Large granular lymphocyte leukemia in rheumatoid arthritis

INTRODUCTION — Large granular lymphocyte (LGL) leukemia is characterized by a clonal proliferation of LGLs. LGLs comprise 5 percent of the population of peripheral blood mononuclear cells, are larger than most circulating lymphocytes, and have characteristic azurophilic granules containing acid hydrolases (picture 1). They may be either T cells (T-LGL), the more common type, or natural killer cells (NK-LGL) [1,2].

LGL leukemia is a heterogeneous disorder characterized by peripheral blood and marrow lymphocytic infiltration with LGLs, splenomegaly, and cytopenias, most commonly neutropenia. Up to one-third of patients with T-LGL leukemia also have rheumatoid arthritis (RA) [3]. LGL leukemia can also occur in association with Sjögren's disease in the absence of RA [4] and with other autoimmune disorders, including inflammatory bowel disease, systemic lupus erythematosus, and autoimmune thyroid disease [4,5].

The pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of LGL leukemia in the setting of RA are discussed here. Detailed discussions of T-LGL leukemia, NK-LGL leukemia, and their treatment are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia" and "Natural killer (NK) cell large granular lymphocyte leukemia" and "Treatment of large granular lymphocyte leukemia".)

EPIDEMIOLOGY — T-cell large granular lymphocyte (T-LGL) leukemia is uncommon among patients with rheumatoid arthritis (RA), despite the frequency of RA among patients with this disorder. In a 1989 report of one study of over 1000 patients with RA, the prevalence of neutropenia that could not be attributed to other causes was 1.7 percent; one-third of the patients with neutropenia (0.6 percent of all patients with RA) exhibited LGL proliferation on bone marrow examination [6]. A 2018 study of 529 RA patients that took advantage of increased sensitivity of flow cytometry and molecular rearrangements to detect clonal LGL describes a prevalence of 3.6 percent in RA, and patients with expanded T-LGLs were more likely to have received treatment with a tumor necrosis factor (TNF) inhibitor (84 versus 57 percent) [7].

The mean age of onset of T-LGL leukemia in RA is 60 years, with a sex distribution that reflects the increased prevalence of RA in females [7,8]. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Clinical features'.)

PATHOGENESIS — Large granular lymphocyte (LGL) leukemia associated with rheumatoid arthritis (RA), like other LGL syndromes, is a clonal lymphoproliferative disease. It appears to represent one part of a spectrum of polyclonal and clonal disorders of LGL, including chronic large granular lymphocytosis, at least a subset of Felty syndrome (FS), and indolent or more aggressive leukemias [8,9]. In patients with rheumatologic disease, LGL leukemia is almost always the T-cell LGL (T-LGL) type and tends to have a benign course [10].

The strong association of this disorder with autoimmune disease has led to the postulate that the clonal population may emerge from a polyclonal response to inciting antigen [3]. Interestingly, it has also been found that T-LGL leukemia is frequently associated with concomitant low-grade B-cell dyscrasias, suggesting the possibility of a common antigen that could drive both T- and B-cell proliferation [11,12]. There is strong evidence that the proliferation of LGL also reflects a failure of Fas-mediated apoptosis [13,14]. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Pathogenesis'.)

Several factors appear to contribute to the neutropenia in the LGL syndrome, including defects in both proliferation and neutrophil survival [15]. Fas-ligand (FasL), a member of the tumor necrosis factor (TNF) family, is an important factor in the pathogenesis of neutropenia. FasL is expressed on the surface of activated cytotoxic T cells, and elevated levels of soluble FasL are found in the serum of most patients with LGL leukemia. Soluble FasL has been shown to increase apoptosis of neutrophils [15,16]. LGLs in the bone marrow may also inhibit myelopoiesis directly by local production of cytokines [17]. Antibody-mediated mechanisms may also contribute to the neutropenia [11,15].

Next generation sequencing studies have identified activating somatic mutations in the signal transducer and activator of transcription 3 gene (STAT3) in LGL leukemia patients. Patients with STAT3 mutations were significantly more likely, compared with LGL leukemia patients without the mutations, to have RA and to exhibit neutropenia (26 versus 6 percent and 77 versus 50 percent, respectively) [18]. The etiology and pathogenesis of T-LGL leukemia is described in detail separately. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia".)

CLINICAL MANIFESTATIONS — In patients with T-cell large granular lymphocyte (T-LGL) leukemia in the setting of rheumatoid arthritis (RA), the most common findings, by definition, are features of RA and the presence of LGL in increased numbers in the peripheral blood. Neutropenia is common. The following features characterize these patients:

Rheumatoid arthritis — RA often precedes the development of T-LGL leukemia, but both conditions may present concurrently [8]. There is a broad range of severity of the arthritis, from mild, intermittent joint swelling to progressive, deforming arthropathy [8,19]. Most patients have positive tests for rheumatoid factor and for anticyclic citrullinated peptide antibodies; these antibodies are also occasionally seen in patients with T-LGL leukemia without arthritis [9,19,20]. Patients with concomitant RA and T-LGL leukemia also frequently have antinuclear antibodies [19,20]. A study of over 500 patients with RA demonstrated no clinical differences between patients with and without clonal LGL except for their greater exposure to TNF-inhibitor therapy [7].

