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Avouac J, Ait-Oufella H, Habauzit C, Benkhalifa S, Combe B. The Cardiovascular Safety of Tumour Necrosis Factor Inhibitors in Arthritic Conditions: A Structured Review with Recommendations. Rheumatol Ther 2025; 12:211-236. [PMID: 40019616 PMCID: PMC11920476 DOI: 10.1007/s40744-025-00753-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 02/13/2025] [Indexed: 03/01/2025] Open
Abstract
There is accumulating evidence that inflammation is a key driver of atherosclerosis development and thrombotic complications. This pathophysiological mechanism explains, at least in part, the increased cardiovascular risk of patients with immune-mediated arthritis. Experimental and clinical studies have shown that tumour necrosis factor (TNF) plays a pathological role in both vascular and joint diseases, suggesting that TNF inhibitors (TNFis) may limit cardiovascular events in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or spondyloarthritis (SpA). This review summarizes studies exploring the effects of TNFis on cardiovascular outcomes in patients with RA, PsA or SpA. Clinical studies suggest that TNFis reduce vascular inflammation and may improve (or prevent worsening of) endothelial dysfunction and arterial stiffness. There is evidence that TNFis reduce the incidence of cardiovascular events in patients with inflammatory arthritis compared with non-biological treatments, particularly in patients with rheumatoid arthritis. Fewer studies have compared the effects of different classes of biological therapy on outcomes, but found no significant difference in the risk of cardiovascular events between patients taking TNFis and other biological therapy. In contrast, patients at high cardiovascular risk may derive greater benefit from a TNFi than from a Janus kinase inhibitor (JAKi). The cardiovascular impact of JAKis is still under debate, with a recent safety warning. Targeted control of inflammation is a key strategy to reduce the risk of major adverse cardiovascular events in patients with inflammatory arthritis. Cardiovascular evaluation and risk stratification, using a multidisciplinary approach involving rheumatology and cardiology teams, are recommended to guide optimal immunomodulatory treatment.
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Affiliation(s)
- Jérôme Avouac
- Service de Rhumatologie, Hôpital Cochin, AP-HP, Centre-Université Paris Cité, Université de Paris, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France.
| | - Hafid Ait-Oufella
- INSERM U970, Paris Cardiovascular Research Center, Université Paris Cité, Paris, France
- Service de Médecine Intensive-Réanimation, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, Paris, France
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Marín-Jiménez I, Carpio D, Hernández V, Muñoz F, Zatarain-Nicolás E, Zabana Y, Mañosa M, Rodríguez-Moranta F, Barreiro-de Acosta M, Gutiérrez Casbas A. Spanish Working Group in Crohn's Disease and Ulcerative Colitis (GETECCU) position paper on cardiovascular disease in patients with inflammatory bowel disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2024:502314. [PMID: 39615874 DOI: 10.1016/j.gastrohep.2024.502314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 11/24/2024] [Indexed: 01/12/2025]
Abstract
Cardiovascular diseases (CVD) are the leading cause of death worldwide. Therefore, it is essential to understand their relationship and prevalence in different diseases that may present specific risk factors for them. The objective of this document is to analyze the specific prevalence of CVD in patients with inflammatory bowel disease (IBD), describing the presence of classical and non-classical cardiovascular risk factors in these patients. Additionally, we will detail the pathophysiology of atherosclerosis in this patient group and the different methods used to assess cardiovascular risk, including the use of risk calculators in clinical practice and different ways to assess subclinical atherosclerosis and endothelial dysfunction. Furthermore, we will describe the potential influence of medication used for managing patients with IBD on cardiovascular risk, as well as the potential influence of commonly used drugs for managing CVD on the course of IBD. The document provides comments and evidence-based recommendations based on available evidence and expert opinion. An interdisciplinary group of gastroenterologists specialized in IBD management, along with a consulting cardiologist for this type of patients, participated in the development of these recommendations by the Spanish Group of Work on Crohn's Disease and Ulcerative Colitis (GETECCU).
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Affiliation(s)
- Ignacio Marín-Jiménez
- Sección de Gastroenterología, Servicio de Aparato Digestivo, Instituto de Investigación Sanitaria (IiSGM), Hospital General Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, España.
| | - Daniel Carpio
- Servicio de Aparato Digestivo, Complexo Hospitalario Universitario de Pontevedra, Pontevedra, España; Grupo de Investigación en Hepatología-Enfermedades Inflamatorias Intestinales, Instituto de Investigación Sanitaria Galicia Sur (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Pontevedra, España
| | - Vicent Hernández
- Servicio de Aparato Digestivo, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, Vigo, Pontevedra, España; Grupo de Investigación en Patología Digestiva, Instituto de Investigación Sanitaria Galicia Sur (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Pontevedra, España
| | - Fernando Muñoz
- Servicio de Digestivo. Complejo Asistencial Universitario de Salamanca, Salamanca, España
| | - Eduardo Zatarain-Nicolás
- Servicio de Cardiología, Instituto de Investigación Sanitaria (IiSGM), Hospital General Universitario Gregorio Marañón, Madrid; CIBERCV, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Universidad Complutense de Madrid, Madrid, España
| | - Yamile Zabana
- Servicio de Aparato Digestivo, Hospital Universitari Mútua Terrassa; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Terrasa, Barcelona, España
| | - Míriam Mañosa
- Servicio de Aparato Digestivo, Hospital Universitari Germans Trias; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Badalona, Barcelona, España
| | - Francisco Rodríguez-Moranta
- Servicio de Aparato Digestivo, Hospital Universitario de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, España
| | - Manuel Barreiro-de Acosta
- Servicio de Gastroenterología, Hospital Clínico Universitario de Santiago, A Coruña, España; Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña, España
| | - Ana Gutiérrez Casbas
- Servicio Medicina Digestiva, Hospital General Universitario Dr Balmis de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), CIBERehd, Alicante, España
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Huang D, Zhong X, Jiang Y, Kong L, Ma R, Lu J, Li Y, Shi Y. Insulin resistance impairs biologic agent response in moderate-to-severe plaque psoriasis: insights from a prospective cohort study in China. Br J Dermatol 2024; 191:616-623. [PMID: 38634691 DOI: 10.1093/bjd/ljae147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 03/26/2024] [Accepted: 03/29/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND Psoriasis and insulin resistance (IR) are closely related, but it remains unclear whether IR affects the treatment of patients with psoriasis. OBJECTIVE To investigate whether IR impairs the treatment response to biologic agents in patients with moderate-to-severe plaque psoriasis. METHODS This project was based on a prospective cohort study design. Data were collected from the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH), which is a prospective cohort exploring treatment strategies for psoriasis in China. IR was assessed using triglyceride glucose-body mass index (TyG-BMI). Psoriasis severity was assessed using Psoriasis Area and Severity Index (PASI) and Physician Global Assessment (PGA). Multiple logistic regression was used to explore the differences between patients with high and low levels of IR. Subgroup and sensitivity analyses were performed to examine the robustness of the study results. RESULTS A total of 290 patients were included in the analysis. Based on median TyG-BMI, the patients were divided into two groups: high and low IR. The high IR group exhibited a higher prevalence of diabetes, a higher BMI, and higher fasting blood glucose and triglyceride levels than the low IR group. Further analysis of treatment efficacy revealed that patients in the high IR group had lower PASI 75 [≥ 75% improvement in Psoriasis Area and Severity Index (PASI)], PASI 90 (≥ 90% improvement in PASI) and PGA 0/1 ('clear' or 'almost clear') response rates after 12 weeks of treatment. In the low IR group, 81.9% of patients achieved PASI 75, 58.3% achieved PASI 90 and 75.7% achieved PGA 0/1. However, the proportion of responses at each endpoint was significantly lower in the high IR group compared with the low IR group. The reduced PGA 0/1 response rate was more significant in the high IR group, indicated by lower odd ratios. Subsequent subgroup and sensitivity analyses produced consistent results. CONCLUSION IR is associated with lower effectiveness of biologics in patients with psoriasis.
