Monograph: Anemia & Rheumatoid Arthritis

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PLEASE NOTE: This monograph provides useful information for medical professionals, but some protocols for treatment using erythropoiesis-stimulating agents (ESAs) have changed since this handbook was originally published. We are in the process of updating the chapters to reflect these developments, so please check back regularly for the next edition of the monograph. Any questions about content can be submitted online through our Ask the Expert section. In the meantime, we recommend practitioners follow approved drug labeling and current clinical practice guidelines.

Key Points
  • Anemia is common in rheumatoid arthritis (RA) and may constitute an important clinical problem for many patients.
  • The two primary types of anemia in patients with RA are anemia of chronic disease and iron deficiency anemia.
  • Erythropoietin therapy in combination with iron supplementation corrects anemia in most patients with RA, and may improve RA outcomes and quality of life.
  • Erythropoietin is useful in facilitating autologous blood donation prior to elective surgery for patients with RA and in reducing transfusion requirements.

RA: A Chronic Inflammatory Disease Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects an estimated 2.1 million Americans.1 Although patients who meet diagnostic criteria for RA for less than 6 months may enjoy a spontaneous remission,2,3 patients with persistent inflammation over a year or longer generally have a chronic progressive disease.4-6 Most patients with RA experience joint destruction, radiographic damage, functional declines, work disability after 10 years of disease,7,8 and premature death by 10 to 15 years.4,9

RA remains a source of significant morbidity in the United States, estimated to involve costs of 1% of the gross domestic product,10,11 much of which are indirect costs secondary to work disability. 12 The goal of therapy is to control inflammation in order to prevent longterm joint damage.13-16 The variables that best identify and predict severe outcomes, including work disability, high costs, and premature mortality, are poor functional status, comorbidities, old age, and low socioeconomic status, and, to a lesser degree, high radiographic scores and rheumatoid factor titer.6

Anemia Common in RA Anemia is the most common extraarticular manifestation of RA, estimated to occur in 30% to 60% of patients.17-19 Patients with RA who are anemic have evidence of more severe disease, with more involved joints and higher levels of functional disability and pain.19-21

Although any type of anemia may be seen in patients with RA, the two primary types of anemia in RA appear to be iron deficiency anemia and anemia of chronic disease. In their retrospective review of 225 patients with RA, Peeters and colleagues identified 64% as anemic. Of the group classified as anemic, 77% were found to have anemia of chronic disease and 23% to have iron deficiency anemia.19

Differential diagnosis may be difficult, as serum iron levels are low in both types of anemia, and bone marrow staining for iron stores may be required. However, serum ferritin testing usually distinguishes between iron deficiency and anemia of chronic disease. Patients with serum ferritin levels >50 µg/mL are likely to have anemia of chronic disease, while those with a lower value of serum ferritin are likely to be iron deficient.22-24

The most common causes of iron deficiency anemia in RA are blood loss through menstrual bleeding and/or gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory drugs. Anemia of chronic disease is an "inflammatory anemia," and its features in RA are similar to those seen in inflammatory bowel disease, HIV, aging, and cancer.

Impact of Inflammatory Cytokines Development of anemia of chronic disease in patients with RA appears to be related to inflammatory cytokines, which cause joint inflammation and interfere with normal red blood cell formation and destruction.25-28

Patients with RA make erythropoietin in response to the inflammatory anemia, as expected. However, the response is blunted in these patients, with both inadequate production of erythropoietin and inadequate bone marrow responses compared to people with similar levels of anemia and no inflammation.17,18,20,29,30 Animal studies suggest that increased levels of the inflammatory cytokines interleukin- 1 (IL-1) and tumor necrosis factor-? (TNF-?) inhibit erythropoietin production and interfere with erythroid colony-forming units in the bone marrow.28,31,32

Figure 7-1. Patients with RA exhibit a blunted erythropoietin response compared to patients without RA. Adapted and reprinted with permission from Brit J Hematol.17

Treatment of Anemia in RA

Antirheumatic Drugs
The first principle of treating anemia in RA is to reduce inflammation to as low a level as possible with diseasemodifying antirheumatic drugs (DMARDs),13-16 using methotrexate as an anchor drug in combination with additional DMARDs and biologic agents, including leflunomide, etanercept, infliximab, and anakinra.33 Treatment of patients with RA with infliximab (an anti–TNF-? agent) and anakinra (an IL-1 receptor antagonist) led to improvement in anemia not seen in patients treated with placebo,34 although improvement of clinical features of RA was not correlated significantly with improvement of anemia.

Iron Supplementation
Iron supplementation is of great importance in patients who have iron deficiency. Furthermore, iron deficiency may occur concomitantly with anemia of chronic disease.28,35 Iron repletion is almost always required as an adjunctive treatment to erythropoietin therapy, as erythroid production is increased.36-39

Erythropoietin Therapy
Erythropoietin therapy is effective in correcting anemia of chronic disease in patients with RA.37,40,41 However, the doses of erythropoietin required are higher than those needed by patients with anemia from noninflammatory causes, such as renal failure.

In most early studies, the increase in Hb levels was not accompanied by improvement of functional status, as measured by capacity to perform activities of daily living and pain scores on patient questionnaires.42-44 As in the studies noted above, patients who were treated with epoetin generally required high doses of iron to maintain erythrocyte production. When the erythropoietin was discontinued, the Hb level declined.

