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rhG-CSF resistant neutropenia in SLE
  1. MICHAEL FROSCH,
  2. JOHANNES ROTH,
  3. ERIK HARMS
  1. Department of Paediatrics, University of Münster, Albert-Schweitzer-Str 33, 48149 Münster, Germany
  1. Dr J Roth.

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Suppression of the haematopoietic system, especially of the myeloid lineage, is a severe complication of systemic lupus erythematosus (SLE).1 In a recent report Euler et al suggested rhG-CSF as an effective treatment of neutropenia during SLE, especially during infection resistant to antibiotic treatment.2 We present a case of a girl with SLE whose neutropenia did not respond to rhG-CSF and who subsequently succumbed to untreatable fungal sepsis.

A previously healthy 9.5 year old girl developed SLE presenting with six of 11 criteria of the American College of Rheumatology including butterfly rash, oral ulcers, arthritis, and serositis. Laboratory investigations demonstrated ANA+, anti-dsDNA+, hypocomplementaemia, but normal white blood cell count. Eight months after initial remission she had a relapse, presenting with neutropenia (650 neutrophils/μl, 800 lymphocytes/μl) and signs of nephritis. Bone marrow biopsy examination showed a general suppression of all myeloid lineages including megacaryocytes but showed a relative increase of the red blood cell lineage. Over the next months neutropenia was resistant to several pulses of intravenous methylprednisolone therapy (250 mg/day), to cyclophosphamide intravenous pulse treatment (500 mg/m2), and to intravenous IgG therapy (2 g/kg). Because of the prolonged increase in serum transaminase activities the cyclophosphamide pulse therapy was interrupted and the immunosuppression was changed to a combination of oral prednisone, azathioprine, and cyclosporine A, which slightly diminished disease activity but had no influence on neutropenia. A second bone marrow biopsy examination gave a similar result as described above. After two months the girl was admitted to hospital presenting with signs of sepsis and went into a coma and developed a progressive respiratory insufficiency. Thoracic and cranial computed tomography and nuclear magnetic resonance showed several abscess-like infiltrates in both lungs and brain. Antibiotic treatment, including amphotericine-B, was ineffective despite detection of aspergillus fumigatus infection by blood cultures. On the assumption that neutropenia (740/μl) is an important factor in the pathogenesis of infection resistant to therapy, we started treatment with rhG-CSF in a dose of 7.5 μg/kg/day over 10 days. Before starting rhG-CSF therapy the bone marrow aspirate showed a hypocellularity but no maturation arrest of the myeloid series. The application of rhG-CSF had no effect on the number of peripheral neutrophils (about 600 cells/μl). Subsequently the condition of the girl worsened and the patient died in terminal respiratory insufficiency.

There are two reports demonstrating successful rhG-CSF treatment of neutropenia during SLE. In a 56 year old woman suffering from SLE and sepsis white blood cell count rose from 400/μl to 17 200/μl after treatment with100 μg/day rhG-CSF over five days.3The second report showed an increase of neutrophil counts in three women (23–36 years) with neutropenia during SLE after application of four cycles of 5 μg/kg/day rhG-CSF from a mean of 1060 to 14 300 cells/μl within 48 hours. Fever of unknown origin subsided in all three cases, in addition, in one case a gluteal abscess healed after this treatment.2 In contrast with our case all of these previously published case reports showed normal or increased granulopoiesis in bone marrow aspirates.2 3 The patients reported by Euler et al did not receive methylprednisolone, cyclophosphamide or IgG pulse therapy, which may have influenced rhG-CSF stimulation on bone marrow cells in our patient by cytotoxic effects. However, neutropenia was present before immunosuppressive therapy and bone marrow analysis did not change significantly during the course of disease. There are at least two possibilities that could explain the failure of rhG-CSF treatment in this case. (1) The block of myeloid cell production may have been located before rhG-CSF action on bone marrow cells. (2) Autoantibodies against rhG-CSF may inhibit the effects of this factor as described earlier for treatment with erythropoietin. Lack of maturation arrest in bone marrow analysis and the fact that this was the first contact of our patient with rhG-CSF do not support these theories. Thus, the pathophysiological mechanisms leading to response or non-response of rhG-CSF treatment in SLE associated neutropenia are still not clear.

In our opinion this case shows that rhG-CSF application is not generally an effective treatment of SLE associated neutropenia. Hypocellularity of bone marrow aspirates and lack of prompt response seem to be a prognostic unfavourable factor regarding the beneficial effect of rhG-CSF treatment.

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