Anna Linda Zignego, Laura Gragnani, Marcella Visentini, Riccardo Bomben, Luca Arcaini, Clodoveo Ferri, Valter Gattei, Cesare Mazzaro
Cryoglobulinemia (CG) is defined by the presence of serum immunoglobulins that precipitate below 37°C and redissolve upon rewarming. It is classified into three types based on immunoglobulin composition. Type I, a rare form, involves monoclonal IgM or IgG and is linked to lymphoproliferative disorders. Types II and III are known as mixed CG (MC): Type II consists of polyclonal IgG and monoclonal IgM with rheumatoid factor (RF) activity, whereas Type III includes polyclonal IgG and polyclonal IgM with RF activity. MC is predominantly associated with hepatitis C virus (HCV) infection and involves B-cell lymphoproliferation and autoantibody production. CG may lead to systemic vasculopathy, ranging from mild symptoms (purpura, asthenia, and arthralgia) to severe complications such as skin ulcers, peripheral neuropathy, renal involvement, and non-Hodgkin lymphoma. Compared to MC, Type I is more often marked by severe cutaneous involvement (ulcers, gangrene), hyperviscosity, and a higher risk of morbidity due to the underlying hematologic malignancy. Management of Type I requires control of vasculopathy and treatment of the hematologic neoplasm, whereas MC demands antiviral therapy in all HCV-associated or hepatitis B virus–associated cases. Severe vasculopathy in both types may benefit from corticosteroids, immunomodulators, anti-CD20 monoclonal antibodies, and plasma exchange. A multidisciplinary approach is essential for addressing both etiology and complications, thereby improving outcomes. This review summarizes the pathophysiology, clinical features, recent etiopathogenetic insights, and therapeutic advances related to the various forms of CG.
{"title":"Cryoglobulinemia: An update on classification, pathophysiology, clinical presentation, and management","authors":"Anna Linda Zignego, Laura Gragnani, Marcella Visentini, Riccardo Bomben, Luca Arcaini, Clodoveo Ferri, Valter Gattei, Cesare Mazzaro","doi":"10.1111/joim.70042","DOIUrl":"10.1111/joim.70042","url":null,"abstract":"<p>Cryoglobulinemia (CG) is defined by the presence of serum immunoglobulins that precipitate below 37°C and redissolve upon rewarming. It is classified into three types based on immunoglobulin composition. Type I, a rare form, involves monoclonal IgM or IgG and is linked to lymphoproliferative disorders. Types II and III are known as mixed CG (MC): Type II consists of polyclonal IgG and monoclonal IgM with rheumatoid factor (RF) activity, whereas Type III includes polyclonal IgG and polyclonal IgM with RF activity. MC is predominantly associated with hepatitis C virus (HCV) infection and involves B-cell lymphoproliferation and autoantibody production. CG may lead to systemic vasculopathy, ranging from mild symptoms (purpura, asthenia, and arthralgia) to severe complications such as skin ulcers, peripheral neuropathy, renal involvement, and non-Hodgkin lymphoma. Compared to MC, Type I is more often marked by severe cutaneous involvement (ulcers, gangrene), hyperviscosity, and a higher risk of morbidity due to the underlying hematologic malignancy. Management of Type I requires control of vasculopathy and treatment of the hematologic neoplasm, whereas MC demands antiviral therapy in all HCV-associated or hepatitis B virus–associated cases. Severe vasculopathy in both types may benefit from corticosteroids, immunomodulators, anti-CD20 monoclonal antibodies, and plasma exchange. A multidisciplinary approach is essential for addressing both etiology and complications, thereby improving outcomes. This review summarizes the pathophysiology, clinical features, recent etiopathogenetic insights, and therapeutic advances related to the various forms of CG.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 2","pages":"196-215"},"PeriodicalIF":9.2,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12789282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627301","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}
Valentine Pagis, Quentin Astouati, Lucas Pacoureau, Yann Nguyen, Pierre Bay, Antoine Roux, Laure Gallay, Vincent Cottin, Benjamin Terrier, Alain Meyer, Charles Cerf, Mathilde Neuville, Baptiste Hervier, Arthur Renaud, Benoit Suzon, Nicolas Schleinitz, Thomas Papo, Pascaline Priou, Arsène Mekinian, Audrey Ullmer, Erwan Oehler, Noémie Gensous, Alice Berezne, Luc De Saint Martin, Thierry Marhadour, Mickaël Martin, Amélie Servettaz, Maxime Samson, Laurent Gilardin, Pierre Charles, Juliette Woessner, Thierry Carmoi, Baptiste Dilly, Wladimir Mauhin, Nicolas Baillet, Sébastien Humbert, Benjamin Thoreau, Marine Lemaitre, Claire Le Pendu, Pierre Loiseau, Thomas Quemeneur, Elodie Blanchard, Nicol Voermans, David Launay, Hilario Nunes, Olivier Benveniste, Yurdagul Uzunhan, Yves Allenbach
Objectives
Anti-MDA5 dermatomyositis (anti-MDA5 DM) is the most severe subtype of dermatomyositis, due to its pulmonary involvement. Current treatment involves corticosteroids and immunosuppressants, but variability in responses exists. This study aims to evaluate the efficacy and safety of Janus kinase (JAK)– and calcineurin–inhibitor combination (JAK–CNI) in anti-MDA5 DM patients.
