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Felty Syndrome

  • Author: Richard M Keating, MD, FACR, FACP; Chief Editor: Herbert S Diamond, MD  more...
 
Updated: Feb 12, 2014
 

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] FS is characterized by the triad of RA, splenomegaly, and granulocytopenia. Although many patients with FS are asymptomatic, some develop serious and life-threatening infections secondary to granulocytopenia.

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Pathophysiology

Although the pathophysiology of FS is not fully understood, evidence points to splenic sequestration and subsequent granulocyte destruction.

Early studies demonstrated that granulocyte counts were lower in the splenic vein than 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 and FS share overlapping pathophysiologic features.[2]

In a 2002 study from Germany, 15 patients with neutropenia due to FS were matched to a control group of 16 patients with normocytic RA, and 16 patients with neutropenia and systemic lupus erythematosus (SLE) were matched to a control group of 16 patients with SLE.[3] Antibodies against granulocyte colony-stimulating factor (G-CSF) were measured.

In this study, 11 patients with FS demonstrated anti–G-CSF immunoglobulin G (IgG); none of the patients in the RA control group demonstrated anti–G-CSF IgG.[3] In addition, 6 of the patients with both neutropenia and SLE and 6 of the patients in the SLE control group had anti–G-CSF antibodies. These antibodies appeared to have a neutralizing effect on G-CSF.

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Etiology

Risk factors for FS include the following:

  • RF positivity in high titers
  • Long-standing disease
  • Aggressive and erosive synovitis – Patient with FS may present with mild RA, but FS is clearly associated with severe disease and extra-articular manifestations
  • Human leukocyte antigen (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
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Epidemiology

United States and international statistics

FS affects approximately 1-3% of all patients diagnosed with RA, and RA occurs in about 1% of the general population. It appears to be rare in children and the African American population. The true prevalence of FS is difficult to ascertain because many affected patients are asymptomatic. Prevalence may be decreasing with the advent of more potent antirheumatic agents. Few data suggest that the international frequency of FS differs significantly from the US frequency.

Age-, sex-, and race-related demographics

FS is most common during the fifth through seventh decades of life and is usually associated with more than 10 years of preceding RA activity. Men are affected with FS earlier in the course of RA than women are. FS is about 3 times more common in females, though underreporting and asymptomatic cases hinder determination of the true sex ratio. FS is most common in whites and is uncommon in blacks. The HLA-DR4 genotype, a marker for more aggressive RA and more frequent extra-articular manifestations in whites, is strongly associated with FS.

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Prognosis

Although many individuals with FS are asymptomatic, others become symptomatic and may develop life-threatening infections. Pulmonary and skin infections are common. Mortality and morbidity are heavily influenced by the level of debilitation due to the underlying RA, along with the extent of immunosuppressive therapy used in treating both RA and FS. 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.[4]

Curiously, over the past 20 years in the United States, the frequency of hospitalization for rheumatoid vasculitis and ultimate splenectomy in patients with FS has dropped, possibly because earlier and more aggressive treatment of RA tends to control the disease before the manifestations of FS appear.

Granulocytopenia is defined as an absolute neutrophil count (ANC) lower than 2000/µL, and the infection risk increases as the ANC drops. Infection incidence increases significantly when the polymorphonuclear leukocyte (PMN) count is lower than 1000/µL.

In a retrospective study of male patients with FS treated at the Department of Veterans Affairs, lymphoproliferative malignancies were more prevalent; in particular, the patients had an increased prevalence of non-Hodgkin lymphoma.[5]

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Patient Education

Educate patients with FS about the warning signs of infection and ensure that they have ready access to medical care.

Some practitioners supply FS patients with a broad-spectrum oral antibiotic that is to be taken at the first signs of a bacterial infection. Instruct patients that the decision to initiate antibiotic therapy is a decision that must be made on an individual basis, and advise them to contact their physician immediately if such a situation develops.

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Contributor Information and Disclosures
Author

Richard M Keating, MD, FACR, FACP Program Director, Rheumatology Fellowship, Scripps Clinic

Richard M Keating, MD, FACR, FACP is a member of the following medical societies: American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

Coauthor(s)

Kavitta B Allem, MD Fellow in Rheumatology, Scripps Clinic

Disclosure: Nothing to disclose.

Dana A Copeland, MD Department of Rheumatology, Scripps Clinic

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

References
  1. Felty AR. Chronic arthritis in the adult associated with splenomegaly and leukopenia. Bull Johns Hopkins Hosp. 1924. 35:16.

  2. Burks EJ, Loughran TP Jr. Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. Blood Rev. 2006 Sep. 20(5):245-66. [Medline].

  3. 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 Sep. 46(9):2384-91. [Medline].

  4. Campion G, Maddison PJ, Goulding N, James I, Ahern MJ, Watt I, et al. The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations. Medicine (Baltimore). 1990 Mar. 69(2):69-80. [Medline].

  5. Gridley G, Klippel JH, Hoover RN, et al. Incidence of cancer among men with the Felty syndrome. Ann Intern Med. 1994 Jan 1. 120(1):35-9. [Medline].

  6. Brücker R, Schlumpf U. [Felty syndrome: a therapy-resistant variant of chronic rheumatoid arthritis? 2 case reports and literature review]. Praxis (Bern 1994). 1996 Apr 16. 85(16):534-40. [Medline].

  7. Ghavami A, Genevay S, Fulpius T, et al. Etanercept in treatment of Felty's syndrome. Ann Rheum Dis. 2005 Jul. 64(7):1090-1. [Medline].

  8. Talip F, Walker N, Khan W, et al. Treatment of Felty's syndrome with leflunomide. J Rheumatol. 2001 Apr. 28(4):868-70. [Medline].

  9. 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. 2003 Feb. 30(2):404-6. [Medline].

  10. Sordet C, Gottenberg JE, Hellmich B, et al. Lack of efficacy of rituximab in Felty's syndrome. Ann Rheum Dis. 2005 Feb. 64(2):332-3. [Medline].

  11. Chandra PA, Margulis Y, Schiff C. Rituximab is useful in the treatment of Felty's syndrome. Am J Ther. 2008 Jul-Aug. 15(4):321-2. [Medline].

  12. Weinreb N, Rabinowitz A, Dellaripa PF. Beneficial response to rituximab in refractory Felty Syndrome. J Clin Rheumatol. 2006 Feb. 12(1):48. [Medline].

  13. Tomi AL, Lioté F, Ea HK. One case of Felty's syndrome efficiently treated with rituximab. Joint Bone Spine. 2012 Mar 6. [Medline].

  14. Narváez J, Domingo-Domenech E, Gómez-Vaquero C, López-Vives L, Estrada P, Aparicio M, et al. Biological agents in the management of Felty's syndrome: a systematic review. Semin Arthritis Rheum. 2012 Apr. 41(5):658-68. [Medline].

 
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