Tuesday, April 4, 2017

Ankylosing Spondylitis

This article is for educational and informational purposes only. Nothing in this article should be taken as personal or general medical advice. Some things here may only be theoretical or experimental.

Ankylosing Spondylitis (AS)

Symptoms of ankylosing spondylitis include morning low back stiffness that improves with activity; other joints may also be involved. Fibroblast proliferation is noted. Early diagnosis and treatment of ankylosing spondylitis is essential to prevent permanent damage. Unfortunately, many people remain undiagnosed or misdiagnosed for years.

Ankylosing spondylitis can co-exist with rheumatoid arthritis, and there are strong links between gut inflammation and AS. Other associated features include uveitis and enthesitis (inflammation where tendons and ligaments connect to bone).

Testing for ankylosing spondylitis is not definitive, but some tests can be helpful in making the diagnosis. X-rays may reveal sacroilitis. ESR may be elevated over 20 mm/hr, and CRP as well as serum IgA (anti-Klebsiella antibodies) may also be elevated. HLA-B27 testing may be positive. Rheumatoid factor may occasionally but not commonly be positive.

Gallbladder function and liver function may also play a part. Because bile acids help keep gut bugs in check, it is possible there may be a link between poor gallbladder or liver function and inflammatory diseases.

C-reactive protein, ESR, and klebsiella in ankylosing spondylitis.
Secretory IgA: immune defence pattern in ankylosing spondylitis and klebsiella.

Genetic Predisposition for Ankylosing Spondylitis
Genetics are a pre-disposing factor, but are not required to develop the condition. 
In people with ankylosing spondylitis, those positive for HLA-B27 tend to be more severely affected than those without, and tend to have more spinal involvement.

HLA-B27 and ERAP1 are the main genes associated with ankylosing spondylitis; other genes are also associated.
TNF-238A may contribute to susceptibility to ankylosing spondylitis in those negative for HLA-B27, although research is conflicting.
HLA-B*2702, B*2704 (see rs3819299), B*2705 and B*2707 have an association with AS, with B*2705 having the strongest association in Chinese.
rs3819299 is a marker for HLA-B27, with allele C being the risk allele.

HLA-B60 is also associated with AS in British and Chinese populations. HLA-DRB1 can also be associated. HLA-B*2706 and 2709 may be protective.

ERAP1/ARTS1 rs30187 each allele T increases the risk of ankylosing spondylitis by 1.5 fold. Other important ERAP1 SNPs may include rs27434, rs27529, and rs27044.

HLA-E rs1264457 allele A is a risk factor for ankylosing spondylitis. HLA-E is ligand for a receptor on Natural Killer cells, NKG2A.

IL-12B rs6871626 : Homozygous AA genotype has a 1.8 fold greater risk for developing ankylosing spondylitis than CC or AC.

Other genes implicated may include IL1, CYP2D6, ERAP1, IL23R rs2201841 / rs11209026 / rs11209032, ANTXR2. RUNX3, CARD9, SNAPC4 rs11145835, and LTBR-TNFRSF1A.
HLA-E gene polymorphism associates with ankylosing spondylitis in Sardinia
B27 patients with ankylosing spondylitis and Reiter's syndrome.
HLA-B27 and human β2-microglobulin affect the gut microbiota of transgenic rats.
Associations between ERAP1 polymorphisms and ankylosing spondylitis susceptibility: An updated meta-analysis.
TNF-238A promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients.
A Genome-Wide SNP Linkage Analysis Suggests a Susceptibility Locus on 6p21 for Ankylosing Spondylitis and Inflammatory Back Pain Trait.

Mediators of Inflammation in Ankylosing Spondylitis
Mediators of inflammation implicated include C3, C4, TNF-alpha, IL17A, IL-22, IFN-gamma.

Affected individuals may have higher levels of Th1 and Th17 cells, as well as higher serum levels of IL-6, IL-17A, TNF-α, IL-33, IL-37 and IL-8. IL37 may play an anti-inflammatory role.
IL-6 tends to be correlated with ESR and CRP. 

Klebsiella and Ankylosing Spondylitis
The presence of Klebsiella species in the gut appears to be associated with higher CRP and ESR in those with ankylosing spondylitis. Elevated antibodies to klebsiella pneumoniae in AS patients may suggest a role of klebsiella in triggering or exacerbating ankylosing spondylitis. Klebsiella and bacteroides may also be linked with enthesitis-related arthritis.

Dr. Alan Ebringer discovered molecular mimicry between anti-Klebsiella antibodies and HLA-B27, which categorizes AS as an autoimmune disease. There may also be some molecular mimicry between HLA-B27, Yersinia and Shigella. Anti-Klebsiella antibodies also can cross react with collagen types I, IV, and V.
There is suggestion that HLA-B27 can affect the microbiome of the gut.

Chabazitic zeolite taken orally may possibly promote intestinal growth of bifidobacterium, which antagonizes klebsiella. 

Bifidobacterium especially likes to eat galactooligosaccharides (GOS), isomaltooligosaccharides (IMOS) and lactulose, but will also eat fructooligosaccharides (FOS). Feeding bifidobacterium may help keep klebsiella in check.

