JAAD online

Cutaneous and pulmonary sarcoidosis-like reaction associated with ipilimumab

Antineoplastic agents that use the immune system have revolutionized cancer treatment. Specifically, implementation of immune checkpoint inhibitors, monoclonal antibodies that block cytotoxic T-lymphocyte–associated antigen-4, programmed cell death protein 1, or programmed cell death ligand 1 show improved and sustained responses in patients with cancer. However, these agents are associated with a plethora of adverse events, many manifesting in the skin. As the clinical application of cancer immunotherapies expands, understanding the clinical and histopathologic features of associated cutaneous toxicities becomes increasingly important to dermatologists, oncologists, and pathologists to ensure timely diagnosis and appropriate care. This review discusses cutaneous reactions to immune checkpoint inhibitors, focusing on histopathologic features.

Therapy for advanced melanoma has deeply changed in the last decade with the introduction of checkpoint and BRAF/MEK inhibitors. Granulomatous reactions have been reported related to these drugs. We performed a systematic review of all the cases described in the medical literature by the search ((“Melanoma”[Mesh]) AND (“Sarcoidosis”[Mesh] OR “Granuloma”[Mesh])). Ninety-one patients under immunotherapy were included in the analyses. The time from the initiation of the immunotherapy until the onset of sarcoidosis or sarcoid-like reaction (SLR) was 7.1 months (SD 9). Peripheral lymph nodes as the mode of onset were seen more frequently in patients under CTLA-4 inhibitors (p = .016) whereas in patients under BRAF/MEK inhibitors used to be in the form of specific skin lesions (p = .006). Chest X-ray stage I-II was the rule in the CTLA-4 and PD-1 groups. On the contrary, stage 0 accounted for 80% of the patients in the BRAF/MEK group examined for pulmonary involvement. Specific skin involvement was the most common manifestation apart from pulmonary involvement. It was more frequent in patients under BRAF/MEK inhibitors and especially in the form of papules. Splenic involvement was found also more frequently in patients under CTLA-4 inhibitors. Specific treatment for sarcoidosis/SLR was prescribed in 50 patients (58.8%), without differences among groups. Almost all patients presented a good prognosis independently of the decision made regarding their previous immunotherapy.

Physicians should bear in mind the possibility of sarcoidosis/SLR after the initiation of checkpoint or BRAF/MEK inhibitors in patients diagnosed with advanced melanoma, especially in the form of skin involvement and mediastinal and peripheral lymph nodes. It is important to achieve an accurate diagnosis to rule out the possibility of cancer involvement. What to do with these drugs is yet to be clarified. It seems reasonable to prioritize cancer treatment so it is not mandatory to stop these drugs.

Immune checkpoint inhibitors (ICPIs) have emerged as a frontline treatment for a growing list of malignancies. Disruption of the negative regulatory immune checkpoints by ICPIs has been associated with many immune-related adverse events. Granulomatous reactions, such as sarcoidosis-like reactions, granulomatous panniculitis, granuloma annulare, and granulomatous dermatitis, are uncommon but increasingly recognized immune-related adverse events seen in patients treated with ICPIs. The frequency and significance of these eruptions, including whether they portend responsiveness to treatment, remain unclear. Additionally, understanding the role of immune checkpoint blockade in these reactions may provide mechanistic insight into the relevant signaling pathways involved in sarcoidosis and other granulomatous disorders.

Unprecedented successes regarding cancer immunotherapy have been achieved, in which therapeutic agents are used to target immune cells rather than cancer cells. The most effective immunotherapy to date is the group of immune checkpoint inhibitors (CPI), targeting, for example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death protein (PD-1). TThe combination of these therapies (anti-PD-1 with anti-CTLA-4) induces high response rates, and seem to be increased further when applied in early-stage disease. However, combined CTLA-4 plus PD-1 blockade causes frequent high-grade immune-related adverse events (irAE). To date, research on biological mechanism of irAEs is scarce and no widely accepted biomarkers predicting onset of severe irAEs have been identified. The similarity of irAEs to autoimmune disorders fuels the hypothesis that irAEs may be linked to susceptible genetic loci related to various autoimmune diseases. In this review, we extensively searched for susceptible loci associated with various autoimmune diseases, and pooled them in groups most likely to be associated with CPI-induced irAEs. These sets could be used in future research on predicting irAEs and guide physicians in a more refined and personal manner.