Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic disorder characterized by recurrent attacks of swelling. Local vasodilation and vascular leakage are stimulated by the vasoactive peptide bradykinin, which is excessively produced due to dysregulation of the activated factor XII (FXIIa)-driven kallikrein–kinin system. There is a need for novel treatments for HAE that provide greater efficacy, improved quality of life, minimal adverse effects, and reduced treatment burden over current first-line therapies. FXIIa is emerging as an attractive therapeutic target for interference with HAE attacks. In this review, we draw on preclinical, experimental animal, and in vitro studies, providing an overview on targeting FXIIa as the basis for pharmacologic interference in HAE. We highlight that there is a range of FXIIa inhibitors in development for different therapeutic areas. Of these, garadacimab, an FXIIa-targeted inhibitory monoclonal antibody, is the most advanced and has shown potential as a novel long-term prophylactic treatment for patients with HAE in clinical trials. The evidence from these trials is summarized and discussed, and we propose areas for future research where targeting FXIIa may have therapeutic potential beyond HAE.
遗传性血管性水肿（HAE）是一种罕见的、可能危及生命的遗传性疾病，其特征是反复发作的浮肿。由于活化因子 XII（FXIIa）驱动的缓激肽-激肽系统失调，导致缓激肽过度分泌，从而刺激局部血管扩张和血管渗漏。与目前的一线疗法相比，HAE 需要新型疗法，以提高疗效、改善生活质量、减少不良反应并减轻治疗负担。FXIIa 正在成为干扰 HAE 发作的一个有吸引力的治疗靶点。在这篇综述中，我们借鉴了临床前、实验动物和体外研究的结果，概述了以 FXIIa 为靶点作为药物干预 HAE 的基础。我们强调，目前有一系列针对不同治疗领域的 FXIIa 抑制剂正在开发中。其中，以 FXIIa 为靶点的抑制性单克隆抗体加拉达西单抗（garadacimab）是最先进的药物，在临床试验中已显示出作为一种新型长期预防性疗法治疗 HAE 患者的潜力。我们对这些试验的证据进行了总结和讨论，并提出了以 FXIIa 为靶点可能具有治疗 HAE 以外的潜力的未来研究领域。
{"title":"Targeting factor XIIa for therapeutic interference with hereditary angioedema","authors":"Danny M. Cohn, Thomas Renné","doi":"10.1111/joim.20008","DOIUrl":"https://doi.org/10.1111/joim.20008","url":null,"abstract":"<p>Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic disorder characterized by recurrent attacks of swelling. Local vasodilation and vascular leakage are stimulated by the vasoactive peptide bradykinin, which is excessively produced due to dysregulation of the activated factor XII (FXIIa)-driven kallikrein–kinin system. There is a need for novel treatments for HAE that provide greater efficacy, improved quality of life, minimal adverse effects, and reduced treatment burden over current first-line therapies. FXIIa is emerging as an attractive therapeutic target for interference with HAE attacks. In this review, we draw on preclinical, experimental animal, and in vitro studies, providing an overview on targeting FXIIa as the basis for pharmacologic interference in HAE. We highlight that there is a range of FXIIa inhibitors in development for different therapeutic areas. Of these, garadacimab, an FXIIa-targeted inhibitory monoclonal antibody, is the most advanced and has shown potential as a novel long-term prophylactic treatment for patients with HAE in clinical trials. The evidence from these trials is summarized and discussed, and we propose areas for future research where targeting FXIIa may have therapeutic potential beyond HAE.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"296 4","pages":"311-326"},"PeriodicalIF":9.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244526","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}
Tadalafil, commonly prescribed for benign prostatic hyperplasia (BPH), may benefit patients with Type 2 diabetes mellitus (T2DM) for glycemic markers and complications. However, the association between the long-term use of tadalafil and the incidence of T2DM has not been investigated.
Methods
We emulated a target trial of tadalafil use (5 mg/day) and the risk of T2DM using a population-based claims database in Japan. Patients who initiated tadalafil or alpha-blockers for BPH and had no history of diabetes diagnosis, no dispensing of glucose-lowering drugs, and no history of hemoglobin A1c levels of ≥6.5% (47–48 mmol/mol) were included. The primary outcome was the incidence of T2DM. Pooled logistic regression was used to estimate adjusted risk ratios (RRs) and 5-year cumulative incidence differences (CIDs).
Results
A total of 5180 participants initiated tadalafil treatment and were compared with 20,049 patients who initiated alpha-blockers. The median follow-up time for each arm was 27.2 months (interquartile range [IQR], 12.0–47.9) in tadalafil users and 31.3 months (IQR, 13.7–57.2) in alpha-blocker users. The incidence rates of T2DM in tadalafil and alpha-blocker users were 5.4 (95% confidence interval [CI], 4.0–7.2) and 8.8 (95% CI, 7.8–9.8) per 1000-person years, respectively. Initiation of tadalafil was associated with a reduced risk of T2DM (RR, 0.47; 95% CI, 0.39–0.62; 5-year CID, −0.031; 95% CI, −0.040 to −0.019).
Conclusion
The incidence of T2DM was lower in men with BPH treated with tadalafil than in those treated with alpha-blockers. Thus, tadalafil may be more beneficial than alpha-blockers in preventing T2DM.
