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Spondyloarthritis (SpA) refers to a spectrum of immune-mediated inflammatory diseases with overlapping features, which differ from other types of inflammatory arthritis in genetic predisposition, pathogenesis and outcome. SpA frequently involves the axial skeleton, and can result in abnormal bone formation with eventual ankylosis of the spine, resulting in substantial disability. SpA often begins as an ’undifferentiated’ disease, the presentation of which differs in children and adults; most notably, spinal involvement is uncommon, while hip arthritis and enthesitis are frequently seen in juvenile-onset disease. Currently, the classification of SpA in adults and children is approached differently. Using the International League of Associations for Rheumatology (ILAR) system for juvenile idiopathic arthritis, most childhood SpA is classified as enthesitis-related arthritis. However, in contrast to adult SpA classification, the presence of, or a family history of, psoriasis dictates a separate category of juvenile idiopathic arthritis. More importantly, the ILAR system does not specifically recognize the presence of axial disease in juvenile SpA. Resolution of these issues will improve communication and the transitioning of patients from pediatric to adult clinics, will facilitate research in genetics and pathogenesis, and will be particularly important in the evaluation of tumor necrosis factor inhibitors and other biologic agents for early, axial SpA.
In contrast to the predominantly pediatric forms of arthritis such as oligoarticular, polyarticular (rheumatoid factor [RF]-negative) and systemic juvenile idiopathic arthritis (JIA), most patients with spondyloarthritis (SpA) begin experiencing symptoms in the third and fourth decades of life. Nevertheless, disease onset extends well into the pediatric age range, and juvenile SpA represents an important form of arthritis in children that needs to be recognized, appropriately managed, and followed carefully for signs and symptoms of progression.
Enthesitis-related arthritis (ERA) is a subtype of JIA as defined by the International League of Associations for Rheumatology (ILAR) classification system for childhood arthritis.1 ERA includes certain forms of SpA, distinguishing them from other subtypes of JIA for optimum treatment and outcome, and for studies aimed at understanding genetic predisposition and pathogenesis. The inclusion and exclusion criteria for ERA recognize phenotypic and genetic differences between this and other forms of childhood arthritis, as well as differences in the presentation of SpA between children and adults.
The ILAR criteria for JIA generally perform well compared with previous systems for classifying juvenile arthritis (‘juvenile rheumatoid arthritis or JRA’ by American College of Rheumatology criteria, and ‘juvenile chronic arthritis or JCA’ by European League Against Rheumatism criteria),2–4 but their application to cases of juvenile SpA has been more controversial.5 Although revisions to the ILAR criteria have addressed some weaknesses,1,6–8 several problems remain, some of which might have been intensified by the recent development of criteria that identify pre-radiographic ‘axial SpA’ in adults.9,10
This Review summarizes the clinical features, genetic susceptibility factors and outcomes of ERA, and discusses some of the implications of using the current ILAR-based JIA classification system for juvenile SpA in the context of how this disease is classified in adults.
The spondyloarthropathies encompass a group of inflammatory arthritic diseases that exhibit overlapping clinical features and shared genetic predisposition (Box 1). The prototype spondyloarthropathy, ankylosing spondylitis (AS), is defined by criteria that require axial disease documented as radiographic sacroiliitis,11 and by clinical signs and symptoms that reflect the involvement of additional joints in and around the spine.12 Common manifestations of AS that vary in frequency include peripheral arthritis, peripheral enthesitis, acute anterior uveitis and subclinical gastrointestinal inflammation (Box 2). The axial inflammatory lesions associated with AS have a tendency to ossify, resulting in ankylosis and contributing to a reduced quality of life and, in many patients with AS, substantial disability.
Abbreviations: ESSG, European Spondyloarthropathy Study Group; IBD, inflammatory bowel disease; SpA, spondyloarthritis.
