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1.
Arthritis Res Ther ; 22(1): 5, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915059

RESUMO

OBJECTIVE: To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy. METHODS: Retrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies. RESULTS: A total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment. CONCLUSION: While corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.

6.
J Neuromuscul Dis ; 6(1): 99-107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30714969

RESUMO

BACKGROUND: Manual muscle testing has been widely used for the evaluation of muscle strength in myositis, yet less attention has been devoted to the evaluation of muscle function and endurance. OBJECTIVE: Our objective was therefore to compare the responsiveness to change of muscle strength, endurance and functional testing following induction therapy for severe myositis flare (requiring high-dose corticosteroids and combined immunotherapy) in patients with a diagnosis of dermatomyositis, immune-mediated necrotizing myopathy, or overlap myositis. METHODS: Muscle status was assessed at baseline and after mean 6.4±1.9 months, using the MRC-5 scale, along with endurance (Barre and Mingazzini maneuvers) and functional evaluation (e.g. chair rise) and responsiveness to change was evaluated using the Standardized Response Mean (SRM) and Standardized Mean Difference. RESULTS: Among the 49 patients included, the strongest responsiveness to change was observed in the muscle testing of the psoas and deltoids (SRM: 1.23 and 1.16, respectively). Noticeably, endurance testing also demonstrated strong responsiveness (SRM: 1.05 and 0.96, respectively), compensating for the poor discriminatory ability of muscle testing and permitting to overcome its ceiling effect. CONCLUSION: Functional and endurance testing provide simple and reliable measures complementing the testing of select proximal muscle groups to evaluate responsiveness to intervention in myositis patients in daily clinical practice. Interest of functional and endurance testing should be evaluated prospectively as outcome measures in myositis clinical trials.


Assuntos
Força Muscular , Miosite/diagnóstico , Resistência Física , Corticosteroides/uso terapêutico , Adulto , Estudos de Coortes , Teste de Esforço , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Miosite/fisiopatologia , Miosite/terapia , Reprodutibilidade dos Testes
7.
J Rheumatol ; 46(6): 623-627, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30554155

RESUMO

OBJECTIVE: A pathogenic role of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies has been proposed. Our objective was to assess efficacy of rituximab (RTX) in anti-HMGCR immune-mediated necrotizing myopathy. METHODS: All patients who had been treated with RTX were retrospectively reviewed to assess features and outcome. RESULTS: Three of 9 patients demonstrated stable or improved muscle strength ± decline in creatine kinase levels, or T2/short-tau inversion recovery hypersignal decrease on magnetic resonance imaging following RTX treatment. RTX permitted intravenous immunoglobulin discontinuation and corticosteroid reduction to low dose in 2 patients. CONCLUSION: One-third of patients with refractory anti-HMGCR had improved strength or other evidence of improved disease activity following RTX treatment.

8.
Neurol Neuroimmunol Neuroinflamm ; 6(1): e523, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30588482

RESUMO

Objective: To determine the prevalence and clinical features of anti-HMGCR myopathy among patients with presumed limb-girdle muscular dystrophy (LGMD) in whom genetic testing has failed to elucidate causative mutations. Methods: Patients with presumed LGMD and unrevealing genetic testing were selected based on a few clinico-pathologic features and tested for anti-HMGCR autoantibodies (n = 11). These clinico-pathologic features are peak creatine kinase (CK) greater than 1,000 IU/L and at least 3 of the following features: (1) limb-girdle pattern of weakness, (2) selective involvement of posterior thigh on clinical examination or muscle imaging, (3) dystrophic changes on muscle biopsy, and (4) no family history of muscular dystrophy. Results: Six patients tested positive for anti-HMGCR autoantibodies. In 4, there was a presymptomatic phase, lasting as long as 10 years, characterized by elevated CK levels without weakness. Muscle biopsies revealed variable degrees of a dystrophic pathology without prominent inflammation. In an independent cohort of patients with anti-HMGCR myopathy, 17 of 51 (∼33%) patients were initially presumed to have a form of LGMD based on clinico-pathologic features but were ultimately found to have anti-HMGCR myopathy. Most of these patients responded favorably to immunomodulatory therapies, evidenced by reduction of CK levels and improved strength. Conclusions: Anti-HMGCR myopathy can resemble LGMD. Diagnosis of patients with a LGMD-like presentation of anti-HMGCR myopathy is critical because these patients may respond favorably to immunotherapy, especially those with shorter disease duration.

