Pub Date : 2025-09-04DOI: 10.1016/S2665-9913(25)00165-1
Edoardo Cipolletta PhD , Georgina Nakafero PhD , Davide Rozza PhD , Satveer K Mahil PhD , Prof Catherine H Smith PhD , Prof Richard D Riley PhD , Prof Abhishek Abhishek PhD
<div><h3>Background</h3><div>Allopurinol, the most prescribed urate-lowering drug, is a known cause of severe cutaneous adverse reactions. We aimed to develop and validate a model to assess the risk of allopurinol-induced severe cutaneous adverse reactions in adults newly prescribed allopurinol.</div></div><div><h3>Methods</h3><div>In this retrospective new-user cohort study, we developed and validated a prognostic model using primary care, hospitalisation, and mortality data extracted from the UK Clinical Practice Research Datalink (CPRD) primary care database, for the period Jan 1, 2001, to March 29, 2021. Data from CPRD Aurum was used for model development and data from and CPRD GOLD was used for model validation. Adults (aged ≥18 years) residing in England who were newly prescribed allopurinol were followed up for 100 days to assess whether a severe cutaneous adverse reaction was recorded in hospitalisation or mortality records. Risk predictors included in the model were age, sex, ethnicity, chronic kidney disease stage, initial allopurinol dose, ischaemic heart disease, and heart failure. The primary outcome was to predict the 100-day risk of allopurinol-induced severe cutaneous adverse reactions in people newly prescribed allopurinol. We developed the model using multivariable Cox regression and pseudo-values, followed by penalisation and external validation. We assessed calibration, discrimination, and clinical utility in the risk range of 0·0001 to 0·003. People with lived experience of allopurinol use or gout were not involved in developing this research question, but will be involved in the dissemination of results.</div></div><div><h3>Findings</h3><div>225 761 patients newly prescribed allopurinol were registered in the CPRD Aurum database (development cohort) and 173 812 were included in the study. 44 630 (25·7%) of 173 812 patients were female, 129 182 (74·3%) were male, 154 323 (88·8%) were White, and the mean age was 63·9 years (SD 15·0). Of the patients newly prescribed allopurinol with data in the CPRD GOLD database (validation cohort), 55 395 patients were screened and 41 610 were included in the study. 10 829 (26·0%) of 41 610 patients were female, 30 781 (74·0%) were male, 37 242 (89·5%) were White and the mean age was 64·4 years (SD 14·9). 63 (0·04%) severe cutaneous adverse events occurred in 173 812 patients in the development cohort and 16 (0·04%) occurred in 41 610 patients in the validation cohort. Age (adjusted hazard ratio 1·03 [95% CI 1·01–1·06]), chronic kidney disease stages 3, 4, and 5 (2·24 [1·20–4·17] for stage 3; 6·65 [2·90–15·23] for stage 4; 18·85 [6·32–56·19] for stage 5), initial allopurinol dose of 300 mg or higher (5·99 [3·56–0·08]), South Asian ethnicity (5·35 [2·37–12·07]), and other Asian ethnicity (5·63 [1·34–23·61]) were associated with the 100-day risk of allopurinol-induced severe cutaneous adverse reactions. In the development dataset, after optimism-adjustment, the model's explained variation (Roy
{"title":"Development and validation of a prognostic model for predicting the risk of allopurinol-induced severe cutaneous adverse reactions: a retrospective new-user cohort study using linked primary care, hospitalisation, and mortality data","authors":"Edoardo Cipolletta PhD , Georgina Nakafero PhD , Davide Rozza PhD , Satveer K Mahil PhD , Prof Catherine H Smith PhD , Prof Richard D Riley PhD , Prof Abhishek Abhishek PhD","doi":"10.1016/S2665-9913(25)00165-1","DOIUrl":"10.1016/S2665-9913(25)00165-1","url":null,"abstract":"<div><h3>Background</h3><div>Allopurinol, the most prescribed urate-lowering drug, is a known cause of severe cutaneous adverse reactions. We aimed to develop and validate a model to assess the risk of allopurinol-induced severe cutaneous adverse reactions in adults newly prescribed allopurinol.