AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

First described in 1924, Felty syndrome (FS) is a potentially serious condition that is associated with seropositive (rheumatoid factor [RF] positive) rheumatoid arthritis (RA). Felty syndrome is characterized by the triad of RA, splenomegaly, and granulocytopenia. Although many patients are asymptomatic, some develop serious and life-threatening infections secondary to granulocytopenia.

Pathophysiology

Although the pathophysiology of Felty syndrome is not fully known, 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.

A recent study in Germany examined 15 patients with neutropenia from 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.

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 patients are asymptomatic. Felty syndrome rarely occurs 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 is different from that of the United States.

Mortality/Morbidity

Although many patients are asymptomatic, others progress and develop life-threatening infections. Pulmonary and skin infections are common. The level of debilitation from the underlying RA as well as the extent of immunosuppression used in treating both RA and Felty syndrome heavily influence mortality and morbidity. One study from the southwest of England observed 32 patients with Felty syndrome; 5 patients died from 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. This drop is theorized to be secondary to earlier and more aggressive treatment of RA, controlling the disease before the manifestations of Felty syndrome appear.

Race

Felty syndrome most often occurs in whites and infrequently occurs 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

The incidence in women exceeds the incidence in men by a ratio of 3:1. Underreporting and asymptomatic cases cause difficulty in determining the true sex ratio.

Age

Patients most commonly develop Felty syndrome 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Many years of aggressive destructive 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 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, although it may not be palpable
• 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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Chronic infection
Drug reactions
Other rheumatologic diseases
Infiltrative diseases
Human immunodeficiency virus (HIV) infection
Neutropenia with large granular lymphocytosis (LGL), also known as pseudo-Felty syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count with differential is as follows:
• • Obtain a white blood cell (WBC) count and differential, which are crucial when determining the degree of granulocytopenia. Studies show that the greatest risk for infection occurs when the patient's granulocyte count is less than 1000/µL. Bear in mind, however, that the level of neutropenia varies over time without medical intervention. Granulocyte dysfunction and an absolute decrease in number of granulocytes are factors that may predispose patients to infection.
  • Anemia and thrombocytopenia may result from hypersplenism.
  • Anemia of chronic disease may result from the underlying inflammatory disease.
• Mild elevations of alkaline phosphatase and transaminase levels may occur.
• High titers of RF are almost always present in patients with Felty syndrome (98%). This is because extra-articular manifestations of RA are strongly associated with RF.
• Antinuclear antibodies (ANAs), found in 67% of cases; antihistone antibodies; and even antineutrophil cytoplasmic antibodies (perinuclear pattern; p-ANCA), found in 77% of cases, commonly occur in patients with Felty syndrome. The significance of autoantibodies in Felty syndrome is unknown, and their contribution, if any, to the disease itself is uncertain.
• Erythrocyte sedimentation rate (ESR) and serum immunoglobulin levels invariably are elevated in patients with Felty syndrome.
• Cryoglobulins may be present.

Imaging Studies

• Radionuclide studies, ultrasonography, or computed tomography (CT) scanning may define the presence and extent of splenomegaly. The same modalities can also be used to assess patient response to therapy.

Procedures

• Bone marrow aspiration and biopsy are especially important to rule out LGL syndrome. The bone marrow of patients with Felty syndrome shows adequate megakaryocytes and myeloid hyperplasia with arrested development at the level of immature cell forms.

Histologic Findings

An unusual type of liver involvement known as nodular regenerative hyperplasia is associated with Felty syndrome. It is characterized by mild portal fibrosis or lymphocyte and plasma cell infiltration but is not typical of cirrhosis. It may be complicated by portal venule occlusion and regenerative nodule formation.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The best treatment for Felty syndrome is to control the underlying RA. Immunosuppressive therapy for RA often improves granulocytopenia and splenomegaly; this finding reflects the fact that Felty syndrome is an immune-mediated disease. Most of the traditional medications used to treat RA have been used in the treatment of Felty syndrome. No well-conducted, randomized, controlled trials support the use of any single agent. Most reports on treatment regimens involve small numbers of patients.

• Historically, most patients have been treated with gold salts, reflective of their long history of use in RA prior to the advent of methotrexate; however, the response of the condition is slow. Older studies report a response rate of 60-80%. Intramuscular aurothioglucose (Solganal) was the agent most commonly used.
• Methotrexate acts faster than gold and now is the preferred agent of rheumatologists for treating RA. As experience using methotrexate in Felty syndrome increases, this drug is likely to become the agent of choice for therapy. If urgent correction of neutropenia is not necessary, most practicing rheumatologists use this drug first when treating Felty syndrome. It is usually combined with folic acid to minimize adverse effects. Note that the beneficial effects of methotrexate may not be evident for 4-8 weeks.
• The potential for leukopenia limits the use of cyclophosphamide, although it may have a role in some cases. A recent report described 2 patients with refractory Felty syndrome who responded to high-dose cyclophosphamide; however, physicians have had far more experience using cyclophosphamide for rheumatoid vasculitis and other serious RA extra-articular manifestations than for Felty syndrome. For this reason, it is not an initial choice of therapy.
• Penicillamine is being used less frequently for RA because of its adverse effect profile. Penicillamine never is a first-choice therapy for patients with Felty syndrome.
• Etanercept, adalimumab, and infliximab are all newer agents prescribed for RA. These agents act by blocking the effects of tumor necrosis factor-a (TNF-a). These drugs are very effective in the treatment and control of RA the experience of using them for Felty syndrome is limited.
• Intravenous immunoglobulin (IVIG) does not show reproducibly demonstrable success.
• Recombinant granulopoietic growth factors, such as G-CSF and granulocyte-monocyte colony-stimulating factor (GM-CSF), effectively and quickly raise the granulocyte count, which is important for patients with life-threatening infections. Initial treatment of patients with Felty syndrome and life-threatening infections should include the administration of a growth factor. Long-term use of G-CSF appears to be well tolerated, although hypersensitivity vasculitis and flare-ups of the underlying RA in these patients have been reported.
• At high doses, corticosteroids can increase the granulocyte count, partly through demargination. This effect does not persist when tapering the patient to a typical low dose ( <10 mg/d) used for RA articular disease. Empiric administration of high-dose intravenous methylprednisolone is often prescribed for Felty syndrome, but the effect is time limited. Long-term use of high-dose corticosteroids further increases the risk for infection. Corticosteroids should probably be viewed as a second-line treatment modality.
• Case reports in the past few years have noted a lack of efficacy with rituximab (Rituxan), a response to leflunomide (Arava), and a response to salazosulfapyridine. These were all single-patient reports.

