Schnitzler Syndrome 

Updated: Mar 12, 2019
Author: Brian J Thomas, MD; Chief Editor: Dirk M Elston, MD 

Overview

Practice Essentials

Schnitzler syndrome is an autoinflammatory disease characterized by chronic, nonpruritic urticaria in association with recurrent fever, bone pain, arthralgia or arthritis, and a monoclonal gammopathy, most often of the immunoglobulin M (IgM) subtype. Approximately 10-15% of patients eventually develop a lymphoproliferative disorder, such as lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, or IgM myeloma. See the image below.

Rash of Schnitzler syndrome. Courtesy of DermNet N Rash of Schnitzler syndrome. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/systemic/schnitzler.jpg).

Signs and symptoms

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

  • Lymphadenopathy

  • Hepatomegaly

  • Splenomegaly

  • Fatigue

  • Weight loss

  • 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

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies

  • Immunoglobulin M (IgM) or rarely IgG monoclonal gammopathy: Detected with serum immunoelectrophoresis, and the titers are low (usually < 10 g/L; 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

Imaging studies

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.

See Workup for more detail.

Management

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.

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 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 of Schnitzler syndrome in a majority of the group, and it provided a steroid-sparing effect for some patients being treated with systemic corticosteroids.[1]

Inhibitors of interleukin (IL)–1 (anakinra, rilonacept and canakinumab) appear to be particularly effective.[2, 3]

See Treatment and Medication for more detail.

Background

Schnitzler syndrome was first described in a 1972 case report by French dermatologist Liliane Schnitzler,[4] who further described it 2 years later with several cases in 1974. Diagnostic criteria were established in 1999 by Lipsker et al.[5] Most cases have been reported in Europe, although more and more are being described in North America and elsewhere.

Pathophysiology

Schnitzler syndrome is an autoinflammatory disease for which the exact pathophysiology remains unclear. Dysfunction of several components of the innate immune system have been described, including the uncontrolled activation of interleukin 1-alpha (IL-1alpha). Increased levels of several members of the cytokine IL-1 family have been found, including IL-18.[6] Others 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 of Schnitzler syndrome.

Etiology

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.[7] In one case, monoclonal IgM was found to target 50-, 31-, and 17-kd proteins within epidermal extracts.[8] 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.[8] 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.[9]

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.[10] What role these cytokines play in the pathogenesis of Schnitzler syndrome is not clear.  

An increase in cytokines associated with the IL-1 family has been demonstrated, in particular IL-18. Disturbances in mitochondrial function have also been reported.[11]

Epidemiology

United States

Only a few cases of Schnitzler syndrome have been reported from the United States.

International

Schnitzler syndrome is rare, with approximately 200 cases reported in the literature. The original case was from France, with the greatest number of cases originating from the same country. The vast majority of cases come from Western Europe.

Race

The majority of Schnitzler syndrome cases are in white western Europeans.

Sex

Males have a slight predominance with a ratio of 1.76:1.

Age

Patients with Schnitzler syndrome have ranged from age 13-71 years at the time of diagnosis. The average age of onset is approximately 52 years,[12, 1] although the average delay to diagnosis is more than 5 years.

Prognosis

Most Schnitzler syndrome patients have a chronic benign course. No spontaneous complete remissions have been reported. Overall, the prognosis for Schnitzler syndrome is good. However, approximately 10-15% of patients develop a lymphoplasmacytic malignancy.

Approximately 10-15% of patients eventually develop a lymphoproliferative disorder, including 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 Schnitzler syndrome patient 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.  

Kidney involvement has been described as a rare complication, but it improved with treatment in the cases reported.[13]

 

Presentation

History

All patients with Schnitzler syndrome present with a chronic, recurrent, urticarial eruption. Pruritus is usually absent at the disease onset, but lesions may become mildly pruritic in approximately 45% of patients after 3-4 years. The skin eruption is usually the first symptom to occur, primarily affecting the trunk and the extremities, and sparing the palms, soles, and head and neck areas

Approximately 90% of Schnitzler syndrome patients experience recurrent fevers. Each febrile episode usually resolves within a few hours; however, fevers can persist for up to 24-48 hours. Episodes may occur daily or as infrequently as twice per year. Chills are rare. In some cases, the fever and rash are not related.

