Help please with pred-induced calcinosis & a pred taper question

[cowanify]

My 2yo boxer is in the midst of a slow pred taper after a SRMA diagnosis in late October, and a suspected relapse in early January. We are just now reducing to 0.25mg/kg q12h. He has been very Cushingoid from the pred but that is seeming to ease somewhat as we lower the dose. He has extreme muscle wastage and has had a severely enlarged liver and astronomically high liver enzymes, which we have been managing with a Hill's Prescription liver care diet and Denamarin liver supplement, which seems to have helped a lot. I also give him fish oil on his food for skin support.

The main worry, and what I'm seeking help about, is the pred-induced calcinosis he has, that is definitely progressing more and more each day, though it seems to wax and wane.

So far he's only had one or two spots that where the calcium plaques have pushed out to the skin and become sores, but those are both slowly drying and healing. However he has more and more lumps and bumps that I can feel under the skin, the largest on either side of the point of his rib cage and the entire bottom of his tongue is covered in calcinosis which bleeds as it pushes out. None of this seems to be painful and his mood is good since we got through the highest doses of prednisolone but I am worried about how much worse it can get before we manage to get completely off the prednisolone which is still probably 6 months away if things go smoothly with no setbacks. I am trying to keep to the slow taper for the sake of dealing properly with the SRMA (and for adrenal recovery once we get to the lower doses). He is on preventive antibiotics to hopefully stomach the calcinosis in the mouth getting infected (he had two mouth infections, one before the calcinosis and one of the calcinosis) earlier in this process which cleared with the antibiotic.

My question is, is there anything topical that we can be using on the calcinosis on the bottom of the tongue to help prevent infection? Would Manuka honey be okay alongside prednisolone and antibiotics? I've read it shouldn't be given to puppies because their immune systems aren't yet equipped to handle the good bacteria that are also in Manuka honey and also that there is some possibility of botulism? In normal adult dogs I don't think there's a problem but wondering if I should avoid Manuka honey in my dog since he's immunosuppressed and since SRMA itself is an immune-mediated disease? ie could the Manuka honey cause problems rather than help? Is there anything else I could be using in the mouth?

Enormously grateful for any help you can give.

Also, a separate question about the pred taper: am I right in thinking the transition from 0.25mg/kg q24h is best done by going to 0.5mg/kg every second day (so you're giving more in one hit but the dose stays effectively the same), rather than going to 0.25mg/kg every second day (which represents a halving of the dose)? Or is it okay to go to 0.25mg/kg every second day?

Jane in Australia

[Jo CIMDA]

Hi and welcome

I am sorry your young Boxer has had SRMA.   I don't know how much prednisolone  was initially prescribed, and for how long, but the best immunosuppressive protocol I have come across is by Prof Michael J Day and it can be confidently used as a guide. See below:

Example: Reduction Protocol for prednisolone:
Clinical Immunology of the Dog & Cat , 2nd Edition,  by Michael J Day
Professor Michael DayBSc, BVMS(Hons), PhD, DSc, DiplECVP, FASM, FRCPath, FRCVS 

Professor of Veterinary Pathology, University of Bristol, UK and WSAVA - Chairman of Scientific Advisory Committee.

This example is based on a dog receiving an induction dose of 1.0mg/kg/q 12hrs (q = every)
Dose                           Duration (based on clinical effect)
1.0mg/kg/q 12h                          10-28 days
0.75mg/kg/q 12h                       10-28 days
0.5mg/kg/q 12h                         10-28 days
0.25mg/kg/q 12h                        10-28 days
0.25mg/kg/q 24h                        10-28 days
0.25-0.5mg/kg EOD                    at least 21 days
0.25-0.5 mg/kg every third day      at least 21 days

Every reduction is made after consideration to improvement of clinical signs, blood results and side effects of the drugs.

Note:  Prednisolone:  "Doses above 2.2mg/kg/day do not give more immunosuppression but do cause more side effects. Many internists believe that prednisolone doses should not exceed 80mg per day, regardless of the dog's weight."  Plumb's Veterinary Drug Handbook Eight Edition.


