Hematologic complications of rheumatoid arthritis

INTRODUCTION — Rheumatoid arthritis (RA) may be associated with a range of extraarticular manifestations, with hematologic complications including anemia and other conditions with hematologic abnormalities, such as Felty syndrome and lymphoproliferative disorders, particularly lymphoma and large granular lymphocyte (LGL) leukemia. Some hematologic complications correlate with disease activity or duration of disease, some are most likely to be medication related, and some are independent of disease activity [1].

Hematologic complications of RA and their evaluation are reviewed here. The clinical manifestations of RA, including both articular and other extraarticular manifestations, are described elsewhere. (See "Clinical manifestations of rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)

Felty syndrome and LGL leukemia associated with RA are also discussed separately:

●Felty syndrome (see "Clinical manifestations and diagnosis of Felty syndrome" and "Drug therapy in Felty syndrome" and "Role of splenectomy for Felty syndrome")

●LGL leukemia (see "Large granular lymphocyte leukemia in rheumatoid arthritis" and "Treatment of large granular lymphocyte leukemia")

OVERVIEW

Likelihood of hematologic findings — The following hematologic complications may be seen in people with rheumatoid arthritis (RA).

●Common

•Anemia of chronic disease/anemia of inflammation (ACD/AI), especially in individuals whose disease is not well controlled

•Medication-induced cytopenias, especially macrocytic anemia and neutropenia

•Iron deficiency anemia

•Vitamin B12 and folate deficiencies, which can cause mild anemia, leukopenia, and thrombocytopenia

●Rare

•Felty syndrome, which is associated with neutropenia and splenomegaly

•Large granular lymphocyte (LGL) leukemia

•Non-Hodgkin lymphoma, including diffuse large B cell lymphoma (DLBCL)

Many of the findings that were seen in the past have become less common as disease control has improved overall.

Findings of special concern (red flags) and indications for hematologist referral — The following are especially concerning and warrant hematologist involvement:

●Fever and neutropenia (absolute neutrophil count [ANC] <1500/microL (calculator 1)), which could indicate life-threatening infection.

●Severe cytopenias (hemoglobin <8 g/dL or with hemodynamic compromise; ANC <1500/microL; platelet count <50,000/microL) or rapidly declining cell counts, which may require urgent transfusions or other interventions.

●Abnormal/immature cells on the peripheral blood smear, which suggest a primary bone marrow disorder or severe infection.

●Cytopenias in combination with abnormal coagulation testing, which may suggest a more serious disorder such as disseminated intravascular coagulation (DIC).

●Suspected thromboembolic complications, which is an indication for urgent evaluation and anticoagulation.

This is not an exclusive list; other concerning findings on the history, examination, laboratory testing, or imaging should also be addressed.

ABNORMAL CBC — The complete blood count (CBC) is often abnormal in people with rheumatoid arthritis (RA). Anemia and thrombocytosis are consistent with chronic inflammation but may have other causes.

Anemia — Anemia was very common in people with RA before the routine use of more effective disease-modifying antirheumatic drugs (DMARDs) and more effective strategies for their use in the decades following the introduction of methotrexate in the mid-1980s. The prevalence of anemia prior to these breakthroughs was in the range of 25 to 70 percent [2-7].

Subsequent to the late 1990s, the prevalence of anemia has trended towards approximately 10 percent. As examples:

●In a cohort of approximately 6000 individuals with RA diagnosed between 2004 and 2016, anemia was present in 16 percent, both at the time of initial diagnosis and when re-evaluated at three years post-diagnosis [8].

●In a cohort of 2000 individuals with RA who were followed over one calendar year (2009) while receiving one or more DMARDs, 199 (10 percent) had anemia [9]. These included 90 with iron deficiency anemia (45 percent of those with anemia) and 78 with anemia of chronic disease/anemia of inflammation (ACD/AI; 39 percent of those with anemia).

While anemia is common at the initial presentation of RA, it often resolves after control of active disease is achieved with antiinflammatory drugs and DMARDs [10,11]. This recovery in hemoglobin concentration ensues because the primary cause of anemia is ACD/AI, which correlates with the extent of systemic inflammation that improves with disease control. Anemia with features other than low ferritin or that does not improve with RA disease control requires further evaluation so as not to miss a second contributing factor such as vitamin B12 deficiency. (See 'Anemia evaluation' below.)