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Affiliation(s)
- Dawei Huang
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Xiaoyuan Zhong
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Yuxiong Jiang
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Luyang Kong
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Rui Ma
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Jiajing Lu
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Ying Li
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
| | - Yuling Shi
- Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
- Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China
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Varra FN, Varras M, Varra VK, Theodosis-Nobelos P. Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation‑mediating treatment options (Review). Mol Med Rep 2024; 29:95. [PMID: 38606791 PMCID: PMC11025031 DOI: 10.3892/mmr.2024.13219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/17/2024] [Indexed: 04/13/2024] Open
Abstract
Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co‑morbidities, including type‑2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular diseases, non‑alcoholic fatty liver disease, kidney diseases, respiratory disorders, sleep apnea, musculoskeletal disorders and osteoarthritis, subfertility, psychosocial problems and certain types of cancers. The underlying inflammatory mechanisms interconnecting obesity with metabolic dysfunction are not completely understood. Increased adiposity promotes pro‑inflammatory polarization of macrophages toward the M1 phenotype, in adipose tissue (AT), with subsequent increased production of pro‑inflammatory cytokines and adipokines, inducing therefore an overall, systemic, low‑grade inflammation, which contributes to metabolic syndrome (MetS), insulin resistance (IR) and T2DM. Targeting inflammatory mediators could be alternative therapies to treat obesity, but their safety and efficacy remains to be studied further and confirmed in future clinical trials. The present review highlights the molecular and pathophysiological mechanisms by which the chronic low‑grade inflammation in AT and the production of reactive oxygen species lead to MetS, IR and T2DM. In addition, focus is given on the role of anti‑inflammatory agents, in the resolution of chronic inflammation, through the blockade of chemotactic factors, such as monocytes chemotractant protein‑1, and/or the blockade of pro‑inflammatory mediators, such as IL‑1β, TNF‑α, visfatin, and plasminogen activator inhibitor‑1, and/or the increased synthesis of adipokines, such as adiponectin and apelin, in obesity‑associated metabolic dysfunction.
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Affiliation(s)
- Fani-Niki Varra
- Department of Pharmacy, School of Health Sciences, Frederick University, Nicosia 1036, Cyprus
- Medical School, Dimocritus University of Thrace, Alexandroupolis 68100, Greece
| | - Michail Varras
- Fourth Department of Obstetrics and Gynecology, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece
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Rakha A, Rasheed H, Altemimi AB, Tul-Muntaha S, Fatima I, Butt MS, Hussain S, Bhat ZF, Mousavi Khaneghah A, Aadil RM. Tapping the nutraceutical potential of industrial hemp against arthritis and diabetes - A comprehensive review. FOOD BIOSCI 2024; 59:104195. [DOI: 10.1016/j.fbio.2024.104195] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Lim WS, Teoh SE, Tang ASP, Tan BJM, Lee JY, Yau CE, Thumboo J, Ng QX. The effects of anti-TNF-α biologics on insulin resistance and insulin sensitivity in patients with rheumatoid arthritis: An update systematic review and meta-analysis. Diabetes Metab Syndr 2024; 18:103001. [PMID: 38604059 DOI: 10.1016/j.dsx.2024.103001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 03/29/2024] [Accepted: 03/31/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND AND AIM Increasing evidence demonstrates a link between the chronic inflammatory state in patients with rheumatoid arthritis (RA) and the development of insulin resistance. It is thought that anti-TNF-α biologic therapy may improve insulin sensitivity and ameliorate insulin resistance by the downregulation of inflammatory cytokines, however, pre-clinical and clinical studies have yielded conflicting results. A meta-analysis on this topic is necessary to summarize current evidence and generate hypotheses for future research. METHODS Literature search was performed in four databases, namely PubMed, EMBASE, Scopus, and The Cochrane Library, from inception till April 9, 2023, querying studies reporting peripheral insulin resistance with and without anti-TNF-α use in patients with RA. Peripheral insulin resistance or sensitivity was quantified by the Homeostasis Model Assessment of Insulin Resistance (HOMA) index or the Quantitative Insulin Sensitivity Check Index (QUICKI) respectively. The difference in insulin resistance or sensitivity between the treatment and control group was calculated using standardized mean difference (SMD) for the purposes of the meta-analysis. RESULTS Twelve articles were reviewed, with 10 longitudinal studies with a total of 297 patients included in the meta-analysis. The pooled standardized mean difference (SMD) from baseline HOMA was -0.82 (95% CI: -1.38 to -0.25) suggesting significant beneficial effects of anti-TNF-α therapy on insulin resistance. CONCLUSION Current evidence supports the significant clinical efficacy of anti-TNF-α biologics in alleviating insulin resistance and improving insulin sensitivity in patients with active RA.
