Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies

Abstract

Background and aims: No consensus exists on how aggressively to treat relapsing–remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC). Methods: RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients 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 disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups. Results: The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5–11.7) years. Mean annual delta-EDSS values were all significantly ( p < 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended 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. Conclusion: Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time.

Neurological Benefits, Clinical Challenges, and Neuropathologic Promise of Medical Marijuana: A Systematic Review of Cannabinoid Effects in Multiple Sclerosis and Experimental Models of Demyelination

“…Among first-line pharmacotherapies in MS is glatiramer acetate; however, the response rate is not greater than 55% due to variability in genetic polymorphisms [72]. Recent studies have demonstrated that long-term disability outcomes tend to be better in MS patients who are treated early with "high-efficacy" medicines including the anti-CD20 monoclonal antibodies rituximab (Rituxan) and ocrelizumab (Ocrevus) targeting B cells, the anti-α4β1 integrin monoclonal natalizumab (Tysabri), the type II topoisomerase inhibitor mitoxantrone (Novantrone), the sphingosine-1-phosphate receptor modulator fingolimod (Gilenya) [73], the monoclonal anti-CD52 alemtuzumab (Campath, Lemtrada) targeting mature lymphocytes, and the purine analogue cladribine (Mavenclad) that delivers "intensive" immune intervention, as compared to patients who are treated with "moderate-efficacy" medications for one or more years prior to "escalation" to the high-potency agents [74,75]. Adverse effects are more complex for the "high-efficacy" treatment strategies and include increased risks of serious infections and cancers associated with immunosuppression, autoimmune diseases associated with immunomodulation, cardiotoxicity, hepatotoxicity, and gastrointestinal and neuropsychiatric disorders [76,77].…”

Escalation vs. Early Intense Therapy in Multiple Sclerosis

“…EIT was significantly associated with lower disability progression measured by mean annual EDSS change compared to baseline value in all time points, including at 5 and 10 years. This effect not only persisted but continued to increase over time despite all patients in the escalation group being escalated to a higher-efficacy DMT [61].…”

“…Recent evidence from several observational studies, suggest that EIT provides a greater benefit than escalation treatment in decreasing the risk of developing SPMS and disability accrual at least in the medium-long term of 5 to 10 years [43,[58][59][60][61][62].…”

No consensus about consensus?

“…When it comes to defining the candidates for higher efficacy treatments Bayas et al [5] restrict this option to treatment failures of "category 1" compounds andin treatment naïve patients -to "probably highly active" disease that they define following recommendations from a recent workshop about "aggressive" MS [8]. Wiendl et al [6] suggest a more open approach to early high efficacy treatment, being encouraged by accumulating evidence from several registry based observational studies supporting the benefits of early high efficacy treatments [9,10]. Both author groups acknowledge that results of controlled prospective studies comparing the benefit-risk balance of the early high efficacy treatment approach ("hit hard and early") versus an escalation approach are still pending.…”

“…If an optimal control of disease activity and progression is our goal only concerns about risk and tolerability can prevent from using the most effective treatment options. The manageable risk and convenience profile emerging from long term extensions of large controlled studies [11][12][13] and from systematic follow up in real world settings [9,10] for some of the high efficacy treatments, namely S1P modulators, anti-CD20 monoclonal antibodies and natalizumab (in JC virus negative patients and probably even more with extended interval dosing) [14] alleviate such concerns more and more.…”