Anemia causes — People with RA can develop anemia from all of the same causes as those without RA. The following are more likely in people with RA than the general population:

●Anemia of chronic disease/anemia of inflammation (ACD/AI) – ACD/AI is probably the most common cause of anemia in people with RA. ACD/AI is typically a mild (hemoglobin range, 10 to 11 g/dL, occasionally lower), normochromic, normocytic anemia with an inappropriately low reticulocyte count. The other cell lines (white blood cells [WBCs] and platelets) are not affected. The serum ferritin level is normal to elevated and the levels of iron, transferrin, and transferrin saturation (TSAT) are generally low [12]. (See "Anemia of chronic disease/anemia of inflammation", section on 'Testing for all individuals'.)

The mechanism of ACD/AI involves inflammatory cytokines that increase levels of hepcidin and in turn restrict iron availability for red blood cell (RBC) production. As a result, many people with newly diagnosed RA (more than 50 percent in some studies) will have mild anemia from this mechanism [13]. Treatment of RA typically improves the anemia, as discussed below. (See 'Anemia management' below.)

●Medications – Medications used to treat RA can cause anemia by several mechanisms.

•Methotrexate, sulfasalazine, leflunomide, azathioprine, and cyclophosphamide can cause direct bone marrow suppression, often with macrocytic anemia [14].

•Nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids may cause gastrointestinal bleeding and iron deficiency, with microcytic anemia.

•Many antibiotics (table 1) can cause autoimmune hemolytic anemia (AIHA), with an increased reticulocyte count. Methotrexate can rarely cause AIHA.

●Iron deficiency – Iron deficiency anemia may be caused by gastrointestinal or menstrual blood loss or pregnancy. Comorbid conditions that interfere with iron absorption may also contribute, including celiac disease, Helicobacter pylori infection, atrophic gastritis, and bariatric surgery. Typical findings include microcytosis and low ferritin, the severity of which depend on the degree of deficiency (table 2). (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Causes and risk factors for iron deficiency' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Stages of iron deficiency'.)

●Hemolysis – Hemolytic anemia is not a typical feature of RA. Antibody-mediated (Coombs-positive) hemolytic anemia has been described infrequently, primarily in patients with Felty syndrome [15]. (See "Clinical manifestations and diagnosis of Felty syndrome" and "Diagnosis of hemolytic anemia in adults".)

●Pure red cell aplasia – Acquired pure red cell aplasia (PRCA) has been reported only rarely in patients with RA [16,17]; it is a form of bone marrow suppression in which erythropoiesis is severely impaired. Causes include autoantibodies, medications, and infections, as summarized in the table (table 3). The anemia is normocytic and normochromic, and the reticulocyte count is very low. Bone marrow examination will show absent erythroblasts. (See "Acquired pure red cell aplasia in adults".)

●Felty syndrome – Felty syndrome, a rare complication of RA, typically includes neutropenia and splenomegaly. Mild anemia and/or thrombocytopenia may also be present due to splenic sequestration of RBCs and platelets [1]. (See "Clinical manifestations and diagnosis of Felty syndrome" and "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

●Other deficiencies – Other deficiencies including vitamin B12 and/or folate deficiency may occur. Some case series suggest that these conditions are more common in individuals with RA than in the general population, although the reasons are unclear [18]. Checking vitamin B12 and possibly folate levels is reasonable in all individuals with RA and unexplained macrocytic anemia. Folate testing may be omitted in some cases, such as individuals with a normal gastrointestinal anatomy and a balanced diet. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

Anemia evaluation — The urgency, pace, and focus of the evaluation depend on the patient's clinical presentation.

●Active RA – In an individual with a new presentation of RA or without good disease control who has a normochromic, normocytic anemia that is not severe (hemoglobin ≥8 to 10 g/dL) and in whom the WBC and platelet counts are normal, disease control using disease-modifying drugs may be sufficient to correct the anemia and allow a retrospective diagnosis of ACD/AI. (See "Anemia of chronic disease/anemia of inflammation", section on 'Treatment of the underlying disorder'.)

