Some anonymous colchicine questions submitted:

Q:  I've heard from some people that they give all their dogs colchicine as a preventative from the time they are young puppies, even though they have had no fevers, swollen hocks, etc.  Is this a good practice?

A.  No.  Colchicine is a potent drug and it should only be used in patients that you believe to be at high risk.  I would not use it prophylactically in all Shar-Pei.  You weigh the risk:benefit and in a patient with no indication of FSF, the risk would out-weigh any potential benefit.  Most patients will have fever events prior to showing signs of amyloidosis.  You will miss some this way but I think it is preferable to putting many dogs on colchicine that don't need it.

Q:  Is there an alternative to colchicine if your dog does not tolerate that drug?

A:  Many people on this list attest to good results with various supplements and homeopathic treatments.  I don't have enough data or experience to recommend one over another.  My feeling is that if I had a dog that wouldn't tolerate colchicine, I would explore these other options since I have also seen no evidence they can hurt.

Q:  Since aspirin can by itself do kidney damage, is that still the best method or reducing fevers during an episode?  And if not, what is?

A:  You'll get a lot of differing opinion on that.  I had a few patients develop perforating gastric ulcers after aspirin was administered by their owners over the years, including one that died.  This experience makes me very wary of the drug in a stressed patient.  I use either Metacam or Dipyrone injectable in my patients with FSF fever events to alleviate the acute signs.  That doesn't necessarily mean this is best – it is just what works for me and what I'm most comfortable with.  I've not had problems to date with these drugs.

Q:  What percentage of patients does not do well on Colchicine & must be taken off it?  

A:  I would say less than 10%.  Most patients will tolerate at least a reduced dosage.

Q:  What period of time do you keep a dog on Colchicine before you remove it due to not acclimating to the drug?

A:  I start out having the owners give it once daily for 2 wks.  If they have GI signs, they are to stop the drug immediately and I have them restart it when they are back to normal.  If they break with diarrhea again, we stop it and return to a normal baseline and then try a half dose, etc.   If they tolerate the drug with no signs for 2 wks, I have them go to twice daily.  Most patients that won't tolerate the drug have trouble at the once daily dosage.  I tell them to stop the drug anytime the dog is experiencing vomiting or diarrhea and not to restart it until they are normal again (and that vomiting/diarrhea that lasts more than a day or if they are acting very sick should be checked out).

Q:  What do you prescribe for that percentage that is intolerant to Colchicine treat the FSF/SHS?

A:  I have been putting some of them on MSM chronically (Glycoflex III) and then treating the fever events symptomatically with Metacam or dipyrone depending on the severity of the fevers.  (Injectable dipyrone will stop a fever in its tracks at low doses - it has been shown to block IL-1 beta induced fever, which I think may be our culprit.)

Q:  What guidelines do you use to evaluate clinical improvement?

A:  As I pointed out in another posting, that's the rub.  Since most patients are expected to have a few fevers while young then have about a 2 yr respite then die of kidney failure, how do you evaluate the impact on fevers?  The ones that have been easy to evaluate are the ones that fevered regularly and routinely before colchicine.  If there is a marked change in their pattern with breaks whenever colchicine is stopped - those were easy.  The biggest difference I've seen is that I think the dogs are living at least 2 yrs longer on colchicine.  I used to see a big number of dogs dying in the 3-5 yr range, now my dogs on colchicine IF they get amyloidosis are in the 5 + yr range and many much older.  But how can I know if they would have gotten it at all??  I can't.  I can only go by my impressions from the group overall.

Q:  We don't have the data for evidence-based medicine yet. I am hoping that the results of current research will allow this soon. But I do think our clinical impressions have the weight of much experience and I'll be shocked to my core if I was totally wrong.  It is most unfortunate that neither of you have been able to have a computerized program that would extrapolate & compile statistics from your patient data with out any identifying information included in regards to these conditions.

A:  Unfortunately neither of us has computerized records.  Someone would have to go through all those files and compile the info from the last 15 yrs.