Prolonged use of high doses of preds, and relapses necessitating an increased dose and duration, all contribute to these adverse effects, and it can be so frustrating.  Calcinosis cutis  can be a stubborn condition and it is only when the preds are given in very low doses or withdrawn altogether that you start to see the skin healing. It can take many months for the skin to repair and grow. Secondary infection is another bug-bear of CC especially when the dog has muscle weakness and has to lever his heavy body up on his elbows. The good news is, it does come right in the end.  Meanwhile, I think Manuka honey is a great soother and healer and well worth trying.  You can also add Natural Vitamin E and essential fatty acids to his diet in an attempt to repair the skin barrier and encourage new cell growth.

You have probably seen these links, but just in case.....

https://healthyy.net/superfoods/6-benefits-of-manuka-honey-in-oral-ulcers

https://www.dogsnaturallymagazine.com/manuka-honey-for-your-dog/

My daughter's cat had her leg ripped very badly by a dog and 3 weeks after the event, and still in hospital,  the vet said if the new skin failed to grow the leg would have to be amputated but he was going to try Manuka honey as a last attempt.  The very next day the necrosis had receded and new skin growth and blood supply to the wound was seen.  Manuka honey saved her leg from being amputated, so it is well worth trying. 

You may consider using an antibiotic called  minocycline.  This may help both the skin lesions and the oral ones, but this should be discussed with your vet.

If a dog is coping well with the side effects of the steroids, you can take the last stages slower.  This can achieve long term remission. So if you can get down to a low daily dose before going to EOD that might be a better way of weaning.  There are no hard and fast rules when it comes to a low dose of pred and if you can take it slower then it is more likely to achieve a long term natural balance - a state of
homoeostasis.  It does depend on the severity of the side effects though.   How much is 0.25mg/kg for your dog? 

Jo

[cowanify]

Jo, thanks so much for this. You're amazing. Thank you so much for engaging in such detail with Shiva's particular situation. You care far more than our neurologist has, and it means the world to us.

I had seen one of those Manuka honey articles, the dog one, but not the one about oral ulcers. It does sound promising. I do note the reference in the dog one that says:

"Manuka is not recommended for dogs under a year of age. Manuka may contain bacteria that your puppy isn't ready to fight off. Adult dogs have no problems with it."

Do you think it's safe for an immunosuppressed dog (due to the pred) with an immune-mediated condition in the SRMA? Might an SRMA dog on pred also have problems with the bacteria in Manuka honey that presents a problem for puppies?

0.25mg/kg for Shiva, who weighs about 30-31kg is 7.5mg. We are just starting the 0.25mg/kg q12h stage and have been doing 6 week blocks basically following the Mark Lowrie protocol, but with a more gradual taper at the start of each 6 weeks that I introduced myself, where instead of just halving the dose in one go, we reduce by 5mg for 5 days and then 5mg again for 5 days and then another 5mg where we stay for the rest of the 6 week period. I have also decided to go to 0.25mg/kg q12h a la the Michael J Day protocol, instead of the 0.5mg/kg q24h that the Lowrie protocol suggests.

I notice the Michael J Day protocol goes down to 0.25mg/kg q24h and then goes EOD. So are you saying it's better in terms of full recovery from the SRMA to go even lower than 0.25mg/kg q24h before going to every other day? How low would you go before going every other day?

Is that also okay for the adrenals to delay progression to the EOD dosing? 

Also, I notice the Michael J Day protocol does give the range of 0.25mg-0.5mg/kg EOD. I gather in serious immune-mediated conditions it's advised to go to 0.5mg/kg EOD when you make the transition to EOD dosing, even if you've just been on 0.25mg/kg q24h. Is that right? Or would it be okay to go from 0.25mg/kg q24h to 0.25mg/kg EOD? Also, my plan when transitioning to EOD dosing would be to gradually reduce the dosing on the second day, so that I slowly phase out to no dose every other day, rather than just going from daily dosing to EOD dosing. Is that okay, to do that gradual phase out, or do the adrenals need a jolt to kick back in?

Thanks again, for everything, Jo.

