Felty Syndrome

Felty Syndrome 

• Felty syndrome (FS) is an uncommon extraarticular manifestation of seropositive rheumatoid arthritis (RA), characterized by RA, splenomegaly, and neutropenia.
• The hallmark feature of FS is a persistent, idiopathic neutropenia and cannot be absent.
• While Felty syndrome characteristically demonstrates chronic arthritis, splenomegaly, and neutropenia, completion of the triad is not necessary for the diagnosis.
• Splenomegaly is extremely variable in its extent and is no longer an absolute diagnostic requirement.

How common is Felty Syndrome?

• •The lifetime risk of Felty Syndrome for a patient initially diagnosed with RA is estimated to be 1% to 3%. The prevalence has been steadily declining over the past two decades due to increased use of methotrexate and biological therapy.
• •Demographics are similar to RA, affecting 60% to 80% women.
• •FS patients tend to have a family history of RA and be HLA-DR4 positive.
• •Recognized in patients in their late 40s or early 50s who have had RA for >10 yr.
• •FS is rare in African Americans because of the infrequency of HLA-DR4 in this population.

What are the symptoms/clinical features?

• •Felty syndrome (FS) is an uncommon extraarticular manifestation of seropositive rheumatoid arthritis (RA). Patients have a positive rheumatoid factor (RF) or anticitrullinated peptide antibodies (ACPA) and present with severe, erosive, long-standing arthritis (at least >10 yr), neutropenia, with absolute neutrophil counts <2000/μl), and splenomegaly.
• •Extraarticular manifestations (rheumatoid nodules, vasculitis, skin lesions, pleuropericarditis) are more frequently found in patients with FS than RA.
• •One third of patients may have relatively inactive synovitis. Erythrocyte sedimentation rate (ESR) is almost always significantly elevated even in patients with inactive synovitis.
• •Splenomegaly and neutropenia are rarely present before the arthritis.
• •Mild hepatomegaly is common (up to 68%).
• •The degree of splenomegaly varies and may be detectable only by imaging studies; the degree of splenomegaly has no correlation with the degree of neutropenia.
• •Patients with FS have a twentyfold increased frequency of bacterial infections compared with other RA patients.
• •FS patients have greater risk of developing non-Hodgkin lymphoma than RA patients. Similarly, FS patients are at increased risk of lung disease.
• •Differentiation between large granular lymphocyte (LGL) leukemia and FS is necessary because both can present with neutropenia and are associated with RA.

What is the Classic triad of Feltys syndrome?

What three findings make up the Classic triad of Feltys syndrome?

Felty’s syndrome is RA in combination with splenomegaly and leukopenia. Felty’s syndrome is seen in 1% of RA patients who have RF, subcutaneous nodules, and other extraarticular manifestations. Most (95%) of patients are HLA-DR4- and RF-positive. Articular disease parallels those of RF-positive patients, but Felty’s syndrome patients have more extraarticular manifestations.

The leukopenia is generally a neutropenia (<2000/mm ³ ); thrombocytopenia may occur. The major complications of Felty’s syndrome include bacterial infections (20-fold increase compared with other RA patients) and chronic non-healing ulcers.

Severe bacterial infections correlate with neutrophil counts of <1000/mm ³ . Patients with Felty’s syndrome also have a 13-fold increased risk of developing non-Hodgkin’s lymphoma, and a subset of patients may have large granular cell lymphocyte syndrome. Some patients develop nodular regenerative hyperplasia of the liver with portal hypertension and varices that can bleed.

What causes Felty Syndrome?

The pathogenesis of Felty Syndrome is probably multifactorial, including immune dysfunction resulting from an imbalance between granulocyte production and destruction from the circulatory pool.

Differential Diagnosis of Felty Syndrome

• •Systemic lupus erythematosus
• •LGL leukemia
• •Drug reaction conventional synthetic disease-modifying antirheumatic drugs (cs-DMARDs) or biologic DMARDs
• •Myeloproliferative disorders
• •Lymphoma or reticuloendothelial malignancies
• •Cirrhosis with portal hypertension
• •Sarcoidosis
• •Tuberculosis
• •Amyloidosis
• •HIV infection
• •Epstein-Barr virus infection
• •Malaria

How is this diagnosed?

Laboratory Tests

• •There is no single diagnostic test for patients with Felty Syndrome.
• •CBC with differential to detect neutropenia <2000/μl, mild to moderate anemia, and mild to moderate thrombocytopenia.
• •Bone marrow usually shows myeloid hyperplasia with relative excess of immature forms “maturation arrest.”
• •Elevated ESR, C-reactive protein.
• •High titer rheumatoid factor and/or anticyclic citrullinated peptide antibody (ACPA) positive in 94% and 77%, respectively.
• •Autoantibody levels are more frequently elevated in FS.
  • 1.Antinuclear antibody (ANA) positive in 65%
  • 2.Circulating antibodies in FS bind peptidylarginine deiminase type 4 (PAD-4)-deiminated histone 3 and 2A over nondeiminated histone and bind to activated neutrophils and neutrophil extracellular chromatin traps.
  • 3.Anti–double-stranded DNA (anti-dsDNA) antibodies are occasionally elevated.
  • 4.Antineutrophil cytoplasmic antibody (ANCA) positive in 83%.
  • 5.Anti-glucose-6-phosphate isomerase antibody positive in 92%.
  • 6.Circulating immune complexes are more commonly found in patients with FS than in other RA patients.
• •HLA-DR4: Positive in 98%.
• •Immunoglobulin levels may be higher and complement levels lower in FS patients than in RA patients.
• •Peripheral smear morphology and immunophenotypic analysis is essential to exclude large granular lymphocytic (LGL) leukemia.
• •Bone marrow examination, which typically shows myeloid hyperplasia with maturation arrest, is often necessary to exclude other causes of neutropenia.

