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78Rheumatoid Disease and Other

Inflammatory ArthropathiesSarah Keidel, Catherine Swales, and Paul Wordsworth

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Oxford, UK

This article is a revision of the previous edition article by Delbert A Fisher and Annette Grueters, volume 2, pp 1932–1950, © 2007, Elsevier Ltd.

© 2013, Elsevier Lt

GLOSSARYAnticitrullinated peptide antibody (ACPA) – Citrulline is

a nonstandard amino acid derived by posttranslational deimination of arginine by the enzyme peptidylarginine deiminase. Compared to rheumatoid factor, ACPA are more specific (95%) and equally sensitive (67%) serological biomarkers of RA.

Enteropathic arthritis – Inflammatory arthritis related to inflammatory bowel disease (e.g. Crohn’s disease or ulcerative colitis).

Endoplasmic reticulum aminopeptidase 1 (ERAP1) – (a.k.a. ARTS-1 (Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator)) A gene with a highly significant association with HLA-B27 positive ankylosing spondylitis. Protein for which it codes trims peptide antigens to optimal length for binding to HLA class 1 molecules.

Felty syndrome – Disease complex of rheumatoid arthritis, lymphadenopathy, neutropenia, and splenomegaly.

Fibroblast-like synoviocyte (FLS) – Cells within the synovial intimal lining which are key players in the inflammation and joint destruction in rheumatoid arthritis.

Genome-wide association studies (GWAS) – These studies involve systematic genotyping of a large number of SNPs with minor allele frequency >1% across the entire genome; comparison between patients with disease and healthy controls aims to identify genetic loci over- or underrepresented in the case cohort.

Receptor activator of nuclear factor-κB (RANK) – Receptor on surface of osteoclasts for receptor activator of nuclear factor-κB ligand (RANKL). RANKL binding to RANK induces differentiation of osteoclast precursors into osteoclasts, and activates mature osteoclasts.

Rheumatoid factor (RF) – Antibody against the Fc portion of IgG.

Seronegative spondyloarthropathy (SpA) – Group of inflammatory conditions including ankylosing spondylitis, reactive arthritis, enteropathic arthritis, and psoriatic arthritis. They are characterized by a number of common features including inflammation of the

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entheses; prominent axial and asymmetric lower limb peripheral large-joint arthritis; extra-articular features including uveitis; the formation of new bone at the site of inflammation; and association with the MHC class I gene HLA-B*27. AS is the hallmark SpA.

Severe combined immunodeficiency (SCID) – A group of rare genetic diseases in which both B cells and T cells are deficient resulting in marked susceptibility to recurrent and overwhelming infection.

Shared epitope (SE) – All rheumatoid-associated DR molecules (encoded by DRB1*0401, *0404, *0405, *0408, *0101, *0102, *10, and *1402) share an identical or similar sequence between amino acids 67 and 74, 67LLEQRRAA74. This sequence codes for a highly conserved sequence along the α-helix derived from the DRβ chain, which forms one side of the antigen-binding site of the DR molecule.

Tumor necrosis factor α (TNFα) – A cytokine with a central role in inflammation.

78.1 INTRODUCTION

The inflammatory arthropathies described in this chapter are multifactorial polygenic disorders. In recent years, the application of genome-wide association studies (GWAS) has played an important part in identifying many of the genes involved. Associations with human leukocyte anti-gens (HLAs) were first described in 1973 although the precise mechanisms by which these cause disease are still unclear. The association with protein tyrosine phospha-tase PTPN22 is now well established as the second stron-gest with rheumatoid arthritis (RA) and is particularly a good example of an association that is common to several autoimmune conditions. There is now convincing evidence for the involvement of more than 30 genes in RA and at least 14 in ankylosing spondylitis (AS). Many of these are key factors in the regulation of inflammatory and immu-nological responses, as expected, but others have less-obvious biological expectations. The association of RA

2 CHAPTER 78 Rheumatoid Disease and Other Inflammatory Arthropathies

with HLA-DRB1 alleles is robust and its interaction with smoking as an environmental factor is strongly suggested. The association of AS with several genes in the IL-17 pro-ducing (Th17) lymphocyte subset has already marked this as a potential therapeutic target (1). The highly significant association of AS with ERAP1 has provided an important example of gene–gene interaction in susceptibility to a complex disease since the association is entirely restricted to those individuals with AS who also carry HLA-B*27 (2). This association has also been evaluated at the level of protein structure and function. ERAP1 variants associated with protection against AS have reduced ability to trim peptide antigens to optimal length for binding to HLA class 1 molecules (3). This raises the possibility that inhibi-tors of ERAP1 could be protective against AS.

78.2 RHEUMATOID ARTHRITIS

Clinical descriptions of RA appeared fairly late in the medical literature and it was only distinguished from gout and osteoarthritis by Garrod 200 years ago. Clas-sical RA is characterized by a destructive inflammatory arthritis affecting the synovial joints, but a wide spec-trum of severity exists. The substantial variation in clini-cal features and severity of the disease underlines the likelihood that its etiology is also heterogeneous, includ-ing the genetic factors that are involved. Familial cluster-ing of cases is well recognized, with a generally accepted fivefold excess sibling recurrence risk over the general population risk (λs ~ 5) although this varies with the severity of the disease in the proband.

Typically, RA presents as a distal small-joint arthrop-athy of the hands (Figure 78-1) and feet that may ini-tially involve relatively few joints. Subsequently, the more proximal load-bearing joints become involved, potentially leading to severe functional disability. Any synovial joint, including the temporomandibular and cri-coarytenoid joints, may be affected. Overall the disease is approximately three times more common in women than

FIGURE 78-1 Classical rheumatoid deformity of the hands with ulnar deviation and subluxation at the metacarpophalangeal joints.

men, but this varies with the age of onset. Thus, at the age of 30 years, women are nearly 10 times more frequently affected than men, while there is no gender difference in incidence by the age of 65 years. RA may present in many different ways. In about two-thirds of cases, there is pau-ciarticular, insidious onset (typically in the hands and feet) with cumulative joint involvement over the course of months/years. This may be difficult to distinguish from other self-limiting causes of synovitis in the early stages of the disease. In contrast, the onset is explosive in a small minority of cases who develop widespread symmetrical polyarthritis over a few days or even overnight. Despite this dramatic onset, a proportion of such cases eventu-ally show complete resolution of synovitis and little joint destruction a year or two later. Systemic features, includ-ing fever, weight loss, and malaise, occasionally domi-nate the onset of RA, particularly in middle-aged men, prompting extensive investigation to exclude alterna-tive causes, such as deep-seated infection or malignancy. Limb girdle symptoms similar to polymyalgia rheumatica may be prominent, particularly in those with later-onset disease. Occasionally, patients present with “palindromic rheumatism;” this consists of short-lived attacks (~48 h) of mono-, oligo- or polyarticular synovitis that initially resolve completely but recur at intervals and may eventu-ally persist. Positive tests for rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPAs) are predic-tive of progression to persistent rheumatoid disease.

Extra-articular features are common in RA. These include skin nodules, cachexia, and normochromic, normocytic anemia. Mild peripheral neuropathy with glove-and-stocking sensory loss is more common than mononeuritis multiplex caused by rheumatoid vasculi-tis of the vasa nervorum. Major rheumatoid vasculitis affects men more commonly than women and can cause life-threatening cutaneous ulceration, myocardial infarc-tion, or bowel ischemia. Serositis is relatively common in RA; pericardial effusions are often asymptomatic and have been reported in up to 30% of those with RA on echocardiography. Rarely, constrictive pericarditis may result, and the heart valves are occasionally affected, par-ticularly in those with nodular disease. Corticosteroids may be required to treat symptomatic pleurisy or pericar-ditis. About 20% of patients develop secondary Sjögren syndrome with keratoconjunctivitis sicca and/or xero-stomia. The eyes are commonly affected by episcleritis, which usually requires no treatment, but, less commonly, there may be scleritis, which may require systemic corti-costeroids or immunosuppression. Lymphadenopathy is common, but <1% of patients develop Felty syndrome (RA, lymphadenopathy, neutropenia, and splenomeg-aly). This disorder rarely develops <10 years from the onset of RA (4). Patients with Felty syndrome prob-ably suffer joint disease of similar severity to non-Felty patients, but have more extra-articular manifestations. Familial recurrence of RA is more common where the proband has Felty syndrome.

atoid Disease and Other Inflammatory Arthropathies 3
CHAPTER 78 Rheum
Historically, despite active treatment with standard disease-modifying drugs, <50% of those with RA have been able to work full-time after 10 years of disease. Mortality is also increased by about 50%, reducing life expectancy by about 11 years (mainly as a result of increased cardiovascular disease and infections). New approaches to treatment with antitumor necrosis factor biologics have had a dramatic effect on joint disease in RA that may eventually be reflected in better mortality statistics too.

78.2.1 Pathology

Despite intensive research, the pathophysiology of RA remains incompletely understood. Animal models of the disease have provided some useful insights, includ-ing the central role of tumor necrosis factor α (TNFα) in rheumatoid inflammation. Such models are imper-fect, however, and much useful information has been gleaned from careful studies of the disease in humans and from dissecting the genetic basis of the disease in GWAS.

There is convincing experimental and clinical evidence of involvement of many cell types, including macrophages, B lymphocytes, T lymphocytes, and synovial fibroblasts, all of which are overrepresented in RA synovium. In RA, the normal synovial lining expands from 1–3 to 10–15 cell layers, which is predominantly composed of macro-phages and synovial fibroblasts; the additional influx and proliferation of immune and resident synovial cells also contribute to synovial hyperplasia. The most abundant stromal cells are the fibroblast-like synoviocytes (FLS) that appear abnormally resistant to apoptosis and accu-mulate in the RA synovium. Activated FLS are detectable early on in rheumatoid disease and although multiple factors from both the innate (primarily TLR2) and adap-tive (e.g. TNFα, IL-1, IL-6 and IL-17) immune systems support FLS activation, at least part of FLS activation appears to be independent of the surrounding inflamma-tory tissue (5). FLS activation leads to the upregulation of numerous chemokines (MIP-1α), cytokines, matrix metalloproteinases, and adhesion molecules (integrins, VCAM-1 and cadherins) required for the recruitment of inflammatory cells and their destructive effects in the joint (6). In particular, the production of interleukin (IL)-15 by FLS induces the production of other cytokines, such as TNFα and IL-17, by T cells through direct cell–cell contact. This further stimulates the expression of IL-15 and IL-6 by FLS, creating a feedback loop that favors persistent inflammation (7). Microarray analysis has sug-gested two subgroups of FLS distinguished by their gene expression signatures. FLS from highly inflamed areas have a TGFβ-activin A-inducible signature characteris-tic of myofibroblasts (which have a particular propen-sity for chemokine and cytokine production), while FLS from less-inflamed synovial tissue have a predominance of insulin-like growth factor-regulated genes (8).

Classification of RA synovial tissue histomorphology has been attempted according to differential synovial infiltration by leukocyte populations. Most patients with RA have diffuse sublining infiltration consisting of scat-tered CD4 T lymphocytes and monocytes, but a signifi-cant proportion (up to 25% in some series (9)) develop more discrete synovial aggregates with T- and B-cell compartmentalization. Intriguingly, these aggregates can progress into ectopic lymphoid structures resembling germinal centers with characteristic follicular dendritic cell networks and proximity to high endothelial venules. A recent study using a severe combined immunodefi-ciency (SCID) mouse model suggested that these follicles are functional, not only expressing activation-induced cystidine deaminase (AID), the key enzyme in somatic hypermutation and class-switch recombination of immu-noglobulin genes, but also supporting the production of ACPA (10). Unfortunately, differences in clinical study design and classification of aggregates have thus far led to contradictory findings on the correlation of lymphoid neogenesis with disease- or treatment-response pheno-types in RA. Indeed, lymphoid neogenesis may simply represent a bystander effect in any form of local inflam-mation (and interestingly such aggregates may also be found in patients with psoriatic arthritis, which is not held to be an autoantibody or B-cell-mediated disease). Despite this, some homogeneity does indeed exist and the synovium as a potential biomarker for disease severity or treatment response remains a tantalizing possibility.

The hypertrophic synovium develops into invasive pannus, eroding the articular cartilage and bone, partic-ularly at the points of synovial attachment, causing loss of joint space, instability, and deformity. Accumulation of osteoclasts at sites of bone erosion is characteristic. These multinucleated cells express receptor activator of nuclear factor-κB (RANK) and are derived from CD14-positive cells of monocyte/macrophage lineage under the influence of macrophage/monocyte colony-stimulating factor, RANK ligand (RANKL), and inflammatory cyto-kines. Increased numbers and activity of osteoclasts are both hallmarks of inflammatory bone loss. The inflam-matory milieu within the RA joint also serves to augment not only osteoclast precursor recruitment from bone mar-row but also their subsequent differentiation into mature osteoclasts. Mature osteoclasts secrete hydrochloric acid to dissolve inorganic bone matrix, while the bone matrix proteins are degraded by proteolytic enzymes (e.g. matrix metalloproteinases and cathepsin K). The main sources of RANKL are osteoblasts, FLS and activated T cells and its expression in these cells is upregulated by proinflammatory cytokines in synovial tissue, including IL-1, IL-6, IL-17 and TNFα. Such cartilage and bone loss is manifested radiologically by juxta-articular osteopo-rosis, narrowing of the joint space and the development of erosions and joint deformity (Figure 78-2); however, the relationship between synovial inflammation and articular erosion is complex and variable. Occasionally,

Inflammatory Arthropathies
4 CHAPTER 78 Rheumatoid Disease and Other
patients with prolonged synovitis do not erode, while erosions may be apparent in others at the time of presen-tation. Erosive disease is more common in those who are HLA-DRB1*04 positive.

