Faculty Bibliography

The Janus kinase-signal transducer and activator of transcription pathway plays a critical role in the pathogenesis of many immune-mediated inflammatory diseases (IMIDs). Although Janus kinase inhibitors (JAKi) are an effective treatment for several IMIDs, they have come under scrutiny as a class because of a potential risk of venous thromboembolism and cardiovascular (CV) events, specifically noted with the oral JAKi, tofacitinib, as reported in the ORAL Surveillance Trial of a high CV risk rheumatoid arthritis population. This trial resulted in a black box warning from the Food and Drug Administration and European Medicines Agency regarding risk of venous thromboembolism and CV events that was extended across several types of JAKi (including topical ruxolitinib) when treating IMIDs, leading to considerable controversy. Included is an up-to-date review of the current and rapidly evolving literature on CV risk in patients with IMIDs on JAKi therapy, including identification of potential risk factors for future venous thromboembolism and CV events on JAKi therapy. We suggest a comprehensive, multimodal, and systematic approach for evaluation of CV risk in patients considering taking JAKi and emphasize that cardiologists play an important role in risk stratification and mitigation for patients with high CV risk factors or on long-term JAKi therapies.

PURPOSE OF REVIEW/OBJECTIVE:Targeting traditional cardiovascular risk factors is effective in reducing recurrent cardiovascular events, yet the presence of residual cardiovascular risk due to underlying systemic inflammation is a largely unaddressed opportunity. This review aims to comprehensively assess the evolving role of colchicine as a therapeutic approach targeting residual inflammatory risk in the context of those with coronary artery disease (CAD). RECENT FINDINGS/RESULTS:Inflammation plays a significant role in promoting atherosclerosis, and targeting anti-inflammatory pathways has the potential to decrease cardiovascular events. Low-dose colchicine (0.5 mg/day orally), when added to guideline-directed medical care for CAD, safely decreases major adverse cardiovascular events (MACE) by 31% in stable atherosclerosis patients and 23% in those after recent myocardial infarctions. Meta-analyses of recent randomized control trials further support both the efficacy and safety of colchicine, particularly when added to other standard cardiovascular therapies, including statin therapy. The European Society of Cardiology and other national guidelines endorse the use of low-dose colchicine in patients across the spectrum of CAD. Recently, colchicine was FDA-approved in the United States as the first anti-inflammatory therapy for the reduction of cardiovascular events. In a period of a rising incidence of CAD across the globe, colchicine represents a unique opportunity to decrease MACE due to its large magnitude of benefits and general affordability. However, challenges with drug interactions must be addressed, especially in those regions where HIV, hepatitis, and tuberculosis are prevalent. Colchicine is safe and effective at reducing cardiovascular events across a broad spectrum of coronary syndromes. The ability to simultaneously target traditional risk factors and mitigate residual inflammatory risk marks a substantial advancement in cardiovascular prevention strategies, heralding a new era in the global battle against CAD.

Alopecia is traditionally classified into scarring and nonscarring subtypes, with etiopathologies ranging from androgen-mediated to immuno-inflammatory. Over 50% of men and almost 50% of women will experience some form of hair loss in their lifetime. Given this prevalence and the psychosocial significance of hair, understanding the pathophysiology and comorbidities of different types of hair loss is imperative. Other proinflammatory dermatologic disorders, such as psoriasis, are recognised to have systemic manifestations including an increased risk of cardiovascular (CV) disease, and are now considered CV risk-enhancing conditions. With increased recognition of the importance of systemic inflammation in promoting atherosclerosis, high prevalence, and improved treatment strategies, there is increased interest in establishing whether a similar association between alopecia and cardiovascular disease (CVD) exists. In this manuscript, we aim to review the current literature regarding CV risk in androgenic alopecia (AGA) and alopecia areata (AA). Additionally, we review the literature for cicatricial alopecias and highlight the need for more research into their potential associations with CV risk. Evidence from the identified AGA publications suggests an association of AGA with CV risk factors including hypertension, dyslipidemia, and insulin resistance, as well as with coronary artery disease. For AA, most of the identified studies found an association between AA and CV risk, though the relationships were not always statistically significant. Research on cicatricial alopecias and CV risk is limited and often contradictory. There is great need for more studies regarding the association between various types of alopecia and the development of CVD, and potential mechanisms. Particularly needed are more studies of cicatricial alopecias and potential associated CV risk. While some literature suggests that patients with alopecia have an increased risk of CVD, the lack of concrete evidence represents a notable gap in our current understanding.