More recent studies have indicated that treatment of patients with RA with epoetin does lead to functional improvement. Peeters and colleagues noted that patients with RA who were treated with epoetin experienced improvement in joint tenderness and swelling, in addition to improvement in Hct.40,41 Another report noted improvement in Nottingham Health Profile scores for energy in patients treated with epoetin.20 Kaltwasser and colleagues found that combined treatment with epoetin and intravenous iron in patients with RA with anemia of chronic disease led to increased Hb levels, decreased disease activity, and improved quality of life (decreased fatigue and increased vitality and muscle strength).37 The beneficial effects of anemia treatment with epoetin appear to extend to children with juvenile RA, improving both quality of life and growth rates in children who are still in their growing phase.45

Treatment with epoetin may also facilitate autologous blood donation by patients with RA prior to total hip or knee arthroplasty.21,46-48 This therapy has also been shown to reduce transfusion requirements in patients with RA who undergo elective joint replacement surgery.33,48,49

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References

  1. National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. Handout on health: rheumatoid arthritis. Available at: http://www.niams.nih.gov/hi/ topics/arthritis/rahandout.htm. Accessed January 12, 2002.
  2. Lichtenstein MJ, Pincus T. Rheumatoid arthritis identified in population based cross sectional studies: low prevalence of rheumatoid factor. J Rheumatol. 1991;18:989-993.
  3. Pincus T, Callahan LF. How many types of patients meet classification criteria for rheumatoid arthritis? J Rheumatol. 1994;21:1385-1389.
  4. Pincus T, Sokka T, Wolfe F. Premature mortality in patients with rheumatoid arthritis: evolving concepts. Arthritis Rheum. 2001;44:1234-1236.
  5. Sokka T, Pincus T. Markers for work disability in rheumatoid arthritis. J Rheumatol. 2001;28:1718-1722.
  6. Pincus T, Sokka T. How can the risk of long-term consequences of rheumatoid arthritis be reduced? Best Pract Res Clin Rheumatol. 2001;15:139-170.
  7. Yelin E, Meenan R, Nevitt M, et al. Work disability in rheumatoid arthritis: effects of disease, social, and work factors. Ann Intern Med. 1980;93:551-556.
  8. Yelin EH, Henke CJ, Epstein WV. Work disability among persons with musculoskeletal conditions. Arthritis Rheum. 1986;29:1322-1333.
  9. Pincus T, Callahan LF, Sale WG, et al. Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum. 1984;27:864-872.
  10. Yelin E, Wanke LA. An assessment of the annual and long-term direct costs of rheumatoid arthritis: the impact of poor function and functional decline. Arthritis Rheum. 1999;42:1209- 1218.
  11. Yelin E. The earnings, income, and assets of persons aged 51-61 with and without musculoskeletal conditions. J Rheumatol. 1997;24:2024-2030.
  12. Yelin E. The costs of rheumatoid arthritis: absolute, incremental, and marginal estimates. J Rheumatol Suppl. 1996;44:47-51.
  13. Pincus T. Rheumatoid arthritis: a medical emergency? Scand J Rheumatol Suppl. 1994;100:21-30.
  14. Weinblatt ME. Rheumatoid arthritis: treat now, not later! Ann Intern Med. 1996;124:773-774.
  15. Emery P, Salmon M. Early rheumatoid arthritis: time to aim for remission? Ann Rheum Dis. 1995;54:944-947.
  16. Pincus T, Breedveld FC, Emery P. Does partial control of inflammation prevent long-term joint damage? Clinical rationale for combination therapy with multiple disease-modifying antirheumatic drugs. Clin Exp Rheumatol. 1999;17:S2-7.
  17. Baer AN, Dessypris EN, Goldwasser E, et al. Blunted erythropoietin response to anaemia in rheumatoid arthritis. Br J Haematol. 1987;66:559-564.
  18. Hochberg MC, Arnold CM, Hogans BB, et al. Serum immunoreactive erythropoietin in rheumatoid arthritis: impaired response to anemia. Arthritis Rheum. 1988;31:1318-1321.
  19. Peeters HR, Jongen-Lavrencic M, Raja AN, et al. Course and characteristics of anaemia in patients with rheumatoid arthritis of recent onset. Ann Rheum Dis. 1996;55:162-168.
  20. Murphy EA, Bell AL, Wojtulewski J, et al. Study of erythropoietin in treatment of anaemia in patients with rheumatoid arthritis. BMJ. 1994;309:1337-1338.
  21. Tanaka N, Ito K, Ishii S, et al. Autologous blood transfusion with recombinant erythropoietin treatment in anaemic patients with rheumatoid arthritis. Clin Rheumatol. 1999;18:293-298.
  22. Porter DR, Sturrock RD, Capell HA. The use of serum ferritin estimation in the investigation of anaemia in patients with rheumatoid arthritis. Clin Exp Rheumatol. 1994;12:179-182.
  23. Hansen TM, Hansen NE, Birgens HS, et al. Serum ferritin and the assessment of iron deficiency in rheumatoid arthritis. Scand J Rheumatol. 1983;12:353-359.
  24. Blake DR, Waterworth RF, Bacon PA. Assessment of iron stores in inflammation by assay of serum ferritin concentrations. Br Med J (Clin Res Ed). 1981;283:1147-1148.
  25. Maury CP, Andersson LC, Teppo AM, et al. Mechanism of anaemia in rheumatoid arthritis: demonstration of raised interleukin 1 beta concentrations in anaemic patients and of interleukin 1 mediated suppression of normal erythropoiesis and proliferation of human erythroleukaemia (HEL) cells in vitro. Ann Rheum Dis. 1988;47:972-978.
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