Metabolica Rheumatica

You don’t just get arthritis because it’s written in your genetic code, so that it suddenly kicks in on your 60th birthday. And it isn’t just a random event that lands on you out of nowhere, you know, randomly. There are reasons.

Arthritis commonly occurs alongside heart disease and diabetes as well as cancer and depression, and this too is not for no understandable or explainable reason. You don’t need to be a medical specialist to work out the main connections, in fact it probably helps if you aren’t. You do have to spend lots of hours reading through physiology texts and studies, and preferably with an open mind.

But I’m going to give you a heads up. The rheumatic diseases have to do with exposure to too much of the things that make it harder for the body to function optimally, and not enough of the things that the body needs in order to protect against those things. I’m not making this up. There are biological principles that help to explain this.

I’ll probably sound like a broken record, but I’m afraid stress and inflammation and the polyunsaturated fats (PUFAs) and sugar and thyroid energy metabolism will all be getting a mention. The way I see it, there is no other way.

“An increasing body of evidence suggests that energy metabolism is crucial for the maintenance of chronic inflammation, not only in terms of energy supply but also in the control of the immune response through metabolic signals.  The interplay between immunology and metabolism thus plays a central role in the pathophysiology of CIDs [chronic inflammatory diseases] and bears great therapeutic potential.”

Which is not to say that you can just wave your magic wand, and miraculously reverse the impact of decades worth of aging and degeneration, but your situation isn’t likely to improve much until you have a genuine understanding of what can make things better, and what can make things worse.

Arthritis and rheumatism are terms often used interchangeably to describe a large number of conditions – most commonly osteoarthritis, rheumatoid arthritis and gout – associated with chronic pain and stiffness, affecting the joints and connective tissue.

In reality there are a number of symptoms or indicators that are ignored, or simply not considered to be relevant. The truth is, however, that there is only one biology, and so applying biological principles honestly, provides a clearer picture of the relationship between symptoms and the progression of a variety of related conditions.

The stress of life is an obvious common denominator, and how great that stress is, how long it goes on for, and how it is dealt with, are probably the most important considerations. This is true for disease in general.

But some things make stress less manageable, and more of a chronic and potentially debilitating problem. The way I understand it (and have experienced it), you need to look for the things in your life that promote the damaging effects of stress, via their interference with energy metabolism. If you can get rid of some of the big ones, in the long run your whole system will function better, and you will be less likely to suffer from a range of conditions.

Exposure to the breakdown products from lipid peroxidation of the highly unstable PUFAs, is central to the progression of the symptoms of arthritis, as well as being a powerful factor causing metabolic interference.

“Several epidemiological studies propose the association of rheumatoid arthritis (RA) with oxidative stress…The levels of lipid peroxidation products in plasma and in urine suggest the relationship between lipid peroxidation and the development of RA.”

“Lipid peroxidation leading to the formation of protein adducts promotes pro-inflammatory responses that characterize a variety of chronic health conditions…MAA [malondialdehyde-acetaldehyde] formation is increased in RA joint tissues and, importantly…co-localize with citrullinated antigen…”

“73 patients with RA and 62 healthy subjects were included into the study. Lipid peroxidation was estimated by the measurement of phospholipid arachidonic acid (AA) and linoleic acid (LA) as well as aldehydes…4-HNE…4-HHE…MDA…acrolein, crotonaldehyde, and…4-ONE…the level of lipid peroxidation products in the plasma and the urine may be the indicator of RA…urine 8-isoprostanes may be the useful and reliable biomarker of RA progression.”

“It was found that the mean levels of MDA…in patients with RA were found to be significantly elevated when compared to the mean of that of controls…”

When stress is high, blood sugar supplies get used up at a fast rate, and low glycogen stores means more fat is released out of storage for fuel. These days unfortunately, free fatty acids are composed of a higher percentage of PUFA, which is highly unstable and inflammatory.

So chronic stress promotes exposure to PUFA, and exposure to PUFA is a fundamental driver of stress and inflammation. This can become a vicious circle, able to be fed by an unlimited number of possible circumstances.