{"title":"Tadalafil use is associated with a lower incidence of Type 2 diabetes in men with benign prostatic hyperplasia: A population-based cohort study","authors":"Atsushi Takayama, Satomi Yoshida, Koji Kawakami","doi":"10.1111/joim.20012","DOIUrl":"10.1111/joim.20012","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Tadalafil, commonly prescribed for benign prostatic hyperplasia (BPH), may benefit patients with Type 2 diabetes mellitus (T2DM) for glycemic markers and complications. However, the association between the long-term use of tadalafil and the incidence of T2DM has not been investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We emulated a target trial of tadalafil use (5 mg/day) and the risk of T2DM using a population-based claims database in Japan. Patients who initiated tadalafil or alpha-blockers for BPH and had no history of diabetes diagnosis, no dispensing of glucose-lowering drugs, and no history of hemoglobin A1c levels of ≥6.5% (47–48 mmol/mol) were included. The primary outcome was the incidence of T2DM. Pooled logistic regression was used to estimate adjusted risk ratios (RRs) and 5-year cumulative incidence differences (CIDs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 5180 participants initiated tadalafil treatment and were compared with 20,049 patients who initiated alpha-blockers. The median follow-up time for each arm was 27.2 months (interquartile range [IQR], 12.0–47.9) in tadalafil users and 31.3 months (IQR, 13.7–57.2) in alpha-blocker users. The incidence rates of T2DM in tadalafil and alpha-blocker users were 5.4 (95% confidence interval [CI], 4.0–7.2) and 8.8 (95% CI, 7.8–9.8) per 1000-person years, respectively. Initiation of tadalafil was associated with a reduced risk of T2DM (RR, 0.47; 95% CI, 0.39–0.62; 5-year CID, −0.031; 95% CI, −0.040 to −0.019).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The incidence of T2DM was lower in men with BPH treated with tadalafil than in those treated with alpha-blockers. Thus, tadalafil may be more beneficial than alpha-blockers in preventing T2DM.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"296 5","pages":"422-434"},"PeriodicalIF":9.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254081","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}
Ann Bugeja, Gregory L. Hundemer, Daniel I. McIsaac
<p>Dear Editor,</p><p>We thank Dr. Huang et al. for their thoughtful response to our published manuscript [<span>1, 2</span>]. Their first concern addresses our interpretation of the adjusted hazard ratio (aHR 0.98 [95% CI 0.96, 0.99]) for antihypertensive medication prescription by sex. Although statistically significant, its clinical significance remains uncertain, though we acknowledge its relevance at the population level in the discussion section of our manuscript. To explore potential effect modifiers, we tested a priori interactions between sex and several plausible variables—age, diabetes status, era of hypertension diagnosis, and preexisting cardiovascular disease—by incorporating these multiplicative terms into our model. We then reported aHRs of each stratum from stratified analyses for those variables that were statistically significant on the multiplicative scale. However, we did not report measures of relative excess due to interaction [<span>3</span>]. It is certainly possible that other covariates may have been effect modifiers of the association between sex and prescription of antihypertensive medication.</p><p>Second, misclassification bias is a recognized issue in observational studies utilizing administrative data. Nonetheless, the case definition for hypertension used in our study has been validated, showing a sensitivity of 75%, specificity of 94%, positive predictive value of 81%, and negative predictive value of 92%, as detailed in our methods section [<span>4</span>]. As the authors correctly note, administrative data do not capture nuances related to gender and patient preferences that can influence hypertension treatment, which may introduce residual confounding [<span>5</span>].</p><p>Third, although the aHR for the prescription of guideline-recommended antihypertensive medication is statistically significant (aHR 0.995, 95% CI [0.994, 0.997]), determining its clinical significance is challenging. We acknowledge that this effect may be clinically relevant at the population level, as discussed in our manuscript. Evaluating antihypertensive medication prescriptions over time, alongside data on actual blood pressure management and drug intolerance, would offer additional insights beyond our current findings.</p><p>Lastly, we aimed to address the observation that better cardiovascular outcomes in females compared to males do not appear to be linked to the completion of hypertension-related investigations or the prescription of antihypertensive medication [<span>6</span>]. We proposed that females might benefit more from antihypertensive treatment compared to males, but we recognize that we cannot draw definitive conclusions due to limitations such as insufficient data on treatment adherence, gender-specific issues, and potential residual confounding. More detailed data would enhance our study and support the development of targeted implementation strategies for older populations.</p><p>The authors declare no conflicts of i
