I know we've discussed steroid-sparing agents a bit in the past, but I can't recall if anyone has actually tried azathioprine?
RBH have suggested to me that I might like to try it to try to get my steroid dose down, as I'm running into increasing problems with steroid side effects. Methotrexate didn't seem to help me much (and MAY have contributed to me getting two episodes of VAP this year, but who knows!) and I can't take ciclosporin because my blood pressure is too high. I know there is less evidence for the use of azathioprine in asthma than there is for the other two, but I have heard ancedotally that some consultants find it useful.
Obviously I'll be doing some reading, but I wondered if anyone had any personal experience they could share?
I have no experience with azathioprine or steroids, however, based on my limited knowledge of the immune system and allergy I would offer the following comments.
It is my understanding that steroids work on the basis of reducing inflammation, thereby reducing the symptoms of asthma/allergy. However, one of the serious side effects of taking steroids long term is their immuno-suppressive characteristic which creates a window of vulnerability making the patient more susceptible to cyclic chest infections, etc.
It is also my understanding that taking immuno-suppressive meds affect the CD4/CD8 ratio (by increasing the ratio). Suppressing CD4 cells may be desirable, but care must be taken not to suppress the CD8 cells at the same time otherwise the opposite effect may happen, in that the CD8 cells are unable to dampen down CD4 activity and the result may be longer and more pronounced immunological reactions. Furthermore, the patient may well become immunocompromised.
I believe immunosuppressive meds (like azathioprine) have their uses but great caution will be required to ensure the health status of the patient is not negatively affected by these meds.
I would agree that stopping/minimising immunological reactions before they cause inflammation is the best way rather than treating the resulting inflammation with steroids, but I am not sure how this can be achieved. Allergists tend to talk of bolstering the immune system rather than suppressing the immune system. I believe its the symptoms (of allergy) that should be suppressed, rather than the immune system.
I hope this helps a wee bit.
Derek
EmH - when I saw the endo the other week he is speaking to resp drs to get me onto this drug too but I dont know ought about it sorry.
Em, ive had both methotrexate and azathioprine. Once on the right dose of metho i found it worked as in i was better but it didnt get my steroids down nuch, then my lfts went sky high so it wes stopped. Then earlier this year i was put on azathioprine 50mgs to start, no difference, increased to 100ngs and did get steroids down to 27.5mgs ( not been bbelow 40mgs for 2yrs) so was working but then hey guess what lfs up shoot again!! Local costa stopped when had pnumonia as you apparently cant take with severe infections? have left off till see Rob at Wythenshawe on wed as he initiated it. So will let you know whta happens now? But even without getting steoids down i found it helped as an add on.
You just need to be carefull with ;iver, but you know the things to loook out for and if its somewhere like the RBH thats initiating it thery know how regularly to check bloods and when to intervene.
Hope this helps
love andrea xxx
Hi Em, I don't have any experience of this drug, though you know I'm considering methotrexate atm. My cons has said, as you did in your post, that there's little evidence for azathioprine's effectiveness in asthma, but if you can't take methotrexate or ciclosporin then I guess it might be worth a try. My cons said that the drug with the best record for steroid-sparing is gold, but won't put me on it because of the high risk of toxicity, but it may be worth you flagging up the idea of this with the docs at RBH. Just a thought.
Becky.
Thanks everyone for the replies.
Derek, I totally agree that what we need in asthma is an immunomodulatory drug that will act on the exact immunological or inflammatory cell imbalance that is causing the problem (I guess montelukast and Xolair are beginnings at this approach). I think at the moment though we simply don't know enough about the underlying imbalances (which are going to be different in different people) or about the differing effects of different drugs - so we're stuck with using the sledge-hammers of steroids and immunosupressants. You are right, they are a very double-edged sword - my consultant thinks that the two episodes of venilator-associated pneumonia I've had this year may have been due to immunosuppression from being on pred and methotrexate. I guess to me it makes sense to keep trying different immunosupressants though - since they all affect the immune system in slightly different ways, and we don't know exactly what the underlying abnormality is, maybe I'll hit on one that does the trick without causing too much immunosuppression. One thing's for sure, I need to reduce my pred somehow, steroids have such a broad and mulit-factorial effect on the immune system, not to mention the other side effects I'm getting like diabetes (itself an immunosuppressing disease!) and hypertension.
