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.

Differential Diagnoses

Simon A, Asli B, Braun-Falco M et al. Schnitzler's Syndrome: diagnosis, treatment and followup. Allergy. 2018. 68(5):562 - 8. [QxMD MEDLINE Link]. [Full Text].
Claves F, Siest R, Lefebvre C, Valmary-Degano S, Carras S. Dramatic efficacy of Ibrutinib in a Schnitzler syndrome case with indolent lymphoma. J Clin Immunol. Aug 2021. 41(6):1380-1383. [QxMD MEDLINE Link]. [Full Text].
Eiling E, Moller M, Kreiselmaier I, Brasch J, Schwarz T. Schnitzler syndrome: treatment failure to rituximab but response to anakinra. J Am Acad Dermatol. 2007 Aug. 57(2):361-4. [QxMD MEDLINE Link].
Krause, K, Tsianakas A, Wagner, N, et al. Effectiveness of canakinumab treatment in Schnitzler's syndrome: a multi-center randomized placebo controlled study. Pediatric Rheumatology. 2015. 13 (supplement 1):066.
Schnitzler L, Schubert B, Boasson M. Urticaire chronique, lons osseuses, macroglobuline IgM: maladie de Waldenstrom. Bull Soc Franc Derm Syph. 1974. 81:363.
Lipsker D, Veran Y, Grunenberger F, Cribier B, Heid E, Grosshans E. The Schnitzler Syndrome> Four new cases and a review of the literature. Medicine. Jan 2001. 80(1):37 - 44. [QxMD MEDLINE Link].
Migliorini P, Italiani P, Pratesi F, Puxeddu I, Boraschi D. Cytokines and soluble receptors of the interleukin-1 family in Schnitzler syndrome. Scand J Rheumatol. 2019 Jan. 22:1-4. [QxMD MEDLINE Link].
Bonnekoh H, Scheffel J, Wu J, Hoffmann S, Maurer M, Krause K. Skin and Systemic Inflammation in Schnitzler's Syndrome Are Associated With Neutrophil Extracellular Trap Formation. Front. Immunol. March 2019. 10:54. [QxMD MEDLINE Link]. [Full Text].
Morita A, Sakakibara S, Yokota M, Tsuji T. A case of urticarial vasculitis associated with macroglobulinemia (Schnitzler's syndrome). J Dermatol. 1995 Jan. 22(1):32-5. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. 1991 Aug. 88(2):244-56. [QxMD MEDLINE Link].
A Sediva, H Hansikova, J Sladkova, M Rodinova, Z Hajkova, J Zeman, et al. PW03-008 – Mitochondrial disturbances in Schnitzler syndrome. Pediatr Rheumatol Online J. 2013. 11(Suppl 1):A234. [QxMD MEDLINE Link].
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. 2007 Dec. 37(3):137-48. [QxMD MEDLINE Link].
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.
Bashi M, Bettendorf B, Hariman R. A rare but fascinating disorder: case collection of patients with Schnitzler syndrome. Case Rep Rheumatol. Mar 8. 2018:7041576. [QxMD MEDLINE Link]. [Full Text].
Basile C, Rossi L, Casucci F, Teutonico A, Libutti P, Lisi P, et al. Kidney involvement in the Schnitzler syndrome, a rare disease. Clin Kidney J. 2017 Dec. 10(6):723-727. [QxMD MEDLINE Link].
Simon A, Asli B, Braun-Falco M, De Koning H, Fermand JP, Grattan C, et al. Schnitzler's syndrome: diagnosis, treatment, and follow-up. Allergy. 2013. 68 (5):562-8. [QxMD MEDLINE Link].
Simon A, van der Meer JWM, Drenth JPH. Familial auto-inflammatory syndromes. Harris ED, Budd RC, Firestein GS. Kelley's textbook of Rheumatology. 7th. Philadelphia: Saunders; 2004. Chapter 112 pp1773-88.
Akimoto R, Yoshida M, Matsuda R, Miyasaka K, Itoh M. Schnitzler's syndrome with IgG kappa gammopathy. J Dermatol. 2002 Nov. 29(11):735-8. [QxMD MEDLINE Link].
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. 2006 Apr. 65(4):542-4. [QxMD MEDLINE Link].
Mamadgi J, Babar L, Bhagavatula R et al. Schnitzler's syndrome: A diagnostic consideration in evaluating the constellation of monoclonal gammopathy and chronic urticaria. J Hematol. June 2021. 10(3):143-146. [QxMD MEDLINE Link]. [Full Text].