亲爱的编辑，我们感谢黄博士等人对我们发表的稿件[1, 2]的深思熟虑的回应。他们提出的第一个问题涉及我们对按性别分列的降压药处方调整危险比（aHR 0.98 [95% CI 0.96, 0.99]）的解释。虽然在统计学上有意义，但其临床意义仍不确定，尽管我们在手稿的讨论部分承认了其在人群水平上的相关性。为了探索潜在的效应调节因子，我们测试了性别与年龄、糖尿病状况、高血压诊断时间和既往心血管疾病等几个可能变量之间的先验交互作用，并将这些乘法项纳入模型。然后，我们报告了分层分析得出的各层的 aHRs，这些变量在乘法尺度上具有统计学意义。但是，我们没有报告交互作用导致的相对过量[3]。当然，其他协变量也可能是性别与抗高血压药物处方之间关系的效应调节因素。其次，误分类偏差是利用行政数据进行观察研究中公认的问题。尽管如此，我们研究中使用的高血压病例定义已经过验证，显示灵敏度为 75%，特异性为 94%，阳性预测值为 81%，阴性预测值为 92%，详见我们的方法部分[4]。正如作者正确指出的那样，行政数据并不能捕捉到与性别和患者偏好有关的细微差别，而这些因素可能会影响高血压的治疗，因此可能会带来残余混杂因素[5]。第三，尽管指南推荐的降压药物处方的 aHR 具有统计学意义（aHR 0.995，95% CI [0.994，0.997]），但确定其临床意义却具有挑战性。我们承认，正如我们手稿中讨论的那样，这种效应在人群水平上可能具有临床相关性。最后，我们的目标是解决这样一个问题：与男性相比，女性更好的心血管预后似乎与完成高血压相关检查或开具降压药处方无关[6]。我们认为，与男性相比，女性可能会从降压治疗中获益更多，但我们认识到，由于治疗依从性数据不足、性别特异性问题以及潜在的残余混杂因素等限制因素，我们无法得出明确的结论。更详细的数据将加强我们的研究，并支持为老年人群制定有针对性的实施策略。
{"title":"Authors reply: Adherence to guideline-recommended care of late-onset hypertension in females versus males: A population-based cohort study","authors":"Ann Bugeja, Gregory L. Hundemer, Daniel I. McIsaac","doi":"10.1111/joim.20010","DOIUrl":"10.1111/joim.20010","url":null,"abstract":"<p>Dear Editor,</p><p>We thank Dr. Huang et al. for their thoughtful response to our published manuscript [<span>1, 2</span>]. Their first concern addresses our interpretation of the adjusted hazard ratio (aHR 0.98 [95% CI 0.96, 0.99]) for antihypertensive medication prescription by sex. Although statistically significant, its clinical significance remains uncertain, though we acknowledge its relevance at the population level in the discussion section of our manuscript. To explore potential effect modifiers, we tested a priori interactions between sex and several plausible variables—age, diabetes status, era of hypertension diagnosis, and preexisting cardiovascular disease—by incorporating these multiplicative terms into our model. We then reported aHRs of each stratum from stratified analyses for those variables that were statistically significant on the multiplicative scale. However, we did not report measures of relative excess due to interaction [<span>3</span>]. It is certainly possible that other covariates may have been effect modifiers of the association between sex and prescription of antihypertensive medication.</p><p>Second, misclassification bias is a recognized issue in observational studies utilizing administrative data. Nonetheless, the case definition for hypertension used in our study has been validated, showing a sensitivity of 75%, specificity of 94%, positive predictive value of 81%, and negative predictive value of 92%, as detailed in our methods section [<span>4</span>]. As the authors correctly note, administrative data do not capture nuances related to gender and patient preferences that can influence hypertension treatment, which may introduce residual confounding [<span>5</span>].</p><p>Third, although the aHR for the prescription of guideline-recommended antihypertensive medication is statistically significant (aHR 0.995, 95% CI [0.994, 0.997]), determining its clinical significance is challenging. We acknowledge that this effect may be clinically relevant at the population level, as discussed in our manuscript. Evaluating antihypertensive medication prescriptions over time, alongside data on actual blood pressure management and drug intolerance, would offer additional insights beyond our current findings.</p><p>Lastly, we aimed to address the observation that better cardiovascular outcomes in females compared to males do not appear to be linked to the completion of hypertension-related investigations or the prescription of antihypertensive medication [<span>6</span>]. We proposed that females might benefit more from antihypertensive treatment compared to males, but we recognize that we cannot draw definitive conclusions due to limitations such as insufficient data on treatment adherence, gender-specific issues, and potential residual confounding. More detailed data would enhance our study and support the development of targeted implementation strategies for older populations.</p><p>The authors declare no conflicts of i","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"296 5","pages":"454-455"},"PeriodicalIF":9.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152728","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}
Yun Chen, Longgang Zhao, Su Yon Jung, Margaret S. Pichardo, Melissa Lopez-Pentecost, Thomas E. Rohan, Nazmus Saquib, Yangbo Sun, Fred K. Tabung, Tongzhang Zheng, Jean Wactawski-Wende, JoAnn E. Manson, Marian L Neuhouser, Xuehong Zhang
Background
We aimed to prospectively evaluate the association between a diabetes risk reduction diet (DRRD) score and the risk of liver cancer development and chronic liver disease-specific mortality.
Methods
We included 98,786 postmenopausal women from the Women's Health Initiative-Observational Study and the usual diet arm of the Diet Modification trial. The DRRD score was derived from eight factors: high intakes of dietary fiber, coffee, nuts, polyunsaturated fatty acids, low intakes of red and processed meat, foods with high glycemic index, sugar-sweetened beverages (SSBs), and trans fat based on a validated Food-Frequency Questionnaire administered at baseline (1993–1998). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for liver cancer incidence and chronic liver disease mortality were estimated using Cox proportional hazards regression models.
Results and conclusion
After a median follow-up of 22.0 years, 216 incident liver cancer cases and 153 chronic liver disease deaths were confirmed. A higher DRRD score was significantly associated with a reduced risk of developing liver cancer (HRTertile 3 vs. Tertile 1 = 0.69; 95% CI: 0.49–0.97; Ptrend = 0.03) and chronic liver disease mortality (HRT3 vs. T1 = 0.54; 95% CI: 0.35–0.82; Ptrend = 0.003). We further found inverse associations with dietary fiber and coffee, and positive associations with dietary glycemic index, SSBs, and trans fat. A higher DRRD score was associated with reduced risk of developing liver cancer and chronic liver disease mortality among postmenopausal women.
