Medication weaning in prednisone - IMPA

[mon67]

Hello everyone, and Jo in particular

I have been going through this forum, cos my 6 years old mixed breed, Ripley, was diagnosed IMPA in January.
Unfortunately she also had endocarditis probably because she was given antibiotics (for no reason actually) that she resulted allergic too.
Also, we are not sure if she responded to Prednisone as immuno-soppressor, because she had endocarditis at the same time and because of the huge muscle waste she had, she was put on 1mg per kilo after two weeks only.

Basically now she is doing well on Prednisone 15mg in totale (she weighs 17k) and we started Cyclosporine two weeks ago at a lower dosage (for fear of upset stomach) 5 mg per kilo per day.
When we weaned Prednisone to 10mg per day, she started to limp again, and her blood test were not as good as before so we put her on 15mg again, and now we are trying 150 mg totale of cyclosporine. Although another vet told us that cyclosporine should be given at high doses to begin with, higher than the efficient threshold actually.

Unfortunately our vet is not specialized for this lousy condition, and we are having a hard time to find specialized vets in Italy.

I have read another post from Jo where she claims: "The problem you may have is if the leflunomide isn't having the desired effect then just putting Cali on pred @ 1mg/kg/24hrs will not be sufficient to suppress the immune system enough for it to return to normal function, without circulating autoantibodies that are targeted against the synovial fluid in the joints, and therefore it might be only tempered so when you get to a low does the disease becomes active again because true remission hasn't been achieved."

I haven't read anything like that in any other study online, so I would really appreciate if you could tell me where did you get this information, so that I can share it with my vet, and convince her that as of now Ripley is not doing any immuno-soppressor at all and she actually did it only for two weeks at the beginning, and that is why, maybe the reason why she has been relapsing.

Thanks for the help and for any other info suggestions any of you might have

Monica

[Jo CIMDA]

Hi Monica

I wish I could give you some wonderful reliable source but I can't.   It is no secret that the most tried and tested, most efficacious drug for immunosuppression is prednisolone - but it has to be given in immunosuppressive doses and the duration has to be long enough to have the desired effect on the immune system resulting in remission. If it does not meet this criteria then it won't work. 

Very rarely will any other solitary immunosuppressive drug have this effect and this is why it is common practice to use prednisolone in immunosuppressive doses, with or without a combination drug, for the treatment of inflammatory AI disease. The vets know it works exceptionally well, and rapidly, and if the immune system is significantly suppressed, thereby removing the aggressor - the targeted and attacking immune cells, the immune system then has the opportunity to return to normal and achieve remission. 

The vets are still learning about the effectiveness, and also the long term advantages and disadvantages, of these relatively new immunosuppressive drugs. It will be some years yet before the true picture is clear, and the same is true in human medicine too. Most of these new drugs are not licenced for animal use anyway and the information comes from human clinical trials and practice, and this is often why the dosages and duration is not yet truly established for animals and it is known that different species respond differently to the same drug.   Many of the dogs receiving these newer immunosuppressive drugs today will contribute to the knowledge and long term management of immune mediated disease in future. 

The main reason for using a combination of prednisolone and other immunosuppressive drugs is to achieve immunosuppression by a different pathway to steroids, or shared pathways (combination therapy), which lessen the side effects of prednisolone.  The objective is to reduce the steroids when the combination drug has reached its full potential, so the mainstay of treatment then becomes the other immunosuppressive drug and not steroids.   Sometimes it works and sometimes it doesn't.   Other considerations when to use a combination drug is the presence of a previously diagnosed disease that would compromise a dog's recovery such as the endocarditis that Ripley had or perhaps an overwhelming infection, recent surgery,  or particularly when treating an immune mediated muscle disease where the weakening muscle side effects of the preds could worsen the situation. 

The sentence you refer to has one big caveat but a small word in the sentence and that is "if  'if the leflunomide isn't having the desired effect'.     The trials done on these new immunosuppressive drugs all say, a proportion of dogs on 'this' drug received remission, so how do you know if this drug is having the desired effect unless remission is achieved?   

