Rheumatoid Arthritis Treatment May Improve Anemia Without Symptom Relief

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Rheumatoid Arthritis Treatment May Improve Anemia Without Symptom Relief

NAAC Review Published: December 3, 2008
Rheumatoid arthritis (RA) patients with anemia often experience reduced quality of life as measured by pain, fatigue, and health assessment scores. While most causes of RA-associated anemia (impaired iron delivery and utilization by erythroid progenitors) are consistent with anemia of chronic disease, production of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor alpha (TNFá) are also contributing factors of RA-associated anemia pathogenesis. Mounting evidence has shown that treating anemia can lead to improvement in quality of life in RA patients, and some studies have shown that treatment with TNFá inhibitors, such as infliximab, can elevate hemoglobin (Hb) levels in RA patients with anemia. Recently, a novel study by Doyle et al evaluated the effects TNFá inhibition by pooling data from three prospective, randomized, double-blind, placebo-controlled clinical trials.

In these three trials – ATTRACT,1 ASPIRE,2 and START3 – RA patients with anemia were randomly assigned to receive a combination of methotrexate (MTX) therapy and infliximab or placebo for 22 weeks. Anemia was defined as Hb levels of <12 g/dL, and the overall primary endpoint was the percentage of treated patients with an anemic baseline who had at least a 1 g/dL increase at week 22. Among anemic patients, infliximab plus MTX treatment showed a significantly greater mean increase at week 22 than in patients who received the placebo. These same results were observed in the severe anemia category (Hb levels <10 g/dL). Regression analysis also showed that infliximab treatment was independently associated with greater improvement in Hb levels after adjusting for demographics and improvement in disease activity. In addition, vitality scores showed a positive correlation between Hb and fatigue. Significant improvements in Hb levels and quality of life scores after infliximab and MTX treatment were seen across all three studies, both collectively and individually.

Although the pathophysiology of anemia in RA is not well understood, these results support evidence that the inhibitory effects of TNFá and other cytokines may be an underlying mechanism. However, the authors concluded further study is needed to elucidate the underlying mechanisms of anemia in RA. For instance, in this study, variables such as the concomitant treatment with anti-ulcer therapies may have contributed to the improvement in Hb levels, as well as a reduction in non-steroidal anti-inflammatory drugs. Furthermore, patients with more severe anemia (Hb levels <8.5 or <8.0 g/dL) were excluded from the study, and thus the results may not be generalizable to patients in these categories.

Doyle MK, Rahman MU, Han C, Han J, Giles J, Bingham CO 3rd, Bathon J. Treatment with Infliximab plus Methotrexate Improves Anemia in Patients with Rheumatoid Arthritis Independent of Improvement in Other Clinical Outcome Measures-A Pooled Analysis from Three Large, Multicenter, Double-Blind, Randomized Clinical Trials. Semin Arthritis Rheum. 2008 Sep 27.

NAAC Expert Commentary:
Without question, the greatest advance in the last decade of rheumatology therapeutics has been the introduction of TNFá blockade. Three medications are currently available, with two more medications to follow in the near future. About half of RA patients treated with these agents improve by at least 50% (a “major response”), and about 20% of patients improve dramatically to a point of “minimal disease activity”.

A post-hoc analysis of the ATTRACT trial4 several years ago demonstrated that, even in those patients who did not enjoy symptomatic improvement with infliximab treatment, the rate of radiographic progression was reduced in infliximab-treated patients compared to placebo. Thus, it was recognized that there is a “disconnect” or discordance between symptomatic improvement and prevention of bone and cartilage damage as evidenced by radiographs.

In a similar fashion, the study by Doyle et al demonstrated that treatment of RA with infliximab resulted in improvement of anemia even in patients who did not improve clinically. The authors stated, “Multiple regression analysis indicated that the effect of infliximab plus MTX on anemia was independent of improvement in disease activity.” In other words, a therapy targeting a major proinflammatory cytokine, produced improvement in anemia, but did so independently of a reduction in joint pain.

The major lessons we can take from this study are that (1) specifically targeted therapies can result in major hematologic benefit, as we have learned from recombinant agents such as erythropoietin and filgrastim, and that (2) reducing “inflammation” in a chronic disease can result in hematologic benefit, even if symptomatic improvement does not occur.

References
St Clair EW, Wagner CL, Fasanmade AA, Wang B, Schaible T, Kavanaugh A, Keystone EC. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002 Jun;46(6):1451-19. Link.
Smolen JS, Van Der Heijde DM, St Clair EW, Emery P, Bathon JM, Keystone E, Maini RN, Kalden JR, Schiff M, Baker D, Han C, Han J, Bala M; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum. 2006 Mar;54(3):702-10. Link.
Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, Rahman MU; START Study Group. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006 Apr;54(4):1075-86. Link.
Smolen JS, Han C, Bala M, Maini RN, Kalden JR, van der Heijde D, Breedveld FC, Furst DE, Lipsky PE; ATTRACT Study Group. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum. 2005 Apr;52(4):1020-30. Link.
Last Updated: December 3, 2008

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