy may be useful to differenti- Timely treatment with high-dose intravenous corticosteroids
ate DLE from lichen planus–like lesions and leukoplakia. Lupus (1–2 mg/kg per day) usually results in a favorable outcome and
mucosal ulcerations demonstrate an interface mucositis and not avoidance of serious complications such as bowel necrosis and
leukocytoclastic vasculitis. perforation. To date there are no randomized trials of immu-
nosuppressive agents for the treatment of intestinal vasculitis.
Gastrointestinal Manifestations
GI symptoms occur commonly in SLE with reported incidences Intestinal Pseudoobstruction
of 15–75%; attribution is critical, as at least half are Though rare, SLE-associated intestinal pseudoobstruction
attributable to side effects of medications and to infectious (SLE-IPO) may be the initial manifestation of SLE. 51,53 Clinical
complications. 51 symptoms (abdominal pain and distension with diminished or
absent peristalsis) and radiographic findings of SLE-IPO mimic
Esophagus those of mechanical obstruction. Distinguishing features of
The prevalence of esophageal involvement varies. Many reviews SLE-IPO include concomitant active SLE in other organ systems
citing a high incidence of dysphagia and odynophagia predate and associations with hematological cytopenias, hypocomple-
the advent of proton pump inhibitors and H 2 blockers, and the mentemia, and serositis. Findings of coexisting ureterohydro-
relationship of medication use to symptoms is not clear. Dysphagia nephrosis and hepatobiliary dilatation in the absence of
and heartburn are reported in 1–50% of patients, although obstructing lesions suggest underlying smooth muscle dysmotility.
esophageal dysmotility is observed in up to 72%. An inflammatory Poor prognosis is associated with older age at SLE diagnosis, GI
process involving esophageal muscle or vasculitic damage to the symptoms as the initial SLE manifestation, longer disease duration,
Auerbach plexus is thought to contribute to the esophageal and delayed diagnosis of IPO.
dysmotility. Ulceration is rarely seen outside the context of
infections such as invasive candidiasis, herpes simplex, or Peritonitis
cytomegalovirus. SLE patients with a secondary Sjögren syndrome Inflammation of serosal membranes is well described in SLE;
may have salivary gland dysfunction, resulting in decreased saliva despite evidence of peritoneal inflammation in 63% of autopsy
contributing to dysphagia. studies, symptomatic pericarditis and pleuritis occur far more
commonly than peritonitis. Acute peritonitis may be attributed
Abdominal Pain/Vasculitis to peritoneal vasculitis or ischemia and presents with abdominal
Acute abdominal pain is common in SLE with reported incidences pain (see above). The finding of ascitic fluid by CT scan or
as high as 40%. The differential diagnosis includes intestinal ultrasound mandates an evaluation of the fluid to exclude infec-
vasculitis (45.5%), pancreatitis (10.8%), hepatobiliary disease tion and malignancy. Rarely, ascites may be attributable to hepatic
52
(18.8%), and intestinal pseudoobstruction (IPO) (3.3%). The or portal vein thrombosis. Chronic peritonitis characterized by
most catastrophic and potentially fatal GI disturbances are related large amounts of painless ascites attributable to SLE and not to
to ischemia of the small and large intestines resulting from heart failure, constrictive pericarditis, or severe hypoalbuminemia
medium- and small-vessel vasculitis or thrombotic complications due to nephrotic syndrome, liver disease, or a protein-losing
of antiphospholipid (APL) antibodies. Approximately half of enteropathy (PLE) is rare. In lupus peritonitis, the ascitic fluid
SLE patients with acute abdominal pain will have intestinal is generally exudative with a predominance of lymphocytes; LE
ischemia; associated mortality is high, so early consideration cells, autoantibodies, and low complement levels are frequent.
and intervention is critical. Intestinal vasculitis is frequently On biopsy, the peritoneum is usually edematous; it is sometimes
associated with active disease elsewhere and increased SLE hemorrhagic with lymphocytic perivascular infiltrates.
Disease Activity Index (SLEDAI) scores, whereas SLE patients
with inactive disease and acute abdominal pain will have different Pancreatitis
intraabdominal pathology unrelated to SLE. The clinical presenta- Pancreatitis attributable to SLE is rare, occurring in 8–11% of
tion may be acute, severe abdominal pain or an insidious, patients with abdominal pain and having an annual reported
stuttering course with nausea, vomiting, bloating, diarrhea, incidence ≤1/1000. Although both corticosteroids and azathioprine
postprandial fullness, anorexia, and weight loss. Mesenteric can trigger pancreatitis, 34% of reported cases are not on these
696 Part SIX Systemic Immune Diseases
medications at the onset of pancreatitis, and most patients respond organ involvement. The diagnosis is confirmed with an increased
to steroid therapy. The clinical presentation and diagnosis of α 1 -antitrypsin level in a 24-hour stool collection or with the
pancreatitis is similar in patients with and without SLE. Specific presence of IV-administered labeled human albumin in the stool.
findings in SLE include leukopenia, thrombocytopenia, and A recent review of 112 cases reported an Asian predominance
anemia. Inflammation and necrosis are common on biopsy; there (65%) and clinical features of edema (805), ascites (38%), pleural
is a single report of pancreatic vasculitis. Mortality rates are effusion (38%), pericardial effusion (21%), and hypocomple-
reported from 18–27%; poor outcome is associated with increased mentemia (79%). Approximately half the patients experienced
systemic SLE activity (particularly, low complement and diarrhea; intestinal histology revealed a range of findings,
thrombocytopenia). including lymphangiectasis, edematous villi, inflammatory
infiltrate, vasculitis, and mucosal atrophy. Biopsy results suggest
Liver a role of TNF-α, IFN-γ, and IL-6 in the increased vascular and
The term “lupoid hepatitis” was coined in the 1950s to describe enterocyte permeability in PLE.
cases of young women with chronic active hepatitis characterized
by a lymphoplasmacytic infiltrate on biopsy, hypergammaglobu- Pulmonary Involvement
linemia, and a positive LE cell test in the blood. With the Lupus affects the lungs in diverse ways involving the pleura, lung
development of ANA testing, it became apparent that “lupoid” parenchyma, and blood vessels. The most frequent and important
and “chronic active hepatitis” were indistinguishable in terms complicating feature is infection.
of clinical presentation, pathology, and response to treatment,
and the term “autoimmune hepatitis” (AIH; Chapter 76) was Pleuritis
54
endorsed in 1993. Importantly, only 10% of AIH meet criteria Pleuritis is the most common pulmonary manifestation
55
for SLE, and 2.4–4.7% of SLE patients have noninfectious hepatitis of SLE, reported in 40–56% of patients. Pleural involvement
51
attributed to SLE. Analysis of SLE liver pathology from 52 in up to 93% of lupus patients at autopsy suggests that
autopsies in Japan revealed a variety of findings, including much pleuritis may be asymptomatic. Clinically, patients note
congestion (40/52), fatty liver (38/52), arteritis (11/52), cholestasis typical pleuritic pain. On physical examination, the most frequent
(9/52), and a few cases each of chronic persistent hepatitis, nodular abnormality is tachypnea; a pleural friction rub is present in
regenerative hyperplasia, hemangioma, and cholangiolitis. Cir- some cases, and pleural effusions occur in more severe cases.
rhosis is an extremely rare complication of liver involvement in Pleural fluid is usually exudative with normal glucose and pH
SLE. The distinction between subclinical liver inflammation and elevated protein levels. The leukocyte count can range
related to SLE (lupus hepatitis [LH]) and AIH is important from several hundred to 20 000 cells/µL; both a lymphocytic
because therapy and prognosis are different. Whereas LH is and neutrophilic predominance are reported. When performed,
associated with mild enzyme abnormalities, AIH is a progressive immunological testing on pleural fluid may show reduced
disease frequently leading to hepatic failure. Both conditions complement levels and the presence of ANA, anti-DNA antibodies,
share a predilection for young women, and both demonstrate and LE cells. Although these tests are commonly obtained,
features of autoimmunity, including hypergammaglobulinemia, these results are neither sensitive nor specific to diagnose
arthralgias, and serum autoantibodies. Histologically, biopsies lupus pleuritis.
of LH reveal lobular and periportal lymphocytic infiltrates, in
contrast to the periportal and piecemeal necrosis with dense Lupus Pneumonitis
lymphocytic infiltrates seen in AIH with progression to panlobular Lupus pneumonitis occurs in up to 10% of patients. Patients
or multilobular necrosis and cirrhosis. Serologically, antiribosomal present with dyspnea, cough, mild pleuritic chest pain, and fever.
P antibodies have been associated with liver disease in LH, whereas Pulmonary infiltrates are present on plain radiograph or CT.
AIH is associated with antibodies to liver and kidney microsomes. This presentation must be distinguished from an infectious
Antismooth-muscle antibodies are observed in 60–80% of patients etiology. Histological examination of affected lung tissue shows
with AIH, compared with 30% of patients with LH. Although alveolar edema and hemorrhage with hyaline membrane forma-
both have a favorable response to steroids, AIH usually requires tion; immunofluorescent staining reveals immune complex
additional immunosuppressive agents. 54 deposition.
Distinguishing LH from hepatitis C (HCV) can be difficult.
Up to 30% of patients chronically infected with HCV have low Pulmonary Hemorrhage
titers of ANA and other autoantibodies (anti-DNA, anticardiolipin Pulmonary hemorrhage is a rare but potentially fatal complication
antibodies, and rheumatoid factor). They can also have cryo- of SLE. Symptoms include shortness of breath and hemoptysis
globulins and associated cryoglobulinemic vasculitis. It is necessary accompanied by a fall in hemoglobin, usually occurring in the
to confirm a positive enzyme-linked immunosorbent assay context of multiorgan involvement from SLE. Imaging may show
(ELISA) for HCV with polymerase chain reaction (PCR) in patchy infiltrates. Pulmonary function testing is marked by an
patients presenting with arthritis, cutaneous vasculitis, and a increased diffusion capacity (DL CO ) secondary to the presence
positive ANA, as SLE patients may have false-positive serological of alveolar blood, whereas arterial O 2 saturation is decreased.
tests for HCV. Histopathology shows bland intraalveolar hemorrhage and
hemosiderin-laden macrophages, although microangiitis with
Protein-Losing Enteropathy (PLE) an inflammatory infiltrate and necrosis of the alveolar septa can
Profound hypoalbuminemia in the absence of severe nephrotic occur. As hemorrhage into the lung may be secondary to throm-
syndrome, liver disease, or constrictive pericarditis should trigger botic thrombocytopenia, infections, or pulmonary hypertension,
concern for PLE. Clinically significant PLE is uncommon in demonstration of an inflammatory process in the pulmonary
SLE, with reported prevalence rates of 1–8%; it can present vessels or tissue is helpful to establish a diagnosis of primary
individually or in the context of severe disease activity with other pulmonary hemorrhage.
CHaPtEr 51 Systemic Lupus Erythematosus 697
well as for determining the extent of active inflammatory disease
Chronic Diffuse Interstitial Lung Disease and fibrosis. Symptoms and signs of myocarditis include unex-
Chronic diffuse interstitial lung disease is a relatively uncommon plained tachycardia, an abnormal electrocardiogram (with ST- and
manifestation of SLE and is occasionally associated with anti-Ro T-wave abnormalities), cardiomegaly, and heart failure. Echo-
antibodies. It usually has a progressive course with a chronic cardiography may show systolic and diastolic ventricular dysfunc-
nonproductive cough, dyspnea, and pleuritic chest pains. Physical tion. Myocardial involvement without overt clinical signs occurs
examination is frequently remarkable for basilar rales with commonly and may be documented using Doppler echocar-
diminished diaphragmatic movement. Pulmonary function tests diography. A noninflammatory cardiomyopathy may be seen in
demonstrate a restrictive pattern with decreased diffusion capacity; association with high-dose cyclophosphamide and, although
oxygen saturation is decreased. Imaging often shows interstitial rarely, with hydroxychloroquine.
fibrosis that is more prominent at the lung bases. High-resolution
CT (HRCT) may also help determine the extent of treatable Valvular Heart Disease
disease, i.e., fibrosis (honeycombing) versus inflammation (ground Valvular abnormalities, with thickening, regurgitation, or ver-
glass). However, the most reliable method to assess the extent rucous vegetations, occur commonly in SLE (50–60%) and
56
of pulmonary inflammation in comparison to fibrotic damage are documented by transesophageal echocardiography. The
is histological examination. Evaluation of bronchial alveolar characteristic Libman–Sacks lesion, nonbacterial verrucous
lavage fluid helps to exclude infection. vegetations, is observed at autopsy in 15–60% of patients. Mitral,
aortic, and tricuspid valves are most frequently involved. Clinically
Pulmonary Hypertension these lesions are usually asymptomatic, and hemodynamic
Pulmonary hypertension unrelated to chronic pulmonary emboli compromise, rupture of the chordae tendineae, or infection are
or interstitial lung disease occurs in SLE. Severe cases are rare; rare events. On histological examination, mononuclear cells,
the recent recognition of milder cases may be partially attributed hematoxylin bodies, fibrin and platelet thrombi, and immune
to increased awareness and findings of elevated pulmonary artery complexes are present. Antiphospholipid antibodies can be
pressures on echocardiograms obtained for evaluation of shortness associated with the development of valvular heart disease,
of breath. Patients typically present with progressive dyspnea although their pathogenic role remains unproven.
occurring in the absence of infiltrates on chest radiographs or
significant hypoxemia. Chest pain and a chronic nonproductive Pericarditis
cough are also frequently present. Pulmonary function testing Pericardial inflammation in SLE is frequent. Although asymp-
reveals a reduced DL CO . Elevated pulmonary artery pressure is tomatic pericarditis occurs in more than 50% of patients, clinically
confirmed with cardiac angiogram. Biopsy or autopsy specimens apparent pericarditis occurs in only 25%, and cardiac tamponade
of the lung reveal “plexiform” lesions that resemble those seen and constrictive pericarditis are infrequent. Pericardial fluid and
in primary pulmonary hypertension. thickening are easily detected by echocardiography; cardiac
silhouette enlargement on plain films is seen in the presence of
Shrinking-Lung Syndrome large effusions. There are no unique signs and symptoms
The shrinking-lung syndrome refers to the rare findings of of pericarditis in lupus patients. The histological findings of
shortness of breath occurring in the absence of pleuritis or acute pericarditis in lupus are inflammation with a mononuclear
interstitial lung disease plus a chest X-ray showing elevated cell infiltrate accompanied by immunoglobulin and complement
hemidiaphragms. Pulmonary function testing shows a restrictive deposition. Results of pericardial fluid analysis are neither sensitive
pattern with loss of lung volume. It had been generally accepted nor specific; the fluid is usually an exudate with elevated protein
that this syndrome results from diaphragmatic weakness (from concentrations, normal or low glucose levels, and an elevated
a myopathic process) or chest wall restriction; however, more WBC count that is primarily neutrophilic. Complement levels
recent studies suggest that pleuritis may play a causative role. in the fluid are low, and autoantibodies (ANA, dsDNA) and LE
There is no definitive therapy, although immunosuppressive cells have been reported.
therapy with cytotoxic agents usually results in an improvement
of lung function and respiratory symptoms. Coronary Artery Disease
Myocardial infarction, angina, and sudden death resulting from
Cardiac Involvement CAD are well described in SLE. Estimates of the prevalence of
There are a number of ways in which lupus affects the cardio- CAD vary widely depending on the methodology used for
vascular system; targets include the myocardium, valves, peri- ascertainment; however, the risk of myocardial infarction has
cardium, and vessels. been estimated to be 50-fold greater in young women with lupus
57
than in normal age-matched controls. Cardiac events occur
Myocardium both late in the course of SLE as well as early, and may even
Myocardial dysfunction in SLE is likely to be secondary to factors predate the SLE diagnosis. Coronary artery vasculitis is a potential
other than lupus, such as hypertension, medications, or coronary cause of CAD but is exceedingly rare, and bland atherosclerotic
artery disease (CAD). However, a cardiomyopathy resulting plaque is typically described in surgical and postmortem speci-
from immune-mediated myocardial inflammation does occur, mens. Traditional risk factors for CAD, such as hypertension,
either in isolation or concomitant with myositis or other mani- diabetes, and hyperlipidemia, are enriched in lupus patients, and
festations of systemic disease. Inflammatory myocarditis is often an increased prevalence of the metabolic syndrome likely con-
associated with anti-RNP antibodies. Histopathology typically tributes additional risk. Lupus-related risk factors include duration
shows a mononuclear, inflammatory cell infiltrate. Perivascular of SLE, duration of corticosteroid use, renal disease, and absence
or myocardial wall deposits of immune complexes and comple- of use of hydroxychloroquine. The potential contributing influence
ment also occur. Myocardial biopsy is critical for diagnosis as of antibodies to phospholipids or disease activity continues to
698 Part SIX Systemic Immune Diseases
be explored. There is a growing body of evidence supporting a have a prognosis similar to that of patients with class IV disease.
