Dottorato in NEUROSCIENZE CLINICO-SPERIMENTALI E PSICHIATRIA

Titolo della tesi: Effects of disease modifying therapies on anti-JCV antibody status in a large population of Multiple Sclerosis patients

Introduction. Treatment options for multiple sclerosis (MS) have changed over the last two decades, ranging between categories of drugs with heterogeneous mechanism of action, in particular B or T depleting profile. However, due to the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by JC virus (JCV), most of the disease modifying therapies (DMTs) are used with caution and a risk stratification algorithm based on determination of titer of anti-JCV antibodies (JCV index) is usually applied to prevent PML infection and its consequences on disease course. Some studies focused on the impact of DMTs on the longitudinal evolution of anti-JCV antibody index, but no studies have considered the interference of Natalizumab (NTZ) discontinuation on JCV status modification on long time period. Moreover, although the risk of PML is also present in MS patients treated with other drugs, few studies have evaluated the JCV index profile during treatment with DMTs different from NTZ. Objective. This project consists of two different studies. The aim of the first study was to investigate the anti-JCV antibody status pre, during and post NTZ treatment and describe the trend of JCV index after a long period of NTZ discontinuation in order to identify possible alternative therapeutic strategies. The aim of the second study was to evaluate JCV status modification during treatment with currently used DMTs different from NTZ in order to possibly define the best possible therapeutic approach, especially in those patients with high JCV index at the beginning of the new treatment or with a higher risk of PML, and to explore if there exists further exit strategies in patients treated with NTZ and high JCV index score. Materials and Methods. This retrospective-prospective study screened all MS patients treated with several DMTs in the period between 2010 and 2020. Two different datasets with demographic and clinical data were created. Inclusion criteria were: diagnosis of MS according to the Mc Donald criteria 2010, treatment for at least six months with NTZ or rituximab/ocrelizumab (RTX/OCRE), fingolimod (FTY), interferons/glatiramer acetate (IFN/GA), teriflunomide (TFN), dimethylfumarate (DMF), alemtuzumab (ALM) and cladribine (CLD), at least two determinations of JCV index during the follow-up period. After a period of NTZ discontinuation more than six months, patients eligible prospectively underwent to the anti-JCV antibody determination. JCV status was evaluated at baseline before starting treatment (T0), at the time of the NTZ discontinuation or during treatment with other DMTs (T1) and at the last follow-up after NTZ discontinuation (T2). Seroconversion was defined as changing status of serum JCV antibody. Main outcomes were the JCV index changes and the rate of seroconversion. Results. In the first study, at baseline 285 patients met inclusion criteria (208 JCV negative, 67 JCV positive and 10 not available). There was a statistically significant increase of JCV index during NTZ treatment period (T0 vs T1, p=0.0009) and during NTZ discontinuation period (T1 vs T2, p=0.04). Patients seroconverted to a positive status more frequently during NTZ treatment than after discontinuation (p=0.008). Moreover, patients who shifted to FTY as exit strategy after NTZ discontinuation, showed a statistically significant increase of JCV index. In the second study, 190 patients were enrolled: 16 (8.4%) were treated with IFN/GA, 34 (17.9%) with RTX/OCRE, 32 (16.8%) with DMF, 18 (9.5%) with TFN, 14 (7.4%) with ALM, 68 (35.8%) with FTY and 8 (4.2%) with CLD. Mean interval time between start of DMTs and determination of JCV index was 25.9±18.4 months. Between T0 and T1, FTY group showed a statistically significant increase in JCV index (p=0.0001), while patients treated with ALM had a significant reduction (p=0.005). A reduction, even if not statistically significant, was also found in RTX/OCRE (p=0.54) and in CLD (p=0.44) groups. Applying a multivariate analysis corrected for disease duration, the use of previous immunosuppressant drugs or NTZ treatment did not modify our results. Conclusion. Our results demonstrated that treatment with DMTs may influence JCV status in MS patients. In particular, an high percentage of patients shift to or remain in a positive JCV status during NTZ treatment and after suspension. NTZ discontinuation seems not to be able to interfere on JCV status modification on long time period. Moreover, the increase of JCV index in those patients subsequently treated with FTY after NTZ discontinuation and the reduction of JCV index in patients treated with drugs with a B depleting profile as ALM or RTX/OCRE or CLD respectively, could suggest a different approach in the treatment decision making process. Our data may indicate that the use of treatments acting selectively on B cells could represent a valid therapeutic approach in those patients who stopped NTZ or in those with an high JCV index before starting a new therapy. Since an increase of JCV index would expose patients to a higher risk of PML, the choice of alternative treatment strategies based on their mechanism of action should be carefully considered because it could negatively influence the PML risk stratification of patients.