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2.
BMJ Case Rep ; 20182018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420560

RESUMO

A 66-year-old man presented with chest pain and a 1-year history of generalised weakness, accompanied with generalised aches and pains. Symptoms worsened when he was initiated on statins. Investigations yielded high creatine kinase, high HMG-coenzymeA reductase (HMGCR) antibody titre, myopathic features on electromyography and muscle biopsy, and muscle atrophy on MRI. These results were in keeping with anti-HMGCR antibody myopathy. The patient responded well to immunosuppressive therapy.


Assuntos
Autoanticorpos/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Debilidade Muscular/complicações , Debilidade Muscular/imunologia , Idoso , Biópsia , Eletromiografia , Humanos , Imunossupressão/métodos , Imagem por Ressonância Magnética , Masculino , Debilidade Muscular/terapia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Necrose/complicações , Necrose/imunologia , Necrose/terapia
3.
Medicine (Baltimore) ; 97(35): e11858, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30170376

RESUMO

The therapeutic approach with statins is widely used in the control of dyslipidemias. However, there is no laboratory evaluation to elect patients to make use of this class of therapeutic drugs.We analyzed the prevalence of anti-signal recognition particle (anti-SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies in a heterogeneous cohort of 85 patients in order to determine cutoff reference values for these antibodies.Serum samples from 85 patients were screened for the presence of anti-HMGCR and anti-SRP autoantibodies by enzyme-linked immunosorbent assay. The demographic, clinical, and morphological features were also correlated with anti-HMGCR and anti-SRP antibodies. The patients were divided in 2 groups: A, statin-exposed, and B, statin-unexposed.There was no significant association (P > .05) among anti-HMGCR and anti-SRP titers in relation to age, sex, statin exposure, and CK level. The concentrations of both antibodies were not correlated with symptoms, CK level, or statin exposure. Eleven (12.9%) patients had anti-HMGCR antibodies. We found a tendency (P = .051) toward greater anti-HMGCR positivity in women with no symptoms. Twelve (14.1%) patients had anti-SRP antibodies. There was no sex predominance, and only 1 patient had muscle complaints. Muscular symptoms were present in 31 (36.5%) patients, 4 (12.9%) were positive for anti-HMGCR antibodies, and 1 (3.2%) was positive for anti-SRP antibodies. A total of 54 (63.5%) patients had no muscle symptoms, 7 (13%) were anti-HMGCR positive, and 11 (20.4%) were anti-SRP positive. We found statistical significance for patients with anti-SRP antibodies when asymptomatic and symptomatic patients were compared (P = .029). In contrast, there was no statistically significant difference between symptoms and positivity for anti-HMG antibodies.One of the main aims of this study was to define a cutoff point in a heterogeneous population with different diagnoses. We also demonstrated that anti-HMGCR and anti-SRP antibodies are not 100% specific to immune-mediated necrotizing myopathy. We believe that these antibodies must be tested and interpreted within the specific context.


Assuntos
Autoanticorpos/imunologia , Hidroximetilglutaril-CoA Redutases/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Músculo Esquelético/imunologia , Partícula de Reconhecimento de Sinal/imunologia , Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miosite/diagnóstico , Miosite/imunologia , Miosite/patologia , Necrose , Valores de Referência , Estudos Retrospectivos , Sensibilidade e Especificidade
4.
J Clin Neurosci ; 57: 13-19, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30205933

RESUMO

This study aimed to clarify the phenotypes and therapeutic responses of statin-naïve anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody-mediated necrotizing myopathy. Anti-HMGCR antibodies were tested with ELISA methodology in the sera sample of 98 patients meeting the idiopathic inflammatory myopathy criteria and with negative anti-signal recognition particle (SRP) antibody. Twenty-one statin-naïve patients with anti-HMGCR antibody were detected (21.4%), with onset age from 6 to 67 years old. Proximal weakness and neck flexion weakness was the core neurological feature. The average maximal creatine kinase (CK) level was 7968.6 ±â€¯4408.7U/L. Muscle MR imaging showed edema (88.2%), moderate or severe fatty replacement (70.6%) and muscle atrophy (88.2%) in lower limbs. Fatty replacement was significantly more prominent in the medial and posterior musculature than the anterior musculature (p = 0.0013). Seven (33.3%) patients were treated with mono-glucocorticoid, and thirteen (61.9%) patients needed adjuvant immunosuppressant. Eight (38.1%) patients experienced symptom relapse. The early-onset patients (<50 years old) were found with higher CK levels, shorter duration course, poorer response to adjuvant immunosuppressant and more recurrent weakness than the late-onset patients (≥50 years old). As a conclusion, Statin-naïve anti-HMGCR antibody-mediated necrotizing myopathy may not be rare. Compared with late-onset statin-naïve patients with anti-HMGCR antibody-mediated necrotizing myopathy, early-onset patients presented severer clinical features and worse therapeutic responses.


Assuntos
Hidroximetilglutaril-CoA Redutases/imunologia , Doenças Musculares/imunologia , Miosite/imunologia , Tecido Adiposo/diagnóstico por imagem , Adolescente , Adulto , Idade de Início , Idoso , Autoanticorpos/sangue , Criança , China , Creatina Quinase/sangue , Edema/diagnóstico por imagem , Feminino , Glucocorticoides/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Imunossupressores/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Atrofia Muscular/diagnóstico por imagem , Doenças Musculares/sangue , Doenças Musculares/diagnóstico , Doenças Musculares/tratamento farmacológico , Miosite/sangue , Miosite/diagnóstico , Miosite/tratamento farmacológico , Estudos Retrospectivos , Partícula de Reconhecimento de Sinal/sangue , Fatores de Tempo , Adulto Jovem
6.
Hum Vaccin Immunother ; 14(3): 790-795, 2018 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-29058516

RESUMO

To prepare for the next influenza pandemic and other emerging virus diseases, scientists and health officials are focused on developing new vaccines and treatments that target these viruses. Ideally, these interventions could be highly effective, but for many practical reasons these "top down" efforts are unlikely to provide clinicians with what they will need to manage their patients. As a "bottom up" alternative, combinations of generic drugs like statins and angiotensin receptor blockers (ARBs) might be used to treat the host response to infection. These drugs counteract endothelial dysfunction, a central abnormality in these diseases. Observational studies in patients with influenza, pneumonia, sepsis and Ebola suggest they might work. During the 1918 influenza pandemic, children were infected more frequently than adults, but their mortality rate was much lower. Their survival was probably due to better tolerance (reduced pathogen damage), not greater resistance (reduced pathogen burden). The same pattern of susceptibility characterizes other infectious diseases, and it probably reflects the heritage of human evolution. Drugs like statins and ARBs can metabolically reprogram the host response and improve tolerance to infection. Treating the host response is not on the research agendas of international agencies responsible for pandemic preparedness. Consequently, clinicians might have to undertake clinical trials in patients hospitalised with seasonal influenza, pneumonia and sepsis in order to show convincingly whether treating the host response would work. Most candidate generic drugs are inexpensive, widely available, known to be safe and used by clinicians every day. Demonstrating their efficacy would mean that patients in all countries would have access to treatment on the first pandemic or epidemic day.


Assuntos
Surtos de Doenças/prevenção & controle , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Medicamentos Genéricos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Sepse/tratamento farmacológico , Sepse/imunologia
7.
Acta Myol ; 37(4): 257-262, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30944904

RESUMO

Statin-induced necrotizing autoimmune myopathy (IMNM) is an autoimmune disorder induced by anti-3-hydroxy-3-methylglutaryl-coenzyme-A reductase (anti-HMGCR) antibodies. We performed a retrospective clinical, histological, and radiological evaluation of 5 patients with a 3-year therapeutic follow-up. All patients used statins and then experienced proximal weakness that persisted after drug cessation. Muscle biopsies revealed a primary necrotizing myopathy without inflammatory infiltrates. All patients required immunomodulant combination therapy to achieve clinical remission. Magnetic resonance imaging (MRI) showed the presence of edema in the medial gastrocnemius, posterior and central loggia of the thigh, posterior loggia of the arm, and the infraspinatus and subscapularis muscles, as well as extensive inflammation of the subcutaneous tissues and muscolaris fasciae. Serum analysis, muscle biopsy, and MRI are fundamental for IMNM diagnosis and follow-up. The growing use of statins in the general population raises the importance of acquaintance with this disease in clinical practice.


