Rheumatologists must consider anemia of inflammation, drug-induced anemia and other possibilities when evaluating their patients.
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Anemia is common in patients with systemic rheumatic disease, yet it may not get the attention it deserves. Anemia can result from chronic inflammation, treatment side effects or other disease factors, or it may signal an unrelated condition. Although diagnosis and treatment of anemia are sometimes challenging, clinicians must do their utmost to rigorously investigate the cause of anemia and treat where appropriate. With new drugs on the horizon to treat the anemia of inflammation, clinicians may soon have new treatment options to manage this condition.1
Background
Many patients with systemic rheumatic disease have anemia of inflammation (sometimes called anemia of chronic disease) as a secondary result of their condition. However, many other kinds of anemia occur in rheumatic patients. If clinicians simply assume anemia is due to disease inflammation, they can miss other important medical conditions, such as chronic gastrointestinal bleeding and malignancy.1
Anemia of inflammation seems to correlate with disease severity and disease activity. In studies of quality of life in patients with rheumatoid arthritis, resolution of anemia often correlates with resolution of symptoms and improved quality of life.2 Hemoglobin levels also correlate with the risk of certain comorbidities like cardiovascular disease.3 Yet it is something of an open question as to how much low-level anemia directly affects patients’ quality of life, disease morbidity and mortality. It may serve more as an indicator of overall disease status.
Guenter Weiss, MD, is professor of medicine and biochemistry and director of the Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology and Pneumology at the Medical University of Innsbruck, Austria. He says, “We have very limited information on the effect or persistence of anemia on the quality of life of such patients, as well as on the course of the underlying rheumatic disease.”
Prevalence varies among different rheumatic diseases. Factors influencing prevalence rates include treatment status, nutritional intake, age, gender, gene polymorphisms and iron homeostasis. Rates of 10–66% have been cited in rheumatoid arthritis patients, with rates on the lower end of this scale in modern patients who have been aggressively treated.1,4
Causes of Anemia in Rheumatic Disease
Iron-deficiency anemia is the most common type worldwide, but anemia of inflammation is historically a more common cause of anemia in rheumatic patients with inflammatory disease.5 However, in certain groups of patients with well-controlled disease, anemia from iron deficiency may actually be more common. For example, a 2011 study of rheumatoid arthritis patients in the U.K. found more patients with iron-deficiency anemia than anemia from inflammation.4
Iron-deficiency anemia most commonly develops as a consequence of blood loss. This can happen due to a number of factors, including gastrointestinal malignancy or severe menstruation. Certain diseases that are more common in rheumatic patients also increase the risk of iron-deficiency anemia, like autoimmune gastritis, inflammatory bowel disease, celiac disease or Helicobacter pylori infection. Some drugs commonly used in rheumatic patients also put patients at increased risk of gastric bleeding, including non-steroidal anti-inflammatory drugs and glucocorticoids.1
Rheumatologists must also consider possible drug-induced anemias when evaluating their patients. Janus kinase inhibitors such as tofacitinib can dampen the effect of erythropoietin on cells, leading to a mild anemia. Immunosuppressant drugs such as methotrexate and azathioprine sometimes cause bone marrow failure and a megaloblastic anemia, and other drugs can cause aplastic anemia. Others such as non-steroidal anti-inflammatory drugs and proton pump inhibitors can also decrease erythropoiesis or erythrocyte half-life.1
Various disease-associated mechanisms can induce anemia, distinct from anemia of inflammation itself. Systemic lupus erythematosus (SLE) can induce anemia from hemolysis, aplasia, pure red cell aplasia, myelofibrosis or thrombotic microangiopathy.6 Secondary kidney complications, such as in SLE or systemic sclerosis, can also cause anemia due to reduced production of erythropoietin.
Vitamin deficiency also plays a role in some patients. Inadequate dietary intake of B12 or folic acid can cause a megaloblastic anemia. Folic acid deficiency can also occur as a result of methotrexate therapy given without adequate folic acid supplementation.1 Evidence also suggests that vitamin D plays a role in iron regulation, and that deficiency can contribute to anemia in patients with rheumatoid arthritis.7
If clinicians simply assume anemia is due to disease inflammation, they can miss other important medical conditions.
