Erythropoiesis-stimulating agents for anemia in rheumatoid arthritis

Researchers in the Cochrane Collaboration conducted a review of the effect of erythropoiesis-stimulating agents for anemia in patients with rheumatoid arthritis.  After searching for all relevant studies, they found three studies covering 133 people. Their findings are summarised below:

The review shows that in people with anemia and rheumatoid arthritis:

- it is uncertain whether erythropoiesis-stimulating agents improve quality of life or hemoglobin levels.
- it is unknown whether erythropoiesis-stimulating agents improve fatigue, as this was not measured by the studies.

We do not have precise information about side effects and complications. This is particularly true for rare but serious side effects, which may include thromboembolic complications. 

What is anemia in rheumatoid arthritis and what are erythropoiesis-stimulating agents? 

When you have rheumatoid arthritis, your immune system, which normally fights infection, attacks the lining of your joints. This makes them swollen, stiff and painful. The small joints of the hands and feet are usually affected first.  As the disease progresses, other complications may appear, including anemia (low hemoglobin level). Hemoglobin is a protein in red blood cells that carries oxygen.  Anemia is a condition in which the body does not have enough healthy red blood cells.  Erythropoietin is a hormone produced in the kidney, which increases the production of red blood cells. Erythropoiesis-stimulating agents work to increase red blood cell production. 

Authors' conclusions: 

We found conflicting evidence for erythropoiesis-stimulating agents to increase quality of life and hemoglobin level by treating anemia in patients with rheumatoid arthritis. However, this conclusion is based on randomized controlled trials with a high risk of bias, and relies on trials assessing human recombinant erythropoietin (EPO). The safety profile of EPO is unclear. Future trials assessing erythropoiesis-stimulating agents for anemia in rheumatoid arthritis should be conducted by independent researchers and reported according to the CONSORT statements. Trials should be based on Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) and The Patient-Centered Outcomes Research Institute (PCORI) approaches for combining both clinician and patient perspectives.

Read the full abstract...

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder that mainly affects the small joints of the hands and feet. Erythropoiesis-stimulating agents have been used to treat anemia, one of the extra-articular manifestations of RA. Although anemia is less of a problem now because of the reduction in inflammation due to disease-modifying antirheumatic drugs (DMARDs), it could still be an issue in countries where DMARDs are not yet accessible.


We assessed the clinical benefits and harms of erythropoiesis-stimulating agents for anemia in rheumatoid arthritis.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (issue 7 2012), Ovid MEDLINE and Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations (1948 to 7 August 2012), OVID EMBASE (1980 to 7 August 2012), LILACS (1982 to 7 August 2012), the Clinical Trials Search Portal of the World Health Organization, reference lists of the retrieved publications and review articles. We did not apply any language restrictions.

Selection criteria: 

We included randomized controlled trials (RCTs) in patients aged 16 years or over, with a diagnosis of rheumatoid arthritis affected by anemia. We considered health-related quality of life, fatigue and safety as the primary outcomes.

Data collection and analysis: 

Two authors independently performed trial selection, risk of bias assessment, and data extraction. We estimated difference in means with 95% confidence intervals (CIs) for continuous outcomes. We estimated risk ratios with 95% CIs for binary outcomes.

Main results: 

We included three RCTs with a total of 133 participants. All trials compared human recombinant erythropoietin (EPO), for different durations (8, 12 and 52 weeks), versus placebo. All RCTs assessed health-related quality of life. All trials had high or unclear risk of bias for most domains, and were sponsored by the pharmaceutical industry. Two trials administered EPO by a subcutaneous route while the other used an intravenous route.

We decided not to pool results from trials, due to inconsistencies in the reporting of results.

Health-related quality of life: subcutaneous EPO – one trial with 70 patients at 52 weeks showed a statistically significant difference in improvement of patient global assessment (median and interquartile range 3.5 (1.0 to 6.0) compared with placebo 4.5 (2.0 to 7.5) (P = 0.027) on a VAS scale (0 to 10)). The other shorter term trials (12 weeks with subcutaneous EPO and eight weeks with intravenous administration) did not find statistically significant differences between treatment and control groups in health-related quality of life outcomes.

Change in hemoglobin: both trials of subcutaneous EPO showed a statistically significant difference in increasing hemoglobin levels; (i) at  52 weeks (one trial, 70 patients), intervention hemoglobin level (median 134, interquartile range 110 to 158 g/litre) compared with the placebo group level (median 112, interquartile range; 86 to 128 g/litre) (P = 0.0001); (ii) at  12 weeks (one trial, 24 patients) compared with placebo (difference in means 8.00, 95% CI 7.43 to 8.57). Intravenous EPO at eight weeks showed no statistically significant difference in increasing hematocrit level for EPO versus placebo (difference in means 4.69, 95% CI -0.17 to 9.55; P = 0.06).

Information on withdrawals due to adverse events was not reported in two trials, and one trial found no serious adverse events leading to withdrawals. None of the trials reported withdrawals due to high blood pressure, or to lack of efficacy or to fatigue.