Assuntos
Doenças Autoimunes , Hidroximetilglutaril-CoA Redutases/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases , Músculo Esquelético/patologia , Doenças Musculares , Autoanticorpos/sangue , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Biópsia/métodos , Correlação de Dados , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/induzido quimicamente , Doenças Musculares/diagnóstico , Doenças Musculares/imunologia , Necrose , Estudos Retrospectivos
8.
Sci Rep ; 7(1): 17855, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259264

RESUMO

Recent studies indicated that in elderly individuals, statin therapy is associated with a reduced response to influenza vaccination. The present study was designed to determine effects on the immune response to influenza vaccination induced by statin administration in a mouse model, and investigate potential approaches to improve the outcome of vaccination on the background of statin therapy. We fed middle aged BALB/c mice a high fat "western" diet (WD) alone or supplemented with atorvastatin (AT) for 14 weeks, and control mice were fed with the regular rodent diet. Mice were immunized with a single dose of subunit A/Brisbane/59/07 (H1N1) vaccine, either systemically or with dissolving microneedle patches (MNPs). We observed that a greater age-dependent decline in the hemagglutinin inhibition titers occurred in systemically-immunized mice than in MNP- immunized mice. AT dampened the antibody response in the animals vaccinated by either route of vaccine delivery. However, the MNP-vaccinated AT-treated animals had ~20 times higher total antibody levels to the influenza vaccine than the systemically vaccinated group one month postvaccination. We propose that microneedle vaccination against influenza provides an approach to ameliorate the immunosuppressive effect of statin therapy observed with systemic immunization.


Assuntos
Formação de Anticorpos/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Pele/imunologia , Administração Cutânea , Animais , Feminino , Imunização/métodos , Camundongos , Camundongos Endogâmicos BALB C , Agulhas , Infecções por Orthomyxoviridae/imunologia , Vacinação/métodos
9.
J Clin Rheumatol ; 23(3): 149-154, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28277343

RESUMO

BACKGROUND: Statins are a group of drugs that reduce the levels of triglycerides and cholesterol in blood by inhibiting HMG-CoA reductase, an enzyme involved in rate limiting step in cholesterol synthesis. About 2-20% patients on statins develop toxic myopathies, which usually resolve on discontinuation of statin. More recently, an immune-mediated necrotizing myopathy has been found to be associated with statin use which in most cases requires treatment with immunosuppressants. OBJECTIVE: To perform a systematic review on published case reports and case series of statin-associated autoimmune myopathy. METHODS: A comprehensive search of PUBMED, EMBASE, Cochrane library and ClinicalTrials.gov databases was performed for relevant articles from inception until March 19, 2016 to identify cases of statin-associated necrotizing myopathy and characterize their symptoms, evaluation and response to treatment. RESULTS: A total of 16 articles describing 100 patients with statin-associated autoimmune myopathy were identified. The mean age of presentation was 64.72 years, and 54.44% were males. The main presenting clinical feature was proximal muscle weakness, which was symmetric in 83.33% of patients. The mean creatine kinase (CK) was 6853 IU/l. Anti-HMG-CoA reductase antibody was positive in all cases tested (n = 57/57, 100%). In patients with no anti-HMG-CoA antibody results, diagnosis was established by findings of necrotizing myopathy on biopsy. Among the 83 cases where muscle biopsy information was available, 81.48% had necrosis, while 18.51% had combination of necrosis and inflammation. Most (83.82%) patients received two or more immunosuppressants to induce remission. Ninety-one percent had resolution of symptoms after treatment. CONCLUSION: Statin-associated necrotizing myopathy is a symmetric proximal muscle weakness associated with extreme elevations of CK. It is common in males and can occur after months of statin use. It is associated with necrosis on muscle biopsy and the presence of anti-HMG-CoA reductase antibodies. It usually requires discontinuation and immune suppression for resolution. Rechallenge with statin is unsuccessful in most cases.


