not sure which Auto immune

[LisaK]

Our journey started 4 yrs ago with my then 2 yr old BC. He develop awful skin lesions around his mouth, eyes, penis and anus, Biopsies were done and i was told it was an auto immune but Ive never found out which. He was started on high dose prednisolone which worked and he started to recover however as soon as we tried to reduce he flared again so he was put on Azathioprine and slowly reduce but I cant get him any lower than 25mg every other day without a flare up so he has remained on the 25 mg. The last couple of weeks at agility training he has become lame, last wk a front leg and then last night he started having problems in the weaves with his back legs. Instructor said it was as if he was loosing control of them, when i watched he was changing technique half way through the weaves which usually indicates pain or a problem so we off to see the vet later tonight. Could this be progression after 4 yrs or is it more likely to be unrelated?

[Jo CIMDA]

Hi and welcome

I am sorry your boy is not well.  As the steroids and Aza brought his skin disease under control I think you can assume that it is a an autoimmune problem and therefore he is likely to be genetically predisposed to other AI diseases.  I presume the 25mg every other day (EOD)  is Aza?   It is not clear if he is still on pred.

Does he have a high temperature? As the dose of drug is only 25mg EOD then it is likely the symptoms you are seeing is due to an AI disease and it could be something like immune mediated polyarthritis (IMPA).  An EOD dose won't be enough to stop the development of an AI disease if it has been triggered.

Immune mediated polyarthritis (IMPA) is diagnosed by performing joint taps but when a dog has been on immunosuppressive treatment there may not be enough evidence from the synovial fluid to make a definitive diagnosis, so the best way to test is to  raise the preds back to an immunosuppressive dose and if he responds well (which may happen within just a few hours of taking the preds) then you know this is the way to go. Alternatively, your vet can give an immunosuppressive dose of an injectable steroid called dexamethasone and if the response is good then you can continue with an immunosuppressive drug protocol 48 hours after the injection. See the protocol below.  What did your vet suggest yesterday?

Below is some information that might be useful to you and also included is the best immunosuppressive drug protocol I have come across and it can be confidently used as a guide.   Prof Day is among the top veterinary immunologists in the world.

I hope your boy feels better very soon.

Jo


Treatment for inflammatory/systemic Autoimmune Disease
Excluding autoimmune diseases where hormone replacement only is required, most of the diseases are treated by significantly suppressing the immune system in order to stop the destruction.  There are only a few exceptions to this.
The drugs most commonly used for the treatment of autoimmune/immune mediated disease are steroids (corticosteroids), such as prednisolone.  These may be used as the sole immunosuppressive agent or used in combination with cytotoxic drugs, such as Azathioprine. Cytotoxic drugs are used in human medicine to prevent the body rejecting transplanted organs. Many vets can be reluctant to use azathioprine with prednisolone as a combination therapy to treat autoimmune disease but there is certainly value in using a combined treatment as azathioprine increases immunosuppression and generally allows the steroids to be weaned down in the shortest possible time whilst maintaining a good level of immunosuppression.  It can make a huge difference to the outcome, and in some cases it makes remission more achievable.
All drugs have the potential to cause side effects and the major concern for treating animals with high doses of steroids and other potent drugs are the unacceptable side effects that may occur.  It is a fine balancing act between bringing the disease into remission and the side effects of the drugs.  All of the above drugs have the potential to cause a degree of liver toxicity but when the drugs are reduced the liver will recover. It has to be stated that without these life- saving drugs, in many cases, the dog would die, but the objective is to use the minimum dose to control the disease, for the minimum duration of time. However, the dose has to be 'immunosuppressive' eg.  Prednisolone 1-2mg/kg/every 12hrs usually starting at 1mg/kg/12hrs (Plumb's Veterinary Drug Handbook). If this dose does not produce the desired effect it can be raised. The action of prednisolone is rapid and at times it works like a 'miracle drug'.  Note: It should be given with food to minimise stomach irritation.
If the dose is too high the side effects may cause other major problems, if it is too low it will not control the disease or achieve remission.  One of the most common accounts are when a dog has been on immunosuppressive doses of prednisolone for too long and they start to display overwhelming signs of iatrogenic Cushing's syndrome (see below) and very often the clinical progress they have made in combating the disease has reached a plateau and the dog now appears to be weak, off their food and quite depressed. Prolonged, high doses of prednisolone can also cause bone marrow depression and the red blood cell count can decrease. These clinical signs can cause confusion for the vet and owner, and a relapse of the autoimmune disease is often suspected. It is not unusual for the steroids to be increased when in fact they should be decreased. 
Azathioprine is usually tolerated well, but as with all drugs individual dogs can be affected in different ways.  Side effects can include reduced bone marrow production, but this is rarely a problem unless the dog is kept on this drug for a long time. In contrast to prednisolone which has a rapid effect on the immune system, azathioprine takes at least 10 days to have some effect and approximately 4-6 weeks to reach its full potential. 
Note:  Azathioprine and all other cytotoxic drugs should be handled with extreme care. Cytotoxic drugs should not be handled by pregnant women.  Rubber gloves should be worn and the tablets should never be split or broken.
Atopica  (cyclosporine) is licensed for treatment of atopic dermatitis in the dog but it's increasingly being used as an immunosuppressant in 'combination' treatment with prednisolone and azathioprine for systemic autoimmune disease, despite the drug sheet stating   'It is not recommended to use other immunosuppressive agents concomitantly'.  I have known many dogs on this triple combination treatment that have eventually become overwhelmed by the side effects of the drugs and the outcome has been poor.  It may be worth, initially, trying a more simple approach to treatment, using immunosuppressive doses of prednisolone, before embarking on a 'prescription overkill' that may prove to be a difficult,  and an unnecessarily heavy drug regime for the dog. Human research suggests that Cyclosporin may also encourage abnormal cells to become cancerous and perhaps even grow more aggressively. Scientists are now looking for ways to block this tumour-promoting effect of Cyclosporin. (Clinical Pharmacology Made Incredibly Easy by Lippincott, Williams & Wilkins)
It must be accepted that sometimes these 'heavy' drugs have to be used, especially if the dog is not responding to treatment; and sometimes an additional drug can make all the difference to the recovery of the dog. In these cases the side effects have to be accepted as a 'trade off', in fact the dog may tolerate it very well.  However, there may be no need to prescribe combination drugs when there is a good chance that using immunosuppressive doses of steroids, and following the correct drug regime, may be all that is required to bring the disease under control.  The severity of the disease has to be taken into consideration when deciding on which combination drug regime to use, but more isn't necessarily best, and introducing one combination drug at a time would limit the side effects for the dog.
In addition to drugs used to suppress the immune system, preventative measures such as administering antibiotics to prevent infection, gastroprotectants to avoid stomach ulcers, and low dose Aspirin to minimise the risk of thromboembolism and DIC (disseminated intravascular coagulation) may be given. 

