Feature Articles

Considering Anemia when Treating Rheumatoid Arthritis Patients

February 4, 2009

Inspecting handsRheumatoid arthritis (RA) is a chronic inflammatory disease that affects approximately 1.3 million adults in the United States.1 The hallmark of RA is chronic inflammation and damage to the joints, but RA is a systemic disease that may also cause progressive multi-system inflammation.2 Anemia is the most common extra-articular manifestation of RA, estimated to occur in 30-60% of RA patients.3-5 There is evidence that these patients who are anemic have more severe RA, and also have more affected joints and higher levels of functional disability and pain.5-7

“Since anemia afflicts such a large proportion of patients with RA, it should be an important consideration in clinical assessment and management,” stated Dr. Daniel Furst, a rheumatologist and Professor at the UCLA David Geffen School of Medicine.

Studies have shown that treating anemia in RA patients leads to functional improvements. Patients with RA who were treated for their anemia experienced, along with an increase in hemoglobin, improvement in joint swelling, and an increase in energy.5,6 Anemia treatment also had a positive effect on quality of life measured as decreased fatigue, increased vitality and muscle strength.8

Differential Diagnosis of
Iron Deficiency Anemia (IDA) and
Anemia of Chronic Disease (ACD)
  ACD IDA
Hemoglobin ↓↓ ↓↓↓
Ferritin -/↑(<50 μg/L) ↓(<50 μg/L)
Transferrin -/↓
Morphology Normocytic
Monochromic
Hypochromic
Microcytic
Wilson A, et al. Am J Med. 2004.2
Weiss G, et al. N Engl J Med. 2005.10

Causes of Anemia in RA Patients

The most common causes of anemia in patients with rheumatoid arthritis are the anemia of chronic disease (ACD) and iron deficiency anemia (IDA). ACD is more common than IDA in RA patients, occurring in up to 77% of anemic RA patients.2 In fact, anemia in RA patients has served as a model for the anemia of chronic disease.2 Differentiating the types of anemia is important in planning diagnostic testing and in guiding therapy. In ACD, hemoglobin levels are higher than in IDA, ferritin levels tend to be steady or increasing, and the anemia is most often normocytic and monochromic.2 If ferritin is decreased, and the anemia is hypochromic, IDA is much more likely.

It is estimated that iron deficiency anemia occurs in approximately 23% of anemic RA patients.2 However, Iron deficiency anemia often coexists with ACD in RA patients.9 It is generally a hypochromic, microcytic anemia most commonly due to gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroid therapy. “It’s important to recognize,” Dr. Furst said, “that iron deficiency anemia is not part of RA. It’s the drugs we use to treat our patients, such as the NSAIDs and the DMARDs (disease-modifying antirheumatic drugs); it can also be from the secondary effects of other concomitant conditions resulting in gastrointestinal blood loss that causes IDA in these patients.”

Furst quoteThe development of ACD in patients suffering from RA is related to the inflammation associated with the condition. The increased production of inflammatory cytokines results in decreased availability of erythropoietin, decreased erythropoietic response in the bone marrow and inadequate erythropoiesis.2 Numerous cytokines, including TNF, IL-1, IL-10, IFN-Υ and IL-6, mediate ACD. Hepcidin, a peptide that controls iron homeostasis, is an acute phase protein that is influenced by inflammation. Hepcidin, secondary to the effects of IL-6 is also associated with ACD. IL-6 has a significant effect, through the increased production of hepcidin, on decreased duodenal iron absorption and reduced iron transport to macrophages, as well as the storage of ferritin in macrophages.10

Inspecting handsTreatment of Anemia in RA Patients

The first principle of treating RA-associated anemia is to reduce inflammation as much as possible using NSAIDS, DMARDs.11 ESA therapy has been shown to be effective in treating RA-induced ACD.5,8 However, RA patients tend to have a blunted response to ESA therapy, and higher than normal ESA doses are often required. In these patients, ACD shows improvement when inflammation has decreased. When iron deficiency occurs concomitantly with ACD, 5,9 iron repletion may be needed, either alone or as adjunct to therapy with erythropoietic stimulating agents (ESAs).8 ESA therapy in combination with iron supplementation corrects anemia in most patients with RA, and may improve RA outcomes and quality of life.

Many physicians feel that anemia is not a major problem in RA patients but in fact it is common in RA and may constitute an important clinical problem for many patients. Dr. Furst advises physicians to “Check your RA patients to make sure they are not iron deficient, look at the differential for clues that they may have ACD, and most importantly treat their disease using the biologics available to reduce inflammation and affect iron homoestasis. Improvement in the anemia is part of the response to better control of their RA.”

References

  1. Centers for Disease Control. National Center for Chronic Disease Prevention and Health Promotion. Arthritis Types: Overview. Link. Accessed January 23, 2009.
  2. Wilson A, Yu HT, Goodnough LT, Nissenson AR. Prevalence and outcomes of anemia in rheumatoid arthritis: a systematic review of the literature. Am J Med. 2004 Apr 5;116 Suppl 7A:50S-57S. Link.
  3. Baer AN, Dessypris EN, Goldwasser E, Krantz SB. Blunted erythropoietin response to anaemia in rheumatoid arthritis. Br J Haematol. 1987 Aug;66(4):559-64. Link.
  4. Hochberg MC, Arnold CM, Hogans BB, Spivak JL. Serum immunoreactive erythropoietin in rheumatoid arthritis: impaired response to anemia. Arthritis Rheum. 1988 Oct;31(10):1318-21. Link.
  5. Peeters HR, Jongen-Lavrencic M, Raja AN, Ramdin HS, Vreugdenhil G, Breedveld FC, Swaak AJ. Course and characteristics of anaemia in patients with rheumatoid arthritis of recent onset. Ann Rheum Dis. 1996 Mar;55(3):162-68. Link.
  6. Murphy EA, Bell AL, Wojtulewski J, Brzeski M, Madhok R, Capell HA. Study of erythropoietin in treatment of anaemia in patients with rheumatoid arthritis. BMJ. 1994 Nov 19;309(6965):1337-78. Link.
  7. Tanaka N, Ito K, Ishii S, Yamazaki I. Autologous blood transfusion with recombinant erythropoietin treatment in anaemic patients with rheumatoid arthritis. Clin Rheumatol. 1999;18(4):293-38. Link.
  8. Kaltwasser JP, Kessler U, Gottschalk R, Stucki G, Möller B. Effect of recombinant human erythropoietin and intravenous iron on anemia and disease activity in rheumatoid arthritis. J Rheumatol. 2001 Nov;28(11):2430-36. Link.
  9. Vreugdenhil G, Swaak AJ. Anaemia in rheumatoid arthritis: pathogenesis, diagnosis and treatment. Rheumatol Int. 1990;9(6):243-57. Link.
  10. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005 Mar 10;352(10):1011-23. Link.
  11. Chijiwa T, Nishiya K, Hashimoto K. Serum transferrin receptor levels in patients with rheumatoid arthritis are correlated with indicators for anaemia. lin Rheumatol. 2001;20(5):307-13. Link.