Clinical manifestations and diagnosis of Felty's syndrome
- Jonathan Kay, MD
Jonathan Kay, MD
- Timothy S. and Elaine L. Peterson Chair in Rheumatology
- Professor of Medicine and Director of Clinical Research, Rheumatology
- University of Massachusetts Medical School
- 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
Patients with Felty’s syndrome (FS) comprise an infrequently occurring but severe subset of seropositive rheumatoid arthritis (RA) complicated by neutropenia and splenomegaly .
The clinical manifestations and diagnosis of this disorder are discussed here. Drug therapy and surgery for FS, as well as a review of large granular lymphocyte leukemia in RA, are presented separately. (See "Drug therapy in Felty's syndrome" and "Indications for splenectomy in Felty's syndrome" and "Large granular lymphocyte leukemia in rheumatoid arthritis".)
The cause of Felty’s syndrome (FS), which occurs within a subset of patients with rheumatoid arthritis (RA), is unknown. Its presence primarily in patients with longstanding active disease who test positive for rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA), and for human leukocyte antigen (HLA)-DR4, suggests important roles for chronic inflammation in a genetically predisposed individual.
Neutropenia in patients with FS results from an imbalance between granulocyte production and granulocyte removal from the circulating pool. One or more of the following can contribute to the development of neutropenia [2-10]:
●Autoantibodies to deiminated histones (predominantly histone H3) and other components of neutrophil extracellular chromatin traps (NETs) that bind to activated neutrophils, which are then sequestered in the spleen (see 'Splenomegaly' below) and depleted.
- Felty AR. Chronic arthritis in the adult associated with splenomegaly and leukopenia. Bull Johns Hopkins Hosp 1924; 35:16.
- Burks EJ, Loughran TP Jr. Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. Blood Rev 2006; 20:245.
- Breedveld FC, Fibbe WE, Cats A. Neutropenia and infections in Felty's syndrome. Br J Rheumatol 1988; 27:191.
- Starkebaum G, Arend WP, Nardella FA, Gavin SE. Characterization of immune complexes and immunoglobulin G antibodies reactive with neutrophils in the sera of patients with Felty's syndrome. J Lab Clin Med 1980; 96:238.
- Dancey JT, Brubaker LH. Neutrophil marrow profiles in patients with rheumatoid arthritis and neutropenia. Br J Haematol 1979; 43:607.
- Abdou NI. Heterogeneity of bone marrow-directed immune mechanisms in the pathogenesis of neutropenia of Felty's syndrome. Arthritis Rheum 1983; 26:947.
- Coakley G, Mok CC, Hajeer AH, et al. Interleukin-10 promoter polymorphisms in rheumatoid arthritis and Felty's syndrome. Br J Rheumatol 1998; 37:988.
- Meliconi R, Uguccioni M, Chieco-Bianchi F, et al. The role of interleukin-8 and other cytokines in the pathogenesis of Felty's syndrome. Clin Exp Rheumatol 1995; 13:285.
- Hellmich B, Csernok E, Schatz H, et al. Autoantibodies against granulocyte colony-stimulating factor in Felty's syndrome and neutropenic systemic lupus erythematosus. Arthritis Rheum 2002; 46:2384.
- Dwivedi N, Upadhyay J, Neeli I, et al. Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps. Arthritis Rheum 2012; 64:982.
- Goldberg J, Pinals RS. Felty syndrome. Semin Arthritis Rheum 1980; 10:52.
- Sibley JT, Haga M, Visram DA, Mitchell DM. The clinical course of Felty's syndrome compared to matched controls. J Rheumatol 1991; 18:1163.
- Bartels CM, Bell CL, Shinki K, et al. Changing trends in serious extra-articular manifestations of rheumatoid arthritis among United State veterans over 20 years. Rheumatology (Oxford) 2010; 49:1670.
- Campion G, Maddison PJ, Goulding N, et al. The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations. Medicine (Baltimore) 1990; 69:69.