BACKGROUND:Cardiometabolic risk factors diabetes, obesity, and hypertension are highly prevalent and contribute to increased cardiovascular disease (CVD). Endothelial dysfunction precedes CVD development. The current study aimed to investigate the EC transcriptome among individuals with varying degree of cardiometabolic risk. METHODS:Adult participants without CVD and various degrees of cardiometabolic risk factor burden (hypertension, diabetes, obesity) were included. Participants underwent brachial vein EC harvesting followed by RNA sequencing. To evaluate the association between cardiometabolic comorbidity burden and outcome transcripts we performed linear regression with multivariable models, adjusting for age, sex, and race/ethnicity. RESULTS:A total of 18 individuals were included in the present analysis (mean age 47 ± 14, 44% female, and 61% White adults). Endothelial cell RNA sequencing revealed 588 differentially expressed transcripts (p-adj <0.05) with excellent discrimination in unsupervised hierarchical clustering analysis. Gene ontology enrichment analysis revealed upregulated pathways associated with T-cell activation (NES = 2.22, p<0.001), leukocyte differentiation (NES= 2.16, p<0.001), leukocyte migration (NES= 2.12, p<0.001), regulation of cell-cell adhesion (NES= 1.91, p=0.006). Downregulated pathways of interest included endothelial cell proliferation (NES= -1.68, p=0.03) and response to interleukin-1 (NES= -1.61, p=0.04). Upregulated genes included VCAM1, CEACAM1, ADAM 17, and CD99L2, all with a log-2-fold change >3 and p-adj <0.05. These genes demonstrated a graded increase in mean normalized counts with increasing number of risk factors. CONCLUSIONS:We demonstrate a proinflammatory and pro-adhesive EC transcriptome associated with increased cardiometabolic risk factor burden offering insight into a potential mechanism linking these risk factors with the development of CVD.

IMPORTANCE/UNASSIGNED:Janus kinase (JAK) inhibitors are an effective treatment option for patients with certain skin-related conditions, such as atopic dermatitis, alopecia areata, and vitiligo, but there is a current US Food and Drug Administration (FDA) boxed warning label for oral and topical JAK inhibitors regarding increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), serious infections, malignant neoplasm, and death. However, this boxed warning was precipitated by results of the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance study, which only included patients with rheumatoid arthritis, and the same association may not be observed in dermatologic conditions. OBJECTIVE/UNASSIGNED:To determine the risk of all-cause mortality, MACE, and VTE with JAK inhibitors in patients with dermatologic conditions. DATA SOURCES/UNASSIGNED:PubMed and ClinicalTrials.gov were searched from database inception to April 1, 2023. STUDY SELECTION/UNASSIGNED:This review included phase 3 randomized clinical trials with a placebo/active comparator group of JAK inhibitors used for a dermatologic indication with FDA approval or pending approval or with European Union or Japanese approval. Studies without a comparison group, case reports, observational studies, and review articles were excluded. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Adverse events using odds ratios (ORs) and 95% CIs were calculated using a random-effects model and the DerSimonian-Laird method. Studies were screened, data abstracted, and quality assessed by 2 independent authors. The protocol was prospectively registered with PROSPERO. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Primary outcomes were a composite of adjudicated MACE and all-cause mortality, and VTE. RESULTS/UNASSIGNED:The analysis included 35 randomized clinical trials with 20 651 patients (mean [SD] age, 38.5 [10.1] years; male, 54%) and a mean (SD) follow-up time of 4.9 (2.68) months. Findings did not show a significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (OR, 0.83; 95% CI, 0.44-1.57) or VTE (OR, 0.52; 95% CI, 0.26-1.04). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this systematic review and meta-analysis, use of JAK inhibitors was not associated with increased risk of all-cause mortality, MACE, and VTE compared to the placebo/active comparator groups. Additional trials with long-term follow-up are needed to better understand the safety risks of JAK inhibitors used for dermatologic indications.

Immune-mediated systemic inflammatory conditions (IMIDs) are associated with an increased risk of atherosclerosis and adverse cardiovascular (CV) events secondary to pathogenic inflammation and derangements in the innate and adaptive immune responses inherent to the underlying rheumatic diseases. As the intersection of cardio-rheumatology continues to expand, a multi-disciplinary approach must be considered to optimize clinical outcomes and long-term survival. This review will highlight acute cardiac manifestations of systemic inflammatory diseases and propose a clinically relevant framework for diagnosis, management, and the role of integrated multimodality imaging.

The Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN) is a nonprofit organization whose mission is to optimize the clinical care of patients with psoriatic disease through multidisciplinary collaboration models. The PPACMAN 2021 Annual Meeting was held virtually on December 11, 2021. In all, 50 stakeholders participated in the meeting including dermatologists, rheumatologists, cardiologists, clinical researchers, patient advocacy representatives, and industry representatives. During the opening session of the meeting, presenters provided an update of several research projects dedicated to predicting and preventing psoriatic arthritis (PsA) such as the Psorcast, PAMPA, HIPPOCRATES, and the ELLIPSS studies. The second session centered around novel approaches to deliver multidisciplinary care in psoriatic disease. PPACMAN leadership introduced its wellness program and invited speakers to discuss new advances in cardiovascular disease, sleep disturbance, mental health problems, and dietary interventions in psoriatic disease. The final session of the meeting focused on how to improve patient engagement in their disease and care.