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Autonomic Dysfunction and Increased Lactate Production with Accumulation in the Body: The Key Factors for the Development of Rheumatoid Arthritis

by Carlos ETB Monteiro(more info)

listed in arthritis, originally published in issue 252 - February 2019

“The first inference deducible from the experiments, according to my reading of them, is, that lactic acid has the power, when existing in an animal body in excess, of producing a class of symptoms attaching themselves mainly to the fibroserous textures, and which, regarded in all points of view, are essentially the symptoms of acute rheumatic inflammation.” Benjamin Ward Richardson -- ‘The Effect of Lactic Acid on Animal Bodies’ (P. 389), 1856 [1,2]


Benjamiin Ward Richardson


The major focus of the present article is Rheumatoid Arthritis (RA).

It tells about:

  1. The history of discovery of the autonomic dysfunction as the precursor of Rheumatoid Arthritis;
  2. The forgotten theory of the accumulation of lactic acid as the cause of arthritis and rheumatism, and its renaissance in the case of RA;
  3. A new hypothesis for the cause of RA that links autonomic dysfunction to the development of increased lactic acid production with its  accumulation in the body;
  4. The risk factors for RA based in this new hypothesis, covering almost all of those already know and in use;
  5.  An old and inexpensive drug comply with the new perspectives above mentioned, representing an adequate and potential solution for prevention and treatment of RA.


Aretaeus, who lived in Cappadocia in Asia Minor during the first century AD and was ranked by some next to Hippocrates as a clinician, described a polyarthritis in phrases reminiscent of features of rheumatoid arthritis: “a general pain of all the joints-the disease lies concealed for a long time, when the pain and the disease are kindled up by any slight cause-it is incredible how far the mischief spreads.”[3]

Sir Alfred Baring Garrod, physician to the West London Hospital, coined the name Rheumatoid Arthritis (RA), in 1859, wishing, as he stated, “to imply an inflammatory affection of the joints, not unlike rheumatism in some of its characters, but differing materially from it.“ At that time rheumatism was the common designation for rheumatic fever: the term rheumatoid arthritis thus may be freely translated as joint inflammation resembling that seen in rheumatic fever.”[3]

RA is considered today as a chronic autoimmune disorder, estimated to affect approximately 1% of the world’s population. It may affect more than the joints, damaging other parts of the body, like the lungs, heart and blood vessels.

Some of the etiological theories presented for RA, through the ages, were neurogenic, vascular, infectious, hypersensitivity, metabolic, endocrine, psychogenic[4] and Selye’s disease of adaptation.[5] More recently other etiological theories for RA were developed as of genetic origin and environment triggers (including smoking).[6] Although, some of the etiologies above mentioned for RA are not really causes, but rather risk factors for RA.

Elapsed many centuries from its initial description by Aretaeus [3], the causative factor of rheumatoid arthritis remains unknown, On the other hand, the cure for RA was not found until today. Existing treatments may only improve symptoms and slow the progress of the disease.

A New Hypothesis

In this paper we postulate a new hypothesis for the cause of RA which has autonomic dysfunction as precursor, by stimulating an increased lactate/lactic acid production and its accumulation in the body.

Also, we present a compatible and fundamental drug, according this hypothesis, for the prevention or in management of RA, eventually with a cure, of some patients.


A.  There are many risk factors leading to dysregulation of the autonomic nervous system, which is related with sympathetic dominance, through sympathetic over-activity or withdrawal of the parasympathetic system. Among these risk factors are stress, smoking, age, high carbohydrate diets and genetic predisposition (ex: familial dysautonomia);

B.  Dysautonomia or autonomic dysfunction is a condition in which the autonomic nervous system (ANS) does not work properly;

C.  Autonomic neuropathies are a collection of syndromes and diseases affecting the autonomic neurons, either parasympathetic or sympathetic, or both;

