Background: Schnitzler syndrome (SS), first reported in 1972, 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 that is usually less than 10 g/dL. Since 1972, approximately 50 cases have been reported.


Pathophysiology: The exact pathogenesis of SS is unclear. Some hypothesize that the deposition of the IgM paraprotein, leading to the formation of immune complexes and the activation of the complement cascade, is responsible for the cutaneous manifestations. Another proposed mechanism involves the uncontrolled activation of interleukin 1-alpha (IL-1alpha).


Frequency:
In the US: Only a few cases have been reported from the United States.
Internationally: SS is rare, with approximately 50 cases reported in the literature. The original case was from France, with most cases from the same country. The vast majority of cases come from Europe.

Mortality/Morbidity: Most patients with SS have a chronic benign course. Spontaneous remissions have not been reported. Approximately 10-15% of patients eventually develop a lymphoproliferative disorder, either a lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, or IgM myeloma. Schnitzler's original patient died at age 88 years, with a diffuse lymphoplasmacytic infiltration of his liver and bone marrow. Thus, the initial workup of a patient with SS should include an examination of the bone marrow, immunoelectrophoresis of serum, and a urinary protein level. A lymph node biopsy should be performed if the nodes are enlarged.

Race: The race distribution is not known.

Sex: Males have a slight predominance.

Age: Patients with SS have ranged from age 29-71 years at the time of diagnosis. The average age of onset is approximately 55 years.

History:
All patients with SS present with a chronic, recurrent, urticarial eruption. Pruritus is usually absent at the disease onset, but lesions may become mildly pruritic in approximately 30% of patients after 3-4 years. The skin eruption is usually the first symptom to occur, primarily affecting the trunk and the extremities, sparing the palms, the soles, and the head and neck areas
Approximately 90% of patients experience recurrent fevers. Each febrile episode usually resolves within a few hours; however, fevers can persist for up to 24-48 hours. Chills are rare. In most cases, the fever and the skin rash are not related.
Concurrent with the fever, patients may complain of relapsing arthralgias (60%), bone pain (50%), and myalgias. The bone pain mostly affects the iliac bone and the tibia. The femur, spin, forearms, and clavicle are less often involved.
Fatigue and weight loss can also be found in a high percentage of patients.

Physical:
The urticarial rash consists of pale-rose slightly elevated papules and plaques. Individual lesions are 0.5-3 cm in diameter. New lesions appear daily. They last 12-24 hours and then disappear without sequelae.
Angioedema is possible, but it very rarely occurs.
Lymphadenopathy may be found in 50% of patients, hepatomegaly in 25% of patients, and splenomegaly in 6.7% of patients.

Causes: The pathogenesis of SS is still not well defined. Cases have shown deposition of IgM in the involved tissue. In 1980, using anti-idiotype antibodies, Olsen et al demonstrated that IgM monoclonal antibodies reacted with epidermal antigens. In one case of SS, Saurat et al found that the monoclonal IgM targeted 50-kd, 31-kd, 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 the activation of the complement system.

IL-1alpha is a known mediator of inflammation, and its injection into the skin causes persistent erythema. In 1991, Saurat et al found that the serum from 6 out of 9 patients with SS 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 found in SS.

Morita et al showed elevated levels of interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) in the serum of some patients with SS. What role these cytokines play in the pathogenesis of the disease is not clear.

Other Problems to be Considered:

Adult-onset Still disease is associated with fever, rash, arthralgias, and/or myalgias. The rash in Still disease is evanescent. The urticarial lesions in SS are chronically recurrent. In addition, monoclonal gammopathy does not occur in Still disease.

Systemic lupus erythematosus (SLE) may be associated with urticaria, fever, arthralgia, and an elevated erythrocyte sedimentation rate (ESR). However, leukopenia, neutropenia, and thrombocytopenia are seen in SLE, compared to the leukocytosis and thrombocytosis in SS. Antinuclear antibodies are present in SLE, but not in SS.