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Affiliation(s)
- Wei Shyann Lim
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Seth En Teoh
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ansel Shao Pin Tang
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Beatrice Jia Min Tan
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jasmine Yiling Lee
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Chun En Yau
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Julian Thumboo
- Health Services Research Unit, Singapore General Hospital, Singapore; SingHealth Duke-NUS Medicine Academic Clinical Programme, Duke-NUS Medical School, Singapore
| | - Qin Xiang Ng
- Health Services Research Unit, Singapore General Hospital, Singapore; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
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Elazab SA, Elsayed WE, Alrahim NM, Elsaid MA, Akab SM, Mohammed Enayet AAE, Mohamed MSE, Elazab SA, Sonbol MM, Fath Allah RM. Relationship between Triglyceride-Glucose Index and Disease Activity and Subclinical Atherosclerosis in Rheumatoid Arthritis. Curr Rheumatol Rev 2024; 20:191-199. [PMID: 37873948 DOI: 10.2174/0115733971259984230922054439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 08/11/2023] [Accepted: 08/21/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND In rheumatoid arthritis (RA), insulin resistance (IR) is related to inflammatory markers, disease activity, and progression of atherosclerotic changes. Triglyceride-glucose (TyG) index is a relatively new indicator of IR. AIMS The present study aimed to investigate the relationship between TyG index, disease activity and subclinical atherosclerosis (SCA) in RA patients. METHODS The present case-control study included 100 RA patients and 50 age- and sex-matched healthy controls. All participants were subjected to careful history taking through clinical examination and standard laboratory assessment. The TyG index was calculated as TyG index = ln (Fasting triglyceride (mg/dL) × fasting glucose (mg/dL))/2. Carotid intima-media thickness (CIMT) measurement was done using B-mode ultrasound. RESULTS Patients had significantly higher TyG index as compared to controls. Patients with high disease activity had significantly higher frequency of extraarticular manifestations (39.6% versus 51.6%, p = 0.028), higher Larsen score (3.8 ± 1.3 versus 2.8 ± 1.2, p < 0.001), higher anti-cyclic citrullinated peptide (anti-CCP) levels (median (IQR): 243.1 (205.0-408.0) U/ml versus 99.0 (78.0-332.5), p < 0.001), higher TyG index (4.8 ± 0.22 versus 4.67 ± 0.24, p = 0.006), and higher CIMT (0.87 ± 0.22 versus 0.77 ± 0.17 mm, p = 0.018). Patients with SCA had higher BMI (34.6 ± 6.2 versus 30.5 ± 5.3 Kg/m2, p < 0.001), higher Larsen score (3.7 ± 1.4 versus 3.1 ± 1.3, p = 0.028) and higher TyG index (4.89 ± 0.23 versus 4.64 ± 0.19, p < 0.001). Binary logistic regression analysis identified patients' age (OR (95% CI): 0.94 (0.89-0.99), p = 0.018), Larsen score (OR (95% CI): 1.93 (1.32-2.82), p = <0.001), anti-CCP (OR (95%): 1.04 (1.02-1.07), p = 0.032), and TyG index (OR (95% CI): 22.67 (2.14-240.4), p = 0.01) as significant predictors of high disease activity in multivariate analysis. CONCLUSION IR estimated by the TyG index is related to disease activity and SCA in RA patients.
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Luciano N, Barone E, Timilsina S, Gershwin ME, Selmi C. Tumor Necrosis Factor Alpha Inhibitors and Cardiovascular Risk in Rheumatoid Arthritis. Clin Rev Allergy Immunol 2023; 65:403-419. [PMID: 38157095 DOI: 10.1007/s12016-023-08975-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/01/2023] [Indexed: 01/03/2024]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by an increased risk of cardiovascular events, due to the complex interplay between traditional and disease-related risk factors. Chronic inflammation and persistent disease activity are the key determinants of this risk, but despite great improvement in the disease management and prognosis, cardiovascular events are still the main cause of morbidity and mortality in RA cohorts1. In the last decades, the advent of new biological and targeted-synthetic DMARDs was accompanied by an improvement in disease activity control, but the role of each class of drugs on CVD risk is still a matter a debate. Since their approval for RA treatment, tumor necrosis factor alpha (TNFα) inhibitors have been widely investigated to better understand their effects on cardiovascular outcomes. The hypothesis that the reduction of chronic inflammation with any treatment may reduce the cardiovascular risk has been recently confuted by the direct comparison of TNFα-inhibitors and JAK inhibitors in patients with RA and coexisting risk factors for cardiovascular disease. The aim of this literature review is to add to the available evidence to analyze the relationship between TNFα-inhibitors and CVD risk in patients with RA and also provide some clinical scenarios to better explain the treatment dilemmas. In particular, while data on major cardiovascular events and thromboembolism seem consistent with an inflammation-mediated benefit with TNFα-inhibitors, there remain concerns about the use of this class of bDMARDs in patients with chronic heart failure.
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Affiliation(s)
- Nicoletta Luciano
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Elisa Barone
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Suraj Timilsina
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, USA
| | - Carlo Selmi
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy.
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
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Macáková K, Tekeľová M, Mlynáriková V, Šebeková K, Vlková B, Celec P, Šteňová E. Metabolic Effects of Anti-TNF-α Treatment in Rheumatoid Arthritis. Diseases 2023; 11:164. [PMID: 37987275 PMCID: PMC10660495 DOI: 10.3390/diseases11040164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/03/2023] [Accepted: 11/04/2023] [Indexed: 11/22/2023] Open
Abstract
Rheumatoid arthritis (RA) is associated with high cardiovascular mortality. It is not clear whether the metabolic consequences of chronic inflammation are involved. Biological disease-modifying anti-rheumatic drugs (bDMARDs) are highly efficient in the treatment of inflammation in RA. In this study, we aimed to describe the metabolic effects of anti-TNF-α treatment in RA patients. The clinical status of 16 patients was assessed using disease activity score-28 (DAS28) and C-reactive protein (CRP). Plasma samples were collected before treatment with anti-TNF-α treatment as well as after three and six months of treatment. Markers of lipid and glucose metabolism, as well as renal biomarkers, were assessed using standard biochemistry. ELISA was used for the quantification of insulin, leptin, and adiponectin. Although fasting insulin decreased by 14% at the end of the study, most of the analyzed parameters did not show any statistically or clinically significant dynamics. The exception was total bilirubin and cholesterol, which increased by 53% and 14%, respectively, after six months of treatment with anti-TNF-α treatment. Anti-TNF-α treatment did not induce major metabolic changes despite the strong anti-inflammatory and clinical symptoms of RA. Further studies will show whether longer observations are required for the detection of the metabolic effects of the anti-inflammatory treatment. Additional research is needed to understand the observed effect of bilirubin as an important endogenous antioxidant.