Q:  I think the most dismaying & difficult thing to deal with is the lack of any stats from breeders, the National club nor anyone! Not that I think it is necessarily the responsibility of yourself or Dr. Vidt to supply this but just the fact that the entire fancy has not been able to pull this together.

A:  I don't disagree.  As I pointed out earlier, there hasn't been a health survey conducted on FSF since the 1991 National Specialty.  It needs to happen and the results openly discussed.   I remember conducting this type  (Q&A) of open forum at Nationals over 10 yrs ago - we've been moving backwards in some areas.

Q:  Hi, I lost your original email reply to my question some time ago (my computer crashed and lost all the emails), but wanted to thank you for personally replying to my email about Bear (the 11 yr old hypothyroid bald horsecoat pei).

(1) I would like to know what are your thoughts on using a homeopathic form of colchicine?

A:  The honest answer is that I don't practice homeopathy routinely and have not used the homeopathic form.  I am not "against" homeopathy at all and do believe that it is a valid form of therapy but western medicine and homeopathy should not be prescribed together by someone inexperienced in the art so I don't. If anyone has any experience, I'd like to hear.

Q:  On your website, www.wvc.vetsuite.com/custom-content.asp, it states:

Colchicine.
* Used in humans for over 3000 years and most commonly used as a treatment for gout.
* Used in FMF patients to reduce the frequency and severity of painful fever episodes and prevent the development of amyloidosis.
* Before colchicine therapy, up to 30% of all FMF patients died prematurely (usually around age 40) of amyloidosis.
* I currently recommend the use of colchicine prophylactically in any Shar-Pei that I believe to have FSF as soon as I am convinced of my diagnosis. I do not recommend waiting until evidence of disease due to amyloidosis is seen. At that point, it is almost too late.
* I personally believe that this drug works in this disorder and is the best treatment option currently available. I would like to see double blind controlled studies done to prove this but so far no research has been conducted or funded.
* Dogs on colchicine may continue to experience some fever episodes. Some cease completely. Others commonly report a decrease in severity and frequency. Some owners report SHS without fever. I believe the colchicine works in dogs as it does in people: the control of fevers and the blocking of amyloid deposition are by two different pathways and on-going fevers are not evidence of worsening amyloidosis.
* There is no association between the number, frequency and severity of the episodes and the development or degree of amyloidosis.  A dog that experiences one single fever episode in his entire life is just as likely to get amyloidosis as the dog that gets them every 7-10 days. Any fever episode typical of FSF should be considered a marker that the patient is at high risk for amyloidosis. This is also why I do not recommend waiting to see if they ever get another episode before starting colchicine!

(2) The only reason why you recommend colchicine for FSF dogs is because it reduces fever and frequency?  If there is no association between number/frequency/severity then why would colchicine be helpful if it doesn't matter how many frequency/severity the dog experiences FSF? I'm trying to wrap my brain around this idea.

A:  No, that is not the "only reason” I would prescribe colchicine even if the only effect it had was to reduce the severity and frequency of the fever events – because sometimes they are so severe, the dog dies.  Sometimes they are frequent and severe – like the dog that regularly and routinely spiked to 108 degrees.  I've seen dramatic improvement in the severity and/or frequency in many dogs on colchicine and if we stop the drug, they return.  The first dog I dared to try it on back in the early 1990's was spiking fevers over 106 degrees every 7-10 days.  Even though the PDR scared me to death, we decided we had to do something and started colchicine. His disease subsided to 1 or 2 mild fevers/year after that and he died of cancer at about 11 ½.  But the real reason I prescribe colchicine is because the fevers are just a marker for their high risk for early death from amyloidosis. And even one fever event tells us that they are at high risk. Colchicine blocks the deposition of amyloid protein. So, there are two very important reasons I Rx colchicine and I consider the latter most important.  We have no idea if the alternative therapies that seem to be helping decrease or prevent fevers have any action on amyloid protein.  We do know that colchicine does.  You have to weigh the risk:benefit in each patient.

