Refractory serum immunoglobulin M elevation during anti‐interleukin (IL)‐1‐ or IL‐6‐targeted treatment in four patients with Schnitzler syndrome

Abstract

Schnitzler syndrome is characterized by chronic urticarial rash, neutrophilic dermal infiltrate, recurrent fever, bone pain, elevated C‐reactive protein, and neutrophilic leukocytosis. The pathophysiology of Schnitzler syndrome is unknown, but it is considered to be an acquired form of an autoinflammatory disease because of the resemblance to clinical phenotypes of cryopyrin‐associated periodic syndrome, in which a gain‐of‐function mutation in NLRP3 causes overexpression of interleukin (IL)‐1β. Schnitzler syndrome is generally accompanied by a monoclonal immunoglobulin (Ig)M gammopathy with a long‐term risk of lymphoproliferation that is possibly associated with an MYD88 mutation. Herein, we present the following four patients with Schnitzler syndrome: a 63‐year‐old woman; a 65‐year‐old man; a 43‐year‐old woman; and a 63‐year‐old woman. Each patient fulfilled the Strasbourg diagnostic criteria, but none of the patients had any mutation in NLRP3 or MYD88 detected in their peripheral blood. Although approved treatment options for Schnitzler syndrome are lacking, our patients were treated with IL‐1‐targeted therapy (anakinra or canakinumab) or anti‐IL‐6 (tocilizumab). The acute inflammatory clinical manifestations improved completely with canakinumab and partially with anakinra and tocilizumab, but the serum IgM levels were gradually increased in all patients, even during treatment. To determine whether treatment with anti‐IL‐1β or IL‐6 prevents conversion to a hematopoietic disorder, further collection of cases and long‐term follow‐up will be needed.

Schnitzler syndrome and Schnitzler-like syndromes

“…After initial response to tocilizumab, half of the patients lost benefit after 16 weeks and discontinued treatment, and at the end of 52 weeks of observation, three out of four patients also showed relapse of the clinical symptoms although C-reactive protein remained normal. Loss of benefit from tocilizumab is also seen in cases reported in Japan recently [51] …”

“…Loss of benefit from tocilizumab is also seen in cases reported in Japan recently. [51] In summary, tocilizumab monotherapy in Schnitzler syndrome showed initial effect but benefit lost over time.…”

“…As mentioned above, despite clinical remission can be achieved by IL-1 or IL-6 blockade, the elevated gamma globuline levels are hardly improved. [ 33 , 50 , 51 ] Thereby, long-term clinical monitoring of the progression of MGUS is still required even in those patients in clinical remission.…”

“…It is interesting and intriguing to note that gammopathy or B cell compartment [49] is not affected by either IL-1 or IL-6 blocking treatment despite remarkable suppression of inflammation and other clinical manifestations. [33,50,51] This suggests that IL-1 is not responsible for B cell clonal expansion or growth, but another factor(s) may be involved. IL-18, another member of IL-1 family, is also cleaved by caspase-1 to become active, which could be such a factor.…”

Case Report: Therapeutic Use of Ibrutinib in a Patient With Schnitzler Syndrome

“…However, conventional therapies, such as rituximab, against the underlying B-cell clone did not always result in organ improvement, which makes Schnitzler syndrome different from other typical monoclonal gammopathies of clinical significance. Moreover, IL-1 blockade did not affect the levels of monoclonal proteins, and IgM MGUS can progress while patients are receiving IL-1 blockade ( 11 ). Overall, the link between IgM monoclonal gammopathy and inflammasome activation in Schnitzler syndrome is still missing.…”