risk conferred by inflammation per se. The atherosclerotic plaque In addition to the number of involved glomeruli, renal biopsy
is infiltrated by activated macrophages and T cells that produce assessment includes measures of activity (proliferative response)
proinflammatory cytokines. Inflammation may accelerate both and chronicity (sclerotic response). Therapeutic intervention in
the formation and the rupture of atherosclerotic plaque. In SLE, class III or IV disease usually requires cytotoxic therapy in addition
the pathology of acute events seems to focus on unstable plaque. to high-dose corticosteroids, provided the chronicity index is not
If endothelial dysfunction and vascular injury are the events too high, indicating irreversible damage. Even with potent immu-
triggering atherosclerosis, there are multiple potentially respon- nosuppressant therapy such as cyclophosphamide or mycophenolate
sible processes in lupus; these include, but are not limited to, mofetil, a complete response is induced in only approximately
autoantibodies directed to endothelial cells, immune complexes, 20%, with a partial response in about 80% of patients. Moreover,
and enhanced cleavage of membrane endothelial protein C repeat histopathological studies of kidney biopsies in patients
receptor. 58 achieving a complete clinical response show ongoing renal inflam-
mation in almost half. Relapses and flares of renal disease are not
Renal Involvement infrequent, particularly when tapering corticosteroids or discontinu-
Lupus nephritis is a common manifestation of disease with sig- ing immunosuppressive treatment. Potential therapies that maintain
nificant impact on morbidity and mortality (Chapter 68). The podocyte integrity or prevent activation of renal endothelial cells
prevalence of nephritis ranges from 50–75% overall, with increased as well as agents directed against inflammatory cytokines, B cells,
prevalence of proliferative nephritis and more aggressive disease or T cells may offer therapeutic advantage and improved renal
in African Americans and Hispanics compared with Caucasians. outcome. 60
Low socioeconomic status, independent of ethnicity, is predictive
of poor prognosis, and pediatric lupus and male lupus are both Hematological
associated with a greater incidence of, and more aggressive, Hemocytopenias occur frequently in SLE, and prevalence varies
nephritis. Onset of nephritis frequently occurs within 2 years after among lupus cohorts (Fig. 51.7). Evaluation for medication effects
diagnosis, but it may occur at any time, so monitoring for potential is essential before attributing a cytopenia to an immune-mediated
renal activity is an ongoing obligation. Clinically, patients are mechanism.
asymptomatic unless they are nephrotic or have developed end-stage
renal disease. Detection typically relies on examination of the Anemia
urine, although a rising creatinine or hypertension may herald Antibody-mediated peripheral destruction of RBCs, autoimmune
61
renal involvement. The presence of proteinuria on urinalysis, hemolytic anemia (AHA), occurs in 5–14% of SLE patients.
hematuria (>5 red blood cells (RBCs)/high-power field), or pyuria In the multiethnic Latin American GLADEL cohort, AHA was
(>5 WBCs/high-power field) in the absence of other etiologies an independent predictor of damage accrual and decreased
62
should prompt an evaluation for nephritis. A 24-hour urine survival and was associated with disease activity. The antieryth-
collection remains the most accurate measurement of urinary rocyte antibody is usually an opsonizing IgG. The specificities
protein loss; however, the protein/creatinine ratio in a spot urine of the antierythrocyte antibodies in SLE have not been clearly
is accepted and more commonly used when monitoring patients. defined; the only nonrhesus-specific antigen reported in SLE is
Monitoring serum creatinine as a surrogate for the glomerular the membrane band 3 anion transporter protein. The presence
filtration rate is standard; however, creatinine is an insensitive of AHA is readily diagnosed by a positive Coombs test, elevated
marker of lupus renal disease and should be used in conjunction lactate dehydrogenase and total bilirubin, low serum haptoglobin,
with other assays. Renal activity is usually preceded or accompanied and the presence of spherocytes on the peripheral smear. AHA
by serological activity. Antibodies to dsDNA are almost always in SLE has also been associated with APL antibodies, which may
elevated or rising, whereas measurements of serum complement reflect cross-reactivity with erythrocyte membrane antigens. 63
(C3, C4, or CH 50 ) are usually low or dropping. Anemia of chronic disease is the most common cause of
Histological findings of the kidney in lupus nephritis can be anemia in SLE; however, if the hemoglobin is <10 g/dL, another
defined using the classification proposed by the International cause of anemia should be considered. The inhibitory effects of
59
Society of Nephrology/Renal Pathology Society (ISN/RPS). In proinflammatory cytokines on erythrocyte production can be
general, membranous nephritis (class V) presents with a bland compounded by increased hepcidin levels and an inadequate
urinary sediment (i.e., no RBCs, WBCs, or casts), nephrotic-range erythropoietin response. Low erythropoietin levels in SLE
proteinuria, a normal to mildly elevated creatinine, a normal blood may be attributable to renal disease as well as antierythropoietin
pressure, and normal serologies. Patients with mesangial disease antibodies. Although hemophagocytosis of hematopoietic
(class II) present with a bland or minimally active sediment, cells is frequently noted on bone marrow biopsies, the hemo-
low-grade proteinuria (less than 500 mg/24 hours), and a normal phagocytic syndrome characterized by spiking fevers, tender
serological profile. Class III (focal) and class IV (diffuse) proliferative hepatosplenomegaly, anemia, leukopenia, and markedly elevated
nephritis are characterized by active urinary sediment, proteinuria serum ferritin is rare.
(>500 mg/24 hours), active serologies, and, frequently, hypertension Lupus is also associated with a thrombotic microangiopathic
and elevated serum creatinine. Class III is defined as ≤50% glo- hemolytic anemia with schistocytes, helmet cells, and triangular
merular involvement, and class IV is defined as >50%. The extent fragments of RBCs. The clinical constellation of high fever, renal
of proteinuria, urinary sediment activity, serological abnormalities, insufficiency, neurological symptoms, and thrombocytopenia is
and creatinine elevation is often less in class III than in class IV characteristic of thrombotic thrombocytopenic purpura (TTP).
renal disease. Most cases of class II nephritis do not require initiation Coexistent TTP and SLE is a rare and frequently fatal phenomenon
of cytotoxic therapy, and progression to end-stage kidney disease that has been associated with antibodies to ADAMTS 13 (von
is rare. The prognosis of class III disease is dependent on the Willebrand factor cleaving protease) in 16% of SLE-associated
degree of activity; patients with 40–50% of glomerular involvement TTP and APL antibodies.
CHaPtEr 51 Systemic Lupus Erythematosus 699
Leukopenia NPSLE Nomenclature
Leukopenia, either neutropenia or lymphopenia, occurs in In 1999 a consensus committee established by the ACR developed
3
64
20–40% of patients. Lymphopenia (lymphocytes <1500/mm ) reporting standards, case definitions, and recommendations for
has a reported prevalence of 15–80%, whereas severe lympho- laboratory and imaging studies for 19 neurological, psychiatric,
3
penia (<500/mm ) occurs in 4–10% of SLE patients. The and cognitive syndromes. Diagnosis of NPSLE requires the
prevalence of neutropenia, variably defined in the literature as exclusion of infections, metabolic disturbances, bleeding disorders,
3
<1800 to <2500/mm , is 20–40%, whereas severe neutropenia malignancy, and medication toxicities. Using this nomenclature,
3
(<1000/mm ) is rare (1–4% prevalence). Both neutropenia and NPSLE is common overall, with a prevalence of 57–95%. Individu-
lymphopenia can reflect disease activity; however, associations ally, headache, mood disorders, cerebrovascular events, cognitive
with infection remain controversial. Carli et al. found that dysfunction, and seizures are frequent; polyneuropathy, demy-
associations between leukopenia and major infection lost elinating disease, mononeuritis, myasthenia gravis, chorea, cranial
significance in half of published studies after controlling for neuropathy, myelopathy, and Guillain–Barré syndrome are
confounding factors. 64 uncommon. NPSLE can be further subdivided into syndromes
Autoantibodies are the pathogenic mechanism generally occurring in the anatomically distinct central (CNS NPSLE) and
implicated in the leukopenias. Antineutrophil antibodies directed peripheral (PNS NPSLE) nervous systems.
against membrane components of mature and progenitor cells, Manifestations of CNS NPSLE include focal neurological
resulting in decreased phagocytosis and accelerated apoptosis, are syndromes (stroke, seizures, aseptic meningitis, movement
implicated, as are antibodies against granulocyte–colony-stimulating disorder, myelopathy, demyelinating syndrome) and diffuse
factor (G-CSF) and hyposensitivity of myeloid cells to G-CSF. psychiatric/neuropsychological syndromes (mood and anxiety
Binding of TNF-related apoptosis-inducing ligand (TRAIL) to disorders, psychosis, acute confusional state, cognitive dysfunction,
65
TRAIL receptors on neutrophils accelerates neutrophil apoptosis. headaches). PNS NPSLE syndromes include cranial neuropathy,
One of four known TRAIL receptors is unable to transduce the polyneuropathy, mononeuropathy, myasthenia gravis, Guillain–
death signal and functions as a decoy receptor; this receptor is Barre syndrome, plexopathy, and autonomic neuropathy
reduced in SLE patients with neutropenia and is upregulated by (Fig. 51.7).
steroid therapy. Lymphocytotoxic antibodies, particularly to CD4
T cells, increased apoptosis related to Fas and Fas ligand upregula- NPSLE Pathogenesis
tion, and increased serum IL-10 levels have all been implicated Many of the focal CNS NPSLE syndromes occur in association
in the pathogenesis of lymphopenia. B cells expressing the 9G4 with APL antibodies and thrombotic events or, more rarely, with
idiotype found on V H 4.34 heavy chains may be responsible for small-vessel vasculitis leading to intraluminal thrombosis. In
production of antilymphocyte antibodies. contrast, proposed mechanisms for the diffuse CNS NPSLE
Treatment of leukopenia is guided by the clinical scenario, syndromes involve autoantibody-mediated neurotoxicity and
and exclusion of drug effects, malignancy, or myelofibrosis is complicated neuroimmune interactions, resulting in increased
required before attribution to SLE. In the absence of recurrent CNS expression of proinflammatory cytokines with deleterious
infection, leukopenia in SLE rarely warrants treatment, as effects on neuronal and microglial cell function and adult neu-
increased steroids can also contribute to the risk of infection. rogenesis. 67,68 Proposed mechanisms for diffuse CNS NPSLE rely
Severe leukopenia has been treated with G-CSF; however, although in large part on disruption of the blood–brain barrier (BBB)—a
it is rapidly effective, G-CSF has also been associated with disease dynamic interface between the brain and circulating hormones
flare in 30% of cases. and inflammatory molecules. Evidence for BBB disruption in SLE
is supported by reports of an elevated albumin concentration
Thrombocytopenia gradient between cerebrospinal fluid (CSF) and plasma, an elevated
Low platelet counts are seen in approximately 25% of patients, IgG index, and elevated serum levels of proteins whose origins
although severe thrombocytopenia is reported in fewer than are exclusive to the brain parenchyma, such as S100B. Proposed
10%. Immune-mediated consumption is the most frequent cause, mechanisms for BBB disruption in SLE include brain endothelial
but in rare instances thrombocytopenia occurs as a manifestation cell disruption mediated by inflammatory cytokines, chemokines,
of microangiopathic hemolytic anemia, TTP, disseminated complement C5a, antiendothelial cell antibodies, anti-NMDAR
intravascular coagulation (DIC), or as part of the hemophagocytic antibodies, and TWEAK (TNF-like weak inducer of apoptosis). 69–71
syndrome, all of which are associated with high mortality and
morbidity. A pathogenic role for antibodies against platelet
66
membrane glycoproteins (IIb/IIIa antigen) is well established.
Other possible mechanisms include antibodies to the thrombo- Central nervous system: BBB Peripheral nervous system
poietin receptor (TPOR), and APL and anti-CD40-ligand antibod-
ies that bind to platelets, resulting in platelet sequestration.
Central and Peripheral Nervous System Diffuse Focal Plexopathy
Neurological and psychiatric manifestations of SLE are diverse Acute confusional state Stroke Mononeuropathy
Myelopathy
Polyneuropathy
and frequently occur irrespective of systemic disease activity. Cognitive dysfunction Seizure disorder Myasthenia gravis
Anxiety disorder
Neuropsychiatric symptoms can be focal or diffuse, peripheral Mood disorders Aseptic meningitis Autonomic DO
or central, isolated or complex, and difficulties with assessment Headaches Movement disorder Polyradiculopathy
and attribution of individual symptoms have hindered progress Psychosis Demyelinating syndrome Cranial neuropathy
in understanding mechanisms for neuropsychiatric disease FIG 51.7 Neuropsychiatric Syndromes in Systemic Lupus
attributable to SLE (NPSLE). Erythematosus.
700 Part SIX Systemic Immune Diseases
This distinction between focal and diffuse CNS NPSLE and potential for the diagnosis of CNS NPSLE syndromes that can also be
mechanisms is essential for the development of treatment strategies. used to monitor therapy.
Thrombotic events associated with APL antibodies are treated PNS NPSLE events are recognized on the basis of clinical
with anticoagulation, whereas high-dose corticosteroids and presentation with diagnostic studies such as electromyography
immunosuppression in combination with neuroleptic and anti- and peripheral nerve biopsy.
seizure medications are generally required for treatment of diffuse Antiphospholipid antibody syndrome is described in detail
CNS events. Because there is no intervening BBB, peripheral nerves in Chapter 61.
are more accessible to circulating complement, autoantibodies,
and inflammatory molecules, and vasculitis of epineural arteries Drug-Induced Lupus
is a common finding in PNS NPSLE. Treatment consists of Until recently, drug-induced lupus referred to a clinical syndrome
corticosteroids and immunosuppression or intravenous immu- characterized by constitutional, musculoskeletal symptoms and
noglobulin (IVIG). serositis that resembles mild lupus and occurs after exposure to
a number of drugs (most notably procainamide, hydralazine,
NPSLE Assessment and Attribution chlorpromazine, and methyldopa). Drug-induced lupus has been
The diagnosis of diffuse CNS NPSLE is frequently difficult, and associated with ANA and antihistone antibodies, whereas genera-
the clinical evaluation of a patient with presumed CNS NPSLE tion of more specific autoantibodies such as anti-DNA antibodies
mandates an exhaustive search for other potential causes. CSF has been rare. Symptoms generally begin weeks to months after
examination is useful for excluding infection or malignant cells. initiation of the inciting therapeutic agent and resolve within
Although CSF in NPSLE can be characterized by a lymphocytosis weeks after the drug is discontinued; autoantibodies can persist
and increased immunoglobulin with elevated total protein, IgG for up to 12 months. Host factors affecting drug metabolization
index, and oligoclonal bands, these abnormalities are not (e.g., slow acetylation of procainamide and hydralazine) contribute
consistently present. Numerous autoantibodies (ANA, anti- to the risk of developing drug-induced lupus. Multiple potential
dsDNA, anticardiolipin, antiribosomal P, anti–N-methyl mechanisms resulting in the loss of self-tolerance have been
D-aspartate receptor [NMDAR], antineuronal, anti-RNP, suggested for this classic model. One of the most extensively
anti-Sm) and various cytokines have been identified in the CSF explored is inhibition of DNA methylation with TLR activation,
of patients with SLE; however, none is specific for active NPSLE resulting in overexpression of costimulatory molecules such as
or individual CNS NPSLE syndromes, and routine testing is leukocyte function–associated antigen-1 (LFA-1) on T cells and
not recommended. MRI is extremely sensitive for detection of enhanced T-cell help. 74
structural lesions and new ischemic lesions associated with focal Since the introduction of anti-TNF agents, a different variant
CNS NPSLE, but it is frequently not helpful in diagnosing active of drug-induced lupus has been recognized. Up to 30% of patients
diffuse CNS NPSLE, as MRI studies may be normal in patients receiving TNF blockade develop autoantibodies, including a
72
with psychiatric syndromes and global CNS dysfunction. positive ANA and antibodies to dsDNA. A minority of patients
Imaging studies of neuronal function, positron emission develop anti-DNA antibodies, nephritis, and vasculitis. The
tomography (PET), and single-photon emission computed pathogenesis of this immunological deregulation is not known.