(3) Bear is experiencing more episodes lately, most unfortunately, though still quite mild as I give him pellets of arnica montana 30c (homeopathic remedy for acute pain relief), belladonna 30c (homeopathic remedy for reducing/breaking fever), rhus tox 30c (chronic pain relief) and a Bone & Infection liquid remedy (just used this all up last Saturday). From the onset of Bear's fever/episode to taking the remedies, the fever/inflammation is gone within 2 hours.  The leg swelling takes a little longer, but he's able to walk around. To me, that says a lot in effectiveness of the remedies in dealing with his pain, fever, inflammation of the FSF episodes. It was not mentioned on the website as to how long the episodes of dogs on colchicine last?

A:  As I said, I don't know much about homeopathy but this sounds very impressive.  Most fevers last anywhere from just a few hrs (many of my patients on colchicine do this) to around 36 hrs.  Sometimes the leg swelling does persist longer than the fever. Some dogs on colchicine get swollen hock syndrome without any fever. I tell people that if the fever goes over 48 hrs, you'd better be looking for another cause. One of the reasons we are trying to measure some of the immune mediators in Dr. Avery's project is so that we can assess other treatments. I want to see alternative therapies explored.

(4) I did send an email to Dr. Avery to confirm that if she really wants a blood drawn DURING an FSF episode. If so, the next episode, I'll bring Bear up to Colo State Vet Hosp and have blood drawn.  Bear's had his blood drawn by Dr. Avery twice (both during non-FSF episode). His CBCs were similar, consistent with anemia findings (he's been pretty much anemic for many years). He will have his hypothyroidism panel re-checked next week by Dr. Jean Dodds. I would like to know if there has been any speculation of hypothyroidism linked to FSF/Amyloid?

A:  Dr. Vidt and I have not seen any association but hypothyroidism is not uncommon.  Thank you so much for participating in Dr. Avery's study. We are all very grateful to the very special people who went so far out of their way to cooperate with this important research!

 
Q:  Is there any correlation between mast cell cancer and the development of amyloidosis?  My understanding is there is a great deal of inflammatory response and autoimmune reaction in mast cell and I've wondered if that situation could set the stage for the development of amyloidosis... or is it more along the lines that it isn't a cause-effect situation, but rather that they're different manifestations of autoimmune dysregulation?

A:  Dr. Jeff Vidt and I have discussed this and we don't think so. My first Shar-Pei had to be euthanized at age 16 1/2 because of a basketball sized mast cell tumor on her neck (at her age, I never thought it would get that big or I'd have taken it off a LOT earlier).

The mast cell is the white blood cell that carries the granules of histamine inside. When they break apart and release them... well, you all know why and when you need an anti-histamine. They are one of the most important mediators of allergic reaction. They are not considered important in the paths that lead to an increase in APP, the precursors to amyloid.

I think it does involve their general dysregulation and predilection for allergic disease. I often find mast cells in areas of cutaneous mucinosis on fine needle aspirate and they are not necessarily a sign of cancer. (This makes it extremely difficult to decide how to proceed - I usually err on the side of wide excision now because if you are wrong, you missed your only chance to save them.)

Q:  What percentages of Shar-Pei, in your estimate, have FSF?  What percentage of those goes on to develop renal failure, and what percentage develop amyloidosis?  What percentage of Shar-Pei who do not have FSF have amyloidosis... basically, how prevalent do you feel these disorders are?

A:  A survey done at the 1991 CSPCA National Specialty and data from records at my own and Dr. Jeff Vidt's practice suggests that the incidence of FSF in Shar-Pei was about 23-28% affected. I believe the incidence may be higher now. It is time for another survey.

Only a very small percentage of Shar-Pei with renal amyloidosis have no history of fevers before the onset of their kidney failure. Some dogs crash and decompensate into failure with their "first" fever episode and I have seen several dogs have fever spikes after they were diagnosed and being treated for chronic kidney disease. It is the background inflammation that causes their amyloidosis.

