Background

to date, no consensus exists on how aggressively and timely treat relapsing-remitting multiple sclerosis (RRMS) patients.

Objectives

To evaluate disability trajectories in a cohort of RRMS patients stratified according to two different disease modifying therapy (DMT) strategies, early intensive treatment (EIT) or moderate-efficacy treatment followed by escalation to higher-efficacy DMT (ESC).

Methods

RRMS patients with ≥5-year follow-up and ≥3 visits after start DMT, and a first visit within 3 years from disease onset were selected from the Italian MS Registry. EIT group included patients who received, as first DMT, fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group included those who received the high efficacy DMT after ≥1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score(PS)-matched for characteristics at the first DMT. The follow-up time from the first DMT start has been segmented into 12-month periods. The disability trajectories were evaluated by applying a longitudinal model for repeated measures with an autoregressive variance-covariance structure. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual EDSS changes compared to baseline values (delta-EDSS) in EIT and ESC groups.

Results

The study cohort included 2,652 RRMS patients from 62 Italian MS centers. The PS matching procedure produced 365 pairs. The median (IQR) follow-up after the first DMT start was 8.5 (6.5–11.7) years. All of the ESC patients escalated to a higher-efficacy DMT after a median time of 5.1 (3.1–8.4) years. The estimated baseline EDSS with relative confidence interval (95% CI) value was 2.52 (2.33-2.71) in the ESC group and 2.45 (2.26-2.64) in the EIT group. Mean delta-EDSS at each 12 month period were all significantly (p<0.02) higher in the ESC group compared to the EIT group. In particular, the mean delta-EDSS differences between the two groups tend to increase from 0.1 (0.01-0.19, p=0.03) at 1 year to 0.30 (0.07-0.53, p=0.009) at 5 years and to 0.67 (0.31-1.03, p=0.0003) at 10 years.

Conclusions

Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression and the effect tends to increase over time despite patients in the ESC group escalated to a higher-efficacy DMT.

Background

Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies.

Objectives

In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group.

Methods

RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ²).

Results

Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ²=4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ²=7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ²=0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ²=0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ²=2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p=0.02; τ²=5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p=0.02; τ²=1.00).

Conclusions

We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies.

Background

The advent of oral first-line disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has expanded considerably the therapeutic landscape. However, here is an important need to gather real-world evidence data regarding long-term treatment effectiveness and safety in comparison to the old first-line injectables DMTs.

Objectives

To compare old injectable and oral first line DMTs for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation in a cohort of RRMS patients extracted from the Italian MS Registry.

Methods

Multicentre, observational, retrospectively acquired and propensity-adjusted cohort study of RRMS-naïve patients in the Italian MS Register starting injective or oral first line DMTs between 1 January 2010 and 31 December 2017 to evaluate their impact on disability outcomes in patients. Enrolled patients were divided into two groups: injectable group (IG) and oral group (OG).

Results

From a cohort of 11,416 patients, 4,602 were enrolled (3,919 on IG and 683 on OG). IG had higher rate of women (67.3% vs 63.4%, p<.05) and a lower mean age (36.1±10.9 vs 38.9±11.8, p<.001). For the event time to first relapse, Cox models after PS adjustment revealed a lower risk for OG patients (HR 0.58 CI95% 0.47-0.70, p<0.001). About the risk of CDP, no differences were found in the two groups (HR 1.14 CI95% 0.88-1.48, p=0.306). About the risk of DMT discontinuation, OG patients showed lower risk (HR 0.70 CI95% 0.57-0.86 p=0.001) than IG patients.

Conclusions

Real-world data from the Italian MS registry suggest that first line oral DMTs are associated to lower risks of experiencing a new relapse and of therapy discontinuation in comparison to injectable DMTs.

Background

No clear metrics for sensitive and reliable identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive (SP)MS are available.

Objectives

To compare diagnostic performances of two different data-driven Secondary Progressive Multiple Sclerosis definitions.

