Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial

Abstract

Background Remission is the primary objective of treating juvenile idiopathic arthritis (JIA). It is still debatable whether early intensive treatment is superior in terms of earlier achievement of remission. The aim of this study was to evaluate the effectiveness of early etanercept+methotrexate (ETA+MTX) combination therapy versus step-up MTX monotherapy with ETA added in refractory disease. Methods A multi-centre, double-blind, randomized study in active polyarticular JIA patients treated with either ETA+MTX (n = 35) or placebo+MTX (n = 33) for up to 24 weeks, followed by a 24-week open-label phase. The efficacy endpoints included pedACR30 criteria improvement at week 12, inactive disease at week 24, and remission at week 48. Patients who failed to achieve the endpoints at week 12 or at week 24 escaped to open-label ETA+MTX. Safety was assessed at each visit. Results By intention-to-treat analysis, more patients in the ETA+MTX group reached the pedACR30 response at week 12 (33 (94.3%)) than in the placebo+MTX group (20 (60.6%); p = 0.001). At week 24, comparable percentages of patients reached inactive disease (11 (31.4%) vs 11 (33.3%)). At week 48, 11 (31.4%) and eight (24.2%) patients achieved remission. The median (+/−IQR) times to achieve an inactive disease state in the ETA+MTX and placebo+MTX groups were 24 (14–32) and 32 (24–40) weeks, respectively. Forty-four (74/100 patient-years) adverse events (AEs) were reported, leading to treatment discontinuation in 6 patients. Conclusions Early combination therapy with ETA+MTX proved to be highly effective compared to the standard step-up regimen. Compared to those treated with the standard regimen, more patients treated with a combination of ETA+MTX reached the pedACR30 response and achieved inactive disease and remission more rapidly.

Attainment of Inactive Disease Following Discontinuation of Adalimumab Monotherapy in Patients With Enthesitis-Related Arthritis

“…The number of patients was small, and we were unable to make a comparison between patients who received synthetic DMARDs compared with TNFi. In addition, because none of the participants received a combined biologic and synthetic DMARD treatment, we were unable to show the potential benefits of additional treatment (if any) as seen in other studies 12,16 …”

Value of Literature Review to Inform Development and Use of Biologics in Juvenile Idiopathic Arthritis

“…A total of 9 studies compared bDMARD or JAK inhibitor arms with placebo, and 3 studies compared with methotrexate monotherapy. In the Alexeeva ( 20 ) study, etanercept combined with methotrexate was compared against methotrexate monotherapy; in the ACUTE-JIA study, infliximab combined with methotrexate was compared against methotrexate monotherapy; and in the BeSt for Kids study, the control arm was methotrexate or sulfasalazine. In the RAPPORT study, the control arm was placebo for the first 4 weeks and then switched to rilonacept until the end of the study.…”

Efficacy and safety of etanercept biosimilar rhTNFR-Fc in Chinese patients with juvenile idiopathic arthritis: An open-label multicenter observational study

“…Etanercept is a fusion protein consisting of a Fc portion of immunoglobulin G linked to human TNF-α receptor with potent antiinflammatory activities, competitively inhibiting the binding of TNF-α to cell surface receptors and attenuating its biological effects. A number of studies have revealed the good effect and safety of etanercept for the treatment of rheumatoid arthritis, JIA, psoriatic arthritis, ankylosing spondylitis and psoriasis (10,(24)(25)(26)(27). Etanercept biosimilar recombinant human TNF-α receptor II: IgG Fc fusion protein (rhTNFR-Fc) is a TNF-α inhibitor targeting soluble TNF-α to inhibit its interaction with cellsurface receptors.…”

“…Compared to those treated with the standard step-up regimen, more patients treated with a combination of etanercept plus MTX reached better response and achieved inactive disease and remission more rapidly ( 26 ). The majority of children with JIA can attain inactive disease within 2 years, even many being able to discontinue treatment ( 6 ).…”

“…In general, patients with JIA did not used biological DMARDs until they were treated with cDMARD at adequate dose for at least 3 months ( 3 , 9 ). However, such a recommendation would prolong the time with active arthritis, reduce the life quality of patients and increase the risk of developing irreversible osteoarticular changes ( 26 ). According to 2019 Arthritis Foundation Guideline, initial biologic therapy may be considered for patients with risk factors and involvement of high-risk joints, high disease activity, and/or those judged by their physician to be at high risk of disabling joint damage ( 9 ).…”