Felty Syndrome

Felty syndrome (FS), also known as ''super rheumatoid'' disease, is a severe form of rheumatoid arthritis (RA), characterized by a triad of RA, splenomegaly and neutropenia, resulting in susceptibility to bacterial infections.

Epidemiology

FS is estimated to occur in about 1- 3% of RA patients after an average of 10 to 15 years of arthritis. FS is uncommon in the African American population.

Clinical description

FS is about 3 times more common in females during the third through fifth decades of life (earlier in men). Clinically, the disorder is characterized by chronic arthritis with severe joint destruction contrasting with moderate or absent joint inflammation and severe extra-articular disease. The knee, wrist, ankle, metacarpophalangeal and proximal interphalangeal joints are most commonly involved. Involvement of axial joints is less common. Symmetrical joint involvement is the characteristic feature of the disease. Hepato-splenomegaly and lymphadenopathy are commonly seen. Other extra-articular manifestations of FS are episcleritis, vasculitis, pleuritis, pulmonary fibrosis, rheumatoid nodules, neuropathy, leg ulcers, skin hyperpigmentation (usually on extensor surface of the lower leg), anemia and weight loss. The most critical manifestation of FS is neutropenia, resulting in a higher incidence of bacterial infections (affecting most frequently skin, mouth, and upper and lower respiratory tract). Rarely, FS may be revealed by neutropenia in an RA patient. FS can be associated with other autoimmune diseases such as Sjögren syndrome, vasculitis and systemic lupus erythematosus (SLE).

Etiology

The pathophysiology of FS is still not well understood butit has been proposed that an autoimmune response against neutrophil antigens might be the underlying mechanism. An increased incidence of infections may stimulate a neutrophil response that includes histone deimination and the expulsion of chromatin from the cell. Neutrophil extracellular chromatin traps (NETs) containing deiminated histones, in complex with bacterial adjuvants, are the most likely antigenic trigger for the production of autoantibodies to deiminated histones. These autoantibodies or their immune complexes may further stimulate neutrophils, thus completing a self-sustaining cycle that drives the depletion of mature neutrophils. A higher incidence of anti-deiminated histone autoantibodies is found in FS patients. About 95% of FS patients have a MHC class II HLA-DR4 allele. African Americans have a low incidence of this antigen.

Diagnostic methods

Diagnosis of FS includes physical examination as well as complete blood count revealing leucopenia, neutropenia, and thrombocytopenia and high serum titers of rheumatoid factor antibodies, antinuclear antibodies, antihistone antibodies and HLA-DR4 positivity. Microscopic analysis of spleen biopsies reveals enlargement of the germinal center in follicles, and infiltration of neutrophils and macrophages. Severe joint destruction may be observed radiologically.

Differential diagnosis

FS differs from RA by more severe arthritis and extra-articular manifestations. Differential diagnosis of FS also includes large granular lymphocyte (LGL) leukemia (when associated with RA, called pseudo Felty), RA, systemic lupus erythematosus (SLE), Still's disease, articular brucellosis, and chronic bacterial endocarditis.

Management and treatment

FS is difficult to treat and the standard of care is directed against underlying RA with an additional goal of treating neutropenia and recurrent infections. This comprises several disease-modifying anti-rheumatic drugs (including sulfasalazine, hydroxychloroquine) and methotrexate. Recombinant granulopoietic growth factors (G-CSF) have also been used to improve neutrophil counts. For treatment-resistant cases with splenomegaly, a splenectomy can be considered. Rituximab (RTX) have been used as second-line therapy in patients with refractory FS.

Prognosis

FS has a poor prognosis and recurrent infections may lead to increased mortality.