Concurrent with the fever, 80% of patients report relapsing arthralgias, 70% report bone pain (usually in the large joints), and myalgias. The bone pain mostly affects the iliac bone and the tibia. The femur, spine, forearms, and clavicle are less often involved. Additionally, fatigue and weight loss occur in a high percentage of patients.

Physical Examination

The urticarial rash of Schnitzler syndrome 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 is very rare. Lymphadenopathy may be found up to 50% of patients, hepatomegaly in 30% of patients, and splenomegaly in 10% of patients. Other signs and symptoms in Schnitzler syndrome include the following:

  • Recurrent fever

  • Arthralgia or arthritis

  • Bone pain

  • Lymphadenopathy

  • Hepatomegaly or splenomegaly

  • Leukocytosis

  • Elevated erythrocyte sedimentation rate (ESR)

  • Bone abnormalities (upon radiologic or histopathologic investigations)

Complications

Roughly 15-20% of patients develop an overt lymphoproliferative disorder.[14]

With Schnitzler syndrome, a lymphoplasmacytic malignancy, such as Waldenström macroglobulinemia, lymphoplasmacytic lymphoma, or IgM myeloma, may occur.

The development of AA amyloidosis is a concern in untreated patients with Schnitzler syndrome.[14]

 

DDx

Diagnostic Considerations

Adult-onset Still disease is associated with fever, rash, arthralgias, and/or myalgias. The rash in Still disease is evanescent. The urticarial lesions in Schnitzler syndrome 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 ESR. However, leukopenia, neutropenia, and thrombocytopenia are seen in SLE, compared with the leukocytosis and thrombocytosis in Schnitzler syndrome. Antinuclear antibodies are present in SLE, but not in Schnitzler syndrome. Monoclonal paraprotein would not be expected in SLE.

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

Chronic idiopathic urticaria often responds symptomatically to antihistamines and lacks the accompanying systemic features and paraprotein seen in Schnitzler syndrome.

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

The cryoprin-associated periodic syndromes (CAPS), which include familial cold urticaria, Muckle-Wells syndrome, and chronic infantile neurologic cutaneous articular (CINCA) syndrome, all can have associated fever and rash. Patients with these disorders have onset before adulthood, lack a paraprotein, and have a family history of the disease. Muckle-Wells syndrome is often associated with amyloidosis and deafness. CINCA syndrome may be associated with chronic sterile meningitis and neurological deficits.[15]

Hyperimmunoglobulin D syndrome shows elevated polyclonal immunoglobulin D levels with onset of recurrent fever, usually in the first year of life.

Delayed pressure urticaria can occasionally be nonpruritic. However, it is not associated with an elevated ESR or an increased white blood cell count, although in severe cases, fever, myalgia, and arthralgias may occur. 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 Schnitzler syndrome, the monoclonal gammopathy is less than that seen in Waldenström macroglobulinemia.

Differential Diagnoses

 

Workup

Approach Considerations

In 2013, an expert consensus panel proposed criteria for diagnosis of suspected Schnitzler syndrome. Definitive diagnosis requires two major criteria and at least two minor criteria. Probable diagnosis is the presence of two major criteria and at least one minor criteria if IgM or two minor criteria if IgG.[14]

Major criteria are as follows:

  • Chronic urticarial eruption

  • Monoclonal IgM or IgG

Minor criteria are as follows:

  • Recurrent fever

  • Bone pain with objective findings of abnormal bone remodeling with or without bone pain (assessed by scintigraphy, MRI, or alkaline phosphatase)

  • A neutrophilic dermal infiltrate seen on skin biopsy

  • Leukocytosis and/or elevated C-reactive protein (neutrophils >10,000/µL or C-reactive protein >30 mg/L

Laboratory Studies

All cases are associated with a monoclonal gammopathy, most commonly IgM and rarely IgG. This is typically 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/L. In 51% of cases, serum protein electrophoresis may not detect the IgM gammopathy because the levels can be very low. A small number of cases have been presented in the literature wherein the patient had clinical features of Schnitzler syndrome but had an associated IgG gammopathy rather than an IgM gammopathy—an IgG variant of Schnitzler syndrome.[16, 17]

The ESR and C-reactive protein level are elevated in most cases. Leukocytosis (70%), thrombocytosis (20%), and anemia (50%) may also be found.

Abnormal lymphoid proliferation can be seen in 20% of bone marrow biopsy samples, with nonspecific polyclonal lymphocytic and plasmacytic infiltrates.

Imaging Studies

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 columns.

Various radiologic findings have been reported with Schnitzler syndrome, including osteosclerosis, hyperostosis, and periosteal reaction.

Typical modalities that have been used include plain radiographs (including skeletal survey), bone scans, CT, MRI, and positron-emission tomography (PET)/CT.

The most common locations for positive findings are the distal femora, proximal tibia, and iliac bones.[18]

The finding of increased signal in the distal femur and proximal tibia is sometimes referred to as the "hot knees" sign and has been reported in multiple cases of Schnitzler syndrome.[18]

One report of 22 patients suggested that the most sensitive and cost-effective test for Schnitzler bone lesions is technetium Tc-99 nuclear scintigraphy.[18]

Histologic Findings

A review of the pathology of Schnitzler syndrome shows that the histopathologic findings are not consistent; features in some patients include a superficial dermal and perivascular infiltrate of polymorphonuclear cells, mostly neutrophils, suggestive of neutrophilic urticaria. A small percentage of specimens demonstrate a superficial perivascular mononuclear infiltrate suggestive of chronic urticaria and lymphocytic inflammation. Vessels are intact, and dilatation of dermal lymphatics with mild superficial edema may 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 are seen in 45% of cases. Rarely are IgM deposits found within vessel walls.

 

Treatment

Approach Considerations

The patient should be evaluated for alterations in quality of life as well as serial evaluation of inflammatory markers. In patients without significant elevations in these markers and without significant quality-of-life impairment, a less aggressive treatment course may be acceptable. This includes observation, colchicine, a short course of NSAIDs, or hydroxychloroquine. However, in patients with significantly impaired quality of life or regularly elevated inflammatory markers, a more aggressive course is recommended. This includes treatment with IL-1 inhibitors, such as anakinra.[14, 19]

Medical Care

Up until about 2005, the urticarial eruption of Schnitzler syndrome was typically resistant to treatment. No treatment was consistently effective.

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.[17, 20] Rituximab, an anti-CD20 monoclonal antibody, was reported to be effective in one patient[21] but unsuccessful in another.[2] 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.[1] 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 reported benefit in Schnitzler syndrome.[22] Anakinra has been shown to induce sustained dramatic improvements in patients with Schnitzler syndrome, allowing for improved quality of life and steroid-sparing effects. Interestingly, it was not shown to impact the levels of monoclonal gammopathy in a series of 29 patients followed over 3 years.[19]

Canakinumab, a selective monoclonal antibody specific to IL-1β, has also been shown effective in improving symptoms and decreasing markers of inflammation.[3, 23]

Ibrutinib has also been used.[24]

Consultations

Consultation with hematologic oncologist should be considered for the monoclonal gammopathy.

Long-Term Monitoring

Schnitzler syndrome requires long-term follow-up because of the potential for the development of lymphoproliferative disorders, especially Waldenström macroglobulinemia. Monitoring patients with periodic serum protein electrophoresis and reevaluation for lymphadenopathy and bone marrow involvement, if clinically indicated, is important. It is recommended that patients’ leukocyte counts and C-reactive protein values be followed every 3 months while on treatment, and then at least twice yearly once stable at normal levels. The monoclonal gammopathy should be monitored as usually recommended for monoclonal gammopathy of undetermined significance, as determined by the serum levels.

 

Anakinra (Kineret)

Anakinra is a recombinant, nonglycosylated form of the human IL-1 receptor antagonist (IL-1Ra). It competitively and selectively inhibits IL-1 binding to the type I receptor.

Canakinumab (Ilaris)

Canakinumab reduces inflammation by preventing interaction of IL-1 beta with cell surface receptors.

Colchicine (Colcrys, Mitigare)

Colchicine inhibits microtubules and, as a result, may inhibit neutrophil chemotaxis and phagocytosis. It also may inhibit prostaglandin generation.

Hydroxychloroquine sulfate (Plaquenil)

This agent inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions, which, in turn, may prevent inflammatory reactions.

Ibrutinib (Imbruvica)

Ibrutinib inhibits the function of Bruton tyrosine kinase (BTK). BTK is a key signaling molecule of the B-cell receptor-signaling complex that plays an important role in the survival of malignant or pathogenic B cells.