Editorial response to Rituxin in journal...

[Palmyra]

Hey Crew,

I haven't been around much lately, but I am back! Happy New Year to all, and I wish everyone the gift of tranquility.

I suscribe to a google notification that alerts me any time a word/phrase comes up on the web. This morning's gift came in the form of a discussion in the editorial section of a scholarly journal that our Weg experts present, discuss and debate all things autoimmune.

I thought the discussion of interest, as it might explain why some continue to have symptoms in certain locations/organ systems despite having had Rituxan on board to calm most of the Weg beast. It appears B-cell depletion is more difficult in certain lymphatic areas or areas of reduced circulation. Makes sense!

http://ajrccm.atsjournals.org/content/173/7/815a.full.pdf


By the by, my daughter is currently fighting a highly unusual bacterial microbe that has invaded her sinuses, post Rituximab. She appears to be responding to round two of antibiotics after a culture and sensitivity test. Her next move is to find an infectious disease specialist to help avoid damaging infections while immunosuppressed. I will keep the group posted!

Again, best wishes to all!

~Knowledge is power. The lack of fear is peace.

[Al]

I read this report, Palmyra--thanks for sharing the link.

The upshot is that RTX may not be as effective for some types of WG as for others. Further, the current protocols may need some tweaking. Finally, the contributors suggest that, in some cases, a combination approach with an unspecified chemo drug (presumably CTX) might be the most efficacious. We'll see, I guess, how all this works out in the wash.

Al

[Sangye]

At my appt last July Dr Seo had mentioned the fact that rtx only affects the B cells which are in circulation-- a mere 10% of the B cells in the body. When I saw him a few weeks ago I asked if I could be having smoldering Wegs even with rtx, because I still have a lot of inflammatory pain and other symptoms. He didn't think so. In fact he was sure that wasn't the case. But I think I do. I think the rest of my B cells are still having quite the party and are staying up late with the Wegs dog.

But even if I'm right there's nothing we can do about it. I can't take ctx again, allergic to mtx, no cellcept with rtx. It would just be nice to have an explanation.

[me2]

Wow. Very interesting. Thanks to all for their input here. I have been dissapointed with my Rituxan results. My doctor acts like Rituxan takes care of everything but my experience is that I have smoldering WGs in the places where I have had the most activity and damage in the past. This all makes more sense to me now. Now if I could talk some sense into my doctor... ha.
So MY guess here would be that part of the picture might be that Rituxan would be most effective for people who have used it early on in their disease. They would not have so much damage, hiding places for the whacky B cells

Thank you also for sharing the Google tool. I have signed up and already gotten some interesting emails. It seems to work really well.

[drz]

At my appt last July Dr Seo had mentioned the fact that rtx only affects the B cells which are in circulation-- a mere 10% of the B cells in the body. When I saw him a few weeks ago I asked if I could be having smoldering Wegs even with rtx, because I still have a lot of inflammatory pain and other symptoms. He didn't think so. In fact he was sure that wasn't the case. But I think I do. I think the rest of my B cells are still having quite the party and are staying up late with the Wegs dog.

But even if I'm right there's nothing we can do about it. I can't take ctx again, allergic to mtx, no cellcept with rtx. It would just be nice to have an explanation.

You didn't mention azathioprine (Imuran) as an option. Has that been tried too or ruled out for other reasons?

[Al]

Wow. Very interesting. Thanks to all for their input here. I have been dissapointed with my Rituxan results. My doctor acts like Rituxan takes care of everything but my experience is that I have smoldering WGs in the places where I have had the most activity and damage in the past. This all makes more sense to me now. Now if I could talk some sense into my doctor... ha.
So MY guess here would be that part of the picture might be that Rituxan would be most effective for people who have used it early on in their disease. They would not have so much damage, hiding places for the whacky B cells....

Turns out, Kirk, that some forms of WG are apparently more amenable to RTX therapy than others. I am personally interested, as I have used up my lifetime quota of CTX, so the next step (if, knock on something arboreal) is likely RTX. Certain kinds of granulomas, for example, seem have somewhat less favorable outcomes than those, like me, whose disease is characterized more by the vasculitis than than by granulomatous lesions. But the research is really in the early stages; no one really knows the optimal RTX protocol for specific contexts.

Al

[Al]

At my appt last July Dr Seo had mentioned the fact that rtx only affects the B cells which are in circulation-- a mere 10% of the B cells in the body. When I saw him a few weeks ago I asked if I could be having smoldering Wegs even with rtx, because I still have a lot of inflammatory pain and other symptoms. He didn't think so. In fact he was sure that wasn't the case. But I think I do. I think the rest of my B cells are still having quite the party and are staying up late with the Wegs dog....