The breakdown products of PUFA directly interfere with blood sugar regulation, and blood sugar dysregulation issues – such as hyperglycemia and insulin resistance – have been shown to be involved in the progression of arthritis.

“…it is clear that chronic systemic inflammation is pivotal in the pathogenesis of both RA [rheumatoid arthritis] and IR [insulin resistance]. Patients with RA in whom disease activity is effectively controlled may experience the additional clinical benefit of improved insulin sensitivity.”

“…systemic inflammation in RA patients played an important effect in the glucose metabolism, and the long-term inflammatory status could lead to β cell dysfunction and apoptosis and affect the liver and hepatic glucose metabolism pathway.”

Too much exposure to PUFA is an obvious common denominator when it comes to inflammatory conditions like diabetes and arthritis, and if PUFA is a bullet, the low sugar high stress state easily pulls the trigger.

“There were 36 studies that included 147,034 cases and 1372,948 controls. This systematic review and meta-analysis of association study…indicates that arthritic patients have 61% higher odds of having diabetes compared to the population without arthritis.”

Proper thyroid function protects against stress and inflammation, and PUFA is powerfully anti-thyroid. Hypothyroidism – which very often goes hand in hand with blood sugar dysregulation – has been shown to be closely tied to the onset and progression of the symptoms of arthritis.

“Hypothyroidism (defined as having a TSH level >4.20 μIU/mL) was observed in 20/52 (38.4%)…Thyroid function test should be included in clinical evaluation of RA patients.”

“Hypothyroidism was the most common thyroid disorder associated with RA, present in 24%, with a significant association with RA disease activity parameters.”

Considering the fact that the modern diagnosis of hypothyroidism commonly ignores what once were well understood symptoms of an under active thyroid metabolism, there is probably a far closer relationship between rheumatic disease and thyroid issues, than is seen in studies.

There is also evidence showing that thyroid related issues are an important reason for the link between arthritis and cardiovascular disease.

“Hypothyroid disease was significantly associated with CVD in patients with RA, even after adjustment for other traditional cardiovascular risk factors.”

“Clinical hypothyroidism was observed three times more often in female RA patients than females in the general population. In female RA patients, clinical hypothyroidism was associated with a fourfold higher risk of CVD in comparison with euthyroid female RA patients independently of the traditional risk factors.”

Unfortunately most studies don’t look closely at the intertwining stress promoting inflammatory things, from a big picture perspective, when considering the connection between arthritis and diabetes and heart disease, as well as even depression and cancer. PUFA, thyroid metabolism and proper blood sugar regulation are important influences with each of these conditions.

A suppressed (blood sugar dysregulated) metabolism often leads to chronically increased levels of a number of inflammatory stress substances, such as bacterial endotoxin (LPS), serotonin, nitric oxide and estrogen.

These substances interfere with oxidative metabolism and encourage greater release of polyunsaturated free fatty acids into circulation. PUFA breakdown products make all of these stress substances more of an issue for metabolism, creating a potentially inflammatory time bomb and a far higher likelihood that arthritis can take hold.

“…bacterial toxins, especially endotoxins such as lipopolysaccharides (LPS), might be important causative agents in the pathogenesis of rheumatoid arthritis (RA)…”

“…patients with seropositive RA had higher serum and plasma levels of 5-HT than the healthy individuals, and higher plasma levels of 5-HT than the seronegative patients… Peripheral serotonergic pain mechanisms seem to be activated by blood 5-HT in patients with seropositive RA, in contrast to seronegative patients.”

“Recent in vitro studies suggest that inducible nitric oxide synthase (iNOS) activity mediates endothelial dysfunction. Rheumatoid arthritis (RA) is a chronic inflammatory condition and is associated with endothelial dysfunction and increased risk of cardiovascular disease…RA patients have endothelial dysfunction and increased iNOS activity in comparison to controls.”

“It has been proposed that physiologic levels of estrogens stimulate immune responses whereas androgens suppress inflammatory reactions…SF levels of estrogens relative to androgens are significantly elevated…in patients with RA compared to controls. This imbalance is most probably due to increased aromatase activity.”

