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Multicenter Study
. 2024 Sep;11(5):e200281.
doi: 10.1212/NXI.0000000000200281. Epub 2024 Jul 11.

Presentation and Outcome in S1P-RM and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: A Multicenter Cohort Study

Julie C Blant  1 , Nicola N De Rossi  1 , Ralf Gold  1 , Aude Maurousset  1 , Markus Kraemer  1 , Lucía Romero-Pinel  1 , Tatsuro Misu  1 , Jean-Christophe Ouallet  1 , Maud Pallix Guyot  1 , Simonetta Gerevini  1 , Christos Bakirtzis  1 , Raquel Piñar Morales  1 , Benjamin Vlad  1 , Panajotis Karypidis  1 , Xavier Moisset  1 , Tobias J Derfuss  1 , Ilijas Jelcic  1 , Guillaume Martin-Blondel  1 , Ilya Ayzenberg  1 , Corey McGraw  1 , David A Laplaud  1 , Renaud A Du Pasquier  1 , Raphael Bernard-Valnet  1 ; for CORPUS and Italian study groups  1
Affiliations
Multicenter Study

Presentation and Outcome in S1P-RM and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: A Multicenter Cohort Study

Julie C Blant et al. Neurol Neuroimmunol Neuroinflamm. 2024 Sep.

Erratum in

Abstract

Background and objectives: Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups.

Methods: A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed.

Results: Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2]).

Discussion: S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.

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Conflict of interest statement

J. Blant received funding for this work from the Solis and CHUV foundations, through an award by the University of Lausanne; N. De Rossi reports no disclosures relevant to the manuscript; R. Gold has received speaker honoraria and research support from Bayer-Schering Healthcare, Biogen-Idec Germany, Chugai, Eisai, Merck Serono, Nikkiso Pharma, Novartis, Roche, Sanofi-Genzyme, and TEVA; has received consulting honoraria from CSL Behring, Baxter, Janssen, and Talecris; and has stock options in Bayer, Merck, and Roche; A. Marousset has received grants, nonpersonal consulting fees, and travel fees from Biogen, Merck, Novartis, Roche, and Alexion; M. Kraemer received honoraria for teaching activities from Chugai Pharma, Novartis Pharma, and Roche Pharma; L. Romero-Pinel received honoraria for participating on advisory boards, for collaborations as consultant and scientific communications, research support as well as funding for travel and congress expenses from Almirall, Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Horizon (Amgen), Janssen, Merck, Novaxpharm, Novartis, Roche, Sandoz, and Sanofi; T. Misu received speaker honoraria from Tanabe Mitsubishi Pharma, Novartis Pharma, Chugai Pharma, Alexion Pharma, Teijin Pharma, Viela Bio, and Biogen Idec Japan, and received research support from Cosmic Corporation, and Medical and Biological Laboratories Co; J.-C. Ouallet reports personal fees from Biogen, Roche, Sanofi, Janssen, Alexion, and grants, personal fees and non-financial support from Novartis, and Merck, outside of the submitted work; M. Pallix-Guyot reports no disclosures relevant to the manuscript; S. Gerevini reports no disclosures relevant to the manuscript; C. Bakirtzis has received travel support and/or lecture fees and/or research grants and/or advisory services by Novartis, Merck, Sanofi, Teva, Roche, Viatris, Biogen, Genesis Pharma, Bristol Mayers Squibb, and Pharmaserve-Lilly; R. Pinar Morales has received consulting or speaking fees from Almirall, Biogen, Genzyme, Merck Serono, Novartis, Roche, Sanofi, Janssen, and Alnylam; B. Vlad reports no disclosures relevant to the manuscript; P. Karypidis reports no disclosures relevant to the manuscript; X. Moisset has received occasional fees from Allergan-Abbvie, Biogen, BMS, Grünenthal, Lilly, Lundbeck, Teva, Merck-Serono, Novartis, Pfizer, Roche, and Sanofi-Genzyme and nonfinancial support from SOS Oxygène, not related to the submitted work; T. Derfuss has received speaker fees, research support, travel support, and/or served on advisory boards, data safety monitoring boards, or Steering Committees of Alexion, Celgene, Polyneuron, Novartis Pharma, Merck Serono, Sanofi, Biogen, GeNeuro, MedDay, and Roche; I. Jelcic has received speaker honoraria or unrestricted grants from Biogen Idec and Novartis and has received compensation for advice or lecturing for Alexion, Biogen, Bristol Myers Squibb, Celgene, Janssen-Cilag, Neuway, Merck, Novartis, Roche, and Sanofi Genzyme; none of these are related to this study; G. Martin-blondel reports no disclosures relevant to the manuscript; I. Ayzenberg has received research support from Diamed and Chugai, speaking honoraria, travel grants, and compensation for serving on a scientific advisory board from Alexion, Horizon, Roche, Merck, and sanofi-aventis/Genzyme, all unrelated to this study; C. McGraw reports no disclosures relevant to the manuscript; D. Laplaud served on scientific advisory boards for Alexion, BMS, Roche, Sanofi, Novartis, Merck, Janssen, and Biogen; received conference travel support and/or speaker honoraria from Alexion, Novartis, Biogen, Roche, Sanofi, BMS, and Merck; and received research support from Fondation ARSEP, Fondation EDMUS, Association Notre Sclerose, and Agence Nationale de la Recherche; R. Du Pasquier reports that the Lausanne University Hospital has received speaker honoraria and travel grants for his activities with Biogen, Genzyme, Merck, Novartis, Roche, and Sanofi. None of them were related to this work; R. Bernard-Valnet has received speaker honoraria and funding for travel from Novartis and Roche, received support for research activities from Novartis Foundation outside of this work, and served as an editorial board member of the Resident and Fellow section of Neurology®. R. Bernard-Valnet is the recipient of a scholarship from the Baasch-Medicus Foundation. Go to Neurology.org/NN for full disclosures.

Figures

Figure 1
Figure 1. Flowchart
Figure 2
Figure 2. Outcome in S1P-RM and Natalizumab-Associated PML
(A) Kaplan-Meier curve of incidence of IRIS over time. HR was obtained through a Cox regression model. (B) Graphical representation of mRS at 12 months (or the last follow-up if ≤12 months). HR = hazard ratio; NTZ = natalizumab; S1P-RM = sphingosine-1-phosphate receptor modulators.
See this image and copyright information in PMC

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