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Objectives: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of several locally advanced and metastatic tumors. They enhance the effector function of the immune system, consequently leading to different immune-related adverse events. The aim of the present study was to describe three cases of dermatomyositis (DM) triggered by ICI diagnosed at our institution and to perform a review of the literature., Methods: We performed a retrospective clinical, laboratory, and pathological evaluation of three cases of DM triggered by ICI belonging to a cohort of 187 DM patients from the Clinic Hospital Muscle Research Group of Barcelona from January 2009 to July 2022. Moreover, we undertook a narrative review of the literature from January 1990 to June 2022., Results: Cases from our institution were triggered by avelumab, an anti-PD-1 ligand (PD-L1), nivolumab, and pembrolizumab, both anti-programmed death-1 (PD-1). One of these patients had locally advanced melanoma, and two had urothelial carcinoma. The severity and response to treatment were heterogeneous among the different cases. All were positive at high titers for anti-TIF1γ autoantibodies; in one of them, serum before the onset of ICI was available, and anti-TIF1γ autoantibodies were already present. RNA expression of IFNB1, IFNG and genes stimulated by these cytokines were markedly elevated in these patients., Conclusions: In conclusion, data from our patients and the narrative review suggest that early positivity to anti-TIF1γ unleashed by ICI may play a role in the development of full-blown DM, at least in some cases., Competing Interests: Declaration of Competing Interest The authors report no disclosures., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Severe Acute Respiratory Syndrome related to Coronavirus-2 (SARS-CoV-2), coronavirus disease-2019 (COVID-19) may cause severe illness in 20% of patients. This may be in part due to an uncontrolled immune-response to SARS-CoV-2 infection triggering a systemic hyperinflammatory response, the so-called "cytokine storm". The reduction of this inflammatory immune-response could be considered as a potential therapeutic target against severe COVID-19. The relationship between inflammation and clot activation must also be considered. Furthermore, we must keep in mind that currently, no specific antiviral treatment is available for SARS-CoV-2. While moderate-severe forms need in-hospital surveillance plus antivirals and/or hydroxychloroquine; in severe and life-threating subsets a high intensity anti-inflammatory and immunomodulatory therapy could be a therapeutic option. However, right data on the effectiveness of different immunomodulating drugs are scarce. Herein, we discuss the pathogenesis and the possible role played by drugs such as: antimalarials, anti-IL6, anti-IL-1, calcineurin and JAK inhibitors, corticosteroids, immunoglobulins, heparins, angiotensin-converting enzyme agonists and statins in severe COVID-19., Competing Interests: Declaration of Competing Interest The author also state that they do not have any commercial or any other type of interest that may have influenced the drawing up and the results of this paper., (Copyright © 2020. Published by Elsevier B.V.)

Background and Objective: Drug-induced myopathy is among the most common causes of muscle disease. An association has recently been described between programmed death-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors and immune-related adverse events (irAE) affecting the muscle. Here, we report the clinical and pathological findings of nine unrelated patients with PD-1 and PD-L1 inhibitors-associated myopathy., Methods: We retrospectively analyzed 317 muscle biopsies performed for diagnostic purposes from January 2017 to June 2019. Patients were attended in two tertiary centers and muscle biopsies were performed and analyzed by two myology experts. Muscle biopsies were frozen in cooled isopenthane, cryostat sectioned and stained. Immunohistochemistry studies were also performed as a routine procedure in our lab., Results: We identified 9 patients receiving anti-PD-1 or PD-L1 inhibitors consulting for either muscle weakness, asthenia, myasthenic-like syndrome or other muscle related-symptoms, along with biopsy-proven inflammatory myopathy. One had concomitant myocarditis. In most of the cases muscle biopsy showed a marked phenomenon of necrosis, macrophagy and muscle regeneration with perivascular inflammatory infiltrates with a large component of macrophagic cells. A tendency to perifascicular atrophy was also noticed. The expression of MHC class I antigens predominated in the perifascicular zones. Raised muscle enzymes were detected in 7 patients., Conclusion: A characteristic clinic-pathological