Take a look at these papers.  They give a better understanding of immunosuppressive treatment. 

http://todaysveterinarypractice.navc.com/wp-content/uploads/2016/06/T1403F04.pdf

https://www.vettimes.co.uk/article/immune-mediated-diseases

IMPA is not a life threatening AI disease and long term remission can be achieved and that is not unrealistic.  As with SRMA, IMPA responds very well to immunosuppressive doses of prednisolone as long as a good protocol, such as Michael Day's protocol, is used as a guide.  If your vet feels Ripley cannot have immunosuppressive doses of prednisolone for the desired length of time then you have no choice but to include another immunosuppressive drug and Cyclosporin has been used for longer than many of the newer combination drugs that are used to treat AI disease, so it might be that you have to get the combination dose of both drugs correct in order to achieve remission or change from Cyclosporin to one of the other immunosuppressive drugs.  Cyclosporin is licenced for atopic skin disease in dogs but not as an immunosuppressant, although it is widely and commonly used as an immunosuppressant. 

Ripley has been on pred since January, even if it has been in an 'anti-inflammatory' dose and not an immunosuppressive dose  there will still be a build up of steroid within her body which might mean that she isn't able to have a full dose of pred at this time.  It depends on the drug induced side effects she is displaying and only you and your vet can decide if this is a factor or not. 

Come back to me with any other questions and I will do my best to answer them.   

Jo
 

[mon67]

Hi Jo

and thanks for your answer and information.

As I have said, Ripley is much better with 15 mg of Prednisone, but not 100% yet. Maybe it's because it's not at immunosuppressive doses but, as said, she has started Pred on January 20th, and our vet, and us, think we can't really give her higher doses because of her muscle wasting.

In a week the cyclosporine should be full effect and we'll see if she gets better and can finally weane Pred.
I am worried on what other options we have if this is not the case. Ripley should really get off the Pred for a while, but if Cyclosporine does not work we won't be able to do that.

Any suggestion? How long can we still keep her on 1mg/kg of Pred a day?

Thanks
Monica

[Jo CIMDA]

Hi Monica

I do hope this works for Ripley.  If the Cyclosporin doesn't suit her or there is the need to introduce another immunosuppressive drug, I would be inclined to try Azathioprine.  This is a tried and tested drug and has been used in veterinary medicine as a 'combination' immunosuppressive for over 20 years.  It is not used as much these days because these other newer drugs have come on the market and seem to be the trend (or the drug companies are pushing their use)  but that doesn't mean Aza isn't up to the job. 

How long can you keep Ripley on 1mg/kg/per day?  How long is a piece of string?   This is impossible to say because individual dogs will respond differently to preds and also some dogs can tolerate the side effects much better than others.  Smaller dogs often amaze me how they can tolerate the side effect abuse of preds, so all you can do is every day when you wake up, take a look at Ripley and if she is fine the you get on with the day but as soon as you start to see any of the unacceptable side effects (that I'm sure you know what they are, if you don't they are on the website) then you must respond and start to lower the dose.  It is a fine balance between the good it does and the side effects.  The dose Ripley is on is half an immunosuppressive dose (it is the usual dose given as an anti-inflammatory) so although the steroid effect can build up it is only half the potency of the usual immunosuppressive dose given to treat AI disease.  A dog on prednisolone should be regularly monitored by the vet for side effects.

Jo

[mon67]

Hi Jo

it looks like Cyclosporine is not working until now.
Ripley has been on 150mg a day for 15 days now, but she had what looks like a relapse two days ago.
She is very lethargic, reluctant to stand, stiff and I think she has pain in her neck and hip as well (she cried when I touched her there). We have done blood test today, I am waiting to see what CPR value is tomorrow.