●Microcytosis (mean corpuscular volume [MCV] <80 fL) – In an individual with microcytosis, iron studies (ferritin, iron, total iron binding capacity or transferrin, and calculated TSAT) are appropriate to evaluate for possible iron deficiency. Iron deficiency is characterized by a low ferritin and low TSAT. Normal ranges for ferritin depend on whether there is an ongoing inflammatory process, as discussed separately. If iron stores are normal, evaluation for thalassemia may be appropriate. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Patients with inconclusive initial testing or comorbidities' and "Microcytosis/Microcytic anemia", section on 'Approach to the evaluation'.)

●Macrocytosis (MCV >100 fL) – In an individual with macrocytic anemia, the first question is whether one of their medications can be causing macrocytosis. Methotrexate therapy is a frequent cause of macrocytic anemia and may be associated with an MCV as high as 105 fL (occasionally higher). Mild macrocytic anemia from methotrexate is not a reason to discontinue the drug, but the vitamin B12 and folate levels should be checked, and deficiencies corrected. The reticulocyte count should also be checked, since reticulocytes are larger than mature RBCs and can increase the MCV. Severe hemolytic anemia or PRCA from a drug would be a reason to stop the drug. For patients in whom the MCV remains high (eg, >101 fL) after vitamin B12 and folate deficiencies and drug-induced causes are excluded, hematology evaluation for other causes is appropriate (eg, bone marrow examination for possible myelodysplastic syndrome). (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Diagnostic evaluation' and "Macrocytosis/Macrocytic anemia", section on 'Evaluation'.)

●Normocytic anemia (MCV 80 to 100 fL) – Multifactorial anemia is more common in RA than in the general population, and the MCV may be normal due to a combination of conditions that independently cause it to be high or low. Because multiple causes may be present, it may be reasonable to do more extensive testing initially rather than sequentially testing for individual causes. Even if one cause of anemia is identified, testing for additional causes is appropriate in any person whose anemia does not respond to treatment as expected. If their disease is well controlled by a medication that may cause anemia, testing for iron deficiency, vitamin B12 deficiency, and other common causes of anemia may be reasonable.

A reasonable panel of initial testing in an individual with relatively well-controlled RA and normocytic anemia includes:

•Iron studies (serum ferritin, iron, total iron binding capacity or transferrin, and calculated TSAT), vitamin B12 and folate levels, and reticulocyte count

•Metabolic panel that addresses kidney and liver function

•Thyroid-stimulating hormone (TSH) and possibly testosterone level (in older males in whom other initial testing is unrevealing)

●Interpretation of iron studies – A ferritin level <30 ng/mL and/or TSAT <19 percent is considered diagnostic of iron deficiency. However, iron studies may be more challenging to interpret in the setting of a chronic inflammatory condition, as ferritin is an acute phase reactant and may be increased due to inflammation. Thus, an individual with a higher ferritin may have iron deficiency. Use of a more liberal ferritin cutoff and additional testing may be helpful, including soluble transferrin receptor (sTFr) or sTFR-ferritin ratio and/or response to a therapeutic trial of iron. Staining of a bone marrow sample for iron is considered the gold standard for confirming iron deficiency, but this is rarely needed. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Patients with inconclusive initial testing or comorbidities' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Response to a therapeutic trial of iron'.)

If the above testing is unhelpful and anemia remains unexplained, additional testing may include serum protein electrophoresis and evaluation for myelodysplasia or other clonal hematologic disorders, typically with bone marrow examination, especially in older individuals. Hematology referral would be appropriate if RA is well controlled and the cause of the anemia remains unclear.

These concepts and a general approach to the anemia evaluation are summarized in the figure (algorithm 1) and discussed in detail separately. (See "Diagnostic approach to anemia in adults".)

Anemia management — Transfusion is not likely to be needed for most people with RA and anemia. However, if anemia is severe (hemoglobin <7 g/dL) or causes hemodynamic compromise, transfusions may be indicated. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

Management of anemia depends on an accurate determination of the underlying cause (see 'Anemia causes' above and 'Anemia evaluation' above):

●ACD/AI – Disease control is the major intervention and typically is sufficient to increase the hemoglobin level. In most cases the hemoglobin returns to the normal range, or at least ≥11 g/dL (women) and ≥12 g/dL (men). (See "General principles and overview of management of rheumatoid arthritis in adults".)

