Review
Schnitzler syndrome, an autoimmune–autoinflammatory syndrome: Report of two new cases and review of the literature

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Abstract

Schnitzler syndrome is a rare disorder characterized clinically by chronic urticarial rash accompanied by fever, arthralgia or arthritis, bone pain and lymphoadenopathy and biochemically by monoclonal gammopathy and elevation of inflammatory indices. The disorder is very likely under-recognized and its origin remains obscure although it may be included among the immune mediated inflammatory diseases with features of autoinflammation and autoimmunity.

We describe here two patients affected by Schnitzler syndrome, both refractory to corticosteroids and immunosuppressive therapy, successfully treated with the interleukin-1 receptor antagonist Anakinra. Unfortunately after two weeks, one patient experienced an important local adverse reaction to the biological drug. We decided to discontinue Anakinra with flare of the disease after 24 h. We therefore switched to Rituximab obtaining a complete remission in two months.

We searched MEDLINE in order to analyze the frequency of the disease, its pathogenesis and outcome. The electronic search was conducted using the following key words “Schnitzler syndrome” and “Treatment of Schnitzler syndrome”. All the selected papers, except the clinical reviews, described at least one case of Schnitzler syndrome. The review of the literature highlighted that Schnitzler syndrome remains an enigmatic disorder hard to categorize and to treat.

Introduction

Schnitzler syndrome is a rare disabling disorder first described in 1972 [1] and characterized by the simultaneous occurrence of chronic urticaria and monoclonal gammopathy, accompanied to varying degrees by intermittent unexplained fever, arthralgias/arthritis, bone pain, bone densification, lymphadenopathy, hepato- or splenomegaly, leukocytosis, and increased erythrosedimentation rate (ESR) and C-reactive protein (CRP). Due to the wide spectrum of signs and symptoms, patients are cared for by different specialists and sometimes it can take years before the correct diagnosis is determined. Moreover the increased risk of lymphoproliferative disorders and the rare association with amyloidosis type A need to be carefully considered [2], [3].

To date approximately a hundred cases have been reported [2], [4], [5]. The pathophysiology of Schnitzler syndrome is largely unclear: both autoimmune [6], [7] and autoinflammation mechanisms may be present in the disease [8], [9], [10]. In addition, Schnitzler syndrome remains a therapeutic challenge. Indeed, despite the administration of numerous immunosuppressive and immunomodulant regimens including methotrexate [11], cyclophosphamide [12], cyclosporine [13], thalidomide [14], interferon [15] and psoralen plus ultraviolet A [16], [17], high doses of steroids are still the major option to control the disease.

Recently biological therapies such as TNFα blockade [18], [19], Anakinra [5], [20] and Rituximab [21], [22] have been used to treat Schnitzler syndrome with conflicting results.

We describe here the cases of two patients with a good response to biological therapies and discuss the reasons why the disease may be considered both autoinflammatory and autoimmune in origin.

Section snippets

Patient 1

DP, a 43 year old Caucasian male, was diagnosed to have Schnitzler syndrome in 2007 at the age of 41. Recurrent fever, chronic urticaria, lymph nodes enlargement, poly-arthralgias and bone pain were the leading symptoms from December 2005. The patient was initially treated with low doses of corticosteroids without remission of symptoms. Laboratory testing revealed a raised CRP (49 mg/L) and ESR (66 mm/Ih), serum electrophoresis showed a monoclonal gammopathy IgM k band of 2 g/l together with

Review of the literature

We searched the MEDLINE database (National Library of Medicine, Bethesda, MD) and selected articles published between 1972 and December 2010 with the headings “Schnitzler syndrome” and “Treatment of Schnitzler syndrome”. All the 99 selected papers, except the clinical reviews, described at least one case of Schnitzler syndrome. The literature reported many additional articles mainly in the English and French literature, but also cases from Bulgaria, Czech Republic, Turkey and the Netherlands.

Definition and clinical features

The diagnosis of Schnitzler syndrome requires the simultaneous presence of chronic urticaria and monoclonal gammopathy IgM or less frequently IgG, that are the major diagnostic criteria, accompanied by at least 2 of the minor criteria (Table 1), represented by intermittent/recurrent fever, arthralgias or arthritis, bone pain, lymphoadenopathy or hepato-splenomegaly, elevated ESR or leukocytosis, abnormal findings on bone morphological investigations [2].

Women are more frequently affected than

Pathogenesis

The pathophysiology of Schnitzler syndrome is largely unclear. Histological studies of skin biopsy have provided little information and have shown a dense perivascular and interstitial infiltrate containing almost exclusively neutrophils with leukocytoclasia but without vasculitis [25], as found in the first patient we have described here. In some cases among neutrophils, infiltrating eosinophils, lymphocytes and histiocytes in the superficial dermis have been described [29]. Deposits of

Treatment

Treatment of Schnitzler syndrome has been considered difficult and unsatisfactory for a long time and both traditional immunosuppressive therapies and novel biological agents have been reported to obtain controversial results (Table 2).

Antihistamines have no efficacy in controlling the rash and pruritus, probably due to the histamine-independent etiology of the rash. The first choice treatment so far consisted of non-steroidal anti-inflammatory drugs and in particular of systemic

Prognosis

Schnitzler syndrome has a favourable prognosis in term of mortality with a survival rate of 94% after 15 years which is comparable to the survival rate of the average population of the same age group in the Netherlands [2]. Although the mortality risk is not increased, patients have an increased risk of malignancy, in particular of lymphoproliferative disease such as Waldenström macroglobulinemia and IgM myeloma [2], [30], [54]. Development of other lymphoproliferative disorders is rare, since

Discussion

Here we describe two patients affected by Schnitzler syndrome; in both cases the correct diagnosis was made about two years after the onset of the disease and both patients had a good clinical response to Anakinra. However in the second case Anakinra had to be suspended because of severe local reaction and Rituximab was well tolerated and obtained remission of the disease.

Schnitzler syndrome remains an enigmatic disorder with an unclear pathogenesis and an obscure evolution, since clinical or

Take-home messages

  • Schnitzler syndrome is a rare disabling disorder that crosses the field of many medical specialties; its real frequency has not been established so far

  • Chronic urticaria and the presence of a monoclonal IgM or IgG are major criteria for the diagnosis

  • The etiopathogenesis is unknown, however both autoimmune and autoinflammatory features are present

  • The disease is frequently refractory to anti-hystamines, corticosteroids and classical immunesuppression

  • Anakinra, Rituximab and Tocilizumab seem to be

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