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Immune checkpoint inhibitor-associated myopathy: a clinicoseropathologically distinct myopathy.

ABSTRACT: Immune checkpoint inhibitors have revolutionized the landscape of cancer treatment. Alongside their many advantages, they elicit immune-related adverse events, including myopathy, which potentially result in substantial morbidity if not recognized and treated promptly. Current knowledge of immune checkpoint inhibitor-associated myopathy is limited. We conducted a 5-year retrospective study of patients with immune checkpoint inhibitor-associated myopathy. Clinical features, survival and ancillary test findings were analysed and compared with those of immune-mediated necrotizing myopathy patients without immune checkpoint inhibitor exposure seen during the same time period. We identified 24 patients with immune checkpoint inhibitor-associated myopathy (median age 69?years; range 28-86) and 38 patients with immune-mediated necrotizing myopathy. Ocular involvement occurred in 9/24 patients with immune checkpoint inhibitor exposure, without electrodiagnostic evidence of neuromuscular transmission defect, and in none of the immune-mediated necrotizing myopathy patients (P?P?P?P?P?P?P?=?0.004). In summary, immune checkpoint inhibitor-associated myopathy is a distinct, treatable immune-mediated myopathy with common ocular involvement, frequent lymphopenia and necrotizing histopathology, which contrary to immune-mediated necrotizing myopathy, is featured by clusters of necrotic fibres and not accompanied by anti-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle antibodies. Normal or mildly elevated creatine kinase level does not exclude the diagnosis.

SUBMITTER: Shelly S

PROVIDER: S-EPMC7713997 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Immune checkpoint inhibitor-associated myopathy: a clinicoseropathologically distinct myopathy.

Shelly Shahar S Triplett James D JD Pinto Marcus V MV Milone Margherita M Diehn Felix E FE Zekeridou Anastasia A Liewluck Teerin T

Brain communications 20201102 2

Immune checkpoint inhibitors have revolutionized the landscape of cancer treatment. Alongside their many advantages, they elicit immune-related adverse events, including myopathy, which potentially result in substantial morbidity if not recognized and treated promptly. Current knowledge of immune checkpoint inhibitor-associated myopathy is limited. We conducted a 5-year retrospective study of patients with immune checkpoint inhibitor-associated myopathy. Clinical features, survival and ancillary ...[more]

PMID: 33305263

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Project description:BackgroundPatients with non-small cell lung cancer may develop pneumonitis after thoracic radiotherapy (RT) and immune checkpoint inhibitors (ICIs). We hypothesized that distinct morphologic features are associated with different pneumonitis etiologies.Materials and methodsWe systematically compared computed tomography (CT) features of RT- versus ICI-pneumonitis. Clinical and imaging features were tested for association with pneumonitis severity. Lastly, we constructed an exploratory radiomics-based machine learning (ML) model to discern pneumonitis etiology.ResultsBetween 2009 and 2019, 82 patients developed pneumonitis: 29 after thoracic RT, 23 after ICI, and 30 after RT + ICI. Fifty patients had grade 2 pneumonitis, 22 grade 3, and 7 grade 4. ICI-pneumonitis was more likely bilateral (65% vs. 28%; p = .01) and involved more lobes (66% vs. 45% involving at least three lobes) and was less likely to have sharp border (17% vs. 59%; p = .004) compared with RT-pneumonitis. Pneumonitis morphology after RT + ICI was heterogeneous, with 47% bilateral, 37% involving at least three lobes, and 40% sharp borders. Among all patients, risk factors for severe pneumonitis included poor performance status, smoking history, worse lung function, and bilateral and multifocal involvement on CT. An ML model based on seven radiomic features alone could distinguish ICI- from RT-pneumonitis with an area under the receiver-operating curve of 0.76 and identified the predominant etiology after RT + ICI concordant with multidisciplinary consensus.ConclusionRT- and ICI-pneumonitis exhibit distinct spatial features on CT. Bilateral and multifocal lung involvement is associated with severe pneumonitis. Integrating these morphologic features in the clinical management of patients who develop pneumonitis after RT and ICIs may improve treatment decision-making.Implications for practicePatients with non-small cell lung cancer often receive thoracic radiation and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. This study identified similarities and differences in pneumonitis morphology on computed tomography (CT) scans among pneumonitis due to radiotherapy (RT) alone, ICI alone, and the combination of both. Patients who have bilateral CT changes involving at least three lobes are more likely to have ICI-pneumonitis, whereas those with unilateral CT changes with sharp borders are more likely to have radiation pneumonitis. After RT and/or ICI, severe pneumonitis is associated with bilateral and multifocal CT changes. These results can help guide clinicians in triaging patients who develop pneumonitis after radiation and during ICI treatment.

Project description:BACKGROUND:The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy. SUBJECTS, MATERIALS, AND METHODS:Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB). RESULTS:Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor ß (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sjögren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low. CONCLUSION:ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sjögren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term. IMPLICATIONS FOR PRACTICE:Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sjögren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.

Project description:Introduction Immune checkpoint inhibitors (ICIs) are increasingly used to treat cancers. Kidney immune-related adverse events (IRAEs) are now well recognized, with the incidence of IRAEs ranging from 2% to 5%. Most of the initial data related to kidney IRAEs have focused on acute interstitial nephritis (AIN). There are minimal data on the types and relative frequencies of glomerular diseases associated with ICIs, their treatment, and outcomes. Methods We performed a systematic review and meta-analysis of all biopsy-proven published cases/series of glomerular pathology associated with ICIs. We searched the MEDLINE, EMBASE, and Cochrane databases from inception to February 2020. We abstracted patient-level data, including demographics, cancer and ICI therapy details, and characteristics of kidney injury. Results After screening, 27 articles with 45 cases of biopsy-confirmed ICI-associated glomerular disease were identified. Several lesion types were observed, with the most frequent being pauci-immune glomerulonephritis (GN) and renal vasculitis (27%), podocytopathies (24%), and complement 3 GN (C3GN; 11%). Concomitant AIN was reported in 41%. Most patients had ICIs discontinued (88%), and nearly all received corticosteroid treatment (98%). Renal replacement therapy (RRT) was required in 25%. Most patients had full (31%) or partial (42%) recovery from acute kidney injury (AKI), although 19% remained dialysis-dependent, and approximately one-third died. Complete or partial remission of proteinuria was achieved in 45% and 38%, respectively. Conclusion Multiple forms of ICI-associated glomerular disease have been described. Pauci-immune GN, podocytopathies, and C3GN are the most frequently reported lesions. ICI-associated glomerular disease may be associated with poor kidney and mortality outcomes. Oncologists and nephrologists must be aware of glomerular pathologies associated with ICIs and consider obtaining a kidney biopsy specimen when features atypical for AIN are present. Graphical abstract

Dataset Information

Immune checkpoint inhibitor-associated myopathy: a clinicoseropathologically distinct myopathy.

Publications

Immune checkpoint inhibitor-associated myopathy: a clinicoseropathologically distinct myopathy.

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