Surgical Care

Splenectomy is only recommended for patients with severe intractable disease who exhibit no improvement with medical therapy and experience recurrent or serious infection. Less commonly, extrinsic hemolysis or recurrent cutaneous ulcers may indicate a need for splenectomy. Granulocytopenia recurs in approximately 25% of patients who have undergone splenectomy.

Consultations

• Rheumatologist
• Hematologist
• Infectious diseases specialist

Activity

Dictate patient activity according to infection risk and spleen size. Recommend that the patient avoid any activity that could result in blunt trauma to the left upper quadrant.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Gold compounds

These agents inhibit immune reactions.

Drug Category: Immunosuppressive agents

These agents inhibit key factors in the immune system responsible for immune reactions.

Drug Category: Colony-stimulating factors

These agents stimulate production, maturation, and activation of neutrophils. Increase migration and cytotoxicity of neutrophils.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admission is mandatory for patients with serious life-threatening infections. Patients need cultures and parenteral antibiotics.
• Acknowledge the possibility of infection with encapsulated organisms because splenomegaly may be a marker for a dysfunctional reticuloendothelial system incapable of clearing these organisms. Staphylococcus aureus, streptococcal species, and gram-negative rods are potential organisms.

Further Outpatient Care

• Schedule patients with Felty syndrome for regular rheumatology follow-up to monitor therapy and assess progress.
• No firm guidelines address immunization practice in these patients, but ensuring vaccination against encapsulated organisms seems prudent.

Complications

• Splenic rupture
• Life-threatening infection
• Toxicity from immunosuppressive regimens
• Portal hypertension and gastrointestinal bleeding from nodular regenerative hyperplasia of the liver

Prognosis

• Granulocytopenia is defined as an absolute neutrophil count (ANC) of less than 2000/µL, and infection risk increases as the ANC drops. Infection incidence increases significantly when the polymorphonuclear leukocyte (PMN) count is less than 1000/µL.
• Lymphoproliferative malignancies were more prevalent in a retrospective study of male patients treated at the Department of Veterans Affairs. In particular, the patients had an increased prevalence of non-Hodgkin lymphoma.

Patient Education

• Educate patients about the warning signs of infection and ensure that they have ready access to medical care.
• Some practitioners supply patients with Felty syndrome with a broad-spectrum oral antibiotic to take at the first signs of a bacterial infection. Instruct patients that this is an individualized decision and advise them to contact their physician immediately if such a situation develops.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to acknowledge that many of the regimens used to treat RA can cause bone marrow suppression and neutropenia
• Failure to diagnose Felty syndrome, thereby attributing the granulocytopenia to the RA treatment regimen
• Failure to realize that active infection can transiently elevate the WBC count and mask the underlying condition
• Failure to perform repeated examination of the abdomen in patients with RA, which is necessary to find early splenomegaly

Special Concerns

• Neutropenia with LGL
• • This condition is often referred to as pseudo-Felty syndrome, and it is a chronic leukemia characterized by a clonal expansion of cytotoxic T cells bearing the CD16 and CD57 markers. The large granular lymphocytes may occur in both the periphery and the bone marrow.
  • LGL is an unusual entity that occurs in less than 1% of patients with RA. LGL usually develops at the onset of RA, while Felty syndrome occurs later in the disease course.
  • The sex incidence is equal, and the severity of the underlying RA is less marked.
  • Neutropenia may occur in conjunction with a normal or increased total WBC count.
  • Thrombocytopenia, anemia, and splenomegaly may occur. In some situations, differentiation from Felty syndrome may require immunophenotype analysis.
  • Therapy for LGL is rarely necessary.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Balint GP, Balint PV. Felty''s syndrome. Best Pract Res Clin Rheumatol. Oct 2004;18(5):631-45. [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.
• Felty AR. Chronic arthritis in the adult associated with splenomegaly and leukopenia. Bull Johns Hopkins Hosp. 1924;35:16.
• Gridley G, Klippel JH, Hoover RN, Fraumeni JF Jr. Incidence of cancer among men with the Felty syndrome. Ann Intern Med. Jan 1 1994;120(1):35-9. [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].
• 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].
• 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].
• Sordet C, Gottenberg JE, Hellmich B, et al. Lack of efficacy of rituximab in Felty's syndrome. Ann Rheum Dis. Feb 2005;64(2):332-3. [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].
• Talip F, Walker N, Khan W, Zimmermann B. Treatment of Felty''s syndrome with leflunomide. J Rheumatol. Apr 2001;28(4):868-70. [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].

Article Last Updated: Dec 5, 2006