How much "partying" your B cells are up to, Sangye, can partially be measured by the ANCA test. How has that dog been behaving for you? Trouble is (or one trouble, anyway), is that there are other autoantibodies produced by certain B cells. The ANCA test doesn't look at them, but they can also cause grief. B cells are a pretty complicated bunch, and RTX, as you note, target only a small subset of them. Then again, with zero antibody production, we would be sitting ducks for a variety of infections.

Al

[Chris G]

At my appt last July Dr Seo had mentioned the fact that rtx only affects the B cells which are in circulation-- a mere 10% of the B cells in the body. When I saw him a few weeks ago I asked if I could be having smoldering Wegs even with rtx, because I still have a lot of inflammatory pain and other symptoms. He didn't think so. In fact he was sure that wasn't the case. But I think I do. I think the rest of my B cells are still having quite the party and are staying up late with the Wegs dog.

But even if I'm right there's nothing we can do about it. I can't take ctx again, allergic to mtx, no cellcept with rtx. It would just be nice to have an explanation.

Sangye - You say "no cellcelt with rtx" - what do you mean by this? They can't be taken together? I've had 2 rounds of rtx (on in May, and one in December), and I feel that I might still need another maintenance drug as a backup or support character, to the rtx. I can't take mtx or aza, and I guess that leaves me with only cellcept as an option. Would this be ruled out too for some reason? :sad:

My doc's ordered the 2nd round of rtx 6 months after the first - which seems to be standard protocol. But, the first round very obviously "wore off" a couple of weeks prior to my second round. Symptoms started returning slowly ie, night sweats, daily sinus headaches, sinus stuffiness, slight SOB, increased fatgue, etc. Now that I'm about a month post infusions, I'm feeling better, except for the ever present fatigue, nasal crusting, and occasional headache. I see my docs again in March, an I plan to tell them about the temporary setback which occurred in late November. I don' want it to happen again in the next 5 months, so I was going to ask them about cellcept.

[Sangye]

Sangye - You say "no cellcelt with rtx" - what do you mean by this? They can't be taken together?
Cellcept targets B cells just like rtx. I think it only kills the ones in circulation, like rtx.

[Sangye]

Wow. Very interesting. Thanks to all for their input here. I have been dissapointed with my Rituxan results. My doctor acts like Rituxan takes care of everything but my experience is that I have smoldering WGs in the places where I have had the most activity and damage in the past. This all makes more sense to me now. Now if I could talk some sense into my doctor... ha.
So MY guess here would be that part of the picture might be that Rituxan would be most effective for people who have used it early on in their disease. They would not have so much damage, hiding places for the whacky B cells

.
Rtx does a great job at stopping lung hemorrhage for me. It seemed to do a better job at controlling joint pain the first couple times I did it. But I am just like you, Kirk-- way too many symptoms even when the rtx is at its peak and the symptoms hit worst in its familiar partying places. Even though my B cells are still gone I'm having tons of active Wegs symptoms these days.

[Sangye]

How much "partying" your B cells are up to, Sangye, can partially be measured by the ANCA test. How has that dog been behaving for you? Trouble is (or one trouble, anyway), is that there are other autoantibodies produced by certain B cells. The ANCA test doesn't look at them, but they can also cause grief. B cells are a pretty complicated bunch, and RTX, as you note, target only a small subset of them. Then again, with zero antibody production, we would be sitting ducks for a variety of infections.

Al
Dr Seo doesn't even order an ANCA on me anymore because it's completely unreliable. The Wegs dog that lives at my house is a NINJA!

[Al]

Dr Seo doesn't even order an ANCA on me anymore because it's completely unreliable. The Wegs dog that lives at my house is a NINJA!

This made me giggle, though in a somewhat nervous way. I suspect that most of us feel like we are harboring NINJA against our will....

Al

[Palmyra]

Yep, so here we are with the refractory question....

My daughter had been diagnosed and treated with all flavors of drugs for Crohn's disease prior to Weg. Much more common (Crohn's), and much more research material related..... After refractory treatment, she developed
Weg (I suspect many drugs later, this scrambled her immune system into fragments beyond recognition). She previously had autoimmune reactions to imuran, humira and remicade. Does anyone see new drugs/devises coming around the bend? Not to bend anyone silly, but messing with the complexities of the immune system with all these fabulous biological agents has its long term affects, no?.

I am very interested in the immune response as well as new treatments. More on the humor sites Sange!

Cheers,
Jane

[Dirty Don]

Does anyone see new drugs/devises coming around the bend? Not to bend anyone silly, but messing with the complexities of the immune system with all these fabulous biological agents has its long term affects, no?.

