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.
| van den Berg, Maarten P; Almomani, Rowida; Biaggioni, Italo et al. (2018) Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome. Circ Res 122:846-854 |
| Bar-Aluma, Bat-El; Efrati, Ori; Kaufmann, Horacio et al. (2018) A Controlled Trial of Inhaled Bronchodilators in Familial Dysautonomia. Lung 196:93-101 |
| Palma, Jose-Alberto; Kaufmann, Horacio (2018) Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies. Mov Disord 33:372-390 |
| Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio; Palma, Jose-Alberto et al. (2018) Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Ann Neurol 83:522-531 |
| Raj, Satish R; Robertson, David (2018) Moving from the present to the future of Postural Tachycardia Syndrome - What we need. Auton Neurosci 215:126-128 |
| Coon, Elizabeth A; Ahlskog, J Eric; Silber, Michael H et al. (2018) Do selective serotonin reuptake inhibitors improve survival in multiple system atrophy? Parkinsonism Relat Disord 48:51-53 |
| McKay, Jake H; Cheshire, William P (2018) First symptoms in multiple system atrophy. Clin Auton Res 28:215-221 |
| Farrell, Maureen C; Brenner, Alexander S; Shibao, Cyndya A (2018) Diagnostic treatment dilemma: baroreflex failure or autoimmune autonomic ganglionopathy? Clin Auton Res 28:589-591 |
| Coon, Elizabeth A; Benarroch, Eduardo E (2018) DNA damage response: Selected review and neurologic implications. Neurology 90:367-376 |
| Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio (2018) Diagnosis of multiple system atrophy. Auton Neurosci 211:15-25 |
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