{"doi":"10.1001/jamanetworkopen.2023.45132","title":"Low-Dose Methotrexate and Serious Adverse Events Among Older Adults With Chronic Kidney Disease","abstract":"<jats:sec id=\"ab-zoi231317-4\"><jats:title>Importance</jats:title><jats:p>Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with chronic kidney disease (CKD).</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-5\"><jats:title>Objectives</jats:title><jats:p>To compare the 90-day risk of serious adverse events among adults with CKD who started low-dose methotrexate vs those who started hydroxychloroquine and to compare the risk of serious adverse events among adults with CKD starting 2 distinct doses of methotrexate vs those starting hydroxychloroquine.</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-6\"><jats:title>Design, Setting, and Participants</jats:title><jats:p>This retrospective, population-based, new-user cohort study was conducted in Ontario, Canada (2008-2021) using linked administrative health care data. Adults aged 66 years or older with CKD (defined as an estimated glomerular filtration rate [eGFR] &amp;amp;lt;60 mL/min/1.73 m<jats:sup>2</jats:sup> but not receiving dialysis) who started low-dose methotrexate (n = 2309) were matched 1:1 with those who started hydroxychloroquine.</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-7\"><jats:title>Exposure</jats:title><jats:p>Low-dose methotrexate (5-35 mg/wk) vs hydroxychloroquine (200-400 mg/d).</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-8\"><jats:title>Main Outcome and Measure</jats:title><jats:p>The primary outcome was a composite of serious adverse events: a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects within 90 days of starting the study drug. Prespecified subgroup analyses were conducted by eGFR category. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RRs) were obtained using modified Poisson regression, and risk differences (RDs) using binomial regression.</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-9\"><jats:title>Results</jats:title><jats:p>In a propensity score–matched cohort of 4618 adults with CKD (3192 [69%] women; median [IQR] age, 76 [71-82] years), the primary outcome was higher in patients who started low-dose methotrexate vs those who started hydroxychloroquine (82 of 2309 [3.55%] vs 40 of 2309 [1.73%]; RR, 2.05 (95% CI, 1.42-2.96); RD, 1.82% [95% CI, 0.91%-2.73%]). In subgroup analysis, the risks increased progressively at lower eGFR (eg, eGFR &amp;amp;lt;45 mL/min/1.73 m<jats:sup>2</jats:sup>: RR, 2.79 [95% CI, 1.51-5.13]). In the secondary comparison with hydroxychloroquine, methotrexate users at 15 to 35 mg/wk had a higher risk of the primary outcome.</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-10\"><jats:title>Conclusions and Relevance</jats:title><jats:p>In this cohort of 4618 older patients with CKD, the 90-day risk of serious adverse events was higher among those who started low-dose methotrexate than those who started hydroxychloroquine. If verified, these risks should be balanced against the benefits of low-dose methotrexate use.</jats:p></jats:sec>","journal":"JAMA Network Open","year":2023,"id":636399,"datarank":0.5375278407684165,"base_score":3.58351893845611,"endowment":3.58351893845611,"self_citation_contribution":0.5375278407684165,"citation_network_contribution":0.0,"self_endowment_contribution":0.5375278407684165,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":246938,"name":"Peter G. Blake","orcid":"0000-0002-0345-5989","position":1,"is_corresponding":false},{"id":905976,"name":"Matthew A. Weir","orcid":"0000-0003-3099-0124","position":2,"is_corresponding":false},{"id":1651654,"name":"Fatemeh Ahmadi","orcid":null,"position":3,"is_corresponding":false},{"id":678653,"name":"Eric McArthur","orcid":"0009-0000-6944-6471","position":4,"is_corresponding":false},{"id":1651655,"name":"Jessica M. Sontrop","orcid":null,"position":5,"is_corresponding":false},{"id":1651656,"name":"Brad L. Urquhart","orcid":null,"position":6,"is_corresponding":false},{"id":1181546,"name":"Richard B. Kim","orcid":"0000-0001-8148-1632","position":7,"is_corresponding":false},{"id":232668,"name":"Amit X. Garg","orcid":"0000-0003-3398-3114","position":8,"is_corresponding":false},{"id":1651653,"name":"Flory T. Muanda","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Low-Dose Methotrexate and Serious Adverse Events Among Older Adults With Chronic Kidney Disease","abstract":"<jats:sec id=\"ab-zoi231317-4\"><jats:title>Importance</jats:title><jats:p>Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with chronic kidney disease (CKD).</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-5\"><jats:title>Objectives</jats:title><jats:p>To compare the 90-day risk of serious adverse events among adults with CKD who started low-dose methotrexate vs those who started hydroxychloroquine and to compare the risk of serious adverse events among adults with CKD starting 2 distinct doses of methotrexate vs those starting hydroxychloroquine.