In this prospective study, 15 patients with acute onset VKHD were treated with early AZA in association with high-dose corticosteroid. Acute inflammatory signs rapidly receded with BCVA recovery of ≥20/40 in 90% of eyes at one month of follow-up and, at final follow-up, all eyes had BCVA ≥20/25. Chronic refractory anterior uveitis was observed in one patient (2 eyes, 6.7%) in spite of IMT increment. ffERG parameters remained stable in 66.7% of the eyes despite persistence of subclinical signs of inflammation in all included eyes.
Immunosuppression therapy as first-line treatment in acute VKHD has been proposed to achieve faster control of the uveitis and to facilitate earlier tapering of the corticosteroids(18). However, there are very few studies that systematically evaluated visual and inflammatory outcomes in acute VKHD with early IMT. In 2012, Abu El-Asrar et al. described the effectiveness of early IMT in acute VKHD(33). These authors used mycophenolate mofetil with high-dose corticosteroid as a first-line therapy in 19 acute VKHD patients and compared their results with a historical group of 68 acute VKHD patients treated with steroid monotherapy with a mean follow-up of 27 months (range, 16-54 months)(33). The early IMT group had better results than the CS group: visual acuity of 20/20 (74% versus 38%); recurrent inflammation (3% versus 18%); complications such as SGF (0% versus 100%)(33). In 2017, the same group confirmed their results by evaluating the long-term effectiveness (mean follow-up period of 37 months; range, 9-120 months) of mycophenolate mofetil (2 g/day) as a first-line therapy associated with CS in 38 prospectively followed patients(33, 34). Other authors did not present such a clear-cut difference between first-line IMT with CS and CS alone or with late IMT. Chee et al, in a retrospective study, compared outcomes of patients with IMT before 6 weeks (n=15) and after 6 weeks of disease onset (n=14) and did not find a difference in SGF prevalence and in the proportion of eyes with resolved or chronic recurrent uveitis(19). Visual acuity was significantly better in the early IMT patients at the 4th year of follow-up. Chee et al. also compared data of patients with IMT within 3 months from disease onset (n=29 patients) and patients with CS only or with late IMT (n=60 patients) and did not find differences in SGF prevalence; the proportion of eyes with resolved (41.4% versus 33.3%), with chronic (51.7% versus 28.3%) or chronic recurrent (6.9% versus 38.4%) indicated significantly more eyes became chronic but fewer chronic recurrent among those with IMT within 3 months. These authors also found significantly better visual acuity in patients with IMT within 3 months at the 3rd year of follow-up(19). Recently a prospective, multicenter, randomized and non-inferiority trial was conducted in Japan comparing the efficacy and safety of a combination therapy of prednisolone and cyclosporine (n=34 patients) and corticosteroid pulse therapy (n=36 patients) in VKHD with a 1 year follow-up. These authors observed lower recurrence/worsening risk, sunset glow fundus grade, and cataract rate in the combination group than in the corticosteroid group (35).
The following considerations could be made, when comparing our data with those previous studies.
Firstly, the timing of introduction of IMT may vary from a very early treatment, defined as within 2 weeks from disease onset(36) to an interval up to 6 months(19, 35, 37, 38). The rapid control of acute inflammatory signs depends primarily on the early use of high-dose systemic corticosteroid followed by its slow tapering(37). Conventional IMT takes at least 2 to 3 months to reach its ideal therapeutic action(17); therefore, the IMT introduction interval should not impact significantly on the outcomes. In our study, 13 patients (86.7%) achieved the AZA therapeutic dose within 4 months. Indeed, in the present study the comparison between patients treated with very early treatment (CS within 14 days and therapeutic dose of AZA within 4 months) and those patients treated otherwise (CS>14 days and/or therapeutic dose of AZA after 4 months) pointed out that very early group had a lower DD score at M1 than the other group and reached CSE in a shorter median time. We did not find differences in other outcomes including inflammatory or functional parameters. In the literature, early IMT has already shown its benefits on CSE(33, 34, 37, 40).
