Dermatomyositis unleashed by immune checkpoint inhibitors. Three additional cases and a review of the literature

Abstract

Objectives: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of several locally advanced and metastatic tumors. They enhance the effector function of the immune system, consequently leading to different immune-related adverse events. The aim of the present study was to describe three cases of dermatomyositis (DM) triggered by ICI diagnosed at our institution and to perform a review of the literature.

Methods: We performed a retrospective clinical, laboratory, and pathological evaluation of three cases of DM triggered by ICI belonging to a cohort of 187 DM patients from the Clinic Hospital Muscle Research Group of Barcelona from January 2009 to July 2022. Moreover, we undertook a narrative review of the literature from January 1990 to June 2022.

Results: Cases from our institution were triggered by avelumab, an anti-PD-1 ligand (PD-L1), nivolumab, and pembrolizumab, both anti-programmed death-1 (PD-1). One of these patients had locally advanced melanoma, and two had urothelial carcinoma. The severity and response to treatment were heterogeneous among the different cases. All were positive at high titers for anti-TIF1γ autoantibodies; in one of them, serum before the onset of ICI was available, and anti-TIF1γ autoantibodies were already present. RNA expression of IFNB1, IFNG and genes stimulated by these cytokines were markedly elevated in these patients.

Conclusions: In conclusion, data from our patients and the narrative review suggest that early positivity to anti-TIF1γ unleashed by ICI may play a role in the development of full-blown DM, at least in some cases.

Keywords: Dermatomyositis; Immune checkpoint inhibitors; Immune-related adverse event; Inflammatory myopathy; Myositis.

Figure 1.

Cutaneous signs characteristic of dermatomyositis triggered by ICI (case 1). A: Periorbital rash and palpebral edema compatible with the heliotrope sign. B: Erythemato-violaceous papules Over the metacarpophalangeal joints compatible with Gottron’s papules.

Figure 2.. A-F (case 1), G-L (case 2), M-R (case 3).

Cross-sectional frozen muscle tissue. H&E staining showing microinfarction (A, G, and M) and perivascular inflammatory infiltrate (B, H, and N). Universal HLA-I immunostaining positivity (C, I, and O). Expression of HLA-DR immunostaining in the inflammatory cells and perifascicular area (D, J, and P). Mild positivity of Mx1 immunostaining (E, K, and Q) and immunostaining for Membrane Attack Complex expression at the capillaries and in some muscle fibers.

Figure 3.

Expression (log2[TMM+1]) of IFNB1, IFNG and representative genes stimulated by IFNB1 (ISG15, and MX1) and IFNG (GBP2, and IFI30) in histologically normal muscle biopsies (NT), muscle biopsies from patients with classical anti-TIF1γ dermatomyositis (Anti-TIF1g), and muscle biopsies from patients with dermatomyositis induced by checkpoint inhibitors associated to Anti-TIF1g (ICI-DM).