Granulomatous skin reactions:
Sarcoidosis or sarcoid-like granulomatous reaction is characterized by the development of epithelioid and multinucleated giant cell granulomas involving multi-organ systems, affecting the skin, lungs, and eyes. The development of these reactions is characterized by compartmentalization of CD4+ T- cells and co-activation of monocyte/ macrophages in the organs involved 30.
Pathogenesis: The immune-pathogenesis of granulomatous skin reactions is characterized by Th-1/Th-17 type inflammation which is mediated primarily by the release of the pro-inflammatory cytokines such as interferon-gamma (IFN-γ), interleukin (IL)-17 producing cells including CD4+ T helper 17(Th17) cells, and tumor necrosis factor (TNF-α). 31, 32. The alteration in the ratio between cytotoxic T cells, Th1/Th17 and regulatory T-cells due to immune checkpoint inactivation leads to hyperactivation of the Th-17 with the secretion of tumor necrosis factor-alpha (TNF-α) and increased expression of interleukin- 17 which act as an inflammatory mediator generating the granulomas with epithelioid and multinucleated giant cells. Additionally, granulomatous skin reactions can also be induced by the activity of CD8+ cells on dendritic cells (DC) and macrophages through the production of cytokines favoring Th1 and Th17 cells33.
Clinical incidence: Twenty-four case reports of granulomatous reactions were reported as adverse reactions. The period of inhibition of PD-1/PD-L1 and onset of granulomatous skin reactions is two weeks to two years. Ten cases of pembrolizumab immunotherapy presented with cutaneous sarcoidosis and sarcoid-like granulomatous reaction34-39; eight cases with nivolumab33, 35, 40-42; one case associated with atezolizumab43; one with avelumab44 and four cases were with durvalumab immunotherapy 45-48. The clinical and histological findings suggest the development of subcutaneous nodules35, 39 and indurated papules and plaques on the skin surface 34, 39. A case of nivolumab therapy was reported which involve pulmonary, mediastinal lymph node, and skin involvement that did not require immunosuppressive therapy and, pulmonary and parotid gland involvement that rapidly improved with steroid treatment.
Treatment: All responded well with systemic prednisolone (30 mg). In one case betamethasone dipropionate 0.05% ointment was used as a treatment 34 while the other cases were treated with prednisolone and hydroxychloroquine combination34, clobetasol propionate 0.05% cream 47.