Hematologic abnormalities — Several hematologic findings are common, including neutropenia, lymphocytic bone marrow infiltration, lymphocytosis, anemia, splenomegaly, and thrombocytopenia:

●The most common presenting finding is neutropenia (about 85 percent); one-third of patients are asymptomatic and are diagnosed with neutropenia as an incidental finding [1]. Neutropenia occurs in approximately 80 percent of patients with T-LGL leukemia overall; 40 to 45 percent develop severe neutropenia (absolute neutrophil count <0.5 x 10⁹/L) with recurrent pyogenic infections [10,21].

●The bone marrow is infiltrated with lymphocytes in almost 90 percent of patients with LGL leukemia, three-fourths of whom have mild to moderate absolute lymphocytosis. Myeloid hypoplasia is noted in some patients and may correlate with the degree of cytotoxic T-lymphocyte infiltration [8].

●Anemia and thrombocytopenia are also common (50 and 20 percent, respectively).

●Splenomegaly is present in 20 to 50 percent of patients with T-LGL leukemia, and hepatomegaly occurs in 10 to 20 percent of patients [8].

Other symptoms — Symptoms other than those directly related to RA, when present, are usually related to neutropenia, including fever with recurrent bacterial infections in 20 to 40 percent of patients, although opportunistic infections are uncommon. Fatigue, fever, night sweats, or weight loss occurs in 20 to 30 percent of patients. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Clinical features'.)

DIAGNOSIS — Large granular lymphocyte (LGL) leukemia should be suspected in any patient with seropositive rheumatoid arthritis (RA) and neutropenia. Some patients may also have concomitant anemia or even pancytopenia. Systemic symptoms are usually restricted to infectious symptoms related to neutropenia (see 'Other symptoms' above). Patients often do not have striking lymphocytosis, nor are atypical lymphocytes a requisite finding. The diagnosis of large granular lymphocyte (LGL) leukemia is based upon the findings of elevated lymphocyte count and marrow infiltration with lymphocytes, a distinctive immunophenotype, and demonstration of clonality by molecular studies.

LGLs in the setting of rheumatoid arthritis are typically CD3+, CD8+, and TCR-alpha/beta-positive T cells, although some may be CD4+, CD8-, and TCR-gamma/delta-positive T cells. They also frequently express the mature T-cell marker CD57 [10,13]. Clonality can be confirmed by evaluating for monoclonal rearrangements of the T-cell receptor by polymerase chain reaction [3]. There is no absolute lymphocyte count or number of circulating LGL that is diagnostic. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Pathologic features' and "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Diagnosis'.)

In patients with established rheumatoid arthritis (RA) who present with severe neutropenia, drug-induced cytopenia should be excluded, and flow cytometry and gene rearrangement studies should be performed on the peripheral blood. It may be necessary to ask specifically for flow for LGL leukemia, since many laboratories do not include assessment of LGL in routine flow cytometry for lymphoma. We obtain consultation with a hematologist for further evaluation, including bone marrow aspiration and biopsy, which are usually required to confirm the diagnosis and to exclude other causes of neutropenia.

Relationship to Felty syndrome — Felty syndrome (FS), the triad of chronic arthritis, splenomegaly, and granulocytopenia, typically occurs in patients with severe, longstanding, seropositive RA, often in association with other extraarticular manifestations. Some of these patients have proliferation of LGL, and some patients previously diagnosed with FS would now be classified instead as having T-cell LGL (T-LGL) leukemia, using immunophenotyping techniques and molecular analyses [8,9,22]. (See "Clinical manifestations and diagnosis of Felty syndrome".)

The distinction between FS and T-LGL leukemia in patients with RA has generally been made based upon the determination of whether the LGL proliferation represents clonal expansion of cells, with those with polyclonality defined as having FS and with those with monoclonality as having LGL-leukemia. However, this distinction is not always clear. Small populations of clonally expanded T cells can be seen in healthy individuals and in patients with RA and other chronic inflammatory conditions, suggesting that clonal expansion alone may not always define a population as malignant [8,9,23,24].

The observation that 85 to 90 percent of patients with both FS and RA-associated LGL leukemia are human leukocyte antigen (HLA)-DR4-positive suggests a shared or very similar immunologic basis for these conditions and has supported the argument that they represent overlapping parts of a spectrum of conditions, rather than entirely distinct entities [3,25]. However, patients with FS, compared with patients with LGL leukemia, are more likely to be identified late in their disease course and to be affected by severe RA and other extraarticular manifestations, including leg ulcers and rheumatoid nodules [9]. Only about 40 percent of patients with FS exhibit LGL proliferation. Additionally, patients with T-LGL leukemia without RA exhibit bone marrow features of a granulocytic proliferation defect, while patients with FS usually show features of a survival defect; however, mixed features may be seen [8].