It’s all well and good for these studies to exist. The information they provide is enlightening and powerful. The problem is that how the different stress and inflammation indicators relate to each other, is not often talked about, and health practitioners are being trained to see things in a manner you could justify calling biologically confusing at best.

Insufficient availability of sugar leads to the release of PUFA out of storage. PUFA is inflammatory and interferes with digestive function, allowing bacteria to become overgrown. This increases exposure to endotoxin. Endotoxin causes inflammation, interferes with energy metabolism, and promotes serotonin and nitric oxide. Serotonin and nitric oxide suppress metabolism further, encouraging rising estrogen. All of these issues feed into each other, creating ongoing stress and inflammatory issues, and there are many variations on the theme.

However if for starters, you are being told that PUFA is a health food, that sugar is a dangerous and addictive substance, and that serotonin is the ‘happiness neurotransmitter’, you are going to struggle to figure out what causes the symptoms of arthritis. And you definitely will be thrown off the scent when it comes to solving the mystery of the connection between arthritis and other illnesses.

“The association between RA (rheumatoid arthritis) and malignancies has been well established, but the exact mechanism for carcinogenesis in RA is lacking. Estrogen metabolites seem to play an important role in RA and cancer…”

“In this study, almost three-fourths of Rheumatoid Arthritis patients were found to have depression. There was a strong association between Rheumatoid Arthritis disease activity and the level of depression.”

“Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by an excess of cardiovascular disease (CVD) risk, estimated to be at least 50% greater when compared to the general population…According to our data, RA seems to be characterized by an elevated prevalence of undiagnosed diabetes, especially in patients with longer disease duration.”

“For overall malignancy, the new studies analyzed here show a similar increase in risk compared with that previously reported. In addition, patients with RA continue to be at an increased risk of lung cancer and lymphoma when compared with the general population.”

The fact that there are close ties between the development of arthritis, cancer, diabetes, depression, heart disease and other metabolic issues is obviously very important. But this won’t make sense, until the relationship between chronic inflammation, PUFA, sugar restriction, thyroid dysfunction, digestive distress, endotoxin, nitric oxide, estrogen, serotonin, even low cholesterol and vitamin D, is clearer.

Low cholesterol, exacerbated by PUFA consumption and sugar restriction, has been shown to promote arthritis, cancer, depression, suicidality and violent behaviour, and numerous other inflammatory issues, and the biological significance and protective role of cholesterol has been misrepresented for decades.

“RA patients experienced a significant decrease in TCh [total cholesterol] and LDL levels during the 5 years before RA incidence as compared to non-RA subjects.”

It’s obvious that there isn’t a relationship between arthritis and metabolic illness for no reason. You could call arthritis type 4 diabetes and not be too far off. But how things are for one person, will vary from the next largely because of diet and lifestyle, as well as hereditary/environmental factors.

The thing is, you don’t need to figure out what causes arthritis. That’s the wrong question. What you want to do is ask what kind of metabolic state is central to arthritic/rheumatic disease. You can then go on to look at how that plays out in relation to other diseases that tend to co-occur, whilst at the same time working out strategies for prevention and reversal.

Antibiotics (like minocycline), aspirin, methylene blue, caffeine, glycine, red light, vitamin K and some other vitamins, progesterone, pregnenolone, niacinamide, thyroid hormone and a number of other things have been shown to be helpful not just with arthritis, but in most cases, with all of the related metabolic diseases. Not by coincidence.

A diet avoiding PUFA and limiting difficult to digest grains and seeds and under cooked vegetable matter, with sufficient protein from milk and cheese and gelatin and plenty of sugar from sweet ripe fruit, fruit juice, white sugar and honey, is one good way to help promote metabolism and reduce inflammatory issues in general.

Lots of calcium and limited phosphorous is intended to be a by-product of this kind of diet, as a high calcium to phosphorous ratio is, metabolically speaking, another important factor protecting against stress and inflammation.

What amazes me most as I write an article like this one, is not that I was able to find the information and write about it, but that the whole world isn’t standing on the rooftops of buildings shouting about what can be found inside the 100 or so studies attached below, published online for everyone, including doctors, to see. Unfortunately sometimes the truth sounds crazier than crazy sounds.

