Jean-Claude Ongagna

JC-virus seroconversion in multiple sclerosis patients receiving natalizumab:

Aim: The objectives of this study were to evaluate the rate of JC virus (JCV) seroconversion/seroreversion in a French cohort of multiple sclerosis (MS) patients receiving natalizumab (NTZ), describe the characteristics of this population, identify risk factors for JCV seropositivity and analyse the additional value of quantitative JCV serology results in this context. Methods: MS patients from two French MS centres, whose JCV serological status in 2011 while receiving NTZ was known (n=357; first-generation enzyme-linked immunosorbent assay (ELISA) test (Gen1)), were proposed for inclusion in this study. We evaluated the rate of JCV seroconversion over a period of one year with a second-generation ELISA test (Gen2; n=303) and analysed the quantitative results. Multivariate analysis was performed to identify risk factors for JCV seropositivity. Results: Among the patients with Gen2 JCV serology (n=303) that had been JCV-seronegative one year before (n=165), the rate of JCV seroconversion was 26.67% (44/165). We observed a higher proportion of anti-JCV antibody seroconverters (14.5%) than expected (≤3%) but also increasing index values of anti-JCV antibody over time. Conclusion: Our data suggest that JCV reactivation occurs during NTZ therapy and leads to an increase in the anti-JCV antibodies titre, thus making them more easily detectable by the second-generation ELISA test.

Reduction of the washout time between natalizumab and fingolimod

Drugs such as natalizumab (Tysabri) and fingolimod (Gilenya) are now available to treat multiple sclerosis (MS) and are usually proposed for patients with active MS. Several studies recently reported that the disease was frequently reactivated between 3 and 6 months after the withdrawal of Tysabri treatment.1–2 These results suggest the need for a therapeutic alternative that can be quickly introduced if Tysabri has to be withdrawn. However, there are also recommendations for a delay of 3 months between two immunosuppressive drugs. We extracted clinical data from the all patients in our region (Alsace, France) who had received at least one month of Gilenya treatment (n=164) between the 1 January 2012 and 1 January 2013. Some 59 patients in this cohort (36%) had switched from Tysabri to Gilenya, mainly due to positive JC virus serology (96.6%). All patients had stopped Tysabri at least 6 months before the time of data analysis, thus allowing us to evaluate the high-risk period (3–6 months) for MS reactivation. We then compared the subgroup of patients with and the subgroup of patients without relapses in terms of the mean delay between stopping Tysabri and starting Gilenya. We also compared the frequency of relapses in patients treated with Gilenya less than 3 months after stopping Tysabri and those treated 3 months or more after. The mean time on Gilenya treatment was 7 months (range: 1–12 months). All patients but three (94.9%) were treated with Gilenya for 6 months or more and were still receiving the treatment at the end of the study. Of the three patients who stopped Gilenya, one stopped because of disease reactivation (three relapses in 5 months) and two stopped because of side effects (gastro-intestinal symptoms) after 1 month. We did not find any differences between the two subgroups regarding age, sex ratio, Expanded Disability Status Scale (EDSS) score or disease duration. Eleven patients (18.6%) had at least one relapse. We observed eight patients (50%) with at least one relapse in the subgroup treated with Gilenya after a delay of 3 months or more (n=16) but only three patients (7%) in the group treated after a delay of less than 3 months (n=43) (p=0.02). The mean delay between the two drugs was 1.7 months (±0.55) for the whole cohort. However, in the subgroup without relapses the mean delay was 1.3 months (±0.32) versus 3.3 months (±1.1) in the group with relapses (p<0.05). Our results clearly argue in favour of an early switch between Tysabri and Gilenya instead of applying the classical washout period of 3 months or more. These results are in accordance with the recent studies showing frequent relapses in patients treated with Gilenya after a delay of 3 months or more.3–5 We recommend reducing as much as possible the delay between the withdrawal of natalizumab and the introduction of fingolimod, to reduce the likelihood of a reactivation of the disease during this high-risk period. One month could be a suitable delay, but this proposition will need to be confirmed in larger studies.

Mycophenolate mofetil in multiple sclerosis: a multicentre retrospective study on 344 patients

Objectives Mycophenolate mofetil (MMF) is an immunosuppressive agent, sometimes used as a disease-modifying therapy for multiple sclerosis (MS). Several studies have reported the relative safety of this treatment but, to date, its efficacy has rarely been described. We performed a retrospective study to assess the safety and efficacy of MMF in patients with MS. Methodology Three French MS centres included all of their patients treated by MMF. The main outcome criterion was annualised relapse rate (ARR) in the 1 year period after onset of MMF compared with the 1 year control period. Treatment with another immunosuppressive drug, such as mitoxantrone or cyclophosphamide, in the 2 years preceding initiation of MMF was included in a subgroup analysis. MMF safety and progression of the Expanded Disability Status Scale (EDSS) score were also assessed. Results 344 patients were included; 149 patients were previously treated with another immunosuppressant (IS group). Mean MMF treatment duration was 25.3±1.1 months. During the 1 year control period, ARR was 1.11±0.08, and for the 1 year treatment period, ARR was reduced significantly to 0.35±0.05 (p<0.0001, Wilcoxon paired test). Adverse events (occurring in 11% of patients) were mainly digestive disorders, benign infections, asthenia and transitory lymphopenia. Concerning the progression of disability, in the subgroup of patients without previous immunosuppressant treatment, EDSS remained stable between initiation and 1 year after the beginning of MMF. Interpretation Our results suggest that MMF can improve or stabilise MS patients and can be used as an alternative therapy.