Urticarial vasculitis can have features of nonpruritic urticaria, persisting for more than 24 hours; myalgia; arthralgia; fever; an elevated ESR; and an increased white count. Skin biopsy of urticarial vasculitis shows fibrinoid necrosis of vessels and a perivascular neutrophilic infiltrate. Fibrinoid necrosis is rarely seen with SS.

Cryoglobulinemia shows clinical signs and symptoms at cold temperatures and demonstrates the presence of cryoglobulins.

Hyperimmunoglobulin D syndrome shows elevated immunoglobulin D levels.

Delayed pressure urticaria can occasionally be nonpruritic. However, it is not associated with an elevated ESR or an increased white count. In addition, anemia is not seen with delayed pressure urticaria.

Waldenström macroglobulinemia shows a lymphoid proliferation in the bone marrow, and the monoclonal IgM gammopathy is found in large amounts, usually more than 10,000 mg/L. Often, it is associated with hepatosplenomegaly. In SS, the monoclonal gammopathy is less than that seen in Waldenström macroglobulinemia.

Lab Studies:
All cases of SS are associated with an IgM monoclonal gammopathy, which is demonstrated by serum immunoelectrophoresis. Most cases are of the IgM-kappa isotype. A few cases of IgM-lambda and IgM-kappa/lambda have occurred. The serum IgM levels are usually less than 10 g/dL. In 51% of cases, serum protein electrophoresis may not detect the IgM gammopathy because the levels can be very low. One case has been presented in the literature where the patient had clinical features of SS but had an associated IgG gammopathy rather than an IgM gammopathy.
The ESR is elevated in approximately 85% of cases. Leukocytosis (60%), thrombocytosis (20%), and anemia (35%) may also be found. Both low serum complement levels and low serum C1 inhibitor levels are seen in nearly 10% of patients. Cryoglobulin, antinuclear antibody (ANA), and rheumatoid factor (RF) test results are positive in a small percentage: 3%, 7%, and 7%, respectively.
Abnormal lymphoid proliferation can be seen in 10% of bone marrow biopsy samples and 10% of lymph node biopsy samples.

Imaging Studies:
Radiologic evaluation shows evidence of hyperostosis in 35%. Often, the areas of hyperostosis coincide with areas of symptomatic bone pain, such as the iliac bone, the tibia, the femur, and the vertebral columns.
Histologic Findings: A recent review of the pathology of SS showed that the histopathologic findings were not consistent; features in some included a superficial dermal and perivascular infiltrate of polymorphonuclear cells, mostly neutrophils, suggestive of neutrophilic urticaria. A small percentage demonstrated a superficial perivascular mononuclear infiltrate suggestive of chronic urticaria and lymphocytic inflammation. Vessels were intact, and dilatation of dermal lymphatics with mild superficial edema was present.

Rare cases show fibrin deposition, extravasation of erythrocytes, or leukocytoclastic vasculitis.

Deposits of IgM and complement in the upper dermis and/or at the dermoepidermal junction were seen in 45% of cases. Rarely were IgM deposits found within vessel walls.

Medical Care: The urticarial eruption of SS is typically resistant to treatment. No treatment is 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. Some patients remain symptomatic to a large degree, and this may have an impact on their day-to-day functioning.

Skin and extracutaneous manifestations respond poorly to H1 and H2 antihistamines. Colchicine and dapsone have been tried with variable success in different patients. Reports using chloroquine, chlorambucil, cyclophosphamide, azathioprine, plasmapheresis, and high-dose intravenous immunoglobulin indicated no response. PUVA may reduce the intensity of the rash in some patients.

Systemic steroids are not effective at controlling the cutaneous eruption. NSAIDs have proved to be of some benefit for the bone pain and fever, but not for the urticaria. NSAIDs, most notably ibuprofen, are the first treatment choices for most patients. Steroids and immunosuppressive agents are only indicated when the systemic symptoms (eg, fever, arthralgias) are disabling and do not respond to first-line therapy.