Until the relationship between the substances of stress, chronic inflammation, blood sugar dysregulation and health propaganda becomes common knowledge, arthritis will most likely continue to be a problem without a solution.

See More Here

Restoring oxidant signaling suppresses pro-arthritogenic T-cell effector functions in rheumatoid arthritis

Toll-Like Receptors Expressed by Synovial Fibroblasts Perpetuate Th1 and Th17 Cell Responses in Rheumatoid Arthritis

Essential roles of Toll-like receptor-4 signaling in arthritis induced by type II collagen antibody and LPS

Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis.

Cancer Morbidity in Rheumatoid Arthritis: Role of Estrogen Metabolites

Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis

Bacterial lipopolysaccharides form procollagen-endotoxin complexes that trigger cartilage inflammation and degeneration: implications for the development of rheumatoid arthritis

Subclinical Hypothyroidism is Associated with Insulin Resistance in Rheumatoid Arthritis

Prevalence of Undiagnosed Diabetes in Rheumatoid Arthritis: an OGTT Study.

Excitatory amino acid profiles of synovial fluid from patients with arthritis.

Vitamin K and rheumatoid arthritis.

The onset of lipid peroxidation in rheumatoid arthritis: consequences and monitoring.

Dietary polyunsaturated fatty acids and cancers of the breast and colorectum: emerging evidence for their role as risk modifiers

The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study.

The use of vitamins in the treatment of chronic arthritis.

Aspirin Use in Rheumatoid Arthritis Patients with Increased Risk of Cardiovascular Disease

Depression in Rheumatoid Arthritis and its relation to disease activity

Abnormal Glucose Metabolism in Rheumatoid Arthritis

Blood serotonin and joint pain in seropositive versus seronegative rheumatoid arthritis.

A reevaluation of aspirin therapy in rheumatoid arthritis.

Lipopolysaccharide increases the incidence of collagen-induced arthritis in mice through induction of protease HTRA-1 expression.

Estrone/17β-estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis

The role of endogenous serotonin in adjuvant-induced arthritis in the rat.

Benefits and risks of minocycline in rheumatoid arthritis.

Assessment of serum nitrite level in patients with rheumatoid arthritis

Malondialdehyde as a sensitive marker of inflammation in patients with rheumatoid arthritis.

Critical Role of Glucose Metabolism in Rheumatoid Arthritis Fibroblast-like Synoviocytes

Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability

Malondialdehyde-acetaldehyde adducts (MAA) and anti-MAA antibody in rheumatoid arthritis

Pain and synovial fluid concentration of serotonin in arthritic temporomandibular joints.

Lipid peroxidation in Rheumatoid arthritis; consequences and monitoring.

Use of minocycline in rheumatoid arthritis: a district general hospital experience Free

Dietary Glycine Prevents Peptidoglycan Polysaccharide-Induced Reactive Arthritis in the Rat: Role for Glycine-Gated Chloride Channel

Pathogenic role of platelets in rheumatoid arthritis and systemic autoimmune diseases

Direct recognition of LPS drive TLR4 expressing CD8+ T cell activation in patients with rheumatoid arthritis

The prevalence and management of hyperglycaemia in patients with rheumatoid arthritis on corticosteroid therapy.

Early diagnosis and treatment of steroid-induced diabetes mellitus in patients with rheumatoid arthritis and other connective tissue diseases.

Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine.

Intraarticular progesterone: effects of a local treatment for rheumatoid arthritis.

Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis

Diabetes mellitus risk factors in rheumatoid arthritis: a systematic review and meta-analysis.

Iron in joint inflammation.

Central role of nitric oxide in the pathogenesis of rheumatoid arthritis and sysemic lupus erythematosus


L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent.

IL-29 Enhances LPS/TLR4-Mediated Inflammation in Rheumatoid Arthritis

The Risk of Diabetes Among Patients with Rheumatoid Arthritis, Psoriatic Arthritis, and Psoriasis

PREGNENOLONE in the treatment of rheumatoid arthritis.