tomography (SPECT) scans measuring cerebral glucose uptake
and blood flow, respectively, magnetic resonance spectroscopy, Treatment
and functional MRI (fMRI) correlate to a limited extent with tHEraPEUtIC PrINCIPLES
diffuse CNS NPSLE. These scans must be interpreted carefully Goals of Therapy in SLE
because atrophy with neuronal cell loss leads to changes in
metabolism and blood flow. Cerebral angiograms can be helpful I. Suppression of inflammation
if a diagnosis of cerebral vasculitis is considered; however, CNS • Induction of remission
vasculitis is rare, with true vasculitis in only 5–8% of autopsies. • Maintenance of remission
• Preservation of organ function
More commonly, a bland vasculopathy with degenerative and II. Suppression of immune activation
proliferative changes in small vessels, perivascular infiltrates, • Modulation of the immune response
microinfarcts, and microhemorrhages is present. III. Treatment/prevention of drug-related toxicities
There are no serological tests specific for CNS NPSLE. Serologi-
cal evidence of disease activity (elevated anti-DNA antibodies
and low complement) may help to diagnose CNS NPSLE,
particularly if combined with other clinical signs of active disease. The goals of lupus treatment are to stop and reverse ongoing
However, CNS NPSLE can also flare in the absence of serological organ inflammation, to prevent or limit irreversible organ damage,
and clinical disease activity. Cognitive impairment in particular and to suppress the immune response driving the inflammation
tends to develop insidiously, irrespective of peripheral disease and prevent flares. Therapeutic agents, and combinations thereof,
activity. Recent data from murine models and in vitro studies can be used for induction of remission, maintenance of remission,
strongly support the role of specific autoantibodies directed or prevention of flare. The efficacy of therapeutic agents must
against NMDAR, phospholipid, α tubulin, neuronal surface P be balanced against their potential toxicity. Thus treatment must
73
antigen, and ribosomal P in NPSLE. Anti-NMDAR and anti-P be tailored to the individual patient based on disease manifesta-
antibodies have been identified in the serum, CSF, and brain of tions. In general, milder disease requires treatment with less
SLE patients and have been associated with cognitive and depres- potent or lower doses of antiinflammatory and immunosup-
sive syndromes in some SLE patients. CSF anti-NMDAR antibod- pressive medications than more active, severe disease affecting
ies have also been reported to be increased in patients with acute major organs such as the kidney or brain (Table 51.4). Individual
confusional state. The current challenge is to identify easily patient responses to a given medication will vary, and patients
accessible, sensitive, and specific serological or imaging biomarkers must be monitored closely for response as well as toxicity.
CHaPtEr 51 Systemic Lupus Erythematosus 701
“Treat-to-target” recommendations in SLE from an international indications, whereas others are still in the developmental stages.
SLE task force include the following more specific guidelines: These therapies, in general, have more specific immunological
the treatment target should be remission of organ manifestations; targets than standard treatments. Although multiple agents have
factors such as pain that negatively influences health-related been tested in animal models of disease, we will focus only on
quality of life should be addressed; maintenance treatment should therapies that have been given to humans. Several of these agents
aim for the lowest glucocorticoid dose needed to control disease; have been recently evaluated in phase III clinical trials and have
and relevant therapies adjuvant to any immunomodulation should been unable to demonstrate superiority over treatment with
be considered to control comorbidity in SLE. 75 placebo or standard of care. Although imperfect trial design may
Some genetic factors predicting risk of toxicity or therapeutic account for some of these failures, the possibility remains that
benefit for individual agents have been identified. Polymorphisms these agents are not effective treatments for SLE and do not confer
of a key enzyme in the metabolism of azathioprine, thiopurine a substantial improvement over current standard-of-care therapies.
methyltransferase (TPMT), are common; 0.3% and 11% of Rituximab (anti-CD20 antibody), a B-cell–directed therapy
Caucasians are homozygous and heterozygous, respectively, for approved for use in rheumatoid arthritis, targeting all B cells
76
mutations associated with altered expression of TPMT. TPMT- except plasma cells, failed to demonstrate improved performance
deficient patients are especially susceptible to leukopenia and over standard of care in trials of patients with active SLE, or in
pancytopenia associated with azathioprine. Cyclophosphamide patients with active lupus nephritis added to a background therapy
is metabolized to its active form by cytochrome P450. Individuals of MMF and corticosteroids. Elevated BAFF levels are present
heterozygous or homozygous for a specific cytochrome P450 after B-cell depletion. These can exacerbate the impaired tolerance
polymorphism (CYP2C19*2) have a lower probability of develop- of SLE. Thus studies are ongoing to evaluate the efficacy of
ing premature ovarian failure, but they also show a poorer rituximab followed by belimumab. Abatacept (CTLA4-Ig), which
response to therapy. 77 is also approved for rheumatoid arthritis and blocks T-cell activa-
Although corticosteroids are the foundation of treatment, tion, was no better than placebo in trials of active lupus and of
exposure must be minimized to the greatest extent given their lupus nephritis, again added to background therapy of
multiple and frequent side effects, including hypertension, diabetes corticosteroids and MMF. A redesigned trial of abatacept for SLE
mellitus, increased susceptibility to infection, bone loss, and is now being conducted. Epratuzumab (anti-CD22 antibody)
weight gain (Chapter 86). Additional disease-modifying agents targeting all B cells failed a phase III clinical trial. TACI-Ig, which
that are also steroid-sparing include antimalarials (hydroxychlo- blocks both BAFF and APRIL, is undergoing clinical study, although
roquine), antimetabolites such as azathioprine (1–2.5 mg/kg per previous clinical trials were terminated prematurely because of
day), methotrexate (7.5–25 mg/week), leflunomide (10–20 mg/ infectious complications. Tocilizumab, an antibody to the IL-6
day), and mycophenolate mofetil ([MMF], 2–3 g/day), and receptor, a cytokine involved in B-cell survival and activation as
alkylating agents such as cyclophosphamide (monthly pulse well as in differentiation of Th17 and Tfh cells, which is approved
2
0.5–1.0 g/m ) (Chapter 87). When more conventional therapies for RA, demonstrated unacceptable toxicity in SLE. Other agents
have failed, anecdotal reports, case series, and open-label studies in earlier clinical development are inhibitors of intracellular B-cell
suggest the use of intravenous immunoglobulin (2 g/kg over signaling molecules designed to block B-cell activation; R406, a
2–5 days), thalidomide (50–100 mg/day), or cyclosporine (3–5 mg/ SYK inhibitor; and Janus tyrosine kinase (JAK) inhibitors. The
kg/day). Medications such as dapsone, danazol, and chlorambucil Jak inhibitors are being studied using topical administration for
may be efficacious in cutaneous disease, hematological disease, discoid lupus and oral administration for systemic disease.
and in severe refractory disease, respectively, but in general these Potential therapies aimed at DCs include vitamin D, which
medications are not commonly used due to their toxicity and blocks DC maturation and T-cell activation, and inhibitory
the introduction and availability of better-tolerated, efficacious oligodeoxynucleotides, which block TLR9 signaling and DC
agents. Belimumab, a monoclonal antibody directed against BAFF maturation. However, a study of vitamin D supplementation
(Chapter 89), was approved by the FDA for treatment of SLE designed to assess vitamin D inhibition of DC activation failed
in 2011 and represents a therapeutic option for patients with to demonstrate efficacy. Hydroxychloroquine, a standard agent
nonrenal, non-CNS active disease. for lupus, interferes with TLR7 and TLR9 signaling by preventing
A number of newer agents are on the horizon for treatment acidification of the endosomal compartment. A study of a novel
of SLE. Some are currently available but approved for other RNase is under way.
TABLE 51.4 treatments for Systemic Lupus Erythematosus Disease Manifestations
Low-Dose Corticosteroids High-Dose Corticosteroids
NSaIDs antimalarials † (<0.5 mg/kg per day) (>0.5 mg/kg per day) ‡ azathioprine MMF CtX
Constitutional + + + +
Musculoskeletal + + + + +
Mucocutaneous + +
Serositis + + + +
Hematological + + +
Renal + + + +
Central nervous system + +
Vasculitis + + + +
CTX, cyclophosphamide; MMF, mycophenolate mofetil; NSAIDs, nonsteroidal antiinflammatory drugs.
† Antimalarials should be given to all patients to sustain remission and reduce damage.
‡ High-dose corticosteroids are required for remission induction or an inadequate response to low-dose therapy.
702 Part SIX Systemic Immune Diseases
Two studies of monoclonal antibodies against IFN-α failed CONCLUSIONS
to demonstrate efficacy; a trial of an antibody to the IFN receptor
is under way. In the past several years much has been learned about genetic
Novel interventions directed at T cells include anti-CD40 susceptibility to SLE, and it is encouraging that many of the
antibodies, abatacept (CTLA4-Ig) in combination with cyclo- genes identified are associated with pathways that also have been
phosphamide for proliferative nephritis, and studies targeting implicated in disease pathogenesis. The role of B cells in disease
ICOS, an inducible T-cell costimulator. pathogenesis has been confirmed, but recent studies have also
Therapies in development for other autoimmune diseases highlighted the role of T cells, DCs, and neutrophils. Enhanced
may also prove useful in SLE. Eculizumab, currently approved understanding of each of these contributing factors and the
for paroxysmal nocturnal hemoglobinuria, is an antibody directed cross-talk between them has allowed identification of numerous
against C5 that blocks cleavage of C5 and the subsequent trig- potential therapeutic targets. The disappointing results from
gering of the complement cascade. Alicaforsen, an antisense clinical trials of immunobiological agents for lupus have
oligodeoxynucleotide that inhibits ICAM-1 expression, decreases highlighted the critical importance of study design and the
inflammation in both rheumatoid arthritis and Crohn disease. complexity of disease in humans. The overall goal in therapy
Efalizumab, a monoclonal antibody against CD11a (an LFA-1 must be to eliminate autoreactivity while maintaining immu-
subunit that interacts with ICAM-1), benefits patients with nocompetence. Among the challenges now faced are the careful
psoriasis. Although no chemokine-targeted therapies are in clinical phenotyping of patients to identify etiopathologically distinct
trial in lupus, a CCR1 antagonist slowed disease progression in subpopulations and new clinical trial designs to allow the use
a mouse model of lupus and has been tested in patients with of combinations of agents, each of which alone may have a
rheumatoid arthritis. FTY720, an agonist for the sphingosine 1 minor effect on disease course.
phosphate receptor that prevents egress of lymphocytes from
secondary lymphoid organs and inflamed tissues, has beneficial Please check your eBook at https://expertconsult.inkling.com/
effects in the MRL/lpr mouse model of lupus; it has been given for self-assessment questions. See inside cover for registration
to transplant recipients and to patients with multiple sclerosis. details.
The use of anti-TNF-α agents for SLE is inhibited by its lupus-like
effects in some patients. Paradoxically, TNF-α is involved in
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Eur J Immunol 2015;45:344–55. 2004;104:184–91.
40. McMurray RW. Bromocriptine in rheumatic and autoimmune diseases. 66. Michel M, Lee K, et al. Platelet autoantibodies and lupus-associated
Semin Arthritis Rheum 2001;31:21–32. thrombocytopenia. Br J Haematol 2002;119:354–8.
41. Zhang W, Wu K, et al. Transforming growth factor beta 1 plays an 67. Mackay M. Lupus brain fog: a biologic perspective on cognitive
important role in inducing CD4(+)CD25(+)forhead box P3(+) regulatory impairment, depression, and fatigue in systemic lupus erythematosus.
T cells by mast cells. Clin Exp Immunol 2010;161:490–6. Immunol Res 2015;63:26–37.
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68. Jeltsch-David H, Muller S. Autoimmunity, neuroinflammation, pathogen 74. Kaplan MJ, Deng C, et al. DNA methylation in the regulation of T cell
load: A decisive crosstalk in neuropsychiatric SLE. J Autoimmun LFA-1 expression. Immunol Invest 2000;29:411–25.
2016;74:13–26. 75. van Vollenhoven RF, Mosca M, et al. Treat-to-target in systemic lupus
69. Abbott NJ, Mendonca LL, et al. The blood-brain barrier in systemic lupus erythematosus: recommendations from an international task force. Ann
erythematosus. Lupus 2003;12:908–15. Rheum Dis 2014;73:958–67.
70. Stock AD, Wen J, et al. Neuropsychiatric lupus, the blood brain barrier, 76. Yates CR, Krynetski EY, et al. Molecular diagnosis of thiopurine
and the TWEAK/Fn14 pathway. Front Immunol 2013;4:484. S-methyltransferase deficiency: genetic basis for azathioprine and
71. O’Carroll SJ, Kho DT, et al. Pro-inflammatory TNFalpha and IL-1beta mercaptopurine intolerance. Ann Intern Med 1997;126:608–14.
differentially regulate the inflammatory phenotype of brain microvascular 77. Takada K, Arefayene M, et al. Cytochrome P450 pharmacogenetics as a
endothelial cells. J Neuroinflammation 2015;12:131. predictor of toxicity and clinical response to pulse cyclophosphamide in
72. Zardi EM, Taccone A, et al. Neuropsychiatric systemic lupus lupus nephritis. Arthritis Rheum 2004;50:2202–10.
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erythematosus: pathogenesis and biomarkers. Nat Rev Neurol
2014;10:579–96.
CHaPtEr 51 Systemic Lupus Erythematosus 704.e1
MUL t IPLE-CHOICE QUES t IONS
1. Mortality in systemic lupus erythematosus (SLE) 3. Treatment in SLE
A. Has been stable for the past 4 decades A. Relies on immunosuppression
B. Is greater in Caucasians than in other racial groups B. Is different for different races
C. Is secondary to both the disease and the therapy C. Has minimal toxicity
2. Autoantibodies in SLE
A. Are an epiphenomenon
B. Are generally tissue specific
C. Form TLR-activating immune complexes
52
Rheumatoid Arthritis
Andrew P. Cope
Rheumatoid arthritis (RA) is one of the most common chronic European League Against Rheumatism (ACR/EULAR) classifica-
inflammatory diseases and in modern times has become a tion criteria are applied. These rates plateau between the ages
prototype disease entity for defining the molecular and pathologi- of 45 and 75 years in some series but can increase steadily with
cal basis of chronic inflammatory syndromes. The term rheumatoid age until the seventh decade, declining thereafter. The largest
arthritis was coined by Garrod in 1859. However, this was probably difference in incidence between the sexes occurs in those under
an inappropriate use of the term because it encompassed poly- 50 years of age. Past evidence indicates that the incidence may
articular osteoarthritis as well as inflammatory polyarthritis. In be in decline, at least for seropositive disease. Large cross-sectional
spite of references to inflammatory afflictions of joints by the population samples indicate that disease prevalence, which ideally
likes of Galen, Sydenham, and Heberden, the first convincing should include all past and inactive cases, ranges from 0.5–2%
case reports of the disease, described in terms that would be for Caucasian European and North American populations over
3
recognizable today, were published in 1800 by Landré-Beauvais, the age of 15, with a female to male excess of 2–4 times. Despite
1
who labeled the disease “la goutte asthénique primitive.” This similar prevalence estimates for these geographically diverse
description was distinct because all patients were female, an populations, greater diversity has been documented for rural
observation that was significant when the most important dif- African populations, where the prevalence has been reported to
ferential diagnosis at that time was polyarticular gout, a disease be as low as 0.1%, and for Native Americans (including the
predominantly of males. Pima, Yakima, and Chippewa tribes), where the prevalence may
Today we recognize RA as a chronic inflammatory disorder be as high as 5%. Such variance across geographical borders
of joints of unknown etiology in which the major target tissue likely reflects distinct environmental factors and sociodemographic
2
is the synovial lining of joints, bursae, and tendon sheaths. determinants as well as a spectrum of genetic admixture. Lifetime
Although traditionally considered an autoimmune disease, RA risk has been estimated at 4% for women and 3% for men.
differs from organ-specific autoimmune disease entities in several Complex polygenic autoimmune syndromes like RA are
respects. From the outset of clinically apparent disease, the diseases of low penetrance, where thresholds of disease expression
systemic immuno-inflammatory process, driven by cytokines may be higher in males. This is based in part on the observation
and other inflammatory mediators, promotes the activation and that the increased risk of disease in siblings of probands (denoted
proliferation of stromal joint tissues, in particular the fibroblastic λs) is rather small; the λs for RA (risk to sibling divided by
synovial lining layer. This appears to contrast with organ-specific population risk) are estimated to be 3, whereas the λs for systemic
autoimmune diseases, such as type 1 diabetes or autoimmune lupus erythematosus (SLE) may be as high as 30; for celiac disease
thyroiditis, characterized by an antigen-driven immune- the λs are closer to 50. Recent insights into familial clustering
inflammatory response in situ leading to targeted cellular indicate that family history remains a strong independent risk
4
destruction of autoantigen-expressing pancreatic β-islet or thyroid factor for RA but that this risk does not differ by gender. This
tissue cells. In RA, once the inflammatory process is established, implies that nongenetic factors influence gender bias. Twin studies
the inflammatory synovium, or pannus, may invade and erode also provide compelling evidence for genetic effects, given the
underlying cartilage and bone. Unlike autoimmune diseases that excess concordance rates for monozygotic (12–15%) compared
4
target single organs or tissues, RA is a systemic inflammatory with dizygotic twins (<5%, and probably nearer to 3.5%). These
disease that likely encompasses a heterogeneous syndrome with concordance rates appear somewhat low, but compared with a
marked variation in clinical expression that most clinicians today background prevalence of 1% in outbred populations, genetic
would acknowledge is more than one disease entity. Indeed, it epidemiology studies report heritability estimates of 68% for
is now apparent that the disease is heterogeneous not only those patients who carry antibodies to citrullinated protein
+
−
clinically but also pathologically, serologically, and genetically. antigens (ACPAs ) and 66% for those who do not (ACPAs ),
5
indicating substantial genetic influence. Human leukocyte antigen
EPIDEMIOLOGY (HLA) is thought to contribute 35–40% of this value. This
“missing heritability” leaves a substantial contribution to disease
The incidence of RA (the rate of new cases arising in a given susceptibility from environmental factors, influenced by occupa-
period) is 0.1–0.2 per 1000 of the population for males and tion, socioeconomic status, exposure to infectious pathogens,
3
0.2–0.4 per 1000 for females. Rates as high as 0.4 per 1000 have and lifestyle factors—a conglomeration of factors termed the
been reported when the 2010 American College of Rheumatology/ “exposome.”
