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. 2023 Jul 25;101(4):e438-e450.
doi: 10.1212/WNL.0000000000207443. Epub 2023 Jun 8.

Rituximab De-escalation in Patients With Neuromyelitis Optica Spectrum Disorder

Stanislas Demuth  1 , Nicolas Collongues  1 , Bertrand Audoin  1 , Xavier Ayrignac  1 , Bertrand Bourre  1 , Jonathan Ciron  1 , Mikael Cohen  1 , Romain Deschamps  1 , Françoise Durand-Dubief  1 , Elisabeth Maillart  1 , Caroline Papeix  1 , Aurélie Ruet  1 , Helene Zephir  1 , Romain Marignier  1 , Jerome De Seze  2 ; NOMADMUS Study Group
Collaborators, Affiliations

Rituximab De-escalation in Patients With Neuromyelitis Optica Spectrum Disorder

Stanislas Demuth et al. Neurology. .

Abstract

Background and objectives: Exit strategies such as de-escalations have not been evaluated for rituximab in patients with neuromyelitis optica spectrum disorder (NMOSD). We hypothesized that they are associated with disease reactivations and aimed to estimate this risk.

Methods: We describe a case series of real-world de-escalations from the French NMOSD registry (NOMADMUS). All patients met the 2015 International Panel for NMO Diagnosis (IPND) diagnostic criteria for NMOSD. A computerized screening of the registry extracted patients with rituximab de-escalations and at least 12 months of subsequent follow-up. We searched for 7 de-escalation regimens: scheduled discontinuations or switches to an oral treatment after single infusion cycles, scheduled discontinuations or switches to an oral treatment after periodic infusions, de-escalations before pregnancies, de-escalations after tolerance issues, and increased infusion intervals. Rituximab discontinuations motivated by inefficacy or for unknown purposes were excluded. The primary outcome was the absolute risk of NMOSD reactivation (one or more relapses) at 12 months. AQP4+ and AQP4- serotypes were analyzed separately.

Results: We identified 137 rituximab de-escalations between 2006 and 2019 that corresponded to a predefined group: 13 discontinuations after a single infusion cycle, 6 switches to an oral treatment after a single infusion cycle, 9 discontinuations after periodic infusions, 5 switches to an oral treatment after periodic infusions, 4 de-escalations before pregnancies, 9 de-escalations after tolerance issues, and 91 increased infusion intervals. No group remained relapse-free over the whole de-escalation follow-up (mean: 3.2 years; range: 0.79-9.5), except pregnancies in AQP+ patients. In all groups combined and within 12 months, reactivations occurred after 11/119 de-escalations in patients with AQP4+ NMOSD (9.2%, 95% CI [4.7-15.9]), from 0.69 to 10.0 months, and in 5/18 de-escalations in patients with AQP4- NMOSD (27.8%, 95% CI [9.7-53.5]), from 1.1 to 9.9 months.

Discussion: There is a risk of NMOSD reactivation whatever the rituximab de-escalation regimen.

Trial registration information: Registered on ClinicalTrials.gov: NCT02850705.

Classification of evidence: This study provides Class IV evidence that de-escalation of rituximab increases the probability of disease reactivation.

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Conflict of interest statement

S. Demuth reports no disclosures. N. Collongues has received honoraria for consulting or presentation from Biogen Idec, Alexion, Novartis, Merck Serono, Bristol-Myers Squibb, Sanofi-Genzyme, and Roche, and is a member of the Editorial Board of the Journal de la Ligue Française contre la Sclérose en plaques. B. Audoin, X. Ayrignac, B. Bourre report no disclosures. J. Ciron has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi-Genzyme, Roche, Celgene-BMS, Alexion, none related to this study. M. Cohen has received honorarium for participating on scientific advisory boards for Ad Scientiam, Alexion, Biogen, BMS, Horizon therapeutics, Merck, Novartis, Roche, and Teva. R. Deschamps, F. Durand Dubief report no disclosures. E. Maillart reports personal fees from Alexion, Biogen, Merck, Novartis, Roche, Sanofi, and Teva, and grants from Biogen, outside the submitted work. C. Papeix reports no disclosures. A. Ruet reports personal fees and research grants from Biogen, personal fees and research grant from Roche, research grant from Genzyme, personal fees and research grant from Merck, research grant from Bayer, outside the submitted work. H. Zéphir has received consulting fees from Biogen Idec, Roche, Alexion, BMS, Sanofi, Merck, and Novartis but reports no disclosures directly related to the manuscript. R. Marignier serves on the scientific advisory board for Viela Bio, Roche, UCB, and Alexion, and has received honoraria from Biogen, Merck, and Novartis. J. de Seze reports no disclosures. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Flowchart
Patients with de-escalations of rituximab were identified through a computerized screening among patients in the NOMADMUS registry. De-escalations were grouped into 7 regimens defined in the lower part of the figure. Colors in the lower part: blue for rituximab, yellow for oral treatments, and pink for pregnancies. AQP4+ = antiaquaporin 4-IgG antibodies.
Figure 2
Figure 2. Absolute Risk of Disease Reactivation Among Different Combinations of De-escalation Groups
(A) Analysis plan of all the combinations of the groups defined in the flowchart with their respective icons. (B) Combined analysis. The forest plot shows the estimated risks of NMOSD reactivation at 12 months and their 95% CIs in AQP4+ patients (blue) and in AQP4− patients (red). For comparability with the other groups, the risk of reactivation during a sequence of increased infusion intervals was adjusted to its duration, yielding annualized risks of reactivation. ARR = annualized relapse rate; AQP4+ = antiaquaporin 4-IgG antibodies.
Figure 3
Figure 3. Exploratory Subgroup Analysis of the Pooled De-escalations
Age, disease duration, time since disease activity, the cumulated number of relapses, and the last EDSS were dichotomized according to their medians. Each increased infusion interval was analyzed as an observation unit. The forest plot shows the estimated absolute risks of reactivation at 12 months and their 95% CIs in AQP4+ patients (blue) and in AQP4− patients (red). *An irreversible EDSS value was not available before 15 (10.9%) de-escalations. **The hazard ratios were computed using a Cox proportional-hazards model adjusting for the five variables. Missing EDSS were imputed. ARR = annualized relapse rate; AQP4+ = antiaquaporin 4-IgG antibodies; EDSS = Expanded Disability Status Scale.
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Comment in

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