Bifidobacterium longum has promising activity against inflammation caused klebsiella pneumoniae, and bifidobacterium breve seems to have the widest antagonistic activity of several bifido strains tested against gram-negative bad gut bugs including klebsiella.
Lactobacillus may also possibly inhibit klebsiella.

Sulphasalazine has been shown to reduce gut klebsiella levels.
More aggressive treatment may consist of gut decontamination using colistin and amikacin, followed by fecal microbiota transplantation.

Low Starch Diet for Ankylosing Spondylitis
While resistant starches and complex carbohydrates can confer health benefits, they may not be so beneficial in those with Klebsiella-related autoimmune conditions.

Because klebsiella feeds on starches and sugars but cannot digest cellulose, a low-starch (or no starch) diet may help decrease klebsiella load, and in turn improve symptoms.

Amylopectin is a branched polymer is resistant to human digestion but can be broken down by bacterial pullulanase. Such resistant starches feed colonic bacteria such as Klebsiella. In contrast, amino acids do not feed Klebsiella as much.

Thus, a diet to potentially reverse ankylosing spondylitis would comprise of non-starchy vegetables, healthy fats and meats, and be low in complex carbohydrates and starches. 

Complex carbohydrates include sweet potatoes, potatoes, tapioca, parsnips, arrowroot, oatmeal, plaintain and unripe bananas, chestnuts, beans, lentils, quinoa, brown rice, peas. 

Once symptoms have improved, some people find they can tolerate small amounts of white rice. Simple sugars are absorbed in the stomach before they reach the colon (where klebsiella lives), so may also be tolerated in small amounts. There is always room for individual variation, and self-experimentation may be required.

The Link between Ankylosing Spondylitis, Crohn’s Disease, Klebsiella, and Starch Consumption
Contribution of diet to the composition of the human gut microbiota

Other Potentially Helpful Measures
(some of these may be experimental)
High serum levels of vitamin D may be of benefit.
Curcumin may be of benefit.
Vitamin K2 may possibly retard fibroblast ossification.
Exercise is beneficial and strongly encouraged.
PEMF may help decrease local inflammation.
LDN may be helpful.
Avoiding or limiting alcohol intake is best, as alcohol overuse decreases intestinal immunity and impairs intestinal barrier function.
Artesunate may help inhibit bacterial translocation and decrease inflammation.
Chitosanase (not to be confused with Chitosan) is an enzyme that may be helpful against klebsiella biofilm.
Propionic acid and butyric acid supplementation may be beneficial and help to suppress inflammation.

Elemene, the essential oil of Curcuma wenyujin, inhibits osteogenic differentiation in ankylosing spondylitis.
Vitamin D in ankylosing spondylitis: review and meta-analysis.
Comparative effect of 25(OH)D3 and 1,25(OH)2D3 on Th17 cell differentiation.
T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis.
Impaired intestinal immunity and barrier function: a cause for enhanced bacterial translocation in alcohol intoxication and burn injury.

Low Dose Naltrexone (LDN)
LDN may inhibit the activity of microglia and reverse central and peripheral inflammation.
People with high ESR (sed rate) tend to respond well to LDN. Conditions where ESR may be elevated include rheumatoid arthritis, SLE, and acute infection.

Naltrexone has antagonistic effects on Toll-like receptor 4 (TLR4) non-opioid receptors as well. TLR4 are found on microglia and macrophages. LDN may also decrease TNF-alpha, IL6, MCP1 and other macrophage produced inflammatory agents.

Some studies have suggested that the response rate to LDN for Crohn's disease may be as high as 80%, and for fibromyalgia around 50%. Results may not be seen for 2 months.

While LDN is generally dosed at bedtime, those who experience the side effect of insomnia may consider dosing in the morning if this side effect does not improve over time.

Stories about using LDN for AS.
More information about LDN.

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain
Low dose naltrexone for induction of remission in Crohn's disease.

Essential Oils and Klebsiella

While many essential oils have anti-klebsiella effects, not all of them are safe for human consumption or use. Even the oils that are safe should often be used in a diluted form. Oils also have other wide-ranging effects, and should be used only under knowledgeable professional advice.

Oils of anise, cinnamon, oregano and thyme appear to have effects against klebsiella. Oil of oregano is a diluted form of oregano essential oil and is safe for ingestion; dosage is measured in drops.

It also appears that some antibacterial essential oils and certain antibiotics may work even better if used together. Carvacrol (oregano) and cumin seed may have synergy with cipro. Oregano, clove, and cinnamon may interact synergistically with doxycycline.

Pennyroyal has good activity even against antibiotic resistant klebsiella, but unfortunately it is considered poisonous, and human use is not recommended.

Oils with good inhibitory activity against klebsiella include foeniculum vulgare (common fennel), mentha piperita (peppermint), mentha spicata (spearmint), ocimum basilicum (basil), origanum majorana (marjoram), origanum onites (Turkish oregano), origanum vulgare (oregano), satureja cuneifolia (savory).

Cumin seed oil also has anti-inflammatory properties.

Efficiency of vanilla, patchouli and ylang ylang essential oils stabilized by iron oxide@C14 nanostructures against bacterial adherence and biofilms formed by Staphylococcus aureus and Klebsiella pneumoniae clinical strains
Empirical prediction and validation of antibacterial inhibitory effects of various plant essential oils on common pathogenic bacteria.

Further reading: