High neutrophils, very low lymphocytes ?

[me2]

Oh, about neutrophils. My scientist doc up at the University of Washington told me some time ago that he thought the next break through would involve cytokines. His studies were on neutrophils so I'm guessing he is talking about cytokine production by neutrophils.

[Mark76]

Well, this discussion is certainly way over my head... but I'll jump in anyway. Maybe I'll get taller.

First of all congrats Mark on the solid improvements. I have not been following people here much lately so it is good to see some good news right off the bat.

I'm not sure if my info is relevant but I tried the anti-TNF drug Etanercept a long time ago. Before there were any studies. I was on it over a year and it didn't help. Later there was a trial done (2005) that concluded it was not helpful. I wasted 17 grand of my own money (insurance wouldn't pay) and more importantly it didn't help. Here is a bit of info from that study:

RESULTS

The mean follow-up for the overall cohort was 27 months. Of the 174 patients who could be evaluated, 126 (72.4 percent) had a sustained remission, but only 86 (49.4 percent) remained in remission for the remainder of the trial. There were no significant differences between the etanercept and control groups in the rates of sustained remission (69.7 percent vs. 75.3 percent, P=0.39), sustained periods of low-level disease activity (86.5 percent vs. 90.6 percent, P=0.32), or the time required to achieve those measures. Disease flares were common in both groups, with 118 flares in the etanercept group (23 severe and 95 limited) and 134 in the control group (25 severe and 109 limited). There was no significant difference between the etanercept and control groups in the relative risk of disease flares per 100 person-years of follow-up (0.89, P=0.54). During the study, 56.2 percent of patients in the etanercept group and 57.1 percent of those in the control group had at least one severe or life-threatening adverse event or died (P=0.90). Solid cancers developed in six patients in the etanercept group, as compared with none in the control group (P=0.01).
Full Text of Results...


CONCLUSIONS

Etanercept is not effective for the maintenance of remission in patients with Wegener's granulomatosis. Durable remissions were achieved in only a minority of the patients, and there was a high rate of treatment-related complications.


-- Me2 here again. Thankfully I have not had complications from that treatment. Or the many others I have tried. I don't know of a WG treatment that I have NOT tried. Methotrexate, Cytoxan, Rituxan, IVIG, Myfortic, etc. Amazing I am still here.
I am super impressed that you have an advanced degree in immunology. I got some basic books from the university I go to for treatment and it was wildly complex. I understood very little.

I have been a guinea pig for many treatments. I took Rituxan long before it was approved. My illness likes to keep me on the cutting edge I guess. Right now, on my own initiative, I am well into experimenting with cannabis. It is a subject that is a horrible quagmire of mis-information and chaos BUT there are massive personal accounts of healing that I can't ignore. I have been working on this for some time.

I have found a ND recently that I think is well informed and is helping me with dosages. She is also having me get genetic testing - but I haven't looked into why yet. I've been super, super busy lately.

If I come up with any useful results or info I plan on sharing it with the forum.

It's great to see Marta here too.

Great read...shame the trial didn't work. Yes immunology is complex whats more what occurs in one person may be different in another same with drugs. The problem with cytokine targeting is its another band aid fix which is why prednisone on its own isnt very effective for wg. In order to cure one needs to know what causes the initiation. I firmly believe that in many wg cases it is pathogen in nature eg staph so along comes a macrophage or t cell and presents it to a b cell and binds or whats called neutralizes the antigen (eg staph) and it remembers what staph looks like. So even after the staph has been eliminated neutrophils are swimming around the blood along with monocytes and heap of chemicals released including vcam, monocytes adhesion protein, cytokines (interleukins and tnf etc) all resulting in more white blood cells and adhesion to endothelium of blood vessels. Once the neutrophils are primed from cytokines the pr3 and mpo which are normally in the granules and lysozomes of neutrophils move to cell surface. Along come the b cells still floating in blood as well and pr3 (not sure about mpo) looks very similar to the staph the antibodies from b cell recognised a little while back and therefore binds forgetting of course that its our own cells...and voila inflammation cycle kicks off again!.

But again finding a drug candidate to fit all wg cases is extremely difficult.

Love this discussion and would love to form a research and support group here in Australia. Problem is getting the funding to get this moving. Also a shame that drug clinical trials takes so long before coming onto market.

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[Alysia]

I understand very little from what you, great minds, wrote above.. you are so amazing ♡♡ I wonder if any of the hypothesis can be checked here among us - maybe something like a poll, comparing certain labs at given times of the illness ??

[Gab122]

Hi Marta, I'm late to this thread... New to this disease. I just got diagnosed 8/1/16. Not a month ago. Trying to understand it all and wondered about why B cells were being killed instead of ANCA. Alysia suggested I read some of your posts and I found this. (Thank you Alysia.) I was mistakenly thinking neutrophils were B cells but I now see they are both just types of WBC.

Am I correct in thinking that ANCA changes the neutrophils and that change somehow in turn causes B cells to attack the blood vessel walls? Can you explain it to me?

Prior to GPA treatment I was on 10 day pred taper plus antibiotic not sure if that skews labs. Before I started high pred and ritux my neutrophils were not super high (11) but my ANCA against PR3 was 1178(!) my sed rate got up to 93 and my crp was 126. I had a lung biopsy that further confirmed GPA. I'm on 60 pred and ritux. Being treated by Mass Genl RA (MGH) in Boston. (My symptoms started early May with ear problems.)