705
706 Part SIX Systemic Immune Diseases
KEY CONCEPtS lower androgenic testosterone and dehydroepiandrosterone
Important Risk Factors for Developing (DHEA) levels, and increased estradiol, compared with healthy
control male subjects.
Rheumatoid Arthritis
• Female gender; impact of X chromosome, microchimerism, ETIOLOGY AND PATHOGENESIS
lifestyle
• Age; associated with accelerated immune aging Environmental and Nongenetic Factors
• Inheritance of genetic variants, e.g., HLADRB1 and PTPN22 Most, but not all, studies have reported an association between
• Autoantibodies to citrullinated protein antigens (ACPAs), rheumatoid RA and smoking. One of the largest studies comprising over
factor 370 000 women from Women’s Health Cohort Study reported
• Family history; first-degree relatives have higher prevalence of genetic
and serological risk factors a relative risk of 1.4 for women who smoked more than 25 ciga- 8
• Hormonal factors; nulliparity, the first 3 months postpartum, low rettes per day for more than 20 years, compared with nonsmokers.
androgen or high estrogen status (in males); longer-duration The association appears to be more closely related to duration
breastfeeding than to the amount of tobacco exposure, with smoking status
• Smoking status; >25 cigarettes/day for >20 years confers a 15-fold being a risk factor for older age of RA onset; smoking also may
9
risk in subjects who carry disease associated human leukocyte antigen influence severity because smokers are more likely to have
(HLA)-DRB1 alleles
• Low alcohol intake seropositive, erosive disease with extraarticular manifestations.
• Environmental antigens (the “exposome”); dietary factors; exposure The effect may be fully reversible in those individuals who stop
to infectious (and noninfectious/microbiota) pathogens at mucosal smoking for 10 years or more. Further evidence of gene-
surfaces such as the lung, periodontium, and gut; noninherited maternal environment interactions with respect to smoking have been
antigens (NIMA) documented in a population-based case–control study of Swedish
• Urban dwelling RA patients. In this study the relative risk of developing
10
+
rheumatoid factor (RF) positive (RF ) RA was calculated according
to smoking status and HLA-DRB1 genotype. The relative risk
of developing RA increased from 2.5 in nonsmokers with disease-
Two of the more intriguing factors contributing to disease associated HLA-DRB1 genes to 7.5 and 15.7 in smokers who
occurrence are age and gender. Age-associated changes in sus- carried one or two copies of the susceptibility alleles, respectively.
ceptibility to infection, neoplastic disease, and autoimmunity Follow-up gene-environment interaction studies demonstrate
suggest that a common mechanism could be responsible. Immune robust associations between heavy smoking, HLA-DRB1 alleles
senescence is one possibility, where age-related decline in host encoding specific amino acids at positions 11 and 13, and the
immunity is characterized at the cellular and molecular level by presence of ACPAs. Strongest associations were with antibodies
dramatic expansions of lymphocyte clones, corresponding to citrullinated α and β chains of fibrinogen (epitopes Fibα580–600
contractions of the naïve T- and B-cell repertoires, and telomere and Fibβ36–52) and α-enolase (CEP-1); IgA ACPAs were especially
erosion of leukocytes, indicative of an extensive proliferative prevalent in smokers.
6
history. When combined with oxidative stress and a range of Being female, a smoker, and carrying specific disease-associated
biochemical derangements of pathways integral to antigen genetic variants may be necessary but not sufficient to initiate
responsiveness and immune regulation, these factors may combine chronic inflammatory arthritis. Other environmental triggers
to (i) increase susceptibility to foreign pathogens, (ii) augment may be involved. Not least among these is exposure to foreign
reactivity to self-tissue antigens (which may be modified post- pathogens. This association has gained credibility because of the
translationally by the aging process), and (iii) generate a repertoire presumed link between not only infection and autoimmunity
of lymphocytes defective in terms of tumor surveillance. Thus but also immunodeficiency and autoimmune disease. Nonetheless,
immune senescence could be considered a risk factor for RA. no single pathogen or group of pathogens has been defined.
The female sex preponderance implies that hormonal and This could imply that aberrant host responses (either exaggerated
reproductive factors strongly influence risk. On the one hand, innate inflammatory responses or failure to terminate such
nulliparity is a risk factor for RA. Women entering the first 3 responses) may arise after a wide range of infectious insults.
months of the postpartum period are also at increased risk. By Indeed, bacterial products including superantigens, mycoplasma
contrast, oral contraceptive use, pregnancy, and hormonal species, viruses (including herpes family, parvovirus, and retro-
replacement therapy have all been associated with reduced risk viruses), and fungi have all been implicated, but data are insuf-
7
or less severe disease, whereas extended periods of breastfeeding ficient to prove causation. Epstein-Barr virus (EBV) infection
appear to increase risk. Several possible immune mechanisms is common, antibodies to EBV nuclear antigens have been reported
have been proposed. For example, maternofetal mismatch at the in patients with RA, EBV is a polyclonal activator of B lympho-
major histocompatibility complex (MHC) locus has been associ- cytes, EBV-specific T cells reactive to EBV gp110 have been
ated with higher disease remission rates during pregnancy. In identified in RA synovial joints, and EBV RNA has been isolated
contrast, noninherited HLA-DRB1 DERAA-positive (occupying from the synovium. There exists a tantalizing link between
the same amino acid positions as the QQRAA/QKRAA/KKRAA infection with Porphyromonas gingivalis, which expresses its own
shared epitope motif) maternal antigens (NIMA) expressed on enzymatic machinery for generating bacterial or host-derived
maternal cells constitute an environmental factor that is protective citrullinated proteins, severe periodontitis (which shares risk
11
to a DERAA-negative child, perhaps through mechanisms relating factors for RA), and RA. According to this model, molecular
to microchimerism. In mouse models pregnancy has been mimicry is underpinned by autoimmune responses to bacterial-
associated with quantitative changes in the numbers of regulatory derived proteins such as enolase and cross-reactivity to the human
T cells (Tregs). An influence of hormonal factors is further orthologue α-enolase, expressed in abundance by myeloid cells
suggested in studies of men where disease is associated with in inflamed periodontal and synovial tissues.
CHaPtEr 52 Rheumatoid Arthritis 707
A comparison of the microbial genomes from the small intes- prospect of fecal transplantation to prevent or treat established
tine and colon of mice housed in conventional versus germ-free disease is an intriguing one.
facilities suggests that a single gut-residing species, in this case
segmented filamentous bacteria, can profoundly influence the Immunogenetics
clinical expression of inflammatory arthritis in mouse models of RA is a clinically heterogeneous disease, and so comprehensive
autoimmune arthritis. In the K/B x N serum transfer model of identification of disease susceptibility genes has been challenging,
arthritis, segmented filamentous bacteria enhanced generation in spite of heritability estimates of at least 60%. With the exception
12
of interleukin (IL)-17 expressing T cells in lamina propria. of the MHC, where extensive gene polymorphism contributes
Together with rapid advances in sequencing technologies, these about one-third of genetic susceptibility, and PTPN22 (odds
data have prompted a systematic analysis of the symbiont ratio 1.8), individual genetic variants confer low to moderate
microbial communities in patients with RA in comparison to risk and have low penetrance (odds ratios in the range 1.1–1.5).
those derived from healthy control populations. Microbiota are Numerous genome-wide linkage scans of multiplex families with
attractive environmental risk factors because they are acquired RA have established and confirmed an important contribution
at around the time of birth and are modified by diet as well of the MHC (Chapter 5). This lends support to a wealth of
as the host genome. Studies from several groups have demon- epidemiological and genetic data describing associations between
strated irrefutable evidence of dysbiosis, with distinct patterns of RA and specific HLA-DRB1 alleles, in particular HLA-DR4
microbiota depending on the stage of disease and the population subtypes. Although this association was first described by Stastny
studied. For example, the first US study reported enrichment in the 1970s, it was shown more than a decade later that sus-
of Prevotella spp. and Bacteroides spp., gram-negative anaerobes ceptibility to RA across different ethnic populations correlated
in the gut of patients with early but not established RA. Metage- closely with the expression of a specific consensus amino acid
nomic sequencing of oral and fecal microbiota from a cohort sequence (referred to as the “shared epitope,” hereafter SE) within
14
of Chinese RA patients revealed enrichment of Lactobacillus, the HLA-DR β chain α-helix (Fig. 52.1). This sequence was
particularly in severe disease, and depletion of Haemophilus subsequently shown by several groups of investigators to be
13
species. Interestingly, microbiota signatures were predictive encoded by HLA-DRB1 alleles, including HLA-DR4 (*04:01,
of response to therapy, suggesting that their composition may *04:04, *04:05, and *04:08), but also HLA-DR1 (*01:01), DR6
be prognostic as well as indicative of the stage of disease. The (*14:02), and DR10 (*10:01) alleles, among others. HLA-DR9
C-terminus Disease associated
DRα chain DRB1*04:01
α-helix β86 Gly
β67 Leu
β70 Gln
β71 Lys
Arg not favoured; +
Cit permissive β71Lys
at P4
P4Asp -
Non-associated
DRB1*04:02
DRβ chain
β86 Val α-helix
β67 Ile
β70 Asp Pocket 4
β71 Glu N-terminus
collagen II peptide
FIG 52.1 Crystal Structure of a Collagen II Peptide/Human Leukocyte Antigen (HLA)-DR4
Complex. Ribbon model of an immunodominant collagen II peptide (1168–1180) complexed to
HLA-DR4 (DRA*01:01/DRB1*04:01); a view of the major histocompatibility complex/peptide
complex as seen from the T-cell surface. DRα and DRβ chain helices are shown in red, whereas
the β-pleated sheet comprising the floor of the peptide binding groove is shown in blue. Residues
67 to 74 of the DRβ chain, components of the third hypervariable region, derive the “shared
epitope.” The ball and stick model of the CII peptide is shown. Interacting residues of the peptide
position 4 (Asp, orange) and DRβ chain residue (β71Lys, green), which make up part of pocket
4, are depicted as van der Waal’s spheres. Differences in amino acid sequence between the
closely related disease-associated DRB1*04:01 and nonassociated DRB1*04:02 gene products
are illustrated. Note that although Arg would not be favored at position 4 in the peptide, modification
of Arg → Cit by deimination would be permissive. Figure generated by R. Visse and A. Cope,
based on crystal data derived by Wiley and colleagues (Courtesy Dessen et al, Immunity 1997;7:473.)
708 Part SIX Systemic Immune Diseases
17
(*09) is also associated, but not in Caucasians. According to locus. These studies, replicated in European and US RA cohorts,
fine-mapping data, RA risk is linked not only to amino acids demonstrated associations between SE frequencies and antibodies
encoded by the RA SE sequence (71 and 74 positions of the to cyclic citrullinated peptides (anti-CCPs), as as opposed to
alpha helix of the DRβ chain) but also to amino acid positions rheumatoid factor (RF). Specifically, compared with healthy
11 and 13, located in the peptide binding groove of the HLA-DR controls, the odds ratio for the association between one or two
15
heterodimer. Single amino acid variants have also been defined copies of the SE and anti-CCPs positivity was 4.4 and 11.8,
in HLA-B (position 9) and HLA-DPβ (position 9). Differences respectively. These findings point to SE associating not with RA
in odds ratios associated with these five amino acid variants per se, but with a clinical phenotype, in this case autoantibodies
17
between ACPAs-positive and ACPAs-negative disease provide to modified proteins. An additional pathogenetic link between
further evidence that seropositive and seronegative disease are HLA and citrullination is supported by the observation that peptides
genetically distinct. On the other hand, the finding of DERAA carrying nonpolar residues such as citrulline (neutral), as opposed
encoding HLA-DRB1 alleles (DRB1*01:03, *04:02, *11:02, *11:03, to arginine (positive charge), in pocket four of the HLA-DRαβ
*13:01, *13:02, and *13:04), conferring lower disease risk, and binding groove (see Fig. 52.1) convert a poorly binding peptide
more importantly the finding of reduced radiographic progression to a higher-affinity epitope that induces robust T- and B-cell
in RA even in the presence of one copy of the SE, raises the responses in vivo. This notion is strongly supported by crystal
possibility that specific subsets of MHC class II genes may confer structures of HLA-DRαβ (DRB1*04:01 and *04:04) complexed
18
an independent protective role. to peptide. Here amino acids 11, 13, 71, and 74 form part of the
Specific genotypes cosegregate with distinct clinical features. fourth anchoring peptide binding pocket, the same positions that
For example, in population-based studies, different HLA-DRB1 confer highest risk of disease, as noted above. Indeed, citrullinated
alleles influence the severity of disease (including radiographic human fibrinogen, but not the nonderivatized protein, induces
progression), with DRB1*04:01 being found in patients with chronic inflammatory arthritis in HLA-DR4 transgenic mice but
severe, seropositive, erosive RA (often with extraarticular features not their nontransgenic C57BL/6 littermates. The importance of
such as vasculitis and Felty syndrome in *04:01 homozygous or citrulline as a molecular feature of human T-cell–specific auto-
*04:01/*04:04 compound homozygote individuals). Valine at antigenic determinants is further suggested through identification
+
position 11 of HLA-DRB1 confers the strongest association with of autoreactive CD4 T lymphocytes by flow cytometry using
18
16
radiological damage and highest all-cause mortality. Statistical HLA-citrullinated-peptide tetramer complexes. These tools also
modeling points to HLA genetic polymorphism being associated permit determination of the relative proportions of antigen-reactive
9
with young-onset RA. DRB1*01:01 and *10:01 are observed at effector and regulatory T-cell subsets.
