Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis
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 high...
Gespeichert in:
| Veröffentlicht in: | Drug safety 2024-04, Vol.47 (4), p.333-354 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 354 |
|---|---|
| container_issue | 4 |
| container_start_page | 333 |
| container_title | Drug safety |
| container_volume | 47 |
| creator | Rindi, Lorenzo Vittorio Zaçe, Drieda Braccialarghe, Neva Massa, Barbara Barchi, Virginia Iannazzo, Roberta Fato, Ilenia De Maria, Francesco Kontogiannis, Dimitra Malagnino, Vincenzo Sarmati, Loredana Iannetta, Marco |
| description | 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 o |
| doi_str_mv | 10.1007/s40264-023-01383-4 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2974586002</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2974586002</sourcerecordid><originalsourceid>FETCH-LOGICAL-c375t-2c6791ad2b5c8340554c2c95f3618493b5630fc6ee66a197b659a2e4e21a888e3</originalsourceid><addsrcrecordid>eNp9kE1P3DAQhi3UCrZb_gCHylIv9GDwd-zeVtACUlag0p4tx5ksodlksRNQ_n0DgfbW0xzmed8ZPQgdMXrCKM1Ok6RcS0K5IJQJI4jcQwvGMkuYlfwdWlDGJFGW6QP0IaV7Sqnh2uyjgwnmTLBsgcrzOGzIVVsOAUp8E7tNhJTqR8Droenrqgu-wTkMvztoA-zufNPtfH834uObdf7lK17h2zH1sPV9HfAPeKzhCfu2xGvoPVm1vhlTnT6i95VvEhy-ziX69f3bz7NLkl9fXJ2tchJEpnrCg84s8yUvVDBCUqVk4MGqSmhmpBWF0oJWQQNo7ZnNCq2s5yCBM2-MAbFEn-feXeweBki9u--GOD2RHLeZVEbTSdYS8ZkKsUspQuV2sd76ODpG3bNYN4t1E-texDo5hT69Vg_FFsq_kTeTEyBmIE2rdgPx3-3_1P4BmluCVg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2974586002</pqid></control><display><type>article</type><title>Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis</title><source>SpringerLink Journals - AutoHoldings</source><creator>Rindi, Lorenzo Vittorio ; Zaçe, Drieda ; Braccialarghe, Neva ; Massa, Barbara ; Barchi, Virginia ; Iannazzo, Roberta ; Fato, Ilenia ; De Maria, Francesco ; Kontogiannis, Dimitra ; Malagnino, Vincenzo ; Sarmati, Loredana ; Iannetta, Marco</creator><creatorcontrib>Rindi, Lorenzo Vittorio ; Zaçe, Drieda ; Braccialarghe, Neva ; Massa, Barbara ; Barchi, Virginia ; Iannazzo, Roberta ; Fato, Ilenia ; De Maria, Francesco ; Kontogiannis, Dimitra ; Malagnino, Vincenzo ; Sarmati, Loredana ; Iannetta, Marco</creatorcontrib><description>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.</description><identifier>ISSN: 0114-5916</identifier><identifier>EISSN: 1179-1942</identifier><identifier>DOI: 10.1007/s40264-023-01383-4</identifier><identifier>PMID: 38321317</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Antigens ; Antiretroviral agents ; Azathioprine ; Confidence intervals ; Copolymer 1 ; Dosage ; Drug development ; Drug dosages ; Drug Safety and Pharmacovigilance ; Drug therapy ; Drugs ; Hematology ; Heterogeneity ; Highly active antiretroviral therapy ; HIV ; Human immunodeficiency virus ; Immune system ; Immunomodulation ; Immunomodulators ; Immunosuppressive agents ; Infliximab ; Leukoencephalopathy ; Malignancy ; Median (statistics) ; Medicine ; Medicine & Public Health ; Meta-analysis ; Monoclonal antibodies ; Multiple sclerosis ; Neoplasms ; Pathology ; Patients ; Pharmacology/Toxicology ; Primary immunodeficiencies ; Progressive multifocal leukoencephalopathy ; Proteins ; Risk ; Rituximab ; Sexually transmitted diseases ; Solid tumors ; Statistical analysis ; STD ; Systematic Review ; Tacrolimus ; Therapy ; Time measurement ; Tumor necrosis factor-α ; Tumors</subject><ispartof>Drug safety, 2024-04, Vol.47 (4), p.333-354</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.