Assessing the association between antiphospholipid syndrome and non-melanoma skin cancers: A case-control study on the role of a chronic inflammatory condition

Abstract Antiphospholipid Syndrome (APLS) is an autoimmune hematological disorder defined by antiphospholipid antibodies and a hypercoagulable state, causing venous and arterial thromboses and pregnancy complications.1APLS is categorized into primary and secondary syndromes, with primary being more common and in the absence of other underlying diseases. Secondary antiphospholipid syndrome is associated with diseases including systemic lupus erythematosus (SLE), malignancy, infections, and various drugs.2 Patients with APLS have had a variety of cutaneous manifestations described including, but not limited to, livedo reticularis, necrotizing vasculitis, and thrombophlebitis.3 Of note, APLS is an inflammatory condition that involves endothelial activation and injury;4 as such, the potential association to skin cancers such as non-melanoma skin cancers (NMSC), in which oxidative damage is involved, is a relevant area of investigation. Such an association is unclear and not been studied or reported in the literature. As such, we aimed to investigate the possible association of APLS with NMSC. We also investigated if having a co-morbid chronic inflammatory skin condition modified the relationship. We retrospectively reviewed charts of patients with APLS and malignant skin cancer diagnosis at Brigham and Women's Hospital and Massachusetts General Hospital from 1979 to 2024. Controls were matched by age, sex, and race 1:1 of skin cancer without APLS. Multivariable logistical regression analysis (adjusted for smoking history) was also conducted using R. This study was approved by the IRB of MGB. Among 1227 patients with APLS and 1262 controls extracted, 296 patients with APLS, defined using APLS diagnostic criteria6-7, and 881 controls were included following chart review. A majority of APLS patients were white (95.9%), female (58.6%), and non-Hispanic (93.8%). 83.0% had primary APLS and 17.0% had secondary. Antibody profiles were 59.9% lupus anticoagulant, 60.6% anticardiolipin, and 13.8% anti-B2 antibodies. A significant positive association was found between APLS and NMSC diagnosis, categorized as both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), (odds ratio (OR): 1.48, unadjusted p=0.014, adjusted OR (aOR): 1.48, p=0.017). 69.8% of the APLS patients with skin cancer, had a skin cancer occur after APLS diagnosis. In subsequent subgroup analysis of APLS patients with a chronic inflammatory skin condition, including eczema, psoriasis, or dermatomyositis, or cutaneous lupus, there was significantly increased risk of BCC (OR: 1.83, unadjusted p=0.0327, aOR: 1.83, p=0.0329) compared to APLS patients without a chronic inflammatory skin condition. Our study suggests that patients with APLS may have an increased risk of NMSC. Our study's limitations include that it is a retrospective study and also utilized one health care system, limiting the generalizability. Overall, skin cancer risk in patients with APLS is an area of understudied work. We provide the first retrospective study on the potential association of APLS and NMSC, opening future studies such as prospective studies and larger retrospective data. References:Hughes GR. BMJ 1983Bick RL, et al. Med Clin North Am 1994Gibson GE, et al. J Am Acad Dermatol. 1997Ambati A, et al. Curr Opin Rheumatol. 2023Sander CS, et al. Br J Dermatol. 2003Bustamante JG, et al. StatPearls Publishing; 2025Miyakis S, et al. J Thromb Haemost. 2006