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Affiliation(s)
- Kristína Macáková
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia; (K.M.); (M.T.); (K.Š.); (B.V.)
| | - Mária Tekeľová
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia; (K.M.); (M.T.); (K.Š.); (B.V.)
| | | | - Katarína Šebeková
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia; (K.M.); (M.T.); (K.Š.); (B.V.)
| | - Barbora Vlková
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia; (K.M.); (M.T.); (K.Š.); (B.V.)
| | - Peter Celec
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia; (K.M.); (M.T.); (K.Š.); (B.V.)
- Institute of Pathophysiology, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
| | - Emöke Šteňová
- 1st Department of Internal Medicine, Faculty of Medicine, University Hospital, Comenius University, Mickiewiczova 13, 82101 Bratislava, Slovakia;
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Sobieh BH, El-Mesallamy HO, Kassem DH. Beyond mechanical loading: The metabolic contribution of obesity in osteoarthritis unveils novel therapeutic targets. Heliyon 2023; 9:e15700. [PMID: 37180899 PMCID: PMC10172930 DOI: 10.1016/j.heliyon.2023.e15700] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/16/2023] Open
Abstract
Osteoarthritis (OA) is a prevalent progressive disease that frequently coexists with obesity. For several decades, OA was thought to be the result of ageing and mechanical stress on cartilage. Researchers' perspective has been greatly transformed when cumulative findings emphasized the role of adipose tissue in the diseases. Nowadays, the metabolic effect of obesity on cartilage tissue has become an integral part of obesity research; hoping to discover a disease-modifying drug for OA. Recently, several adipokines have been reported to be associated with OA. Particularly, metrnl (meteorin-like) and retinol-binding protein 4 (RBP4) have been recognized as emerging adipokines that can mediate OA pathogenesis. Accordingly, in this review, we will summarize the latest findings concerned with the metabolic contribution of obesity in OA pathogenesis, with particular emphasis on dyslipidemia, insulin resistance and adipokines. Additionally, we will discuss the most recent adipokines that have been reported to play a role in this context. Careful consideration of these molecular mechanisms interrelated with obesity and OA will undoubtedly unveil new avenues for OA treatment.
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Affiliation(s)
- Basma H. Sobieh
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Hala O. El-Mesallamy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
- Faculty of Pharmacy, Sinai University, Sinai, Egypt
| | - Dina H. Kassem
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
- Corresponding author. Associate Professor of Biochemistry Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, street of African Union Organization, 11566, Cairo, Egypt.
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Effects of biologic and target synthetic disease-modifying anti-rheumatic drugs on sarcopenia in spondyloarthritis and rheumatoid arthritis: a systematic review and meta-analysis. Clin Rheumatol 2023; 42:979-997. [PMID: 36462127 DOI: 10.1007/s10067-022-06454-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 12/04/2022]
Abstract
Sarcopenia is a syndrome defined by generalized and progressive loss of skeletal muscle mass, strength, and function. Besides affecting elderly population, it is actually common among inflammatory rheumatic diseases (IRD) patients. We performed a systematic literature review with a meta-analysis to investigate the influence of biologic and target synthetic disease-modifying anti-rheumatic drugs (bDMARDs/tsDMARDs) on sarcopenia in IRD. A systematic search has been performed on Pubmed, Scopus, and Web of science. Studies characteristics were collected. Assessment tools were body composition (total lean mass (TLM) and percentage, appendicular skeletal mass (ASM), fat-free mass and index (FFM and FFMI), skeletal mass index (SMI) and segmental lean mass (SLM)), and muscle strength and physical performance tests. Treatment effect defined the difference in change from baseline to the end of follow-up treatment was divided by the pooled SD of the difference. Twenty-two studies on 778 patients receiving bDMARDs/tsDMARDs and 157 controls were reviewed. They investigated rheumatoid arthritis (RA) (N = 14), spondyloarthritis (SpA) (N = 6), psoriatic arthritis (N = 1), and both RA and SpA (N = 1). tsDMARDs were used in one study with no effect on sarcopenia. Ten studies demonstrated that bDMARDs increased significantly muscle measures in 347 patients (44.6%) with a significant increase in TLM (6/15 studies; 57.4%), FFMI (4/6 studies; 59.9%), ASM (2/5 studies; 17.6%), SMI (2/5 studies; 18.1%), and SLM (2/2 studies; 3.6%). bDMARDs showed also a positive effect on handgrip strength in 1/3 of studies (45.2%) and on physical performance in 1/2 of studies (61%). In 1/5 of comparative studies, IRD patients on bDMARDs showed significantly higher increase of TLM in comparison to controls naïve bDMARDs. Regarding diagnosis, positive effect of bDMARDs was seen in 67.4% in SpA versus 49.3% in RA, with a significant increase of TLM, ASM and FFMI in 59.4%, 100%, and 65.2% in SpA versus 54.9%, 24.1%, and 54.8% in RA, respectively. Meta-analysis assessed the effect of bDMARD on TLM in 10 studies. There was no statistically significant difference [SMD - 0.10 (95% Confidence Interval - 0.26 - 0.06; tau2 = 0). Heterogeneity across studies was null, and the 95% confidence interval (index of precision) was equal to the 95% predictive interval. The first systematic literature review showed that bDMARDs have a significant improve effect in nearly half of RA and SpA patients on muscle mass and muscle strength, assessed separately. However, the meta-analysis concluded that bDMARDs have no significant effect on TLM.
