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Master_Sergeant_AS_Kicker
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Hi SimplySouthern,

You know its sad that so called 'experts' were able to wipe you so completely - sad because they were showing their own ignorance - perhaps they could be excused back in the 80's because then AS only applied to the worst of the worst - young men with bamboo spines.
The broader grouping of spondlyoarthropathies now encompasses lesser conditions like reactive arthritis, psoriatic arthritis and undifferentiated spondyloarthropathy (which sounds like you) - but each still overwhelming and difficult to deal with in their own right - as you and I both know - made all the worse by even close family and friend suspecting us as being borderline hypochondriacs - which probably I am!

Also sad that unless you have Grade 2 changes to the SI joints on plain X-ray one doesn't qualify for financial support for the biologics. The reality is that the mechanism of SI attack is the same as that of the hands, feet, ankles, ribs, knees, wrists, manubrio-sternal joint, etc - each is preceded by an inflammatory enthesitis.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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Fifth_Degree_AS_Kicker
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I've got to agree with you there. I remember walking into a Rheumatology appointment and without any images or blood work, I was criticized for taking his time because if I had AS, I would be bent over with a fused spine. He was supposedly one of the best in that area at the time....wrong! Unfortunately because of those comments in my file, I couldn't get another referral.

That was in 1987 and thankfully things have changed considerably but still, that initial diagnose was breath taking and with it, I walked away after being humiliated as one, as I didn't want to believe I had it and two, didn't want to be so to speak on trial to beg for help.

As far as the Grade 2 or above, I have what appears to be Grade 3 (bilateral clear erosion and narrowing) but was told it's just OA....that with years of symptoms wasn't sufficient for the last Rheumy...lots of folks that could use better training before dismissing a diagnosis.

In 2010, I fell down a small flights of brick stairs and ripped the tendons from my left foot. Although told it would heal on it's on (6 weeks in a boot cast). It has never been since (unbearable pain that limits the time I can be on my feet, movement and I have to wear tight socks all the time to prevent the pain and it's in some of my toes as well). A GP said it sounds like enthesitis and another said, it could be. Not sure what to do with that but I do know the pain can be out of control.

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Hi SimplySouthern,

I made these notes in relation to IL23R a couple of years ago and thought you might find them of interest - I hope most of it is still relevant:

IL23R Interleukin 23 Receptor is located on Chromosome 1p31.3
IL23R is a cytokine receptor present on T-cells, NK lymphocytes, monocytes, and dendritic cells. These cells identify foreign substances and defend the body against infection and disease. IL23R is a critical cytokine receptor on a subset of CD4+ T-cells called T helper 17 (Th17) cells. The receptor for IL-23 is formed by the IL12Rβ1 subunit and an IL23 specific subunit, IL23R. Note that Th17 cells express a high level of the cytokine IL-17 in response to stimulation.

The primary articular site of inflammation in the spondylarthropathies are the entheses (tendon-bone attachments) and the aortic root and valve (which are structurally similar to entheses). Recent studies have shown that IL23 acts on previously unidentified IL23R+ ROR-γt+ CD3+ CD4- CD8- Sca1+ entheseal resident T cells, which normally act to repair and remodel these sites. In response to high levels of gut derived circulating IL-23 these cells elaborate inflammatory mediators including IL-6, IL-17, IL-22 and CXCL1 with the specific and characteristic development of enthesitis and entheseal new bone formation in the initial complete absence of synovitis. Thus, dysregualtion of IL-23 results in lesions at precise and predictable anatomical sites. Moreover, these cells express the molecule PLZF, which allows them to respond to cytokines extremely rapidly, and indeed entheses respond within hours to IL23 in vitro.

At the cell surface IL23R binds with IL23 and triggers intracellular signalling that promotes inflammation. Genetic alleles of IL23R substantially affect susceptibility to AS, Crohn’s Disease, and psoriasis and this may in part explain the clinical association of these diseases. IL23R polymorphism is also associated with MS susceptibility. It is known that up to 70% of AS patients have subclinical ileal inflammation resembling Crohn’s and that about 10% of AS patients have clinical IBD. The strong association with susceptibility to disease suggests that IL23/IL23R targeted therapies may even be capable of disease prevention.

