Classification of juvenile spondyloarthritis: Enthesitis-related arthritis and beyond

Abstract

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.

Figure 1

ASAS classification criteria for axial spondyloarthritis., ‘Sacroiliitis on imaging’ is defined as active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA (see Figure 2), or as ‘definite radiographic sacroiliitis’ according to the modified New York criteria. ‘Features of SpA’ include inflammatory back pain, arthritis, enthesitis (heel), uveitis, dactylitis, psoriasis, Crohn disease or ulcerative colitis, good response to treatment with NSAIDs, positive family history of SpA, HLA-B27, and elevated CRP level (considered a feature of SpA in the context of chronic back pain). The entire criteria have a sensitivity 82.9% and specificity 84.4%, as tested in 649 patients with chronic back pain and age at onset <45 years, and the imaging (sacroiliitis) arm alone has a sensitivity of 66.2% and a specificity of 97.3%., Abbreviations: ASAS, Assessment of SpondyloArthritis International Society; CRP, C-reactive protein; SpA, spondyloarthritis.

Figure 2

MRI demonstrating acute inflammation highly suggestive of sacroiliitis associated with spondyloarthropathy in a 12-year-old HLA-B27-positive male. The patient presented with right-hip pain, and on physical examination exhibited a decreased range of motion and tenderness to palpation of the right sacroiliac joint. Radiographs were normal at presentation, but the MRI revealed asymmetric high signal in the right sacroiliac joint suggestive of sacroiliitis. The patient responded well to treatment with NSAIDs initially, but required a corticosteroid hip injection approximately 2 years later. At that time, radiographs revealed slight sclerosis of the right sacroiliac joint with normal hip-joint spaces and no definite bony erosions. The author thanks Drs Egla Rabinovich (Duke University, Durham, NC, USA) and Edward Fels (Rheumatology Associates, Portland, ME, USA) for providing the image.

Figure 3

Hypothetical functional interactions between gene products associated with ankylosing spondylitis. The genes HLA-B27, ERAP1, IL23R, IL1R2, TRADD, TNFR1, CARD9, and ANTXR2 (not shown) have definite or suggested associations with AS. One mechanism linking HLA-B27 to the IL-23/IL-17 (T_H17) axis involves misfolding and UPR activation triggered by MHC class I upregulation. UPR activation enhances production of IL-23 and IFN-β in response to certain PRR agonists. CARD9 mediates IL-23 induction in response to fungal cell wall components through the PRR, Dectin-1. ERAP1 influences the quality and/or quantity of peptides available for MHC class I molecules, and might impact not only cell-surface complexes, but also the folding efficiency of HLA-B27. ERAP1 (also known as ARTS1) is also an aminopeptidase regulator of TNF (TNFR1) receptor shedding, and also influences IL-6 and IL-1R2 (IL1R2) receptors. Polymorphisms in TNFR1 and TRADD, a mediator of TNF signaling, could influence downstream effects perhaps contributing to phenotypic differences between patients with different TNF overexpression diseases such as RA and AS. Abbreviations: AS, ankylosing spondylitis; BiP, immunoglobulin-heavy-chain-binding protein; CARD9, caspase recruitment domain-containing protein 9; ER, endoplasmic reticulum; ERAP1, endoplasmic reticulum aminopeptidase 1; IFN, interferon; IL, interleukin; NK, natural killer; PRR, pattern recognition receptor; RA, rheumatoid arthritis; T_H17, type 17 helper T cell; TNF, tumor necrosis factor; TNFR1, tumor necrosis factor receptor type 1; TRADD, TNFR1-associated DEATH domain protein; UPR, unfolded protein response; XBP1, X-box-binding protein 1.