Metabolic Disorders Causing Fatigue and Exercise intolerance in Sjogren’s Syndrome, 2014 Suresh et al

Metabolic Disorders Causing Fatigue in Sjogren’s Syndrome

ABSTRACT NUMBER: 2546
Metabolic Disorders Causing Fatigue in Sjogren’s Syndrome
Lakshmanan Suresh1, Julian Ambrus2, Long Shen3 and Sahana Vishwanath4, 160 Pineview Drive, State University of New York/Buffalo, Buffalo, NY, 2100 High St., University Of Buffalo, Buffalo, NY, 3Department of Medicine, SUNY at Buffalo, Buffalo, NY, 4Medicine, SUNY- Buffalo, buffalo, NY
Meeting: 2014 ACR/ARHP Annual Meeting

SESSION INFORMATION
Title: Sjogren's Syndrome: Clinical Science
Session Type: Abstract Submissions (ACR)
Background/Purpose
Sjogren’s syndrome (SS) is a complex disorder involving both the innate and immune system. Fatigue is a common feature of the disease. Mitochondrial dysfunction has been associated with chronic inflammatory diseases, including SLE, and can result in fatigue and exercise intolerance.
Methods
We evaluated 32 patients meeting the ACR criteria for SS who presented with profound fatigue for disorders of aerobic and anaerobic metabolism. Serum lactate, carnitine and ischemic forearm tests were performed. In selected patients, muscle biopsies were done for genetic and biochemical studies.
Results
Of these SS patients, 30 had elevated lactic acid at rest and 3 had abnormal ischemic forearm tests. Nine of the patients underwent muscle biopsies. Four had mitochondrial respiratory chain abnormalities, 2 had carnitine palmitoyl transferase deficiency, 1 had very long chain acyl CoA dehydrogenase deficiency and 2 had glycogen storage diseases (myophosphorylase deficiency, lactate dehydrogenase deficiency). Appropriate treatment led to symptomatic improvement in all cases.
Conclusion
Metabolic disorders are common in patients with SS and contribute to symptoms such as fatigue and exercise intolerance. Treatment of these disorders leads to symptomatic improvement. Further studies are needed to determine the incidence of metabolic disorders in SS, the incidence of SS in patients with metabolic disorders and the mechanisms by which SS and metabolic disorders are interrelated.

 

Not sure what exactly is meant by "exercise intolerance" here. But people often use "exercise intolerance" to mean inability to exercise. That is not the same thing as post-exertional malaise that allows people to exercise, only to make them sick afterwards.

 

I consider "exercise intolerance" to be a superset of both rapid and delayed effects. So one can't tolerate exercise as a healthy person would because you fail early and/or you suffer later.

[Rapid fatiguability; muscle weakness; cardiovascular instability eg chronotropic incompetence]

+

[Post-exertional malaise / symptom exacerbation]

= "Exercise intolerance"

 

That will lead to a problem of distinguishing PEM from the exercise intolerance from the likes of COPD. Some of the "rapid effects" are clearly caused by metabolic/cardiopulmonary/conditioning issues. PEM is not. Which in turn will lead to inability to distinguish MECFS from the likes of cardiopulmonary/metabolic/ mitochondrial disfunction,

 

I cant exercise, because dysautonomia. And fatigue I had 2005-2019, then got rid of it after IVIG + abx (I guess something metabolic) but at the same time, GPCR aabs went to 0 so prob related (personally I think metabolic like this article suggests, due to low intestinal mobility...from neuropathy.. gives me some dysabiosis, SIBO lactic acidosis etc).