Reactivation of antigen-induced arthritis in mice by oral administration of lipopolysaccharide.

Energy metabolism and rheumatic diseases: from cell to organism

The Effect of Low-Level Laser in Knee Osteoarthritis: A Double-Blind, Randomized, Placebo-Controlled Trial

[Osteoporosis in Rheumatoid Arthritis: role of the vitamin D/parathyroid hormone system].

Total Cholesterol and LDL levels decrease before rheumatoid arthritis

Risk of diabetes in patients with rheumatoid arthritis: a 12-year retrospective cohort study.

Plasma lipid peroxidation and antioxidant levels in patients with rheumatoid arthritis.

Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells.

Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction.

Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism.

Chronic Toll-like receptor 4 stimulation in skin induces inflammation, macrophage activation, transforming growth factor beta signature gene expression, and fibrosis

The effect of niacinamide on osteoarthritis: a pilot study.

Diabetes mellitus and arthritis: is it a risk factor or comorbidity?

Risk of Rheumatoid Arthritis in Patients with Type 2 Diabetes: A Nationwide Population-Based Case-Control Study

The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan.

Niacinamide therapy for osteoarthritis–does it inhibit nitric oxide synthase induction by interleukin 1 in chondrocytes?

Diabetes mellitus risk in rheumatoid arthritis: reduced incidence with anti-tumor necrosis factor α therapy.

The independent association between parathyroid hormone levels and hyperuricemia: a national population study

Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide

Lipid peroxidation and antioxidant status in patients with rheumatoid arthritis

Bacterial lipopolysaccharide acts as an adjuvant to induce autoimmune arthritisin mice

Treatment of Arthritis by Nicotinic Acid and Nicotinamide

Prevalence of hypothyroidism in rheumatoid arthritis and its correlation with disease activity.

Immunolocalization of inducible nitric oxide synthase in synovium and cartilage in rheumatoid arthritis and osteoarthritis.

Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis.

Hypothyroidism in patients with rheumatoid arthritis and its relation to disease activity

Polymorphisms in the promoter region of iNOS predispose to rheumatoid arthritis in south Indian Tamils.

The effect of hyperparathyroidism on the course of rheumatoid arthritis.

Improvement of thyroid function in hypothyroid patients with rheumatoid arthritis after 6 months of adalimumab treatment: a pilot study.

A Cytokine Signalling Network for the Regulation of Inducible Nitric Oxide Synthase Expression in Rheumatoid Arthritis

Lipopolysaccharide accelerates collagen-induced arthritis in association with rapid and continuous production of inflammatory mediators and anti-type II collagen antibody.

Diabetes mellitus and insulin resistance in patients with rheumatoid arthritis: Risk reduction in a chronic inflammatory disease

Lipid peroxidation and antioxidant status in blood of rheumatoid arthritis patients

Collagen‐induced arthritis increases inducible nitric oxide synthase not only in aorta but also in the cardiac and renal microcirculation of mice

Thyroid disorders in patients with newly diagnosed rheumatoid arthritis is associated with poor initial treatment response evaluated by disease activity score in 28 joints-C-reactive protein (DAS28-CRP): An observational cohort study

Risk of cancer among rheumatoid arthritis patients in California

Caffeine downregulates inflammatory pathways involved in autoimmunity

Bone and joint manifestations of hypothyroidism.

Thyroid dysfunction in rheumatoid arthritis: a controlled prospective survey.

Hypothyroidism as a risk factor for development of cardiovascular disease in patients with rheumatoid arthritis

Stimulation of inducible nitric oxide synthase by monosodium urate crystals in macrophages and expression of iNOS in gouty arthritis.

Oral administration of lipopolysaccharide exacerbates collagen-induced arthritis in mice.

NF-κB in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction

Rheumatoid arthritis is associated with a high prevalence of hypothyroidism that amplifies its cardiovascular risk

High prevalence of thyroid autoimmunity and hypothyroidism in patients with psoriatic arthritis.

The role of lipopolysaccharide injected systemically in the reactivation of collagen-induced arthritis in mice



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