Methods
A nested case–control study was conducted within a retrospective cohort of 234 anti-MDA5 DM patients. Patients receiving JAK–CNI were matched 1:2 with comparators. All-cause mortality or transplant within a year was compared using Cox proportional hazards models. Infectious and noninfectious side effects were also assessed.
Results
Twenty-seven patients receiving JAK–CNI were compared to 52 matched controls. Almost all these patients had pulmonary involvement. Thirty-nine (49%) died or were transplanted during follow-up. No significant improvement in survival or transplant-free survival was observed with JAK–CNI compared with comparators (hazard ratios 1.02, 95% confidence intervals [0.48–2.16]). Results were consistent regardless of intensive care unit (ICU) admission status and when analyses were restricted to patients with rapidly progressive interstitial lung disease. A trend toward a beneficial effect of the JAK–CNI combination was observed in non-ICU patients. Infectious complications were frequent (n = 49, 62%), with no excess risk in patients receiving JAK–CNI.
Conclusion
JAK–CNI showed a similar outcome to other immunosuppressive combinations. However, as the study included the most severe cases, the potential benefit of early JAK–CNI introduction in less severe forms cannot be dismissed, as suggested by the nonsignificant trend in non-ICU patients. Future studies are needed to clarify the optimal timing and patient selection for JAK–CNI therapy in anti-MDA5 DM.
{"title":"Janus kinase and calcineurin-inhibitor combination in anti-MDA5 dermatomyositis: No significant survival benefit but reassuring safety profile","authors":"Valentine Pagis, Quentin Astouati, Lucas Pacoureau, Yann Nguyen, Pierre Bay, Antoine Roux, Laure Gallay, Vincent Cottin, Benjamin Terrier, Alain Meyer, Charles Cerf, Mathilde Neuville, Baptiste Hervier, Arthur Renaud, Benoit Suzon, Nicolas Schleinitz, Thomas Papo, Pascaline Priou, Arsène Mekinian, Audrey Ullmer, Erwan Oehler, Noémie Gensous, Alice Berezne, Luc De Saint Martin, Thierry Marhadour, Mickaël Martin, Amélie Servettaz, Maxime Samson, Laurent Gilardin, Pierre Charles, Juliette Woessner, Thierry Carmoi, Baptiste Dilly, Wladimir Mauhin, Nicolas Baillet, Sébastien Humbert, Benjamin Thoreau, Marine Lemaitre, Claire Le Pendu, Pierre Loiseau, Thomas Quemeneur, Elodie Blanchard, Nicol Voermans, David Launay, Hilario Nunes, Olivier Benveniste, Yurdagul Uzunhan, Yves Allenbach","doi":"10.1111/joim.70047","DOIUrl":"10.1111/joim.70047","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Anti-MDA5 dermatomyositis (anti-MDA5 DM) is the most severe subtype of dermatomyositis, due to its pulmonary involvement. Current treatment involves corticosteroids and immunosuppressants, but variability in responses exists. This study aims to evaluate the efficacy and safety of Janus kinase (JAK)– and calcineurin–inhibitor combination (JAK–CNI) in anti-MDA5 DM patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A nested case–control study was conducted within a retrospective cohort of 234 anti-MDA5 DM patients. Patients receiving JAK–CNI were matched 1:2 with comparators. All-cause mortality or transplant within a year was compared using Cox proportional hazards models. Infectious and noninfectious side effects were also assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Twenty-seven patients receiving JAK–CNI were compared to 52 matched controls. Almost all these patients had pulmonary involvement. Thirty-nine (49%) died or were transplanted during follow-up. No significant improvement in survival or transplant-free survival was observed with JAK–CNI compared with comparators (hazard ratios 1.02, 95% confidence intervals [0.48–2.16]). Results were consistent regardless of intensive care unit (ICU) admission status and when analyses were restricted to patients with rapidly progressive interstitial lung disease. A trend toward a beneficial effect of the JAK–CNI combination was observed in non-ICU patients. Infectious complications were frequent (<i>n</i> = 49, 62%), with no excess risk in patients receiving JAK–CNI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>JAK–CNI showed a similar outcome to other immunosuppressive combinations. However, as the study included the most severe cases, the potential benefit of early JAK–CNI introduction in less severe forms cannot be dismissed, as suggested by the nonsignificant trend in non-ICU patients. Future studies are needed to clarify the optimal timing and patient selection for JAK–CNI therapy in anti-MDA5 DM.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 2","pages":"228-240"},"PeriodicalIF":9.2,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12789280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585529","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}
Birger Sourander, Kirsten Mehlig, Fredrik Olsen, Martin Lindgren, Ulrika Snygg-Martin, Magnus Gisslén, Annika Rosengren, Maria Åberg, Josefina Robertson
Background
Obesity and poor physical fitness in youth are established risk factors for future cardiovascular disease and cancer. However, their potential impact on the risk of severe bacterial infections later in life remains unclear.
