Disease-modifying therapies and progressive multifocal leukoencephalopathy in multiple sclerosis: A systematic review and meta-analysis

J Neuroimmunol. 2021 Nov 15;360:577721. doi: 10.1016/j.jneuroim.2021.577721. Epub 2021 Sep 15.


Background High efficacy disease modifying therapies (DMT) in the management of Multiple Sclerosis (MS) have a favorable effect on relapse rate and disability progression; however, they can expose patients to significant risks, such as progressive multifocal leukoencephalopathy (PML). Objective The study aims to investigate prognostic factors that can determine outcome in MS-related PML patients. Methods We conducted a literature review and meta-analysis of 194 patients from 62 articles in PubMed, SCOPUS and EMBASE. Results Out of 194 patients (66.5% women, 33.5% men), 81% had progression in their EDSS score by at least 1 point from the time of PML diagnosis (EDSS-P group). The remaining patients had either stable or improved EDSS (EDSS-S group). In univariate analysis, older age at the time of PML diagnosis was associated with higher probability of disability accumulation and worsening of EDSS by at least 1 point (mean age = 44.8, p = 0.046). After adjusting for other variables, age at time of PML diagnosis remained a significant predictive variable in the multivariable logistic model (OR = 0.93, 95% CI: 0.88-0.99, p = 0.037). Natalizumab is the most commonly associated DMT linked to PML, followed by fingolimod and others including dimethyl fumarate, ocrelizumab, alemtuzumab. Among the different treatments used, no therapeutic agent was found to be superior in improving post-PML EDSS. Conclusions Younger age and lower JCV viral load at the time of PML diagnosis were associated with better outcome in MS-associate PML, while none of the PML therapies was superior over the others or associated with favorable outcome.

Keywords: Disease modifying therapy; EDSS; Fatality; Fingolimod; Multiple sclerosis; Natalizumab; Ocrelizumab; PML.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Age Factors
  • Antirheumatic Agents / adverse effects*
  • Antirheumatic Agents / therapeutic use
  • Cerebrospinal Fluid / virology*
  • Disability Evaluation
  • Disease Progression
  • Endemic Diseases
  • Female
  • Humans
  • Immunocompromised Host
  • JC Virus / isolation & purification*
  • Leukoencephalopathy, Progressive Multifocal / cerebrospinal fluid
  • Leukoencephalopathy, Progressive Multifocal / etiology*
  • Leukoencephalopathy, Progressive Multifocal / virology
  • Male
  • Multiple Sclerosis / complications
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / virology
  • Natalizumab / adverse effects
  • Natalizumab / therapeutic use
  • Prognosis
  • Severity of Illness Index
  • Viral Load


  • Antirheumatic Agents
  • Natalizumab