11.
J Neuromuscul Dis ; 5(2): 241-249, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29865089

RESUMO

BACKGROUND: Several retrospective case series have suggested rituximab (RTX) might improve patients with refractory Myasthenia Gravis (MG). OBJECTIVE: In this study, we aimed to evaluate prospectively the efficacy of RTX on muscle function in refractory generalized anti-acetylcholine receptor (AChR) MG patients. METHODS: Enrolled patients received 1 g of RTX at day 0, day 14, and 6-month follow-up (M6). The primary endpoint was improvement of muscle function at 12-month (M12) based on myasthenic muscle score (MMS). Secondary endpoints were an improvement of the MG Foundation of America Postintervention Status (MGFA-PIS), respiratory forced vital capacity, occurrences of acute MG exacerbation and requirement of associated immunosuppressants and immunomodulatory agents. RESULTS: Twelve patients were enrolled, and 11 completed the study. Only a single patient presented an improvement of at least 20 points on MMS at M12, although 2 patients displayed an increase of at least 18 points at M12. MGFA-PIS had improved in 55% of patients by M12. The clinical improvement was not associated with a reduction of immunosuppressant burden. CONCLUSIONS: These results provide data on the effect of RTX in patients with severe, refractory anti-AChR Abs generalized MG. Even though primary outcome was only reached in a single patient at M12, a beneficial effect of RTX on muscle function was seen in half of the patients at M12 and persisted in a third of patients at M18.


Assuntos
Fatores Imunológicos/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Autoanticorpos/imunologia , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia , Miastenia Gravis/imunologia , Miastenia Gravis/fisiopatologia , Projetos Piloto , Qualidade de Vida , Receptores Colinérgicos/imunologia , Testes de Função Respiratória , Resultado do Tratamento , Adulto Jovem
12.
Brain ; 141(6): 1609-1621, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29741608

RESUMO

Dermatomyositis is an acquired auto-immune disease characterized by skin lesions and muscle-specific pathological features such as perifascicular muscle fibre atrophy and vasculopathy. Dermatomyositis patients display an upregulation of type I interferon-inducible genes in muscle fibres, endothelial cells, skin and peripheral blood. However, the effect of type I interferon on muscle tissue has not yet been determined. Our aim was to study the pathogenicity of type I interferon in vitro and to evaluate the efficacy of the type I interferon pathway blockade for therapeutic purposes. The activation of type I interferon in differentiating myoblasts abolished myotube formation with reduced myogenin expression while in differentiated myotubes, we observed a reduction in surface area and an upregulation of atrophy-associated genes. In vitro endothelial cells exposure to type I interferon disrupted vascular network organization. All the pathogenic effects observed in vitro were abolished by ruxolitinib. Finally, four refractory dermatomyositis patients were treated with ruxolitinib and improvement ensued in skin lesions, muscle weakness and a reduced serum type I interferon levels and interferon-inducbile genes scores. We propose JAK inhibition as a mechanism-based treatment for dermatomyositis, a finding that is relevant for the design of future clinical trials targeting dermatomyositis.


Assuntos
Dermatomiosite , Interferon Tipo I/toxicidade , Inibidores de Janus Quinases/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Pirazóis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Transformada , Dermatomiosite/induzido quimicamente , Dermatomiosite/tratamento farmacológico , Dermatomiosite/patologia , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas de Resistência a Myxovirus/genética , Proteínas de Resistência a Myxovirus/metabolismo , Neovascularização Patológica/induzido quimicamente , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Regulação para Cima/efeitos dos fármacos
14.
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
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