The clinicopathologic characteristics of our patient indicated a chronic disease course. Thus, we assumed that he had developed sIBM more than 3 years before receiving the anti-PD-1 therapy. The PD-1/PD-L1 pathway is thought to be involved in the pathogenesis of sIBM [6]. Anti-PD-1 therapy in our patient may have affected the PD-1/PD-L1 pathway, activated CD8- and PD-1-positive T cells targeting the muscle, and finally revealed the existence of sIBM.
Few studies have been conducted on PD-L1 expression in muscle fibers. Wiendl et al. firstly reported that PD-L1 was expressed in inflamed skeletal muscle fibers in polymyositis, dermatomyositis, and sIBM [7]. We also found upregulated PD-L1 expression in non-necrotic skeletal muscle fibers in ICI-induced myositis [1]. Furthermore, PD-L1 expression in inflamed cardiac muscle fibers was reported in ICI-induced cardiomyositis [8]. The significance of PD-L1 expression in muscle fibers is not fully understood, but PD-L1 expression in muscles was proposed to be a protective mechanism to inflammation [1, 7, 8]. Additional studies are needed to elucidate the function of PD-L1 on muscle fibers in inflammation and the effect of ICI therapy on the expression of PD-L1.
In our case, pembrolizumab maintained stable disease for 3 months after the first infusion, suggesting the possible efficacy for his cancer. This finding is consistent with the association between development of irAEs and better responses to ICI and favorable outcomes in patients with lung cancer [9]. More cases should be accumulated to identify factors that may influence patient outcomes for cancers.
Our patient showed no further CK elevation after the second pembrolizumab infusion. Recent papers reported patients with moderate myositis who had no exacerbation after ICI reintroduction [2, 10]. These reported cases and our case suggest that ICI reintroduction does not always cause exacerbation of pre-existing myositis. Notably, a large study on irAEs showed that the recurrence of irAE symptoms after ICI reintroduction is associated with severity and a long duration of initial irAEs [11].
ICI therapy can alter the patient’s immune environment and tumor antigenicity by the upregulation of immune checkpoint molecules, including PD-L1, in a time-dependent manner [12]. In our case, changes in the immune environment due to the ICI administration may have reduced susceptibility to the development of irAE and increased the resistance of the tumor to ICI.
Regarding the judgment of restarting ICI, classifying the severity of an irAE is important, because grade 4 (life-threatening) irAEs are an absolute contraindication for ICI therapy [9]. In our case, the patient’s muscular symptoms were classified as a grade 2 (moderate) myositis, and the highest CK level was also classified as grade 2 (moderate). After confirming that the patient’s CK levels had decreased and noticing his brain metastasis, the doctor in charge decided to resume pembrolizumab for the following reasons: (i) the first infusion showed the potential efficacy in treating his tumor; (ii) the patient was unaware of the chronic symptoms of sIBM; and (iii) the patient strongly desired to continue the therapy. It is reasonable that the decision to restart ICI be judged based on multiple factors that affect each patient individually in the clinical setting.
Guidelines for ICI therapy recommend general pre-therapy work-up to predict irAEs, including physical examination, exploration of pre-existing autoimmune diseases and baseline laboratory and imaging studies [13]. sIBM, the most common and chronic myopathy in the elderly, is often overlooked by patients and unacknowledged by non-neurologists. Considering the increasing opportunities for ICI therapy with elderly patients, we believe that sIBM should be added to the list of autoimmune diseases needed to be explored before ICI therapy. Furthermore, once patients develop irAEs with high CK levels, it is necessary to confirm whether they have sIBM to avoid unnecessary immunosuppressive therapies and to assess whether the patients can tolerate ICI reintroduction.