Journal of Internal Medicine最新文献

{"title":"Co-pathologies and biological processes beyond amyloid-beta and tau in people with Alzheimer's disease: Evidence from clinical cohort studies.","authors":"Daniel Ferreira, Tomasz Chmiela, Maria Eriksdotter, Clifford R Jack, Grégoria Kalpouzos, Anna Marseglia, Patrizia Mecocci, Agneta Nordberg, Dorota Religa, Eric Westman","doi":"10.1111/joim.70096","DOIUrl":"10.1111/joim.70096","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is neuropathologically defined by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. However, co-pathologies and other pathobiological processes are involved in the pathogenesis of AD, contributing to neurodegeneration and clinical symptoms. The most common co-pathologies in people with AD are alpha-synucleinopathy, vascular brain injury and transactive response DNA-binding protein of 43 kDa-related pathology. Neuroinflammation, iron accumulation, cholinergic dysfunction and cellular senescence are recognized pathobiological processes beyond Aβ- and tau-related pathology. However, the exact mechanisms by which these co-pathologies and pathobiological processes contribute to the neurodegeneration and clinical symptoms in people with AD remain unclear. The individual combination of these co-pathologies and pathobiological processes increases phenotypical heterogeneity in people with AD. This highlights the unmet need to advance their current understanding, and the field strives to develop accurate biomarkers for personalized assessment and investigation. Elucidating this biologic-clinical complexity and heterogeneity is crucial for increasing our current understanding of AD, with implications for diagnosis, prognosis and therapeutics.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":" ","pages":"694-710"},"PeriodicalIF":7.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13137405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flare risk after oral glucocorticoid bridging with methotrexate or intra-articular bridging with triple therapy in early rheumatoid arthritis.","authors":"Kristina Lend, Jos W R Twisk, Frieda A Koopman, Anna Rudin, Merete Lund Hetland, Till Uhlig, Dan C Nordström, Michael T Nurmohamed, Bjorn Gudbjornsson, Kim Hørslev-Petersen, Marte Schrumpf Heiberg, Tuulikki Sokka-Isler, Gerdur Grondal, Espen A Haavardsholm, Mikkel Østergaard, Jon Lampa, Ronald van Vollenhoven","doi":"10.1111/joim.70094","DOIUrl":"10.1111/joim.70094","url":null,"abstract":"<p><strong>Objectives: </strong>To investigate, in early rheumatoid arthritis, whether bridging with glucocorticoids (GCs) is associated with an increased risk of flare following GC tapering and withdrawal.</p><p><strong>Methods: </strong>A total of 810 NOrdic Rheumatic Diseases Strategy Trials And Registries (NORD-STAR) patients were included in this post hoc analysis: all received methotrexate (MTX), in addition to which 135 patients received oral GC bridging therapy ('oral GC group'); 80 received intra-articular (IA) GC bridging therapy, sulfasalazine and hydroxychloroquine ('injection GC group'); and 595 received one of three (certolizumab pegol, abatacept and tocilizumab) biologic disease-modifying antirheumatic drugs (bDMARDs), hereafter the ('bDMARD group'). Clinical disease activity index (CDAI) flares (≥4.5 increase in CDAI score) were assessed longitudinally.</p><p><strong>Results: </strong>Up to 48 weeks, flare occurred at least once in 43% of oral GC, 24% of injection GC and 28% of bDMARD patients. Over-time relative risk (RR) was higher with oral GC bridging (adjusted RR, 1.54; 95% CI, 1.16-2.03) but similar with injection GC bridging (adjusted RR 0.93; 95% CI, 0.54-1.55) versus bDMARD. Flare rates were numerically higher in the oral GC versus bDMARD group at all time points (12, 24, 32, 40 and 48 weeks), with a significant difference at w.40, the visit after protocol-defined GC discontinuation; at this visit 27% of patients who discontinued GC experienced flare; 29% among those in remission; 33% remained on low-dose prednisolone at 48 weeks.</p><p><strong>Conclusion: </strong>Discontinuation of oral GC bridging therapy on background MTX is associated with increased flare risk, even among patients in remission. Flare rates with IA GC bridging plus triple therapy did not differ from the bDMARD group.</p><p><strong>Trial registration number: </strong>EudraCT 2011-004720-35; ClinicalTrials.gov NCT01491815.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":" ","pages":"741-753"},"PeriodicalIF":7.