Methods
This register-based cohort study followed almost 1 million Swedish conscripts (mean age 18.3 years) over a period of three decades. Measured body mass index (BMI) and cardiorespiratory fitness (CRF) at conscription to military service served as exposure variables, whereas outcomes included morbidity and mortality attributed to bacterial pneumonia, sepsis, and infective endocarditis.
Results
High BMI and low CRF in late adolescence were strongly associated with an increased risk of bacterial pneumonia, sepsis, and infective endocarditis in adulthood. The highest risk was seen among the obese for sepsis (hazard ratio [HR] 3.1 (2.7–3.5)), with elevated hazards observed already at high-normal BMI levels (22.5–25 kg/m2), compared with BMI 18.5–19.9. The risk of dying due to bacterial infections increased gradually with higher BMI. High, compared with low CRF, was associated with lower risk of contracting bacterial infections (0.78, 0.76–0.80), and dying from them (0.58, 0.51–0.65).
Conclusion
High BMI and low CRF in adolescence are associated with an increased risk of contracting and dying of severe bacterial infections later in life. Hence, addressing these preventable risk factors in youths may serve as an effective measure to improve their long-term health.
{"title":"High BMI and low cardiorespiratory fitness in adolescence are associated with increased risk of severe bacterial infections in adulthood","authors":"Birger Sourander, Kirsten Mehlig, Fredrik Olsen, Martin Lindgren, Ulrika Snygg-Martin, Magnus Gisslén, Annika Rosengren, Maria Åberg, Josefina Robertson","doi":"10.1111/joim.70043","DOIUrl":"10.1111/joim.70043","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Obesity and poor physical fitness in youth are established risk factors for future cardiovascular disease and cancer. However, their potential impact on the risk of severe bacterial infections later in life remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This register-based cohort study followed almost 1 million Swedish conscripts (mean age 18.3 years) over a period of three decades. Measured body mass index (BMI) and cardiorespiratory fitness (CRF) at conscription to military service served as exposure variables, whereas outcomes included morbidity and mortality attributed to bacterial pneumonia, sepsis, and infective endocarditis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>High BMI and low CRF in late adolescence were strongly associated with an increased risk of bacterial pneumonia, sepsis, and infective endocarditis in adulthood. The highest risk was seen among the obese for sepsis (hazard ratio [HR] 3.1 (2.7–3.5)), with elevated hazards observed already at high-normal BMI levels (22.5–25 kg/m<sup>2</sup>), compared with BMI 18.5–19.9. The risk of dying due to bacterial infections increased gradually with higher BMI. High, compared with low CRF, was associated with lower risk of contracting bacterial infections (0.78, 0.76–0.80), and dying from them (0.58, 0.51–0.65).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>High BMI and low CRF in adolescence are associated with an increased risk of contracting and dying of severe bacterial infections later in life. Hence, addressing these preventable risk factors in youths may serve as an effective measure to improve their long-term health.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 1","pages":"158-171"},"PeriodicalIF":9.2,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585534","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}
Maria Tydén, Gorav Batra, Bengt Fellström, Claes Held, Johan Lindbäck, Inga Soveri, Maria K. Svensson, Ralph Stewart, Harvey D. White, Lars Wallentin
Background
Renal dysfunction increases cardiovascular (CV) risk. We compared cystatin C-based estimated glomerular filtration rate (eGFRcys), creatinine-based eGFR (eGFRcr), and their ratio (eGFRcys/eGFRcr) in relation to major adverse cardiovascular events (MACE) and all-cause mortality in chronic coronary syndrome, assessing the added prognostic value of the eGFRratio.
Methods
In this post hoc analysis of 14,513 Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial patients, we investigated associations between baseline eGFRcys, eGFRcr, their ratio, and MACE and all-cause death using Cox regression models, unadjusted and adjusted for eGFRcys, eGFRcr, and their combination. Discrimination was assessed using Harrell's C-index; added value by the fraction of new information (FNI).