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Carneiro ADA, Sinoti SBP, de Freitas MM, Simeoni LA, Fagg CW, Magalhães PDO, Silveira D, Fonseca-Bazzo YM. Hydroethanolic Extract of Morus nigra L. Leaves: A Dual PPAR-α/γ Agonist with Anti-Inflammatory Properties in Lipopolysaccharide-Stimulated RAW 264.7. PLANTS (BASEL, SWITZERLAND) 2022; 11:plants11223147. [PMID: 36432875 PMCID: PMC9693183 DOI: 10.3390/plants11223147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/08/2022] [Accepted: 11/15/2022] [Indexed: 05/14/2023]
Abstract
Inhibition of systemic inflammation has been a beneficial strategy in treating several non-communicable diseases, which represent one of the major causes of mortality in the world. The Peroxisome Proliferator-Activated Receptors (PPAR) are interesting pharmacological targets, since they can act both through the metabolic and anti-inflammatory pathways. Morus nigra L. has flavonoids in its chemical composition with recognized anti-oxidant activity and often associated with anti-inflammatory activity. Therefore, this study aimed to evaluate the hydroethanolic extract of M. nigra leaves' ability to activate PPAR and promote anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated murine macrophage cells. The leaf extract was prepared by cold maceration, and the chemical profile was obtained by HPLC-DAD. Activation of PPAR α and γ was evaluated by the luciferase reporter assay. The anti-inflammatory activity was assessed by measuring the reactive oxygen species (ROS), nitric oxide (NO), and Tumor Necrosis Factor-α (TNF-α) in RAW 264.7 cells after stimulation with LPS from Escherichia coli. The HPLC-DAD analysis identified two major compounds: rutin and isoquercitrin. The extract showed agonist activity for the two types of PPAR, α and γ, although its major compounds, rutin and isoquercitrin, did not significantly activate the receptors. In addition, the extract significantly reduced the production of ROS, NO, and TNF-α. Treatment with the specific PPAR-α antagonist, GW 6471, was able to partially block the anti-inflammatory effect caused by the extract.
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Affiliation(s)
- Amanda de Assis Carneiro
- Natural Products Laboratory, Department of Pharmacy, Health Sciences School, University of Brasília (UnB), Campus Darcy Ribeiro, Asa Norte, Brasilia 70910-900, Brazil
| | - Simone Batista Pires Sinoti
- Molecular Pharmacology Laboratory, Department of Pharmacy, Health Sciences School, University of Brasília (UnB), Campus Darcy Ribeiro, Asa Norte, Brasilia 70910-900, Brazil
| | - Marcela Medeiros de Freitas
- Natural Products Laboratory, Department of Pharmacy, Health Sciences School, University of Brasília (UnB), Campus Darcy Ribeiro, Asa Norte, Brasilia 70910-900, Brazil
| | - Luiz Alberto Simeoni
- Molecular Pharmacology Laboratory, Department of Pharmacy, Health Sciences School, University of Brasília (UnB), Campus Darcy Ribeiro, Asa Norte, Brasilia 70910-900, Brazil
| | - Christopher William Fagg
- Department of Botany, Institute of Biological Science, School of Pharmacy, Ceilândia Campus, University of Brasília, Brasilia 70910-900, Brazil
| | - Pérola de Oliveira Magalhães
- Natural Products Laboratory, Department of Pharmacy, Health Sciences School, University of Brasília (UnB), Campus Darcy Ribeiro, Asa Norte, Brasilia 70910-900, Brazil
| | - Dâmaris Silveira
- Natural Products Laboratory, Department of Pharmacy, Health Sciences School, University of Brasília (UnB), Campus Darcy Ribeiro, Asa Norte, Brasilia 70910-900, Brazil
| | - Yris Maria Fonseca-Bazzo
- Natural Products Laboratory, Department of Pharmacy, Health Sciences School, University of Brasília (UnB), Campus Darcy Ribeiro, Asa Norte, Brasilia 70910-900, Brazil
- Correspondence:
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Evangelatos G, Bamias G, Kitas GD, Kollias G, Sfikakis PP. The second decade of anti-TNF-a therapy in clinical practice: new lessons and future directions in the COVID-19 era. Rheumatol Int 2022; 42:1493-1511. [PMID: 35503130 PMCID: PMC9063259 DOI: 10.1007/s00296-022-05136-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 04/12/2022] [Indexed: 11/22/2022]
Abstract
Since the late 1990s, tumor necrosis factor alpha (TNF-α) inhibitors (anti-TNFs) have revolutionized the therapy of immune-mediated inflammatory diseases (IMIDs) affecting the gut, joints, skin and eyes. Although the therapeutic armamentarium in IMIDs is being constantly expanded, anti-TNFs remain the cornerstone of their treatment. During the second decade of their application in clinical practice, a large body of additional knowledge has accumulated regarding various aspects of anti-TNF-α therapy, whereas new indications have been added. Recent experimental studies have shown that anti-TNFs exert their beneficial effects not only by restoring aberrant TNF-mediated immune mechanisms, but also by de-activating pathogenic fibroblast-like mesenchymal cells. Real-world data on millions of patients further confirmed the remarkable efficacy of anti-TNFs. It is now clear that anti-TNFs alter the physical course of inflammatory arthritis and inflammatory bowel disease, leading to inhibition of local and systemic bone loss and to a decline in the number of surgeries for disease-related complications, while anti-TNFs improve morbidity and mortality, acting beneficially also on cardiovascular comorbidities. On the other hand, no new safety signals emerged, whereas anti-TNF-α safety in pregnancy and amid the COVID-19 pandemic was confirmed. The use of biosimilars was associated with cost reductions making anti-TNFs more widely available. Moreover, the current implementation of the "treat-to-target" approach and treatment de-escalation strategies of IMIDs were based on anti-TNFs. An intensive search to discover biomarkers to optimize response to anti-TNF-α treatment is currently ongoing. Finally, selective targeting of TNF-α receptors, new forms of anti-TNFs and combinations with other agents, are being tested in clinical trials and will probably expand the spectrum of TNF-α inhibition as a therapeutic strategy for IMIDs.
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Affiliation(s)
- Gerasimos Evangelatos
- Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
| | - Giorgos Bamias
- Gastrointestinal Unit, Third Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - George D Kitas
- Department of Rheumatology, Russells Hall Hospital, Dudley Group NHS Foundation Trust, Dudley, UK
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, UK
| | - George Kollias
- Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Institute for Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Petros P Sfikakis
- Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Zhou Y, Xie W, Wang L, Zhu X, Li J, Liu L, Zhu S, Wang L. Anti-tumor Necrosis Factor-Alpha Therapy and Hypoglycemia: A Real-World Pharmacovigilance Analysis. Drug Saf 2022; 45:951-959. [PMID: 35857191 DOI: 10.1007/s40264-022-01210-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 12/23/2022]
Abstract
INTRODUCTION An association between tumor necrosis factor (TNF)-α inhibitors and hypoglycemia has been detected in a few case reports and small case series; however, no relevant pharmacovigilance data have been published yet. OBJECTIVE The objective of this study was to detect and characterize relevant safety signals between hypoglycemia and TNF-α inhibitor use. METHODS Indication-focused disproportionality analysis was conducted to detect increased reporting of TNF-α-associated hypoglycemia compared with all other reports with the same indication during the same time period. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated to determine disproportionality. To reduce potential confounding factors, adjusted RORs were further calculated by logistic regression to control for age, sex, diabetes status, and concomitant drugs that potentially affect blood glucose levels. RESULTS In all, 1086 adverse drug reactions related to TNF-α inhibitors were reported as 'hypoglycemia'. There were no disproportionality signals of hypoglycemia in TNF-α inhibitor users with indication of inflammatory bowel disease. When TNF-α inhibitors were considered as a class, disproportion for hypoglycemia only emerged in indication of psoriasis (n = 267, ROR 1.20, 95% CI 1.02-1.41). In further analyses of specific TNF-α inhibitor type, significant RORs for hypoglycemia were found in indication of rheumatic disease, including adalimumab in ankylosing spondylitis (n = 37, ROR 1.97, 95% CI 1.28-3.04), psoriasis (n = 160, ROR 1.64, 95% CI 1.37-1.97), and rheumatoid arthritis (n = 230, ROR 1.35, 95% CI 1.16-1.56) and infliximab in psoriasis (n = 18, ROR 2.14, 95% CI 1.33-3.42). After adjusting for confounding factors, only the signals of adalimumab were stable. CONCLUSIONS Our study identified some potential pharmacovigilance signals between hypoglycemia and TNF-α inhibitors, which warrants further validation.
