Aetiology

The precise aetiology of FS remains uncertain. Typically, it occurs in patients with long-standing (>10 years' duration) seropositive, erosive rheumatoid arthritis (RA) with extra-articular features, including rheumatoid nodules, lymphadenopathy, leg ulcers, and vasculitis.[2] Rheumatoid factor is positive (usually high titres) in 95% to 100% of patients and anti-nuclear antibodies in 47% to 100% of patients. FS patients often have high levels of circulating immune complexes, which implicate immune dysfunction in its aetiology.[7] Although none of these serological features is likely to be solely responsible for the development of neutropenia in FS, they may contribute to the shortened survival of neutrophils.[2][7]

There may be a genetic contribution to the development of FS. HLA-DR4 antigen is strongly associated with FS.[3] More than 90% of patients with FS are HLA-DR4-positive, compared with 60% to 70% of patients with RA and 30% of healthy white people. There is an excess of DR4 homozygotes in FS, and primarily the *0401 allele is associated with progression to the disease.[8][9] The exact genetic role of HLA-DR4 is unclear, other genetic determinants are likely implicated in FS.

Pathophysiology

The cause of neutropenia characteristic of FS is multi-factorial, resulting from an imbalance between neutrophil production in the bone marrow and increased destruction in peripheral blood. Bone marrow examination most commonly shows increased cellularity, with maturation arrest of the granulocyte lineage.[2] Increased neutrophil sequestration and peripheral destruction are thought to occur through the action of neutrophil-bound immune complexes or anti-neutrophil antibodies against cell-surface antigens. Impaired granulopoiesis has been proposed to result from the decrease in bone marrow cytokine production, antibody binding of granulocyte growth factor, or T-cell-mediated immune suppression of myeloid precursors.[3][4][7][10][11]

Several studies have shown that spleen size does not correlate with degree of neutropenia. There is no histological evidence to suggest that neutrophils are sequestered or destroyed in the spleen.[11]

Although the neutropenia itself predisposes to recurrent bacterial infections, defects in neutrophil function may also contribute to this. Patients with the lowest neutrophil counts tend to have bacterial infections, but in some patients infections persist despite normalisation of neutrophil count. Abnormal neutrophil function with defective chemotaxis and phagocytosis has been demonstrated.[2]

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