Introduction

• Cause: impaired regulation of hyaluronan (HA) synthesis due to a genetic mutation leads to excessive HA concentrations provoking autoinflammation.
• Associated with breed-specific mutation responsible for thickened wrinkled skin (hyaluronosis).
• Presents with episodic fever that typically first occurrs before 18 months of age.
• Autoinflammatory disorder that encompasses episodic fever, arthritis, recurrent otitis, hereditary cutaneous hyaluronosis, and systemic amyloidosis.
• Fever events may be accompanied by periarticular joint swelling +/- associated sterile neutrophilic non-erosive intra-articular inflammation, usually affecting the tibiotarsal joint. Occasionally swollen, painful muzzle.
• Diagnosis: breed, rule out other causes of fever of unknown origin. Genetic test.
• Treatment: supportive, prophylactic.
• Prognosis: guarded due to risk for amyloidosis.

Pathogenesis

Etiology

• Selection by breeders for increased wrinkling and skin thickness may have inadvertently selected for the CNV 16.1|5 meatmouth mutation, predisposing to autoinflammation.
• Hyaluronan is a fundamental barrier molecule of the innate immune system and is a major component of the skin and gastrointestinal tract lining. Its function varies with its molecular weight. 
• Shar-Pei have chronically increased levels of IL-6. Interleukin-6 is a trigger for APP production. Some, but not all, Shar-Pei may develop reactive systemic (AA) amyloidosis Amyloidosis as a result of chronic inflammation.
• Hyaluronosis may be associated with increased presence of dermal mast cells.

Pathophysiology

• Breed selection has targeted a thickened, wrinkled skin and a meatmouth padded muzzle appearance). 
• This phenotype is a result of excessive hyaluronan deposition in the dermis.  
• Hyaluronan plays a complex role in the body and when fragmented can act as a danger-associated molecular pattern (DAMP) activating pro-inflammatory cytokines (eg interleukin 1β and IL-6).  
• Increased IL-6 provokes increased acute phase proteins (APP) Acute phase proteins. 
• Reactive systemic amyloidosis may occur as a result of chronically increased (APP).  
• Persistence of APPs (even between fever episodes) can precipitate amyloid deposition (predominantly in the kidney causing irreversible damage and progressive chronic renal insufficiency).

Timecourse

• Recurrent bouts of fever, most commonly lasting 24-36 hours.
• Death due to renal failure Kidney: chronic kidney disease (CKD) has been seen as early as 9 months of age but is most commonly seen between 2-5 and 8-10 years of age, with the presence of two groups hypothesized (but yet unproven) to be due to presence or absence of the modifier locus associated with amyloidosis.
• Many dogs with recurrent fevers may live out lifespans greater than 10 years of age without succumbing to amyloidosis. The presence of fever is a marker, not a cause, of greater risk.

Diagnosis

Treatment

Outcomes