Improvement in Hemoglobin in patients with Rheumatoid Arthritis treated with Infliximab plus Methotrexate
Authors: M.K. Doyle, M.U. Rahman, C. Han, J. Han, J.T. Giles, C.O. Bingham III, J.M. Bathon
[FRI0241] Anemia is an independent factor associated with physical disability among patients with Rheumatoid Arthritis.
Authors: C. Han, M.U. Rahman, M.K. Doyle, J.M. Bathon, J. Smolen, A. Kavanaugh, R. Westhovens, D. Baker, M. Bala
Disclaimer: Drs. Bingham, Bathon, and/or Giles are authors on some of these presentations
Background:
Anemia is a common feature of rheumatoid arthritis that may be multifactorial in nature. This anemia may be due to the anemia of chronic inflammation, iron deficiency, or potentially to medication effects, or combinations of all of these. Anemia may contribute to decreased vitality and affect quality of life for patients with RA. These studies were conducted to evaluate the possible effects of a TNF antagonist, infliximab (IFX), on anemia.
Methods:
In the study by Doyle et al (TH0142) data from RA patients receiving any infusion of study agent (IFX or placebo) in the multicentered placebo-controlled, double-blind, randomized studies (ATTRACT, ASPIRE, and START) were included in a post-hoc pooled analysis. In these studies, IFX doses of 3 to 10mg/kg were administered every 4 or 8 wks; all patients received stable methotrexate (MTX). The primary endpoint was the percentage of patients with baseline hemoglobin (Hb)<12 g/dL with an increase from baseline ≥1 g/dL at week 22. In the study by Han et al (FRI 0241), additional analyses were conducted to determine the association of Hb and HAQ at baseline and week 22 by Spearman correlation. Multivariate linear regression models were used to adjust for effects from demographic differences, disease duration and disease activity (measured with DAS28). A logistic regression model was used to estimate the Odds Ratio (OR) for a clinically meaningful improvement (at least 0.25) in HAQ associated with a 1 g/dL improvement in Hb from baseline at week 22.
Results:
Approximately 37% of RA patients had anemia based on World Health Organization (WHO) criteria: Hb <12g/dL in females (39%) and <13 g/dL in males (32%). Patients with severe long-standing RA had a higher prevalence of anemia (47%) than patients with early RA (34.6%). Among the 832 patients with baseline Hb<12g/dL, IFX plus MTX resulted in a significantly greater mean (±SD) increase in Hb from baseline to wk 22 (0.79±1.13, p<0.001) than placebo plus MTX (0.37±0.92). Significantly (p<0.001) larger proportions of anemic patients treated with IFX plus MTX (n=588)had either a ≥1g/dL (39.8%) or 2g/dL (12.1%)increase in Hb from baseline to wk 22 compared with patients receiving placebo plus MTX (n=244; 19.3% and 4.5%,respectively). Greater improvement in Hb among IFX-treated patients was consistently observed across demographic and clinical outcome subgroups, even among patients without clinical (ACR20) response at wk 22..
Male and female patients with anemia had more severe disability at baseline. Hb was statistically significantly correlated with HAQ at baseline (Spearman's r =-0.23, <0.001). Disease duration and disease activity (DAS28) were associated with HAQ (all p<0.001) in multiple regression models. Even after adjustment for these variables, low Hb level was independently associated with severe physical disability at baseline (p<0.001). After adjustment for improvement in disease activity, improvement in Hb after treatment at week 22 was an independent contributor to improvement in HAQ (p<0.001), and at least a 1 g/dL improvement in Hb after treatment was associated with a clinically meaningful improvement in the HAQ score at week 22 (OR [95% CI] of 1.43 [1.10-1.86], p<0.01).
Conclusion:
These analyses showed that the combination of infliximab with MTX was better at improving anemia than MTX plus placebo. Anemia associated with RA was independently associated with disability.
Editorial Comment:
These studies are important in demonstrating the numerous effects of TNF antagonists in RA. In addition to the relief of signs and symptoms, these studies show that anemia, a common RA associated co-morbidity, is improved with infliximab in combination with methotrexate compared with MTX alone. Interestingly using multiple regression analyses the effect of infliximab on anemia was independent of other outcome measurements. The second analysis demonstrated that anemia was an independent risk factor for disability, with improvements in anemia also associated with improvements with disability. It is likely that these effects would be seen with other TNF antagonists. The mechanisms by which TNF inhibition may contribute to improvements in anemia may be multifactorial, but likely involve decreasing systemic inflammation and mediators such as hepcidin and erythropoietin. These studies highlight that anemia is frequent in RA and may also be important to treat in addition to signs and symptoms as it also affects quality of life.