One of the alleles of IL23R appears to reduce the likelihood of developing AS. This allele results from the substitution of a single amino acid, glutamine for arginine at protein position 381, written R381Q or Arg381Gln. The same allele is protective against Crohn’s disease and psoriasis. Researchers believe that the role of IL23R in triggering inflammation in the intestinal wall may underlie its connection with Crohn’s and probably with AS. Accumulating evidence suggests that IL-23 is a likely master regulator of mucosal immunity during gastrointestinal infection and inflammation.

Genome wide association studies have previously shown that a single nucleotide polymorphism (SNP) in the IL23R gene (R381Q ) is significantly higher among healthy controls than in patients with psoriasis, Crohn’s Disease, sarcoidosis or AS. The associated SNP (rs11209026) which consists of a guanine (G) to adenine (A) substitution at the DNA level results in an arginine (R) to glutamine (Q) substitution at position 381 (R381Q) within the cytoplasmic domain of IL23R.
The possible Genotypes are : GG - Typical odds of AS; AG - moderately lower odds of AS and AA - substantially lower odds of AS.

Th17 cells generated from A allele carriers and G allele carriers are capable of producing similar amounts of Th17 cytokines. However, IL-23 mediated effector function was impaired, as Th17 helper cells from the protective A allele carriers had significantly reduced IL-23 induced IL-17A production and reduced STAT3 phosphorylation compared to the common G allele carriers.

The functional consequences of carrying the protective gene variant are elaborated in the 2011 paper “Functional studies of the IBD susceptibility gene IL23R implicate reduced receptor Function in the protective genetic variant R381Q” by Pidasheva, S et al.
‘We investigated the effects of this variant in primary T cells from healthy donors carrying IL23RR381 and IL23RQ381 haplotypes. Using a proprietary anti-IL23R antibody, ELISA, flow cytometry, phosphoflow and real-time RT-PCR methods, we examined IL23R expression and STAT3 phosphorylation and activation in response to IL-23. IL23RQ381 was associated with reduced STAT3 phosphorylation upon stimulation with IL-23 and decreased number of IL-23 responsive T-cells. We also observed slightly reduced levels of proinflammatory cytokine secretion in IL23RQ381 positive donors. Our study shows conclusively that IL23RQ381 is a loss-of-function allele, further strengthening the implication from GWAS results that the IL-23 pathway is pathogenic in human disease. This data provides an explanation for the protective role of R381Q in CD and may lead to the development of improved therapeutics for autoimmune disorders like CD.’
That is, the IL23R R381Q SNP protects against multiple immune mediated diseases by impairing IL-23 mediated Th17 responses, namely, reduced IL17A production and STAT3 phosphorylation.

Early studies of Han Chinese suggested there was NO association of IL23R with AS, presumably because there was no polymorphism within the IL23R gene at rs11209026 . In a contradictory result from another study (2009) the difference in the genotypes rs11209032 and the differences in the genotypes and allele frequencies of rs6677188 between AS cases and controls in a Han population WERE significant. The two SNP’s rs11209032 and rs 6677188 were in strong linkage disequilibrium.

A more recent study has implicated rare IL23R variants with AS aetiopathogenesis, and has identified a low frequency nsSNP with predicted loss of function effects that is protectively associated with AS in Han Chinese, suggesting that decreased IL-23R function protects against AS. These findings further support an important role for IL23-signalling in AS.

A new injectible monoclonal antibody treatment, Stelara, is an Anti-IL12p40 antibody given (45mg) every 3 months (cost ~$5000 /shot) and it is currently only approved for psoriasis but may be available soon for psoriatic arthritis.