I am a bit at loss. She has been on 15mg of Pred per day since January 25th. So 3 months! I think we should try and give her the immunosuppressive dose of Pred, but the vet feels it could not be beneficial for her because of her muscle wasting. In someway she's right, I think Ripley never really recovered in full even because of her muscle waste, it's not easy to get strong again with almost no muscle. Also, she could get tendons and bone problems, that I know.

The vet wants to try Azathioprine, but that would still take a few days to kick in, and Ripley is really miserable now. 
We are trying with the pain killer, but that could work on the pain but not on the inflammation.

I don't know if we should give Cyclosporine more time to kick in, or if we should raise the Pred and lose all the rest, or switch to Azathioprine.

Anyone has a good story to share? It's been 3 months now, and Ripley never really got back 100% not even for one day! Best she could get was 70%, but only for a few days.

Thanks for anyone's help. I would really appreciate it
Monica

[Jo CIMDA]

Hi Monica

I am so sorry to hear that Ripley is not so good.

Because she has been on preds since January she may have more advanced Cushing's problems if the pred dose is increased to a full immunosuppressive dose, but only you and you vet can decide if this is a risk by looking at her clinical signs and blood results.  Personally, if preds can be tolerated and safely used then it is the better option, and unlike other immunosuppressive drugs it has an immediate effect. 

Cyclosporin isn't always successful in treating AI disease in dogs and it can take longer than they say before you start to see positive signs of recovery. Also some dogs can't tolerate the side effects.

I feel your options are:

Azathioprine is very slow to take effect.  It does not start to have any impact at all until at least ten days and it can take 6-8 weeks before the full potential is seen.  I think Aza is a good immunosuppressive drug when it is used along side pred, but it should be started at the beginning of treatment, or soon after, as opposed to when immediate immunosuppression is needed.  So this, for me, wouldn't be a good option at this time.

How about leflunomide or mycophenolate?   I can't remember if Ripley has been on either of these drugs before but they certainly kick in much sooner than Azathioprine, and usually has some effect within 4+ days.

If the pain is due to a relapse of IMPA, or as her neck is involved, it sounds a bit like SRMA, Tramadol or any other pain killer tablet won't correct the problem and it might cause more, but different, side effects. It might lessen the pain but it won't rid her of the pain and the AI disease will only get worse.  When a dog is being treated with various drugs it is very difficult to differentiate between the adverse effects of individual drugs and the clinical signs of the disease, and ultimately one doesn't' know what is causing what - if you see what I mean.

Can you get Ripley to a specialist?   From horrible symptoms  you describe, she needs to be clinically assessed and medications reviewed. 

After an assessment, if at all possible,  your best option would be raising the preds to an immunosuppressive dose to see if this improves the clinical signs.  Typically if the pain is due to a relapse of the AI disease the I would expect to see an improvement within hours.  Alternatively a shot of Dexamethasone is a really good test to see if an immunosuppressive dose of preds is the way to go.   Sometimes you have to bite the bullet and make a brave decision to treat but only you and your vet can decide this. 

One thing for sure you have to start a different treatment regime because the current one isn't working.   15mg of preds a day will not control an AI disease in a 17kg dog. For an immunosuppressive dose it will have to be 35mg preds a day (1mg/kg/12hours).

I do hope you can get a good treatment plan together today.  The sooner the better.

Jo

[mon67]

Thanks Jo for your feedback.

Ripley has good blood test results, except for PCR which is now 1.10.
RBC and WBC count are, extraordinarily, in the norm. The other two results that are a bit off are platelet (508) and ALP (165), but nothing terrible, after 3 months of Pred.
Yesterday I have tried to raise Pred to 20mg a day, it didn't work at all.
She is still in pain. The pain is in the bones, and the neck pain is gone (pain migrates a lot).
I have taken off the pain killer, but maybe I should give it to her to help her a bit.

Unfortunately it looks like there aren't any good specialists near where I live, but I am still searching (I am from Italy).