Results
Median age was 65 years; 82% were male. Median eGFRcys was 77 (interquartile range [IQR]: 61–94) and eGFRcr 79 (IQR: 65–91) mL/min/1.73 m2. Over 3.7 years, 1449 MACE and 1063 deaths occurred. Lower eGFR values and eGFRratio were associated with increased MACE risk, primarily driven by CV death. For eGFRcys 60 versus 90, the hazard ratio (HR) for MACE adjusted for eGFRcr was 1.77 (95% CI: 1.49–2.09, FNI 54%). In contrast, eGFRcr adjusted for eGFRcys showed no positive association (HR 0.82, 95% CI: 0.68–0.97, FNI 3%). A lower eGFRratio was linked to higher MACE risk (HR 1.99, 95% CI: 1.80–2.21), which remained after eGFRcr adjustment (HR 1.89, 95% CI: 1.70–2.10, FNI 54%) but was attenuated after eGFRcys adjustment (HR 1.29, 95% CI: 1.13–1.46, FNI 5%).
Conclusion
In chronic coronary syndrome, lower eGFRcys, eGFRcr, and eGFRratio were associated with higher MACE and mortality risk. eGFRcys had the strongest association; eGFRcr and eGFRratio added limited incremental value.
{"title":"Different eGFR markers and prediction of cardiovascular risk","authors":"Maria Tydén, Gorav Batra, Bengt Fellström, Claes Held, Johan Lindbäck, Inga Soveri, Maria K. Svensson, Ralph Stewart, Harvey D. White, Lars Wallentin","doi":"10.1111/joim.70050","DOIUrl":"10.1111/joim.70050","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Renal dysfunction increases cardiovascular (CV) risk. We compared cystatin C-based estimated glomerular filtration rate (eGFRcys), creatinine-based eGFR (eGFRcr), and their ratio (eGFRcys/eGFRcr) in relation to major adverse cardiovascular events (MACE) and all-cause mortality in chronic coronary syndrome, assessing the added prognostic value of the eGFRratio.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this post hoc analysis of 14,513 Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial patients, we investigated associations between baseline eGFRcys, eGFRcr, their ratio, and MACE and all-cause death using Cox regression models, unadjusted and adjusted for eGFRcys, eGFRcr, and their combination. Discrimination was assessed using Harrell's <i>C</i>-index; added value by the fraction of new information (FNI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Median age was 65 years; 82% were male. Median eGFRcys was 77 (interquartile range [IQR]: 61–94) and eGFRcr 79 (IQR: 65–91) mL/min/1.73 m<sup>2</sup>. Over 3.7 years, 1449 MACE and 1063 deaths occurred. Lower eGFR values and eGFRratio were associated with increased MACE risk, primarily driven by CV death. For eGFRcys 60 versus 90, the hazard ratio (HR) for MACE adjusted for eGFRcr was 1.77 (95% CI: 1.49–2.09, FNI 54%). In contrast, eGFRcr adjusted for eGFRcys showed no positive association (HR 0.82, 95% CI: 0.68–0.97, FNI 3%). A lower eGFRratio was linked to higher MACE risk (HR 1.99, 95% CI: 1.80–2.21), which remained after eGFRcr adjustment (HR 1.89, 95% CI: 1.70–2.10, FNI 54%) but was attenuated after eGFRcys adjustment (HR 1.29, 95% CI: 1.13–1.46, FNI 5%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In chronic coronary syndrome, lower eGFRcys, eGFRcr, and eGFRratio were associated with higher MACE and mortality risk. eGFRcys had the strongest association; eGFRcr and eGFRratio added limited incremental value.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 1","pages":"143-157"},"PeriodicalIF":9.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572731","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}
Jasmin Elkin, Chris Schilling, Michael W. Hii, Peter F. Choong, Michelle Dowsey, Cade Shadbolt
{"title":"Diagnostic performance of a new framework for identifying obesity","authors":"Jasmin Elkin, Chris Schilling, Michael W. Hii, Peter F. Choong, Michelle Dowsey, Cade Shadbolt","doi":"10.1111/joim.70049","DOIUrl":"10.1111/joim.70049","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 1","pages":"172-175"},"PeriodicalIF":9.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572718","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}
Rasmus Mortensen, Cecilia S. Lindestam Arlehamn, Rhea N. Coler, Michael Y. Gerner, Delia Goletti, Deborah A. Lewinsohn, Robert L. Modlin, Munyaradzi Musvosvi, Jyothi Rengarajan, Kevin B. Urdahl, Gerhard Walzl, Samuel M. Behar, Daniel L. Barber, For the Collaboration for Tuberculosis Vaccine Discovery – Conventional T cells Research Community, Gates Foundation
Tuberculosis (TB) remains a leading infectious cause of morbidity and mortality, and the development of a new, highly effective vaccine would have a tremendous beneficial impact on global health. Although conventional memory CD4 and CD8 T cells will likely be key mediators of long-lived, vaccine-elicited protection, a potent T cell–inducing vaccine against TB has been elusive. Protection by Mycobacterium tuberculosis (Mtb)-specific T cells is mediated primarily through their communication with Mtb-infected macrophages. Here, we discuss emerging evidence of multiple structural and immunoregulatory factors that limit effective T cell–macrophage interactions in TB granulomas, posing a unique challenge to vaccine-induced protection. Developing new TB vaccination strategies will require a better understanding of the crosstalk between T cells and infected pulmonary macrophages and strategies to enhance these interactions.
