Results of a 10-year follow-up on the safety and efficacy of etanercept treatment in patients with juvenile idiopathic arthritis
Juvenile idiopathic arthritis (JIA) is defined as persistent arthritis of unknown etiology lasting > 6 weeks with the first onset before the age of 16. In the treatment of JIA, non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroid injections, and conventional disease-modifying antirheumatic drugs (DMARDs) are typically utilized. In case of inadequate response, targeted biological therapy can also be used. An effective and well-tolerated drug for the treatment of polyarticular JIA is the tumor necrosis factor alpha (TNF-α) inhibitor etanercept. The results of its use in various forms of JIA were examined in the CLIPPER and CLIPPER2 studies.
Study Methodology and Population
The CLIPPER study included patients aged 2–17 years with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA – arthritis with enthesitis), and psoriatic arthritis (PsA). Patients received etanercept at a dose of 0.8 mg/kg subcutaneously once a week, and their follow-up lasted 2 years. The CLIPPER study was followed by CLIPPER2, which primarily tracked the occurrence of malignancies during etanercept treatment over an additional 8 years, and secondarily its efficacy and long-term safety profile. Treatment efficacy was assessed using ACR (American College of Rheumatology) criteria.
Of the 127 CLIPPER participants, 86% (a total of 109; eoJIA n = 55; ERA n = 31; PsA n = 23) participated in the CLIPPER2 study. 84 patients remained in the study throughout its duration, and 32 of them were still using etanercept at the end of the study. The study population was 56.7% female, with a higher proportion of males among patients with ERA (78.9%). The average age of participants at study initiation was 11.7 years. The median duration of the disease before beginning follow-up was 26.8 months, and most patients (85.8%) used additional concomitant DMARDs (most commonly methotrexate) along with etanercept.
Findings
Clinical improvement corresponding to JIA ACR50 was observed in 45% of participants from the second month of the study until the end of follow-up. While the efficacy of etanercept gradually increased or remained stable during the CLIPPER study, it gradually decreased during the subsequent follow-up. Despite this, more than 95% of the patients achieved improvement corresponding to JIA ACR30 at all check-ups within the CLIPPER2 study. Continuous clinical remission according to the JADAS (Juvenile Arthritis Disease Activity Score) for 12 months was achieved by 33% of patients.
During the entire follow-up period, one case of malignancy was recorded. It was Hodgkin's lymphoma diagnosed in an 18-year-old patient with eoJIA who had also been treated with methotrexate for 8 years. The incidence of adverse events during etanercept treatment gradually decreased, from 193 cases in the first year to 9 cases in the tenth year. The most frequently reported adverse events during etanercept treatment included headaches, arthralgia, fevers, diarrhea, and leukopenia. There were no reported cases of active tuberculosis or patient deaths.
Infectious diseases occurred in 85% of participants, most commonly upper and lower respiratory tract infections and gastroenteritis. Most of these were not considered treatment-related and were mild to moderate in intensity. Infections likely related to etanercept were observed in 29 patients. The incidence of severe infections was low (14 cases in 11 participants). Two cases of opportunistic infection with the herpes zoster virus were reported.
Injection site reactions (itching, redness, swelling, and pain) occurred in just under 13% of patients, but only during the first 2 years of follow-up; no reactions occurred later. Additionally, there were 14 cases of autoimmune uveitis (3 considered a serious adverse event) and 3 cases of Crohn's disease.
Conclusion
The clear benefit of the CLIPPER and CLIPPER2 studies was the duration of patient follow-ups under continuous treatment, which lasted up to 120 months for many. The study results are comparable to those of previously published works focused on JIA and etanercept. They confirmed that this substance is among the well-tolerated, safe, and effective drugs in the treatment of juvenile idiopathic arthritis.
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Source: Vojinović J., Foeldvari I., Dehoorne J. et al.; Paediatric Rheumatology International Trials Organisation (PRINTO). Ten-year safety and clinical benefit from open-label etanercept treatment in children and young adults with juvenile idiopathic arthritis. Rheumatology (Oxford) 2023; May 4: kead183, doi: 10.1093/rheumatology/kead183 [Epub ahead of print].
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