Hematologic manifestations of rheumatoid arthritis

Hematologic manifestations of rheumatoid arthritis

Authors
Michael Ehrenfeld, MD
Yehuda Shoenfeld, MD

Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS

Deputy Editor
Paul L Romain, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2016. &#124 This topic last updated: Jun 03, 2016.

INTRODUCTION — Patients with rheumatoid arthritis (RA) may exhibit a variety of hematologic abnormalities. Common changes associated with active disease include anemia of chronic disease (ACD; also termed anemia of chronic inflammation), thrombocytosis, and sometimes a mild leukocytosis. There is an increased risk of lymphoproliferative disease, including non-Hodgkin lymphoma. Felty’s syndrome, with neutropenia and splenomegaly, is very infrequent.
An overview of the hematologic manifestations of RA is presented here. The clinical manifestations of RA; clinical manifestations, diagnosis, and treatment of Felty’s syndrome; and large granular lymphocyte (LGL) leukemia in RA are discussed in detail separately. (See "Clinical manifestations of rheumatoid arthritis" and "Clinical manifestations and diagnosis of Felty's syndrome" and "Drug therapy in Felty's syndrome" and "Indications for splenectomy in Felty's syndrome" and "Large granular lymphocyte leukemia in rheumatoid arthritis".)
ANEMIA — Anemia is common in patients with rheumatoid arthritis (RA). Among the most prevalent hematologic abnormalities in patients with rheumatologic disorders are the anemia of chronic disease (ACD), a mild anemia that is generally asymptomatic, and iron deficiency anemia [1,2]. Other forms of anemia occur less commonly. (See 'Anemia of chronic disease' below and 'Iron deficiency anemia' below and 'Macrocytic anemia' below and 'Hemolytic anemia' below and 'Bone marrow hypoplasia with anemia' below and 'Pure red cell aplasia' below.)
Studies from the early 1980s estimate the prevalence of anemia to range between 30 to 70 percent [3,4]. A 2004 analysis of the available data was similar, with an estimated prevalence of 54 percent [5]. However, some evidence suggests that the prevalence of anemia decreased between 2001 and 2007 [6].
Causes of anemia in rheumatoid arthritis
Anemia of chronic disease — ACD is common in patients with active RA. The pathogenesis of ACD is incompletely understood, but ACD is thought to primarily reflect a reduction in red blood cell (RBC) production by the bone marrow, with a component due to mild shortening of RBC survival. The pathogenesis, clinical manifestations, diagnosis, and treatment of ACD are described in detail separately. (See "Anemia of chronic disease/inflammation".)
A number of factors are thought to contribute to this hypoproliferative state in RA and in other conditions, including hepcidin-induced alterations in iron metabolism, inability to increase erythropoiesis in response to anemia, a relative decrease in erythropoietin (EPO) production, and, to a lesser extent, decreased red cell survival. Endogenous EPO synthesis appears to be impaired in RA patients as well as in their response to EPO [7]. Low EPO levels and the diminished response to EPO contribute significantly to the anemia in RA [2,8,9]. (See "Anemia of chronic disease/inflammation", section on 'Pathogenesis'.)
Tumor necrosis factor (TNF)-alpha and polymorphisms in TNF receptor genes may be particularly important in RA, and TNF may have a role as one of the factors mediating ACD in patients with RA [10-12] (see "Pathogenesis of rheumatoid arthritis"). TNF-inhibition with infliximab, a chimeric mouse human monoclonal antibody, has been shown to lead to a dose-dependent increase in hemoglobin levels in RA patients with ACD compared with placebo. These changes were also accompanied by a reduction in serum levels of both EPO and interleukin (IL)-6 [11].
ACD is associated with the following laboratory abnormalities:
●The two red cell indices, mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC), tend to be normal (ie, normocytic and normochromic) but can be decreased due to concurrent iron deficiency, often to values characteristic of microcytic hypochromic anemias.
●The serum levels of ferritin are elevated and the levels of transferrin and iron are low [13].
●Reduced iron absorption and impaired release of iron from the reticuloendothelial system are typically observed.
●Bone marrow examination usually reveals the presence of hemosiderin and normal cellularity, with increased numbers (in most cases) of plasma cells that are associated with lymphoid aggregates. However, bone marrow findings are unpredictable and usually reflect the diverse causes of cytopenias in patients with rheumatic diseases.