a higher frequency in patients with less severe, seronegative, Genome-wide association studies (GWASs) of large patient
nonerosive disease. Inheriting two copies of alleles expressing cohorts, stratified by autoantibody serology, have contributed
the consensus sequence increases disease penetrance, time of significantly to our understanding of RA genetics. Meta-analyses
onset, and severity. Thus these genetic associations manifest as and fine-mapping studies, including custom-designed SNP arrays
clinically distinct disease entities. covering nearly 130 000 genetic variants selected from 186 loci-
On the basis of early observations, two principal models were poly defined in GWASs of autoimmune and immune-mediated
proposed to account for the association between RA and the inflammatory diseases (the Immunochip), have identified more
consensus DR β-chain sequence. Both were based on the assump- than 100 susceptibility loci, many of which have been validated
19
tion that the SE is the critical genetic element linked directly to in RA populations of diverse ancestry. Among the strongest
disease. The first model proposed that the SE determines specific associations outside HLA is PTPN22, initially identified in
peptide binding and that “pathogenic” peptides bind only to candidate gene association studies. The PTPN22 gene variant
disease-associated HLA class II molecules (Fig. 52.1). This model confers risk with odds ratios ranging from 1.5 to 1.9 in Caucasian
predicted that a gradient of affinities of disease inducing peptide and European populations, and it is unusual among most genetic
for MHC class II molecules might account for the differences in variants in that it is a coding frame mutation (R620W). PTPN22
susceptibility and/or severity conferred by different HLA-DR encodes a hematopoietic cytoplasmic protein tyrosine phosphatase
molecules. Along the same lines, disease-associated alleles may whose substrates include Src and Syk family kinases, CD3ε, TCRζ,
20
preclude the binding of peptides required for the generation of and signaling intermediates such as Vav. It comes as no surprise
naturally occurring Tregs specific for self-peptide antigens. The that the PTPN22 mutation, as a negative regulator of antigen
second model proposed that the SE influences T-cell receptor receptor and integrin signaling, has also been described in type
(TCR) recognition by binding and selecting autoreactive T cells 1 diabetes, a subset of SLE patients, oligoarticular juvenile
during thymic maturation and expanding these populations in idiopathic arthritis, vitiligo, Addison disease, and autoimmune
the peripheral compartment; again perturbations of a repertoire thyroid disease but not in multiple sclerosis or psoriasis. The
of Tregs could arise through opposing influences of the SE sequence. link with autoimmune diseases associated with pathogenic
Two recent lines of experimental evidence provide further autoantibodies is also intriguing. Whether the PTPN22-R620W
insights into HLA-disease associations. The first is the association variant is a loss- or gain-of-function mutant in man remains
between HLA-DR4 subtypes and telomere erosion in RA patients somewhat controversial. However, studies of Ptpn22-deficient
6
and healthy donors, detectable before the age of 20. Telomere mice, and mice expressing the R620W mouse orthologue
loss has been associated with aging and immune senescence. Ptpn22-R19W, share features in T, B, and myeloid lineage indica-
Whether this implies a direct contribution of HLA-DR4 expression tive of loss of function for the R619W mutation, associated
21
to accelerated differentiation of hematopoietic cells in the context with increased antigen receptor signaling. The relative contribu-
of a chronic inflammatory process is intriguing, but the relationship tions of the mutant to perturbationsin central and peripheral
certainly warrants further investigation. The second line of evidence tolerance mechanisms remain to be determined.
+
pointing to specific functions of SE alleles has arisen through Scrutiny of other, non-MHC susceptibility loci point to genes
analysis of autoantibodies in RA patients typed at the HLA-DRB1 whose products are involved in proximal signaling pathways that
CHaPtEr 52 Rheumatoid Arthritis 709
regulate T-cell activation, differentiation, and persistence. Besides N mice indicates that enhanced vasopermeability at sites destined
HLA and PADI4, which influence the molecular determinants to become arthritic is a crucial early event, at least in antibody-
of T-cell “input signals,” these include CD28, CTLA-4, and induced disease. This process is dependent on mast cells
CD2-CD58 (regulation of T-cell costimulation); CD247, PTPN22, and neutrophils and on the release of the vasoactive amines
PRKCQ, TAGAP, and REL (transducer modules of TCR signaling); histamine and serotonin, which contribute to heightened vascular
STAT4 and TNFRSF14 (inducers of lineage-specific cytokine gene permeability.
expression and persistence of memory T cells); and REL, IL2-IL-21, Neovascularization further promotes influx of inflammatory
IL2RA, and IL2RB (regulators of IL-2 gene expression and IL-2R cells. To what extent this is driven by the hypoxic environment
signaling). Notable overlap with these and other allelic variants is not entirely clear, but angiogenic growth factors such as vascular
has been reported in other autoimmune diseases, indicating that endothelial growth factor (VEGF), angiopoietin, Tie-2, and
susceptibility to RA is linked to fundamental perturbations of hypoxia inducible factor (HIF), as well as lymphangiogenic factors
immune tolerance. Variants mapping to cell surface receptors VEGF-C and VEGF-R3, make important contributions. It has
(IL6R, CCR6, CD40, CD5, FCGR2A) and intracellular signaling been proposed that influx of inflammatory lymphocytes and
intermediates (TNFAIP3, TYK2, TRAF1, TRAF6, RASGRP1, BLK) cells of monocytic lineage far outweighs the egress of cells from
are well represented, as are transcription factors linked to cell synovial tissue, likely due to chemokine gradients and engagement
differentiation and effector function (GATA3, IRF5, IRF8, IKZF3, of sphingosine 1 phosphate receptor 1 (S1P1) by CD69 expressed
RBPJ, RUNX1). Perturbations in expression or function of these on activated lymphocytes. This leads to downregulation of S1P1
genes will influence the function of a broad range of immune and retention of cells in tissues. Once in the synovium, egress
cell subsets. may be promoted by specific mediators such as sphingosine 1
phosphate, which actively regulates cellular egress, or blocked
Synovial Pathology through integrin/adhesion molecule interactions, e.g., between
RA targets diarthrodial joints, structures characterized by hyaline antigen-specific T cells and dendritic cells/APC, through TCR-
cartilage lining opposing articulating surfaces and a cavity of dependent “stop” signals, or perhaps through highly selective
viscous synovial fluid lined by synovial membrane lacking a and specific inactivation of chemokines by proteolysis, e.g., stromal
basement membrane, but encased by a fibrous joint capsule. derived factor (SDF)-1 cleavage by cell surface dipeptidyl peptidase
Normal synovial tissue comprises a lining layer, no more than CD26. The abundance of lymphatic vessels in inflamed synovium,
a few cells in depth, of stromal fibroblast-like synoviocytes suggested by expression of podoplanin and CD31 in situ, suggests
(FLSs—also known as type B synoviocytes) and sublining that active lymphangiogenesis exists that may promote efflux of
22
macrophages (type A synoviocytes). The synovium serves to line cells and fluid from the synovium. Interestingly, enhanced
noncartilaginous surfaces, and although blood vessels are sparse, proliferation of lymphatic vessels and increased lymphatic
it functions to provide essential nutrients to avascular structures drainage have been documented after tumor necrosis factor
including cartilage, tendons, and bursae. Recent insights from (TNF) blockade. Lymphatic growth factors such as VEGF-C
synovial biopsies of “at-risk” subjects who have both joint pain (which signal through VEGFR-3/Flt-4) have been implicated in
(arthralgia) and serum RA-associated autoantibodies (i.e., systemic promoting this joint-protective effect.
autoimmunity) suggest that the transition from “normal” to
inflamed synovium may occur over a period of only a few weeks Organization of Lymphoid Tertiary Microstructures
22
or months. Subtle T-cell infiltration was detected in those Tissue microstructure both dictates and facilitates immune
subjects who went on to develop clinically apparent synovitis. responses in secondary lymphoid organs and mucosa-associated
lymphoreticular tissues (MALTs). These structures have evolved
Increased Vascularity and Cell Migration to coordinate responses to pathogens and to direct lymphocyte
The range of pathology observed in patients with RA perhaps recirculation, and although their role in immune homeostasis
22
most convincingly underscores the heterogeneity of the disease. is established, quite how they contribute to pathological states
The earliest changes observed relate to increases in vascularity is less well understood. Thus the inflamed synovium appears to
characterized by vascular congestion and thrombosis with be uniquely suited to supporting distinct patterns of cellular
obliteration of small vessels in association with perivascular infiltrates—noncapsulated, as opposed to capsulated—inducible
inflammatory infiltrates. Hyperplasia of the synovial lining layer lymphoid structures, that could play a role in pathways of cell
22
is another typical early finding. These changes are rather non- activation, differentiation, and survival. These include diffuse,
specific and certainly not diagnostic. rather disorganized lymphocytic infiltrates which comprise the
A key checkpoint defining the switch from acute to chronic most common form of synovitis, occurring in ~30% in prospective
persistent inflammation is the sustained activation of microvascular cohort studies; up to 70% has been described in late-stage disease
endothelium, phenotypic changes in the high endothelial venules (at arthroscopy, joint replacement surgery). In 40–50% of patients
(reminiscent of tissue injury), and the concomitant upregulation more organized follicular structures may exist (Fig. 52.2). Based
of adhesion molecules such as intercellular adhesion molecule on immunohistochemical analysis, approximately 25% of these
(ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (Chapter follicular structures include organized germinal centers in which
11). According to current thinking, the expression of chemoat- there are zones of proliferating B cells with affinity maturation,
tractants derived from synovial stromal cells heralds the rolling, in addition to a distinct T-cell zone. In aggregates lacking germinal
adhesion, and transmigration of mononuclear cells through centers, follicular dendritic cells (DCs) are absent.
endothelial barriers into the synovial membrane. It also contributes A fourth histological pattern, characterized by granulomatous
to the progressive synovial hypertrophy and hyperplasia, sometimes reactions, has been described in a much smaller subset of patients.
with villous-like projections more typical of chronic, established The cellular and molecular determinants of these structures include
inflammation. Intravital imaging of synovial joints of mice injected the homeostatic lymphoid chemokines CXCL13 and the CCR7
+
+
+
with arthritogenic antibodies derived from the serum of K/B × ligands CCL21 and CCL19, VCAM-1 ICAM-1 LTβR mesenchymal
710 Part SIX Systemic Immune Diseases
further evidence of disease heterogeneity. This strategy assumes
that each disease phenotype should be represented in gene
expression signatures of multiple genes. Remarkable variation
in gene expression signatures has been observed, and initial
reports seemed to suggest that these signatures could be divided
23
broadly into two groups. The first is characterized by upregula-
tion of immune response and inflammatory genes; these tissues
are enriched for MHC and immunoglobulin gene products. In
some tissues this signature may resemble an antiviral response
consistent with prior infectious insult and, more specifically, a
signal transducer and activator of transcription 1 (STAT1)–depen-
dent gene signature (promoting protective or proinflammatory
23
effects). This has also been observed in peripheral blood
lymphocytes (PBL) from patients. The second group is more
indicative of tissue remodeling, more reminiscent of that seen
in osteoarthritis. Most interestingly, distinct fibroblast-like
synoviocytes (FLSs), genotypes, and phenotypes match the type
FIG 52.2 Lymphoid Follicular Structures in Inflamed Rheu- of RA tissue from which they derived. For example, FLS signatures
matoid Arthritis Synovial Tissue. A characteristic hematoxylin from high-intensity inflammatory tissue resemble signatures of
and eosin–stained tissue section from a patient with active RA transforming growth factor (TGF)-β/activin-A–induced expres-
showing a large follicular-like structure (original magnification sion profiles in myofibroblasts, whereas growth factors such as
×100). This section is also stained with monoclonal antibodies insulin-like growth factor 2 and insulin-like growth factor binding
to CD3ε, followed by a three-step immunoperoxidase staining protein 5 characterize FLSs from tissues with low-intensity
+
protocol (CD3 T cells stained dark red). (Courtesy Tak, et al. inflammation. These data support the notion of RA heterogeneity
Arthritis Rheum 1996;39:1077, with permission from J. Wiley being reflected in FLSs as a stable, if not transformed, trait. They
and Sons, Inc.) would also be consistent with a model in which there is a transi-
tion from an antigen-driven phase of disease to a relatively
antigen-independent process, characterized by autonomous,
+
+
−
organizer cells, and hematopoietic-derived CD3 CD4 IL-7R R invasive, and aggressive FLSs and manifested as persistence of
+
ANK lymphoid inducer cells. Lymphoid tissue inducer cells the inflammatory state. Subsequent disease flares might arise as
produce LT-β, which is required for high endothelial venule dif- a consequence of repeated exposure of lymphocytes to antigen
ferentiation, amplification of chemokine expression, and develop- after infectious or mechanical insult.
ment of the stromal architecture. The mechanisms that sustain Gene expression signatures have clinical utility. For example,
these lymphoid structures over time are not fully characterized a type I IFN signature in peripheral blood cells negatively predicts
but could involve persistence of antigen and augmented antigen- the response to B-cell–depleting therapy rituximab, but its
presenting function through the differentiation of follicular DCs, detection in neutrophils predicts a good response to
localized and autonomous expression of cytokines and growth anti-tumor necrosis factor (TNF) therapy. Enrichment of TNF-
factors, chemokine gradients favoring cellular interactions, and induced genes in early RA synovial biopsies is associated with
dysregulation of leukocyte homing and/or egress. Documentation higher disease activity and predicts poor response to first-line
of class-switch recombination and somatic mutation of immu- therapy, regardless of the drug therapy, while enrichment of
noglobulin genes in situ is further evidence of active adaptive synovial myeloid, but not lymphoid, gene expression signatures
immunity within synovial lymphoid follicles, and suggests that at baseline is associated with good clinical responses to TNF
supporting in situ production of pathogenic antibodies is of blockade at 16 weeks.
considerable pathobiological importance. Aberrant expression of microRNA (miRNA) in cells or plasma
24
Cross-sectional studies have indicated that, from a clinical of patients with RA has been widely reported, with circulating
standpoint, these distinct patterns reflect not only the heterogene- miRNA, such as miR-223 and MiR-16, correlating with disease
ity of the disease but also a spectrum of disease severity, with activity. This is of particular relevance because of the unique
each pattern requiring a distinct targeted approach to therapy. role for miRNA in regulating expression of multiple gene sets.
More recent prospective studies, however, seem to indicate that A recent report indicates that baseline expression of miR-125b
the presence of lymphoid aggregates is one aspect of a rather in peripheral blood mononuclear cells of drug-naïve early RA
dynamic process. Although the lymphoid aggregates are associated patients predicts response to therapy at 3 months.
with the degree of synovial tissue cellularity and vascularity, they
are neither diagnostic for RA nor predictive of radiographic Immunobiology of RA
outcome such as joint erosions. The dynamic nature of these Initiation of the Immune Response
lymphoid structures is supported by their dissolution after therapy Synovial fibroblasts are exquisitely sensitive to inflammatory
with rituximab (anti-CD20) and TNF inhibitors, in the latter cytokines such as IL-1, TNF-α, and IL-6. Accumulating evidence
case enhancing lymphatic flow. indicates that FLSs also express a range of toll-like receptors
(TLRs) that can respond to exogenous, pathogen-associated
Gene Expression Signatures molecular patterns (PAMPs) or indeed a growing range of self-
Gene array technology has permitted unbiased and systematic tissue proteins, some of which could be considered damage
analysis of synovial tissue at the whole-genome level and, as associated molecular patterns (DAMPS). Endogenous ligands
with genetic, serological, and histological analysis, has provided especially relevant to inflammatory arthritis include heat shock
CHaPtEr 52 Rheumatoid Arthritis 711
proteins, fibrinogen fragments, antibody-DNA complexes, high- of inflammatory leukocytes, including polymorphonuclear
mobility group box (HMGB)-1, and hyaluronan oligosaccharides. leukocytes and immature or undifferentiated monocytes, orches-
Recent data suggest that synovial FLSs, as well as synovial trated by chemokines produced by resident stromal as well as
macrophages, express TLR2 in situ. Expression is upregulated infiltrating cells (Fig. 52.3). CXC, CC, C, and CX 3 C chemokines
after stimulation with IL-1 and the TLR2 ligand peptidoglycan. all play a role, exerting chemotactic activity toward neutrophils,
TLR2 engagement induces cytokines such as IL-6, matrix metal- lymphocytes, and monocytes but also influencing the topology
loproteinases, adhesion molecules, and an array of chemokines of inflammatory infiltrates. They are invariably early activation
including granulocyte chemotactic protein (GCP)-2, RANTES, genes (e.g., type I IFN response genes), in response to inflam-
monocyte chemoattractant protein (MCP)-2, IL-8, growth-related matory stimuli. Besides the homeostatic chemokines described
oncogene-2 and, to a lesser extent, macrophage-inflammatory above, the key players include IL-8/CXCL8, RANTES/CCL5,
protein 1α, MCP-1, EXODUS, and CXCL-16. Data suggest that MIP-1α/CCL3, SDF-1/CXCL12, IP-10/CXCL10, and MCP-1/
27
TLR3, TLR4, TLR7, and TLR9 are also expressed at messenger CCL2. Upregulation on endothelium of cell surface adhesion
25
ribonucleic acid (mRNA) and possibly protein level and may molecules, including ICAM-1, VCAM-1, and E-selectin, permits
augment inflammatory cytokine expression by DCs from patients the rolling and adhesion of leukocytes as they migrate. In synovial
with RA. joints, resident stromal cells and infiltrating macrophages are a
DCs are thought to be the most important antigen-presenting dominant source of such factors. Crucially, the expression of
cells in RA. Indeed, the proinflammatory environment favors cognate chemokine receptors such as CCR4, CCR5, CCR6, CXCR3,
DC maturation in regional lymph nodes as well as inflamed and CX3CR1 on inflammatory cell subsets contribute selectivity
26
27
tissue. Thus in peripheral blood, DC precursors express either of cellular recruitment. Within the T-cell compartment, there
−
dim
dim
an immature CD33 CD14 CD16 phenotype or a more mature exist distinct profiles of chemokine receptor expression, patterns
+
dim
MHC class II bright CD11c CD33 bright CD14 surface phenotype evolved perhaps to facilitate eradication of pathogens. For
typical of conventional myeloid DC (mDC); neither population example, T-helper 1 cells preferentially express CXCR3 and CCR5;
expresses costimulatory molecules. In contrast, synovial fluid Th2 cells express CCR3; Th17 cells express CCR6 and CCR4;
and tissue DC subsets resemble mature peripheral blood cells; and Tfh cells express CXCR5. Data suggest that CCR5, CCR6,
in addition, a subset expresses high levels of CD86 and can CCR7, CXCR3, CXCR4, and CXCR5 may all be important for
support allogeneic mixed leukocyte reactions. More recent data B-cell migration into synovium. Together, these events characterize
indicate that they may differentiate further in situ as suggested the acute phase of an innate immune response, a key checkpoint
by nuclear translocation of RelB in DC localized within peri- that precedes the progression to subsequent events that herald
vascular infiltrates, consistent with prior cytokine receptor or the onset of the chronic inflammatory phase.