Niederhauser BD, Dingli D, Kyle RA, Ringler MD. Imaging findings in 22 cases of Schnitzler syndrome: characteristic para-articular osteosclerosis, and the "hot knees" sign differential diagnosis. Skeletal Radiol. 2014 Jul. 43 (7):905-15. [QxMD MEDLINE Link].
Néel A, Henry B, Barbarot S, Masseau A, Hamidou M, et al. Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler's syndrome: a French multicenter study. Autoimmun Rev. 2014 Oct. 13 (10):1035-41. [QxMD MEDLINE Link].
Jani P, Vissing MB, Ahmed S, Sluzevich JC, Aulakh S, Alegria V, et al. Ibrutinib for the Management of Schnitzler Syndrome: A Novel Therapy for a Rare Condition. J Oncol Pract. 2018 Jun. 14(6):387-388. [QxMD MEDLINE Link].
Krause K, Weller K, Stefaniak R, Wittkowski H, Altrichter S, Siebenhaar F, et al. Efficacy and safety of the interleukin-1 antagonist rilonacept in Schnitzler syndrome: an open-label study. Allergy. 2012 May 15. [QxMD MEDLINE Link].
de Koning HD, Schalkwijk J, van der Ven-Jongekrijg J, Stoffels M, van der Meer JW, Simon A. Sustained efficacy of the monoclonal anti-interleukin-1 beta antibody canakinumab in a 9-month trial in Schnitzler's syndrome. Ann Rheum Dis. 2013 Oct. 72 (10):1634-8. [QxMD MEDLINE Link].
Worm M, Kolde G. Schnitzler's syndrome: successful treatment of two patients using thalidomide. Br J Dermatol. 2003 Mar. 148(3):601-2. [QxMD MEDLINE Link].
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.
Vandenhende MA, Bentaberry F, Morlat P, Bonnet F. Anakinra: An effective treatment in the Schnitzler syndrome. Joint Bone Spine. 2011 Dec. 78(6):636-7. [QxMD MEDLINE Link].
Pathak S, Rowczenio DM, Owen RG et al. Exploratory study of MDY88 L265P, rare NLRP3 variant, and clinical hematopoesis prevalence in patients with Schnitzler syndrome. Arthritis Rheumatol. 2019. 71(12):2121-5. [Full Text].

Media Gallery

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

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Author

Jami L Miller, MD Associate Professor, Department of Dermatology, Vanderbilt University Medical School; Vice Chair for Education, Director of Phototherapy Unit, Medical Director of Dermatology Clinic at 100 Oaks, Vanderbilt University Medical Center

Jami L Miller, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

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, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Joel G DeKoven, MD, MHSc, FRCPC Associate Professor, Division of Dermatology, Department of Medicine, University of Toronto Faculty of Medicine, Sunnybrook Health Sciences Centre and St Michael's Hospital, Canada

Joel G DeKoven, MD, MHSc, FRCPC is a member of the following medical societies: American Academy of Dermatology, American Contact Dermatitis Society, Canadian Dermatology Association, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

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, Canadian Medical Protective Association

Disclosure: Nothing to disclose.

Brian J Thomas, MD Chief Resident, Department of Dermatology, Vanderbilt University School of Medicine

Brian J Thomas, MD is a member of the following medical societies: Alpha Omega Alpha

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

Schnitzler Syndrome Clinical Presentation

History

Physical Examination

Complications

References

Tables

Contributor Information and Disclosures

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