Efficacy and safety of tofacitinib by background methotrexate dose in psoriatic arthritis: post hoc exploratory analysis from two phase III trials

Abstract

Objective: Analyze tofacitinib efficacy and safety by background methotrexate (MTX) dose in patients with psoriatic arthritis (PsA).

Methods: This post hoc analysis pooled data from two phase III, double-blind trials (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) including patients receiving tofacitinib 5 or 10 mg twice daily (BID), or placebo, with stable MTX. Efficacy outcomes at month 3 stratified by MTX dose (≤ 15 month 3 stratified by MTX dose vs > 15 mg/week) were American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI); Psoriasis Area and Severity Index (PASI)50/75; change from baseline in HAQ-DI; physician's global assessment of PsA (PGA-PsA-visual analog scale [VAS]); patient's global joint and skin assessment (PGJS-VAS), Leeds Enthesitis Index (LEI); and Dactylitis Severity Score (DSS). Safety assessments included adverse events and laboratory parameters.

Results: Five hundred fifty-six patients received tofacitinib 5 mg BID (n = 186), 10 mg BID (n = 178), or placebo (n = 192), plus MTX (≤ 15 mg/week, n = 371; > 15 mg/week, n = 185). At month 3, tofacitinib efficacy was generally greater than placebo. Patients receiving tofacitinib 5 mg BID demonstrated greater numerical improvements in efficacy outcomes at month 3 with MTX > 15 mg/week vs MTX ≤ 15 mg/week; patients receiving tofacitinib 10 mg BID displayed the opposite. The safety profile was generally consistent between groups; headache was associated with MTX > 15 mg/week; decreased hemoglobin levels were observed in patients receiving tofacitinib 10 mg BID and MTX ≤ 15 mg/week.

Conclusion: Efficacy of tofacitinib was generally numerically greater than placebo, regardless of MTX dose. Tofacitinib 5 mg BID was generally more efficacious with MTX > 15 mg/week vs ≤ 15 mg/week; the opposite was observed for tofacitinib 10 mg BID. Headache was more frequent with MTX > 15 mg/week.

Trial registration: ClinicalTrials.gov . Identifier: NCT01877668 (registration: June 14, 2013) and NCT01882439 (registration: June 20, 2013). Key Points • Methotrexate is widely used in the treatment of psoriatic arthritis; however, there are limited data on the impact of varying background methotrexate doses on the efficacy and safety of Janus kinase inhibitors in patients with psoriatic arthritis. • This post hoc analysis assessed the impact of background methotrexate dose (≤ 15 or > 15 mg/week) on tofacitinib efficacy and safety in patients with psoriatic arthritis. • Results indicated that tofacitinib efficacy was generally numerically greater than placebo, regardless of methotrexate dose. Tofacitinib 5 mg twice daily, in combination with a higher dose of background methotrexate, was more efficacious compared with a lower dose of background methotrexate; the opposite was observed for tofacitinib 10 mg twice daily. • Headache was more frequent with the higher methotrexate dose. Data should be interpreted with caution due to the small sample sizes.

Keywords: Disease activity; Disease-modifying anti-rheumatic drugs; Methotrexate; Psoriatic arthritis; Tofacitinib.

Conflict of interest statement

AJK has been a consultant for AbbVie, Genentech, Genzyme, Janssen, Novartis, Pfizer Inc., Sanofi-Regeneron, and UCB and has been involved in speakers’ bureaus for Celgene, Genentech, Genzyme, Horizon, Novartis, Pfizer Inc., and Sanofi-Regeneron. OF has received research grants from AbbVie, Bristol-Myers Squibb, Novartis, and Pfizer Inc. and has been a consultant for AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc., and UCB. PN has received research grants and honoraria for lectures and advice on behalf of AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Roche, Sanofi, Pfizer Inc., and UCB and has received consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer Inc., Sun Pharma, and UCB. SP has been involved in speakers’ bureaus for Celgene and Novartis. VFA has been a consultant for AbbVie, Eli Lilly, Genentech, GSK, Pfizer Inc., and UCB and has been involved in speakers’ bureaus for AbbVie, Janssen, Merck-Serono, Novartis, Pfizer Inc., and Sanofi. CW and LT are employees and shareholders of Pfizer Inc.

© 2021. The Author(s).

Figures

Fig. 1

ACR20/50/70a, HAQ-DIb, and PASI50/75c response rate (SE) by background MTX dose (month 3). (a) ACR20, (b) ACR50, (c) ACR70, (d) HAQ-DI, (e) PASI50, and (f) PASI75 report the proportion of patients (% [SE]) achieving the specific response at month 3. A missing response was considered a non-response to treatment. This analysis included all patients who received MTX as background therapy only on day 1 in the FAS. Eight patients who used both MTX and other csDMARDs on day 1 were excluded, as were two patients who exceeded the protocol-defined maximum dose of MTX for the analysis (20 mg/week), and one patient without dosing frequency to calculate the dose. aACR20/50/70 response is defined as achieving ≥20/50/70% reduction from baseline in tender and swollen joints and at least three of five other domains (patient’s assessment of arthritis pain, patient’s global assessment of arthritis, physician’s global assessment of arthritis, C-reactive protein, and HAQ-DI). bHAQ-DI response is defined as a decrease ≥0.35 among patients with baseline HAQ-DI score ≥ 0.35. cPASI50/75 response is defined as a ≥ 50/75% reduction from baseline in PASI among patients with a baseline BSA ≥ 3% and a baseline PASI score > 0. ACR, American College of Rheumatology; BID, twice daily; BSA, body surface area; csDMARD, conventional synthetic disease-modifying anti-rheumatic drug; FAS, full analysis set; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate or methotrexate sodium; N, number of patients included in the analysis; PASI, Psoriasis Area and Severity Index; SE, standard error

