The efficacy and safety of tacrolimus in patients with dermatomyositis/polymyositis: A meta-analysis and systematic review.

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus for dermatomyositis (DM) and polymyositis (PM) treatment. METHODS: We searched the Embase, PubMed, the Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure were used as searching tools from inception up to October 2022. Two authors independently selected studies. The available studies were comprehensively reviewed and investigated. RESULTS: A total of 9 studies, including 350 patients, were analysed. Pooled results showed a higher overall survival rate in tacrolimus therapy group. Creatine kinase (CK) levels and forced vital capacity (FVC) showed significant improvement after tacrolimus therapy. The incidence of adverse events including infection and renal dysfunction showed no significant differences between the tacrolimus therapy group and conventional therapy group. CONCLUSION: The results of this meta-analysis indicated that GC therapy in combination with tacrolimus therapy could help improving overall survival rate, pulmonary function and had similar safety outcomes compared to conventional therapy in DM and PM patients.

Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial.

BACKGROUND: Patients with advanced type B3 thymoma and thymic carcinoma resistant to chemotherapy have few treatment options. We report the efficacy and safety results of the combination of the anti-PD-L1 inhibitor avelumab with the anti-angiogenesis drug axitinib in patients with advanced type B3 thymoma and thymic carcinoma. METHODS: CAVEATT was a single-arm, multicentre, phase 2 trial, conducted in two Italian centres (the European Instituteof Oncology and the Humanitas Institute, Milan) in patients with histologically confirmed type B3 thymoma or thymic carcinoma, with advanced stage of disease who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis drug was allowed but not with immune checkpoint inhibitors. Other inclusion criteria were age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, progressive disease, and presence of measurable disease according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Patients received avelumab 10 mg/kg intravenously every 2 weeks and axitinib 5 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was the centrally assessed overall response rate according to RECIST version 1.1. Patients who received at least one cycle of treatment and had at least one CT scan after treatment start at scheduled time point by protocol were judged assessable for response and were included in efficacy and safety analyses. This study is registered with EUDRACT, 2017-004048-38; enrolment is completed and follow-up is ongoing. FINDINGS: Between April 22, 2019, and June 30, 2021, 32 patients were enrolled. 27 patients had a thymic carcinoma, three a type B3 thymoma, and two a mixed type B3 thymoma and thymic carcinoma. 29 (91%) of 32 patients had stage IVB disease and 13 (41%) of 32 had been pretreated with an anti-angiogenesis drug. 11 of 32 patients had an overall response; thus the overall response rate was 34% (90% CI 21-50); no patients had a complete response, 11 (34%) had a partial response, 18 (56%) had stable disease, and in two patients (6%) progressive disease was the best response. The most common grade 3 or 4 adverse event was hypertension (grade 3 in six [19%] of 32 patients). Four (12%) of 32 patients developed serious adverse events that were new-onset immune-related adverse events, including one grade 3 interstitial pneumonitis, one grade 4 polymyositis, and two grade 3 polymyositis. There were no treatment-related deaths. INTERPRETATION: Avelumab combined with axitinib has promising anti-tumour activity and acceptable toxicity in patients with advanced type B3 thymoma and thymic carcinoma progressing after chemotherapy, and could emerge as a new standard treatment option in this setting. FUNDING: Pfizer.

Life-threatening polymyositis with spontaneous hematoma induced by nivolumab in a patient with previously resected melanoma.

Single-agent anti-PD1 antibodies are usually very well tolerated, but serious toxicity can still occur. Despite the PD-1 pathway seems to be relevant in the pathogenesis of immune-related myositis, anti-PD1-related myositis is generally a rare side effect of the treatment and usually not serious. However, its frequency is likely to increase as the use of immune checkpoint blockades. We present here a case of life-threatening polymyositis with associated spontaneous muscular hematoma in a patient treated with single-agent nivolumab in the adjuvant setting. Spontaneous hematoma is an extremely rare complication with unclear etiology of idiopathic myositis. Very few cases have been reported in the literature and their outcome has been often fatal. To our knowledge, this is the first case of autoimmune myositis and spontaneous heamatoma associated with the administration of single-agent checkpoint blockade. Anti-PD1 antibodies have changed the treatment landscape for a number of cancer entities in the past few years. When given as single agent they are usually very well tolerated, but serious rare toxicity can still occur. We present here a case of polymyositis with associated spontaneous muscular hematoma in a patient treated with single agent nivolumab.

