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Rituximab-related late-onset neutropenia in a patient with severe rheumatoid arthritis
  1. H Marotte1,
  2. G Paintaud2,
  3. H Watier2,
  4. P Miossec1
  1. 1
    Departments of Immunology and Rheumatology, Lyon, France
  2. 2
    François Rabelais University, Tours, France
  1. Professor P Miossec, Clinical Immunology Unit, Departments of Immunology and Rheumatology, Hôpital Edouard Hérriot, 69437 Lyon Cedex 03, France; miossec{at}

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Rituximab is effective in B-cell lymphomas but also in inflammatory diseases such as rheumatoid arthritis (RA).1 Several cases of late-onset neutropenia (LON) have been described in lymphomas.24 Reversible rituximab-related LON tends to occur 2–6 months after rituximab administration. The post-marketing rate of LON appears very low (<0.02% in a total of 300 000 patients).2 Its mechanism is unknown, although several hypotheses have been suggested.

We report one case of rituximab-related LON for the first time outside the lymphoma field and explore some of the proposed mechanisms. A 34-year-old white woman, with a 22-year history of refractory and destructive RA, had been treated with a long list of disease-modifying antirheumatic drugs (gold salts, thiopronine, d-penicillamine, sulfasalazine, azathioprine, ciclosporin, methotrexate (MTX) and etanercept). Rheumatoid factor was positive and antinuclear and anti-DNA antibodies were negative. Because of persistent active disease (28 joint count Disease Activity Score 5.86) despite treatment with MTX (25 mg/week), etanercept (50 mg/week) and prednisone (10 mg/day), rituximab (two 1 g infusions at a 2-week interval) was started, combined with MTX and steroids in December 2005. The rituximab infusions were perfectly tolerated and the disease improved after 9 weeks (fig 1).

Figure 1 Kinetics of rituximab concentrations and neutrophil counts. The figure shows the predicted pharmacokinetic of rituximab calculated from observed rituximab concentrations (open circles). Because of the limited number of samples, a one-compartment model was used. Black circles show neutrophil counts. Grey circles show the CD19+ cell count. G-CSF, granulocyte colony-stimulating factor.

During the routine monthly blood follow-up, a severe neutropenia was observed with 40 neutrophils/mm3. Haemoglobin and platelets showed no change. A bone marrow aspiration showed a maturation arrest with accumulation of promyelocytes and myelocytes. She received two injections of granulocyte colony-stimulating factor and recovered without relapse or infection. No deficiency of folic acid or vitamin B12 was seen.

Of the possible mechanisms, a direct cytotoxic effect of rituximab appears unlikely. Granulocytes and uncommitted haematopoietic precursor stem cells are not known to express CD20. In addition, no unusual accumulation of rituximab was seen as plasma concentration of rituximab was low at the time of neutropenia (fig 1). No uncommon genetic marker affecting Fcγ receptor affinity or changes in the concentration–effect relationship of rituximab were seen. The patient was FcγRIIIA (158V/158F), FcγRIIA (131H/131R) and FcγRIIIB (HNA-1b/1b) as 49%, 27% and 40% of the French population, respectively.5 No transient production of antigranulocyte autoantibodies was observed in sequential plasma samples, using an indirect granulocyte immunofluorescence assay with flow cytometry analysis.

In summary, this observation seems to be the first case of neutropenia related to rituximab in a patient with RA. The clinical history was similar to that of previous cases described in haematology. We have not been able to confirm a bone marrow toxicity with drug accumulation or an induction of antigranulocyte antibodies. Additional reports of this unusual side effect are needed to better understand the mode of action of the drug in this case.



  • Competing interests: None declared.