Familial Shar-Pei Fever
Shar-Pei Fever and Amyloidosis
Linda J.M. Tintle DVM
Familial Shar-Pei Fever (FSF)
is a periodic fever syndrome that is characterized by random
inflammatory events with high fever, sometimes with swelling about
joint/s or muzzle, that usually last 12-36 hrs.
autoinflammatory syndrome (not autoimmune).
Hyaluronanosis: Shar-Pei over-express Hyaluronan Synthase 2
and excess hyaluronan (HA) leads to their unique skin
thickening and wrinkles because of a regulatory mutation.
The mutation is a duplication that occurs in multiple copies.
Individual Shar-Pei dogs vary in the number of copies of this mutation
from dog to dog. The mutation is a copy number variant or “CNV”.
Excess cutaneous mucin may form vesicles or bubbles in the fragile
skin. Hyaluronan health is integral to Shar-Pei health. Damaged or
degraded low molecular weight hyaluronan is a “damage associated
molecular pattern” (DAMP) that can activate the innate immune system.
Native high molecular weight HA is health promoting and healing. You
may improve Shar-Pei health by preventing or offsetting damage to their
Their underlying genetic defect is an unstable duplication in a
regulatory gene upstream of Hyaluronan Synthase 2 (HAS2) that is
described as the “meatmouth” mutation in our March 2011 article
published in PLoS Genetics. Original, traditional-type Shar-Pei with
less padded muzzles, less skin thickening and wrinkling have a slightly
different mutation in this same location. The “meathmouth” mutation
appears to predispose Shar-Pei (and some Shar-Pei mixed breeds) to
inappropriate inflammatory responses. This may result in chronic
elevations of inflammatory chemical messengers in the bloodstream.
Shar-Pei may have abnormal initiation and also amplification of
inflammation as a result of this genetic copy number variant (CNV)
mutation. They may over-react to infection and damage.
The greater the number of copies of the mutation present in the dog, the
more reactive inflammation may result when HAS2 is up-regulated.
Hyaluronan is also degraded and turned over rapidly: in hours, days, or
weeks depending on its location. The breakdown of HA into fragments for
elimination may also contribute to autoinflammation.
Low molecular weight fragments of hyaluronan both activate and prime the
inflammasome leading to the release of IL-1beta and then IL-6, two major
drivers of fever and inflammation. Mutations leading to aberrant
inflammasome function have been associated with the human
autoinflammatory syndromes Familial Mediterranean Fever (FMF), TRAPS,
CAPS and gout.
Shar-Pei with Familial Shar-Pei Fever (FSF) may show the following
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. Fever greater
than 106 degrees is a medical emergency and owners should seek
veterinary treatment for the hyperthermia.
Without fever, it is NOT “classic” 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. It
is possible for the fever events to be brief, lasting only a few
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 (swollen
hock syndrome). Of the dogs that had experienced
periodic fever episodes, approximately 53% had experienced swollen
hock/s at some time along with the fever when owners at the CSPCA
National Specialty were surveyed in 1994. Be careful not to mistake
the normal "socks" (excess wrinkling around the hocks) on some
individual Shar-Pei for the acute swelling that occurs surrounding
the hock during or around the time of a fever episode.
Sometimes a swollen painful muzzle.
Abdominal pain, reluctance to move, "roached" back, mild vomiting or
diarrhea, shallow rapid breathing. The proinflammatory cascade give
the dogs flu-like symptoms and similar discomfort.
CBC blood test will usually show neutrophilia (although neutropenia
may occur early in the course), and often monocytosis due to
activation of neutrophil and monocyte chemotaxis. Shar-Pei with FSF
may have elevated alkaline phosphatase, hypercholesterolemia,
hypomagnesemia, hyperglobulinemia and slight elevations in total
bilirubin on blood chemistry panel.
is a disease caused by abnormal deposition of the breakdown products of
chronic inflammation in the extracellular matrix (between cells). The
severity of disease and risk for amyloidosis will vary with the amount
of inflammation initiated and the autoinflammatory over-reaction. The
chronic background inflammation puts affected dogs at risk for
developing reactive systemic amyloidosis which can lead to early death
from kidney failure.
Not every dog with FSF will develop amyloidosis but the fevers are a
warning sign that they have aberrant autoinflammation and are at high
risk for kidney disease.
