Schnitzler syndrome

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Schnitzler syndrome
Classification and external resources
ICD-9-CM 273.1
DiseasesDB 31345
eMedicine derm/489
MeSH D019873
Orphanet 37748

Schnitzler syndrome is a rare disease characterised by chronic hives (urticaria) and periodic fever, bone pain and joint pain (sometimes with joint inflammation), weight loss, malaise, fatigue, swollen lymph glands and enlarged spleen and liver.[1]

The urticarial rash is non-itching in more than half of cases, which is unusual for hives. It is most prominent on the trunk, arms and legs, sparing the palms, soles, head and neck. Associated angioedema has been reported in a few patients. A review of 94 cases found a mean age at onset of 51 years, and only four patients developed symptoms before the age of 35.[1] The cause and disease mechanism of Schnitzler syndrome remain largely unknown.[1]

Schnitzler syndrome is considered an autoinflammatory and autoimmune disorder.[2] Chronic hives and a monoclonal gammopathy have been proposed as the major criteria, while the others represent minor criteria.[3]



Blood tests show a high concentration of specific gamma-globulins (monoclonal gammopathy) of the IgM type. It almost always has light chains of the κ-type. A variant in which IgG is raised has been described, which appears to be ten times as rare. The immunoglobulins may show up in the urine as Bence Jones proteins. Signs of inflammation are often present: these include an increased white blood cell count (leukocytosis) and a raised erythrocyte sedimentation rate and C-reactive protein. There can be anemia of chronic disease.[3] Bone abnormalities can be seen on radiological imaging (often increased density or osteosclerosis) or biopsy.

Because it is such a rare condition (as of September 2014, only 281 cases have been reported[4]), it is important to rule out other conditions which can cause periodic fevers, paraproteins or chronic hives. These include (and are not limited to) autoimmune or autoinflammatory disorders such as adult-onset Still's disease, angioedema, hematological disorders such as lymphoma or monoclonal gammopathy of undetermined significance, other causes of hives, cryoglobulinemia, mastocytosis, chronic neonatal onset multisystem inflammatory disease or Muckle–Wells syndrome. It is however possible to have more than one rare condition as seen by a patient with Schnitzler's syndrome and cold induced urticaria.[5]

A meeting of experts, including Dr Liliane Schnitzler (then retired) took place in Strasbourg in May 2012 and drew up diagnostic criteria known as the "Strasbourg Criteria". These included two obligate criteria (chronic urticarial rash and monoclonal IgM or IgG) and several minor criteria; a definite diagnosis requires the two obligate criteria and two minor criteria if IgM, three if IgG; a probable diagnosis requires the two obligate criteria and one (IgM) or two (IgG) minor criteria.[6]


Antihistamines are not effective in treating the hives in this condition. It may respond to immunosuppressant drugs such as corticosteroids, cyclooxygenase inhibitors, interferon alpha, interleukin 1 receptor antagonists (Anakinra),[7] perfloxacin, colchicine, cyclosporine or thalidomide. The hives may respond to treatment with PUVA, and the bone pain may respond to bisphosphonates.

Because Schnitzler's syndrome is so rare, the efficacy of different treatments cannot be compared using statistics. Nevertheless, case studies provide evidence that anakinra (otherwise known as kineret) is much more effective for Schnitzler's syndrome than any other drug, and that the improvement in symptoms associated with this treatment is dramatic. For example, Beseda and Nossent (2010)[8] reviewed the literature concerning IL1-RA treatment (i.e. anakinra) for Schnitzler's syndrome. They concluded that, “Twenty-four patients with Schnitzler's syndrome... have been successfully treated with anakinra.” They add that “seven out of seven patients [with Schnitzler’s syndrome], that either interrupted or used anakinra every other day, had relapse of their symptoms within 24-48 h; anakinra was restarted in all patients with the same clinical efficiency.” Kluger et al. (2008) investigated the effectiveness of anakinra for a range of conditions. They searched MEDLINE for English-language trials of anakinra and abstracts from rheumatologial scientific meetings. They conclude that, “Over the last few years it has become increasingly evident that anakinra is highly effective and safe in patients with ... Schnitzler’s syndrome”. The year before, De Koning et al. (2007)[1] reviewed the disease characteristics of Schnitzler syndrome and collected follow-up information to gain insight into long-term prognosis and treatment efficacy. They used data from 94 patients, and their conclusions about treatment for the condition are that, “There have been promising developments in therapeutic options, especially antiinterleukin-1 treatment, which induced complete remission in all 8 patients treated so far.”

