| 31. |
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| 32. |
- Oikonomou, Vasileios, et al.
(författare)
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The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.
- 2024
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Ingår i: The New England journal of medicine. - 1533-4406. ; 390:20, s. 1873-1884
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood.We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses.Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients.Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
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| 33. |
- Piehl, F., et al.
(författare)
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Cardiovascular disease in patients with multiple sclerosis : a nationwide cohort study in Sweden
- 2019
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 25:Suppl. 2, s. 49-50
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: The cardiovascular disease (CVD) rate among multiple sclerosis (MS) patients has been shown to be elevated; however, studies involving more recently diagnosed patients are rare. Here we estimated the rate of CVD in patients before and after MS diagnosis as compared with a matched MS-free population.Methods: Incident MS patients diagnosed in 2008-2016 were identified in the Swedish National Patient Register. MS patients were matched with 10 MS-free individuals by age, sex, and region of residence. Incidence rates (IR) per 10,000 person-years (PY) and incidence rate ratios (IRR) of cardiovascular outcomes were calculated after MS diagnosis (equivalent date for those without MS) and among those with no history of CVD before this date.Results: In total, 6,602 MS patients and 61,828 without MS (female, 69%; median age, 40 years) were identified. Before MS diagnosis, patients showed higher proportions of stroke (2.0% vs 0.6%), transient ischaemic attack (TIA) (0.4% vs 0.2%) and peripheral vascular disease (0.3% vs 0.2%) compared with the MS-free cohort. The year before MS diagnosis, larger proportions were prescribed diuretics (8.4% vs 6.9%), peripheral vasodilators (1.4% vs 1.0%), lipid-modifying agents (5.6% vs 4.8%), and calcium channel blockers (3.7% vs 3.1%).After MS diagnosis, patients had a higher risk of major adverse cardiovascular events (MACE) (IRR 1.35; 95% confidence interval [CI] 1.06-1.71), heart failure (HF) (IRR 1.36; 95% CI 1.02-1.80), and TIA (IRR 1.59; 95% CI 1.05-2.42) compared with the MS-free cohort. The risk of bradycardia (IRR, 2.61; 95% CI 1.14-5.97) was higher only in MS patients with no history of CVD. CVD incidence rates in MS patients were comparable between sexes except for the HF rate, which was higher among males (28.28 per 10,000 PY, 95% CI 18.79-40.87) than females (11.81 per 10,000 PY, 95% CI 7.71-17.30). The relative risk of MACE (IRR 2.40; 95% CI 1.15-5.00), TIA (IRR 7.03; 95% CI 2.62 -18.87), HF (IRR 3.28; 95% CI 1.46-7.37), and bradycardia (IRR 4.51; 95% CI 1.54-13.20) were higher among younger MS patients (aged < 40 years at diagnosis).Conclusions: After MS diagnosis, MS patients showed an increased incidence of MACE, TIA, and HF compared with those without MS, irrespective of CVD history. The age-matched rela-tive risk was particularly high among younger MS patients. In particular, the relative risk of bradycardia was only higher among younger patients and patients with no history of CVD.
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| 34. |
- Piehl, F., et al.
(författare)
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Risk of comorbidity in patients with multiple sclerosis : a nationwide cohort study in Sweden
- 2019
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 25:Suppl. 2, s. 102-102
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Substantial progress in the treatment of multiple sclerosis (MS) has been made since the 1990s. However, the presence of comorbidity and the impact of treatment are less defined. Here we determined rates of comorbidity before and after MS diagnosis as compared with a matched MS-free population.Methods: A national incident MS cohort diagnosed in 2008-2016 was identified in the Swedish National Patient Register with data further linked to the national Prescribed Drug Register and Cause of Death Register. In addition, a sub-cohort of MS patients was identified in the electronic medical records (EMR) of the Karolinska University Hospital. MS patients were matched with and compared to 10 MS-free individuals by age, sex, and region of residence. Incidence rates (IR) per 10,000 person-years and incidence rate ratios (IRR) of comorbidities were calculated after MS diagnosis.Results: In total, 6,602 MS patients were identified in the national cohort and were compared with 61,828 MS-free controls (female, 69%; median age, 40 years), while a sub-cohort from one hospital of 1,289 patients had a MS diagnosis recorded in EMR and was compared with 11,721 individuals without MS (female, 68%; median age, 37 years). The national MS cohort had higher proportions before MS diag-nosis compared with MS-free controls of autoimmune disease (1.3% vs 0.7%), bladder dysfunction (1.2% vs 0.2%), retinal disorders (2.4% vs 1.2%) and epilepsy (1.5% vs 0.8%). Similar patterns were observed for the single-hospital cohort, except for epilepsy. Bipolar disorder was more common among single-hospital MS patients (1.6% vs 0.7%).After MS diagnosis, patients in the national cohort had higher IR compared with MS-free controls of autoimmune disease (IRR 3.60; 95% confidence interval [CI], 2.88-4.51), bladder dysfunction (IRR 47.44; 95% CI, 36.81-61.14) and epilepsy (IRR 2.36; 95% CI, 1.75-3.17). Similar patterns were observed in the single-hospital cohort. Toxic liver disease was higher (IRR 3.51; 95% CI 1.37-8.98) in the MS cohort in the national cohort only, while bipolar disorder was higher only in the single-hospital cohort (IRR 1.88; 95% CI 1.10-3.22).Conclusions: Before a diagnosis of MS, patients already displayed an increased rate of comorbidity compared with MS-free controls. After diagnosis, patients with MS continued to display increased risk of several comorbidities, some of which may be explained by surveillance bias due to more frequent contact with healthcare.
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| 35. |
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| 36. |
- Pinto, Ana Margarida, et al.
(författare)
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Emotion regulation and the salience network : a hypothetical integrative model of fibromyalgia
- 2023
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Ingår i: Nature Reviews Rheumatology. - : Springer Nature. - 1759-4790 .- 1759-4804. ; 19:1, s. 44-60
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Tidskriftsartikel (refereegranskat)abstract
- Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances and other symptoms, and has a substantial socioeconomic impact. Current biomedical and psychosocial treatments are unsatisfactory for many patients, and treatment progress has been hindered by the lack of a clear understanding of the pathogenesis of fibromyalgia. We present here a model of fibromyalgia that integrates current psychosocial and neurophysiological observations. We propose that an imbalance in emotion regulation, reflected by an overactive 'threat' system and underactive 'soothing' system, might keep the 'salience network' (also known as the midcingulo-insular network) in continuous alert mode, and this hyperactivation, in conjunction with other mechanisms, contributes to fibromyalgia. This proposed integrative model, which we term the Fibromyalgia: Imbalance of Threat and Soothing Systems (FITSS) model, should be viewed as a working hypothesis with limited supporting evidence available. We hope, however, that this model will shed new light on existing psychosocial and biological observations, and inspire future research to address the many gaps in our knowledge about fibromyalgia, ultimately stimulating the development of novel therapeutic interventions.
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| 37. |
- Pinto, Ana Margarida, et al.
(författare)
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Neurophysiological and psychosocial mechanisms of fibromyalgia : A comprehensive review and call for an integrative model
- 2023
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Ingår i: Neuroscience and Biobehavioral Reviews. - : Elsevier. - 0149-7634 .- 1873-7528. ; 151
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Forskningsöversikt (refereegranskat)abstract
- Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fi-bromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the under-standing, assessment, and intervention for fibromyalgia.
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