Rheumatoid arthritis RMD Open: first published as 10.1136/rmdopen-2018-000742 on 23 February 2019. Downloaded from ORIGINAL ARTICLE Treatment outcomes in patients with seropositive versus seronegative rheumatoid arthritis in Phase III randomised clinical trials of tofacitinib Paul Bird,1 Stephen Hall,2 Peter Nash,3 Carol A Connell,4 Kenneth Kwok,5 David Witcombe,6 Krishan Thirunavukkarasu6 To cite: Bird P, Hall S, Nash P, ABSTRACT et al. Treatment outcomes Objectives Tofacitinib is an oral JAK inhibitor for the Key messages in patients with seropositive treatment of rheumatoid arthritis (RA). We examined versus seronegative response to tofacitinib 5 or 10 mg two times a day in What is already known about this subject? rheumatoid arthritis in Phase patients with seropositive vs seronegative RA. ► The efficacy and safety of tofacitinib in patients with III randomised clinical trials rheumatoid arthritis (RA) have been demonstrated Methods Data were pooled from five Phase III studies of of tofacitinib. RMD Open previously in Phase II and Phase III clinical trials of conventional synthetic disease-modifying antirheumatic drug 2019;5:e000742. doi:10.1136/ up to 24 months’ duration and in long-term exten- rmdopen-2018-000742 (csDMARD)- or biological DMARD-inadequate responders sion studies with up to 114 months of observation. (ORAL Step [NCT00960440]; ORAL Scan [NCT00847613]; ► Elevated levels of rheumatoid factor (RF) and/or ORAL Solo [NCT00814307]; ORAL Sync [NCT00856544]; ► Prepublication history and anticyclic citrullinated peptide (CCP) antibodies (se- additional material for this ORAL Standard [NCT00853385]). ‘Serotype’ subgroups were: ropositivity) are common in patients with RA and paper are available online. To anticyclic citrullinated peptide (CCP) and rheumatoid factor may indicate greater disease severity, a higher risk view these files, please visit (RF) positive (anti-CCP+/RF+); anti-CCP+/RF negative (-); of disease progression and may influence responses the journal online (http:// dx. doi. anti-CCP-/RF+; anti-CCP-/RF-. At month 3, ACR20/50/70 org/ 10. 1136/ rmdopen- 2018- to treatments for RA. response rates, Disease Activity Score (DAS28-4[ESR])- 000742). defined remission (DAS28-4[ESR]<2.6) and low disease What does this study add? In a posthoc, pooled analysis of five Phase III studies, http://rmdopen.bmj.com/ Received 14 June 2018 activity (LDA; DAS28-4[ESR]≤3.2), changes from baseline ► Revised 13 November 2018 (CFB) in Health Assessment Questionnaire-Disability Index tofacitinib 5 or 10 mg two times a day significantly Accepted 3 December 2018 (HAQ-DI), Short Form-36 Health Survey (SF-36) physical improved ACR20/50/70 response rates, DAS28- 4(ESR) low disease activity (LDA) rates and change functioning and Functional Assessment of Chronic Illness from baseline in Health Assessment Questionnaire- Therapy-Fatigue (FACIT-F) were evaluated. Safety endpoints Disability Index and Functional Assessment of were compared. Chronic Illness Therapy-Fatigue vs placebo in pa- Results Baseline demographics/characteristics were © Author(s) (or their tients with seropositive or seronegative RA. similar across subgroups. Tofacitinib significantly employer(s)) 2019. Re-use ► Patients who were anti-CCP+/RF+ were more likely improved ACR20/50/70 response rates, DAS28-4(ESR) permitted under CC BY-NC. No to achieve ACR20/50/70 responses with tofacitinib on September 24, 2021 by guest. Protected copyright. commercial re-use. See rights LDA rates and CFB in HAQ-DI and FACIT-F vs placebo than anti-CCP-/RF- patients (ACR20/50: both tofac- and permissions. Published across subgroups. More anti-CCP+/RF+ than anti-CCP-/ by BMJ. itinib doses; ACR70: tofacitinib 10 mg two times a RF- patients had ACR20/50/70 responses (ACR20/50: 1University of New South Wales, day); anti-CCP+/RF+ or anti-CCP+/RF- patients re- both tofacitinib doses; ACR70: 10 mg two times a day). Sydney, New South Wales, ceiving tofacitinib 10 mg two times a day were more Australia SF-36 physical functioning improved in anti-CCP+/ likely to achieve DAS28-4(ESR) remission or LDA 2Cabrini Health and Monash RF+, anti-CCP+/RF- and anti-CCP-/RF+ patients (both than anti-CCP-/RF- patients. University, Melbourne, Victoria, tofacitinib doses) and anti-CCP-/RF- patients (10 mg two Australia times a day) vs placebo. More anti-CCP+/RF+ and anti- How might this impact on clinical practice? 3 University of Queensland, CCP+/RF- than anti-CCP-/RF- patients achieved DAS28- ► This study adds to the collective evidence on the relationship between seropositivity and the efficacy Brisbane, Queensland, Australia 4(ESR) remission and LDA with tofacitinib 10 mg two 4Pfizer Inc, Groton, Connecticut, of tofacitinib, which may help to inform future ther- times a day. Frequency of adverse events (AEs), serious USA apeutic strategies. 