Background
Interleukin-6 (IL-6) signaling plays a key role in mediating the underlying disease pathophysiology and clinical manifestations of rheumatoid arthritis (RA), including pain and fatigue [
1‐
5]. Sarilumab is an investigational novel human immunoglobulin G1 (IgG1) monoclonal antibody that inhibits IL-6-mediated signaling by selectively binding to soluble and membrane-bound IL-6 receptor α [
6].
Patients report a significant number of adverse events (AEs) associated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), particularly with methotrexate (MTX) [
7,
8]. Consequently, at least 30% of patients with RA using biologic DMARDs (bDMARDs) do not use concomitant background therapy, highlighting the importance of bDMARD monotherapy as a therapeutic option [
9,
10]. As previously reported, sarilumab in combination with csDMARDs reduces disease activity and improves patient-reported outcomes (PROs) with a manageable safety and tolerability profile consistent with IL-6 receptor blockade [
6,
11‐
13]. The superior efficacy of sarilumab monotherapy in comparison with adalimumab monotherapy was shown in the phase III, multicenter, randomized controlled trial (RCT) MONARCH (NCT02332590) [
14]. Rates of AEs and serious AEs observed in MONARCH were similar between treatment groups. Although neutropenia was more common with sarilumab, infection rates were comparable between groups [
14].
PROs supplement physician-reported clinical assessments and acute-phase reactant measurements, and they present a more complete understanding of disease, treatment, and treatment impact on patients. Using the American College of Rheumatology (ACR) core dataset alone to define disease activity and treatment benefit does not account for other disease symptoms that are important to patients with RA or for the significant physical, social, and psychological impacts of RA on a patient’s daily life and functioning [
15‐
19]. Quantifying fatigue, the effect of RA symptoms on participation (work within and outside the home, family, and social and leisure activities), and ultimately on broad health status or health-related quality of life (HRQOL), is vital for a comprehensive evaluation of RA treatments such as sarilumab [
20]. PROs, measured by validated and reliable instruments in appropriately designed trials, offer a means to obtain these data in a clinically meaningful way [
21]. This paper reports our comparison of PROs of patients with active RA who received sarilumab monotherapy vs. adalimumab monotherapy.
Discussion
These results from the MONARCH study show that sarilumab monotherapy is superior to adalimumab monotherapy according to a number of patient-reported endpoints, including physical function. Improvements were demonstrated by week 12, and between-group differences increased over time, despite the allowance of adalimumab or matched placebo (but not sarilumab) dose escalation in patients with poor responses. Results from these PRO analyses support the clinical efficacy data previously reported [
14].
As in previous clinical trials of sarilumab and adalimumab [
11,
13,
37], baseline PRO scores indicate a substantial impairment of general health status, physical function, and participation when compared with an age- and sex-matched U.S. general population. Considerable improvements in PROs were reported after treatment with both sarilumab and adalimumab. This is consistent with previous RCTs of sarilumab administered in combination with csDMARDs in MTX-IR and tumor necrosis factor inhibitor (TNFi)-IR RA populations [
11,
13] and of adalimumab administered in combination with MTX in patients with early RA or as a monotherapy in patients with active RA who are intolerant of or inappropriate for continued MTX treatment [
37,
38]. Notably, the proportion of patients reporting normative values in HAQ-DI, FACIT-F, and SF-36 PCS and MCS and all individual SF-36 domains was substantially increased with both therapies, with numerically greater increases reported with sarilumab than with adalimumab. These data indicate that attainment of normative values is now a reasonable goal for RA therapy.
Compared with adalimumab, sarilumab resulted in significantly greater improvements in PtGA, physical function, and indicators of health status (HAQ-DI, SF-36 PCS) and pain. Sarilumab monotherapy also resulted in greater improvements in RAID than adalimumab monotherapy, providing further evidence of the broad benefits of sarilumab monotherapy in reducing the impact of RA on patients’ lives. RAID is a relatively new disease-specific measure that provides a weighted profile of seven patient-valued domains: pain, functional disability, fatigue, sleep, physical/emotional well-being, and coping [
26]. Improvements in RAID with sarilumab monotherapy are consistent with those previously reported with sarilumab plus csDMARDs in a TNFi-IR RA population [
13].
The impact of fatigue is a key consideration for patients with active RA [
39,
40]. Improvements in fatigue based on FACIT-F, the VT domain of SF-36, and the fatigue domain of RAID were reported in both the sarilumab and adalimumab groups. Improvements in the fatigue domain of RAID, FACIT-F, and SF-36 VT were numerically greater with sarilumab than with adalimumab; however, between-group differences in FACIT-F, which was part of the hierarchy, did not reach statistical significance. Morning stiffness has also been shown to have a significant impact on the lives and well-being of patients with RA and can result in frustration, distress, and absenteeism [
41]. Both sarilumab and adalimumab resulted in improvements in morning stiffness [
11,
13,
42,
43], with greater improvements with sarilumab than with adalimumab.
WPS-RA scores demonstrated that the interference of RA with work inside and outside the home and participation in family, social, and leisure activities were reduced with both sarilumab and adalimumab. Improvements in the global WPS-RA score were greater with sarilumab than with adalimumab. However, numerical between-group differences in the elements of the score that assess the impact of RA on work outside the home were small, although only 40% of the study population were employed, which may limit the ability to detect a difference.