*Assessment of SpondyloArthritis International Society 2009 definition of inflammatory back pain: age at onset <40 years; insidious onset; improvement with exercise; no improvement with rest; and pain at night (with improvement on rising).70
Many individuals with signs and symptoms of SpA do not meet the criteria for AS because they either lack axial involvement or do not show radiographic evidence of sacroiliitis. Instead, such patients often meet classification criteria for ‘undifferentiated SpA’, as defined by European Spondyloarthropathy Study Group (ESSG)13 or Amor criteria14 (Box 1). The criteria for undifferentiated disease overlap with those for other forms of SpA, including reactive arthritis, and for arthritis accompanying inflammatory bowel disease (IBD) or psoriasis. Outcome studies reveal that undifferentiated SpA is not merely an early form of AS since, even after a decade, almost half of patients still do not meet criteria for AS.15
Striking advances in the treatment of AS have been realized over the past decade. Several biologic agents that target tumor necrosis factor (TNF) have been shown to be rapidly beneficial in a high proportion of patients with AS, with substantial reductions in pain, inflammation, and disease activity.16 However, it seems that TNF inhibition might not modify the radiographic progression of spinal disease, at least in patients whose treatment was initiated after they fulfilled criteria for AS.17,18 These observations, along with the prospect of new biologic agents, have intensified interest in identifying early (pre-radiographic) axial disease, which might be more amenable to disease modification than late-stage disease. Since the criteria for undifferentiated SpA do not specifically identify individuals with axial disease, the development by the assessment of SpondyloArthritis International Society (ASAS) of new criteria for this purpose is both noteworthy and timely (Figure 1).9,10 This achievement is in large part attributable to the use of MRI to identify early, pre-radiographic axial lesions (for example, see Figure 2), although the usefulness of HLA-B27 testing is also recognized. Application of the ASAS criteria reveals that they identify both radiographic SpA (that is, individuals who meet the modified New York criteria for AS) and pre-radiographic axial SpA. This major advance will facilitate the identification of patients who are appropriate for early intervention, and will enable further discovery and validation of biomarkers associated with axial involvement.19
Recognizing SpA in children, particularly early in the course of disease, presents a unique set of challenges. The signs and symptoms at disease onset differ from those seen in adults, with inflammatory back pain being less prominent, reflecting the infrequent involvement of the sacroiliac and other vertebral joints in juvenile disease.20 By contrast, hip and peripheral arthritis, together with enthesitis, are common presenting features in children. As a consequence, juvenile SpA might be missed or confused with other forms of juvenile arthritis. In recognition of these differences, Rosenberg and Petty proposed criteria for a syndrome of seronegative enthesopathy and arthropathy (SEA), including the presence of enthesitis with arthralgia or arthritis, the absence of RF and anti-nuclear antibodies, and symptom onset before 17 years of age.21 SEA provided a category that recognized undifferentiated juvenile SpA in the absence of axial symptoms, and thus became a useful means to distinguish this syndrome from JRA as it was defined at the time (1980s) by ACR criteria.
In the mid-1990s, the ILAR classification criteria were proposed, using the umbrella term JIA.6,7 The primary intent of these criteria was “to delineate, for research purposes, relatively homogeneous, mutually exclusive categories of idiopathic childhood arthritis based on predominant clinical and laboratory features”.1 Six categories of JIA were proposed, with a seventh (originally called “undefined arthritis”, now referred to as “undifferentiated arthritis”) applied if the criteria for other categories were either not met or did not enable unambiguous classification. The practical application of these criteria, however, identified a large number of children as having ‘undefined arthritis’,22,23 prompting revision and further clarification of the categories (Table 1).1
Under the revised ILAR classification system published in 2004 (Table 1), juvenile SpA is largely categorized in one of three ways: as ERA, psoriatic arthritis (PsA), or undifferentiated arthritis (if features of both ERA and PsA are present). The definition of ERA is based on criteria similar to those of SEA, but applied differently and with some important distinctions. Coexisting arthritis and enthesitis are sufficient for the classification of ERA, provided other exclusions are absent. If the patient does not have both arthritis and enthesitis, then additional features suggestive of SpA must be present (Table 1). By contrast, enthesitis without arthritis would be sufficient for the classification of SEA. Other major differences include an upper age limit of 16 for ERA rather than 17 for SEA, and how psoriasis influences the classification. In the ILAR system, the presence of psoriasis in the patient or a first-degree relative is an exclusion criterion for ERA and all other subgroups of JIA except PsA. A classification of PsA is considered if the patient has both arthritis and psoriasis, or has arthritis plus at least two of dactylitis, characteristic nail changes and a first-degree relative with psoriasis (Table 1).
