Research Themes Inflammatory diseases Schnitzlers syndrome a 12-year quest at the Radboudumc
This is about a rare disease called Schnitzler’s syndrome (SchS), a systemic interleukin-1-beta-driven-disease. It took us 12 years to understand its pathogenesis, to find a specific, safe and effective new therapy, and finally to discover the genetic defect that explains this enigmatic disease. It is an example of research that started at the bedside, went to the lab bench, and again returned to the patient. Although it is a rare disease, its implications are far-reaching and relevant for many other, late on-set, apparently non-genetic inflammatory diseases. SchS is a disabling autoinflammatory disorder, characterized by chronic urticaria, fever, gammopathy, arthralgia or arthritis and bone pain. As such it resembles a genetic disease called CAPS, which is a monogenic autosomal dominant disease, caused by mutations in the NLRP3 gene. SchS is highly underdiagnosed, and for many patients it may have taken years before a diagnosis was made. The etiology is unknown, and familial clustering has never been reported, suggesting that the disease is caused by environmental factors rather than genetic polymorphisms. We started collecting SchS cases in 2003, and identified nearly all known Dutch patients, most of whom have participated in both our clinical and laboratory studies of the last decade. The intense contact between the major stakeholders has been very productive and motivating both for clinicians, scientists, and patients. The group of van der Meer published a paper in 2006 on the beneficial effect of the general IL-1 inhibitor anakinra in three patients, and soon this became a standard therapy for the disease. In 2011, de Koning, a PhD candidate supervised by Simon, Schalkwijk and van der Meer, published a paper showing that the drug canakinumab, a monoclonal antibody specific for IL-1beta, was highly effective in SchS (JACI 2011). This was a major advancement both clinically and scientifically. Patients could now be treated by an injection on a monthly instead of daily basis. The selective inhibition of only IL-1beta, leaving IL-1alpha to do its physiological work, is therefore a more targeted approach than the general IL-1 inhibition by anakinra. It also pointed at IL-1beta as the pivotal mediator in the disease (Arthritis Res Ther 2015), which opened the way to further dissect its etiology and pathophysiology. Although the phenotypical similarities to CAPS had prompted us in an early stage to perform Sanger sequencing of the exons of the NLRP3 gene in SchS patients, causative mutations in the gene were not found. The advent of next generation sequencing enabled us to perform an unbiased genome-wide analysis in 2014 by exome sequencing. We identified mutations in the NLRP3 gene that were unnoticed in the Sanger sequencing. For example, a F523L mutation was found in 17% of NLRP3 copies in whole blood of a SchS patient. As this mutation was already known to be disease-causing in a CAPS patient who had severe congenital disease, it was evident that this patient was mosaic for the mutation in blood cells. The mosaicism for NLRP3 mutations, which was found in several, but not all SchS patients, explained the late onset and milder phenotype in SchS patients compared to CAPS patients (JACI 2015). This finding was conceptually important, as it is the first example of myeloid-lineage-restricted mosaicism in a non-malignant disease. We would hypothesize that low-grade somatic mosaicism may be the cause of many more unexplained late onset inflammatory diseases. This is why the study of rare diseases is essential and instrumental.