I often get referrals of patients with chronic kidney disease so my practice population is skewed so I couldn't say what the overall incidence of amyloidosis is.

Q:  You mention that there is a "tendency for amyloidosis to skip a generation" and to never breed two "known affected or carriers to each other".   How can we determine who is a carrier?  Do we have to assume that all offspring from a dog who is CRS-positive are carriers and thus not be bred?  What about a dog who dies in old age from causes unrelated to FSH/A and is incidentally found to be CRS+ positive.... does that carry a different weight in terms of breeding decisions than a dog who did die because of amyloidosis?  If such a dog was healthy otherwise and its offspring were healthy (and bred and produced their own offspring, who are also healthy), how does one make heads or tails of that in making breeding decisions?  (I know, it's probably easier to pick the winning lottery number than to answer that :)

A:  I almost never say "never" VBG  The biggest problem facing breeders today is the lack of diagnostic and prognostic tests for this disease.  You have no way of knowing for sure who is affected and who is not.  The heredity paper I published with Cornell:

Rivas A L, Tintle L, Meyers-Wallen V, Scarlett J, van Tassell C, Quimby F W. Inheritance of Renal Amyloidosis in Chinese Shar-Pei Dogs. J Heredity (1993)84/6:438-442  (this is up in its entirety on my website under "published papers")


This project allowed me to look at hundreds of pedigrees and talk with most of the original-founding breeders of our dogs.   This is the Abstract from that paper:

Renal amyloidosis (RA) and recurrent fever of unknown origin (RFUO) are characteristics of Familial Mediterranean Fever (FMF), a human disorder inherited as an autosomal-recessive trait.  Although no animal model has been established for FMF, a similar syndrome of RFUO and RA has been reported in Chinese Shar-Pei (CSP) dogs. This report addressed two questions: 1) is RA inherited in CSP dogs and 2) if so, is it possible to hypothesize the type of inheritance involved? Two studies were conducted to answer these questions. A historical cross-sectional comparison, which included CSP and non-CSP dogs with RA; and a prospective study that included CSP dogs with RA, RFUO or both. The cross-sectional comparison resulted in an odds ratio of 10 for RA in CSP dogs under 7 years of age.  A prospective study of 28 dogs with RA or RFUO identified 20 that had RFUO and RA, three with RA alone, and five with RFUO alone. RFUO preceded RA in all cases with both conditions. RFUO/RA were observed in both sexes.  Four dogs with RFUO with/without RA were born to parents that either were alive at age 7 or died because of conditions other than kidney failure/RA. When one parent was known to express one of these conditions, prevalence of RA was between 25% and 50% among littermates.  The results of both cross-sectional and prospective studies support the hypothesis that RA is inherited in CSP dogs in association with RFUO, that they develop RA at a younger age than non-CSP dogs, and that the acquisition of this trait is compatible with autosomal recessive inheritance.  However, further studies are needed to discriminate between simple (single-gene) and polygenic (multiple-gene) autosomal recessive inheritance of this condition.  In sum, these finding support previous reports that indicate that CSP dogs with combined RFUO/RA may provide an animal model for human FMF.

I hope the DNA studies at NIH will clarify the situation further (and soon).  But I would at this time assume all the offspring of a dog that died of A. to be carriers.  And carrier X carrier can yield 25% affected (amyloid affected) dogs even if those two have never spiked a fever in their lives.  This is why I think we see it often "skip a generation".  I have seen fevers but never amyloidosis in Shar-Pei mixed breed dogs and this would support this hypothesis.  I don't know if it increases the amount of APP in the offspring when you double up or if the mutation must be homozygous for the amyloid to be improperly eliminated.  All that is speculation.

And right now, breeding a "healthy" Shar-Pei is impossible to do with complete certainty and it is not any breeder's "fault".

