eMedicine Specialties > Dermatology > Allergy & Immunology

Schnitzler Syndrome

Author: Joel G DeKoven, MD, FRCPC, Associate Professor, Division of Dermatology, Department of Medicine, University of Toronto, Sunnybrook Health Sciences Centre and St Michael's Hospital, Canada
Coauthor(s): Kucy Pon, MD, FRCPC, Assistant Professor, Division of Dermatology, Department of Medicine, University of Toronto Faculty of Medicine
Contributor Information and Disclosures

Updated: Jun 30, 2009

Introduction

Background

Schnitzler syndrome (SS), first reported in 1972,1 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/L. Since 1972, approximately 100 cases of Schnitzler syndrome have been reported.2,3

Pathophysiology

The exact pathogenesis of Schnitzler syndrome 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 of Schnitzler syndrome. Another proposed mechanism involves the uncontrolled activation of interleukin 1-alpha (IL-1alpha).

Frequency

United States

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

International

Schnitzler syndrome is rare, with approximately 100 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.

Mortality/Morbidity

Most Schnitzler syndrome patients have a chronic benign course. Spontaneous remissions have not been reported. 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.

Race

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

Sex

Males have a slight predominance.

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,2,3 although the average delay to diagnosis is more than 5 years.

Clinical

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

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.

A set of diagnostic criteria have been proposed.4 This defines Schnitzler syndrome as a combination of chronic urticaria and IgM gammopathy and at least 2 of the following criteria:

  • Recurrent fever
  • Arthralgia or arthritis
  • Bone pain
  • Lymphadenopathy
  • Hepatomegaly or splenomegaly
  • Leukocytosis
  • Elevated erythrocyte sedimentation rate (ESR)
  • Bone abnormalities (upon radiologic or histopathologic investigations)

The diagnosis would apply after exclusion of other causes.

Causes

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.5 In one case, monoclonal IgM was found to target 50-, 31-, and 17-kd proteins within epidermal extracts.6 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.6 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.7 What role these cytokines play in the pathogenesis of Schnitzler syndrome is not clear.

More on Schnitzler Syndrome

Overview: Schnitzler Syndrome
Differential Diagnoses & Workup: Schnitzler Syndrome
Treatment & Medication: Schnitzler Syndrome
Follow-up: Schnitzler Syndrome
References
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References

  1. Schnitzler L, Schubert B, Boasson M. Urticaire chronique, lons osseuses, macroglobuline IgM: maladie de Waldenstrom. Bull Soc Franc Derm Syph. 1974;81:363.

  2. de Koning HD, Bodar EJ, van der Meer JW, Simon A,. Schnitzler syndrome: beyond the case reports: review and follow-up of 94 patients with an emphasis on prognosis and treatment. Semin Arthritis Rheum. Dec 2007;37(3):137-48. [Medline].

  3. Asli B, Bievenu B, Cardoliani F, et al. Chronic Urticaria and Monoclonal IgM gammopathy (Schnitzler Syndrome). Report of 11 cases treated with Pefloxacin. Arch Dermatol. 2007;143:1046-1050.

  4. Lipsker D, Veran Y, Grunenberger F, Cribier B, Heid E, Grosshans E. The Schnitzler syndrome. Four new cases and review of the literature. Medicine (Baltimore). Jan 2001;80(1):37-44. [Medline].

  5. Olsen E, Forre O, Lea T, Langeland T. Unique antigenic determinants (idiotypes) used as markers in a patient with macroglobulinemia and urticaria. Similar idiotypes demonstrated in the skin and on peripheral blood lymphocytes. Acta Med Scand. 1980;207(5):379-84. [Medline].

  6. Saurat JH, Schifferli J, Steiger G, Dayer JM, Didierjean L. Anti-interleukin-1 alpha autoantibodies in humans: characterization, isotype distribution, and receptor-binding inhibition--higher frequency in Schnitzler's syndrome (urticaria and macroglobulinemia). J Allergy Clin Immunol. Aug 1991;88(2):244-56. [Medline].

  7. Morita A, Sakakibara S, Yokota M, Tsuji T. A case of urticarial vasculitis associated with macroglobulinemia (Schnitzler's syndrome). J Dermatol. Jan 1995;22(1):32-5. [Medline].

  8. Simon A, van der Meer JWM, Drenth JPH. Familial auto-inflammatory syndromes. In: Harris ED, Budd RC, Firestein GS. Kelley's textbook of Rheumatology. 7th. Philadelphia: Saunders; 2004:Chapter 112 pp1773-88.