BeckyG - gold, hey? Well, I always said I had expensive tastes! Actually, I'd never heard of this, but somewhat to my surprise there are a couple of papers in the literature. I will have to investigate, although from a toxicity and mode of delivery point of view I think azathioprine is going to win.
Well, Donna, Andrea, BeckyG, let me know how you get on, and we will return in a few months for Adventures with Steroid-Sparing Agents, Part Deux!
Myself, I think I might just give azathioprine a go - well, that's today's plan, I'll probably change my mind again tomorrow!
Thanks again all
Em H
EmH,
I came across the following (minor) statement about azathioprine which you probably will know, but I decided to post just in case:
Together with corticosteroids, the purine antagonist azathioprine, was the drug that first made organ transplantation possible. This drug impairs both T and B cell function, and myelosuppression is common (TenBerge and Schellekens, 1983).
The above is an extract from Fungal Infection in the Compromised Patient by DW Warnock & MD Richardson. This is a very interesting medical book which provides evidence of acquired immunosuppression which often leads to respiratory fungal infections. And as you know, respiratory infections cause/exacerbate asthma.
Apparently, functional T cell defects have been detected in a large number of patients with fungal infection. Various investigations have helped establish that T cells, in conjunction with MN phagocytic cells, have an important role in host protection against most, if not all, fungal infections.
Treatment with corticosteroids leads to a profound, but transient reduction in the number of circulating T cells; the number of B cells is also reduced, but to a lesser extent. Although corticosteroids do not abolish lymphokine production by activated T cells, the response of macrophages to these mediators is often reduced or abolished. The production of a number of macrophage products is also inhibited and this will affect T cell function.
On these boards there appears to be compelling anecdotal evidence that supports the view that many asthmatics suffer exacerbations due to yeasts, moulds and spores. Now, in my opinion, if these same asthmatics take (long term) immunosuppressive meds like prednisolone or azathioprine then the risk of developing respiratory fungal infections must increase considerably. The never ending cycle of respiratory infections in asthmatics seen on these boards seems much too common to be a co-incidental.
Derek
Deek,
I agree with your post relating fungal infections to immune suppressants but for some (myself included) immune suppressants are the only option and for me anyway the only thing the stops me slipping over the edge completely. I believe without them I wouldn't be here and I think some others on this board would say that too. For me the risk of severe life threatening symptoms out weighs that of fungal infections. Of course I'm not saying thats the same for everyone.
Tks xxx
Derek, I agree with everything you are saying re the harm that taking immunosuppressive drugs can cause.
But…
Asthma is generally regarded as a Th2 type ‘disorder’ especially when associated with atopy,
However as asthma becomes more chronic and severe it adopts additional characteristics…
For example corticosteroid refractoriness – in plain English speak – is resistant to control by taking oral corticosteroids – step 4 - in asthma goals, the phrase which, in my humble personal opinion, should be changed to ‘standards’ for ALL people who suffer from asthma, whatever their diagnosed status. The ball is then put back into the court it belongs. But I’m digressing.
Severe uncontrolled asthma – after all standard medication has been adhered to, and is unsuccessful - is suggestive of an altered inflammatory profile towards a Th1 response.
Hence the development of ‘steroid sparing’ therapies such as azathioprine and similar.
Mia
dear Emily, I don't know a great deal about Azathioprine. But i thought you might like to know about the trial i am on. It is for a new treatment to help asthmatics reduce their steroid intake, which is why I was recommended for it.
It is bronchial Thermoplasty, basically they microwave your lungs with an attachment to a bronchiscope, to reduce the smooth muscle in your lungs, and therefore to stop it constricting so much. Obviously it is not licensed yet, and I don't know if I had the treatment or not. But the chief consultant says that the trial has gone so well world wide that they have stopped recruiting.
Although I am not as severe asthmatic as you, (mine is labled moderate to severe, not well controlled by inhaled steroids). You might like to know that a previous trial for this treatment was done at the RBH by doctor Shah with 10 very severe asthmatics. According to what I was told all who recieved the treatment have had benefit from it.
Anyway as you are a doctor you might be able to get some more info from Dr. Shah as to whether this treatment could posssibly help you in the future. His e.mail is (removed by passing moderator - please use PM system to exchange contact details, thanks!!)
I do hope that you manage to get things a bit stablised, i am not sure that this will help, but prehaps there is hope for the future. I too am trying to reduce steroids before they reck my health, but it is hard when they also keep you alive as well.
Best
RI
Tks, I whole heartedly agree with your comments.