Q:  There seems to be a very high number of dogs with FSF who go on to develop renal failure, which I have come to think is an autoimmune glomerulonephritis caused by their autoimmune dysregulation.  Could you speak a little about what you see as the incidence of renal failure in FSF, is it one of the biggest complications of FSF (as it seems to me).... and if the renal failure is not an autoimmune glomerulonephritis, what would you characterize it as, and what steps might one take to help protect/preserve renal function in an FSF dog?

A:  The majority of dogs that died of kidney failure and had a history of FSF that were examined histopathologically post-mortem at Dr. Vidt's practice and mine had amyloidosis.  However, there was a very significant portion of dogs that were not CRS positive and had glomerulonephritis.  When we looked at these dogs, they did have immune complexes in the glomerular region.  So IMO, these dogs very likely also died of complications of their auto-inflammatory disease even if they did not have amyloidosis.  I also saw quite a few dogs with old evidence of pyelonephritis so I do think their immune dysregulation can lead to low-grade kidney infections too.  (I think some of the "Baytril-responsive" FSF dogs may fall in this category).   Re: protect and preserve kidney function:  We now know that dogs need a diet rich in high quality protein but that once their kidney values (BUN, creatinine, phosphorus) become elevated, they do better over time on a carefully formulated protein restricted diet.  I think it is very risky to feed a high % protein diet to any Shar-Pei unless it is a strenuous working dog (like hauling sleds or something) because you don't know when the dogs that have latent (hidden) kidney disease will decompensate and be unable to handle the excess.  What you want to do is feed them exactly what they need, no more and no less.  I would recommend a diet with high quality protein (many lower grade commercial dog foods are from unidentifiable parts of the carcass - they make these into hot dogs and dog food) - not more than 24% and I think Shar-Pei can often thrive on 16-18% if its from good sources and they are couch potatoes - a diet that is well-balanced in favor of omega-3 fatty acids, high in anti-oxidants, vitamins and minerals (getting enough calcium can be tough).  Avoid diets rich in polyunsaturated fatty acids that may become quickly rancid.  (I like coconut oil myself but it is expensive.)  I commend those of you trying to cook for your dogs.  I am trying to eat a healthy diet and finding it almost impossible since I don't eat meat - I don't have time for all this cooking!  The best way to reduce their incidence of renal disease is to decrease their overall levels of chronic inflammation and evaluating how to do this safely is one of main reasons we are measuring the immune mediators in Shar-Pei at Dr. Avery's lab.  The pathologist that looked at the lesions in the Familial Amyloidosis study at Cornell described the histopathology of S-P with amyloidosis as this:

Gross lesions are limited to the kidneys and lymph nodes. Kidneys of dogs in renal failure are of normal size or moderately shrunken, and have an irregular, nodular subcapsular surface due to multifocal cortical fibrosis.  Histologically, there is multifocal non-suppurative tubulointerstitial nephritis with fibrosis.  Medullary amyloidosis predominates and glomerular deposition, although consistent, is highly variable in its extent.  Uncommon findings include pyelonephritis, suppurative subcapsular inflammation and cortical pseudocyst formation.  Lymph nodes may have a normal gross appearance or may be enlarged.  Medullary pseudocysts containing inflammatory debris may be present.  Histologic changes occur consistently, even in animals without a history of recurrent fevers and include cortical atrophy, sinus histiocytosis, medullary hemorrhage, erythrophagocytosis and hemosiderosis.  Lymph node sclerosis is seen in chronic cases.  Amyloid is consistently deposited in vessel walls and the lymph node capsule and may occasionally be seen within macrophages.  The spleen frequently has marked follicular atrophy.  Amyloid deposition occurs within the Space of Disse in the liver, at the corticomedullary junction of the adrenal gland and in vessels throughout the body.

Amyloid deposits are secondary or reactive in nature.  Renal cortical biopsies may fail to diagnose this condition if insufficient medullary tissue is obtained.