Iron deficiency anemia — Iron deficiency anemia and ACD are the two most common causes of anemia in RA, with an estimated prevalence in the past of 50 to 75 percent of patients with RA who have chronic active RA. These figures have decreased over the years, and one study found the prevalence of anemia in RA to decrease from more than 24 percent in years before 2001 to 15 percent in 2007 [6].
Iron deficiency is most often caused by chronic blood loss from gastritis (induced by nonsteroidal antiinflammatory drugs [NSAIDs]), peptic ulcer, or gastroesophageal reflux due to a diaphragmatic hernia. In some populations, dietary deficiency of iron is fairly common as well. (See "Causes and diagnosis of iron deficiency anemia in the adult".)
Most cases of iron deficiency anemia are asymptomatic; but if severe, dyspnea on exertion, fatigue, tachycardia, and palpitations may occur. (See "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Clinical manifestations'.)
Patients with RA frequently have concurrent iron deficiency anemia and ACD. When this occurs, the hemoglobin level usually drops to below 9.5 g/dL and the MCV is less than 80 [14,15].
Macrocytic anemia — A megaloblastic anemia due to folic acid deficiency, vitamin B12 deficiency, methotrexate, or azathioprine is found in some patients with RA, but is less frequent than ACD or iron-deficiency anemia [1]. Generally, in about 75 percent of RA patients who are found to have anemia, it is due to an ACD, and about 25 percent of anemic patients with RA will respond to iron therapy; however, both these subgroups of anemia may be found to have a superimposed vitamin B12 or folate deficiency [16]. One study of 25 patients with RA and anemia noted vitamin B12 and folic acid deficiency in 29 and 21 percent of patients, respectively [1]. The characteristic morphologic changes of a macrocytic anemia may be masked by the changes induced by other causes of anemia. (See "Macrocytosis/Macrocytic anemia".)
The clinical manifestations of macrocytic anemia may involve cardiopulmonary manifestations secondary to the anemia, gastrointestinal manifestations with or without malabsorption, as well as the typical neurologic and psychiatric features. (See "Macrocytosis/Macrocytic anemia" and "Etiology and clinical manifestations of vitamin B12 and folate deficiency".)
Folic acid deficiency anemia in RA is usually due to the combination of increased requirements and reduced intake (eg, pregnancy in a patient on a restricted diet) or to concurrent iron deficiency.
Hemolytic anemia — Hemolytic anemia is not a typical feature of RA, although antibody-mediated, Coombs-positive hemolytic anemia has been described, primarily in Felty's syndrome [17]. Drug-induced hemolysis may also occur. As an example, autoimmune hemolytic anemia has been induced by NSAIDs as well as by methotrexate. Although extremely rare, this anemia may be severe. The condition tends to be reversible when the offending drug is withdrawn, but most patients require glucocorticoid therapy. In some patients, the hemolytic anemia is accompanied by signs of hypersensitivity. Reticulocytosis and low haptoglobin, as well as positive direct and indirect Coombs tests, are clues for diagnosis. (See "Clinical manifestations and diagnosis of Felty's syndrome" and "Approach to the diagnosis of hemolytic anemia in the adult".)
Bone marrow hypoplasia with anemia — Bone marrow hypoplasia with anemia is another rare but serious complication of RA. When present, it is principally observed in association with (see "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis"):
●Felty's syndrome
●Renal failure
●The administration of azathioprine, cyclophosphamide, or other immunosuppressive agents
●TNF-alpha antagonists, which have been rarely associated with bone marrow suppression resulting in severe cytopenia, transient pancytopenia, or even aplastic anemia
Pure red cell aplasia — Pure red cell aplasia is a very rare but treatable cause of anemia in RA. It should be considered when there is a severe normochromic anemia with a very low absolute reticulocyte count in the absence of obvious blood loss or hemolysis. Autoimmune suppression of erythroid stem cells, antirheumatic drugs, and parvovirus infection has been implicated in this complication [18,19], although single case reports suggest that pure red cell aplasia could very rarely be an extraarticular manifestation of RA [18].
Pure red cell aplasia is characterized as a normocytic anemia associate with the absence of erythroblasts in the bone marrow. There are no signs of regeneration in the peripheral blood, no polychromasia, and no reticulocytes, with normal leukopoiesis and thrombopoiesis and no enlargement of the spleen or lymph nodes. (See "Acquired pure red cell aplasia in the adult".)