Triggers of inflammatory myopathy: insights into pathogenesis.

The inflammatory myopathies, which include dermatomyositis, polymyositis, and the immune-mediated necrotizing myopathies, are a heterogeneous group of autoimmune diseases that manifest with muscle, skin, or lung damage. Collectively, these autoimmune diseases result from loss of tolerance to a select group of self-antigens, although the precise mechanism through which this occurs is not known. Infection, malignancy, and certain medications including statins and the immune checkpoint inhibitors used in cancer therapy have been identified as potential immunologic triggers of the inflammatory myopathies. Some of these triggers are classically associated with specific myositis-specific autoantibodies (MSAs). The strong association between certain triggers and MSAs provides insights into how an immunologic event can lead to loss of tolerance to specific self-antigens, resulting in autoimmune disease. In this review, we discuss the proposed triggers of the inflammatory myopathies and their associations with MSAs, and provide insights into how these triggers may result in the inflammatory myopathies.

Lipid-lowering agent-triggered dermatomyositis and polymyositis: a case series and literature review.

Lipid-lowering agent-triggered dermatomyositis (DM) or polymyositis (PM) is a rare event. Therefore, the aim of the present study was to describe a series of such cases. A retrospective cohort study of 5 DM and 4 PM cases triggered by prior exposure to lipid-lowering agents between 2001 and 2017 was carried out. All patients, except for two cases, had muscle biopsy compatible with inflammatory myopathy and no serum autoantibodies positive for anti-SRP or anti-HMGCoAR. Median age of the patients at time of diagnosis was 68 years. Seven patients had previously taken simvastatin 20 mg/day (exposure period from 2 days to 4 years) and two bezafibrate 100 mg/day (3-4 months). Median time from symptom onset to disease diagnosis was 6 months. All patients with DM had a heliotrope and/or Gottron's papules. All patients had symmetrical, predominantly proximal muscle weakness of limbs, with median serum creatine phosphokinase of 3087U/L (interquartile 25-75% range 1293-13,937 U/L). All patients received glucocorticoid and immunosuppressants. Complete reversal of clinical symptoms and normalization of serum creatine phosphokinase level occurred within a median of 12 months after starting the treatment. There was disease relapse in three cases, and one case of death was unrelated to the disease (pulmonary infectious complications resulting from lymphoma). In contrast to cases described in the literature, the patients in the present study had a relatively more aggressive course, requiring glucocorticoids and immunosuppressants, in addition to a tendency for a longer period to achieve disease remission.

Progressive hypoventilation due to mixed CD8+ and CD4+ lymphocytic polymyositis following tremelimumab - durvalumab treatment.

BACKGROUND: The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. CASE PRESENTATION: We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. CONCLUSIONS: This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.

Febuxostat-associated eosinophilic polymyositis in marginal zone lymphoma.

Febuxostat is an orally administered selective inhibitor of xanthine oxidase approved for the treatment of gout and prevention of tumor lysis syndrome. It is a relatively safe medication. Hypersensitivity reactions associated with the use of febuxostat are quite rare with only one reported case of DRESS syndrome. Recently, two case reports of rhabdomyolysis following the initiation of febuxostat were published. We hereby present the first case of rhabdomyolysis with hypereosinophilia following the administration of febuxostat to a 50-year-old patient newly diagnosed with marginal zone lymphoma. Three weeks after the initiation of febuxostat for tumor lysis syndrome prophylaxis, the patient presented with generalized weakness, diffuse myalgia and low-grade fever. Initial studies showed creatinine kinase level of 4471, hypereosinophilia of 1900/mm3, and LDH of 2691. All infectious and autoimmune diseases were ruled out. TSH level was normal. Muscle biopsy showed myonecrosis in addition to an eosinophilic inflammatory infiltrate in the endomysium and perimysium. Discontinuation of febuxostat led to prompt symptom resolution and normalization of blood tests eight days later.

Myasthenic crisis and polymyositis induced by one dose of nivolumab.

