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Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.
Mathey, CM, Maj, C, Eriksson, N, Krebs, K, Westmeier, J, David, FS, Koromina, M, Scheer, AB, Szabo, N, Wedi, B, et al
The Journal of allergy and clinical immunology. 2024;(4):1073-1082
Abstract
BACKGROUND Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.
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2.
A core outcome set for efficacy of acute treatment of hereditary angioedema.
Petersen, RS, Fijen, LM, Apfelbacher, C, Magerl, M, Weller, K, Aberer, W, Adatia, A, Audhya, P, Bara, NA, Betschel, S, et al
The journal of allergy and clinical immunology. In practice. 2024
Abstract
BACKGROUND Clinical trials investigating drugs for acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE To achieve consensus on a Core Outcome Set comprising key outcomes that should ideally be utilized in all clinical efficacy trials involving acute treatment of hereditary angioedema attacks. METHODS A Delphi consensus study was conducted involving all relevant parties: hereditary angioedema patients, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS Fifty-eight worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of ≥90% was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSION This international study obtained a high level of consensus on a core outcome set for acute treatment of hereditary angioedema attacks consisting of five key outcomes.
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3.
Outcomes of Systemic Treatment in Children and Adults With Netherton Syndrome: A Systematic Review.
Nouwen, AEM, Schappin, R, Nguyen, NT, Ragamin, A, Bygum, A, Bodemer, C, Dalm, VASH, Pasmans, SGMA
Frontiers in immunology. 2022;:864449
Abstract
BACKGROUND Comèl-Netherton syndrome (NS) is a rare disease caused by pathogenic variants in the SPINK5 gene, leading to severe skin barrier impairment and proinflammatory upregulation. Given the severity of the disease, treatment of NS is challenging. Current treatment regimens are mainly topical and supportive. Although novel systemic treatment options for NS have been suggested in recent literature, little is known about their outcomes. OBJECTIVE to provide an overview of systemic treatment options and their outcomes in adults and children with NS. METHODS Embase, MEDLINE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar were searched up to July 22, 2021. Empirical studies published in English language mentioning systemic treatment in NS were enrolled. Studies that did not define a treatment period or report at least one outcome were excluded. Methodological quality was evaluated by the Joanna Briggs Institute critical appraisal checklist for case reports or case series. Overall quality of evidence of the primary outcome, skin, was assessed by the GRADE approach. RESULTS 36 case series and case reports were included. The effects of 15 systemic therapies were described in 48 patients, of which 27 were children. Therapies included retinoids, prednisolone, cyclosporine, immunoglobulins, and biologicals. In retinoids both worsening (4/15 cases) and improvement (6/15 cases) of the skin was observed. Use of prednisolone and cyclosporine was only reported in one patient. Immunoglobulins (13/15 cases) and biologicals (18/21 cases) showed improvement of the skin. Certainty of evidence was rated as very low. CONCLUSION NS is a rare disease, which is reflected in the scarce literature on systemic treatment outcomes in children and adults with NS. Studies showed large heterogeneity in outcome measures. Adverse events were scarcely reported. Long-term outcomes were reported in a minority of cases. Nonetheless, a general beneficial effect of systemic treatment was found. Immunoglobulins and biologicals showed the most promising results and should be further explored. Future research should focus on determining a core outcome set and measurement instruments for NS to improve quality of research. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=217933, PROSPERO (ID: 217933).
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4.
Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.
Brüggen, MC, Le, ST, Walsh, S, Toussi, A, de Prost, N, Ranki, A, Didona, B, Colin, A, Horváth, B, Brezinova, E, et al
The British journal of dermatology. 2021;(3):616-626
Abstract
BACKGROUND Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.
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5.
Impact of red meat, processed meat and fibre intake on risk of late-onset chronic inflammatory diseases: prospective cohort study on lifestyle factors using the Danish 'Diet, Cancer and Health' cohort (PROCID-DCH): protocol.
Rasmussen, NF, Rubin, KH, Stougaard, M, Tjønneland, A, Stenager, E, Lund Hetland, M, Glintborg, B, Bygum, A, Andersen, V
BMJ open. 2019;9(3):e024555
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Free full text
Plain language summary
Chronic inflammatory diseases (CIDs) can be considered as systemic diseases which primarily affect one organ such as the intestine, skin, joints or the brain. The primary aim of this study was to investigate the impact of fibre, red meat and processed meat on disease risk outcomes of late-onset CID in the ‘Diet, Cancer and Health’ (DCH) cohort. The study is an observational prospective cohort study. The study will use data from 57,053 persons from the prospective Danish cohort study ‘Diet, Cancer and Health’ together with National Health Registry data. The study does not only target one CID but it looks at several CIDs. Furthermore, the linkage to Danish health registries will ensure almost complete follow-up of the study population since the Danish health registries are considered the internationally most comprehensive with high validity.
