Beyond the Surface: Investigating the Relationship Between Autoimmune Blistering Disorders and Venous Thromboembolism

Venous thromboembolism (VTE), which encompasses deep vein thrombosis and pulmonary embolism, refers to the formation of blood clots within the venous system. ¹ VTE is a complex disease, and its pathogenesis remains incompletely elucidated. Stasis, vascular injury, and a hypercoagulable state, known collectively as Virchow's triad, play a vital role in the onset of thrombosis. The intersection of these conditions amplifies the likelihood of venous thrombosis, which may consequently precipitate the progression of VTE. Immune alterations and vascular inflammation are also known to play a pivotal role in the thrombogenic mechanism and the pathogenesis of VTE. ²

Several medical conditions are known to increase the risk of developing VTE. These include blood clotting disorders or a history of blood clots, cancer and its treatments (including chemotherapy and surgery), diabetes, heart conditions (eg, heart attack or congestive heart failure), infections, pregnancy, immobilization, antiphospholipid syndrome, kidney disease, spinal cord injury, and obesity. ³ As an illustration, patients with COVID‐19 may have thrombotic and coagulation abnormalities, promoting a hypercoagulable state and resulting in an increased rate of thrombotic and thromboembolic events. ⁴

Pemphigus and pemphigoid represent distinct, albeit related, autoimmune blistering disorders, defined by the production of autoantibodies that target desmosomes or hemidesmosomes, structures vital for skin integrity. ⁵ In pemphigus, the immune system targets desmogleins, a component of desmosomes, the intercellular junctions maintaining adhesion between keratinocytes. ⁶ This results in a phenomenon known as acantholysis, the dissolution of epidermal cellular bonds, causing intraepidermal blistering. Pemphigus often presents with painful blisters on mucous membranes such as the mouth and throat, and may progress to involve the skin extensively. Conversely, pemphigoid encompasses a group of subepidermal autoimmune bullous diseases, characterized by autoantibodies against components of the hemidesmosome, essential for dermal‐epidermal junction integrity. In pemphigoid, blister formation occurs beneath the epidermis, yielding tense blisters. Both disorders exemplify the sophisticated and delicate interrelationship between the immunological processes and skin tissue homeostasis. ⁷

Several studies have demonstrated an increased risk of VTE in patients with bullous pemphigoid (BP) or pemphigus vulgaris (PV). ⁸ , ⁹ Nevertheless, it should be noted that these studies mainly focused on people in Western countries, which limits their generalizability to a broader population. In this issue of the Journal of the American Heart Association (JAHA), Chen et al ¹⁰ conducted a nationwide cohort analysis using data from the National Health Insurance Research Database, and subsequently performed a comprehensive meta‐analysis by amalgamating all available data. The National Health Insurance Research Database is a comprehensive health data repository in Taiwan, providing an invaluable resource for population‐based research. It contains comprehensive information on health care use for over 99% of the Taiwanese population, including outpatient visits, hospital admissions, prescriptions, and disease diagnoses. ¹¹ Researchers use these data for epidemiological studies, drug safety evaluations, and investigations into health care disparities, among other areas. ¹² The National Health Insurance Research Database's extensive coverage and rich detail make it a pivotal tool for health research, facilitating insights that can inform policy decisions and enhance public health outcomes.

Chen et al ¹⁰ recruited adults (aged ≥20 years) with BP or PV newly diagnosed by dermatologists between 2001 and 2017. For every individual in the exposed group, a corresponding control subject from the unexposed group was identified, matching in terms of age and sex. The cohort study encompassed a total of 24 324 participants. The incidence of VTE was recorded at 6.38 and 2.20 per 1000 person‐years in the BP and PV cohorts, respectively, indicating a substantial increase in risk. Furthermore, the study demonstrates a significant increase in VTE risk among patients with BP (hazard ratio, 1.72) and PV (hazard ratio, 1.97). This suggests that the elevated risk extends beyond specific demographic groups, making it a widespread phenomenon. Furthermore, the meta‐analysis, which included their own study along with 8 others, provided further evidence supporting the correlation between BP and PV and an increased risk of developing VTE. The pooled relative risk revealed a significant association, with a value of 2.15, indicating a >2‐fold increase in risk. Interestingly, a recent nationwide cohort study in the United States also demonstrated that BP was associated with a 2‐fold increase in VTE. ¹³

The significance of the risk associated with VTE in patients with autoimmune blistering diseases is underscored, especially in this era of continuous medical advancements and new drug development. For instance, Janus kinase (JAK) inhibitors function by blocking the activity of ≥1 of the JAK family proteins (JAK1, JAK2, JAK3, TYK2), reducing inflammation and immune activation in diseases such as rheumatoid arthritis and psoriasis. Recently, JAK inhibitors have been reported to be effective in treating PV and BP. ¹⁴ However, JAK inhibitors have been scrutinized for their potential association with VTE. A systematic review and meta‐analysis were conducted on 66 randomized clinical trials involving 38 574 patients, revealing a numerically higher rate of VTE in patients treated with JAK inhibitors, especially in trials with a follow‐up duration of ≥12 months. ¹⁵ Physicians must exercise caution when using new drugs like JAK inhibitors to treat autoimmune blistering diseases, as there is a potential increase in the risk of VTE in these patients.

However, it would be intriguing to see further research exploring the underlying mechanisms that link BP and PV with an increased risk of VTE. Previous studies have provided some insights in this regard. First, patients with active BP have been found to exhibit significantly higher levels of plasma prothrombin fragments F1+2 and d‐dimer, as compared with controls. Furthermore, the presence of skin tissue factor, a coagulation initiator, has also been noted in patients with BP. ¹⁶ Second, the levels of interleukins 4, 5, and 13 are elevated in the serum, blister fluid, and skin biopsy specimens of patients with BP. ¹⁷ These cytokines may also involve the pathogenesis of VTE. ¹⁸ Third, antiphospholipid antibodies have been detected in patients with BP and PV. ¹⁹ , ²⁰ Understanding these mechanisms could provide insights into potential therapeutic targets and strategies for managing this risk.

In conclusion, this study provides valuable insights into the correlation between BP and PV and the risk of VTE. It underscores the need for increased awareness and preventive measures in managing patients diagnosed with these conditions. The findings have significant implications for clinical practice and highlight the need for further research in this field.

Disclosures

None.