DIFFERENTIAL DIAGNOSIS

Felty syndrome — In patients with rheumatoid arthritis (RA), Felty syndrome (FS) is the condition most likely to be confused with large granular lymphocyte (LGL) leukemia and is sometimes considered to be part of a common spectrum. (See 'Relationship to Felty syndrome' above.)

Other LGL proliferative disorders — Other conditions associated with LGL proliferation are not associated with RA, including natural killer cell LGL (NK-LGL) leukemia, an aggressive and difficult-to-treat syndrome which comprises about 5 percent of LGL disorders. This condition is diagnosed by immunophenotypic analysis. (See "Natural killer (NK) cell large granular lymphocyte leukemia".)

Reactive benign large granular lymphocytosis may occur in association with a number of viral syndromes and following splenectomy or bone marrow transplant [9]. These conditions can be distinguished from RA-associated T-cell LGL (T-LGL) leukemia by their polyclonality and by the absence of RA. (See "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Evaluation of the child with lymphocytosis'.)

T cell leukemias and lymphomas — A number of other conditions affecting T cells that are not associated with RA may also be considered in the differential diagnosis, including NK-like T-cell lymphoma, hepatosplenic T-cell lymphoma, posttransplant T-cell lymphoproliferative disorders, S100 positive T-cell lymphoproliferative disorders, and acute lymphoblastic leukemia. These are discussed in more detail elsewhere. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Differential diagnosis'.)

PROGNOSIS — Patients with T-cell large granular lymphocyte (T-LGL) leukemia and rheumatoid arthritis (RA) usually have a chronic, indolent course with a median survival of over 10 years, although most eventually require therapy [5,9,26]. In the absence of infectious death, most patients survive for many years unless other problems intervene, although a small number of patients will succumb to progressive lymphoproliferative disease [1]. Infection is the leading cause of death in this disorder. In contrast, patients with natural killer cell LGL (NK-LGL), which has not been associated with RA, typically have a more aggressive course [5,8]. (See "Natural killer (NK) cell large granular lymphocyte leukemia", section on 'Clinical presentation' and "Natural killer (NK) cell large granular lymphocyte leukemia", section on 'Prognosis'.)

TREATMENT — Treatment is indicated in symptomatic patients, including those with recurrent neutropenia-related infections, with other symptomatic cytopenias, or with transfusion dependence. The approach to asymptomatic patients, indications for treatment, and treatment of large granular lymphocyte (LGL) leukemia in patients with rheumatoid arthritis (RA) are discussed in detail elsewhere. (See "Treatment of large granular lymphocyte leukemia" and "Treatment of large granular lymphocyte leukemia", section on 'Initial treatment'.)

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

●Large granular lymphocyte (LGL) leukemia is characterized by peripheral blood and bone marrow lymphocytic infiltration with LGLs, splenomegaly, and cytopenias, most commonly neutropenia. Up to one-third of patients with LGL leukemia have rheumatoid arthritis (RA). (See 'Introduction' above.)

●LGL leukemia associated with RA is a clonal lymphoproliferative disease. It appears to represent one part of a spectrum of polyclonal and clonal disorders of LGL, including at least a subset of patients with Felty syndrome (FS). In patients with rheumatologic disease, LGL leukemia is almost always the T-cell LGL (T-LGL) type. (See 'Pathogenesis' above.)

●RA often precedes the development of T-LGL leukemia, but both conditions may present concurrently. Most patients have positive tests for rheumatoid factor and anticyclic citrullinated peptide antibodies; many patients also have antinuclear antibodies. (See 'Hematologic abnormalities' above.)

●Several factors appear to contribute to the neutropenia in the LGL syndrome, including defects in both proliferation and neutrophil survival. Patients also may exhibit anemia and thrombocytopenia. Splenomegaly may be present in up to half of patients and hepatomegaly in up to 20 percent. (See 'Pathogenesis' above and 'Hematologic abnormalities' above.)

●One-third of patients are asymptomatic, other than from RA, but others experience fever, bacterial infections, fatigue, night sweats, or weight loss. (See 'Other symptoms' above.)

●The diagnosis of LGL leukemia is based upon the findings of an elevated lymphocyte count and marrow infiltration with lymphocytes, a distinctive immunophenotype, and demonstration of clonality by molecular studies. LGLs in the setting of RA are typically CD3+, CD8+, and TCR-alpha/beta-positive T cells. Clonality can be confirmed by evaluating for monoclonal rearrangements of the T-cell receptor by polymerase chain reaction. Clonality is the feature that is generally considered to distinguish this condition from FS associated with LGL, although these conditions are sometimes considered as parts of a single disease spectrum. (See 'Diagnosis' above and 'Relationship to Felty syndrome' above.)

●Patients with RA-associated T-LGL leukemia usually have a chronic, indolent course with a median survival of over 10 years, although most eventually require therapy. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert Pinals, MD, who contributed to an earlier version of this topic review.