(1)The allele G frequency of rs11209032 is higher in AS groups than in the controls (A vs. G: OR = 1.173, 95% CI = 1.107–1.243, P < 0.001). (2) The allele A of rs1004819 is higher in the AS groups than in the controls in both all-pooled population (A vs. G: OR = 1.147, 95% CI = 1.022–1.287, P = 0.02) and Europe-pooled population (A vs. G: OR = 1.199, 95% CI = 1.007–1.429, P = 0.042). (3) The allele frequency T of rs1343151, G of rs10489629, and A of rs11209026 is lower in AS groups than in the controls. (4) No significant differences are found in allele frequency of rs10889677 polymorphism between cases and controls by random effects model. The conclusion is that the genetic susceptibility to AS is associated with the IL-23R gene polymorphisms. The protective SNPs include rs1343151, rs10489629, and rs11209026 while rs1004819 and rs11209032 may be the susceptibility SNPs.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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Interesting article in todays edition of "The Australian" newspaper:
Cut-Price shortcut to what ails us
A shortcut developed by Australian scientists could slash the costs of genetic analysis by 95 per cent, fast-tracking cures for common illnesses such as dementia, schizophrenia and heart disease.
Queensland researchers say their new method of "imputing" genetic mutations allows DNA to be analysed for as little as $70 a pop, with only marginally less precision than full genomic sequencing that costs 20 times as much. The technique, outlined this morning in Nature Genetics, offers a cost effective way to analyse huge banks of tissue samples. "The greater the sample size the increased statistical power of the result," said lead author Jian Yang, from the Queensland Brain Institute at the University of Queensland. "When we study the genome for genes linked to diseases we need to test tens or even hundreds of thousands of samples because for most common diseases the effect of a single gene is tiny."
Advances have cut the cost of genome sequencing colossally, from $US119 million ($166m) in 2001 to about $1400. The new approach slashes costs further using tests known as "single nucleotide polymorphism arrays", which directly measure only a fraction of the genome.
Geneticists then guess the remaining DNA variants based on known genetic associations, using statistical imputation.
Last week University of Hong Kong researchers unveiled their own "user-friendly" imputation software tool and Californian company 23andMe uses imputation methods in a saliva test that costs consumers about $138.
Doubts over accuracy led the US Food and Drug Administration to stop 23andMe from using its tests for health advice in 2013, putting it out of the genetic testing business for 15 months.
But the UQ researchers say they have put these concerns to rest. In a study of more than 44,000, their imputation technique obtained results almost on par with full sequencing.
Project leader Peter Visscher said, while full sequencing would still be used to hunt for cures for rare illnesses, imputation could become favoured for some of the most common scourges.
"(They are) the diseases where we already know that there are hundreds - if not thousands - of variants that contribute to risk," he said.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
Joined: Apr 2013
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Fifth_Degree_AS_Kicker
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I am all for "Being in the Know" but in reading some group responses on the 23andme website it is clear many are new to Spondylitis. I have learned more in groups and forums in the last two years than I have known in the last nearly 30 years since my diagnosis.

Here's wishing more of the medical community takes heart to DNA studies as well. smile as what you don't see is not always what you don't have!

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I had another thought/question about the odds ratios for the ERAP1 SNPs. The relative risks listed for Rs30187(C;T) and Rs27044(C;G) are 1.5x and 1.4x. If those are the odds ratios for the general population, but the increased risk is only associated with HLA-B27+ people (~8% of the population), then wouldn't the relative risk of those SNPs in an HLA-B27+ person be much higher?

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Jroc

you would think BUT, are the results taking into consideration you have the genes because you are positive? IDK

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I'm not familiar with this publication but found it interesting (of what I could make sense of). I did check and all but one gene mentioned was on my report.

http://www.nature.com/ng/journal/v43/n8/full/ng.873.html

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Here's a bit of background information on what ERAP1 does.
ERAP1 stands for Endoplasmic Reticulum Amino Peptidase 1
It is located on Chromosome 5q15 and is composed of 20 Exons (Transcription Length 5,488 bps Translational Length 948 aa) and 19 Introns (Transcription length ~42 kb (total 47.28 kb).

