Approach

There is no specific treatment for FS. The goal of treatment is to raise the neutrophil count and prevent recurrent infections while controlling systemic rheumatoid disease activity. Patients with neutrophil count <1 x 10⁹/L (<1000/microlitre) are at high risk of severe infection.

The evidence for the treatment options is not strong, as there are no randomised trials, only case series and case reports.

All patients

Most patients with FS have long-standing rheumatoid arthritis (RA) and have received multiple disease-modifying anti-rheumatic drugs (DMARDs). Therefore, the choice of agent will be determined by prior effectiveness, adverse-effect profile, and physician experience with the various agents.

Methotrexate

  • The first-line agent in FS.[3] It has been shown to increase granulocyte count and decrease erythrocyte sedimentation rate in patients with FS 4 to 8 weeks after initiation of therapy.

  • Data from a small retrospective cohort suggest that the effect of methotrexate persists for up to 1 year, and that the frequency of intercurrent infections tends to decrease.[16] Other small studies have shown that low-dose methotrexate is effective in managing FS.[17]

  • Methotrexate is usually combined with folic acid to minimise adverse effects. A low starting dose is recommended, increased every month until the neutrophil count returns to normal.

Rituximab

  • May be useful in patients who are unresponsive to or intolerant of methotrexate.

  • Rituximab is preferred over other biologic or synthetic disease-modifying agents.

  • Case reports of rituximab-treated patients with FS have found sustained neutrophil response (14 months after initial treatment in one patient), and reduced rheumatoid factor, synovitis, and pain score.[18][19][20][21]

Leflunomide or sulfasalazine

  • Results from case reports suggest that leflunomide and sulfasalazine can be used as add-on therapy to methotrexate or for patients with FS who are intolerant of or have an inadequate response to methotrexate.[22][23]

  • Sulfasalazine has been shown to reduce neutrophil-bound immunoglobulin G.[23]

Colony-stimulating factors

  • Most useful in patients with severe neutropenia, those with recurrent infections despite other therapy, or patients needing a rapid rise in neutrophil count (e.g., patients undergoing surgery).[4][24]

  • Granulocyte-macrophage colony-stimulating factor (GM-CSF or sargramostim) and granulocyte colony-stimulating factor (G-CSF or filgrastim) are effective in raising neutrophil counts, stimulating neutrophil function, and reducing infections in FS patients.[4][17][24]​ They can resolve neutropenia within 2 weeks of treatment. However, neutrophil levels fall on therapy withdrawal.

  • Long-term G-CSF in patients with recurrent infections has been shown to exacerbate arthritis and can cause a leukocytoclastic vasculitis. Therefore, the lowest dose should be used that maintains neutrophil counts >1 x 10⁹/L (>1000/microlitre).[3][4]

  • White blood cell (WBC) count should be monitored twice a week in the first 3 weeks of treatment and weekly thereafter.[25] Long-term treatment has been reported to be safe if doses are kept as low as possible.

Splenectomy

  • Splenectomy should be considered as a last resort. It leads to an increase in granulocyte count within hours.[17] No randomised trials have evaluated splenectomy in the treatment of FS, and its use has been superseded by other therapies.

  • Granulocytopenia recurs in about 24% of patients following splenectomy, and only 45% of patients remain free of infection. Moreover, an increased WBC count after splenectomy is not necessarily associated with reduced infection rates, and patients with recurrent infections before surgery usually continue to have infections.[17][25]

  • Splenectomy may improve synovitis temporarily and lead to leg ulcer healing.[26]

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