Xiaokun Li, Weiqin Lu, Alexei Kharitonenkov, Yongde Luo
Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial crosstalk between the BA-activated ileal farnesoid X receptor and the hepatic Klotho beta (KLB) coreceptor complexed with fibrobalst growth factor receptor 4 (FGFR4) kinase. Additionally, FGF19 regulates glucose, lipid, and energy metabolism by coordinating responses from functional KLB and FGFR1-3 receptor complexes on the periphery. Pharmacologically, native FGF19 or its analogs decrease elevated BA levels, fat content, and collateral tissue damage. This makes them effective in treating both cholestatic diseases such as primary biliary or sclerosing cholangitis (PBC or PSC) and metabolic abnormalities such as nonalcoholic steatohepatitis (NASH). However, chronic administration of FGF19 drives oncogenesis in mice by activating the FGFR4-dependent mitogenic or hepatic regenerative pathway, which could be a concern in humans. Agents that block FGF19 or FGFR4 signaling have shown great potency in preventing FGF19-responsive hepatocellular carcinoma (HCC) development in animal models. Recent phase 1/2 clinical trials have demonstrated promising results for several FGF19-based agents in selectively treating patients with PBC, PSC, NASH, or HCC. This review aims to provide an update on the clinical development of both analogs and antagonists targeting the FGF19–FGFR4 signaling pathway for patients with cholestatic, metabolic, and cancer diseases. We will also analyze potential safety and mechanistic concerns that should guide future research and advanced trials.
{"title":"Targeting the FGF19–FGFR4 pathway for cholestatic, metabolic, and cancerous diseases","authors":"Xiaokun Li, Weiqin Lu, Alexei Kharitonenkov, Yongde Luo","doi":"10.1111/joim.13767","DOIUrl":"10.1111/joim.13767","url":null,"abstract":"<p>Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial crosstalk between the BA-activated ileal farnesoid X receptor and the hepatic Klotho beta (KLB) coreceptor complexed with fibrobalst growth factor receptor 4 (FGFR4) kinase. Additionally, FGF19 regulates glucose, lipid, and energy metabolism by coordinating responses from functional KLB and FGFR1-3 receptor complexes on the periphery. Pharmacologically, native FGF19 or its analogs decrease elevated BA levels, fat content, and collateral tissue damage. This makes them effective in treating both cholestatic diseases such as primary biliary or sclerosing cholangitis (PBC or PSC) and metabolic abnormalities such as nonalcoholic steatohepatitis (NASH). However, chronic administration of FGF19 drives oncogenesis in mice by activating the FGFR4-dependent mitogenic or hepatic regenerative pathway, which could be a concern in humans. Agents that block FGF19 or FGFR4 signaling have shown great potency in preventing FGF19-responsive hepatocellular carcinoma (HCC) development in animal models. Recent phase 1/2 clinical trials have demonstrated promising results for several FGF19-based agents in selectively treating patients with PBC, PSC, NASH, or HCC. This review aims to provide an update on the clinical development of both analogs and antagonists targeting the FGF19–FGFR4 signaling pathway for patients with cholestatic, metabolic, and cancer diseases. We will also analyze potential safety and mechanistic concerns that should guide future research and advanced trials.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"295 3","pages":"292-312"},"PeriodicalIF":11.1,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.13767","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139424161","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}
Alexis Dechosal, Erwan Le Tallec, Nicolas Belhomme, Alain Lescoat
<p>Dear Editor,</p><p>We read with great interest the article by Chevalier et al. recently published in the <i>Journal of Internal Medicine</i>, which explores the clinical trajectory of 330 patients with mixed connective tissue disease (MCTD) [<span>1</span>]. This multicenter retrospective study demonstrated that only 85 (25.6%) patients evolved toward a diagnostic of another CTD, the most represented CTD being systemic sclerosis (SSc) in 52 patients (15.8%) according to the ACR/EULAR 2013 classification criteria. Based on this result, the authors concluded that “MCTD is a distinct entity.” The strength of this study is the exclusion of patients fulfilling criteria for other CTDs at baseline. Nonetheless, the way the ACR/EULAR 2013 classification criteria were used in this study could be questioned. In the absence of proximal skin thickening, the ACR/EULAR 2013 classification criteria for SSc includes seven additive items with varying weights for each: skin thickening of the fingers (sclerodactyly four points or puffy fingers two points), fingertip lesions (digital ulcers two points, pitting scars three points), telangiectasia (two points), abnormal nailfold capillaries (two points), interstitial lung disease or pulmonary arterial hypertension (two points), Raynaud's phenomenon (three points), and SSc-related autoantibodies (three points) [<span>2</span>]. The total score is determined by adding the maximum weight in each category. Patients with a total score of ≥9 are classified as having definite SSc. Based on this classification, almost no U1-RNP patients can obtain the three points for autoantibodies, as only anti-centromere, anti-topoisomerase, and anti-RNA polymerase III antibodies are included in this classification. Because autoantibodies are mutually exclusive in SSc, the positivity for SSc-related antibody is largely unlikely—although not impossible, as suggested by the two patients with anti-centromere antibodies—in the case of U1-RNP positivity. To reach the nine point-threshold, U1-RNP patients needed to have many SSc-related clinical manifestations, even more SSc-related clinical manifestations than a patient with definite SSc and SSc-specific antibodies as defined in the ACR-EULAR classification criteria for SSc. Therefore, one could argue that at least six points based on non-immunological parameters from the classification criteria for SSc should be sufficient to be classified as SSc in a population of U1-RNP patients (e.g., Raynaud's phenomenon, SSc-capillaroscopic landscape, and ILD; or Raynaud's phenomenon and pitting scars), because such patients may only lack the three points from SSc-specific autoantibodies to reach nine points and to be classified as SSc. Before concluding that “MCTD is a distinct entity,” we would suggest, (1) assessing the prevalence of patients with six points from the classification criteria for SSc in this large population of 330 MTCD patients and (2) comparing the clinical trajectories of these “SS