Pathophysiology of Anemia of Inflammation
In anemia of inflammation, the pathophysiology of the underlying disease also leads to anemia. This is why treating the underlying condition often adequately treats the anemia as well. Anemia of inflammation usually induces a mild to moderate anemia that is normochromic and normocytic on peripheral blood smear.5
In recent years, researchers have come to understand the important role of the iron-regulatory hormone hepcidin in anemia of inflammation. Abnormally high levels of hepcidin are thought to play a large role in triggering the condition. Hepcidin production is induced by increasing plasma and hepatic iron concentrations, as well as certain inflammatory cytokines.5
Molecularly, hepcidin targets the only known cellular iron exporter, ferroportin, which is expressed on cell membranes in tissues that deliver iron to plasma. When hepcidin binds ferroportin, it causes ferroportin endocytosis and its subsequent destruction. This results in proportional reduction of iron export to the plasma. Hepcidin regulates the iron delivery to plasma from the macrophages that recycle old erythrocytes. It also regulates the delivery of iron from the duodenal enterocytes absorbing dietary iron, as well as from hepatocytes participating in iron storage. Thus, high hepcidin limits the absorption, remobilization and recycling of iron, resulting in reduced levels of plasma iron.5
In anemia of inflammation, high concentrations of hepcidin triggered by IL-6, TNF-α and other cytokines cause reticuloendothelial cells to sequester iron, via hepcidin. This leads to iron-restricted erythropoiesis, even though bodily supplies of iron are adequate. Inflammatory mediators also trigger shortened red blood cell survival and blunted production of erythropoietin.5
Workup/Diagnosis of Anemia
Anemia is diagnosed on the basis of reduced hemoglobin concentrations (<12 g/dL for women and <13 g/dL for men). Standard analyses include mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), reticulocyte count, peripheral smear and iron markers, such as serum iron, ferritin, transferrin and transferrin saturation. A standard workup should also include renal function tests, haptoglobin and lactate dehydrogenase (to screen for hemolysis), as well as folic acid, B12 and vitamin D to rule out vitamin deficiencies. Other tests may be needed if clinically suspected or if further investigation is required.1
Dr. Weiss notes that the proper diagnosis of anemia in these patients can be challenging. “Apart from the underlying rheumatic disease, other pathophysiological mechanisms or disorders may contribute to anemia which need to be identified and treated. One major problem in treating such patients is the lack of good surrogate markers, which can correctly identify true iron deficiency in the setting of inflammation.”
For rheumatologists, one of the most common problems is distinguishing anemia of inflammation, true iron-deficiency anemia and anemia with both components. In both iron-deficiency anemia and anemia of inflammation, both serum iron and transferrin saturation are reduced. In anemia of inflammation, the concentration of ferritin is normal or increased and circulating transferrin is low. This contrasts with iron-deficiency anemia, in which ferritin is low and transferrin is normal to increased.1,5
Traditionally, marrow iron staining has been used to distinguish the two entities in cases of diagnostic uncertainty. Anemia with inflammation reveals stainable iron in bone marrow macrophages, whereas iron-deficiency anemia does not. However, this test has been criticized due to its invasive and qualitative nature, and because iron therapy sometimes causes marrow iron deposition that may be poorly bioavailable. Measures of serum ferritin have largely replaced this measure, but ferritin may be influenced by iron loading and inflammation, making it difficult to diagnose true iron deficiency if inflammation is also present.1,5 As a rule of thumb, a ferritin concentration greater than 150 ng/mL is rare in anemia of inflammation concomitant with absolute iron deficiency.
