Another Nika set back

[Hobart999]

Our poor dachshund is once again a medical disaster.  We have been on 200 mg/24 h of mycophenolate for several months now with increasing/decreasing amounts of pred depending on her limping.  A few months ago we noticed she was limping on her back foot which is unusual for her because almost all of her IMPA symptoms have been in the front paws or her jaw.  We upped her pred to 10 mg/24 h and this helped for a few weeks but soon she started limping again.  It was then we noticed her 3rd toe on her back paw was swollen.  We took her to the vet and x-rays showed she had new/significant bone formation on both sides of her existing toe bone.  Worried that it was due to an infection we tried an array of antibiotics for several weeks but to no avail.  We were left with either autoimmune or bone cancer.  Since we were already on high doses of mycophenolate we suspected bone cancer and on the advice of multiple specialists had her toe amputated 3 weeks ago and sent out for pathology.  We have since received the results showing no cancer and no infection.  The lesion on her toe showed mass inflammatory cells that must have caused a periosteal reaction.  Recovery from the amputation has been slow due to her immunosuppresion, 3 weeks in and they still cannot take out the stitches. 
While we are happy that she does not have cancer we still have no way to slow down the progression of this disease.  It has eaten away her jaw joint and now caused the loss of her toe all while on high doses of immunosuppresive medications.  My wife and I both have great fear for what it will claim next.  We are going to see if our specialist will recommend switching her to leflunomide since the mycophenolate does not seem to be helping.  We have run out of ideas on what to do for this poor little dog.       

[Jo CIMDA]

Hi

I am sorry your little girl is having more problems. 

There are so many adverse reactions caused by immunosuppressive treatment that can be mistaken for the return of an AI disease.  The natural reaction is to increase the  medication to further suppress the immune system - but this is not always the best path to take.

Generally, if a limp is on one leg or paw only then it will not be due to an inflammatory AI disease process and it is very likely to be caused by the effects of the medication, whether it be due to stretched ligaments or tendons, muscle loss or a sprain injury.  Likewise, many dogs who have been on prolonged immunosuppressive therapy get skin problems, in the form of nodules and lesions etc., due to inflammation and thin skin.  Cutaneous vasculitis is quite common and this can show in a variety of different forms.

I would ask your specialist if he or she is absolutely sure that the symptoms you are seeing are due to IMPA, or if the medication she has been on for a long while may be causing, or at least contributing to, the clinical signs you are seeing.  Often the best course of action is to lower the dose to see if the symptoms improve.  If a dog has been on immunosuppressive treatment for many months it is unlikely that the AI disease will still be very active.  The 'heavy' drugs used to bring the disease under control are necessary but when the dog has been on them for a long while the drugs can cause more problems than the disease itself.  It is just something to consider.

I do hope your see an improvement very soon.

Jo

[Hobart999]

Wouldn't there be a pathology difference between an autoimmune process and drug induced process upon autopsy?  I suppose I just don't understand if there is any way to tell the difference without lowering her mycophenolate.  Normally she doesn't limp on all legs when she has a relapse.  Generally speaking it starts in one of her front paws and if we do not do anything it will eventually spread.  I think our vet and specialist agree that they don't have any right answers when it comes to her case and everything we do from here on out is a trial.  They really don't have many further recommendations.   

[Jo CIMDA]

I doubt there would be any pathological difference between drug induced disease and naturally occurring disease, but I am not a vet or a pathologist, so I can't say for sure.

Unfortunately, many dogs with an AI disease have serious drug side effects if they have been on medication for a prolonged period.  All you, or your specialist, can do is to look at the drug prescription records and consider if there is a good case for drug induced clinical symptoms, and if there is any possibility then you have nothing to lose by lowering the drugs. You may be pleasantly surprised how quickly symptoms can improve when the effects of the drugs are significantly reduced and out of the system.  Sometimes there is no choice but to lower the drugs because the risks outweigh the benefits.

It is not uncommon for a dog to be suffering from the side effects of prolonged drug use, and the vet to assume it is a relapse of the disease and increase the medication when it should be decreased. This may not apply in your case but if you have no other options then a reduction in medication could be considered.  Very often a general biochemical blood test and a complete blood count will show if the body is struggling to cope with the effects of the drugs, so that might be worth doing.

Jo

[Hobart999]

Just a follow up for my dachshund.  We have weaned her off of mycophenolate over the last month and a half on the slim chance it was medication induced problems she was having.  She has only been on 2.5 mg of pred EOD now for the last few months as well.  Blood work all looks uneventful except a mild elevation in ALP.  Unfortunately we have not seen any improvement and things are now getting worse.  Both toes on either side of the toe that was amputated are now swollen and one has shown new bone formation since the last x-ray in april.  She limps every morning and does not put much pressure on the foot.  We have tried some laser therapy in the last few weeks to try and reduce inflammation to no avail.  Yesterday we made the decision to start her on leflunomide (20 mg/d, 9 kg dog) but within 4 hours of taking it she vomited 3 times.  We will try again tomorrow with half that does but it does not look promising that she will be able to tolerate it.  We have tried everything else (cyclosporin, mycophenolate, azathioprine ) and have yet to achieve remission or find something she can tolerate.  Our last resort will be to try high doses of pred again to see if we can at least alleviate some of the swelling.