But PEM ? My PEM mostly exploded in 2017 again after antibiotic ; IV ceftriaxone, first 10+ days I felt much better, clearer brain, more mobile,... less flu feeling... I was like: how can abx do this? because I got them at the ER for suspected infection (I didn't have it, it was a drug allergy so CRP shoot up, .. ), . but then after 10days of ceftriaxone, I started having gastric issues. I was an idiot and didn't take probiotics bc they made me feel bad before, so then I suddenly crashed, couldn't walk much, felt weak, had gastric issues: and worst of all I began having these 'attacks' in my brain, frontal lobe, i couldn't read, watch screens, couldn't talk to people, needed ear plugs while driving on a bus or sleeping, I'd crash if someone enters my room or be irritable bc their presence drains me, I couldn't handle someone talks to me because would crash/tire me.
what do you think is this PEM?

I couldn't use much computer next 2 years... took loong long time to recover and I never did fully.
So I'd say not physical PEM but mental. But physically I cant even develop cos I can't push myself bc mobility issues from autonomic neuropathy /POTS.

P.S. My diagnosis is Sjogrens, and no I don't always test positive to ANA, in most labs don't have SSA, I don't have dryness, or at least I didn't for 15 years, it's absolutely not needed for Sjogrens, very well documented. GPCR are more linked to Sjogrens than SSA, and I had those for prob 15 yrs

If it's able to distinguish we wouldn't know a bunch of people who were diagnosed with MECFS for decades, even were advocates for MECFS, and then did better blood analysis and found antibodies like SSA, or dsDNA and get a diagnosis of Sjogrens or lupus etc. PEM exists in other illnesses

 

That may well be. The problem is with the ambiguity of "exercise intolerance". People with cardiopulmonary/metabolic problems, often described as exercise-intolerant, are VO2MAX-impaired before the exercise. They are unable to generate energy in other words. MECFS people, on the other hand, are VO2MAX-impaired after the exercise. We know that from the 2-day CPET test trial that compared MECFS to similarly deconditioned subjects. They are able to generate energy, but they get sick afterwards.

One big problem with MECFS research is that they often focus on people severe/moderate half of the spectrum. They are in permanent state of PEM and therefore look constantly impaired (incapable of exercise to begin with). If they looked at those at moderate/mild side with good day/bad day cycles, they would see what CPET trial showed: they don't have VO2 Max problem before the exercise. This is why I insist that MECFS researches should include all spectrum of MECFS. (An elephant looks like a snake to a blind man who feels the trunk only).

One way is to define: exercise-inability = VO2MAX-impaired before the exercise, exercise-intolerance = VO2MAX-impairment after the exercise. But the term "exercise intolerance" is so misused, we should just stick to "post-exertional malaise" to mean VO2MAX impairment after the exercise and call everything else as "exercise intolerance". If other diseases include PEM, then it should call it PEM, not exercise intolerance.

 

When I read this I went searching and haven't found anything yet. If you are able, could you point me towards some literature about this? Thanks.

 

I'd prefer to stick with post-exertional malaise. As soon as you call it whatever-intolerance, MECFS will get conflated with other fatigue diseases without PEM. And, if other diseases indeed have PEM as a symptom, they should call it PEM rather than exercise-intolerance.

 

See the studies below. Also, note, as you mentioned with ME, in Sjogrens research the problem is they do it on some cohort they had recognized, and almost nobody I know with dysautonomia is part of that, because we're on average 20 years younger. So delay in dryness symptoms is even longer than mentioned in studies, and the % of people without dryness or ANA or SSA is larger.
Also, SFN, tilt-up tests are very rarely, if ever, performed by rheumatologists.

And what is not mentioned often enough is that GPCR autoantibodies, to adrenergic and muscarinic receptors especially, are known to be the hallmark of Sjogrens for decades. M3 antibodies mostly, but all GPCR. It's nothing new, it's known for like 20 years.
Neurologic involvement frequently preceded the diagnosis of SS
(81% of patients).
https://pubmed.ncbi.nlm.nih.gov/15342972/
Neurological manifestations may precede the sicca symptoms in 40 to 93% of
the cases [8, 14]. As described by Mori et al. [11], 93% of patients were
diagnosed with pSS after neuropathy symptoms appeared.