One could argue that PsA, as defined by the ILAR criteria, is not SpA. Recent studies suggest that ILAR-defined psoriatic and nonpsoriatic JIA can have similar clinical features, with the main differences being an increased frequency of dactylitis and nail pitting (in addition to the presence of psoriasis) in PsA.24,25 One study revealed small differences in outcomes, with juvenile PsA resulting in poorer physical health and more pain than oligoarticular or polyarticular JIA,25 and axial involvement was either absent25 or not specifically noted in psoriatic JIA.24 By contrast, application of the Vancouver criteria for juvenile PsA,26 which pre-date the ILAR classification and are more inclusive,1,7 reveals two distinct populations of patients: a young group (age at onset <5 years) with a disease that resembles JIA27 and is similar to ILAR-defined PsA, and an older group (age at onset ≥5 years) with a tendency to have enthesitis, axial arthritis and persistent oligoarthritis. Patients in the latter group are often excluded from a classification of ILAR-defined PsA (for example, because they are male and HLA-B27 positive, and/or have features of, or a family history of, SpA), and are instead classified as having undifferentiated arthritis (Table 1).28 The question of how to best define PsA in children, and in particular whether one should subdivide oligoarticular JIA and polyarticular JIA according to the presence or absence of psoriasis in the patient or their family, is an area of active debate.29 This issue extends to juvenile SpA, where the question is whether children with ERA who also have features of psoriasis or a family history of disease should be excluded from a classification of ERA.
The ERA classification criteria do not address reactive arthritis or coexisting IBD,30 which are considered features of SpA in adults. A diagnosis of IBD does not exclude a patient from having ERA, as long as the inclusion criteria are met. Nevertheless, one consequence of not recognizing IBD as a possible feature of SpA is that a 15-year-old male with IBD and arthritis, but not enthesitis, HLA-B27, or a family history of SpA, would not be considered to have SpA until he turned 16 years old, unless the criteria for undifferentiated SpA in adults (ESSG criteria13 or Amor criteria14) were to be applied before that time. In addition, the criteria for ERA actually contradict those for JIA, since arthritis does not have to be present for a classification of ERA. The correct approach to the classification of ERA is uncertain, and this issue is clearly confusing to both pediatric and adult rheumatologists.
The ILAR classification system for JIA, and the ERA subgroup in particular, does not specifically address children who meet the criteria for AS. Approximately 10% to 20% of patients eventually diagnosed with AS begin to experience symptoms before the age of 16,31 and a proportion of these individuals would fulfill the modified New York criteria for AS at this early age. The criteria for AS do not specify a lower age limit, and when children fulfill these criteria it is logical to classify them as having AS, even if they also meet the criteria for ERA. The term ‘juvenile AS’, then, could be used to describe children who meet the criteria for AS before age 16, whereas ‘juvenile-onset AS’ would describe those whose symptoms began before age 16 but who do not fulfill the AS criteria until they are older.
Estimates of the prevalence of juvenile SpA, and ERA specifically, are based on figures for juvenile arthritis, which vary considerably depending on geographic location and case definition. The worldwide prevalence of juvenile arthritis is reportedly between 7 and 400 per 100,000 children (0.007% to 0.4%), although the latter figure seems to be an outlier and probably overestimates the number of cases in the USA.32 ERA and PsA each comprise 2–11% of those cases,33 which would give an estimated combined total of 0.28–88 cases per 100,000 children. These figures do not seem to include juvenile AS, which, based on the prevalence of AS in adults and the frequency of childhood-onset among AS patients, is prevalent in 0.01% to 0.09% of the pediatric population.31,33
There is virtually no published evidence for the treatment of ERA.34 Sulfasalazine might be beneficial for peripheral arthritis in this subgroup of JIA patients, although this benefit is not well established.35 TNF inhibitors have shown promise in a small open-label trial of juvenile SpA patients who met the ILAR criteria for ERA and the ESSG criteria for SpA,36 and, given their benefit in AS, their efficacy in reducing symptoms and inflammation is not surprising. NSAIDs are frequently used to manage symptoms in most forms of inflammatory arthritis, including SpA, and could be of benefit in reducing radiographic progression in AS if used continually.37 Education, exercise, and physical and occupational therapy for stretching and maintaining range of motion are usually key components of management.38
The majority of recent efforts to understand genetic susceptibility to SpA using genome-wide approaches have focused on AS. This is a complex genetic disease, and evidence indicates that over 90% of the risk of developing the disease is heritable, suggesting that environmental influences, although potentially important, are most likely ubiquitous.39 Genetic susceptibility to AS is dominated by one family of MHC class I alleles, HLA-B27, which accounts for close to 40% of heritability.40 It is almost necessary for disease (present in more than 90% of AS patients compared with 7–8% of healthy controls), but is clearly not sufficient, as only around 5% of HLA-B27 carriers develop AS.