[Jo CIMDA]

Hi

I am sorry Nika is still having problems with her toes.  My opinion, based on what you have written, is I have never known this scenario to be due to an AI disease.  Yes, you can have localised inflammation, but this toe problem, in isolation, doesn't fit with any AI disease that I know of, but I may be wrong. 

Are you sure that Nika hasn't reached remission of her autoimmune disease and what you are seeing now is a fall out of the prolonged drug use?   I have known this sort of thing to happen as a result of high and prolonged doses of preds, but not a primary AI disease.  Osteoporosis and thin skin is a common result of drug induced Cushing's syndrome and perhaps this is causing Nika's problem with her toes. 

http://www.saem.org.ar/departamentos/departamento-neuroendocrinologia/cushing-exogeno.pdf

Osteoporosis is a common and severe adverse effect of glucocorticoid
excess and one of the major limitations to long-term glucocorticoid therapy.
A significant number of patients on long-term steroid therapy will have at
least some loss of bone density [7,8], and oral and inhaled corticosteroid use
are associated with increased bone fractures [9,10]. The bone loss caused by
glucocorticoids tends to be in trabecular bone as opposed to cortical bone.

The leflunomide clearly isn't suiting her and  this is causing her to feel unwell and vomit. I do wonder if more immunosuppression is needed.  Have you considered stripping back Nika's drugs in order to produce a clearer picture of what might be symptoms of a disease and what might be side effects of the drugs?

This may be over simplifying things but has your vet tried using Manuka honey on Nika's toes? 

I do hope she feels much better very soon.

Jo

[Hobart999]

Thanks Jo for the suggestions.  We have weaned her off of all meds except for the 2.5 mg EOD of pred and metronidazole and have seen no improvement.  The belief that this is an AI problem is because of the biopsy report that came back on her amputated toe.  The pathologist said the soft tissue and joint showed mass inflammatory cells consistent with her history of AI problems.  I don't believe she is showing any signs of bone loss according to the x-rays just bony proliferation presumably due to the swelling.  Since her blood work has also been normal I don't think much else has been considered.  I'm not sure there is a right answer here.  If it is an AI problem and we reduce meds and do nothing else we risk permanent damage to her foot.  Our hope was if it is was mycophenolate or pred that was causing problems we could try leflunomide so we wouldn't have to increase anything else to immunosuppressive levels.  I keep going back to what my vet has said to me...in AI diseases nothing is normal, it is the body and it can do whatever it wants whenever it wants.     

[Jo CIMDA]

Hi

If your vet thinks this is an AI problem and it is localised to the foot, have they considered using a topical ointment, such as tacrolimus, to see if this can be brought under control without using much harder, systemic drugs?  See this link to give you some idea of this topical treatment.

https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012280/

Jo

[Hobart999]

Jo - we asked about topical treatments but the specialist said there would not be enough skin penetration to make any difference.  A quick update.  We started Nika on 10 mg/24 h of leflunomide and found no change in her ailing foot after a few weeks.  Drug monitoring suggested we were only at half the recommended blood levels for immunosuppression.  We doubled her dose of luflunomide to 20 mg and found on an empty stomach she was able to tolerate.  After a couple of days still no improvement and seeing as she was in a great deal of pain we decided to add some pred (5 mg/24 h) and tramadol to help with inflammation and pain relief.  After 24 h with steroids she stopped limping and I could convince myself that her foot looked less swollen after a few weeks.  Unfortunately, after 3 weeks of 20 mg of leflunomide and 5 mg of pred her liver values again skyrocketed (>500 ALT, >2200 ALP).  We could only contribute this to the combo of drugs.  We decided to cut her pred to 2.5 mg/24 h and after two weeks she just started limping again and her foot now appears to be swollen.  We are awaiting her blood work to check liver values again but if they remain high we will most likely have to stop leflunomide.  We are now out of options as we have tried all recommended immunosuppression drugs (aza, cyclosporin, mycophenolate, leflunomide) and either they are not sufficient or the side effects (hepatoxicity, GI) are too much for her.   

[Jo CIMDA]

Hi

I'm sorry Nika is not doing well on the drugs.  It seems you are damned if you do and damned if you don't!

Clearly though the steroids have some good effect on reducing the inflammation, so, not withstanding what you specialist said,  why not try Tacrolimus (Protopic)?  It is known to have good effect on localised inflammation without causing systemic problems, and what have you got to lose?  Also, I would start Nika on therapeutic doses of evening primrose oil and fish oil and natural Vitamin E.  Essential fatty acids in therapeutic doses are known as 'steroid sparing' and this has been proven, so why not start Nika on EFA's - but it has to be in therapeutic doses otherwise it will not be sufficient to have good effect.

Is Nika on a liver support such as Milk Thistle and SAMe?  If she isn't then you should start this straight away.  It will help her liver cope with the onslaught of any drugs given.

Another option, which would have to be discussed with your vet,  might be to give a lower dose of Cyclosporin with powered grapefruit or ketoconazole.  Grapefruit and Ketoconazole enhance the effect of Cyclosporin and this may allow a lower dose to be given and thereby limiting the harmful effect on Nika's liver.   

I hope you can sort this out very soon.  It is very frustrating when a problem is localised can't be brought under control.

Jo