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Felty’s syndrome (FS) is an uncommon extra-articular manifestation of rheumatoid arthritis (RA). It is more prevalent among women around 60 with a long history of severe articular disease, positive rheumatoid factor, and who carry the HLA-DR4 allele.1 Felty’s syndrome has a poor prognosis, with an increased mortality due to a higher incidence of severe infection.2 We describe a patient with seropositive, erosive RA and history of extra-articular manifestations, including vasculitis and FS. Treatment with etanercept gradually decreased the neutrophil count over 20 months. Discontinuation of etanercept and initiation of methotrexate was followed by a dramatic and sustained improvement of neutrophil count.
A 75 year old white woman with a 19 year history of seropositive RA with extra-articular manifestations including mononeuritis multiplex (1998) and at least a 4 year history of FS (idiopathic neutropenia reported since 1994 and splenomegaly described on abdominal ultrasonography since 1999) was followed up at the Division of Rheumatology at the Geneva University Hospital.
She was treated with azathioprine and prednisone and had a mean white blood cell (WBC) count of 2.0×109/l (ranging from 1.6 to 2.7×109/l) and absolute neutrophil count (ANC) of 1.4×109/l (ranging from 1.1 to 2.2×109/l) since May 1999. In October 2000 treatment with azathioprine was decreased and replaced by etanercept 25 mg (twice a week, subcutaneously) due to synovitis, morning stiffness, and biological signs of inflammation. Improvement in morning stiffness and synovitis was noted, with a decrease of the mean erythrocyte sedimentation rate and C reactive protein. Prednisone was tapered to 5–7.5 mg daily. During the treatment with etanercept the patient had one infectious complication (right knee septic arthritis in February 2001). Treatment with azathioprine was then discontinued.
Despite the improvement of inflammatory articular manifestations, the WBC count and ANC decreased during a 14 month follow up, resulting in a total WBC count of 1.6×109/l and an ANC of 0.3×109/l (fig 1). Haematological disorders were excluded by flow cytometry. Treatment with etanercept was discontinued and replaced by oral methotrexate 10 mg and folic acid 5 mg weekly. The WBC count and ANC increased immediately to achieve a normal range (ANC >2.0×109/l) within 3 months. The initial dose of methotrexate was increased from 10 mg to 12.5 mg weekly owing to wrist synovitis, with subsequent improvement of articular inflammation. A 2 year follow up shows that the WBC count stabilised.
In this patient with seropositive, erosive RA and extra-articular manifestations, administration of etanercept resulted in progressive neutropenia. Discontinuation of etanercept and initiation of methotrexate was associated with a dramatic increase in the WBC count and ANC.
Systemic immunosuppressive treatment is considered to be the most appropriate form of treatment for FS. Experience with cyclophosphamide, ciclosporin, azathioprine, or leflunomide in FS is limited.3,4 Methotrexate is usually effective in FS. Low dose oral pulse therapy results in improvement in most patients.5,6
Although articular inflammation in our patient responded well to etanercept, a threatening decrease in the WBC count and ANC occurred. The exact mechanism of this observation remains unclear. On the basis of a few reports on pancytopenia and aplastic anaemia after etanercept treatment,7 a direct effect of etanercept on the WBC count cannot be ruled out completely. Natural evolution of FS might also be postulated. However, the rapid increase of the WBC count and ANC after the introduction of methotrexate and the sustained effect during the following years does not support this hypothesis. Finally, a lack of efficacy of etanercept in controlling FS must also be considered. This possibility is supported by a recent report on the lack of efficacy of etanercept on FS in a patient with RA and secondary amyloidosis.8 At present, we call for caution when etanercept is used for patients with FS.