Methods

patient with RRMS with a follow-up ≥5 years, with a current age ≥18 years, and with ≥3 EDSS scores recorded were selected from the Italian MS Registry. Annual incidence of SPMS conversion was reported as number of patients converting to SP every 100 patients/year. Three different SPMS definitions have been used. Data-driven definitions based on the Lorscheider’s algorithm (LA) and on the EXPAND trial inclusion criteria were validated, using the neurologist’s definition as gold standard, in terms of calibration, discrimination and goodness of fit by calculating: sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), the Akaike information criterion (AIC), the Area Under the Curve (AUC). The overall calibration of the data-driven definitions was evaluated by the Calibration Slope test.

Results

a cohort of 10,240 RRMS patients was extracted from the Italian MS Registry. According to the neurologist judgment, 880 (8.59%) patients were classified as SPMS in the dataset. By applying the LA and the EXPAND definition, 1,806 (17.64%) and 1,134 (11.07%) patients, respectively, were classified as SPMS. The annual rate of SP conversion during the follow-up was 0.74 every 100 patients/year based on the neurologist’s definition, 1.57 every 100 patients/year using the LA and 0.94 every 100 patients/year applying the EXPAND definition. Both the data-driven definitions were well calibrated, with a p-value of the Calibration Slope test higher than 0.05 (LA=0.55; EXPAND definition=0.57). The AIC (LA=4301; EXPAND definition=5510) and the R-Square (LA=0.15 vs EXPAND definition=0.05), were in favor of the LA. The LA showed a greater discrimination power (AUC: 0.83 vs 0.65) and a higher sensitivity (77.1% vs 38.0%) in comparison to the EXPAND definition. Both definitions showed similar specificity (88.0% vs 91.5%). The PPV and the NPV were both higher using the LA than those obtained by the EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%, respectively).

Conclusions

An accurate definition of SP transition is needed for a timely and efficacious treatment of SPMS patients. Real-world data from the Italian MS Registry suggests that data-driven definitions had a greater ability to capture SP transition than neurologist’s definition and that the global accuracy of LA seems to be higher than a definition based on the EXPAND trial inclusion criteria.

Background

A wash-out duration lasting >1–2 months between the majority of sequential disease-modifying therapies (DMTs) is associated with an increased risk of disease reactivation in Multiple Sclerosis (MS) patients.

Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1-2 months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if lymphocyte recovery is still incomplete and that shorter wash-out periods do not affect the disease reactivation risk.

Objectives

To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent initiation in relation to the duration of wash-out between the drugs using data from the Italian MS Registry.

Methods

Patients who initiated alemtuzumab, rituximab, ocrelizumab or cladribine within six months of FTY discontinuation, and with a follow-up of at least six months, or until a relapse occurred, were included in the study. The risk of relapses was assessed in relation to different wash-out durations (<6, 6-11, 12-17 and >/=18 weeks) using a Poisson regression analysis (and reported as incidence rate ratio - IRR) and a Cox proportional hazards model including age, disease duration, relapses during FTY treatment, EDSS and reason for FTY discontinuation as covariates.

Results

Inclusion criteria were met by 329 patients (226F, 103M; mean age 41±10 years). Following a median wash-out period of 11 weeks [IQR: 6-16], 175 patients started alemtuzumab, 69 rituximab, 68 ocrelizumab and 17 cladribine. Ninety patients relapsed during the wash-out period and 72 during the subsequent cell-depleting therapy. During the cell-depleting treatment, IRR for a relapse was significantly greater in patients with a washout-period of 12-17 (IRR (95%CI): 2.4 (1,1-5,5); p=0.037) and >/=18 weeks (6.0 (2.8-12.7); p<0.001) compared to the reference period (<6 weeks).

The multivariable Cox analysis showed that the time to a relapse was significantly influenced by the occurrence of relapses during FTY treatment (HR (95%CI): 1.4 (1.2-1.7); p<0.001). Moreover, wash-out durations of 6-11, 12-17 and >/=18 weeks were associated with a higher risk of a relapse in comparison to wash-out durations shorter than 6 weeks (3.8 (1.1-13.2); p=0.037; 6.0 (1.7-21.9); p=0.006; 16.3 (4.8-56.3); p<0.001, respectively).

Conclusions

The risk of relapses during a cell-depleting therapy following a sequestering agent, namely FTY, increases progressively with the duration of wash-out, underlining the need of a short wash-out period also in this type of treatment sequence.