https://www.hindawi.com/journals/ad/2012/645967/
Furthermore, CNS involvement may precede clinical diagnosis by many
years and may lead to an underestimation of other neurological and/or
systemic diseases [10].
Neurological onset often precedes by many years both the appearance of
systemic symptoms and the immunological diagnosis. Thus, pSS should
always be considered in patients with relatively nonspecific neurological
symptoms associated with sicca syndrome. MRI and neuropsychological
assessment are necessary for an early diagnosis, particularly when
neurological symptoms precede systemic involvement. Because of the great
heterogeneity of neurological involvement in pSS, neurological
complications should be the subject of large prospective cohort studies.
https://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-019-2086-8
Neurological symptoms preceded the diagnosis of SS in eight patients.
Conclusions
Peripheral neuropathies are frequent in SS patients. Neurologists should be aware of possible
autoimmune causes of neuropathies because clinical manifestations of neuropathy may
precede the development of other symptoms of the autoimmune disease.
Peripheral neuropathy may be the first symptom, but may also develop later in
the course of the disease.
In 8 (35%) of 23 PNS+ patients, neurological symptoms preceded the diagnosis
of pSS.
Some of the previous studies suggest that nervous system involvement can be the
presenting feature of SS, while others report that it is rather a late finding in the course
of the disease (Govoni et al., 1999; Grant et al., 1997; Griffin et al., 1990; Malinow
et al., 1986; Mori et al., 2005; Vrethem et al., 1990). Berkowitz et al. found that
neurological symptoms preceded the diagnosis of SS in 81% of patients (Berkowitz &
Samuels, 2014). In another study, conducted by Seeliger et al., a diagnosis of Sjögren's
syndrome was made in 44 of 184 (24%) patients with symptoms and signs of a severe
progressive symmetric or asymmetric peripheral neuropathy (Seeliger et al., 2019). In
our group, neurological symptoms preceded the diagnosis of pSS in 35% of patients.
This fact implies that these are patients who will first report to a neurologist.
https://onlinelibrary.wiley.com/doi/full/10.1002/brb3.1665
In our cohort, neurological manifestations preceded the sicca symptoms in 72.1% of the
patients, which is consistent with the findings of other studies. 17–19
https://journals.lww.com/md-
journal/fulltext/2015/07030/the_clinical_characteristics_of_primary_sjogren_s.22.aspx
In 25-92% of patients affected by Sjögren’s syndrome, neurological symptoms may precede
the sicca syndrome.
https://www.reumatismo.org/index.php/reuma/article/view/1241
“At least one-third of patients with pSS can present with extraglandular involvement, with
neurological dysfunction being one of the most frequent conditions… In 25–60% of cases,
neurological symptoms are the first clinical manifestation and can precede the diagnosis of pSS
on an average of two years,” the scientists wrote.
https://sjogrenssyndromenews.com/2019/09/10/examinations-primary-sjogrens-syndrome-
patients-include-cognitive-function-tests/
Neurological manifestations may precede. SICCA symptoms, so all patients with
polyneuropathy would be tested for Sjogren';s syndrome.
However, neurological manifestations occur in 10 to 60% of patients with Sjögren's
syndrome and can often precede classic sicca symptoms in Sjögren's syndrome in some
cases up to several years. Rarely, cranial neuropathy can be the initial presentation. Thus, it
is important to consider screening for Sjögren's syndrome in the evaluation of pediatric
patients with new onset of isolated cranial neuropathy even in the absence of classic sicca
symptoms.
https://www.scholars.northwestern.edu/en/publications/a-presentation-of-pediatric-
sj%C3%B6grens-syndrome-with-abducens-nerve
https://dysautonomiainternational.org/blog/wordpress/early-sjogrens-antibodies-in-
dysautonomia-patients/
Q: Can you explain this study in plain English?
A: Sure. Dysautonomia International collaborated with the neurologists at South Shore Neurologic
Associates in New York and Sjögren’s researchers at SUNY Buffalo. We looked at the records of all
of South Shore Neurologic Associates’ patients over the past year who reported either dry eye or
dry mouth symptoms, plus some kind of other autonomic problem, who didn’t have an
identifiable cause (meaning their dysautonomia was “idiopathic”), and who didn’t have the SS-A
and SS-B antibodies doctors common rely upon to diagnose Sjögren’s. Out of 95 idiopathic
dysautonomia patients included the study, we found that 41% of them had one or more novel
early Sjögren’s antibodies (salivary protein-1 [SP-1], parotid secretory protein [PSP], and/or
carbonic anhydrase-6 [CA-6]). Then we looked at the symptoms found in the antibody positive
patents compared to the symptoms in the antibody negative patients. They essentially had the
same symptom profiles, but the antibody positive patients were more likely to have constipation.
Q: Is Sjögren’s common in dysautonomia patients?
A: Sjögren’s is the second most common cause of autonomic neuropathy, after diabetes, and has
been associated with postural orthostatic tachycardia syndrome, orthostatic hypotension,
orthostatic intolerance, autoimmune autonomic ganglionopathy, gastroparesis, and other forms
of dysautonomia. In fact, the dry eye that Sjögren’s is well known for is a symptom of
dysautonomia, since the tear glands are controlled by the autonomic nervous system. 1 in 10
people who have dry eye have Sjögren’s syndrome. Sjögren’s impacts 4 million Americans, but 3
million of them are undiagnosed.
Q: Isn’t Sjögren’s an older woman’s disease?
A: The stereotypical Sjögren’s patients is a Caucasian woman over age 40. However,
Sjögren’s can occur in any race or ethnicity, and 10% of patients are male. While Sjögren’s
is not as common in children as it is in adults, it can occur at any age. The youngest novel
Sjögren’s antibody positive patient in our study was 13. Younger Sjögren’s patients tend
to present with different symptoms than older patients, with more neurological
symptoms and less dryness. The dryness usually develops slowly over time as the
disease progresses.
The current diagnostic criteria for Sjögren’s were developed based on studies of older
patients who have advanced/severe dryness associated with their Sjögren’s. Many experts
now agree that the current diagnostic criteria are not catching patients who are at an
earlier stage of the disease, who tend to be younger and have less severe dryness, when
you may actually be able to prevent some of the long term damage from occurring. People
diagnosed with Sjögren’s in their 50s have probably been dealing with it for 20-30 years
before they were “sick enough” to get diagnosed.
Neurologic Complications