Shar-Pei with FSF can live to over 10 yrs of age. Two
of my mother’s Shar-Pei lived to 12 ½ and 15 ½ years respectively with
lifelong FSF and this is not uncommon in my patients. By doing
everything you can to reduce their chronic inflammation and monitor
their disease, you can help them live their best possible lives -
however long that may be. Unfortunately, a combination of genetic
predisposition (increased CNV) and environmental influences may lead to
early death from kidney or, more rarely, liver failure due to
amyloidosis in some individuals.
diagnosis of Shar-Pei Fever is made after ruling out other causes of
fever with diagnostic tests indicated by the dog’s
condition but a minimum baseline of first morning urinalysis, CBC,
chemistry profile, T4, +/- panel for tick-borne diseases is common.
Other tests, including those for autoimmune disorders, may be needed.
It is a diagnosis by exclusion at this time. I am collaborating with
Dr. Kerstin Lindblad-Toh and Mia Olsson on a
genetic test using the CNV mutation that is currently in
development and undergoing validation studies at the Broad Institute of
MIT and Harvard and Uppsala
Sweden. A commercial test that is
accurate, meaningful and useful to veterinarians, Shar-Pei owners, and
breeders is the goal of the on-going study.
Because fever events are a marker for the presence of autoinflammatory
therapy should be started early to prevent complications.
Some dogs have only one observed fever event yet die prematurely from
amyloidosis – the number and frequency of fever events does not
correlate with the severity of underlying chronic inflammation. In rare
instances, dogs may die of amyloidosis without any observed fever events
or may have their first fever after going into kidney failure.
My current treatment recommendations for Shar-Pei Fever include
0.025-0.03 mg/kg of
colchicine twice daily or less to bowel tolerance. I
recommend that the dog be started on a low dose once daily and then
gradually increased to the maximum recommended amount (up to the
calculated dose above) as tolerated without diarrhea once or twice
daily. For most average weight Shar-Pei, this is one 0.6 mg tablet
given twice daily. Colchicine is a potent drug but it accumulates in
white blood cells (the desired target for treatment) and GI signs occur
long before other serious side-effects.
I have never seen evidence of any damage from colchicine except for a
transient, treatable diarrhea that goes away when the drug is withdrawn
in sensitive patients. Colchicine treats the underlying pathology by
blocking the movement of neutrophils (one of the white blood cells),
decreasing levels of cytokines (the messengers of inflammation) and
blocking the formation of amyloid protein (a waste by-product of
inflammation). In humans, it has proven to be safe in infants, pregnant
women and when given lifelong. Treatment is for life. I have been using
the drug since 1993 and have had individual patients on the drug safely
for over 10 yrs. Some dogs cannot tolerate colchicine without chronic
diarrhea and they are given smaller amounts or none if it is severe.
Colchicine and cyclosporine (Atopica®) should not be given together
because of increased risk of bone marrow suppression.
Currently, sale of colchicine has been restricted by the FDA
to one manufacturer, URL Pharma, under the brand name "Colcrys®" with an
exorbitant price increase. URL Pharma is instituting a Patient
Assistance Program for Shar-Pei that is to be administered by NeedyMeds.
There is an application for the program (income adjusted fee structure)
but the application is not yet on
www.NeedyMeds.org website as of April 4, 2011. The application may
be obtained by calling
888-811-8423 at this time. Applicants must provide a
valid Colcrys prescription from a licensed veterinarian, and must attest
that Colcrys will be used solely for their Shar-Pei dog. Applicants who
qualify for the program will be able to select a 30-day supply (60
tablets), 60-day supply (120 tablets) or 90-day supply (180 tablets) of
Colcrys. Those receiving financial assistance must re-apply for the
program annually. The prescribing veterinarian must complete and sign
several portions of the application. Colchicine may also be prescribed
and purchased legally through compounding pharmacists in tablets or
I treat the fever events with 50%
dipyrone (500mg/ml) injectable (usually 0.5-1.0 ml/dog
under the skin), or meloxicam (Metacam®),
a non-steroidal anti-inflammatory drug or NSAID (by weight per package
insert instructions). Dipyrone is an IL-1 beta inhibitor that is
available from compounding pharmacists as injectable or in oral
suspension or may be purchased over-the-counter in many non-U.S.
Aspirin has also been
reported to be effective. Some fevers are very serious and
can require emergency veterinary
treatment if they approach or exceed 106 degrees F (41° C).