</div></div><div><h3>Methods</h3><div>In this retrospective new-user cohort study, we developed and validated a prognostic model using primary care, hospitalisation, and mortality data extracted from the UK Clinical Practice Research Datalink (CPRD) primary care database, for the period Jan 1, 2001, to March 29, 2021. Data from CPRD Aurum was used for model development and data from and CPRD GOLD was used for model validation. Adults (aged ≥18 years) residing in England who were newly prescribed allopurinol were followed up for 100 days to assess whether a severe cutaneous adverse reaction was recorded in hospitalisation or mortality records. Risk predictors included in the model were age, sex, ethnicity, chronic kidney disease stage, initial allopurinol dose, ischaemic heart disease, and heart failure. The primary outcome was to predict the 100-day risk of allopurinol-induced severe cutaneous adverse reactions in people newly prescribed allopurinol. We developed the model using multivariable Cox regression and pseudo-values, followed by penalisation and external validation. We assessed calibration, discrimination, and clinical utility in the risk range of 0·0001 to 0·003. People with lived experience of allopurinol use or gout were not involved in developing this research question, but will be involved in the dissemination of results.</div></div><div><h3>Findings</h3><div>225 761 patients newly prescribed allopurinol were registered in the CPRD Aurum database (development cohort) and 173 812 were included in the study. 44 630 (25·7%) of 173 812 patients were female, 129 182 (74·3%) were male, 154 323 (88·8%) were White, and the mean age was 63·9 years (SD 15·0). Of the patients newly prescribed allopurinol with data in the CPRD GOLD database (validation cohort), 55 395 patients were screened and 41 610 were included in the study. 10 829 (26·0%) of 41 610 patients were female, 30 781 (74·0%) were male, 37 242 (89·5%) were White and the mean age was 64·4 years (SD 14·9). 63 (0·04%) severe cutaneous adverse events occurred in 173 812 patients in the development cohort and 16 (0·04%) occurred in 41 610 patients in the validation cohort. Age (adjusted hazard ratio 1·03 [95% CI 1·01–1·06]), chronic kidney disease stages 3, 4, and 5 (2·24 [1·20–4·17] for stage 3; 6·65 [2·90–15·23] for stage 4; 18·85 [6·32–56·19] for stage 5), initial allopurinol dose of 300 mg or higher (5·99 [3·56–0·08]), South Asian ethnicity (5·35 [2·37–12·07]), and other Asian ethnicity (5·63 [1·34–23·61]) were associated with the 100-day risk of allopurinol-induced severe cutaneous adverse reactions. In the development dataset, after optimism-adjustment, the model's explained variation (Roy","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 12","pages":"Pages e840-e850"},"PeriodicalIF":16.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic (VEXAS) syndrome is a newly identified disorder caused by an acquired monogenic somatic UBA1 gene mutation, affecting nuclear and cytoplasmic ubiquitination. This mutation triggers immune dysregulation, leading to diverse clinical and pathological features resembling inflammatory rheumatic diseases. Blood abnormalities stem from myeloid precursor dysfunction, presenting as elevated concentrations of inflammatory markers and cytokines, leukopenia, and macrocytosis. These abnormalities can lead to inflammatory arthritis, vasculitis, polychondritis, thrombosis, and connective tissue disease-like syndromes. This Review explores the clinical and mechanistic links between VEXAS syndrome and rheumatic diseases, offering guidance on current best management strategies. Although rare, VEXAS syndrome has high morbidity and mortality, providing valuable insights into how genetic mutations drive immune system activation and rheumatic disease development.
