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.