TLR engagement in vivo. Perivascular RA synovium also contains
+
−
+
populations of MHC class II CD11c CD123 plasmacytoid DC Autoantigens in RA
(pDC); in contrast to the conventional myeloid DC subset, these Although current models of adaptive immune responses would
−
are RelB and comprise ~30% of all synovial DC. A subset suggest that DC carry antigens derived from damaged or dying
of pDC express BDCA2, capable of producing IFN-α in situ. synovial tissue, the molecular nature of disease-associated antigens
Unlike their peripheral blood counterparts, synovial pDC effi- has, until recently, remained an enigma. Many RA-associated
ciently activate allogeneic T cells to proliferate as well as to produce autoantigens have been described (see Table 52.1 for examples),
28
IFN-γ, TNF-α, and IL-10. and for some there exist in vivo arthritis model correlates.
Although the common myeloid precursor cell is the precursor The best described are collagen II, proteoglycans, HCgp-39,
for all myeloid cells, including DC and tissue macrophages, the
+
+
+
−
precise role of monocytes—namely CD14 CD16 , CD14 CD16 ,
+
dim
and the more recently described CD14 CD16 subset—in TABLE 52.1 autoantigens in
synovial inflammation is uncertain. They are good candidates rheumatoid arthritis
as persistence factors through their capacity to activate and
polarize T-cell subsets, to respond to the environment through t or B Molecular
TLR expression, and to produce a wide range of inflammatory Established Cell a Specificity assay b
mediators, including IL-1, TNF, IL-6, IL-8, CCL2, NO, and type Immunoglobulin G B Human Fc IgG Rheumatoid factor
+
dim
I IFN. In contrast a more recently described CD14 CD16 subset Cyclic peptides T and B Citrullinated Anti-CCPs
may function to sense damage, to scavenge cell debris and peptides
higher-order molecular complexes, and to promote angiogenesis Fibrin T and B α- and β-chain Research b
and tissue repair. More work is needed to establish the contribu- epitopes b
tion of these distinct functional subsets to the chronic inflam- Fibrinogen T and B Multiple epitopes Research b
T and B CEP-1 dominates Research
Enolase
matory process. Nonetheless, multiple cellular and molecular Vimentin T and B Citrullinated MCV assay
determinants exist in RA synovium that could serve both to vimentin
initiate and perpetuate the immune inflammatory response. Collagen II T and B Multiple epitopes Research b
This initial wave of inflammation has two major consequences. HnRNPA2 B Multiple epitopes Research b
First, inflammatory cytokines will promote the activation of Aggrecan T and B Multiple epitopes Research b b
vascular endothelium, changes that occur very early in disease HCgp-39 T Multiple epitopes Research b
Multiple epitopes Research
Glucose-6-phosphate B
(see above and Fig. 52.3). Under the influence of locally generated isomerase
cytokines and chemokines, synovial postcapillary venules undergo
morphological changes to an extent that they resemble high a b Denotes autoantigens recognized by T or B cells, or both.
Assay is either not commercially available or not in routine clinical use. Details of
endothelial venules similar to those observed in secondary assays may be found in primary research communications.
lymphoid organs. The second major consequence is the migration CCPs, cyclic citrullinated peptides; MCV, modified citrullinated vimentin.
712 Part SIX Systemic Immune Diseases
Acute Phasic Chronic
Counter-regulatory networks TLR inhibitors IL-4, IL-10, TGFβ, IL-13, L-11, IL-2 IL-1Ra, sTNF-R, IL-10, IL-18bp, OPG, adiponectin
Tissue damage, IL-12, IL-23 IL-2, deficiency
LTβR
TLR ligands IL-15, IL-18 +IL-6
TLR IFNs + TGFβ CD28 null
survival T reg TCRζ dim
factors IL-10
IL-2 BlyS T reg Adipo
IL-1, TNF, IL-6, IL-22, TCR April
PGE , bFGF, PDGF, EGF, CXCL5/8/9/10/12/13, TGFβ T eff
2
VEGF, TGFβ COX, LOX CCL2/3/5/20/21, CX3CL1 CD28 IL-10
CD40 Mφ Adipokines
T eff B IL-17+
CD40L RANKL Oncostatin M
TNF TNF MMP
Transmigration of monocytes M-CSF IL-1 ADAM
PMN, mast cells, and NK cells OPG PGE 2 ADAM-TS
Early Late IL-6 IL-1, IL-6, TNF
IL-2, IL-4, IFNγ IL-10 IL-15, IL-32
activation of endothelium, IL-13, TGFβ IL-17 chemokines GM-CSF
↑ adhesion molecules IL-15 RANTES AutoAb oncostatin M
GM-CSF TNF M-CSF, VEGF Osteoclasts Chondrocyte
LTα/β Chemokines
IL-10 adipokines features of inflammation and repair
HMGB1 tissue response
IL-10
Initiation Antigen Mode Inflammation Mode
FIG 52.3 Cytokine Networks in Rheumatoid Arthritis. The pathogenesis of rheumatoid arthritis
can be thought of as a series of complex and closely related pathways temporally and spatially
regulated. These include (1) an acute insult that may trigger the disease, characterized by stimulation
of FLSs by inflammatory stimuli and the generation of cytokines and chemokines that promotes
the migration and infiltration by cells of the innate immune system; (2) repeated episodes of
antigen-specific adaptive immune responses (in lymph node, bone marrow, and in situ). Failure
to resolve adaptive immunity is a key checkpoint that may lead to (3) a cytokine-driven chronic
inflammatory phase when multiple cellular and molecular components sustain the response.
Through multiple pathways acting on many cell types, this process leads to tissue injury. Proinflam-
matory pathways are shown in blue (text) and red (arrows), whereas antiinflammatory, counter-
regulatory pathways are shown in black (text and arrows). Adipo, adipocyte; AutoAb, autoantibodies;
B, B cell; DC, dendritic cell; FLSs, fibroblast-like synoviocytes; MΦ, macrophage; TCR, T-cell
antigen receptor; T eff , effector T-helper cell; Treg, regulatory T cell.
glucose-6-phosphate isomerase, α-enolase, vimentin, and citrul- autoantibody epitopes. Utilizing MHC class II tetramers loaded
linated fibrinogen. However, when used as recombinant native with derivatized peptides, it has been possible to demonstrate
antigen, few have been found to elicit reproducible and/or robust in peripheral blood and synovial fluid from RA patients low
6
PB or SF T- or B-cell responses in a significant proportion of frequencies of T cells (<1 per 10 ), recognizing citrullinated
patients, as opposed to healthy donors. There are several plausible cognate peptides derived from aggrecan, vimentin, α-enolase,
explanations for this. The most obvious is that antigens that cartilage intermediate layer protein (CILP), and fibrinogen α
29
drive autoimmune arthritis are not the same in mouse and man; and β. The impact of posttranslational modifications on the
another factor is that effector T-cell responses are more important cleavage of peptide epitopes is just beginning to be appreciated,
very early but are blunted in established disease, or they may but it is an attractive and highly plausible mechanism for the
simply present at very low frequency. Another possibility is that generation of self neoepitopes.
the autoantigens used to test lymphocyte reactivity in vitro do
not carry the posttranslational modifications (i.e., the neoepit- The Discovery of Citrulline as a Key Target for
opes) recognized by autoantibody or antigen receptor. Good Autoimmunity in RA
examples are the carbohydrate moieties of collagen II epitopes In 1998, van Venrooij and colleagues first reported that patients
that serve as key TCR contacts in collagen II immunity, or the with RA carried antibodies that recognized deiminated peptides
30
citrullination of key arginine residues in triple-helical CII or of fillagrin, the substrate that was found to be the antigen
fibrinogen peptides that appear to be the immunodominant recognized in rat keratinized epithelium. This substrate formed
CHaPtEr 52 Rheumatoid Arthritis 713
anti-CPA
“stress” ?
IgG1 synovial
plasma cells
B-cell
inflammation response
T H
Reactivity to T-cell
infiltration
modified self response
mΦ, PMN
PAD2/4 HLA class II
deimination
Ca 2 +
citrullinated
PAD4 genetic ↑mRNA proteins
polymorphism stability
vimentin, fibrin,
inflammation specific histones, α-enolase disease specific
FIG 52.4 The Generation of Autoantibodies to Citrullinated Protein Antigens. The stressed
and inflamed synovium is characterized by an influx of inflammatory cells, including macrophages
and neutrophils that express peptidyl-arginine deiminases (PAD). In the presence of sufficient
2+
Ca , PADs deiminate target proteins including, among others, vimentin, fibrinogen, aggrecan,
type II collagen, histones, and α-enolase. This reaction is inflammation, but not disease-specific.
The combination of environmental stimuli (including inflammation and exposure to tobacco smoke)
and the inheritance of specific HLA-DRB1 alleles favor T- and B-cell immune responses to the
host’s derivatized neoepitope peptide antigens. Neoepitopes may also be generated by changes
in peptide cleavage during antigen processing as a consequence of the Arg → Cit modification.
Anti-CPA, autoantibodies to citrullinated protein antigens; T H , T-helper effector cell.
the basis of the antiperinuclear factor (APF) assay, reported many of positively charged arginine at key residues in antigenic peptides
years before. Using new-generation anti-cyclic citrullinated peptide from candidate autoantigens such as fibrinogen to neutral citrul-
(anti-CCP) based assays, the presence of these antibodies, now line is permissive for peptide binding and recognition by autoreac-
collectively termed ACPAs, is now confirmed to be both sensitive tive T cells in vivo. 18
(up to 80%) and highly specific (>95%) for the diagnosis of Finally, citrullination is widespread in multiple tissues in
30
RA. Indeed, serum anti-CCPs levels are stable in established response to appropriate provocations. Although the molecular
disease, they have been detected as early as 14 years before disease basis for these triggers is poorly understood, recent data point
onset and have been shown to be predictors of radiographic to a link between smoking—an environmental exposure known
progression. Changes in isotype usage and spreading of antigenic to be linked with RA—citrullination, and individuals carrying
31
specificities suggest that the ACPAs response matures before SE. Thus cells derived from bronchoalveolar lavage from
disease onset. Citrullination is not specific for RA. Indeed, smokers, but not from nonsmokers, express citrulline. The
citrullination may be inflammation specific, because it has been association between the development of RA and smoking has
+
documented in inflamed synovium derived from patients with now been linked to ACPAs patients, whose relative risk increases
+
reactive arthritis and psoriatic arthritis as well as RA, but not 20-fold if they smoke and carry two copies of the SE DRB1
−
in those with OA. What appears specific for RA is the immune alleles; in comparison, the relationship in ACPAs patients appears
response to citrulline (Fig. 52.4). As outlined above, a link between to be much weaker or nonexistent. A second example relates to
+
ACPAs and HLA-DRB1 alleles, specifically SE alleles, has now the fact that Porphyromonas gingivalis, a pathogen associated
17
been established. Linkage analysis across chromosome 6 has with severe periodontitis, expresses its own deiminating enzyme
+
documented a peak with LOD scores in excess of 10 for ACPAs and has the capacity to modify host proteins such as fibrinogen
patients but not for those that do not carry these antibodies. and α-enolase in inflamed gingival tissue. Molecular mimicry
This relationship is independent of RF status, because the SE is suggested by the finding that anti-α-enolase autoantibodies
−
+
allele frequencies in ACPAs patients are twice those of ACPAs from patients with RA cross-react with P. gingivalis–derived
+
patients, even those patients who are RF . Indeed, the risk of α-enolase. The links between autoantibodies to the immuno-
+
−
+
carrying SE in RF ACPAs patients is no different from that in dominant α-enolase epitope CEP1, smoking, SE DRB1, and
the healthy control population. These data would be consistent disease-associated PTPN22 alleles are the strongest defined to
with a model where T cells from patients with RA can recognize date. These data are among the first to show a direct link between
+
peptide autoantigens modified by citrullination if they carry SE environmental exposure and disease-specific immune responses
DRB1 alleles. Crystallographic studies suggest that the conversion governed by immune response genes.
714 Part SIX Systemic Immune Diseases
Lymphocyte Biology TNF IL-6 IL-1 –rich synovial environment is capable of sup-
+
+
+
Flow cytometric analysis of dissociated synovial mononuclear porting the differentiation of Th17 cells. Sustained IL-17 expres-
cell cultures indicates that infiltrating T lymphocytes make up sion and stimulation of IL-17R–expressing stromal cells,
approximately 10–35% of cells in inflamed tissue. The ratio of macrophages, chondrocytes, and osteoclast precursors are
CD4 to CD8 T cells seen in peripheral blood is skewed in favor implicated in promoting local tissue responses. These include
of the CD4 subset. Much of the information relating to phenotype induction of chemokines, matrix metalloproteinases, nitric oxide,
and function is derived from detailed analyses of synovial fluid and cyclooxygenase and promotion of osteoclastogenesis, which
and, to a lesser extent, synovial tissue subsets. Similar enrichment are key mechanisms underpinning pathways of cartilage destruc-
of these subsets is commonly detected in PBL. Synovial T cells tion and bone erosion.
express phenotypic markers of antigen experienced, terminally
differentiated T cells with enhanced migratory capacity. Thus Molecular Basis of Persistence
synovial T cells typically carry cell surface markers such as Understanding the molecular basis of persistence is of major
+
+
+
+
−
+
HLA-DR , LFA-1 , VLA-1 , CXCR3, CD69 , CD45RO , CD45RA , importance in diseases such as RA. It is now well established
−
−
dim
CD45RB , CD29 bright , CD27 , and CD25 . Recent analysis of that enhanced expression of inflammatory cytokines is one of
36
citrulline-reactive B cells from RA patients indicate that they the hallmarks of chronic inflammatory diseases such as RA.
display markers of class-switched memory B cells and plasmablasts With few exceptions most cytokines are expressed in inflamed
−
+
+
(CD20 CD27 IgD ). Analysis of the variable (V) regions of the synovium at mRNA or protein levels. For example, unlike PBL
immunoglobulin heavy and light chains confirm that antigen- from healthy donors, explants of synovial mononuclear cells
specific activation and differentiation of B cells into plasma cells constitutively express IL-1, IL-6, IL-8, granulocyte macrophage–
takes place in draining lymph nodes as well as in the chronically colony-stimulating factor (GM-CSF), and a vast array of che-
inflamed synovial tissue of patients with RA. Likewise, analysis mokines as well as growth factors including FGF, VEGF, and
of the T-cell repertoire indicates that the synovium provides a PDGF (Fig. 52.3). Although antiinflammatory or immunoregula-
niche for supporting expansion of specific T cells, whose clonality tory cytokines, including IL-4, IL-10, IL-11, and TGF-β, as well
is shared between different joints from the same patient, but not as specific inhibitors of IL-1α/β (IL-1Ra) and TNF-α (soluble
substantially with clones from paired blood samples. 32 TNF-R) may also be detected, functional bioassays suggest that
Analysis of synovial T cells reveals that expression of the TCR levels of these naturally occurring inhibitors may be deficient
invariant chain subunits CD3ε and TCRζ is found at lower density in relative terms. Indeed, levels of IL-1Ra and soluble TNF-R
than that found in corresponding peripheral blood T cells, are significantly upregulated in synovial fluid compared with
evidence of prior antigen engagement. While synovial fluid T serum from patients with RA, and yet IL-1 and TNF bioactivity
−
+
cells are also FasL , Bcl2 , Bax bright , favoring a proapoptotic state, persists in spite of this, suggesting that attempts to suppress
it is thought that environmental cues transduced through common cytokine bioactivity are insufficient. The specific activity of
γ chain receptor signaling cytokines such as IL-2, IL-7, and IL-15, cytokine subsets, their networks, and their contribution to RA
33
as well as type I interferons, prevent apoptosis of T cells in situ. are illustrated in Fig. 52.3. In many cases, the pathogenic roles
Synovial tissue–derived lymphocytes may be different. Consistent of cytokines have been established in rodent models, either by
with their state of terminal differentiation, a subset of synovial selectively blocking their function (e.g., with specific monoclonal
−
T cells are CD28 , while at the same time expressing a range of antibodies or soluble receptor fusion proteins), by gene-targeting
natural killer (NK) cell surface receptors that are thought to approaches, or by transgenesis.
contribute to effector function independently of cognate antigen.