As for new drugs, just read a couple of articles a few days ago on MS, which is classified as AI, but most likely isn't. The MS patient on stem cells has had MS for about 30 years, she couldn't walk...she can now. BUT, docs are working on stem cell applications for MS which may relate to WG and other AIs in the future.

And long term effects? Well, right now I'm into trading those effects off for feeling better and recovering as well as I can now...it's a choice I guess.

[drz]

Yep, so here we are with the refractory question....

My daughter had been diagnosed and treated with all flavors of drugs for Crohn's disease prior to Weg. Much more common (Crohn's), and much more research material related..... After refractory treatment, she developed
Weg (I suspect many drugs later, this scrambled her immune system into fragments beyond recognition). She previously had autoimmune reactions to imuran, humira and remicade. Does anyone see new drugs/devises coming around the bend? Not to bend anyone silly, but messing with the complexities of the immune system with all these fabulous biological agents has its long term affects, no?.

I am very interested in the immune response as well as new treatments. More on the humor sites Sange!

Cheers,
Jane

My wife has RTX for her lymphoma a couple years before I had it for Wegs. The oncologist at Mayo in Rochester told her yesterday they now have several new ways of treating lymphoma since 2009. I wonder if any of these treatments will be useful or helpful for us Weggies. I will ask next time I got to Mayo.

[Dirty Don]

I'm at doc on Monday, will put that on my list drz...well worth asking...seems there is a bit of research activity going on in that area...my methotrexate is one such drug...as long as it's been used, it really was for lymphomas...ours is just a lesser dosage for different reasons.

[Al]

Yep, so here we are with the refractory....Not to bend anyone silly, but messing with the complexities of the immune system with all these fabulous biological agents has its long term affects, no?.
You are surely right, Jane, that "messing with the complexities of the immune system with all these fabulous biological agents has its long term affects." Problem is, no one knows any better approach. So, if one side of the sword doesn't get you, the other side will; and if neither sides get you, it'll drops its point straight into your bean. I personally believe that, within a few decades, global suppression of the immune system will be a matter for the Dark Ages. However, this is 2012, and we live with what we have, for as long as we can. and manage our affairs as best we can--with a little help from our friends and families.

Concerning refractory cases, the only drug I am aware of that is approved for WG (at least, it is so approved in Europe) that I have not seen mentioned on the forum is gusperimus, also know as deoxispergualin. It works on T cell differentiation, so may deplete the T17 cells heavily involved with triggering pro-inflammatory cytokines. As it, like all of our drugs, suppresses parts of the immune system, it suffers from similar drawbacks to them--the increased risk of infection being chief among them.

New drugs are always possible, but are unlikely to come out of specifically WG reasearch. No pharmaceutical company is going to develop a product just for WG. There are some proposals for research using a C5 binder. C5 is protean of the complement system, and blocking it with Eculizumab, at least in lab animals, prevents glomerulonephritis, common in some forms of WG. One trouble is the drug it is hideously expensive (Soliris, the trade name of Eculizumab, has been called the world's most expensive drug, which is saying a lot!), and is sold for a completely different use. Getting approval for WG treatment would, even if pursued, take years. (True, doctors could prescribe it off-label, but how many insurers wold pony up that kind of cash for such a use?) Another suggestion is to bind the ANCA before they reach the target antigen's Fc recoptor. There are, in fact a few enzymes known to do this with certain IgG antibodies, but the holy grail would be an enzyme specific to subtype 3 antibodies. To my knowledge, no one knows what this might be.

It might be that drugs used for other autoimmune diseases could be useful for WG as well. The search for a common thread among autoimmune diseases is truly in its infancy, however. While I personally believe that this will be the most productive direction ultimately, there is, at present, little political will--or, indeed--public support, for the large expenditures necessary. On the other hand, to not go in this direction is also very costly, and will incur mounds of carcasses for the (as yet) undiagnosed to trip over.

The immune system is not often viewed as an organ unto itself, as it is far more amorphous and changing than, say, the liver or spleen. However, it is an "organ" in every other sense--and every bit as complicated as the brain, and it has a dedicated purpose: to promote homeostasis--that is, life regulation in a complex context. Indeed, as the brain is integral to the immune system, it can be viewed as an organelle of it! To mess with it is to, well, mess with it. Our meds are specifically designed to through a spanner into its molecular works. No wonder "stuff" happens. Whether good or bad or both is a matter of risk management.

Al

[Trudy]

Concerning refractory cases, the only drug I am aware of that is approved for WG (at least, it is so approved in Europe) that I have not seen mentioned on the forum is gusperimus, also know as deoxispergualin. It works on T cell differentiation, so may deplete the T17 cells heavily involved with triggering pro-inflammatory cytokines. As it, like all of our drugs, suppresses parts of the immune system, it suffers from similar drawbacks to them--the increased risk of infection being chief among them.

