Differences and similarities in clinical and functional responses among patients receiving tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate: a post hoc analysis of data from ORAL Strategy

Abstract

Background: This post hoc analysis assessed clinical and functional responses to tofacitinib monotherapy, tofacitinib + methotrexate (MTX), and adalimumab + MTX, in patients with rheumatoid arthritis enrolled in the ORAL Strategy study, including evaluation of patient-level data using cumulative probability plots.

Methods: In the 12-month, phase IIIb/IV ORAL Strategy study, patients with rheumatoid arthritis and an inadequate response to MTX were randomized to receive tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID + MTX, or adalimumab 40 mg every other week + MTX. In this post hoc analysis, cumulative probability plots were generated for mean percent change from baseline (%∆) in the Clinical Disease Activity Index (CDAI; clinical response) and mean change from baseline (∆) in the Health Assessment Questionnaire-Disability Index (HAQ-DI; functional response) at month 12. Median C-reactive protein (CRP) levels by time period were summarized by CDAI remission (≤ 2.8) status at months 6 and 12.

Results: Data for 1146 patients were analyzed. At month 12, cumulative probability plots for %∆CDAI and ∆HAQ-DI were similar across treatments in patients with greater response. At lower levels of response, patients receiving tofacitinib monotherapy did not respond as well as those receiving combination therapies. With tofacitinib + MTX, numerically higher baseline CRP levels and numerically larger post-baseline CRP reductions were seen in patients achieving CDAI remission at months 6 and 12 vs those who did not.

Conclusions: These results suggest that patients with a greater response did well, irrespective of which therapy they received. Patients with lesser response had better outcomes with combination therapies vs tofacitinib monotherapy, suggesting they benefitted from MTX. High pre-treatment CRP levels may be associated with better response to tofacitinib + MTX.

Trial registration: ClinicalTrials.gov, NCT02187055. Registered on 08 July 2014.

Keywords: Adalimumab; Methotrexate; Rheumatoid arthritis; Tofacitinib.

Conflict of interest statement

TT has received research grants from AbbVie, Asahi Kasei, Astellas, AYUMI, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, and Takeda; has received consulting fees or other remuneration from AbbVie, Astellas, AstraZeneca, Chugai, Eli Lilly Japan, GlaxoSmithKline, Janssen, Mitsubishi-Tanabe, Nippon Kayaku, Novartis, Taiho, Taisho Toyama, and UCB Japan; and has participated in speakers, bureaus for AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Novartis, Pfizer Japan Inc, Sanofi, Takeda, and Teijin. RF has received grants/research support from, and is a consultant for, AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, EMD Serono, Genentech, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi-Aventis, Taiho, and UCB. NI, HS, KS, and TH are employees and shareholders of Pfizer Inc. JP is an employee of Syneos Health, who were paid contractors to Pfizer Inc in the development of this manuscript and in providing statistical support. JSS has received research grants from AbbVie, AstraZeneca, Eli Lilly, Janssen, MSD, Pfizer Inc, and Roche; and has received consulting fees or other remuneration from AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, GlaxoSmithKline, ILTOO, Janssen, MedImmune, MSD, Novartis, Pfizer Inc, Roche, Samsung, Sanofi, and UCB.

© 2021. The Author(s).

Figures

Fig. 1

Cumulative probability plots at month 12. Plots show the cumulative probability for a %∆CDAIa, b ACR-Nb, and c ∆HAQ-DI. aOne extreme value for %∆CDAI is not shown: tofacitinib monotherapy, %∆CDAI = 175%. bTen extreme values for ACR-N are not shown: tofacitinib monotherapy, ACR-N =  − 1700, − 200, − 167, − 160, and − 150; cumulative probability = 0.003, 0.006, 0.009, 0.013, 0.019; tofacitinib + MTX, ACR-N =  − 106, cumulative probability = 0.003; ADA + MTX, ACR-N =  − 463, − 167, − 158, and − 129; cumulative probability = 0.003, 0.006, 0.010, and 0.013. ∆, change from baseline; ACR20/50/70, American College of Rheumatology ≥ 20%, ≥ 50%, or ≥ 70% response rates; ACR-N, American College of Rheumatology response rate, where ACR is the percentage improvement from baseline in American College of Rheumatology components, and N represents the minimum percentage achieved by each patient; ADA, adalimumab; CDAI, Clinical Disease Activity Index; HAQ-DI, Health Assessment Questionnaire-Disability Index; MCID, minimum clinically important difference; MTX, methotrexate

Fig. 2

Patients with normalized HAQ-DI scores/HAQ-DI MCID at month 12, categorized by CDAI remission and LDA. Plots show a patients with normalized HAQ-DI scores (< 0.5) at month 12 and b patients achieving HAQ-DI MCID (decrease from baseline of ≥ 0.22) at month 12, categorized by CDAI remission/LDA (≤ 10) status at months 6 and 12, and c patients with normalized HAQ-DI scores (< 0.5) at month 12 and d patients achieving HAQ-DI MCID (decrease from baseline of ≥ 0.22) at month 12, categorized by TA-CDAI remission/LDA and moderate/high disease activity status. TA-CDAI was defined as CDAI AUC divided by 12. ADA, adalimumab; AUC, area under the curve; CDAI, Clinical Disease Activity Index; HAQ-DI, Health Assessment Questionnaire-Disability Index; LDA, low disease activity; MCID, minimum clinically important difference; MTX, methotrexate; TA, time-averaged; SE, standard error

Fig. 3

Median CRP levels by time period, categorized by CDAI remission at months 6 and 12. Plots show median CRP levels by time period for a patients who achieved CDAI remission (≤ 2.8) at month 6, b patients who did not achieve CDAI remission (> 2.8) at month 6, c patients who achieved CDAI remission (≤ 2.8) at month 12, and d patients who did not achieve CDAI remission (> 2.8) at month 12. Error bars represent the interquartile range (Q1‒Q3). ADA, adalimumab, CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; MTX, methotrexate; Q1, 25th percentile; Q3, 75th percentile

Fig. 4

Median CRP levels by time period, categorized by HAQ-DI status at month 12. Plots show the median CRP levels for a patients who achieved normalized HAQ-DI (< 0.5) at month 12, b patients who did not achieve normalized HAQ-DI (≥ 0.5) at month 12, c patients who achieved HAQ-DI MCID (decrease from baseline of ≥ 0.22) at month 12, and d patients who did not achieve HAQ-DI MCID (increase, or decrease < 0.22 from baseline) at month 12. Error bars represent the interquartile range (Q1–Q3). ADA, adalimumab; CRP, C-reactive protein; HAQ-DI, Health Assessment Questionnaire-Disability Index; MCID, minimum clinically important difference; MTX, methotrexate; Q1, 25th percentile; Q3, 75th percentile