Anti-Ku + myositis: an acquired inflammatory protein-aggregate myopathy.

Myositis with anti-Ku-autoantibodies is a rare inflammatory myopathy associated with various connective tissue diseases. Histopathological studies have identified inflammatory and necrotizing aspects, but a precise morphological analysis and pathomechanistic disease model are lacking. We therefore aimed to carry out an in-depth morpho-molecular analysis to uncover possible pathomechanisms. Muscle biopsy specimens from 26 patients with anti-Ku-antibodies and unequivocal myositis were analyzed by immunohistochemistry, immunofluorescence, transcriptomics, and proteomics and compared to biopsy specimens of non-disease controls, immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Clinical findings and laboratory parameters were evaluated retrospectively and correlated with morphological and molecular features. Patients were mainly female (92%) with a median age of 56.5 years. Isolated myositis and overlap with systemic sclerosis were reported in 31%, respectively. Isolated myositis presented with higher creatine kinase levels and cardiac involvement (83%), whereas systemic sclerosis-overlap patients often had interstitial lung disease (57%). Histopathology showed a wide spectrum from mild to pronounced myositis with diffuse sarcolemmal MHC-class I (100%) and -II (69%) immunoreactivity, myofiber necrosis (88%), endomysial inflammation (85%), thickened capillaries (84%), and vacuoles (60%). Conspicuous sarcoplasmic protein aggregates were p62, BAG3, myotilin, or immunoproteasomal beta5i-positive. Proteomic and transcriptomic analysis identified prominent up-regulation of autophagy, proteasome, and hnRNP-related cell stress. To conclude, Ku + myositis is morphologically characterized by myofiber necrosis, MHC-class I and II positivity, variable endomysial inflammation, and distinct protein aggregation varying from IBM and IMNM, and it can be placed in the spectrum of scleromyositis and overlap myositis. It features characteristic sarcoplasmic protein aggregation on an acquired basis being functionally associated with altered chaperone, proteasome, and autophagy function indicating that Ku + myositis exhibit aspects of an acquired inflammatory protein-aggregate myopathy.

Pathologic Features of Anti-Ku Myositis.

OBJECTIVE: Characteristics of myositis with anti-Ku antibodies are poorly understood. The purpose of this study was to elucidate the pathologic features of myositis associated with anti-Ku antibodies, compared with immune-mediated necrotizing myopathy (IMNM) with anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, in muscle biopsy-oriented registration cohorts in Japan and Germany. METHODS: We performed a retrospective pathology review of patients with anti-Ku myositis samples diagnosed in the Japanese and German cohorts. We evaluated histologic features and performed HLA phenotyping. RESULTS: Fifty biopsied muscle samples in the Japanese cohort and 10 in the German cohort were obtained. After exclusion of myositis-specific autoantibodies or other autoimmune connective tissue diseases, 26 samples (43%) of anti-Ku antibody-positive myositis were analyzed. All the samples shared some common features with IMNM, whereas they showed expression of MHC class II and clusters of perivascular inflammatory cells more frequently than the anti-SRP/HMGCR IMNM samples (71% vs 7%/16%; p < 0.005/<0.005; 64% vs 0%/0%; p < 0.005/<0.005). Anti-Ku myositis biopsies could be divided into 2 subgroups based on the extent of necrosis and regeneration. The group with more abundant necrosis and regeneration showed a higher frequency of MHC class II expression and perivascular inflammatory cell clusters. HLA phenotyping in the 44 available patients showed possible associations of HLA-DRB1*03:01, HLA-DRB1*11:01, and HLA-DQB1*03:01 (p = 0.0045, 0.019, and 0.027; odds ratio [OR] 50.2, 4.6, and 2.8; 95% CI 2.6-2942.1, 1.1-14.5, and 1.0-7.0) in the group with less conspicuous necrosis and regeneration. On the contrary, in the group of more abundant necrosis and regeneration, the allele frequencies of HLA-A*24:02, HLA-B*52:01, HLA-C*12:02, and HLA-DRB1*15:02 were lower than those of healthy controls (p = 0.0036, 0.027, 0.016, and 0.026; OR = 0.27, 0, 0, and 0; 95% CI 0.1-0.7, 0-0.8, 0-0.8, and 0-0.8). However, these HLA associations did not remain significant after statistical correction for multiple testing. DISCUSSION: While anti-Ku myositis shows necrotizing myopathy features, they can be distinguished from anti-SRP/HMGCR IMNM by their MHC class II expression and clusters of perivascular inflammatory cells. The HLA analyses suggest that anti-Ku myositis may have different subsets associated with myopathologic subgroups.

Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, specifically troponin-I (cTnI), troponin-T (cTnT), and creatine kinase (CK), are used for diagnosis. However, the association between temporal elevations of these biomarkers with disease trajectory and outcomes has not been established. METHODS: We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT, and CK in patients with ICI myocarditis (n=60) through 1-year follow-up in 2 cardio-oncology units (APHP Sorbonne, Paris, France and Heidelberg, Germany). A total of 1751 (1 cTnT assay type), 920 (4 cTnI assay types), and 1191 CK sampling time points were available. Major adverse cardiomyotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular or sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and sudden cardiac death. Diagnostic performance of cTnI and cTnT was also assessed in an international ICI myocarditis registry. RESULTS: Within 72 hours of admission, cTnT, cTnI, and CK were increased compared with upper reference limits (URLs) in 56 of 57 (98%), 37 of 42 ([88%] P=0.03 versus cTnT), and 43 of 57 ([75%] P<0.001 versus cTnT), respectively. This increased rate of positivity for cTnT (93%) versus cTnI ([64%] P<0.001) on admission was confirmed in 87 independent cases from an international registry. In the Franco-German cohort, 24 of 60 (40%) patients developed ≥1 MACE (total, 52; median time to first MACE, 5 [interquartile range, 2-16] days). The highest value of cTnT:URL within the first 72 hours of admission performed best in terms of association with MACE within 90 days (area under the curve, 0.84) than CK:URL (area under the curve, 0.70). A cTnT:URL ≥32 within 72 hours of admission was the best cut-off associated with MACE within 90 days (hazard ratio, 11.1 [95% CI, 3.2-38.0]; P<0.001), after adjustment for age and sex. cTnT was increased in all patients within 72 hours of the first MACE (23 of 23 [100%]), whereas cTnI and CK values were less than the URL in 2 of 19 (11%) and 6 of 22 (27%) of patients (P<0.001), respectively. CONCLUSIONS: cTnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis. A cTnT:URL ratio <32 within 72 hours of diagnosis is associated with a subgroup at low risk for MACE. Potential differences in diagnostic and prognostic performances between cTnT and cTnI as a function of the assays used deserve further evaluation in ICI myocarditis.

Anti-SAE autoantibody in dermatomyositis: original comparative study and review of the literature.

OBJECTIVE: Among specific autoantibodies in DM, the anti-small ubiquitin-like modifier activating enzyme (SAE) antibody is rare. We aim to describe the clinical characteristics, cancer prevalence, and muscle pathology of anti-SAE-positive DM. METHODS: Patients with a diagnosis of DM and sera positive for the anti-SAE antibody were recruited from 19 centres in this retrospective observational study. The available muscular biopsies were reviewed. We conducted a comparison with anti-SAE-negative DM and a review of the literature. RESULTS: Of the patients in the study (n = 49), 84% were women. Skin involvement was typical in 96% of patients, with 10% having calcinosis, 18% ulceration and 12% necrosis; 35% presented with a widespread skin rash. Muscular disease affected 84% of patients, with mild weakness [Medical Research Council (MRC) scale 4 (3, 5)], although 39% of patients had dysphagia. Muscular biopsies showed typical DM lesions. Interstitial lung disease was found in 21% of patients, mainly with organizing pneumonia pattern, and 26% of patients showed dyspnoea. Cancer-associated myositis was diagnosed in 16% of patients and was responsible for the majority of deaths, its prevalence being five times that of the general population. IVIG therapy was administered to 51% of the patients during the course of the disease. Comparison with anti-SAE-negative DM (n = 85) showed less and milder muscle weakness (P = 0.02 and P = 0.006, respectively), lower creatinine kinase levels (P < 0.0001) and less dyspnoea (P = 0.003). CONCLUSION: Anti-SAE positive DM is a rare subgroup associated with typical skin features but a potentially diffuse rash, a mild myopathy. Interstitial lung disease defines an organizing pneumonia pattern. Cancer associated DM prevalence is five times that of the general population. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT04637672.