For over a decade it has been known that one of the dominant Immune Regulation
cytokines expressed in synovial T cells from patients with Investigation of regulatory cell subsets and their antiinflam-
established disease is IFN-γ. Somewhat surprisingly, a significant matory properties has perhaps more firmly established the
+
proportion of IFN-γ cells also express IL-10. Recent data support concept that failure of the host’s intrinsic mechanisms of
a model in which there exists, during differentiation, a transition immune regulation can underpin autoimmune diseases. Experi-
+
+
+
from IFN-γ Th1 T cells through an IFN-γ IL-10 double-positive ments in gene-deficient mice (e.g., Foxp3, IL-2, IL-2R, IL-2R
+
stage to a single-positive IL-10 stage. This last phase could signaling, STAT5, IL-10, TGF-β) lend support to this concept.
36
represent part of the normal lifecycle of an effector T cell, where In RA the data remain less clear. For example, there is in vitro
IL-10 expression promotes the resolution of the adaptive immune evidence for a relative deficiency of constitutive IL-10 expression
response, attenuating the function of DCs. Interestingly data in synovial cell cultures, and yet clinical trials of IL-10 have
indicate that this Th1 lifecycle involving a switch from IFN-γ to been disappointing. These results may reflect the complex role
IL-10 production may be defective in patients with active RA, of these cytokines in disease pathogenesis. The identification
+
providing an important mechanism for persistence of effector of defective numbers and/or function of CD4 CD25 bright Tregs
34
responses in vivo. Treatment of RA patients with anti-TNF has been suggested by several investigators, but reports are
appears to restore IL-10 production through induction of specific conflicting. 37,38 Some studies have shown clear reductions in
transcription factors. 35 numbers of peripheral blood Tregs in patients with RA, whereas
Emerging evidence, supported by preclinical models, points others have shown no difference; interestingly, Tregs appear
to a role for IL-17 in the pathogenesis of inflammatory arthritis. deficient in cell number in subsets of children with juvenile
Immunohistochemistry of RA synovium indicates that the idiopathic arthritis (JIA) whose disease tends to progress. In
dominant source is CD4 T cells, although γδ T cells, NK cells, synovial joints, the data are more consistent, with many reports
and mast cells also contribute. Flow cytometric analysis reveals showing substantial increases in Treg numbers in synovial tissue
+
+
that the frequency of IL-17 T cells is less than that of IFN-γ T and fluid compared with paired PB. However, some studies
cells and that a subset expresses both IL-17 and IFN-γ. The have reported normal function at a cellular level, whereas others
CHaPtEr 52 Rheumatoid Arthritis 715
39
have shown depressed regulatory function. An emerging concept, of OPG. This indicates that Wnt signals negatively regulate
whose mechanism is yet to be proven, is that synovial effector osteoclastogenesis. Oxidative stress and hypoxia within the
T cells are refractory to regulatory pathways. synovial compartment may contribute to attenuation of
osteoblast-promoting Wnt signals.
Impact of the Immune Response on Cartilage and Bone The interplay between bone formation and resorption is
For many years, it was considered that the terminal effector fundamental to bone homeostasis, especially in the context of
phase of chronic inflammation that led to cartilage destruction chronic inflammatory disease. Recent evidence suggests that the
and bone resorption was driven almost exclusively by inflam- molecular basis for this so-called coupling lies with the osteo-
matory cytokines and proteinases. IL-1, MMPs (MMP1, 3, 8, protective factor semaphorin 3A. This factor regulates bone mass
13), and aggrecanases (ADAMTS 4 and 5) were, and remain, in both osteoblasts (through effects on the canonical Wnt/β-
major culprits. Attempts to establish more directly a link between catenin signaling pathway) and osteoclasts (by inhibiting
41
adaptive immunity and destruction of target tissue failed, not RANKL-dependent osteoclast differentiation). Together these
least because of the lack of a direct physical link between lym- data support the view that bone and joint integrity are regulated
phocytes, chondrocytes, and bone. A breakthrough came in the by a delicate balance of catabolic and anabolic immune and
late 1990s with the identification of the TNF/TNFR family inflammatory mediators influencing the maturation and function
member receptor for activation of nuclear factor (NF)-κB ligand of osteoblasts (Wnt:DKK1) and osteoclasts (RANKL:OPG).
(RANKL)/TRANCE/ODF and its counter-receptor RANK, and
the dissection of the molecular and cellular components required CLINICAL FEATURES
39
for osteoclast differentiation from monocyte precursors. Accord-
ing to contemporary paradigms, RANKL is necessary and suf- Disease Onset
ficient for osteoclast differentiation. TNF, M-CSF, IL-1, and IL-17 RA is a heterogeneous disease that does not conform to a single
2
contribute, and RANKL-independent pathways may also play a clinical entity. Whereas 10% of patients may have an acute severe
role. RANKL is expressed on synovial fibroblasts and osteoblasts onset and 20% a more subacute onset, the onset of signs and
but also on activated T cells, its counter-receptor being expressed symptoms may be insidious in up to 70% of patients. A more
on myeloid lineage cells including monocytes, osteoclast precur- episodic or palindromic onset has also been described. A common
sors, and DCs. Its expression is regulated by inflammatory presentation, more likely during the winter months, will be that
mediators including TNF and PGE 2 . RANKL is shed, probably of a female in her fifth to sixth decade of life who complains of
through the action of several membrane-associated proteases diffuse symmetrical joint pain, swelling, and stiffness of peripheral
including MT1-MMP (MMP14). Gene targeting of RANKL or joints. Patients may complain that they can no longer make a fist,
RANK in mice leads to inhibition of osteoclastogenesis and a especially in the early morning. The targeting of afflicted synovial
profound osteoporotic bone phenotype. Deletion of osteopro- joints may be symmetrical in most but not all cases, typically
tegerin (OPG), the naturally occurring decoy soluble receptor affecting small joints of the hands and feet as well as wrists. Less
for RANK, leads to unbridled osteoclast differentiation and bone frequent are those presenting with slow-onset monoarticular disease.
resorption and substantially reduced bone mass. A good example Patients not fulfilling the diagnostic classification criteria for RA
of the link between adaptive immunity and bone resorption (see below) may, at this point, be ascribed the more appropriate
−/−
comes from cytotoxic T lymphocyte antigen-4 (CTLA-4) mice, diagnostic label of undifferentiated arthritis, because in a proportion
39
characterized by sustained chronic T-cell activation. T cells of cases, signs and symptoms may resolve spontaneously. At 1
from these mice overexpress RANKL. Importantly, the bone but year, approximately 30% will progress to develop the syndrome
not the inflammatory phenotype is rescued by inhibition of recognized as RA. Systemic disease is much less common in current
RANK/RANKL signaling. In RA, several studies have demonstrated clinical practice, in part through application of earlier, more
perturbations of serum RANKL/OPG ratios, a parameter currently intensive treatment regimens (see below). Nonetheless, the systemic
under investigation as a biomarker for bone homeostasis. Recent nature of the disease may be manifested through a wide array of
clinical experience with denosumab, a fully humanized mono- systemic, extraarticular clinical features that may occur in patients
clonal antibody that binds to RANKL, demonstrates increased with disease at the more severe end of the spectrum. A spectrum
bone mineral density and reduced bone turnover in patients of disease severity may also be evident from hand radiographs;
with RA. examples are shown in Fig. 52.5.
Distinct from enhanced bone resorption, bone formation is
impaired in RA, although until recently the pathways involved Diagnosis
were rather obscure. The inflammatory process itself, along with Classification Criteria
its effects on osteoblast maturation and function, has been directly The American College of Rheumatology criteria for the classifica-
implicated because bone formation at surfaces adjacent to bone tion of RA are a set of clinical and laboratory parameters,
marrow, as opposed to inflamed synovium, are relatively well established largely for epidemiological purposes, that serve as a
preserved. Recent data also suggest that ACPAs can also directly guide for the diagnosis of RA. They are relatively straightforward
promote osteoclastogenesis, providing a mechanistic link between and easy to apply, especially to patients with established disease.
autoantibodies and joint destruction that also depends on IgG However, failure of a patient with early signs and symptoms of
40
glycosylation status. Evidence now points to the canonical an inflammatory arthropathy to fulfill them does not mean that
Wingless (Wnt) signaling pathway as being an essential control the individual does not have RA. The 1987 criteria were simplified
point in osteoblast function, based on the observation that in further by removing the “probable,” “definite,” and “classic”
42
animal models of RA antibodies to dickkopf homologue 1 subclassifications. These criteria returned a sensitivity for RA
(DKK1), a secreted antagonist of Wnt blocking signals at the of 91–94% and a specificity of 89% in the clinical setting. New
level of its cognate receptor Frizzled, promote bone formation criteria, established by a steering group comprising members of
43
and inhibit bone resorption indirectly by increasing production the ACR and EULAR and published in 2010, are based on a
716 Part SIX Systemic Immune Diseases
A C
D
B
FIG 52.5 Photomicrographs and Radiographs of the Rheumatoid Hand. Chronic, severe, and
erosive RA, refractory to treatment and showing joint swelling and classical deformities (A and
B), is compared with erosive disease whose progression has been attenuated by combination
and biological therapy (C and D). White arrows indicate major areas of bone and cartilage destruc-
tion. Reproduced with kind permission from the patients.
weighted score around four domains, including distribution and Laboratory Findings
type of joint involvement (tender as well as swollen joints are Until the late 1990s, IgM RFs, autoantibodies that recognize the
included, scoring 0–5 points), serology (0–3) that includes RF Fc subunit of IgG, remained one of the few parameters of value
or ACPAs and is weighted according to antibody levels, duration in the clinical setting, forming the basis of the seropositive versus
of synovitis (0–1), and acute-phase reactants erythrocyte sedi- seronegative RA stratification and identifying those patients more
mentation rate or C-reactive protein (0–1). A score of 6 or above likely to progress to erosive disease with or without extraarticular
is indicative of an early disease state requiring initiation of features. Nevertheless, RF can be detected in up to 5% of the
disease-modifying antirheumatic drugs (DMARDs) such as healthy population and in 10–20% of the elderly population
43
methotrexate (Table 52.2), and so these criteria are thought to (>65 years of age); RF is found in a range of rheumatic conditions
better reflect an intention to treat on the part of the supervising including Sjögren syndrome, SLE, and cryoglobulinemia as well
physician. Although the presence of synovitis in at least one joint as in acute infectious and neoplastic disease entities, influencing
is required (in the absence of an alternative diagnosis that better its diagnostic utility. In general RF is not of value for monitoring
explains the synovitis), there remains debate as to whether responses to therapy.
subclinical synovitis of specific joints, defined by magnetic reso- The discovery of ACPAs, which can be detected very early in
nance imaging (MRI) or high-resolution ultrasonography the disease process, has had a major impact on diagnostic practice
30
(HRUS), should be included in the joint score. as the assays have become more widely available. They also
CHaPtEr 52 Rheumatoid Arthritis 717
TABLE 52.2 2010 aCr/EULar Insights Into the Preclinical Phase of Disease
Classification Criteria for rheumatoid arthritis ON tHE HOrIZON
Weighted The Preclinical Phase of Rheumatoid Arthritis
Domain Score
Joint Involvement (0–5) • High-risk individuals include those with inflammatory joint pain (arthralgia)
and serum RA–associated autoantibodies. From 40–50% of those
1 medium to large joint 0 with high-titer ACPAs (with or without rheumatoid factor) may develop
2–10 medium to large joints 1 clinical synovitis within 24 months.
1–3 small joints 2 • Targeting these high-risk individuals with preventative strategies
4–10 small joints 3 provides the best chance of achieving cure. Trials of rituximab,
>10 joints (with at least one small joint) 5 abatacept, or hydroxychloroquine are ongoing.
• In-depth molecular and cellular studies for characterizing the preclinical
Serology (0–3) phase of disease will be critical to the success of this endeavor.
Neither RF- or ACPAs-positive (≤ULN) 0 • Models for progression to RA have identified the following phases:
At least one test, low positive titer (>1 ≤3 × ULN) 2 (I) Genetic risk
At least one test, high positive titer (>3 × ULN) 3 (II) Genetic risk with autoimmunity (e.g., ACPAs, rheumatoid factor)
(III) Genetic risk with autoimmunity and arthralgia (but absence of
Duration of Synovitis (0–1) clinically apparent synovitis)
<6 weeks 0 (IV) Undifferentiated arthritis (clinically apparent synovitis, not fulfilling
≥6 weeks 1 RA classification criteria)
(V) Early RA (fulfilling disease criteria; need for DMARDs)
acute-Phase reactants (0–1) • Stratification of risk, including genetic, serological, and demographic
factors, will permit the identification of subjects most suitable for
Neither ESR or CRP abnormal 0 intervention studies.
Abnormal ESR or CRP 1 • Studying the impact of lifestyle modifications, e.g., diet, stopping
TOTAL (≥6 indicates definite RA): ______ smoking, would be of great interest.
• Reestablishing immune homeostasis and/or induction of immune
ACPAs, antibodies to citrullinated protein antigens; ACR, American College of
Rheumatology; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; tolerance may provide the best chance of achieving cure in subjects
EULAR, European League Against Rheumatism; RF, rheumatoid factor; ULN, upper during the preclinical phase of disease. Early-phase studies of peptide
limit of normal. immunotherapy indicate that this approach is well tolerated.
• Establishing robust assays for signatures of immune tolerance (e.g.,
immune phenotyping by flow cytometry, extended autoantibody
have prognostic value in terms of radiographic progression, and serotyping, multiplex assays for detection of inflammatory mediators
titers may alter with therapy. The new-generation anti-CCPs in serum, whole-blood transcriptomic profiles) that reflect a healthy
immune system will greatly facilitate these endeavors.
kits have demonstrated diagnostic sensitivity of 80% and specific-
ity of 98%. As the range of RA-associated autoantigens has ACPAs, antibodies to citrullinated protein antigens; DMARDs,
expanded and the repertoire of citrullinated target autoantigens disease-modifying antirheumatic drugs; RA, rheumatoid arthritis.
has become better defined, multiplex assays of serum autoantibod-
ies are likely to play an increasingly important role in the diagnosis
and prognosis of subsets of autoantibody-positive inflammatory
arthritides.