Angiogenesis is a key event in the maintenance of syno-vial inflammation, delivering nutrients and immune cells to the site of inflammation. Despite new vessel forma-tion, inflamed synovial tissue is invariably hypoxic: syno-vial proliferation leads not only to increased metabolic demand but also regional hypoperfusion as tissue hyper-plasia increases the distance between proliferating cells and infiltrating vessels. The resultant low tissue oxygen tension drives the transcription of hypoxia-inducible factor (HIF) regulated genes, not least vascular endothelial growth fac-tor (VEGF), the most potent proangiogenic molecule.

The complex pathophysiology of RA has been amply demonstrated in recent years by the efficacy of several different immunomodulatory drugs that target discrete elements of the immune system. These include biologic agents targeting cytokines, such as TNFα (therapeutic monoclonal antibodies and a recombinant TNF recep-tor/Ig fusion protein) and the IL6 receptor; T-cell activa-tion (recombinant CTLA4/Ig fusion protein); and B cells (anti-CD20 agents).

78.2.2 Diagnostic Criteria

RA is regarded by many as a heterogeneous group of conditions with overlapping phenotypes. Over the years, many attempts have been made to define the disease

FIGURE 78-2 Radiographic appearances of advanced rheumatoid arthritis.

more accurately using classification criteria, including those developed by the American College of Rheuma-tology (or its antecedents and collaborators) in 1958, 1987 and 2010. Comparisons between population stud-ies are therefore somewhat complicated by differences in the diagnostic criteria that have been used. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria (Table 78-1) have a high degree of sensitivity and specificity. They have been modified particularly to detect early disease more effectively than the previous criteria because it is now recognized that early treatment of RA can prevent irreversible joint damage (11). The diagnosis is not dif-ficult in typical cases once the disease has been present for several months, but in early disease, a confident diag-nosis may be difficult, particularly where there is palin-dromic onset, limited synovitis or normal inflammatory markers. As many as one-fifth of patients presenting at an early synovitis clinic may turn out not to have RA after 1 year or so (12,13). The recognition that ACPA occur with high frequency in RA has led to their develop-ment as diagnostic aids in early inflammatory arthritis. ACPA have a similar sensitivity to RF for RA [~80%] but are more specific [~98%]. Both RF and ACPA may preceed the development of clinical disease by months or years (14).

78.2.3 Differential Diagnosis

The diagnosis of RA is relatively straightforward except in the early phase, when distinction from self-limiting arthropathies (e.g. reactive arthritis, viral arthropa-thies, and crystal arthropathies) may be more difficult.

TABLE 78-1 2010 American College of Rheumatology/European League against Rheumatism Classification Criteria for Rheumatoid Arthritis (15)

Score ≥6/10 required for classification as definite RA: Add scores A–D

A. Joint involvement1 large joint 0 points; 2–10 large joints 1 point; 1–3 small joints 2

points; 4–10 small joints 3 points; >10 joints including at least 1 small joint 5 points.

B. SerologyNegative RF and negative ACPA 0 points; Low positive RF or low

positive ACPA 2 points; high positive (>3 times upper limit of normal) RF or high positive ACPA 3 points.

C. Acute-phase reactantsNormal CRP and ESR 0 points; Abnormal ESR or CRP 1 point.D. Duration of symptoms<6 weeks 0 points; ≥6 1 point.

Adapted from Aletaha, D.; Neogi, T.; Silman, A.; et al. 2010 Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology/Euro-pean League Against Rheumatism Collaborative Initiative. Arthritis Rheum. 2010, 62, 2569–2581.

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CHAPTER 78 Rheumat
Distinction from the seronegative arthropathies, nota-bly psoriatic arthritis and reactive arthritis, may some-times be problematic. Generalized nodal osteoarthritis is occasionally similar and may coexist with RA; typically it affects the proximal and distal interphalangeal joints but usually spares the metacarpophalangeal joints and wrists. Osteoarthritis affecting the knees and hips is very common and is partly genetic in origin; large-joint osteo-arthritis requiring joint replacement has an excess sibling recurrence risk of 2.3 (16).

Crystal arthritis is common and may be difficult to dis-tinguish from RA, particularly in the elderly. For exam-ple, gout is polyarticular in onset in 10% of cases and quite commonly is not associated with elevated uric acid levels in the acute phase. On the other hand, its typical presentation with monoarticular lower limb arthropathy is quite distinct (50% of initial attacks involve the great toe, “podagra”). The diagnosis is correctly established by demonstrating intracellular needle-shaped crystals of monosodium urate in aspirates from affected tissues that are strongly negatively birefringent under polarized light. It is strongly familial, and its genetic etiology is reviewed in Chapter 95. Pyrophosphate arthropathy may cause a “pseudorheumatoid” pattern of chronic arthropathy, as well as the more widely recognized acute episodes of “pseudogout,” which can also punctuate the more chronic forms of pyrophosphate arthropathy. The diag-nosis of crystal arthritis is best established by aspiration of the affected joint and demonstration of the relevant intracellular crystals under polarized light. Familial forms of chondrocalcinosis, characterized by early-onset pyro-phosphate arthropathy, often have a dominant inheri-tance pattern. Some are linked to chromosome 5p (17), where gain-of-function mutations in ANKH, encoding a transmembrane transporter of inorganic pyrophosphate, have been described. Polymorphic variants of ANKH are also associated with sporadic forms of pyrophosphate arthritis (18). Pyrophosphate arthropathy is also a classic component of hemochromatosis (Chapter Iron Metabo-lism and Related Disorders), in which abnormal iron han-dling causes its deposition in numerous tissues, including the liver, myocardium, and synovium. The defective HFE gene is a member of the immunoglobulin superfamily and has a very high mutant allele frequency (~0.1) in north-ern Europe. Premature degenerative arthritis, particularly in atypical sites, such as the metacarpophalangeal joints, wrists, and ankles, should raise suspicions, especially if articular calcification is present. The diagnosis is best established by demonstrating saturation of transferrin and elevated ferritin levels. Elevated ferritin levels alone may be spurious, since ferritin, an acute-phase reactant, is commonly elevated in inflammatory states including RA.

78.2.4 Population Prevalence

Depictions of RA in art and literature seem to be lacking until about 200 years ago in Europe. As a consequence,

there has been speculation that the disease appeared rela-tively late in Europe and may even have been imported from the New World. RA has rarely been identified convincingly in the archeological record, but it may be mistaken for other diseases. Nonetheless, there is some evidence that the disease existed in Egypt in the third mil-lennium B.C. and also in Roman Britain (19).

The disease has a peak incidence in the age of 40–50, but may present at almost any age. There is an excess of incidence in the puerperium, and it has been suggested that oral contraceptives may confer some protection. Although most women also experience remission in pregnancy, unfortunately, recrudescence in the puerpe-rium is almost invariable and may be severe.

The prevalence of RA in many populations worldwide is remarkably similar (~1%), but with some important exceptions that may give clues to the etiology of the dis-ease. Environmental and/or genetic factors could account for the variations in the prevalence observed in certain ethnic groups (20,21). For example, the disease is rare in most of sub-Saharan Africa (prevalence = 0.3%) but com-mon in certain American Indian groups (5–7%). South African blacks in a rural environment exhibit the same low prevalence of the disease as in most of sub-Saharan Africa. This contrasts starkly with the high frequency of the disease in their urban counterparts, similar to that in South Africans of European descent, which strongly suggests an environmental influence. By contrast, the high frequency of RA in the Chippewa and Yakima Indi-ans of North America may be due to the high frequency of certain HLA class II alleles (see Section 78.2.5.2.1) associated with RA: HLA-DRB1*04 and the rare HLA-DRB1*1402 allele, respectively (22,23). In most popula-tions that have been studied, there are strong associations with various HLA-DRB1*04 alleles (relative risk ~5) (21,24,25). The HLA-DRB1*04 series, originally defined serologically as the HLA-DR4 transplantation antigen, can be subdivided into numerous HLA-DRB1 alleles, not all of which are associated with rheumatoid. Thus, HLA-DRB1*0402 (originally defined as Dw10 in the mixed lymphocyte reaction) is the dominant HLA-DRB1*04 subtype in Jews, but since DRB1*0402 is not associated with RA, there is no apparent association of RA with DRB1*04 overall in Jews, as discussed in Ref. (26). In contrast, associations are seen with HLA-DRB1*01 and HLA-DRB1*10 in Jews, which are relatively weaker associations in other populations where the associa-tion with HLA-DRB1*04 is more obvious. The rarity of HLA-DRB1*04 in Nigeria could account for the low incidence of RA in this population, but by contrast, in nearby Gambia, where HLA-DRB1*04 is relatively com-mon (~15%), RA is still very rare (our own survey in the 1990s revealed only one case in 2000 individuals). This suggests that either non-HLA genetic effects and/or environmental factors are also important. Indeed, it has been speculated that chronic stimulation of the immune system by tropical infections, including malaria, may in


some way be protective against the development of auto-immunity (27). The lack of geographic case clustering is in stark contrast to other forms of inflammatory arthritis, such as Lyme disease (28) or postenteric reactive arthritis (see Section 78.3.3), in which there is a clear evidence for an infective trigger. No convincing epidemiologic data have yet been provided to support a role for infection although it is widely believed that microbial agents are involved (29). Several viruses, including Epstein–Barr virus, rubella, and parvovirus B19, can cause acute and occasionally more persistent arthropathies, but neither viruses nor bacteria have been consistently isolated from the joints of affected individuals.

78.2.5 Genetics

Concordance rates in monozygotic twins vary between studies from 12% to 30%, which is not surprising in view of the different methodologies used. In the United Kingdom in the 1960s, concordance in identical twins with seropositive erosive disease was estimated as 30% (30). This contrasts with a lower rate of 12% obtained in a nationwide survey of twins in Finland that included individuals with less-severe disease (31). A more recent UK study (32) found 15% concordance in identical twins and demonstrated that this was highest in those twin pairs that were HLA-DRB1*04 positive (33). In all of these studies, the rates for monozygotic twin concor-dance were four to five times higher than for dizygotic twins, highlighting the likely importance of genetic fac-tors. There seems little doubt that nongenetic factors are important, not only in the development of RA but also in its progression. On the basis of these relatively small studies, broad sense heritability has been estimated to be about 55% (34).78.2.5.1 Sibling Recurrence Risk. Sibling recurrence risk varies according to the severity of the disease in the proband. In Lawrence’s UK studies in the 1960s (30), the excess risk to the sibs of individuals with mild nonerosive seronegative disease was barely greater than the general population frequency (λs 1.1). This is increased to sixfold in the siblings of individuals with seropositive, erosive disease, where as many as 15% of individuals will have an affected first-degree relative (35). Family recurrence risks of RA are also around seven times greater when the proband has Felty syndrome and are probably also increased when the index case has early-onset disease. The observation that the sibs of those with RA who share both HLA haplotypes identical by descent with the proband are at particular risk (36) is especially interest-ing as this group may be more likely than others to be HLA-DRB1*04 homozygous (37,38). The excess sibling recurrence risk over the general population risk (λs) is critically dependent on the criteria used in diagnosis. Thus mild, nonerosive disease is relatively common in the community at large and sib recurrence risks are rela-tively low. In contrast, seropositive, erosive rheumatoid

disease (that is typically followed up in hospital clinics) is much less common in the community and has higher sib recurrence risks. For this type of chronic, erosive disease, λs is probably nearer 12 to 14 and the genetic contribu-tion is correspondingly higher.78.2.5.2 HLA and RA. RA is clearly linked to the major histocompatibility complex (MHC) (39), as demon-strated in many populations (Table 78-2). The appli-cation of DNA-based approaches amply confirmed these linkages (40–43) and has now been applied at the genome-wide level for non-MHC loci. HLA class I asso-ciations with RA are invariably weaker than those in the HLA class II region, particularly with HLA-DRB1 alleles (21,24,25,44). With the application of high-density map-ping techniques, it is now clear that there are important associations not only with HLA-DRB1 but also with the HLA-B and HLA-DP loci (45).

78.2.5.2.1 Associations with the Classic Serologic HLA-DR (HLA-DRB1) Specificities. Although these associations were originally defined by serology, they have been amply replicated and refined latterly at the DNA level. Associations with HLA-DRB1*04 are well established in most ethnic groups globally, typically with a relative risk of approximately 5. Some impor-tant exceptions to this general rule have been observed, particularly among Jews (26), some Indian populations (46), Chileans (47), and the Yakima American Indians (23), in whom alternative associations have been found with DRB1*01, DRB1*09, and DR6 (DRB1*1402). The association with HLA-DRB1*09 originally described in Chileans has also been found as a min-ior association in the UK (48). Although the associa-tion with DRB1*04 predominates in most populations, other weaker associations are not uncommon. Thus, associations with HLA-DRB1*10 have been observed in Spaniards (49,50), Indians (51), and Jews (52), and with HLA-DRB1*01 (DR1) in Indians (46,51), Jews (52,53), and southern European populations, in partic-ular (54). While the strongest associations in the United Kingdom are with HLA-DRB1*04, weaker associations can also be detected with both DRB1*01 and DRB1*10 (44,55).

