Safety and efficacy of tofacitinib for the treatment of patients with juvenile idiopathic arthritis: preliminary results of an open-label, long-term extension study

Abstract

Objectives: We report the safety, tolerability and efficacy of tofacitinib in patients with juvenile idiopathic arthritis (JIA) in an ongoing long-term extension (LTE) study.

Methods: Patients (2-<18 years) with JIA who completed phase 1/3 index studies or discontinued for reasons excluding treatment-related serious adverse events (AEs) entered the LTE study and received tofacitinib 5 mg two times per day or equivalent weight-based doses. Safety outcomes included AEs, serious AEs and AEs of special interest. Efficacy outcomes included improvement since tofacitinib initiation per the JIA-American College of Rheumatology (ACR)70/90 criteria, JIA flare rate and disease activity measured by Juvenile Arthritis Disease Activity Score (JADAS)27, with inactive disease corresponding to JADAS ≤1.0.

Results: Of 225 patients with JIA (median (range) duration of treatment, 41.6 (1-103) months), 201 (89.3%) had AEs; 34 (15.1%) had serious AEs. 10 patients developed serious infections; three had herpes zoster. Two patients newly developed uveitis. Among patients with polyarticular course JIA, JIA-ACR70/90 response rates were 60.0% (78 of 130) and 33.6% (47 of 140), respectively, at month 1, and generally improved over time. JIA flare events generally occurred in <5% of patients through to month 48. Observed mean (SE) JADAS27 was 22.0 (0.6) at baseline, 6.2 (0.7) at month 1 and 2.8 (0.5) at month 48, with inactive disease in 28.8% (36 of 125) of patients at month 1 and 46.8% (29 of 82) at month 48.

Conclusions: In this interim analysis of LTE study data in patients with JIA, safety findings were consistent with the known profile of tofacitinib, and efficacy was maintained up to month 48.

Trial registration number: NCT01500551.

Keywords: Antirheumatic Agents; Arthritis, Juvenile; Therapeutics.

Figure 1. Patient disposition. *The data cut-off date was 11 July 2022. †Patients who entered the LTE study included 26 patients with either pcJIA, jPsA or ERA from a phase 1 qualifying/index study (NCT01513902), and 199 patients with either pcJIA, jPsA or ERA from a phase 3 qualifying/index study (NCT02592434). ‡The 185 patients with pcJIA were classified as follows: extended oligoarthritis, n=27; rheumatoid factor-positive polyarthritis, n=36; rheumatoid factor-negative polyarthritis, n=111; and systemic JIA without active systemic features, n=11. AEs, adverse events; ERA, enthesitis-related arthritis; jPsA, juvenile psoriatic arthritis; LTE, long-term extension; n, number of patients; pcJIA, polyarticular course juvenile idiopathic arthritis.

Figure 2. Efficacy in the pcJIA cohort up to month 48 (observed data): JIA-ACR30/50/70/90/100 response,* JIA-ACR-ID† and JIA-ACR-CR‡ rates. Baseline values for determining JIA-ACR30/50/70/90/100 response and JIA-ACR-ID rates were those of the qualifying/index study, except for patients with >14 days between the last visit of the qualifying/index study and enrolment into the LTE study, for whom baseline values were derived from the final pre-drug visit (ie, LTE baseline) on entry to the LTE study. Baseline values from the qualifying/index study were used for 177 (95.7%) patients with pcJIA; baseline values from the LTE study baseline were used for 8 (4.3%) patients with pcJIA. *The JIA-ACR30/50/70/90/100 response criteria were: ≥3 of 6 JIA core set variables improving by ≥30/50/70/90/100%, respectively, with ≤1 variable worsening by ≥30%. In patients with sJIA, the absence of fever due to sJIA in the preceding 7 days was also required. †JIA-ACR-ID was defined as absence of all of the following signs/symptoms attributable to JIA activity: active arthritis; fever, rash, serositis, splenomegaly, hepatomegaly or generalised lymphadenopathy; active uveitis; abnormal ESR or CRP levels, and morning stiffness of ≤15 min; plus a physician’s global evaluation of overall disease activity as ‘best possible’ (assessed in this study as a score of 0 on a 21-numbered circle Visual Analogue Scale, indicating no activity). Uveitis assessment was imputed using last observation carried forward, prior to patient discontinuation. ‡Clinical remission was defined as JIA-ACR-ID for 6 months continuously while on medications. ACR, American College of Rheumatology; CR, clinical remission; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; ID, inactive disease; JIA, juvenile idiopathic arthritis; LTE, long-term extension; N, number of patients evaluated at each time point; pcJIA, polyarticular course juvenile idiopathic arthritis; sJIA, systemic juvenile idiopathic arthritis.

Figure 3. Efficacy in the pcJIA cohort up to month 48 (observed data): (A) mean JADAS* and (B) JADAS-ID rates. Baseline values were those of the qualifying/index study, except for patients with >14 days between the last visit of the qualifying/index study and enrolment into the LTE study, for whom baseline values were derived from the final pre-drug visit (ie, LTE baseline) on entry to the LTE study. Baseline values from the qualifying/index study were used for 177 (95.7%) patients with pcJIA; baseline values from the LTE study baseline were used for 8 (4.3%) patients with pcJIA. *Disease activity cut-offs are for patients with pcJIA, and jPsA or ERA with >4 active joints. Shaded areas indicate the score thresholds for JADAS disease activity classifications: green, high disease activity (scores >8.5); blue, moderate disease activity (scores >3.8–≤8.5); grey, low disease activity (scores >1.0–≤3.8); and red, inactive disease (scores ≤1). Mean JADAS data with JADAS10 2021 disease activity cut-offs are provided in online supplemental figure 7. ERA, enthesitis-related arthritis; ID, inactive disease; JADAS, Juvenile Arthritis Disease Activity Score in 27 joints, based on C reactive protein; jPsA, juvenile psoriatic arthritis; LTE, long-term extension; N, number of evaluable patients; pcJIA, polyarticular course juvenile idiopathic arthritis.

Figure 4. Efficacy in the pcJIA cohort up to month 48 (observed data): (A) median CHAQ-DI*; (B) median patient/parent assessment of child’s pain†; and (C) median patient/parent assessment of overall well-being.† Baseline values were those of the qualifying/index study, except for patients with >14 days between the last visit of the qualifying/index study and enrolment into the LTE study, for whom baseline values were derived from the final pre-drug visit (ie, LTE baseline) on entry to the LTE study. Baseline values from the qualifying/index study were used for 177 (95.7%) patients with pcJIA; baseline values from the LTE study baseline were used for 8 (4.3%) patients with pcJIA. *The dotted lines in (A) (except for most severe disability) represent clinically meaningful median CHAQ-DI scores, which have been reported previously. †The dotted lines in (B) represent interpretations of pain scores as reported previously. CHAQ-DI, Childhood Health Assessment Questionnaire–Disability Index; LTE, long-term extension; N, number of evaluable patients; pcJIA, polyarticular course juvenile idiopathic arthritis; Q1, 25th percentile; Q3, 75th percentile.