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Affiliation(s)
- Yu Zhou
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Wenhuo Xie
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Linyao Wang
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Xinyan Zhu
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Jianbin Li
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Libin Liu
- Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Shuaijun Zhu
- Department of Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, China.
| | - Lijing Wang
- Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China.
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de Souza MPGU, Guimarães NS, de Resende Guimarães MFB, de Souza VA, Kakehasi AM. Effect of biological disease-modifying antirheumatic drugs on body composition in patients with rheumatoid arthritis: a systematic review and meta-analysis. Adv Rheumatol 2022; 62:16. [DOI: 10.1186/s42358-022-00249-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 05/17/2022] [Indexed: 12/12/2022] Open
Abstract
Abstract
Background
Rheumatoid arthritis (RA) generates an inflammatory profile that predisposes to total and visceral fatty accumulation and reduced fat free mass (FFM). This metabolic disorder contributes to poor functionality, increased cardiovascular risk and higher mortality. This study aimed to address a systematic review with meta-analysis to determine the effect of biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) on body composition (BC) of patients with RA.
Methods
The search was conducted at the electronic databases PubMed, Cochrane Library, Embase, Lilacs and grey literature. This investigation was carried until July 2021. Outcomes of interest were total weight, body mass index (BMI), fat mass (FM) and FFM. A meta-analysis comparing these outcomes in RA patients under bDMARD treatment versus controls was performed.
Results
Out of 137 studies reviewed, 18 were selected: fifteen prospective cohorts, two retrospective cohorts, and one cross-sectional study. The studies comprised 1221 patients, 778 on bDMARD treatment and 443 controls, which included RA patients under conventional synthetic DMARD (csDMARD). No study addressing BC analysis in patients using tsDMARD was found. The mean age and duration of the disease was 56.7 years and 6.77 years, respectively. Ten studies demonstrated a significant increase of total weight in 88.2% of patients and 42.3% for BMI. In studies that analyzed BC by double X-ray absorptiometry (DXA), the increase in total weight and BMI correlated positively to the increase in FFM. The meta-analysis carried out in five studies showed no significant difference of the mean difference for total weight 0.12 kg (95% CI − 5.58, 5.82), BMI 0.08 kg/m2 (95% CI − 1.76, 1.92), FM − 0.08 kg (95% IC − 5.31, 5.14), and FFM − 2.08 kg (95% CI − 7.37, 3.21).
Conclusion
This systematic review suggests a possible impact of bDMARDs on BC of RA patients, even though, the meta-analysis carried out in a small part of these studies was not able to confirm significant variation in BC components.
Trial registration: PROSPERO code: CRD42020206949.
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Li J, Chen Y, Liu Q, Tian Z, Zhang Y. Mechanistic and therapeutic links between rheumatoid arthritis and diabetes mellitus. Clin Exp Med 2022; 23:287-299. [DOI: 10.1007/s10238-022-00816-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/24/2022] [Indexed: 02/07/2023]
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Causal Biological Network Model for Inflammasome Signaling Applied for Interpreting Transcriptomic Changes in Various Inflammatory States. Int J Inflam 2022; 2022:4071472. [PMID: 35126992 PMCID: PMC8813300 DOI: 10.1155/2022/4071472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/27/2021] [Indexed: 11/17/2022] Open
Abstract
Virtually any stressor that alters the cellular homeostatic state may result in an inflammatory response. As a critical component of innate immunity, inflammasomes play a prominent role in the inflammatory response. The information on inflammasome biology is rapidly growing, thus creating the need for structuring it into a model that can help visualize and enhance the understanding of underlying biological processes. Causal biological network (CBN) models provide predictive power for novel disease mechanisms and treatment outcomes. We assembled the available literature information on inflammasome activation into the CBN model and scored it with publicly available transcriptomic datasets that address viral infection of the lungs, osteo- and rheumatoid arthritis, psoriasis, and aging. The scoring inferred pathway activation leading to NLRP3 inflammasome activation in these diverse conditions, demonstrating that the CBN model provides a platform for interpreting transcriptomic data in the context of inflammasome activation.
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Sánchez-Díaz M, Salvador-Rodríguez L, Montero-Vílchez T, Martínez-López A, Arias-Santiago S, Molina-Leyva A. Cumulative Inflammation and HbA1c Levels Correlate with Increased Intima-Media Thickness in Patients with Severe Hidradenitis Suppurativa. J Clin Med 2021; 10:jcm10225222. [PMID: 34830503 PMCID: PMC8625299 DOI: 10.3390/jcm10225222] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/02/2021] [Accepted: 11/05/2021] [Indexed: 12/31/2022] Open
Abstract
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that has been associated with a greater risk of metabolic and cardiovascular comorbidities. The aim of this study is to assess cardiovascular risk by means of intima-media thickness (IMT), metabolic syndrome, and other potential biomarkers in patients with severe hidradenitis suppurativa who are candidates for biologic therapy and to explore potentially associated factors. A cross-sectional study was performed. Body mass index (BMI), carotid intima-media thickness (IMT), and blood tests, including glycemic and lipid profile, insulin, vitamin D, and inflammation markers were performed. Fifty patients were included in the study; the male/female ratio was 3:2. The mean age was 38 years, and the mean disease duration was 21.8 years. The mean carotid IMT was 651.39 μm. A positive association of IMT with disease duration, tobacco consumption, and HbA1c levels was observed. HbA1c correlated with the age of onset, hypertension, metabolic syndrome, and glucose levels. Vitamin D levels inversely correlated with the number of areas affected. In conclusion, patients with severe HS present a higher cardiovascular risk, but it is not distributed equally within the patients: Tobacco consumption, inadequate glycemic control, and disease duration could be useful clinical and biochemical markers to identify patients at higher risk.
