• Have one or more bouts of unexplained fever, usually 103-107 degrees F (39.4-41.7 degrees C) but rare cases may go higher.
• If they do not have a fever, it is NOT FSF. (Assuming not on colchicine).
• Fevers usually start before they are 18 months old but adult-onset attacks are not uncommon.  Fever episodes usually become less frequent with age.
• Fever episodes last 24-36 hours in most cases without treatment.
• Of the dogs that experienced fevers, approximately 53% had experienced Swollen Hock Syndrome (SHS) at some time along with the fever.
• Be very careful not to mistake the normal "socks" (excess wrinkling around the hocks on some Shar-Pei) for SHS.
• One or more of the following signs may accompany fever episodes:
  
  • Swelling around a joint (cellulitis) with or without inflammation of the joint itself.  One or more joints may be affected but most cases involve the tibiotarsal or hock joint (SHS).
  • Sometimes a swollen painful muzzle.
  • Abdominal pain, reluctance to move, "roached" back, mild vomiting or diarrhea, shallow rapid breathing.

Familial Mediterranean Fever (FMF) vs. FSF - FMF is:

• An autosomally recessive inherited periodic fever disorder of humans. The hereditary fever syndromes are inherited disorders characterized by self-limited episodes of fever with inflammation of joint or body cavity linings without any apparent infectious cause.
  
• Characterized by recurrent bouts of fever, usually starting in childhood.
  
• Polyserositis (inflammation of the thin membranes that line certain cavities of the body... joints, abdomen, chest, etc.) resulting in abdominal, chest and joint pain, usually involving the knee or ankle.
  
• Swelling/inflammation of the skin about the ankles or top of the foot.
  
• Free from symptoms between attacks.
  
• May develop amyloidosis.

Shar-Pei with FSF have abnormally high resting levels of a cytokine called Interleukin-6 (IL-6).

• IL-6 turns on various parts of the immune system.  It is involved in controlling the fever response and is a trigger, alone or with other cytokines, for the production of the acute phase reactant proteins (APP) of inflammation... the precursors of Amyloid AA. Chronically elevated levels of IL-6 and other cytokines lead to chronically elevated levels of the APP.
• The APP are normally produced during active inflammation.  The healthy animal breaks down the APP soon after the injury or disease and the toxic wastes are excreted from the body.
• Amyloidosis occurs when the APP cannot be broken down normally by the animal because of a defect in metabolism or when a large amount of APP continuously overwhelms the body's ability to get rid of it.  Amyloid is then deposited outside the cell walls and not eliminated from the body.  The build-up of the waste product amyloid is what causes the disease.  Amyloid may be detected in many different organs and in blood vessels.  In the kidneys, the damage is irreversible and usually results in kidney failure and subsequent death of the dog.
  

FSF is an autoinflammatory disease characterized by dysregulation of the normal paths of inflammation.

Inheritance of FSF and Amyloidosis in Chinese Shar-Pei.

• Published research indicates that this trait is compatible with an autosomal recessive inheritance. (AL Rivas, L Tintle, JM Scarlett, CP van Tassel, & FW Quimby Journal of Heredity 1993; 84:438-442.)
• My personal opinion, based on my experience and pedigree analysis, is that heterozygous carriers may (or may not) experience fevers +/- SHS but do not die prematurely from amyloidosis.  I believe the homozygous animals (which usually but not always experience fevers +/- FSF) are the ones dying prematurely from amyloidosis. There is evidence that environmental influences are also important in whether or not an at-risk individual develops amyloidosis.
• Private communication with many of the original breeders and importers of these dogs has led me to believe that many of these imported foundation dogs were affected by this immune system dysregulation.  Since all lines go back to this same small genetic pool of dogs, it is not surprising that the problem is widespread throughout the breed and throughout the world.
  

In people with "Phenotype II" FMF, signs of amyloidosis may precede outbreaks of fever or the patient may never experience or report any fever.

Fever episodes should be considered to be an important marker that the dog is at extremely high risk to develop amyloidosis and should be carefully monitored BUT not all FSF patients will develop amyloidosis.

Amyloidosis>>> kidney failure or, less commonly, liver disease/ failure.

Amyloidosis is a killer.

• Deaths have been reported to me as young as 8 months of age and as old as 12 years of age.  It most commonly strikes between 3 and 5 years of age.
• Amyloidosis can only be diagnosed by surgical biopsy or by tissues obtained at autopsy.  The abnormal amyloid protein is identified with special stains when examined under the microscope.

Frequency of FSF.

• 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 is about 23-28% affected.  I believe the incidence may be higher now.

How is FSF diagnosed?

• No single test is yet available
• Still a clinical diagnosis by history, signs and excluding the other possibilities.
• Blood tests are usually negative/normal except that an elevated white blood count with a left shift is not uncommon as is mildly elevated alkaline phosphatase levels.

I perform the following minimum database on patients with possible FSF and then at least annually thereafter:

• Complete blood count (CBC) with differential, serum chemistry panel, and complete urinalysis (UA) on a first morning urine sample.

