Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer
Mehdi TouatThierry MaisonobeSamuel KnaußOmar Ben Hadj SalemB. HervierKarine AuréTali‐Anne SzwebelN. KramkimelClaire LethrosneJean-Frédéric BruchPauline LalyJacques CadranelNicolas WeissAnthony BéhinYves AllenbachOlivier BenvenisteTimothée LengletDimitri PsimarasWerner StenzelSarah Léonard-Louis
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To report the clinicopathologic features and outcome of myositis in patients treated with immune checkpoint inhibitors (ICIs) (irMyositis).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).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 ICI treatment was withdrawn in all patients; 9 patients received immunosuppressive therapy, which consistently led to marked clinical improvement.irMyositis presents with remarkably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.Keywords:
Immune checkpoint
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The inhibitory regulators, known as immune checkpoints, prevent overreaction of the immune system, avoid normal tissue damage, and maintain immune homeostasis during the antimicrobial or antiviral immune response. Unfortunately, cancer cells can mimic the ligands of immune checkpoints to evade immune surveillance. Application of immune checkpoint blockade can help dampen the ligands expressed on cancer cells, reverse the exhaustion status of effector T cells, and reinvigorate the antitumor function. Here, we briefly introduce the structure, expression, signaling pathway, and targeted drugs of several inhibitory immune checkpoints (PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, and IDO1). And we summarize the application of immune checkpoint inhibitors in tumors, such as single agent and combination therapy and adverse reactions. At the same time, we further discussed the correlation between immune checkpoints and microorganisms and the role of immune checkpoints in microbial-infection diseases. This review focused on the current knowledge about the role of the immune checkpoints will help in applying immune checkpoints for clinical therapy of cancer and other diseases.
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Aim To establish an experimental animal myocarditis model.Methods BALB/c mice were inoculated intraperitoneally with coxsackievirus B3.Results Severe myocarditis was caused.Yellowish white patches were seen on the surface of the right ventricle of the hart from the 4 th to the 33 rd day after challenged.On the 4 th day,myocardial fibres appeared fragmented,and inflammatory cells were sparse;then,morphonuclear leukocytes and lymphcytes infilleated increased,and reached to the peak 14 days after infection;in this stage,the mortality was higher.After the 14 th day,the inflammatory infiltration decreased gradually,fibrosis can be observed.Conclusion This animal myocarditis model can be used in the research of nature course of myocarditis,the sequela,and the effect and mechanism of certain drugs used in myocarditis therapy.
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Dilated Cardiomyopathy
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We recently recorded a high prevalence of inclusion body myositis (IBM) in patients with Sjögren's syndrome (SS). Whether myositis patients with SS differ from myositis patients without SS in terms of the characteristics of the myositis is currently unknown. Anti-cytosolic 5'-nucleotidase 1 A (cN1A) has recently been proposed as a biomarker for IBM but is also frequent in SS. Whether anti-cN1A is independently associated with IBM is still an open question. We aimed to assess the significance of SS and anti-cN1A in myositis patients.Cumulative data on all myositis patients (EULAR/ACR 2017 criteria) screened for SS (ACR/EULAR 2016 criteria) in a single centre were analysed. Ninety-nine patients were included, covering the whole spectrum of EULAR/ACR 2017 myositis subgroups and with a median follow-up of 6 years (range 1.0-37.5). The 34 myositis patients with SS (myositis/SS+) were compared with the 65 myositis patients without SS (myositis/SS-).. IBM was present in 24% of the myositis/SS+ patients vs 6% of the myositis/SS- group (P = 0.020). None of the IBM patients responded to treatment, whether they had SS or not. Anti-cN1A was more frequent in myositis/SS+ patients (38% vs 6%, P = 0.0005), independently of the higher prevalence of IBM in this group (multivariate P value: 0.02). Anti-cN1A antibody specificity for IBM was 0.96 (95% CI: 0.87, 0.99) in the myositis/SS- group but dropped to 0.70 (95% CI: 0.48, 0.85) in the myositis/SS+ group.In myositis patients, SS is associated with IBM and with anti-cN1A antibodies, independently of the IBM diagnosis. As a consequence, anti-cN1A has limited specificity for IBM in myositis patients with SS.
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Myocarditis is an important but incompletely understood cause of cardiac dysfunction. Children with fulminant myocarditis often require inotropic or mechanical circulatory support, and researchers in some studies suggest that up to 42% of children who die suddenly have evidence of myocarditis. Recurrent myocarditis is extremely rare, and the vast majority of reported cases involve adult patients. Pediatric providers who suspect a recurrence of myocarditis have limited evidence to guide patient management because the literature in this domain is sparse. Here we present a unique, illustrative pediatric case of recurrent myocarditis. A 14-year-old boy presented for the second time in 2 years with a clinical history strongly suggestive of myocarditis. Although myocarditis was suggested in the results of cardiac MRI, no pathogen was identified during his first presentation. During his second episode of myocarditis, parvovirus was confirmed by polymerase chain reaction testing of an endomyocardial specimen that also met Dallas criteria for myocarditis. With each presentation, he had decreased ventricular function that subsequently normalized. To the best of our knowledge, there are no reports of recurrent myocarditis in children in whom the diagnosis was confirmed by using MRI and/or biopsy data. Reviewing this distinctive case and the existing literature may help characterize this entity and raise awareness among care providers.