Also I am wondering if the cyclosporine dosage is right. One doctor I have contacted told me that cyclosporine should be given at very high doses to make an impact. But in the past few days I have seen a wart on Ripley's tongue, and if it's a papilloma virus caused by cyclosporine in only a month, I wouldn't feel too confident in raising the cyclosporine.

Leflumonide we don't have it in Italy for dogs, so I am trying to convince the vets to use the human Leflumonide. Do you have any feedback with this at all?
Mycophenolate I was told it's probably one of the most aggressive drugs, but if nothing else available, I think I will have to try.

I will probably see the doctor who suggested high doses of cyclosporine, because he worked on a follow up study with a dog with SLE giving him high dosage of cyclosporine, and the dog died at 16 of old age, which is amazing I think. I will let you know what he says.

Thanks
Monica

[Jo CIMDA]

Hi  Monica

Mycophenolate and leflunomide are all human drugs, neither are licenced for animal use.  I have known leflunomide to have good effects when treating IMPA.  Mycophenolate is a newer drug in veterinary medicine and the reports are still mixed but it promises to be effective.  I suppose a lot depends on the individual and what condition it being treated. 

Sometimes when a dog's immune system is very suppressed they get mouth ulcers and ulcers on the tongue.  How about adding natural Vitamin E and essential fatty acids to help the skin? 

Immunosuppressive dose of Cyclosporin:  Empirical dosages generally range from 3-6mg/kg twice a day; or 5-7.5mg/kg/once  a day.  Plumb's Veterinary Drug Handbook, 8th Edition. 

I hope you find the answer very soon.

Jo

[mon67]

Hello Jo

Ripley got a bit worse on Friday so we went to a vet who gave her a shot of Dexamethasone, she improved, she is not completely well, but definitely better (she can stand and walk).

We have also got the results of the cyclosporine dosage, and it's below the effective range, so she still hasn't been receiving an immunosuppressive treatment at all.

The new vet suggested to have three shots of Dexamethasone (so three days) and then switch to Prednisone for a while and introducing the Cyclosporine at the highest dosage, so we can take her off the Prednisone when the time comes.
I am wondering now, if the cyclosporine takes at least 15 days to kick in, shall we give Ripley 2 weeks of 35 mg Prednisone and 300mg Cyclosporine?
And then, how should we taper the Pred? I was thinking that since she is on Cyclosporine, we might be going a little bit faster than the standard protocol, as Cyclosporine should work on keeping her immune system at bay.

What do you think?
Thanks for all your precious suggestion, you are really helping me and Ripley

Monica

[Jo CIMDA]

Hi Monica

I am so pleased Ripley is doing better. 

The dexamethasone test indicates the way you should go.    Usually, if the response is good then the glucocorticoid drug regimen is continued 48 hours after the injection of dex, by giving oral prednisolone at 1mg/kg/12hours.

Dexamethasone is a long acting injectable glucocorticoid that has a duration of 48-72 hours.    I don't really see the point in giving successive shots of dex when you are going to continue immunosuppressive treatment with prednisolone anyway.  I suppose it depends on the dose Ripley has received.  The idea is to see the response,  and if it is good then you switch to immunosuppressive doses of prednisolone tablets. 

If you look at the quote from Plumb's Veterinary Drug Handbook 8th Edition,  the maximum recommended dose of Cyclosporin for immunosuppression is: 

Immunosuppressive dose of Cyclosporin:  Empirical dosages generally range from 3-6mg/kg twice a day; or 5-7.5mg/kg/once  a day.   

The highest dose recommended is 6mg twice a day, so for dog weighing 17kg then the maximum recommended daily dose is 6mg twice a day equalling a daily dose of 204mg. 

Ripley already has some build up of Cyclosporin so I can't see why 200mg a day of Cyclosporin shouldn't be enough, but you have to take this up with the vet.    Doubling the current dose of Cyclosporin is a huge leap. 