Evaluation and diagnosis of anemia in patients with rheumatoid arthritis — The approach to the patient with unexplained anemia is largely the same for patients with RA as for patients with other disorders or in the general population (algorithm 1); it is further informed by greater likelihood of certain conditions seen more often in association with RA (see 'Causes of anemia in rheumatoid arthritis' above). This approach to the patient with unexplained anemia is described in detail separately. (See "Approach to the adult patient with anemia".)
Patients suspected of iron deficiency or ACD should undergo measurement of the serum iron and iron-binding capacity as well as the serum ferritin. The diagnosis of iron deficiency anemia in patients with RA may be difficult, since the routine laboratory indices with mild to moderate iron deficiency may overlap with the ACD [20,21]. Thus, if iron deficiency is suspected, it may be most reliably verified by the absence of iron stores on bone marrow examination [20]. However, bone marrow examination is usually unnecessary if the patient has clear signs of iron deficiency such as a mean cell volume below 85, serum ferritin concentration below 40 mcg/L, and transferrin saturation ≤7 percent (table 1) [21].
In patients with RA with a hemoglobin less than 8 g/dL, other contributory causes, such as hemolysis or bleeding, should also be excluded. Patients with evidence of occult blood in the stool should be referred for evaluation by a gastroenterologist, just as in patients without RA. An upper gastrointestinal endoscopic examination is usually indicated in the patient with some combination of iron deficiency anemia, epigastric pain, and/or occult blood in the stool. (See "Causes and diagnosis of iron deficiency anemia in the adult".)
Iron-deficient RA patients are characterized by high iron stores (high ferritin levels) but low iron availability (low transferrin saturation). ACD is typically associated with a significantly higher ferritin concentration than found in pure iron deficiency anemia. By contrast, EPO levels are higher in patients with iron deficiency anemia compared with those with ACD. The erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), as well as interleukin (IL)-6, correlate inversely with the magnitude of the anemia in RA patients.
Although not done routinely in clinical practice, measurement of serum soluble transferrin receptor (TfR) can help differentiate iron deficiency anemia from ACD. This was illustrated in a study of 27 patients with RA and anemia who had bone marrow aspiration that provided diagnostically useful specimens [22,23]. Among the 15 patients with iron deficiency anemia (absent stainable iron), elevated serum levels (>28.1 nmol/L) of soluble TfR were found in 14 (sensitivity 93 percent), while only one of 12 patients with adequate iron stores had an elevated soluble TfR level (specificity 92 percent) [24]. RA patients with iron deficiency anemia show a rise in their serum EPO levels as the hemoglobin concentration falls, contrary to patients with ACD and RA, who do not increase their EPO levels [25].
Treatment of anemia in rheumatoid arthritis — Effective therapy of the patient with RA and anemia is based upon an accurate determination of the cause of the anemia (see 'Causes of anemia in rheumatoid arthritis' above and 'Evaluation and diagnosis of anemia in patients with rheumatoid arthritis' above). The main intervention for ACD is control of disease activity, while iron and vitamin deficiencies are treated both by remediation of their respective causes and repletion. Immunosuppressive therapy may be needed for hemolytic anemia and pure red cell aplasia, while identification and removal of the offending drug may be required in patients with bone marrow hypoplasia.
Issues of importance in patients with RA and particular forms of anemia include:
●Anemia of chronic disease – ACD often responds to therapy directed against RA, including a disease-modifying antirheumatic drug (DMARD) and/or glucocorticoids (prednisone at a dose of 0.5 to 1.0 mg/kg per day) [2]. Nevertheless, therapy is optimally directed at improving the arthritis and not the anemia, since the severity of the anemia may correlate with disease activity and patients would often require high doses of EPO, the availability of which may be restricted by cost [26,27]. Decisions to use EPO should be limited to patients with marked, symptomatic anemia and to those who demonstrate persistent anemia despite specific RA treatment [28]. (See "Anemia of chronic disease/inflammation", section on 'Erythropoietin'.)