Shar-Pei owners should discuss treatment of acute fever events with
their veterinarian because treating the fever as early as possible in
the inflammatory cascade can often stop it from becoming
life-threatening and it is best to have medication available on-hand at
home. Avoid giving NSAIDs with corticosteroids like prednisone and your
veterinarian should be alerted your dog is vomiting because gastric
ulcers can be a common complication.
Use caution with ice packs or baths: external cooling efforts should be
reserved only for those dogs with fevers approaching 106 degrees while
en route to a veterinarian. Unless the dog’s internal thermostat is
reset with medication, the dog’s body will simply work harder to keep
the fever up and may prolong the fever event. An ice pack wrapped in a
damp towel that is placed in the groin area will help cool the patient
en route to emergency care.
Some fever events may be initiated by
infection. If the fever is severe, persistent and/or
poorly responsive to anti-fever drugs like dipyrone, aspirin or NSAIDs,
there may be an underlying infection that needs treatment. Veterinary
care should be sought whenever the fever is severe, worse than usual for
that dog, lasts longer than 48 hrs or is not responding to
anti-inflammatory medication. In rare instances, a neutrophilic
vasculitis and/or septic shock-like syndrome (STSS) with skin sloughing
can occur. The latter is often associated with bacterial hyaluronidases
that break down the abundant mucin in Shar-Pei skin.
Your Shar-Pei should get
regular and routine monitoring of first morning urine with urinalysis
(UA) as well as a CBC, blood chemistry profile and T4.
Urine Specific Gravity at or below 1.020 is often the first sign of Shar-Pei
kidney trouble and, if present, the UA should be repeated to see if the
dog has a consistently low specific gravity. Medullary
amyloidosis is the most common kidney disorder in Shar-Pei and
proteinuria is usually a late-stage event. Urine protein levels should
also be monitored and a urine protein to creatinine ratio performed if
proteinuria is found on routine UA. FSF patients should be examined
and tests performed whenever they are not eating normally, if they are
vomiting, having diarrhea for more than a few days, acting sick in any
way or if they are just “not right”. The bare minimum is annually in
the healthy active young dog and many dogs should be checked more often.
Shar-Pei are prone to mast
cell disease including mast cell tumors. The binding of
HA to its receptor CD44 has been shown to play a critical role in
regulation of murine cutaneous and connective tissue mast cell
proliferation. It appears that CD44-HA regulates resident cutaneous
mast cell populations. As the CD44-HA interaction may modulate local
immune responses through regulation of mast cell functions, excessive HA
and its subsequent damage and degradation may also play a role in the
breed’s predilection for allergic skin disease and other mast cell
Corticosteroids (for example medications like prednisone or
dexamethasone) or cortisol produced by the dog’s body during stress
(this may happen during a high fever or when ill) can shut down the
production of hyaluronan by HAS2. These
steroids may shrink the Shar-Pei’s muzzle and they may
lose wrinkles. Very low dose prednisone is sometimes used for this
reason to treat severe vesicular cutaneous mucinosis (bubbles of mucin
in skin) or lymphedema of the hocks (chronic swelling due to fluid
buildup). A Shar-Pei that has a suddenly shrunken muzzle for no
apparent reason should get a full physical exam and lab tests.
Addressing Hyaluronosis (the downside
to Shar-Pei Wrinkles):
1. Feed a High Quality diet low in simple
carbohydrates: grain-free or containing small amounts of whole healthy
fresh grains if possible. Pasture-fed meat source is preferable if
money is no object (grain-fed meat has a high ratio of omega 6 to omega
3 fats and is lower in antioxidants and conjugated linoleic acid). The
goal is to shift the arachidonic acid pathway away from pro-inflammatory
end-products. A high dietary omega 3 to omega 6 fatty acid ratio may
help reduce inflammation and result in improved overall health
(including decreased anxiety!).
2. High dose omega 3 fatty acids from fish oil daily.
Again, shift to anti-inflammatory end-products but also for its
resolvins and other inflammation-resolving mechanisms at high doses. A
high dietary omega 3 to omega 6 fatty acid ratio may help reduce
inflammation and result in improved overall health including decreased
(900-1800mg EPA, 450-900mg DHA/day – source is important to ensure no
rancidity or contaminants).
1-2 Tbl of granules (7.5 – 15 gms) per day in food. To alter the
choline composition of the “hyaluronasome” in plasma membrane lipid
rafts; may impact how HA fragments are internalized for further
a formulation of my recommended vitamins, minerals, antioxidants and
phytochemicals that were chosen for their HA health promoting effects.
