Kickas.org Forums Ankylosing Spondylitis General Discussion #1 AS Web Support Group Diff btwn TNF Responders and Non-Responders

INteresting Abstract from PubMed


Rheumatology (Oxford). 2006 May 23; [Epub ahead of print]

The -308 tumour necrosis factor-{alpha} gene polymorphism predicts therapeutic response to TNF{alpha}-blockers in rheumatoid arthritis and spondyloarthritis patients.

Seitz M, Wirthmuller U, Moller B, Villiger PM.

Department of Rheumatology and Clinical Immunology/Allergology, University Hospital, Inselspital, Berne, Switzerland.

Objective. To examine whether the G-to-A polymorphism at position -308 in the promoter of the tumour necrosis factor-alpha (TNFalpha) gene influences the therapeutic response to TNFalpha-blockers in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS).Methods. A total of 54 patients with RA, 10 with PsA and 22 with AS were genotyped by polymerase chain reaction for the -308 TNFalpha promoter polymorphism. They were treated with infliximab (n = 63), adalimumab (n = 10) or etanercept (n = 13). Clinical response was assessed after 24 weeks by the Disease Activity Score in 28 joints (DAS28) for RA and PsA, and the Bath Ankylosing Spondylitis Activity Index (BASDAI) for AS patients.Results. All patients with the A/A genotype (n = 3, all RA) and two patients with the A/G genotype (AS) failed to respond to anti-TNF treatment. Irrespective of the underlying disease, moderate response (n = 44) was predominantly associated with the A/G genotype (A/G 18/22, G/G 4/22), whereas good response (n = 59) was exclusively seen in patients with the G/G genotype. The average improvement in the DAS28 score was 0.83 in the A/A, 1.50 in the A/G and 2.64 in the G/G group of RA and PsA patients (P < 0.0001). The BASDAI score in AS improved on average by 1.21 in the A/G and by 3.30 in the G/G group (P < 0.005).Conclusions. The data suggest that humans with a TNFalpha -308 G/G genotype are better responders to anti-TNFalpha treatment than those with A/A or A/G genotypes independent of the treated rheumatic disease (RA, PsA or AS).

PMID: 16720636 [PubMed - as supplied by publisher]

Very interesting, thanks for posting. I'll run that one off tomorrow morning!

Hi Paul, Megan and everyone else,

It looks like a good article, but I hope this doesn't sound stupid but could someone put this in plain english or laymans terms? Sometimes my mind doesn't wrap around this medical jargon. Thanks, I'd appreciate it. Wanda

I'm with you Nonnie, after the few first lines I kind of blank out....

angie

Paul, that's very interesting. Thanks for posting it (and good to see you).

Nonnie and Angie, I tend to blank out too, but after almost five years of trying to read these things, I think my brain has learned to latch onto the words I do understand and then I use context and supposition for the rest. It works to a point.

So, basically, what it's saying is that just having one of these diseases doesn't mean the anti-TNF meds will work for you. People who have a specific genotype (G/G) will respond better to these treatments than people who don't have it.

I guess the next step would be genetic testing for patients to see if they have one of the more responsive genotypes before starting treatment with the TNF inhibitors. 'Twould be logical, anyway.

If logic has anything to do with it.

Hugs,

> So, basically, what it's saying is that just having one of > these diseases doesn't mean the anti-TNF meds will work
> for you. People who have a specific genotype (G/G) will
> respond better to these treatments than people who don't
> have it.


That's basically the way I read it, too.

I also find the very fact that responsiveness is genetic to be intriguing...Maybe it means there are two different inflammation mechanisms at work?


> <Testing to determine responsiveness would be logical>
> If logic has anything to do with it.

The converse would be more likely ;-)

By the way, I make it a habit to hit up PubMed (http://www.ncbi.nlm.nih.gov) once a month or so to see what's going on.


Good to see you again, too, Kat, if only virtually...

Paul, given the number of people who have good results with the NSD, I would imagine you are correct in the idea that there are two different inflammation mechanisms at work. Some have the genetic auto-immune based AS; others have the kleb p/IBS/IBD inflammation based AS.