 

@Pibee - thank you very much for going to the trouble. I look forward to delving into it all.

I was persuaded by a rheumatologist a couple of years ago to not undergo a lip biopsy because apparently my mouth wasn't dry enough which, I was told, would have made a diagnosis of SS most likely negative. No blood tests were indicative either.

My longstanding peripheral neuropathy is spreading and becoming quite a bit more painful lately and and I have severe dry eyes (with four punctal plugs plus drops every 2 hours at least), as well as several other listed symptoms that could most definitely tie in. From a quick skim of your post I should perhaps reconsider SS. I've certainly had 'something' for decades and I'm definitely not convinced it's ME.

 

I can barely spit, and recently had my saliva volume measured and they said it's normal. I couldn't believe it. The ref. range for saliva volume is not standardized as per age. So if you're a younger person it's even harder to have it told it's dry.

I had absolutely no complaints of dryness from 2005-2019, "only" severe fatigue, POTS/SFN, AND then 2019 dryness exploded. and I cant believe that 5 years later I still randomly test negative on ANA, SSA, and even measure of dryness even though I consider myself among dryer people because I notice some don't even have complaints.

90% info they tell you on Sjogrens will be wrong...

UWS -Unstimulated Whole Saliva. think the ref range is < 0.5ml/5 minutes, so basically you need to have only 20% of average saliva if you're 30 year old, to count as abnormal, LOL.. some studies suggest 1.0 ml/5min threshold, but again they dont have separate for age groups.

 

I have never heard that. Muscarinic receptor antibodies (and in fact all types of GPCR) occur in everyone and the general view is they don't mean much. A meaningful diagnosis of Sjogren's, as far as I am aware, requires either dryness or SSA antibodies and the central concept of Sjogren's is based on the association of these two features.

