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Rapid Anti-Inflammatory Effects of Gonadotropin-Releasing Hormone Antagonism in Rheumatoid Arthritis

deleder2k

Senior Member
Messages
1,129
Norwegian media: Researcher and doctor Anita Kåss is behind a medicine that treats rheumatoid arthritis, psoriasis and M.S. The licence agreement is now sold to the Japanese pharmaceutical company Astellas for 800 MNOK (100M USD, or 77M Sterling). Test results (not sure if this is the study i've pasted in or not) show effect within 5 days, compared to 12 weeks compared to todays medicines.



"Gonadotropin-releasing hormone (GnRH) and pituitary gonadotropins, which appear to be proinflammatory, undergo profound secretory changes during events associated with rheumatoid arthritis (RA) onset, flares, or improvement e.g. menopausal transition, postpartum, or pregnancy. Potential anti-inflammatory effects of GnRH-antagonists may be most pronounced in patients with high GnRH and gonadotropin levels. Therefore, we investigated the efficacy and safety of a GnRH-antagonist, cetrorelix, in RA patients with high gonadotropin levels.

METHODS:
We report intention-to-treat post hoc analyses among patients with high gonadotropin levels (N = 53), i.e. gonadotropin levels>median, from our proof-of-concept, double-blind AGRA-study (N = 99). Patients with active longstanding RA, randomized to subcutaneous cetrorelix (5mg days1-2; 3mg days 3-5) or placebo, were followed through day 15. Only predefined primary and secondary endpoints were analyzed.

RESULTS:
The primary endpoint, Disease Activity Score of 28-joint counts with C-reactive protein (DAS28-CRP), improved with cetrorelix compared with placebo by day 5 (-1.0 vs. -0.4, P = 0∙010). By day 5, more patients on cetrorelix achieved at least a 20% improvement in the American College of Rheumatology scale (44% vs. 19%, P = 0.049), DAS28-CRP≤3.2 (24% vs. 0%, P = 0.012), and European League against Rheumatism 'Good-responses' (19% vs. 0%, P = 0.026). Tumor necrosis factor-α, interleukin-1β, interleukin-10, and CRP decreased with cetrorelix (P = 0.045, P = 0.034, P = 0.020 and P = 0.042 respectively) compared with placebo by day 15. Adverse event rates were similar between groups.

CONCLUSIONS:
GnRH-antagonism produced rapid anti-inflammatory effects in RA patients with high gonadotropin levels. GnRH should be investigated further in RA."


I think they said on the news that it was all based on the idea that many with R.A and other diseases improved while being pregnant. I know that many PWME improves while they are pregnant. Could this have to do with GnRH? What is your take on this @Jonathan Edwards?


https://www.ncbi.nlm.nih.gov/pubmed/26460564
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Norwegian media: Researcher and doctor Anita Kåss is behind a medicine that treats rheumatoid arthritis, psoriasis and M.S. The licence agreement is now sold to the Japanese pharmaceutical company Astellas for 800 MNOK (100M USD, or 77M Sterling). Test results (not sure if this is the study i've pasted in or not) show effect within 5 days, compared to 12 weeks compared to todays medicines.

I think they said on the news that it was all based on the idea that many with R.A and other diseases improved while being pregnant. I know that many PWME improves while they are pregnant. Could this have to do with GnRH? What is your take on this @Jonathan Edwards?

It does not fill me with great enthusiasm. They show a response at 5 days. I would like to know what the response is like after 3 months. Gonadotrophin's are there for a reason. They control sex hormone levels. Nobody is going to like having their sex hormones blocked for ever.

The story about RA getting better in pregnancy was actually the reason why Hench discovered cortisol in about 1950. That is to say we owe aour knowledge of adrenal steroids to a search for an RA treatment! I think he thought he was looking for a pregnancy hormone. Cortisol variants (steroids) are very good for RA at first and then you develop lots of awful unwanted effects.

The other thing is that the level of response they give of 44% ACR20 (vs 19% placebo) would be considered a bit feeble in comparison to Infliximab or Etanercept or Rituximab or any of the new drugs which tend to give 70% ACR20 vs ~19% placebo (i.e. an extra 51% as opposed to 25%).

IN general this seems to be harking back to ideas from fifty years ago. We now understand the detailed immunology and as far as I am concerned the sensible thing is to go upstream and try to switch off the whole disease, not just develop another downstream anti-inflammatory tactic.
 

kangaSue

Senior Member
Messages
1,851
Location
Brisbane, Australia
I was looking into this from a GI dysmotility perspective recently and I think one would need to wary here if GI issues were a part of the symptoms too, something that I think is common in RA.

The use of Gonadotropin-releasing hormone (GnRH) analogues can lead to having GnRH antibodies for some people which can impact as GI dysmotility but antibodies against GnRH are common in patients with Diabetes, IBS and GI dysmotility for which, the greater majority have never taken an analogue before.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2982.2011.01744.x/full
[Conclusions & Inferences; Higher levels of GnRH IgM antibodies were detected in patients with IBS and dysmotility, but not organic GI diseases, compared with healthy controls. These findings suggest that IBS and dysmotility to some extent may be of an autoimmune origin.]

https://www.ncbi.nlm.nih.gov/pubmed/17241858/ Chronic intestinal pseudo-obstruction due to busrelin-induced formation of anti-GnRH antibodies.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227618/