Magnesium is integral to stabilizing HA in its high molecular form and
magnesium deficiency is a very common finding in the breed. Severe
cobalamin (Vitamin B12) deficiency is also common in Shar-Pei. This
supplement was developed because it was difficult for clients to
purchase the correct canine dosages using over-the-counter products
designed for humans. Working with a trusted manufacturer has allowed me
to be assured of purity and quality: Made in
in a cGMP facility.
(Average Shar-Pei dose contains 50-80mg Alpha Lipoic Acid, 60mg Coenzyme
Q10, 100-200mg Magnesium citrate, 1000 mcg Methylcobalamin, 25mcg
Vitamin K2 and a proprietary blend of Boswellia Serrata, Curcumin,
Diosvein™ Diosmin & Biotivia™ Trans-Resveratrol).
HyVitality is dosed by weight. More information at
500mg. Shar-Pei with excess HA may need more antioxidants like Vitamin
C. Also, I suspect that Shar-Pei may not synthesize adequate Vitamin C
because Vitamin C and HA compete for similar biochemical synthetic
pathways (both are formed by glucuronidation).
Vitamin D3. Active Vitamin D modulates the over-active
toll like receptors (TLRs) in inflammatory disease, returning them to a
more normal functionality. HA fragments bind to TLRs to activate the
pro-inflammatory cascade. Shar-Pei on home-cooked diets or who are fed
commercial diets and supplemented more than 10% of their calories with
"extras" or who have active inflammation may have additional or
increased need for Vitamin D3. Need for Vitamin D3 in dogs has been
estimated to be 50-475 IU per 10 lbs of body weight per day. Most dogs
on commercial diets get at least this in their diets but more may be
needed if a dog is not on a balanced commercial dog food, has severe
allergies, arthritis or chronic inflammation. Discuss baseline testing
with your veterinarian if you are concerned that your dog may need
7. Thyroid Function: Treat any signs of secondary
hypothyroidism with thyroid supplementation. Common signs include very
sparse or missing coat, particularly along the back and inside of the
thighs and hindquarters, with a generally brittle, lighter coat on the
torso. HA fragments may down-regulate TSH releasing hormone via TLR2
binding, leading to clinical hypothyroidism characterized by low or low
normal TSH and very low to low normal T3/T4 and I am looking this in
Shar-Pei now. Response to therapy will be softer, thicker, and richer
colored fur with hair re-growth, especially on hindquarters, and
improved overall health and activity if the dog is functionally
hypothyroid. Your veterinarian will monitor therapy to keep T4 below 4
8. Probiotics and attention to bowel health. Skin and bowel
are the immune system's biggest barriers and they are both HA rich
areas. Inflammatory bowel diseases including colitis are very common in
the breed. Some cases of FSF flare-ups and increased frequency of fever
events have responded to treatment directed to eliminating over-growth
of pathogenic GI bacteria in IBD patients or stress colitis.
diarrhea is frequent or persistent, discuss diagnosis and possible
treatment with prescription drugs with your veterinarian.)
9. Fanatical attention to skin and ear issues. Bathing
by shampoo or washcloth wipe-downs as needed (microfiber dust cloths
work well) - up to daily when skin is inflamed and at least every 2
weeks in a "healthy" Shar-Pei. Remove superficial yeast, bacteria
(potential sources of hyaluronidases, enzymes that damage HA) and
allergens like pollens, molds, dust that may activated mast cells. At
least weekly ear cleaning/flush unless the Shar-Pei has a large, open,
healthy ear canal.
10. Low dose 81 mg aspirin:
¼ - ½
tablet per day in
dogs with no signs of gastric upset. Platelet derived growth
factor might be an important mediator in their disease and aspirin
also decreases risk of thromboembolic events. Be cautious as the breed
has an increased risk for GI ulceration.
11. Detect problems early: Your veterinarian should see your
Shar-Pei regularly for a complete physical examination and regular,
routine monitoring of first morning urine with urinalysis (UA) as well
as a CBC, blood chemistry profile and T4.
Eliminating inflammatory triggers, supporting healthy hyaluronan,
reducing silent chronic inflammation wherever possible, providing good
nourishment and playful daily exercise are key to Shar-Pei health.
More Information from Dr. Tintle
Listen to a podcast from AKC on Shar-Pei Fevers