Impact of COVID-19 on pregnancy and fetal outcomes in women with multiple sclerosis.

BACKGROUND: In the general population, maternal COVID-19 is associated with worse maternal and fetal outcomes. Two previous studies have assessed COVID-19 clinical outcomes in pregnant women with multiple sclerosis (MS), but there are no data about maternal and fetal outcomes. OBJECTIVES: In this multicenter study, we aimed to assess maternal and fetal outcomes in pregnant women with MS and COVID-19 infection. METHODS: We recruited pregnant patients with MS who contracted COVID-19 and were followed up in Italian and Turkish Centers, during 2020-2022. A control group was extracted from a previous Italian cohort. Associations between group (COVID-19 or healthy patients) and clinical outcomes (maternal complications, fetal malformations, and spontaneous abortion) were investigated with a weighted logistic regression where propensity score-based inverse probability of treatment weighting (IPTW) approach was applied for adjusting for difference in baseline confounders. RESULTS: In the multivariable analysis, COVID-19 during pregnancy was associated with a higher risk of maternal complications (odd ratio (OR) = 2.12; 95% confidence interval (CI) = 1.32-3.48; p = 0.002), while it was not associated with higher risk of spontaneous abortion and fetal malformations. CONCLUSION: Our data indicate that COVID-19 during pregnancy increases the risk of maternal complications, while it seems to have no significant impact on fetal outcomes.

Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop).

BACKGROUND AND PURPOSE: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited. METHODS: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course. RESULTS: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event. CONCLUSIONS: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.

Symptomatic COVID-19 course and outcomes after three mRNA vaccine doses in multiple sclerosis patients treated with high-efficacy DMTs.

BACKGROUND: Little is known about COVID-19 course and outcomes after a third booster dose of mRNA vaccine against SARS-CoV-2 (mRNA-Vax) in patients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR) and fingolimod (FNG), which showed a weakened immune response to mRNA-vax. OBJECTIVES: The aim of this study was to evaluate COVID-19 course and outcomes in pwMS on OCR and FNG after receiving the third dose of mRNA-Vax and to compare it with pwMS on natalizumab (NTZ). METHODS: Inclusion criteria: >18 years of age, being treated with OCR/FNG/NTZ since the first mRNA-Vax dose; COVID-19 after a third booster dose of mRNA-Vax; no steroids use. RESULTS: Overall, 290 pwMS (79 NTZ, 126 OCR, and 85 FNG) from 17 Italian MS centers were included. Age, Expanded Disability Status Scale (EDSS) score, MS phenotype, disease, and treatment duration were significantly different across groups. PwMS who had COVID-19 on OCR and FNG compared with those on NTZ were slightly more symptomatic with higher hospitalization rates (11.1% vs 7.1% vs 1.3%, respectively). Regression models showed that the majority of the differences observed were not related to the disease-modifying treatments (DMTs) used. No fatal cases were observed. CONCLUSION: Our results support the effectiveness of the third booster dose of mRNA-Vax against severe forms of COVID-19 in pwMS treated with OCR and FNG.

Sars-CoV2 infection in pregnant women with multiple sclerosis.

BACKGROUND: In the general population, maternal SARS-CoV-2 infection during pregnancy is associated with worse maternal outcomes; however, only one study so far has evaluated COVID-19 clinical outcomes in pregnant and postpartum women with multiple sclerosis, showing no higher risk for poor COVID-19 outcomes in these patients. OBJECTIVE: In this multicenter study, we aimed to evaluate COVID-19 clinical outcomes in pregnant patients with multiple sclerosis. METHODS: We recruited 85 pregnant patients with multiple sclerosis who contracted COVID-19 after conception and were prospectively followed-up in Italian and Turkish Centers, in the period 2020-2022. A control group of 1354 women was extracted from the database of the Multiple Sclerosis and COVID-19 (MuSC-19). Univariate and subsequent logistic regression models were fitted to search for risk factors associated with severe COVID-19 course (at least one outcome among hospitalization, intensive care unit [ICU] admission and death). RESULTS: In the multivariable analysis, independent predictors of severe COVID-19 were age, body mass index ⩾ 30, treatment with anti-CD20 and recent use of methylprednisolone. Vaccination before infection was a protective factor. Vaccination before infection was a protective factor. Pregnancy was not a risk nor a protective factor for severe COVID-19 course. CONCLUSION: Our data show no significant increase of severe COVID-19 outcomes in patients with multiple sclerosis who contracted the infection during pregnancy.