{"title":"T cell–macrophage interactions in tuberculosis: What we've got here is failure to communicate","authors":"Rasmus Mortensen, Cecilia S. Lindestam Arlehamn, Rhea N. Coler, Michael Y. Gerner, Delia Goletti, Deborah A. Lewinsohn, Robert L. Modlin, Munyaradzi Musvosvi, Jyothi Rengarajan, Kevin B. Urdahl, Gerhard Walzl, Samuel M. Behar, Daniel L. Barber, For the Collaboration for Tuberculosis Vaccine Discovery – Conventional T cells Research Community, Gates Foundation","doi":"10.1111/joim.70028","DOIUrl":"10.1111/joim.70028","url":null,"abstract":"<p>Tuberculosis (TB) remains a leading infectious cause of morbidity and mortality, and the development of a new, highly effective vaccine would have a tremendous beneficial impact on global health. Although conventional memory CD4 and CD8 T cells will likely be key mediators of long-lived, vaccine-elicited protection, a potent T cell–inducing vaccine against TB has been elusive. Protection by <i>Mycobacterium tuberculosis</i> (Mtb)-specific T cells is mediated primarily through their communication with Mtb-infected macrophages. Here, we discuss emerging evidence of multiple structural and immunoregulatory factors that limit effective T cell–macrophage interactions in TB granulomas, posing a unique challenge to vaccine-induced protection. Developing new TB vaccination strategies will require a better understanding of the crosstalk between T cells and infected pulmonary macrophages and strategies to enhance these interactions.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 1","pages":"44-65"},"PeriodicalIF":9.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572645","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}
Adipose mass is homeostatically maintained within a narrow range despite fluctuations in daily calorie intake and activity levels. Constituting an adipose mass “set point,” this homeostatic regulation includes sensing mechanisms in the form of hormones reflecting caloric intake that serve as mediators of appetitive behaviors and adipose mass amount; integrating centers in the brain and brainstem; and response or effector systems. During adipose mass fluctuations beyond daily short-term changes, typically during low-calorie dieting, these effector systems include adaptive responses in metabolism (energetics), hormone production, and appetitive behaviors that resist further loss and restore adipose mass to baseline. Although our understanding of the disease of obesity is still evolving, within the context of this paper we consider the disease a manifestation of the pathophysiological processes when the expression of leptin resistance leads to the establishment of a new, higher adipose mass set point. Effective obesity therapies lower the adipose mass set point by improving appetite control and preventing the normal adaptive responses that lead to weight regain, effectively establishing a new adipose mass set point at a lower, healthier level. Conveying this biology to patients with obesity provides them with an understanding of their disease state, why drug and surgical treatments in combination with lifestyle are necessary for most people, and the mediators of the changes in appetitive behaviors expected from effective obesity therapies. Future research will need to advance the evidence base that supports this theoretical framework and generate even deeper insights into the disease of obesity.
{"title":"Metabolic and appetitive regulation of adipocyte mass during treatment of obesity","authors":"Jonathan Q. Purnell, Carel W. Le Roux","doi":"10.1111/joim.70045","DOIUrl":"10.1111/joim.70045","url":null,"abstract":"<p>Adipose mass is homeostatically maintained within a narrow range despite fluctuations in daily calorie intake and activity levels. Constituting an adipose mass “set point,” this homeostatic regulation includes sensing mechanisms in the form of hormones reflecting caloric intake that serve as mediators of appetitive behaviors and adipose mass amount; integrating centers in the brain and brainstem; and response or effector systems. During adipose mass fluctuations beyond daily short-term changes, typically during low-calorie dieting, these effector systems include adaptive responses in metabolism (energetics), hormone production, and appetitive behaviors that resist further loss and restore adipose mass to baseline. Although our understanding of the disease of obesity is still evolving, within the context of this paper we consider the disease a manifestation of the pathophysiological processes when the expression of leptin resistance leads to the establishment of a new, higher adipose mass set point. Effective obesity therapies lower the adipose mass set point by improving appetite control and preventing the normal adaptive responses that lead to weight regain, effectively establishing a new adipose mass set point at a lower, healthier level. Conveying this biology to patients with obesity provides them with an understanding of their disease state, why drug and surgical treatments in combination with lifestyle are necessary for most people, and the mediators of the changes in appetitive behaviors expected from effective obesity therapies. Future research will need to advance the evidence base that supports this theoretical framework and generate even deeper insights into the disease of obesity.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 1","pages":"66-78"},"PeriodicalIF":9.2,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145561918","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}
Elena Di Pierro, Isabel Solares, Daniel Jericó, Francisco J. Castelbón, Javier Tomás Solera, Antoni Riera-Mestre, María Barreda-Sánchez, Carlo Poci, Annamaria Nicolli, Francesco Urigo, Ana Sampedro, Rafael Enríquez de Salamanca, Matteo Marcacci, Matías A. Ávila, Pauline Harper, Marta G. Fanlo-Maresma, Encarna Guillén-Navarro, Giovanna Graziadei, Andrea Wenzel, Bodo B. Beck, Paolo Ventura, Montserrat Morales-Conejo, Antonio Fontanellas
Background
Dysfunction of δ-aminolevulinic acid dehydratase (ALAD), the second enzyme involved in heme biosynthesis, leads to two pathologies: genetic and acquired. The genetic form is an ultrarare, severe childhood-onset disease inherited in an autosomal recessive manner, whereas the acquired form usually affects adults due to enzyme inhibition by specific chemicals.