WHAT TO EXPECT ONCE TREATMENT HAS STARTED
If a dog has a serious autoimmune disease, then the sooner treatment commences the better chance the dog has of survival.  The main delay to starting treatment is obtaining a diagnosis or at least your vet being sure that he hasn't missed anything that could be made worse by giving high doses of steroids.  Achieving a diagnosis can be a fight against time. 
If your vet has decided that in all probabilities your dog has an autoimmune disease, then to a certain extent, which autoimmune disease your dog has, as far as treatment is concerned, is irrelevant because with the exception of a few diseases, they are all treated the same, that is, with immunosuppressive drugs.  The main objective is to 'knock out' the immune system and virtually stop it from working (or near enough) so the destruction will cease and give the body a chance to recover.  As previously stated, this treatment regime works in most cases, that is, if it has been given early enough and the dosage is correct.  All dogs are different and some can tolerate the drugs better than others. In proportion to their size, small dogs seem more able to tolerate higher doses of steroids than large ones. Some diseases are more serious than others and carry a poorer prognosis. So the initial crisis is a crucial time, however anecdotal evidence shows that many more dogs survive than die if correct treatment is administered in good time.
It is hoped that a positive response can be seen within 4-6 hours of starting treatment (depending on the disease), but in a serious, life threatening situation, the first 2-7-14 days can be a very worrying time.  Assuming the dog has stabilised he will quickly feel much better, and if he is in hospital may be allowed home within a week.
When he comes home he will probably have a 'goody bag' full of drugs.  He will be on a high dose of steroid, usually prednisolone, and he may also be on another immunosuppressive drug, such as Azathioprine.  Your dog will be weaned off in a controlled manner according to his wellness and clinical observations. 
Note: High doses of steroids must not be stopped abruptly.  Your dog could go into an adrenal crisis if the medication is withdrawn too quickly. 
In addition to immunosuppressive drugs he should have something to protect his stomach from excess acid.  The last thing your dog needs when he is feeling poorly is a bleeding stomach ulcer caused by the drugs.  Sometimes, Antepsin is given to coat and protect the stomach (but this must not be given within two hours of other medication otherwise it will stop the drugs from being absorbed).  Zantac (Ranitidine) may also be prescribed to take away the excess acid. Another gastroprotectant used is Omeprazole. To minimise irritation to the stomach it is usual for the daily dose of steroid to be split into two doses and given with food, one dose in the morning with breakfast and the other dose with his evening meal. I have known several dogs, who did not receive a gastroprotectant as a part of their treatment regime, and went on to develop anaemia. This is not autoimmune haemolytic anaemia but iron deficiency anaemia caused by bleeding stomach ulcers. Using a gastroprotectant is a good preventative measure. When the steroids have been significantly reduced to a low dose, a gastroprotectant may not be necessary.
Excess acid, produced because of the drugs, may make a dog prone to developing pancreatitis. A dog with pancreatitis will appear in pain and his back may be arched as if he can't straighten up.  He may be lethargic, seem bloated and have a tender abdomen. Dogs usually go off food and water, may vomit and look depressed.  If you suspect that your dog has pancreatitis, don't try to feed him because it will make the condition worse. Take him to the vet as soon as possible as he may require treatment or need to go on an intravenous drip to stop him dehydrating.  Again, the risk of pancreatitis should be minimal once the dog is on a lower dose of steroids.   A low fat diet is best when your dog is on high dose steroids or prone to pancreatitis. 
As your dog's immune system is being significantly suppressed, he will be more likely to pick up infections, and will not have the ability to fight against them.  As a precaution a broad spectrum antibiotic is often prescribed. Also it is sensible not to exercise him in areas where he is more likely to encounter infections, for example, a park or a popular dog walking area. 
Whilst your dog is on high dose steroids he will want to eat and drink excessively. However, this also means that he will want to urinate more and this can sometimes cause temporary incontinence.  You may have to get up to let him out during the night and if you leave the garden door open during the day, it may save some mopping up!  He cannot help it and won't like it either, so don't be too hard on him, it's only temporary. You will notice as he is weaned off the drugs the unwanted side effects will subside and he should return to normal habits and behaviour.  Urinary tract infections and/or bacterial skin pustules are not uncommon when a dog's immune system is suppressed, and this is often the reason for a dog to be off colour during this time.  Note: Always consider a urine infection if your dog seems under par.  A course of antibiotics will usually sort this out quickly.
Depending on what autoimmune disease your dog has, he will probably need to have regular blood tests.  Biochemical blood tests will also keep an eye on other body functions, such as those of the liver and kidneys, which is important at this stage.
Assuming good progress is being made, the clinical signs of his illness are diminishing and positive signs of improvement are apparent, your vet will want to start weaning him down from the high doses of steroid.  This process can take 3-6 months or more, and usually begins any time after 10 - 28 days from the start of treatment, depending on the results of his blood tests and his clinical signs.
Relapses are not uncommon, especially in diseases that are difficult to control, for example SLE.  A relapse may mean that initially, your dog needed to be on a higher dose of immunosuppressive drugs for a longer period of time, or your dog may have been weaned off a little too quickly and then the dose withdrawn too soon.
If a relapse occurs he will probably show similar clinical signs to his initial crisis.  He will have to go back on an immunosuppressive dose of prednisolone, but it may not have to be quite as high as before. A combination drug may need to be added at this stage. The weaning process will then have to start all over again. Returning to an immunosuppressive dose will mean that he has to go back on a gastroprotectant.

