Severe multiple sclerosis reactivation under fingolimod 3 months after natalizumab withdrawal

Daelman, L.; Maitrot, A.; Maarouf, Adil; Chaunu, M.-P.; Papeix, Caroline; Tourbah, Ayman

doi:10.1177/1352458512458009

Cited by 48 publications

(37 citation statements)

References 9 publications

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“…Interestingly, ablation of the RMS with ARA-c also impeded cell egress from the CNS, perhaps identifying a role for immune cell trafficking along the RMS in the resolution of CNS inflammation. The accumulation of inflammatory cells and the prevention of their egress in the continued inflammation associated with active MS plaques may provide an explanation for the increasing numbers of adverse events associated with fingolimod treatment in MS (45). However, the identity of the inflammatory cell(s) that might be detrimental in this context is not clear.…”

Section: Discussionmentioning

confidence: 99%

Immune cell trafficking from the brain maintains CNS immune tolerance

Mohammad¹,

Tsai²,

Ruitenberg³

et al. 2014

J. Clin. Invest.

113

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In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.

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Section: Discussionmentioning

confidence: 99%

Immune cell trafficking from the brain maintains CNS immune tolerance

Mohammad¹,

Tsai²,

Ruitenberg³

et al. 2014

J. Clin. Invest.

113

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“…The only available data derive from case reports and observational studies on MS patients who switched from natalizumab to fingolimod, generally showing a disease reactivation after the switch with few exceptions [16,17,18,19,20,21]. It has been suggested that early fingolimod start (i.e., before the end of the recommended natalizumab 3-month washout interval) might prevent relapse occurrence [22,23].…”

Section: Discussionmentioning

confidence: 99%

Are Natalizumab and Fingolimod Analogous Second-Line Options for the Treatment of Relapsing-Remitting Multiple Sclerosis? A Clinical Practice Observational Study

Gajofatto

Mr²,

Deotto³

et al. 2014

Eur Neurol

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Background: It is unclear whether natalizumab and fingolimod have analogous efficacy for relapsing-remitting multiple sclerosis (RRMS). Objective: To compare the outcome of RRMS patients treated with either therapy. Methods: RRMS patients treated with natalizumab or fingolimod at Verona Hospital, Italy, were included. The study design was retrospective, based on prospectively collected clinical and MRI data. As efficacy outcomes, time to relapse, relapse rate, expanded disability status scale (EDSS) score change, and new T2/gadolinium-enhancing lesions on brain MRI were compared over treatment period between the two groups. Multivariate Cox and logistic regression models were used to control for potential confounders. Results: Fifty-seven subjects receiving natalizumab and 30 receiving fingolimod for a median duration of 23 (1-63) and 22 (2-35) months, respectively (p = 0.22) were included. Patients treated with natalizumab had a more active pre-treatment disease course compared to those treated with fingolimod. In multivariate analysis, the relapse risk was reduced in patients on natalizumab (Hazard Ratio = 0.33; 95% CI = 0.11-1.03; p = 0.056) compared to those on fingolimod. There was no significant difference in EDSS and MRI outcomes. No relevant unexpected adverse events occurred. One patient discontinued natalizumab for progressive multifocal leukoencephalopathy. Conclusions: RRMS patients receiving natalizumab had higher baseline disease activity and lower relapse risk over 20 months of treatment compared to those receiving fingolimod. Head-to-head randomized clinical trials are needed.

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“…Rinaldi et al observed that, in a cohort of 22 patients exposed to NAT and subsequently treated with FTY after a washout period of three months, the rate of clinical and/or radiological relapses was 31.8% during the first month of therapy and that there was a rebound in 14% of patients in the first nine months of therapy [19]. There are several other reports of clinical and radiological relapses after NAT discontinuation despite treatment with FTY after at least three months of washout [20,21,22,23]. Havla et al compared a cohort of 26 patients previously exposed to NAT and subsequently treated with FTY with a cohort of 10 patients who received no immunomodulatory treatment after discontinuation of NAT and found a significant decrease in the median ARR after NAT (0.0 vs. 1.5) and in the number of patients with gadolinium-enhancing lesions (9 vs. 67%) [24].…”

Section: Discussionmentioning

confidence: 99%

Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab

et al. 2014

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Background: To evaluate efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis, particularly in patients previously exposed to natalizumab. Method: Prospective observational single-centre second-line cohort study. Results: Among 71 patients treated with fingolimod 0.5 mg/day for a mean duration of 21.75 w 12.60 months, the annualized relapse rate was 0.66 (C.I. 95% 0.27-1.05) with a significant difference between 26 patients with prior natalizumab exposure (1.15; C.I. 95% 0.12-2.17) and 45 not exposed (0.38; C.I. 95% 0.18-0.57; p = 0.002). In a multivariate negative regression model, only previous exposure to natalizumab (p = 0.049) and duration of fingolimod treatment (p < 0.001) significantly correlated with the annualized relapse rate. Previous exposure to natalizumab (p = 0.028) and duration of treatment with fingolimod (p < 0.001) were confirmed by restricting the analysis to the first 12 months of treatment with fingolimod, but were no longer statistically significant by analysing only patients (n = 51) with at least 12 months of treatment with fingolimod (0.32; C.I. 95% 0.08-0.55 vs. 0.22; C.I. 95% 0.11-0.32; p = NS). No differences were observed in neuroradiological outcomes and disability progression in patients exposed to natalizumab and not exposed. The rate of discontinuation due to adverse events was 11.3%, with no differences between the two groups. Conclusions: Our study confirms efficacy and side effects of fingolimod in a second-line clinical practice cohort. Prior natalizumab exposure and duration of treatment with fingolimod are independent predictors of annualized relapse rate during the first 12 months of treatment with fingolimod, but not in the long-term, and may be influenced by the 3 months washout period between the two drugs. i 2014 S. Karger AG, Basel

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Severe multiple sclerosis reactivation under fingolimod 3 months after natalizumab withdrawal

Cited by 48 publications

References 9 publications

Immune cell trafficking from the brain maintains CNS immune tolerance

Immune cell trafficking from the brain maintains CNS immune tolerance

Are Natalizumab and Fingolimod Analogous Second-Line Options for the Treatment of Relapsing-Remitting Multiple Sclerosis? A Clinical Practice Observational Study

Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab

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