Researchers have developed newer clinical markers, including soluble transferrin receptor (sTfR) in serum, an indicator of the needs of iron for erythropoiesis. However, the test has some limits in clinical utility because of a lack of standardization, and because age, ethnicity and inflammation influence its normal range.1
To address these concerns, researchers developed a ferritin index, a calculated ratio of sTfR:log ferritin, to provide a more accurate indicator of true iron deficiency in patients with anemia of inflammation. A low ratio indicates anemia of inflammation, while a higher index reveals true iron-deficiency anemia in association with anemia of inflammation. Unfortunately at this time, the cutoff value is largely dependent on the specific diagnostic test used, and some clinicians may find interpretation difficult.8 However, some evidence suggests that when used correctly the test can help improve the clinical diagnosis of iron-deficiency anemia, especially in the presence of inflammatory disease.9
Another potentially helpful test is reticulocyte hemoglobin content (CHr), which predicts iron availability for erythropoiesis. It tends to be reduced in anemia of inflammation present along with iron-deficiency anemia compared to anemia of inflammation alone. However, the test shows some overlap between anemia of inflammation alone and anemia of inflammation present with iron deficiency, and the determination may be limited based on the specific technical equipment. The percentage of hypochromic cells can also provide an indicator of iron availability (showing a higher percentage in true iron deficiency), but determination is dependent on the specific equipment.1,8
However, simple indices, such as mean corpuscular hemoglobin and mean cellular volume, can also be helpful, although their diagnostic sensitivity and specificity for iron-deficiency anemia are lower than for a ferritin index.1,8
Mark Koury, MD, is a practicing hematologist and an emeritus professor of medicine at Vanderbilt University School of Medicine in Nashville. In his own approach to diagnosis, Dr. Koury tends to first look at whether or not microcytosis is present. “I would say that most people who have chronic conditions seen by rheumatologists probably have normocytic anemia, not microcytic. When microcytic anemia occurs, I am always concerned about iron deficiency. And of course that occurs in rheumatology patients for a number of reasons. They’ve been bleeding in most cases; they’ve been taking NSAIDs or steroids that results in occult bleeding. They may have had a large number of lab tests, and blood taken for diagnostic testing can actually contribute to iron deficiency.”
Dr. Koury explains that in anemia of inflammation, high hepcidin keeps iron in the red cell precursors for a longer period of time than in simple iron deficiency, so microcytosis doesn’t occur as rapidly. “I use MCV; some people might use MCH, but basically these RBC indices give you a good hint to whether or not a patient has iron deficiency overlapping with anemia of chronic disease. If you see a declining MCV over a period of months, I would be concerned, especially when you dip down to 80 femtoliters or so. That’s a sign that the patient is getting iron deficient.”
He continues, “Once you start seeing that MCV approaching the lower end of the normal range, you can confirm it with a test like retic hemoglobin concentration, and then I think it is incumbent upon you to look for the source of blood loss.” According to recommended guidelines, all adult men and postmenopausal women with iron-deficiency anemia require screening for gastrointestinal malignancy. It is also important to note that other medical causes can less commonly be the source of a microcytic anemia, like lead poisoning.10
Dr. Koury recommends getting a hematology consult if there is any clinical confusion about a case or in particularly severe situations.
Diagnosis of Other Types of Anemia
Rheumatologists may also see some patients with a macrocytic anemia due to treatments like methotrexate, which slow the division of the cell and allow more protein accumulation between cell divisions. Dr. Koury notes, “Especially when I see an MCV of 100 or higher, it’s usually the methotrexate, and you can cut back the dosage and get improved red cell production, whereas if you have a heavy inflammatory component, you probably won’t see the response to reduced dosage.” Pernicious anemia, hypothyroidism, alcoholism, liver dysfunction and myelodysplastic syndrome are some other possible causes of a macrocytic anemia.11
Dr. Koury cautions rheumatologists to be aware of the possibility of a specific diagnostic situation in patients on medications that can increase the MCV. “If you have patients on a medication that is going to increase your MCV, and you have them on other medications that can lead them to have occult blood loss, they could develop a normocytic anemia. You might miss iron deficiency, because the microcytosis induced by too little iron is counterbalanced by methotrexate or other medications that induce macrocytosis.”
