Killing Two Birds with One Stone: the Therapeutic Role of Ibrutinib in Schnitzler Syndrome

Excerpt

Claves et al. reported dramatic therapeutic efficacy of ibrutinib in a 60-year-old female with Schnitzler syndrome and underlying splenic diffuse red pulp small B cell lymphoma [1]. Although the chronic urticaria with biopsy proven neutrophilic infiltration was typical for Schnitzler syndrome, her constitutional symptoms and polyarthritis could be contributed by the concurrent type 2 cryoglobulinemia. Her relapsing–remitting disease course despite multiple lines of prior treatments, including steroid, interleukin-1 blockade, and rituximab with chlorambucil was accompanied by persistently detectable cryoglobulin and complement activation (low CH50). Of note, ibrutinib not only led to resolution of clinical symptoms but also resulted into disappearance of IgM monoclonal protein and cryoglobulinemia, as well as improvement of CH50. Monoclonal IgM, the major diagnostic component of Schnitzler syndrome, may recognize autoantigens on the myeloid cells to trigger NLRP3 inflammasome activation with resultant proinflammatory cytokine production, particularly interleukin-1β [2]. Therefore, diminishing the monoclonal protein and cryoglobulin in this case by ibrutinib targeting lymphoma cells showed dramatic clinical response despite stable lymphoma burden on imaging assessment. Moreover, ibrutinib may also interrupt NLRP3 inflammasome activation in myeloid cells of Schnitzler patients, given the known interaction between Bruton tyrosine kinase and NLRP3 [3]. Intriguingly, MYD88 L265P was found in the lymphoma cells of this patient, while the same mutation was also detectable in the peripheral blood of a subset of Schnitzler patients (30%) and half of them did not have documented underlying lymphoproliferative disorders [4]. This MYD88 L265P mutation was postulated to be somatically acquired in myeloid cells, resulting in hyperactive NLRP3 inflammasome. Overall, ibrutinib represents a novel and unique therapeutic option for patients with Schnitzler syndrome, targeting not only underlying IgM monoclonal gammopathy (or concurrent overt lymphoproliferative disease if present) but also NLRP3 inflammasome activation. It controls the production of both upstream triggers (i.e., monoclonal protein) from lymphoid cells and downstream effectors (i.e., proinflammatory cytokines, in particular IL-1β) from myeloid cells (Fig. 1). Whether those who with MYD88 L265P mutation has better response requires further studies. In addition, ibrutinib may be a promising therapeutic option for other B cell-mediated autoimmune conditions (e.g., systemic sclerosis [5]) or NLRP3-related autoinflammatory disorders (e.g., cryopyrin-associated periodic syndrome).

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