Rheumatology Advance Access originally published online on April 19, 2007
Rheumatology 2007 46(6):1041-1042; doi:10.1093/rheumatology/kem048
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Schnitzler's syndrome—exacerbation after anti-TNF treatment
Department of Internal Medicine, State Hospital Muerzzuschlag, and 1Department of Rheumatology, Medical University Graz, Austria
Correspondence to: Rene Thonhofer, MD, Landeskrankenhaus Mürzzuschlag, Grazer Strasse 63-65, 8680 Mürzzuschlag, Austria. E-mail: rene_thonhofer{at}hotmail.com
SIR, Schnitzler's syndrome (SS) is a rare combination of symptoms first described in 1972. SS is characterized by the association of urticarial rash, intermittent fever, monoclonal gammopathy, mostly of IgM type, acute phase response, bone pain, arthralgia, lymphadenopathy, hepatomegaly and splenomegaly [1]. The aetiology and exact pathogenesis of SS are still unknown [2, 3], but cytokines like IL-1 may play an important role [2, 4–9]. A good prognosis was reported in most of the cases, although an underlying lymphoproliferative disorder [10] can be revealed later.
We report on a 45-yr-old woman diagnosed with SS 8 yrs after disease onset, fulfilling the criteria proposed by Lipsker [1]. At the time of presentation a classical urticarial rash on the face, trunk and arms, as well as fever up to 39°C, cervical lymphadenopathy and hepatosplenomegaly were observed. The patient complained about severe arthralgia and bone pain. Bone technetium scanning showed small areas of increased tracer uptake in the medial and proximal parts of the tibial bones. Clinical examination of all joints by bimanual palpation as well as Doppler US and MRI proved inconspicuous cartilage, bone and periarticular soft tissues. In our patient, infectious diseases, malignant and rheumatological disorders were carefully excluded. Treatment regimens including non-steroidal anti-rheumatic drugs, colchicine, dapsone, azathioprin and ciclosporin had been unsuccessful, while high dosages of steroids (100 mg of prednisolone equivalent) caused the urticarial rash, the arthralgia and the fever to disappear within 2 days. Steroids were slowly tapered, but with a dosage below 35 mg the disease flared. Further proposed therapies including cyclophosphamide [9] were denied by the patient. The patient continued the steroid therapy and after 9 months presented with Cushing habitus and diabetes mellitus.
Alterations of the cytokine network [4–6] and abnormalities of circulating T-cell subsets may play an important role in the development of SS. IL-1, IL-6 and granulocyte colony-stimulating factor [2, 8, 9] were hypothesized to have central role in the pathogenesis of the disease. TNF-
has a pivotal role for the proliferation and activation of B-cells, macrophages, endothelial and synovial lining cells and these activated cells are the major source of the cytokines mentioned above. Therefore, we hoped that the use of an anti-TNF agent would be beneficial in SS. Adalimumab (ADA) treatment was initiated and within 24 h after the first injection the symptoms of SS decreased, but about 72 h later the patient presented with fever up to 41°C, severe urticaria, massive bone pain and polyarthritis. Infectious disorders were ruled out and steroids (1 mg/kg bodyweight) were administered intravenously. The symptoms resolved and were interpreted as caused by ADA. Nearly the same symptomatic was triggered after the administration of etanercept (ETA). As shown for ADA the signs of SS decreased, but after 72 h reoccurred as described earlier. (Written informed consents were obtained for the therapy attempts containing ADA and ETA. Possible side effects were discussed with the patient at two different time points prior to the initiation of each treatment.)
Contrary to our hypothesis, the use of ADA and ETA was not successful. The complications after the ADA injection were initially interpreted as hypersensitivity reaction. Therefore a second therapy attempt with ETA was initiated but caused the same symptoms. The course of disease after the use of both TNF inhibitors was interpreted retrospectively as increased inflammatory activity of SS initiated by the administration of ADA and ETA. This might have been isolated reaction of this special patient, however, to the best of our knowledge the use of TNF inhibitors and their potential side effects in SS had never been described in literature until now. In the patient being reported on ADA and ETA therapies were initiated prior the study of de Koning et al. [7] was published and other possible treatments (like cyclophosphamide) were denied by the patient.
Because of the worsening clinical condition of our patient a therapy with daily injections of anakinra 100 mg in combination with methotrexate 20 mg once weekly was started. This combination therapy was well tolerated by the patient and we were able to taper steroids continuously to a dosage of 5 mg daily. No clinical signs and symptoms of SS were documented, for the now overseen time period of 8 months, after the initiation of the anakinra and methotrexate combination therapy.
We recommend that anti-TNF agents should be used with great care in patients suffering from SS, especially because other effective therapy strategies [7–10] exist.
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  R. Thonhofer, E. Uitz, and W. Graninger Comment on: Schnitzler's syndrome exacerbation after anti-TNF treatment: reply Rheumatology, November 1, 2007; 46(11): 1741 - 1741. [Full Text] [PDF]
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H. D. de Koning, J. W. M. van der Meer, and A. Simon Comment on: Schnitzlers syndrome exacerbation after anti-TNF treatment Rheumatology, November 1, 2007; 46(11): 1741 - 1741. [Full Text] [PDF]
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