Connective Tissue Diseases/inflammatory Myopathies--polymyositis/dermatomyositis

结缔组织和疾病科研究炎症性肌病（多发性肌炎、皮肌炎和相关疾病），以了解自身抗体与自身免疫性疾病的关系。它们非常罕见，因此与其他自身免疫性疾病相比，研究相对较少，而且它们非常衰弱，因此需要改进治疗。为了吸引患者进行更详细的临床、免疫学、遗传和病毒研究，我们进行了几项治疗试验，并完成了一些这样的研究。在这种难以治疗的家族疾病中，他们是为数不多的发表的对照试验之一。这些试验包含了多种免疫抑制方法。在过去的一年里，我们已经完成了一项抗tnf AGENT英夫利昔单抗（REMICADE）的试验，这是一种小鼠-人嵌合抗体，已被批准用于治疗类风湿性关节炎和炎症性肠病。开展该试验的理由是有证据表明，在肌炎活检的活动性病变中存在TNF；它降低了肌肉细胞的收缩能力；它会损害肌肉形成。该试验由制造商Centocor根据临床CRADA提供资金支持。患者群体与我们在其他研究中使用的相似-对常规免疫抑制治疗反应不满意的患者。这项为期40周的随机、双盲、安慰剂对照试验包括受试者和RT；18岁，符合Bohan和Peter标准；有活动性疾病的证据，肌肉酶升高，STIR MRI信号异常，基线手工肌肉测试（MMT）评分为80-120（满分160）；参与前4周稳定的强的松< 0.5 mg/kg/天和DMARD剂量；以及之前免疫抑制治疗失败或对治疗不耐受的患者。排除标准包括恶性肿瘤、中枢神经系统疾病、既往英夫利昔单抗治疗、感染、狼疮和心力衰竭。报名人数比我们早期的试验要慢，但没有一个单一的因素是造成这种情况的原因。当我们达到计划收益的50%时，我们结束了试验。受试者在0、2、6和14周接受4次安慰剂或英夫利昔单抗5mg /kg的盲法输注。根据国际肌炎评估和临床研究小组（IMACS）的标准，在第16周评估主要改善（从第0周开始改善15% MMT）和次要结果后，进行了解盲。在英夫利昔单抗组中，根据MMT标准没有改善的受试者（无反应）在第22、30和38周增加到开放标签英夫利昔单抗7.5 mg/kg。安慰剂组无应答者在第16、18、22、30和38周接受开放标签5mg /kg。每个组的应答者都可以选择继续相同的治疗或改变到该研究组的无应答治疗。在第40周重新评估结果。12名受试者（11F/1M， 6名非裔美国人，5名高加索人，1名亚洲人，11名PM /1名DM）完成研究至第16周。这些受试者的平均年龄为45.4 + 10.9岁，平均病程为5.6 + 4.0年，平均皮质类固醇剂量为17.3 + 10.8 mg/天；甲氨蝶呤平均剂量（N=9）为16.4 + 11.3 mg/周，硫唑嘌呤平均剂量（N=3）为50.0 + 86.1 mg/天。平均基线MMTs为104.2 + 9.9（安慰剂组，N=6）和104.2 + 17.3（英夫利昔单抗组，N=6）。英夫利昔单抗组的3名受试者在第16周后退出；3例患者完成英夫利昔单抗7.5 mg/kg给药方案。安慰剂组的所有6名患者在第16周后转入5mg /kg给药方案。在英夫利昔单抗组中，3/12名受试者在16周时通过手动肌肉测试得到改善，另外1名受试者在40周时通过MMT得到改善。6名受试者接受安慰剂治疗后均无改善（主要结局p=0.50，次要结局p=0.63）。在反应者和无反应者之间没有发现临床或实验室差异。在研究期间发生了两起与研究药物无关的SAEs。其他不良事件轻微且可逆。这是首次报道的英夫利昔单抗在肌炎患者中的随机对照临床试验，表明英夫利昔单抗耐受性良好，但对成人PM和DM的疗效有限。在一项由NIH支持、NIAMS和NIEHS参与的大型多国合作试验中，一种抗b细胞药物已经完成，目前正在分析结果。我们的转诊诊所继续看到相当多的患者谁已被诊断为肌炎，并已治疗不成功的标准疗法。这些患者中有相当一部分患有可证实的遗传性疾病（如mccardle 's， PFK缺乏症或酸麦尔糖酶缺乏症，许多类型的肢体带状营养不良之一）或等待精确诊断的推定遗传性疾病（无法诊断的营养不良，无法诊断的空泡性肌病或无法诊断的通道病）。我们继续与埃里克·霍夫曼在国家儿童医学中心基因医学中心的实验室合作，利用基因表达来提高诊断水平。约翰霍普金斯大学的Lisa Christopher-Stine博士已获得K-23资助，对700多名患者进行了深入分析，根据我们目前的自然历史协议（91-AR-0196）评估了关键的诊断和预测预后特征。近年来，研究人员收集了数百名患者的冷冻肌肉活检标本和DNA，并对其进行了分类，以供未来的研究使用。美国国立卫生研究院霍夫曼博士的研究小组正在对选定的肌炎患者的某些营养不良基因进行测序，以确定治疗抵抗性肌炎在某些情况下是否为营养不良并伴有类似肌炎的附带炎症。

The Connective Tissue and Diseases Section studies inflammatory myopathies (polymyositis, dermatomyositis, and related diseases) to understand the relationship of autoantibodies to autoimmune disease. They are very uncommon and hence relatively less studied than other autoimmune diseases, and they are very debilitating and hence in need of improved therapy. In order to attract patients to allow increased detailed clinical, immunological, genetic, and viral studies, we have carried out several therapy trials, and have completed a number of such studies. They are among the very few published controlled trials in this difficult to treat family of illnesses. These trials have encompassed a variety of approaches to immunosuppression. In the past year we have completed a trial of the anti-TNF AGENT, infliximab (REMICADE), a mouse-human chimeric antibody that has been approved for use in rheumatoid arthritis and inflammatory bowel disease. The rationale for carrying out the trial was the evidence that TNF is present in the active lesions in myositis biopsies; that it diminishes muscle cell contractility; and that it impairs myogenesis. The trial was carried out with financial support from the manufacturer, Centocor, under a clinical CRADA. The patient population was similar to that used in our other studies - patients who had unsatisfactory responses to conventional immunosuppressive therapy. This 40-week randomized, double-blind, placebo-controlled trial included subjects and RT; 18 years old who: fulfilled Bohan and Peter criteria; had evidence of active disease with muscle enzyme elevation, STIR MRI signal abnormalities, and a baseline manual muscle testing (MMT) score of 80-120 (out of 160); stable prednisone < 0.5 mg/kg/day and DMARD doses for 4 weeks prior to participation; and who failed previous immunosuppressive treatment or had intolerance to therapy. Exclusion