Mia,
I liked EmH’s very fitting analogy about immunosuppressive meds; “the sledge hammer effectâ€. I think this really sums up the effect of these meds on T-cells as I don’t think it is possible for immunosuppressive drugs to differentiate/modulate between CD4 T-cell subsets Th1 and Th2.
I have however, read that cyclosporin is a more selective immunosuppressant because its main site of action is the CD4 T helper-inducer cell population; it has no direct effects on B cells or MN or PMH phagocyctic cells (Cohen, et al., 1984; Kim & Perfect, 1989), although cyclosporin still does not appear to differentiate between Th1 & Th2 cells. If you are aware of any papers that do confirm immunosuppressive meds can differentiate between Th1 & Th2 then I would be grateful if you could post a link so that I can read further on this.
My comments about immunosuppression and its association with fungal infections are not really specific to asthma, albeit that respiratory fungal infections often lead to/exacerbate asthma. I was just trying to demonstrate that a causal link between immunosuppression and respiratory fungal infections appears to be a real threat to asthmatics who take long term courses of immunosuppressive meds like azathioprine, methotrexate and prednisolone.
With regard to your comment about the development of ‘steroid sparing’ therapies, I think it would be more correct to say that the use of immunosuppressive meds like azathioprine is (in most cases) simply the last resort, the last ‘tool’ in the box. The one that the cons turn to when steroids like prednisolone have already wrecked untold havoc on adrenal function. I also believe that this decision (to use immunosuppressants under these circumstances) has little to do with the suggestion of an altered inflammatory profile towards a Th1 response. I think when the cons start suggesting using immunosuppressive meds things are already well down the slippery slope and the focus has moved to damage limitation rather than investigating another possible route of treatment.
Derek
(OK have finished lots of marking and am SO looking forward to a sort of holiday…)
Derek,
Like EmH and yourself I’m in total agreement about the ‘sledgehammer’ – or even engineer’s hammer! - effects of many if not nearly all immunosuppressive drugs. (Have often used this analogy when describing the effects of pred many AUK post moons ago now).
And yes, there is a real risk of respiratory fungal infections and TB in patients when taking these sorts of immunosuppressants.
However as you have already indicated, there are some immunosuppressive drugs that could be described as being a little more selective, and that can mean the difference between ‘slipping over the edge’ -THANK YOU Tks xxx - for your pertinent comment – or, maintaining some sort of control and hopefully improvement in lung function.
Like other organs in the body, the lungs CAN start to repair themselves from prolonged triggers and subsequent damaging inflammatory processes. Some of the immunosuppressive meds – carefully prescribed and used - could allow that window of opportunity to occur, particularly as we seem to be moving to more individualised treatments… thank goodness.
One or two links in particular that describe steroid sparing treatments and which can be categorised as immunosuppressant drugs that could focus upon an altered inflammatory profile towards a Th1-type response are:-
(Ref 14 might be of personal interest to you Derek and… Katharine?) Ref 39 is of interest to those whose asthma is severe and chronic.
Allergology International(2004)53: 47–54
Doctors and researchers seem unable to offer any sort of overarching ‘one size fits all’ asthma treatment/medication. We are all so different in our responses to standard and ‘out of the box’ medication for all categories of asthma let alone our reaction to documented side effects.
I like your toolbox metaphor Derek, but how about not calling it the ‘last tool in the box’ rather, the same tool used to fix different problems?
Haven’t you ever used a Phillips screwdriver when you should have used a Posidrive? Usually works!
Mia
sorry mia can't find link what is it under got website but then stuck?
Thanks for the links Mia very interesting reading.
Katherine, there is a space in the link (the usual AUK glitch when adding web links). There appears to be a space in 'allergy', closing the space should do the trick!
Hi Mia,
Thanks for your reply and useful link.
I am trying to stay clear from debating immunological mechanisms in asthma, simply because my comments are relative to respiratory fungal infections only.
However, if I may pick your G-cells (grey cells - LOL). I note from your recent (and previous) posts that you do not appear to acknowledge the roll of CD8 suppressor cells in immune system regulation, or for that matter the importance of the CD4/CD8 ratio, particulary since it is widely recognised that in acquired immunological dysfunction and viruses that altering the CD4/CD8 ratio will have serious impact on the immune system ranging from immunocompromised at one end of the spectrum to autoimmune disease at the other.
Your further thought on this would be much appreciated.