[Jo CIMDA]

Hi Jane

The most common problems that arise when a dog is on immunosuppressive doses of prednisolone for more than 4 weeks is numerous side effects resulting from drug induced Cushing's syndrome.  This is especially true in larger dogs like Shiva. Then if a relapse occurs you have potentially added complications because the dose of prednsiolone has to be raised back to immunosuppressive when the dog already had a build up of glucocorticoid in the body.

You are wise to take the reductions a little slower. There are several different immunosuppressive protocols but over the years these have been tweaked here and there to establish, hopefully the best, but always, it has to be tailored to the individual.    In Practice, and anecdotally, the starting dose need not be more than 1.1mg/kg/12hours.  A higher dose than this does not achieve more immunosuppression and it creates much greater side effects. See this quote from Plumb's which is considered the veterinary drug bible.

Note:  Prednisolone:  "Doses above 2.2mg/kg/day do not give more immunosuppression but do cause more side effects. Many internists believe that prednisolone doses should not exceed 80mg per day, regardless of the dog's weight."  Plumb's Veterinary Drug Handbook Eight Edition.

Reducing the dose every 3-4 weeks and by 25%, gives a better outcome, less side effects and less chance of a relapse - Obviously this depends on the individual dog etc., etc......  For a dog of Shiva's size, after several reductions of 25%,  when you get down to about 10mg pred per day if you can take the next stages slowly it seems to reap benefits.  There is no guarantee but it often works well.

When you get down to a low dose of say 10mg a day, and your dog is coping well,  then you have many options.  You can then go to 7.5mg a day for 2-3 weeks or more if you feel it necessary.  Then you can go to, say 5mg a day, and then you could go to 5mg every other day (EOD) or even reduce it to 2.5mg a day and then after a few weeks go to EOD etc........  You can then go to every third day if you wish.  There is no hard and fast rule and taking it slowly is not wrong either. You should see the clinical signs of Cushing's reduce as you reduce the preds.    Relapses are more likely to occur when the daily dose of pred is still relatively high and then it is reduced EOD dosing. Anecdotally, it is far better to reduce the daily dose until it is quite low and then go to EOD dosing  - but it has to be tailored to the individual and clinical signs of Cushing's has to be taken into consideration. .

Whether Shiva is able to cope with any risk from bacterial spores in Manuka honey is unknown. That is for you to decide, but as you lower the dose of preds you gradually reduce the effect from an immunosuppressive dose, to an anti-inflammatory dose, to an adrenal replacement dose, meaning that gradually the dog's own immune system becomes active again and the dog is no longer immunocompromised.   After you have reduced Shiva's preds to 7.5mg/12hours he will be on an 'anti-inflammatory' dose (0.5-1mg/24hours - Plumb's Veterinary Drug Handbook, 8th Edition).

If you are hesitant to use Manuka honey (and I can understand your reluctance) then try putting some Natural Vit E or Evening Primrose oil onto the mouth ulcers.  It coats the sore and often gives relief.

https://thehappypuppysite.com/manuka-honey-for-dogs/

The adrenals don't need a jolt to start working again, in fact I feel it is better to take it slowly and let them gradually wake up and realise that they need to start working again.

A replacement dose for adrenal function is pred:  0.1mg/kg/once a day,  so when an immunosuppressive, reducing protocol goes from 1mg/kg a day to 1mg/kg EOD, because there is a half life effect of prednisolone and for 12 hours of the 48 hours, there will be no active glucocorticoid effect,  for at least 12 hours of the day you don't give pred, the adrenal glands have to kick back in, but on the day you give the 1mg/kg/day they don't work at all.  I don't know if that is written clearly enough.

What you mustn't do is to stop the pred suddenly because the adrenal glands will not be able to function and the dog may go into a life threatening adrenal crisis. 

I hope the above hasn't confused you even more.

Jo

[cowanify]

Hi Jo

Thanks so much for this. You continue to engage even once it gets complicated and for that I am so grateful. I'm following what you're saying there except for this paragraph:

A replacement dose for adrenal function is pred:  0.1mg/kg/once a day,  so when an immunosuppressive, reducing protocol goes from 1mg/kg a day to 1mg/kg EOD, because there is a half life effect of prednisolone and for 12 hours of the 48 hours, there will be no active glucocorticoid effect,  for at least 12 hours of the day you don't give pred, the adrenal glands have to kick back in, but on the day you give the 1mg/kg/day they don't work at all.  I don't know if that is written clearly enough.