</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-6\"><jats:title>Design, Setting, and Participants</jats:title><jats:p>This retrospective, population-based, new-user cohort study was conducted in Ontario, Canada (2008-2021) using linked administrative health care data. Adults aged 66 years or older with CKD (defined as an estimated glomerular filtration rate [eGFR] &amp;amp;lt;60 mL/min/1.73 m<jats:sup>2</jats:sup> but not receiving dialysis) who started low-dose methotrexate (n = 2309) were matched 1:1 with those who started hydroxychloroquine.</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-7\"><jats:title>Exposure</jats:title><jats:p>Low-dose methotrexate (5-35 mg/wk) vs hydroxychloroquine (200-400 mg/d).</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-8\"><jats:title>Main Outcome and Measure</jats:title><jats:p>The primary outcome was a composite of serious adverse events: a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects within 90 days of starting the study drug. Prespecified subgroup analyses were conducted by eGFR category. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RRs) were obtained using modified Poisson regression, and risk differences (RDs) using binomial regression.</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-9\"><jats:title>Results</jats:title><jats:p>In a propensity score–matched cohort of 4618 adults with CKD (3192 [69%] women; median [IQR] age, 76 [71-82] years), the primary outcome was higher in patients who started low-dose methotrexate vs those who started hydroxychloroquine (82 of 2309 [3.55%] vs 40 of 2309 [1.73%]; RR, 2.05 (95% CI, 1.42-2.96); RD, 1.82% [95% CI, 0.91%-2.73%]). In subgroup analysis, the risks increased progressively at lower eGFR (eg, eGFR &amp;amp;lt;45 mL/min/1.73 m<jats:sup>2</jats:sup>: RR, 2.79 [95% CI, 1.51-5.13]). In the secondary comparison with hydroxychloroquine, methotrexate users at 15 to 35 mg/wk had a higher risk of the primary outcome.</jats:p></jats:sec><jats:sec id=\"ab-zoi231317-10\"><jats:title>Conclusions and Relevance</jats:title><jats:p>In this cohort of 4618 older patients with CKD, the 90-day risk of serious adverse events was higher among those who started low-dose methotrexate than those who started hydroxychloroquine. If verified, these risks should be balanced against the benefits of low-dose methotrexate use.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38010652","pmcid":"PMC10682837","openalex_id":"https://openalex.org/W4389058182","authors":[],"funders":[{"funder_name":"Canadian Institutes of Health Research","grant_id":"unidentified","title":"unidentified"},{"funder_name":"CIHR","grant_id":"","title":null},{"funder_name":"CIHR","grant_id":"","title":null}],"total_grants":3,"fwci":6.4168,"citation_percentile":0.97552678,"influential_citations":0,"citation_trend":[{"year":2023,"count":1},{"year":2024,"count":6},{"year":2025,"count":17},{"year":2026,"count":10}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2812155/muanda_2023_oi_231317_1699908735.90921.pdf","host_type":"journal"},{"url":"https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2812155/muanda_2023_oi_231317_1699908735.90921.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1001/jamanetworkopen.2023.45132","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38010652","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/10682837","host_type":"repository"},{"url":"https://pdf.hres.ca/dpd_pm/00064334.PDF","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC10682837","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1001/jamanetworkopen.2023.45132","host_type":""}],"fields_of_study":["Rheumatoid Arthritis Research and Therapies","Psoriasis: Treatment and Pathogenesis","Chronic Kidney Disease and Diabetes","03 medical and health sciences","0302 clinical medicine","Humans","Female","Aged","Male","Methotrexate","Hydroxychloroquine","Cohort Studies","Retrospective Studies","Renal Dialysis","Renal Insufficiency, Chronic","Ontario"],"mesh_terms":["Aged","Female","Renal Dialysis","Humans","Hydroxychloroquine","Male","Methotrexate","Ontario","Retrospective Studies","Cohort Studies","Renal Insufficiency, Chronic"],"keywords":["Medicine","Kidney disease","Hydroxychloroquine","Adverse effect","Renal function","Internal medicine","Poisson regression","Population","Cohort","Retrospective cohort study","Methotrexate","Rheumatoid arthritis","Dialysis","Disease","Male","Ontario","Cohort Studies","Renal Dialysis","Humans","Female","Renal Insufficiency, Chronic","Original Investigation","Aged","Retrospective Studies"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T16:58:24.373179Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}