Derek
*reaches for the dictionary* :-\
Any chance of someone explaining all this in easy to understand terms please. My son will be starting this drug in a couple of weeks so am interested in all available info.
thanks
Hi Derek, and everyone else,
Am definitely on holiday now! Yay!
Have been using the old grey cells not to mention old 'A' level Biology textbooks (Got an 'A' in this subject a trillion years ago , although Maths and Chem was dire! LOL)
Correct me if I’m wrong –doctors and Derek please! – it is my understanding that T cells play a key role in the initiation, maintenance and control of the immune system.
Specific groups of T cells include cytotoxic T cells, (kill truly, madly, deeply ‘bad guy’ including cancer cells amongst others), suppressor T cells, (cells that moderate the immune response) and helper T cells, Th2 I think? (vital to the immune response in that they stimulate cell-mediated and antibody-mediated immunity).
CD8markers are found on cytotoxic T cells and suppressor T cells and are commonly called CD8 T cells.
CD4 markers are found on helper T cells and are commonly called CD4 T cells
(CD stands for ‘cluster of differentiation’ –markers- and is a membrane protein.) The membrane structure is extremely important because it determines whether or not a T cell will respond to an antigen – a substance which has the ability to provoke an immune response.
I won’t even attempt to describe CD3 receptors – which all T cells have in their membranes,- just to say that that CD8 and CD4 markers are bound to the CD3 receptor complex which in turn ultimately activates the T cell. Bit like the opposites attract response like you get with magnets.
Before I forget, B cells are also important because these cells differentiate into anti-body producing plasma cells and work with helper T cells to amplify antibody production which in turn stimulates the inflammatory response. If the balance of activities and communication is altered in these cells you get the autoimmune diseases occurring like rheumatoid arthritis, SLE and so on.
A less jargonistic explanation of the above could be described by the following example of the importance attached to the CD8 T cell/ CD4 T cell ratio….
Most people are aware that one of the major problems associated with organ transplantation is that of graft rejection. In graft rejection T cells are activated by contact with the foreign protein on cell membranes in donated tissue. The cytotoxic T cells that develop then attack and destroy the foreign cells. Obviously we don’t want this to happen hence the development of immunosuppressive drugs to reduce the sensitivity of the immune system.
In the early days of immunosuppressant treatment, to try and combat graft rejection, drugs like prednisolone were prescribed, because, as we all know it has anti-inflammatory effects that reduce the number of circulating white blood cells and depresses the immune system. However this sort of drug causes undesirable side effects in other parts of the body and, as importantly leaves an already weakened person even more vulnerable to everyday viruses and pathogens that a ‘normal’ person’s immune system will easily overcome.
It wasn’t until further research brought about a greater understanding of the communication among T cells, B cells and macrophages -cells that ‘eat’ bad guy cells – that more ‘selective’ immunosuppressive drugs were developed, for example Cyclosporin. This drug suppesses all aspects of the immune system by primarily suppressing helper T cell activity, whilst leaving suppressor T cells relatively unaffected.
Back to your original ‘further thoughts’ question Derek….
I would argue that maintaining the ratio of CD4 to CD8cells is of crucial importance for the immune system as a whole, but by using more selective immunosuppressant drugs such as cyclosporine, azathioprine and similar, the focus shifts towards the communication between these cells - then subsequent treatment - rather than the destruction of key immunonological defence systems, aka those T cells.
Mia
(My brain hurts!)
Julie,
Sorry for the confusion. It looks like me and Mia have veered a wee bit off topic with our high browed/wigged immunological discussions.
The best advice I would offer (being a non-medic), is that if the con suggests Azathioprine for Sean then I think this would be the best course of treatment, regardless of my personal views posted/shared on AUK.
I have posted a new thread entitled 'A Basic Guide to Immunology' which may go some way to explain the various immunological mechanisms. If you need further clarification, please pm me, I would be more than happy to help.
Derek
Well the high browed/wigged convo was fascinating , well it would have been if I had understood beyond receptor cells
As per norm when Sean prescribed anything I read about the said drug for hours online but you can never have too much info!
j x
Hi Julie,
Have tried to find some more info about azathioprine, but like others say, there doesn't seem to be much out there in relation to asthma.
But I believe you should trust your con because he must have the best interests, clinical expertise and knowledge concerning the most appropriate treatment for Sean.
As for understanding 'receptors' and beyond, - LOL. Me too! Try getting hold of some AS/A2 Biology or Human Biology textbooks. Explanations are usually written in almost plain English!
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