Reports of individual patients treated with anakinra illustrate its effectiveness. Beseda and Nossent (ibid.) report treating a longstanding multidrug resistant Schnitzler’s syndrome patient with anakinra: “Within 24 h after the first injection, both the urticaria and the fever disappeared and have not recurred. For the past 6 months, the patient has been in clinical and biochemical remission.” Other authors report “a complete resolution of symptoms” (Dybowski et al., 2008).[9] Crouch et al. (2007)[10] report the effective treatment of a 52-year-old man who had been diagnosed with Schnitzler’s syndrome 8 years earlier: “On review, one week later, the patient’s systemic symptoms had resolved, and his previously elevated white cell count and inflammatory markers had normalised. The use of anakinra in our patient resulted in resolution of symptoms and has enabled cessation of oral prednisolone. Our patient remains symptom free on anakinra after 14 months of follow-up”. Similar stories are reported by Frischmeyer-Guerrerio et al. (2008),[11] Wastiaux et al. (2007),[12] and Eiling et al. (2007),[13] Schneider et al. (2007).[14] De Koning et al. (2006)[7] treated three patients with Schnitzler’s syndrome with thalidomide and anakinra. Thalidomide was only effective for one of the three patients and was discontinued because of polyneuropathy. In contrast, for all three patients, anakinra “led to disappearance of fever and skin lesions within 24 hours. After a follow-up of 16-18 months, all patients are free of symptoms”. The authors concluded that anakinra as a treatment for Schnitzler’s syndrome “is preferable to thalidomide... as it has fewer side effects”.

As well as being more effective, anakinra is safer than the other treatments available for Schnitzler's syndrome. The Cochrane review entitled, ‘Anakinra for rheumatoid arthritis’ (Mertens and Singh, 2009[15] ) evaluates the (clinical effectiveness and) safety of anakinra in adult patients with rheumatoid arthritis, using data from 2876 patients, from five trials which constituted 781 randomized to placebo and 2065 to anakinra. The authors conclude, “There were no statistically significant differences noted in most safety outcomes with treatment with anakinra versus placebo - including number of withdrawals, deaths, adverse events (total and serious), and infections (total and serious). Injection site reactions were significantly increased, occurring in 1235/1729 (71%) versus 204/729 (28%) of patients treated with anakinra versus placebo, respectively”. These injection site reactions last for no more than four months, and are trivial compared to the very debilitating symptoms of Schnitzler's syndrome.


The life span in patients with Schnitzler syndrome has not been shown to differ much from the general population.[1] Careful follow-up is advised, however. A significant proportion of patients develops a lymphoproliferative disorder as a complication, most commonly Waldenström's macroglobulinemia. This may lead to symptoms of hyperviscosity syndrome. AA amyloidosis has also been reported in people with Schnitzler syndrome.


The disease is named after the French dermatologist Liliane Schnitzler who first described this syndrome in 1972.[16][4]

See also[edit]