In a series of 93 patients with RA, 61 (66 percent) had mild anemia at baseline (mean hemoglobin, 11.3 g/dL) [19]. Hemoglobin values increased within two weeks of active therapy (tocilizumab or a tumor necrosis factor [TNF] inhibitor) and continued to rise, in most cases into the normal range. Other studies have reported similar findings [20-25].

The role of erythropoietin is very limited in RA, and it is rarely used. A systematic review from 2013 identified three randomized trials that included 133 individuals >16 years with RA and anemia; one reported improvements in health-related quality of life with erythropoiesis-stimulating agents (ESAs) and one did not [26]. It noted that the safety of ESAs is unclear. Small randomized trials from the 1980s and 1990s showed that erythropoietin could increase the hemoglobin level, but these trials preceded the modern era of RA therapy [27,28]. ESAs have fallen out of favor as a treatment for ACD/AI due to other conditions as well. (See "Anemia of chronic disease/anemia of inflammation", section on 'ESAs'.)

●Medication-induced, macrocytic anemia – Administration of folate following methotrexate dosing is routine. Isolated macrocytosis or mild macrocytic anemia due to an RA medication without evidence of vitamin B12 or folate deficiency can be observed and monitored without stopping the drug, provided the macrocytosis and/or anemia does not progressively worsen. Worsening anemia should prompt additional evaluations, and the methotrexate dose may need to be reduced or the drug discontinued if another cause is not identified. (See "Macrocytosis/Macrocytic anemia".)

●Iron deficiency – Iron repletion with oral or intravenous iron, and determination of the cause of the deficiency. (See "Treatment of iron deficiency anemia in adults".)

●Hemolytic anemia – Drug discontinuation is appropriate if a medication cause is suspected. Warm AIHA is treated with a glucocorticoid, often combined with rituximab (especially if symptomatic), along with folic acid supplementation, as discussed separately. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Initial management'.)

●Pure red cell aplasia – Immunosuppression is considered first-line therapy for individuals with no concurrent self-limited illness who have severe or prolonged anemia for more than three to four weeks. Hematologist input is advised. (See "Acquired pure red cell aplasia in adults", section on 'Management'.)

●Felty syndrome – The management of Felty syndrome is described in detail separately. (See "Drug therapy in Felty syndrome" and "Role of splenectomy for Felty syndrome".)

●Other deficiencies – Repletion of the deficient vitamin and determination of the cause of the deficiency. (See "Treatment of vitamin B12 and folate deficiencies".)

Hematologist input is appropriate if standard interventions are ineffective. The hematologist may determine that bone marrow evaluation or other specialized testing is needed to determine the cause of anemia, or that other interventions are required. (See 'Findings of special concern (red flags) and indications for hematologist referral' above.)

Neutropenia

Neutropenia causes — Neutropenia is typically defined as an absolute neutrophil count (ANC) <1500/microL; however, the reference range depends on the individual’s Duffy antigen status. For Duffy-null individuals, the lower limit of the reference range is 1210 /microL, and some individuals will have lower neutrophil counts (referred to as Duffy-null-associated neutrophil count [DANC]). (See "Red blood cell antigens and antibodies", section on 'Duffy antigens' and "Gene test interpretation: ACKR1 (Duffy blood group gene)", section on 'Reference ranges for Duffy-null and non-Duffy-null' and "Approach to the adult with unexplained neutropenia", section on 'Normal variants <1500/microL'.)

Some laboratories report the ANC; in some cases, it must be calculated by multiplying the total WBC count by the percent of neutrophils (calculator 1).

It is important to review previous ANC values when the individual was well. A decreasing ANC is of concern, even if it is not <1500/microL; individuals with a decrease in ANC should have the value repeated to determine a downward trend and need for further evaluation. (See 'Neutropenia evaluation' below.)

