MICA: Targeting the RA synovial fibroblast via cyclin dependent kinase inhibition - a phase IIa study

类风湿性关节炎（RA）是一种关节发炎和疼痛的疾病。在英国，每100个成年人中就有1人患有此病。它被认为是由病人的免疫系统错误地攻击他们的关节引起的。由此产生的炎症不仅会引起疼痛，还会减少关节活动，最终导致关节损伤和畸形。类风湿性关节炎还会影响其他器官，如肺，而且类风湿性关节炎患者患心脏病和中风的风险也高于平均水平。他们也更容易受到感染。许多患者在确诊后不久就失去了工作。目的和目标目前用于治疗类风湿性关节炎的大多数药物（抗炎药，类固醇）或免疫系统细胞及其产物（生物疗法或“灵丹妙药”）。在过去的20年里，类风湿性关节炎患者的预后有所改善，部分原因是早期和更“积极”的治疗（更多的药物，更高的剂量），部分原因是新疗法的发展（特别是“灵丹妙药”）。然而，许多患者对这些治疗没有完全反应，有些根本没有反应。我们认为有另一种类型的细胞导致了这些患者的症状。成纤维细胞是存在于健康关节中的一种细胞，它对正常关节功能很重要。然而，在类风湿性关节炎关节中，成纤维细胞分裂不当，数量增多且具有“侵袭性”。它们通过产生侵蚀软骨和骨骼的化学物质来损害关节，同时自身也会产生炎症化学物质。因此，一个健康的有用细胞变成了引起关节炎炎症和关节损伤的细胞。据我们所知，目前的治疗方法都不会影响成纤维细胞的行为。我们的计划是在类风湿性关节炎患者身上测试一种药物，我们认为这种药物可以起到作用。这种药物干扰细胞分裂所必需的机制。类风湿性关节炎关节中的成纤维细胞似乎对这种药物特别敏感，因此我们相信这种药物可以纠正它们的异常行为。这种药物已经在某些类型的癌症（细胞也分裂不正常）患者身上进行了测试，并且似乎足够安全，可以用于类风湿性关节炎的测试。我们的目标是证明这种治疗在类风湿性关节炎中是安全的，并且它可以为类风湿性关节炎患者提供一种有用的治疗方法。本研究分为两部分。在第一部分中，我们将在4周的治疗中测试不同剂量药物的安全性。我们将确定一个既安全又合适的剂量，在更多的患者中进行更长时间的试验。在第二部分，我们将给12名RA患者服用这种剂量，持续12周。同时，6名患者将接受相同的“安慰剂”治疗。这一点很重要，可以确保我们看到的任何影响都是由药物引起的，而不是其他因素（更多地去医院，更多地与医生和护士互动）。除了检查病人的症状，我们还会在治疗开始和结束时对他们的关节进行扫描。我们还将采集关节组织的小样本（活检）。这些扫描和活组织检查将帮助我们确定治疗是否有效以及如何起作用。这对于帮助我们决定试验是否“成功”以及是否在以后进行进一步的试验非常重要。潜在的应用和益处在这项试验中，我们将治疗患有类风湿性关节炎至少一年，并且已经接受治疗但反应不够好的患者。这将验证我们的想法，即我们可以通过改变成纤维细胞的行为来改善症状。如果这项研究成功，那么我们将需要在类风湿性关节炎患者中测试治疗方法，在他们疾病的不同阶段采用不同的治疗方法。由于这种治疗方法与现有药物的作用方式不同，我们相信它可能对许多不同类型的类风湿性关节炎患者有用。后来，如果安全有效，它也可能对其他疾病有用。

Context Rheumatoid arthritis (RA) is a condition in which the joints become inflamed and painful. It affects about 1 in every 100 adults in the UK. It is thought to be caused by the patient's immune system mistakenly attacking their joints. The resulting inflammation is not only painful but reduces joint movement and eventually causes joint damage and deformity. RA can also affect other organs such as the lungs, and patients with RA also have a higher than average risk of developing heart attacks and strokes. They are also more susceptible to infections. Many patients lose their jobs soon after the diagnosis is made.Aims and objectivesMost drugs currently used to treat RA neutralise the inflammation (anti-inflammatory drugs, steroids) or the cells of the immune system and their products (biological therapies or 'magic bullets'). Over the past 20 years the outcome for RA patients has improved, partly because of earlier and more 'aggressive' treatment (more drugs, higher doses) and partly because of new therapies that have been developed (particularly the 'magic bullets'). However, many patients don't respond completely to these treatments and some don't respond at all. We believe that there is another type of cell responsible for the symptoms in these patients. The fibroblast is a cell that is present in healthy joints, where it is important for normal joint function. However, fibroblasts divide inappropriately and become more numerous and 'aggressive' in RA joints. They damage the joint by producing chemicals that eat into cartilage and bone, and also produce inflammatory chemicals themselves. Thus, a useful cell in health becomes one that causes inflammation and joint damage in RA. As far as we know none of the current treatments affect the behaviour of fibroblasts. Our plan is test a drug in RA patients that we think will do so. The drug interferes with the machinery that is necessary for cells to divide. Fibroblasts in the RA joint seem particularly sensitive to this drug, which we therefore believe can correct their abnormal behaviour. The drug has already been tested in patients with certain types of cancer (in which cells also divide inappropriately) and seems safe enough to test in RA. We aim to show that the treatment is safe in RA, and that it could provide a useful treatment for RA patients. The research is divided into two parts. In the first part we will test the safety of different doses of the drug over 4 weeks of treatment. We will identify a dose that is both safe and appropriate to test in more patients for a longer period of time. In the second part we will give this dose to 12 RA patients for 12 weeks. At the same time 6 patients will receive an identical 'placebo' treatment. This is important to ensure that any effects we see are due to the drug and not other factors (more visits to the hospital, more interaction with doctors and nurses). As well as checking the patients' symptoms, we will also perform scans of their joints at the start and end of the treatment. We will also take small samples of joint tissue (biopsies). These scans and biopsies will help us to decide whether the treatment is working and how it is working. This is important to help us to decide whether the trial has been a 'success' and whether to perform further trials later on. Potential applications and benefitIn this trial we will treat patients who have had RA for at least a year and who are already taking treatment but not responding well enough. This will test our idea that we can improve their symptoms by altering the behaviour of the fibroblasts. If this research is successful then we will need to test the treatment in RA patients taking different treatments, at different stages of their illness. Because this treatment works in such a different way to existing drugs, we believe it could be useful for many different types of RA patient. Later on, if safe and effective, it may also be useful in other diseases.