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. SIGNIFICANCE: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.

Deep phenotyping of an international series of patients with late-onset dysferlinopathy.

BACKGROUND: To describe the clinical, pathological, and molecular characteristics of late-onset (LO) dysferlinopathy patients. METHODS: Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30 years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early-onset (EO) dysferlinopathy (<30 years) were randomly selected from the COS study as a control group, and the North Star Assessment for Dysferlinopathy (NSAD) and Activity Limitation (ACTIVLIM) scores were used to assess functionality. Muscle biopsies obtained from 11 LO and 11 EO patients were revisited. RESULTS: Forty-eight patients with LO dysferlinopathy were included (28 females). Median age at onset of symptoms was 37 (range 30-57) years and most patients showed a limb-girdle (n = 26) or distal (n = 10) phenotype. However, compared with EO dysferlinopathy patients (n = 48), LO patients more frequently showed atypical phenotypes (7 vs. 1; p = 0.014), including camptocormia, lower creatine kinase levels (2855 vs. 4394 U/L; p = 0.01), and higher NSAD (p = 0.008) and ACTIVLIM scores (p = 0.016). Loss of ambulation in LO patients tended to occur later (23 ± 4.4 years after disease onset vs. 16.3 ± 6.8 years; p = 0.064). Muscle biopsy of LO patients more frequently showed an atypical pattern (unspecific myopathic changes) as well as significantly less necrosis regeneration and inflammation. Although LO patients more frequently showed missense variants (39.8% vs. 23.9%; p = 0.021), no differences in dysferlin protein expression were found on Western blot. CONCLUSIONS: Late-onset dysferlinopathy patients show a higher frequency of atypical presentations, are less severely affected, and show milder dystrophic changes in muscle biopsy.

Treatment strategies and safety of rechallenge in the setting of immune checkpoint inhibitors-related myositis: a national multicentre study.

OBJECTIVES: The occurrence of immune-related myositis (irM) is increasing, yet there are no therapeutic guidelines. We sought to analyse the current therapeutic strategies of irM and evaluate the outcomes of immune checkpoint inhibitors (ICIs) rechallenge. METHODS: We conducted a nationwide retrospective study between April 2018 and March 2020 including irM without myocardial involvement. Depending on the presence of cutaneous signs or unusual histopathological features, patients were classified into two groups: typical or atypical irM. Therapeutic strategies were analysed in both groups. The modalities and outcomes of ICI rechallenge were reviewed. RESULTS: Among the 20 patients, 16 presented typical irM. Regardless of severity, most typical irM were treated with steroid monotherapy (n = 14/16) and all had a complete response within ≤3 weeks. The efficacy of oral steroids for non-severe typical irM (n = 10) was the same with low-dose (≤0.5 mg/kg/day) or high-dose (1 mg/kg/day). Severe typical irM were successfully treated with intravenous methylprednisolone. Atypical irM (n = 4) had a less favourable evolution, including one irM-related death, and required heavy immunosuppression. ICIs were safely reintroduced in nine patients presenting a moderate (n = 6) or a severe (n = 3) irM. CONCLUSION: Our data highlight that steroid monotherapy is an effective treatment for typical irM, either with prednisone or with intravenous methylprednisone pulses depending on the severity. The identification of unusual features is important in determining the initial therapeutic strategy. The outcomes of rechallenged patients are in favour of a safe reintroduction of ICI following symptom resolution and creatin kinase (CK) normalization in moderate and severe forms of irM.

Ganglionopathies Associated with MERRF Syndrome: An Original Report.

Neuropathies in Myoclonic Epilepsy with Ragged Red Fibers (MERRF) syndrome are frequent but ganglionopathies have never been reported. We retrospectively identified 24 patients with MERRF mutations in the neuromuscular center Nord/Est/Ile de France (Pitié-Salpêtrière, Paris, France). Seventeen nerve conduction studies (NCS) were available. Five patients had MERRF syndrome and ganglionopathy, a pure sensory neuropathy. All of them displayed ataxia and mild clinical sensory abnormalities. Ganglionopathies have been reported in mitochondrial diseases but never in MERRF syndrome. We suggest that patients presenting with ganglionopathy, especially if associated with myopathy, lipomatosis or epilepsy, should be screened for MERRF mutations.