You talk in the first instance about 0.1mg/kg per day but then you are talking about 1mg/kg? Was that a typo and you mean to be saying 0.1mg throughout?

A few other follow-up questions if I can?

1. I had thought a physiologic dose of pred was 0.2-0.25mg/kg per day? But it's 0.1mg/kg per day, is it?

2. Given all you've outlined, does that mean it would be best, both for the SRMA and for the adrenals, to actually stay on daily dosing until we get below a physiologic dose and only after we've been there for a while (and presumably if all is well, we know the adrenals are successfully kicking back in) then go to EOD?

3. Another follow up question if I can: You talk about each block in the taper being 3-4 weeks, and I know the Michael J Day protocol talks about 10-28 days for each step. But the Michael J Day protocol is a general immunosuppressive protocol, isn't it and not specific for SRMA? Whereas the Lowrie protocol is specific for SRMA and says 6 week blocks? Just trying to get my head around the reason for the difference in timeframes between the two protocols so I can decide which is most appropriate for Shiva? Obviously it would help us get off the pred faster to do 3-4 week blocks instead of 6 week blocks, and that would be best for the calcinosis, but is 3-4 weeks just as good for banishing the SRMA? Because we don't want to go faster only to relapse and end up on the pred longer again. If 3-4 weeks is just as good as 6 weeks why does Lowrie say 6 weeks? Shiva already had one suspected relapse last time, when we dropped from 0.5mg/kg q12h to (on that occasion) 0.5mg/kg q24h after 4 weeks (2 weeks earlier than the planned 6 weeks because the neurologist was worried about the calcinosis). It was on the advice of the neurologist but I've since decided this time to reduce further at twice daily dosing before going to once daily, and I also kept Shiva at 0.5mg/kg q12h for the full 6 weeks given what happened last time.

4. Also, the steps in the Day and Lowrie protocols are always a halving of the dose in one go... but are you saying it's better to go even more gradually than that? If that's better why don't they do it in more gradual increments in the protocols?

Cannot thank you enough, Jo.

[Jo CIMDA]

Hi Jane

I can see how I have confused you.  Your first query about a possible typo of 0.1mg/kg/day for a replacement dose of glucocorticoid when a dog has adrenal insufficiency (Addison's disease) and is on replacement hormone therapy, is not a typo and is correct when a dog is on Florinef replacement hormone.  It is a higher when a dog is on injectable mineralocorticoid hormone therapy, Percorten (0.2-0.3mg/kg/day). As a matter of interest, Addisonian dogs on Percorten are generally needing less than this dose.

This was just to illustrate a comparison between  how little glucocorticoid the adrenal glands need to produce in a healthy dog, or if Addisonian, and on hormone replacement therapy, how little glucocorticoid therapy the dog needs to lead a normal life, and how much excess to adrenal needs a dog is receiving when on immunosuppressive prednisolone therapy.  My reason for mentioning this was to stress the difference in dosage between immunosuppressive therapy and hormone replacement therapy or natural production.

The point I wanted to make is, when a dog is on a dose of pred @ 1mg/kg/a day (high end anti-inflammatory dose) and the next step in the particular  drug protocol is to go EOD with the same dose, this must be a huge shock to the body and all of a sudden for at least 12 hours of the 48, the adrenal glands have to go from being totally inactive, to having to return to immediate normal function.  This may explain it better:

"Animals that have received glucocorticoids systemically, other than 'burst' therapy, should be tapered off the drugs.  Patients who have received  the drugs chronically should be tapered off slowly as endogenous ACTH and corticosteroid function may return slowly. "  Plumb's Veterinary Drug Handbook, 8th Edition.

