Schnitzler Syndrome: a Review

  • L. Gusdorf
  • D. LipskerEmail author
Orphan Diseases (B Manger, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Orphan Diseases


Purpose of Review

We focus on recent advances in diagnosis and therapeutic strategies, as well as on pathogenesis of Schnitzler syndrome.

Recent Findings

New diagnostic criteria were established, and their external validity was assessed in a retrospective cohort study. The cytokine interleukin-1 (IL-1) plays a crucial role in the pathogenesis of the Schnitzler syndrome, and this explains the spectacular efficiency of IL-1 blocking therapies.


The Schnitzler syndrome is now considered as a late-onset acquired autoinflammatory syndrome in which the cytokine IL-1 plays a crucial role. IL-1 blocking therapies are efficient on the inflammation-linked symptoms but not on the monoclonal component. Therefore, they probably don’t reduce the risk of the development of lymphoproliferative disorders that remains the main prognostic issue. The link between autoinflammation and the monoclonal component needs to be further elucidated.


Schnitzler syndrome Interleukin-1 Autoinflammation IL-1 blocking therapy Neutrophilic urticarial dermatosis Anakinra 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Recently published papers of particular interest have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Schnitzler L. Lésions urticariennes chroniques permanentes (érythème pétaloïde?). Journées Dermatologiques d’Angers. 1972; Cas Clinique. N°46b.Google Scholar
  2. 2.
    •• Lipsker D. Monoclonal gammopathy of cutaneous significance: review of a relevant concept. J Eur Acad Dermatol Venereol. 2017;31:45–52. This article introduces the concept of monoclonal gammopathy of cutaneous significance and reviews the main entities that fit into it. CrossRefPubMedGoogle Scholar
  3. 3.
    De Koning HD, van Gijn ME, Stoffels M, Jongekrijg J, Zeeuwen PLJM, Elferink MG, et al. Myeloid lineage-restricted somatic mosaicism of NLRP3 mutations in patients with variant Schnitzler syndrome. J Allergy Clin Immunol. 2015;135:561–4.CrossRefPubMedGoogle Scholar
  4. 4.
    Ryan JG, de Koning HD, Beck LA, Booty MG, Kastner DL, Simon A. IL-1 blockade in Schnitzler syndrome: ex vivo findings correlate with clinical remission. J Allergy Clin Immunol. 2008;121:260–2.CrossRefPubMedGoogle Scholar
  5. 5.
    De Koning HD, Schalkwijk J, Stoffels M, Jongekrijg J, Jacobs JFM, Verwiel E, et al. The role of interleukin-1 beta in the pathophysiology of Schnitzler’s syndrome. Arthritis Res Ther. 2015;17:187.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    De Koning HD, van Vlijmen-Willems IMJJ, Rodijk-Olthuis D, van der Meer JWM, Zeeuwen PLJM, Simon A, et al. Mast-cell interleukin-1beta, neutrophil interleukin-17 and epidermal antimicrobial proteins in the neutrophilic urticarial dermatosis in Schnitzler’s syndrome. Br J Dermatol. 2015;173:448–56.CrossRefPubMedGoogle Scholar
  7. 7.
    Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, et al. Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by. Nature. 2012;484:514–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Noster R, de Koning HD, Maier E, Prelog M, Lainka E, Zielinski CE. Dysregulation of proinflammatory versus anti-inflammatory human TH17 cell functionalities in the autoinflammatory Schnitzler syndrome. J Allergy Clin Immunol. 2016;138:1161–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Mulla E, Neame R. Delayed development of the IgM paraprotein in Schnitzler’s syndrome. Scand J Rheumatol. 2015;44:521–2.CrossRefPubMedGoogle Scholar
  10. 10.
    Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med. 2012;367:826–33.CrossRefPubMedGoogle Scholar
  11. 11.
    • De Koning HD. Schnitzler’s syndrome: lessons from 281 cases. Clin Transl Allergy. 2014;4:41. This study summarizes the clinical, biological, histological, and morphological data of all the patients with a Schnitzler syndrome reported to date. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Akimoto R, Yoshida M, Matsuda R, Miyasaka K, Itoh M. Schnitzler’s syndrome with IgG kappa gammopathy. J Dermatol. 2002;29:735–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Welsh B, Tate B. Schnitzler’s syndrome: report of a case with progression to Waldenstrom’s macroglobulinaemia. Australas J Dermatol. 1999;40:201–3.CrossRefPubMedGoogle Scholar
  14. 14.
    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). 2001;80:37–44.CrossRefGoogle Scholar
  15. 15.
    Simon A, Asli B, Braun-Falco M, De Koning H, Fermand J-P, Grattan C, et al. Schnitzler’s syndrome: diagnosis, treatment, and follow-up. Allergy. 2013;68:562–8.CrossRefPubMedGoogle Scholar
  16. 16.
    •• Gusdorf L, Asli B, Barbarot S, Neel A, Masseau A, Puechal X, et al. Schnitzler syndrome: validation and applicability of diagnostic criteria in real-life patients. Allergy. 2017;72:177–82. This study confirms the applicability and the validity of the existing diagnostic criteria in real-life patients. CrossRefPubMedGoogle Scholar
  17. 17.