Aims and patient cohort
This study reports the molecular characterization of three pediatric patients with genetic ALAD deficiency porphyria (ADP), including two siblings, and five adults who exhibited features suggestive of heavy metal poisoning. Furthermore, using an innovative mouse liver model, we performed in vivo functional analysis of the pathogenic variants and lead susceptibility alleles identified in the ALAD gene.
Results
Siblings (one female) were found to carry the c440_441delinsTT (p.Arg147Leu) variant in homozygosis. However, the vector expression system confirmed a pathogenic role only for the c.440C > T substitution. The third patient exhibited compound heterozygosity, with a c.839G > A (p.Gly280Glu) dominant variant and a hypomorphic c.724G > A (p.Val242Ile) allele. The rs1805313 and rs8177800 common intron variants were most prevalent in patients with acquired ADP. However, increased ALAD activity for the rs1139488 synonymous variant and a hexameric ALAD conformation for the rs1800435 missense variant have been established.
Conclusion
These findings underscore the molecular heterogeneity of the ALAD gene and present the first reported case of ADP in a female patient.
背景：δ-氨基乙酰丙酸脱水酶（ALAD）是第二种参与血红素生物合成的酶，其功能障碍可导致遗传和获得性两种病理。遗传形式是一种罕见的、严重的儿童期发病疾病，以常染色体隐性遗传的方式遗传，而获得性形式通常影响成年人，由于特定化学物质的酶抑制。目的和患者队列：本研究报告了3例遗传性ALAD缺乏性卟啉症（ADP）儿童患者的分子特征，包括2名兄弟姐妹和5名表现出重金属中毒特征的成年人。此外，利用一种创新的小鼠肝脏模型，我们对ALAD基因中鉴定的致病变异和铅易感等位基因进行了体内功能分析。结果：兄弟姐妹（1名女性）在纯合子中携带c440_441delinsTT （p.a g147leu）变异。然而，载体表达系统证实只有c.440C . > T替代具有致病作用。第三例患者表现为复合杂合性，其显性等位基因为c.839G > a (p.Gly280Glu)，次胚等位基因为c.724G > a （p.Val242Ile）。rs1805313和rs8177800常见内含子变异在获得性ADP患者中最为普遍。然而，rs1139488同义变体的ALAD活性增加，rs1800435错义变体的ALAD六聚体构象已经建立。结论：这些发现强调了ALAD基因的分子异质性，并提出了首次报道的女性患者ADP病例。
{"title":"New cases of δ-aminolevulinic acid dehydratase deficiency: Functional insights into gene variants using an innovative mouse liver model","authors":"Elena Di Pierro, Isabel Solares, Daniel Jericó, Francisco J. Castelbón, Javier Tomás Solera, Antoni Riera-Mestre, María Barreda-Sánchez, Carlo Poci, Annamaria Nicolli, Francesco Urigo, Ana Sampedro, Rafael Enríquez de Salamanca, Matteo Marcacci, Matías A. Ávila, Pauline Harper, Marta G. Fanlo-Maresma, Encarna Guillén-Navarro, Giovanna Graziadei, Andrea Wenzel, Bodo B. Beck, Paolo Ventura, Montserrat Morales-Conejo, Antonio Fontanellas","doi":"10.1111/joim.70044","DOIUrl":"10.1111/joim.70044","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Dysfunction of δ-aminolevulinic acid dehydratase (ALAD), the second enzyme involved in heme biosynthesis, leads to two pathologies: genetic and acquired. The genetic form is an ultrarare, severe childhood-onset disease inherited in an autosomal recessive manner, whereas the acquired form usually affects adults due to enzyme inhibition by specific chemicals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims and patient cohort</h3>\u0000 \u0000 <p>This study reports the molecular characterization of three pediatric patients with genetic ALAD deficiency porphyria (ADP), including two siblings, and five adults who exhibited features suggestive of heavy metal poisoning. Furthermore, using an innovative mouse liver model, we performed in vivo functional analysis of the pathogenic variants and lead susceptibility alleles identified in the <i>ALAD</i> gene.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Siblings (one female) were found to carry the c440_441delinsTT (p.Arg147Leu) variant in homozygosis. However, the vector expression system confirmed a pathogenic role only for the c.440C > T substitution. The third patient exhibited compound heterozygosity, with a c.839G > A (p.Gly280Glu) dominant variant and a hypomorphic c.724G > A (p.Val242Ile) allele. The rs1805313 and rs8177800 common intron variants were most prevalent in patients with acquired ADP. However, increased ALAD activity for the rs1139488 synonymous variant and a hexameric ALAD conformation for the rs1800435 missense variant have been established.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings underscore the molecular heterogeneity of the <i>ALAD</i> gene and present the first reported case of ADP in a female patient.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 1","pages":"126-142"},"PeriodicalIF":9.2,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562063","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}
Jay B. Lusk, Vinit Nalawade, Lauren E. Wilson, Stephanie Yarnell, Ailin Song, Matthew Schrag, Sven Poli, Bradley Hammill, Fan Li, Brian Mac Grory
Background
The impact of first prescription of oral anticoagulation on ischemic stroke and major bleeding events among Medicare beneficiaries with atrial fibrillation (AF) is not known.
