Schnitzler Syndrome: Beyond the Case Reports: Review and Follow-Up of 94 Patients with an Emphasis on Prognosis and Treatment
Section snippets
Definition
Lipsker and coworkers introduced a set of diagnostic criteria for Schnitzler syndrome (1). They proposed that a diagnosis of Schnitzler syndrome could be made in a patient with a combination of an urticarial skin rash, a monoclonal IgM component, and at least 2 of the following criteria: (recurrent) fever, arthralgia or arthritis, bone pain, lymphadenopathy, hepato- or splenomegaly, leukocytosis, an elevated ESR, and abnormal findings on bone morphologic investigations (Table 1) (1).
Methods
We performed a literature search of Medline and PubMed (1966-2006), using the key words “Schnitzler syndrome,” and the combination of “urticaria” with “monoclonal gammopathy,” “IgM,” or “paraproteinemia.” References revealed many additional articles mostly in the English and French literature. Personal communication yielded 4 additional unpublished cases, from Bulgaria, the United Kingdom, Turkey, and the Netherlands (Nikolova, Akhras, Lachmann, Gül, and Brinkman, personal communication). We
Epidemiology
During the 1970s to early 1990s, Schnitzler syndrome was reported solely in western European countries, especially in France. The majority of reported cases is still of French origin (Table 2). Presumably this is due to the fact that the disorder was originally published in French by a French physician (2). In the last decade, however, cases have been reported in countries all over the world, ranging from Australia (67) to the Czech Republic (50). As shown in Table 2, the vast majority of
Etiology/Pathophysiology
The etiology of Schnitzler syndrome remains unknown. Several hypotheses have been proposed, most of which suggest the involvement of autoreactive antibodies. Lipsker and coworkers showed monoclonal IgM deposits in the skin of patients along basement membranes or in capillary walls and suggested that the in situ IgM-mediated complement activation and subsequent tissue damage might cause the urticarial skin lesions (73). However, these IgM skin deposits were only detected in approximately 25% of
Medical History and Physical Examination
The main clinical findings and the frequencies that were reported in patients with Schnitzler syndrome are shown in Table 3.
Differential Diagnosis
Before the diagnosis of Schnitzler syndrome can be made, a number of disorders have to be excluded (Table 5); we will discuss a few of them in more detail.
Treatment
Table 6 shows the effects of the main therapies reported in the literature. For many years, no treatment option had proved satisfactory. Antihistamines are not effective in controlling the rash, and they are not indicated. The fact that antihistamines are ineffective, and that the urticarial rash in Schnitzler syndrome is nonpruritic in more than half of the cases, suggests a histamine-independent etiology of the rash.
Corticosteroids decrease symptoms significantly in 39% of patients. However,
Prognosis
Overall, Schnitzler syndrome has a favorable prognosis in terms of mortality, with 91% survival after 15 years (Fig. 3). Since the average age of onset is 51 years, this does not seem to differ from the general population at this age (eg, 89% 15-year survival rate in the general Dutch population; Statistics Netherlands 2005, www.cbs.nl).
Schnitzler syndrome does require long-term follow-up due to the potential development of lymphoproliferative disorders, in particular, WM. In the group of 94
Discussion
Analysis of follow-up data on 94 patients with Schnitzler syndrome in the present review reveals new information on the long-term prognosis and complications of this disorder. For this review, we adopted the definition of Schnitzler syndrome from Lipsker and coworkers (1). This raises a problem for Schnitzler syndrome-like cases which lack 1 of the 2 major criteria. For example, 1 patient presented with bone pain, bone densification, and a monoclonal IgMκ gammopathy, in the absence of urticaria
Acknowledgments
The following participants of the Schnitzler syndrome study group contributed to the present study.
We thank the following persons for data on not previously published patients and their permission to include them in this study: Akhras V, Department of Dermatology, St. George’s Hospital, London, United Kingdom; Branten A, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Brinkman K, Department of Internal Medicine, Onze Lieve Vrouwen Gasthuis, Den
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H.D.K. is supported by a grant from Studiefonds Ketel 1; A.S. is supported by a ZonMW Veni grant.