Connective Tissue Diseases/inflammatory Myopathies--polymyositis/dermatomyositis

结缔组织和疾病部分研究炎症性肌病（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，因此比其他自身免疫性疾病研究相对较少，并且它们非常虚弱，因此需要改进治疗。为了吸引患者接受更多详细的临床、免疫学、遗传学和病毒研究，我们进行了多项治疗试验，并完成了多项此类研究。他们是这个难以治疗的疾病家族中极少数发表的对照试验之一。这些试验包括多种免疫抑制方法。在过去的一年里，我们完成了一项抗肿瘤坏死因子药物英夫利昔单抗（类克）的试验，英夫利昔单抗是一种鼠-人嵌合抗体，已被批准用于类风湿性关节炎和炎症性肠病。进行该试验的基本原理是有证据表明TNF存在于肌炎活检的活动性病变中;它降低了肌细胞的收缩性;并且它损害了肌生成。该试验是在临床CRADA下，在制造商Centocor的财政支持下进行的。患者人群与我们其他研究中使用的人群相似-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;有活动性疾病伴肌酶升高、STIR MRI信号异常和基线手动肌肉测试（MMT）评分为80-120的证据（160人中）;参与前稳定泼尼松< 0.5 mg/kg/天和DMARD剂量4周;以及既往免疫抑制治疗失败或对治疗不耐受者。排除标准包括恶性肿瘤、中枢神经系统疾病、既往接受过英夫利西单抗治疗、感染、狼疮和心力衰竭。入组比我们早期的试验慢，但没有单一因素是导致这种情况的原因。当我们达到50%的计划收益时，我们结束了试验。受试者在第0、2、6和14周接受安慰剂或英夫利西单抗5 mg/kg的4次盲法输注。根据国际肌炎评估和临床研究组（IMACS）标准的定义，在第16周评估主要结局（MMT较第0周改善15%）和次要结局的改善后揭盲。英夫利西单抗组中根据MMT标准未改善的受试者（无应答者）在第22、30和38周增加至开放标签英夫利西单抗7.5 mg/kg。安慰剂组的无应答者在第16、18、22、30和38周接受开放标签5 mg/kg。每组中的应答者可以选择继续相同的治疗或改变为该研究组的非应答者治疗。12例受试者（11例F/1例M; 6例非裔美国人，5例高加索人，1例亚洲人; 11例PM /1例DM）完成了研究，直至第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;平均甲氨蝶呤剂量（N=9）为16.4 ± 11.3 mg/周，平均硫唑嘌呤剂量（N=3）为50.0 ± 86.1 mg/天。平均基线MMT为104.2 ± 9.9（安慰剂组，N=6）vs. 104.2 ± 17.3（英夫利西单抗组，N=6）。英夫利西单抗组3例受试者在第16周后退出; 3例受试者完成英夫利西单抗7.5 mg/kg给药方案。安慰剂组的所有6例患者在第16周后交叉至5 mg/kg给药方案。在英夫利西单抗组中，3/12例受试者在16周时通过手动肌肉测试改善，另外1例受试者在40周时通过MMT改善。6例受试者在安慰剂治疗后均无改善（主要结局p=0.50，次要结局p=0.63）。应答者和非应答者之间未检测到临床或实验室差异。研究期间发生了2起与研究药物无关的SAE。其他不良事件为轻度和可逆。首次在肌炎患者中进行的英夫利西单抗随机对照临床试验表明，英夫利西单抗耐受性良好，但对成人PM和DM的疗效有限。在NIH支持下，NIAMS和NIEHS参与的一项大型多国合作抗B细胞药物试验已经完成，目前正在分析结果。我们的转介诊所继续看到相当多的患者谁已被诊断为肌炎，并已与标准治疗不成功。这些患者中有相当一部分患有可证实的遗传性疾病（如McArdle's，PFK缺乏症或酸性麦芽糖酶缺乏症，许多类型的肢带营养不良之一）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的实验室在遗传医学中心在儿童的国家医疗中心，使用基因表达，以提高诊断。约翰霍普金斯大学的丽莎克里斯托弗-斯廷博士已获得K-23基金，对根据我们目前的自然史方案（91-AR-0196）评估的700多名患者的关键诊断和预测预后特征进行深入分析。近年来，研究中发现的数百名患者的冷冻肌肉活检标本和DNA已被收集并编目用于未来的研究。NIH的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是一种类似肌炎的附带炎症的营养不良。

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.