Methods
A retrospective, observational, cohort study was performed based on a 5% sample of United States fee-for-service Medicare beneficiaries aged ≥66 years who developed AF from 2007 to 2020. The principal exposure was first prescription of an oral anticoagulant. The primary effectiveness end point was ischemic stroke (including cerebral or retinal ischemic stroke [central retinal artery occlusion]). The primary safety end point was major bleeding. To reduce the impact of selection bias and immortal time bias, unadjusted and adjusted hazard ratios (HRs) and rate differences were computed in a dataset comprised of pooled, sequential clinical trial replicates starting 1 month apart.
Results
In total, 144,969 patients (60.8% female; mean age 77.7 years [standard deviation (SD) 7.1]) were included in the study. First prescription of oral anticoagulation was not associated with a reduced hazard of ischemic stroke (adjusted HR [aHR] 1.01 [95% confidence interval (CI): 0.97–1.05]). However, first prescription of oral anticoagulation was associated with an increased hazard of a major bleeding event (aHR 1.38 [95% CI: 1.36–1.40]) and increased hazards of intracerebral hemorrhage (ICH) and major gastrointestinal hemorrhage.
Conclusions
In this cohort study of Medicare beneficiaries aged 66 years and older with incident AF, the first anticoagulant prescription was not associated with a reduced hazard of ischemic stroke. Furthermore, unadjusted models suggested that clinicians are likely appropriately selecting patients for anticoagulation in routine clinical practice.
{"title":"Association between first anticoagulant prescription and embolic and hemorrhagic events among older adults with atrial fibrillation","authors":"Jay B. Lusk, Vinit Nalawade, Lauren E. Wilson, Stephanie Yarnell, Ailin Song, Matthew Schrag, Sven Poli, Bradley Hammill, Fan Li, Brian Mac Grory","doi":"10.1111/joim.70041","DOIUrl":"10.1111/joim.70041","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The impact of first prescription of oral anticoagulation on ischemic stroke and major bleeding events among Medicare beneficiaries with atrial fibrillation (AF) is not known.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A retrospective, observational, cohort study was performed based on a 5% sample of United States fee-for-service Medicare beneficiaries aged ≥66 years who developed AF from 2007 to 2020. The principal exposure was first prescription of an oral anticoagulant. The primary effectiveness end point was ischemic stroke (including cerebral or retinal ischemic stroke [central retinal artery occlusion]). The primary safety end point was major bleeding. To reduce the impact of selection bias and immortal time bias, unadjusted and adjusted hazard ratios (HRs) and rate differences were computed in a dataset comprised of pooled, sequential clinical trial replicates starting 1 month apart.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In total, 144,969 patients (60.8% female; mean age 77.7 years [standard deviation (SD) 7.1]) were included in the study. First prescription of oral anticoagulation was not associated with a reduced hazard of ischemic stroke (adjusted HR [aHR] 1.01 [95% confidence interval (CI): 0.97–1.05]). However, first prescription of oral anticoagulation was associated with an increased hazard of a major bleeding event (aHR 1.38 [95% CI: 1.36–1.40]) and increased hazards of intracerebral hemorrhage (ICH) and major gastrointestinal hemorrhage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In this cohort study of Medicare beneficiaries aged 66 years and older with incident AF, the first anticoagulant prescription was not associated with a reduced hazard of ischemic stroke. Furthermore, unadjusted models suggested that clinicians are likely appropriately selecting patients for anticoagulation in routine clinical practice.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 1","pages":"109-125"},"PeriodicalIF":9.2,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487275","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}
Sarah Reid, Johanna K. Sandling, Pascal Pucholt, Ahmed Sayadi, Martina Frodlund, Karoline Lerang, Iva Gunnarsson, Andreas Jönsen, Ann-Christine Syvänen, Øyvind Molberg, Solbritt Rantapää-Dahlqvist, Anna Rudin, Christopher Sjöwall, Elisabet Svenungsson, Anders A. Bengtsson, Lars Rönnblom, Dag Leonard
Background
Systemic lupus erythematosus (SLE) is an autoimmune disease with a heterogenous clinical picture. This study aimed to link genetic SLE predisposition with relevant clinical manifestations.
