Hereditary systemic autoinflammatory diseases and Schnitzler's syndrome.

The systemic autoinflammatory diseases are disorders of the innate immune system distinguished by severe inflammation resulting from dysregulation of the innate immune system. Hereditary fever syndromes, such as FMF, TNF receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes and mevalonate kinase deficiency, were the first group of systemic autoinflammatory diseases for which a genetic basis was established, between 1999 and 2001. Currently according to the latest report of the international union of immunological societies, 37 separate monogenic disorders were classified as autoinflammatory. In addition to the abovementioned monogenic conditions, we describe Schnitzler's syndrome, a well-defined, acquired autoinflammatory condition without a clear genetic basis. For the purposes of this review, we discuss several conditions defined by the latest consensus process as systemic autoinflammatory diseases. We focus on those disorders where recent studies have contributed to further phenotypic characterization or had an impact on clinical management.

Schnitzler syndrome: an under-diagnosed clinical entity.

Schnitzler syndrome is considered to be a rare disorder characterized by a monoclonal IgM protein and chronic urticaria that is associated with considerable morbidity. We hypothesized that the syndrome may be under-recognized and patients may be deprived of highly effective therapy in the form of anakinra. We performed a retrospective search of the dysproteinemia database at Mayo Clinic as well as the medical records of all patients with chronic urticaria to determine the true incidence of the disease. We compared patients with the diagnosis of Schnitzler syndrome and those who met the criteria but in whom the syndrome was not recognized. Comparisons between groups were performed and survival curves determined. We identified 16 patients with diagnosed Schnitzler syndrome and an additional 46 patients who met diagnostic criteria. The monoclonal protein was IgMκ in 94% of patients. Therapy with anakinra in 4 patients led to rapid and complete resolution of symptoms. The median overall survival for this syndrome is over 12.8 years. Progression to lymphoma was only observed in 8% of patients; this is lower than previous reports. Schnitzler syndrome may be present in up to 1.5% of patients with a monoclonal IgM in their serum and likely under-recognized as a clinical syndrome.

Schnitzler syndrome: beyond the case reports: review and follow-up of 94 patients with an emphasis on prognosis and treatment.

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.