I am aware of the Lowrie protocol.  I remember when it was first published. Immunosuppressive treatment isn't a case of one size fits all.   There are many different immunosuppressive protocols, and as time goes on and more dogs develop AI disease, the more the clinicians learn and adjust their protocols based on field trials and their own experience. This can only be good for our dogs.   22 years ago when my first dog developed SLE, a multi-systemic AI disease, the usual protocol was to reduce the preds by 50% each time.  Relapses were very common and because of the whole-body negative effect of long term pred use, this is when the addition of a combination drug was introduced.  The vets were trying to balance control of the AI disease by significantly suppressing the immune system, and the dreadful side effects of the steroids, so combination therapy became common place.  If preds alone can be used to achieve a balance between controlling the disease and limiting the side effects then a 'combination' drug isn't necessary, and this is what the Michael J Day protocol is trying to do.  It is the best protocol I have come across and, in practice, it usually works very well, but of course there are no guarantees.  The first three reductions are by 25% and then it goes to 50% and overall it is quite a long drawn out process.  The wide duration window of 10-28 days is because a dog has to be monitored every step of the way and whereas one dog may tolerate the duration of 28 days or even 6 weeks, as other protocols may suggest, always clinical signs have to be monitored and taken notice of because sometimes the adverse effects can be serious.  One of my dogs died of a blood clot 5 days after starting immunosuppressive treatment of pred, 2mg/kg/12hours.  The veterinary specialist didn't listen to my concerns, that she was on too high a dose of pred, and she told me if I reduced the dose "I would kill her".  I bowed to her expertise and my dog died because the high dose of pred caused a blood clot to her lung.  She said afterwards that it is clear that larger dogs cannot tolerate high doses of preds. It was too late for my girl.   Since that time the recommended dosage of no more than 2.2mg/kg/per day pred has been widely used.  See the quote from Plumb's. 
Whether the reduction is 50% or 25%, or weaning down slower when you get to the lower doses, is largely a decision for the clinician or the owner, or both, but every reduction should be based on resolution of the disease and the tolerance of the adverse effects of the drug, and this should be monitored by the owner on a daily basis and by the clinician every week or so.  I have known clinicians to prescribe preds at 1mg or 2mg/kg/12hours for 6 weeks and not monitor the dog. This is wrong. 
Clinicians have learned a lot about treating autoimmune disease with immunosuppressive drugs over the last 20 or so years, and the only exception to giving more than 1.1mg/kg/12hours pred, is if the dog is small in size or a puppy, and this is because their metabolism is quicker and higher doses are necessary.  Larger dogs should not be given more than 1.1mg/kg/12hours pred and if they need more immunosuppression then a 'combination' drug should be used.

The recommended duration for immunosuppressive therapy with prednisolone in Plumb's is: "Doses up to 2.2mg/kg per day.  A sample prednisolone immunosuppressive protocol for dogs follows but doses and dosage schedule must be tailored to the ongoing requirements of the individual patient:  2.2mg/kg/day (not to exceed 80mg total per day) for 3 weeks, then 1mg/kg/day for 3 weeks, then 0.5mg/kg/day for 3 weeks, the, 0.5mg/kg/EOD."

So Plumb's recommend that the protocol is tailored to the individual and the duration they recommend as a guideline is 3 weeks and they reduce by 50%.

The regimen that you ultimately follow has to be determined by you and your vet and as long as you monitor the side effects and are willing to change the regimen if necessary, then that should be fine.

Many of the people here who have experienced a relapse of their dog's condition (IMPA and SRMA commonly relapse for the first couple of years) take the end stage of therapy of the second and subsequent relapses much lower in the hope that long term remission is achieved.   If Shiva relapses again it would be a good idea to introduce a 'combination' drug such as Azathioprine or leflunomide or a relatively new drug to veterinary medicine, that is having really good results with few side effects, is Mycophenolate.

Whether a dog has SRMA or IMPA or one of the other inflammatory AI diseases, the treatment protocol is the same.  As Plumb's mentions, you can only suppress the immune system to the degree that it is totally suppressed, any more drugs or any higher dosage won't suppress it any further but it will cause significant side effects and perhaps complicate the situation. I have known some dogs to be on so many different drugs the vet cannot differentiate between the clinical signs of the disease and the side effects of individual drugs.

The good news is SRMA has an excellent prognosis and long term remission can be achieved.  Make sure you limit the trigger factors that are known to cause a dog to relapse or to get another AI disease. 

I hope I have covered most , if not all of your queries, but if I haven't please get back to me.

Jo