{"title":"Diabetes risk reduction diet and risk of liver cancer and chronic liver disease mortality: A prospective cohort study","authors":"Yun Chen, Longgang Zhao, Su Yon Jung, Margaret S. Pichardo, Melissa Lopez-Pentecost, Thomas E. Rohan, Nazmus Saquib, Yangbo Sun, Fred K. Tabung, Tongzhang Zheng, Jean Wactawski-Wende, JoAnn E. Manson, Marian L Neuhouser, Xuehong Zhang","doi":"10.1111/joim.20007","DOIUrl":"10.1111/joim.20007","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>We aimed to prospectively evaluate the association between a diabetes risk reduction diet (DRRD) score and the risk of liver cancer development and chronic liver disease-specific mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 98,786 postmenopausal women from the Women's Health Initiative-Observational Study and the usual diet arm of the Diet Modification trial. The DRRD score was derived from eight factors: high intakes of dietary fiber, coffee, nuts, polyunsaturated fatty acids, low intakes of red and processed meat, foods with high glycemic index, sugar-sweetened beverages (SSBs), and <i>trans</i> fat based on a validated Food-Frequency Questionnaire administered at baseline (1993–1998). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for liver cancer incidence and chronic liver disease mortality were estimated using Cox proportional hazards regression models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results and conclusion</h3>\u0000 \u0000 <p>After a median follow-up of 22.0 years, 216 incident liver cancer cases and 153 chronic liver disease deaths were confirmed. A higher DRRD score was significantly associated with a reduced risk of developing liver cancer (HR<sub>Tertile 3 vs. Tertile 1</sub> = 0.69; 95% CI: 0.49–0.97; <i>P</i><sub>trend</sub> = 0.03) and chronic liver disease mortality (HR<sub>T3 vs. T1</sub> = 0.54; 95% CI: 0.35–0.82; <i>P</i><sub>trend</sub> = 0.003). We further found inverse associations with dietary fiber and coffee, and positive associations with dietary glycemic index, SSBs, and <i>trans</i> fat. A higher DRRD score was associated with reduced risk of developing liver cancer and chronic liver disease mortality among postmenopausal women.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"296 5","pages":"410-421"},"PeriodicalIF":9.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138801","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}
Christiane Engelbertz, Ursula Marschall, Jannik Feld, Lena Makowski, Stefan A. Lange, Eva Freisinger, Joachim Gerß, Günter Breithardt, Andreas Faldum, Holger Reinecke, Jeanette Köppe
Background
Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials.
Methods
Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding.
Results
Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all p < 0.001) but not for dabigatran (p = 0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all p < 0.001) and 13.0% for dabigatran versus 12.8% for VKA (p = 0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine–Gray regression models on the basis of the entire cohort.
Conclusions
In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs.
{"title":"Apixaban, edoxaban and rivaroxaban but not dabigatran are associated with higher mortality compared to vitamin-K antagonists: A retrospective German claims data analysis","authors":"Christiane Engelbertz, Ursula Marschall, Jannik Feld, Lena Makowski, Stefan A. Lange, Eva Freisinger, Joachim Gerß, Günter Breithardt, Andreas Faldum, Holger Reinecke, Jeanette Köppe","doi":"10.1111/joim.20006","DOIUrl":"10.1111/joim.20006","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all <i>p </i>< 0.001) but not for dabigatran (<i>p</i> = 0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all <i>p</i> < 0.001) and 13.0% for dabigatran versus 12.8% for VKA (<i>p</i> = 0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine–Gray regression models on the basis of the entire cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"296 4","pages":"362-376"},"PeriodicalIF":9.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102693","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}
Shanshan Huang, Yanli Chen, Dan Shan, Renquan Wang
<p>Dear Editor,</p><p>Bugeja et al. offered significant insights into the management of late-onset hypertension [<span>1</span>]; however, several methodological and interpretive issues warrant further scrutiny.</p><p>The study's statistical analysis, while robust, may overlook subtle but clinically significant interactions between sex and other covariates. For instance, the adjusted hazard ratios (aHR) for the prescription of antihypertensive medications (aHR 0.98 for females vs. males) suggest a minor statistical difference that the authors deem non-clinically significant. However, given the large sample size, even small differences can translate into meaningful impacts at the population level. A more nuanced statistical approach, such as the use of interaction terms and stratified analyses, might uncover important sex-specific differences in treatment efficacy and adherence. Austin et al. emphasized the importance of understanding interactions in epidemiological research, which can provide a more detailed understanding of how sex may influence treatment outcomes [<span>2</span>].</p><p>Furthermore, the study's reliance on retrospective data from administrative databases introduces potential biases. Although the authors adjusted for numerous covariates, the inherent limitations of such data sources, such as coding inaccuracies and unmeasured confounders, cannot be fully mitigated. The use of the ICD-10 coding system for hypertension diagnosis and subsequent treatment prescriptions may not accurately reflect the clinical nuances of patient management. Quan et al. noted that administrative data, while useful, often lack the granularity needed for precise clinical studies, potentially leading to misclassification biases that can skew results [<span>3</span>]. Future research should consider these limitations and possibly integrate clinical data to enhance the accuracy of findings.</p><p>The interpretation of the results also warrants reconsideration. The authors conclude that there are no clinically meaningful sex-based differences in the initial management of late-onset hypertension. However, this interpretation might be premature. The study finds that females are less likely to be prescribed certain antihypertensive medications, such as Angiotensin-converting enzyme (ACE) inhibitors, compared to males (aHR 0.995). This subtle difference, while statistically modest, could reflect underlying disparities in clinical decision-making processes, possibly influenced by provider biases or patient preferences. Evidence has shown that such disparities can have long-term implications for health outcomes, suggesting the cumulative impact of small biases in clinical care over time [<span>4</span>]. This highlights the need for a more detailed examination of prescribing practices and their long-term effects on patient outcomes.</p><p>Lastly, although the discussion section is comprehensive, it occasionally overgeneralizes findings. The assertion that “females
