Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints. This inflammation can damage the joints over time, leading to deformity and disability. In addition to joint problems, RA can also affect other tissues and organs, including the blood. Anemia, meaning low levels of red blood cells or hemoglobin, is one of the extra-articular manifestations that can occur with RA.
Anemia is common in RA, affecting 30-60% of patients. There are several reasons why anemia may develop, most relating to the underlying inflammatory processes of the disease. Understanding the connection between anemia and RA is important, as proper diagnosis and treatment of anemia can greatly improve a patient’s symptoms and quality of life.
What is anemia?
Anemia refers to having a lower than normal number of red blood cells (RBCs) or reduced hemoglobin levels in the blood. Hemoglobin is the iron-containing protein within RBCs that carries oxygen. When hemoglobin or RBC counts drop, the blood has a reduced capacity to transport oxygen to tissues throughout the body. This can cause symptoms such as fatigue, shortness of breath, dizziness, pale skin, chest pain, and more.
Anemia is diagnosed through blood tests measuring hemoglobin, hematocrit (the proportion of blood that is made up of RBCs), and RBC indices. Normal hemoglobin ranges are:
– Adult males: 13.5-17.5 g/dL
– Adult females: 12.0-15.5 g/dL
– Pregnant females: 11.0-12.0 g/dL
Anemia is defined as hemoglobin levels below the lower end of the normal range. It can be categorized as mild (10.0-12.0 g/dL for women, 10.0-13.0 g/dL for men), moderate (8.0-10.0 g/dL) or severe (What causes anemia in rheumatoid arthritis?
There are several mechanisms by which RA is believed to contribute to anemia development:
Chronic inflammation
The chronic widespread inflammation of RA inhibits the production of RBCs and hemoglobin. Inflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) suppress the function of erythropoietin, a hormone produced by the kidneys that promotes RBC production in the bone marrow. Increased hepcidin levels during inflammation also reduce available iron for hemoglobin synthesis.
Medications
Certain RA medications like methotrexate and leflunomide can impair bone marrow function, leading to decreased RBC and platelet production. Long-term NSAID use can cause gastrointestinal ulcers and blood loss over time. Corticosteroids may suppress bone marrow activity.
Autoantibodies against RBCs
Some RA patients develop autoantibodies directed against their own RBCs (anti-RBC autoantibodies). These can lead to premature destruction of RBCs.
Nutritional deficiencies
Chronic inflammation drives up metabolic demands for iron, vitamin B12, folate and other nutrients required for RBC production. Deficiencies in these can contribute to anemia risk. Poor nutrition and reduced appetite associated with illness can also lead to low intake of these essential nutrients.
Kidney disease
A small proportion of RA patients can develop kidney problems like glomerulonephritis and amyloidosis. This may impair the kidneys’ ability to produce adequate erythropoietin.
| Cause of Anemia | Mechanism |
|---|---|
| Chronic inflammation | Inhibition of erythropoietin, reduced iron availability |
| Medications | Bone marrow suppression, blood loss, reduced erythropoietin |
| Autoantibodies | Destruction of red blood cells |
| Nutritional deficiencies | Inadequate iron, B12, folate for hemoglobin synthesis |
| Kidney disease | Impaired erythropoietin production |
What types of anemia occur in RA?
There are several classifications of anemia that may arise in the context of RA:
Anemia of chronic disease (ACD)
This is the most common type, occurring in around 75% of anemic RA patients. It results from the chronic inflammatory response suppressing erythropoiesis and limiting iron availability. Blood levels of iron are usually low normal or low, along with low transferrin saturation. Ferritin levels, however, are normal or increased due to iron being trapped in macrophages.
Iron deficiency anemia (IDA)
This results when iron stores in the body become depleted, reducing iron available for hemoglobin production. It accounts for around 20-30% of anemia cases in RA. Contributing factors include blood loss from gastrointestinal ulcers, poor dietary iron intake, and iron sequestration by inflammation. Serum iron levels, transferrin saturation, and ferritin are decreased.
Anemia of mixed origin
In about 20% of patients, anemia has characteristics of both ACD and IDA. There is iron deficiency along with evidence of an inflammatory process impairing erythropoiesis.