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Abstract Background Immune checkpoint inhibitor (ICI)-mediated myocarditis results in significant morbidity and mortality. At our institution, we noted an increased incidence of ICI-mediated myocarditis cases, leading to further investigation in our database of advanced melanoma patients treated with ICI therapy. Methods A single-center, retrospective cohort analysis of patients with advanced melanoma identified cases of ICI-mediated myocarditis and myositis. Results 366 patients with advanced melanoma received a dose of ICI from September 2014 to October 2019. Of these patients, there were 0 cases of ICI-mediated myocarditis (0%, 95% CI 0%–1.0%) and 2 cases of ICI-mediated myositis (0.55%, 95% CI 0.07%–1.96%). From November 2019 to December 2021, an additional 246 patients with advanced melanoma were identified. Of these patients, 10 (4.1%, 95% CI 1.97%–7.35%) developed ICI-mediated myocarditis and 10 developed ICI-mediated myositis. Conclusion Our study suggests an increase in prevalence of ICI-mediated muscle damage including myositis and myocarditis in the COVID-19 era. Differentiation of these patients and further risk stratification may allow for development of guidelines for nuanced management of this serious complication.
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Background: Myositis are characterized by weakness and muscle inflammation. They encompass heterogeneous conditions, which include dermatomyositis (DM), inclusion body myositis (IBM) and polymyositis (PM) according to the EULAR/ACR 2017 criteria. We recently recorded a high prevalence of IBM in a cohort of primary Sjögren’s syndrome (SS) (1). The signification of SS in the setting of myositis is unanswered. Objectives: To refine the signification of SS in the setting of myositis. Methods: Among a monocentric myositis cohort (according to the EULAR/ACR 2017 criteria), SS patients (according to the ACR/EULAR 2016 criteria) were identified (myositis/SS+ group) and compared to myositis patients without SS (myositis/SS- group). Results: Among 414 myositis patients, SS criteria were available for 96 patients. Thirty two (33%) presented SS. Patients with SS tended to be more frequently women (F/M ratio 9.7 vs 3.0, p = 0.07). Age at diagnosis of myositis was similar in both groups (53 years [range 21-74] vs 53 years [range 16-77], p = 0.51). Myositis subtypes repartition (as defined by EULAR/ACR 2017 criteria) was different in myositis/SS+ and myositis/SS- groups (p = 0.021), IBM being four-fold more prevalent in myositis/SS+ group (25% vs 6%, p = 0.018). Accordingly, the delay between the first muscle symptoms and myositis diagnosis was longer in myositis/SS+ group (7 months [0-336] vs 4 months [0-122], p = 0.041). Moreover, aside anti-cN1A antibodies, myositis-specific antibodies were less frequently found in myositis/SS+ patients than in myositis/SS- ones (16/32 [50%] vs 46/64 [72%], p = 0.035). Anti-cN1A antibodies were more prevalent in myositis/SS+ patients (33% vs 5.8%, p = 0.0032). However, in myositis/SS+ group, anti-cN1A were frequent in each of the EULAR/ACR 2017 myositis subtypes and the association between SS and anti-cN1A positivity was maintained in a multivariate analysis adjusted with the diagnosis of IBM (p = 0.023). Seven of the myositis/SS+ patients (22%) had systemic involvement typical of SS (vs 6 [9%] of the myositis/SS- patients, p = 0.12) including polyneuropathy (6 [20%] vs 6 [10%]) and type 2 cryoglobulinaemic vasculitis (1 [3%] vs 1 [1.6%]). In addition, 2 (6%) myositis/SS+ patients developed a lymphoma (one B diffuse large cell lymphoma of the parotid and one non-Hodgkin lymphoma), vs none of the myositis/SS- patients (p = 0.11). Only one (3%) of the myositis/SS+ patients developed myositis-associated cancer (diagnosed within 3 years of myositis diagnosis) versus 6 (9%) of the myositis/SS- patients (p = 0.66). Aside hydroxychloroquine, more frequently used in myositis/SS+ group (38% vs 16%, p = 0.018), no significant difference was found in the management of the patients (taking into account the myositis subtype). Conclusion: Myositis patients with SS have more frequently IBM than myositis patients without SS. They also have more frequently anti-cN1A antibodies, independently of the myositis subtype. They might develop systemic complications of SS. References: [1]Felten R, Seror R, Vittecoq O, Hachulla E, Perdriger A, Dieude P, et al. SAT0470 Myositis, often suspected, is actually rare in primary Sjögren’s syndrome: data from the French cohort ASSESS. In BMJ Publishing Group Ltd and European League Against Rheumatism; 2018. p. 1093.1–1093. Available from: http://ard.bmj.com/lookup/doi/10.1136/annrheumdis-2018-eular.2945 Disclosure of Interests: Dan LEVY: None declared, Benoit Nespola: None declared, Margherita Giannini: None declared, Renaud FELTEN: None declared, Coralie Varoquier: None declared, Marina Rinagel: None declared, Anne-Sophie Korganow: None declared, Vincent Poindron: None declared, Thierry Martin: None declared, Francois Maurier: None declared, Hassam Chereih: None declared, Bastien Bouldoires: None declared, Baptiste Hervier: None declared, Cédric Lenormand: None declared, Laurent Arnaud: None declared, Bernard Geny: None declared, Jean Sibilia: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, alain meyer: None declared
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