78.2.5.2.2 Differential Association of the DR4 (HLA-DRB1*04) Allelic Subtypes with RA. Not all DR4 haplotypes are equally associated with RA, despite the fact that SNP analysis indicates a high degree of con-servation in the DNA flanking the HLA-DRB1 locus that encodes the polymorphic DRβ1 chain (56). Thus, HLA-DRB1*0401, *0404, *0408, and *0405 are positively associated with RA, but *0402, *0403 and *0407 are negatively associated (44,57,58). In the United Kingdom, there is a hierarchy of HLA-DRB1 susceptibility alleles (Table 78-3). The most widely held explanation for this observation (shared epitope hypothesis) is that there is a conserved functional epitope in the HLA-DR molecules positively associated with RA (encoded by DRB1*0401, *0404, *0405, *0408, *0101, *0102, *10, and *1402).

CHAPTER 78 Rheumatoid Disease and Other Inflammatory Arthropathies 7

TABLE 78-2 HLA Sharing in Rheumatoid Arthritis—Affected Sib-Pairs

Ethnic Group Criteria

Haplotype Sharing

0 1 2

French 1958 ARA C/D 0 1 0Mixed 1958 ARA C/D 3 11 7American 1958 ARA C/D 0 4 1North Sweden 1958 ARA C 2 8 4American Seropositive erosive 2 0 1Caucasoid 1958 ARA C/D 2 7 4Italian 1958 ARA n/s 1 0 1Canadians 1958 ARA C/D 1 0 2Australasian 1958 ARA C/D 4 9 4German 1958 ARA C/D 0 0 1Norwegian 1958 ARA C/D 1 4 2American 1958 ARA C/D 3 6 3Dutch 1958 ARA C/D 1 8 0North Sweden 1958 ARA C/D 1 1 0UK white 1958 ARA n/s 5 20 17Southern Irish 1958 ARA C/D/Pr/Po 6 12 16UK white 1958 ARA D/Pr 6 24 23Mixed 1958 ARA C/D 1 7 7Dutch 1958 ARA D 0 0 2American 1958 ARA C/D 4 8 4North Indian, Hindu n/s 0 3 6English 1958 ARA C/D 3 6 6American 1958 ARA C/D 4 15 18Egyptian 1958 ARA n/s 0 7 10German 1958 ARA C/D 7 4 1Total 57 165 140Percentage 16 45 39Expected Percentage 25 50 25

ARA, American Rheumatism Association; C, classical; D, definite; ns, not specified; Po, possible; Pr, probable.Original studies in this table are referenced elsewhere.

In particular, a highly conserved sequence between amino acids 67 and 74 along the α-helix derived from the DRβ chain, which forms one side of the antigen-binding site of the DR molecule, is incriminated in susceptibility as shown in Figure 78-3. All the rheumatoid-associated DR molecules share an identical or similar sequence,

TABLE 78-3 Hierarchy of DRB1 Allelic Associations with Rheumatoid Arthritis Using Relative Predispositional Effects Analysis

Allele

*0401 ↑ <10−38

*0404,8 ↑ <10−43

*0405 ↑ <10−8

*10 ↑ <10−3

*0101,2 ↑ <10−2

*0403 ¬ 0.02

This analysis included 576 HLA-DRB1 alleles from the patient group and 1000 alleles from ethnically matched controls.Adapted from Hall, F. C.; Weeks, D. E.; Camilleri, J. P., et al. Infl uence of the HLA-DRB1 Locus on Susceptibility and Severity in Rheumatoid Arthritis. Q. J. Med. 1996, 89, 821–829.

FIGURE 78-3 Antigen-binding site of an HLA-DR molecule. Charged amino acids at position 71 in Dw10 (DRB1*0402) and 74 in Dw13 (DRB1*0403 and *0407) abolish susceptibility to rheumatoid arthritis; noncharged substitutions at position 71 in Dw4 (DRB1*0401) do not.


67LLEQRRAA74; with the exception of DRB1*0401, where the substitution of a basic lysine for arginine at position 71 is a relatively conservative change. This hypothesis probably accounts for the lack of association with HLA-DRB1*04 in Israeli Jews, in whom *0402 is the predominant DR4 subtype. This allele encodes a quite distinct 67ILEDERAA74 sequence in the DR4 molecule, including two acidic substitutions, compared to HLA-DRB1*0404/8 (57). It has therefore been speculated that the capacity of the HLA-DR molecules to bind a potentially arthritogenic peptide may trigger an autoim-mune response within the synovial joint, leading to the chronic process of inflammation and destruction that ensues (24,25,58,59). Crucially, this same 67LEDERAA74 motif is also found in the uncommon variant of HLA-DR1 (HLA-DRB1*0103), which is not associated with RA (44). It should be noted that the shared epitope has been associated predominantly with ACPA positivity. In addition, there is a pronounced and dose-dependent risk of smoking in individuals carrying the shared epitope in developing ACPA-positive, but not ACPA-negative, RA (60). It has been postulated that this gene– environment interaction in RA may be explained by smoke-induced citrullination of pulmonary peptides resulting in increased binding affinity to shared epitope MHC class II receptors, and thereby T-cell activation (60).

Associations with other MHC genes have been sug-gested by some studies. For example, it has been suggested that TNF polymorphisms might influence responses to anti-TNF therapies (61). It is extremely difficult to sepa-rate possible effects from the TNF locus and those aris-ing from HLA-DRB1 haplotypes because of the linkage disequilibrium between the two loci (62). To achieve this, association studies must be both adequately pow-ered and also very carefully matched for controls (e.g. for HLA-DRB1 status). We have previously suggested that there may be an extended TNF haplotype marking a 126-kb region centromeric to TNF that is particularly interesting (63). This region contains the gene AIF1, encoding allograft inflammatory factor that has previ-ously been implicated in inflammatory states (64); how-ever, such suggestions require very careful validation in carefully controlled, high-density genetic mapping. The longstanding suggestion that numerous HLA alleles, par-ticularly in the MHC class II region, are involved in RA (65) has been confirmed by recent high-density mapping studies of the MHC. It is now clear that contributions arise not only from HLA-DRB1 but also from HLA-B and HLA-DP (45). It has also been possible to refine the precise epitopes within each of these HLA molecules that are associated with susceptibility. This is analagous to the complex HLA associations that have also been described with type 1 diabetes mellitus (66).

78.2.5.2.3 Non-Inherited Maternal HLA Anti-gens and RA. Despite the relatively strong association between RA and HLA-DRB1 alleles, at least 15% of patients do not carry the conserved DRB1 epitope. It has

been proposed that, in these circumstances, some form of immunogenetic modulation may occur as a result of exposure of the host immune system to the noninherited HLA-DRB1*04 from the mother in utero (67). HLA-DRB1*04 appears to be overrepresented among non-inherited maternal HLA antigens in patients with RA (68). It has also been demonstrated that noninherited maternal HLA-DR antigens can exert a protective effect. HLA-DR antigens containing the protective sequence 67ILEDERAA74 are substantially underrepresented in the mothers of those with RA. The functional significance of these observations remains to be established. It could reflect an impact on the shaping of the T-cell receptor repertoire or an influence on tolerance mediated through exposure of the developing immune system to maternal antigens resulting from long-term microchimerism (69).

78.2.5.2.4 Associations between HLA and Disease Severity. HLA-DR associations with RA are depen-dent on the method of ascertainment. Community-based surveys pick up many milder cases compared with hospital-based studies, and interesting differences are apparent in their respective HLA associations. Community-ascertained case studies find relatively weak or absent association with HLA-DR4 (70,71) in contrast to hospital-based studies, in which about 70% of patients are DR4 positive. The progression of erosions has been correlated with presence of DRB1*04 and DRB1*0401 (72), and twin concordance is greatest in DR4-posi-tive identical twins (33). Patients with Felty syndrome have a particularly strong association with DR4 (up to 95%), and the DRB1*0401 allele (>50%) in particular (73). In populations where the DRB1*0401 is uncom-mon (Greeks, Chinese, and Japanese), Felty syndrome is either rare or absent. There is also an excess of DRB1*04 homozygotes in hospital patients with the disease (37,38) that is particularly obvious in Felty syndrome (73).78.2.5.3 Non-HLA Genetic Contribution to RA. The heritability of RA attributable to HLA is no greater than 40% of the whole genetic component (74–76), and in recent years, much research has been focused on identi-fying the remainder of this genetic contribution. Initial studies using whole genome linkage approaches had only limited success but more recent GWAS have proved very effective, identifying more than 30 genetic regions likely to be involved in the disease. It appears that there are no other major genetic effects of the size of the MHC and that the majority of loci have small effect sizes with odds ratios (ORs) ≤ 1.05.

Genome-wide linkage scans using microsatellite markers in affected sib-pair families from Europe, Japan (77), United Kingdom, and North America unsurpris-ingly reported varied results. The first systematic link-age study, reported by Cornélis et al. (40), identified numerous microsatellites exhibiting nominal evidence of linkage, including two (IDDM6 and IDDM9) that had previously shown suggestive evidence of linkage to insulin- dependent diabetes mellitus. The first large-scale

CHAPTER 78 Rheum
systematic genome scan from North America also reported overlapping linkages with other autoimmune disorders (41), but by far, the most striking linkage was with HLA, as in other similar studies. Most of these link-ages were not confirmed subsequently in a UK study of 183 multicase families (43). However, there is a weak association of IDDM6 haplotypes on chromosome 18 with RA (78). A replication study from North America subsequently confirmed some of these loci in a combined analysis of 512 families (42). Evidence for linkage was seen at 1p13, 1q43, 6q21, 10q21, 12q12, 17p13, and 18q21 as well as HLA (5 < 10–12).

Two particularly striking successes have been achieved at least in part using this approach. First, susceptibility to RA was identified in the 1p13 region with a missense mutation in a hematopoietic-specific protein tyrosine phosphatase (“Lyp”) encoded by PTPN22. The risk allele PTPN22 C1858T (R620W), present in 10–17% of the white population, disrupts its interaction with a cytoplasmic tyrosine kinase and thereby alters its nor-mal function as a negative regulator of T-cell activation (79). It is possible that there are cis-regulatory elements in PTPN22 that regulate its expression in RA (80); how-ever, others have suggested that there is no evidence of any other effects arising from the PTPN22 locus inde-pendent of C1858T (81). It is particularly interesting that this gene is also implicated in the etiology of several other autoimmune diseases, including autoimmune thyroid disease, type 1 diabetes and SLE (82). It is also notewor-thy that the association seems to be restricted to patients with RF-positive disease (83,84). Studies in the murine equivalent have shown increased T-cell activation and CD4 and CD8 accumulation in the tissues of the affected animals and the development of spontaneous germinal centers. B-cell function may also be affected (85). Sec-ond, Suzuki et al. (86) identified a linkage interval on 1p36 in RA containing four plausible candidate genes, encoding peptidylarginine deiminases, which posttrans-lationally modify arginine to citrulline. RA is strongly associated with the development of ACPA even before the onset of clinical disease, suggesting that citrullination could be an important etiologic factor. Strong evidence for association with PADI4 in Japanese (P = 0.000008) has been presented although the association appears very much weaker in other populations (87,88). It has recently been suggested that PADI4 polymorphisms par-ticularly predispose male smokers to RA (89).78.2.5.4 Genome-Wide Scans. With the introduction of GWAS, the number of genetic regions implicated in susceptibility to RA has grown rapidly. The landmark. study conducted by the Wellcome Trust Case Control Consortium (WTCCC) in 2007 examined cohorts of patients with a variety of common diseases, including 2000 RA patients, and 3000 controls (90). In addition to confirming the association of RA with HLA-DRB1 and PTPN22, nine novel SNPs with nominal association to the disease, and many others with modest association,

were identified. There is now compelling evidence for the involvement of dozens of regions in RA from GWAS, and meta-analysis of such data has substantiated 35 RA-risk loci in Caucasians of European origin, including HLA-DRB1, PTPN22, CCR6, TNFAIP3, and STAT4 (91). The increased power afforded by meta-analysis has also led to identification of novel RA loci, such as CD40 (92), which was later validated in a UK study (93). Recently, the Gene Relationships Across Implicated Loci (GRAIL) method has been developed and employed to confirm many genetic associations including CD28 (94). GRAIL involves statistical mining of published abstracts to identify and prioritize genes from related biological pathways (95).

On the basis of the GWAS data, it has been demon-strated that certain combinations of alleles compound RA risk, similar to the case with HLA compound hetero-zygosity (e.g. OR ~21 in ACPA-positive individuals with the genotype HLA-DRB1 + PTPN22 + STAT4 + TRAF1/C5) (96). In addition, differential genetic associations within seropositive disease are emerging and may pro-vide insights into pathogenesis; for example, PTPN22 was recently found to associate primarily with ACPA positivity, while HLA-DRB1 is associated with both RF and ACPA (97).