Fig. 2

Treatment differences versus placebo (% and 95% CI): ACR20/50/70a, HAQ-DIb, and PASI50/75c responses by background MTX dose (month 3). (a) Tofacitinib 5 mg BID and (b) tofacitinib 10 mg BID versus placebo (95% CI) at month 3. A missing response is considered a non-response to treatment. This analysis included all patients who received MTX as background therapy only on day 1 in the FAS. Eight patients who used both MTX and other csDMARDs on day 1 were excluded, as were two patients who exceeded the protocol-defined maximum dose of MTX for the analysis (20 mg/week), and one patient without dosing frequency to calculate the dose. Cochran-Mantel-Haenszel weights adjusting for study were used to estimate the difference, along with 95% CIs (generated by large sample approximation), in response proportions between treatment groups. aACR20/50/70 response is defined as achieving ≥20/50/70% reduction from baseline in tender and swollen joints and at least three of five other domains (patient’s assessment of arthritis pain, patient’s global assessment of arthritis, physician’s global assessment of arthritis, C-reactive protein, and HAQ-DI). bHAQ-DI response is defined as a decrease ≥0.35 among patients with a baseline HAQ-DI score ≥ 0.35. cPASI50/75 response is defined as a ≥ 50/75% reduction from baseline in PASI among patients with a baseline BSA ≥ 3% and a baseline PASI score > 0. ACR, American College of Rheumatology; BID, twice daily; BSA, body surface area; CI, confidence interval; csDMARD, conventional synthetic disease-modifying anti-rheumatic drug; FAS, full analysis set; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate or methotrexate sodium; N, number of patients included in the analysis; PASI, Psoriasis Area and Severity Index

Fig. 3

Treatment differences versus placebo (least squares mean and 95% CI): ΔHAQ-DI, ΔPGA-PsA-VASa, ΔPGJS-VASa, ΔLEIb, and ΔDSSc by background MTX dose (month 3). (a) Tofacitinib 5 mg BID and (b) tofacitinib 10 mg BID versus placebo (95% CI) at month 3. Change from baseline (Δ) values at month 3 is presented in the Online Resource (Supplementary Table 1). The analysis included all patients who received MTX as background therapy only on day 1 in the FAS. Eight patients who used both MTX and other csDMARDs on day 1 were excluded, as were two patients who exceeded the protocol-defined maximum dose of MTX for the analysis (20 mg/week), and one patient without dosing frequency to calculate the dose. Each endpoint was analyzed using a mixed model for repeated measures without imputation for missing values. The model included the fixed effects of treatment, visit, treatment-by-visit interaction, geographic location, study, and baseline value, as well as fixed effects of MTX dose and its two-way and three-way interactions with treatment and visit; an unstructured covariance matrix was used. aVAS is reported from 0 to 100 mm. bFor patients with baseline LEI >0. cFor patients with baseline DSS > 0. BID, twice daily; CI, confidence interval; csDMARD, conventional synthetic disease-modifying anti-rheumatic drug; DSS, Dactylitis Severity Score; FAS, full analysis set; HAQ-DI, Health Assessment Questionnaire-Disability Index; LEI, Leeds Enthesitis Index; MTX, methotrexate or methotrexate sodium; N, number of patients evaluable for change from baseline in the endpoint at month 3; PGA-PsA-VAS, physician’s global assessment of psoriatic arthritis-visual analog scale; PGJS-VAS, patient’s global joint and skin assessment-visual analog scale; Δ, change from baseline

Fig. 4

Proportion of patients with ALT and AST ≥ 1, ≥ 2, ≥ 3, ≥ 5, and ≥ 10× ULN by month 3, by treatment group and background MTX dose. (a) ALT (tofacitinib 5 mg BID), (b) ALT (tofacitinib 10 mg BID), (c) ALT (placebo), (d) AST (tofacitinib 5 mg BID), (e) AST (tofacitinib 10 mg BID), and (f) AST (placebo) by month 3. The analysis included all patients who received MTX as background therapy on day 1 in the safety analysis set. Eight patients who used both MTX and other csDMARDs on day 1 were excluded, as were two patients who exceeded the protocol-defined maximum dose of MTX for the analysis (20 mg/week), and one patient without dosing frequency to calculate the dose. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; csDMARD, conventional synthetic disease-modifying anti-rheumatic drug; MTX, methotrexate or methotrexate sodium; N, number of patients evaluable for changes from baseline in ALT or AST at each visit; ULN, upper limit of normal