Alysia mentioned her neutrophils were really high but other markers down and (I think) you wondered if the neutrophils were the place to focus treating this disease. I love how your brain is churning its best in the middle of the night 😊 (Am I confusing your post with someone else's post?)

Could it be that there is a chain of events. Different bloodmarkers rising and falling in a sequence of events in an active disease? So depending on when we have a blood draw we may see a certain portion of that chain of events?

Maybe that could explain why sometimes ANCA correlate and sometimes it doesn't?

Would love any insight you and anyone has!
Thanks
Gab

[Gab122]

Hi Max D

You mentioned on page one of this thread: "Also, ANCA (the bad guys) are produced by plasma cells which are themselves produced by B-cells. ANCA are harmful because they make neutrophils clump into granulomas, essentially removing them from the blood stream and onto blood vessel walls."

So B cells-->plasma cell ---> ANCA ---> effects neutrophils to clump and attack vessel walls? Is that right? It's not B cells attacking walls?

Thanks for any help!
Gab

[Mark76]

Hi Gab

Thanks for your response and hopefully your treatment is going well. The pathogenicity of GPA is extremely complex and there are various models of what occurs. Most likely there is more than one process that occurs leadibg to disease. For example there is one model that suggests and research indicates a slight homology or similar structure of staphylococcus aureus bacteria carried in a high %of population abd proteinase 3 (pr3). So in this model some form of antigen eg bacteria and it is detected by cells called antigen presenting cells as they present antigen eg bacteria or viruses to other immune cells such as b cells. So when the b cells bind it recognises it and for unknown reasons (faulty gene silencing perhaps) recognises the antigen as being a self antigen eg pr3 or mpo. So the b cells then mature in the bone marrow and expand and are called plasma cells. So b cells have antibodies but they stay intact to the b cells whereas plasma cells are mature b cells and the antibodies are able to detach.
Ok now there are antibodies to pr3 or mpo floating around. At the same time neutrophils which reside near blood vessels as they are one of the first line of wbc to encounter a foreign object or antigen. So the antigen presentibg cells also release chemicals that stimulate neutrophils and recruit more and they also make pr3 and mpo inside the cells which when activated express pr3 and or mpo onto cell surface. The free antibodies released from plasma cells (anca) and also more b cells bind to the pr3 on neutrophils and this then through various chemical mechanisms cause the b cells to release chemicals including reactive oxygen species. These reactive oxygen species causes oxidative damage to the blood vessel walls and hence vasculitis.

Very simplified explanation but hope it gives some sort of explanation. Check out my website www.vasculitisoz.com and go to immune tab and it explains it more there

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[Gab122]

Wow! Thank you mark76!

That's the simplified explanation?! 🤔 I started to be able to follow along a bit the 2nd time I read it... I think if I sit down and draw it I'll better understand what you said tho.... My project for tomorrow. 👍😊

You mentioned this as one model of how the disease works. I'm assuming it's believed to be the most current consensus of the medical community? Or a front runner in any case?

I'm tempted to go back to school and get a graduate degree in Rhrumatology now. I'm only 49. 😏
I haven't been in school since 1989! 😳

I will check out your website! Thank you for the link!!

Almost 3 weeks in and my treatment has helped me feel somewhat better already. I have my 2nd infusion this Thursday. I am not on any pain meds for ear pain anymore. My biggest complaint currently is a cough and tight feeling in my lungs. The ct scan did show 3 granulomas (3+ cm in size) and two smaller nodules. So I'm guessing they aren't gone yet.

I know I'm VERY fortunate to not have my kidneys involved or damaged at all (though I read that only 20% present with renal involvement, 80% develop renal involvement) so I know I am not necessarily out of the woods with that.

I'm astonished that my c-ANCA to pr3 was 1178. What do you make of that? Any theory on why it was so high? I know ANCA is not always correlated with disease activity - yet they use it as part of making a diagnosis. I'm confused on its true importance. Any thoughts?

My RA last week said I'm "moderate to severe" when I asked him to label my disease. And yet I'm also most likely an early diagnosis. And I was on high pred dose and first infusion within a week of dx. (3 months of symptoms before dx) ~ Side note: I did have chest X-ray confirmed pneumonia twice last year but both became resolved symptomatically with antibiotics. Wondering now if GPA was "simmering" back then.

Thanks again for sharing your knowledge with this newbie.
Gabrielle

[Mark76]

You sound almost identical to me...diagnosed in jan but had blocked ear nose bleeds severe sinus pain and lung nodules in november. Lung biopsy proved gpa. Yes thankfully no renal involvement and detected early which is normally good. Mine too was moderate to severe. Believe it or not often the greater the severity the greater the effectiveness of treatment. Yes anca shows only slight correlation of disease activity however significant titre changes often shows when a flare is about to occur possibly. They are looking at better markers inclyding mettaloprotein and cd8 t cells believe it or not.

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[Gab122]

Hi Alysia,
Decided to reply to your message in one of the threads... In case you still have difficulties

My message to you was that I thought you might find this post interesting. I did.