Schnitzler syndrome is characterized by chronic, nonpruritic urticaria in association with recurrent fever, bone pain, arthralgia or arthritis, and a monoclonal immunoglobulin M (IgM) gammopathy in a concentration of usually less than 10 g/L. Approximately 10-15% of patients eventually develop a lymphoproliferative disorder, such as lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, or IgM myeloma.
Schnitzler syndrome is characterized by the following signs and symptoms:
Chronic, recurrent, urticarial eruption: Occurs in all patients, usually as the first sign of the disease; primarily affects the trunk and the extremities and spares the palms, soles, and head and neck areas
Pruritus: Usually absent at disease onset, but lesions may become mildly pruritic in approximately 45% of patients after 3-4 years
Recurrent fevers: In approximately 90% of patients
Relapsing arthralgias: Concurrent with fever; reported in 80% of patients
Bone pain: Concurrent with fever; reported in 70% of patients
Myalgias: Concurrent with fever
Angioedema: Very rare
The urticarial rash is characterized as follows:
Pale-rose, slightly elevated papules and plaques
Individual lesions are 0.5-3 cm in diameter
New lesions appear daily
Lesions last 12-24 hours and then disappear without sequelae
No risk factors have so far been identified. The pathogenesis of Schnitzler syndrome is still not well defined. Patients have shown deposition of IgM in the involved tissue. Using anti-idiotype antibodies, IgM monoclonal antibodies were demonstrated to react with epidermal antigens. In one case, monoclonal IgM was found to target 50-, 31-, and 17-kd proteins within epidermal extracts. These findings suggest that the IgM deposits may be involved in the pathogenesis, perhaps via the formation of immune complexes and activation of the complement system.
IL-1alpha is a known mediator of inflammation, and its injection into the skin causes persistent erythema. One report noted that the serum from 6 of 9 patients with Schnitzler syndrome contained polyclonal immunoglobulin G (IgG)–type autoantibodies directed against IL-1alpha. These autoantibodies have been shown to prolong the half-life of IL-1alpha, to change its tissue distribution, and to enhance its effects. Therefore, this increase in IL-1alpha activity could account for the symptoms of urticaria and fever. In recent years, treatment with the IL-1alpha and IL-1beta receptor antagonist, anakinra, has led to complete remissions.
Elevated levels of interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) have been found in the serum of some patients. What role these cytokines play in the pathogenesis of Schnitzler syndrome is not clear.
- Immunoglobulin M (IgM) gammopathy: Detected with serum immunoelectrophoresis; occurs in all patients; in 51% of cases, however, serum protein electrophoresis may not detect it
- Elevated erythrocyte sedimentation rate (ESR): Found in most cases
- Elevated C-reactive protein level: Also detected in most cases
- Leukocytosis: 70% of patients
- Thrombocytosis: 20% of patients
- Anemia: 50% of patients
- Abnormal lymphoid proliferation: 20% of bone marrow biopsy samples, with nonspecific polyclonal lymphocytic and plasmacytic infiltrates
Radiologic evaluation shows evidence of hyperostosis in 35% of Schnitzler syndrome patients. Often, the areas of hyperostosis coincide with areas of symptomatic bone pain, such as the iliac bone, tibia, femur, and vertebral column.
Up until about 2005, the urticarial eruption of Schnitzler syndrome was typically resistant to treatment. No treatment was consistently effective.
Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and immunosuppressive agents have been reported to provide variable relief from the symptoms of bone pain and arthralgias associated with Schnitzler syndrome.
Skin and extracutaneous manifestations respond poorly to H1 and H2 antihistamines. Colchicine and dapsone have been tried with variable success in different patients. A few patients were responsive to treatment with thalidomide but the occurrence of peripheral neuropathy limits its use. Rituximab, an anti-CD20 monoclonal antibody, was reported to be effective in one patient but unsuccessful in another. Reports of using chloroquine, chlorambucil, cyclophosphamide, azathioprine, plasmapheresis, and high-dose intravenous immunoglobulin have indicated no response. Psoralen plus UV light (PUVA) may reduce the intensity of the rash in some patients.
NSAIDs have proved to be of some benefit for the bone pain and fever, but not for the urticaria. Systemic steroids may be somewhat effective at controlling the cutaneous eruption, but usually at doses that can cause significant long-term adverse effects.
Pefloxacin mesylate administered at a dose of 800 mg/d may be a therapeutic option. In a case series of 11 patients, it was shown to significantly reduce the intensity and frequency of many of the manifestations in a majority of the group, and it provided a steroid-sparing effect for some patients being treated with systemic corticosteroids. It was less active on the osteoarticular component of Schnitzler syndrome.
Anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, and rilonacept, a dimeric fusion protein that acts as a decoy IL-1 receptor, are two agents with recently reported benefit in Schnitzler syndrome.