Abstract
INTRODUCTION Chronic inflammatory diseases (CIDs) (Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, rheumatoid arthritis and multiple sclerosis) are diseases of the immune system that have some shared genetic and environmental predisposing factors, but still few studies have investigated the effects of lifestyle on disease risk of several CIDs. The primary aim of this prospective cohort study is to investigate the impact of fibre, red meat and processed meat on risk of late-onset CID, with the perspective that results of this study can contribute in supporting future diet recommendations for effective personalised prevention. METHODS AND ANALYSIS The study will use data from 57 053 persons from the prospective Danish cohort study 'Diet, Cancer and Health' together with National Health Registry data. The follow-up period is from December 1993 to December 2018. Questionnaire data on diet and lifestyle were collected at entry to the Diet, Cancer and Health study. The outcome CID is defined as having a diagnosis of one of the CIDs registered in the National Patient Registry or, for multiple sclerosis, in the Danish Multiple Sclerosis Registry during follow-up and being treated with a drug used for the specific disease. The major outcome of the analyses will be to detect variability in risk of late onset of any CID and, if power allows, disease risk of late onset of each CID diagnosis between persons with different fibre and red meat, and processed meat intake. The outcome will be adjusted for age, sex, body mass index, physical activity, energy, alcohol, fermented dairy products, education, smoking status, hormone replacement therapy and comorbidity. ETHICS AND DISSEMINATION The study is approved by the Danish Data Protection Agency (2012-58-0018). The core study is an open register-based cohort study. The study does not need approval from the Ethics committee or Institutional Review Board by Danish law. Study findings will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences. TRIAL REGISTRATION NUMBER NCT03456206; Post-results.
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Diagnosing diabetes mellitus in patients with porphyria cutanea tarda.
Christiansen, AL, Bygum, A, Hother-Nielsen, O, Rasmussen, LM
International journal of dermatology. 2018;(7):763-769
Abstract
The prevalence of diabetes mellitus is increased in patients with porphyria cutanea tarda. Different tests are available for diagnosing and screening for type II diabetes mellitus, however choosing the most suitable test is challenging. The pitfalls in the different tests along with the interfering comorbidities and treatments concerning patients with porphyria cutanea tarda complicate diagnosing these patients with diabetes mellitus. HbA1c, fasting glucose, or oral glucose tolerance are the current available tests, with HbA1c as first choice. Measuring HbA1c requires no fasting, however HbA1c can be false low if the patient is treated with phlebotomy or has liver cirrhosis or chronic hepatitis. Instead fasting glucose and oral glucose tolerance tests can be used if the patient is not acutely ill. If either of the tests give a result in the diagnostic range, the test should be repeated if the patient has no clinical symptoms of diabetes. Diagnosing diabetes mellitus is important for the purpose of early intervention, and this review provides the knowledge needed to diagnose this special patient group properly.
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7.
[Clinical review of pseudoporphyria].
Velander, MJ, Þorsteinsdóttir, S, Bygum, A
Ugeskrift for laeger. 2015;(6)
Abstract
Pseudoporphyria is a photosensitive bullous disease, which resembles porphyria cutanea tarda. Normal porphyrin levels in urine, stool and blood define pseudoporphyria. Pseudoporphyria is associated with chronic renal failure, haemodialysis, a variety of drugs (e.g. naproxen, nabumetone, furosemide, ciprofloxacin, voriconazole, acitretin), tanning beds and UVA exposure. Treatment consists of UV protection and cessation of suspected agents. Patients in haemodialysis can benefit from treatment with N-acetylcysteine or glutathione.
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[New classification and genetic background of inherited ichthyoses].
Andersen, RE, Hertz, JM, Bygum, A
Ugeskrift for laeger. 2014;(29):V11130688
Abstract
A new classification of inherited ichthyoses is presented based on clinical features, genetic background and pathophysiology. Ichthyoses are disorders of cornification and may be part of syndromes. Ichthyosis vulgaris, X-linked ichthyosis, autosomal recessive congenital ichthyosis and syndrome-related variants are described. Severe forms can be potentially life-threatening. Dry scaly skin can be disabling and time-consuming, as the patient needs topical therapy and sometimes also systemic retinoids. Treatment today is symptomatic, but hopefully new knowledge will lead to targeted therapies.
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[Calciphylaxis].
Yderstraede, KB, Clemmensen, O, Nielsen, AM, Marckmann, P, Bygum, A
Ugeskrift for laeger. 2009;(22):1860-4
Abstract
Calciphylaxis is a serious condition including ischaemic, nodular necrosis of the subcutaneous tissue and occlusion of small and medium-sized arteries. The prevalence of calciphylaxis among patients on chronic haemodialysis constitutes 1-4 percent. The condition is associated with high mortality due to co-morbidity. Calciphylaxis seems to be preventable by optimized control of calcium-phosphorous metabolism in susceptible individuals. New and promising therapies are evolving. It is important to focus on this condition in order to provide the relevant therapy to the affected cases.