The immune system is not often viewed as an organ unto itself, as it is far more amorphous and changing than, say, the liver or spleen. However, it is an "organ" in every other sense--and every bit as complicated as the brain, and it has a dedicated purpose: to promote homeostasis--that is, life regulation in a complex context. Indeed, as the brain is integral to the immune system, it can be viewed as an organelle of it! To mess with it is to, well, mess with it. Our meds are specifically designed to through a spanner into its molecular works. No wonder "stuff" happens. Whether good or bad or both is a matter of risk management.

Al

Al, I am 'semi-quoting' you for my question. I found this all very interesting. I take Imuran. Do you happen to know what it is doing inside me? Since so far I have diminished lung and kidney function along with sinus, ear, and sometimes brain stem inflamation, I am wondering how effective Imuran or even Rituxin will be if they only target one cell type. So far my breathing is better, my kidney function is staying at 46%, but my sinus (and general head involvement) is the same at 3 months into treatment.

I have a question for those who have had Rituxin, but am going to start a new thread so it will be easier for guests that are researching to find. Please participate, if you can.

I thank you, Al, for the hours you must spend in research and then sharing with us.

Trudy

[Al]

...I take Imuran. Do you happen to know what it is doing inside me? Since so far I have diminished lung and kidney function along with sinus, ear, and sometimes brain stem inflamation, I am wondering how effective Imuran or even Rituxin will be if they only target one cell type....

Lymphocytes come in many flavors, Trudy. That is, immature B and T cells have not yet "differentiated"; mature cells have "chosen" a specialty. It is hard to know precisely why and how they come to make their "career" decision, but it has to do with the needs of the total organism, but directed by the local chemical environment, the signaling bits like cytokines and the already existing lymphocyte specialists. ANCA and other antibodies are produced by a subset of "manufacturing" B cells, but the whole process depends on many components and processes. For ANCA diseases, the current thinking is that there needs to be a kind of perfect (though evil) storm: heavy production of ANCA; heavy production of "granules": MPO or PR-3; "primed" neutrophils and monocytes (that is, cells that have de-granulated--the granules have been brought to the cell's surface); and a "cytokine storm", a vast army of chemical signaling molecules quickly called up, often in response to a real or perceived infection, but also, locally, to any perceived stress.

A therapeutic agent can try to interrupt any of the parts of this perfect storm. Cyclophosphamide (cytoxan) doesn't discriminate, but, rather, goes for the "kill 'em all" approach. (I take that expression from this famous story, dating to Pope Innocent III’s 13th century war against the Cathars of Languedoc. This is often referred to as the Albigensian Crusade. As the holy armies, under Arnaud Amaury, the Abbot of Cîteaux, closed in on Béziers, the townspeople of all stripes, reportedly some 20,000 in all, took refuge in the Cathedral. A commander is said to have thrown up his hands, asking the future Archbishop of Narbonne how to tell the believers from the heretics. The response: “Caedite eos. Novit enim Dominus qui sunteius.” [“Kill them all. God will know his own.”] Rituxan tries to slow down the production of ANCAs (and, of course, other antibodies, some of which can be quite useful for fighting infections). Imuaran (AZA, for azathioprine) is used in treatment for a large variety of autoimmune diseases. It iinhibits DNA synthesis. As lymphocytes reproduce very rapidly, AZA selectively tamps down the immune response. AZA is actually a precursor to the active drug that is synthesized by the body. In theory, this cuts down on the toxicity and provides better bio-availability. There are several possible short-term side effects, including nausea and digestive issues. The long-term side effects have been less studied, but, like with all our drugs, include some nasty possibilities which I won't bother to mention here. AZA is, these days, not considered a first-line "induction" drug, but rather a maintenance drug (though it it is still important at the early stages of organ transplant). In cases where it is not well tolerated, the option usually is CellCept (mycophenolate, or MMF), which typically has fewer side effects but is less preferred by the insurance companies because of the designer price. In all cases, you are indeed doing weird things to body chemistry, but the option is unthinkable.

As for the research, this has been a veritable voyage of discovery, visiting vast new worlds that I had not known existed, or, if I did, that there was so much that was interesting (and important) in them. It was also educational in another sense: I had to learn an entirely new language in order to make sense of the sacred medical texts. This process has given me a good deal of enjoyment, as I can now (and will) have, shall we say, a "lively dialog" with any doctor that tries to dumb down his or her message to me. And, I sincerely hope, can be put to good use by my forum family and other suferers.

Al