Background and Clinical Features of a Unique and Mysterious Autoinflammatory Disease, Schnitzler Syndrome

Abstract

Schnitzler syndrome is a unique autoinflammatory disease, of which 747 cases have been described worldwide to date. The main features of the syndrome are a triad of recurrent urticaria, monoclonal IgM gammopathy, systemic inflammation associated with recurrent fever, joint and bone pain, and atypical bone remodeling (osteosclerosis). The abnormal activation of the NLRP3 inflammasome produces IL-1, which drives the disease pathology, but it also involves IL-6 and IL-18. Unlike other autoinflammatory diseases, Schnitzler syndrome lacks evidence of the gene divergence causing the abnormal activation of NLRP3. However, mutations in the MEFV and MYD88 genes can be associated with the development of the disease. Due to its rarity, diagnosing the disease can be a challenging task. IL-1 inhibitors (i.e., anakinra, canakinumab, and rilonacept) are prominent in the treatment of the disease, but the IL-6 receptor inhibitor tocilizumab and the Bruton's tyrosine kinase inhibitor ibrutinib are also promising alternatives. In this summary article, we aim to provide a comprehensive overview of the clinical and molecular background of the disease and potential therapeutic targets, based on the cases reported so far. We diagnosed a patient who, to the best of our knowledge, represents the 748th documented case of this specific pathology. In the context of this patient, we would also like to draw attention to the potential pathogenic role of two novel gene mutations (variants of the MEFV gene "c.2084A>G" and the F2 gene "3'UTR c.*97G>A").

Keywords: F2 gene; MEFV gene; Schnitzler syndrome; anakinra; autoinflammatory disease; canakinumab; diagnosis; monoclonal IgM; urticaria.

Figure 1

NLRP3 and B cells are activated by an unknown stimulus. The activated NLRP3 cleaves pro-caspase-1 into active caspase-1, which activates inactive IL-1β and IL-18. IL-1β induces cutaneous urticarial rash and other clinical symptoms, while IL-18 promotes the expansion of B-cell clonality and the production of monoclonal antibodies, the majority of which are IgM kappa. NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3; IL: interleukin; IgM: immunoglobulin M. The figure was partially created with https://www.biorender.com (accessed on 2 December 2024).

Figure 2

Proposed correlations between sustained inflammation and monoclonal IgM production. Chronic inflammation promotes the clonal expansion of plasma cells. This could result in the synthesis of monoclonal IgM, leading to the activation of the NLRP3 inflammasome in myeloid cells. This exacerbates chronic inflammation. Chronic inflammation elevates IL-6 concentrations. This may consequently promote the emergence of plasma cell dyscrasias. Through activating NF-kB, the MYD88 mutation makes a link between Schnitzler syndrome, Waldenström disease, and other lymphoproliferative diseases. NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3; IL: interleukin; IgM: immunoglobulin M; MYD88: myeloid differentiation primary response 88; NF-kB: nuclear factor-kB. The figure was partially created with https://www.biorender.com (accessed on 2 December 2024).

Figure 3

The patient with Schnitzler syndrome has urticarial rashes on her thigh (A), leg (B), and forearm (C). Coronal CT scan of the thighs (D) indicated ill-delineated marrow infiltration (arrows) in the distal metaphyses and epiphyses of both femurs and vague intramedullary sclerosis (arrows) of the proximal tibias (E). L: left, R: right, CT: computed tomography.