Short CommunicationRituximab treatment in seronegative autoimmune autonomic neuropathy and autoimmune autonomic ganglionopathy: Case-report and literature review
Introduction
Autoimmune autonomic ganglionopathy (AAG) is a rare acquired disease, characterized by diffuse autonomic failure involving sympathetic, parasympathetic and enteric functions. Main symptoms include orthostatic hypotension (OH), anhidrosis, xerostomia, reduced lacrimation, mydriasis, urinary retention and gastrointestinal dysmotility (constipation mainly, ileus, vomiting, more rarely diarrhea). Onset of disease is generally acute or subacute and less commonly chronic (Vernino et al., 2009; Imrich et al., 2009; Muppidi, 2018; Koike et al., 2010a; Klein et al., 2003; Mazzeo et al., 2013). AAG is mainly idiopathic, but can also be due to paraneoplasic syndrome (especially in thymoma, lymphoma and small-cell lung cancer) or may be associated with an autoimmune disease (e.g. Sjögren syndrome) (Vernino et al., 2009; Gupta et al., 2015). Until recently, AAG was sometimes associated with ganglionic (α3-type) nicotinic acetylcholine receptor (Gα3NAChR) antibodies, which were found in 50 to 60% of patients (Gupta et al., 2015; Iodice et al., 2009a). However, in early 2018, Golden et al. proposed to distinguish these two forms of the disease, separating seropositive patients for Gα3NAChR antibodies from seronegative patients, designating this latter form “seronegative autoimmune autonomic neuropathy” (SAAN) (Golden et al., 2018). In the following, AAG refers to seropositive autoimmune autonomic ganglionopathy.
Due to the rarity of SAAN and AAG, there is no well-established treatment. To date, recommendations for treatment are based on case-reports (Gupta et al., 2015). The most frequently described treatments are intravenous immunoglobulin (IVIG) and plasma exchange (PE), which are often used as first-line therapy (Iodice et al., 2009b; Nishihara et al., 2015). Providing only poor or transient benefits in some cases, some patients remain dependent on therapy to maintain remission, and for this reason, other immunomodulatory therapies may be used (Nishihara et al., 2015). In recent years, rituximab has been used successfully (Gupta et al., 2015; Hollenbeck et al., 2011). We report here the case of a SAAN patient treated in our Department with rituximab as third-line treatment after unsuccessful IVIG and PE therapies. We also provide a review of case-reports published in literature reporting the use of rituximab for the treatment of SAAN and AAG, in order to assess the efficacy of this drug in both forms of the disease.
Section snippets
Methods
To identify articles reporting AAG and SAAN treatment with rituximab, we searched the PubMed database using the terms “autoimmune autonomic ganglionopathy” or “autoimmune autonomic neuropathy” or “seronegative autoimmune autonomic neuropathy”, associated with “rituximab”. We selected articles written in English or French. Our patient gave consent for us to publish her case. No ethics committee approval was required according to local legislation.
Case-report
In February 2014, a 24-year-old woman was referred to our department for bilateral nonreactive mydriasis, dysuria, dysphagia and constipation. She had a history of mild asthma treated with on-demand bronchodilator, but no allergies.
At the end of January 2014, the patient had come back to France after travelling to Mexico and New York. Two weeks after her return, she had flu-like syndrome with fever and myalgia. Three days later, she presented to the emergency department of a peripheral hospital
Discussion
To the best of our knowledge, this is the first review of case-reports assessing the efficacy of rituximab in SAAN and AAG. Rituximab is a chimeric monoclonal antibody that selectively depletes CD20+ B-cells, sparing other cell lineages (Iodice et al., 2009b). In the cases included in our review, rituximab was mostly used when PE or IVIG failed to treat SAAN or AAG, and was used on median as third-line therapy. The median dose of rituximab was 2 g in the 4 cases in which it was reported.
Until
Sources of funding
None.
Conflicts of interest
None.
Role of funding source
No funding source was needed.
Ethics committee approval
No ethics committee approval was needed.
Acknowledgements
We thank Fiona Ecarnot (EA3920, University Hospital Besancon, France) for editorial assistance.
MB collected the data. MB, GN and FBS wrote the first manuscript draft. All authors were involved in the care of the patient. All authors participated in the writing of the final manuscript and all authors approved final manuscript. FBS was responsible for the overall supervision of the present work.
References (22)
- et al.
Antibody titers predict clinical features of autoimmune autonomic ganglionopathy
Auton. Neurosci.
(2009) - et al.
Immunotherapy for autoimmune autonomic ganglionopathy
Auton. Neurosci.
(2009) - et al.
COMPASS 31: a refined and abbreviated composite autonomic symptom score
Mayo Clin. Proc.
(2012) - et al.
Seronegative and seropositive autoimmune autonomic ganglionopathy (AAG): same clinical picture, same response to immunotherapy
J. Neuroimmunol.
(2018) Auton Neurosci
(2009)- et al.
Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy
Auton. Neurosci.
(2009) - et al.
Clinical problem solving: a tobacco merchant who can't Spit
Isr. Med. Assoc. J.
(2017) - et al.
Opsoclonus-myoclonus syndrome during rituximab treatment for autoimmune autonomic ganglionopathy
Neurol. Neuroimmunol. Neuroinflam.
(2017) - et al.
Seronegative autoimmune autonomic neuropathy: a distinct clinical entity
Clin. Auton. Res.
(2018) - et al.
Rituximab-based therapy and long-term control of autoimmune autonomic ganglionopathy
Clin. Auton. Res.
(2015)
Long-term treatment with rituximab of autoimmune autonomic ganglionopathy in a patient with lymphoma
Arch. Neurol.
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