{"title":"Regarding: Adherence to guideline-recommended care of late-onset hypertension in females versus males: A population-based cohort study","authors":"Shanshan Huang, Yanli Chen, Dan Shan, Renquan Wang","doi":"10.1111/joim.20009","DOIUrl":"10.1111/joim.20009","url":null,"abstract":"<p>Dear Editor,</p><p>Bugeja et al. offered significant insights into the management of late-onset hypertension [<span>1</span>]; however, several methodological and interpretive issues warrant further scrutiny.</p><p>The study's statistical analysis, while robust, may overlook subtle but clinically significant interactions between sex and other covariates. For instance, the adjusted hazard ratios (aHR) for the prescription of antihypertensive medications (aHR 0.98 for females vs. males) suggest a minor statistical difference that the authors deem non-clinically significant. However, given the large sample size, even small differences can translate into meaningful impacts at the population level. A more nuanced statistical approach, such as the use of interaction terms and stratified analyses, might uncover important sex-specific differences in treatment efficacy and adherence. Austin et al. emphasized the importance of understanding interactions in epidemiological research, which can provide a more detailed understanding of how sex may influence treatment outcomes [<span>2</span>].</p><p>Furthermore, the study's reliance on retrospective data from administrative databases introduces potential biases. Although the authors adjusted for numerous covariates, the inherent limitations of such data sources, such as coding inaccuracies and unmeasured confounders, cannot be fully mitigated. The use of the ICD-10 coding system for hypertension diagnosis and subsequent treatment prescriptions may not accurately reflect the clinical nuances of patient management. Quan et al. noted that administrative data, while useful, often lack the granularity needed for precise clinical studies, potentially leading to misclassification biases that can skew results [<span>3</span>]. Future research should consider these limitations and possibly integrate clinical data to enhance the accuracy of findings.</p><p>The interpretation of the results also warrants reconsideration. The authors conclude that there are no clinically meaningful sex-based differences in the initial management of late-onset hypertension. However, this interpretation might be premature. The study finds that females are less likely to be prescribed certain antihypertensive medications, such as Angiotensin-converting enzyme (ACE) inhibitors, compared to males (aHR 0.995). This subtle difference, while statistically modest, could reflect underlying disparities in clinical decision-making processes, possibly influenced by provider biases or patient preferences. Evidence has shown that such disparities can have long-term implications for health outcomes, suggesting the cumulative impact of small biases in clinical care over time [<span>4</span>]. This highlights the need for a more detailed examination of prescribing practices and their long-term effects on patient outcomes.</p><p>Lastly, although the discussion section is comprehensive, it occasionally overgeneralizes findings. The assertion that “females","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"296 5","pages":"452-453"},"PeriodicalIF":9.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118565","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}
<p>Dear Editor,</p><p>Clarkson's disease, also known as idiopathic systemic capillary leak syndrome (ISCLS), is a rare and potentially lethal paroxysmal permeability disorder characterized by unpredictable episodes of massive plasma leakage from the intravascular to the extravascular compartment, most often into muscular tissues, leading to shock and ultimately multiple organ failure.</p><p>The underlying pathophysiological mechanisms of ISCLS are not well understood. They are believed to involve hypersensitivity of the capillaries to inflammatory or immune system triggers, which result in the transitory derangement of inter-endothelial junctions, causing the abrupt loss of endothelial barrier function. Most ISCLS patients have a monoclonal gammopathy of undetermined significance, which is a characteristic trait in the adult form of ISCLS and has been hypothesized to play a role in the pathophysiology, although not yet characterized. Therefore, the term “monoclonal gammopathy of clinical significance” appears more appropriate with respect to Clarkson's disease. Patients’ sera, collected during the acute and intercritical phases, have been reported to significantly increase the permeability of human umbilical vein endothelial cells (ECs) compared to sera from healthy controls [<span>1</span>].