Effect of tobacco use on disease activity and DMT discontinuation in multiple sclerosis patients treated with dimethyl fumarate or fingolimod.

BACKGROUND: Tobacco exposure is a modifiable risk factor for multiple sclerosis (MS). Studies evaluating the relationship between tobacco, disease activity, and disease modifying therapy (DMT) persistence yielded conflicting results. We sought to address this issue with data from clinical practice. OBJECTIVE: To compare 24-month disease outcomes in tobacco versus non-tobacco users treated with dimethyl fumarate (DMF) or fingolimod (FTY) in clinical practice. METHODS: We retrospectively identified 659 MS patients treated with DMF or FTY, stratified by patient-reported tobacco use. DMT discontinuation and measures of disease activity at 24 months were assessed using propensity score (PS) weighting. Outcome estimates were calculated as tobacco vs non-tobacco use. RESULTS: 164 tobacco users (DMF n = 101; FTY n = 63) and 495 non-tobacco users (DMF n = 294; FTY n = 201) were identified. Tobacco (39.4%) and non-tobacco (34.4%) users were equally likely to discontinue DMT (OR = 1.17, 95% CI 0.79, 1.75), but tobacco users discontinued therapy earlier (HR = 1.53, 95% CI 1.06, 2.43). There were no differences in ARR (rate ratio = 1.39, 95% CI 0.97, 1.96). However, tobacco users had decreased odds of NEDA-2 (OR = 0.61, 95% CI 0.44, 0.83). CONCLUSION: Our findings suggest that tobacco is a negative risk factor for inflammatory disease activity and earlier DMF and FTY discontinuation.

Disease activity outcomes with different washout periods after switching from natalizumab to an alternative disease-modifying therapy.

BACKGROUND: Washout periods (WPs) are increasingly shortened due to concerns of disease rebound when patients on natalizumab are switched to alternative disease-modifying therapies (DMTs). OBJECTIVE: To characterize disease activity outcomes with different WPs when switching from natalizumab. METHODS: We conducted a retrospective review of patients switching from natalizumab in our MS clinics. Disease activity (relapse, new T2 lesions and/or gadolinium enhancing lesions) between different WPs (days): 0-30, 31-60, and 61-180 were compared, during the first year after switching from natalizumab. To determine predictors of disease activity when switching to any DMT, multivariate logistic regression analysis was used. Post hoc analyses were performed to evaluate the impact of individual DMTs on disease activity. RESULTS: 335 patients discontinued natalizumab with WP: 0-30 (n = 104), 31-60 (n = 113), and 61-180 (n = 136). Disease activity occurred in 44.2% of patients in the 0-30 WP group, 18.6% in the 31-60 WP group, and 27.2% in the 61-180 WP group. There was a significant decrease in odds of disease activity with longer WP when compared to the 0-30 group: 31-60 (OR 0.241, 95% CI 0.108-0.514, p value < 0.001), and 61-180 (OR 0.439, 95% CI 0.218-0.871, p value < 0.05). CONCLUSIONS: Unexpectedly, in our study, patients who had the shortest WP 0-30 days had the most disease activity. Shortening WPs may not be enough to suppress disease activity post-natalizumab switch.

Duration of natalizumab therapy and reasons for discontinuation in a multiple sclerosis population.

OBJECTIVE: To determine multiple sclerosis patient characteristics that predict a shorter duration of natalizumab treatment. METHODS: The Tysabri Outreach: Unified Commitment to Health database was reviewed to identify patients treated with natalizumab at our centers. Cox proportional hazards models were used to evaluate patient characteristics associated with shorter treatment durations on natalizumab. Associations were also assessed with respect to specific reasons for stopping natalizumab. RESULTS: We identified 554 patients who began and stopped natalizumab treatment during the observation period. The average disease duration at natalizumab initiation was 7.6 years, and the average number of infusions was 30. The multivariable Cox proportional hazards model identified greater age (P = 0.035), longer disease duration (P < 0.001), progressive relapsing multiple sclerosis phenotype (P = 0.003), current smoking (P = 0.031), and greater depression (P = 0.026) as significant predictors for natalizumab discontinuation. Greater disability levels (P = 0.022) and gadolinium-enhancing lesions on baseline magnetic resonance imaging (P < 0.001) were significantly associated with longer natalizumab treatment. Individuals with progressive relapsing multiple sclerosis had a 14-fold increased hazard of discontinuing natalizumab due to inflammatory events (P < 0.001) than those with relapsing-remitting multiple sclerosis. Smokers had an 80% increased hazard of discontinuation due to intolerance (P = 0.008). CONCLUSIONS: Our results suggest that smoking, depression, and a progressive relapsing multiple sclerosis phenotype are associated with shorter natalizumab treatment durations.

Effect of switching from natalizumab to moderate- vs high-efficacy DMT in clinical practice.

