Correlation between visual acuity and human leukocyte antigen DRB1*04 in patients with Vogt-Koyanagi-Harada disease

Vogt-Koyanagi-Harada (VKH) disease is a systemic disorder that is considered to represent an autoimmune disease against melanocytes [1]. In the eye, the disease presents as acute bilateral granulomatous panuveitis, which responds to systemic corticosteroid therapy and generally shows good visual prognosis with relatively short follow-up [2]. A role of genetic factors such as HLA alleles in the development of VKH was first considered in 1976, and was supported by the simultaneous development of VKH in monozygotic twins [3]. The human leukocyte antigen (HLA) system is the locus of genes that encode for major histocompatibility complex (MHC), representing a set of cell surface molecules mediating the interaction of leukocytes [4]. HLA, and HLA-DRB1*04 in particular, therefore plays a key role in immune systemic function, as well as in the pathogenesis of autoimmune diseases, including VKH [5]. A Korean study found that the HLA DRB1*0405 allele conferred an increased relative risk of developing VKH compared with the general population, and that the HLA DRB1*0405-DQA1*0302-DQB1*0401 haplotype was associated with poorer visual prognosis [6]. On the other hand, despite systemic corticosteroid approach, VKH patients often prove refractory to systemic corticosteroid therapy with long follow-up [7, 8]. For predicting prognosis and refractoriness to treatment, the focus in recent years has transitioned from the identification of HLA genes associated with increased risk of VKH to the identification of alternate genes [9, 10]. However, in Japan, HLA has traditionally been examined for uveitis, and accumulated data are available for our facilities. For that reason, we report an investigation of correlations between HLA04 allele type and visual outcomes before and after steroid treatment in the real world.

This retrospective case series included 57 eyes from 29 consecutive patients with treatment-naïve VKH disease who visited the ophthalmology department at Osaka City University Hospital between December 2009 and January 2019 and were followed up for more than 6 months after the start of systemic corticosteroid therapy. VKH disease was diagnosed according to the criteria of Sugiura [11] and the VKH Disease Committee [12]. None of the patients had any medical or ocular history at the initial visit. Changes in central retinal thickness (CRT) and central choroidal thickness (CCT) were assessed by vertically and horizontally oriented enhanced depth imaging optical coherence tomography (EDI-OCT) of the macula (Spectralis HRA + OCT Heidelberg Engineering, Heidelberg, Germany) for up to 3 months after treatment. Measurements of CRT and CCT in each eye were then reconfirmed by three experts (NM, MT, and SH) by checking the OCT images. Patients received corticosteroid regimens of pulse therapy according to the timing of their first visit. Recurrences were defined as the recurrence of anterior chamber cells and/or posterior segment lesions detected by ophthalmic examinations.

In HLA typing by polymerase chain reaction amplification with sequence-specific primers (PCR-SSP), typing specificity is part of the amplification step [9].

The Kruskal-Wallis test and Fisher’s exact test were used to analyze and compare baseline patient characteristics. The relationship between HLA04 allele and visual outcomes was determined using univariate linear regression analysis. Analysis of covariance was used to analyze final visual acuity to clarify the influence of baseline visual acuity. In addition, in the case of regression analysis, an explanatory variable that roughly divided the number of cases by 15 was considered appropriate [13].

The present study revealed a correlation between HLA04 allele and visual outcomes before and after initiating systemic corticosteroid therapy in treatment-naïve patients with VKH disease. In this study, linear regression showed significant differences in logMAR BCVA at baseline and at 3 months after treatment between the three groups of homozygotes, heterozygotes, and normal subjects. There were no significant differences at 6 months after treatment. We can guess that Alleles of HLA-DRB1*04 might affect visual prognosis and be related to early response after initiation of treatment in VKH disease. From these results. Also, although the statistical study did not yield significant results, we speculate that CRT and CCT might show significant differences with greater numbers of cases of homozygotes, heterozygotes, and normal subjects. These thicknesses may be associated with the final prognosis of the disease [14]. The duration from first visit to steroid administration was very short. This was taken as a likely reason for the low recurrence rate for VKH compared with other reports without the use of immunosuppression therapy [7]. Cyclosporine was approved in 2012, and Adalimumab was also approved by the government for several years. But not all recommended approaches are government approved in Japan. For these reasons, steroid-centered treatment has always been used. But future treatments for recurrent VKH may be changed [15].

Previous studies have reported that HLAs represent a set of cell surface molecules mediating leukocyte interactions. HLA therefore plays an important role in immune system function as well as in the pathogenesis of autoimmune diseases, including VKH. Almost 40 years ago, an association between HLA-BW22J and VKH was reported [16]. Since then, more articles have been published regarding the associations of different HLA types to VKH. Among these, most investigations have focused on the HLA-DR4 serotype and its corresponding allele, HLA-DRB1*04 [17]. Shi et al. reported a meta-analysis confirming the association between VKH and HLA-DR4/DRB1*04, finding that the strength of association differed between ethnic groups, and identifying HLA-DRB1*0404, 0405, and 0410 as risk sub-alleles, and 0401 as a protective sub-allele [18, 19].

For groups not having HLA-DR4/DRB1*04, the diagnosis may be not typical for VKH. However, both homozygous and heterozygous groups showed findings above the regression equation line, and were considered to have certain statistical meaning.

In the study of type 1 diabetes in Japanese, disease susceptibility has been found to differ between homozygotes and heterozygotes [20]. Similarly, disease susceptibility to VKH may differ between homozygotes and heterozygotes. Both before and after steroid treatment, homozygotes displayed the best post-treatment visual acuity. Normal subjects (no HLA-DRB1*04 allele) showed the poorest visual acuity after treatment. This indicates that therapeutic response and sensitivity to steroid treatment may depend on allele HLA-DRB1*04. An understanding of the pathogenic conditions that must exist to explain these results is difficult to reach. However, previous reports using methods such as haplotype linkage disequilibrium have suggested associations with genes closely related to immunity and inflammation, such as the IKBL gene and TNFA gene present in HLA class III [21‐23].

The HLA-DRB1*04 allele is known to represent a disease-associated gene that is frequently found in VKH, but our study suggested the possibility of disease resistance in association with this allele. On the other hand, another report found that presence of the HLA-DRB1*04 allele was related to the prolongation of VKH in Japanese patients [24].

We know that the HLA-DRB1*04 allele is the key to VKH, but the details remain elusive. According to the previous report, CCT correlates with vision prognosis in VKH [25]. However, in this case series with possible problems in the limited number of cases, the correlation between allele HLA-DRB1*04 and CCT could not be determined. Another limitation is following periods had variations and the bias cannot be denied completely.

We report that alleles of HLA-DRB1*04 might affect visual prognosis and be related to early response after initiation of treatment in VKH disease. In the future, the complete genetic predisposition of VKH is expected to be elucidated, leading to the development of next-generation treatments and preventive measures. We acknowledge these potential issues, as well as the need for future worldwide studies into the correlation between the HLA-DRB1*04 allele and visual outcomes in VKH.