Early Versus late Immunomodulatory Therapy in Vogt-Koyanagi-Harada Disease

Purpose: To evaluate early versus late immunomodulatory therapy (IMT) for patients following initial diagnosis of Vogt-Koyanagi-Harada (VKH) disease. Methods: Retrospective review including all VKH patients seen 5/1/2014 to 4/1/2016 at LAC+USC. Early IMT was defined as starting an immunomodulatory agent within 3 months of corticosteroid initiation. Results: Twenty-seven patients were included, of whom 15 received early IMT and 8 received late IMT. Early IMT patients trended toward greater improvement in vision compared to late IMT (logMAR 0.59 vs. 0.11; p=0.14) with no differences in ocular complications including ocular hypertension (p=0.53) and cataract (p=1.0). Patients receiving early IMT averaged 0.93 recurrences versus 2.13 recurrences for late IMT (p=0.092). Of patients successfully taper off oral corticosteroids, the early IMT group was tapered in an average of 8.3 months versus 19.8 months for late IMT (p=0.0019). Conclusions: Early IMT in VKH may allow for shorter duration of corticosteroids with similar visual outcomes, ocular complications, and disease recurrences. DOI : 10.14302/issn.2470-0436.jos-17-1666 Corresponding Author: Philip P. Storey, MD, MPH, USC Roski Eye Institute, Los Angeles, California, Wills Eye Hospital, Philadelphia, Pennsylvania, Email: storey.p@gmail.com Running Title: Early vs. late IMT for VKH


Introduction
Vogt-Koyanagi-Harad disease (VKH) is a bilateral panuveitis that primarily affects pigmented ethnicities including Hispanic, Asian, and Native Americans. 1 Also known as uveomeningitis syndrome, VKH is an idiopathic inflammatory disease characterized by chronic, diffuse, granulomatous panuveitis frequently associated with neurological, auditory, and integumentary manifestations. 2While the exact cause of the disease remains unknown, T-lymphocyte-mediate autoimmunity against tyrosinase peptides of melanocytes is present. 3,4[7] While the disease is more prevalent in Asia, VKH accounts for between 1% to 4% of uveitis referrals within the United States. 8,9gt-Koyanagi-Harada disease generally presents in four phases: 1) a prodromal phase with auditory and neurologic symptoms 2) an acute uveitic phase, which may include diffuse choroiditis, exudative retinal detachment, and intraocular inflammation 3) a chronic phase, consisting of variable depigmentation of the fundus and limbus in addition to vitiligo, poliosis, and alopecia and 4) a chronic-recurrent phase with iridocyclitis, which may be chronic, recurrent or both. 10e majority of people treated for VKH are prescribed high dose corticosteroids with a gradual taper and often require immunomodulatory therapy (IMT) such as methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, and occasionally, cyclophosphamide.

Discussion
It is generally agreed that Vogt-Koyanagi-Harada disease requires systemic treatment.Early studies reported that patients with VKH receiving systemic corticosteroids achieved superior outcomes compared to patients receiving no systemic treatment. 12Subsequent evaluations compared VKH patients receiving intravenous versus oral corticosteroids and found no significance differences in visual outcomes or complications. 13As our armamentarium of immunomodulatory therapies has increased, our options to treat systemic uveitis have improved.
However, the exact role and timing of IMT in VKH is still being elucidated.

Some physicians have elected to use immunomodulatory therapy alone as first line treatment
for VKH and have reported similar visual outcomes compared to patients treated with corticosteroids alone. 14However, given the limitations of previous reports, including small numbers and lack of prospective design, we have expressed caution towards using IMT as first line therapy for VKH. 11 In terms of common complications, previous studies of VKH have reported glaucoma or ocular hypertension to occur in 6-45% of eyes and cataracts to develop in 11-42% of eyes. 1,16,17In our study, ocular hypertension was the most common complication occurring in 46.5% of patients, which is at the high range of previous estimates.Previous evaluations of patients with VKH have shown that the development of complications is directly associated with increased follow-up time. 16We hypothesize that our relatively high rate of ocular hypertension may be due to the long average follow-up of our patients (39.While corticosteroids were only tapered when a patient's inflammation was controlled, we did not directly evaluate the speed of resolution of the inflammation.By analyzing visual acuity at only the first and last clinical visits, we do not capture the effect of the treatment at intermediate time points.Disease complications were limited to ocular findings as systemic complications have been shown to be less common in Hispanic patients. 22While the majority of patients at our institution were treated with IMT at some point during their disease, four patients were treated with corticosteroids alone.While we included this group in our overall tabulations, we did not do a subgroup analysis given the small number of individuals.Our study does not address when patients may be treated with corticosteroids alone or whether outcomes differ compared to patients treated with IMT.
In summary, we found that patients treated with both early and late IMT for VKH generally do well as most patients achieve visual acuity of 20/40 or better.Ocular complications were similar between the groups and early IMT therapy was associated with better visual acuity outcomes although this finding was not significant.Early IMT may be associated with shorter duration of corticosteroid use with no difference in recurrence rates although further research is needed to fully assess the role and timing of immunomodulation in VKH.

Table 1 :
Characteristics of patients with Vogt-Koyanagi-Harada disease 11The purpose of this study was to evaluate the clinical course and outcomes in patients following initial diagnosis of May 1, 2014 and April 1, 2016.The diagnosis of VKH was based on features typically present in the disease with the exclusion of other causes of uveitis by history, examination, and ancillary testing. 10rder to capture the entire clinical course from first diagnosis of the disease, patients were excluded if they had been treated for VKH at an outside institution beginning more than one month prior to evaluation in our clinic.Overall, the average age at diagnosis was 35.0 years and a majority of patients (63.0%) were female.Regarding ethnicity, one patient was Asian while 26 patients were Hispanic.The average length of follow-up was 39.2 months and 81.5% of patients had at least one year of follow-up.Average logMAR visual acuity at first presentation was 1.08 (approximately 20/250 Snellen equivalent).On first presentation, the majority of patients (70.4%) had acute VKH while 29.6% of patients had signs of chronic VKH.No significant difference was found in any of the above-mentioned variables when comparing patients who received early vs. late IMT.Of the 15 patients receiving early IMT, 12 patients started IMT at the same time that corticosteroids were initially prescribed while 3 patients started IMT between 1 and 2 months following initiation of steroids.Patients in the late IMT group started IMT between 4 and 12 months following steroid initiation.Immunomodulatory agents used included mycophenolate mofetil, cyclosporine, azathioprine, methotrexate, infliximab, and adalimumab.Clinical outcomes are summarized in Table2.The majority of patients (59.3%) achieved best corrected visual acuity of 20/40 or better at the final clinic visit.The early IMT group trended toward better final logMAR visual acuity (0.55 vs. 0.92) and better decrease oral prednisone to 10mg or less daily with no statistical difference between the early and late IMT groups.For the patients who were able to successfully taper off steroids, the time to achieve the steroid taper

Table 2 :
Outcomes of patients with Vogt-Koyanagi-Harada disease was significantly shorter for the early IMT group compared to the late IMT group.Patients receiving early IMT tapered off oral prednisone in an average of 8.3 months while patients treated with late IMT tapered off steroids in an average of 19.8 months (p=0.0019).

Table 3 :
We continue Outcomes of patients with Vogt-Koyanagi-Harada disease to view first line therapy for acute VKH to consist of high-dose systemic corticosteroids with the possible