Introduction
Background
Felty syndrome (FS), which was first described in 1924, is a potentially serious condition that is associated with seropositive (rheumatoid factor [RF]–positive) rheumatoid arthritis (RA).1 Felty syndrome is characterized by the triad of RA, splenomegaly, and granulocytopenia. Although many patients with Felty syndrome are asymptomatic, some develop serious and life-threatening infections secondary to granulocytopenia.
For additional information on rheumatoid arthritis, see Medscape’s Rheumatoid Arthritis Resource Center.
Pathophysiology
Although the pathophysiology of Felty syndrome is not fully understood, evidence points to splenic sequestration and subsequent granulocyte destruction. Studies performed almost 50 years ago demonstrated lower granulocyte counts in the splenic vein compared with those in the splenic artery. Researchers have shown immune complexes coating granulocytes, diminished granulocyte growth factor levels, and numerous circulating autoantibodies, including those against granulocyte surface antigens. T-cell large granular lymphocyte leukemia (TLGL) and Felty syndrome share overlapping pathophysiologic features.2
In 2002, a study in Germany examined 15 patients with neutropenia due to Felty syndrome and matched them to a control group of 16 patients with normocytic RA. In addition, 16 patients with neutropenia and systemic lupus erythematosus (SLE) were matched to a control group of 16 patients with SLE. Antibodies against granulocyte colony-stimulating factor (G-CSF) were measured. Eleven patients with Felty syndrome demonstrated anti–G-CSF immunoglobulin G (IgG); none of the patients in the RA control group demonstrated anti–G-CSF IgG. Six patients with both neutropenia and SLE and 6 patients in the SLE control group also had anti–G-CSF antibodies. These antibodies appeared to have a neutralizing effect on G-CSF.3
Frequency
United States
Felty syndrome affects approximately 1-3% of all patients diagnosed with RA, and RA occurs in about 1% of the general population. The true prevalence of Felty syndrome is difficult to ascertain because many affected patients are asymptomatic. Felty syndrome is rare in children. The prevalence of Felty syndrome may be decreasing with the advent of more potent antirheumatic agents. It seems to be quite rare in the African American population.
International
Few data suggest that the international frequency of Felty syndrome differs from that of the United States.
Mortality/Morbidity
Although many individuals with Felty syndrome are asymptomatic, others progress and develop life-threatening infections. Pulmonary and skin infections are common. The level of debilitation due to the underlying RA, along with the extent of immunosuppression used in treating both RA and Felty syndrome, heavily influence mortality and morbidity. One study from southwest England observed 32 patients with Felty syndrome; 5 patients died of overwhelming bronchopneumonia during a mean follow-up period of 5.2 years. Curiously, in the past 20 years in the United States, the frequency of hospitalization for rheumatoid vasculitis and ultimate splenectomy in patients with Felty syndrome has dropped, possibly because of earlier and more aggressive treatment of RA, controlling the disease before the manifestations of Felty syndrome appear.
Race
Felty syndrome is most common in whites and is uncommon in blacks. The human leukocyte antigen DR4 (HLA-DR4) genotype, which is a marker for more aggressive RA and more frequent extra-articular manifestations in whites, is strongly associated with Felty syndrome.
Sex
Felty syndrome is more common in females, with an approximate female-to-male ratio of 3:1. Underreporting and asymptomatic cases cause difficulty in determining the true sex ratio.
Age
Felty syndrome is most common during the fifth through the seventh decades of life. The condition is usually associated with more than 10 years of preceding RA activity. Men are affected with Felty syndrome earlier in the course of RA than women are.
Clinical
History
- Many years of aggressive destructive rheumatoid arthritis (RA) precede the onset of Felty syndrome. On occasion, RA and Felty syndrome simultaneously develop. The extra-articular manifestations of RA (eg, rheumatoid nodules, pleuropericarditis, vasculitis, peripheral neuropathy, episcleritis, other forms of eye involvement, Sjögren syndrome, adenopathy, skin ulcers) are more common in patients who develop Felty syndrome.
- Patients with Felty syndrome often report current symptoms of mild inflammatory joint disease caused by synovitis. The patient's history, however, usually reveals a long preceding period of active and aggressive joint disease, which can be confirmed by physical examination and plain radiography. Some patients present with quiescent or so-called "burned-out" joint disease. A lack of synovitis or active joint disease should not dissuade the clinician from considering the diagnosis of Felty syndrome.