Assuntos
Doenças Autoimunes , Inibidores de Hidroximetilglutaril-CoA Redutases , Imunossupressores/administração & dosagem , Doenças Musculares , Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Diagnóstico Diferencial , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Doenças Musculares/diagnóstico , Doenças Musculares/etiologia , Doenças Musculares/imunologia , Doenças Musculares/terapia , Indução de Remissão/métodos
10.
Curr Opin Lipidol ; 28(2): 186-192, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28207435

RESUMO

PURPOSE OF REVIEW: In the last 6 years, our understanding of statin-associated myopathy expanded to include not only a toxic myopathy with limited and reversible side-effects but also an autoimmune variety in which statins likely induce an autoimmune myopathy that is both associated with a specific autoantibody and responsive to immunosuppression and immune modulation. This review widens the reader's understanding of statin myopathy to include an autoimmune process. RECENT FINDINGS: Statin-associated immune-mediated myopathy provides an example of an environmental trigger (statins) directly implicated in an autoimmune disease associated with a genetic predisposition as well as potential risk factors including concomitant diseases and specific statins. Given a median exposure to statins of 38 months, providers should be aware that anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy may occur even after several years of statin exposure. SUMMARY: It is important for the reader to understand the clinical presentation of statin-associated immune-mediated myopathy and the difference in its clinical presentation to that of statins as direct myotoxins. Prompt recognition of such an entity allows the clinician to immediately stop the offending agent if it has not already been discontinued as well as to recognize that statin rechallenge is not a likely option, and that prompt treatment with immunosuppression and/or immunomodulation is usually of enormous benefit to the patient in restoring muscle strength and physical function. VIDEO ABSTRACT.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Doenças Musculares/imunologia , Animais , Autoanticorpos/imunologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Músculos/efeitos dos fármacos , Músculos/imunologia , Doenças Musculares/patologia , Necrose/induzido quimicamente
12.
Medicine (Baltimore) ; 96(3): e5694, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28099331

RESUMO

The general aim of this study was to evaluate the disease spectrum in patients presenting with a pure polymyositis (pPM) phenotype. Specific objectives were to characterize clinical features, autoantibodies (aAbs), and membrane attack complex (MAC) in muscle biopsies of patients with treatment-responsive, statin-exposed necrotizing autoimmune myositis (NAM). Patients from the Centre hospitalier de l'Université de Montréal autoimmune myositis (AIM) Cohort with a pPM phenotype, response to immunosuppression, and follow-up ≥3 years were included. Of 17 consecutive patients with pPM, 14 patients had a NAM, of whom 12 were previously exposed to atorvastatin (mean 38.8 months). These 12 patients were therefore suspected of atorvastatin-induced AIM (atorAIM) and selected for study. All had aAbs to 3-hydroxy-3-methylglutaryl coenzyme A reductase, and none had overlap aAbs, aAbs to signal recognition particle, or cancer. Three stages of myopathy were recognized: stage 1 (isolated serum creatine kinase [CK] elevation), stage 2 (CK elevation, normal strength, and abnormal electromyogram [EMG]), and stage 3 (CK elevation, proximal weakness, and abnormal EMG). At diagnosis, 10/12 (83%) patients had stage 3 myopathy (mean CK elevation: 7247 U/L). The presenting mode was stage 1 in 6 patients (50%) (mean CK elevation: 1540 U/L), all of whom progressed to stage 3 (mean delay: 37 months) despite atorvastatin discontinuation. MAC deposition was observed in all muscle biopsies (isolated sarcolemmal deposition on non-necrotic fibers, isolated granular deposition on endomysial capillaries, or mixed pattern). Oral corticosteroids alone failed to normalize CKs and induce remission. Ten patients (83%) received intravenous immune globulin (IVIG) as part of an induction regimen. Of 10 patients with ≥1 year remission on stable maintenance therapy, IVIG was needed in 50%, either with methotrexate (MTX) monotherapy or combination immunosuppression. In the remaining patients, MTX monotherapy or combination therapy maintained remission without IVIG. AtorAIM emerged as the dominant entity in patients with a pPM phenotype and treatment-responsive myopathy. Isolated CK elevation was the mode of presentation of atorAIM. The new onset of isolated CK elevation on atorvastatin and persistent CK elevation on statin discontinuation should raise early suspicion for atorAIM. Statin-induced AIM should be included in the differential diagnosis of asymptomatic hyperCKemia. Three patterns of MAC deposition, while nonpathognomonic, were pathological clues to atorAIM. AtorAIM was uniformly corticosteroid resistant but responsive to IVIG as induction and maintenance therapy.