Imaging Studies

Ultrasonography or CT scan may be useful in diagnosing splenomegaly but is not necessary.

How is Felty Syndrome treated?

Acute General treatment

The principal treatment interventions include nonpharmacologic measures to reduce the risk for infection and medications to control RA disease and alleviate the granulocytopenia.

• •Splenectomy:
  • 1.For many years, splenectomy was the principal therapy for FS. However, it has been largely replaced by medical therapy. Splenectomy is reserved for patients with profound neutropenia (<1000/mm³) and severe recurrent infections despite treatment with conventional synthetic disease-modifying antirheumatic drugs (cs-DMARDs) and/or biologic disease-modifying antirheumatic drugs (bDMARDs).
  • 2.Acutely reverses hematologic abnormalities.
  • 3.25% to 30% have recurrent neutropenia, but the granulocyte count usually remains above the pre-splenectomy level.
  • 4.Improvement in frequency of recurrent infection is variable and not correlated with degree of hematologic improvement.
• •DMARDs conventional synthetic (csDMARDs) and biologic (bDMARDs):
  • 1.Methotrexate (MTX) and rituximab (RTX) are the DMARDs that are preferred in patients with FS, as their benefits have been described in case reports and case series. Leflunomide may be used as an alternative to MTX in patients unable to take MTX. Abatacept is recommended forpatients with inadequate response to MTX and RTX, and who require prednisone at dosages greater than 10 to 15 mg daily for control of arthritis and granulocytopenia.
  • 2.Tumor necrosis factor (TNF) inhibitors are avoided because they have been found to be an ineffective treatment for FS. There are case reports regarding clinical efficacy of tocilizumab (TCZ) in FS. No studies of tofacitinib have been reported, and its use is avoided as it may cause neutropenia.
  • 3.Penicillamine, sulfasalazine, hydroxychloroquine, gold salt: Limited experience; infrequently used; not the first choice for FS.
• •Corticosteroids:
  • 1.Overwhelming infection is the main barrier to the use of corticosteroids.
  • 2.Prednisone 30 to 40 mg/day can elevate the neutrophil count, but this effect is often not sustained when the dose is reduced (less than 10 mg daily) for RA unless other treatments are added.
  • 3.Pulse dosing is a potential alternative for short-term elevation of neutrophils.
• •Granulocyte colony-stimulating factor/granulocyte-macrophage colony-stimulating factor:
  • 1.Improves neutrophil count but not arthritis and anemia of FS.
  • 2.May be useful as adjunctive therapy during serious infection or in preparation for surgery.

Treatment is the same as that for RA patients with joint disease and can include use of methotrexate or other DMARD therapy. With control of the RA, leukopenia may improve.

Granulocyte colony-stimulating factor (G-CSF) has been used and shown effective at increasing WBC counts and decreasing infections in some patients (neutrophils <1000/mm3).

However, G-CSF can be associated with increased arthritis and vasculitis in some Felty’s syndrome patients when the WBC count is raised. Splenectomy is reserved for patients with severe, recurrent bacterial infections or patients with chronic non-healing leg ulcers who are not responsive or tolerant to drug therapy.

Unfortunately, neutropenia recurs in 25% of patients who undergo splenectomy.

Disposition

• •Poor prognosis with recurrent infections because of neutropenia. The average mortality rate after diagnosis is 25% in 5 yr.
• •Articular involvement can be severe in FS.

Referral

• •To a hematologist for treatment of neutropenia
• •To a rheumatologist for treatment of RA

Pearls & Considerations

• •Recurrent infections are the major cause of death.
• •Neutropenia of FS can be effectively treated with DMARDs, with the greatest experience with methotrexate.

Seek Additional Information

1. Hamada-Ode K., et al.: Efficacy of abatacept for Felty’s syndrome. Rheumatology (Oxford) 2020; 59 (1): pp. 256-259.
2. Lazaro E., et al.: Management of neutropenia in patients with rheumatoid arthritis. Joint Bone Spine 2015; 82 (4): pp. 235-239.
3. Li R., et al.: Tocilizumab treatment in Felty’s syndrome. Rheumatol Int 2020; 40 (7): pp. 1143-1149.
4. Moore D.F., Vadhan-Raj S.: Sustained response in Felty’s syndrome to prolonged administration of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Am J Med 1995; 98 (6): pp. 591-594.
5. Narvaez J., et al.: Biological agents in the management of Felty’s syndrome: a systematic review. Semin Arthritis Rheum 2012; 41 (5): pp. 658-668.
6. Rudeman M., et al.: Clinical and serological observations on 27 patients with Felty’s syndrome. Arthritis Rheum 1968; 11 (3): pp. 377-384.
7. Sarp U., Ataman S.: A beneficial long-term and consistent response to rituximab in the treatment of refractory neutropenia and arthritis in a patient with Felty syndrome. J Clin Rheumatol 2014; 20 (7): pp. 398.