Causes of neutropenia specific to RA include:

●Drug-induced, such as with:

•Tumor necrosis factor (TNF) inhibitors [29]

•Interleukin (IL) 6 inhibitors [29]

•Janus kinase (JAK) inhibitors

•Methotrexate

•Leflunomide [30]

•Hydroxychloroquine [31]

●Felty syndrome

●Large granular lymphocyte (LGL) leukemia, formerly also called LGL syndrome

A literature review from 2012 identified transient neutropenia in 16 percent of individuals treated with a TNF inhibitor [32]. Another study that included 298 individuals with RA treated with a TNF inhibitor reported an episode of neutropenia in 19 percent; of these patients, 6 percent had a serious infectious complication [33]. The possibility of neutropenia is the rationale for periodic monitoring of the CBC during TNF inhibitor therapy, as discussed separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Neutropenia'.)

A few reports have described severe delayed-onset neutropenia following rituximab therapy (up to several months after administration). (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Late-onset neutropenia'.)

Other RA therapies may cause neutropenia and/or agranulocytosis, including drugs that can lead to bone marrow suppression, such as methotrexate, azathioprine, and cyclophosphamide (although the last is now rarely used other than for selected extraarticular complications); as well as drugs acting through other mechanisms, including sulfasalazine, NSAIDs, and medications used for comorbid conditions. Drugs implicated in causing neutropenia and agranulocytosis are summarized in the table (table 4) and reviewed in detail separately. (See "Drug-induced neutropenia and agranulocytosis", section on 'Implicated agents'.)

Felty syndrome and LGL leukemia are discussed below. (See 'Felty syndrome' below and 'Hematologic malignancies' below.)

Neutropenia evaluation — The pace of the evaluation depends on the severity of the neutropenia and whether the person has signs of a serious infection. If a serious infection is present, it should be treated aggressively with appropriate antibiotics and possibly granulocyte colony-stimulating factor (G-CSF), as illustrated in the algorithm (algorithm 2) and discussed separately. Notably, use of G-CSF in patients with RA may trigger a disease flare. G-CSF is most important in people who do not have adequate bone marrow production of neutrophils. (See "Management of the adult with non-chemotherapy-induced neutropenia".)

In some cases, the cause of neutropenia may be obvious, typically with drug-induced neutropenia and/or infections. Other causes may be related to RA, such as Felty syndrome or LGL leukemia, or they may be due to separate causes such as vitamin B12 deficiency. (See "Approach to the adult with unexplained neutropenia".)

An approach to the evaluation includes the following:

●Review prior CBCs to determine if neutropenia is chronic or new (algorithm 2).

●Review of medications and their temporal relationship to the onset of neutropenia. (See 'Neutropenia causes' above.)

●Review the CBC report (and blood smear if possible) for signs myelodysplasia (dysplastic WBCs) or leukemia (immature cells).

●Evaluate for splenomegaly by physical examination, with a low threshold for obtaining an abdominal ultrasound to determine spleen size.

●Obtain vitamin B12 and folate levels.

●Evaluate for infection if appropriate (eg, if fever or other signs of active infection).

●Flow cytometry to assess T cell clonality, especially if there are features of LGL leukemia (eg, immature lymphocytes, other cytopenias); clonality is present in LGL leukemia but not in Felty syndrome [34].

Much of this testing can be done by the primary clinician. For patients in whom the cause cannot be determined, and/or the neutropenia is worsening, referral a hematologist is indicated. The hematologist can review the blood smear, perform a bone marrow examination with special studies including flow cytometry, and determine the appropriateness of other evaluations for possible hematologic malignancy.

Neutropenia management — Neutropenia can be a medical emergency when associated with a severe or systemic infection.

Conversely, neutropenia may not require intervention if it is mild (ANC 1500 to 2000/microL) (calculator 1).

General management considerations include the following:

●As with other cytopenias, addressing the underlying cause is paramount. The drug should be discontinued if a drug-induced cause is suspected and the neutropenia is severe, and G-CSF can be administered, especially if there is fever or other indication of infection. For patients in whom the neutropenia is mild (eg, not <1500/microL), the patient can be observed and the drug continued, either at the same dose or with a reduced dose or less frequent dosing interval. (See 'Neutropenia causes' above and 'Neutropenia evaluation' above.)

●For those with fever, appropriate antibiotics should be administered without delay. Ideally, cultures and imaging are obtained to determine the site of infection and identify the infectious organism and antibiotic sensitivities before antibiotics are started, but antibiotics should not be withheld while obtaining this testing, especially in an acutely ill individual.