D.  The vagus nerve is the main component of the parasympathetic nervous system;

E.  Hyperlactatemia is defined here as a mild to moderate persistent increase in blood lactate concentration (2-4 mmol/L) without metabolic acidosis, whereas lactic acidosis is characterized by persistently increased blood lactate levels (usually >4-5 mmol/L) in association with metabolic acidosis; Lactic acidosis results from increased production of lactate, the final product in the pathway of glucose metabolism. Lactate and lactic acid are not synonymous. Lactic acid is a strong acid which, at physiological pH, is almost completely ionized to lactate. The measurement of lactate concentration can also be made in cerebrospinal fluid, synovial fluid and other fluids and tissues of the body.

The Autonomic Dysfunction in RA

Related to this topic a fundamental theory is the Selye’s diseases of adaptation, developed in 1936, when he coined the term stress.[5] This theory from Hans Selye involves a complex neurohormonal model of stress that implicates pituitary and adrenal function in the etiology of many chronic diseases, including rheumatism. [6]


Paul Rosch with Hans Selye


L. J. Michotte, in a presentation occurred in 1953 at the 7th International Congress at Geneva, has linked the autonomic nervous system to RA. He found that the spleen of patients with rheumatoid arthritis does not contract under the action of adrenaline injected intravenously, This led to his proposition of the hypothesis that RA may be a perturbation of the autonomous nervous system bearing on the chemical transmitters noradrenaline and adrenaline. [7, 8]

Edmonds and colleagues have written in 1979[9]: “Peripheral neuropathy is a well-described complication of rheumatoid arthritis, but few reports on autonomic neuropathy exist. In 1963 Kalliomaki et al showed a deficient sweating response to an intradermal injection of nicotine in patients with RA. In 1965 Bennett and Scott found areas of deficient sweating corresponding to cutaneous sensory disease in patients with seropositive RA with peripheral neuropathy but did not examine seronegative patients. In three of their patients a deficient sweating response was found in the absence of peripheral neuropathy, suggesting the presence of a lone autonomic neuropathy.”

In the same paper from 1979, Edmonds and colleagues have written about their investigation involving 68 subjects which were divided into four groups: patients with classical and definite RA, both seropositive and seronegative (mean age 54-6 (range 22-67) years); patients with osteoarthritis (mean age 54-2 (range 4265) years); old controls (mean age 51-0 (range 41-67) years); and young controls (mean age 24-6 (range 2028) years).

The summary on their investigation[9] presented the following results:

“Significantly more patients with RA had abnormal autonomic function, suggesting that autonomic neuropathy occurs more commonly in RA than hitherto suspected. The existence of an autonomic neuropathy may be an important complicating factor in rheumatoid disease and may lead to increased morbidity and mortality.”

A study published in 2004 found that cardiac sympathetic nervous system activity is elevated in RA, whereas cardiac parasympathetic activity remains at a normal level.[10]

A study by Koopman et al, published in 2016, made the postulation that autonomic dysfunction precedes the development of RA, which would suggest that it plays a role in its etiopatogenesis.[11]

Lactic Acid Accumulation in the Body and RA

In 1856, Benjamin Ward Richardson, a famous British physician, published the results of extensive experiments  on dogs in which the injection of large quantities of lactic acid, intraperitoneally , was followed by severe joint involvement. The condition of the joints showed in his studies were similar to that seen in acute arthritis. These results led Richardson to suggest that the acute arthritis was due to an accumulation of lactic acid in the body (pages 371 - 396).[1, 2]

In 1874, Balthazar Foster found that the administration of lactic acid by the mouth to two diabetic patients resulted in painful and swollen joints. These manifestation persisted so long as the lactic acid was continued and disappeared when it was discontinued [12]. This discovery by Foster gave some support to the Richardson’s theory at that time.[1]

In 1922, the theory that arthritis is characterized by an excessive accumulation of lactic acid in the body was revived by Percy Wilde, mainly on the clinical area.[13]