{"title":"VEXAS syndrome and immune-mediated rheumatic diseases: overlaps in clinical features and mechanisms","authors":"Arvind Kaul PhD , Adam Al-Hakim MRCP , Prof Helen Lachmann FMedSci , Austin Kulasekararaj MD , Prof Sinisa Savic PhD","doi":"10.1016/S2665-9913(25)00197-3","DOIUrl":"10.1016/S2665-9913(25)00197-3","url":null,"abstract":"<div><div>Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic (VEXAS) syndrome is a newly identified disorder caused by an acquired monogenic somatic <em>UBA1</em> gene mutation, affecting nuclear and cytoplasmic ubiquitination. This mutation triggers immune dysregulation, leading to diverse clinical and pathological features resembling inflammatory rheumatic diseases. Blood abnormalities stem from myeloid precursor dysfunction, presenting as elevated concentrations of inflammatory markers and cytokines, leukopenia, and macrocytosis. These abnormalities can lead to inflammatory arthritis, vasculitis, polychondritis, thrombosis, and connective tissue disease-like syndromes. This Review explores the clinical and mechanistic links between VEXAS syndrome and rheumatic diseases, offering guidance on current best management strategies. Although rare, VEXAS syndrome has high morbidity and mortality, providing valuable insights into how genetic mutations drive immune system activation and rheumatic disease development.</div></div>","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 10","pages":"Pages e719-e733"},"PeriodicalIF":16.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-04DOI: 10.1016/S2665-9913(25)00153-5
Venkatesh Krishnan PhD , Stuart Y Keller BSc , Christine Chew PhD , Jonathan T Sims PhD , Ching-Yun Chang PhD , Ernst R Dow PhD , Robert J Benschop PhD , Rona Wang MD , Prof Athimalaipet V Ramanan FMedSci
<div><h3>Background</h3><div>Baricitinib has previously been shown to improve clinical response in patients with juvenile idiopathic arthritis (JIA) in the JUVE-BASIS trial. In this post-hoc analysis we aimed to identify whether pharmacodynamic changes in serum biomarkers in response to baricitinib treatment could help reaffirm the clinical utility of baricitinib in patients with JIA.</div></div><div><h3>Methods</h3><div>JUVE-BASIS was a randomised, double-blind, placebo-controlled, withdrawal, efficacy, safety, phase 3 trial, done in 75 centres in 20 countries. Eligible patients were children and adolescents (aged 2 to <18 years), with polyarticular JIA (positive or negative for rheumatoid factor), extended oligoarticular JIA, enthesitis-related arthritis, or juvenile psoriatic arthritis, as per the International League of Associations for Rheumatology criteria and an inadequate response (≥12 weeks) or intolerance to one or more conventional synthetic or biological disease-modifying antirheumatic drugs (DMARDs). Here we report post-hoc analyses of serum samples from patients who received open-label baricitinib in the 12-week lead-in period of the JUVE-BASIS trial. Samples were assessed using an Olink Explore 3072 panel at baseline and week 12. Baricitinib-mediated pharmacodynamic changes in serum protein markers were measured as changes from baseline to week 12 derived from a mixed model with repeated measurement. Pearson correlations of the change in serum biomarkers and clinical disease activity (JADAS-27 scores) comparing baseline with week 12 were examined. Proportional changes in biomarkers were classified into three response subsets based on JIA-ACR response rates: JIA-ACR <30% (non-responders), JIA-ACR 30–70% (responders), and JIA-ACR 70–100% (super-responders). People with lived experience of JIA were not involved in the design or conduct of this study. The JUVE-BASIS trial was registered with <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span>, <span><span>NCT03773978</span><svg><path></path></svg></span>, and is completed.