The identification of a preclinical phase of RA, through the
detection in serum of autoantibodies up to 14 years before disease
onset, has sparked considerable interest in characterizing the
CLINICaL PEarLS RA prodrome in more detail. Work has centered around evaluation
Predictors of Poor Outcome in of acute-phase proteins and serum cytokines and chemokines,
Rheumatoid Arthritis which appear to rise 1–2 years before onset of clinical disease;
ACPAs isotype usage and epitope spreading; whole-blood gene
• Chronic, unremitting disease onset, especially at advanced age expression analysis, which shows similarities to patients with
• High disease activity scores at baseline established disease (including type I interferon-inducible gene
• Female gender
• Poor functional status as determined by validated functional disability signatures in a subset); imaging by MRI and ultrasonographic
indices such as the Stanford Health Assessment Questionnaire (HAQ) modalities; and, most recently, analysis of lymph node immune
and the Arthritis Impact Measurement Scale (AIMS) phenotypes, showing evidence of lymphocyte activation. The
• Low socioeconomic status strongest predictors of progression in those at-risk subjects are
• Systemic and extraarticular features joint pains without clinically detectable synovitis (arthralgia)
• Depression and anxiety combined with the presence of high-titer ACPAs and RF auto-
• Comorbidity, e.g., infection, cardiovascular disease, renal
impairment antibodies. Risk scores, which take into account other demographic
• Early erosive disease (in first 6–12 months; may be associated with factors, have been developed and are currently being evaluated.
+
ACPAs autoantibodies) Progression rates for ACPAs arthralgia patients with subclinical
• Persistent acute-phase response (e.g., time-integrated CRP levels) synovitis detected by ultrasound examination are of the order
• Autoantibodies (RF and ACPAs) and HLA-DRB1 status (SE ) of 20% over a median of 28 months, while arthritis-free survival
+
44
• Significant delay in early use of DMARDs and corticosteroids curves suggest that 40–50% of those at highest risk will develop
ACPAs, antibodies to citrullinated protein antigens; CRP, C-reactive clinically apparent synovitis in 2–3 joints within 24 months.
protein; DMARDs, disease-modifying antirheumatic drugs; RF, This rate of progression is considered to be sufficient to justify
rheumatoid factor; SE, shared epitope. secondary prevention intervention studies. Somewhat surprisingly,
718 Part SIX Systemic Immune Diseases
genetic markers, such as HLA-DRB1 SE, have not contributed that intensive treatment when combined with intensive control
dramatically to risk estimates. most convincingly influences outcome measures, including clinical
response, retention, functional status, and radiographic progres-
TREATMENT sion. The benefits of tight control have been substantiated in
many subsequent clinical trials as well as in “real life” clinical
Disease-Modifying Antirheumatic Drugs practice. 45,46
tHEraPEUtIC PrINCIPLES
Treatment Paradigms in RA Anticytokine Therapy
The introduction of targeted therapy to the clinic using biological
• Education and counseling through early involvement of a multidisciplinary agents (e.g., chimeric or fully humanized antibodies to ligands
team, including specialist nurse and other health care professionals; or receptors, soluble receptor fusion proteins, or recombinant
appropriate balance of rest and exercise during disease flares receptor antagonists) has transformed the treatment of RA. The
• Adequate nutrition (especially important with severe, active disease) prototype biological is TNF-α blockade. The rationale for
47
• Comprehensive assessment of disease activity, especially during early
phase of disease to achieve rapid disease control inhibiting TNF-α bioactivity is based upon its pleiotropic effects
• Complete suppression of inflammation early in the disease, with tight on cell activation, cellular adhesion and migration, induction
control through regular and frequent reassessments focused around of cytokine and inflammatory gene mRNA and protein, neoan-
disease activity scores giogenesis, and the regulation of cartilage catabolic factors such
• Yearly imaging assessments, e.g., X-rays or high-resolution ultraso- as IL-1 and matrix metalloproteinases (Fig. 52.3). TNF-α and
nography of hands and feet to monitor radiographic progression other inflammatory cytokines such as IL-1, IL-6, IL-15, IL-17,
• Early use of DMARD/SAARDs and GM-CSF are expressed constitutively in inflamed synovial
• Early use of corticosteroids, including use of intraarticular joint injections
to suppress inflammation, and use of step-up combination therapy in tissue at mRNA and protein level. In many cases the expression
severe disease of their high-affinity cognate receptors is upregulated and the
• Appropriate use of biologicals, e.g., early use of anticytokine, T- or functional activity of the corresponding naturally occurring
B-cell–targeted therapies in severe disease inhibitors (e.g., soluble TNF-R or IL-1Ra) is reduced (although
• Early relief of pain with judicious use of NSAID or COX2 inhibitors levels of protein may be increased, reflecting an attempt at restoring
according to safety/risk profile homeostasis). As proof of principle, inhibition of cytokine activity,
• Monitoring for drug toxicity
• Effective contraception, where appropriate including TNF-α, IL-1, IL-6, IL-15, and IL-17, have all been
• Bone protection shown to have benefit in animal models of arthritis.
• Monitoring for risk factors of key comorbidities, including cardiovascular Chimeric anti-TNF monoclonal antibodies (infliximab) were
47
disease first used to treat RA in open-label clinical trials in 1992.
• Prevention of infection through vaccination (preferably before instituting Humanized antibodies (adalimumab) and the soluble p75 TNF-R
immunosuppressive agents), e.g., against influenza, pneumococcus, IgG fusion protein (etanercept) were tested subsequently with
and herpes zoster
comparable therapeutic effects; golimumab and a construct
COX, cyclooxygenase; DMARD, disease-modifying antirheumatic comprising a PEGylated anti-TNF antibody Fab fragment
drugs; NSAID, nonsteroidal antiinflammatory drugs; SAARD, (certolizumab) are also licensed for use in patients with RA, as
slow-acting antirheumatic drugs. are a growing number of “biosimilar” TNF inhibitors. TNF-α
blockade leads to dramatic and rapid reductions in symptoms
(pain, stiffness, and fatigue) and signs (joint pain and swelling)
Over the past two decades there has been a dramatic paradigm of arthritis in a dose-dependent fashion, and in a significant
shift in the therapy of RA from control of symptoms to the proportion of patients (~60–70%) who have failed conventional
47
control of the disease process and aggressive suppression of DMARDs. As a class, these biological agents can be used repeat-
inflammation. This shift has come about through a growing edly, and when used in combination with methotrexate, they
appreciation of the relationship between joint inflammation and are superior to either drug alone. The mechanism is not clear
joint destruction and also through the development of imaging but may be related to reductions in immunogenicity of the
technology that has documented evidence of erosive changes therapeutic antibody (the antidrug antibody [ADA] response),
within the first 6–12 months of disease. The impact of this effects on the half-life of the biological, or perhaps the combined
paradigm shift in therapeutic terms is striking. Traditional “go-low, immunological effects of anticytokine and anti-T-cell agents.
go-slow” regimens of the 1970s and 1980s included the initiation Radiographic progression may be attenuated, even in subsets of
of nonsteroidal antiinflammatory drugs (NSAIDs), followed by patients with poor clinical responses; in some patients radio-
implementation of DMARDs only after destructive disease became graphic scores improve, suggesting that healing of joint tissues
evident. Depending on the clinical response, sequential mono- may take place. TNF-α blockers when used early demonstrate
therapy was the norm. Although this strategy may still be superior remission rates. Some studies have shown that a sig-
appropriate for patients with mild disease, current practice now nificant proportion of patients remain in remission even after
dictates aggressive combination therapy (two or more conven- withdrawal of anti-TNF, providing evidence suggestive of immune
tional DMARDs) from the outset for patients with poor prognostic modulation. Regardless of the TNF inhibitor used, the contribu-
factors, with preference for the faster-acting DMARDs such as tion of TNF to host defense is further suggested by an approxi-
methotrexate, leflunomide, and sulfasalazine (onset 3–6 weeks) mately twofold increased risk, especially during the first 6 months,
over slower-acting agents such as hydroxychloroquine, gold, and of serious infections of the upper respiratory tract, skin, and
d-penicillamine (onset 3–6 months), but with the addition of joint as well as by a significantly increased risk of reactivation
oral or parenteral prednisolone. More recent data suggest that of latent tuberculosis. The global risk of malignancy, particularly
the specific choice of therapy may be less important than the lymphoma, which already is increased in the RA population as
strategy. For example, the TICORA and BeST studies both indicate a whole, does not appear to be increased with anti-TNF therapy,
CHaPtEr 52 Rheumatoid Arthritis 719
although an increased risk of melanoma has been reported extent, JAK2; baricitinib blocks JAK1 and JAK2 to a similar extent.
through biologicals registries. The development of antinuclear Tofacitinib has been studied in head-to-head studies with
antibodies in 8–15% of patients, as well as rare cases of demyelin- methotrexate and with TNF inhibitors. In methotrexate-naïve
ation, points to effects that may be related to restoration of patients, tofacitinib was superior to methotrexate in reducing
autoimmune responses in predisposed subjects after TNF-α signs and symptoms of RA and in inhibiting the progression of
inhibition. structural joint damage. In patients taking background methotrex-
The clinical benefit of TNF-α blockade has prompted extensive ate therapy, tofacitinib was similar in efficacy to adalimumab.
47
mechanism of action studies. Anti-TNF reduces the acute-phase JAK1- and JAK3-selective jakinibs are under evaluation. Inhibition
response, including IL-6 serum levels. Leukocyte trafficking is of another kinase, spleen tyrosine kinase (Syk) with R788
inhibited, as demonstrated through an early (within hours) and (fostamatinib), has also shown clinical efficacy in RA.
dramatic rise in lymphocyte counts through demargination, a
more prolonged and sustained exclusion of leukocytes based on Anti-T-Cell Therapy
reductions in cellularity of synovial tissue biopsies after treatment The contribution of costimulatory signals (“signal 2”) transduced
and suppression of markers of angiogenesis, including VEGF; through CD28 to priming and activation of naïve T cells and
TNF blockade promotes lymphangiogenesis and may facilitate amplification of cytokine gene expression and proliferative
cell egress from inflamed synovium. TNF-α blockade has also responses has provided a rationale for testing costimulatory
been shown to downregulate markers of cartilage and bone blockade in patients. This has been achieved using a nondepleting
destruction, including the collagenases MMP1 and 3, and to humanized IgG1-CTLA-4 fusion protein that prevents CD80
reduce the ratio of RANKL and OPG in serum, effects that might and CD86 (expressed on antigen-presenting cells) from engaging
explain in part the joint-preserving effects of anti-TNF in vivo. CD28 (but also CTLA-4) expressed on T cells. Initial studies
50
Finally, there is additional evidence of anti-TNF-induced immune confirmed that the agent was safe and well tolerated. When
homeostasis, based on restoration of cell-mediated immune administered as an intravenous infusion on days 1, 14, and 28,
responses to recall antigens as well as mitogens, but also on an and then monthly thereafter at a 10-mg/kg dose in combination
+
increase in both the numbers and function of CD4 CD25 high with methotrexate, 60% of patients achieved a 20% improvement
Tregs and on increases in expression of the immunoregulatory in tender or swollen joint counts as well as 20% improvement
cytokine IL-10. 35,37 This effect could be explained in part by the in three of the other five ACR criteria (ACR20) compared with
effect of TNF blockade on restoring the expression of the Treg- 35.3% of controls; ACR50 responses were 36.5% versus 11.8%,
associated transcription factor FOXP3. respectively. CTLA-4-Ig (licensed as abatacept) has since been
The IL-1 receptor antagonist (IL-1Ra) is the only IL-1 inhibitor shown to inhibit radiographic progression and structural damage
currently licensed for use in RA. It has disease-suppressing effects by ~50%, and it is also effective in treating those patients who
in animal models of arthritis, with potent joint protection, but have had inadequate responses to TNF blockade as well as to
has proven less effective than anti-TNF in patients with RA. methotrexate. Abatacept can also be administered subcutaneously
Nevertheless, it has been used effectively to treat patients who on a weekly basis with efficacy comparable to that of the intra-
have failed TNF-α blockade, slowing radiographic progression, venous preparation. From an immunological standpoint the data
and may be efficacious in a subset of individuals with systemic are interesting in several respects. First, head-to-head studies
autoinflammatory syndrome–like features. Anti-IL-6R blockade indicate that the kinetics of response are remarkably similar to
(tocilizumab) is licensed for use in patients with established RA. those of anti-TNF. This likely reflects the significant number of
Evidence suggests that in early disease, tocilizumab as mono- costimulation-dependent T cells actively participating in the
therapy is as effective in suppressing signs and symptoms of RA ongoing inflammatory response. Clinical improvement may
as when it is combined with methotrexate. These effects are continue beyond 12 months. Second, recent data suggest that
mediated through blocking IL-6 actions on the immune response, inhibition of CD28 signals does reduce the number of Tregs, as
the acute-phase response, osteoclastogenesis, B-cell activation might have been predicted from mouse studies.
and immunoglobulin production, angiogenesis, and cell adhesion
48
(reviewed in Kishimoto). Clinical responses are comparable Anti-B-Cell Therapy
to those observed with TNF blockade. Unlike in psoriasis, the Rituximab is a humanized monoclonal antibody that recognizes
effect of inhibiting IL-17 in RA (with humanized monoclonal human CD20, a 33- to 37-kDa membrane-associated phospho-
antibodies ixekizumab or secukinumab that block IL-17A) has protein expressed on pre-B, immature, and mature B cells but
been more modest, although there may exist a subset of RA not on plasma cells. It was initially developed, and then licensed,
patients in whom IL-17-driven inflammatory responses dominate. for the treatment of non-Hodgkin lymphoma. While CD20
A role for blocking GM-CSF is awaited. Blockade of cell adhesion ligation promotes B-cell activation, differentiation, and cell cycle
or chemokine function has proved disappointing in RA for reasons progression, the function of CD20 is still poorly understood.
that may lie in the redundancy of these complex systems. The therapeutic effects of anti-CD20 are related to B-cell deple-
Finally, the impact of using small molecule inhibitors of tion, which can vary between patients due to antibody-dependent
cytokine signals, transduced through receptors that utilize cell cytotoxicity, complement-mediated cell lysis, and/or triggering
49
members of the Janus kinase (JAK) family of tyrosine kinases, of intracellular pathways for apoptotic cell death. 51
has been evaluated in some detail. These are interesting, immu- The initial open-label studies in RA patients combined
nologically important kinases, because gain-of-function mutants rituximab with cyclophosphamide and steroids, and so the precise
are associated with leukemia and lymphoma, whereas loss-of- contribution of rituximab to the clinical response was unclear.
function is associated with primary immunodeficiency. Jakinibs, A pivotal placebo-controlled trial of rituximab therapy random-
including tofacitinib and baricitinib, have been studied in phase ized 161 patients with RF-positive RA to compare the efficacy
III clinical trials of RA patients. Tofacitinib has high affinity for and safety of methotrexate alone (standard therapy) versus
JAK3 but is also able to partially inhibit JAK1 and, to a lesser methotrexate plus rituximab (1000 mg on days 1 and 15),
720 Part SIX Systemic Immune Diseases
51
rituximab alone, or rituximab plus cyclophosphamide. All Please check your eBook at https://expertconsult.inkling.com/
groups received a 17-day course of steroids, which may facilitate for self-assessment questions. See inside cover for registration
B-cell depletion. Up to 43% of patients receiving the combination details.
of rituximab and methotrexate achieved 50% improvement in
clinical and laboratory parameters after 24 weeks (ACR50), and REFERENCES
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CHaPtEr 52 Rheumatoid Arthritis 721.e1
MUL t IPLE-CHOICE QUES t IONS
1. Which of the following statements is correct regarding D. The shared epitope refers to a common sequence in a
autoantibodies in rheumatoid arthritis (RA)? subset of major histocompatibility complex class II alleles.
A. Antibodies to citrullinated peptides are highly specific for E. The shared epitope causes rheumatoid arthritis.
rheumatoid arthritis. 3. Which of the following characteristics are NOT typical features
B. Citrullination is found only in joint tissues. of individuals at high risk of developing RA?
C. Citrullination requires the presence of the amino acid A. A family history of RA
asparagine. B. Low body mass index (BMI)
D. Citrullination generates antigenic epitopes by posttrans- C. Inflammatory joint pain
lational modification of pathogen-derived peptides. D. A history of tobacco exposure
E. Antibodies to citrullinated peptides are generated after E. Low alcohol intake
onset of disease.
2. Which of the following statements is correct regarding the
shared epitope?
A. The shared epitope refers to a common bacterial antigen.
B. The shared epitope refers to a common viral antigen.
C. Antibodies to the shared epitope are characteristic for RA.
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