VOGT-KOYANAGI-HARADA AND UVEODERMATOLOGIC SYNDROMES: THE SIMILARITIES BETWEEN TWO AUTOIMMUNE BASED DISORDERS
 
Charles Darwin published a watershed work in 1859 that has radically changed the scientific perception of flora and fauna origins.  On the Origin of Species is considered to be the foundation of evolutionary biology, and the concept of evolution by natural selection has become the unifying theory of the life sciences.  The publication served as a stimulus for new research in numerous fields ranging from behavior and fitness, to genetics and disease, and recent advances in genomics have allowed scientists to characterize the evolution of various species and compare them to each other.  A 2013 study comparing the genomes of grey wolves and domesticated dogs to humans concluded that due to the shared environmental pressures of the recent past, natural selection may have worked on a similar set of genes within the genomes.¹  Multiple genes that have experienced positive selection in both species appear to be involved in the manifestation of similar diseases, particularly digestive, metabolic, neurologic, and neoplastic related maladies.¹   While genomic study of this parallel evolution is in its infancy, it does provide a plausible explanation for the similar manifestation of diseases that are seen in both species today.  Likeness of the Vogt-Koyanagi-Harada (VKH) syndrome, a multi-systemic autoimmune disorder of humans, and the Uveodermatologic Syndrome (UDS) of dogs provides one such example of comparable disease presentation.
 
Historical origin and diagnostic criteria of Vogt-Koyanagi-Harada syndrome
The tenth century ophthalmologist, Ali-ibn Isa al-Kahhal, was the first to record an association between poliosis and ocular inflammation in his work, Notebook of the Oculists.²  The connection between these two signs, in addition to vitiligo (Figure 1), dysacousia, and meningitis, was also reported by physicians throughout the 19^th and 20^th centuries.  In 1949, Bruno and McPherson merged independent observations made by Swiss and Japanese ophthalmologists, and the association between ocular, dermal, auditory, and neural signs was officially coined VKH syndrome.³  Despite this attempt to compile a determined set of signs and symptoms, researchers that published subsequent VKH studies and case reports continued to find strict classification difficult due to varying clinical manifestations.  “Atypical VKH” and “Harada syndrome” were subjectively used in an attempt to distinguish between the variety of cases seen, but the use of those terms is now discouraged.⁴  In addition, VKH designation is made even more problematic because the cause is not known, and therefore there are no specific diagnostic tests available for clinicians to rely on.⁴ 
The First International Workshop on Vogt-Koyanagi-Harada Disease was held at the University of California, Los Angeles in 1999 and consisted of researchers experienced with VKH syndrome, among other consultants from neurology, otolaryngology, pathology, and veterinary medicine backgrounds.⁴  The committee recognized that VKH is a single syndrome, and that clinical manifestation is largely dependent on the stage the patient is examined in.  It was noted that despite the disparity of presentations, the use of VKH syndrome should be used in all cases.  To enable characterization of the signs being seen, the committee decided to allow further division of the syndrome into “definite” disease with “complete” and “incomplete” categories, and “probable” disease, in which signs were inconclusive.⁴  The criteria for these divisions are noted in a table within the report. 
 

Figure 1) Note the periocular vitiligo and eyelash leukotrichia in this human VKH patient.
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Historical origin and breed predisposition of Uveodermatologic syndrome
Purebred dogs have a disproportionately high incidence of immunologic diseases,⁵ and the Akita is no exception.  UDS, also known as VKH-like syndrome, was first described as a bilateral granulomatous uveitis and concurrent skin depigmentation of the eyelids and nose in two Akita dogs in Japan in 1977.⁶  Since the initial report, other breeds afflicted with the same condition have been noted in the literature, and include the Siberian Husky, Alaskan Malamute, Shetland Sheepdog, Samoyed, Dachshund, Chow-Chow, Brazilian Fila, Fox Terrier, Border Collie, Saint Bernard, Bernese Mountain Dog, Irish Setter, Old English Sheepdog, and Golden Retriever, among others.^6,7,8,9  Highest incidence is seen with the Akita,¹⁰ and because it is not limited to a single geographic area, it is suggested that there are heritable components of the disease.¹¹  As of 1998, 58 of the 72 cases (80.5%) described in the literature affected akitas.⁷  Young to middle-aged male dogs are most commonly impacted.  While the condition is similar to the human form of VKH, neurologic and auditory manifestations have generally not been reported in dogs,⁵ hence the more appropriate name of UDS.  There is a single report of a Japanese Akita presenting with clinical central nervous signs, as demonstrated by behavioral changes that preceded blindness and a concurrent head tilt, though further neurologic testing was not performed.^6,12  The lack of dysacousia and meningitis in dogs is currently attributed to the absence of melanocytes within their auditory and meningeal tissues.¹¹
 