    Kieffer C, Cribier B, Lipsker D. Neutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature. Medicine (Baltimore). 2009;88:23–31.CrossRefGoogle Scholar
  18. 18.
    Broekaert SMC, Boer-Auer A, Kerl K, Herrgott I, Schulz X, Bonsmann G, et al. Neutrophilic epitheliotropism is a histopathological clue to neutrophilic urticarial dermatosis. Am J Dermatopathol. 2016;38:39–49.CrossRefPubMedGoogle Scholar
  19. 19.
    Gusdorf L, Bessis D, Lipsker D. Lupus erythematosus and neutrophilic urticarial dermatosis: a retrospective study of 7 patients. Medicine (Baltimore). 2014;93:e351.CrossRefGoogle Scholar
  20. 20.
    Lipsker D. The Schnitzler syndrome. Orphanet J Rare Dis. 2010;5:38.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Sokumbi O, Drage LA, Peters MS. Clinical and histopathologic review of Schnitzler syndrome: the Mayo Clinic experience (1972-2011). J Am Acad Dermatol. 2012;67:1289–95.CrossRefPubMedGoogle Scholar
  22. 22.
    Carlesimo M, Abruzzese C, Narcisi A, La Verde G, De Marco G, Verga E, et al. Chronic vasculitis urticaria associated to a monoclonal gammopathy of IgM and IgA type, a Schnitzler syndrome? Eur J Dermatol. 2010;20:838–9.PubMedGoogle Scholar
  23. 23.
    Ricci M, Bettazzi LG, Varenna M, Marchesoni A. Atypical bone sclerosis. Arthritis Rheumatol Hoboken NJ. 2016;68:816.CrossRefGoogle Scholar
  24. 24.
    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. Skelet Radiol. 2014;43:905–15.CrossRefGoogle Scholar
  25. 25.
    Willekens I, Walgraeve N, Goethals L, De Geeter F. Correlative bone imaging in a case of Schnitzler’s syndrome and brief review of the literature. Hell J Nucl Med. 2015;18:71–3.PubMedGoogle Scholar
  26. 26.
    Ferrando FJ, Pujol J, Hortells JL, Navarro M, Pinol J, Carapeto FJ. Schnitzler’s syndrome: report of a case with bone osteolysis. J Investig Allergol Clin Immunol. 1994;4:203–5.PubMedGoogle Scholar
  27. 27.
    Terpos E, Asli B, Christoulas D, Brouet J-C, Kastritis E, Rybojad M, et al. Increased angiogenesis and enhanced bone formation in patients with IgM monoclonal gammopathy and urticarial skin rash: new insight into the biology of Schnitzler syndrome. Haematologica. 2012;97:1699–703.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    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. 2005;52:2226–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Lipsker D, Lenormand C. Management of Schnitzler’s syndrome. Expert Opin Orphan Drugs. 2014;2:947–55.CrossRefGoogle Scholar
  30. 30.
    Neel A, Henry B, Barbarot S, Masseau A, Perrin F, Bernier C, et al. Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler’s syndrome: a French multicenter study. Autoimmun Rev. 2014;13:1035–41.CrossRefPubMedGoogle Scholar
  31. 31.
    Perrin F, Neel A, Graveleau J, Ruellan A-L, Masseau A, Hamidou M. Two cases of anakinra-induced neutropenia during auto-inflammatory diseases: drug reintroduction can be successful. Presse Med. 2014;43:319–21.CrossRefPubMedGoogle Scholar
  32. 32.
    De Koning HD, Schalkwijk J, van der Ven-Jongekrijg J, Stoffels M, van der Meer JWM, 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;72:1634–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Vanderschueren S, Knockaert D. Canakinumab in Schnitzler syndrome. Semin Arthritis Rheum. 2013;42:413–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Pesek R, Fox R. Successful treatment of Schnitzler syndrome with canakinumab. Cutis. 2014;94:E11–2.PubMedGoogle Scholar
  35. 35.
    Krause K, Tsianakas A, Wagner N, Fischer J, Weller K, Metz M, et al. Efficacy and safety of canakinumab in Schnitzler syndrome: a multicenter randomized placebo-controlled study. J Allergy Clin Immunol. 2017;139:1311–20.CrossRefPubMedGoogle Scholar
  36. 36.
    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;67:943–50.CrossRefPubMedGoogle Scholar
  37. 37.
    Krause K, Feist E, Fiene M, Kallinich T, Maurer M. Complete remission in 3 of 3 anti-IL-6-treated patients with Schnitzler syndrome. J Allergy Clin Immunol. 2012;129:848–50.CrossRefPubMedGoogle Scholar
  38. 38.
    Asli B, Brouet JC, Fermand JP. Spontaneous remission of Schnitzler syndrome. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 2011;107:87–8.CrossRefGoogle Scholar
  39. 39.
    Conlon NP, Hayden P, Barnes L, Doran M, O’Shea F, Feighery C. Schnitzler’s syndrome: a case highlighting the complications of long-standing acquired autoinflammation. Eur J Dermatol. 2014;24:405–6.PubMedGoogle Scholar
  40. 40.
    Gameiro A, Gouveia M, Pereira M, Tellechea O, Goncalo M. Clinical characterization and long-term follow-up of Schnitzler syndrome. Clin Exp Dermatol. 2016;41:461–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Margerin F, Gottenberg JE, Lipsker D. Occurrence of rheumatoid arthritis in a patient treated with anakinra for Schnitzler syndrome: a case report. J Rheumatol. 2016;43:1447.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Faculté de Médecine, Université de Strasbourg et Clinique DermatologiqueHôpitaux Universitaires de StrasbourgStrasbourgFrance

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