MS disease activity in RESTORE : a randomized 24-week natalizumab treatment interruption study

/pdf/ms-disease-activity-in-restore-a-randomized-24-week-36700o55fe.pdf

MS disease activity in RESTORE: A randomized 24-week natalizumab treatment interruption study

A number of studies have reported flare-up of multiple sclerosis (MS) disease activity after cessation of natalizumab, increasing to a level beyond the pre-natalizumab treatment level. Our aim was to describe the development in clinical disease activity following cessation of natalizumab therapy in a large unselected cohort of highly active patients. We studied 375 highly active patients who had suffered at least two significant relapses within 1 year or three relapses within 2 years, or had been treated with mitoxantrone for highly active disease. All patients had discontinued therapy with natalizumab after at least 24 weeks on therapy, and had been followed 3–12 months (mean 8.9 months) after cessation of natalizumab therapy. The annualised relapse rate before start of natalizumab therapy was 0.94 (95 % confidence interval [CI] 0.88–1.00), 0.47 (95 % CI 0.43–0.52) during natalizumab therapy, 0.63 (95 % CI 0.51–0.76) 1–6 months after natalizumab and 0.55 (95 % CI 0.42–0.70) 7–12 months after natalizumab. However, 83 (22 %) of the patients could be classified as showing rebound of relapses, defined as a higher individual relapse rate after cessation of natalizumab than before natalizumab. These patients had a higher annualised relapse rate during natalizumab therapy. For the whole patient group, the relapse rate after discontinuation did not exceed the pre-natalizumab relapse rate at any time, but 22 % of the patients showed rebound of relapses after discontinuation of natalizumab.

Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients

Because the treatment of multiple sclerosis (MS) may span decades, the need often arises to make changes to the treatment plan in order to accommodate changing circumstances. Switching drugs, or the discontinuation of immunomodulatory agents altogether, may leave patients vulnerable to relapse or disease progression. In some cases, severe MS disease activity is noted clinically and on MRI after treatment withdrawal. When this disease activity is disproportionate to the pattern observed prior to treatment initiation, patients are said to have experienced rebound. Of the US Food and Drug Administration (FDA)-approved agents to treat MS, the drugs most commonly implicated in rebound are natalizumab and fingolimod. In this review based on the reported cases and data from clinical trials, we characterize disease rebound after fingolimod cessation. We also outline fingolimod rebound management considerations, summarizing what evidence is available to help clinicians mitigate the risk of rebound, switch therapies, and treat rebound events when they occur. The commonly encountered situation of fingolimod discontinuation prior to pregnancy is also discussed.

/pdf/fingolimod-rebound-a-review-of-the-clinical-experience-and-4idycaknra.pdf

Fingolimod Rebound: A Review of the Clinical Experience and Management Considerations.

Clinical and/or neuroimaging evidence of disease reactivation has been described in multiple sclerosis (MS) patients after a break from natalizumab. Whether fingolimod might be a therapeutic option following natalizumab needs to be evaluated. Twenty-two relapsing remitting MS patients having JC virus antibodies (JCVAb+) in serum were shifted from natalizumab to fingolimod after a three-month washout period. Neurological evaluation with the Expanded Disability Status Scale (EDSS) was performed monthly for a mean follow-up period of nine months. In 20/22 patients, brain magnetic resonance imaging (MRI) was obtained within one month after therapy initiation. Disease reactivation was observed in 11/22 (50%) patients: clinical relapses in six patients (four patients within the first month of therapy) and MRI activity in a further five patients (three patients within the first month of therapy). Clinical and/or MRI signs suggestive of disease rebound were observed in three patients. Our data indicate that fingo...

Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings.

The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patient's choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting.

/pdf/fingolimod-versus-interferon-beta-glatiramer-acetate-after-1g0u0ka1fu.pdf

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis

Natalizumab and drug holiday in clinical practice: An observational study in very active relapsing remitting Multiple Sclerosis patients

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Natalizumab and drug holiday in clinical practice: An observational study in very active relapsing remitting Multiple Sclerosis patients