CD62L test at 2 years of natalizumab predicts progressive multifocal leukoencephalopathy

Flashes of light or phosphenes are the sensation of light without light actually entering the eye. This phenomenon can be evoked by stimulation of the retina or the visual cortex of the brain and can appear unilaterally or bilaterally. From an ophthalmologic perspective, phosphenes can arise from photoreceptor induction by mechanical,1,2 inflammatory,3 or vascular4 stimuli. Therefore, it is necessary to determine the origin of phosphenes for further management. We encountered a patient who reported having phosphenes while moving his eyes laterally. We performed various ophthalmologic imaging studies to identify the origin of these phosphenes.

Air pollution by particulate matter PM10 may trigger multiple sclerosis relapses

Background: Seasonal variation of relapses in multiple sclerosis (MS) suggests that season‐dependent factors, such as ambient air pollution, may trigger them. However, only few studies have considered possible role of air pollutants as relapses risk factor. Objective: We investigated the effect of particulate matter of aerodynamic diameter smaller than 10 &mgr;m (PM10) on MS relapses. Methods: In total, 536 relapsing MS patients from Strasbourg city (France) were included, accounting for 2052 relapses over 2000–2009 period. A case‐crossover design was used with cases defined as the days of relapse and controls being selected in the same patient at plus and minus 35 days. Different lags from 0 to 30 days were considered. Conditional logistic regressions, adjusted on meteorological parameters, school and public holidays, were used and exposure was considered first as a quantitative variable and second, as a binary variable. Results: The natural logarithm of the average PM10 concentration lagged from 1 to 3 days before relapse onset was significantly associated with relapse risk (OR =1.40 [95% confidence interval 1.08–1.81]) in cold season. Consistent results were observed when considering PM10 as a binary variable, even if not significant. Conclusion: With an appropriate study design and robust ascertainment of neurological events and exposure, the present study highlights the effect of PM10 on the risk of relapse in MS patients, probably through oxidative stress mechanisms. HighlightsPM10 has an effect on the risk of relapse in patients with multiple sclerosis.Effect of PM10 on multiple sclerosis relapses seemed to be season‐dependent.Effect of PM10 was found when considered as both continuous variable and peak.

Sclérose en plaques sans traitement de fond : analyse des caractéristiques de 70 patients non traités sur une cohorte de 1187 patients

INTRODUCTION First treatment protocols for multiple sclerosis (MS) have been established in France for over 15 years. Presently, a large majority of patients are treated, or has been treated in the past years, with one or more disease modifying drugs. However, despite a long-term follow-up, a certain patients remain untreated. OBJECTIVE The aim of this study was to determine in a large cohort the proportion of patients who never received any medication for MS and to analyze their profiles and reasons for no treatment. PATIENTS AND METHODS We studied a cohort of 1187 MS patients followed in a French (Alsace) cohort, all included in the EDMUS (European database for Multiple Sclerosis). We then performed a retrospective study on patients followed from at least 5 years (724 patients) and retained those who had never received MS medication. RESULTS Seventy patients (9.8% of the whole cohort) corresponded to the inclusion criteria. They were 57 women and 13 men, mean age 54.9 years (range 33-81). The mean duration of the disease was 20.6 years (range 5-56). MS was of relapsing remitting type in 46 patients (65.7%), primary progressive in 11 patients (15.7%) and secondary progressive in 13 patients (18.6%). In patients with relapsing remitting disease, the annualized relapse rate was 0.33 (range 0.08-1). Mean EDSS was 3.4 after a mean follow-up of 20.6 years. Progression index was 0.16 without any differences between progressive and relapsing remitting forms (0.15 and 0.16 respectively). Reasons for not treating were: lack of disease activity (65.8%), very slow disease progression (10%), patients initial decision followed by very slow progression (14.2%), contraindication for treatment in patients with longstanding progressive disease (10%). There were also patients (4.3%) whose initially well-stabilized disease recently became active again, leading to reconsideration about starting treatment. CONCLUSION After a mean follow-up of 20 years, the proportion of treatment-free patients was around 10%. Most of these patients had a relapsing remitting form with a low rate of relapse or a progressive form with very slow progression.