Most of the identified genetic associations are with seropositive RA; seronegative RA may represent a patho-genetically distinct disease and further studies on this cohort are warranted. Similarly, the majority of stud-ies have been conducted in populations of European origin. To address this, a meta-analysis and replication study was performed in the Japanese, which identified nine novel associations reaching genome wide signifi-cance (p < 5 × 10−8), including PTPN2, CD83, NFKBIE, ANXA3, ARID5B, B3GNT2, CSF2, PDE2A-ARAP1, and PLD4 (98). Although a multiancestry comparative analy-sis of Japanese and European RA heritability indicated a high degree of overlap, the differential contribution of PADI4 to RA risk (see Section 78.2.5.3) demonstrates the need for GWAS in all ethnic populations (98).

It is interesting that many genetic variants conferring RA risk are associated with multiple autoimmune or inflammatory diseases, e.g. STAT4 (SLE, type 1 diabetes, inflammatory bowel disease), TRAF/C5 (SLE, JIA), and the chromosome 6q23 locus (SLE, type 1 diabetes, celiac disease) (99). A recent meta-analysis identified eight non-HLA-risk loci common to both celiac disease and RA, bringing the number of shared loci to 14 (100). Seven of these genes are also common to type 1 diabetes (101). The themes of these common risk alleles include innate immunity (e.g. TRAF/C5), T-cell differentiation (STAT4), and T-cell signaling (PTPN22) (102). It has been postu-lated that the unique and dominant HLA associations result in presentation of disease-specific autoantigens to T cells; the common non-HLA risk determinants may in turn influence the response of the immune cells to these autoantigens (100). In many cases, additional work is

flammatory Arthropathies
10 CHAPTER 78 Rheumatoid Disease and Other In
required, including fine mapping or deep resequencing of the genetic regions of interest, to precisely identify the causative allelic variants underlying the SNP associa-tions (99). An example is the association of RA with SNP rs6920220 on chromosome 6q23, positioned between the TNFAIP3 and OLIG3 genes (103). Subsequent fine mapping determined that there are actually three RA risk alleles within this region, one of which confers protec-tion (104). The functional and pathogenic significance of these allelic variants also require further study.

Despite these advances, more than 50% of the genetic contribution to RA remains unexplained. This may be due to as yet unidentified rare genetic variants with large effect, or large numbers of risk alleles of small effect not yet identifiable reliably by current methods (98). The expectation that copy number variants (CNVs) would represent a significant proportion of human disease risk was recently largely discounted; a large GWAS covering approximately half of the genomic CNVs >500 bp found no association with eight common diseases (105). Fur-ther large-scale association studies with saturation map-ping of the relevant loci are currently nearing completion and should further advance the field in the near future.78.2.5.5 Genetic Models and Pathologic Mecha-nisms. The shared epitope hypothesis put forward to explain the disparate HLA-DR associations with RA (106) implies the presentation of a single or limited range of potentially arthritogenic peptides by antigen- presenting cells within the joint to a subset of T lym-phocytes capable of initiating a specific inflammatory response. This would most obviously produce a domi-nant model of susceptibility, but several studies have cast doubt on this, suggesting that the involvement of HLA genes fits best with a recessive model (75,107). The hypothesis of HLA-DQ-mediated susceptibility would fit with this model (65) as would the role of the HLA genes in shaping the T-cell receptor repertoire by posi-tive and negative thymic selection. Another possibility invokes molecular mimicry between the shared epitope on rheumatoid-associated DR molecules with potential triggering pathogens although firm evidence for this has not been forthcoming, and such cross-reactive immune responses have not routinely been observed.

Early reports using PCR to detect expanded T-cell populations, particularly in the rheumatoid synovial

compartment, were somewhat suggestive of an antigen- or superantigen-driven response (108). Although numer-ous subsequent studies have sought such oligoclonal expansions in patients with RA, there seems little consis-tency between individual studies to support such an idea (24,109,110). This contrasts with some interesting data in reactive arthritis and psoriatic arthritis (111,112).

The association with HLA-DRB1 variants and RA suggests that engagement of specific immune responses is important at some stage in the development of the dis-ease. It is well known that additional signaling through costimulatory molecules in this “immunologic syn-apse” is critical to this process. Interactions between the CD80/86 molecules on antigen-presenting cells and their potential ligands on T cells (CD28 or cytoxic T lympho-cyte associated antigen-4 (CTLA-4)) play an important role in determining activation. Variation in CTLA-4 is involved in susceptibility to autoimmune diabetes mel-litus and thyroiditis. A large collaborative study from Sweden and North America suggests that there is also a weak association (OR 1.2) with RA (113). It is cer-tainly of interest in this context that the fusion protein CTLA4Ig has impressive disease-modifying effects in RA (114). Other components of the immunologic synapse are potential candidates in the etiology of the disease. For example, CD28 is also associated with RA (94) and there is weak evidence that the inhibitory product of the programmed cell death 1 gene (PDCD1) may also be involved (115).

A list of the major genetic effects in RA identified to date is shown in Figure 78-4. Major challenges remain in the identification of all the major genetic effects in RA, particularly those attributable to rare alleles. Even weak genetic influences could herald the identification of crucial pathogenic pathways and the means to modulate them.

78.2.6 Management

About half of patients presenting with early undifferen-tiated polyarthritis have self-limiting disease, but only 15% of patients fulfilling criteria for RA go into remis-sion (116). In those with persistent arthritis, agents that modify the course of the inflammation are required. These include sulfasalazine, methotrexate, antimalarials,

WTCCC2 CD40 REL Common CC121 BLK + CD244 TAGAP S1AE Rare variantsPIP4K2C CD28 SPRED2 DDX6 implicated IL2RA TRAF6 RBPJ CD247

TNFA1P3 PRKCQ PTPRC CCR6 UBE2L3 HLA-B

Shared STAT4 IL2RB FCGR2A IRF5 UBASH3A HLA-DR

Epitope PTPN22 TRAF1/C5 AFF3 PRDM1 PXK SH2B3 HLA-DP

HLA-DR4 Hypothesis PAD14 CTLA4 IL2-IL21 TNFRSF14 CD2/CD58 IL6S 8q24.2

17q12

_________________________________________________________________________________________________________________________________

1978 1987 2003 2005 2007 2008 2009 2010 2011 2012

FIGURE 78-4 Progress in the identification of genes involved in rheumatoid arthritis.

CHAPTER 78 Rheumat

gold salts, d-penicillamine, azathioprine, and lefluno-mide (often used in combination). Corticosteroids (either in low doses orally or as intramuscular pulses) may be used in the early phases of the disease to suppress inflam-mation and erosive damage as second-line drugs are com-menced (117). From the early 1990s, the treatment of the more severe forms of RA changed dramatically with the introduction of anti-TNF biologic agents (118,119). In clinical trials recruiting patients with very active disease, these drugs routinely induced remission in a quarter of patients within 3 months. Further, they could be shown to completely suppress the progression of erosions. Quite suddenly, it became unacceptable for rheumatologists to aim for anything less than complete suppression of the disease. This stimulated the use of combinations of the older disease modifying anti-inflammatory drugs, such as methotrexate, sulfasalazine and leflunomide, and if these failed to suppress the disease adequately, escalation to biologic therapies would follow. This has had a profound knock-on effect in the clinical practice of rheumatology with the development of sophisticated clinical and imag-ing tools to assess the degree of residual disease activ-ity and the presence of potentially destructive synovitis. Patients are now treated much more aggressively early in the disease to prevent irreversible structural joint dam-age. Good responses to anti-TNF therapy can be antici-pated in the majority of patients with ACR 20%, 50% and 70% responses being achieved within 3 months by 60%, 40% and 20% of patients with substantial disease activity before treatment (DAS28 ≥ 5.1). In those failing anti-TNF therapy, other options with broadly compa-rable efficacy include rituximab, an anti-CD20 mono-clonal antibody B-cell depleting agent (120), tocilizumab (anti-IL6 receptor monoclonal antibody), and abatacept (recombinant CTLA4/immunoglobulin fusion protein).

Even with the improved therapeutic armory, effective management of RA still requires a coordinated approach by a multidisciplinary team because of the chronic nature of the condition. The primary objectives are the relief of pain and preservation of function. A combination of drugs, physical therapy, orthotics, and appliances to pre-vent or accommodate increasing long-term disability will be required. Surgical intervention is frequently needed at some stage in the course of the disease, but requires care-ful planning, particularly in patients with more severe forms of the disease, who may require many procedures.

The development of reliable methods of total joint replacement, particularly in the large weight-bear-ing joints of the hip and knee, has otherwise been the most important single development in the treatment of patients with RA. Good results from both hip and knee replacement can be anticipated in more than 90% of patients, and, typically, the prosthesis will last for 15 years or more. Subluxation of the cervical spine is rela-tively common, particularly in patients with severe ero-sive disease, and may require surgical stabilization. The median standard mortality ratio for RA is approximately

oid Disease and Other Inflammatory Arthropathies 11

1.5 compared with the general population (121), mainly from infection and cardiovascular disease. Only half of this can be attributed to classic risk factors such as smoking, hyperlipidemia and hypertension, all of which should be tightly controlled.

78.3 SERONEGATIVE SPONDYLOARTHROPATHIES

The term seronegative spondyloarthropathy (SpA) refers to a group of inflammatory conditions characterized by inflammation of the entheses (sites of mechanical stress where ligaments or fibrocartilage interface with bone, e.g. sacroiliac joints). In contrast to RA, RF and ACPA are absent. These two characteristics differentiate these conditions from the somewhat more common RA, which is characterized pathologically by synovitis rather than enthesitis and in which RF is present in 85%.

Other features of SpA include an association with the MHC class I gene HLA-B*27; characteristic distribu-tion of joint involvement with prominent axial, sacro-iliac, and asymmetric lower limb peripheral large-joint arthritis; characteristic extra-articular features, particu-larly uveitis; and the formation of new bone at the site of inflammation, eventually leading to ankylosis. By con-trast, seropositive RA is associated with the class II HLA-DRB1 genes, typically causes a small-joint symmetrical polyarthritis, has a different range of extra-articular fea-tures, and causes erosion of cartilage and bone rather than ankylosis.

Several forms of SpA are described:

1. Ankylosing spondylitis 2. Reactive arthritis 3. Enteropathic arthritis (associated with inflammatory

bowel disease) 4. Psoriatic arthritis.

Some patients with SpA fail to meet the criteria for any of these individual diseases and are said to have “undifferentiated spondyloarthritis.” The features that distinguish these conditions from one another are pre-sented in Table 78-4.

78.3.1 Diagnostic Criteria

A variety of diagnostic criteria have been proposed for AS (122–124), reactive arthritis (125), and psoriatic arthri-tis (126,127). Criteria for AS have historically relied heavily on the presence of radiographic sacroiliitis for diagnostic specificity. As there is a mean delay of 9 years between the onset of symptoms and the development of radiographic changes, the sensitivity of these criteria in early disease is poor (128). These criteria have also been criticized for being too restrictive as they exclude a sig-nificant group of patients with clear features of SpA, but who do not clearly fit into any of the currently defined disease groups. In response to these shortcomings, the


TABLE 78-4 Clinical Features of the Spondyloarthropathies

Ankylosing Spondylitis

Reactive Arthritis

Psoriatic Spondyloarthritis

Enteropathic Spondyloarthritis

Sex M > F M > F F > M M = FAge of onset (yr) 15–35 Any age Any age Any ageUveitis ++ ++ + +Conjunctivitis — ++ — —Urethritis — ++ — —Skin involvement — ++ ++ —Mouth ulcers — ++ — +Sacroiliitis +++ ++ ++ ++Peripheral arthritis Lower > upper Lower > upper Upper > lower Lower > upperSpinal symmetry +++ + + ++Enthesopathy ++ ++ ++ ++Aortitis + + ?+ +HLA-B*27 (%) 95 80 50 50Risk for B*27-positive 2–8 10–20 Unknown Unknown individual (%)Self-limiting — ++ — —

—, rarely; ++, occasional; ++, frequent; ++++++, always.

Assessment of Spondyloarthritis International Society (ASAS) has developed criteria based on clinical features and magnetic resonance imaging (MRI), which are much more sensitive at picking up early disease (129). As dis-cussed later, a combination of simple screening questions designed to identify inflammatory back pain combined with HLA-B*27 testing and the use of MRI to detect sac-roiliitis, can have a considerable impact on the diagnosis of early disease. Early diagnosis is of increasing impor-tance since the advent of anti-TNF treatment, which can have life-changing efficacy in those with AS.

78.3.2 Ankylosing Spondylitis

78.3.2.1 Epidemiology. The most widely used diagnostic criteria for AS are the modified New York criteria (Table 78-5). Those are heavily reliant on the presence of radiographic evidence of sacroiliitis, which may take several years to develop. MRI allows much earlier detection of sacroiliac joint abnormalities, particularly active inflammation, and is the imaging technique of choice for early diagnosis (130). AS typically develops in early adulthood, with more than 90% of cases diagnosed before the age of 40 years. There is typically considerable delay in diagnosis, particularly in females among whom atypical patterns of joint involvement appear to be more common. Overall, men are also more commonly affected than women (ratio ~2.8:1). Estimates of the prevalence of AS in western Europe and North America vary between 0.05% and 1.4%, depending on study methodologies. Recent studies from Berlin suggest a prevalence of around 0.5%.