</div></div><div><h3>Findings</h3><div>Between Dec 17, 2018 and March 3, 2021, 220 patients were enrolled in JUVE-BASIS and received at least one dose of baricitinib in the open-label lead-in period. In this post-hoc analysis, 168 serum samples from 84 patients were analysed: 67 (80%) of 84 patients were female, 17 (20%) were male, 67 (80%) were White and the mean age was 14 years (SD 2). 10 (12%) of 84 were non-responders, 27 (32%) were responders, and 47 (56%) were super-responders based on clinical response. Several serum biomarkers showed significant changes following 12 weeks of baricitinib treatment for all patients with higher magnitude changes seen in responders and super-responders. Changes in biomarkers associated with macrophage activation (CCL7, CCL18, and IL-6) and regulation of matrix composition (matrix metalloproteinase-3) were positively correlated with clinical response.</div><
背景：Baricitinib先前在JUVE-BASIS试验中被证明可以改善幼年特发性关节炎（JIA）患者的临床反应。在这项事后分析中，我们旨在确定baricitinib治疗后血清生物标志物的药效学变化是否有助于重申baricitinib在JIA患者中的临床应用。方法：JUVE-BASIS是一项随机、双盲、安慰剂对照、停药、疗效、安全性的3期试验，在20个国家的75个中心进行。研究结果：在2018年12月17日至2021年3月3日期间，220名患者入组juv - basis，并在开放标签导入期间接受了至少一剂巴西替尼。在这项事后分析中，分析了84例患者的168份血清样本：84例患者中67例（80%）为女性，17例（20%）为男性，67例（80%）为白人，平均年龄为14岁（SD 2）。84例患者中10例（12%）为无反应者，27例（32%）为反应者，47例（56%）为基于临床反应的超反应者。baricitinib治疗12周后，所有患者的几种血清生物标志物均出现显著变化，反应者和超反应者的变化幅度较大。与巨噬细胞活化相关的生物标志物（CCL7、CCL18和IL-6）和基质组成调节（基质金属蛋白酶-3）的变化与临床反应呈正相关。解释：据我们所知，这是首次在baricitinib对JIA患者进行干预试验的背景下测量血清蛋白标志物的研究。与临床反应相关的生物标志物变化可能允许医生潜在地识别最有可能对巴西替尼治疗有反应的患者。融资：礼来公司（Eli Lilly and Company）获得Incyte许可。
{"title":"Serum biomarkers associated with baricitinib response in patients with juvenile idiopathic arthritis: a post-hoc analysis of the phase 3 JUVE-BASIS trial","authors":"Venkatesh Krishnan PhD , Stuart Y Keller BSc , Christine Chew PhD , Jonathan T Sims PhD , Ching-Yun Chang PhD , Ernst R Dow PhD , Robert J Benschop PhD , Rona Wang MD , Prof Athimalaipet V Ramanan FMedSci","doi":"10.1016/S2665-9913(25)00153-5","DOIUrl":"10.1016/S2665-9913(25)00153-5","url":null,"abstract":"<div><h3>Background</h3><div>Baricitinib has previously been shown to improve clinical response in patients with juvenile idiopathic arthritis (JIA) in the JUVE-BASIS trial. In this post-hoc analysis we aimed to identify whether pharmacodynamic changes in serum biomarkers in response to baricitinib treatment could help reaffirm the clinical utility of baricitinib in patients with JIA.</div></div><div><h3>Methods</h3><div>JUVE-BASIS was a randomised, double-blind, placebo-controlled, withdrawal, efficacy, safety, phase 3 trial, done in 75 centres in 20 countries. Eligible patients were children and adolescents (aged 2 to <18 years), with polyarticular JIA (positive or negative for rheumatoid factor), extended oligoarticular JIA, enthesitis-related arthritis, or juvenile psoriatic arthritis, as per the International League of Associations for Rheumatology criteria and an inadequate response (≥12 weeks) or intolerance to one or more conventional synthetic or biological disease-modifying antirheumatic drugs (DMARDs). Here we report post-hoc analyses of serum samples from patients who received open-label baricitinib in the 12-week lead-in period of the JUVE-BASIS trial. Samples were assessed using an Olink Explore 3072 panel at baseline and week 12. Baricitinib-mediated pharmacodynamic changes in serum protein markers were measured as changes from baseline to week 12 derived from a mixed model with repeated measurement. Pearson correlations of