Schnitzler Syndrome as an Autoinflammatory Disease Driven by B‐Cell‐Specific Somatic MYD88 Mutation

Schnitzler syndrome (SchS) is a rare adult-onset autoinflammatory disorder defined by the Strasbourg diagnostic criteria 1, which require a chronic urticarial rash and a monoclonal gammopathy, most commonly of the IgM class. Because its clinical manifestations resemble those of cryopyrin-associated periodic syndrome (CAPS), IL-1 blockade has been evaluated and shown remarkable efficacy. However, the mechanism linking monoclonal gammopathy to IL-1-driven inflammation remains unclear. Genetic studies targeting autoinflammatory pathways, including analyses of NLRP3 2, UBA1, and MEFV 3, have not supported their involvement in SchS. Somatic MYD88 p.L265P mutations, frequently associated with IgM monoclonal gammopathy, have been reported in 9 of 30 patients with SchS 4, yet inconsistent detection has left their relevance to SchS pathogenesis unresolved 5. In this study, seven patients were included (Table 1). Two patients (SCAN01 and SCAN02) participated in the investigator-initiated clinical trial (jRCT2051220139) and responded to canakinumab, while an additional patient (SA3) responded to anakinra. The methods used to isolate each cellular fraction from peripheral blood are described in the Data S1. Whole-exome sequencing (WES) detected the somatic MYD88 p.L265P mutation in peripheral blood mononuclear cells (PBMCs) from 2 of 3 patients examined (Table 2). However, fractionated analysis revealed that the mutation was present in purified B cells in all three cases and was not detected in T cells, monocytes, or neutrophils. To validate and extend these findings, we developed an allele-specific quantitative PCR (AS-qPCR) assay targeting MYD88 p.L265P (Table S1 and Figure S2). In SCAN02, AS-qPCR detected a mutant allele at 25.72% in B cells, closely matching the WES result of 26.8% (Table 2). We then examined three additional patients (SCAN03, SCAN04, SCAN05), whose PBMC samples had been cryopreserved during a previous canakinumab trial, together with one newly identified patient (SA4) from whom fresh PBMCs were obtained. In all four cases, MYD88 p.L265P was undetectable in bulk PBMCs and in CD19-negative fractions but was reproducibly detected in purified B cells, with variant allele fractions ranging from 1.24% to 8.57% (Table 2). Thus, across all seven cases analyzed, MYD88 mutations were identified exclusively in B cells. Peripheral blood-based sequencing strategies focused on myeloid cells, as used in the previous study 4, are therefore likely to miss low-level MYD88 mutations in SchS, because circulating B cells are typically scarce. The identification of B cell-restricted MYD88 mutations in patients fulfilling the Strasbourg criteria and responding to IL-1 blockade supports the biological coherence of SchS as a distinct disease entity. For context, MYD88 p.L265P is detected in approximately 50%–70% of patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and in more than 90% of patients with Waldenström's macroglobulinemia, whereas its prevalence in other B-cell lymphomas varies widely depending on subtype. The clonal expansion of MYD88-mutant B cells may therefore explain the reported progression of some patients to overt B-cell malignancies. However, because many individuals harboring MYD88-mutated IgM gammopathy do not develop SchS, the mutation alone is not sufficient to account for the autoinflammatory phenotype, suggesting that additional pathogenic events may be required to drive IL-1-mediated systemic inflammation. This study demonstrates that SchS is an acquired autoinflammatory disease driven by lineage-specific somatic mosaicism. In that a small clone can shape the systemic clinical phenotype through the production of pathogenic signals, SchS aligns with the concept of “clonal disorders of clinical significance” proposed by Lipsker 6. Together with prior reports of somatic mosaicism in CAPS and VEXAS syndrome, our findings place SchS within a growing class of mosaic-driven autoinflammatory diseases. Given the rarity of SchS and the need for purified B cells to detect low-level somatic mutations, further validation will require international collaborative studies. N.K. designed the study. Y.Z. and N.K. drafted the manuscript. All authors contributed to data collection and reviewed and approved the final version of the manuscript. We gratefully acknowledge Drs. Riko Takimoto-Ito, Fuuka Minami, and Kaori Tomari (Kyoto University) for their expert technical assistance. We also thank Dr. Mayuko Yamamoto (Kochi University), Drs. Koji Takemura and Shin-ichiro Kagami (Asahi General Hospital), and Dr. Yoshie Kawahara (Keiyu Hospital) for providing valuable clinical specimens. We further acknowledge Dr. Ryuta Nishikomori and the members of our research team for their longstanding contributions to research on somatic mosaicism in autoinflammatory syndromes. Finally, we sincerely thank the patients and their families for their participation and cooperation in this study. This work was supported in part by a research grant from the Ministry of Health, Labour and Welfare of Japan (Research Program on Intractable Diseases) and the Practical Research Project for Rare/Intractable Diseases (JP24ek0109582) from the Japan Agency for Medical Research and Development (AMED). N.K. received canakinumab free of charge for an investigator-initiated clinical trial for Schnitzler syndrome (jRCT2051220139) and received consulting fees from Novartis. The remaining authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1: all70338-sup-0001-DataS1.pdf. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.