criteria included malignancy, central nervous system disease, prior infliximab therapy, infection, lupus and heart failure. Enrollment was slower than in our earlier trials, but no single factor stands out as the cause for this. We ended the trial when we had reached 50 of the planned accrual. Participants received four blinded infusions of either placebo or infliximab 5 mg/kg at 0, 2, 6 and 14 weeks. Unblinding occurred at week 16 following assessment of improvement by the primary (15% MMT improvement from week 0) and secondary outcomes, as defined by the International Myositis Assessment and Clinical Studies Group (IMACS) criteria. Subjects in the infliximab arm who did not improve based on MMT criteria (nonresponders) were increased to open-label infliximab 7.5 mg/kg at weeks 22, 30, and 38. Nonresponders in the placebo arm received open-label 5 mg/kg at weeks 16, 18, 22, 30, and 38. Responders in each arm had the option of either continuing the same treatment or changing to the non-responder treatment for that study arm. Outcomes were reassessed at week 40. Twelve subjects (11F/1M; 6 African American, 5 Caucasian, 1 Asian; 11 PM /1 DM) completed the study to week 16. For these subjects, the mean age was 45.4 + 10.9 years, mean disease duration 5.6 + 4.0 years, mean corticosteroid dose was 17.3 + 10.8 mg/day; mean methotrexate dose (N=9) was 16.4 + 11.3 mg/week and mean azathioprine dose (N=3) 50.0 + 86.1 mg/day. Mean baseline MMTs were 104.2 + 9.9 (placebo arm, N=6) vs. 104.2 + 17.3 (infliximab arm, N=6). Three subjects in the infliximab arm withdrew after week 16; 3 subjects completed the infliximab 7.5 mg/kg dosing regimen. All 6 patients in the placebo arm crossed over to the 5 mg/kg dosing regimen after week 16. In the infliximab arm 3/12 subjects improved by manual muscle testing at 16 weeks and one additional subject improved by MMT at 40 weeks. None of the 6 subjects improved with placebo treatment (p=0.50 for the primary outcome and p=0.63 for the secondary outcome). No clinical or laboratory differences were detected between responders and nonresponders. Two SAEs, unrelated to study drug, occurred during the study. Adverse events were otherwise mild and reversible. This first randomized, controlled clinical trial of infliximab reported in patients with myositis suggests that infliximab is well tolerated but has only limited efficacy in adult PM and DM. In a large, multinational cooperative trial of an anti-B cell agent, supported by NIH, and of which NIAMS and NIEHS were a part, was completed and the results are currently being analyzed. Our referral clinic continues to see quite a number of patients who have been diagnosed with myositis and have been treated unsuccessfully with standard therapy. A substantial proportion of these patients have either a demonstrable genetic disease (such as McArdle's, PFK deficiency, or acid maltase deficiency, one of the many types of limb girdle dystrophy) or a presumptive genetic disease awaiting precise diagnosis (undiagnosable dystrophy, undiagnosable vacuolar myopathy, or undiagnosable channelopathy.) We continue to work with Eric Hoffman's lab in the Center for Genetic Medicine at the Children's National Medical Center, using gene expression to sharpen diagnosis. Dr. Lisa Christopher-Stine at Johns Hopkins has received K-23 funding to carry out an in-depth analysis of the critical diagnostic and predictive prognostic features in over 700 patients evaluated under our current Natural History protocol (91-AR-0196). Frozen muscle biopsy specimens and DNA from several hundred of the patients seen in the study in recent years have been gathered and catalogued for future studies. Certain dystrophy genes from selected patients with myositis are being sequenced by Dr. Hoffman's group at NIH to determine if treatment-resistant myositis is in some cases a dystrophy with incidental inflammation that resembles myositis.