the change in serum biomarkers and clinical disease activity (JADAS-27 scores) comparing baseline with week 12 were examined. Proportional changes in biomarkers were classified into three response subsets based on JIA-ACR response rates: JIA-ACR <30% (non-responders), JIA-ACR 30–70% (responders), and JIA-ACR 70–100% (super-responders). People with lived experience of JIA were not involved in the design or conduct of this study. The JUVE-BASIS trial was registered with <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span>, <span><span>NCT03773978</span><svg><path></path></svg></span>, and is completed.</div></div><div><h3>Findings</h3><div>Between Dec 17, 2018 and March 3, 2021, 220 patients were enrolled in JUVE-BASIS and received at least one dose of baricitinib in the open-label lead-in period. In this post-hoc analysis, 168 serum samples from 84 patients were analysed: 67 (80%) of 84 patients were female, 17 (20%) were male, 67 (80%) were White and the mean age was 14 years (SD 2). 10 (12%) of 84 were non-responders, 27 (32%) were responders, and 47 (56%) were super-responders based on clinical response. Several serum biomarkers showed significant changes following 12 weeks of baricitinib treatment for all patients with higher magnitude changes seen in responders and super-responders. Changes in biomarkers associated with macrophage activation (CCL7, CCL18, and IL-6) and regulation of matrix composition (matrix metalloproteinase-3) were positively correlated with clinical response.</div><","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 11","pages":"Pages e799-e807"},"PeriodicalIF":16.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-04DOI: 10.1016/S2665-9913(25)00225-5
Valentine Ribier MD , Jérôme Hadjadj MD , Vincent Jachiet MD , Prof Arsène Mekinian MD , Prof Benjamin Terrier MD , Prof Sophie Georgin-Lavialle MD , Peter C Grayson MD , David B Beck PhD , Prof Sinisa Savic MD , Prof Vincent Dubée MD , Valentin Lacombe MD
Infections are increasingly recognised as a major cause of morbidity and mortality in patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. We conducted a systematic review to characterise the infectious burden of VEXAS syndrome and propose preventive strategies. We included 57 studies (813 patients) showing that infections in patients with VEXAS syndrome were frequent, severe in 40–60% of cases, and fatal in 6–15% of cases. Pulmonary infections were most common, followed by cutaneous infections and bacteraemia. Opportunistic pathogens, such as Pneumocystis jirovecii, Legionella pneumophila, non-tuberculous mycobacteria, and varicella zoster virus, were frequently reported, even in patients not receiving immunosuppressive therapy, which suggests intrinsic immune dysfunction. Prophylaxis with co-trimoxazole (or other Pneumocystis prophylaxis, such as atovaquone or pentamidine) and valaciclovir should particularly be considered for patients at high risk of infection, including those receiving immunosuppressive therapy and those with lymphopenia, pMet41Val mutation, or previous severe or recurrent infections. Posaconazole might be appropriate in patients with neutropenia who are taking azacitidine. Vaccination against Streptococcus pneumoniae, varicella zoster virus, influenza, and SARS-CoV-2 is recommended. These data highlight the need to integrate infectious risk into VEXAS syndrome management and to evaluate preventive strategies in prospective studies.
