Schnitzler Syndrome

Schnitzler syndrome is a very rare autoinflammatory disease that seems to arise from an IgM monoclonal gammopathy [1] [2] [3] [4]. The pathogenesis still remains incompletely understood, but the clinical presentation has been well-documented in the literature. The cardinal feature of patients suffering from Schnitzler syndrome is a chronic urticarial rash [1] [2] [3]. Urticaria is the presenting manifestation in many individuals and appears years before other notable symptoms and signs of Schnitzler syndrome [3] [4] [5] [6]:

• Fever - A chronic course of fever that possesses an intermittent pattern is seen in 75% of patients [1] [3] [6] [7]. Fever often accompanies the onset of urticaria, while some cases have been described in whom the rash appeared after fever [1] [2].
• Pain - Myalgia, arthralgia, and bone pain are frequent manifestations seen in this syndrome, together with fatigue [1] [3] [4].
• Peripheral neuropathy - From 7%-56% of individuals suffer from peripheral neuropathy according to different studies [1] [3].
• Night sweats, weight loss, hepatomegaly, and splenomegaly are less commonly encountered [1] [2] [7].

Lymphadenopathy is also an important sign, being present in more than 40% of cases [1]. The clinical course of Schnitzler syndrome is often described as several-years long before the diagnosis is made [1] [6]. It is important to mention that similarly to other monoclonal gammopathies, a significant risk exists toward the development of a lymphoproliferative disorder, such as IgM myeloma or marginal B-cell lymphoma [1] [6].

A high index of suspicion is necessary in order to make the diagnosis of Schnitzler syndrome [1]. A thorough history should be obtained first, during which the onset of symptoms (particularly the rash and relapses of fever), their progression, as well as severity must be covered. The physical examination can only confirm the nonspecific findings, which is why laboratory studies are the crucial step in the workup. A complete blood count (CBC) will show anemia and leukocytosis with neutrophilia in a significant number of patients, whereas basic inflammatory parameters will reveal elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) [1] [4]. The detection of an IgM kappa chain raises solid evidence toward Schnitzler syndrome (the presence of IgG is also reported but in very few patients), although their levels may be paradoxically low at the time of diagnosis [1] [2] [4] [6]. Skin biopsy and subsequent histopathological examination is an equally important diagnostic tool, showing a neutrophilic infiltrate in a significant portion of tested patients [7]. Bone marrow biopsy could be recommended in some cases.

1. Jain T, Offord CP, Kyle RA, Dingli D. Schnitzler syndrome: an under-diagnosed clinical entity. Haematologica. 2013;98(10):1581-1585.
2. De Koning HD. Schnitzler’s syndrome: lessons from 281 cases. Clin Transl Allergy. 2014;4:41.
3. Lipsker D. The Schnitzler syndrome. Orphanet J Rare Dis. 2010;5:38.
4. Simon A, Asli B, Braun-Falco M, et al. Schnitzler's syndrome: diagnosis, treatment, and follow-up. Allergy. 2013;68(5):562-568.
5. Gouveia AI, Micaelo M, Pierdomenico F, Freitas JP. Schnitzler Syndrome: A Dramatic Response to Anakinra. Dermatol Ther (Heidelb). 2016;6(2):299-302.
6. Kurian A, Lee JK, Vadas P. Schnitzler syndrome with cold-induced urticaria. J Dermatol Case Rep. 2010;4(4):50-53.
7. 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(6):1289-1295.