5Pfizer Inc, New York City, New AEs and discontinuations due to AEs were similar across York, USA subgroups. 6PfizerA ustralia, Sydney, New Conclusion Generally, tofacitinib efficacy South Wales, Australia (ACR20/50/70 responses) and safety were similar INTRODUCTION across subgroups. DAS28-4(ESR) remission rates and Rheumatoid arthritis (RA) is a chronic and Correspondence to SF-36 physical functioning appeared lower in anti-CCP- debilitating autoimmune disease that has a Dr David Witcombe; patients. david. witcombe@ pfizer. com major effect on health status and quality of Bird P, et al. RMD Open 2019;5:e000742. doi:10.1136/rmdopen-2018-000742 1 RMD Open RMD Open: first published as 10.1136/rmdopen-2018-000742 on 23 February 2019. Downloaded from life.1 2 RA is characterised by inflammation of the artic- structural damage early in the course of the disease than ular synovium leading to deformity, progressive disability detection of individual markers.20 and ultimately destruction of joints. Tofacitinib is an oral Janus kinase (JAK) inhibitor for The current guidelines of both the European League the treatment of RA. The efficacy and safety of tofacitinib against Rheumatism and the American College of Rheu- 5 and 10 mg two times a day administered as monotherapy matology (ACR) recommend a ‘treat-to-target’ approach, or in combination with csDMARDs, mainly MTX, in with the primary goals of treating patients with RA identi- patients with moderately to severely active RA, have been fied as the attainment of remission or low disease activity demonstrated in Phase II21–27 and Phase III randomised (LDA) if remission is not achievable.3 4 The use of the controlled trials of up to 24 months’ duration28–33 and conventional synthetic (cs) disease-modifying antirheu- in long-term extension studies with up to 114 months of matic drug (DMARD) methotrexate (MTX) in conjunc- observation.34–36 tion with glucocorticoids (GC), either as monotherapy or This posthoc subgroup analysis used pooled data from in combination with other csDMARDs, is recommended five Phase III studies of tofacitinib to examine treatment as first-line therapy, with the aim of target attainment by response in patients with seropositive vs seronegative RA. 6 months. If this treatment fails, or if unfavourable prog- nostic markers such as early erosions, autoantibodies or METHODS high disease activity are present, the addition of other Clinical trials csDMARDs, biologic DMARDs or targeted synthetic DMARDs is recommended.3 4 However, clinical outcomes Subgroup data were pooled across five Phase III of current treatments remain variable. randomised, placebo-controlled, double-blind studies of Conflicting efficacy results have been observed for 6 to 24 months’ duration. Tofacitinib was administered at 5 or 10 mg two times a day, either as monotherapy (ORAL tumour necrosis factor inhibitors (TNFi) in different 29 studies. Previously, a randomised double-blind study of Solo, ClinicalTrials. gov number: NCT00814307) or in etanercept in combination with MTX resulted in 85% of combination with csDMARDs, mainly MTX (ORAL Sync: NCT00856544;30 ORAL Standard: NCT00853385;33 ORAL patients achieving a 20% improvement in RA according 32 28 to ACR criteria (ACR20 response).5 However, an Scan: NCT00847613 and ORAL Step: NCT00960440 ) earlier study investigating the same treatment regimen in patients with moderately to severely active RA and reported an ACR20 response rate of 71%.6 Furthermore, an inadequate response to ≥1 csDMARD or biologic contrasting results have also been observed in different DMARD. One Phase III study (ORAL Standard) included studies of infliximab. While one study from 2000 found an active comparator of adalimumab (40 mg subcutane- ACR20 responses in 42% of patients following treat- ously once every 2 weeks). Patients were permitted stable ment with infliximab in combination with MTX,7 other, background doses of low-dose oral GCs and non-steroidal anti-inflammatory drugs. more recent studies with the same treatments resulted http://rmdopen.bmj.com/ 8 9 10 in ACR20 responses in 62.4%, 60% and 58.6% of Serotype subgroups patients. Therefore, gaining a better understanding of The seropositivity status of each patient was recorded at the underlying differences in patient characteristics that baseline. For this analysis, patients were categorised as: give rise to variation in response to treatment would be anti-CCP and RF positive (anti-CCP+/RF+); anti-CCP+/ of benefit and would allow the identification of patient RF negative (-); anti-CCP-/RF+; anti-CCP-/RF-. subpopulations most likely to respond to specific treat- ment modalities. Efficacy endpoints and patient-reported outcomes Elevated levels of rheumatoid