  1. ^ a b c d e de Koning HD, Bodar EJ, van der Meer JW, Simon A (December 2007). "Schnitzler syndrome: beyond the case reports: review and follow-up of 94 patients with an emphasis on prognosis and treatment". Seminars in arthritis and rheumatism. 37 (3): 137–48. doi:10.1016/j.semarthrit.2007.04.001. PMID 17586002. 
  2. ^ Tinazzi, Elisa; Puccetti, Antonio; Patuzzo, Giuseppe; Sorleto, Michele; Barbieri, Alessandro; Lunardi, Claudio (May 2011). "Schnitzler syndrome, an autoimmune–autoinflammatory syndrome: Report of two new cases and review of the literature". Autoimmunity Reviews. 10 (7): 404–409. doi:10.1016/j.autrev.2011.01.003. 
  3. ^ a b Lipsker D, Veran Y, Grunenberger F, Cribier B, Heid E, Grosshans E (January 2001). "The Schnitzler syndrome. Four new cases and review of the literature". Medicine. 80 (1): 37–44. doi:10.1097/00005792-200101000-00004. PMID 11204501. 
  4. ^ a b de Koning, Heleen D (2014). "Schnitzler's syndrome: lessons from 281 cases". Clinical and Translational Allergy. 4 (1): 41. doi:10.1186/2045-7022-4-41. 
  5. ^ Kurian A, Lee JK, Vadas P (2010). "Schnitzler syndrome with cold-induced urticaria". J Dermatol Case Rep. 4: 50–3. doi:10.3315/jdcr.2010.1060. PMC 3157821Freely accessible. PMID 21886751. 
  6. ^ Simon, A.; Asli, B.; Braun-Falco, M.; De Koning, H.; Fermand, J-P.; Grattan, C.; Krause, K.; Lachmann, H.; Lenormand, C.; Martinez-Taboada, V.; Maurer, M.; Peters, M.; Rizzi, R.; Rongioletti, F.; Ruzicka, T.; Schnitzler, L.; Schubert, B.; Sibilia, J; Lipsker, D. (2013). "Schnitzler's syndrome: diagnosis, treatment, and follow-up". Allergy. 68: 562−568. doi:10.1111/all.12129. Retrieved 27 October 2017. 
  7. ^ a b de Koning HD, Bodar EJ, Simon A, van der Hilst JC, Netea MG, van der Meer JW (April 2006). "Beneficial response to anakinra and thalidomide in Schnitzler's syndrome". Annals of the rheumatic diseases. 65 (4): 542–4. doi:10.1136/ard.2005.045245. PMC 1798111Freely accessible. PMID 16096327. 
  8. ^ Beseda E; Nossent H (May 2010). "Dramatic response to IL1_RA treatment in longstanding multidrug resistant Schnitzler's syndrome: a case report and literature review". Clinical Rheumatology. 29 (5): 567–71. doi:10.1007/s10067-010-1375-9. 
  9. ^ Dybowski F; Sepp N; Bergerhausen HJ; Braun J (Mar–Apr 2008). "Successful use of anakinra to treat refractory Schnitzler's syndrome". Clinical and Experimental Rheumatology. 26 (2): 354–7. 
  10. ^ Crouch R; Akhras V; Sarkany R (Aug 2007). "Schnitzler's syndrome: successful treatment with anakinra". Australasian Journal of Dermatology. 48 (3): 178–81. doi:10.1111/j.1440-0960.2007.00375.x. 
  11. ^ Frischmeyer-Guerrerio PA; Rachamalla R; Saini SS (June 2008). "Remission of Schnitzler's syndrome after treatment with anakinra". Annals of Allergy, Asthma & Immunology. 100: 617–9. doi:10.1016/s1081-1206(10)60064-6. 
  12. ^ Wastiaux H; Barbarot S; Gagey-Caron V; Berthelot JM; Hamidou M; Stalder JF (Jan 2009). "Schnitzler syndrome: a dramatic improvement with anakinra". Journal of the European Academy of Dermatology and Venereology. 23 (1): 85–7. doi:10.1111/j.1468-3083.2008.02708.x. 
  13. ^ Eiling E; Moller M; Kreiselmaier I; Brasch J; Schwarz T (May 2007). "Schnitzler syndrome: Treatment failure to rituximab but response to anakinra". Journal of the American Academy of Dermatology. 57 (2): 361–4. doi:10.1016/j.jaad.2007.03.036. 
  14. ^ Schneider SW; Gaubitz M; Luger TA; Bonsmann G (May 2007). "Prompt response of refractory Schnitzler syndrome to treatment with anakinra". Journal of the American Academy of Dermatology. 56 (5 Supplement): 120–22. doi:10.1016/j.jaad.2006.05.057. PMID 17434038. 
  15. ^ Mertens M; Singh JA (2009). "Anakinra for rheumatoid arthritis". Cochrane Database of Systematic Reviews (1): CD005121. doi:10.1002/14651858.CD005121.pub3. PMID 19160248. 
  16. ^ L. Schnitzler, Lésions urticariennes chroniques permanentes (érythème pétaloïde?) Cas cliniques No 46 B, J Dermatol Angers (1972) Abstract 46.

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