Another site/tool for DNA Health Risk

In my last post I did used DNA to evaluate if a person was a good candidate for using Infliximab aka  Remicade. During the research I discovered a free tool and site to further ease DNA analysis. This site is actually easily to use than https://livewello.com/

The gotcha is you need to use the Safari Browser [Install here] and the site is http://www.eupedia.com/genetics/autoimmune_diseases_snp.shtml. It will prompt you to install  SnpTips Add On: https://addons.mozilla.org/en-US/firefox/addon/snptips/

What do you get then?

Before the above (or on a different browser) you will see

Screen Shot 2015-03-29 at 3.43.09 PM

You will see:
Screen Shot 2015-03-29 at 3.47.38 PM

Clicking on this change item will show your values, plus quick links..

Screen Shot 2015-03-29 at 3.50.08 PM

The extra sweet thing is that this applies to ANY PAGE. For example, while browsing Pub Med pages

Screen Shot 2015-03-29 at 3.55.01 PM

This can save a lot of time, for example, for the SNPs above, I immediately know if I have the SNPs that are being investigated — in this case, I have one of them, so further reading may be worth while.

Honesty in informing Patients

As a statistician I like to know the actual odds so I can make a rational decision. I have encounter situations where the operation was successful and there was a 40% risk of patient death within 6 months — and that was never disclosed to the patient or the family. Personally, I would love to see printed risk statement required to be given with each drug (and compulsory reporting of any or odd reaction — typically MDs will dismiss them and not report them). – the patient reports  (giving the MD’s name) and the MD reports giving patient name.

“There is a low risk of ….”  is misinformation.. numbers are needed!

” Idiosyncratic DILI is like other adverse effects of drugs underestimated and under reported in most epidemiological studies.” [2015]

Another post from a different blogger that found studies suggesting that the risk of cancer was 12x higher with some anti-TNF drugs. (i.e. from a 0.4% risk to a 5% risk of cancer [source])

Case Study: Infliximab

Infliximab aka  Remicade, Remsima, Inflectra has been cited in the immediate prior posts and is likely a good example because it has been heavily used — including for:

So what are the risks if you use it? A PubMed search returned over 3000 articles dealing with adverse effects.

  • “Infliximab caused liver injury in 8.3% of treated patients” [2015]
  • “10~20 % of patients was Remicade-resistant.” [2014]
    • “primary-non response” 22% [2014]
    • “65.5%/69.4% for clinical response”[2014]
      • high pre-treatment hemoglobin was also a predictor of good response [2014]
      • The sensitivity and specificity in predicting response to IFX based on this gene profiling was 95% and 85%, respectively.[2014]
      • all of these studies more severe disease was associated to adverse outcomes and less favorable response to anti-TNF [2014]
  • “Chronic sinusitis.. approximately 2%”[2014]
  • infusion reactions and delayed hypersensitivity 10% [2014] 27% [2014]
    • Mild and moderate IR occurred in 17% [2014]
  • Adverse drug reaction: 41.4% [2014] 35%[2014]
  • Serious adverse events: 67.9% [2014]
  • 48.48 % of patients who received infliximab presented (ANA, ENA, anti-dsDNA) autoantibodies [2014]
  • Infections and elevation of transaminases occurred in 28.40% [2014]
    • severe infections 6%  [2014]
  • [2014]
    • Anaphylaxis:  6%
    • mild acute infusion reaction in 6%
    • hypotension in 6%
    • respiratory distress 6%
    • skin rash and eruptions 6%
    • hypertension 3%
    • tightness in the chest 3%

No statistics on, but..

  • ” an increase in weight” [2015]
  • “an association between focal mucinosis and thyroid dysfunction, as well as possible adverse effects of biological therapy with TNF-α antagonists.”[2014]
  • ” probably exert a direct, toxic effect on the bone marrow”[2014]
  • Mycobacterium chelonae bacteremia [2014]
  • Hepatitis [2013]
  • Herpes zoster[2014]
  • Aseptic meningitis [2014] – 5 cases at least reported
  • a significant association with lupus [2014]

Bottom Line

While the analysis is not complete, we may sum it up as: This drug as a 70-80% response (and for many diseases it is used for, less than 25% chance of remission) with probablity a 10% of having liver damage (regardless of outcome), 30% change of getting an infection (with the immune system depressed), 70% chance of adverse reaction. The odds of taking it and everything going “fine” is about 1 in 15. 14 in 15 people will have problems.