Whether it be preds or any other medicine, more isn't necessarily better and often the side effects become a problem. The mainstay of treatment will be the immunosuppressive dose of preds and after two weeks it is hoped that the Cyclosporin will have good effect so the preds can be successfully lowered and take over the primary role of immunosuppression. 

You must see how Ripley is coping with this new drug regimen before you can decide how to lower the preds.  Ideally, following a drug regimen such as the one written by  Prof. Michael J Day  is best but you must see how Ripley is coping with the preds and go by her clinical signs.  If she is coping well then you may be able to follow the protocol but if she is not coping with the pred dose then you may have to lower it sooner.  It has to be assessed  on a daily  basis and adjust as necessary. 

Please make sure Ripley is on a gastroprotectant.

Good luck with this new regimen.

Jo

[mon67]

Hello Jo

Ripley did get better, but she is not well, I could say she looks like slowly recovering.
Her paws are still warm, and therefore inflamed, and she is lame mainly in the morning. She usually lies on her couch, even if she stands up more often than before.

Anyway, I have just found out, to my horror, that the shot the vet gave her was 1.5 mg, not immunosuppressive dose but just anti-inflammatory, that's why maybe he decided to do it for three days! So, all in all Ripley is very well I can say.
I will start tomorrow with Prednisone at 35 mg again (which I gave to her on Tuesday, when she actually did get better) and see what happens.

I will talk with another vet tomorrow, we saw him a while ago when Ripley was getting better, and maybe he can help us more.
We need someone who is ready to learn and study things they don't know, because this is a very rare condition, so not all the vets are prepared.

This is really wearing me out, I would like so much to help my lovely dog, but there's only so much I can do

I will keep you posted.
Thanks
monica 

[Jo CIMDA]

Hello Monica

Ripley needs to show a good response and I hope this will improve over the next couple of days. 

It is difficult for me to comment on your vet's experience, and perhaps he has a point.

You know the immunosuppressive dose of Cyclosporin given in the Plumb's Veterinary Drug Handbook.  I can't challenge your vet when he has successfully treated a dog with 50mg/kg per day.  The dog was due to be euthanized so there was nothing to be lost by trying a large dose - and it worked!

The relative glucocorticoid activity of dexamethasone is 6 times greater than prednisolone, and the duration of biological effect is: 
Prednisolone 12-36 hrs and Dexamethasone 36-72 hours (Canine Medicine and Therapeutics by Neil Gorman) so I suppose it depends on what dose of Dex your vet is giving.

Have a thorough discussion with this other vet tomorrow and come up with the best plan for Ripley.  All dogs are individuals and must be treated as such.  What works for one won't necessarily work for another.  Also, the vet must take into consideration the blood results the response to therapy and most importantly the side effects of the drugs that you are seeing at that time.

All the best and good luck with the vet. 

Jo

[mon67]

Hi Jo

we have now trying with Pred at 35mg a day (20mg in the morning and 15mg in the evening) and 200mg a day/12hrs of cyclosporine.
We started this on thursday, and she has seemed to get much better (I have to say that she was getting better with lower doses of dexa as well, although slower).

I would expect she would get better and better and that now we should only wait for the drugs to be able to control the disease and then in 10 days time we could assess what's going on and start reducing Pred first.

I feel that Ripley has been better before this relapse, though. She was more lively (now she is a bit more depressed, sleeps more and reacts less).
Also, this morning she did some leg shifting, although she's not limping and she gets up very quickly.

Would you expect the drugs to take a few days to have full effect? Prednisone too?

Also, since we would like to take her off Preds sooner, and this is why we have introduced Cyclosporine, did you come across some good protocol in reducing Prednisone when another immunosuppressant is given?

I am still trying to understand if Cyclosporine is good for her, as I feel that she gets a bit worse as soon as we start giving it to her, but I think we will have to wait for a few days before we rule it out.

