Secukinumab in enthesitis-related arthritis and juvenile psoriatic arthritis.

Juvenile rheumatoid arthritis is a common connective tissue disease in children. It is characterized by chronic arthritis and can be accompanied by systemic damage. The International Federation of Rheumatology Pediatric Standing Committee expert group unanimously defined juvenile idiopathic arthritis (JIA) as unexplained joint swelling lasting more than 6 weeks in childhood, replacing former definitions of juvenile rheumatoid arthritis and juvenile chronic arthritis. JIA is diagnosed as a heterogeneous group of inflammatory disorders that encompasses all forms of chronic arthritis of unknown origin, starting before 16 years of age and persisting for ≥6 weeks. Enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) are two categories of JIA based on expert opinions of the International League of Associations for Rheumatology. Treatment options for patients with the JIA subtypes of ERA and JPsA are limited. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), glucocorticoids, and non-steroidal anti-inflammatory drugs provide limited efficacy and are unsafe for long-term use. Studies have demonstrated the efficacy of the biologic DMARD (bDMARD) anti-tumor necrosis factor (anti-TNF) agents in patients with ERA or JPsA, but many patients have persistent uncontrolled disease or treatment-related adverse effects.1, 2 Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has demonstrated efficacy and safety in adult patients with PsA, ankylosing spondylitis, and non-radiographical axial spondylosis.3, 4 Secukinumab treatment has also shown rapid improvement of arthritis, dactylitis, and enthesitis in children with ERA and JPsA. Nicolino Ruperto and his team recently reported a randomized, double-blind, placebo-controlled, treatment withdrawal, phase 3 trial on secukinumab treatment for ERA and JPsA.5 In the double-blind, randomized, placebo-controlled, event-driven treatment withdrawal phase 3 study, the time to JIA disease flare was statistically longer in patients treated with secukinumab compared with placebo-treated patients from week 12 to week 104 (27% vs. 55%, hazard ratio 0.28; 95% confidence interval 0.13–0.63; p < .001). Improvements in JIA American College of Rheumatology (ACR) responses, JIA ACR inactive disease, JIA ACR core set components, and Juvenile Arthritis Disease Activity Score were reported in patients treated with secukinumab for up to 12 weeks. No new safety signals were reported with secukinumab for up to 2 years. The potential adverse effects of secukinumab include infection, hypersensitivity, malignancy, major adverse cardiovascular events and other long-term safety data from either the adult real-world practice or the pediatric trails. The need for hepatitis B virus, hepatitis C virus, and tuberculosis assessment before drug administration is not necessary for secukinumab. In order to limit or avoid the negative impact of ERA and JPsA on patients' development, quality of life, or disease-related joint injury, rapid and sustained control of disease symptoms is recommended,6, 7 which can be achieved by starting anti-inflammatory therapy early. Current treatment guidelines recommend initial bDMARD therapy in patients with risk factors, high disease activity, and intolerance to csDMARDs.8 Given the lack of tested therapies, there is an urgent need for therapies for ERA and JPsA. Ruperto's study showed that in the overall JIA population, treatment period 2 patients treated with secukinumab had significantly longer time to disease flare than those treated with placebo. Brunner's results early in treatment suggest secukinumab is rapidly effective in treating PsA associated with psoriasis.5 Given the known serious detrimental effects of enthesitis, including pain, on adults and children, the resolution of enthesitis is very important.9 Secukinumab is considered to be an important new treatment option for children with ERA and JPsA because its use resulted in a rapid and major improvement of signs and symptoms of both ERA and JPsA in Ruperto's study, including the resolution of dactylitis and enthesitis. By week 12, more than 30% of patients had achieved non-active disease, the preferred treatment target for JIA, and more than 40% of patients treated with secukinumab throughout Brunner's study.5 Enthesitis-related arthritis is considered to be the pediatric counterpart of non-radiological axial spondylosis, and children with ERA have also experienced profound improvements in signs and symptoms of the disease.1 The role of interleukin-17A in the skin, joints, and articular manifestations of spinal arthritis is well known, and significant improvement has been reported with secukinumab in patients with psoriasis and PsA, providing sustained reductions in clinical manifestations, inhibition of radiographic progression, and improvement in C-reactive protein levels, erythrocyte sedimentation rate, and patients' quality of life.10 Earlier studies on JIA have shown that exposure to previous bDMARDs in drug trials reduces the response rate to subsequent treatment.11 Although the trial did not provide information on secukinumab's efficacy in previous bDMARD exposure, a retrospective study of ERA patients who had failed anti-TNF therapy reported significant improvement in JIA disease activity measured using the Juvenile Arthritis Disease Activity Score (JADAS) after treatment with secukinumab.12, 13 Secukinumab has shown a more than 75% response rate in children with ERA and may be a good alternative to anti-TNF therapy.9 Consistent with Brunner's finding, patients in the study experienced a rapid, profound, and sustained decrease in disease activity, as measured by JADAS-27, for up to 2 years.5 Responses in children with JPsA treated with secukinumab in Brunner's study are consistent with previous studies of patients with PsA, where secukinumab showed sustained improvement in ACR response, resolution of enthesitis and dactylitis, sustained improvement in skin clearance, and sustained improvement over 5 years in six key manifestations of PsA.5 There are no significant differences in treatment retention or treatment response between secukinumab and adalimumab as a first-, second-, or third-line treatment in PsA and regardless of whether the patients had failed a previous TNF inhibitor (TNFi) due to lack of effect. This implies that, on a group level, in patients with PsA who have failed one or more TNFi, advancing to either another TNFi or secukinumab appears to be equally successful, although inflammatory domains other than arthritis may also be of importance when choosing a mode of action.14 Anterior chronic non-infectious uveitis is typically asymptomatic and may become chronic affecting ocular structures and vision. In Brunner's study, there was no uveitis observed in children with JPsA who were treated with secukinumab.5 In conclusion, in children and adolescents with ERA and JPsA, secukinumab demonstrated significantly longer time to flare and number of flares versus placebo. There was sustained improvement of signs and symptoms up to week 104. Safety in this pediatric population is consistent with the known safety profile of secukinumab. Ping Wu drafted the manuscript and managed the submission. Chunlin Huang and Pei-Fen Liao provided editorial support. Nicolino Ruperto and Huasong Zeng reviewed the manuscript several times. We thank all the authors to participate in the study. The authors declare no conflicts of interest. Not applicable.