Autoimmune basis of VKH and UDS
            As previously mentioned, it is thought that VKH and UDS are immune-mediated disorders.  The mechanism responsible for triggering the autoimmune reaction is unknown, but the multi-organ granulomatous inflammatory condition has been associated with sensitization to melanocytic antigens and is thought to be a T-lymphocyte mediated process.  Cutaneous injury or viral infections have been implicated for VKH, and though little evidence is present for UDS trigger factors, bacterial and fungal sources have been suggested.¹²    
Human leukocyte antigen (HLA) class II alleles have been closely associated with VKH in humans.  Immunohistochemical studies have shown that abnormal expression of the major histocompatibility complex (MHC) class II cell surface receptor (HLA-DR) encoded by the HLA antigen complex has abnormal expression on the surface of choroidal melanocytes in eyes affected with VKH.¹³ The canine leukocyte antigen (DLA) complex structure is similar to that of HLA.¹¹  A study involving 13 unrelated Akita dogs found differences between distribution and frequency of DLA class II alleles, with a certain haplotype seen in higher levels in Europe than in North America.¹¹  This finding is consistent with variations in HLA antigens also seen with different geographic location and race of humans.¹¹  These disparities in MHC genes are critical from an evolutionary stand point to the survival of a species.⁵  If each individual of a species had the same MHC molecules and T-cell receptors, exposure to one pathogen not recognized by those molecules could end with species extinction.  The same can be said about a genetic basis for susceptibility to autoimmune disorders.    
 
Uveodermatologic Disease Syndrome characterization and diagnosis
            Uveodermatologic Disease Syndrome is most commonly associated with bilateral (unless uveal pigmentation is asymmetric) anterior or panuveitis, and dermal depigmentation (Figure 2).^11,14,15  Patients may present with reduced Schirmer Tear Test results, which may be due to keratoconjunctivitis sicca that is also of autoimmune derivation.  Intraocular pressures may be reduced or elevated, depending on the stage of disease and degree of ocular inflammation.  Common ophthalmic clinical exam findings include reduced to absent pupillary light responses, photophobia, blepharospasm, and other manifestations of acute or chronic uveitis that include keratic precipitates, aqueous flare, hyphema, hypopyon, posterior synechia/iris bombe, iris depigmentation, cataract, bullous retinal detachment, and choroidal depigmentation.^6,15  Early recognition of UDS can present a challenge because ocular signs often (not always) precede dermatologic evidence by months or years.  Dermatologic changes include depigmentation of the facial mucocutaneous junctions, nasal planum, perianal region, scrotum, and footpads, though generalized leukotrichia may occur (Figure 3).⁶ 
Due to the lack of diagnostic criteria available for UDS, diagnosis is based upon clinical signs and histopathology.  Serum biochemistry, complete blood count, and urinalysis tend to yield no significant findings.¹⁵  Results from immune function tests and titers for multiple infectious diseases have been reported as negative.⁶  Signalment, histopathology, ophthalmic examination, and immune function tests and titers aid differentiation of UDS from other integumentary diseases.¹⁵  Uveal inflammation consists of either diffuse granulomatous or non-granulomatous cellular infiltrate along the uveal tract, causing an increase in thickness that has been associated with retinal detachment.⁷  Dermis histopathology results from patients with UDS reveal absence of pigment within the keratinocytes in combination with a histiocytic lichenoid dermatitis.¹⁴  Dermal cellular infiltrate of a lympho-mononuclear composition is typically seen, and melanophages may also be present.¹⁴ 
A recent retrospective study of 50 dogs with UDS found that at initial presentation, 36% of dogs had glaucoma in at least one eye and 57% of dogs were blind in both eyes.¹⁶  Some patients regained vision and 50% of subjects were visual in at least one eye at the last documented visit.¹⁶
 

Figure 2) Depigmented and ulcerated lesions of skin with chronic uveitis changes in both eyes of
an Akita with Uveodermatologic Syndrome. Gelatt Ophthalmology Atlas (2017)
 

Figure 3) (A) Labrador with periocular/nasal erythema and crusting at
initial presentation, followed by (B) leukotrichia 3 months later. Zarfoss et al., 2018
 
Treatment and prognosis of UDS
Treatment of UDS is primarily directed toward controlling inflammation related to the immune system.  Immune suppression via long-term oral corticosteroid and/or other immune modulating medications like azathioprine or cyclosporine is warranted.¹⁶  These medications are not without risk of serious side effects, and appropriate monitoring of systemic health and laboratory values during use is critical.  Topical anti-inflammatory therapy with medications that have adequate intraocular penetration is crucial, in addition to anti-glaucoma therapy if indicated.  Despite aggressive therapy, UDS often results in glaucoma and/or blindness in affected patients.¹⁶  Client education regarding the multi-faceted nature of this disease and guarded visual outcome is crucial.
 
