Exploratory Study of MYD88 L265P, Rare NLRP3 Variants, and Clonal Hematopoiesis Prevalence in Patients With Schnitzler Syndrome

Abstract

Objective. To assess the prevalence of the MYD88 L265P mutation and variants within NLRP3 and evaluate the status of oligoclonal hematopoiesis in 30 patients with Schnitzler syndrome (SchS).Methods. Thirty patients with SchS were recruited from 3 clinical centers. Six patients with known acquired cryopyrin-associated periodic syndromes (aCAPS) were included as controls. Allele-specific oligonucleotidepolymerase chain reaction was used for the detection of the MYD88 L265P variant, next-generation sequencing was applied to analyze NLRP3 and 28 genes associated with myelodysplastic syndrome, and gene scanning was performed for the detection of X chromosome inactivation.Results. Activating NLRP3 mutations were not present in 11 SchS patients who had not been sequenced for this gene previously. The MYD88 L265P variant was present in 9 of 30 SchS patients, and somatic mutations associated with clonal hematopoiesis were identified in 1 of 30 patients with SchS and 1 of 6 patients with aCAPS. Evidence of nonrandom X chromosome inactivation was detected in 1 female patient with SchS and 1 female patient with aCAPS.Conclusion. A shared molecular mechanism accounting for the pathogenesis of inflammation in SchS remains elusive. Clonal hematopoiesis is not associated with other somatic mutations found in individuals with SchS or aCAPS.

<p>Schnitzler Syndrome in a 27-Year-Old Man: Diagnostic and Therapeutic Dilemma in Adult Auto-Inflammatory Syndromes A Case Report and Literature Review</p>

“…1,4,[8][9][10][11] , The pathogenesis involves IL −1, interleukin 6 (IL−6), interleukin 17 (IL−17) activation, but the relation to monoclonal gammopathy remains obscure. [12][13][14][15] The diagnosis is based on Lipsker's or Strasbourg's criteria with high sensitivity and specificity. [16][17][18]…”

Evidence of B Cell Clonality and Investigation Into Properties of the IgM in Patients With Schnitzler Syndrome

“…However, our recent study found that only 9/30 SchS patients carry the p.L265P MYD88 variant (1). Furthermore, the same study found that SchS patients did not demonstrate increased incidence of clonal hemopoiesis, which has previously been linked with enhanced pyroptosis (inflammatory cell death) and NLRP3 activation (2,6).…”

“…The latter feature, in particular, is suggestive of shared aetiology with Cryopyrin (NLRP3)associated periodic syndrome (CAPS or NLRP3-AID), which is an inherited or, in rare circumstances, an acquired disorder associated with gain of function mutations in NLRP3 leading to uncontrolled release of IL-1. However, extensive studies have failed to demonstrate the presence of NLRP3 mutations (hereditary or somatic) in SchS patients (2,3). In the majority of SchS patients the presence of paraprotein is due to underlying monoclonal gammopathy of undetermined significance (MGUS).…”

A Chinese case series of Schnitzler syndrome and complete remission in one tocilizumab-treated patient

“…In regard to the genotype, it had been confirmed that MyD88 L256P mutation was detected in a third of SchS, and was the most common genetic factor found among SchS patients to date. Meanwhile, no activating NLRP3 mutations were presented in SchS patients except occasional myeloid-lineage-restricted mosaicism [8,9]. Anti-IL-1 receptor and IL-1β antibodies are preferred treatment of SchS, with highly effective in 90% patients.…”

“…Anti-IL-6 agent tocilizumab also worked in five patients who had no response to anakinra [4]. SchS conventionally presents with no germline NLPR3 mutation [8], but with the exception of somatic mosaicism occasionally seen in the myeloid lineage [9]. Additionally, monoclonal IgM in NLRP3-AID is not observed whereas it elevates in SchS.…”