  9. Akimoto R, Yoshida M, Matsuda R, Miyasaka K, Itoh M. Schnitzler's syndrome with IgG kappa gammopathy. J Dermatol. Nov 2002;29(11):735-8. [Medline].

  10. de Koning HD, Bodar EJ, Simon A, van der Hilst JC, Netea MG, van der Meer JW. Beneficial response to anakinra and thalidomide in Schnitzler's syndrome. Ann Rheum Dis. Apr 2006;65(4):542-4. [Medline].

  11. Worm M, Kolde G. Schnitzler's syndrome: successful treatment of two patients using thalidomide. Br J Dermatol. Mar 2003;148(3):601-2. [Medline].

  12. Ramadan KM, Eswedi HA, El-Agnaf MR. Schnitzler syndrome: A case report of successful treatment using the anti-CD20 momoclonal antibody rituximab. Br J Dermatol. 2007;156:1072-74.

  13. Eiling E, Moller M, Kreiselmaier I, Brasch J, Schwarz T. Schnitzler syndrome: treatment failure to rituximab but response to anakinra. J Am Acad Dermatol. Aug 2007;57(2):361-4. [Medline].

  14. Martinez-Taboada VM, Fontalba A, Blanco R, Fernandez-Luna JL. Successful treatment of refractory Schnitzler syndrome with anakinra: comment on the article by Hawkins et al. Arthritis Rheum. Jul 2005;52(7):2226-7. [Medline].

  15. Bonnetblanc JM, Drouet M, Laplaud P, Bedane C, Bernard P. Urticaria with macroglobulinaemia. Disease activity associated alterations in immunoglobulins profile and bone marrow hypodiploidy. Dermatologica. 1990;181(1):41-3. [Medline].

  16. Borradori L, Rybojad M, Puissant A, Dallot A, Verola O, Morel P. Urticarial vasculitis associated with a monoclonal IgM gammopathy: Schnitzler's syndrome. Br J Dermatol. Jul 1990;123(1):113-8. [Medline].

  17. Harati A, Brockmeyer NH, Altmeyer P, Kreuter A. Skin disorders in association with monoclonal gammopathies. Eur J Med Res. Mar 29 2005;10(3):93-104. [Medline].

  18. Machet L, Vaillant L, Machet MC, Reisenleiter M, Goupille P, Lorette G. Schnitzler's syndrome (urticaria and macroglobulinemia): evolution to Waldenström's disease is not uncommon. Acta Derm Venereol. Sep 1996;76(5):413. [Medline].

  19. Nashan D, Sunderkotter C, Bonsmann G, Luger T, Goerdt S. Chronic urticaria, arthralgia, raised erythrocyte sedimentation rate and IgG paraproteinaemia: a variant of Schnitzler's syndrome?. Br J Dermatol. Jul 1995;133(1):132-4. [Medline].

  20. Puddu P, Cianchini G, Girardelli CR, Colonna L, Gatti S, de Pita O. Schnitzler's syndrome: report of a new case and a review of the literature. Clin Exp Rheumatol. Jan-Feb 1997;15(1):91-5. [Medline].

  21. Sanmartín O, Febrer I, Botella R, Grau M, de la Cuadra J, Aliaga A. Urticarial lesions and monoclonal IgM gammopathy. Schnitzler's syndrome. Arch Dermatol. Sep 1994;130(9):1195, 1198. [Medline].

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Further Reading

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Keywords

Schnitzler syndrome, Schnitzler's syndrome, chronic urticaria, nonpruritic urticaria, monoclonal immunoglobulin M gammopathy, monoclonal IgM gammopathy

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Contributor Information and Disclosures

Author

Joel G DeKoven, MD, FRCPC, Associate Professor, Division of Dermatology, Department of Medicine, University of Toronto, Sunnybrook Health Sciences Centre and St Michael's Hospital, Canada
Joel G DeKoven, MD, FRCPC is a member of the following medical societies: American Academy of Dermatology, American Contact Dermatitis Society, Canadian Medical Association, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Coauthor(s)

Kucy Pon, MD, FRCPC, Assistant Professor, Division of Dermatology, Department of Medicine, University of Toronto Faculty of Medicine
Kucy Pon, MD, FRCPC is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for Laser Medicine and Surgery, Canadian Medical Association, and Canadian Medical Protective Association
Disclosure: Nothing to disclose.

Medical Editor

Jean-Hilaire Saurat, MD, Chair, Professor, Department of Dermatology, University of Geneva, Switzerland
Jean-Hilaire Saurat, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society
Disclosure: Nothing to disclose.

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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