Snitching on Schnitzler syndrome: The continuing search for an optimal biomarker

By Warren R. Heymann, MD
August 7, 2019
Vol. 1, No. 22

Urticarial dermatoses confound our even our most sagacious dermatologists. It is no surprise that patients with systemic autoinflammatory diseases such as Schnitzler syndrome (SS) go undiagnosed for years after failed trials of antihistamines, steroids, and other immunosuppressive therapies. In a recent survey of 134 academic German-speaking departments (dermatology, rheumatology, and pediatrics), the median delay in diagnosing SS was up to 6 years. (1)

SS is a rare, acquired autoinflammatory, neutrophilic disorder with fewer than 300 reported cases. (I suspect that SS is not that rare — while researching this commentary, I can think of several patients when I should have considered the diagnosis — I surmise that SS is underreported.) According to Bashir et al: “Initially described in 1972 by the French dermatologist Liliane Schnitzler, the disorder is diagnosed when patients meet the Strasbourg criteria. This includes two obligate criteria: recurrent, nonpruritic urticaria and monoclonal gammopathy (IgM kappa light chain in >90%). At least two of the following minor criteria are also required: recurrent fever, objective findings of abnormal bone remodeling with or without bone pain (assessed by bone scintigraphy, MRI, or elevation of bone alkaline phosphatase), neutrophilic dermal infiltrate on skin biopsy, and elevated CRP and/or leukocytosis (CRP > 30 mg/L and/or neutrophils > 10,000/mm3). The diagnosis is considered definite if the two obligate criteria and at least two minor criteria are met if the patient has IgM monoclonal gammopathy. The two obligate criteria and three minor criteria are required if there is IgG monoclonal gammopathy.” Long-term follow-up of SS patients is essential because approximately 20% will develop either Waldenstrom macroglobulinemia or another lymphoproliferative disorder. Other associations include AA amyloidosis in untreated patients, sensorimotor neuropathy, anemia, and hearing loss. (2)

Although the precise etiology of SS is an enigma, activation of the inflammasome, leading to the production proinflammatory cytokines, particularly interleukin-1β (IL-1β), plays a key role in the pathogenesis of the disorder. Perturbations in signaling by the transcription nuclear factor κB, ubiquitination, cytokine signaling, and protein folding are also involved. (3) Additionally, IL-18 and free IL-18 are increased in SS patients compared to controls. Inflammasome dysregulation leading to activation of caspase-I is responsible for excessive IL-18 production. (4)

Neutrophil extracellular traps (NETs) are web-like structures of decondensed chromatin, histones, and antimicrobial peptides released by neutrophils. NETs were initially described in the context of pathogen defense but are also involved in autoimmune-mediated skin diseases. Bonnekoh et al performed immunofluorescence co-staining of myeloperoxidase and subnucleosomal complex on lesional skin samples from patients with SS and other neutrophilic dermatoses (cryopyrin-associated periodic syndrome, Sweet syndrome, and pyoderma gangrenosum), urticarial vasculitis and chronic spontaneous urticaria, as well as healthy control skin. Widespread and substantial NET formation was observed in lesional skin of Schnitzler syndrome patients (and other neutrophilic dermatoses) but not in chronic spontaneous urticaria or control skin, suggesting that NETosis plays a role in the inflammatory process. (5)

Krause et al demonstrated that CCL2, a chemoattractant for mononuclear immune cells, was found to be significantly elevated in patients with SS. CCL2 levels showed a positive association with global disease activity, especially bone pain, but not disease duration, gammopathy, neutrophilia, or skin disease. Therapeutic IL‐1β blockade decreased CCL2 blood levels in these patients as early as one week after the initiation of treatment, enabling the authors to suggest that CCL2 may be an important component of the pathogenetic cascade leading to bone alterations, and a suitable marker of disease activity in patients with SS. (6)

Current treatment of SS focuses on blocking the effects of IL-1β. Treatment with the IL-1 receptor antagonist anakinra results in complete control of symptoms in more than 80% of patients. Other IL-1 blocking medications, such as canakinumab, an anti-IL-1β antibody, and rilonacept, a fusion protein consisting of the ligand-binding domains of IL-1 receptor and IL-1 receptor accessory protein fused to the Fc region of human IgG1 that binds and neutralizes IL-1, have demonstrated clinical benefit. (3)

I first became cognizant of SS 30 years ago after reading cases reported by Janier et al (7), where they noted that the pathogenesis is unclear and no adequate treatment has yet been found. Unquestionably, much has been learned about the etiology and management of SS since, but many questions remain. What predisposes patients to SS? What triggers the inflammasome? How can the therapeutic blockade be perpetuated to induce disease remission? Will specific biomarkers be available to both diagnose and follow SS patients? I predict that it will not take 30 years for an affirmative answer to each of these questions, which will be tremendously beneficial to those unfortunate patients afflicted with SS.

Point to remember: Schnitzler syndrome is an autoinflammatory disorder with neutrophilic urticarial lesions, bone involvement, elevated IgM, and risk of lymphoproliferative disease. Symptoms may be controlled by IL-1 blockade. We are on the cusp of having biomarkers for SS to assist in diagnosis and management. 

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Our expert’s viewpoint

Edward W. Cowen, MD, MHSc
Senior Clinician and Head, Dermatology Service
Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease

Autoinflammatory skin diseases are uncommon, but dissection of their molecular and pathologic basis allows us to better understand skin disease in general. The pathway responsible for neutrophilic urticaria in the monogenic cryopyrinopathy syndromes, activation of the NLRP3 inflammasome with resultant IL-1 β overproduction, appears to be of similar fundamental importance in Schnitzler syndrome, an acquired disease that typically develops late in life. There are now even reports of ‘atypical Schnitzler syndrome’ — adult onset fever and neutrophilic urticaria in the absence of a circulating paraprotein, due to somatic mosaicism in NLRP3. In such cases, affected tissue must be tested as the mutation may not be identified by whole blood genetic testing methods.

1. Chuamanochan M, Weller K, Feist E, Kallinich, et al. State of care for patients with systemic autoinflammatory diseases – Results of a tertiary care survey. World Allergy Organ J World Allergy; 2019; 12(3): 100019.
2. Bashir M, Bettendorf B, Hariman R. A rare but fascinating disorder: Case collection of patients with Schnitzler syndrome. Case Rep Rheumatol 2018; 2018:7041576.
3. Palladini G. Merlini G. The elusive pathogenesis of Schnitzler syndrome. Blood 2018; 131: 944-946. 
4. 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 [Epub ahead of print].
5. Bonnekoh H, Scheffel J, Wu J, Hoffman S, et al. Skin and systemic inflammation in Schnitzler’s syndrome are associated with neutrophil extracellular trap formation. Front Immunol 2019; 10:546.
6. Krause K , Sabat R, Witte-Händel E, Schulze A, et al. Association of CCL2 with systemic inflammation in Schnitzler syndrome. Br J Dermatol 2019; 180: 859-868. 
7. Janier M, Bonvalet D, Blanc MF, Lemarchand F, et al. Chronic urticarial and macroglobulinemia (Schnitzler’s syndrome): Report of two cases. J Am Acad Dermatol 1989; 20: 206-211.

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