Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by the presence of autonomic failure in association with specific antibodies directed against the neuronal acetylcholine receptor (AChR) of the autonomic ganglia. Patients typically present over weeks to months with severe orthostatic hypotension, syncope, constipation, urinary retention, fixed and dilated pupils, dry mouth and dry eyes. Symptomatic treatment of autonomic failure is sufficient in only mildly afflicted patients. Many patients remain incapacitated by autonomic symptoms and require disease modifying therapy but there is no established therapeutic regimen. Several case reports and case series of immunomodulatory treatments for AAG exist but in none of these is the treatment blinded or randomized. Furthermore, the natural history of untreated AAG is not known. Plasma exchange and intravenous immunoglobulin are usually the first interventions but in all reports the response appears transient and follow-up immunosuppression (typically with several agents) is required. It is likely that autoreactive B-cells and autoantibodies play a central pathogenetic role in AAG but to date agents targeting B-cells have not been used in the treatment of this disorder. The long term goals of the project are to find an effective, safe and durable treatment for AAG.
The specific aims of this proposal are: (1) To determine the effect of intravenous immunoglobulin (AAG) treatment on orthostatic hypotension and quality of life scores in patients with AAG and to determine the effect of targeted immunomodulatory, with the anti-CD20 immunosuppressive agent, rituximab, treatment on orthostatic hypotension and quality of life scores in patients with AAG who have failed therapeutic trials with IVIG and other immunosuppressant agents. We anticipate that IVIG will produce a clinically significant but transient improvement whereas rituximab will be an efficacious treatment for patients with AAG.
In this proposal, we plan to carry out consecutive, blinded, randomized trials in patients with AAG, initially using IVIG, followed by targeted B cell immunosuppression with rituximab. There are no reported randomized clinical trials with any immunosuppressive agent in AAG and no reported trials using rituximab. Thus, the proposed studies, if successful, will provide the first definitive clinical evidence, that immunomodulatory therapy is effective treatment of AAG.
|Loavenbruck, A; Iturrino, J; Singer, W et al. (2015) Disturbances of gastrointestinal transit and autonomic functions in postural orthostatic tachycardia syndrome. Neurogastroenterol Motil 27:92-8|
|Palma, Jose-Alberto; Kaufmann, Horacio (2015) Novel therapeutic approaches in multiple system atrophy. Clin Auton Res 25:37-45|
|Piccione, Ezequiel A; Sletten, David M; Staff, Nathan P et al. (2015) Autonomic system and amyotrophic lateral sclerosis. Muscle Nerve 51:676-9|
|Figueroa, Juan J; Bott-Kitslaar, Darlene M; Mercado, Joaquin A et al. (2014) Decreased orthostatic adrenergic reactivity in non-dipping postural tachycardia syndrome. Auton Neurosci 185:107-11|
|Mai, Tu H; Wu, Jing; Diedrich, André et al. (2014) Calcitonin gene-related peptide (CGRP) in autonomic cardiovascular regulation and vascular structure. J Am Soc Hypertens 8:286-96|
|Macefield, Vaughan G; Norcliffe-Kaufmann, Lucy; Löken, Line et al. (2014) Disturbances in affective touch in hereditary sensory & autonomic neuropathy type III. Int J Psychophysiol 93:56-61|
|Gamboa, Alfredo; Okamoto, Luis E; Arnold, Amy C et al. (2014) Autonomic blockade improves insulin sensitivity in obese subjects. Hypertension 64:867-74|
|Ramirez, Claudia E; Okamoto, Luis E; Arnold, Amy C et al. (2014) Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure. Hypertension 64:1235-40|
|Wada, Naoki; Singer, Wolfgang; Gehrking, Tonette L et al. (2014) Comparison of baroreflex sensitivity with a fall and rise in blood pressure induced by the Valsalva manoeuvre. Clin Sci (Lond) 127:307-13|
|Palma, Jose-Alberto; Kaufmann, Horacio (2014) Autonomic disorders predicting Parkinson's disease. Parkinsonism Relat Disord 20 Suppl 1:S94-8|
Showing the most recent 10 out of 65 publications