{"title":"Regarding: Clinical presentation, course, and prognosis of patients with mixed connective tissue disease","authors":"Alexis Dechosal, Erwan Le Tallec, Nicolas Belhomme, Alain Lescoat","doi":"10.1111/joim.13766","DOIUrl":"10.1111/joim.13766","url":null,"abstract":"<p>Dear Editor,</p><p>We read with great interest the article by Chevalier et al. recently published in the <i>Journal of Internal Medicine</i>, which explores the clinical trajectory of 330 patients with mixed connective tissue disease (MCTD) [<span>1</span>]. This multicenter retrospective study demonstrated that only 85 (25.6%) patients evolved toward a diagnostic of another CTD, the most represented CTD being systemic sclerosis (SSc) in 52 patients (15.8%) according to the ACR/EULAR 2013 classification criteria. Based on this result, the authors concluded that “MCTD is a distinct entity.” The strength of this study is the exclusion of patients fulfilling criteria for other CTDs at baseline. Nonetheless, the way the ACR/EULAR 2013 classification criteria were used in this study could be questioned. In the absence of proximal skin thickening, the ACR/EULAR 2013 classification criteria for SSc includes seven additive items with varying weights for each: skin thickening of the fingers (sclerodactyly four points or puffy fingers two points), fingertip lesions (digital ulcers two points, pitting scars three points), telangiectasia (two points), abnormal nailfold capillaries (two points), interstitial lung disease or pulmonary arterial hypertension (two points), Raynaud's phenomenon (three points), and SSc-related autoantibodies (three points) [<span>2</span>]. The total score is determined by adding the maximum weight in each category. Patients with a total score of ≥9 are classified as having definite SSc. Based on this classification, almost no U1-RNP patients can obtain the three points for autoantibodies, as only anti-centromere, anti-topoisomerase, and anti-RNA polymerase III antibodies are included in this classification. Because autoantibodies are mutually exclusive in SSc, the positivity for SSc-related antibody is largely unlikely—although not impossible, as suggested by the two patients with anti-centromere antibodies—in the case of U1-RNP positivity. To reach the nine point-threshold, U1-RNP patients needed to have many SSc-related clinical manifestations, even more SSc-related clinical manifestations than a patient with definite SSc and SSc-specific antibodies as defined in the ACR-EULAR classification criteria for SSc. Therefore, one could argue that at least six points based on non-immunological parameters from the classification criteria for SSc should be sufficient to be classified as SSc in a population of U1-RNP patients (e.g., Raynaud's phenomenon, SSc-capillaroscopic landscape, and ILD; or Raynaud's phenomenon and pitting scars), because such patients may only lack the three points from SSc-specific autoantibodies to reach nine points and to be classified as SSc. Before concluding that “MCTD is a distinct entity,” we would suggest, (1) assessing the prevalence of patients with six points from the classification criteria for SSc in this large population of 330 MTCD patients and (2) comparing the clinical trajectories of these “SS","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"295 4","pages":"574-575"},"PeriodicalIF":11.1,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.13766","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139096999","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>We thank Dechosal et al. for their comments on our article [<span>1</span>]. The authors raise questions about the nosology of mixed connective tissue diseases (MCTDs), systemic sclerosis (SSc), and its classification criteria [<span>2</span>] and, thus, the status of MCTD as a distinct connective tissue disease (CTD) or as a subgroup of SSc. They propose that, in a population of anti-U1 RNP patients, a lower point threshold (e.g., 6 points) based on non-immunologic parameters from the ACR/EULAR 2013 criteria might be sufficient to classify a patient as SSc. They recommend comparing the clinical course of MCTD patients with ≥6 points in the ACR/EULAR 2013 SSc classification to definite SSc patients with different antibody subtypes, suggesting a potential reclassification of MCTD as SSc if outcomes are comparable.</p><p>First, we would like to emphasize that anti-ribonucleoprotein U1 (anti-U1RNP) antibodies are not specific to SSc because they can be found in all differentiated CTD. Thus, their prevalence is high in systemic lupus erythematosus (SLE) (25%–35%) [<span>3, 4</span>] or myositis with nonspecific/associated antibodies (15%) [<span>5</span>] compared to 6%–8% in SSc (6%–8%) [<span>6, 7</span>], 4.7% in Sjögren's syndrome (SS) [<span>8</span>], and below 1% in rheumatoid arthritis patients [<span>9</span>]. Therefore, anti-U1RNP antibodies cannot and should not be considered SSc-specific. Furthermore, the authors contend that “because autoantibodies are mutually exclusive in SSc, the positivity for SSc-related antibody is largely unlikely—although not impossible, as suggested by the two patients with anti-centromere antibodies—in case of U1-RNP positivity.” This assertion does not hold true for anti-U1RNP in SSc. In 2022, our colleagues from the Royal Free Hospital reported on 119 SSc patients with anti-RNP antibodies. Among these, 43 patients (36.1%) had anti-U1RNP antibodies in association with another SSc-specific or related autoantibody, including anti-topoisomerase 1 in 21 patients (48.8%), anti-centromere in 8 (18.6%), anti-RNA polymerase III in 4 (9.3%), anti-U3RNP in 6 (14%), and anti-PmScl in 4 (9.3%). In this study, anti-U1RNP was the most common antibody associated with an SSc-specific antibody (anti-topoisomerase, anti-centromere, and anti-RNA polymerase III), accounting overall for 73% of the 63 patients with more than one autoantibody [<span>10</span>].</p><p>Second, as Dechosal et al. will recall, the ACR/EULAR 2013 criteria were established with the aim of assembling homogeneous patient groups for SSc studies. To achieve this, van den Hoogen et al. evaluated candidate items for classification using both data and expert clinical judgment. They subsequently reduced the number of these items and assigned weights. The classification system underwent repeated testing and adaptation using prospectively collected SSc cases and “scleroderma-like disorder” derivation cohorts, which included MCTD patients. The
