Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability ...because of greater capacity for repair.
To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS).
This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73 564 patients from 120 MS centers were available in the register.
The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors.
Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT.
After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median IQR age at onset, 28.7 22.8-36.2 years; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001).
PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.
Background
Cognitive impairment (CI) is a prevalent and debilitating manifestation of multiple sclerosis (MS); however, it is not included in the widely used concept of No Evidence of Disease ...Activity (NEDA-3). We expanded the NEDA-3 concept to NEDA-3 + by encompassing CI assessed through the Symbol Digit Modality Test (SDMT) and evaluated the effect of teriflunomide on NEDA3 + in patients treated in a real-world setting. The value of NEDA-3 + in predicting disability progression was also assessed.
Methods
This 96-weeks observational study enrolled patients already on treatment with teriflunomide for ≥ 24 weeks. The predictiveness of NEDA-3 and NEDA-3 + at 48 weeks on the change in motor disability at 96 weeks was compared through a two-sided McNemar test.
Results
The full analysis set (n = 128; 38% treatment naïve) featured relatively low level of disability (baseline EDSS = 1.97 ± 1.33). NEDA-3 and NEDA-3 + statuses were achieved by 82.8% and 64.8% of patients, respectively at 48 weeks vs. baseline, and by 57.0% and 49.2% of patients, respectively at 96 weeks vs. baseline. All patients except one were free of disability progression at Week 96, and NEDA-3 and NEDA-3 + were equally predictive. Most patients were free of relapse (87.5%), disability progression (94.5%) and new MRI activity (67.2%) comparing 96 weeks with baseline. SDMT scores were stable in patients with baseline score ˃35 and improved significantly in those with baseline score ≤ 35. Treatment persistence was high (81.0% at Week 96).
Conclusion
Teriflunomide confirmed its real-world efficacy and was found to have a potentially beneficial effect on cognition.
Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking.
To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a ...real-world population of patients with PPMS.
This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up.
The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models.
Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective).
From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean SD age, 43.0 10.7 years; 366 female patients 55.0%), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio aHR, 1.32; 95% CI, 1.13-1.55; P < .001), superimposed relapses (aHR, 2.37; 95% CI, 1.24-4.54; P = .009), and DMT exposure (aHR, 1.75; 95% CI, 1.04-2.94; P = .03) were associated with a higher risk of an EDSS score of 7.0, whereas the interaction term between DMT and superimposed relapses was associated with a reduced risk of EDSS score of 7.0 (aHR, 0.33; 95% CI, 0.16-0.71; P = .004). Similar findings were obtained when treatment according to DMT class was considered and when DMT was included as a time-dependent covariate. These results were confirmed in the subgroup of patients with available magnetic resonance imaging data.
Results of this comparative effectiveness research study suggest that inflammation also occurs in patients with PPMS, may contribute to long-term disability, and may be associated with a reduced risk of becoming wheelchair dependent by current licensed DMTs.
Background
Active relapsing–remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as “relapsing MS” (RMS). The aim of this cross-sectional study was to assess ...drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD).
Methods
RRMS and SPMS patients with at least one relapse in a time window of 2 years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT’s class moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs.
Results
A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (
p
< 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02–0.37), Natalizumab (0.48, 0.30–0.76), Ocrelizumab (0.1, 0.02–0.45) and Rituximab (0.23, 0.06–0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31–0.59), especially anti-CD20 drugs (0.14, 0.05–0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs.
Conclusions
More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch.
To assess relapses, disability progression and the role of disease modifying drugs (DMDs) in the year after delivery in women with multiple sclerosis (MS).
We prospectively followed-up pregnancies ...occurring between 2002 and 2008 in women with MS, recruited from 21 Italian MS centres. The risk of relapses and disability progression in the year after delivery was assessed using time-dependent Cox regression analysis.