●Neutrophil growth factors can be used to raise the ANC. G-CSF is appropriate for fever and neutropenia if the neutropenia is thought to be due to underproduction of neutrophils, especially if it is severe (ANC <500/microL). Administration of G-CSF is individualized with input from the consulting hematologist. A typical dose of filgrastim is 5 mcg/kg daily until ANC recovery; additional details of dosing and administration are discussed separately. (See "Introduction to recombinant hematopoietic growth factors", section on 'Dose and schedule'.)

Additional considerations such as choice of antibiotic (for fever) and other interventions are presented separately. (See "Management of the adult with non-chemotherapy-induced neutropenia".)

High WBC or eosinophil count — A high white blood cell (WBC) count or high eosinophil count may be related to disease activity or another cause:

●High WBC

•RA or infection – An inflammatory flare of RA can increase the WBC count, primarily due to an increase in neutrophils. However, a high WBC count or neutrophil count should not be attributed to RA until the patient has been evaluated for an infectious cause. WBCs above 15,000/microL are distinctly uncommon in active RA without another identifiable cause. There may be a left shift, with increased numbers of bands and other immature neutrophils.

The extent of the evaluation depends on the person's clinical status. An acutely ill individual requires a thorough history and physical examination, cultures, chest radiograph, and other testing. An otherwise well individual may have a more limited evaluation, as long as plans for follow-up are in place. (See "Approach to the patient with neutrophilia".)

•Drug induced – Glucocorticoids can often cause drug-induced leukocytosis due to neutrophilia. The mechanism involves combination of demargination from reduced adhesion to endothelial cells and increased release from the bone marrow. Patients with neutrophilia due to glucocorticoid use often do not have an obvious increase in early forms. (See "Major adverse effects of systemic glucocorticoids", section on 'Other effects' and "Approach to the patient with neutrophilia", section on 'Medications'.)

A WBC count that persists >15,000/microL in a person with RA who is receiving low to moderate doses of glucocorticoids should prompt consideration of an alternative explanation.

●High eosinophil count

•RA – Significant eosinophilia occurs in some patients with RA. Extraarticular features of RA associated with eosinophilia include vasculitis, pleuropericarditis, pulmonary fibrosis, and subcutaneous nodules; gold-induced skin rash was also associated with eosinophilia [35]. Early studies suggested that eosinophilia might predict greater disease activity. Treatment may be less effective in people with mild baseline eosinophilia [36,37].

•Other causes – Numerous other causes of eosinophilia are possible, including parasitic infestations, allergic diseases, adrenal insufficiency, and drug-induced eosinophilia. The evaluation is presented separately. (See "Approach to the patient with unexplained eosinophilia".)

As noted above, hematology (or infectious diseases) referral is appropriate for individuals with significant elevations of the WBC or eosinophil count that remain unexplained after the initial evaluation. (See 'Findings of special concern (red flags) and indications for hematologist referral' above.)

High or low platelet count — A mild to moderate elevation in the platelet count, typically not exceeding two to three times the person's baseline, can correlate with RA disease activity [38,39]. Extreme thrombocytosis, even counts >1,000,000/microL, may be seen, often associated with extraarticular disease manifestations, particularly pulmonary involvement, peripheral neuropathy, and vasculitis [40]. The mechanism is not well understood and may include proinflammatory cytokines [38].

Thrombocytopenia is rare in RA, except when it is related to drug treatment or Felty syndrome. Among the drugs that can produce thrombocytopenia are methotrexate, azathioprine, TNF antagonists, IL-6 receptor blockers (eg, tocilizumab and sarilumab), and JAK inhibitors (eg, tofacitinib, baricitinib, and upadacitinib) [41-44]. Gold and penicillamine were previous causes of thrombocytopenia but are no longer commonly used [45,46].

Individuals with RA may also have other causes of high or low platelet counts unrelated to RA, which are discussed separately. (See "Approach to the patient with thrombocytosis" and "Diagnostic approach to thrombocytopenia in adults".)

