Role of Radiographic Imaging
Radiology is the standard for diagnosing JSpA.[4,6,7] Radiographs can show soft tissue swelling, joint space narrowing, and other changes. However, radiography is complicated in children, who have more cartilage and joint space than adults. Several studies support the superiority of MRI for detecting early sacroiliitis, enthesitis, and bone marrow edema in children with JSpA.[4,5,7] MRI is also useful for assessing synovitis and identifying complications, such as cervical spine subluxation. A recent study of MRI in newly diagnosed JSpA found 20% of children had sacroiliitis, and 88% of those children had erosions or sclerosis. Two-thirds of children with MRI-confirmed sacroiliitis were asymptomatic. Sacroiliitis was more common in children who were HLA-B27 positive or who had an elevated C-reactive protein level. When using MRI, the consensus is to use shot tau inversion recovery imaging without gadolinium contrast. Photo credit: BSIP / Science Source
Measuring and Tracking Disease Activity
Tools such as the BASDAI, DC-ART, ASDAS, and ASAS were designed to measure disease activity in adults with SpA and have limited usefulness in JSpA. The JADAS and JSpADA are new tools developed specifically for measuring disease activity in juveniles with arthritis. Although JADAS has been validated, studies included only a small percentage of children with SpA. In contrast, JSpADA was developed specifically for evaluating children with axial symptoms and enthesitis. JSpADA is still being validated but may provide clinicians with an effective tool for evaluating treatment response.[1,6,7]
Up to one-quarter of children experience acute anterior uveitis (AAU), which is the most common extra-articular manifestation in JSpA and can cause permanent damage to vision.[7,9] Half of patients with AAU who are HLA-B27 positive later receive another SpA diagnosis, such as AS. An estimated two-thirds of children have gastrointestinal involvement, manifesting IBD-like symptoms. Cardiac manifestations are less common in JSpA than in adult SpA and tend to be mild.[7,9] In adults with PsA, arthritis and psoriasis commonly occur together. While children with SpA may develop psoriasis, arthritis precedes psoriasis by several years in 23% to 58% of patients. Children with PsA who do not have psoriatic rash may exhibit subtle psoriatic symptoms, however, such as dactylitis and nail pits. (Photo credit: Paul Whitten/Science Source
Use of Other Biologic Agents
Several biologic agents that are not TNF inhibitors are approved for adults with SpA or in development. These include secukinumab, an anti-IL-17A monoclonal antibody approved for PsA and AS; rituximab, a B-cell depleting therapy used to treat certain malignancies; abatacept, a T-cell co-stimulation inhibitor approved for rheumatoid arthritis; apremilast, a PDE4 inhibitor approved for PsA and being studied in AS; and ustekinumab, a novel IL-12/23 monoclonal antibody approved for psoriatic arthritis that has shown efficacy in AS.[2,6,7] None of these treatments has been evaluated in JSpA.
TNF Inhibitors in Juvenile Spondyloarthritis
Several tumor necrosis factor (TNF) inhibitors are approved for adult SpA and are an important strategy for axial disease. TNF inhibitors are also approved for children with JIA and for Crohn’s disease and ulcerative colitis in children (common comorbidities in AS). Trials in adults found earlier introduction of a TNF inhibitor produced better outcomes, whereas delayed use increased the risk of progression. Younger adults with SpA derived more benefit from TNF inhibitors than older adults, which may have implications for JSpA. Clinical trials in JSpA have established the efficacy of TNF inhibitors for treating joint inflammation, enthesitis, or symptomatic axial disease. ACR guidelines for active sacroiliac arthritis recommend TNF inhibitors for children who have high disease activity after NSAID use or whose inflammation persists despite DMARD use.[7,11] TNF inhibitor use may increase the risk of tuberculosis and malignancy.
Pharmacologic Agents for Peripheral Disease
Treatments for JSpA are based on agents evaluated in adult SpA.[7,11] The 2011 ACR guidelines are for JIA and are not specific to JSpA. The algorithms for peripheral disease consider the number of active joints and prognosis. First-line treatment is essentially a brief trial of NSAID monotherapy. For persistent activity, the ACR suggests adding or switching to a disease-modifying anti-rheumatic drug (DMARD), such as methotrexate, sulfasalazine, or leflunomide. Glucocorticoid intraarticular injections are advised for all children with active arthritis. DMARDs are effective for peripheral JIA but have not been proven effective for axial disease or enthesitis in JSpA. However, open-label studies indicate sulfasalazine improves symptoms in juvenile AS, ERA, and PsA. For JIA refractory to NSAIDs and DMARDs, ACR guidelines recommend a tumor necrosis factor (TNF) inhibitor. The rate and type of treatment escalation depends on disease activity.
Etiology of Juvenile Spondyloarthritis
The onset of JSpA is typically in early adolescence. Its etiology is not fully understood but involves genetic and environmental factors. Human leukocyte antigen (HLA)-B27 has been implicated in AS, uveitis, reactive arthritis, IBD, ERA, and PsA.[2,7,8] HLA-B27 misfolding may trigger release of inflammatory cytokines. While 95% of adults with AS test positive for HLA-B27, only 50% of juveniles with AS are HLA-B27 positive, suggesting differences exist in the pathogenesis of adult and juvenile AS. The fact that <5% of people with HLA-B27 develop SpA points to involvement of other genetic factors. Studies have identified genetic aberrations of TLR4, NLRP3, CXCR4, and PTPN12 as possible contributors to JSpA. Changes in the intestinal microbiome, possibly linked to HLA-B27, may also play a role in JSpA.[7,8] Studies show juveniles with JSpA have lower levels of Clostridium leptum or fecalibacterium prausnitzii than healthy controls and other differences in microbiota.