Megaloblastic anemia
This less common type is caused by folate or vitamin B12 deficiency. Megaloblastic changes can be seen in the morphology of RBCs. Causes include poor intake, malabsorption, and medications like methotrexate inhibiting folate metabolism.
Hemolytic anemia
This arises from shortened RBC survival. Causes include autoantibodies targeting RBCs, mechanical destruction from heart valves or prosthetic joints, infections, certain drugs, or hematologic disorders.
| Type | Cause | Key Laboratory Findings |
|---|---|---|
| Anemia of chronic disease | Inflammation | Low/normal iron, normal/elevated ferritin |
| Iron deficiency anemia | Iron deficiency | Low iron, low transferrin saturation, low ferritin |
| Anemia of mixed origin | Inflammation and iron deficiency | Low iron, low transferrin, low/normal ferritin |
| Megaloblastic anemia | Folate/B12 deficiency | Megaloblastic RBCs, low folate/B12 |
| Hemolytic anemia | Increased RBC destruction | Elevated indirect bilirubin, low haptoglobin, high reticulocytes |
What are the symptoms of anemia in RA?
Symptoms of anemia often overlap with general symptoms of RA itself, like fatigue and weakness. Additional symptoms that may be present include:
– Shortness of breath or dizziness with exertion
– Pale skin, lips, nails and inner eyelids
– Chest pain
– Headache
– Lightheadedness upon standing
– Heart palpitations
– Brittle nails
– Strange food cravings like ice or dirt
– Difficulty concentrating
– Insomnia
The severity of symptoms tends to correlate with the degree of anemia. Mild cases may have minimal symptoms, while moderate to severe anemia has more noticeable effects. Symptoms also tend to develop gradually over time, so patients may not appreciate small changes. Treating the anemia is often the best way to alleviate symptoms.
How is anemia related to rheumatoid arthritis disease activity?
The presence and severity of anemia correlates with more active, severe rheumatoid arthritis. Lower hemoglobin levels are linked to higher disease activity scores, more aggressive progression of joint damage, and increased inflammation markers like ESR and CRP.
Some of this relationship may be attributed to higher inflammation in active disease leading to more anemia. However, anemia itself also appears to independently worsen RA disease activity and progression through several mechanisms:
Fatigue and muscle weakness
Anemia leaves patients physically run down, which can make it harder for them to stay active and maintain muscle strength. This leads to deconditioning, joint immobility, and weakness. Lack of activity promotes more inflammation.
Impaired oxygen delivery to tissues
With reduced hemoglobin, less oxygen reaches the synovium and joint tissues. Hypoxia promotes angiogenesis, pannus growth, and destructive processes in the joints.
Increased disease activity markers
Lower hemoglobin elevates ESR and CRP, suggesting higher disease activity to clinicians. This may prompt unnecessary increases in RA medications.
Blunted response to treatments
Studies show anemic RA patients have poorer responses to medications like methotrexate and biologic DMARDs. Anemia may reduce delivery of therapies to affected tissues.
Controlling anemia is an important complement to treating joint inflammation in RA patients. Improving hemoglobin levels reduces RA disease activity scores and markers like DAS28. Patients report improvements in pain, functioning and quality of life.
How is anemia diagnosed in rheumatoid arthritis patients?
Diagnosing anemia involves blood tests including:
Complete blood count (CBC)
This gives information on hemoglobin concentration, hematocrit, RBC indices, and RBC morphology. Results consistent with anemia include:
– Low hemoglobin and hematocrit
– Low MCV, MCH, MCHC (suggests microcytic anemia)
– High RDW (indicates heterogeneity in RBC size)
– Abnormal RBC shapes like tear drops or ovalocytes
Iron studies
These help differentiate between iron deficiency anemia and anemia of chronic disease:
– Serum iron – decreased in iron deficiency
– Transferrin saturation – decreased in iron deficiency
– Ferritin – decreased in iron deficiency, normal/elevated in inflammation
Vitamin B12 and folate levels
Important when megaloblastic anemia is suspected. Both are typically decreased.
Reticulocyte count
Elevated when hemolysis causes anemia, indicating a compensatory increase in RBC production.
Liver enzymes and bilirubin
Indirect bilirubin may be elevated in hemolytic anemia. Transaminases may rise if anemia is due to liver disease.