FELTY SYNDROME — Felty syndrome is classically defined as a triad:

●Rheumatoid arthritis (RA)

●Neutropenia

●Splenomegaly, although this may be absent or unappreciated in some individuals

Thus, Felty syndrome is typically suspected in an individual with RA who develops neutropenia and usually splenomegaly. The clinical manifestations and treatment of Felty syndrome are discussed in detail separately. (See "Clinical manifestations and diagnosis of Felty syndrome" and "Drug therapy in Felty syndrome" and "Role of splenectomy for Felty syndrome".)

Briefly, Felty syndrome most typically occurs in individuals with longstanding, deforming RA, with a prevalence of approximately 1 to 3 percent, although the prevalence has declined in the era of effective disease-modifying therapy [47]. People with Felty syndrome have a greater risk of developing large granular lymphocyte (LGL) leukemia than those who have RA without Felty syndrome. The mechanisms of Felty syndrome and LGL leukemia in RA are incompletely understood.

The diagnosis of Felty syndrome is made based upon clinical features after excluding other causes of neutropenia and splenomegaly such as drug-induced cytopenias, infection, lymphoproliferative disorders, or LGL leukemia. (See 'LGL leukemia' below.)

The management of Felty syndrome involves nonpharmacologic measures to reduce the risk of infection and nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs) such as methotrexate or rituximab to control RA disease activity. Granulocyte colony-stimulating factor (G-CSF), and, rarely, splenectomy may also be used in some patients to alleviate the neutropenia. (See "Drug therapy in Felty syndrome" and "Role of splenectomy for Felty syndrome".)

HEMATOLOGIC MALIGNANCIES

Overview and pathogenesis — People with rheumatoid arthritis (RA) have an increased risk for lymphoproliferative disorders, including non-Hodgkin lymphoma and large granular lymphocyte (LGL) leukemia [48]. Any individual with abnormal or immature lymphoid or myeloid cells on the blood smear should be evaluated by a hematologist. (See 'Findings of special concern (red flags) and indications for hematologist referral' above.)

A mature lymphocyte count that is persistently >5000/microL often warrants additional hematologic evaluation and may herald the development of chronic lymphocytic leukemia. This requires hematologist evaluation but is not in and of itself an emergency. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

The mechanism of increased risk of lymphoid malignancies is likely to include immune dysregulation and/or chronic immune activation [49]. Drugs used to treat RA, including cyclophosphamide, azathioprine, and methotrexate, may contribute to the risk, although not all patients with RA who develop hematologic malignancies have been treated with any of these drugs. In a case-control study of 23,810 patients with RA, an increased risk of developing hematologic malignancies was associated with the use of immunosuppressive agents; the relative risks were 1.2 for methotrexate, 1.4 for azathioprine, and 2.2 for cyclophosphamide [50]. Other studies have shown similar findings [51,52]. The role of tumor necrosis factor (TNF) inhibitors in the pathogenesis of hematologic malignancies in RA is unclear. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Major adverse effects of low-dose methotrexate" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

Lymphoma — Lymphoproliferative disorders occur with increased frequency in patients with RA; incidence and mortality rates due to leukemia or lymphoma, including non-Hodgkin lymphoma, are approximately twofold higher than expected [53-57].

The incidence of non-Hodgkin lymphoma increases as active RA persists and correlates with disease activity. As an example, in a retrospective case-controlled analysis of 378 people with RA and lymphoma and 378 matched RA controls, the risk of lymphoma increased in association with greater cumulative disease activity (ninth decile of disease activity, odds ratio [OR] 9.4, 95% CI 3.1-28.0; tenth decile of disease activity, OR 61.6, 95% CI 21.0-181.0) [58]. The most common type of lymphoma was diffuse large B cell lymphoma (DLBCL; in 48 percent); 12 percent of lymphomas tested positive for Epstein-Barr virus (EBV).

LGL leukemia — Large granular lymphocyte (LGL) leukemia (historically referred to as LGL syndrome) is a clonal lymphoproliferative disorder characterized by an increase in large granular lymphocytes (typically, 2000 to 20,000/microL). Almost all individuals with RA who develop LGL leukemia have the T cell type (T-LGL), and nearly one-third of people with T-LGL have RA. In a series of 529 individuals with RA for a median of 12 years who underwent flow cytometry, a clonal T cell population indicative of T-LGL was present in 19 (3.6 percent) [59-61].

