Felty's Syndrome

Felty's Syndrome is a complication of rheumatoid arthritis. It is the triad of seropositive (rheumatoid factor positive) rheumatoid arthritis, neutropenia and splenomegaly. It was first described by Dr Augustus Felty in 1924.¹

• Occurs in < 1% of those with rheumatoid arthritis (RA).² It is difficult to know the true incidence as many patients with the disease are asymptomatic.
• Incidence is likely to be decreasing with the development and use of more effective treatment for RA.
• Most common in people who have had rheumatoid arthritis for more than 10 years³ and who have more severe disease with extra-articular manifestations.
• Rare in children, although juvenile rheumatoid arthritis, called Still's disease, tends to be associated with splenomegaly.
• 3 times more women affected than men
• More common in caucasians

• Exact cause unknown. Hypotheses include sequestration of white blood cells in the spleen, an immune-mediated destruction of white blood cells and abnormal white blood cell development in the bone marrow.³
• Felty's Syndrome is associated with the HLA-DR4 genotype. This genotype is a marker for more aggressive RA with greater extra-articular manifestations.⁴

Many people with Felty's Syndrome are asymptomatic. However, others can develop life-threatening infection. There is usually a history of longstanding RA with extra-articular features including rheumatoid nodules, vasculitis, peripheral neuropathy, eye involvement and Sjögren's syndrome.

Symptoms

• Fatigue
• Anorexia
• Weight loss
• Eye symptoms (including dry eyes and irritation due to Sjögren's syndrome and red and painful eyes due to episcleritis).
• Recurrent infections due to neutropenia (lung and skin infections are most common).
• Left upper quadrant pain (due to splenomegaly or splenic infarcts).
• Symptoms related to rheumatoid arthritis including joint swelling, pain, stiffness and deformity.

Signs

• Splenomegaly
• Hepatomegaly
• Lymphadenopathy
• Typical RA joint deformities ± active synovitis causing joint swelling and tenderness.
• Pallor
• Extra-articular RA features including rheumatoid nodules and vasculitis (blood vessel inflammation causing leg ulceration, brown pigmentation on the legs, periungual infarcts, ischaemia of the extremities).
• Peripheral neuropathy
• Eye involvement including episcleritis

• Full blood count: This will show neutropenia and may show anaemia and thrombocytopenia. Anaemia can be a result of both hypersplenism and chronic disease leading to a normochromic, normocytic anaemia. It can be also be complicated by treatment with NSAIDs causing iron deficiency anaemia or methotrexate treatment giving a folate deficient picture. Neutropenia is defined as a neutrophil count < 2 x 10⁹/L. Infection risk increases the lower the neutrophil count. Active infection will elevate the white cell count and may mask the condition.
• Rheumatoid factor: 95% of patients with Felty's syndrome are positive for rheumatoid factor.²
• Autoantibodies: Antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA) may be present but their significance is unknown.
• Liver function tests: These may show moderate elevation of alkaline phosphatase and transaminases.
• ESR: May be raised.
• Immunoglobulins: May be raised.
• Imaging: Ultrasound or CT scanning can confirm and show the degree of splenomegaly.
• Bone marrow biopsy: This helps to differentiate Felty's syndrome from other diseases such as large granular lymphocyte (pseudo-Felty's syndrome) syndrome. This is a type of chronic leukaemia which can result in neutropenia, anaemia and thrombocytopenia but rarely requires any treatment.
• Plain x-rays of joints: These will show the typical deformities and erosions of rheumatoid arthritis.

• Control of the underlying RA: This is paramount. Treatment with disease-modifying anti-rheumatic drugs (DMARDs) should be used. This generally improves the splenomegaly and neutropenia. Methotrexate is most commonly used as there is the widest experience with this drug.^2,5 Leflunomide has been used alone or combined with methotrexate to good effect.^6,7 There is limited experience in using the newer monoclonal antibody drugs used to treat RA (etanercept, adalimumab and infliximab) for Felty syndrome. So far, there are no good quality RCTs to support the use of any single agent and many trials have few subjects.
• Avoidance of infection: Influenza immunization should be given. Hygiene should be meticulous. Prompt treatment of infection: Infections need to be treated promptly and appropriately. The patient should be advised to seek medical attention at the first sign of infection and antibiotics should be started as appropriate.
• Granulocyte stimulating factor (GSF): If there are recurrent severe infections or life-threatening infection, injections of GSF can be given to boost white blood cell counts.
• Corticosteroids: These are sometimes used in high doses to increase white blood cell levels. However, there is a further increased risk of infection.
• Splenectomy: This is reserved for people who do not respond to medical treatment and have intractable disease with recurrent or serious infection. There is immediate improvement of neutropenia in 80% of patients.²

• Splenic rupture
• Life-threatening infection
• Liver involvement (rarely fibrosis, and lymphocyte and plasma cell infiltration can occur in the liver. This is known as nodular regenerative hyperplasia and can lead to portal hypertension and gastrointestinal bleeding).

• Serious infection can lead to death.
• Spontaneous remission can occur.²
• There is an increased risk of developing malignancies in Felty's syndrome. All cancers are about twice as common but non-Hodgkin's lymphoma is about 12 times more frequent. The risk of developing leukaemia is increased but only within the first 5 years of being hospitalised for Felty's syndrome.⁸

Drug development and improved treatment of rheumatoid arthritis may mean that the incidence of Felty's syndrome begins to decrease. Indeed, one article reports a reduction in splenectomy for Felty's syndrome over the last 19 years. This may be related to improved disease management.⁹