In 1924, a study by Cajori and colleagues[14] presented findings that conflicted with the idea that arthritis and rheumatism are caused or characterized by abnormal production or disposal of lactic acid. According to their study the lactic acid contents of the blood, urine and sweat of patients suffering from arthritis and rheumatic disabilities has been determined and the results have been compared with the respective lactic acid contents from nonarthritic persons. The lactic acid was determined also in the synovial fluid from a case of joint effusion. In no case have they observed abnormal quantities of lactic acid in the arthritic patients. Therefore, to the authors, their findings lend no support to the idea that arthritis, at least of the types studied, is caused or characterized by abnormal production or disposal of lactic acid.

However, the study by Cajori and colleagues was based in insufficient measurements of lactic acid in synovial fluid (just one case), for their judgement on the Richardson’s medical theory.[1]

This is because, years later, starting in the seventies, many studies have shown accumulation of lactic acid in synovial fluid of patients with rheumatoid arthritis, These later studies demonstrated that the measurement of lactic acid or lactate in synovial fluid is the correct place for analysis and determination of cases with RA.

So, in practice, the precipitated conclusion of the study from Cajori et al[14] led the lactic acid theory, as cause of arthritis and rheumatism, to be erroneously abandoned and almost forgotten until the present day.

For example, a study from 1971 by Lindy and colleagues measured total lactate dehydrogenase activity in the synovial tissue from 19 patients with rheumatoid arthritis and from 13 control subjects. It found that total enzyme activity in synovium was increased about two-fold in rheumatoid arthritis when compared to controls. It suggested an increased glycolytic metabolism in the RA synovial joints.[15]

Also, in a study by Gobelet et al, published in 1984, lactate concentration was measured in 383 synovial fluid specimens from patients with various arthritides. The highest concentrations of lactate occurred in nongonococcal septic synovial fluids. High values were recorded in seropositive rheumatoid arthritis and crystal induced arthritides, medium values in synovial fluids from seronegative rheumatoid arthritis, seronegative spondylarthritides, gonococcal arthritis and haemarthrosis, and the lowest values in aspirates from osteoarthritic joints. There was a positive correlation between synovial pH and lactic acid concentration with the finding of high values of lactate in seropositive RA and crystal-induced arthritides.[16]

In their paper from 2011 Chang and Wei said in conclusion: “Studies to date regarding the roles of glucose metabolism in RA have confirmed the increased glycolytic activity and autoimmune responses to some enzymes involved in glycolysis, which provides new perspectives to understand the pathogenesis of RA. In view of the important roles of glycolysis in RA pathogenesis, we suggest inhibiting the activity of glycolysis as a means of treating RA.”[17]

Some risk factors for RA, based in our hypothesis:

  • Stress [18, 19];
  • Age [20, 21, 22];
  • High carbohydrate diets [23-30];*
  • Smoking [31-34];
  • Obesity [35-37];
  • Air pollution [38,39];
  • Vitamin D deficiency [40, 41].

* Some Important Facts about High Carbohydrate Diets as Risk Factors for RA:

  1. Old studies have already show that patients with chronic arthritis do best when their intake of vitamins is increased and their intake of carbohydrate reduced [23];
  2. After the intake of refined sugar and sweets there is an aggravation of symptoms in RA, what may be explained by metabolic changes, such as an increased concentration of blood glucose; [24];
  3. Evidence of high carbohydrate diets in the stool of patients with RA compared to controls. Starch in stools is prone to occur in patients with chronic arthritis, and adds further evidence that diets low in starch are of use in this disease;[25];
  4. High carbohydrate diets cause greater sympathetic nervous system activation while fat ingestion does not result in any appreciable changes; [26];
  5. High carbohydrate diets may increase significantly the activity of serum lactate; [27];
  6. The Ingestion of monosaccharides (simple sugars like glucose, fructose and galactose) may have the effect to raise blood lactic acid with this increase being most marked and lasting longest after fructose, that is largely used today as sweetener in soft drinks, fruit punches, pastries and processed foods; [28,29];
  7. Sweetened soda have been associated with an increased risk of RA. When compared to no consumption of sugar sweetened soda or  <1 soda per month, consumption of ≥1 sugar-sweetened soda per day has 63% increased risk of developing seropositive RA [30].