{"title":"Authors reply: Clinical presentation, course, and prognosis of patients with mixed connective tissue disease","authors":"Kevin Chevalier, Benjamin Chaigne, Luc Mouthon","doi":"10.1111/joim.13765","DOIUrl":"10.1111/joim.13765","url":null,"abstract":"<p>Dear Editor,</p><p>We thank Dechosal et al. for their comments on our article [<span>1</span>]. The authors raise questions about the nosology of mixed connective tissue diseases (MCTDs), systemic sclerosis (SSc), and its classification criteria [<span>2</span>] and, thus, the status of MCTD as a distinct connective tissue disease (CTD) or as a subgroup of SSc. They propose that, in a population of anti-U1 RNP patients, a lower point threshold (e.g., 6 points) based on non-immunologic parameters from the ACR/EULAR 2013 criteria might be sufficient to classify a patient as SSc. They recommend comparing the clinical course of MCTD patients with ≥6 points in the ACR/EULAR 2013 SSc classification to definite SSc patients with different antibody subtypes, suggesting a potential reclassification of MCTD as SSc if outcomes are comparable.</p><p>First, we would like to emphasize that anti-ribonucleoprotein U1 (anti-U1RNP) antibodies are not specific to SSc because they can be found in all differentiated CTD. Thus, their prevalence is high in systemic lupus erythematosus (SLE) (25%–35%) [<span>3, 4</span>] or myositis with nonspecific/associated antibodies (15%) [<span>5</span>] compared to 6%–8% in SSc (6%–8%) [<span>6, 7</span>], 4.7% in Sjögren's syndrome (SS) [<span>8</span>], and below 1% in rheumatoid arthritis patients [<span>9</span>]. Therefore, anti-U1RNP antibodies cannot and should not be considered SSc-specific. Furthermore, the authors contend that “because autoantibodies are mutually exclusive in SSc, the positivity for SSc-related antibody is largely unlikely—although not impossible, as suggested by the two patients with anti-centromere antibodies—in case of U1-RNP positivity.” This assertion does not hold true for anti-U1RNP in SSc. In 2022, our colleagues from the Royal Free Hospital reported on 119 SSc patients with anti-RNP antibodies. Among these, 43 patients (36.1%) had anti-U1RNP antibodies in association with another SSc-specific or related autoantibody, including anti-topoisomerase 1 in 21 patients (48.8%), anti-centromere in 8 (18.6%), anti-RNA polymerase III in 4 (9.3%), anti-U3RNP in 6 (14%), and anti-PmScl in 4 (9.3%). In this study, anti-U1RNP was the most common antibody associated with an SSc-specific antibody (anti-topoisomerase, anti-centromere, and anti-RNA polymerase III), accounting overall for 73% of the 63 patients with more than one autoantibody [<span>10</span>].</p><p>Second, as Dechosal et al. will recall, the ACR/EULAR 2013 criteria were established with the aim of assembling homogeneous patient groups for SSc studies. To achieve this, van den Hoogen et al. evaluated candidate items for classification using both data and expert clinical judgment. They subsequently reduced the number of these items and assigned weights. The classification system underwent repeated testing and adaptation using prospectively collected SSc cases and “scleroderma-like disorder” derivation cohorts, which included MCTD patients. The","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"295 4","pages":"576-578"},"PeriodicalIF":11.1,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.13765","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139096998","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>During the last 3 years, the world has faced an unprecedented and unexpected challenge as the SARS-CoV-2 pandemic unfolded. Despite best efforts from healthcare professionals, governments and organizations, many people have died, more have been hospitalized and even more have suffered consequences from SARS-CoV-2 infection, in the short or long term.</p><p>In this issue of the <i>Journal of Internal Medicine</i>, Bergthorsdottir et al. have analysed the COVID-19-related outcomes in patients with adrenal insufficiency (AI) in Sweden [<span>1</span>]. Through a nationwide project that involved the entire Swedish population in the development of a unified healthcare database, they designed a matched-control study of mortality and morbidity associated with SARS-CoV-2 infection that yielded concerning results. With 5430 enrolled patients and a 10:1 ratio of sex- and age-matched controls, the authors have provided a relevant sample size for their investigations, gaining the leverage to answer a question that most cross-sectional studies could not: How did the COVID-19 pandemic impact patients with AI compared to the general population?</p><p>The primary study outcomes were the rate of positive SARS-CoV-2 tests, hospitalization, intensive care admission and death due to COVID-19. Even after adjusting for socio-economic factors, patients with AI had more than twice the risk for hospitalization, intensive care admission and death compared to non-AI controls, with an overall mortality rate of 0.8% compared to 0.2% in the matching cohort.</p><p>Interestingly, the authors have not found a significant difference in the positive testing rate and confirmed diagnosis of SARS-CoV2 infection. This seems to suggest that patients with AI are not increasingly susceptible to SARS-CoV2 infection but, rather, more prone to developing severe COVID-19. However, as Bergthorsdottir et al. argued, patients might have been more proactive in establishing containment measures such as isolating, hand washing or mask-wearing compared to the general population. This should have rather resulted in a decreased rate of infection, but the study is not powered to make further assumptions on this topic. Moreover, patients with AI and their healthcare providers could be more liable to search advanced medical care for SARS-CoV2 infection, but results on post-hospitalization outcomes seem to rule out this aspect as a potential confounder.</p><p>Aside from the results on prevalence, mortality and severity of disease on the overall population, the authors also ran further analyses that shed more light on a large AI cohort. Surprisingly, sex stratification did not result in differences in terms of severity or outcomes of COVID-19 disease. Early research [<span>2</span>] highlighted an increased severity of the SARS-CoV2 infection and related disease in the male population. Several speculations have been made, mostly pointing towards an increased inflammatory response in males firing an unc
充足的替代品、生理疗法和在必要情况下及时施用应激剂量是人工流产管理的基石，而偏离正确方案[7]可能会对 COVID-19 大流行期间的死亡率和发病率产生影响。然而，在一个对人工流产的认识和了解普遍较高的国家，这项研究准确地反映了现行标准护理的结果。尽管错过了根据治疗方法、剂量或其他临床指标（如体重指数或临床表现）对结果进行分层的机会，但我们必须承认无偏见结果的价值。最后，由于选定的研究时间框架，该试验并未就人工流产人群接种疫苗的有效性提供有力的结果。总之，这项临床试验证实了 AI 免疫反应的全面失调。总之，这项临床试验证实了 AI 患者免疫反应失调的广泛性。COVID-19 的特点是对炎症反应增强的患者打击更大。根据以往的研究，我们可以推断人工流产患者属于这一类。尽管我们尽了一切努力来充分替代内源性皮质醇分泌、实现电解质平衡、使动脉压恢复正常，以及对慢性肾上腺功能衰竭进行常规评估的所有其他结果，但免疫系统仍然是整个链条中的 "薄弱环节"。COVID-19大流行为大多数关于人工智能等罕见病症的细粒度研究的 "我们为什么要关心？相反，努力实现比 "良好 "控制疾病更多的目标正是当前该领域研究的期望。正如 Bergthorsdottir 等人的文章所言，关心的理由既简单又重要：万一风暴再次来袭，我们绝不能丢下任何人。
{"title":"Only as strong as the weakest link: Adrenal insufficiency in the COVID-19 storm","authors":"Valeria Hasenmajer","doi":"10.1111/joim.13763","DOIUrl":"10.1111/joim.13763","url":null,"abstract":"<p>During the last 3 years, the world has faced an unprecedented and unexpected challenge as the SARS-CoV-2 pandemic unfolded. Despite best efforts from healthcare professionals, governments and organizations, many people have died, more have been hospitalized and even more have suffered consequences from SARS-CoV-2 infection, in the short or long term.</p><p>In this issue of the <i>Journal of Internal Medicine</i>, Bergthorsdottir et al. have analysed the COVID-19-related outcomes in patients with adrenal insufficiency (AI) in Sweden [<span>1</span>]. Through a nationwide project that involved the entire Swedish population in the development of a unified healthcare database, they designed a matched-control study of mortality and morbidity associated with SARS-CoV-2 infection that yielded concerning results. With 5430 enrolled patients and a 10:1 ratio of sex- and age-matched controls, the authors have provided a relevant sample size for their investigations, gaining the leverage to answer a question that most cross-sectional studies could not: How did the COVID-19 pandemic impact patients with AI compared to the general population?</p><p>The primary study outcomes were the rate of positive SARS-CoV-2 tests, hospitalization, intensive care admission and death due to COVID-19. Even after adjusting for socio-economic factors, patients with AI had more than twice the risk for hospitalization, intensive care admission and death compared to non-AI controls, with an overall mortality rate of 0.8% compared to 0.2% in the matching cohort.</p><p>Interestingly, the authors have not found a significant difference in the positive testing rate and confirmed diagnosis of SARS-CoV2 infection. This seems to suggest that patients with AI are not increasingly susceptible to SARS-CoV2 infection but, rather, more prone to developing severe COVID-19. However, as Bergthorsdottir et al. argued, patients might have been more proactive in establishing containment measures such as isolating, hand washing or mask-wearing compared to the general population. This should have rather resulted in a decreased rate of infection, but the study is not powered to make further assumptions on this topic. Moreover, patients with AI and their healthcare providers could be more liable to search advanced medical care for SARS-CoV2 infection, but results on post-hospitalization outcomes seem to rule out this aspect as a potential confounder.</p><p>Aside from the results on prevalence, mortality and severity of disease on the overall population, the authors also ran further analyses that shed more light on a large AI cohort. Surprisingly, sex stratification did not result in differences in terms of severity or outcomes of COVID-19 disease. Early research [<span>2</span>] highlighted an increased severity of the SARS-CoV2 infection and related disease in the male population. Several speculations have been made, mostly pointing towards an increased inflammatory response in males firing an unc","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"295 3","pages":"278-280"},"PeriodicalIF":11.1,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.13763","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139065084","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>Hypothyroidism is one of the most common autoimmune diseases, especially in older women [<span>1</span>]. Moreover, autoimmune thyroiditis has been associated with different genetic polymorphisms, suggesting a genetic predisposition for developing autoimmune hypothyroidism. In general, hypothyroidism has been considered an organ-specific autoimmune disease, whereas other autoimmune diseases have a more systemic pattern, for example rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Traditionally, individuals suffering from one autoimmune disease have a higher susceptibility to another, and therefore, autoimmune diseases have a tendency to cluster within patients and their relatives. Intriguingly, the manifestations of autoimmune disease may differ between patients, although the patients share a common genetic background—a concept known as the kaleidoscope of autoimmunity [<span>2</span>].</p><p>In this issue of the <i>Journal of Internal Medicine</i>, Waldenlind et al. [<span>3</span>] presented a nationwide cohort study from Sweden assessing the incidence of hypothyroidism in patients with RA treated with disease-modifying antirheumatic drugs (DMARDs). This cohort study aimed to investigate whether DMARDs, as used in RA, may have a protective effect on the development of autoimmune thyroid disease (AITD). In this study, ∼16000 patients with RA were identified from the nationwide Swedish Rheumatology Quality Register initiated in 1996. These patients with RA were matched with approximately 63,000 controls as comparators, and the incidence of AITD was assessed between January 2006 and January 2019 in both groups. After RA diagnosis, 2.3% of the patients developed AITD—compared to 2.9% in the matched non-RA comparators—showing a lower risk of AITD development in RA. Intriguingly, the lower risk of incident AITD was even more pronounced in patients with RA treated with immunomodulatory agents receiving biological DMARDs (bDMARDs), especially in bDMARD-treated patients with concomitant use of MTX. Subset analyses stratified by sex and seropositivity showed that this lower risk remained for AITD development in patients treated with bDMARDs compared to non-bDMARD-treated patients with RA. Additional analyses for specific age groups revealed that the lower risk for AITD development was even more pronounced in younger age groups. The novel observation that AITD may be influenced by immunomodulating agents such as TNF inhibitors may have several clinical implications.</p><p>First, hypothyroidism has long been considered an organ-specific autoimmune disease, and therefore, the treatment of AITD is also organ-specific. Nowadays, AITD is treated with thyroid hormone replacement at the time that thyroid tissue is destroyed by immunological processes and the thyroid gland has lost its endocrine function. However, if AITD is considered a systemic autoimmune disease, treating it in a more systemic way—such as with immunomodulatory agents, as wi