Secondly, besides azathioprine and mycophenolate mofetil, other drugs have been used, e.g., methotrexate, cyclosporine, cyclophosphamide and biologics, with slight differences in CSE and frequency of ocular complications(18, 37, 40-45). The most frequent IMT used in VKHD patients by Chee et al. was azathioprine, followed by methotrexate and mycophenolate mofetil(19). Concerning the differences in antimetabolites prescribed, azathioprine is approved by the Public Brazilian Healthcare System to be used in non-infectious uveitis, while mycophenolate mofetil is not. Both immunosuppressive drugs are effective in controlling non-infectious uveitis(17, 40, 44).
Thirdly, study designs differ. The unique characteristics of the present study are as follows: prospective with all included patients with the same 24-month follow-up period; clinical, multimodal and electroretinogram exams at predefined intervals and treatment management based on clinical inflammation and on electroretinogram parameters. On the other hand, most studies analyzed, as main outcomes, visual acuity, recurrences based on clinical signs and ocular complications. Few studies included systematic multimodal imaging, but the results are not described (33, 34, 37, 38). An exception is Chee´s study in which choroidal thickness decreased over time and average ICGA score decreased throughout the follow-up period and, at the 5-year follow-up, 2 patients had persistent DD(19). Most studies had varied follow-up periods after the minimum initial six months.
Concerning subclinical signs in the non-acute phase of VKHD, they may indicate choroidal inflammation; however, in our study, even after 24-month of follow-up, we could observe that they did not impact in visual function when evaluated by VA, and, in at least two thirds of our patients, when evaluated by ffERG. It should be noted that subclinical signs, more importantly those observed on ICGA, are difficult to quantify and interpret. Herbort et al. evaluated all ICGA and FA signs and their fluctuation(24), while Chee et al. only evaluated the ICGA signs as a categorical item(19). In the present study, they were systematically evaluated but their isolated presence was not used to indicate systemic treatment increment; retinal function measurements were carried out and worsening of ffERG parameters then directed treatment change or not. Sakata et al. had previously demonstrated that choroidal subclinical inflammation fluctuated along the course of the disease, i.e. worsened and improved without treatment change(13). Souto et al. demonstrated that this subclinical choroiditis improved along the course of the disease even after systemic treatment is discontinued(46) and, further, Souto et al. also demonstrated that this subclinical choroiditis did not impact on patients’ quality of life(47). On the other hand, Herbort et al. strongly suggest that monitorization of VKHD through ICGA is essential to avoid chronicity and sunset glow fundus(36). Therefore, subclinical signs may be important to a global understanding of the inflammatory status of the disease but, if presented isolated, may be not enough to dictate treatment intervention. Nevertheless, our study pointed out that a portion of the 33% of patients with worsening ERG could deserve a more aggressive treatment. Thus, biomarkers of disease severity and the understanding of timing for being more aggressive should be pursued. Our study is the first prospective study with systematic multimodal and ffERG evaluation and early IMT; therefore, further studies are compelling to still clarify these points.
Despite the prospective study design with a systematic follow-up, some limitations should be considered. Firstly, a larger cohort sample size and a longer follow-up could add statistical power to detect differences. Secondly, ffERG was used as an objective method to evaluate retinal function and ffERG parameters were defined to compare groups. Nevertheless, the definition of retinal dysfunction progression was based on other inflammatory and non-inflammatory retinal/choroidal diseases(27-29) due to very scarce literature using ERG in VKHD. Furthermore, ffERG is a complex exam, which is not always available and the definition of worsening or not should be validated in future studies (Supplemental Table 2). Thus, besides ffERG, other means of evaluating the impact of inflammation on visual function may play a role in VKHD appraisal, e.g., visual field, microperimetry, contrast sensibility and self-reported quality of life questionnaires(47-49). It is important to highlight that all of these methods are subjective and their interpretation should be done cautiously. Thirdly, no control group using late IMT was presented to compare with the early IMT group. Nevertheless, our group recently published a study with a similar prospective design using corticosteroid only or late IMT in acute VKHD(13). Lastly, even though patients were recruited from early disease onset, there is heterogeneity in the interval to diagnosis and in disease severity.
In conclusion, early azathioprine with high-dose corticosteroid was effective in improving BCVA with control of clinical inflammation in more than 90% of patients. Isolate subclinical choroidal inflammation persistence may not be enough to indicate treatment increment, since VA was 20/25 in 100% of patients and visual function evaluated by ffERG remained stable in two thirds of patients, even after 24 months of follow-up. However, selected patients, particularly those with worsening ffERG, may deserve further treatment.