What is not in doubt is that the prevalence of AS roughly parallels the prevalence of the main susceptibility factor, HLA-B*27, in different populations (126). Thus a high prevalence of AS is found in some populations,

including North American Indians (B27 prevalence, 18–50%), Norwegian Lapps (25–30%), and Alaskan Eskimos (25–40%). Populations with a low prevalence of HLA-B*27, including most sub-Saharan African eth-nic groups, Australian Aborigines, and South American Indians, have correspondingly low prevalences of AS. However, the relationship is not simple since other envi-ronmental and genetic factors play a significant role in the etiology of the disease. HLA-B*27 itself is polymorphic, and there is considerable interest in the possibility that allelic differences may be responsible for different degrees of disease susceptibility associated with the B27 subtypes (see Section 78.3.2.4.1).78.3.2.2 Pathology. As in all spondyloarthropathies, the basic pathologic lesion of AS is enthesitis. Entheses represent specialized areas of bone adapted to cope with stress loading at interfaces with ligaments or fibrocarti-lage. Entheses have large vascular beds and are the site of relatively high connective tissue metabolic activity, and are thus vulnerable to the effects of inflammation. Plas-macytic and lymphocytic infiltrates are seen. Localized

TABLE 78-5 Revised New York Criteria for Ankylosing Spondylitisa

Low back pain ≥3 months’ duration (improved by exercise and not relieved by rest)

Limited back movement (sagittal and coronal)Reduced chest expansion (compared to age- and sex-matched

values)Bilateral sacroiliitis (grade ≥2)Unilateral sacroiliitis (grade ≥3)

aAnkylosing spondylitis is diagnosed if significant radiographic evidence of sacroiliitis is present along with one or more clinical criteria.Modified from van der Linden, S.; Valkenburg, H. A.; Cats, A. Evaluation of Diagnostic Criteria for Ankylosing Spondylitis: A Proposal for Modification of the New York Criteria. Arthritis Rheum. 1984, 27, 361–368.

CHAPTER 78 Rheum
osteitis and osteoporosis occur initially. Later granula-tion tissue forms, fibrosis occurs, and reactive new bone formation begins. This process may continue until anky-losis occurs across the involved joint. Analogous changes occur at the attachment of the joint capsule to periarticu-lar bone.

Although entheses and fibrocartilagenous joints are primarily affected, inflammation sometimes also involves synovial joints. In some patients, AS may even present as peripheral arthritis involving synovial joints. Eventu-ally approximately 20% of cases develop significant hip arthritis, and involvement of the zygapophysial joints is universal. Synovial tissue from these joints shows changes similar to RA, although typically less severe. There is villous hypertrophy, synovial cell hyperplasia, and lymphocytic, plasmacytic, and histiocytic infiltra-tion. The cellular infiltrate is diffuse, but also shows some perivascular aggregation. Although the disease is charac-terized systemically by raised immunoglobulin (Ig)A lev-els, plasma cells in the synovium secrete principally IgG. Attention has recently been drawn to the high proportion of CD4 T cells expressing the killer immunoglobulin-like receptor KIR3DL2 and their production of IL-17 (231). The synovial fluid contains fewer polymorphs and more lymphocytes than rheumatoid synovial fluid (131).

The earliest changes detectable by imaging are bone marrow edema of the sacroiliac joints (Figure 78-5) and osteitis at the vertebral corners of the spine (Figure 78-6) on fat-suppressed MRI, which reflect underlying inflam-mation. On plain radiographs, the earliest changes are sclerosis and erosions in the juxta-articular bone, but these may take years to develop. In the sacroiliac joints, erosions are seen as irregular variations in the width of the sacroiliac joint space and loss of clear definition of the joint line. This is usually most obvious in the inferior iliac aspect of the synovial component of the joint. Late

FIGURE 78-5 Tilted coronal STIR MRI of sacroiliac joints showing bone marrow edema (high signal) before (A) and after (B) anti-TNF therapy.

disease is characterized by new bone formation under-neath inflamed periosteum; this is reflected on plain radiographs by “squaring” of the vertebral bodies (loss of the normal concave anterior surface) and the presence of syndesmophytes. In the sacroiliac joints, radiographs demonstrate periarticular sclerosis and later ankylosis. MRI scans may also show fibrosis and fatty replacement of the periarticular bone marrow but are inferior to plain radiographs in demonstrating the extent of new bone growth (syndesmophytes) (Figure 78-7).78.3.2.3 Other Clinical Features. Osteoporosis is com-mon in AS, often from an early stage (132–134). Spinal fractures are common in advanced disease (135), reflect-ing both increased bone fragility and reduced flexibility. The eye is the most common extraskeletal site of involve-ment in AS. Anterior uveitis (involving the structures anterior to the lens—the iris and ciliary body) occurs in around 40% of cases of AS and 5–10% of cases of reac-tive arthritis (136). It runs a relapsing/remitting course, is usually easily treated with cycloplegics and topical steroids, and is rarely sight-threatening unless neglected.

FIGURE 78-6 “Shiny corners” demonstrated on sagittal STIR MRI of the thoracolumbar spine due to osteitis in ankylosing spondylitis.

FIGURE 78-7 Florid syndesmophytes contributing to the appear-ance of a “bamboo spine” in long-standing AS.

mmatory Arthropathies
14 CHAPTER 78 Rheumatoid Disease and Other Infla
Idiopathic anterior uveitis is also strongly associated with HLA-B*27 (95%) independent of AS.

Other uncommon overt extraskeletal manifestations of AS include cardiac and proximal aortic involvement by fibrosis and endarteritis. This rarely results in clini-cally significant reduction in left ventricular function. Heart block and aortic regurgitation due to dilation of the aortic valve ring are described and may be dramatic in onset. Standardized mortality rates are increased by about 50% in AS, much of which is due to the increased risk of cardiovascular disease. Pulmonary involvement is predominantly mechanical because of the fusion of the costovertebral joints and thoracic kyphosis, reducing vital capacity. AS is occasionally complicated by upper lobe pulmonary cavitation or fibrosis (~1% of cases), which is usually of little clinical significance but may need to be distinguished from pulmonary tuberculosis or aspergillosis.78.3.2.4 Genetic Studies. A major role for genetic factors in the etiology of AS is emphasized by the high recurrence risks for AS among close relatives of patients (126,137). Several relatively small twin studies have sug-gested a significant genetic component to AS. The larg-est study, undertaken in the UK, estimated monozygotic twin concordance at 75% compared to only 12.5% of dizygotic twins. Even in B27-concordant dizygotic twins, concordance for AS was only 27%. Variance modeling using these data suggests that broad sense heritability for AS is in excess of 92%, and that HLA-B*27 accounts for less than half of the genetic contribution (138). Envi-ronmental factors are probably important but are very common or ubiquitous, therefore playing little part in determining population variance. It has become increas-ingly apparent that the genetic contribution to AS is poly-genic. At least two HLA genes have already been clearly demonstrated to increase susceptibility to AS. HLA-B*27 was the first in 1973 (139,140). Subsequently, HLA-B*60 has also been shown to be associated with AS in both B27-positive and -negative individuals (141,142), although this has not been a universal finding (143,144). Our results from a large UK survey suggest that HLA-B*60 is associated with a two- to threefold excess risk (145).

78.3.2.4.1 HLA-B*27. In the United Kingdom, more than 90% of patients with AS carry HLA-B*27 (relative risk ∼160), but only 2–8% of B27-positive individuals develop AS. The incidence of reactive arthritis (see Section 78.3.3) following bacterial enteritis may be as high as 20% in B27-positive individuals, who are also at increased risk of subsequent AS. The fact that relatively few B27-positive individuals develop B27-related diseases probably reflects the role of other genes, rather than the environ-mental exposure.

There are at least 70 different HLA-B*27 alleles, differing from one another by between one and eight amino acids, which have evolved from the ancestral HLA-B*2705 subtype (146). Different ethnic groups

have distinct subtype distributions. In most white popu-lations, more than 90% of B27 alleles are HLA-B*2705 and the remainder almost entirely HLA-B*2702.

Association between AS and most HLA-B*27 sub-types has been described, at least sporadically, (par-ticularly HLA-B*2702, *2704, and *2705), although systematic studies have not always been possible because of the rarity of some subtypes, such as HLA-B*2701, *2707, and *2708. There has been particular interest in two subtypes (B*2703 and *2709) that appeared to be less obviously associated with AS. Early suggestions that the HLA-B*2703 allele might not be associated with AS were based on the relatively high frequency of this allele in The Gambia where, nonetheless, AS is extremely rare (147,148), although sporadic cases of the disease in B*2703-positive individuals have been reported in neigh-boring Senegal. Approximately 50% of the B27-positive individuals in The Gambia carry the most common white subtype, HLA-B*2705, which is positively associ-ated with disease in all other populations studied so far. Despite this, AS is vanishingly rare in The Gambia, per-haps suggesting the influence of other protective genetic or environmental effects in this population. In Europe there is good evidence from Sardinia that HLA-B*2709 is protective against AS (149).

As a diagnostic test, HLA-B*27 has a low positive pre-dictive value, unless the patient already has a moderately high prior probability of disease. When the pretest prob-ability of spondylitis is 0.5, the presence of B27 increases the likelihood of the disease to 0.92, whereas a negative result reduces it to 0.08 (150). When the prior probabil-ity is low (e.g. in population screening programs), the main use of the test is its negative predictive value. In the clinical situation of early SpA with a suspicious his-tory and examination but normal radiographs, a positive B27 test increases the probability from as low as 0.12 to only slightly greater than chance (0.62), adding very little to the clinical decision-making process (151). Rudwaleit et al. have developed a very useful algorithm for the diagnosis of early AS, based on simple clinical questions to identify inflammatory back pain, HLA-B*27 typing and MRI of the spine (Table 78-6) (152). The other set-ting in which B27 tests may be useful, is in determining the likelihood of the offspring of patients developing AS themselves. The pretest probability here is only 0.1, and positive testing for B27 increases this to only 0.2. A nega-tive result makes it highly unlikely that the individual will develop disease and may in some circumstances be reassuring and justified.

Many theories have been proposed to explain the asso-ciation with HLA-B*27, but none is universally accepted (153). Doubts about whether HLA-B*27 itself was directly involved or whether it was a marker for a nearby linked gene have been resolved. Transgenic HLA-B*27-positive rats have proved susceptible to an SpA-like con-dition, albeit one in which inflammation of the bowel, psoriasiform skin lesions, and orchitis are prominent in

toid Disease and Other Inflammatory Arthropathies 15
CHAPTER 78 Rheuma
addition to peripheral arthritis (154). Although these rats only develop disease if a relatively high copy number (>10) of the B*27 transgene is present, no other gene is inserted and control animals do not express disease with high copy numbers of other HLA class I alleles (155). Some doubts remain about the relevance of the model to human disease, but further insights could come from study of this or other animal models (156). For example, the genetic background of the transgenic animal influ-ences susceptibility; Dark Agouti strains of rat transgenic for HLA-B*27 are susceptible, but this is lost when they are backcrossed with other strains. Rats bred in sterile conditions also fail to develop the disease, consistent with the hypothesis that exposure to common bacteria or even gut commensal organisms might trigger disease. It has also been suggested that cell-surface expression of HLA-B*27 may not be necessary for the development of SpA since β2-microglobulin knockout mice (β2m−/−) can develop disease (β2m is necessary for the stability of the B27 heavy chain (HC), with which it noncova-lently associates) (157). Suggestions that presentation of B27-derived peptides by HLA class II molecules could account for this observation seem unlikely because class II knockouts can also get disease. Molecular mimicry has been expounded as a plausible theory for many years as the description of antibodies cross-reacting between Klebsiella species and HLA-B27. Initial reports of an increase in Klebsiella carriage in the stools of patients with active AS have not been reproduced, and such

TABLE 78-6 Assessment of SpondyloArthritis International Society (ASAS) Classification Criteria for Axial Spondyloarthropathy 2009 (152)

In patients with age at onset of symptoms <45 years and back pain ≥3 months

EITHER 1. Sacroiliitis (active inflammation on MRI/X-ray changes per modi-

fied New York criteria) 2. PLUS at least one SpA feature from:

a. Inflammatory back painb. Arthritisc. Heel enthesitisd. Uveitise. Dactylitisf. Psoriasisg. Inflammatory bowel diseaseh. Good response to NSAIDsi. Family history of SpAj. HLA-B*27k. Elevated CRP

OR1. Positive for HLA-B2*7 PLUS at least 2 SpA features

Adapted from Rudwaleit, M.; van der Heijde, D.; Landewe, R., et al. The Development of Assessment of SpondyloArthritis International Society Clas-sification Criteria for Axial Spondyloarthritis (Part II): Validation and Final Selection. Ann. Rheum. Dis. 2009, 68, 777–783.

cross-reactive antibodies seem unlikely to account for the tissue specificity of AS. Most likely, the role of HLA-B*27 in antigen presentation plays an important part. In common with other HLA class I molecules, HLA-B27 binds antigenic peptides (typically 9-mers) derived from self-proteins and presents them to CD8-positive T lym-phocytes for immune surveillance. Viral and tumor anti-gens are particularly detected in this way. Precisely how HLA-B*27-associated antigens might trigger the disease is not clear, but CD8-positive T cells with specificity for organisms have been identified in the joints of patients with reactive arthritis (158). In contrast to other class I molecules, HLA-B27 can exist in atypical forms. B27 can form homodimers (B272) that are not associated with β2m, through a disulfide bond between Cys67 resi-dues (159). How these homodimers induce AS remains unknown. They are known to be expressed at the cell surface, and may be involved in aberrant antigen presen-tation or in triggering the innate immune system (160). Conditions that may increase the chances of B272 forma-tion include peptide deficiency; excess HCs, as seen in the B*27 transgenic rat (161); or β2m deficiency, seen in the B*27 transgenic β2m−/− mouse (162).