</rights><rights>Copyright Springer Nature B.V. Apr 2024</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-2c6791ad2b5c8340554c2c95f3618493b5630fc6ee66a197b659a2e4e21a888e3</citedby><cites>FETCH-LOGICAL-c375t-2c6791ad2b5c8340554c2c95f3618493b5630fc6ee66a197b659a2e4e21a888e3</cites><orcidid>0009-0008-6049-2410 ; 0009-0001-5168-7477 ; 0009-0004-9687-4841 ; 0009-0009-5714-034X ; 0000-0003-1452-0333 ; 0000-0003-3623-6800 ; 0009-0007-7378-1871 ; 0009-0008-6520-932X ; 0000-0003-1233-7965 ; 0009-0004-5725-2628 ; 0000-0002-6561-5298 ; 0000-0002-6938-8627</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s40264-023-01383-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s40264-023-01383-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38321317$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rindi, Lorenzo Vittorio</creatorcontrib><creatorcontrib>Zaçe, Drieda</creatorcontrib><creatorcontrib>Braccialarghe, Neva</creatorcontrib><creatorcontrib>Massa, Barbara</creatorcontrib><creatorcontrib>Barchi, Virginia</creatorcontrib><creatorcontrib>Iannazzo, Roberta</creatorcontrib><creatorcontrib>Fato, Ilenia</creatorcontrib><creatorcontrib>De Maria, Francesco</creatorcontrib><creatorcontrib>Kontogiannis, Dimitra</creatorcontrib><creatorcontrib>Malagnino, Vincenzo</creatorcontrib><creatorcontrib>Sarmati, Loredana</creatorcontrib><creatorcontrib>Iannetta, Marco</creatorcontrib><title>Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis</title><title>Drug safety</title><addtitle>Drug Saf</addtitle><addtitle>Drug Saf</addtitle><description>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.</description><subject>Antigens</subject><subject>Antiretroviral agents</subject><subject>Azathioprine</subject><subject>Confidence intervals</subject><subject>Copolymer 1</subject><subject>Dosage</subject><subject>Drug development</subject><subject>Drug dosages</subject><subject>Drug Safety and Pharmacovigilance</subject><subject>Drug therapy</subject><subject>Drugs</subject><subject>Hematology</subject><subject>Heterogeneity</subject><subject>Highly active antiretroviral therapy</subject><subject>HIV</subject><subject>Human immunodeficiency virus</subject><subject>Immune system</subject><subject>Immunomodulation</subject><subject>Immunomodulators</subject><subject>Immunosuppressive agents</subject><subject>Infliximab</subject><subject>Leukoencephalopathy</subject><subject>Malignancy</subject><subject>Median (statistics)</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Meta-analysis</subject><subject>Monoclonal antibodies</subject><subject>Multiple sclerosis</subject><subject>Neoplasms</subject><subject>Pathology</subject><subject>Patients</subject><subject>Pharmacology/Toxicology</subject><subject>Primary immunodeficiencies</subject><subject>Progressive multifocal leukoencephalopathy</subject><subject>Proteins</subject><subject>Risk</subject><subject>Rituximab</subject><subject>Sexually transmitted diseases</subject><subject>Solid tumors</subject><subject>Statistical analysis</subject><subject>STD</subject><subject>Systematic Review</subject><subject>Tacrolimus</subject><subject>Therapy</subject><subject>Time measurement</subject><subject>Tumor necrosis factor-α</subject><subject>Tumors</subject><issn>0114-5916</issn><issn>1179-1942</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp9kE1P3DAQhi3UCrZb_gCHylIv9GDwd-zeVtACUlag0p4tx5ksodlksRNQ_n0DgfbW0xzmed8ZPQgdMXrCKM1Ok6RcS0K5IJQJI4jcQwvGMkuYlfwdWlDGJFGW6QP0IaV7Sqnh2uyjgwnmTLBsgcrzOGzIVVsOAUp8E7tNhJTqR8Droenrqgu-wTkMvztoA-zufNPtfH834uObdf7lK17h2zH1sPV9HfAPeKzhCfu2xGvoPVm1vhlTnT6i95VvEhy-ziX69f3bz7NLkl9fXJ2tchJEpnrCg84s8yUvVDBCUqVk4MGqSmhmpBWF0oJWQQNo7ZnNCq2s5yCBM2-MAbFEn-feXeweBki9u--GOD2RHLeZVEbTSdYS8ZkKsUspQuV2sd76ODpG3bNYN4t1E-texDo5hT69Vg_FFsq_kTeTEyBmIE2rdgPx3-3_1P4BmluCVg</recordid><startdate>20240401</startdate><enddate>20240401</enddate><creator>Rindi, Lorenzo