Immunotherapeutic rescue of steroidogenic function in autoimmune Addison's disease: Pilot Study

Autoimmune Addison`s disease is a chronic disease caused by the body`s immune system attacking and eventually destroying the adrenal glands. This causes deficiency of certain steroid hormones that are essential for life and wellbeing, which the healthy adrenal glands normally produce. The current approach to treating Addison`s disease is simply to replace the missing adrenal steroid hormones using tablets. This makes people feel better, but often not fully back to normal and leaves them chronically dependent upon steroid medications (2 or 3 doses daily), with several long-term side effects, as well as a reduced life-expectancy.

We plan a radical new approach to treatment of Addison`s disease, which is to try to switch off the immune system, so the attack on the adrenal glands ceases. We will use a safe but powerful treatment called rituximab that removes a certain type of immune cell, called the B lymphocyte, from the bloodstream and tissues. This treatment has been used on more than a million people with blood conditions over the last 10 years, and is given as two 4-hour infusions, 14 days apart. The results of rituximab therapy in several other autoimmune disease show great promise, with substantial amelioration of disease. As adrenal tissue is already known to have a great capacity for regeneration, it is highly likely that the remaining (not destroyed) adrenal cells will regenerate, restoring the secretion of the vital steroid hormones to normal, once the immune attack has gone. The body naturally makes an adrenal gland stimulating hormone, ACTH-adrenocorticotropic hormone, when adrenal secretions are deficient or below the necessary levels. People with Addison`s have very high levels of ACTH, and this would cause the regeneration of the adrenal glands once the immune attack has been removed. This strategy could lead to a permanent cure of autoimmune Addison s disease, for the first time.

Autoimmune Addison`s disease (AAD) is a rare and debilitating disease in which an autoimmune attack progressively destroys the adrenal cortex. Untreated it is universally fatal and treated people are absolutely dependent upon steroid medications lifelong, with a consequent excess in morbidity and mortality. Treatment is supportive only, with no attempt to modify the natural history of the disease process. A key feature of AAD is that in recent years it is often diagnosed at a stage when subjects have some residual adrenal steroidogenic capacity. As adrenal tissue is highly plastic, this residual steroidogenic tissue may be able to regenerate and restore adrenal functional to normality, if the autoimmune process can be arrested.
We will perform a pilot study of B cell depletion therapy (rituximab) to salvage adrenal steroidogenic capacity in six subjects with autoimmune Addison`s disease. During the first twelve weeks of treatment, additional glucocorticoid therapy will be given to ensure wellbeing and to rest the steroidogenic apparatus that is the target of the autoimmune attack. Response to treatment will be judged by gold-standard endocrine indices of adrenocortical function and autoantibody assays. We believe that this therapy may have the potential to ameliorate the autoimmune attack against adrenal cells, allowing a state of immune tolerance to be restored with subsequent regeneration of adrenal steroidiogenic capacity.
If successful, this study would mark a sea-change in thinking about the therapeutic approach to autoimmune Addison`s disease. In addition to demonstrating proof of principle, it would also provide the key mechanistic insight that B cells have a central role in promulgation or maintenance of adrenal autoimmunity.