Familial 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 face, that usually last 12-36 hrs. FSF is an autoinflammatory syndrome (not autoimmune). The underlying genetic defect appears to cause inappropriate inflammatory responses to danger signals recognized by the innate immune system and chronic elevations of inflammatory chemical messengers in the bloodstream. This complex disorder may involve multiple interactive genetic mutations. Shar-Pei may have abnormal initiation and also amplification of inflammation.
Amyloidosis 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. 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 and environmental influences may lead to early death from kidney or, more rarely, liver failure due to amyloidosis in some individuals.
Your veterinarian will usually make the diagnosis of Shar-Pei Fever after ruling out other causes of fever with diagnostic tests indicated by your 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 that is currently in development and undergoing validation studies at the Broad Institute of MIT and Harvard and Uppsala University in Sweden. I am also very grateful for the many years of support and assistance of Drs. Dan Kastner, Elaine Remmers, Francesca Puppo and the team at the NIH-NIAMS in discovering why Shar-Pei suffer from this fever disorder. The current research is very much an international team effort.
Because fever events are a marker for the presence of autoinflammatory disease, 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.
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 available from compounding pharmacists. 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). You will need to discuss treatment with your 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 alert your veterinarian if 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 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.
Hyaluronosis: Shar-Pei overexpress Hyaluronan Synthase 2 (HAS2) and excess hyaluronan (HA) leads to their unique skin thickening and wrinkles. 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 danger associated molecular pattern that can activate the innate immune system.
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):
High Quality diet low in simple carbohydrates: grain-free or containing small amounts of whole healthy fresh grains (not corn) 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). Shift the arachidonic acid pathway away from the pro-inflammatory end-products.
High dose omega 3 fatty acids daily. Again, to shift arachidonic acid path to anti-inflammatory end-products but also for its resolvins and other inflammation-resolving mechanisms at high doses. (900-1800mg EPA, 450-900mg DHA/day – source is important to ensure no rancidity or contaminants).
Lecithin: 1-2 tbl/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 degradation.
HyVitality™: contains magnesium, methylcobalamin, antioxidant and many other 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. HyVitality is a formulation of my recommended vitamins, minerals, antioxidants and phytochemicals. It had proved difficult for clients to purchase the correct canine dosages using OTC human supplement products and working with a trusted manufacturer has allowed me to be assured of purity and quality. (Average Shar-Pei dose contains 50-80mg Alpha Lipoic Acid, 200mg Boswellia Serrata, 60mg Coenzyme Q10, 200mg Curcumin, 450mg Diosmin, 100-200mg Magnesium citrate, 1000 mcg Methylcobalamin, 50mg trans-Resveratrol, 25mcg Vitamin K2). Available through my office at 845-888-4884. HyVitality is dosed by weight.
500 mg Vitamin C. Shar-Pei with excess HA have a high need for antioxidants. Also, I suspect that Shar-Pei do not synthesize adequate Vitamin C because of competition with HA for substrate (both formed by glucuronidation).
Ensure Adequate Vitamin D3. Active Vitamin D modulates the over-active toll like receptors in inflammatory disease, returning them to a more normal functionality. 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 commercial balanced dog food, has severe allergies, arthritis or chronic inflammation.
Treat any signs of secondary hypothyroidism with thyroid supplementation. Common Signs: sparse coat on caudal/medial thighs and perineum along with a brittle, lighter coat. I think that HA fragments 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 am studying 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 activity if the dog is functionally hypothyroid. Monitor to keep T4 below 4.
Probiotics and attention to bowel health. Skin and bowel are the immune system’s biggest barriers and they are both HA rich areas. 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. (Metronidazole, tylosin powder or enrofloxacin are usually effective.)
Fanatical attention to skin and ear issues. Bathing by shampoo or washcloth (microfiber dust cloths are best) wipe-downs as needed – up to daily when skin inflamed and at least every 2 wks in a “healthy” Shar-Pei. Remove superficial yeast, bacteria (potential sources of hyaluronidases) and allergens like pollens, molds, dust. At least weekly ear cleaning/flush unless the Shar-Pei has a large open healthy ear canal.
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.
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.