350 out of 423 pregnancies were assessed (pregnancies not resulting in live birth and with a postpartum follow-up period shorter than 1 year were excluded from the analysis). 148 patients (42.3%) had at least one relapse in the year after delivery. An Expanded Disability Status Scale (EDSS) score at conception ≥2.0 (HR=1.4; 95% CI 1.1 to 2.0; p=0.046) and a higher number of relapses before (HR=1.5; 95% CI 1.2 to 1.8; p<0.001) and during pregnancy (HR=2.3; 95% CI 1.6 to 3.4; p<0.001) were related to a higher risk of postpartum relapses. On the contrary, early DMD resumption after delivery marginally reduced the risk of postpartum relapses (HR=0.7, 95% CI 0.4 to 1.0; p=0.079). Moreover, 44/338 women progressed by at least one point on the EDSS. Disability progression was associated with a higher number of relapses before (HR=1.4, 95% CI 1.1 to 1.9; p=0.047) and after delivery (HR=2.7, 95% CI 1.4 to 5.2; p=0.002).
Our findings show an increased risk of postpartum relapses and disability accrual in women with higher disease activity before and during pregnancy. Since it may reduce the risk of postpartum relapses, early DMD resumption should be encouraged, particularly in patients with more active disease.
Introduction
EASIER is a multicenter, observational, cross-sectional study investigating the consumption of healthcare resources, including healthcare professional (HCP) active working time, the ...costs associated with the current natalizumab intravenous (IV) administration, and the potential impact of the adoption of subcutaneous (SC) route.
Methods
The EASIER study has three parts: (1) time and motion study to measure healthcare resources and working time needed for natalizumab IV administration using a digital data collection tool operated directly by HCPs; (2) HCP structured questionnaire-based estimation of the potential impact of natalizumab SC vs. IV administration; and (3) patient survey on the burden of natalizumab administration.
Results
Nine Italian multiple sclerosis (MS) centers measured 404 IV natalizumab administration procedures and administered 26 HCP questionnaires and 297 patient questionnaires. Patients had a mean of 52 (range 1–176) previous IV administrations and spent a mean (median, IQR) of 152 (130, 94–184) minutes in the center per each IV procedure, with IV infusion covering 50% of the total. Including patient travel time, an average of 5 h was dedicated to each IV administration. Active working time by HCP amounted to 29 min per IV administration procedure, 70% of which by nursing staff.
With adoption of the SC route, HCPs estimated a 50% reduction in patient procedure time and 55% lower HCP active working time. This translated into a 63% cost reduction for the MS center per natalizumab administration procedure.
Conclusions
SC natalizumab administration will consistently reduce consumption of patient and HCP times per procedure and associated costs.
Background and purpose
Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions TDLs) is a diagnostic and therapeutic challenge. We performed a ...multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS.
Methods
One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected.
Results
TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11–68 years, interquartile range IQR: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute‐phase treatment was administered, and almost one‐half of the patients (46.6%) were treated with high‐efficacy treatments. After a median follow‐up of 2.3 years (range: 0.1–10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0–7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio OR: 1.08, 95% confidence interval CI: 1.03–1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02–2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18–9.5, p < 0.001) at baseline.
Conclusions
The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.
Multiple sclerosis (MS) presenting at onset with tumefactive demyelinating lesions (shown here, a representative magnetic resonance image) should be considered a part of the MS spectrum, but with its own peculiar features. Among them, tumefactive MS frequently has a multifocal clinical onset, which often requires acute‐phase retreatments. The recurrence of further tumefactive lesions is rare, and the median 2‐year Expanded Disability Status Scale score is 1.5, though patients were frequently treated with high‐efficacy drugs, a therapeutic choice that may have influenced the disease course. Among tumefactive MS‐specific prognostic factors, tumefactive lesions, with an infiltrative magnetic resonance imaging pattern at onset, are associated with worse disability outcomes.
Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the ...disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 53.2% females, mean age 45.3 ± 25.4 years) and 353 with IFNb-1b (133 37.8% females, mean age 48.5 ± 19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p = 0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p = 0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67–5.7; p = 0.006 and HR 2.04, 25%CI 1.22–3.35; p = 0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04–4.87; p = 0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.
