Canis ISSN: 2398-2942

Shar-Pei fever and Shar-Pei autoinflammatory disease

Synonym(s): Shar Pei hock, Familial Shar-Pei Fever, Swollen Hock Syndrome, Familial amyloidosis, Shar-Pei Autoinflammatory Disease (SPAID)

Contributor(s): Linda J M Tintle

Introduction

  • Cause: autoinflammation resulting from mutation in regulation of hyaluronan synthesis.
  • Associated with breed specific mutation responsible for thickened wrinkled skin (hyaluronosis).
  • Most commonly presents with episodic fever first occurring before 18 months of age but adult onset attacks are not uncommon.
  • Autoinflammatory disorder associated with episodic fever, recurrent otitis, hereditary cutaneous hyaluronosis, systemic amyloidosis and other chronic inflammatory disease.
  • 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 inadvertently selected for  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. Hyaluronan bound to its receptor CD44 acts as a biological rheostat: surveillance of homeostasis vs. inflammatory conditions.
  • Shar-Pei have chronically elevated levels 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

  • Inherited copy number variation in mutation in regulatory element upstream to gene for hyaluronan synthase 2.
  • Inappropriate inflammasome activation and release of Interleukin-1 beta (IL-1β). Low molecular weight (fragmented, damaged, degraded) hyaluronan can both activate and prime the NLRP3 inflammasome leading to IL-1β release, a critical driver of fever and inflammation and signal for IL-6. Activation of toll-like receptors by low molecular weight hyaluronan bound to its receptor CD44 may lead to release of Interleukin-8 release and neutrophil chemotaxis.
  • Increased IL-6 levels → elevated levels of the acute phase proteins (APP) of inflammation.
  • Amyloidosis may occur where the body has been overwhelmed by large volumes of APP or where there is a defect in the breakdown pathway. The CNV 16.1 mutation and a modifier locus on a chromosome 14 have been associated with increased risk for amyloidosis in the breed. Interleukin-6, along with IL-1β, is a driver of fever and inflammation and is a trigger for APP production. Amyloid may be deposited in the extracellular matrix throughout organs and vasculature. In the kidneys, damage is irreversible, usually resulting in kidney failure and death. Less commonly, hepatic failure may be seen.
  • Hyaluronan makes up the bulk of the endothelial glycocalyx lining the vasculature. Damage to hyaluronan may result in vasculitis and leakage of protein and fluid to the interstitium. Sterile neutrophilic vasculitis and bacterial hyaluronidase induced necrotizing neutrophilic vasculitis may be seen, sometimes with extensive skin sloughing in rare cases (Streptococcal Toxic Shock-like Syndrome).
  • A highly viscous gel, hyaluronan is large component of joint fluid and fragmentation may cause sterile neutrophilic arthritis.
  • Low molecular weight hyaluronan bound to its receptor CD44 directs the terminal differentiation of mast cells in skin and connective tissue.
  • Many pathogens release hyaluronidases that may trigger autoinflammatory events. Underlying infection should be ruled out in cases of persistent fever and inflammation lasting more than 48 hours.

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

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Treatment

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Outcomes

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
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  • Olsson M, Tintle L, Kierczak M et al (2013) Thorough investigation of a canine autoinflammatory disease (AID) confirms one main risk locus and suggests a modifier locus for amyloidosis. PLOS One 8 (10), e75242 PubMed.
  • Segev G, Cowgill L D, Jessen S et al (2012) Renal amyloidosis in dogs: A retrospective study of 91 cases with comparison of the disease between Shar-Pei and non-Shar-Pei dogs. JVIM 26 (2), 259-268 PubMed.
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Other sources of information

  • Moriello K A (2011)Familial shar-pei fever & hyaluronan.Clin Brief11, 37.
  • Puppo F, Tintle L, Wong Aet al(2005)Recurrent fever in Chinese Shar-Pei dogs is a model of human autoinflammatory diseases: mutational screening in canine MEFV and TNFRSF1A.[Abstract]Fourth International Congress on Systemic Autoinflammatory diseases, November 6-10, Bethesda, MD..


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