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

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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.