Hemolytic anemia can occur in patients with SLE or other autoimmune disorders. Hemolysis is associated with normal to elevated mean corpuscular volume, increased unconjugated bilirubin, increased lactate dehydrogenase and decreased haptoglobin levels. Dr. Koury notes, “Once you see a drop in the hematocrit, you probably need to look at the bilirubin—that’s a quick indicator, and you can look at haptoglobin. One of the best indicators is looking at the peripheral blood smear for spherocytes.” He also recommends getting a hematology consult if there is any clinical confusion about a case or in particularly severe situations.
Treatment of Anemia of Inflammation
We still lack good information about the best way to treat anemia of inflammation. It’s not clear in what specific situations iron, transfusions or erythropoietin-stimulating agents should be used. Clinicians may need to vary their therapeutic approach based on the underlying chronic condition, comorbidities and the specific needs of the individual patient.
Dr. Weiss explains, “Primarily, we treat the underlying disease. Successful response often results in resolution of anemia if the underlying anemia is anemia of chronic disease.” Patients may need a new or added agent to bring their disease under control or a higher dose of an existing treatment.
Because of their mechanism, certain types of treatment may provide particular benefit in treating anemia of inflammation. Studies of TNF-α-blocking drugs have shown specific improvements, as have IL-6-blocking drugs such as tocilizumab. “These drugs act mainly by treating the underlying disease and reducing the inflammatory stimulus (via IL-6), which leads to the production of the master regulator of iron homeostasis, hepcidin,” explains Dr. Weiss. He notes that at this point the data do not support the use of one of these agents over any other.12,13
However, anemia may persist in some patients who do receive adequate treatment. Dr. Weiss explains, “It appears that a considerable number of patients with rheumatic diseases suffer from a combination of inflammatory anemia in association with true iron deficiency or vitamin deficiencies, which does not normalize after successful treatment of the rheumatic disease.” Because of this, he urges clinicians to gain a solid diagnostic understanding of the anemia and its underlying pathology.
It’s not clear in what specific situations iron, transfusions or erythropoietin-stimulating agents should be used. Clinicians may need to vary their therapeutic approach based on the underlying chronic condition, comorbidities & the specific needs of the individual patient.
Iron Therapy
Dr. Weiss emphasizes that the true cause of an iron deficiency must be evaluated. Any underlying iron deficiency should be treated with iron supplementation either orally or intravenously. Oral iron absorption can be limited in some patients with anemia of inflammation due to the inhibition of iron transfer from enterocytes to the circulation.1
Dr. Weiss notes, “If ferritin is low, then both options are feasible, because minute amounts of iron are absorbed under these circumstances, even when inflammation is present (as for example shown in patients with inflammatory bowel disease). Intravenous iron appears to be more appropriate in patients with normal ferritin and more inflammation; however, we are lacking pharmacokinetics and efficacy data of intravenous iron in this setting.”
Iron administration can also be used as a type of diagnostic measure in and of itself in differentiating anemia of inflammation from iron-deficiency anemia. “You can give supplemental iron and check their reticulocyte count about a week to 10 days later,” notes Dr. Koury. “If you see the retic count go up sharply, that would indicate a significant component of iron deficiency.”
Some patients without clear-cut iron-deficiency anemia seem to benefit from iron-replacement therapy, although this may partially represent a degree of undiagnosed iron deficiency. However, caution should be used in giving extended iron treatments in patients who do not have an underlying iron deficiency, because this may actually aggravate underlying rheumatic disease. Iron overload is also a risk for patients receiving repeated iron therapy.8
Erythropoietin-Stimulating Agents, Blood Transfusions & Target Hemoglobin
Erythropoietin-stimulating agents may be helpful in some patients with anemia of inflammation. Patients may also benefit if they have both anemia of inflammation and true iron deficiency but fail to respond to iron therapy. Erythropoietin-stimulating agents have been shown to improve anemia in patients with systemic inflammatory diseases, but response rates vary based on disease type, activity, iron availability and other factors. Use of erythropoietin-stimulating agents has been associated with gains in quality of life and reduced blood transfusions. However, treatment can result in iron deficiency due to increasing demands of iron for red blood cell production.1
Dr. Koury explains some other concerns with the use of these agents. “The degree of anemia with chronic disease is not usually that severe, and whenever you give [erythropoietin] to patients, you should be aware of the possibility of thromboses. When a patient is receiving EPO and producing red cells at an increased level, the retic[ulocyte] count can become high relative to the degree of anemia. There may be occasions for EPO administration, but it should be specific to the individual patient.”