So, it would be interesting to do a study looking at this. See if the difference in efficacy could be based along those line.

Of course, mainstream medicine would have to admit the potential of a kleb p/ibs/ibd link to AS in some patients, so that study may never happen.

Hugs,

It seems to me that the primary issue here is whether or not TNF-alpha is part of the inflammatory cascade....

I'm not sure that the autoimmune/"reactive" arthritis distinction is the determining factor--I'll troll Medline for primary literature later, but this article from CNN
says that some folks with reactive arthritis are helped by TNF blockers:



http://www.cnn.com/HEALTH/library/DS/00486.html


Of course it would also be entertaining to know how many people diagnosed with "reactive arthritis" actually have AS, and how many people diagnosed with "AS" actually have reactive arthritis.

And here's another interesting article:

http://microvet.arizona.edu/courses/mic419/Tutorials/autoimmunity.html


"Risk factors for autoimmune diseases are genetically linked to the presence of specific Class I or Class II HLA alleles. Two possible models attempt to explain HLA linkage to autoimmunity. One scenario is that certain HLA alleles are better at presenting pathogen peptides which resemble self peptides to mature T cells. The HLA B27 (Class I) allele is associated with an 80-fold increased risk of alkylosing spondylitis, characterized by inflammation and damage to the spine. Recent research shows that B27 can bind peptides in the absence of tapasin. This is an advantage in certain virus infections, where the virus interferes with production of tapasin. However, the peptides bound in the absence of tapasin are different from those bound in the presence of tapasin, and might include some self peptides that could induce autoimmunity. Therefore, people with the B27 Class I MHC allele might be more likely to respond to virus infections by producing CTL that can recognize self peptides and kill uninfected cells."

Anyway, enough for now...

Paul, thanks for those links. The one on reactive was quite informative and I learned a fair bit. Now I just have to remember it.

I'm afraid my tendency to go cross-eyed when trying to read medical literature kicked in on the second link. However, did I understand correctly that my B27+ means that I can fight off certain viruses better, but it's a double edged sword?

It's too bad that there isn't a test to properly differentiate between the various SPa's (ie. reactive vs AS). I do believe that there is a lot of cross-over in diagnosis.

Hugs,

There might be a distinction possible between reactive arthritis and what Dr. Khan has called "primary AS" - "primary AS" being AS which occurs in the absence of other associated factors (associated factors include psoriasis, inflammatory bowel disease, or known/likely prior triggering infection). However, chronic reactive arthritis can clearly evolve into AS, and reactive arthritis vs AS represents more like a continuum than entirely separate entities. (Chronic reactive arthritis which has evolved into AS would represent one of the categories of "secondary AS" rather than "primary AS", according to how "primary AS" is defined, but it is still AS.)

That being said, a couple of features weigh in to point to reactive arthritis RATHER than primary AS.

1)known or likely preceding infection. If spondyloartropathy symptoms set in several weeks after a bout of diarrhea, or a genitourinary tract infection - that points to reactive arthritis

2) sudden onset. If a person can pinpoint the start of symptoms to some exact time, this points to reactive arthritis. As a generality, primary AS tends to be gradual in onset,

3)symptom pattern - Reactive arthritis tends to be more peripheral and primary AS TENDS to be more axial and less peripheral, though primary AS can have peripheral pattern of involvement, especially in females. Along with this, dactylitis, which is swelling of finger or toe, suggests reactive arthritis (or psoriatic arthritis) and is not a common feature of primary AS.

4)symptom complex - the symptom complex of urethritis, conjunctivitis and arthritis forms a "triad" of symptoms, previously indicated as "Reiter's syndrome." and is suggestive of reactive arthritis. Two of the three symptoms from this "triad" can still be suggestive of reactive arthritis.


Recent articles suggest a less promissing outcome to reactive arthritis than what was described in the older literature

see references within these old posts:

https://www.kickas.org/ubbthreads/showthreaded.php?Cat=0&Number=223202&page=&vc=1

https://www.kickas.org/ubbthreads/showthreaded.php?Cat=0&Number=224014&page=&vc=1