An 80-year-old man, who developed multiple lymph node and skin metastasis of malignant melanoma, received nivolumab monotherapy. Two weeks after the first dose, he experienced anorexia and fatigue, and suffered from progressive, severe dyspnea and muscle weakness. We diagnosed him with myocarditis, myositis, and myasthenic crisis induced by nivolumab. We commenced steroid therapy, immune absorption therapy, plasma exchange therapy, and i.v. immunoglobulin therapy, and succeeded in saving his life. Because his serum level of anti-acetylcholine receptor antibodies in a sample collected before nivolumab treatment were positive and were elevated significantly after nivolumab, we suspected that nivolumab triggered a severe autoimmune response, which progressed subclinical myasthenia gravis to myasthenic crisis. We carried out T cell receptor repertoire analysis using next-generation sequencing technologies and identified infiltration of clonally expanded T cell populations in the skeletal muscle after nivolumab treatment, implying a very strong T cell immune response against muscular cells. To avoid severe immune-related adverse events, the exclusion of patients with subclinical autoimmune disease is very important for treatment with immune checkpoint inhibitors.

A crucial role of L-selectin in C protein-induced experimental polymyositis in mice.

OBJECTIVE: To investigate the role of adhesion molecules in C protein-induced myositis (CIM), a murine model of polymyositis (PM). METHODS: CIM was induced in wild-type mice, L-selectin-deficient (L-selectin(-/-) ) mice, intercellular adhesion molecule 1 (ICAM-1)-deficient (ICAM-1(-/-) ) mice, and mice deficient in both L-selectin and ICAM-1 (L-selectin(-/-) ICAM-1(-/-) mice). Myositis severity, inflammatory cell infiltration, and messenger RNA expression in the inflamed muscles were analyzed. The effect of dendritic polyglycerol sulfate, a synthetic inhibitor that suppresses the function of L-selectin and endothelial P-selectin, was also examined. RESULTS: L-selectin(-/-) mice and L-selectin(-/-) ICAM-1(-/-) mice developed significantly less severe myositis compared to wild-type mice, while ICAM-1 deficiency did not inhibit the development of myositis. L-selectin(-/-) mice that received wild-type T cells developed myositis. Treatment with dendritic polyglycerol sulfate significantly diminished the severity of myositis in wild-type mice compared to treatment with control. CONCLUSION: These data indicate that L-selectin plays a major role in the development of CIM, whereas ICAM-1 plays a lesser role, if any, in the development of CIM. L-selectin-targeted therapy may be a candidate for the treatment of PM.

Statin-associated polymyositis following omeprazole treatment.

Statins are an extensively used class of drugs, and myopathy is an uncommon, but well-described side effect of statin therapy. Inflammatory myopathies, including polymyositis, dermatomyositis, and necrotizing autoimmune myopathy, are even more rare, but debilitating, side effects of statin therapy that are characterized by the persistence of symptoms even after discontinuation of the drug. It is important to differentiate statin-associated inflammatory myopathies from other self-limited myopathies, as the disease often requires multiple immunosuppressive therapies. Drug interactions increase the risk of statin-associated toxic myopathy, but no risk factors for statin-associated inflammatory myopathies have been established. Here we describe the case of a man, age 59 years, who had been treated with a combination of atorvastatin and gemfibrozil for approximately 5 years and developed polymyositis after treatment with omeprazole for 7 months. Symptoms did not resolve after discontinuation of the atorvastatin, gemfibrozil, and omeprazole. The patient was treated with prednisone and methotrexate followed by intravenous immunoglobulin, which resulted in normalization of creatinine kinase levels and resolution of symptoms after 14 weeks. It is unclear if polymyositis was triggered by interaction of the statin with omeprazole and/or gemfibrozil, or if it developed secondary to long-term use of atorvastatin only.

T lymphocytes and muscle condition act like seeds and soil in a murine polymyositis model.