Autonomic Dysfunction and the Development of Lactate / Lactic Acid

The sympathetic dominance leads to a raised catecholamine (adrenaline/epinephrine and noradrenaline) release, accelerating glycolysis metabolism, therefore increasing lactic acid and lactate concentration in blood and tissues.

We hypothesize that a raised catecholamine release may equally produce the same effects of lactic acid measurements in cerebrospinal and synovial fluids

The first to observe the influence of adrenaline on lactic acid production was Carl F Cori in 1925. Together with his wife Gerty Cori, received a Nobel Prize in 1947 for their discovery of how glycogen - a derivative of glucose - is broken down and resynthesized in the body.[42, 43]


Carl Ferdinand Cori and Gerty Cori

John R Williamson confirmed in 1964 the effects of adrenaline infusion on the increased production of lactate in isolated heart tissue, up to five times the normal production.[44]

An article published in 1982 by Schade[45] supported the following points for a direct participation of catecholamines in the development and/or maintenance of lactic acidosis:

  1. The common association of stress and lactic acidosis;
  2. The rise in plasma lactate concentration during adrenaline infusion;
  3. The precipitation of lactic acidosis by adrenaline intoxication and phaeochromocytoma;
  4. The vasoconstrictor effects of catecholamines leading to tissue anoxia and lactic acid production.

However, according to new findings, hyperlactatemia is not a consequence of anaerobic glycolysis, tissue hypoperfusion, or cellular hypoxia, as believed in the past. Such hyperlactatemia is probably indicative of a stress response, with increased metabolic rate and sympathetic nervous system activity.[46]

The relationship between the autonomic dysfunction and increased lactic acid/lactate concentration was recently discussed by us as having a causal role for atherosclerosis,[47, 48] acute myocardial infarction,[49] cancer [50, 51] and stroke [52].

Cardiac Glycosides, the Fundamental Drugs for RA

The fundamental therapeutic for prevention and management of RA, according to our hypothesis, are old drugs called cardiac glycosides. The cardiac glycosides family include digitalis (foxglove plants) from which are derived the drugs digitoxin and digoxin.

Digitalis was used for more than 200 years in the treatment of heart failure and more than 100 years in the treatment of atrial fibrillation.

Recent studies have confirmed that low doses of digoxin (< 0.25 mg daily, by oral route) are associated with better outcomes for both heart failure and atrial fibrillation.

Remembering  the words of August M. Watanabe, from 1985 [53]:

“Although there is not total agreement on the nature and clinical significance of the effects of digitalis on the autonomic nervous system, the following points seem well established and generally accepted:

  1. The actions of digitalis on the autonomic nervous system are very important clinically and play a major role in determining the clinical pharmacodynamic effects of the drug;
  2. With therapeutic concentrations of the drug, the predominant effect is activation of vagal tone; and;
  3. With toxic concentrations of the drug there may be activation of sympathetic tone.”

In recent articles, where we have presented an equivalent hypothesis for the cause of other diseases, was shown the information that cardiac glycosides at low concentration doses may also be beneficial in the prevention and in the treatment of atherosclerosis/ischemic heart disease [47, 49], cancer [51] and stroke [52].

Cardiac glycosides like digoxin and Lanatoside C are drugs approved by the US Federal Drugs Administration (FDA), and by other similar organizations around the world, with some of these having also approval for the use of digitoxin and other CGs . Therefore, these drugs can be prescribed for prevention and in the management of rheumatoid arthritis, with no major obstacles, by a well-informed physician.