Peripheral and Axial Involvement
The main subsets of SpA are axial (affecting the spine and sacroiliac joints) and peripheral (affecting the entheses or joints of the hands, arms, feet, or legs). Children with JSpA typically present with peripheral arthritis. Often, the arthritis is asymmetric, oligoarticular, and affects joints of the lower extremities, such as the hip.[2,7] Hip involvement is a risk factor for sacroiliitis. Approximately one-third of children have tarsitis at onset, which is painful inflammation and swelling of the midfoot. Although axial involvement is uncommon at diagnosis, 30% of patients have evidence of axial involvement within 15 months of diagnosis and up to two-thirds have axial involvement within 10 years of diagnosis. Axial involvement is typified by morning stiffness or discomfort in the lower back or buttocks that worsens with prolonged inactivity. Sacroiliitis may be asymptomatic in juveniles. (Photo credit (Modified from Burgos-Vargas R, Vázquez-Mellado J. Reactive arthritides. In: Cassidy JT, Petty RE (eds): Textbook of Pediatric Rheumatology. 5th Edition. Philadelphia. Elsevier Saunders. 2005:604–612 and Burgos-Vargas, R. 2006, The juvenile-onset spondyloarthritides. In: Weisman MH, van der Heijde D, Reveille JD. Ankylosing spondylitis and the Spondyloarthropathies. Mosby. Philadelphia. pp 94–106).
Different groups have provided different diagnostic criteria for SpA. Most physicians use the ILAR classification system for JIA. ILAR describes JIA as “arthritis of unknown etiology, onset before age 16 years, symptoms persistent for ≥6 weeks. The only SpA diagnoses included in the ILAR system are ERA, PsA, and undifferentiated arthritis (combines features of ERA and PsA). ILAR excludes reactive arthritis, AS, and IBD-related arthritis.[2,7] The European SpA Study Group (ESSG) criteria for SpA specify inflammatory spinal pain or synovitis plus any of several clinical signs (eg, psoriasis, IBD, buttock pain, enthesitis, sacroiliitis). The Amor criteria uses a scoring system that combines clinical symptoms, radiologic findings, genetic background, and response to NSAIDs. None of the current classification systems are ideal for JSpA. (Photo Credit: Burgos-Vargas R)
Clinical Outcomes in Juvenile Spondyloarthritis
Children with JSpA experience more pain and have worse health outcomes than children with other types of JIA. They are also less likely to achieve or sustain remission. In fact, only 17% of children with SpA achieve remission within 5 years of diagnosis. Predictors of unremitting disease activity include a family history of AS, HLA-B27 positivity, hip arthritis, and ankle arthritis in the first 6 months after diagnosis. Data show disease activity that persists for ≥5 years predicts an increased risk of subsequent disability. Persistent enthesitis is associated with joint damage and an increased risk of AS. In addition, juvenile-onset SpA is associated with an increased risk of impairment and disability in adulthood compared with adult-onset SpA. Prompt diagnosis and earlier treatment with biologic agents might contribute to better outcomes.
Enthesitis in Juvenile Spondyloarthritis
Between 60% and 80% of children with JSpA experience enthesitis, which is inflammation where tendons, ligaments, and joint capsules attach to bone. Common sites of enthesitis are patellar ligament insertions at the inferior patella, plantar fascia insertions into the metatarsal heads or calcaneus, and Achilles tendon insertion into the calcaneus. Sites of enthesitis are usually painful, tender to the touch, and swollen. ERA should be suspected in children with knee, foot, or heel pain. Juveniles usually have more sites of enthesitis than adults. ERA may be persistent, especially in children with more active sites at diagnosis. A higher number of active enthesitis sites is predictive for sacroiliitis. In general, children with ERA have greater disease activity and worse prognosis than children with other types of JIA. They are less likely to achieve or sustain remission.
Spondyloarthritis (SpA) is used to describe a family of related autoimmune diseases associated with chronic inflammation of the spine, pelvis, peripheral joints, entheses, eyes, skin, and/or intestines. Types of spondyloarthritis include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, inflammatory bowel disease (IBD)-associated arthritis, and undifferentiated SpA.1 Spondyloarthritis with onset before 16 years of age is termed juvenile SpA (JSpA). The same spondyloarthritides that affect adults also affect children. However, most children with JSpA have enthesitis-related arthritis (ERA), psoriatic arthritis, or undifferentiated arthritis, which are also considered manifestations of juvenile idiopathic arthritis (JIA) under the International League of Associations for Rheumatology classification system.
Although JSpA is clinically distinct from adult SpA, the assessment of JSpA is often based on criteria used for adult SpA.[1,3] The development of new tools such as the Juvenile Arthritis Disease Activity Score (JADAS) and the JSpA Disease Activity Score (JSpAdA), along with efforts to qualify the role of radiographic imaging in the evaluation of JSpA, may lead to better management of these debilitating conditions.[4,5]
The treatment approach for JSpA typically follows recommendations for treating adult SpA. In 2011, the American College of Rheumatology (ACR) released treatment guidelines for JIA based on number of active joints and the presence or absence of active sacroiliac arthritis.[6,7] The goal of pharmacologic therapy in patients with JSpA is to decrease pain and inflammation, preserve joint function, and improve function.
Children with JSpA typically respond worse to treatment than children with other types of JIA or than adults with SpA.6 Greater knowledge about the pathogenesis, assessment, and treatment of JSpA has the potential to improve outcomes for this hard-to-treat population.