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Schnitzler syndrome is a rare, underdiagnosed disorder in adults characterized by recurrent febrile rash, bone and/or joint pain, enlarged lymph nodes, fatigue, a monoclonal IgM component, leukocytosis and systemic inflammatory response.
ORPHA:37748Classification level: Disorder
- Chronic urticaria with gammopathy
- Chronic urticaria with macroglobulinemia
- Prevalence: <1 / 1 000 000
- Inheritance: Not applicable
- Age of onset: Adult
- ICD-10: L50.8
- OMIM: -
- UMLS: C0524988
- MeSH: D019873
- GARD: 12390
- MedDRA: 10062908
Prevalence is unknown and about 150 cases have been reported, primarily in Europe.
There is a slight male predominance and mean age of disease onset is 51 years. Time to diagnosis often exceeds 5 years. The first clinical sign is usually a mildly or non-pruritic skin rash. Elementary lesions are rose or red macules or slightly elevated plaques, which resolve within 24 hours. Lesions can occur on every body part, though involvement of face and extremities is rare. The frequency and duration of flares are variable. Almost all patients develop intermittent fever and body temperature can rise above 40°C. Fever is usually well tolerated and chills are rare. About 80% of patients experience bone and/or joint pain. Bone involvement is common, and 30 to 40% of patients show bone lesions on imaging studies. IgM levels can remain stable or progressively increase at a rate of about 0.5 to 1 g/L/year. Other signs include elevated erythrocyte sedimentation rate (ESR), inflammatory anemia sometimes with thrombocytosis (up to 50 % of cases), palpable lymph nodes (45%), and hepatic or splenic enlargement (30%). The monoclonal IgM component is a defining feature of the disease. Inflammatory AA amyloidosis may be a serious complication. The disease follows a chronic course.
Etiology remains unclear but the syndrome is probably an acquired auto-inflammatory disorder. It shares many features with genetically determined auto-inflammatory diseases.
Diagnosis is based on a combination of clinical, laboratory and radiological findings and on exclusion of another cause. Histopathological skin findings are noteworthy showing a neutrophilic infiltrate of the dermis, without vasculitis and without significant edema, characteristic of neutrophilic urticarial dermatosis. An immediate and marked response to anakinra treatment is supportive of the diagnosis. The initial work-up should include an examination of bone marrow, immunoelectrophoresis of serum and urinary proteins, and determination of immunoglobulin subtypes. The two latter examinations can then be used for follow-up on a biannual basis. Lymph nodes should be biopsied when they are enlarged.
Differential diagnosis includes adult-onset Still's disease, hypocomplementic urticarial vasculitis, cryoglobulinemia, hyper IgD syndrome, and acquired C1 inhibitor deficiency (see these terms).
Management and treatment
Some treatments provide only incomplete and/or transient improvement or control of symptoms (steroids, non-steroidal anti-inflammatory drugs, colchicine, dapsone, peflacine, phototherapy) while others are mostly ineffective (anti-histamines, rituximab, intravenous immunoglobulins, TNF-blocking agents, immunosuppressive drugs). In contrast, the IL-1 receptor antagonist anakinra relieves all symptoms within hours after the first injection. Injection-site reactions are frequent with anakinra and sometimes severe, and can be a real concern. The neutrophil count must be monitored.
The overall prognosis depends on the development of lymphoproliferative complications such as lymphoma, IgM myeloma or Waldenström's disease (see these terms). Although these complications have only been reported in about 20% of cases, their incidence may be higher since they generally develop more than 10 to 20 years after the first signs of the syndrome.
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