pattern, including a myasthenia gravis-like syndrome plus myositis was found in patients receiving PD-1 and PD-1 L inhibitors. A large component of macrophages resembling granulomas seems to be the pathological hallmark of the syndrome. Further information is required to understand the wide spectrum of immune-related adverse events involving the muscle during or after treatment with anti-PD-1 inhibitors, but the pathological picture seems to be characteristic., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Emerging data have shown an increased risk of malignancy among patients diagnosed with systemic sclerosis (SSc) so identification of risk factors linking both disorders might have prognostic implications. The aim of this study was to assess the clinical and treatment-related risk factors for cancer in a single-center cohort of patients with SSc., Methods: Demographic, clinical, capillaroscopic, immunological and treatment-related data from 432 consecutive SSc patients were retrospectively analyzed. Variables that reached significant association in the univariate analysis were entered into a logistic regression in order to identify independent risk factors for cancer., Results: Malignancy was diagnosed in 53 patients (12.2%). Fifty-eight neoplasms were identified, among which breast (n=15), lung (n=10) and hematologic (n=9) malignancies were the most prevalent. In 19 patients the diagnosis of both scleroderma and tumour was made in <3years apart. Cancer significantly decreased the probability of survival (OR=2.61; 95%CI 1.46-4.69; p=0.001). No association with age, sex, smoking, cutaneous subset or RNA polymerase-III antibodies was found. However, risk of cancer was directly associated with the presence of anti-PM/Scl antibodies (OR=3.90; 95%CI 1.31-11.61; p=0.014), and inversely related to aspirin use (OR=0.33; 95%CI 0.12-0.90; p=0.031), which remained as independent risk factors for cancer on multivariate analysis., Conclusions: PM/Scl antibodies seem to be associated with a higher risk of cancer in scleroderma. In contrast, the use of aspirin is related to a lower risk of cancer in our series. More studies are needed to ascertain the role of anti PM/Scl antibodies and aspirin in the development of malignancy among patients with SSc., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Objective: Statin-associated autoimmune myopathy (SAAM) with anti-HMGCR antibodies has recently been described. Several specific immunoassays are in use to detect HMGCR antibodies. In the course of systematic autoantibody screening we recognized a new distinct IFL staining pattern on rat liver sections that regularly coincided with anti-HMGCR antibodies. In this study we investigated whether this new IFL pattern is specifically associated to statin-associated autoimmune myopathy and corresponds to anti-HMGCR antibodies., Patients and Methods: Twenty-three patients positive for anti-HMGCR antibodies (14 diagnosed with SAAM) were investigated for anti-HMGCR antibodies by two ELISA assays and confirmed by immmunoblot. HMGCR associated liver IFL pattern (HALIP) was detected by indirect IFL and the reactivity against HMGCR was confirmed by immunoabsorption using purified human HMGCR antigen. 90 patients with other autoimmune diseases and 45 non-autoimmune statin treated patients were studied as controls., Results: 21 out of 23 (91%) anti-HMGCR positive patients were HALIP positive. The staining was completely and specifically removed by immunoabsorption with human purified HMGCR. None of the control sera from autoimmune patients or non-autoimmune statin treated subjects was positive for HALIP. Statistical concordance between HALIP and anti-HMGCR antibody specific tests was 98.7%, kappa 0.95., Conclusions: A new and distinct IFL staining pattern (HALIP) is associated to HMGCR associated myopathy. Absorption and concordance studies indicate that the antigen recognized in the liver by HALIP is HMGCR or a closely related protein. Awareness of this new pattern can help to detect HMGCR autoantibodies in statin treated patients tested for autoimmune serology., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: The aim of this study is to describe a novel myositis-associated autoantibody (anti-cortactin antibody) and assess related clinical and immunological manifestations and its clinical significance., Methods: Adult patients with myositis (dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and inclusion body myositis), as well as patients with other autoimmune diseases and non-inflammatory myopathies were analyzed for the presence of anti-cortactin antibody using in-house developed ELISA and immunoblotting techniques with a commercial source of purified cortactin. The cut-off for positive status was determined in a group of healthy