Prospective Exploration of Vascular Complications Associated With the Use of Immune Checkpoint Inhibitors

The development of immune checkpoint inhibitors (ICIs) has revolutionized the management of many oncological diseases, and their use continues to increase. ICIs are monoclonal antibodies that target immune checkpoints such as PD-1 (programmed cell death protein 1, as seen in nivolumab, pembrolizumab, and cemiplimab), PD-L1 (programmed cell death protein 1 ligand, as seen in atezolizumab, avelumab, and durvalumab), CTLA-4 (cytotoxic T-lymphocyte antigen 4, as seen in ipilimumab and tremelimumab), or LAG-3 (lymphocyte-activating gene 3, as seen in relatlimab), which play a crucial role in immune tolerance to cancer cells. However, the surge in ICI prescriptions has been accompanied by the occurrence of numerous side effects, some of which are severe or even fatal. ICIs have a different toxicity spectrum than conventional chemotherapy, and most toxicities result from excessive immunity against different organs. This immune-mediated toxicity can affect various organ systems, including the heart and blood vessels. Pharmacovigilance data from clinical trials conducted by Bristol-Myers Squibb, which marketed ipilimumab (anti-CTLA-4) and nivolumab (anti-PD1), revealed 18 cases (0.09%) of myocarditis among 20,594 subjects. While cardiac complications induced by immune checkpoint inhibitors (ICIs), particularly autoimmune myocarditis, are widely described, the impact of these treatments on the vascular system remains poorly understood. However, a variety of vascular complications have been reported, ranging from vasculitis of large, medium, and small vessels to a possible increase in arterial thrombotic events, ischemic strokes, and acute coronary syndromes. The incidence of vasculitis appears to be between 1% and 2% of patients treated with immune checkpoint inhibitors (ICIs). This is emerging as a significant signal in various pharmacovigilance studies, suggesting the involvement of immune checkpoint derepression in the pathophysiology of vasculitis. A translational study demonstrated the major role of CTLA-4 in the pathophysiology of giant cell arteritis (GCA), although the precise mechanisms involved remain to be determined. Therefore, a specific immune environment could promote the development of vasculitis, a phenomenon reproduced by ICI administration. The increase in arterial thrombotic vascular events was primarily observed in a matched cohort study, which showed a threefold increased risk of arterial thrombotic vascular events following the initiation of ICI therapy. These thrombotic events would coincide with the acceleration of atherosclerosis in patients treated with ICIs. This "accelerated" atherosclerosis could be linked to inflammatory changes within the plaques, causing plaque destabilization or rupture. It is also unreasonable to rule out the possibility that the accelerated atherosclerosis is related to the development of vasculitis in these patients.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Patient treated with an ICI (nivolumab, pembrolizumab, atezolizumab, ipilimumab, cemiplima, or any novel antibody directed against PD-1, PD-L1, CTLA-4, or LAG-3) as monotherapy or in combination with another ICI or with radiotherapy,
* Patient over 18 years of age,
* WHO performance status: 0 to 2,
* Oral informed consent,
* Patient affiliated with or beneficiary of a social security scheme.

Exclusion Criteria:

* History of ICI treatment,
* History of chemotherapy or targeted therapy within the last 4 weeks,
* Stage 4 PAD,
* Severe Raynaud's syndrome,
* Removal of both hands and/or both feet,
* Removal of the right hand/left foot or the left hand/right foot,
* Patient deprived of liberty by an administrative or judicial decision or patient under legal protection, guardianship, or curatorship,
* Pregnant or breastfeeding woman,
* Patient unable to understand the study for any reason or to comply with the trial requirements (language barrier, psychological, geographical, etc.).