甲状腺功能减退症是最常见的自身免疫性疾病之一，尤其是在老年妇女中[1]。此外，自身免疫性甲状腺炎还与不同的基因多态性有关，这表明自身免疫性甲状腺功能减退症具有遗传易感性。一般来说，甲状腺功能减退症被认为是一种器官特异性自身免疫性疾病，而其他自身免疫性疾病，如类风湿性关节炎（RA）和系统性红斑狼疮（SLE），则具有更系统的模式。传统上，患有一种自身免疫性疾病的人对另一种疾病的易感性较高，因此，自身免疫性疾病有在患者及其亲属中聚集的趋势。在本期《内科学杂志》（Journal of Internal Medicine）上，Waldenlind等人[3]发表了瑞典的一项全国性队列研究，评估了接受疾病修饰抗风湿药（DMARDs）治疗的RA患者中甲状腺功能减退症的发病率。这项队列研究旨在探讨在RA中使用DMARDs是否会对自身免疫性甲状腺疾病（AITD）的发生产生保护作用。在这项研究中，从1996年启动的瑞典全国风湿病学质量登记册中确定了16000名RA患者。这些RA患者与约6.3万名对照组患者进行了比对，并在2006年1月至2019年1月期间对两组患者的AITD发病率进行了评估。在确诊为RA后，2.3%的患者出现了AITD，而在匹配的非RA对照组中，这一比例为2.9%，这表明RA患者出现AITD的风险较低。耐人寻味的是，在接受生物DMARDs（bDMARDs）免疫调节剂治疗的RA患者中，尤其是在同时使用MTX的bDMARD治疗患者中，发生AITD的风险更低。按性别和血清阳性率分层的子集分析表明，与未接受生物DMARD治疗的RA患者相比，接受生物DMARD治疗的患者发生AITD的风险仍然较低。对特定年龄组进行的其他分析表明，AITD发病风险较低的情况在较年轻的年龄组中更为明显。AITD可能会受到TNF抑制剂等免疫调节药物的影响，这一新颖的观察结果可能会产生一些临床意义。首先，甲状腺功能减退症一直被认为是一种器官特异性自身免疫性疾病，因此AITD的治疗也具有器官特异性。首先，甲减一直被认为是一种器官特异性自身免疫性疾病，因此，AITD的治疗也具有器官特异性。目前，AITD的治疗是在甲状腺组织被免疫过程破坏、甲状腺失去内分泌功能时进行甲状腺激素替代。然而，如果将AITD视为一种全身性自身免疫性疾病，那么以一种更全身性的方式来治疗它--比如使用免疫调节剂，就像治疗RA或系统性红斑狼疮一样--可能会为AITD等器官特异性自身免疫性疾病带来一种新的治疗模式。尽管 Waldenlind 等人的研究发现，与 TNF 抑制剂一样，使用 bDMARDs 可减少 AITD 的发生，但这些结果还需要在其他研究中进一步证实，才能得出明确的结论。这一点具有临床意义，因为先前的研究表明，RA 与甲状腺功能减退症的发病率升高有关，更重要的是，RA 患者的心血管疾病（CVD）风险升高，这在伴有甲状腺功能减退症的 RA 患者中更为明显[4]。这不仅体现在传统的心血管风险因素（即高血压和血脂异常）上[5]，还体现在合并甲状腺功能减退症的 RA 患者的心血管疾病缺血性事件的流行和发生上[6, 7]。Waldenlind等人的研究结果引人入胜，但需要指出的是，由于该研究是全国性的，因此似乎具有普遍性，但主要局限之一是AITD诊断的不确定性。作者指出，AITD 的诊断是基于首次甲状腺激素替代处方，但 AITD 应由临床医生根据临床参数（如血液检测，包括甲状腺抗体）来诊断。此外，众所周知，甲状腺功能减退症多见于老年人。因此，年龄和体弱是RA患者开始使用bDMARDs的主要障碍，这一事实可能会使研究结果产生偏差。这或许可以解释为什么观察到的较低的AITD发病风险在年轻群体中更为明显。
{"title":"Hypothyroidism and rheumatoid arthritis: Missing a link?","authors":"Hennie G Raterman","doi":"10.1111/joim.13762","DOIUrl":"10.1111/joim.13762","url":null,"abstract":"<p>Hypothyroidism is one of the most common autoimmune diseases, especially in older women [<span>1</span>]. Moreover, autoimmune thyroiditis has been associated with different genetic polymorphisms, suggesting a genetic predisposition for developing autoimmune hypothyroidism. In general, hypothyroidism has been considered an organ-specific autoimmune disease, whereas other autoimmune diseases have a more systemic pattern, for example rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Traditionally, individuals suffering from one autoimmune disease have a higher susceptibility to another, and therefore, autoimmune diseases have a tendency to cluster within patients and their relatives. Intriguingly, the manifestations of autoimmune disease may differ between patients, although the patients share a common genetic background—a concept known as the kaleidoscope of autoimmunity [<span>2</span>].</p><p>In this issue of the <i>Journal of Internal Medicine</i>, Waldenlind et al. [<span>3</span>] presented a nationwide cohort study from Sweden assessing the incidence of hypothyroidism in patients with RA treated with disease-modifying antirheumatic drugs (DMARDs). This cohort study aimed to investigate whether DMARDs, as used in RA, may have a protective effect on the development of autoimmune thyroid disease (AITD). In this study, ∼16000 patients with RA were identified from the nationwide Swedish Rheumatology Quality Register initiated in 1996. These patients with RA were matched with approximately 63,000 controls as comparators, and the incidence of AITD was assessed between January 2006 and January 2019 in both groups. After RA diagnosis, 2.3% of the patients developed AITD—compared to 2.9% in the matched non-RA comparators—showing a lower risk of AITD development in RA. Intriguingly, the lower risk of incident AITD was even more pronounced in patients with RA treated with immunomodulatory agents receiving biological DMARDs (bDMARDs), especially in bDMARD-treated patients with concomitant use of MTX. Subset analyses stratified by sex and seropositivity showed that this lower risk remained for AITD development in patients treated with bDMARDs compared to non-bDMARD-treated patients with RA. Additional analyses for specific age groups revealed that the lower risk for AITD development was even more pronounced in younger age groups. The novel observation that AITD may be influenced by immunomodulating agents such as TNF inhibitors may have several clinical implications.</p><p>First, hypothyroidism has long been considered an organ-specific autoimmune disease, and therefore, the treatment of AITD is also organ-specific. Nowadays, AITD is treated with thyroid hormone replacement at the time that thyroid tissue is destroyed by immunological processes and the thyroid gland has lost its endocrine function. However, if AITD is considered a systemic autoimmune disease, treating it in a more systemic way—such as with immunomodulatory agents, as wi","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"295 3","pages":"276-277"},"PeriodicalIF":11.1,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.13762","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138826145","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}
Cristina Blanco-Duque, Diane Chan, Martin C. Kahn, Mitchell H. Murdock, Li-Huei Tsai
Alzheimer's disease (AD) is the most common type of neurodegenerative disease and a health challenge with major social and economic consequences. In this review, we discuss the therapeutic potential of gamma stimulation in treating AD and delve into the possible mechanisms responsible for its positive effects. Recent studies reveal that it is feasible and safe to induce 40 Hz brain activity in AD patients through a range of 40 Hz multisensory and noninvasive electrical or magnetic stimulation methods. Although research into the clinical potential of these interventions is still in its nascent stages, these studies suggest that 40 Hz stimulation can yield beneficial effects on brain function, disease pathology, and cognitive function in individuals with AD. Specifically, we discuss studies involving 40 Hz light, auditory, and vibrotactile stimulation, as well as noninvasive techniques such as transcranial alternating current stimulation and transcranial magnetic stimulation. The precise mechanisms underpinning the beneficial effects of gamma stimulation in AD are not yet fully elucidated, but preclinical studies have provided relevant insights. We discuss preclinical evidence related to both neuronal and nonneuronal mechanisms that may be involved, touching upon the relevance of interneurons, neuropeptides, and specific synaptic mechanisms in translating gamma stimulation into widespread neuronal activity within the brain. We also explore the roles of microglia, astrocytes, and the vasculature in mediating the beneficial effects of gamma stimulation on brain function. Lastly, we examine upcoming clinical trials and contemplate the potential future applications of gamma stimulation in the management of neurodegenerative disorders.