Method
Datasets best corresponding to the 11 American College of Rheumatology 1982 (ACR-82) classification criteria for SLE in a large, public database (FinnGen consortium, >218,000 individuals) were identified. Mendelian randomization analysis was conducted to evaluate the effect of a high genetic SLE predisposition on each manifestation. Next, validation was conducted in a clinical SLE cohort comprising 1487 genotyped Scandinavian patients with detailed clinical data. Based on the public datasets, genetic risk scores (GRSs) for each relevant manifestation were constructed for each patient. Associations between each GRS and the corresponding ACR-82 criterion were evaluated using logistic regression.
Results
In the FinnGen biobank, the cumulative effect of the 57 SLE risk SNPs was associated with an increased risk of rosacea, OR 1.09 (1.03–1.16), polyarthropathies, OR 1.10 (1.06–1.14), pleural effusions, OR 1.09 (1.04–1.14), and hemolytic anemia, OR 1.32 (1.10–1.58). In the clinical cohort, 5 of the 11 GRSs generated from the public datasets were associated with their corresponding ACR-82 criterion: arthritis, OR 1.15 (1.02–1.31), renal disorder, OR 1.15 (1.04–1.29), neurologic disorder, OR 1.24 (1.04–1.47), hematologic disorder, OR 1.12 (1.00–1.24), and immunologic disorder, OR 1.37 (1.22–1.56).
Conclusion
The findings demonstrate that known SLE risk gene variants play a role in the development of at least half of the ACR-82 criteria for SLE, indicating a future possibility of using genetics to predict a variety of disease sub-phenotypes in SLE.
{"title":"Genetic risk factors and clinical manifestations of systemic lupus erythematosus: Large-scale analysis of genetic predisposition and disease subtypes","authors":"Sarah Reid, Johanna K. Sandling, Pascal Pucholt, Ahmed Sayadi, Martina Frodlund, Karoline Lerang, Iva Gunnarsson, Andreas Jönsen, Ann-Christine Syvänen, Øyvind Molberg, Solbritt Rantapää-Dahlqvist, Anna Rudin, Christopher Sjöwall, Elisabet Svenungsson, Anders A. Bengtsson, Lars Rönnblom, Dag Leonard","doi":"10.1111/joim.70040","DOIUrl":"10.1111/joim.70040","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Systemic lupus erythematosus (SLE) is an autoimmune disease with a heterogenous clinical picture. This study aimed to link genetic SLE predisposition with relevant clinical manifestations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Datasets best corresponding to the 11 American College of Rheumatology 1982 (ACR-82) classification criteria for SLE in a large, public database (FinnGen consortium, >218,000 individuals) were identified. Mendelian randomization analysis was conducted to evaluate the effect of a high genetic SLE predisposition on each manifestation. Next, validation was conducted in a clinical SLE cohort comprising 1487 genotyped Scandinavian patients with detailed clinical data. Based on the public datasets, genetic risk scores (GRSs) for each relevant manifestation were constructed for each patient. Associations between each GRS and the corresponding ACR-82 criterion were evaluated using logistic regression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the FinnGen biobank, the cumulative effect of the 57 SLE risk SNPs was associated with an increased risk of rosacea, OR 1.09 (1.03–1.16), polyarthropathies, OR 1.10 (1.06–1.14), pleural effusions, OR 1.09 (1.04–1.14), and hemolytic anemia, OR 1.32 (1.10–1.58). In the clinical cohort, 5 of the 11 GRSs generated from the public datasets were associated with their corresponding ACR-82 criterion: arthritis, OR 1.15 (1.02–1.31), renal disorder, OR 1.15 (1.04–1.29), neurologic disorder, OR 1.24 (1.04–1.47), hematologic disorder, OR 1.12 (1.00–1.24), and immunologic disorder, OR 1.37 (1.22–1.56).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The findings demonstrate that known SLE risk gene variants play a role in the development of at least half of the ACR-82 criteria for SLE, indicating a future possibility of using genetics to predict a variety of disease sub-phenotypes in SLE.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 1","pages":"95-108"},"PeriodicalIF":9.2,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145456946","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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