The possibility that other genes within the MHC, in addition to HLA-B*27 and HLA-B*60, play a role remains somewhat controversial. Weak associations with HLA-DRB1*01 (OR 1.5; 95% confidence interval, 1.1–2.0), and the possibility that there is an extended B*27 haplotype containing another relevant locus have been suggested (163,164); however, subsequent data from large-scale GWAS do not lend much support.

78.3.2.4.2 Other genes. Since genetic predisposi-tion to AS is polygenic and B27 accounts for less than half of heritability, it is reasonable to screen the remain-der of the genome for susceptibility candidates. In 1998, we published our initial genome screen on 120 affected sib-pairs in 105 families (165,166). Linkage with HLA was confirmed, but six other regions outside the MHC showed some evidence of linkage, with LOD scores of >1.00. The peak non-MHC linkage was on chromo-some 16q (LOD = 2.6). Nominal linkage to the CYP2D6 microsatellite on chromosome 22 was found, and sub-sequent linkage and association studies with intragenic CYP2D6 markers have also proved positive (167). This gene (otherwise known as debrisoquine hydroxylase) is one of the cytochrome P-450 enzyme complex genes. The poor metabolizer phenotype is found in 6% of the UK population, but how this might contribute to the eti-ology of AS is unclear.

Initial attempts to identify non-MHC genes using linkage analysis of affected sib-pair pedigrees met with only limited success. Subsequent meta-analysis of all published studies of linkage analysis was undertaken, which confirmed highly significant linkage to the MHC (p < 3 × 10−7) but also suggested linkage (p < 7.4 × 10−4) to regions on chromosome 6q, 10q and 16q. Several other regions including the IL-1 gene cluster on chromosome


2 showed moderate evidence of linkage. The λ (LOCUS) value for the MHC was 4.5, suggesting that it accounted for around 34% of the familiality of AS.

GWAS have rapidly supplanted linkage analysis in identifying genetic effects in AS, building on the work of the WTCCC in other polygenic diseases including RA. In AS, two major international consortia have been established for these studies with sufficient power to reli-ably identify genes increasing the risk of AS by around 5–10%. First, the Triple A (Australo-Anglo-American) Spondyloarthritis Consortium (TASC) and second, the International Genetics of AS (IGAS) consortium have generated samples of up to 13,000 cases for analysis. This has resulted in major genetic discoveries.

In 2007, TASC and WTCCC reported the results of a limited gene-targeted GWAS of 15,000 nonsynonymous single nucleotide polymorphisms (ns SNPs) in 1000 cases (103). The association with the MHC was con-firmed (OR ~ 120, p < 10−120) as expected. Outside the MHC, the most striking association was with ERAP1, encoding the endoplasmic reticulum aminopeptidase 1 (p ~ 10−6), which was subsequently replicated in an independent data set. Numerous SNPs in ERAP1 were associated with AS; rs30187 encoding K528R was asso-ciated with an OR of 1.3 (p ~ 10−9). This association has been robustly replicated in several further studies (2,168–170), including a relatively large GWAS in Han Chinese (n = 3937) in which the strongest association was also with rs30187 (p < 7 × 10−4) (171). In this study, the other interesting observation was of weak associa-tion (p < 1.7 × 10−3) with IL23R, encoding the IL23 receptor expressed by a subset of CD4 lymphocytes pro-ducing the cytokine IL17, known as T helper 17 (Th17) cells. IL23R is of particular interest because it is also associated with Crohn’s disease and psoriasis, two con-ditions that are known to be overrepresented in patients with AS. This association was replicated in an indepen-dent data set and subsequently in an independent UK study and meta-analysis of previously published stud-ies (168,170,172). The coding SNP rs11209026 is most strongly associated with AS (OR = 0.61, p < 10−10) as in Crohn’s disease.


A subsequent GWAS reported by TASC in 2010 con-firmed the association with the MHC, ERAP1 and IL23R but, in addition, identified several new associations (170). This study was more heavily powered than pre-vious studies, comparing 2053 unrelated subjects with AS with 5140 ethnically matched controls. Cases were genotyped for 370,000 SNPs on the Illumina HumHap 370 genotyping platform and independent replication of positive results was undertaken in a further 898 cases and 1518 controls. Strong association was observed with two “gene deserts” on chromosomes 2p15 (p < 10−19) and 21q22 (p < 10−9) and also the genes ILIR2 (the decoy receptor for IL1) and ANTXR2 (encoding a receptor for anthrax toxin, but also functioning as a capillary growth factor). The region of chromosome 2p15 was again repli-cated in Han Chinese (171) with the marker rs10865331 most strongly associated (p = 2 × 10−8).

Several major breakthroughs in our understanding of the genetic basis of AS have recently been made. These relate in particular to the likely role of ERAP1, the key role of the Th17 lymphocyte development pathway and the overlap between AS and other inflammatory disor-ders, including psoriasis and inflammatory bowel dis-ease. In 2011, the TASC and WTCCC published the results of another large GWAS, in which a discovery set of 3023 cases of European ancestry were genotyped on the Illumina 660W-Quad microarray and compared with 8779 controls. A limited replication study of the top 50 “hits” was then undertaken in an independent set of 2111 cases and 4483 controls (2). The major find-ings are included in Figure 78-8. Of particular interest was the observation that the association with ERAP1 was limited to the B27-positive subset of patients, con-trasting with the B27-negative minority (~9%) in whom no such association was apparent. Other associations, such as IL23R, were not influenced by HLA-B*27 status of the patients. It is therefore clear that there is synergy between HLA-B*27 and ERAP1 in susceptibility to AS. This most likely reflects a role for ERAP1 in trimming peptide antigens in the endoplasmic reticulum to optimal length (eight or nine amino acids) for binding to HLA class I molecules, including HLA-B27. The solution of

HLA-B*27 HLA-B*60Structure

of HLA-B*27

1q32

2p15

21q22

CMG2

IL1R2

CARD9

STAT3

RUNX3

PTGER4

TBKBP1

TNFRSF1A

IL12B

ERAP1/B27

synergy

Structure

of ERAP1

WTCCC2

ERAP1

IL23R

1973 1989 1991 2007 2010 2011 FIGURE 78-8 Manhattan Plot showing association of AS with ERAP1 in (A) all patients, (B) B27-positive patients, and (C) B27-negative patients.


the crystal structure of ERAP1 at around the same time presented a structural basis for the understanding of this function of ERAP1. Furthermore, we were able to show that particular variants associated with protection against AS, such as K528R (rs30187), showed signifi-cantly reduced peptide processing characteristics (3). At least in theory, this would suggest that small molecule inhibitors of ERAP1 could be of value in the treatment or prevention of AS. The role of Th17 lymphocytes in AS is highlighted by the associations of a number of genes involved in this pathway (2,173). These include not only IL23R (expressed on Th17 lymphocytes) but also IL12B (encoding the common p40 chain of IL23 and IL12) and STAT3 (a key transcription factor for Th17 lym-phocytes). Similar associations are seen in both psoriasis and inflammatory bowel disease, highlighting the shared genetic predisposition of these conditions (Chapters 150 and 68). Other associations include the transcrip-tion factor RUNX3, which is involved in lymphocyte differentiation, which is driven by IL-7. In this respect, it is interesting that we have also observed a moderate association with the IL-7 receptor (8 × 10−5). The lat-est TASC/WTCCC study also shows a strong association with PTGER4 (prostaglandin E receptor 4), which is also associated with Crohn’s disease. Prostaglandin E2 acts through this receptor to induce the production of IL23 and IL17, both of which are elevated in AS. Synovial lev-els of PTGER4 are increased in spondyloarthropathies. Of interest, β-glucan, a component of certain fungal and bacterial cell walls, induces PGE2 through interactions with components of the innate immune system, includ-ing CARD9 that is also associated with AS (174). This would be consistent with the hypothesis that AS might be induced by ubiquitous organisms carrying β-glucan by stimulation of the Th17 pathway. PTGER4 is also part of the anabolic bone response to stress. Its expression is increased in the synovium of those with spondyloar-thropathies and this could potentially explain the new bone formation at sites of mechanical stress (entheses) in AS. These associations and doubtless many more will be further refined by the current IGAS consortium “Immu-noChip” experiment nearing completion in 2012. This will study known and candidate genes of inflammatory/immunological importance in 13,000 individuals glob-ally and is likely to increase the number of target genes and pathways for study substantially.78.3.2.5 Management. Pain relief and minimization of disability are the major aims of treatment. Physical exercises to maintain flexibility of the axial skeleton and good posture must be undertaken regularly, if necessary, under the supervision of a physiotherapist, since the ben-efit of intensive exercise regimens in hospital has been well recorded. Because of the likelihood of pronounced costovertebral joint involvement, lung function is often markedly reduced, and smoking should be strongly discouraged. Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually highly effective although there is

only very weak evidence to suggest that they have any effect on the underlying rate of paraspinal ossification. Continuous treatment may be more effective at prevent-ing new bone formation than on-demand therapy (175). Sulfasalazine and methotrexate are valuable for patients with active peripheral joint involvement but have no dis-cernable effect on the spinal disease. Likewise, cortico-steroids administered systemically are usually ineffective for spinal disease. In contrast, local injection of corti-costeroids may be very valuable for the management of peripheral joint synovitis and occasionally for costover-tebral joint disease and sacroiliitis. Management of active axial inflammation refractory to NSAIDs has been revo-lutionized by the demonstration that anti-TNF agents are highly effective in this condition (176). Whether these expensive drugs also retard the progression of joint ankylosis is as yet unknown. Promising results were dem-onstrated in early trials of anti-IL17 therapy in active AS, but larger studies are awaited. Uveitis is common (up to 40%) and is usually responsive to topical corticosteroids and mydriatics. Osteoporosis is recognized as a relatively early complication of the condition and may contribute to spinal deformity if wedge fractures occur. Bone den-sitometry measurements in the lumbar spine may be misleading because of the presence of syndesmophytes, which may cause spuriously high values. Joint surgery, particularly hip and knee arthroplasty, may be required in about 10% of patients but is particularly likely in those with juvenile-onset disease. Finally, a range of aids for daily living may be required, ranging from prismatic spectacles to allow severely kyphotic individuals to see where they are going, through to adaptations to cars (particularly additional mirrors for all-around vision) and wheelchairs for those with extreme disability and handicap.

78.3.3 Reactive Arthritis (Previously Reiter Syndrome)

Classic reactive arthritis (previously Reiter syndrome) represents the triad of arthritis, conjunctivitis, and urethritis, developing after a triggering bacterial infec-tion; however, incomplete forms of this triad are more common.78.3.3.1 Clinical Features. Reactive arthritis usually develops between 1 and 3 weeks after a precipitating infection. The arthritis typically affects a few large lower limb joints asymmetrically. Diffuse swelling of fingers and toes, referred to as “sausage digits,” is typical of reactive or psoriatic arthritis. Axial skeletal involvement (particularly sacroiliitis), affects up to 50% of those affected, particularly those who are HLA-B*27 positive. Plantar fasciitis and Achilles tendonitis are common. Mild conjunctivitis commonly precedes the arthritis. Mucocutaneous involvement may include mouth ulcers, sterile urethritis, circinate balanitis, and keratoderma blennorrhagica (a rash resembling pustular psoriasis).


The illness can be very severe and associated with marked systemic features of fever, malaise, and weight loss. It runs a variable course depending on the nature of the triggering organism and host genetic factors. Many cases are extremely mild and last only a few days. For those with more sustained synovitis, the average duration is <5 months. About 15% proceed to chronic disease and about one quarter may develop recurrent episodes (177). Chronic arthritis is much more likely in patients who are HLA-B*27 positive, 20% of whom may ultimately develop AS. Patients with concurrent human immuno-deficiency virus (HIV) infection tend to develop more severe arthritis and are probably at greater risk of dis-ease because of increased exposure to the relevant genital tract pathogens.78.3.3.2 Epidemiology and Etiology. While environ-mental triggers and genetic susceptibility contribute to reactive arthritis, it is not known how these interact to cause arthritis. Between 68% and 85% of cases of reac-tive arthritis occur in B27-positive individuals, and, in epidemics of arthritogenic bacterial infections, approxi-mately 20% of B27-positive individuals will develop reactive arthritis.