阿尔茨海默病（AD）是神经退行性疾病中最常见的一种，也是对健康的一大挑战，对社会和经济造成了重大影响。在这篇综述中，我们将讨论伽马刺激在治疗阿尔茨海默病方面的治疗潜力，并深入探讨其产生积极影响的可能机制。最近的研究表明，通过一系列 40 赫兹多感官和无创电或磁刺激方法诱导 AD 患者的 40 赫兹大脑活动是可行且安全的。尽管对这些干预措施临床潜力的研究仍处于初级阶段，但这些研究表明，40 赫兹刺激可对注意力缺失症患者的大脑功能、疾病病理和认知功能产生有益影响。具体而言，我们将讨论涉及 40 赫兹光、听觉和振动触觉刺激以及经颅交流电刺激和经颅磁刺激等非侵入性技术的研究。γ刺激对AD有益作用的确切机制尚未完全阐明，但临床前研究提供了相关的见解。我们讨论了可能涉及神经元和非神经元机制的临床前证据，涉及神经元间、神经肽和特定突触机制在将γ刺激转化为大脑内广泛神经元活动方面的相关性。我们还探讨了小胶质细胞、星形胶质细胞和血管在介导伽马刺激对大脑功能的有益影响方面的作用。最后，我们研究了即将进行的临床试验，并探讨了伽玛刺激在治疗神经退行性疾病方面的潜在应用前景。
{"title":"Audiovisual gamma stimulation for the treatment of neurodegeneration","authors":"Cristina Blanco-Duque, Diane Chan, Martin C. Kahn, Mitchell H. Murdock, Li-Huei Tsai","doi":"10.1111/joim.13755","DOIUrl":"10.1111/joim.13755","url":null,"abstract":"<p>Alzheimer's disease (AD) is the most common type of neurodegenerative disease and a health challenge with major social and economic consequences. In this review, we discuss the therapeutic potential of gamma stimulation in treating AD and delve into the possible mechanisms responsible for its positive effects. Recent studies reveal that it is feasible and safe to induce 40 Hz brain activity in AD patients through a range of 40 Hz multisensory and noninvasive electrical or magnetic stimulation methods. Although research into the clinical potential of these interventions is still in its nascent stages, these studies suggest that 40 Hz stimulation can yield beneficial effects on brain function, disease pathology, and cognitive function in individuals with AD. Specifically, we discuss studies involving 40 Hz light, auditory, and vibrotactile stimulation, as well as noninvasive techniques such as transcranial alternating current stimulation and transcranial magnetic stimulation. The precise mechanisms underpinning the beneficial effects of gamma stimulation in AD are not yet fully elucidated, but preclinical studies have provided relevant insights. We discuss preclinical evidence related to both neuronal and nonneuronal mechanisms that may be involved, touching upon the relevance of interneurons, neuropeptides, and specific synaptic mechanisms in translating gamma stimulation into widespread neuronal activity within the brain. We also explore the roles of microglia, astrocytes, and the vasculature in mediating the beneficial effects of gamma stimulation on brain function. Lastly, we examine upcoming clinical trials and contemplate the potential future applications of gamma stimulation in the management of neurodegenerative disorders.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"295 2","pages":"146-170"},"PeriodicalIF":11.1,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.13755","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138796708","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}
Chao Jiang, Manlin Zhao, Mingxiao Li, Zhiyan Wang, Yu Bai, Hang Guo, Sitong Li, Yiwei Lai, Yufeng Wang, Mingyang Gao, Liu He, Xueyuan Guo, Songnan Li, Nian Liu, Chenxi Jiang, Ribo Tang, Deyong Long, Caihua Sang, Xin Du, Jianzeng Dong, Craig S. Anderson, Changsheng Ma
Background
Effects of intensive blood pressure (BP) control on cognitive outcomes in patients with excess orthostatic BP changes are unclear. We aimed to evaluate whether orthostatic BP changes modified the effects of BP intervention on cognitive impairment.
Methods
We analyzed 8547 participants from the Systolic Blood Pressure Intervention Trial Memory and cognition IN Decreased Hypertension. Associations between orthostatic BP changes and incident cognitive outcomes were evaluated by restricted cubic spline curves based on Cox models. The interactions between orthostatic BP changes and intensive BP intervention were assessed.
Results
The U-shaped associations were observed between baseline orthostatic systolic BP changes and cognitive outcomes. However, there were insignificant interactions between either change in orthostatic systolic BP (P for interaction = 0.81) or diastolic BP (P for interaction = 0.32) and intensive BP intervention for the composite outcome of probable dementia or mild cognitive impairment (MCI). The hazard ratio of intensive versus standard target for the composite cognitive outcome was 0.82 (95% CI 0.50–1.35) in those with an orthostatic systolic BP reduction of >20 mmHg and 0.41 (95% CI 0.21–0.80) in those with an orthostatic systolic BP increase of >20 mmHg. Results were similar for probable dementia and MCI. The annual changes in global cerebral blood flow (P for interaction = 0.86) consistently favored intensive BP treatment across orthostatic systolic BP changes.
Conclusion
Intensive BP control did not have a deteriorating effect on cognitive outcomes among hypertensive patients experiencing significant postural BP changes.
背景：强化血压控制对正压变化过大的患者认知结果的影响尚不明确。我们旨在评估正静态血压变化是否会改变血压干预对认知障碍的影响：我们分析了 8547 名收缩压干预试验（Systolic Blood Pressure Intervention Trial Memory and cognition IN Decreased Hypertension）的参与者。通过基于 Cox 模型的限制性立方样条曲线评估了正压变化与认知结果事件之间的关联。评估了正压变化与强化降压干预之间的相互作用：结果：观察到基线收缩压正压变化与认知结果之间存在 U 型关联。然而，对于可能痴呆或轻度认知障碍（MCI）的综合结果，正压收缩压变化（交互作用 P = 0.81）或舒张压变化（交互作用 P = 0.32）与强化血压干预之间的交互作用并不显著。在正压收缩压降低 >20 mmHg 的人群中，强化目标与标准目标对复合认知结果的危险比为 0.82（95% CI 0.50-1.35）；在正压收缩压升高 >20 mmHg 的人群中，强化目标与标准目标对复合认知结果的危险比为 0.41（95% CI 0.21-0.80）。可能痴呆症和 MCI 的结果相似。全球脑血流量的年度变化（交互作用 P = 0.86）始终有利于强化血压治疗，而不受正压收缩压变化的影响：结论：在体位性血压发生显著变化的高血压患者中，强化血压控制不会对认知结果产生恶化影响。
