24PImmune-checkpoint inhibitor-induced myositis – myopathology revealing novel phenotypes

The established use of immune checkpoint inhibitors (ICI) in cancer therapy has proven to be a highly beneficial approach for many oncology patients with also metastatic diseases. However, ICI can cause life-threatening immune-related adverse events (irAEs) with myositis being among the most prevalent neurological side-effects with dismal prognosis especially if associated with myocarditis. In 2018, we described the first series of patients highlighting clinicopathological features of immune checkpoint inhibitor-induced myositis. Those myopathological characteristics consisted of necrotic myofibers with a diffuse distribution and focal clusters as well as endomysial lymphomonocytic infiltrates. Others described patterns consisting of a perimysial pathology. A transcriptomic profiling-based study revealed three subgroups of ICI induced-myositis, consisting of ICI-DM, ICI-MYO1 and ICI-MYO2. The ICI-DM subgroup was accompanied by dermatomyositis features like a type I interferon signature and typical autoantibodies (anti-TIF1ɣ), while ICI-MYO1 patients had highly inflammatory features and myocarditis with dismal prognosis and ICI-MYO2 patients had mild necrotizing myositis. Here, we report on two additional myopathological patterns that have not yet been described either morphologically or by transcriptomic profiling, namely antisynthetase syndrome (ASyS)-like and immune myopathy with abundant macrophages (IMAM)-like morphology. In ASyS-like ICI-myositis we could detect MHC class I and II expression on myofibers but without complement deposition on fibers and necrotic fibers. Furthermore, macrophages but also CD8-positive T cells are detectable in the peri- and endomysium. In IMAM-like ICI-myositis we found strong MHC class II and strong, but less pronounced MHC class I sarcoplasmatic expression with massively endo- and perimysial infiltration of macrophages, myophagocytosis as well as focal necrotic fibers. The subtype was clinically correlating with very severe rhabdomyolysis and tetraparesis. The two new identified subtypes illustrate the key role of morphological analysis of ICI-myositis patients. Precise identification of the entire spectrum of myositis that can occur after/during treatment with ICIs is important to further evaluate pathogenetic hypotheses and improve clinical management, as depending on the subtype, initiation of treatment might be necessary even more rapidly and aggressively.