Blood transfusions can be used to rapidly treat patients with life-threatening anemia. However, concerns about long-term safety of blood transfusions make this an option that should be used only when necessary. Dr. Koury notes, “I think it’s pretty clear if you are having angina or TIAs and your hematocrit and hemoglobin are low, you have to treat, but you have to be careful. You don’t want to overshoot those situations, because you could actually precipitate a stroke or a heart attack.”
There are no randomized controlled trials on target hemoglobin levels in patients with rheumatic disease. Dr. Weiss notes, “In patients with persistent inflammation, it appears that a hemoglobin of 11–12 is better than a normalization based on data obtained with patients on hemodialysis who also suffer from a chronic inflammatory state.”
New Treatment Options on the Horizon
“New therapeutic strategies are emerging based on our expanding knowledge of the pathophysiology of inflammatory anemia,” notes Dr. Weiss. “Anti-hepcidin strategies, which either block hepcidin formation or neutralize this peptide, have been developed and are currently in phase I–III trials for the treatment of inflammatory anemia in different diseases.” The hope is that compounds targeting hepcidin may provide safer and more effective ways of addressing anemia of inflammation.
It remains to be seen which of these treatments may prove beneficial for rheumatic patients with anemia of inflammation. As more therapeutic options become available, we will need well-designed clinical trials to determine the optimal management of patients with anemia of inflammation.
Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.
References
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- 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.
- Furst DE, Chang H, Greenberg JD, et al. Prevalence of low hemoglobin levels and associations with other disease parameters in rheumatoid arthritis patients: Evidence from the CORRONA registry. Clin Exp Rheumatol. 2009 Jul–Aug;27(4):560–566.
- Bloxham E, Vagadia V, Scott K, et al. Anaemia in rheumatoid arthritis: Can we afford to ignore it? Postgrad Med J. 2011 Sep;87(1031):596–600.
- Nemeth E, Ganz T. Anemia of inflammation. Hematol Oncol Clin North Am. 2014 Aug;28(4):671–681.
- Giannouli S, Voulgarelis M, Ziakas PD, et al. Anaemia in systemic lupus erythematosus: From pathophysiology to clinical assessment. Ann Rheum Dis. 2006 Feb;65(2):144–148.
- Kostoglou-Athanassiou I, Athanassiou P, Lyraki A, et al. Vitamin D and rheumatoid arthritis. Ther Adv Endocrinol Metab. 2012 Dec;3(6):181–187.
- Nairz M, Theurl I, Wolf D, Weiss G. Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation. Wien Med Wochenschr. 2016 Oct;166(13):411–423.
- Koulaouzidis A, Said E, Cottier R, Saeed AA. Soluble transferrin receptors and iron deficiency, a step beyond ferritin. A systematic review. J Gastrointestin Liver Dis. 2009 Sep;18(3):345–352.
- Short MW, Domagalski JE. Iron deficiency anemia: Evaluation and management. Am Fam Physician. 2013 Jan;87(2):98–104.
- Nagao T, Hirokawa M. Diagnosis and treatment of macrocytic anemias in adults. J Gen Fam Med. 2017;18:200–204.
- Corrado A, Di Bello V, d’Onofrio F, et al. Anti-TNF-α effects on anemia in rheumatoid and psoriatic arthritis. Int J Immunopathol Pharmacol. 2017 Sep;30(3):302–307.
- Song SN, Iwahashi M, Tomosugi N, et al. Comparative evaluation of the effects of treatment with tocilizumab and TNF-α inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients. Arthritis Res Ther. 2013 Oct 2;15(5):R141.