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Dysautonomia in Sjögren's

October is Dysautonomia Awareness month, and to honor the month, we are highlighting Sjögren’s and Dysautonomia. Sjögren’s is the second leading cause of dysautonomia behind diabetes. Our experts state that approximately 50% of patients with Sjögren’s present with some form of dysautonomia,1,2,3 the vast majority of Sjögren’s patients are underdiagnosed with dysautonomia.3

What is dysautonomia?

Dysautonomia, which doctors may also call autonomic dysfunction, occurs when there is an underlying malfunction of the autonomic nervous system (ANS). The ANS is made up of both the sympathetic (“fight or flight” response) and the parasympathetic (“rest or digest” response) nervous systems and controlled by the autonomic nerves and ganglia. A malfunction in the ANS can be caused by physical damage to the autonomic nerves or ganglia- called autonomic neuropathy- and/or by an imbalance of neurotransmitter responses, which can lead to impaired ANS signaling. Autonomic nerves and ganglia relay messages from the brain to the internal organs and tissues, including but not limited to the heart, blood vessels, gastrointestinal system, lungs, pupils, sweat glands, and bladder.2,3

The ANS is responsible for maintaining balance of the involuntary body functions such as heart rate, blood pressure, breathing, temperature regulation, and kidney function among others. Interestingly, the ANS highly regulates the function of the exocrine glands- the primary affected organ system in Sjögren’s.2

Dysautonomia can range in disease severity. Mild symptoms include dizziness and syncope (fainting), whereas moderate and more severe symptoms can include numbness and pain in the arms and legs, Guillain-Barre syndrome that can cause muscle weakness and paralysis, or full autonomic failure. The most common symptoms experienced by patients with dysautonomia are pain and fatigue.

How does dysautonomia manifest in Sjögren’s?

Sjögren’s is a heterogeneous disease and patients can have different clinical manifestations present before Sjögren’s diagnosis and as their main symptoms. For many Sjögren’s patients, especially younger patients, neurological manifestations like dysautonomia could be their initial presentation. The ANS is more vulnerable in Sjögren’s patients and autonomic dysfunction is more prevalent in Sjögren’s than any other autoimmune disease.3

In Sjögren’s patients, impairment of the ANS can cause dysregulation of one or more of the following:

  • heart rate and blood pressure with or without syncope (fainting)
  • esophagus and intestinal motility (muscle movement)
  • bladder function, increased urination frequency
  • dilation and constriction of the pupils of the eyes
  • secretory glands including decreased lacrimation, salivation, and mucus production
  • sweating, increased or decreased and heat intolerance
  • respiration (breathing in and/or out)

Common forms of dysautonomia in Sjögren’s patients

Orthostatic Intolerance, including Postural Orthostatic Tachycardia Syndrome (POTS) and Orthostatic hypotension (low blood pressure when standing upright)

  • Postural (standing upright) lightheadedness
  • Postural heart racing, chest pain
  • Presyncope or syncope (fainting)
  • Postural dizziness
  • Postural leg weakness
  • Exercise Intolerance
  • Postural visual symptoms

Gastrointestinal dysmotility (impairment of muscle movement in the esophagus, colon, intestines, stomach)

  • impaired swallowing
  • nausea
  • vomiting
  • early satiety
  • constipation
  • abdominal pain
  • diarrhea
  • gastroparesis (delayed stomach emptying)

Autonomic neuropathy

  • Impairment and damage to the autonomic nerves and/or ganglia
  • Patients can also experience POTS, orthostatic hypotension, and gastrointestinal impairment

How is dysautonomia diagnosed?

Sjogren’s patients do not necessarily have to see an autonomic neurologist to be diagnosed with dysautonomia or orthostatic intolerance. A primary care provider can measure vital signs after postural changes to determine if there is dysregulation in heart rate or blood pressure. Tilt table testing can be done for more formal autonomic dysfunction testing. However, a neuromuscular specialist will need to be seen to diagnose autonomic neuropathy and assess the extent of damage to the autonomic nerves. Other types of neuropathies such as small fiber neuropathy, which affects the small sensory neurons, can also cause autonomic dysfunction.

Diagnostic criteria3 for POTS and orthostatic hypotension from postural and/or tilt table testing:

Postural Orthostatic Tachycardia Syndrome (POTS)

  • Increased Heart rate greater than or equal to 30 bpm with standing/tilt in adults and 40 bpm in children and adolescents  
  • Heart rate greater than or equal to 120 bp with standing/tilt, absence of hypotension
  • Absence of conditions associated with orthostatic hypotension postural symptoms

Orthostatic hypotension (low blood pressure after standing upright)

  • Sustained decrease in blood pressure within 3 mins of standing/tilt usually greater than 20 mmHg systolic BP or greater than 10 mmHg diastolic BP
  • Vasovagal syncope (fainting due to a vagus nerve response)
  • Transient loss of consciousness due to decrease in blood pressure and often including decreased heart rate

What causes dysautonomia in Sjögren’s?

