MICA: A randomised, double blind, controlled mechanistic study of obinutuzumab versus rituximab in ANCA-associated vasculitis (ObiVas)

什么是血管炎？血管炎是一种罕见的医学疾病，在英国每百万人中约有250人受到影响。它的特点是炎症和血管壁的损伤。血管将血液输送到全身，为我们的器官提供氧气和营养。因此，任何器官都可能受到血管炎的影响，但某些器官受到的影响比其他器官更多。例如，肾脏、肺、耳鼻和咽喉区域通常受到影响。血管炎是一种所谓的“自身免疫”疾病，身体自身的免疫系统攻击自己（在这种情况下是血管），而不是防御它们免受感染。如果不治疗，炎症会导致受影响的器官停止工作。如果不迅速开始适当的治疗，患者可能会变得非常不适并可能死亡。研究表明，某种类型的免疫细胞（B细胞）产生Y形蛋白质（称为ANCA的抗体），这对启动炎症很重要。我们还知道，另一种细胞类型（T细胞）似乎在血管炎患者中过度活跃和行为不端。问题是，目前最好的治疗方法是一种叫做利妥昔单抗的药物，它是通过静脉滴注直接给药的。利妥昔单抗清除血液中的B细胞。患者在利妥昔单抗治疗后很快感觉良好，但大约6-12个月后，炎症再次开始，因此需要越来越多的利妥昔单抗，这可能会对免疫系统造成长期不良影响。我们的解决方案。我们观察了从接受利妥昔单抗治疗的患者鼻内取出的组织样本。我们已经证明B细胞仍然存在，这表明利妥昔单抗并没有像我们需要的那样起作用。此外，我们还使用了最先进的遗传分析，表明鼻子中的B细胞与T细胞相互作用。我们的理论是利妥昔单抗无法清除组织中的B细胞，导致疾病继续发展这就是为什么利妥昔单抗不能使血管炎消失很长一段时间。有一种名为obinutuzumab的新药也针对B细胞，但经过改造，使用略有不同的机制。动物研究显示，与利妥昔单抗相比，组织中B细胞的减少更大，人体临床试验显示，obinutuzumab对某些血癌和另一种自身免疫性疾病（狼疮）效果良好。我们认为在血管炎患者中使用obinutuzumab将导致更好地靶向组织中的B细胞，从而减少B细胞和T细胞之间的相互作用，并更好地控制血管炎和炎症。我们提出了一个小的实验研究利妥昔单抗与obinutuzumab在血管炎患者。我们将给6名患者常规药物和6名患者新药。每位患者在治疗前和治疗后3个月将进行鼻内活检。我们将能够评估这两种药物的效果，即它们清除鼻子内B细胞的能力以及对T细胞的间接影响。然后，我们将对患者进行2年的随访，届时B细胞应该已经返回血液中。通过定期的血液检查，我们将能够检查返回的B细胞的类型，以及obinutuzumab是否使它们不太可能导致血管炎和炎症返回。重要性和更广泛的使用。这项研究将让我们评估和比较这两种药物的作用机制，并深入研究驱动疾病组织炎症的过程。这是一项重要的研究，因为找到比利妥昔单抗更好的治疗方法将改善血管炎患者的生活。此外，靶向B细胞是许多其他疾病的常用方法，因此本研究的发现可能会提高对其他自身免疫性疾病的理解和治疗。

What is vasculitis?Vasculitis is a rare medical condition that affects around 250 per million people in the UK. It is characterised by inflammation and damage to the walls of blood vessels. Blood vessels carry blood around the body supplying our organs with oxygen and nutrients. Thus, any organ can be affected by vasculitis, but some organs are affected more than others. For example, the kidneys, lungs, ear nose and throat regions are commonly affected. Vasculitis is a so-called 'auto-immune' disease where the body's own immune system attacks itself (blood vessels in this case) instead of defending them against infection. Without treatment, inflammation causes the affected organs to stop working. Patients can become very unwell and can die if proper treatment is not started quickly. Research has shown that a certain type of immune cell (B cell) produces Y-shaped proteins (antibodies called ANCAs) which are important in starting the inflammation. We also know that another cell type (T cell) seems to be overactive and misbehaving in patients with vasculitis. The problem.The current best treatment is a medicine called rituximab, which is given directly in the vein by a drip. Rituximab gets rid of B cells from the blood. Patients feel better quite quickly after rituximab, but after about 6-12 months, the inflammation starts up again, so more and more rituximab is needed, which can cause unwanted effects to the immune system in the long-term. Our solution.We have looked at samples of tissue taken from the inside of the nose in patients who have received rituximab. We have shown that B cells are still present, suggesting that rituximab is not working as well as we need it to. Furthermore, we have used cutting-edge genetic analysis to show that B cells in the nose are interacting with the T cells. Our theory is that the inability of rituximab to get rid of the B cells in the tissues, allows the mechanisms driving the disease to continue which is why rituximab cannot make the vasculitis go away for a very long time. There is a new medicine called obinutuzumab that also targets B cells but has been engineered to use slightly different mechanisms. Animal studies show greater reductions of B cells in tissues compared to rituximab, and clinical trials in humans have shown that obinutuzumab works well for some blood cancers and another autoimmune disease (lupus). We think that using obinutuzumab in patients with vasculitis will lead to better targeting of B cells in the tissues, resulting in less interaction between B cells and T cells, and better control of vasculitis and inflammation. We propose a small experimental study of rituximab versus obinutuzumab in patients with vasculitis. We will give 6 patients the normal medicine and 6 patients the new medicine. Each patient will have a biopsy of the inside of the nose before treatment and 3 months after treatment. We will be able to assess the effects of the two medicines in terms of their ability to get rid of the B cells inside the nose and the indirect effect this has on the T cells. We will then follow patients up for 2 years by which time the B cells should have returned in the blood. Through regular blood tests, we will be able to examine the type of the returning B cells, and whether or not obinutuzumab has made them less likely to cause the vasculitis and inflammation to return. Importance and wider use. This study will let us assess and compare the mechanism of action of these 2 medicines, and also dig deep into the processes that drive inflammation in the disease tissue. This is an important study because finding a better treatment than rituximab will improve the lives of patients with vasculitis. Furthermore, targeting B cells is a commonly used approach for many other diseases, so the findings of this study may improve the understanding and treatments of other autoimmune diseases.