As a side note, I found two of the studies found success (or issues, such as developing APS) was predictable from DNA. I really doubt that more than 1% of patients prescribe this are testing for DNA, exposing patients to needless risks with little chance of success.

Addendum

After the above article, someone who was about to take  aka  Remicade, contacted me and allow access to their DNA (from 23andMe.com ).  I found a beautiful table at: http://www.nature.com/tpj/journal/v13/n4/fig_tab/tpj201253t2.html (Gene polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases (Aug 2013) R Prieto-Pérez, T Cabaleiro, E Daudén and F Abad-Santos) and both created a LiveWello.com panel from it and walked their DNA SNPS. The result was a strong prediction that they would be a non-responder (i.e. 6x more ↓ than ↑). I wonder how the MD is going to respond to “According to the latest studies (2013), my DNA says that I am going to be a non-responder to Infliximab and other anti-TNF-Alpha drugs. What do you suggest next?”

The sweet thing would be for Insurance Companies to demand DNA testing before approving the use of Remicade — it will save them money (and cut premiums too!) and save patients side-effects!

TNF-Alpha Suppressors and Histamines

After the last post, a reader sent me some articles showing the relationship between TNF-Alpha and Histamines. Earlier on this blog, I have discussed the possibility of some CFS patients having histamine sensitivity. It turns out that reducing histamines may increase the inflammatory response :-(. Things are never simple – unfortunately.

“These results suggest that histamine may act as an autocrine regulator of cytokine release by MC and thus modulate inflammatory responses[TNF-Alpha] in allergic asthma.” [1996]

“Histamine injection into human skin engrafted on immunodeficient mice similarly caused shedding of TNFR1 and diminished TNF-mediated induction of endothelial adhesion molecules. These results both clarify relationships among TNFR1 populations and reveal a novel anti-inflammatory activity of histamine.” [2003]

Digging a bit deeper we find:

Histamine is recognized as a neurotransmitter or neuromodulator in the brain, and it plays a major role in the pathogenic progression after cerebral ischemia. Extracellular histamine increases gradually after ischemia, and this may come from histaminergic neurons or mast cells. Histamine alleviates neuronal damage and infarct volume, and it promotes recovery of neurological function after ischemia; the H1, H2, and H3 receptors are all involved. Further studies suggest that histamine alleviates excitotoxicity, suppresses the release of glutamate and dopamine, and inhibits inflammation and glial scar formation. Histamine may also affect cerebral blood flow by targeting to vascular smooth muscle cells, and promote neurogenesis. Moreover, endogenous histamine is an essential mediator in the cerebral ischemic tolerance. Due to its multiple actions, affecting neurons, glia, vascular cells, and inflammatory cells, histamine is likely to be an important target in cerebral ischemia. But due to its low penetration of the blood-brain barrier and its wide actions in the periphery, histamine-related agents, like H3 antagonists and carnosine, show potential for cerebral ischemia therapy.” [2012] and similar in Cerebral ischemia and brain histamine[2005]

This raises an interesting prospect that histamine levels in CFS may increase in response to the brain trauma which is a typical part of CFS (as seen by SPECT scans). Checking PubMed, we find nothing about histamine levels with Chronic Fatigue Syndrome. On the general internet, there appear to be conjecture and speculation:

  • ” Dr. Cheney has speculated..”  “Tufts University researcher Theorharis Theorharides. For years Theorharides has believed that mast cell activities play a role in a number of chronic illnesses including autism, fibromyalgia, ME/CFS, interstitial cystitus, IBS, migraines, cardiovascular disorders, asthma and multiple sclerosis.” [Phoenix Rising, 2012]

What we find is hypersensitive and not over-production

“What is more, most ME patients are also hypersensitive to biogenic amines (histamine and tyramine) and alcohol.” Prof. K. De Meirleir /  Christine Tobback

 

Hypersensitive does not mean over-production. “These results demonstrate, that increased reactivity to histamine and airway contraction to allergen induced by passive sensitization, occur through independent mechanisms and that, unlike allergen-sensitivity, histamine hypersensitivity is caused by a serum factor other than IgE.” [1998 this is echo by another study ” In patients with low serum IgE current smoking is associated with increased bronchial responsiveness to histamine in vitro” [2001].

The bottom line is that we do not know the mechanism for hypersensitivity to histamine. :-( We should be careful not to go down the over production of histamines route because it may result in increase (and permanent) cognitive issues.

 

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