Cardiac Glycosides and Sympatho-Inhibitory Effects

Evidences that the following cardiac glycosides have a sympatho-inhibitory response:

  • Cedilanid* [54];
  • Digoxin  [55-56];
  • Digitoxin [57];
  • Ouabain [58].

*Cedilanid is the trade name. The active ingredient is Lanatoside C

Cardiac Glycosides in Reduction of Lactate Production

A recent paper has demonstrated that inhibiting the overproduction of catecholamine by digoxin, digitoxin and ouabain may induce a potent inhibition of glycolysis (glucose consumption and lactate).[59] It confirms the results of old studies on this matter. [60]

The “Anti-inflammatory” Effects of Cardiac Glycosides

Beneficial effects of cardiac glycosides have also been observed through anti-inflammatory pathways.[61 - 67] Among these, a recent study has investigated whether digoxin would supress pathogenic Th17 and consequently ameliorate arthritis and joint damage in the collagen-induced arthritis (CIA) model, a prototype animal of RA. As result, digoxin regulated pathogenic Th17 differentiation and suppressed autoimmune arthritis in mice, appearing to be able to prevent the incidence and ameliorate the severity of CIA.[67]


However, inflammation is a result of an injury, not its cause.

According to a study published in 2014: “Over the past decades evidence has accumulated clearly demonstrating a pivotal role for the sympathetic nervous system (SNS) and its neurotransmitters in regulating inflammation”[68] A study from 2013 suggested that acidic environment represents a novel endogenous danger signal alerting the innate immunity. Low pH may thus contribute to inflammation in acidosis-associated pathologies, such as atherosclerosis and post-ischemic inflammatory responses.[69]

Also, a study published in 2016 has demonstrated that moderate extracellular acidosis which is a common finding in different pathological conditions such as inflammation, ischemia or in solid growing tumours affects the functional behaviour of monocytes and macrophages and can therefore modulate the immune response.[70]

And, a study published in 2016 has shown that vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. [71]

Acidosis and Bone Loss in RA

Finally, studies have shown a strong evidence that osteoclasts may be the primary effectors of the bone erosions that are typical in RA. So, to prevent the progression of the erosive damage of bones seems to be an important initiative in RA.[72,73]

Moreover, we must take into account the proposition from A. Wachman and DS. Bernstein, made in 1968, that the body draws minerals from the bones to neutralize acid challenges.[74]


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About Carlos ETB Monteiro

Carlos ETB Monteiro is an independent researcher and scientist from Brazil with 43 years’ experience in dealing with medical matters. In 1972 he became a follower in the scientific plan from Dr Quintiliano H de Mesquita, originator of the myogenic theory of myocardial infarction and other pioneer medical contributions (QHM Memorial). In 1999 he participated in the foundation of Infarct Combat Project and elected president by the board of directors. Carlos Monteiro is still supporting Dr Mesquita’s medical and scientific ideas, through Infarct Combat Project. Recently he has developed a new hypothesis to explain atherosclerosis that was named acidity theory of atherosclerosis. The blog new evidences about his Acidity Theory you can find here.

He is a non-official member of "The International Network of Cholesterol Skeptics (THINCS - and Fellow of the American Institute of Stress ( and is also a  member of the honorary board of Weston A Price Foundation ( His recent book Acidity Theory of Atherosclerosis - New Evidences, 2012 is available for Kindle readers and in paperback at  also in paperback. Carlos Monteiro is one of the signatories of a letter to The Academy Obesity Steering Group entitled “Obesity is an Iatrogenic Disease”. He recently presented two lectures in  the Fourth International Conference of Advanced Cardiac Sciences - The King of Organs Conference, 2012, Saudi Arabia: the first about the Myogenic Theory of Myocardial Infarction (Powerpoint presentation and video),  the second about the Acidity Theory of Atherosclerosis (Powerpoint presentation and video). Carlos Monteiro may be contacted via

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