</p><p>Recently, it has been demonstrated experimentally that ECs derived from ISCLS patients were functionally hyperresponsive to the two permeabilizing factors vascular endothelial growth (VEGF) and histamine [<span>2</span>]. There is evidence that the main alteration lies in the hyperactivation of the endothelial nitric oxide synthase (eNOS) in ISCLS-derived ECs. Furthermore, eNOS blockade by the administration of NG-nitro-<span>l</span>-arginine methyl ester (NAME) improved vascular leakage in a mouse model of ISCLS after histamine or VEGF challenge [<span>2</span>]. On the other hand, methylene blue, which blocks the nitric oxide (NO) pathway by inhibiting the guanylate cyclase [<span>3</span>] and is generally used in conditions characterized by increased levels of NO, like septic shock [<span>4</span>], did not show efficacy in ISCLS. There is only an anecdotal report of a patient who was successfully treated with methylene blue during an ISCLS crisis. Remarkably, this patient suffered from several attacks per year, and repeated administrations of methylene blue did not yield positive results [<span>5</span>]. Furthermore, the measurement of circulating NO metabolites in both acute and intercritical sera revealed no significant difference in NO levels in samples from ISCLS patients compared to control [<span>1</span>].</p><p>Given the suggested central role of the NO pathway in the pathogenesis of ISCLS flares and considering the intrinsic hyperresponsiveness of ISCLS ECs, we decided to assess the endothelial function of ISCLS patients in vivo using a NO-dependent noninvasive functional methodology. Specifically, we employed peripheral arterial tonome
{"title":"Role of NO pathway in the clinical picture of idiopathic systemic capillary leak syndrome","authors":"Maddalena Alessandra Wu, Chiara Cogliati, Emanuele Catena, Riccardo Colombo","doi":"10.1111/joim.20005","DOIUrl":"10.1111/joim.20005","url":null,"abstract":"<p>Dear Editor,</p><p>Clarkson's disease, also known as idiopathic systemic capillary leak syndrome (ISCLS), is a rare and potentially lethal paroxysmal permeability disorder characterized by unpredictable episodes of massive plasma leakage from the intravascular to the extravascular compartment, most often into muscular tissues, leading to shock and ultimately multiple organ failure.</p><p>The underlying pathophysiological mechanisms of ISCLS are not well understood. They are believed to involve hypersensitivity of the capillaries to inflammatory or immune system triggers, which result in the transitory derangement of inter-endothelial junctions, causing the abrupt loss of endothelial barrier function. Most ISCLS patients have a monoclonal gammopathy of undetermined significance, which is a characteristic trait in the adult form of ISCLS and has been hypothesized to play a role in the pathophysiology, although not yet characterized. Therefore, the term “monoclonal gammopathy of clinical significance” appears more appropriate with respect to Clarkson's disease. Patients’ sera, collected during the acute and intercritical phases, have been reported to significantly increase the permeability of human umbilical vein endothelial cells (ECs) compared to sera from healthy controls [<span>1</span>].</p><p>Recently, it has been demonstrated experimentally that ECs derived from ISCLS patients were functionally hyperresponsive to the two permeabilizing factors vascular endothelial growth (VEGF) and histamine [<span>2</span>]. There is evidence that the main alteration lies in the hyperactivation of the endothelial nitric oxide synthase (eNOS) in ISCLS-derived ECs. Furthermore, eNOS blockade by the administration of NG-nitro-<span>l</span>-arginine methyl ester (NAME) improved vascular leakage in a mouse model of ISCLS after histamine or VEGF challenge [<span>2</span>]. On the other hand, methylene blue, which blocks the nitric oxide (NO) pathway by inhibiting the guanylate cyclase [<span>3</span>] and is generally used in conditions characterized by increased levels of NO, like septic shock [<span>4</span>], did not show efficacy in ISCLS. There is only an anecdotal report of a patient who was successfully treated with methylene blue during an ISCLS crisis. Remarkably, this patient suffered from several attacks per year, and repeated administrations of methylene blue did not yield positive results [<span>5</span>]. Furthermore, the measurement of circulating NO metabolites in both acute and intercritical sera revealed no significant difference in NO levels in samples from ISCLS patients compared to control [<span>1</span>].</p><p>Given the suggested central role of the NO pathway in the pathogenesis of ISCLS flares and considering the intrinsic hyperresponsiveness of ISCLS ECs, we decided to assess the endothelial function of ISCLS patients in vivo using a NO-dependent noninvasive functional methodology. Specifically, we employed peripheral arterial tonome","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"296 5","pages":"449-451"},"PeriodicalIF":9.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102694","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}
Munaza Riaz, Haesuk Park, Carl J. Pepine, Ashutosh M. Shukla
Background
Hydroxychloroquine (HCQ) reduces cardiovascular events among patients with autoimmune disorders and is being evaluated as a therapeutic option for populations with high-risk cardiovascular disease. However, recent studies have raised concerns about HCQ use and cardiovascular events.
Objective
To assess the association of HCQ initiation with heart failure–related and all-cause hospitalizations among patients with heart failure and preserved ejection fraction (HFpEF).
Methods
We conducted a cohort study of patients aged ≥18 years with diagnosed HFpEF and autoimmune disease using MarketScan Commercial and Medicare Supplemental databases (2007–2019). Patients were required to initiate HCQ after their first HFpEF diagnosis (HCQ users) or not (HCQ nonusers). For the patients in the HCQ users group, the first HCQ prescription date was assigned as the index date. Index date for the HCQ nonuser group was assigned by prescription-time distribution matching HCQ users, by utilizing the number of days from HFpEF diagnosis to the first HCQ prescription. After 1:≥3 propensity score (PS) matching, Cox proportional hazards regression models were used to compare HF-related and all-cause hospitalizations between users and nonusers.
Results
After PS matching, 2229 patients (592 HCQ users and 1637 HCQ nonusers) were included. After controlling for covariates, patients who received HCQ had lower risks of HF-related hospitalization (adjusted hazard ratio, 0.44; 95% CI, 0.24–0.82) and all-cause hospitalization (adjusted hazard ratio, 0.69; 95% CI, 0.57–0.83) compared with patients not using HCQ.
Conclusions
Among patients with HFpEF and autoimmune disease, initiation of HCQ use was associated with a decreased risk of HF-related and all-cause hospitalizations.
