PMID- 38321317
OWN - NLM
STAT- MEDLINE
DCOM- 20240321
LR  - 20240321
IS  - 1179-1942 (Electronic)
IS  - 0114-5916 (Linking)
VI  - 47
IP  - 4
DP  - 2024 Apr
TI  - Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic 
      Review and Meta-Analysis.
PG  - 333-354
LID - 10.1007/s40264-023-01383-4 [doi]
AB  - INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) was first 
      described among patients affected by hematological or solid tumors. Following the 
      human immunodeficiency virus (HIV) epidemic, people living with HIV have 
      represented most cases for more than a decade. With the diffusion of highly 
      active antiretroviral therapy, this group progressively decreased in favor of 
      patients undergoing treatment with targeted therapy/immunomodulators. In this 
      systematic review and meta-analysis, the objective was to assess which drugs are 
      most frequently related to PML development, and report the incidence of 
      drug-induced PML through a meta-analytic approach. METHODS: The electronic 
      databases MEDLINE, EMBASE, ClinicalTrials.gov, Web of Science and the Canadian 
      Agency for Drugs and Technologies in Health Database (CADTH) were searched up to 
      May 10, 2022. Articles that reported the risk of PML development after treatment 
      with immunomodulatory drugs, including patients of both sexes under the age of 
      80 years, affected by any pathology except HIV, primary immunodeficiencies or 
      malignancies, were included in the review. The incidence of drug-induced PML was 
      calculated based on PML cases and total number of patients observed per 100 
      persons and the observation time. Random-effect metanalyses were conducted for 
      each drug reporting pooled incidence with 95% confidence intervals (CI) and 
      median (interquartile range [IQR]) of the observation time. Heterogeneity was 
      measured by I(2) statistics. Publication bias was examined through funnel plots 
      and Egger's test. RESULTS: A total of 103 studies were included in the systematic 
      review. In our analysis, we found no includible study reporting cases of PML 
      during the course of treatment with ocrelizumab, vedolizumab, abrilumab, 
      ontamalimab, teriflunomide, daclizumab, inebilizumab, basiliximab, tacrolimus, 
      belimumab, infliximab, firategrast, disulone, azathioprine or danazole. 
      Dalfampridine, glatiramer acetate, dimethyl fumarate and fingolimod show a 
      relatively safe profile, although some cases of PML have been reported. The 
      meta-analysis showed an incidence of PML cases among patients undergoing 
      rituximab treatment for multiple sclerosis (MS) of 0.01 cases/100 persons (95% CI 
      - 0.08 to 0.09; I(2) = 20.4%; p = 0.25) for a median observation period of 23.5 
      months (IQR 22.1-42.1). Treatment of MS with natalizumab carried a PML risk of 
      0.33 cases/100 persons (95% CI 0.29-0.37; I(2) = 50%; p = 0.003) for a median 
      observation period of 44.1 months (IQR 28.4-60) and a mean number of doses of 
      36.3 (standard deviation [SD] +/- 20.7). When comparing data about patients treated 
      with standard interval dosing (SID) and extended interval dosing (EID), the 
      latter appears to carry a smaller risk of PML, that is, 0.08 cases/100 persons 
      (95% CI 0.0-0.15) for EID versus 0.3 cases/100 persons (95% CI 0.25-0.34) for 
      SID. CONCLUSIONS: A higher risk of drug-related PML in patients whose immune 
      system is not additionally depressed by means of neoplasms, HIV or concomitant 
      medications is found in the neurological field. This risk is higher in MS 
      treatment, and specifically during long-term natalizumab therapy. While this drug 
      is still routinely prescribed in this field, considering the efficacy in reducing 
      MS relapses, in other areas it could play a smaller role, and be gradually 
      replaced by other safer and more recently approved agents.
CI  - (c) 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
FAU - Rindi, Lorenzo Vittorio
AU  - Rindi LV
AUID- ORCID: 0000-0003-1233-7965
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Zace, Drieda
AU  - Zace D
AUID- ORCID: 0000-0003-3623-6800
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Braccialarghe, Neva
AU  - Braccialarghe N
AUID- ORCID: 0009-0001-5168-7477
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Massa, Barbara
AU  - Massa B
AUID- ORCID: 0009-0009-5714-034X
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Barchi, Virginia
AU  - Barchi V
AUID- ORCID: 0009-0004-5725-2628
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Iannazzo, Roberta
AU  - Iannazzo R
AUID- ORCID: 0009-0008-6520-932X
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Fato, Ilenia
AU  - Fato I
AUID- ORCID: 0009-0008-6049-2410
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - De Maria, Francesco
AU  - De Maria F
AUID- ORCID: 0009-0004-9687-4841
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Kontogiannis, Dimitra
AU  - Kontogiannis D
AUID- ORCID: 0009-0007-7378-1871
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Malagnino, Vincenzo
AU  - Malagnino V
AUID- ORCID: 0000-0002-6561-5298
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
AD  - Infectious Disease Clinic, Policlinico Tor Vergata, Viale Oxford, 81, 00133, 
      Rome, Italy.
FAU - Sarmati, Loredana
AU  - Sarmati L
AUID- ORCID: 0000-0003-1452-0333
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy.
AD  - Infectious Disease Clinic, Policlinico Tor Vergata, Viale Oxford, 81, 00133, 
      Rome, Italy.
FAU - Iannetta, Marco
AU  - Iannetta M
AUID- ORCID: 0000-0002-6938-8627
AD  - Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 
      00133, Rome, Italy. marco.iannetta@uniroma2.it.
AD  - Infectious Disease Clinic, Policlinico Tor Vergata, Viale Oxford, 81, 00133, 
      Rome, Italy. marco.iannetta@uniroma2.it.
LA  - eng
PT  - Meta-Analysis
PT  - Systematic Review
DEP - 20240207
PL  - New Zealand
TA  - Drug Saf
JT  - Drug safety
JID - 9002928
RN  - 0 (Natalizumab)
RN  - 0 (Immunologic Factors)
SB  - IM
MH  - Male
MH  - Female
MH  - Humans
MH  - Aged, 80 and over
MH  - Natalizumab/adverse effects
MH  - *Leukoencephalopathy, Progressive Multifocal/chemically induced/epidemiology
MH  - Canada
MH  - Immunologic Factors/adverse effects
MH  - *Multiple Sclerosis/drug therapy
MH  - *HIV Infections/drug therapy
EDAT- 2024/02/07 00:42
MHDA- 2024/03/21 12:45
CRDT- 2024/02/06 23:31
PHST- 2023/11/15 00:00 [accepted]
PHST- 2024/03/21 12:45 [medline]
PHST- 2024/02/07 00:42 [pubmed]
PHST- 2024/02/06 23:31 [entrez]
AID - 10.1007/s40264-023-01383-4 [pii]
AID - 10.1007/s40264-023-01383-4 [doi]
PST - ppublish
SO  - Drug Saf. 2024 Apr;47(4):333-354. doi: 10.1007/s40264-023-01383-4. Epub 2024 Feb 
      7.