Schnitzler Syndrome: Beyond the Case Reports: Review and Follow-Up of 94 Patients with an Emphasis on Prognosis and Treatment

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Objective

Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash and monoclonal gammopathy, accompanied by intermittent fever, arthralgia or arthritis, bone pain, and lymphadenopathy. Our objectives are to systematically review disease characteristics of Schnitzler syndrome and collect follow-up information to gain insight into treatment efficacy and long-term prognosis.

Methods

PubMed and MEDLINE databases (1966-2006) were searched, using the key words “Schnitzler syndrome,” and the combination of “urticaria” with “monoclonal gammopathy,” “immunoglobulin M (IgM),” or “paraproteinemia,” as well as secondary references. Data on a total of 94 patients who met the criteria for Schnitzler syndrome were reviewed. Questionnaires sent to all authors retrieved additional follow-up data on 43 patients, resulting in a mean follow-up of 9.5 years after onset of symptoms, and a follow-up of 20 years or more in 10 patients.

Results

Symptoms, signs, and laboratory findings as found in the 94 patients are reviewed in detail. There have been promising developments in therapeutic options, especially antiinterleukin-1 treatment, which induced complete remission in all 8 patients treated so far. To date, no spontaneous complete remissions have been reported. Patients with Schnitzler syndrome showed no increased mortality during the present follow-up. However, they had a 10-year risk of 15% of developing a lymphoproliferative disorder, most notably Waldenström’s macroglobulinemia. Three cases of type amyloid A (AA) amyloidosis associated with Schnitzler syndrome were reported.

Conclusions

Schnitzler syndrome is a disabling disorder which affects multiple systems and which can be considered as an autoinflammatory syndrome. There are new, effective treatment options, but close monitoring remains warranted because of the increased risk of lymphoproliferative disease.

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.

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