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13137394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 6","pages":""},"PeriodicalIF":9.2,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148065411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 6","pages":"776-780"},"PeriodicalIF":9.2,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148079321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 6","pages":"694-710"},"PeriodicalIF":9.2,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148079322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 6","pages":"754-775"},"PeriodicalIF":9.2,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148074012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic analyses suggest different pathways during pregnancy for development of type 1 diabetes in children with high versus low-neutral human leukocyte antigen-risk","authors":"Shamila D. Alipoor,&nbsp;Angelica Ahrens,&nbsp;Julia Åkesson,&nbsp;Thomas Hillerton,&nbsp;Mika Gustafsson,&nbsp;Maria Lerm,&nbsp;Johnny Ludvigsson","doi":"10.1111/joim.70077","DOIUrl":"10.1111/joim.70077","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and objective</h3>\u0000 \u0000 <p>The development of Type 1 diabetes (T1D) is shaped by genetic predisposition and epigenetic regulation. Human leukocyte antigen (HLA) risk alleles are major genetic determinants, but the epigenetic landscape in relation to disease onset remains unclear. Early-life epigenetic modifications may reveal how environmental and epigenetic factors interact in T1D pathogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated epigenetic differences in cord blood DNA from individuals with different HLA risk alleles who later developed T1D using epigenome-wide association studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>High-risk HLA carriers showed differentially methylated genes (DMGs) mainly involved in immune and autoimmune processes, resembling patterns in other autoimmune diseases. In contrast, low-to-neutral risk carriers exhibited DMGs linked to signaling cascades, metabolic pathways, and Type 2 diabetes–related mechanisms such as beta cell function and insulin signaling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings indicate that heterogeneity in T1D pathogenetic mechanisms based on HLA background may influence disease development.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 5","pages":"570-586"},"PeriodicalIF":9.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13061103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colorectal cancer screening and incidence and mortality of colorectal and other cancers in the United Kingdom","authors":"Marko Mandic,&nbsp;Fatemeh Safizadeh,&nbsp;Michael Hoffmeister,&nbsp;Hermann Brenner","doi":"10.1111/joim.70075","DOIUrl":"10.1111/joim.70075","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Randomized controlled trials (RCTs) have demonstrated that colorectal cancer (CRC) screening, including screening by fecal occult blood tests (FOBTs), reduces CRC incidence and mortality under trial conditions. A 2019 meta-analysis of RCTs found that screening by annual guaiac-based FOBTs (gFOBTs) was associated with a 31% decrease in CRC mortality (95% CI: −44% to −20%), and a nonsignificant 14% reduction in CRC incidence (95% CI: −28% to +3%) [&lt;span&gt;1&lt;/span&gt;]. Although RCTs are crucial for establishing the efficacy of screening offers under trial conditions, additional evidence is needed to evaluate the effectiveness of screening under real-life conditions. Large-scale observational epidemiological studies comparing cancer incidence and mortality between screening users and nonusers under real-life conditions may serve that purpose. However, such studies may be subject to residual confounding factors associated with screening behavior, even if every effort is made to adjust for potential confounders. One way of addressing these concerns is to examine whether the associations with CRC screening are specific to CRC incidence and mortality [&lt;span&gt;2&lt;/span&gt;]. If similar associations appear for other cancers that share similar confounding factors but would not plausibly benefit from CRC screening, this would suggest residual confounding.&lt;/p&gt;&lt;p&gt;Therefore, we aimed to assess the associations between CRC screening and CRC incidence and mortality and to compare these associations with the associations with incidence and mortality of other cancers in a very large cohort from the United Kingdom, where organized gFOBT screening began in 2006, initially limited to individuals aged 60–69 years [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;We analyzed data from 342,164 individuals aged 50–69 years recruited to the UK Biobank [&lt;span&gt;4&lt;/span&gt;] between 2006 and 2010. Details of the study population selection, baseline characteristics, and statistical analysis are provided in the Supplement. CRC screening was defined as (self-reported) ever use of CRC screening, which at the time of recruitment primarily consisted of gFOBTs in the United Kingdom. Associations with CRC incidence and mortality and with anatomic subsites were ascertained using multivariable Cox models and compared with those for other cancers. During a median follow-up of 11.7 years, 5391 participants were diagnosed with CRC, 39,503 with other cancers, and 1465 died from CRC and 13,465 from other cancers (Supporting Information).&lt;/p&gt;&lt;p&gt;CRC screening was associated with a 14% (95% CI: 10%–18%) lower CRC incidence and a 26% (95% CI: 18%–34%) lower CRC mortality (Fig. 1). No associations were observed for other cancers. Particularly strong associations were seen with distal colon cancer incidence and mortality, with 30% (95% CI: 22%–37%) and 44% (95% CI: 27%–58%) lower risk among screening users, respectively. However, no significant associations were found for proximal colon cancer. These subsite-speci","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 5","pages":"639-642"},"PeriodicalIF":9.