The short and unappealing answer is that no one knows for certain. A definitive cause for dysautonomia in Sjögren’s may not have been elucidated, but it is widely supported that immune-mediated responses may damage autonomic nerves and ganglia as well as block important autonomic signaling through the muscarinic receptors.2 Many studies have shown anti-muscarinic autoantibodies, which block autonomic signaling, in the saliva, serum, gastrointestinal tract, and other tissues associated with autonomic dysfunction in patients with Sjögren’s.4,5,6,7 Cholinergic dysfunction, which can be caused by impaired muscarinic receptor signaling, is considered a hallmark of dysautonomia in patients with Sjögren’s.4,5,6,7

How is dysautonomia treated in patients with Sjögren’s?

Since the underlying causes of both dysautonomia and Sjögren’s have not been elucidated, the primary course of therapy is symptomatic treatment and stabilization of the ANS. Although symptoms of dysautonomia are common in patients with Sjögren’s, the severity and clinical manifestations vary among patients. Patients should speak with their doctors for a personalized plan to treat their dysautonomia.

Some lifestyle changes can be used to treat orthostatic intolerance, such as wearing compression stockings/socks or an abdominal binder, controlling salt and fluid intake, and exercises. Pharmacological treatments can be used to stabilize the autonomic nervous system using blood vessel constriction or dilation to control blood pressure or low-dose beta blockers to control heart rate as well as blood pressure. Antihistamines can also be used to help stabilize heart rate and blood pressure.3  

Autonomic nerves have the ability to regenerate, which gives optimism that immunomodulatory drugs may be beneficial in restoring nerve function in patients with autonomic neuropathy as seen in patients with Guillain-Barre Syndrome that are treated with immunoglobulin. Common immunomodulatory drugs used for treating general dysautonomia and autonomic neuropathy in Sjogren’s patients are hydroxychloroquine, rituximab, low-dose naltrexone, and immunoglobulin.3,8,9

Editor’s note: Please be aware that clinicians may use medical terms synonymously. For example, a clinician may use autonomic neuropathy to encompass both general symptoms of dysautonomia and autonomic nerve damage or clinicians may use autonomic neuropathy for each separate condition.

The Sjögren’s Foundation and dysautonomia research in Sjögren’s patients

Earlier this year, the Foundation committed to expanding research for dysautonomia in Sjögren’s patients. The Foundation awarded Kamal Chémali, MD, an associate professor of neurology at University Hospitals Cleveland Medical Center, with a $50,000 grant to study the prevalence of elevated Mycoplasma pneumoniæ titers in Sjögren’s and other autoimmune disorder-associated neuropathic postural orthostatic tachycardia syndrome (neuropathic POTS). Dr. Chémali  has focused his research and career on autonomic nervous system disorders, small fiber neuropathies (SFN) and autoimmune autonomic neuropathies.

A synopsis of what Dr. Chémali will study and hopes to achieve is shared below in an abstract of his proposal:

Sjögren’s is notorious for causing SFN, which is present in a majority of POTS cases (the combination is termed “neuropathic POTS”). Mycoplasma pneumoniae (MP) causes up to 40% of community acquired pneumonias and is a possible cause of immune-mediated large-fiber neurologic disorders, such as Guillain-Barré syndrome. Its effect of small fibers is less known. We found significant elevation of MP IgG titers in the serum of most individuals with neuropathic POTS associated with autoimmune disorders, predominantly Sjögren’s, departing significantly from the general population prevalence. We propose the pathogen may therefore contribute to autonomic C and A delta nerve fibers dysfunction, leading to autonomic disorder through an autoimmune mechanism. Such a conclusion would trigger the search for an autoimmune disease, mainly Sjögren’s, in patients with neuropathic POTS and elevated MP titers, leading to a more targeted and effective core treatment of these conditions with immune modulation.

If you have any questions about your medical condition, please seek additional advice from your healthcare provider.


References:

