Background Anemia of chronic disease, a common comorbidity of rheumatoid arthritis (RA), is detrimental to patients' (pts) quality of life, productivity, and long-term health.
Objectives Sirukumab (SIR), a human monoclonal antibody that selectively binds to the IL-6 cytokine with high affinity, has recently demonstrated efficacy in RA. It was hypothesized that SIR, compared to placebo (pbo) and tumor necrosis factor-inhibitors (TNFi), increases hemoglobin (Hb) concentrations in RA pts by decreasing levels of iron-scavenging proteins and increasing transferrin levels, thus ameliorating anemia. This hypothesis was tested in post hoc analyses of 4 phase 3 studies of SIR in RA: SIRROUND-M (methotrexate [MTX] inadequate responders [IR]); -D (disease-modifying antirheumatic drug [DMARD] IR); -T (TNFi-IR); -H (MTX-IR, monotherapy).
Methods Standard hematology measurements, including Hb levels, were made throughout the studies by a central laboratory. Anemia was defined as Hb levels <125 g/L (males) and <115 g/L (females). In a subset of pts, iron-regulatory proteins (hepcidin, haptoglobin, hemopexin, transferrin) were measured in serum at baseline (BL) and Wk 4 using the SomaLogic SOMAscanTM platform (for SIRROUND-M, -D, -T, and -H studies, respectively: SIR 100mg q2w, n=61, 205, 136, 0; SIR 50mg q4w, n=61, 201, 128, 100; pbo, n=0, 118, 56, 0; adalimumab [ADA], n=0, 0, 0, 98).
Results SIR consistently reduced the prevalence of anemia to a greater extent than was observed for pbo (p<0.05; eg, in SIRROUND-D, anemia decreased from 25% of pts at BL to 10% at Wk 16 post-treatment with SIR 50mg q4w vs increase from 24% of pts to 28% with pbo) and ADA (SIRROUND-H). Across studies on SIR 50mg q4w, increases in Hb levels ranged from 7±10 to 10±11 g/L (mean±SD) through Wk 16; however, greater changes were seen in pts anemic at BL (13±13 to 16±12 g/L increase). Significant Hb elevations were observed by Wk 2, with comparable results for SIR 100mg q2w. Statistically significant increases in Hb levels were not observed with ADA (Fig.1) or pbo, regardless of BL anemia status. Changes in Hb levels with SIR were independent of changes in RA disease activity. Mean haptoglobin levels were modestly higher at BL in RA pts with anemia compared to pts without anemia. Across studies, both SIR doses similarly strongly decreased levels of hepcidin, haptoglobin, and hemopexin and increased transferrin levels at Wk 4, regardless of BL anemia status. The modulation of these proteins by ADA was considerably less (Fig.1) and by pbo non-significant. After SIR treatment, greater decreases in hepcidin levels were consistently observed in pts with vs without BL anemia across studies by Wk 4.
Conclusions SIR consistently increased Hb levels in RA pts (DMARD-IR, TNFi-IR, monotherapy), most prominently in pts with BL anemia, resulting in significant reductions in the prevalence of anemia. These effects were independent of the extent of improvement in RA disease activity, suggesting additional benefits of SIR beyond clinical response in RA. By inhibiting IL-6, SIR may decrease key iron-regulatory proteins, such as hepcidin, and shift homeostasis towards an increase in the pool of iron available for red blood cell Hb, thus ameliorating anemia of chronic inflammation associated with RA.
Disclosure of Interest M. Loza Employee of: Janssen Research & Development, LLC, K. Campbell Employee of: Janssen Research & Development, LLC, K. Sweet Employee of: Janssen Research & Development, LLC, B. Hsu Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, S. Daga Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, B. Dasgupta Employee of: Janssen Research & Development, LLC
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