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.

OBJECTIVE: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). METHODS: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. RESULTS: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. INTERPRETATION: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.

Exposure to natalizumab throughout pregnancy: effectiveness and safety in an Italian cohort of women with multiple sclerosis.

OBJECTIVE: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG_EXP) compared with women interrupting treatment before (NO_EXP) and within >-30 days and ≤90 days from conception (SHORT_EXP), and describing newborns' outcomes. METHODS: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO_EXP, SHORT_EXP, LONG_EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis. RESULTS: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG_EXP (n=66, 0.02 (0.001-0.09)) compared with NO_EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT_EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG_EXP (0.12 (0.05-0.24)) compared with SHORT_EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG_EXP (n=6/50, 2.00%) compared with NO_EXP (n=9/21, 42.86%) and SHORT_EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG_EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population. CONCLUSIONS: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes.

SARS-CoV-2 serology after COVID-19 in multiple sclerosis: An international cohort study.

BACKGROUND: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available. OBJECTIVE: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test. METHODS: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model. RESULTS: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was significantly associated with a reduced probability of developing antibodies after COVID-19 (odds ratio (OR) = 0.20, p = 0.002). CONCLUSION: Patients with MS maintain the capacity to develop humoral immune response against SARS-COV-2, although to a lesser extent when treated with anti-CD20 drugs. Overall, our results are reassuring with respect to the possibility to achieve sufficient immunization with vaccination.

Breakthrough SARS-CoV-2 infections in MS patients on disease-modifying therapies.

BACKGROUND: Patients with multiple sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines. OBJECTIVE: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different disease-modifying therapies (DMTs). METHODS: Data on the number of vaccinated patients and the number of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT. RESULTS: 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. Compared with other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, risk ratio (RR) = 3.55, 95% CI = 2.74-4.58, p < 0.001) and fingolimod (0.58% vs 1.62%, RR = 2.65, 95% CI = 1.75-4.00, p < 0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% versus 19.4% in the pre-vaccination era (RR = 0.86, p = 0.74) and it was 3.9% in all the other DMT groups versus 11.9% in the pre-vaccination period (RR = 0.33, p = 0.02). CONCLUSIONS: The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.

The effect of air pollution on COVID-19 severity in a sample of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID-19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID-19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID-19 severity amongst PwMS. METHODS: Data were retrieved from an Italian web-based platform (MuSC-19) which includes PwMS with COVID-19. PM2.5 2016-2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID-19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID-19 severity. RESULTS: In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID-19 course (odds ratio 1.90; p = 0.009). CONCLUSIONS: Even if several other factors explain the unfavourable course of COVID-19 in PwMS, the role of air pollutants must be considered and further investigated.

Signs and symptoms of COVID-19 in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation. METHOD: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number. RESULTS: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p < 0.001). All cases should be referred to variants up to Delta. CONCLUSION: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms.

A real-world study of alemtuzumab in a cohort of Italian patients.

BACKGROUND AND PURPOSE: Real-world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease-modifying therapies (DMTs). Our aim was to provide real-world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab. METHODS: Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation. RESULTS: We studied 322 patients (mean age 36.8 years, median EDSS score 3, median follow-up 1.94 years). Previous treatments were: fingolimod (106), natalizumab (80), first-line oral agents (56), first-line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty-five patients were treatment-naïve. The pre-alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p < 0.001). The number of previous-year relapses was associated with alemtuzumab ARR (adjusted risk ratio [RR] 1.38, p = 0.009). Progression-free survival was 94.5% after 1 year, and 89.2% after 2 years of alemtuzumab treatment. EDSS score improvement occurred in 13.5% after 1 year, and 20.6% after 2 years. Re-baselining patients after 6 months of alemtuzumab treatment, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years. CONCLUSIONS: Alemtuzumab decreases ARR independent of previous therapy, including patients with disease activity during natalizumab treatment. Overall, 90% of patients showed no disease progression, and 20% an improvement after 2 years of alemtuzumab.

