Cutaneous Adverse Effects of Hydroxychloroquine and Leflunomide in Connective Tissue Diseases: A Report of Three Cases and a Literature Review.

Connective tissue diseases (CTDs) are a group of systemic autoimmune disorders that require long-term treatment with immunomodulatory and immunosuppressive agents to control disease progression and inflammation. Among the most frequently used agents are hydroxychloroquine and leflunomide, which have proven efficacy in conditions such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome. The use of these drugs has been correlated with dermatologic adverse reactions of varying severity, spanning from common and mild skin eruptions to rare but severe cutaneous syndromes. This article presents three clinical cases of patients undergoing treatment with hydroxychloroquine or leflunomide who developed dermatological manifestations, such as annular erythema, mucocutaneous hyperpigmentation, and phototoxic reactions. The pathophysiological mechanisms underlying these adverse effects are discussed, and a literature review is provided to contextualize the frequency, risk factors, and management strategies for these adverse reactions. The findings emphasize the importance of early recognition and monitoring of cutaneous adverse effects in patients receiving long-term immunomodulatory therapy. Further research is needed to better understand the molecular mechanisms involved in drug-induced dermatologic side effects and to develop strategies for minimizing these risks while ensuring optimal therapeutic outcomes.