Looking beyond the MHC, ERAP1 (formerly known as ARTS1) and IL23R have been associated with AS, with population-attributable risk estimates of 26% and 9%, respectively.41,42 The first genome-wide association study of AS confirmed the associations of ERAP1 and IL23R, and identified ANTXR2 and IL1R2 as additional susceptibility genes.43 Associations with single-nucleotide polymorphisms in gene deserts (2p15 and 21q22)43 and in or near TNFR1, CARD9 and TRADD, suggest that additional candidate genes or gene regions are still to be confirmed. Together, these genes could account for nearly 70% of genetic susceptibility to AS, with other genes such as IL1A also implicated.40 It is worth noting that IL23R polymorphisms, which are also implicated in psoriasis and IBD,44,45 are independently associated with AS. This observation could explain, at least in part, the coexistence of and phenotypic overlap between various forms of SpA, and underscores the difficulty in defining nonoverlapping subtypes of disease for the purposes of classification.
The role of newly discovered AS risk genes in ERA and other forms of undifferentiated SpA has not been investigated. HLA-B27 is strongly associated with juvenile SpA, being found in 60% to 90% of affected individuals depending on the type of SpA.46–48 The strength of the association between HLA-B27 and ERA cannot be assessed since the presence of HLA-B27 antigen is used as a minor inclusion criterion for the classification of ERA (Table 1). Since risk alleles for genes such as IL23R and ERAP1 were discovered in the context of AS, and only a proportion of ERA patients will develop the complete AS phenotype, the frequency of AS risk alleles in patients with ERA could be closer to that seen in healthy individuals than in patients with AS. Whether there are independent risk alleles for ERA remains to be determined. It seems probable that the presence of AS risk alleles in individuals with ERA (or with other forms of undifferentiated SpA) could predict progression to axial involvement and eventual ankylosis. Long-term outcome studies of ERA will be important if predictive genetic tests are to be developed.
An in-depth discussion of the pathogenesis of SpA is beyond the scope of this Review, and has been covered recently elsewhere.49,50 However, a few developments are worth noting. The predominant place of HLA-B27 in determining genetic predisposition to SpA has shaped many ideas about the pathogenic mechanisms of the disease, and a transgenic animal model has enabled some of these hypotheses to be tested.50 In HLA-B27 transgenic rats with SpA-like disease, the lack of a critical role for CD8+ T cells has been confirmed.51,52 This finding essentially eliminates a causative role for the recognition of arthritogenic peptides by autoreactive CD8+ T cells, although skeptics would argue that the rat model does not adequately represent human AS.
Interest is growing in the intracellular effects of HLA-B27 expression. HLA-B27 misfolding, and the ensuing unfolded protein response induced by endoplasmic reticulum stress, results in increased IL-23 production in response to pattern-recognition receptor agonists; IL-23 might then activate existing IL-17-expressing CD4+ T cells (type 17 T helper [TH17] cells).49,50,53,54 TH17 cytokines, either alone or in combination with TH1 cytokines, have been implicated in a variety of pathogenic processes in animals and humans.55 Strong evidence in support of this concept comes from studies of colitis lesions in HLA-B27 transgenic rats, but data from human studies are needed and links to other aspects of the AS phenotype have not been addressed. In addition, this mechanism could explain why IL23R polymorphisms are linked to a predominantly MHC class I (HLA-B27)-associated disease and to TH17 cell activation, findings that have now been documented in humans with AS and other forms of SpA.56–59
One function of the enzyme encoded by ERAP1, an endoplasmic reticulum aminopeptidase, is to trim and optimize peptides that are presented by MHC class I molecules.60–62 Thus, ERAP1 polymorphisms might logically be expected to influence the immunobiology of HLA-B27 through its peptide repertoire, including putative arthritogenic or spondylogenic peptides.50 If the results from transgenic rats are correct and peptides per se are not critical for disease, then another effect on HLA-B27 could be involved, such as alterations to its folding–misfolding dynamics in the endoplasmic reticulum or its behavior after reaching the cell surface. These possibilities need to be addressed experimentally. Possible functional interactions between the products of genes associated with AS are displayed in Figure 3.
The reported long-term prognosis for patients with juvenile SpA is variable, and depends on which study one examines. This inconsistency is probably a consequence of several factors, including the use of different case definitions for juvenile SpA, but also depends on the population being studied. The original report of SEA described 39 children, 13 of whom had classical features of SpA including 8 with bilateral sacroiliitis, 2 with IBD, and 3 with reactive arthritis.21 Thirty-six of the 39 were followed for a mean of 11 years, and were found to have a variable disease course.63 Half of the original group who did not have definite SpA at onset (but who fit the criteria for SEA) eventually developed definite or possible SpA. The presence of HLA-B27, arthritis rather than arthralgia, and disease onset after age 5 years predicted eventual SpA.