Edematous myositis: a clinical presentation first suggesting dermatomyositis diagnosis.

AIMS: Edema of the limbs is uncommon in idiopathic inflammatory myopathies (IIM). The few reported cases have been associated with severe and refractory dermatomyositis (DM), sometimes in association with cancers. We aimed to determine if edematous myositis is a homogeneous subtype based on clinical, serological and pathological features. METHODS: This is a retrospective observational study performed between 2008 and 2015 in the French national referral center for myositis. All adult patients with an inflammatory muscle biopsy and upper limbs edema were included as well as IIM cases without limb edema as controls. Clinical, biological and pathological features were collected. RESULTS: Seventeen edematous myositis were included and compared to 174 IIM without edema, including 50 DM controls. Edema was the first manifestation in 23% of patients. Muscle weakness was severe and symmetric, 71% of patients presented dysphagia and a restrictive ventilatory pattern was found in 40%. Fifty-two percent of patients had a typical DM skin rash and 23% had cancer within 3 years of diagnosing myositis. Fifty-three percent of patients presented a myositis specific antibody and only DM-specific antibodies were detected. Classic pathological DM features (perifascicular atrophy, perifascicular/perimysial perivascular inflammation) were uncommon but capillary C5b-9 deposition and MxA expression were seen in 79% and 73% of cases, respectively. A perimysial edema was found in 82% of cases. Seventeen percent of patients died (median follow up of 18 months). Edematous myositis demonstrated more marked capillary C5b-9 deposition compared to IIM controls. There was no clinical, biological or pathological difference with DM controls except for limb edema. CONCLUSION: Our study underlines that limb edema could be a symptom of IIM and that edematous myositis are mostly DM. The vasculopathy seems to play a key role in its pathophysiology. Limb edema associated with muscle impairment should suggest the diagnosis of DM in clinical settings.

Granulomatosis-associated myositis: High prevalence of sporadic inclusion body myositis.

OBJECTIVE: To refine the predictive significance of muscle granuloma in patients with myositis. METHODS: A group of 23 patients with myositis and granuloma on muscle biopsy (granuloma-myositis) from 8 French and Belgian centers was analyzed and compared with (1) a group of 23 patients with myositis without identified granuloma (control-myositis) randomly sampled in each center and (2) a group of 20 patients with sporadic inclusion body myositis (sIBM) without identified granuloma (control-sIBM). RESULTS: All but 2 patients with granuloma-myositis had extramuscular involvement, including signs common in sarcoidosis that were systematically absent in the control-myositis and the control-sIBM groups. Almost half of patients with granuloma-myositis matched the diagnostic criteria for sIBM. In these patients, other than the granuloma, the characteristics of the myopathy and its nonresponse to treatment were similar to the control-sIBM patients. Aside from 1 patient with myositis overlapping with systemic sclerosis, the remaining patients with granuloma-myositis did not match the criteria for a well-defined myositis subtype, suggesting pure sarcoidosis. Matching criteria for sIBM was the sole feature independently associated with nonresponse to myopathy treatment in patients with granuloma-myositis. CONCLUSION: Patients with granuloma-myositis should be carefully screened for sIBM associated with sarcoidosis in order to best tailor their care.

Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment.

Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene.In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model.In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples.These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.

LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2.

