Developmental Clinical Studies- Combined Immunotherapy and Trophic Adrenocortical Stimulation in New Onset Autoimmune Addison's Disease

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Autoimmune Addison's disease is caused by the immune system attacking and destroying the cortex of the adrenal glands, which gives people a life-threatening problem owing to lack of the adrenal steroid hormones. Symptoms typically include exhaustion, light-headedness, vomiting, weight loss, poor appetite, muscle weakness and cramps. In addition, Addison's people are prone to unpredictable episodes of severe illness, termed adrenal crisis. This means that people with Addison's disease have a life-long dependency on steroid medications, and may become ill within hours of a missed dose. There have been no significant advances in therapy for Addison's disease for sixty years. However, the adrenal cortex is one of the most plastic tissues in the body and this study aims to exploit this innate regenerative capacity to produce a cure for people who have just been diagnosed with Addison's disease.The idea of this study is to combine a hormone therapy that is a synthetic version of the body's natural adrenal stimulating hormone, termed ACTH (adrenocorticotropic hormone), with a treatment to dampen down the immune system's attack on the adrenal cortex. In a previous study, we have found that alternate day injections with synthetic ACTH is effective in stimulating adrenal gland regeneration, but we do not know what sort of treatment will be effective in dampening down the immune response. This will be important to make sure any adrenal regeneration isn't just rapidly destroyed again by the immune attack. The study will take place in 3 stages, each involving 4 people with newly-diagnosed Addison's disease. In each stage of the study, the participants will receive the same dose of alternate day ACTH. However, the first part of the study will use a drug called rituximab, that removes the antibody-producing B lymphocytes from the blood and tissues for about 6 months, to see if this stops the immune attack on the adrenals and allows permanent regeneration. If this doesn't work, we will try a different sort of immunotherapy called abatacept, that affects the function of the T lymphocytes, which act both as the immune system's radar and assassination team. Both these treatments are antibody therapies that are administered for a short period of time (either 2 or 5 doses), but produce long lasting effects on immune system function, for several months. If neither of these immune system treatments work, we will then use a combination of 3 high-dose steroid infusions followed by a daily immunosuppressive tablet called mycophenolate which will be taken for 12 weeks. After each of these treatments adrenal function will be retested in participants at regular intervals for a year to see if the hormonal function of the adrenal gland had been improved. We believe that this therapeutic approach, combining both a drug to quash the immune system attack on the adrenal glands with hormonal stimulation to promote adrenal regeneration, holds genuine promise for cure of this chronic condition.