{"title":"Mapping the infectious burden in VEXAS syndrome: a systematic review and rationale for prevention","authors":"Valentine Ribier MD , Jérôme Hadjadj MD , Vincent Jachiet MD , Prof Arsène Mekinian MD , Prof Benjamin Terrier MD , Prof Sophie Georgin-Lavialle MD , Peter C Grayson MD , David B Beck PhD , Prof Sinisa Savic MD , Prof Vincent Dubée MD , Valentin Lacombe MD","doi":"10.1016/S2665-9913(25)00225-5","DOIUrl":"10.1016/S2665-9913(25)00225-5","url":null,"abstract":"<div><div>Infections are increasingly recognised as a major cause of morbidity and mortality in patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. We conducted a systematic review to characterise the infectious burden of VEXAS syndrome and propose preventive strategies. We included 57 studies (813 patients) showing that infections in patients with VEXAS syndrome were frequent, severe in 40–60% of cases, and fatal in 6–15% of cases. Pulmonary infections were most common, followed by cutaneous infections and bacteraemia. Opportunistic pathogens, such as <em>Pneumocystis jirovecii</em>, <strong>Legionella pneumophila</strong>, non-tuberculous mycobacteria, and varicella zoster virus, were frequently reported, even in patients not receiving immunosuppressive therapy, which suggests intrinsic immune dysfunction. Prophylaxis with co-trimoxazole (or other <em>Pneumocystis</em> prophylaxis, such as atovaquone or pentamidine) and valaciclovir should particularly be considered for patients at high risk of infection, including those receiving immunosuppressive therapy and those with lymphopenia, pMet41Val mutation, or previous severe or recurrent infections. Posaconazole might be appropriate in patients with neutropenia who are taking azacitidine. Vaccination against <em>Streptococcus pneumoniae</em>, varicella zoster virus, influenza, and SARS-CoV-2 is recommended. These data highlight the need to integrate infectious risk into VEXAS syndrome management and to evaluate preventive strategies in prospective studies.</div></div>","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 10","pages":"Pages e734-e744"},"PeriodicalIF":16.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-04DOI: 10.1016/S2665-9913(25)00189-4
Stephanie KA Wong , Marinka Twilt
{"title":"Biomarkers for juvenile idiopathic arthritis treatment response—have we identified them?","authors":"Stephanie KA Wong , Marinka Twilt","doi":"10.1016/S2665-9913(25)00189-4","DOIUrl":"10.1016/S2665-9913(25)00189-4","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 11","pages":"Pages e752-e754"},"PeriodicalIF":16.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-03DOI: 10.1016/S2665-9913(25)00255-3
Dafna D Gladman
{"title":"Challenges in the therapeutic management of psoriatic arthritis","authors":"Dafna D Gladman","doi":"10.1016/S2665-9913(25)00255-3","DOIUrl":"10.1016/S2665-9913(25)00255-3","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 11","pages":"Pages e749-e750"},"PeriodicalIF":16.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-03DOI: 10.1016/S2665-9913(25)00156-0
Gabriele De Marco PhD , Elizabeth M A Hensor PhD , Prof Philip S Helliwell PhD , Shabina Sultan MD , Sayam R Dubash MD , Xabier Michelena PhD , Prof Laura C Coates PhD , Prof Paul Emery PhD , Ai Lyn Tan MD , Prof Dennis McGonagle PhD , Prof Helena Marzo-Ortega PhD
<div><h3>Background</h3><div>The optimal treatment strategy in early psoriatic arthritis remains unknown. We aimed to assess whether the combination of methotrexate and golimumab plus corticosteroids is superior to methotrexate plus corticosteroids in reducing disease activity in early, untreated psoriatic arthritis.