{"title":"Orthostatic blood pressure changes do not influence cognitive outcomes following intensive blood pressure control","authors":"Chao Jiang, Manlin Zhao, Mingxiao Li, Zhiyan Wang, Yu Bai, Hang Guo, Sitong Li, Yiwei Lai, Yufeng Wang, Mingyang Gao, Liu He, Xueyuan Guo, Songnan Li, Nian Liu, Chenxi Jiang, Ribo Tang, Deyong Long, Caihua Sang, Xin Du, Jianzeng Dong, Craig S. Anderson, Changsheng Ma","doi":"10.1111/joim.13758","DOIUrl":"10.1111/joim.13758","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Effects of intensive blood pressure (BP) control on cognitive outcomes in patients with excess orthostatic BP changes are unclear. We aimed to evaluate whether orthostatic BP changes modified the effects of BP intervention on cognitive impairment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed 8547 participants from the Systolic Blood Pressure Intervention Trial Memory and cognition IN Decreased Hypertension. Associations between orthostatic BP changes and incident cognitive outcomes were evaluated by restricted cubic spline curves based on Cox models. The interactions between orthostatic BP changes and intensive BP intervention were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The U-shaped associations were observed between baseline orthostatic systolic BP changes and cognitive outcomes. However, there were insignificant interactions between either change in orthostatic systolic BP (P for interaction = 0.81) or diastolic BP (P for interaction = 0.32) and intensive BP intervention for the composite outcome of probable dementia or mild cognitive impairment (MCI). The hazard ratio of intensive versus standard target for the composite cognitive outcome was 0.82 (95% CI 0.50–1.35) in those with an orthostatic systolic BP reduction of >20 mmHg and 0.41 (95% CI 0.21–0.80) in those with an orthostatic systolic BP increase of >20 mmHg. Results were similar for probable dementia and MCI. The annual changes in global cerebral blood flow (P for interaction = 0.86) consistently favored intensive BP treatment across orthostatic systolic BP changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Intensive BP control did not have a deteriorating effect on cognitive outcomes among hypertensive patients experiencing significant postural BP changes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"295 4","pages":"557-568"},"PeriodicalIF":11.1,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138796710","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}
Karin Wahlberg, Bengt Winblad, Amanda Cole, William L. Herring, Joakim Ramsberg, Ilona Torontali, Pieter-Jelle Visser, Anders Wimo, Lieve Wollaert, Linus Jönsson
The development of disease-modifying therapies (DMTs) for Alzheimer's disease (AD) has progressed over the last decade, and the first-ever therapies with potential to slow the progression of disease are approved in the United States. AD DMTs could provide life-changing opportunities for people living with this disease, as well as for their caregivers. They could also ease some of the immense societal and economic burden of dementia. However, AD DMTs also come with major challenges due to the large unmet medical need, high prevalence of AD, new costs related to diagnosis, treatment and monitoring, and uncertainty in the therapies’ actual clinical value. This perspective article discusses, from the broad perspective of various health systems and stakeholders, how we can overcome these challenges and improve society's readiness for AD DMTs. We propose that innovative payment models such as performance-based payments, in combination with learning healthcare systems, could be the way forward to enable timely patient access to treatments, improve accuracy of cost-effectiveness evaluations and overcome budgetary barriers. Other important considerations include the need for identification of key drivers of patient value, the relevance of different economic perspectives (i.e. healthcare vs. societal) and ethical questions in terms of treatment eligibility criteria.
在过去十年中，阿尔茨海默病（AD）的疾病修饰疗法（DMTs）的开发取得了进展，美国首次批准了有可能延缓疾病进展的疗法。阿兹海默症 DMT 可为患者及其护理者提供改变生活的机会。它们还能减轻痴呆症带来的巨大社会和经济负担。然而，由于大量医疗需求未得到满足、AD 发病率高、诊断、治疗和监测相关的新成本以及疗法实际临床价值的不确定性，AD DMTs 也面临着重大挑战。本视角文章从不同医疗系统和利益相关者的广阔视角出发，讨论了我们如何才能克服这些挑战并改善社会对 AD DMTs 的准备情况。我们提出，创新的支付模式（如基于绩效的支付）与学习型医疗保健系统相结合，可能是使患者及时获得治疗、提高成本效益评估的准确性并克服预算障碍的前进方向。其他重要考虑因素包括：需要确定患者价值的关键驱动因素、不同经济视角（即医疗保健与社会）的相关性以及治疗资格标准方面的伦理问题。
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Helene Kildegaard, Mikkel Brabrand, Jakob Lundager Forberg, Pyotr Platonov, Annmarie Touborg Lassen, Ulf Ekelund
Background
Hypokalemia is common in hospitalized patients and associated with ECG abnormalities. The prevalence and prognostic value of ECG abnormalities in hypokalemic patients are, however, not well established.
Methods
The study was a multicentered cohort study, including all ault patients with an ECG and potassium level <4.4 mmol/L recorded at arrival to four emergency departments in Denmark and Sweden. Using computerized measurements from ECGs, we investigated the relationship between potassium levels and heart rate, QRS duration, corrected QT (QTc) interval, ST-segment depressions, T-wave flattening, and T-wave inversion using cubic splines. Within strata of potassium levels, we further estimated the hazard ratio (HR) for 7-day mortality, admission to the intensive care unit (ICU), and diagnosis of ventricular arrhythmia or cardiac arrest, comparing patients with and without specific ECG abnormalities matched 1:2 on propensity scores.
Results
Among 79,599 included patients, decreasing potassium levels were associated with a concentration-dependent increase in all investigated ECG variables. ECG abnormalities were present in 40% of hypokalemic patients ([K+] <3.5 mmol/L), with T-wave flattening, ST-segment depression, and QTc prolongation occurring in 27%, 16%, and 14%. In patients with mild hypokalemia ([K+] 3.0–3.4 mmol/L), a heart rate >100 bpm, ST-depressions, and T-wave inversion were associated with increased HRs for 7-day mortality and ICU admission, whereas only a heart rate >100 bpm predicted both mortality and ICU admission among patients with [K+] <3.0 mmol/L. HR estimates were, however, similar to those in eukalemic patients. The low number of events with ventricular arrhythmia limited evaluation for this outcome.
Conclusions
ECG abnormalities were common in hypokalemic patients, but they are poor prognostic markers for short-term adverse events under the current standard of care.