 

Many of us were diagnosed without dryness and/or SSA, with lip biopsy.
My lip biopsy showed 1 focus score even before I developed dryness, over 5 years ago
If you want, the fact we tend to develop dryness (and SSA) after small fiber neuropathy, can be viewed as a coincidence or comorbidity. For me, that is just strange because so big % of patients.

They contemplate muscarinic antibodies are significant in MECFS, and in Sjogren's...and a number of other diseases, but if you read lately everyone in patient circles thinks that's something new and mentioned only in LC and MECFS, they dont hear it is at least suspected to be linked to Sjogrens.
The proof they matter in MECFCS, LC, or Sjogrens is equally lacking, that's what I meant. But also, I wouldn't fully dismiss all the work by Prof. Scheibenbogen and much research in Sjogren's too, about GPCR, as we obviously can't claim either way...One of the more prescribed drug for Sjogren's is muscarinic agonist (cevimeline or pilocarpine) so I think to mention GPCR for Sjogrens is obviously important enough until proven otherwise.


The definition of Sjogren's was arbitrary, set as a "dry eye disease", but who says you need to have that? It's just a common agreement. Can and should be unlearned... because of the studies I listed before, showing dryness comes after neuropathy in a huge % of patients.
From what I know the dryness is just the first described symptom. In a middle-aged man. If they first caught it in a young teen with POTS, then maybe POTS would be in the main diagnostic criteria, and you can't get a diagnosis if you didn't develop POTS regardless of how dry you are?!

 

Papers show that GPCR receptor autoantibodies occur in similar concentrations in ME/CFS patients and healthy controls, with a very large overlap in distributions. Therefore, they are not causing the disease. This was explained on another thread very recently.

 

Other MECFS patients have noted benefits from ceftriaxone. It increases EAAT2 activity.

From wiki:
Ceftriaxone seems to increase excitatory amino acid transporter-2 pump expression and activity in the central nervous system, so has a potential to reduce glutamatergic toxicity.[36][37]

Ceftriaxone has been shown to have neuroprotective properties in a number of neurological disorders, including spinal muscular atrophy[38] and amyotrophic lateral sclerosis (ALS).[39]

 

I think the benefits in my case were from reducing bacterial overgrowth /SIBO in the beginning, 10+ days, and then overkill. I get the same improvement and then crash with nearly all broad-spectrum antibiotics - oregano oil pills did the same and then I almost ended up in a wheelchair with a massive attack to nerves, looked like GBS, but prob wasn't (I wasnt examined few months but I am pretty sure it's just bad SFN).

 

Depends on the study, testing method etc. So can't be concluded yet. Thus, open discussion. Same applies for Sjogrens...you'll find study saying both. Why kill it with conclusive answers...

Anti-M3R was significantly elevated in SjS plasma in comparison with HC, SLE, or RA (P < 0.01). SjS anti-M3R intensities were greater than two-standard deviations above the HC mean for both unadsorbed (16/24, 66.67%) and adsorbed (18/24, 75%) plasma samples. Furthermore, anti-M3R was associated with anti-SjS-related-antigen A/Ro positivity (P = 0.0353). Linear associations for anti-M3R intensity indicated positive associations with focus score (R2 = 0.7186, P < 0.01) and negative associations with saliva flow rate (R2 = 0.3052, P < 0.05). Our study strongly supports our rationale to propose inclusion of anti-M3R for further testing as a non-invasive serological marker for SjS diagnosis.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036946/

 

This study from 2016 in SS, did it actually pan out in the end? 8 years is a long time. This paper has few citations, mostly some crappy reviews, so I presume no one in rheumatology is taking this very seriously. The problem with citing primary literature in medicine is that most findings turn out to be false in the sense that the experiments end up not being able to get replicated elsewhere. So, the value of any individual study is limited and doesn't justify strong definitive statements like