- Turesson C, Schaid DJ, Weyand CM, et al. The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis. Arthritis Res Ther 2005; 7:R1386.
- Bradley JD, Pinals RS. Felty's syndrome presenting without arthritis. Clin Exp Rheumatol 1983; 1:257.
- Ruderman M, Miller LM, Pinals RS. Clinical and serologic observations on 27 patients with Felty's syndrome. Arthritis Rheum 1968; 11:377.
- Sienknecht CW, Urowitz MB, Pruzanski W, Stein HB. Felty's syndrome. Clinical and serological analysis of 34 cases. Ann Rheum Dis 1977; 36:500.
- Barnes CG, Turnbull AL, Vernon-Roberts B. Felty's syndrome. A clinical and pathological survey of 21 patients and their response to treatment. Ann Rheum Dis 1971; 30:359.
- Laszlo J, Jones R, Silberman HR, Banks PM. Splenectomy for Felty's syndrome. Clinicopathological study of 27 patients. Arch Intern Med 1978; 138:597.
- Starkebaum G. Chronic neutropenia associated with autoimmune disease. Semin Hematol 2002; 39:121.
- Breedveld FC, Fibbe WE, Hermans J, et al. Factors influencing the incidence of infections in Felty's syndrome. Arch Intern Med 1987; 147:915.
- Hellmich B, Csernok E, de Haas M, et al. Low Fcgamma receptor III and high granulocyte colony-stimulating factor serum levels correlate with the risk of infection in neutropenia due to Felty's syndrome or systemic lupus erythematosus. Am J Med 2002; 113:134.
- Pinals RS. Polyarthritis and fever. N Engl J Med 1994; 330:769.
- Thorne C, Urowitz MB, Wanless I, et al. Liver disease in Felty's syndrome. Am J Med 1982; 73:35.
- Wanless IR, Godwin TA, Allen F, Feder A. Nodular regenerative hyperplasia of the liver in hematologic disorders: a possible response to obliterative portal venopathy. A morphometric study of nine cases with an hypothesis on the pathogenesis. Medicine (Baltimore) 1980; 59:367.
- Gridley G, Klippel JH, Hoover RN, Fraumeni JF Jr. Incidence of cancer among men with the Felty syndrome. Ann Intern Med 1994; 120:35.
- Turesson C, Jacobsson LT, Sturfelt G, et al. Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann Rheum Dis 2007; 66:59.
- Luthra HS, Hunder GG. Spontaneous remission of Felty's syndrome. Arthritis Rheum 1975; 18:515.
- HUME R, DAGG JH, FRASER TN, GOLDBERG A. ANAEMIA OF FELTY'S SYNDROME. Ann Rheum Dis 1964; 23:267.
- Cohen MG, Webb J. Antihistone antibodies in rheumatoid arthritis and Felty's syndrome. Arthritis Rheum 1989; 32:1319.
- Coremans IE, Hagen EC, van der Voort EA, et al. Autoantibodies to neutrophil cytoplasmic enzymes in Felty's syndrome. Clin Exp Rheumatol 1993; 11:255.
- van Gaalen FA, Toes RE, Ditzel HJ, et al. Association of autoantibodies to glucose-6-phosphate isomerase with extraarticular complications in rheumatoid arthritis. Arthritis Rheum 2004; 50:395.
- Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271.
- Hastings R, Ding T, Butt S, et al. Neutropenia in patients receiving anti-tumor necrosis factor therapy. Arthritis Care Res (Hoboken) 2010; 62:764.
- Oran B, Wright DG, Seldin DC, et al. Spontaneous rupture of the spleen in AL amyloidosis. Am J Hematol 2003; 74:131.
- CLINICAL MANIFESTATIONS
- Major features
- - Rheumatoid arthritis
- - Neutropenia
- - Splenomegaly
- Associated clinical features
- - Bacterial infection
- - Extraarticular rheumatoid arthritis
- - Portal hypertension
- - Malignancy
- Laboratory findings
- DIFFERENTIAL DIAGNOSIS
- SUMMARY AND RECOMMENDATIONS