{"title":"Prevalence and prognostic value of electrocardiographic abnormalities in hypokalemia: A multicenter cohort study","authors":"Helene Kildegaard, Mikkel Brabrand, Jakob Lundager Forberg, Pyotr Platonov, Annmarie Touborg Lassen, Ulf Ekelund","doi":"10.1111/joim.13757","DOIUrl":"10.1111/joim.13757","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hypokalemia is common in hospitalized patients and associated with ECG abnormalities. The prevalence and prognostic value of ECG abnormalities in hypokalemic patients are, however, not well established.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study was a multicentered cohort study, including all ault patients with an ECG and potassium level <4.4 mmol/L recorded at arrival to four emergency departments in Denmark and Sweden. Using computerized measurements from ECGs, we investigated the relationship between potassium levels and heart rate, QRS duration, corrected QT (QTc) interval, ST-segment depressions, T-wave flattening, and T-wave inversion using cubic splines. Within strata of potassium levels, we further estimated the hazard ratio (HR) for 7-day mortality, admission to the intensive care unit (ICU), and diagnosis of ventricular arrhythmia or cardiac arrest, comparing patients with and without specific ECG abnormalities matched 1:2 on propensity scores.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 79,599 included patients, decreasing potassium levels were associated with a concentration-dependent increase in all investigated ECG variables. ECG abnormalities were present in 40% of hypokalemic patients ([K<sup>+</sup>] <3.5 mmol/L), with T-wave flattening, ST-segment depression, and QTc prolongation occurring in 27%, 16%, and 14%. In patients with mild hypokalemia ([K<sup>+</sup>] 3.0–3.4 mmol/L), a heart rate >100 bpm, ST-depressions, and T-wave inversion were associated with increased HRs for 7-day mortality and ICU admission, whereas only a heart rate >100 bpm predicted both mortality and ICU admission among patients with [K<sup>+</sup>] <3.0 mmol/L. HR estimates were, however, similar to those in eukalemic patients. The low number of events with ventricular arrhythmia limited evaluation for this outcome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>ECG abnormalities were common in hypokalemic patients, but they are poor prognostic markers for short-term adverse events under the current standard of care.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"295 4","pages":"544-556"},"PeriodicalIF":11.1,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138679754","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}
Daniel D. DiLena, E. Margaret Warton, David R. Vinson, Marcos H. Siqueiros, Adina S. Rauchwerger, Dustin G. Mark, Jacek Skarbinski, S. Madhavi Cholleti, Edward J. Durant, Mary E. Reed, Dustin W. Ballard, the Kaiser Permanente CREST Network
<p>Dear Editor,</p><p>It is well established that olfactory dysfunction, including partial smell loss (hyposmia), total smell loss (anosmia), and distorted smell (parosmia), is associated with COVID-19. Case studies reporting this association appeared as early as April 2020. It was estimated that olfactory disturbances affected more than 60% of patients with symptomatic SARS-CoV-2 infection, with olfactory symptoms often developing after other infectious symptoms [<span>1, 2</span>]. Loss of taste or smell, if persistent, can affect eating habits and overall wellness and has even been linked to serious mental health disorders like anxiety and depression [<span>3</span>]. Predictors of these symptoms in the setting of COVID-19 include female sex, younger age, and fever [<span>4, 5</span>]. More recent data suggest that the positive predictive value of olfactory dysfunction for COVID-19 diminished with the emergence of vaccines and later variants [<span>6</span>]. Most notably, two related studies indicate that chemosensory loss due to COVID has declined dramatically, suggesting prevalence rates of 3%–4% during omicron waves [<span>7, 8</span>]. We sought to assess variations in the prevalence of olfactory disturbance diagnoses in a large healthcare system before and during the COVID-19 pandemic and compare these to population rates of SARS-CoV-2 infection.</p><p>We conducted a retrospective cohort study among patients 18 years or older between 1/1/2019 and 10/31/2022 with active membership in Kaiser Permanente Northern California (KPNC) and with at least one olfactory disturbance diagnosis with or without taste disturbances (ICD-10 codes R43.0, R43.1, R43.8, and R43.9) for any encounter type (inpatient, outpatient, in-system, and claims). Our cohort includes patients with diagnoses at any time during our study period, not limited to those temporally associated with a documented SARS-CoV-2 infection. We assigned 32 months to five distinct periods of variant dominance and examined temporal trends in olfactory disturbance diagnoses alongside the population incidence of SARS-CoV-2 infection. We calculated the monthly rate of olfactory disturbance diagnoses per COVID-19 diagnoses (per 100,000 health plan members) for each variant and tested for differences with a Kruskal–Wallis test.</p><p>Our retrospective review identified 66,067 olfactory disturbance diagnoses among a cohort of 23,570 patients, with 72.1% of patients receiving more than one related diagnosis during the study period. The most common encounter types were outpatient clinic visits and scheduled telephone visits. Patient median age was 46.1 (IQR 32.1–61.4) years, and 61.0% were female, with a median of 2 encounters for olfactory disturbance diagnoses per patient (IQR 1–4). Figure 1 depicts temporal trends of index olfactory disturbance diagnoses alongside the population incidence of COVID-19 (per 100,000 patients). The median monthly rate of olfactory disturbance diagnoses varied with st
{"title":"Smells like a variant: How the association between COVID-19 and olfactory dysfunction changed between 2019 and 2022","authors":"Daniel D. DiLena, E. Margaret Warton, David R. Vinson, Marcos H. Siqueiros, Adina S. Rauchwerger, Dustin G. Mark, Jacek Skarbinski, S. Madhavi Cholleti, Edward J. Durant, Mary E. Reed, Dustin W. Ballard, the Kaiser Permanente CREST Network","doi":"10.1111/joim.13760","DOIUrl":"10.1111/joim.13760","url":null,"abstract":"<p>Dear Editor,</p><p>It is well established that olfactory dysfunction, including partial smell loss (hyposmia), total smell loss (anosmia), and distorted smell (parosmia), is associated with COVID-19. Case studies reporting this association appeared as early as April 2020. It was estimated that olfactory disturbances affected more than 60% of patients with symptomatic SARS-CoV-2 infection, with olfactory symptoms often developing after other infectious symptoms [<span>1, 2</span>]. Loss of taste or smell, if persistent, can affect eating habits and overall wellness and has even been linked to serious mental health disorders like anxiety and depression [<span>3</span>]. Predictors of these symptoms in the setting of COVID-19 include female sex, younger age, and fever [<span>4, 5</span>]. More recent data suggest that the positive predictive value of olfactory dysfunction for COVID-19 diminished with the emergence of vaccines and later variants [<span>6</span>]. Most notably, two related studies indicate that chemosensory loss due to COVID has declined dramatically, suggesting prevalence rates of 3%–4% during omicron waves [<span>7, 8</span>]. We sought to assess variations in the prevalence of olfactory disturbance diagnoses in a large healthcare system before and during the COVID-19 pandemic and compare these to population rates of SARS-CoV-2 infection.</p><p>We conducted a retrospective cohort study among patients 18 years or older between 1/1/2019 and 10/31/2022 with active membership in Kaiser Permanente Northern California (KPNC) and with at least one olfactory disturbance diagnosis with or without taste disturbances (ICD-10 codes R43.0, R43.1, R43.8, and R43.9) for any encounter type (inpatient, outpatient, in-system, and claims). Our cohort includes patients with diagnoses at any time during our study period, not limited to those temporally associated with a documented SARS-CoV-2 infection. We assigned 32 months to five distinct periods of variant dominance and examined temporal trends in olfactory disturbance diagnoses alongside the population incidence of SARS-CoV-2 infection. We calculated the monthly rate of olfactory disturbance diagnoses per COVID-19 diagnoses (per 100,000 health plan members) for each variant and tested for differences with a Kruskal–Wallis test.</p><p>Our retrospective review identified 66,067 olfactory disturbance diagnoses among a cohort of 23,570 patients, with 72.1% of patients receiving more than one related diagnosis during the study period. The most common encounter types were outpatient clinic visits and scheduled telephone visits. Patient median age was 46.1 (IQR 32.1–61.4) years, and 61.0% were female, with a median of 2 encounters for olfactory disturbance diagnoses per patient (IQR 1–4). Figure 1 depicts temporal trends of index olfactory disturbance diagnoses alongside the population incidence of COVID-19 (per 100,000 patients). The median monthly rate of olfactory disturbance diagnoses varied with st","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"295 4","pages":"569-571"},"PeriodicalIF":11.1,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.13760","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138679700","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}
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