volunteers., Results: Antibody against cortactin was positive in 7/34 (20%) polymyositis patients, 9/117 (7.6%) dermatomyositis, 2/7 (26%) immune-mediated necrotizing myopathy, and none of the 4 patients with inclusion body myositis. The antibody also tested positive in 3/101 patients with other autoimmune diseases (2 systemic sclerosis and 1 systemic lupus erythematosus), and in 1/29 patients with non-inflammatory myopathy. No relevant association with specific clinical features was found in patients with these antibodies. Anti-cortactin antibody was more frequently positive in patients with polymyositis and immune-mediated necrotizing myopathy than in the remaining myositis patients, and was the only myositis autoantibody found in sera of 3 patients from these groups., Conclusions: Our data indicate that cortactin is a novel target antigen in patients with autoimmune diseases, especially patients with polymyositis or immune-mediated necrotizing myopathy. Anti-cortactin can be considered a new myositis-associated antibody., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease in elderly individuals, particularly men. Its prevalence varies among ethnic groups but is estimated at 35 per one million people over 50. Genetic as well as environmental factors and autoimmune processes might both have a role in its pathogenesis. Unlike other inflammatory myopathies, sIBM causes very slowly progressive muscular weakness and atrophy, having a distinctive pattern of muscle involvement and different forms of clinical presentation. In some cases a primary autoimmune disease coexists. Diagnosis is suspected on clinical grounds and is established by typical muscle pathology. As a rule sIBM is refractory to conventional forms of immunotherapy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Eosinophilia-associated myopathies are clinically and pathologically heterogeneous conditions characterized by the presence of peripheral and/or muscle eosinophilia. There are at least three distinct subtypes: focal eosinophilic myositis, eosinophilic polymyositis, and eosinophilic perimyositis. Infiltrating eosinophils are not always identified in conventional muscle histologic examination, but the eosinophil major basic protein, whose extracellular diffusion is considered a hallmark of eosinophilic cytotoxicity, is usually detected by immunostaining in muscle biopsy. Whereas focal eosinophilic myositis seems to be a benign and isolated condition, and perimyositis is usually related with the inflammatory infiltrate due to fasciitis, eosinophilic polymyositis can be associated with muscular dystrophy or be a feature of multiorgan hypereosinophilic syndrome. Muscle biopsy remains the cornerstone for the diagnosis. Parasitic infections, connective tissue disorders, hematologic and non-hematologic malignancies, drugs, and toxic substances are the main etiologic agents of eosinophilia-associated myopathy. However, in some cases, no known etiologic factor is identified, and these are considered idiopathic. Glucocorticoids are the mainstay therapy in idiopathic forms. Imatinib and mepolizumab, a humanized anti-interleukin 5 monoclonal antibody, may be useful in patients with eosinophilic myositis as part of a hypereosinophilic syndrome., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Myotilinopathies are a group of muscle disorders caused by mutations in the MYOT gene. It was first described in two families suffering from limb girdle muscle dystrophy type 1 (LGMD 1A), and later identified in a subset of dominant or sporadic patients suffering from myofibrillar myopathy, as well as in a family with spheroid body myopathy. Disease phenotypes associated with MYOT mutations are clinically heterogeneous and include pure LGMD forms as well as late-onset distal myopathies. We report here on a 53-year-old male suffering from a unique clinical profile characterized by generalized symmetrical increase in muscle bulk leading to a Herculean appearance. Muscle weakness and stiffness in the lower extremities were the patient's main complaints. Muscle MRI showed extensive fatty infiltration in the thigh and leg muscles and a muscle biopsy showed a myofibrillar myopathy with prominent protein aggregates. Gene sequencing revealed a Ser55Phe missense mutation in the myotilin gene. The mutation was identified in his older brother, who presented a mild hypertrophic appearance and had a myopathic pattern in EMG, despite not presenting any of the complaints of the proband and having normal muscle strength. This finding, and his deceased father and paternal aunt's similar gait disorders, suggest that this is in fact a new autosomal dominant kindred. The present observations further expand the spectrum of clinical manifestations associated with mutations in the myotilin gene.