Reducing the Tablets
When significant improvement in the dog's condition is seen, usually between 10-28 days, the initial steroid dose is usually reduced by up to half. The dose is generally given for another 10 - 28 days and depending on the dog's progress and clinical signs the dose is significantly reduced once more for a further 10-28 days; and again in another 10-28 days. Anecdotal evidence has shown that if at this stage the dose is lowered more slowly, or reduced to an every other day dose over a period of months rather than weeks, relapse are less likely to occur.  It is always tempting to get your dog off steroids as soon as possible, but when treating autoimmune disease, as long as the dog is on a low, every other day dose then taking the last stage slowly seems to work best, depending, of course, on the severity of the disease and allowing for the difference in individual response - no two dogs reactions are exactly the same.  With some autoimmune diseases such as SLE, the dog is likely to be on steroids for the rest of his life. Usually an every other day dose can be achieved, but you risk a relapse if you take the dose too low. Below is the best example of a reducing immunosuppressive protocol I have come across. It is an excellent guide and can be adjusted to the individual.

Example: Reduction Protocol for prednisolone:

Clinical Immunology of the Dog & Cat , 2nd Edition,  by Michael J Day
Professor Michael Day BSc, 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.

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.


The dose of azathioprine 2mg/kg/24 or 48 hrs, can be reduced initially by giving a lower dose tablet per day, or gradually reducing from daily dosing to every 2nd day, every 3rd day, every 4th day etc.....  Remember, azathioprine tablets should not be broken or handled without gloves.


How Do I Know if My Dog Will Relapse?
Until you have attempted to wean your dog off of the tablets for the first time you will not know if he is likely to relapse or not.  Sometimes during the weaning off process, before you even get down to an every other day dose, he may relapse.  If this happens then the drug dosage has to be raised, probably up to the last dose before the relapse (maybe a little higher, depending on the severity of the relapse) and then start the weaning process again.  If this happens again, then you and your vet may have to settle for keeping him on a low maintenance dose to achieve a good quality of life. A low, every other day maintenance dose of prednisolone is preferred to enable the dog's liver to rest in between doses. There are many autoimmune diseases that carry a good, drug free prognosis.  The more common, serious autoimmune diseases that may not need long term steroid therapy are: primary immune-mediated polyarthritis, autoimmune haemolytic anaemia and thrombocytopenia. However, as previously stated, all dogs are different and it very much depends on the individual dog, the severity of the disease, the experience of the vet and the vigilance and compliance of its owner.
If a relapse occurs whilst the dog is still being treated then true remission has not been achieved.  If the dog has achieved remission and has enjoyed a period without drugs or is on EOD maintenance drugs, when a relapse occurs or he develops another autoimmune disease, he has encountered a 'trigger factor' which has induced this change.