{"doi":"10.1111/jdv.20017","title":"<scp>TNF</scp> inhibitors and cardiovascular risk: Friend or foe?","abstract":"Immune-mediated inflammatory diseases (IMIDs) such as psoriasis and rheumatoid arthritis (RA) are defined as cardiovascular (CV) risk enhancers and studies demonstrate that, independent of traditional risk factors, the more severe the disease, the greater the risk of incident major cardiovascular events (MACE).1, 2 Chronic inflammation including the type that drives psoriasis and RA is a causal risk factor for atherosclerosis and MACE. Indeed, the immune targeted treatments canakinumab and colchicine have been proven to lower the risk of MACE in patients at high risk for cardiovascular events due to underlying atherosclerotic cardiovascular disease in large scale, placebo-controlled trials.3 It is therefore logical to hypothesize that treatment of IMIDs will lower the risk of CV disease. For example, a randomized placebo-controlled trial in psoriasis demonstrated that the TNF inhibitor adalimumab lowers IL6, a cytokine elevated across many IMIDs and causal for atherosclerosis and CV events, compared to placebo.4 However, immune-targeted treatments are notorious for paradoxical effects, reducing inflammation in one organ and increasing it in another. For example, circulating TNF is elevated in advanced heart failure, yet TNF inhibitors in randomized placebo-controlled trials of patients with CHF associated with worse CV outcomes despite the predicted beneficial effects based on clinical and preclinical data.5 More recently, a meta-analysis of randomized controlled trials of IMIDs found that inhibitors of TNF, IL12/23 and Janus Kinase were all associated with an increased risk of MACE compared to placebo.6 However, while meta-analyses are typically considered the pinnacle of evidence-based medicine, they can often be unreliable when evaluating rare events using methods that fail to account for individual follow-up time.7 In this context, Galajda et al.8 conducted a large meta-analysis of the effects of TNF inhibitors compared to conventional therapies in patients predominantly with RA and psoriasis but also psoriatic arthritis, spondylarthritis and inflammatory bowel disease to evaluate outcomes of MACE, cerebrovascular accident and myocardial infarction. They included 29 studies (virtually all were observational in nature) in their meta-analysis and found that the TNFi group had a reduced risk of MACE (HR = 0.74, 95% confidence interval (CI) 0.58–0.95, p = 0.025). Analyses restricted to psoriasis and psoriatic arthritis also demonstrated a reduced risk of MACE (IRR = 0.79, 95% CI 0.64–0.98). So, what are we to make of these results? The findings appear to rule out that TNF inhibitors are a foe when it comes to CV risk, albeit important outcomes such as congestive heart failure and CV mortality were not fully evaluated due to lack of reporting or limited data. But are TNF inhibitors protective of CV events? Here, we are at the limit of observational data because there is likely a strong healthy user effect that could explain these results and is difficult to account for in observational approaches. Indeed, large scale meta-analyses of observational studies suggested that methotrexate was cardioprotective in patients with RA and psoriasis but a large scale randomized placebo-controlled trial of methotrexate in patients at high risk for cardiovascular events demonstrated no benefit of methotrexate on MACE.9 Nevertheless, the breadth of observational and experimental mechanistic data suggest that TNF inhibitors should be explored in large scale, pragmatic, randomized, controlled studies to finally answer the question, do TNF inhibitors reduce the risk of cardiovascular events and mortality. Dr. Gelfand served as a consultant for Abbvie, Artax (DSMB), BMS, Boehringer Ingelheim, Celldex (DSMB), FIDE (which is sponsored by multiple pharmaceutical companies), GSK, Inmagene (DSMB), Lilly, Leo, Moonlake (DSMB), Janssen Biologics, Novartis Corp, UCB (DSMB), Neuroderm (DSMB) and Veolia North America receiving honoraria; and received resear","journal":"Journal of the European Academy of Dermatology and Venereology","year":2024,"id":459568,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":228053,"name":"Michael Garshick","orcid":"0000-0002-6649-3755","position":1,"is_corresponding":false},{"id":284625,"name":"Joel M. Gelfand","orcid":"0000-0003-3480-2661","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:03:59.428859Z","pmid":"38794923","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}