Assuntos
Atorvastatina/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Polimiosite/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Quimioterapia de Indução , Estudos Longitudinais , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Polimiosite/tratamento farmacológico , Polimiosite/metabolismo , Polimiosite/patologia
15.
J Am Coll Cardiol ; 67(20): 2395-2410, 2016 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-27199064

RESUMO

Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins are well tolerated, but associated with various statin-associated symptoms (SAS), including statin-associated muscle symptoms (SAMS), diabetes mellitus (DM), and central nervous system complaints. These are "statin-associated symptoms" because they are rare in clinical trials, making their causative relationship to statins unclear. SAS are, nevertheless, important because they prompt dose reduction or discontinuation of these life-saving mediations. SAMS is the most frequent SAS, and mild myalgia may affect 5% to 10% of statin users. Clinically important muscle symptoms, including rhabdomyolysis and statin-induced necrotizing autoimmune myopathy (SINAM), are rare. Antibodies against HMG-CoA reductase apparently provoke SINAM. Good evidence links statins to DM, but evidence linking statins to other SAS is largely anecdotal. Management of SAS requires making the possible diagnosis, altering or discontinuing the statin treatment, and using alternative lipid-lowering therapy.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Lesão Renal Aguda/induzido quimicamente , Anticorpos/sangue , Doenças Autoimunes/induzido quimicamente , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Depressão/induzido quimicamente , Diabetes Mellitus/induzido quimicamente , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Testes de Função Hepática , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Musculares/induzido quimicamente , Mialgia/induzido quimicamente , Necrose/induzido quimicamente , Rabdomiólise/induzido quimicamente , Fatores de Risco , Ruptura/induzido quimicamente , Transtornos do Sono-Vigília/induzido quimicamente , Acidente Vascular Cerebral/induzido quimicamente , Traumatismos dos Tendões/induzido quimicamente , Testosterona/sangue
16.
Muscle Nerve ; 54(1): 142-4, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27038110

RESUMO

INTRODUCTION: Patients with self-limited statin-related myopathy improve spontaneously when statins are stopped. In contrast, patients with statin-associated autoimmune myopathy have autoantibodies recognizing 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) and usually require immunosuppressive therapy to control their disease. On initial presentation, it can sometimes be difficult to distinguish between these 2 diseases, as both present with muscle pain, weakness, and elevated serum creatine kinase (CK) levels. The goal of this study was to determine whether patients with severe self-limited statin-related myopathy also make anti-HMGCR autoantibodies. METHODS: We screened 101 subjects with severe self-limited cerivastatin-related myopathy for anti-HMGCR autoantibodies. RESULTS: No patient with severe self-limited cerivastatin-related myopathy had anti-HMGCR autoantibodies. CONCLUSION: Anti-HMGCR autoantibody testing can be used to help differentiate whether a patient has self-limited myopathy due to cerivastatin or autoimmune statin-associated myopathy; these findings may apply to other statins as well. Muscle Nerve 54: 142-144, 2016.


