Large granular lymphocyte leukemia in rheumatoid arthritis
- Nancy Berliner, MD
Nancy Berliner, MD
- Professor of Medicine
- Harvard Medical School
- Chief, Division of Hematology
- Brigham and Women's Hospital
- Section Editor
- Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
- Section Editor — Rheumatoid Arthritis
- Emeritus Professor of Rheumatology, Imperial College London
- Visiting Professor, Oxford University
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) .
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) . LGL leukemia can also occur in association with Sjögren’s syndrome in the absence of RA  and with other autoimmune disorders, including inflammatory bowel disease, systemic lupus, and autoimmune thyroid disease [3,4].
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".)
T-cell large granular lymphocyte (T-LGL) leukemia is very uncommon among patients with rheumatoid arthritis (RA), despite the frequency of RA among patients with this disorder. In 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 .
The mean age of onset of T-LGL leukemia in RA is 60 years, with no gender differences, which is similar to patients without arthritis . (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Clinical features'.)
- Loughran TP Jr. Clonal diseases of large granular lymphocytes. Blood 1993; 82:1.
- Wlodarski MW, Schade AE, Maciejewski JP. T-large granular lymphocyte leukemia: current molecular concepts. Hematology 2006; 11:245.
- Friedman J, Schattner A, Shvidel L, Berrebi A. Characterization of T-cell large granular lymphocyte leukemia associated with Sjogren's syndrome-an important but under-recognized association. Semin Arthritis Rheum 2006; 35:306.
- Lamy T, Loughran TP Jr. Current concepts: large granular lymphocyte leukemia. Blood Rev 1999; 13:230.
- Saway PA, Prasthofer EF, Barton JC. Prevalence of granular lymphocyte proliferation in patients with rheumatoid arthritis and neutropenia. Am J Med 1989; 86:303.
- Burks EJ, Loughran TP Jr. Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. Blood Rev 2006; 20:245.
- Shah A, Diehl LF, St Clair EW. T cell large granular lymphocyte leukemia associated with rheumatoid arthritis and neutropenia. Clin Immunol 2009; 132:145.
- Sokol L, Loughran TP Jr. Large granular lymphocyte leukemia. Oncologist 2006; 11:263.
- Viny AD, Lichtin A, Pohlman B, et al. Chronic B-cell dyscrasias are an important clinical feature of T-LGL leukemia. Leuk Lymphoma 2008; 49:932.
- Pawarode A, Baer M. T/B and not T/B: high frequency of B-cell dyscrasias in T-LGL leukemia. Leuk Lymphoma 2008; 49:845.
- Shah MV, Zhang R, Loughran TP Jr. Never say die: survival signaling in large granular lymphocyte leukemia. Clin Lymphoma Myeloma 2009; 9 Suppl 3:S244.
- Yang J, Epling-Burnette PK, Painter JS, et al. Antigen activation and impaired Fas-induced death-inducing signaling complex formation in T-large-granular lymphocyte leukemia. Blood 2008; 111:1610.
- Mohan SR, Maciejewski JP. Diagnosis and therapy of neutropenia in large granular lymphocyte leukemia. Curr Opin Hematol 2009; 16:27.
- Liu JH, Wei S, Lamy T, et al. Chronic neutropenia mediated by fas ligand. Blood 2000; 95:3219.
- Coakley G, Iqbal M, Brooks D, et al. CD8+, CD57+ T cells from healthy elderly subjects suppress neutrophil development in vitro: implications for the neutropenia of Felty's and large granular lymphocyte syndromes. Arthritis Rheum 2000; 43:834.
- Koskela HL, Eldfors S, Ellonen P, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med 2012; 366:1905.
- Prochorec-Sobieszek M, Rymkiewicz G, Makuch-Łasica H, et al. Characteristics of T-cell large granular lymphocyte proliferations associated with neutropenia and inflammatory arthropathy. Arthritis Res Ther 2008; 10:R55.
- Barton JC, Prasthofer EF, Egan ML, et al. Rheumatoid arthritis associated with expanded populations of granular lymphocytes. Ann Intern Med 1986; 104:314.
- Lamy T, Loughran TP Jr. Clinical features of large granular lymphocyte leukemia. Semin Hematol 2003; 40:185.
- Snowden N, Bhavnani M, Swinson DR, et al. Large granular T lymphocytes, neutropenia and polyarthropathy: an underdiagnosed syndrome? Q J Med 1991; 78:65.
- Fitzgerald JE, Ricalton NS, Meyer AC, et al. Analysis of clonal CD8+ T cell expansions in normal individuals and patients with rheumatoid arthritis. J Immunol 1995; 154:3538.
- Hingorani R, Monteiro J, Furie R, et al. Oligoclonality of V beta 3 TCR chains in the CD8+ T cell population of rheumatoid arthritis patients. J Immunol 1996; 156:852.
- Starkebaum G, Loughran TP Jr, Gaur LK, et al. Immunogenetic similarities between patients with Felty's syndrome and those with clonal expansions of large granular lymphocytes in rheumatoid arthritis. Arthritis Rheum 1997; 40:624.
- Dhodapkar MV, Li CY, Lust JA, et al. Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance? Blood 1994; 84:1620.
- CLINICAL MANIFESTATIONS
- Rheumatoid arthritis
- Hematologic abnormalities
- Other symptoms
- Relationship to Felty's syndrome
- DIFFERENTIAL DIAGNOSIS
- Felty's syndrome
- Other LGL proliferative disorders
- T cell leukemias and lymphomas
- SUMMARY AND RECOMMENDATIONS