Lung involvement correlates with disability in MS patients with COVID-19 pneumonia.

INTRODUCTION: The visual-well aerated lung (V-WAL) is a score for the visual quantification of the well aerated lung on CT scan in COVID-19 patients and its value at admission seems to predict future COVID-19 severity. The aim of the present study was to analyze the association between V-WAL and risk factors for severe COVID-19 evolution in people with multiple sclerosis. MATERIALS AND METHODS: This is an observational retrospective study, including people with multiple sclerosis and concomitant COVID-19, who were investigated with a lung CT scan at Hospital admission. The association of V-WAL with age, sex, EDSS, comorbidities, recent steroid use, and treatment (anti-CD20 vs other) was assessed by a multivariate linear regression model. RESULTS: In this observational retrospective study, the only factor that was significantly associated to a lower V-WAL at multivariable analysis was an increasing level of the EDSS (R2 = 0.41, p = 0.001), with an average decrease of 8% of V-WAL for each additional EDSS point. DISCUSSION AND CONCLUSION: This analysis shows that a high EDSS level is the main factor associated to the severity of lung involvement in a group of people with multiple sclerosis who were hospitalized for Covid-19.

Switching to ocrelizumab in RRMS patients at risk of PML previously treated with extended interval dosing of natalizumab.

Discontinuation of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) at risk of progressive multifocal leukoencephalopathy (PML) is associated with disease reactivation. Forty-two RRMS patients, who switched from an extended interval dose (EID) of natalizumab to ocrelizumab, underwent magnetic resonance imaging (MRI) and clinical monitoring during washout and after ocrelizumab starting. During the first 3 months, disease reactivation was observed in five (12%) patients; 6 months after ocrelizumab starting, no further relapses were recorded, and Expanded Disability Status Scale (EDSS) remained stable in 38 (90%) patients. In conclusion, ocrelizumab could be considered a choice to mitigate the risk of disease reactivation in patients previously treated with natalizumab-EID.

Pegylated interferon beta-1a (Plegridy) Italian real-world experience: a Delphi analysis of injection-site reaction and flu-like symptom management.

BACKGROUND AND AIM: Peginterferon beta-1a (Plegridy) offers the advantage of a prolonged half-life with less-frequent administration and a higher patient adherence. However, the use of an interferon may lead to flu-like symptoms (FLS) and injection-site reactions (ISR) that results in drug discontinuation. The objective of this Delphi analysis was to obtain consensus on the characteristics and management of FLS/ISR of peginterferon beta-1a in patients with relapsing-remitting MS based on real-world clinical experiences.4 METHODS: A steering committee of MS neurologists and nurses identified issues regarding the features and management of adverse events and generated a questionnaire used to conduct three rounds of the Delphi web survey with an Italian expert panel (54 neurologists and nurses). RESULTS: Fifty-three (100%), fifty-one (96.22%), and forty-two (79.24%) responders completed questionnaires 1, 2, and 3 respectively. Responders reported that, during the first 6 months of treatment, FLS generally occurred 6-12 h after injection; the fever tended to resolve after 12-24 h; otherwise, FLS lasted up to 48 h. FLS improved or disappeared after 6 months of treatment in most cases. Paracetamol was recommended as the first choice for managing FLS. Erythema was the most common ISR and usually resolved within 1 week after injection. Responders reported that the adherence to treatment increases after adequate patient education on the drug's tolerability profile. CONCLUSIONS: Patient education and counseling play a key role in promoting adherence to treatment especially in the first months also in patients switching from nonpegylated IFNs to peginterferon beta-1a.

Minimal evidence of disease activity (MEDA) in relapsing-remitting multiple sclerosis.