In comparison with other forms of juvenile arthritis, juvenile SpA tends to have a poorer outcome. In one 3-year study, patients with either juvenile AS or SEA had poorer health outcomes than patients with oligoarticular JRA and RF− polyarticular JRA, and similar outcomes to those with RF+ polyarticular JRA, with a high disability index and poor well-being at baseline being the best predictors of poor outcomes.64 In the largest study to date, similar findings of worse physical outcomes were observed for ERA compared with oligoarticular or polyarticular JIA after a median of 15.3 years and also after a median of 23.0 years.65 At 15.3 years, 44% (24/55) of patients with ERA were in remission while 56% (31/55) had reduced anterior spinal flexion. Radiographic sacroiliitis was present in 35% (19/55) and inflammatory back pain in 47% (26/55). Predictors of failure to achieve remission included genetic components, as measured by a positive family history of AS in a first-degree relative and the presence of HLA-DRB1*08 in the patient, and clinical features of ankle or hip arthritis within the first 6 months of disease. Predictors of sacroiliitis included persistently elevated erythrocyte sedimentation rate and ankle arthritis. HLA-B27 was not a predictor of poor outcome in this study, perhaps because it was present in the vast majority of patients (85%). These data suggest that, even after 15 years, less than half of patients classified as having ERA have evidence of active spinal disease, a key feature of AS. This pattern differs slightly from that of undifferentiated SpA in adults classified according to ESSG criteria. One study demonstrated that undifferentiated SpA progressed to AS in 60% of patients after an average of 10 years of follow-up.15 The sometimes slow but persistent progression of this disease underscores the need for better biomarkers including genetic predictors of outcome.
The value of testing for the presence of HLA-B27 antigen has historically been a matter of debate, since it neither rules in nor excludes a diagnosis of juvenile AS. However, its use as a minor inclusion criterion for ERA, and as an exclusion criterion (along with age and sex) for other forms of JIA, argues that it should be routinely ascertained when using the ILAR classification system. In support of the usefulness of this test, HLA-B27 predicts increasingly extended disease within the first 3 years with increasing age at onset in boys with JIA.66 It is also associated with involvement of small joints in the lower extremities (primarly subtalar and tarsal joints) in boys but not in girls, and with inflammatory back pain in both sexes.
Age at onset appears to influence outcomes for patients with AS. In one study, patients with disease onset before age 16 years tended to have more-severe hip disease, as reflected by a greater need for arthroplasty (17.7% versus 8.7% for patients with juvenile-onset and adult-onset AS, respectively) and radiographic changes, while patients with adult-onset disease exhibited worse spinal radiographic scores.67 Another study demonstrated adult-onset AS to have more-prominent axial features such as pain and stiffness in the neck and back, with worse functional outcome, quality of life and fatigue.68 Disease duration was similar between the two groups, although disease activity was higher in patients with AS onset during adulthood. This study also confirmed differences in presentation of SpA between adults and children, with 26% of patients with juvenile-onset AS having only peripheral arthritis at onset, compared with 4.6% of patients with adult-onset disease.
The ILAR system for classifying JIA has been adopted worldwide, and represents an improvement over previous classification systems.8 Ideally, classification criteria for juvenile SpA should be both sensitive and specific, recognizing differences in the presentation of SpA in childhood as opposed to adulthood, but should also be sufficiently similar to adult criteria to include conditions that fall under the SpA umbrella such as juvenile AS and ‘juvenile’ axial SpA. This would facilitate communication between adult and pediatric physicians and rheumatologists, and would be particularly important for patients who are at the age to begin their transition into adult care. This consistency is also important for investigators in the field. The recent development of criteria that identify patients with axial SpA before the appearance of radiographic changes or the fulfillment of criteria for AS9,10 represents an important advance that will facilitate therapeutic trials to test whether early treatment with TNF inhibitors could change the course of axial disease.
Articles in the reference list were selected by searching PubMed for English-language publications using the terms “pediatric and/or juvenile spondyloarthritis”, “undifferentiated spondyloarthritis”, “classification”, “juvenile psoriatic arthritis”, “treatment”, “TNF-α”, “outcome”, “radiographic progression”, “axial spondyloarthritis”, “HLA-B27”, “genome-wide association study”, “ERAP1”, “IL23R”, and “Th17”. Additional references related to spondyloarthritis in adults and children, its genetic basis and pathogenesis, and other related topics were retrieved from the author’s personal collection.
The author declares no competing interests.