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Background and ObjectivesInflammasomes are involved in the pathogenesis of different neuroimmune and neurodegenerative diseases, including multiple sclerosis (MS). In a previous study by our group, the nucleotide-binding oligomerization domain, leucine-rich repeat receptor and pyrin-domain–containing 3 (NLRP3) inflammasome was reported to be associated with the response to interferon-beta in MS. Based on recent data showing the potential for the oral therapy fingolimod to inhibit NLRP3 inflammasome activation, here we investigated whether fingolimod could also be implicated in the response to this therapy in patients with MS.MethodsNLRP3gene expression levels were measured by real-time PCR in peripheral blood mononuclear cells at baseline and after 3, 6, and 12 months in a cohort of patients with MS treated with fingolimod (N = 23), dimethyl fumarate (N = 21), and teriflunomide (N = 21) and classified into responders and nonresponders to the treatment according to clinical and radiologic criteria. In a subgroup of fingolimod responders and nonresponders, the percentage of monocytes with an oligomer of ASC was determined by flow cytometry, and the levels of interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor (TNF)α, and galectin-3 were quantified by ELISA.ResultsNLPR3expression levels were significantly increased in fingolimod nonresponders after 3 (p= 0.03) and 6 months (p= 0.008) of treatment compared with the baseline but remained similar in responders at all time points. These changes were not observed in nonresponders to the other oral therapies tested. The formation of an oligomer of ASC in monocytes after lipopolysaccharide and adenosine 5′-triphosphate stimulation was significantly decreased in responders (p= 0.006) but increased in nonresponders (p= 0.0003) after 6 months of fingolimod treatment compared with the baseline. Proinflammatory cytokine release from stimulated peripheral blood mononuclear cells was comparable between responders and nonresponders, but galectin-3 levels on cell supernatants, as a marker of cell damage, were significantly increased in fingolimod nonresponders (p= 0.02).DiscussionThe differential effect of fingolimod on the formation of an inflammasome-triggered ASC oligomer in monocytes between responders and nonresponders could be used as a response biomarker after 6 months of fingolimod treatment and suggests that fingolimod may exert their beneficial effects by reducing inflammasome signaling in a subset of patients with MS.

Personalized medicine; Responder and non-responder Medicina personalizada; Respondedor y no respondedor Medicina personalitzada; Contestador i no contestador Background The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients. Methods Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients’ peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed. Results Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment. Conclusion Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod. This work was supported by the Instituto de Salud Carlos III (PI18/00357, RD16-0015/0019, PI21/00302, all co-funded by the European Union), the Fundación Merck Salud (FMS_2020_MS), Esclerosis Múltiple España (REEM-EME-S5 and REEM-EME_2018), ADEMTO, ATORDEM and AELEM. CC-T holds a predoctoral fellowship from the Instituto de Salud Carlos III (FI19/00132, co-funded by the European Union). LC and JG-A were hired under PI18/00357 and RD16/0015/0019, respectively. DC, MCO and IM-D were hired by SESCAM.

Supplemental material, sj-pdf-6-msj-10.1177_13524585221134213 for Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis by Harald Hegen, Janette Walde, Klaus Berek, Georgina Arrambide, Sharmilee Gnanapavan, Batia Kaplan, Michael Khalil, Ruba Saadeh, Charlotte Teunissen, Hayrettin Tumani, Luisa M Villar, Maria Alice V Willrich, Henrik Zetterberg and Florian Deisenhammer in Multiple Sclerosis Journal

Supplemental material, sj-pdf-7-msj-10.1177_13524585221134213 for Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis by Harald Hegen, Janette Walde, Klaus Berek, Georgina Arrambide, Sharmilee Gnanapavan, Batia Kaplan, Michael Khalil, Ruba Saadeh, Charlotte Teunissen, Hayrettin Tumani, Luisa M Villar, Maria Alice V Willrich, Henrik Zetterberg and Florian Deisenhammer in Multiple Sclerosis Journal

Supplemental material, sj-pdf-2-msj-10.1177_13524585221134213 for Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis by Harald Hegen, Janette Walde, Klaus Berek, Georgina Arrambide, Sharmilee Gnanapavan, Batia Kaplan, Michael Khalil, Ruba Saadeh, Charlotte Teunissen, Hayrettin Tumani, Luisa M Villar, Maria Alice V Willrich, Henrik Zetterberg and Florian Deisenhammer in Multiple Sclerosis Journal

Supplemental material, sj-pdf-19-msj-10.1177_13524585221134213 for Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis by Harald Hegen, Janette Walde, Klaus Berek, Georgina Arrambide, Sharmilee Gnanapavan, Batia Kaplan, Michael Khalil, Ruba Saadeh, Charlotte Teunissen, Hayrettin Tumani, Luisa M Villar, Maria Alice V Willrich, Henrik Zetterberg and Florian Deisenhammer in Multiple Sclerosis Journal

Supplemental material, sj-pdf-8-msj-10.1177_13524585221134213 for Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis by Harald Hegen, Janette Walde, Klaus Berek, Georgina Arrambide, Sharmilee Gnanapavan, Batia Kaplan, Michael Khalil, Ruba Saadeh, Charlotte Teunissen, Hayrettin Tumani, Luisa M Villar, Maria Alice V Willrich, Henrik Zetterberg and Florian Deisenhammer in Multiple Sclerosis Journal

Supplemental material, sj-pdf-9-msj-10.1177_13524585221134213 for Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis by Harald Hegen, Janette Walde, Klaus Berek, Georgina Arrambide, Sharmilee Gnanapavan, Batia Kaplan, Michael Khalil, Ruba Saadeh, Charlotte Teunissen, Hayrettin Tumani, Luisa M Villar, Maria Alice V Willrich, Henrik Zetterberg and Florian Deisenhammer in Multiple Sclerosis Journal

Supplemental material, sj-pdf-4-msj-10.1177_13524585221134213 for Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis by Harald Hegen, Janette Walde, Klaus Berek, Georgina Arrambide, Sharmilee Gnanapavan, Batia Kaplan, Michael Khalil, Ruba Saadeh, Charlotte Teunissen, Hayrettin Tumani, Luisa M Villar, Maria Alice V Willrich, Henrik Zetterberg and Florian Deisenhammer in Multiple Sclerosis Journal

Supplemental material, sj-pdf-3-msj-10.1177_13524585221134213 for Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis by Harald Hegen, Janette Walde, Klaus Berek, Georgina Arrambide, Sharmilee Gnanapavan, Batia Kaplan, Michael Khalil, Ruba Saadeh, Charlotte Teunissen, Hayrettin Tumani, Luisa M Villar, Maria Alice V Willrich, Henrik Zetterberg and Florian Deisenhammer in Multiple Sclerosis Journal

Supplemental material, sj-pdf-5-msj-10.1177_13524585221134213 for Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis by Harald Hegen, Janette Walde, Klaus Berek, Georgina Arrambide, Sharmilee Gnanapavan, Batia Kaplan, Michael Khalil, Ruba Saadeh, Charlotte Teunissen, Hayrettin Tumani, Luisa M Villar, Maria Alice V Willrich, Henrik Zetterberg and Florian Deisenhammer in Multiple Sclerosis Journal