OBJECTIVE: This study aimed to define the minimal evidence of disease activity (MEDA) during treatment that can be tolerated without exposing patients with relapsing-remitting multiple sclerosis at risk of long-term disability. METHODS: We retrospectively collected data of patients followed up to 10 years after starting interferon beta or glatiramer acetate. Survival analyses explored the association between the long-term risk of reaching an Expanded Disability Status Scale≥6.0 and early clinical and MRI activity assessed after the first and second year of treatment. Early disease activity was classified by the so-called 'MAGNIMS score' (low: no relapses and <3 new T2 lesions; medium: no relapses and ≥3 new T2 lesions or 1 relapse and 0-2 new T2 lesions; high: 1 relapse and ≥3 new T2 lesions or ≥2 relapses) and the absence or presence of contrast-enhancing lesions (CELs). RESULTS: At follow-up, 148/1036 (14.3%) patients reached the outcome: 61/685 (8.9%) with low score (reference category), 57/241 (23.7%) with medium score (HR=1.94, p=0.002) and 30/110 (27.3%) with high score (HR=2.47, p<0.001) after the first year of treatment. In the low score subgroup, the risk was further reduced in the absence (49/607, 8.1%) than in the presence of CELs (12/78, 15.4%; HR=2.11, p=0.01). No evident disease activity and low score in the absence of CELs shared the same risk (p=0.54). Similar findings were obtained even after the second year of treatment. CONCLUSIONS: Early marginal MRI activity of one to two new T2 lesions, in the absence of both relapses and CELs, is associated with a minor risk of future disability, thus representing a simple and valuable definition for MEDA.

Determinants of therapy switch in multiple sclerosis treatment-naïve patients: A real-life study.

BACKGROUND: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences. OBJECTIVES: To identify prognostic factors for early switch after first therapy choice. METHODS: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models. RESULTS: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p = 0.001), and spinal cord lesions (HR = 1.46; p = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p = 0.001), fingolimod (HR = 0.35; p = 0.002), and dimethyl-fumarate (HR = 0.57; p = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p = 0.047). CONCLUSION: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

Age as a risk factor for early onset of natalizumab-related progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare but potentially fatal opportunistic infection that arises almost exclusively in immunocompromised patients or in those treated with monoclonal antibodies, especially natalizumab. Here, we aimed at exploring if age at treatment start affects the time to onset of natalizumab-related PML. PubMed was searched for the terms "natalizumab and progressive multifocal leukoencephalopathy" in articles published from January 2005 to March 2017. We collected information on each identified PML case, including demographic and clinical variables at natalizumab start and at PML onset. The number of natalizumab infusions until PML onset was investigated in time-to-event analyses. We identified 238 cases who developed PML after a median number of 33 natalizumab infusions (range 6 to 103). Risk factors for an earlier onset of natalizumab-related PML were prior immunosuppressant exposure (hazard ratio [HR] = 1.43, p = 0.017) and older age at treatment start (HR = 1.02, p = 0.016). In particular, patients older than 50 years had a more than doubled-increased risk for an earlier PML onset (HR = 2.11, p = 0.006). Our findings suggest that the age at natalizumab start may represent a risk factor for an earlier PML onset, thus claiming further investigations about the interplay between immunosenescence and MS treatments.

Assessing long-term prognosis improvement as a consequence of treatment pattern changes in MS.

OBJECTIVE: To assess whether the age at which multiple sclerosis (MS) patients reach Expanded Disability Status Scale (EDSS) milestones changed as long as new drugs for the treatment of MS became available. METHODS: We evaluated the long-term impact of therapies on disability progression assessing whether there is a detectable delay in the age at which patients reached EDSS milestones in more recent years. We used data collected over more than 30 years in the Center of Brescia, Italy. We compared the age at EDSS = 6 among patients diagnosed with relapsing-remitting MS in different time periods, adjusting for age at diagnosis and median interval among EDSS visits, by a multivariate Cox model. RESULTS: A total of 1324 MS patients were included. Patients diagnosed in more recent periods reached EDSS = 6 at an older age: the rate at which patients reached EDSS = 6 in those diagnosed in 1991-1995 was similar to those diagnosed in 1980-1990 (hazard ratio ( HR) = 1.09, p = 0.68) and to those diagnosed in 1996-2000 ( HR = 0.85, p = 0.44), it was reduced by 37% in patients diagnosed in 2001-2005 ( HR = 0.63, p = 0.05), by 46% in patients diagnosed in 2006-2010 ( HR = 0.54, p < 0.02). CONCLUSION: A clear modification of MS course is observed after 2000; among other causes, this can be associated to the changes in the treatment patterns experienced in those years.