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13061097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Who can safely discontinue lifelong follow-up among patients with sporadic pheochromocytoma and paraganglioma?","authors":"Min Jeong Park,&nbsp;Seung Shin Park,&nbsp;Won Woong Kim,&nbsp;Su-Jin Kim,&nbsp;Yu-Mi Lee,&nbsp;Kyu Eun Lee,&nbsp;Tae-Yon Sung,&nbsp;Jae-Kyung Won,&nbsp;Dong Eun Song,&nbsp;Jung-Min Koh,&nbsp;Sara Talvacchio,&nbsp;Tamara Prodanov,&nbsp;Hussam Alkaissi,&nbsp;Karel Pacak,&nbsp;Seung Hun Lee,&nbsp;Jung Hee Kim","doi":"10.1111/joim.70080","DOIUrl":"10.1111/joim.70080","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Current guidelines recommend at least 10 years of follow-up for all pheochromocytoma and paraganglioma (PPGL) patients and lifelong monitoring for high-risk individuals. Nonetheless, data identifying patients who may not require routine lifelong follow-up are scarce.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Among 999 patients with PPGL, 703 who were non-metastatic, non-hereditary, and had undergone complete resection were included. Variables that significantly differed between the recurrence (<i>n</i> = 50) and non-recurrence groups over 10 years (<i>n</i> = 83) were identified, and cutoff values were determined using receiver-operating characteristic curve analysis. These very low-risk criteria were validated in an internal cohort and an external dataset from the National Institutes of Health.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The non-recurrence group was older and had smaller pheochromocytomas (PCCs) than the recurrence group, with cutoffs of 37 years and 5.7 cm, respectively. The non-recurrence group had a higher percentage of patients with pheochromocytoma of the adrenal gland scaled score (PASS) &lt;4 or grading system for adrenal pheochromocytoma and paraganglioma (GAPP) score &lt;3 (<i>p </i>= 0.027). Age &gt;40 years (hazard ratio [HR] [95% confidence intervals] of 0.36 [0.17–0.76]), PCC size &lt;6 cm (HR = 0.43 [0.19–0.98]), and PASS &lt;4 or GAPP score &lt;3 (HR = 0.37 [0.16–0.89]) were associated with lower recurrence risk. None of the patients meeting all these criteria in the internal (<i>n</i> = 114) and external (<i>n</i> = 13) validation sets experienced recurrence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study suggests that routine lifelong follow-up may be unnecessary for patients with sporadic PCC aged &gt;40 years, size &lt;6 cm, and PASS &lt;4 or GAPP score &lt;3.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 5","pages":"615-627"},"PeriodicalIF":9.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13061095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perioperative immune checkpoint inhibitor therapy across tumors: Insights and shared lessons from a rapidly evolving field","authors":"Karl Björkström,&nbsp;Alexios Matikas,&nbsp;Fernanda Costa Svedman,&nbsp;Einar Björgvinsson,&nbsp;Mark Zupancic,&nbsp;Lisa Villabona,&nbsp;Hanna Eriksson,&nbsp;Marcus Skribek,&nbsp;Josefin Fernebro,&nbsp;Magnus Lindskog,&nbsp;Jan-Erik Frödin,&nbsp;Anders Ullén,&nbsp;Simon Ekman,&nbsp;Hildur Helgadottir","doi":"10.1111/joim.70073","DOIUrl":"10.1111/joim.70073","url":null,"abstract":"<p>The integration of immune checkpoint inhibitors into perioperative management marks a major evolution in curative-intent oncology. This review examines the current evidence for perioperative immunotherapy encompassing neoadjuvant, adjuvant, and combined strategies in melanoma and non-melanoma skin cancers, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), esophageal and gastroesophageal junction cancer, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, colorectal cancer, gynecological malignancies, and hepatocellular carcinoma. Neoadjuvant immunotherapy demonstrates biological advantages by exposing the immune system to intact tumor antigens, consistently improving event-free survival and pathological response rates across tumor types. Notable successes include CheckMate 816 in NSCLC, KEYNOTE-522 in TNBC, and emerging trials in melanoma that show superior outcomes compared to adjuvant-only approaches. Pathological complete response and major pathological response have emerged as robust surrogate endpoints correlating with long-term survival. In contrast, adjuvant immunotherapy shows more variable results, with demonstrated recurrence-free survival benefits but inconsistent overall survival (OS) advantages—particularly concerning given the risk of overtreatment in patients potentially cured by surgery alone. Critical challenges include the absence of predictive biomarkers in most cancer types, immune-related adverse events occurring in up to 30% of patients, substantial healthcare costs, and insufficient OS follow-up duration in many approved indications. Future priorities include biomarker development, adaptive trial designs incorporating response-guided therapy, and long-term toxicity assessment. Although perioperative immunotherapy is reshaping curative-intent cancer treatment, optimal patient selection, treatment sequencing, and safety optimization remain essential for widespread implementation.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 5","pages":"538-569"},"PeriodicalIF":9.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.70073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}