Thanks for your feedback, it's always so helpful
Monica

[mon67]

One more thing.
Today she's panting a lot and not willing to walk. How would I diagnose the Cushing syndrome? It's hot here now, but I see her panting even indoor, so I am a little worried

Thanks

[Jo CIMDA]

Hi Monica

I have copied below the signs of iatrogenic Cushing's syndrome.    She will pant a lot when on high doses of preds, especially if the weather is hot.  Do you think she is unwilling to walk because of muscle weakness (due to the side effects of the preds) or Joint pain?  Her muscles will have a degree of weakness so difficulty in walking can be expected somewhat but if she starts to go off her food then it is likely that the preds are becoming too much for her and perhaps you have to reduce them now.  Also make sure she is on something to protect her stomach and it might be prudent to put Ripley on a low antithrombotic dose of Aspirin. 
It is such a worry for you but look at her clinical signs and reduce the preds if you have to because she is now on a higher dose of Cyclosporin.  Have a chat with your vet about this.   


Jo




Side Effects of the Drugs – Iatrogenic Cushing's Syndrome

Iatrogenic Cushing's syndrome is a side effect of high dose steroids and is caused by too much corticosteroid in the body. To a lesser extent, the immediate side effects observed when the dog initially goes on steroids eg., drinking, eating and urinating excessively is a mild example of Cushing's syndrome.  Personally I like to see dogs responding to high doses of prednisolone in this way, as it means that they are responding to the drugs as they should.

Usually, Cushing's syndrome only becomes a real problem when exceptionally high doses, or prolonged high doses of steroids are administered, maybe due to a relapse, or in some cases where the vet is inexperienced in reducing steroid doses and keeps the dog on a high dose for longer than necessary; or when the dog is not responding to treatment and higher doses are necessary to control the disease.  This is where the cytotoxic drug Azathioprine is very useful. 

All drugs carry side effects and Azathioprine is no exception, but it does not carry the same side effects as prednisolone, therefore by using this drug in combination with prednisolone it reduces the risk of iatrogenic Cushing's syndrome.  As Azathioprine takes at least 10 days to take effect, starting the 'combination' therapy at the beginning of treatment may enable the prednisolone to be lowered within the 10-28 day band and still maintain a good level of immunosuppression. If your dog is not responding to treatment then your vet may consider changing his treatment to other immunosuppressive drugs.

How Can I Tell if My Dog Develops Iatrogenic Cushing's Syndrome?

Iatrogenic means 'drug induced'.  Clinical signs of Iatrogenic Cushing's syndrome are the same as primary Cushing's syndrome but can present with acute clinical signs. It reflects the level of corticosteroid in the body.

The most notable side effects are, heavy panting, some hair loss, and an increase in drinking and urinating, excessive pigmentation.  This is something everyone seems to be aware of and accepts as normal when a dog is on high dose steroids. Very often the dog will be weaned down to a low dose before any major problems arise. 

Acute Cushing's syndrome due to overdosing of corticoid steroids can be very serious.  Blood results will reflect this, especially the liver enzymes which may be extremely high. Red blood cells and blood platelets may also be high and blood clotting may be a risk.

So when should you alert your vet to suspected, unacceptable level of corticosteroid?  The owner should take note when other clinical signs occur, such as: Depression, anorexia, muscle wasting and extreme weakness, continuous panting, lethargy - unwillingness to exercise, skin lesions and thinning of the skin, excessive hair loss, pot-bellied appearance and sagging back, behavioural changes (aggression).

If your dog is showing these signs it will probably mean that the dose of steroids needs to be lowered. It is important that it is not confused with a relapse of the dog's condition or an infection. The dilemma is that steroids must not be withdrawn too quickly otherwise the dog may go into an adrenal insufficiency crisis.  If the clinical signs of iatrogenic Cushing's syndrome is intolerable, it is hoped that the high dose of steroids that he has been on will have already done their job and that his autoimmune disease will be stable. As long as the steroids are lowered in a controlled manner and in time, all the symptoms of Cushing's will subside and your dog will return to normal, but extreme signs must not be ignored.