RA often precedes the development of T-LGL leukemia, but both conditions may present concurrently. Some of these individuals fulfill the clinical criteria for Felty syndrome (see 'Felty syndrome' above). Most people with T-LGL have an indolent clinical course, and many are asymptomatic at presentation. Neutropenia is present in approximately 85 percent. Details are presented separately. (See "Large granular lymphocyte leukemia in rheumatoid arthritis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)

SUMMARY AND RECOMMENDATIONS

●Overview – Common hematologic complications of rheumatoid arthritis (RA) include anemia and cytopenias. Rare complications include Felty syndrome, large granular lymphocyte (LGL) leukemia, and lymphoma. Hematologist evaluation is appropriate for individuals with immature white blood cells (WBCs) on the blood smear, unexplained findings after a standard evaluation, and abnormalities that do not improve as expected with treatment. (See 'Overview' above.)

●Anemia – Management is based on the underlying cause, with transfusions reserved for severe anemia (hemoglobin <7 g/dL or anemia with hemodynamic compromise). (See 'Anemia' above.)

•ACD/AI – The most common cause of anemia is the anemia of chronic disease/anemia of inflammation (ACD/AI), which correlates with disease activity and is most often seen on initial presentation or when disease is not well controlled; disease-modifying antirheumatic drug (DMARD) therapy usually improves the hemoglobin.

•Medications – Drug-induced bone marrow suppression often causes macrocytic anemia; the drug can be continued if anemia is mild. Drug-induced hemolytic anemia or pure red cell aplasia (PRCA) are more concerning and warrant drug discontinuation in most cases.

•Other causes – Multifactorial anemia may include combined iron deficiency, vitamin B12 or folate deficiency, and/or other causes. Initial testing may be broader than in the general population, including iron studies, vitamin B12 and folate levels, metabolic panel that addresses kidney and liver function, thyroid-stimulating hormone (TSH), and possibly testosterone in males (algorithm 1).

●Neutropenia – Neutropenia (absolute neutrophil count [ANC] <1500/microL) can lead to life-threatening sepsis; neutropenia with fever is a medical emergency that may require immediate evaluation and empiric antibiotics, especially when neutrophil production is impaired (see 'Neutropenia' above):

•Causes – Causes include drugs (tumor necrosis factor [TNF] inhibitors, interleukin [IL] 6 inhibitors, Janus kinase [JAK] inhibitors, other RA medications, antibiotics). Rare but important causes include Felty syndrome and LGL leukemia.

•Evaluation – First, consider "red flags" that warrant immediate intervention (algorithm 2). If these are absent, review the blood smear and other cell counts, examine for splenomegaly, and consult hematology.

•Role of G-CSF – If neutropenia is thought to be drug-induced, reduce the dose or stop the drug. Granulocyte colony-stimulating factor (G-CSF) can be used for active infection or fever if neutropenia is thought to be due to underproduction, especially if severe (ANC <500/microL). A typical dose of filgrastim is 5 mcg/kg daily until ANC recovery. (See "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Treatment of infection'.)

●Other CBC abnormalities – Causes and diagnostic approaches to other complete blood count (CBC) abnormalities are discussed above. (See 'High WBC or eosinophil count' above and 'High or low platelet count' above.)

●Felty syndrome – Felty syndrome is the triad of RA, neutropenia, and splenomegaly; the prevalence is 1 to 3 percent but may be lower with effective RA therapy. Diagnosis is based on clinical and laboratory features after excluding other causes of neutropenia and splenomegaly. Management includes methotrexate or rituximab and G-CSF, if needed. Refractory disease can be treated by splenectomy. (See 'Felty syndrome' above and "Clinical manifestations and diagnosis of Felty syndrome" and "Drug therapy in Felty syndrome" and "Role of splenectomy for Felty syndrome".)

●LGL leukemia – RA increases the risk for lymphoproliferative disorders, including LGL leukemia and diffuse large B cell lymphoma (DLBCL), a type of non-Hodgkin lymphoma. Any individual with abnormal or immature lymphoid or myeloid cells on the blood smear or unexplained leukocytosis, lymphocytosis, or pancytopenia should be evaluated by a hematologist. (See 'Hematologic malignancies' above and "Large granular lymphocyte leukemia in rheumatoid arthritis".)