Observations regarding the role of EPO in ACD in RA led to trials of recombinant EPO in patients with RA, resulting in improvement of the anemia in a few patients without apparent change in overall arthritic status [2,8,29]. In one report, for example, 10 of 11 patients treated for 24 weeks had at least a 6 percentage point increase in hematocrit [29]. Several randomized trials have demonstrated the efficacy of recombinant EPO in treating the anemia of RA [28,30]; however, only a limited number of patients with RA and ACD may require this treatment. There are, however, no guidelines or recommendations for the treatment of anemic RA patients with EPO, since the goal of EPO therapy is usually to increase the hemoglobin level above 11 to 12 /dL, and with the available therapies for RA hemoglobin levels below 11 g/dL due to ACD are uncommon.
A systematic review of the trials raised concerns regarding trial methods and noted that two of the three principal trials found no improvement in health-related quality-of-life measures, despite improvement in the level of anemia [30]. High doses (usually 300 to 800 units/kg/week given subcutaneously once or twice weekly) are required, making this an expensive form of therapy. One specific role for EPO among patients with RA might be in the preparation for elective surgery. Correction of the anemia in this specific setting may obviate the need for transfusion or may facilitate the donation of blood for autologous transfusions [2].
The hallmark of correcting the anemia of RA is to ensure systemic disease control via therapy with a potent nonbiologic or biologic DMARD, such as either methotrexate, TNF-alpha inhibitors, rituximab, tocilizumab, or abatacept. Since IL-6 induces the production of hepcidin, which causes iron deficiency anemia, the treatment of active RA with tocilizumab attracted a lot of attention in this regard, and such studies demonstrated a significant increase in the hemoglobin level of treated patients [31]. This approach is consistent with the generally recommended approach to ACD. (See "Anemia of chronic disease/inflammation", section on 'Treatment issues'.)
●Iron deficiency anemia – Iron should not be given unless iron deficiency has been documented. In juvenile idiopathic arthritis, eight severely anemic children who were unresponsive to oral iron therapy responded to intravenous iron saccharate with an increase in the median hemoglobin value from 8 to 11 g/dL [32]. The treatment of iron deficiency is described in detail separately. (See "Treatment of iron deficiency anemia in adults".)
●Macrocytic anemia – Vitamin deficiencies leading to anemia should be corrected by the administration of folic acid or vitamin B12, as indicated by laboratory findings. (See "Diagnosis and treatment of vitamin B12 and folate deficiency".)
●Hemolytic anemia – Hemolysis should be treated with glucocorticoids (prednisone 60 mg/day), as well as withdrawal of the offending drug, if one is identified (see 'Hemolytic anemia' above). If no response is observed after one to two weeks, an immunosuppressive agent may be administered, such as azathioprine (50 to 150 mg/day). The approach to the treatment of autoimmune hemolytic anemia is described in detail separately. (See "Warm autoimmune hemolytic anemia: Treatment".)
●Bone marrow hypoplasia – Antirheumatic drug-induced bone marrow suppression should be treated by dose alteration or complete withdrawal of the suspected drug. (See 'Bone marrow hypoplasia with anemia' above.)
●Pure red cell aplasia – Isolated case reports have noted improvement in patients treated with glucocorticoids, cyclophosphamide, and azathioprine or cyclosporine [18,33]. Additionally, the efficacy of anti-CD20 monoclonal antibody rituximab has been reported in remission induction of resistant cases of pure red cell aplasia. The treatment of pure red cell aplasia is described in detail separately. (See "Acquired pure red cell aplasia in the adult".)
NEUTROPENIA
Felty's syndrome — The principal leukopenic disorder among patients with rheumatoid arthritis (RA) is Felty's syndrome, which is the triad of neutropenia, splenomegaly, and deforming RA. Splenomegaly, however, is not necessarily present. This disorder occurs in less than 1 percent of patients with RA. Patients who develop Felty's syndrome often have a severe and longstanding form of nodular RA, with high levels of rheumatoid factor, which may be accompanied by vasculitis, ulcers, neuropathy, pulmonary fibrosis, Sjögren's syndrome, hepatomegaly, and lower extremities hyperpigmentation. The clinical manifestations, diagnosis, and treatment of Felty’s syndrome are discussed in detail separately. (See "Clinical manifestations and diagnosis of Felty's syndrome" and "Drug therapy in Felty's syndrome" and "Indications for splenectomy in Felty's syndrome".)