Assuntos
Autoanticorpos/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Doenças Musculares/induzido quimicamente , Doenças Musculares/imunologia , Piridinas/toxicidade , Idoso , Creatina Quinase/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/sangue , Estudos Retrospectivos
17.
Expert Rev Clin Immunol ; 12(1): 33-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26515829

RESUMO

Statin-induced necrotizing autoimmune myopathy (SINAM) is associated with a unique clinical 5 phenotype of severe proximal muscle weakness during or after exposure to statins in patients with high creatine kinase (CK) levels. Electromyography (EMG) and muscle biopsy reveal features of a necrotizing myopathy and the anti-HMGCR autoantibody is frequently detected. Treatment requires a combination of statin discontinuation as well as immunomodulatory or immunosuppressive therapy. HLA typing (HLADRB1*1101) is strongly associated with anti-10 HMGCR autoantibody positivity in statin-exposed patients. It is well documented that statin triggers autoimmune disease in those with a genetic susceptibility. With the commercial availability of an accurate ELISA test, the natural history of the disease and its phenotypic features are becoming increasingly understood.


Assuntos
Doenças Autoimunes/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças Musculares/imunologia , Anticorpos/metabolismo , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/tratamento farmacológico , Predisposição Genética para Doença , Antígenos HLA/genética , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Testes Imunológicos , Imunossupressores/uso terapêutico , Doenças Musculares/induzido quimicamente , Doenças Musculares/tratamento farmacológico , Polimorfismo Genético
20.
Am J Respir Cell Mol Biol ; 53(5): 689-702, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25874372

RESUMO

Statins are widely used to prevent cardiovascular disease. In addition to their inhibitory effects on cholesterol synthesis, statins have beneficial effects in patients with sepsis and pneumonia, although molecular mechanisms have mostly remained unclear. Using human airway epithelial cells as a proper in vitro model, we show that prior exposure to physiological nanomolar serum concentrations of simvastatin (ranging from 10-1,000 nM) confers significant cellular resistance to the cytotoxicity of pneumolysin, a pore-forming toxin and the main virulence factor of Streptococcus pneumoniae. This protection could be demonstrated with a different statin, pravastatin, or on a different toxin, α-hemolysin. Furthermore, through the use of gene silencing, pharmacological inhibitors, immunofluorescence microscopy, and biochemical and metabolic rescue approaches, we demonstrate that the mechanism of protection conferred by simvastatin at physiological nanomolar concentrations could be different from the canonical mevalonate pathways seen in most other mechanistic studies conducted with statins at micromolar levels. All of these data are integrated into a protein synthesis-dependent, calcium-dependent model showing the interconnected pathways used by statins in airway epithelial cells to elicit an increased resistance to pore-forming toxins. This research fills large gaps in our understanding of how statins may confer host cellular protection against bacterial infections in the context of airway epithelial cells without the confounding effect from the presence of immune cells. In addition, our discovery could be potentially developed into a host-centric strategy for the adjuvant treatment of pore-forming toxin associated bacterial infections.


Assuntos
Toxinas Bacterianas/antagonistas & inibidores , Células Epiteliais/efeitos dos fármacos , Proteínas Hemolisinas/antagonistas & inibidores , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Imunidade Inata/efeitos dos fármacos , Sinvastatina/farmacologia , Estreptolisinas/antagonistas & inibidores , Animais , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/toxicidade , Toxinas Bacterianas/toxicidade , Linhagem Celular Transformada , Células Epiteliais/imunologia , Células Epiteliais/patologia , Proteínas Hemolisinas/toxicidade , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Injeções Intraperitoneais , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pravastatina/imunologia , Pravastatina/farmacologia , Cultura Primária de Células , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Sinvastatina/imunologia , Staphylococcus aureus/química , Streptococcus pneumoniae/química , Estreptolisinas/toxicidade
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