Are You Confident of the Diagnosis?
In 1972, Schnitzler first described a patient with combined symptoms of chronic urticaria, intermittent fever, osteosclerotic bone lesions and monoclonal gammopathy. This syndrome was also reported by other groups and now bears her name.
Characteristic findings on physical examination
Clinical signs including skin rash, pruritus, periodic fever, arthralgia, and bone pain are the findings suggestive of Schnitzler’s syndrome (Figure 1). Physical examination and imaging studies sometimes reveal palpable lymph nodes, hepatosplenomegaly, and abnormal bone morphology.
Expected results of diagnostic studies
Laboratory findings may demonstrate a variety of abnormalities including elevated erythrocyte sedimentation rate (>30mm/h), leukocytosis, gammaglobulinemia, immunoglobulin M (IgM) globulinemia, monoclonal IgM component (kappa light chain), and Bence-Jones proteinuria. To assess the cause of paraproteinemia, a bone marrow biopsy may be needed.
The definite diagnosis of Schnitzler’s syndrome will be achieved with the help of the diagnostic criteria after considering differential diagnosis such as adult-onset Still disease, hypocomplementemic urticarial vasculitis, acquired C1 esterase deficiency, cryogloblinemia, hyper-IgD syndrome, erythema marginatum, systemic lupus erythematosus, CINCA syndrome, Muckle-Wells syndrome, etc.
The diagnostic criteria for the Schnitzler’s syndrome are as follows:
Major: Urticarial skin rash and monoclonal IgM component
Minor: At least 2 of the following:
arthralgia or arthritis
palpable lymph nodes
liver or spleen enlargement
elevated erythrocyte sedimentation rate
abnormal findings on bone morphologic investigations.
Who is at Risk for Developing this Disease?
Epidemiology: Schnitzler’s Syndrome Study Group (SSSG) had summarized the previous literatures and reported that the majority of reported cases were of western European origin (especially in France). There was a sex difference in incidence of the disease, with a male: female ratio of 1.6:1. No risk factors have been identified.
What is the Cause of the Disease?
Unknown. It has been discussed that monoclonal IgM and IgG autoantibodies might play a role in the etiology of Schnitzler’s syndrome. The finding of granular deposit of IgM in the dermis of lesional skin was observed in patients and was thought to be associated with the pathogenesis of Schnitzler’s syndrome. Some authorities have reported the correlation with the presence of IgG antibodies against certain cellular proteins, Fc epsilon receptor 1 alpha, and interleukin-1 alpha.
Pathologic investigation of urticarial skin lesions shows heterogeneous findings. Neutrophilic infiltration is observed in relatively large numbers in patients with Schnitzler’s syndrome.
Systemic Implications and Complications
Prognosis: Schnitzler’s syndrome has a good prognosis. The SSSG reported that about 91% of patients live for 15 years.
Associated systemic diseases: Schnitzler’s syndrome is thought to be associated with the potential development of lymphoproliferative disorders, in particular, Waldenström macroglobulinemia (WM) and lymphoplasmacytic lymphoma. It has been reported that the incidence of WM in patients with Schnitzler’s syndrome gradually increases with time, with WM occurring in 15% of cases 10 years after the onset of skin symptoms. Therefore, the clinicians should keep in mind that Schnitzler’s syndrome has an increased chance of developing B-cell-related lymphoproliferative diseases as part of the natural evolution of the disorder.
Ordinary antihistamines, H2-antagonists, hydroxychloroquine, chloroquine are ineffective. Plasmapheresis, interferon alpha-2a, and intravenous gamma globulin administration also have been tried and were only marginally effective. Any of the following treatments would be beneficial at least partially.
Non-steroidal anti-inflammatory drugs (NSAIDS), mostly ibuprofen, have been reported to reduce symptoms such as fever and bone pain, and with a variable effect on urticaria. Many previous reviews recommended to use NSADS as first-line choice.
Dapsone: If neutrophils are suspected of contributing to the disease, dapsone will be considered as inhibitors of neutrophil migration, as well as colchicine. The results are unpredictable.
Colchicine: conform to the description for dapsone.
Corticosteroids: It has been reported that high dose of prednisolone (up to 60mg/day in the past literature) was required to control the disease activity. Older literature has questioned the effect of corticosteroids and recommended considering the risk-to-benefit of the agent in this syndrome.
Immunosuppressants: Cyclophosphamide, chlorambucil and azathioprine have been tried and showed partial effect on intermittent fever without considerable improvement of other symptoms.
Interleukin-1 receptor antagonist (anakinra): Anakinra has been reported to cause complete remission in 8 of 8 cases. Be forewarned—a flare-up of symptoms may occur within a few days of drug withdrawal.
Rituximab: According to the literature, 2 of 4 cases achieved complete remission by rituximab treatment. Two cases were associated with B-cell related lymphproliferative disease, while the other cases were not. With this treatment, another case showed improved renal failure and partially improved urticaria and bone pain.
Thalidomide: While thalidomide was reported to lead three cases to remission of symptoms, it was discontinued by side effect of polyneuropathy in two of three cases.
PUVA therapy had been reported to ameliorate the symptom of urticaria.
Optimal Therapeutic Approach for this Disease
Figure 2 summarizes the optimal therapeutic approach for Schnitzler’s syndrome (Figure 2).
Symptoms such as urticaria, periodic fever, bone pain and arthralgia in Schnitzler’s syndrome might not affect one’s life prognosis, but quality of life. From this point of view, therapeutic intervention providing symptomatic relief should be considered. However, as mentioned above, a long-term follow-up to evaluate the signs of lymphproliferative disorders should be the overriding concern for Schnitzler’s syndrome. Laboratory tests for IgM, soluble IL-2 receptor, leukocytosis, and beta2 microglobulin and imaging tests are useful as screening tests for lymphoma.
Unusual Clinical Scenarios to Consider in Patient Management
If the patients with chronic urticaria are resistant to common therapy, Schnitzler’s syndrome should be considered in the differential diagnosis.
What is the Evidence?
de Konig, HD, Bodar, EJ, van der Meer, JW, Simon, A. “Schnitzler's Syndrome Study Group. Schnitzler's syndrome: beyond the case reports: review and follow-up of 94 patients with an emphasis on prognosis and treatment”. Semin Arthritis Rheum. vol. 37. 2007. pp. 137-48. (This review spells out the factors influencing prognosis, and yields useful information to all clinicians.)
Lipskar, D, Veran, Y, Gruenberger, F, Cribier, B, Heid, E, Grosshans, E. “The Schnitzler's syndrome. Four new cases and review of the litterature”. Medicine (Baltimore). vol. 80. 2001. pp. 37-44. (This review highlights the important topics for management of Schnitzler's syndrome, along with case reports and diagnostic criteria.)
Murota, H, Shoda, Y, Ishibashi, T, Sugahara, H, Matsumura, I, Katayama, I. “Improvement of recurrent urticaria in a patients with Schnitzler's syndrome associated with B-cell lymphoma with combination rituximab and radiotherapy”. J Am Acad Dermatol. vol. 61. 2009. pp. 1070-5. (This literature provides concrete coping strategies for Schnitzler's syndrome complicated with lymphoproliferative diseases.)
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- Are You Confident of the Diagnosis?
- Who is at Risk for Developing this Disease?
- What is the Cause of the Disease?
- Systemic Implications and Complications
- Treatment Options
- Optimal Therapeutic Approach for this Disease
- Patient Management
- Unusual Clinical Scenarios to Consider in Patient Management
- What is the Evidence?