High levels of interleukin-6 in patients with rheumatoid arthritis are associated with greater improvements in health-related quality of life for sarilumab compared with adalimumab

Abstract

Background: Increased levels of cytokines, including interleukin-6 (IL-6), reflect inflammation and have been shown to be predictive of therapeutic responses, fatigue, pain, and depression in patients with rheumatoid arthritis (RA), but limited data exist on associations between IL-6 levels and health-related quality of life (HRQoL). This post hoc analysis of MONARCH phase III randomized controlled trial data evaluated the potential of baseline IL-6 levels to differentially predict HRQoL improvements with sarilumab, a fully human monoclonal antibody directed against both soluble and membrane-bound IL-6 receptor α (anti-IL-6Rα) versus adalimumab, a tumor necrosis factor α inhibitor, both approved for treatment of active RA.

Methods: Baseline serum IL-6 levels in 300/369 randomized patients were categorized into low (1.6-7.1 pg/mL), medium (7.2-39.5 pg/mL), and high (39.6-692.3 pg/mL) tertiles. HRQoL was measured at baseline and week (W)24 and W52 by Short Form 36 (SF-36) physical/mental component summary (PCS/MCS) and domain scores, Functional Assessment of Chronic Illness Therapy -fatigue, and duration of morning stiffness visual analog scale (AM-stiffness VAS). Linear regression of changes from baseline in HRQoL (IL-6 tertile, treatment, region as a stratification factor, and IL-6 tertile-by-treatment interaction as fixed effects) assessed predictivity of baseline IL-6 levels, with low tertile as reference. Pairwise comparisons of improvements between treatment groups were performed by tertile; least squares mean differences and 95% CIs were calculated. Similar analyses evaluated W24 patient-level response on minimum clinically important differences (MCID).

Results: At baseline, patients with high versus medium or low IL-6 levels (n = 100, respectively) reported worse (nominal p < 0.05) SF-36 MCS and role-physical, bodily pain, social functioning, role-emotional domain, and AM-stiffness VAS scores. There was a greater treatment effect with sarilumab versus adalimumab in high tertile versus low tertile groups in SF-36 PCS, physical functioning domain, and AM-stiffness VAS (nominal interaction p < 0.05). PCS improvements ≥MCID were higher in high (odds ratio [OR] 6.31 [2.37, 16.81]) versus low (OR 0.97 [0.43, 2.16]) tertiles with sarilumab versus adalimumab (nominal interaction p < 0.05). Adverse events between IL-6 tertiles were similar.

Conclusions: Patients with high baseline IL-6 levels reported better improvements in PCS, physical functioning domain, and AM-stiffness scores with sarilumab versus adalimumab and safety consistent with IL-6R blockade.

Trial registration: NCT02332590 . Registered on 5 January 2015.

Keywords: Adalimumab; Biomarkers; Fatigue; Health-related quality of life; Interleukin-6; Morning stiffness; Pain; Physical function; Rheumatoid arthritis; Sarilumab.

Conflict of interest statement

Vibeke Strand is a consultant for AbbVie, Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Celltrion, CORRONA, Crescendo, Genentech/Roche, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi, and UCB. Toshio Kimura and Anita Boyapati are employees of, and shareholders in, Regeneron Pharmaceuticals, Inc. Susan Boklage was an employee and shareholder in Regeneron Pharmaceuticals, Inc. during the preparation of the manuscript. Florence Joly and Jerome Msihid are employees of, and shareholders in, Sanofi.

Figures

Fig. 1

LSM change (95% CI) from baseline to week 24 on HRQoL endpoints by IL-6 tertile† and overall population for SF-36 PCS scores (a), AM-stiffness scores (b), and FACIT-fatigue scores (c). Adalimumab: low tertile, n = 45; medium tertile, n = 53; high tertile, n = 54. Sarilumab: low tertile, n = 55; medium tertile, n = 47; high tertile, n = 46. AM-stiffness duration of morning stiffness visual analog scale, CFB change from baseline, CI confidence interval, FACIT-fatigue Functional Assessment of Chronic Illness Therapy-fatigue, HRQoL health-related quality of life, IL-6 interleukin-6, LSM least squares mean, LSM∆ LSM difference between sarilumab and adalimumab, SF-36 Short Form 36, PCS physical component summary, VAS visual analog scale. †Low (1.6–7.1 pg/mL), medium (7.2–39.5 pg/mL), high (39.6–692.3 pg/mL). *Nominal interaction p value versus low IL-6 tertile < 0.05

Fig. 2

Mean SF-36 domain scores for adalimumab and sarilumab (combined baseline† and week 24) by IL-6 tertile§. The nominal p value for the IL-6 tertile-by-treatment interaction using the low tertile as reference was ≥ 0.05 for all SF-36 domains except PF. †Baseline combined scores are presented; change from baseline for each group cannot be inferred from the figure alone. Each 10-point interval represents twice the MCID for the SF-36 domain scores. ‡p value of the between-group difference in LSM change from baseline < 0.05 within each IL-6 tertile. §Low (1.6–7.1 pg/mL), medium (7.2–39.5 pg/mL), high (39.6–692.3 pg/mL). BP bodily pain, FACIT Functional Assessment of Chronic Illness Therapy, GH general health, IL-6 interleukin-6, LSM least squares mean, MCID minimal clinically important differences, MH mental health, PF physical functioning, RE role-emotional, RP role-physical, SF social functioning, SF-36 Short Form 36, VAS visual analog scale, VT vitality

Fig. 3

Forest plot of odd ratios from patients reporting improvements ≥ MCID by baseline IL-6 tertile for SF-36 PCS score (a), SF-36 MCS score (b), and AM-stiffness (c) for sarilumab 200 mg q2w versus adalimuma12321b 40 mg q2w. *Nominal p < 0.01 for interaction test for patients reporting improvements ≥cvbnm,./MCID (using low IL-6 tertile as the reference group). CI confidence interval, MCID minimal clinically important differences, AM-stiffness duration of morning stiffness, OR odds ratio, PCS physical component summary, SF-36 Short Form 36,VAS visual analog scale