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Affiliation(s)
- Manuel Sánchez-Díaz
- Dermatology Unit, Hospital Universitario Virgen de las Nieves, IBS Granada, 18002 Granada, Spain; (M.S.-D.); (L.S.-R.); (T.M.-V.); (A.M.-L.); (A.M.-L.)
| | - Luis Salvador-Rodríguez
- Dermatology Unit, Hospital Universitario Virgen de las Nieves, IBS Granada, 18002 Granada, Spain; (M.S.-D.); (L.S.-R.); (T.M.-V.); (A.M.-L.); (A.M.-L.)
| | - Trinidad Montero-Vílchez
- Dermatology Unit, Hospital Universitario Virgen de las Nieves, IBS Granada, 18002 Granada, Spain; (M.S.-D.); (L.S.-R.); (T.M.-V.); (A.M.-L.); (A.M.-L.)
| | - Antonio Martínez-López
- Dermatology Unit, Hospital Universitario Virgen de las Nieves, IBS Granada, 18002 Granada, Spain; (M.S.-D.); (L.S.-R.); (T.M.-V.); (A.M.-L.); (A.M.-L.)
| | - Salvador Arias-Santiago
- Dermatology Unit, Hospital Universitario Virgen de las Nieves, IBS Granada, 18002 Granada, Spain; (M.S.-D.); (L.S.-R.); (T.M.-V.); (A.M.-L.); (A.M.-L.)
- Dermatology Department, School of Medicine, University of Granada, 18016 Granada, Spain
- Correspondence: ; Tel.: +34-958023465
| | - Alejandro Molina-Leyva
- Dermatology Unit, Hospital Universitario Virgen de las Nieves, IBS Granada, 18002 Granada, Spain; (M.S.-D.); (L.S.-R.); (T.M.-V.); (A.M.-L.); (A.M.-L.)
- Hidradenitis Suppurativa Clinic, Hospital Universitario Virgen de las Nieves, 18002 Granada, Spain
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Murray EC, Nosalski R, MacRitchie N, Tomaszewski M, Maffia P, Harrison DG, Guzik TJ. Therapeutic targeting of inflammation in hypertension: from novel mechanisms to translational perspective. Cardiovasc Res 2021; 117:2589-2609. [PMID: 34698811 PMCID: PMC9825256 DOI: 10.1093/cvr/cvab330] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 10/14/2021] [Accepted: 10/21/2021] [Indexed: 01/18/2023] Open
Abstract
Both animal models and human observational and genetic studies have shown that immune and inflammatory mechanisms play a key role in hypertension and its complications. We review the effects of immunomodulatory interventions on blood pressure, target organ damage, and cardiovascular risk in humans. In experimental and small clinical studies, both non-specific immunomodulatory approaches, such as mycophenolate mofetil and methotrexate, and medications targeting T and B lymphocytes, such as tacrolimus, cyclosporine, everolimus, and rituximab, lower blood pressure and reduce organ damage. Mechanistically targeted immune interventions include isolevuglandin scavengers to prevent neo-antigen formation, co-stimulation blockade (abatacept, belatacept), and anti-cytokine therapies (e.g. secukinumab, tocilizumab, canakinumab, TNF-α inhibitors). In many studies, trial designs have been complicated by a lack of blood pressure-related endpoints, inclusion of largely normotensive study populations, polypharmacy, and established comorbidities. Among a wide range of interventions reviewed, TNF-α inhibitors have provided the most robust evidence of blood pressure lowering. Treatment of periodontitis also appears to deliver non-pharmacological anti-hypertensive effects. Evidence of immunomodulatory drugs influencing hypertension-mediated organ damage are also discussed. The reviewed animal models, observational studies, and trial data in humans, support the therapeutic potential of immune-targeted therapies in blood pressure lowering and in hypertension-mediated organ damage. Targeted studies are now needed to address their effects on blood pressure in hypertensive individuals.
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Affiliation(s)
- Eleanor C Murray
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8TA Glasgow, UK
| | - Ryszard Nosalski
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8TA Glasgow, UK,Department of Internal Medicine, Collegium Medicum, Jagiellonian University, 31-008 Kraków, Poland
| | - Neil MacRitchie
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8TA Glasgow, UK
| | - Maciej Tomaszewski
- Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, M13 9PL Manchester, UK,Manchester Heart Centre and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, M13 9WL Manchester, UK
| | - Pasquale Maffia
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8TA Glasgow, UK,Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8TA Glasgow, UK,Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - David G Harrison
- Division of Clinical Pharmacology, Department of Medicine, Vanderbildt University Medical Centre, Nashville, 37232 TN, USA
| | - Tomasz J Guzik
- Corresponding author. Tel: +44 141 3307590; fax: +44 141 3307590, E-mail:
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Mazhar F, Battini V, Gringeri M, Pozzi M, Mosini G, Marran AMN, Akram S, van Manen RP, Radice S, Clementi E, Carnovale C. The impact of anti-TNFα agents on weight-related changes: new insights from a real-world pharmacovigilance study using the FDA adverse event reporting system (FAERS) database. Expert Opin Biol Ther 2021; 21:1281-1290. [PMID: 34191656 DOI: 10.1080/14712598.2021.1948529] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Studies in patients with immune-mediated inflammatory diseases (IMIDs) have inconsistently suggested that anti-TNFα therapy may be associated with excessive weight gain. AREAS COVERED We performed a nested case/non-case analysis to investigate the anti-TNF-α inhibitor-associated body-changes in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. The risk was expressed as a measure of disproportionality using the reporting odds ratio (ROR) while adjusting for sex, drugs known to cause weight gain and reporter type. We also performed a time-to-onset (TTO) analysis of body weight-related events. RESULTS Infliximab was the most commonly involved TNF-α inhibitor in body weight-related changes, reaching an aROR of 1.42 (95%CI:1. 26; 1.59). An increased risk was especially found in patients affected by rheumatic disorders, both in the adult and pediatric population. The median TTO after the start of anti- TNFα therapy was about 6-7 months for both children and adults. CONCLUSIONS Given the potential effect of these agents on the excess weight gain in IMIDs patients, continuous attention for this side effect with appropriate counseling regarding lifestyle modifications are warranted, especially in those at high risk for obesity.