OBJECTIVE: To assess the real-world comparative effectiveness of switching from natalizumab (NTZ) to a moderate-efficacy (Mod) disease-modifying therapy (DMT) vs high-efficacy therapy (HET) in patients with multiple sclerosis (MS). METHODS: Patients discontinuing NTZ at two MS centers (n = 556) who switched to Mod DMT (n = 270) vs HET (n = 130) were assessed using propensity score (PS) weighting. PS model covariates included demographics and baseline clinical and MRI characteristics. All outcomes were reported as Mod DMT vs HET. RESULTS: Of the patients included in the study, 48.6% switched to Mod DMT (dimethyl fumarate, n = 130; fingolimod, n = 140) vs 23.4% who switched to HET (ocrelizumab, n = 106; rituximab, n = 17; alemtuzumab, n = 7). Within the first 6 months post-NTZ, switchers to Mod DMT experienced comparable relapses (odds ratio [OR] = 1.36, 95% confidence interval [CI] [0.72-1.66], p = 0.724), although they had increased MRI activity on treatment (OR = 2.59, 95% CI [1.09-3.57], p = 0.037). By 24 months post-NTZ, there was no difference in the annualized relapse rate (OR = 1.44, 95% CI [0.69-1.59], p = 0.334) or time to first clinical relapse (HR = 2.12, 95% CI [0.87-5.17], p = 0.090), although switchers to Mod DMT had higher gadolinium-enhancing (GdE) lesions (OR = 3.62, 95% CI [1.56-5.21], p = 0.005), earlier time to first GdE lesion (HR = 6.67, 95% CI [2.06-9.16], p = 0.002), lower proportion with the absence of disease activity (OR = 0.41, 95% CI [0.21-0.71], p = 0.004), and higher risk of disability progression on T25FW (OR = 1.83, 95% CI [1.06-3.02], p = 0.043) and 9-HPT (OR = 1.81, 95% CI [1.05-3.56], p = 0.044). CONCLUSION: Patients switching from NTZ to Mod DMT vs HET were at relatively increased risk of disease activity within the first 6 months of NTZ withdrawal that was sustained at 24 months, yielding greater disability progression.

Comparative discontinuation, effectiveness, and switching practices of dimethyl fumarate and fingolimod at 36-month follow-up.

BACKGROUND: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMTs) for relapsing multiple sclerosis (MS). There are currently no known head-to-head studies comparing DMF and FTY over 36 months, which leaves their relative effectiveness unknown. OBJECTIVE: To assess real-world discontinuation, effectiveness, and switching practices of DMF and FTY over 36 months along with disease activity after switching DMT. METHODS: Patients prescribed DMF (n = 737) and FTY (n = 535) from two academic MS centers were retrospectively reviewed. Discontinuation and effectiveness outcomes were assessed using propensity score (PS) weighting. PS model covariates included sociodemographics and clinical and MRI characteristics. RESULTS: Discontinuation was more common in DMF (58.3%) versus FTY (45.2%) over 36 months [OR = 1.81, 95% CI (1.41-2.31), p < .001], largely driven by intolerance [OR = 1.63, 95% CI (1.18-1.73), p < .001]. There were no differences in clinical relapses [OR = 1.27, 95% CI (0.90-1.79), p = .17], gadolinium-enhancing (GdE) lesions [OR = 1.25, 95% CI (0.85-1.84), p = .26], or new T2-hyperintense lesions [OR = 0.99, 95% CI (0.74-1.32), p = .93]. Within 12 months of DMF/FTY discontinuation, switchers to highly effective therapy (HET) versus other DMTs (injectables/orals) had fewer relapses (DMF/HET, 5.9% versus DMF/Other, 14.2%, p = .03; FTY/HET, 11.6% versus FTY/Other, 18.0%, p = .04) and fewer GdE lesions post-FTY (DMF/HET, 10.3% versus DMF/Other, 14.3%, p = .36; FTY/HET, 11.9% versus FTY/Other, 21.5%, p = .04). CONCLUSION: This combined analysis showed similar effectiveness for DMF and FTY over 36 months with higher DMF discontinuations. Disease activity was lower in switchers to HET versus injectable/oral therapies after DMF/FTY cessation.

Changes in patient-reported outcomes between continuers and discontinuers of disease modifying therapy in patients with multiple sclerosis over age 60.

BACKGROUND: The risk benefit ratio of continuing immunomodulating disease modifying therapy (DMT) in older MS patients is unknown. To date, only retrospective observational studies on DMT discontinuation have been published. In these studies, DMT discontinuation was based solely on disease stability and patients frequently had to restart treatment. Our prior study demonstrated that discontinuing DMT can be more successful when age is also considered. The impact of discontinuing DMT on patients' quality of life has not been previously explored. The objective of this study is to determine changes in outcomes over time between those who continued versus discontinued DMT using patient-reported outcomes (European Quality of Life 5 Dimensions (EQ-5D) index, Performance Scales (PS), and Patient Health Questionnaire (PHQ9)) and walking speed (Timed 25-foot walk) in MS patients over age 60. METHODS: We conducted a retrospective, observational study in which we identified patients from our MS clinics who were 60 years of age or older and had been on DMT ≥2 years. We compared outcome evolution over time among treatment groups (continuers, discontinuers before discontinuation (DBD), and discontinuers after discontinuation (DAD)), by creating separate mixed-effects linear regression models that included an interaction term between time from age 60 and treatment group to study outcome trajectories. Independent variables were time from age 60 and treatment group, with the following covariates: age at diagnosis, gender, disease course at MS diagnosis, time on DMT, baseline DMT, and ambulation status at age 60. RESULTS: 178 of 600 patients discontinued DMT, and 89.3% (n = 159) of those who discontinued remained off DMT. Only the EQ-5D mixed-effects linear regression model with the interaction term was statistically significant (omnibus p-value = 0.043). The slope relating time to EQ-5D was significantly different when comparing continuers to DBD (0.009, 95% CI 0.002-0.016, p-value = 0.015). The slopes were not significantly different when comparing continuers to DAD, or when comparing the before and after discontinuation slopes among the discontinuers. With the interaction term removed, there were no significant differences between the three groups for any other outcome. CONCLUSION: Most patients over age 60 who discontinued DMT remained off treatment. Among the outcomes, only EQ-5D demonstrated significant differences over time, with continuers having lower quality of life scores compared to DBD. There were no significant group differences in PS, T25FW and PHQ-9. Overall, stopping DMT appears to have minimal effect on outcomes over the study period in patients over age 60.