Although the triggering bacteria cannot be cultured from the affected joints, there is reasonable evidence for the presence of bacterial proteins and nucleic acid in the joints (178). Cellular immunity to triggering bacteria has been demonstrated among both CD4- and CD8- positive B27-restricted T cells (158). These T cells are of the helper T cell type 1 subset of lymphocytes (179), which are thought to protect against intracellular infection. This seems appropriate as most arthritogenic pathogens are intracellular organisms, and it is consistent with theories suggesting a primary role for persistence of bacterial frag-ments within joints as the cause of reactive arthritis. The occurrence of reactive arthritis in face of CD4 lymphocyte depletion in HIV infection suggests that these cells are not critical in the development of the illness, in contrast with the situation in RA (in which the disease often improves as the CD4 lymphocyte count falls). Other theories implicate B27 itself as the autoimmune target, due to either molec-ular mimicry or loss of tolerance resulting from chemi-cal alteration of the molecule. Evidence that B27 may be associated with lesser protection against invasion by, and less-efficient clearance of, enteric bacteria provides a further possible explanation for B27-related arthritis.78.3.3.3 Management. Pain relief from the musculo-skeletal manifestations of reactive arthritis is the primary objective in non-persistent disease. Nonsteroidal anti-inflammatory drugs are commonly used but have only a moderate beneficial effect. Local steroid injections are appropriate for peripheral arthritis and enthesopathy and may need frequent repetition. Sulfasalazine, metho-trexate, and azathioprine have demonstrated beneficial effects and are appropriate to use in cases in which a protracted or recurrent course seems likely. Anti-TNF therapy may be effective in refractory cases. In cases of

presumed urogenitally acquired reactive arthritis, appro-priate cultures should be taken for Chlamydia and Neis-seria gonorrheae, as well as syphilis and HIV serology. Short courses of antibiotics are appropriate to clear any triggering infection, but there is also some evidence that longer courses of antibiotics may improve the late out-come of the arthritis (180).

78.3.4 Enteropathic Arthritis

Arthritis may complicate up to 10% of cases of inflam-matory bowel disease. It may affect the axial skeleton and/or peripheral joints and is approximately twice as common in Crohn’s disease as in ulcerative colitis. Axial arthritis occurs in 10–15% of individuals with inflamma-tory bowel disease, but the association of sacroiliitis with HLA-B*27 may be weaker (50–60%) in this group of patients than in those suffering from AS without inflam-matory bowel disease or psoriasis (~95%). These figures are heavily dependent on the means of ascertainment. For example, using a UK database of patients with known AS, we found the prevalence of HLA-B*27 to be 83% in those with spondylitis and bowel disease (181). It seems possible that limited sacroiliitis (frequently asymptom-atic) may be relatively common in inflammatory bowel disease, but HLA-B*27 increases the likelihood of devel-oping more extensive axial disease.

Peripheral arthritis exists in two distinct clinical forms that are also immunologically distinct (182). Both forms occur about twice as commonly with Crohn disease as ulcerative colitis. The type 1 arthropathy (self-limiting, pauciarticular, and associated with flares of the bowel disease) is positively associated with HLA-B*27, HLA-B*35, and HLA-DRB1*0103 but the type 2 arthropathy (polyarticular, symmetrical, persistent, and not related to activity of the bowel disease) is associated with HLA-B*44 (183). In view of the fact that AS has a high fre-quency of subclinical ileitis (184), it is interesting that peripheral arthropathy may predate the onset of clini-cally apparent inflammatory bowel disease by months or occasionally years. In type 1 arthropathy, the knees and ankles are most frequently affected, whereas in type 2 arthropathy, the metacarpophalangeal joints, wrists, and knees are most commonly affected.

78.3.5 Psoriatic Arthritis

Arthritis associated with psoriasis exhibits a considerable variety of clinical patterns and was only distinguished as a separate entity relatively recently (185). The arthropa-thy ranges through forms resembling RA to classical SpA. The extent to which these different expressions of psoriatic arthritis are under genetic controls is debatable since they do not appear to breed true in families with psoriatic arthritis (186).78.3.5.1 Epidemiology. Psoriasis itself occurs in 1–2% of whites with an equal gender frequency. Common


forms of arthritis may thus occur fortuitously with pso-riasis, without there being any causal relationship. Pso-riatic arthritis typically occurs in 7% of patients with psoriasis although frequencies of up to 42% have been reported in some series (187,188). Arthritis is particu-larly common where there is nail involvement, but it may predate the onset of skin lesions. Although it usually starts in the third or fourth decade, pediatric onset is also quite common (see Section 78.4).78.3.5.2 Pathogenesis. Inappropriate activation of the immune system appears to underlie both the skin and joint disease of psoriasis. In the psoriatic epidermis, keratino-cytes proliferate and mature rapidly, leading to deficient adhesion of corneocytes that causes the characteristic scales of the psoriatic skin plaques. Significant infiltration of both the skin and joint synovium by T cells suggests a role for specific antigen presentation. Exacerbation of the skin lesions by CD4 depletion and HIV and/or acquired immunodeficiency syndrome has been observed, while specific T-cell-targeted therapy (e.g. cyclosporin A) may be effective. Furthermore, the efficacy of T-cell-targeted biologic therapies (alefacept directed against CD2 and efalizumab against LFA-1) in around 50% of patients supports this concept although the latter has been with-drawn from the market over safety concerns. An impor-tant role for TNFα in skin and joint lesions is emphasized by the efficacy of anti-TNF biologics although this is a complex relationship as anti-TNF agents have also been reported to precipitate flares of skin disease.

In the synovial membrane, there is evidence of new blood vessel growth, and substantial increase in the amounts of transforming growth factor-β, platelet-derived growth factor, vascular endothelial growth fac-tor, and angiopoietins has been observed (189).78.3.5.3 Genetics. The genetic basis of psoriasis is pre-sented in detail in Chapter 150. The heritability of psori-atic arthritis is substantial with a recurrence risk among first degree relatives (λ1 = 30–55) and siblings (λs = 30) estimated to be at least threefold higher than in psoriasis (190,191). Evidence from linkage and association studies led to the designation of the major psoriasis and psoriatic arthritis susceptibility locus within the MHC as PSORS1 (MIM*177900). It has been shown to be primarily asso-ciated with type 1 psoriasis (onset <40 years of age), as no association was found in patients with psoriatic arthritis and late-onset psoriasis (192). The precise loca-tion of the PSORS1 risk allele is debated and is difficult to establish because of the extensive linkage disequilib-rium within the MHC region; possibilities include HLA-Cw*0602 (193) and the SNP rs10484554*T (194).

Several other HLA associations have been reported in the literature; however, dissecting the contribution to psoriatic arthritis risk from the contribution to psoriasis risk is complex. A recent study, including a significant cohort of psoriatic arthritis patients, analyzed HLA asso-ciations by logistic regression. Alleles specifically asso-ciated with arthritis independently of cutaneous disease

included HLA-B*27, B*08, and B*38 (195). Subgroup analysis demonstrated association of HLA-C*06 and HLA-B*27 with peripheral arthritis. HLA-B*27 was strongly associated with the development of sacroiliitis, and B*08, B*38, and B*39 were also associated with spondyloarthritis (195). Sacroiliitis is a common find-ing in patients with psoriatic arthritis; our survey of 105 unselected hospital outpatients showed abnormalities on MRI in one-third, but these were frequently asymptom-atic (196). In psoriatic spondyloarthritis, the association with HLA-B*27 is less strong (50–60%) than in the idio-pathic forms of AS (95%), and we postulate that it cor-relates with more severe forms of spinal involvement.

Non-HLA genes within the MHC region, which may contribute to psoriatic arthritis risk include MICA*002 (197), and the TNF promoter polymorphisms TNF-238A and TNF-857T (190), although the evidence is contradictory (190,198). An exploratory GWAS and replication study identified a single nucleotide polymor-phism (SNP) rs2395029, which confers psoriatic arthri-tis risk with a high OR (3.2). This SNP lies within the MHC class I gene HCP5 positioned between the MICA and MICB loci (194).

GWAS have demonstrated significant associations with non-MHC gene loci including IL23R, IL12B, TNIP1, and TRAF3IP2 (190,199). Significant associa-tions have also been linked with regions on chromo-some 4q27 containing the IL2 and IL21 genes, and to chromosome 15q21 (194). Suggestive associations that have not reached significance, although have been rep-licated, include IL13, IL21, NFKBIA, NFAIP3, NOS2, and FBXL19 (190). These associations hint at patho-genic mechanisms underlying PsA as they include genes encoding Th2 (IL13) and Th17 (IL12B, IL23R) cytokines and signaling pathways including multiple associations with NF-кB signaling (TNIP1, TRAF3IP2, NFKBIA, TNFAIP3, NOS2, FBXL19).

Children of affected fathers are more likely to develop psoriasis or psoriatic arthritis (16.2%) than children of affected mothers (8.3%) (200,201). Evidence for imprinting is supported by the association of psoriatic arthritis with a region on chromosome 16q, which only confers risk when conditioned on paternal inheritance (202). Prognostically, males with axial psoriatic arthritis are more severely affected than females, in the absence of any differences in HLA distribution (203). A higher risk of progressive or erosive arthritis is found in patients carrying HLA-B*39, HLA-DRB1*04, HLA-DQ3 with-out HLA-DR7, HLA-B*27 plus HLA-DR7, or the AA variant of the IL4 SNP rs1805010, while patients with the combination HLA-Cw*6 plus HLA-DRB1*07 have a better prognosis (204).

Approximately 75% of the genetic risk of psoriatic arthritis remains unidentified and further studies are required to identify risk alleles with smaller effect sizes, or indeed rare genetic variants conferring high risk (199,204). The emerging field of epigenetics will help to

elucidate how heritable pathways affecting gene expres-sion may influence clinical risk and disease phenotype.78.3.5.4 Clinical Manifestations. Classically, psoriatic arthritis has been divided into five subsets depending on clinical and radiographic criteria: (i) “classical” psoriatic arthritis, confined to the distal interphalangeal joints of the hands and feet (5%); (ii) arthritis mutilans (5%); (iii) symmetrical polyarthritis, resembling RA (15%); (iv) asymmetrical oligoarthritis (70%); and (v) spondylo-arthritis (5%) (205). Recent studies have demonstrated that the pattern of onset of peripheral arthritis does not predict outcome in most cases, supporting the develop-ment of classification criteria, in which all patients with peripheral arthritis are pooled together (206).

Dactylitis (sausage digits) is characteristic of reactive or psoriatic arthritis, occurring in more than one-third of patients. Achilles tendonitis and plantar fasciitis (both forms of enthesitis) are also common. Dystrophic nail changes, including pitting, ridging, discoloration, and onycholysis, are associated particularly with distal inter-phalangeal joint disease. Overall, approximately 80% of patients with psoriatic arthritis have nail changes, com-pared with only 20% of psoriatics without arthritis.

Psoriatic arthritis is often a benign illness, but severe joint damage is not uncommon. Patients may present with severe acute monoarthritis and marked constitu-tional symptoms, mimicking sepsis or reactive arthri-tis. Typically, an increasing number of joints become involved with time although there is little relationship between this and the severity of the skin disease. Arthri-tis mutilans, although rare, causes severe joint destruc-tion and disability. Axial disease is common but highly variable and tends to cause less functional impairment than in idiopathic AS. Compared to the “pure” form of AS, psoriatic spondyloarthritis also tends to be less symmetrical; radiographs may show non-marginal ori-gin of syndesmophytes (origin not from the anterolateral border of the vertebral end plate); radiographic changes may skip vertebral segments; atlantoaxial involvement is more common; and unilateral sacroiliitis is not unusual. In reality, these divisions into subgroups are somewhat arbitrary; of those patients with peripheral joint disease, probably one-third have evidence of axial disease on MRI, although this is commonly asymptomatic (196).78.3.5.5 Management. Nonsteroidal anti- inflammatory drugs similar to those used in RA are helpful for the peripheral joint arthritis. Intra-articular corticosteroids can be useful in peripheral arthritis and enthesitis, but oral corticosteroids have been associated with severe flares of cutaneous disease on withdrawal and are there-fore not widely used. Anti-TNF biologic agents are highly effective in both the peripheral and axial joint manifestations of the disease although etanercept is con-siderably less effective at treating the skin manifestations (207,208).

Slow-acting disease-modifying antirheumatic drugs, such as sulfasalazine, methotrexate, and leflunomide,

may be effective in some cases, but cyclosporin A, despite its proven efficacy in skin disease, is relatively ineffec-tive on the joints. In contrast to their helpful effects in peripheral arthritis, these agents are generally ineffective for psoriatic spondylitis.

78.4 JUVENILE IDIOPATHIC ARTHRITIS

Historically, this has been a somewhat ill-defined entity, a situation exacerbated by the differences in nomencla-ture in Europe and North America. Until recently, the term juvenile chronic arthritis has been used in Europe, whereas in North America, these disorders were often called juvenile chronic RA (in contrast to the use of this term in Europe specifically for seropositive juvenile-onset RA). Further confusion may arise from the use of the eponymous term Still disease for juvenile idio-pathic arthritis (JIA). In 1897, Sir George Frederick Still distinguished juvenile forms of arthritis from adult RA, commenting on the fever found in the systemic form. Subsequently, in 1959, Ansell and Bywaters dis-tinguished these childhood forms on the basis of their mode of onset. Thereafter, in general, “Still disease” was reserved for the systemic onset form of the disease although it has also been sometimes loosely applied to juvenile arthritis overall. These problems of classification can make comparisons between studies difficult. It has also complicated analysis of the genetic component of these disorders since many studies have not adequately distinguished between the various forms.