- Patients with Felty syndrome commonly present with bacterial infections of the skin and respiratory tract. An aggressive level of immunosuppression directed at the underlying RA may contribute to the susceptibility to infection.
- Patients may present with left upper quadrant pain, initiated by splenic infarcts or capsular distension.
Physical
- Splenomegaly, possibly nonpalpable
- Hepatomegaly, usually mild
- Lymphadenopathy
- Weight loss
- Rheumatoid nodules
- Sjögren syndrome
- Articular findings of long-standing RA
- Joint deformities typical of RA
- Synovitis (joint swelling and tenderness), may be mild at presentation
- Small-vessel inflammation (vasculitis)
- Lower-extremity ulcers
- Palpable purpura and brownish pigmentary changes of the lower extremities
- Periungual infarcts
- Signs of systemic vasculitis
- Mononeuritis multiplex
- Extremity ischemia
- Others findings, including pleuritis, peripheral neuropathy, episcleritis, and signs of portal hypertension
Causes
- Risk factors for Felty syndrome include the following:
- RF positivity in high titers
- Long-standing disease
- Aggressive and erosive synovitis: Patients with Felty syndrome may present with mild RA, but Felty syndrome is clearly associated with severe disease and extra-articular manifestations.
- HLA-DR4 positivity and DR4 homozygosity: This may be due to the presence of HLA-DR4 in patients who have severe disease.
- Extra-articular RA manifestations
More on Felty Syndrome |
 Overview: Felty Syndrome |
| Differential Diagnoses & Workup: Felty Syndrome |
| Treatment & Medication: Felty Syndrome |
| Follow-up: Felty Syndrome |
| References |
| Next Page » |
References
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. Sep 2006;20(5):245-66. [Medline].
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. Sep 2002;46(9):2384-91. [Medline].
Ghavami A, Genevay S, Fulpius T, et al. Etanercept in treatment of Felty's syndrome. Ann Rheum Dis. Jul 2005;64(7):1090-1. [Medline].
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Ishikawa K, Tsukada Y, Tamura S, et al. Salazosulfapyridine-induced remission of Felty's syndrome along with significant reduction in neutrophil-bound immunoglobulin G. J Rheumatol. Feb 2003;30(2):404-6. [Medline].
Gridley G, Klippel JH, Hoover RN, et al. Incidence of cancer among men with the Felty syndrome. Ann Intern Med. Jan 1 1994;120(1):35-9. [Medline].
Balint GP, Balint PV. Felty's syndrome. Best Pract Res Clin Rheumatol. Oct 2004;18(5):631-45. [Medline]. [Full Text].
Barton JC, Prasthofer EF, Egan ML, et al. Rheumatoid arthritis associated with expanded populations of granular lymphocytes. Ann Intern Med. Mar 1986;104(3):314-23. [Medline].
Breedveld FC, Fibbe WE, Hermans J, et al. Factors influencing the incidence of infections in Felty's syndrome. Arch Intern Med. May 1987;147(5):915-20. [Medline].
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). Mar 1990;69(2):69-80. [Medline].
Ellman MH. Leukocyte colony-stimulating factors for rheumatologists. J Clin Rheumatol. 1997;3(4):217-223.
Rashba EJ, Rowe JM, Packman CH. Treatment of the neutropenia of Felty syndrome. Blood Rev. Sep 1996;10(3):177-84. [Medline].
Rosenstein ED, Kramer N. Felty's and pseudo-Felty's syndromes. Semin Arthritis Rheum. Dec 1991;21(3):129-42. [Medline].
Starkebaum G. Use of colony-stimulating factors in the treatment of neutropenia associated with collagen vascular disease. Curr Opin Hematol. May 1997;4(3):196-9. [Medline].
Ward MM. Decreases in rates of hospitalizations for manifestations of severe rheumatoid arthritis, 1983-2001. Arthritis Rheum. Apr 2004;50(4):1122-31. [Medline].
Further Reading
Keywords
Felty syndrome, FS, Felty's syndrome, pseudo-Felty syndrome, pseudo-Felty's syndrome, rheumatoid arthritis, RA, splenomegaly, granulocytopenia, rheumatoid factor, RF, large granular lymphocytosis syndrome, LGL
