Immunosuppressive Therapy of Biopsy-Proven, Virus-Negative, Autoimmune/Immune-Mediated Myocarditis—Focus on Azathioprine: A Review of Existing Evidence and Future Perspectives

SIMPLE SUMMARY: Myocarditis is one of the leading causes of acute and chronic heart failure, adverse ventricular remodelling, and progression to dilated cardiomyopathy, life-threatening arrhythmias, and sudden cardiac death. According to recent guidelines, azathioprine, in association with steroids, is a cornerstone of first-line therapy regimens in biopsy-proven, autoimmune/immune-mediated, virus-negative myocarditis. Despite that the majority of published clinical studies seem to show an overall benefit of immunosuppressive therapy in the treatment of myocarditis/inflammatory cardiomyopathy, a targeted therapy has still not been standardized, and there is a need for further controlled, multicentric, clinical studies to provide further data on the efficacy and safety of IT in myocarditis. The aim of this review is to describe the pharmacological properties of azathioprine and to explore future perspectives for its usage in the cardioimmunology field. ABSTRACT: The use of immunosuppressive therapy (IT) in biopsy-proven, autoimmune/immune-mediated (AI), virus-negative myocarditis has become the standard of care. In particular, according to recent guidelines, azathioprine (AZA), in association with steroids, is a cornerstone of first-line therapy regimens. IT may have a crucial impact on the natural history of AI myocarditis, preventing its progression to end-stage heart failure, cardiovascular death, or heart transplantation, provided that strict appropriateness and safety criteria are observed. In particular, AZA treatment for AI virus-negative myocarditis requires the consideration of some crucial aspects regarding its pharmacokinetics and pharmacodynamics, as well as a high index of suspicion to detect its overt and/or subclinical side effects. Importantly, besides a tight teamwork with a clinical immunologist/immuno-rheumatologist, before starting IT, it is also necessary to carry out a careful “safety check-list” in order to rule out possible contraindications to IT and minimize patient’s risk. The aim of this review is to describe the pharmacological properties of AZA, as well as to discuss practical aspects of its clinical use, in the light of existing evidence, with particular regard to the new field of cardioimmunology.