{"title":"Hospitalization after hydroxychloroquine initiation in patients with heart failure with preserved ejection fraction and autoimmune disease","authors":"Munaza Riaz, Haesuk Park, Carl J. Pepine, Ashutosh M. Shukla","doi":"10.1111/joim.20004","DOIUrl":"10.1111/joim.20004","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hydroxychloroquine (HCQ) reduces cardiovascular events among patients with autoimmune disorders and is being evaluated as a therapeutic option for populations with high-risk cardiovascular disease. However, recent studies have raised concerns about HCQ use and cardiovascular events.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To assess the association of HCQ initiation with heart failure–related and all-cause hospitalizations among patients with heart failure and preserved ejection fraction (HFpEF).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a cohort study of patients aged ≥18 years with diagnosed HFpEF and autoimmune disease using MarketScan Commercial and Medicare Supplemental databases (2007–2019). Patients were required to initiate HCQ after their first HFpEF diagnosis (HCQ users) or not (HCQ nonusers). For the patients in the HCQ users group, the first HCQ prescription date was assigned as the index date. Index date for the HCQ nonuser group was assigned by prescription-time distribution matching HCQ users, by utilizing the number of days from HFpEF diagnosis to the first HCQ prescription. After 1:≥3 propensity score (PS) matching, Cox proportional hazards regression models were used to compare HF-related and all-cause hospitalizations between users and nonusers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After PS matching, 2229 patients (592 HCQ users and 1637 HCQ nonusers) were included. After controlling for covariates, patients who received HCQ had lower risks of HF-related hospitalization (adjusted hazard ratio, 0.44; 95% CI, 0.24–0.82) and all-cause hospitalization (adjusted hazard ratio, 0.69; 95% CI, 0.57–0.83) compared with patients not using HCQ.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Among patients with HFpEF and autoimmune disease, initiation of HCQ use was associated with a decreased risk of HF-related and all-cause hospitalizations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"296 5","pages":"399-409"},"PeriodicalIF":9.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078657","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}
Weng Ian Che, Ralf Kuja-Halkola, Karin Hellgren, Ingrid E. Lundberg, Helga Westerlind, Fredrik Baecklund, Marie Holmqvist
Background
Patients with idiopathic inflammatory myopathies (IIM) have an increased risk of cancer, but their cancer-related disease burden remains unclear.
Objectives
To explore how cancer might impact the mortality of patients with IIM and examine the associated prognostic factors for cancer and death.
Methods
We identified patients with IIM diagnosed between 1998 and 2020 and ascertained their cancer and death records via linkage to the Swedish healthcare and population registers. Transition hazards from IIM diagnosis to cancer and death were estimated in multistate models using flexible parametric methods. We then predicted the probability of having cancer or death, and the duration of staying alive at a given time from IIM and cancer diagnoses from a crude model. We also explored prognostic factors for progression to cancer and death in a multivariable model.
Results
Of 1826 IIM patients, 310 (17%) were diagnosed with cancer before and 306 (17%) after IIM diagnosis. In patients diagnosed with cancer after IIM, the 5-year probability of death from cancer and from other causes was 31% and 18%, respectively, compared to 7% and 15% in patients without cancer after IIM. We reported several factors associated with risk of progression to cancer and death. Specifically, patients with first cancer after IIM who were older at IIM diagnosis, had cancer history, dermatomyositis and a cancer diagnosis within 1 year following IIM faced a greater cancer-specific mortality.
Conclusion
We observed a substantial increase in mortality from cancer, compared to before, rather than other causes after a cancer diagnosis following IIM, suggesting an unmet medical need for effective cancer management in IIM patients. This finding, along with the identified prognostic factors, provides useful insight into future research directions for improving cancer management in IIM patients.
{"title":"Impact of cancer on the mortality of patients with idiopathic inflammatory myopathies by flexible parametric multistate modelling","authors":"Weng Ian Che, Ralf Kuja-Halkola, Karin Hellgren, Ingrid E. Lundberg, Helga Westerlind, Fredrik Baecklund, Marie Holmqvist","doi":"10.1111/joim.20003","DOIUrl":"10.1111/joim.20003","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Patients with idiopathic inflammatory myopathies (IIM) have an increased risk of cancer, but their cancer-related disease burden remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To explore how cancer might impact the mortality of patients with IIM and examine the associated prognostic factors for cancer and death.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We identified patients with IIM diagnosed between 1998 and 2020 and ascertained their cancer and death records via linkage to the Swedish healthcare and population registers. Transition hazards from IIM diagnosis to cancer and death were estimated in multistate models using flexible parametric methods. We then predicted the probability of having cancer or death, and the duration of staying alive at a given time from IIM and cancer diagnoses from a crude model. We also explored prognostic factors for progression to cancer and death in a multivariable model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 1826 IIM patients, 310 (17%) were diagnosed with cancer before and 306 (17%) after IIM diagnosis. In patients diagnosed with <i>cancer after</i> IIM, the 5-year probability of death from cancer and from other causes was 31% and 18%, respectively, compared to 7% and 15% in patients without <i>cancer after</i> IIM. We reported several factors associated with risk of progression to cancer and death. Specifically, patients with <i>first cancer after</i> IIM who were older at IIM diagnosis, had cancer history, dermatomyositis and a cancer diagnosis within 1 year following IIM faced a greater cancer-specific mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We observed a substantial increase in mortality from cancer, compared to before, rather than other causes after a cancer diagnosis following IIM, suggesting an unmet medical need for effective cancer management in IIM patients. This finding, along with the identified prognostic factors, provides useful insight into future research directions for improving cancer management in IIM patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"296 4","pages":"336-349"},"PeriodicalIF":9.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873693","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}
Xinyuan Liu, Huiwen Xue, Karin Wirdefeldt, Huan Song, Karin Smedby, Fang Fang, Qianwei Liu
Background
Little is known regarding the association between clonal hematopoiesis of indeterminate potential (CHIP) and risk of neurodegenerative diseases.
Objective
To estimate the risk of neurodegenerative diseases among individuals with CHIP.