The clinical efficacy data from the MONARCH trial are consistent with those of the ADACTA trial, which demonstrated superior clinical efficacy of tocilizumab monotherapy, another IL-6 receptor inhibitor, compared with adalimumab monotherapy, despite the allowance of adalimumab (or matched placebo) dose escalation [
38]. However, in ADACTA, between-group differences in HAQ-DI and SF-36 PCS did not reach statistical significance, whereas improvements in SF-36 MCS were greater with tocilizumab than with adalimumab [
38]. In MONARCH, sarilumab resulted in statistically significant and clinically meaningful improvements in HAQ-DI and SF-36 PCS compared with adalimumab, but between-group differences in SF-36 MCS were not significantly different.
PROs are an essential supplement to clinical data and provide a true measurable insight into treatment effects that are not completely assessed by clinical endpoints included in the ACR core set. Key strengths of this head-to-head trial are the wide range of PROs evaluated, including general and specific measures, which allow for a comprehensive evaluation of patient-reported benefits of two different bDMARD monotherapies, and the range of analyses undertaken to understand the level of benefit observed from a patient perspective. One limitation of the study was that several of the PROs were not included in the formal statistical testing hierarchy, which may limit the conclusions that can be made.
Conclusions
In patients with RA who are unsuitable candidates for treatment with MTX owing to intolerance or inadequate response, treatment with sarilumab monotherapy resulted in greater patient-reported improvements in PtGA, pain, HAQ-DI, SF-36 PCS and PF, RP, BP and SF domain scores, morning stiffness, RAID, and WPS-RA compared with adalimumab monotherapy. Reducing the impact of RA on patients’ lives is an important treatment objective, and these data indicate that sarilumab monotherapy may result in better patient-reported benefits than monotherapy with a widely used bDMARD, adalimumab.
Acknowledgements
The authors thank the patients, their families, and all investigators involved in this study. Medical writing support, including developing the outline and initial manuscript draft and incorporation of comments, was provided by Alex Mellors, and editorial support, including formatting, proofreading, and submission, was provided by Sinead Stewart, both of Prime Global Medical Communications, Knutsford, Cheshire, UK, and supported by Sanofi and Regeneron Pharmaceuticals, Inc., according to good publication practice guidelines (http://annals.org/aim/article/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3). The research sponsor was involved in the study design; the collection, analysis, and interpretation of data; and data checking of information included in the article. However, the authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication.
Ethics approval and consent to participate
The protocol received approval from the institutional review board and independent ethics committee of the investigational centers and was performed in accordance with the Declaration of Helsinki. All patients provided written consent prior to study participation, and the trial was conducted in compliance with institutional review board regulations, the International Conference on Harmonisation Guidelines for Good Clinical Practice, and the Declaration of Helsinki. The specific ethical bodies that approved study are as follows: Comité de Ética Científico, S.S.M. Oriente, Chile; Eticka komise, Revmatologickeho ustavu, Czech Republic; EK FN Královské, Vinohrady, FN Kralovske Vinohrady, Czech Republic; Eticka komise, Uherskohradistske nemocnice, a.s., Czech Republic; Ethik-Kommission des Landes Berlin, Landesamt für Gesundheit und Soziales, Berlin, Germany; Medical Research Council, Ethics Committee for Clinical Pharmacology, Hungary; Ethics Committee of Tel Aviv, Sourasky Medical Center, Israel; EC of Sheba Medical Center, The Chaim Sheba Medical Center, Israel; Ethics Committee of Carmel Medical Center, Israel; Seoul National University Hospital, Republic of Korea; Eulji University Hospital, Republic of Korea; Keimyung University, Dongsan Medical Center, Republic of Korea; CE de la asociación benéfica Prisma Carlos Gonzales, Peru; Komisja Bioetyczna przy Okregowej Radzie Lekarskiej WIL, Poland; National Bioethics Committee of Medical Product and Medical Devices, Romania; LEC of the Scientific Research Institute of Rheumatology, Russian Federation; Ethics Board at Ministry of Health of the Russian Federation, Russian Federation; LEC of the Kemerovo State Medical Academy, Russian Federation; LEC of the Saintpetersburg I.I. Dzhanelidze Research Institute, Russian Federation; LEC of Saratov Regional Clinical Hospital, Russian Federation; LEC of ‘Applied Medicine’, Russian Federation; LEC of the Moscow City Hospital n.a. S. P. Botkin, Russian Federation; LEC of the City Clinical Hospital n.a. M.E. Zhadkevich, Russian Federation; Pharma Ethics (Pty) Ltd., South Africa; CEIC Corporació Sanitària del Parc Taulí, Spain; LEC of the Regional Clinical Hospital n.a. N.I. Pyrogov, Ukraine; LEC of Consultative Diagnostic Center of Pechersky District, Ukraine; LEC of the Ivano-Frankivsk Regional Clinical Hospital, Ukraine; LEC of Lutsk Regional Hospital, Ukraine; LEC of Vinnytsya City Clinical Hospital #1, Ukraine; LEC of Lviv Regional Clinical Diagnostic Center, Ukraine; LEC Kyiv City Clinical Hospital #3, Ukraine; LEC of MIHC Regional Clinical Hospital, Ukraine; LEC of Poltava Regional Clinical Hospital n.a. Sklyfosofsky, Ukraine; NRES Committee London – London Bridge National Research Ethics Service, United Kingdom; Chesapeake IRB, United States; Comité de Protection des Personnes Est III Hôpital de Brabois, France; Ethics Committee of Bnei Zion Medical Center Bnei Zion, Israel; Ethics Committee of Rambam Medical Center, Israel; Ajou University Hospital, Republic of Korea; Chungnam National University Hospital, Republic of Korea; Chosun University Hospital, Republic of Korea; Dong-A University Hospital, Republic of Korea; Wits Human Research EC, South Africa; Dartmouth Medical School IRB, United States.