Childhood arthropathy has many potential causes, and it is important to exclude sepsis and viral infection, in particular, before concluding that the child has JIA. A World Health Organization/International League Against Rheumatism report proposed a widely accepted classification based on clinical patterns of disease (209) that defines seven subtypes of JIA:

• Systemic onset (11%) • Oligoarthritis and extended oligoarthritis (50%) • RF-positive polyarthritis (3%) • RF-negative polyarthritis (17%) • Enthesitis-related arthritis (10%) • Psoriatic arthritis (7%).

Specific diseases associated with joint inflammation, such as SLE, rheumatic fever, septic arthritis, and neo-plasia, are excluded from this classification.

78.4.1 Systemic-Onset JIA (Still Disease)

Still disease is the form of childhood arthropathy that carries the most adverse prognosis, with a significant mortality of 10%. It is characterized by systemic features including quotidian fevers, evanescent rash, lymphade-nopathy, hepatosplenomegaly, arthropathy, and polyse-rositis (210). These features, coupled with a pronounced neutrophilia (>13 × 109/L in 75% or more of patients),

toid Disease and Other Inflammatory Arthropathies 21
CHAPTER 78 Rheuma
may suggest infection, particularly when systemic fea-tures predate the arthropathy, which may happen by weeks or months. Other causes of fever and serositis should be considered, such as familial Mediterranean fever, particularly in patients of the appropriate ethnic background. Other important differential diagnoses include infection and malignancy. The disease has been reported in most populations worldwide and affects the sexes equally. The age of onset is variable but is usually between 4 and 6 years. It can also occur in adults, in whom it frequently causes diagnostic problems, particu-larly if systemic features predominate.

While some patients exhibit complete remission within 2 years of onset and others have repeated cycles of activity, the majority follow a chronic course (211). Some of the systemic features, including the fever and malaise, may respond well to short-term nonsteroi-dal anti-inflammatory drugs. For patients with more severe disease or poor prognostic signs such as active fever and high physician’s global score, the systemic features may require moderate- to high-dose cortico-steroids (including intravenous methylprednisolone). Anti-IL1 biologic therapy (e.g. Anakinra) may also be indicated in these patients and is frequently dramati-cally effective (212).

Multiple intra-articular injections of corticosteroids can be very effective in managing mild joint disease, but in patients with persistent or severe polyarticular involvement, disease-modifying antirheumatic drugs may be necessary. Weekly methotrexate (either orally or subcutaneously) has proved particularly beneficial com-pared to other second-line antirheumatic agents (e.g. gold salts, d-penicillamine, sulfasalazine), which have, in general, been disappointing. For resistant articular disease, biologic therapies, including anti-TNF (213), but particularly anti-IL1 and anti-IL6 agents, may be effective (212).

78.4.2 Oligoarticular JIA

Oligoarticular JIA affects young girls at least six times more frequently than boys, with a peak incidence at under 3 years of age, although the disease may also pres-ent for the first time in teenage life. The prevalence is between 20 and 30 per 100,000 and most ethnic groups are affected (214). By definition, children with this form of JIA have four or fewer joints affected within the first 6 months of disease, although in as many as one–third, the disease may subsequently extend to polyarticular involvement (210).78.4.2.1 Clinical Features. Constitutional symptoms are not prominent in contrast to Still disease. Although joint pain is usually an obvious feature, the presentation is sometimes less obvious. Thus, a parent may notice a swollen joint in the absence of symptoms or observe nonspecific features, such as poor behavior or cessa-tion from walking. Almost two-thirds of patients have

only one joint involved, and more than 90% have no more than two joints involved, in the first 6 months. Those children who remain oligoarticular for 5 years are unlikely subsequently to develop more extensive disease.

Levels of acute-phase reactants, such as C-reactive protein, may be normal or only slightly risen. If there is marked elevation, a search for alternative explanations is merited. This group of patients is classically associ-ated with the presence of antinuclear antibodies in the serum (40–75%), usually in low titer (<1:640). Positive antinuclear antibodies indicate a higher risk of devel-oping chronic anterior uveitis, which is the most seri-ous potential complication of early-onset oligoarticular JIA (215), although all children with JIA are at risk. It causes blindness in up to 10% of patients, but this is avoidable if the appropriate screening and treatment steps are exercised. Ocular disease affects up to 57% of patients with oligoarticular JIA, usually with ante-rior uveitis although isolated posterior disease rarely may be present. Only a few of those with iritis (5%) have polyarticular disease at onset. JIA-related uveitis is usually asymptomatic and the onset of ocular fea-tures may be delayed. Therefore, slit-lamp examination is mandatory in all patients at diagnosis and regularly for many years thereafter (Guidelines for Screening for Uveitis in Juvenile Idiopathic Arthritis (JIA), BSPAR and the RCPOphth 2006). The uveitis is chronic, last-ing between 2 and 15 years, and most commonly affects both eyes.

The joint disease associated with oligoarticular JIA typically resolves within 5 years, but chronic arthritis may sometimes recur, even many years later. Those chil-dren whose arthropathy extends to become polyarticular (about 20% overall) account for the majority exhibiting significant functional handicap at 15 years.78.4.2.2 Management. It is important to keep the joints as normal as possible while the arthropathy is in its active phase. This can usually be accomplished by the use of nonsteroidal anti-inflammatory drugs and intra-articular corticosteroids (best administered under general anesthetic in young patients). In general, there is a good response, and second-line drugs, such as methotrexate, are reserved for patients with persistent or severe disease. Physical methods of treatment to prevent contracture and preserve muscle strength are beneficial. Surgery is rarely needed except in those cases in which severe con-tractures develop or abnormalities of bone growth occur secondary to epiphyseal involvement. Anti-TNF biolog-ics are potentially very effective in resistant cases. Topi-cal corticosteroids and mydriatics are effective in 40% of patients with uveitis, but intraocular steroids or systemic corticosteroids are frequently required to prevent the formation of posterior synechiae between the lens and the iris. In some cases, immunosuppressive drugs such as azathioprine, chlorambucil, and cyclosporin A may be necessary to control the uveitis. The ocular disease is

22 CHAPTER 78 Rheumatoid Disease and Other Infl

potentially sight-threatening and demands regular oph-thalmologic review.

78.4.3 Polyarticular JIA

Polyarticular JIA is much less clearly defined than the oligoarticular and systemic-onset forms. It is apparent that some patients whose disease begins with limited joint involvement subsequently progress to a more widespread form of arthropathy with a correspondingly poorer outcome (these patients are included under the extended oligoarticular disease subset). If this occurs, it is invariably within the first 5 years of disease. Other patients have polyarticular symptoms from the outset, but these appear to represent a relatively heterogeneous group with the exception of the subgroup with juve-nile-onset seropositive RA (3% of all JIA). The progno-sis of this specific subset is similar to the adult form of RA, with similar immunogenetic associations. Indeed, the HLA associations are even more striking in the juvenile form of the disease, and the association with the HLA-DRB1*0401/*0404 genotype is particularly striking (33).

78.4.4 Genetics of JIA

It has been estimated that JIA has a prevalence of between 20 and 120 per 100,000 and an annual incidence of 10–20 per 100,000. The prevalence appears to be simi-lar in Europe and North America in general although a threefold excess risk to Native American children com-pared with their white counterparts in British Columbia has been reported. No differences have been observed in the prevalence in North American black and white children, but, by contrast, the condition appears to be rare in China. The available family studies provide sup-port for a genetic component to JIA, but many of these studies predate the more accurate classification of JIA into various subgroups. Thus, Lawrence (216) found an excess concordance in monozygotic twins (40%) versus dizygotic twins (9%), but these studies included only 16 twin pairs. Subsequently Moroldo et al. (217) studied 71 sib-pairs affected by juvenile chronic arthritis and found substantial concordance (70–80%) for the type of dis-ease between the sibs. There is a slight excess recurrence in sibs for systemic-onset JIA, and a genetic component to the disease arising from HLA-linked genes has been suggested although these results are inconsistent.

HLA-DR alleles have been estimated to confer almost 20% of the total sibling recurrence risk in JIA (218) although the risks associated with HLA alleles differ between the JIA subtypes. HLA-DRB1*08 (a rare allele in most white populations) is consistently found in between 25% and 50% of patients with oligoarticular JIA (rela-tive risk ~12). HLA-DRB1*11 (relative risk ~5) is also increased, and some studies have suggested a weak asso-ciation with HLA-DRB1*13. Our results suggest that

ammatory Arthropathies

HLA-DRB1*13 is most closely associated with the pres-ence of uveitis (OR 3.4) in oligoarticular disease (219). HLA-DRB1*04, which is associated with RA in adults is associated with juvenile seropositive polyarthritis (OR 3.2), but is protective against many other JIA subtypes (220). DRB1*07 is associated with decreased risk of JIA (220). There is considerable evidence for a marked compound heterozygote effect with predisposing DRB1 alleles (e.g. HLA-DRB1*08/DRB1*11) (221–223), anal-ogous to the situation in RA with DRB1*0401/*0404 (see Section 78.2.5). Gender has a significant influence on the age that the HLA risk is conferred (224). HLA analysis has been particularly useful in distinguishing a subset of children with pauciarticular disease, typically boys older than 9 years, in whom limited joint involve-ment with an associated enthesopathy is the first sign of spondyloarthritis (see Section 78.3.2). This variant is strongly associated with HLA-B*27 and is known to be associated with an excess of family members with sac-roiliitis. Many of these children go on to develop AS although others appear to continue with a more periph-eral form of enthesopathy without AS.

Other HLA alleles also contribute to risk. HLA-DQA1*0103 is associated with oligoarticular disease and HLA-DQA1*05 with oligoarticular and systemic-onset arthritis. HLA-DQA1*02 is protective against oligoarticular and seropositive polyarthritis (220). DPB1*0201 confers risk of early-onset arthritis (221). Previously reported HLA–DRB1/DQB1 risk associations were found to be solely due to the effect of the DRB1 locus (221).

It has been suggested that particular combinations of HLA-A*2, DPB1*0201, and other DRB1 susceptibil-ity alleles (*08,*11,*13) are associated with onset of oligoarticular disease under 3 years of age (224). The DRB1*1501–DQA1*0102–DQB1*0602 haplotype pro-tects against oligo- and polyarticular JIA (221).

Conducting studies of sufficient power to examine the risk contribution of non-HLA alleles is made difficult by the rarity of JIA and the phenotypic heterogeneity of the disease. While studies encompassing JIA as an umbrella disease may mask genetic associations with individ-ual JIA subsets, subset subanalysis may fail to detect genetic risk alleles with small effects (225). Therefore, approaches to identifying candidate genes have included investigating loci associated with other autoimmune dis-eases (226).

More than 100 non-MHC risk alleles have been exam-ined (225), and although many were found to be posi-tively associated, only a small number of these have been replicated to date. The PTPN22 and IL2RA gene associa-tions have reached genome-wide significance. PTPN22 is involved with T-cell signaling and confers risk of oligo- and polyarticular arthritis, while IL2RA, which codes for the high-affinity IL2 receptor alpha chain, is particu-larly associated with ANA positivity, female gender, and oligoarthritis (227,228). Other significant associations


include genes implicated in T-cell signaling and activation (STAT4, VTCN1), innate immunity (TNFA, TNFAIP3, TRAF1/C5, MIF, SCL11A1) and cartilage homeostasis (WISP3). Many of these genes are associated with risk of other autoimmune conditions such as RA (229). For example, the ERAP1 and IL23R gene variants, which are associated with AS in adults, have been found to increase risk of enthesitis-related arthritis (230) and juvenile pso-riatic arthritis, respectively. These findings await replica-tion (230).

The strong association of oligo- and polyarticu-lar JIA with HLA class II alleles suggests pathogenic involvement of CD4 T cells (227). No etiologic agents have yet been identified in this disorder although auto-antigens present in the eyes and the joints are strongly suggested as being responsible for the chronic inflam-matory process in oligoarticular disease. The non-HLA associations implicate Tregs, which may influence the balance between pro- and anti-inflammatory processes, as well as innate immune cells, which may contribute to cytokine production and CD4 T-cell activation. The distinct HLA and non-HLA genetic association between the JIA subsets implies differences in pathogenic mechanisms (227).

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Biographies

Professor Paul Wordsworth is at the National Institute for Health Research Oxford Muscu-loskeletal Biomedical Research Unit. He is honorary consultant rheumatologist to the Oxford University Hospitals NHS Trust and a Fellow of Green Templeton College, University of Oxford.

Dr Catherine Swales is a Clinical Lecturer in Rheumatology at the University of Oxford Institute of Musculoskeletal Sciences Botnar Research Centre, and a Fellow in Clinical Medicine at St Hilda’s College, University of Oxford.

Dr Sarah Keidel is a rheumatology registrar and a Clinical Fellow in Rheumatology at the University of Oxford Institute of Musculoskeletal Sciences Botnar Research Centre.

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