Methods
We conducted a community-based cohort study based on UK Biobank and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of any neurodegenerative disease, subtypes of neurodegenerative diseases (including primary neurodegenerative diseases, vascular neurodegenerative diseases, and other neurodegenerative diseases), and specific diagnoses of neurodegenerative diseases (i.e., amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], and Parkinson's disease [PD]) associated with CHIP.
Results
We identified 14,440 individuals with CHIP and 450,907 individuals without CHIP. Individuals with CHIP had an increased risk of any neurodegenerative disease (HR 1.10, 95% CI: 1.01–1.19). We also observed a statistically significantly increased risk for vascular neurodegenerative diseases (HR 1.31, 95% CI 1.05–1.63) and ALS (HR 1.50, 95% CI 1.05–2.15). An increased risk was also noted for other neurodegenerative diseases (HR 1.13, 95% CI 0.97–1.32), although not statistically significant. Null association was noted for primary neurodegenerative diseases (HR 1.06, 95% CI 0.96–1.17), AD (HR 1.04, 95% CI 0.88–1.23), and PD (HR 1.02, 95% CI 0.86–1.21). The risk increase in any neurodegenerative disease was mainly observed for DNMT3A-mutant CHIP, ASXL1-mutant CHIP, or SRSF2-mutant CHIP.
Conclusion
Individuals with CHIP were at an increased risk of neurodegenerative diseases, primarily vascular neurodegenerative diseases and ALS, but potentially also other neurodegenerative diseases. These findings suggest potential shared mechanisms between CHIP and neurodegenerative diseases.
背景：人们对不确定潜能克隆造血（CHIP）与神经退行性疾病风险之间的关系知之甚少：人们对不确定潜能克隆造血（CHIP）与神经退行性疾病风险之间的关系知之甚少：目的：估算CHIP患者罹患神经退行性疾病的风险：我们在英国生物数据库的基础上开展了一项社区队列研究，并使用 Cox 回归估算了任何神经退行性疾病、神经退行性疾病亚型（包括原发性神经退行性疾病、血管性神经退行性疾病和其他神经退行性疾病）和特定神经退行性疾病诊断（即：肌萎缩性脊髓侧索硬化症）的危险比（HRs）和 95% 置信区间（CIs）、结果：我们发现了 14,440 名患有 CHIP 的患者和 450,907 名未患有 CHIP 的患者。CHIP患者罹患任何神经退行性疾病的风险都有所增加（HR 1.10，95% CI：1.01-1.19）。我们还发现，血管神经退行性疾病（HR 1.31，95% CI 1.05-1.63）和 ALS（HR 1.50，95% CI 1.05-2.15）的患病风险在统计学上明显增加。其他神经退行性疾病的风险也有所增加（HR 1.13，95% CI 0.97-1.32），但无统计学意义。原发性神经退行性疾病（HR 1.06，95% CI 0.96-1.17）、AD（HR 1.04，95% CI 0.88-1.23）和帕金森病（HR 1.02，95% CI 0.86-1.21）的相关性为零。任何神经退行性疾病的风险增加主要出现在DNMT3A突变型CHIP、ASXL1突变型CHIP或SRSF2突变型CHIP中：结论：CHIP 患者罹患神经退行性疾病（主要是血管神经退行性疾病和渐冻症）的风险增加，但也可能罹患其他神经退行性疾病。这些发现表明，CHIP 与神经退行性疾病之间存在潜在的共同机制。
{"title":"Clonal hematopoiesis of indeterminate potential and risk of neurodegenerative diseases","authors":"Xinyuan Liu, Huiwen Xue, Karin Wirdefeldt, Huan Song, Karin Smedby, Fang Fang, Qianwei Liu","doi":"10.1111/joim.20001","DOIUrl":"10.1111/joim.20001","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Little is known regarding the association between clonal hematopoiesis of indeterminate potential (CHIP) and risk of neurodegenerative diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To estimate the risk of neurodegenerative diseases among individuals with CHIP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a community-based cohort study based on UK Biobank and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of any neurodegenerative disease, subtypes of neurodegenerative diseases (including primary neurodegenerative diseases, vascular neurodegenerative diseases, and other neurodegenerative diseases), and specific diagnoses of neurodegenerative diseases (i.e., amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], and Parkinson's disease [PD]) associated with CHIP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified 14,440 individuals with CHIP and 450,907 individuals without CHIP. Individuals with CHIP had an increased risk of any neurodegenerative disease (HR 1.10, 95% CI: 1.01–1.19). We also observed a statistically significantly increased risk for vascular neurodegenerative diseases (HR 1.31, 95% CI 1.05–1.63) and ALS (HR 1.50, 95% CI 1.05–2.15). An increased risk was also noted for other neurodegenerative diseases (HR 1.13, 95% CI 0.97–1.32), although not statistically significant. Null association was noted for primary neurodegenerative diseases (HR 1.06, 95% CI 0.96–1.17), AD (HR 1.04, 95% CI 0.88–1.23), and PD (HR 1.02, 95% CI 0.86–1.21). The risk increase in any neurodegenerative disease was mainly observed for <i>DNMT3A</i>-mutant CHIP, <i>ASXL1</i>-mutant CHIP, or <i>SRSF2</i>-mutant CHIP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Individuals with CHIP were at an increased risk of neurodegenerative diseases, primarily vascular neurodegenerative diseases and ALS, but potentially also other neurodegenerative diseases. These findings suggest potential shared mechanisms between CHIP and neurodegenerative diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"296 4","pages":"327-335"},"PeriodicalIF":9.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786657","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号