Vittorio</creator><creator>Zaçe, Drieda</creator><creator>Braccialarghe, Neva</creator><creator>Massa, Barbara</creator><creator>Barchi, Virginia</creator><creator>Iannazzo, Roberta</creator><creator>Fato, Ilenia</creator><creator>De Maria, Francesco</creator><creator>Kontogiannis, Dimitra</creator><creator>Malagnino, Vincenzo</creator><creator>Sarmati, Loredana</creator><creator>Iannetta, Marco</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>4T-</scope><scope>7T2</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>NAPCQ</scope><orcidid>https://orcid.org/0009-0008-6049-2410</orcidid><orcidid>https://orcid.org/0009-0001-5168-7477</orcidid><orcidid>https://orcid.org/0009-0004-9687-4841</orcidid><orcidid>https://orcid.org/0009-0009-5714-034X</orcidid><orcidid>https://orcid.org/0000-0003-1452-0333</orcidid><orcidid>https://orcid.org/0000-0003-3623-6800</orcidid><orcidid>https://orcid.org/0009-0007-7378-1871</orcidid><orcidid>https://orcid.org/0009-0008-6520-932X</orcidid><orcidid>https://orcid.org/0000-0003-1233-7965</orcidid><orcidid>https://orcid.org/0009-0004-5725-2628</orcidid><orcidid>https://orcid.org/0000-0002-6561-5298</orcidid><orcidid>https://orcid.org/0000-0002-6938-8627</orcidid></search><sort><creationdate>20240401</creationdate><title>Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis</title><author>Rindi, Lorenzo Vittorio ; Zaçe, Drieda ; Braccialarghe, Neva ; Massa, Barbara ; Barchi, Virginia ; Iannazzo, Roberta ; Fato, Ilenia ; De Maria, Francesco ; Kontogiannis, Dimitra ; Malagnino, Vincenzo ; Sarmati, Loredana ; Iannetta, Marco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-2c6791ad2b5c8340554c2c95f3618493b5630fc6ee66a197b659a2e4e21a888e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Antigens</topic><topic>Antiretroviral agents</topic><topic>Azathioprine</topic><topic>Confidence intervals</topic><topic>Copolymer 1</topic><topic>Dosage</topic><topic>Drug development</topic><topic>Drug dosages</topic><topic>Drug Safety and Pharmacovigilance</topic><topic>Drug therapy</topic><topic>Drugs</topic><topic>Hematology</topic><topic>Heterogeneity</topic><topic>Highly active antiretroviral therapy</topic><topic>HIV</topic><topic>Human immunodeficiency virus</topic><topic>Immune system</topic><topic>Immunomodulation</topic><topic>Immunomodulators</topic><topic>Immunosuppressive agents</topic><topic>Infliximab</topic><topic>Leukoencephalopathy</topic><topic>Malignancy</topic><topic>Median (statistics)</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Meta-analysis</topic><topic>Monoclonal antibodies</topic><topic>Multiple sclerosis</topic><topic>Neoplasms</topic><topic>Pathology</topic><topic>Patients</topic><topic>Pharmacology/Toxicology</topic><topic>Primary immunodeficiencies</topic><topic>Progressive multifocal leukoencephalopathy</topic><topic>Proteins</topic><topic>Risk</topic><topic>Rituximab</topic><topic>Sexually transmitted diseases</topic><topic>Solid tumors</topic><topic>Statistical analysis</topic><topic>STD</topic><topic>Systematic Review</topic><topic>Tacrolimus</topic><topic>Therapy</topic><topic>Time measurement</topic><topic>Tumor necrosis factor-α</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rindi, Lorenzo Vittorio</creatorcontrib><creatorcontrib>Zaçe, Drieda</creatorcontrib><creatorcontrib>Braccialarghe, Neva</creatorcontrib><creatorcontrib>Massa, Barbara</creatorcontrib><creatorcontrib>Barchi, Virginia</creatorcontrib><creatorcontrib>Iannazzo, Roberta</creatorcontrib><creatorcontrib>Fato, Ilenia</creatorcontrib><creatorcontrib>De