ESR and CRP
These nonspecific inflammatory markers are often elevated in RA, especially with active disease contributing to anemia of chronic disease.
Creatinine and GFR
Kidney dysfunction can cause anemia by reducing erythropoietin production. Creatinine may be increased and GFR decreased.
Thyroid studies
Hypothyroidism is a possible cause of anemia needing exclusion. TSH is elevated and T3/T4 decreased.
RA antibodies
Rheumatoid factor and anti-CCP antibodies may be present in RA patients. RBC autoantibodies can also be directly tested for.
Bone marrow biopsy
Rarely needed but can help exclude hematologic causes like myelodysplastic syndrome. Often shows reduced iron stores.
Identifying the type of anemia is essential for proper treatment. Anemia of chronic disease responds best to control of RA inflammation, while iron deficiency requires iron supplementation. Diagnosing complications like kidney disease or hypothyroidism also impacts management.
How is anemia treated in rheumatoid arthritis patients?
Treatment is aimed at correcting the underlying cause of anemia. Key strategies include:
Treat rheumatoid arthritis inflammation
Inflammation is a major driver of anemia, so controlling joint and systemic inflammation is essential. This is done with medications like:
– NSAIDs
– Corticosteroids
– Conventional DMARDs (methotrexate, hydroxychloroquine, sulfasalazine)
– Biologic DMARDs (TNF inhibitors, IL-6 blockers, T-cell modulators)
Lowering inflammation reduces cytokines that impair erythropoiesis and mobilize iron. Hemoglobin levels often improve.
Iron supplementation
Oral or IV iron is given for iron deficiency anemia. Oral iron absorbs poorly in inflammation, so IV formulations are often preferred.
Erythropoiesis stimulating agents
Medications like erythropoietin and darbepoetin stimulate RBC production and are used in more severe, refractory cases.
Folate and B12 supplementation
Required in megaloblastic anemia. Can be given orally or via injection.
Blood transfusions
May provide rapid symptomatic relief in severe symptomatic anemia. Not routinely required in most RA patients.
Treat other medical conditions
Any contributing factors like hypothyroidism, kidney disease or GI blood loss need to be managed.
An integrated approach combining RA disease control, iron supplementation as needed, management of comorbidities and other supportive care provides the best outcome for anemia. Hemoglobin levels and symptoms can improve significantly when the underlying inflammatory process is adequately treated.
What medications for rheumatoid arthritis can cause or worsen anemia?
Some medications commonly used to treat RA inflammation may also contribute to anemia risk:
Methotrexate
Methotrexate impairs folic acid metabolism and can lead to megaloblastic anemia. Higher doses above 12.5 mg/week are associated with increased risk. Folic acid supplementation helps prevent this side effect.
Leflunomide
Leflunomide inhibits pyrimidine synthesis, which can impair bone marrow function. It may cause a reversible mild anemia in some patients.
Sulfasalazine
Sulfasalazine can cause hemolytic anemia in patients with G6PD deficiency. This risk is higher with daily doses over 2 grams.
NSAIDs
Prolonged NSAID use can cause GI ulcers and bleeding, contributing to iron deficiency over time. They may also blunt erythropoiesis.
Corticosteroids
Higher dose steroids (>10 mg/day prednisone equivalent) may suppress erythropoietin production and bone marrow function.
While RA medications can negatively impact hemoglobin levels, uncontrolled inflammation has a far greater effect on promoting anemia. Carefully selecting appropriate medications and doses helps control joint damage while minimizing complications. Addressing any resulting anemia with iron supplementation or erythropoiesis agents is also key.
Conclusion
Anemia is a common extra-articular manifestation in rheumatoid arthritis, affecting 30-60% of patients. Chronic inflammation appears to be the major driver of anemia development through impairment of erythropoiesis and reduced iron availability. Anemia then acts to independently worsen RA disease activity and outcomes. Screening for and properly treating anemia in RA is essential for comprehensive patient care.
While anemia in RA most often arises from the inflammatory process, iron deficiency, medication effects and other medical conditions can also contribute. Determining the underlying mechanism through laboratory studies allows targeted treatment with RA medications, iron, erythropoiesis agents, and management of contributing factors. Controlling both joint inflammation and anemia offers the best opportunity to improve patients’ symptoms and quality of life.