Large granular lymphocyte syndrome and pseudo-Felty's syndrome — Large granular lymphocyte (LGL) leukemia associated with RA, which has also been referred to as LGL syndrome in RA, is a clonal lymphoproliferative disease. Neutropenia is present in about 85 percent of patients. LGL syndrome appears to represent one part of a spectrum of polyclonal and clonal disorders of LGL, including at least a subset of patients with Felty’s syndrome. In patients with rheumatologic disease, LGL leukemia is almost always the T-cell LGL (T-LGL) type. Nearly one-third of patients with LGL leukemia also have RA, and some fulfill the clinical criteria for Felty's syndrome. RA often precedes the development of T-LGL leukemia, but both conditions may present concurrently. The pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of LGL leukemia in the setting of RA are discussed in detail separately. (See "Large granular lymphocyte leukemia in rheumatoid arthritis".)
Drug-induced neutropenia — Neutropenia, which may be transient, has been described with the use of tumor necrosis factor (TNF)-inhibitors in 16 to 19 percent of patients receiving these medications [34,35]. This risk is significantly higher in patients with a low baseline neutrophil count. A few reports have describing severe delayed-onset neutropenia following rituximab therapy. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Neutropenia' and "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Late-onset neutropenia'.)
In addition to these agents, a number of other medications used in the treatment of patients with RA may cause neutropenia and can cause agranulocytosis, including drugs that can lead to bone marrow suppression, such as methotrexate, azathioprine, and cyclophosphamide; as well as drugs acting through other mechanisms, including sulfasalazine, nonsteroidal antiinflammatory drugs (NSAIDs), and medications used for comorbid conditions. Drug-induced neutropenia and agranulocytosis is reviewed in detail separately. (See "Drug-induced neutropenia and agranulocytosis", section on 'Implicated agents'.)
LEUKOCYTOSIS — Leukocytosis with a proliferation of polymorphonuclear leukocytes and a predominance of early forms (eg, a shift to the left) can occur during an inflammatory flare of rheumatoid arthritis (RA). Another potential cause of leukocytosis in patients with RA is an associated bacterial infection, which should be considered and rigorously excluded in such patients. Leukocytosis is also a common finding in systemic juvenile idiopathic arthritis. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)
Drug-induced leukocytosis due to neutrophilia is often associated with use of glucocorticoids. This occurs due to a combination of demargination from reduced adhesion to endothelial cells and from increased release from bone marrow stores. Patients with neutrophilia due to glucocorticoid use often do not exhibit a detectable increase in early forms. (See "Major side effects of systemic glucocorticoids", section on 'Neutrophilia' and "Causes of neutrophilia", section on 'Glucocorticoids and other drugs'.)
EOSINOPHILIA — Significant eosinophilia occurs in some patients with rheumatoid arthritis (RA). Extraarticular features of RA that may be associated with eosinophilia include vasculitis, pleuropericarditis, pulmonary fibrosis, subcutaneous nodules, and gold-induced skin rashes [36].These early studies suggested that eosinophilia might predict greater disease activity. A subsequent study confirmed that while eosinophilia is rare, mild, and transient in recent-onset RA, the patients with mild baseline eosinophilia might respond less well to treatment due to greater disease activity [37].
PLATELET ABNORMALITIES — Thrombocytosis is common in rheumatoid arthritis (RA), and a positive correlation has been found between the platelet count and disease activity. Extreme thrombocytosis, even above one million, in patients with RA may be associated with extraarticular disease manifestations, particularly pulmonary involvement, peripheral neuropathy, and vasculitis [38]. Although the mechanism of thrombocytosis is uncertain, increased intravascular coagulation with a compensatory increase in platelet production has been suggested as a possible cause.
Thrombocytopenia is rare in RA, except when related to drug treatment or Felty's syndrome. Among the drugs that can produce thrombocytopenia are gold, penicillamine, methotrexate, azathioprine, and tumor necrosis factor (TNF) antagonists [39-42]. (See "Major side effects of gold therapy", section on 'Hematologic toxicity'.)
HEMATOLOGICAL MALIGNANCIES IN RHEUMATOID ARTHRITIS — Various studies have suggested an increased risk of malignancy among patients with rheumatoid arthritis (RA), and malignant diseases contribute significantly to the morbidity and mortality of the disease. Lymphoproliferative disorders occur with increased frequency in patients with RA; incidence and mortality rates due to leukemia or lymphoma are approximately twofold higher than expected. The lymphoma incidence increases as active RA persists and correlates with the severity of disease activity. Non-Hodgkin lymphoma, particularly diffuse large B-cell lymphoma, is the most common type. Lymphoproliferative malignancy in RA is discussed in more detail separately. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Lymphoproliferative disorders'.)