Maria, Francesco</creatorcontrib><creatorcontrib>Kontogiannis, Dimitra</creatorcontrib><creatorcontrib>Malagnino, Vincenzo</creatorcontrib><creatorcontrib>Sarmati, Loredana</creatorcontrib><creatorcontrib>Iannetta, Marco</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Docstoc</collection><collection>Health and Safety Science Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Drug safety</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rindi, Lorenzo Vittorio</au><au>Zaçe, Drieda</au><au>Braccialarghe, Neva</au><au>Massa, Barbara</au><au>Barchi, Virginia</au><au>Iannazzo, Roberta</au><au>Fato, Ilenia</au><au>De Maria, Francesco</au><au>Kontogiannis, Dimitra</au><au>Malagnino, Vincenzo</au><au>Sarmati, Loredana</au><au>Iannetta, Marco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis</atitle><jtitle>Drug safety</jtitle><stitle>Drug Saf</stitle><addtitle>Drug Saf</addtitle><date>2024-04-01</date><risdate>2024</risdate><volume>47</volume><issue>4</issue><spage>333</spage><epage>354</epage><pages>333-354</pages><issn>0114-5916</issn><eissn>1179-1942</eissn><abstract>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.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>38321317</pmid><doi>10.1007/s40264-023-01383-4</doi><tpages>22</tpages><orcidid>https://orcid.org/0009-0008-6049-2410</orcidid><orcidid>https://orcid.org/0009-0001-5168-7477</orcidid><orcidid>https://orcid.org/0009-0004-9687-4841</orcidid><orcidid>https://orcid.org/0009-0009-5714-034X</orcidid><orcidid>https://orcid.org/0000-0003-1452-0333</orcidid><orcidid>https://orcid.org/0000-0003-3623-6800</orcidid><orcidid>https://orcid.org/0009-0007-7378-1871</orcidid><orcidid>https://orcid.org/0009-0008-6520-932X</orcidid><orcidid>https://orcid.org/0000-0003-1233-7965</orcidid><orcidid>https://orcid.org/0009-0004-5725-2628</orcidid><orcidid>https://orcid.org/0000-0002-6561-5298</orcidid><orcidid>https://orcid.org/0000-0002-6938-8627</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0114-5916 |
| ispartof | Drug safety, 2024-04, Vol.47 (4), p.333-354 |
| issn | 0114-5916 1179-1942 |
| language | eng |
| recordid | cdi_proquest_journals_2974586002 |
| source | SpringerLink Journals - AutoHoldings |
| subjects | Antigens Antiretroviral agents Azathioprine Confidence intervals Copolymer 1 Dosage Drug development Drug dosages Drug Safety and Pharmacovigilance Drug therapy Drugs Hematology Heterogeneity Highly active antiretroviral therapy HIV Human immunodeficiency virus Immune system Immunomodulation Immunomodulators Immunosuppressive agents Infliximab Leukoencephalopathy Malignancy Median (statistics) Medicine Medicine & Public Health Meta-analysis Monoclonal antibodies Multiple sclerosis Neoplasms Pathology Patients Pharmacology/Toxicology Primary immunodeficiencies Progressive multifocal leukoencephalopathy Proteins Risk Rituximab Sexually transmitted diseases Solid tumors Statistical analysis STD Systematic Review Tacrolimus Therapy Time measurement Tumor necrosis factor-α Tumors |
| title | Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-18T17%3A00%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Drug-Induced%20Progressive%20Multifocal%20Leukoencephalopathy%20(PML):%20A%20Systematic%20Review%20and%20Meta-Analysis&rft.jtitle=Drug%20safety&rft.au=Rindi,%20Lorenzo%20Vittorio&rft.date=2024-04-01&rft.volume=47&rft.issue=4&rft.spage=333&rft.epage=354&rft.pages=333-354&rft.issn=0114-5916&rft.eissn=1179-1942&rft_id=info:doi/10.1007/s40264-023-01383-4&rft_dat=%3Cproquest_cross%3E2974586002%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2974586002&rft_id=info:pmid/38321317&rfr_iscdi=true |