OBJECTIVE: It has been reported that polymyositis (PM) is driven by CD8+ cytotoxic T lymphocytes. The C protein-induced myositis (CIM) model we have established is similar to PM in pathology except that it undergoes spontaneous remission. We undertook the present study to delineate the roles of innate and acquired immunity in myositis. METHODS: C57BL/6 mice were immunized with recombinant C protein fragments together with Freund's complete adjuvant (CFA) and Toll-like receptor (TLR) ligands at hind leg footpads and tail bases. CIM mediated by adoptive transfer of T cells to naive mice was treated with cytokine antagonists. RESULTS: Second immunization with C protein fragments revealed no induction of tolerance. Injection of CFA and TLR ligands at the hind leg footpads reinduced myositis in the same legs. Interestingly, initial myositis was observed only in the CFA-treated forelegs. Transfer of C protein fragment-specific T cells from mice with CIM induced myositis in CFA- and TLR ligand-treated legs of recipient mice. CFA treatment resulted in the recruitment of macrophages producing inflammatory cytokines. Induction of myositis was inhibited by blocking interleukin-1 receptor or tumor necrosis factor α. CONCLUSION: Myositis development requires activation of autoaggressive T cells and conditioning of muscle tissue. CIM regression is due to attenuation of local CFA-induced immune activation. These results are in accordance with a "seed and soil" model of disease development and might offer clues to decipher clinical aspects of PM.

Statins as a possible cause of inflammatory and necrotizing myopathies.

BACKGROUND: Hydroxy-methyl-glutaryl Co-A reductase (HMGCR) inhibitors or statins are a well recognized cause of a variety of skeletal myopathic effects which generally resolve on stopping the medication. Recent reports, however, suggest that statins are associated with a unique autoimmune myopathy wherein symptoms persist or even progress after statin discontinuation and require immunosuppressive therapy. We performed a systematic review to examine the association of statins with inflammatory (dermatomyositis/polymyositis) and necrotizing myopathies. METHODS: We searched PubMed, Ovid and Scopus for English language articles addressing statin associated inflammatory and necrotizing myopathies. Given the paucity of cases, we extended the search to include articles in all languages. RESULTS: The search yielded 14 articles reporting a possible association of statins with inflammatory myopathies describing 10 cases of polymyositis and 14 cases of dermatomyositis, and 4 articles reporting a possible association of statins with necrotizing myopathies describing 63 cases. One study identified a unique antibody directed against HMGCR in patients with necrotizing myopathy. Systemic immunosuppressive therapy was required in majority of these cases for resolution of symptoms. CONCLUSION: Statins have recently been associated with a variety of inflammatory myopathies including polymyositis, dermatomyositis, and a necrotizing myopathy. The association of statins with necrotizing myopathy is strengthened by the discovery that the serum of some of these patients contains an anti-HMGCR antibody. This suggests that statins can cause or unmask an immune mediated myopathy.

Pancreatic adenocarcinoma-associated polymyositis treated with corticosteroids along with cancer specific treatment: case report.

BACKGROUND: Adenocarcinoma of the pancreas only rarely is associated with inflammatory myopathy. In this setting, polymyositis may be treated with glucocorticoids in combination with cancer specific treatment. CASE PRESENTATION: We present the case of a 52-year-old man with stage IIA pancreatic tail adenocarcinoma who underwent surgical treatment and six months into therapy with gemcitabine he developed symmetrical, painful, proximal muscle weakness with peripheral oedema. Re-evaluation with imaging modalities, muscle histology and biochemistry conferred the diagnosis of polymyositis associated with pancreatic cancer progression. The patient was treated with glucocorticoids along with gemcitabine and erlotinib which resulted in complete remission within six months. He remained in good health for a further six months on erlotinib maintenance therapy when a new computer tomography scan showed pancreatic cancer relapse and hence prompted 2nd line chemotherapy with gemcitabine. CONCLUSIONS: Polymyositis associated with pancreatic cancer may respond to glucocorticoids along with cancer specific treatment.

Acrylamine-induced autoimmune phenomena.

The objective of this study is to document a series of cases of occupationally derived autoimmune disease. Individuals with occupational exposure to acrylamides were evaluated clinically and biochemically/immunologically for evidence of autoimmune disease. Symptoms and signs and immuno-reactivity were monitored during exposure-free and re-exposure as part of the individuals' clinical evaluation. Six individuals with occupational acrylamide exposure had clinical and laboratory alterations characteristic of drug-induced autoimmune disease, specifically lupus, anti-phospholipid syndrome, Sjogren's syndrome, scleroderma, and polymyositis. The similarity of the full spectrum of disease in the reported patients to that found with procainamide strongly suggests the effects of occupational exposure. This uncontrolled study suggests the need for a full epidemiologic analysis of all individuals working with such occupational exposure, including full clinical and immunological examination.