Up to one-third of patients with the large granular lymphocyte (LGL) syndrome also have RA and may fulfill the clinical criteria for Felty's syndrome. (See 'Large granular lymphocyte syndrome and pseudo-Felty's syndrome' above.)
Drugs used to treat the disease, including alkylating agents (eg, cyclophosphamide), azathioprine, and methotrexate, may contribute to the risk, although not all patients with RA who develop malignancies have been treated with any of these drugs. The etiology of neoplasia in such patients may include immune dysregulation and/or chronic immune activation. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Major side effects of low-dose methotrexate" and "Overview of biologic agents in the rheumatic diseases".)
Whether tumor necrosis factor (TNF) inhibitor use is associated with increased risk of malignancy is uncertain. The possible risk of malignancy associated with the use of TNF inhibitors is discussed in detail elsewhere. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Lymphoproliferative disorders' and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)
SUMMARY AND RECOMMENDATIONS
●Among the most common hematologic abnormalities in patients with rheumatologic disorders are the anemia of chronic disease (ACD; also termed anemia of chronic inflammation), a mild anemia that is generally asymptomatic, and iron deficiency anemia. Other less frequent causes include megaloblastic anemias from vitamin deficiency or medications. In patients with rheumatoid arthritis (RA), the prevalence of anemia ranges from 30 to 70 percent in various studies. (See 'Anemia' above and 'Anemia of chronic disease' above and 'Iron deficiency anemia' above and 'Macrocytic anemia' above.)
●The approach to the patient with unexplained anemia is largely the same for patients with RA as for patients with other disorders or in the general population (algorithm 1) (see "Approach to the adult patient with anemia"); it is further informed by greater likelihood of certain conditions seen more often in association with RA. (See 'Evaluation and diagnosis of anemia in patients with rheumatoid arthritis' above.)
●Effective therapy of the patient with RA and anemia is based upon identification of the specific cause of the anemia. The main intervention for ACD is control of disease activity, while iron and vitamin deficiencies are treated both by remediation of their respective causes and repletion. Immunosuppressive therapy may be needed for hemolytic anemia and pure red cell aplasia, while identification and removal of the offending drug may be required in patients with bone marrow hypoplasia. (See 'Treatment of anemia in rheumatoid arthritis' above.)
●The principal leukopenic disorder among patients with RA is Felty’s syndrome, the triad of neutropenia, splenomegaly, and deforming RA; it occurs in about 1 percent of patients with RA. Patients who develop Felty’s syndrome often have a severe and longstanding form of nodular RA, with various other extraarticular manifestations and high levels of rheumatoid factor. (See 'Neutropenia' above and 'Felty's syndrome' above.)
●Large granular lymphocyte (LGL) leukemia associated with RA, which has also been referred to as LGL syndrome, is a clonal lymphoproliferative disease; when seen in RA, it is almost always the T-cell LGL (T-LGL) type. Nearly one-third of patients with LGL leukemia also have RA, and some fulfill the clinical criteria for Felty’s syndrome. (See 'Large granular lymphocyte syndrome and pseudo-Felty's syndrome' above.)
●Leukocytosis with a proliferation of polymorphonuclear leukocytes and a predominance of early forms (eg, a shift to the left) can occur during an inflammatory flare of RA. Glucocorticoid therapy can also cause neutrophilia. (See 'Leukocytosis' above.)
●Significant eosinophilia occurs in some patients with RA. It usually correlates with the presence of vasculitis, pleuropericarditis, pulmonary fibrosis, subcutaneous nodules, or drug-induced skin rashes. (See 'Eosinophilia' above.)
●Thrombocytosis is common in RA, and a positive correlation has been found between the platelet count and disease activity. Thrombocytopenia is rare in RA, except when related to drug treatment or Felty’s syndrome. (See 'Platelet abnormalities' above.)
●Various studies have suggested an increased risk of malignancy among patients with RA, particularly for the development of lymphoproliferative diseases, especially non-Hodgkin lymphoma. (See 'Hematological malignancies in rheumatoid arthritis' above.)