Currently only 25-30% of patients with axonal forms of Charcot-Marie-Tooth disease (CMT) receive a genetic diagnosis. We aimed to identify the causative gene of CMT type 2 in 8 non-related French families with a distinct clinical phenotype. We collected clinical, electrophysiological, and laboratory findings and performed genetic analyses in four different French laboratories. Seventy-two patients with autosomal dominant inheritance were identified. The disease usually started in the fourth decade and the clinical picture was dominated by sensory ataxia (80%), neuropathic pain (38%), and length-dependent sensory loss to all modalities. Electrophysiological studies showed a primarily axonal neuropathy, with possible isolated sensory involvement in milder phenotypes. Disease severity varied greatly but the clinical course was generally mild. We identified 2 novel variants in LRSAM1 gene: a deletion of 4 amino acids, p.(Gln698_Gln701del), was found in 7 families and a duplication of a neighboring region of 10 amino acids, p.(Pro702_Gln711dup), in the remaining family. A common haplotype of ~450 kb suggesting a founder effect was noted around LRSAM1 in 4 families carrying the first variant. LRSAM1 gene encodes for an E3 ubiquitin ligase important for neural functioning. Our results confirm the localization of variants in its catalytic C-terminal RING domain and broaden the phenotypic spectrum of LRSAM1-related neuropathies, including painful and predominantly sensory ataxic forms.

A novel nonsense PIEZO2 mutation in a family with scoliosis and proprioceptive defect.

PIEZO2 mutations have been described in dominant arthrogryposis, but homozygous mutations of PIEZO2 may also be responsible for more complex clinical patterns, associating distal arthrogryposis, neonatal respiratory insufficiency, scoliosis and proprioceptive impairment. We report here two sisters presenting with these clinical and genetic features. They had a similar phenotype, with severe hypotonia and respiratory distress at birth, delayed acquisition of motor milestones and need of scoliosis surgery. Hypotonia and alteration of proprioception were at the forefront of clinical examination for both, along with areflexia, hyperlaxity, cutis laxa, and discrete facial dysmorphy. Electrophysiological studies, including electroneuromyography and sensory evoked potentials, showed a mild sensory axonopathy without any myopathic features, but revealed a peripheral proximal lemniscal defect. Creatine kinase, muscular MRI and biopsy were normal, as well as cerebral MRI and neurometabolic biological explorations. They had a moderate restrictive syndrome on respiratory function tests and cardiac function was normal. Molecular studies performed on a panel of genes involved in distal arthrogryposis disclosed a nonsense homozygous c.3241C > T (p.Arg1051*) mutation in the PIEZO2 gene, which was also present at the heterozygous state in their mother's DNA. This new PIEZO2 mutation was in accordance with the phenotype combining arthrogryposis, scoliosis, hyperlaxity and proprioceptive impairment.

Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer.

OBJECTIVE: To report the clinicopathologic features and outcome of myositis in patients treated with immune checkpoint inhibitors (ICIs) (irMyositis). METHODS: We retrospectively analyzed patients diagnosed with irMyositis in tertiary centers in Paris, France, and Berlin, Germany, from January 2015 to July 2017. The main outcomes were clinical manifestations and muscle histology, which included major histocompatibility complex class I (MHC-I), C5b-9, CD3, CD4, CD8, CD20, CD68, programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L) 1, and programmed cell death 1 ligand 2 (PD-L2). RESULTS: Ten patients with metastatic cancer were included; median age was 73 (range 56-87) years. Median follow-up duration was 48 (range 16-88) weeks. Six patients developed myositis during nivolumab therapy, 1 patient during pembrolizumab, 1 patient during durvalumab, and 2 patients during combined nivolumab and ipilimumab. Median delay between ICI initiation and myositis onset was 25 (range 5-87) days. Clinical manifestations were dominated by acute or subacute myalgia (8 patients) and limb-girdle (7), axial (7), and oculomotor (7) weakness. Four patients had evidence of myocarditis. In all patients, creatine kinase levels were elevated (median 2,668, range 1,059-16,620 U/L), while anti-acetylcholine receptor and myositis-associated antibodies were negative. Electrodiagnostic studies showed myopathic process without decrement in all patients. Muscle biopsy constantly showed multifocal necrotic myofibers, sarcolemmal MHC-I, and endomysial inflammation, consisting mainly of CD68+ cells expressing PD-L1 and CD8+ cells expressing PD-1. ICI treatment was withdrawn in all patients; 9 patients received immunosuppressive therapy, which consistently led to marked clinical improvement. CONCLUSIONS: irMyositis presents with remarkably homogeneous and unique clinicopathologic features, expanding the nosologic spectrum of inflammatory myopathies in patients with cancer. ICI withdrawal and treatment with corticosteroids improve outcome.