Conclusion
Study of parallel, and possibly convergent evolution between humans and dogs that have shared a common set of environmental pressures in recent millennia has the potential to advance our understanding of similar disease processes between species. Genomics research of other domesticated animals would add further insight.  The analogy between VKH syndrome and UDS is only one example in a spectrum of diseases that humans and canines share, including obesity, epilepsy, and breast cancer.  Deciphering these conditions at a gene level may aid in targeted treatment protocols that allow for better control, or even cure of these conditions.
 
Bibliography

1. Wang, G., Zhai, W., Yang, H., Fan, R., Cao, X., Zhong, L., Wang, L., L, F., Wu, H., Cheng, L., Poyarkov,A., Poyarkov, N., Tang, S., Zhao, W., Gao, Y., Lv, X., Irwin, D., Savolainen, P., Wu, C., & Zhang, Y. (2013).The genomics of selection in dogs and the parallel evolution between dogs and humans.Nature Communications 4:1860
2. Moorthy, R., Inomata, H., & Rao, N. (1995).  Vogt-Koyanagi-Harada Syndrome.  Survey ofOphthalmology 39(4): 266-292

3. Bruno, M., & McPherson, S. (1949).  Harada’s disease.  American Journal of Ophthalmology 32: 513-522
4. Read, R., Holland, G., Rao, N., Tabbara, H., Ohno, S., Arellanes-Garcia, L., Pivetti-Pezzi, P., Tessler, H.,& Usui, M. (2001).Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of international committee on nomenclature.American Journal of Ophthalmology 131(5): 647-652
5. Pedersen, N. (1999).  A review of immunologic diseases of the dog.  Veterinary Immunology and Immunopathology 69: 251-342.
6. Gelatt, K., Gilger, B., & Kern, T. (2013).  Veterinary Ophthalmology 5e.  Ames, IA:  John Wiley & Sons,
7. Herrera, H. & Duchene, A. (1998).  Uveodermatologic syndrome (Vogt-Koyanagi-Harada-like syndrome)with generalized depigmentation in a Dachshund.Veterinary Ophthalmology 1(1): 47-51
8. Kang, M., Sung, H., Kim, D., & Park, H. (2013).  Uveodermatologic syndrome in a Siberian Husky:clinical and histopathological findings.Pakistan Veterinary Journal
9. Thomas, O. & Chahory, S. (2009).  A case of uveodermatologic syndrome in a Bernese Mountain Dog.Pratique médicale et chirurgicale de l’animal de compagnie 44:55-61
10.  Barros, P., Safatle, A., Malerba, T. (1991).  Uveitis and dermal depigmentation (Vogt–Koyanagi–Harada-like syndrome) in Akita dogs I. Clinical aspects. Brazilian Journal of Veterinary Research and Animal Science (1): 75–79
11. Angles, J., Famula, T., & Pedersen, N. (2005).  Uveodermatologic (VKH-like) syndrome in Amerian Akitadogs is associated with an increased frequency of DQA1*00201.Tissue Antigens 66: 656-665
12. Carter, W., Crispin, S., Gould, D., & Day, M. (2005).  An Immunohistochemical study ofuveodermatologic syndrome in two Japanese Akita dogs.Veterinary Ophthalmology 8(1): 17-24
13. Sakamoto, T., Murata, T., & Inomata, H. (1991).  Class II major histocompatibility complex onmelanocytes of Vogt Koyanagi Harada disease.Archives of Ophthalmology 1270
14. Laus, J., Sousa, M., Cabral, V., Mamede, F., & Tinucci-Costa M. (2004).  Uveodermatologic syndrome in aBrazilian Fila Dog. Veterinary Ophthalmology 7:193–196
15. Tilley, L. & Smith, F. (2004).  The Five Minute Veterinary Consult. 3rd Edition Baltimore: Lippincott,2004: 1319
16. Zarfoss, M., Tusler, C., Kass, P., Montgomery, K., Lim, C., Mowat, F., & Thomasy, S. (2018). Clinicalfindings and outcomes for dogs with Uveodermatologic syndrome.Journal of the American Veterinary Medical Association252(10): 1263-1271