I also routinely recommend these tests on all bitches prior to breeding and studs at least annually!  There are few worse horrors for a breeder than having the stress of pregnancy cause a bitch to go into kidney failure and die before the pups are a few weeks old and then having to raise a litter of orphan puppies which you know are carrying the gene for amyloidosis.

• Lyme Disease (Borreliosis) and other tick borne diseases should be ruled out in endemic areas.  Do not forget to consider Leptospirosis where endemic.
• If UA suggests an increased amount of protein is being lost in the urine, I recommend a urine protein to creatinine ratio be run on the urine.  Most affected Shar-Pei have medullary amyloid and may or may not have proteinuria (unlike humans) but proteinuria is always a significant finding.  Loss of ability to concentrate urine (specific gravity consistently 1.010 to 1.022) is a more common early indicator of a problem.
• Immune panels, joint taps, radiographs, cultures, immunoglobulin levels, and other diagnostic procedures are sometimes needed in individual cases.

Treatment of FSF episodes.

• Tender loving care, close observation of body temperature and otherwise benign neglect.
• Buffered aspirin, Metacam (metacarpfen) - Canadian S-P owners have reported that this has worked very well in reducing fever and I am starting to recommend having it on hand to my clients' whose dogs experience episodes of fever now that it is available in the U.S.
• 1.0 ml of 50% Dipyrone SQ, or Banamine (flunixin meglumine) to reduce fever and provide pain relief, particularly for fevers > 105 degrees.
• Extremely high fevers or other systemic inflammatory response syndrome (SIRS) may indicate that rapid aggressive iv fluid therapy and shock treatment is necessary in some very rare cases.  FSF episodes can be fatal and should never be shrugged off as inconsequential.
• There is no infection and therefore, antibiotics are unnecessary unless the veterinarian is concerned that the stressed dog may be secondarily infected.
  

Recently, a few cases of severe pustular dermatosis with high fevers and vast sloughing of skin have been reported to or seen by Dr Jeff Vidt and I.  These seem to resemble the "flesh eating" Streptococcus infections reported in humans (although other bacteria have been cultured as well) and require aggressive antibiotic and supportive treatment.  These can be fatal even with treatment.  A recent reports suggest that this is an immune mediated vasculitis and steroids +/- azathioprine may be indicated.

Acute febrile neutrophilic vasculitis of the skin of young Shar-Pei dogs.
Aust Vet J 80[4]:200-6 2002 Apr

Immune-mediated vasculitis in a shar-pei with swollen hock syndrome.
Can Vet J 42[2]:137-9 2001 Feb

I have seen most of my cases of this start with a “routine” FSF episode which for some unknown reason triggers the immune mediated vasculitis and sloughing.  Here is a photo of a very severe case that did survive despite lesions covering large portions of her body:

This is a very, very rare complication of an FSF episode.

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.
• We have had some Shar-Pei on colchicine for over 7 years and I have yet to see evidence of any serious side effects other than gastrointestinal disturbances (diarrhea +/- vomiting) which resolve when the drug is withdrawn.  Some dogs are, however, unable to tolerate the drug because of associated diarrhea.  Others seem to tolerate a reduced dosage.
• In FMF treatment, the drug has been shown to be safe in children as young as 3 years of age, in pregnant women, and when given lifelong.  Fatalities associated with massive overdoses have been due to bone marrow suppression.  I have monitored CBC's in my patients and have not seen evidence of bone marrow suppression but this should always be kept in mind.
• I recommend once daily treatment with 0.025-0.03mg/kg for 2 weeks and if no gastrointestinal problems have occurred, I double the dose to twice daily. For your average Shar-Pei, this is one 0.6 mg tablet twice daily. 
• 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!

Most Common Signs of Advanced Amyloidosis.

• Unexplained weight loss.
• Increased thirst and frequency of urination.
• Vomiting
• "Bad Breath" as a result of uremia (the buildup of toxins/wastes in the bloodstream as the kidney +/- liver fails to process them).

How is Amyloidosis Treated?

• Slow the progression of irreversible kidney disease with dietary management and supportive care... prescription kidney diets, omega 3 fatty acids, low dose aspirin therapy, ACE-inhibitors (benazepril or enalapril), and antioxidants may be indicated in individual cases.
• Thromboembolism "throwing a clot" is not uncommon in these patients and is why ultra-low dose (0.23mg/lb/day or roughly 1/4 of an 81mg baby aspirin once daily) may be recommended.
• Liver disease often shows up as severe jaundice along with weight loss, vomiting and inappetance.  These cases seem to have a better prognosis than those primarily affecting the kidneys and have shown good response to colchicine therapy with survival times over 4 years possible.

Other causes of kidney failure in Shar-Pei (or... Why you need to get the biopsy/necropsy specimens).

• Glomerulonephritis
• Pyelonephritis
• Renal Infarcts

You cannot assume that every Shar-Pei that died of kidney failure had amyloidosis.  It is, however, the overwhelming cause of premature death in the breed.

rev. 6-10-05