The association of ERAP1 and disease is a major breakthrough in AS research. The gene product has two known functions, firstly within the Endoplasmic Reticulum of a cell, ERAP1 (in association with the closely related ERAP2) is responsible for trimming short peptides to optimal length for MHC Class I presentation. Since AS is primarily an MHC Class I mediated disease, this has implications favouring mechanisms of disease generation that involve abnormalities of peptide presentation. The second known function of ERAP1 is (when secreted), ectodomain shedding of cell surface cytokine receptors of the pro-inflammatory cytokines IL-1 (IL1R2, decoy IL-1 receptor), IL-6 (IL6Rα) and TNFα (TNFRSF1A).
So far there is no evidence for the association of ERAP1 with Crohn’s Disease or Ulcerative colitis, both of which are not Class I mediated diseases; whereas up-regulation of IL-1, IL-6, TNFα and IL-23 is a feature of these conditions. This would suggest that it is the peptide trimming function of ERAP1, and not cytokine receptor cleavage, that explains the mechanism of association with AS.
ERAP1 is a Zn containing metallopeptidase that is a member of the ‘M1/gluzincin family’ of peptidases. It is most clearly related to ERAP2 and P-LAP and together ERAP1, ERAP2 and P-LAP form the oxytocinase subfamily of M1 peptidases. All three have highly conserved C-terminal domains that allow the recognition and cleaving of peptide precursors. ERAP1 has a modular organisation that explains its molecular ruler mechanism. When a precursor peptide’s C-terminus is bound to ERAP1’s regulatory domain it induces a conformational change of ERAP1 from the open to the closed position thereby allosterically activating the catalytic zinc site 30 Angstroms distant which trims the last amino acid, provided the precursor peptide is long enough to reach the catalytic site. It has been shown that peptides shorter than 8 residues are not long enough to be efficiently trimmed by ERAP1. Longer antigenic precursors could be accommodated by bulging or zig-zagging of the middle of the peptide within the binding groove.
The structure of the soluble domain of ERAP1 has recently been determined. A central wide channel leads to the active site Zn(II) and it is the obvious candidate to accommodate the peptide substrate. The enzyme undergoes conformational changes which represent snapshots of the catalytic cycle. Interactions between ERAP1 and the peptide mainly involve hydrophobic and van der Waal contacts, plus a H-bond contact with the carboxylate end of the peptide. ERAP1 has four domains: domain I (residues 46-254); domain II (residues 255-529, which contains the catalytic site; domain III (residues 530-614 forming a β sandwich with two β-sheets) and domain IV (residues 615-940 forming a large bowl shaped α-helix domain containing 16 α-helices). The ERAP1 regulatory domain is composed of sub-domains III and IV which can interact with domain II through conformational changes to either shield or expose the catalytic site.

For proteolysis to occur domain IV must swing back over the catalytic domain, and in so doing activate the protease. After the N-terminal residue is cleaved, the cavity must open in order to release the products, which can then bind for another round of proteolysis. This is supported by peptide intermediates when monitoring the shortening of the ERAP substrates. The non-processive nature of peptide trimming is a result of N- and C-terminal anchoring, requiring active site closure, and subsequent release of the N-terminally cleaved amino acid residue. For a new round of cleavage to occur, the trimmed peptide needs also to be released to allow another round of productive binding due to the necessity to attach the free amino terminus at the S1 binding site. Note that all trimming intermediate products can be observed with different maxima at successive time points. ERAP1 functions as a molecular ruler because cleavage efficiency is significantly reduced for peptides shorter than eight residues. Proteolysis only occurs if there is a secondary binding site within the internal cavity where the C-terminal part of the substrate is bound and hence this defines the minimal product length. The internal cavity is large enough to accommodate large peptides (9-15 peptides) but peptides shorter than 8 or 9 peptides are not cleaved because both binding sites cannot be occupied. The 8-mer is still able to bind ERAP1 but is not further processed and acts as a competitor for the 9-mer.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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Fascinating information DavidP. Thank you!

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