Schnitzler Syndrome

Updated: Feb 02, 2023
Author: Jami L Miller, MD; Chief Editor: Dirk M Elston, MD 

Overview

Practice Essentials

Schnitzler syndrome is an autoinflammatory disease characterized by chronic, nonpruritic urticaria in association with monoclonal gammopathy.  Associated sympoms include recurrent fever, bone pain and arthralgia or arthritis.  The gammonpathy is most often of the immunoglobulin M (IgM) subtype; those with an  immunoglobulin G (IgG) monoclonal gammopathy are considered to be a distinct group.. 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 NRash of Schnitzler syndrome. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/systemic/schnitzler.jpg).

Signs and symptoms

The diagnosis of Schnitzler syndrome is made by using the Strausborg criteria[1] :  

Major criteria:  

Recurrent urticarial eruption 

Monocolonal gammopathy. Titers may be low (< 10 g/L).

Minor criteria: 

Recurrent fever - present in ~ 90% 

Elevated C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR)

Leukocytosis

Skin biopsy showing a neutrophilic infiltrate without vasculitis 

Evidence of abnormal bone remodeling with or without bone pain ( abnormal MRI, elevated bone alkaline phosphatase or bone scintigraphy)

For a definitive diagnosis:

2 major and 2 minor criteria if the monoclonal gammopathy is IgM.  

2 major and 3 minor criteria if the monoclonal gammopathy is IgG.

See Clinical Presentation for more detail.

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

Ibrutinib, a blocker of Bruton's tyrosine kinase (BTK),  has been shown to be successful in treating Schnitzler sybdrome, with or without an accompaying hematologic malignancy.[2]  

Inhibitors of interleukin (IL)–1 (anakinra, rilonacept, and canakinumab) are often effective.[3, 4]

See Treatment and Medication for more detail.

Background

Schnitzler syndrome was first described in a 1972 case report by French dermatologist Liliane Schnitzler,[5] who further described it 2 years later with several cases. The diagnostic criteria were established in 1999 by Lipsker et al.[6] 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 but seems to involve the innate immune system.  Current data suggests activation of the inflammasome, leading to overproduction of proinflammatory cytokines, is central to the development of Schnitzler syndrome.  

Interleukin 1-beta(IL-1beta) appears to play an important role, and inhibitors of IL-1 beta are often helpful in treatment.  Increased levels of several other members of the cytokine IL-1 family have been found, including IL-18.[7]    Neutrophil extracellular traps (NETs) are net-like structures released by neutrophils to combat pathogens but also have immune-modulating properties that may be important in the pathogenesis of neutrophil mediated disorders including Schnitzler, Sweet syndrome and pyoderma gangrenosum[8]    Hypersensitivity to lipo-polysaccharide IL-1 production has been found in peripheral blood cells, particularly mononuclear cells.  

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.[9] .  

Several genetic mutations have been found in Schnitzler syndrome patients, though not consistently.  Mutations in the NLRP3 gene (nucleotide-binding oligoisomerization domain [NOD]-like [NLR] family pyrin domain containing 3) that are also found in cryopyrin-associated periodic syndrome (CAPS) has been found in a few  Schnitzler syndrome patients. Mutations in MYD88 L265P have also been observed in a few patients.

Patients have shown deposition of IgM in the involved tissue, and using anti-idiotype antibodies, IgM monoclonal antibodies were demonstrated to react with epidermal antigens.[10]  In one case, monoclonal IgM was found to target 50-, 31-, and 17-kd proteins within epidermal extracts.[11] 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.   

Disturbances in mitochondrial function have also been reported.[12]

Epidemiology

United States

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

International

Schnitzler syndrome is relatively rare, though more and more cases are being reported in the literature. The original case was from France, with the greatest number of cases originating from Western Europe.

Race

Occurs in all races.

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. Itis generally considered to be of  "late onset" with the average age of onset approximately 52 years,[13, 14] although the average delay to diagnosis is more than 5 years.

Prognosis

Most Schnitzler syndrome patients have a chronic benign course, though quality of life may be lowered due to symptoms. No spontaneous complete remissions have been reported. Neuropathy, both sensory and motor, has been reported as well as hearing loss and anemia[15] . 

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. Other associated diseases include AA amyloidosis.  

Kidney involvement has been described as a rare complication, but it improved with treatment in the cases reported.[16]

 

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 with the femur, spine, forearms, and clavicle less often involved. Additionally, fatigue and weight loss are common.

 

 

 

 

 

 

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 include the following:

  • Fever 

  • Arthritis

  • Bone pain

  • Lymphadenopathy

  • Hepatomegaly or splenomegaly

Complications

Roughly 15-20% of patients develop an overt lymphoproliferative disorder.[17]

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.[17]

Neuropathy, both sensory and motor, have been asslciated with Schnitzler syndrome.

 

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.[18]

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

Evaluation of urticarua patients with symptoms of fever or lack of response to antihistamines should include testing for Schnitzler syndrome.  Definitive diagnosis requires 2 major criteria and at least 2 minor criteria.[17]

  • The diagnosis of Schnitzler syndrome is made by using the Strausborg criteria [1]  :  

    Major criteria:  

    Recurrent urticarial eruption 

    Monocolonal gammopathy. Titers may be low (< 10 g/L).

    Minor criteria: 

    Recurrent fever - present in ~ 90% 

    Elevated CRP and/or ESR

    Leukocytosis, 

    Skin biopsy showing a neutrophilic infiltrate without vasculitis 

    Evidence of abnormal bone remodeling with or without bone pain ( abnormal MRI, elevated bone alkaline phosphatase or bone scintigraphy)

    For a definitive diagnosis:

    2 major and 2 minor criteria if the monoclonal gammopathy is IgM.  

    2 major and 3 minor criteria if the monoclonal gammopathy is IgG.

     

Laboratory Studies

Serum immunoelectrophoresis to investigate for monoclonal gammopathy. 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.[19, 20]

ESR and CRP are elevated in most cases. 

CBC with differrntial and platelets: Leukocytosis (70%), thrombocytosis (20%), and anemia (50%) may be found.

 

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.  X-rays of painful joints should be considered as joint destruction may be present.[21]

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.[22]

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.[22]

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

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, thus true vasculitis is absent, 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.

Procedures

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

 

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 the Btk inhibitor ibrutinib or IL-1 inhibitors, such as anakinra.[17, 23] .

Medical Care

There is not an FDA approved treatment for Schnitzler syndrome, thus these recommendations shoudl be considered "off label."

Inhibitors of Btk: recent evidence has shown ibrutinib to be helpful[24, 2] . Time to improvement has ranged from 2 weeks to 2-3 months.  

Inhibitors of IL-1:  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.[25]  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.[23]   Canakinumab, a selective monoclonal antibody specific to IL-1β, has also been shown effective in improving symptoms and decreasing markers of inflammation.[4, 26]

Despite the urticarial appearance, 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.[20, 27]

Rituximab, an anti-CD20 monoclonal antibody, was reported to be effective in 1 patient[28] but unsuccessful in another.[3]

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.[14] It was less active on the osteoarticular component of Schnitzler syndrome.

Consultations

Consultation with hematology/oncology 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.

 

Medication

Antineoplastics, Tyrosine Kinase Inhibitor

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.

Interleukin-1 Receptor Antagonist

Class Summary

Agents in this category antagonize immune responses activated by interleukin (IL)‒1 receptor binding.

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.

Anti-Interleukin 1-beta Antibody

Class Summary

Agents in this class have been shown to be effective in improving symptoms and decreasing markers of inflammation.

Canakinumab (Ilaris)

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

Uricosuric Agents

Class Summary

Agents in this class can reduce acute inflammation and pain.

Colchicine (Colcrys, Mitigare)

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

Antimalarial Agents

Class Summary

Antimalarials may work through numerous proposed mechanisms, mediating subtle immunomodulation without causing overt immunosuppression.

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.

Btk inhibitor