  1. Wallace DJ. The Sjögren’s Book. 5th ed. Oxford University Press, 2022.
  2. Davies K, Ng WF. Autonomic Nervous System Dysfunction in Primary Sjögren's Syndrome. Front Immunol. 2021;12:702505. Published 2021 Jul 26. doi:10.3389/fimmu.2021.702505
  3. Goodman, BP. Out of balance, Autonomic Dysfunction in Sjögren’s. Oral presentation presented at: The Sjögren’s Foundation National Patience Conference, 2023.
  4. Mandl T, Granberg V, Apelqvist J, Wollmer P, Manthorpe R, Jacobsson LT. Autonomic nervous symptoms in primary Sjogren's syndrome. Rheumatology (Oxford). 2008;47(6):914-919. doi:10.1093/rheumatology/ken107
  5. Reina S, Sterin-Borda L, Passafaro D, Borda E. Anti-M(3) muscarinic cholinergic autoantibodies from patients with primary Sjögren's syndrome trigger production of matrix metalloproteinase-3 (MMP-3) and prostaglandin E(2) (PGE(2)) from the submandibular glands. Arch Oral Biol. 2011;56(5):413-420. doi:10.1016/j.archoralbio.2010.08.017
  6. Imrich R, Alevizos I, Bebris L, et al. Predominant Glandular Cholinergic Dysautonomia in Patients with Primary Sjögren's Syndrome. Arthritis Rheumatol. 2015;67(5):1345-1352. doi:10.1002/art.39044
  7. Mukaino A, Nakane S, Higuchi O, et al. Insights from the ganglionic acetylcholine receptor autoantibodies in patients with Sjögren's syndrome. Mod Rheumatol. 2016;26(5):708-715. doi:10.3109/14397595.2016.1147404
  8. Rist S, Sellam J, Hachulla E, et al. Experience of intravenous immunoglobulin therapy in neuropathy associated with primary Sjögren's syndrome: a national multicentric retrospective study. Arthritis Care Res (Hoboken). 2011;63(9):1339-1344. doi:10.1002/acr.20495
  9. Chaaban N, Shaver T, Kshatriya S. Sjogren Syndrome-Associated Autonomic Neuropathy. Cureus. 2022;14(6):e25563. Published 2022 Jun 1. doi:10.7759/cureus.25563

Comments

— Nov 7, 2023

I have Sjogrens with neurological involvement. I am getting IVIG for the paralytic, and wide array of other neuro symptoms.
It worked well for 18 mos and then had a really bad relapse. Since then, it has not worked as well. My immunologist said that the next step, if this doesn’t work, is plasmapheresis, but that I would need a neurologist to order it. My navigating the healthcare system has left me with unbelievably bad doctors. I can’t find a neurologist who will work with Sjogrens.
My current Rheum is not even convinced that I have Sjogrens because the blood tests and lip biopsy were negative, but my QSART was abnormal 3 times, and 3 shirmers tests were, as one doc said, so dry it was @through the roof.
My clinical picture couldn’t be more consistent with Sjogrens.
I cannot find a neurologist who is interested, or knows much about it.
Can you help me find a doctor?

Yup. Same boat. There is something in the teaching of rheum that allows doctors to believe that sjogren doesn’t exist and it’s just a dry eye thing that doesn’t warrant time. Sad life.

Very humilating and it dimishes your trust and belief and self worth....but you will be stronger and more resolved because of it!
Take Care All.
Phenomenal amount of women turning up with RA/Fibromyalgia since COVID immunsation and post C Section or surgery period???
They should be learning from us to improve a global understanding/empathy...instead they do the opposite....???

— Feb 17, 2024

In reply to by Ronna watson (not verified)

If you live in Australia.....good luck with diagnose and treatment.
I am 29 years on.
Def had Dry Eyes/Mouth & Juvenille RA from about the age of 6years.
Only got diagnosed with "that" RA when I had a combo of Rheumatic Fever & Scarlet Fever at the age 0f 11 years.
COVID Immunisations & Adult Whooping Cough have sent body spirally on a downhill slope....with even more delibitating events that stay for for good.
Be active as possible...GSOH...Healthy Diet...Avoid the Stress where and whenever possible (Very nearly impossible these days LOL!).

— Dec 20, 2023

I had many of these symptoms pre-diagnosis. All pieces of a lifetime puzzle. Thank you for the clinical information website. It is invaluable and I wish Rheumatology was a more common choice for practitioners as there seem to be so many patients to attend to.

— Mar 27, 2024

Has anyone had GI dysautonomia with Sjogren's? I had two episodes of constipation in December of 2023. No motility at all. I mean dead. No bm x 7 days and then x 5 days (can you say miserable??!!) and no reason as to why. I am an RN and was freaking out that I had a bowel obstruction or something. Then I discovered how Sjogren's can affect the gut. I am seeing my GI about it and he agrees it could be from that and wants to do a colonoscopy. He started me on Linzess which has helped enormously. Unfortunately, there is no definitive test to prove it is Sjogren's associated except by a process of elimination of other diagnoses ( per my GI doctor and any research I have done). I also started have a lot of premature ventricular contractions and am now seeing a cardiologist for a complete work up. Was symptomatic with them. This was TOTALLY new for me also. My neurologist did an ANS study and said I did not have small fiber neuropathy but I have since learned that that result isn't completely trustworthy. I live in Central Florida and there really are no resources from physicians here. Although my doctors agree this could all be dysautonomia, there is only symptomatic treatment anyway. Sorry about the descriptive GI issues but honestly this is the only place I could try to get other input.

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