</div></div><div><h3>Methods</h3><div>We did a double-blind, randomised, placebo-controlled, parallel-group, single-centre study in adults with treatment-naïve active psoriatic arthritis. Participants were required to have been diagnosed up to 24 months before enrolment and had to be naïve to conventional synthetic, biologic, or targeted synthetic disease-modifying antirheumatic drugs or systemic treatments before enrolment. Participants were randomly assigned (1:1) to receive either combination therapy of golimumab and methotrexate or placebo and methotrexate, stratified by the number of involved peripheral joints at baseline. Investigators and participants were masked to treatment allocation. At baseline, all participants received methylprednisolone (120 mg intramuscular administration, single dose) and commenced weekly methotrexate (increased to 25 mg within 28 days). Golimumab or placebo were administered by subcutaneous injections every 4 weeks. By week 24, additional methylprednisolone was permitted once (totalling up to 240 mg exposure). The primary endpoint was the difference in mean Psoriatic Arthritis Disease Activity Score (PASDAS) at week 24 in the intention-to-treat population, compared using analysis of covariance via multiple linear regression. People with lived experience of psoriatic arthritis were involved in the design and conduct the study. The study was registered with EudraCT, 2013-004122-28, and is complete.</div></div><div><h3>Findings</h3><div>Between Nov 3, 2015 and Jan 26, 2022, 106 people were assessed for eligibility, 22 were excluded, and 84 were randomly assigned (43 to the golimumab and methotrexate group and 41 to the placebo and methotrexate group). 46 (55%) participants were male and 38 (45%) were female. The mean age was 42·5 years (SD 12·4) and 61 (73%) participants were White and seven (8%) were from any Asian, Black, or other ethnic background. PASDAS did not differ between treatment groups at week 24 (unadjusted mean 3·09 [SD 1·32] in the placebo and methotrexate group and 2·70 [1·38] in the golimumab and methotrexate group; adjusted difference –0·55 [95% CI –1·12 to 0·03]; p=0·064). More participants in the placebo and methotrexate group received additional corticosteroids before week 24 (20 [49%] of 41 <em>vs</em> nine [21%] of 43; odds ratio 0·28 [95% CI 0·11 to 0·72]; p=0·009). Similar numbers of participants had adverse events (38 [93%] of 41 in the placebo and methotrexate group <em>vs</em> 41 [95%] of 43 in the golimumab and methotrexate group; risk difference 0·03 [95% CI –0·09 to 0·15]), although altered laboratory investigations and infections occurred more frequently in the golimumab
背景：早期银屑病关节炎的最佳治疗策略尚不清楚。我们的目的是评估甲氨蝶呤和戈利单抗加皮质类固醇联合治疗在降低早期未经治疗的银屑病关节炎的疾病活动性方面是否优于甲氨蝶呤加皮质类固醇。方法：我们对患有treatment-naïve活动性银屑病关节炎的成人患者进行了一项双盲、随机、安慰剂对照、平行组、单中心研究。受试者被要求在入组前24个月进行诊断，并且必须在入组前naïve接受常规合成、生物或靶向合成疾病改善抗风湿药物或全身治疗。参与者被随机分配（1:1）接受戈利木单抗和甲氨蝶呤联合治疗或安慰剂和甲氨蝶呤联合治疗，根据基线时受累的外周关节数量分层。调查人员和参与者对治疗分配不知情。在基线时，所有参与者接受甲强的松龙（120 mg肌肉注射，单剂量），并开始每周服用甲氨蝶呤（28天内增加到25 mg）。Golimumab或安慰剂每4周皮下注射一次。到第24周，甲强的松龙被允许额外使用一次（总计240毫克）。主要终点是意向治疗人群第24周平均银屑病关节炎疾病活动评分（PASDAS）的差异，通过多元线性回归进行协方差分析进行比较。有银屑病关节炎生活经验的人参与了研究的设计和实施。本研究已在EudraCT注册，编号为2013-004122-28，现已完成。研究结果：在2015年11月3日至2022年1月26日期间，106人被评估为合格，22人被排除，84人被随机分配（43人被分配到戈利单抗和甲氨蝶呤组，41人被分配到安慰剂和甲氨蝶呤组）。46人（55%）为男性，38人（45%）为女性。平均年龄为42.5岁（标准差为12.4），白人61人（73%），亚洲人、黑人或其他种族背景的人7人（8%）。治疗组间PASDAS在第24周无差异（安慰剂组和甲氨蝶呤组未经校正的平均值为3.09 [SD 1.32]，戈利单抗组和甲氨蝶呤组未经校正的平均值为2.70[1.38]；校正后的差异为- 0.55 [95% CI - 1.12至0.03];p= 0.064）。安慰剂和甲氨蝶呤组更多的参与者在第24周之前接受了额外的皮质类固醇治疗（41例中有20例[49%]vs 43例中有9例[21%]；优势比为0.28 [95% CI 0.11 ~ 0.72]; p= 0.009）。相似数量的参与者出现不良事件（安慰剂和甲氨蝶呤组41人中的38人[93%]vs戈利单抗和甲氨蝶呤组43人中的41人[95%]；风险差异为0.03 [95% CI - 0.09至0.15]），尽管戈利单抗和甲氨蝶呤组改变了实验室调查和感染发生的频率。未发生死亡、严重或意外不良事件。解释：两种干预措施均可改善早期未经治疗的银屑病关节炎患者的疾病活动性，在第24周时，两组间PASDAS无临床或统计学显著差异。安慰剂组和甲氨蝶呤组需要更多的皮质类固醇。在52周时，两组均观察到持续的结果，未发生严重或意外的不良事件。资助：Janssen Biologics BV。
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