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Affiliation(s)
- Faizan Mazhar
- "Luigi Sacco" University Hospital, Università Di Milano, Milan, Italy
| | - Vera Battini
- "Luigi Sacco" University Hospital, Università Di Milano, Milan, Italy
| | - Michele Gringeri
- "Luigi Sacco" University Hospital, Università Di Milano, Milan, Italy
| | - Marco Pozzi
- Scientific Institute, IRCCS E. Medea, Bosisio Parini, LC, Italy
| | - Giulia Mosini
- "Luigi Sacco" University Hospital, Università Di Milano, Milan, Italy
| | | | - Shahzad Akram
- Pharmaceutical Care Department, King Abdullah Specialist Children Hospital, King Abdul-Aziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia
| | | | - Sonia Radice
- "Luigi Sacco" University Hospital, Università Di Milano, Milan, Italy
| | - Emilio Clementi
- "Luigi Sacco" University Hospital, Università Di Milano, Milan, Italy.,Scientific Institute, IRCCS E. Medea, Bosisio Parini, LC, Italy
| | - Carla Carnovale
- "Luigi Sacco" University Hospital, Università Di Milano, Milan, Italy
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Pannu S, Rosmarin D. Psoriasis in Patients with Metabolic Syndrome or Type 2 Diabetes Mellitus: Treatment Challenges. Am J Clin Dermatol 2021; 22:293-300. [PMID: 33586126 DOI: 10.1007/s40257-021-00590-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2021] [Indexed: 12/14/2022]
Abstract
Psoriasis is a chronic inflammatory disease that affects 2-3% of the population worldwide. It is associated with plaques, psoriatic arthritis, and metabolic syndrome and its components, including obesity, diabetes, dyslipidemia, nonalcoholic fatty liver disease, and cardiovascular disease. In this review, we highlight the shared pathogenic pathways leading to the comorbid existence of both diseases and the impact of drugs used for psoriasis on metabolic syndrome and vice versa. Persistent inflammation is common to both diseases. They share increased inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin-6. Biologics have revolutionized the treatment of plaque psoriasis and also have a positive impact on metabolic syndrome. There is some evidence that TNFα inhibitors decrease insulin resistance and improve glycemic indices. Some psoriasis treatments may result in decreased body weight. Lifestyle measures used in the management of metabolic syndrome, such as weight loss, exercise, and healthy diet, are beneficial in patients with psoriasis. Considering the association between metabolic syndrome and psoriasis, we recommend screening patients with psoriasis for metabolic syndrome with clinical examinations and laboratory tests. Patients with a co-diagnosis of these diseases deserve special attention for optimal treatment.
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Affiliation(s)
- Sukhmani Pannu
- The Department of Dermatology, Tufts Medical Center, Boston, MA, USA
| | - David Rosmarin
- The Department of Dermatology, Tufts Medical Center, Boston, MA, USA.
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22
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Wang CR, Tsai HW. Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. World J Diabetes 2021; 12:238-260. [PMID: 33758645 PMCID: PMC7958474 DOI: 10.4239/wjd.v12.i3.238] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/07/2021] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
In addition to β-cell failure with inadequate insulin secretion, the crucial mechanism leading to establishment of diabetes mellitus (DM) is the resistance of target cells to insulin, i.e. insulin resistance (IR), indicating a requirement of beyond-normal insulin concentrations to maintain euglycemic status and an ineffective strength of transduction signaling from the receptor, downstream to the substrates of insulin action. IR is a common feature of most metabolic disorders, particularly type II DM as well as some cases of type I DM. A variety of human inflammatory disorders with increased levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, have been reported to be associated with an increased risk of IR. Autoimmune-mediated arthritis conditions, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with the involvement of proinflammatory cytokines as their central pathogenesis, have been demonstrated to be associated with IR, especially during the active disease state. There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders. In this review, we focus on the effects of anti-TNF-α- and non-TNF-α-targeted therapies on IR in patients with RA, PsA and AS. Anti-TNF-α therapy, IL-1 blockade, IL-6 antagonist, Janus kinase inhibitor and phospho-diesterase type 4 blocker can reduce IR and improve diabetic hyper-glycemia in autoimmune-mediated arthritis.
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Affiliation(s)
- Chrong-Reen Wang
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan
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23
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Pelechas E, Voulgari PV, Drosos AA. Insulin resistance in patients with rheumatoid arthritis. Rheumatol Int 2021; 41:1185-1186. [PMID: 33635386 DOI: 10.1007/s00296-021-04814-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 02/13/2021] [Indexed: 01/10/2023]
Affiliation(s)
- Eleftherios Pelechas
- Department of Internal Medicine, Medical School, Rheumatology Clinic, University of Ioannina, 45110, Ioannina, Greece
| | - Paraskevi V Voulgari
- Department of Internal Medicine, Medical School, Rheumatology Clinic, University of Ioannina, 45110, Ioannina, Greece
| | - Alexandros A Drosos
- Department of Internal Medicine, Medical School, Rheumatology Clinic, University of Ioannina, 45110, Ioannina, Greece.
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24
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Lu Z, Li Y, Song J. Characterization and Treatment of Inflammation and Insulin Resistance in Obese Adipose Tissue. Diabetes Metab Syndr Obes 2020; 13:3449-3460. [PMID: 33061505 PMCID: PMC7535138 DOI: 10.2147/dmso.s271509] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 09/01/2020] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue is the largest energy storage and protection organ. It is distributed subcutaneously and around the internal organs. It regulates metabolism by storing and releasing fatty acids and secreting adipokines. Excessive nutritional intake results in adipocyte hypertrophy and proliferation, leading to local hypoxia in adipose tissue and changes in the release of adipokines. These lead to recruit of more immune cells into adipose tissue and release of inflammatory signaling factors. Excess free fatty acids and inflammatory factors interfere with intracellular insulin signaling. In this review, we summarize the characteristics of obese adipose tissue and analyze how its inflammation causes insulin resistance. We further discuss the latest clinical research progress on the control of insulin resistance and inflammation resulting from obesity through anti-inflammatory therapy and bariatric surgery. Our review shows that targeted anti-inflammatory therapy is of great significance for obese patients with insulin resistance.
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Affiliation(s)
- Zhenhua Lu
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
| | - Yao Li
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
| | - Jinghai Song
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
- Correspondence: Jinghai Song Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing100730, People’s Republic of ChinaTel +8619800315020 Email
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