Behçet Uveitis

Behçet disease (BD) is a serious, systemic disorder characterized by recurrent bouts of inflammation.^1–4 Over two-thirds of patients with BD will develop ocular inflammation – most often bilateral panuveitis with retinal vasculitis. Common sight-threatening ocular complications of Behçet Uveitis (BU) include edema, non-perfusion, neovascularization, and atrophy of the retina and/or optic disc.^5,6 Treatment typically involves regional and systemic corticosteroids in the short-term, followed by long-term, non-corticosteroid, systemic immunomodulatory therapy¹ – often involving either a tumor necrosis factor (TNF) inhibitor^7–9 or interferon.^10–13 Even with conventional immunosuppressive therapy, nearly 25% of patients with long-standing BU experience reduced vision to 20/200 or less in their better seeing eye.¹⁴ The etiology of BD is unknown, although a concentration of cases in the Mediterranean basin and both the Middle and Far East supports combined contributions from both genetic and environmental factors.¹⁵ A comprehensive review¹⁶ and nine original articles^17–25 in this issue of Ocular Immunology & Inflammation (OII) address important aspects of the pathogenesis, diagnosis, and management of BU.

Tugal-Tutkun et al.¹⁶ systematically reviewed the use of multimodal imaging in BU. The authors emphasized the importance of routine color fundus photography and fluorescein angiography (FA) to document and monitor the location, extent, and progression of posterior segment involvement. The degree and extent of retinal vascular leakage and non-perfusion, in particular, have been correlated with long-term visual prognosis.^26,27 Ultra-widefield (UW) color and angiographic imaging of the mid- and far-periphery appeared to be particularly important and have been shown to provide additional, therapeutically important information in a majority of patients.^28,29 Routine indocyanine green angiography (ICGA) and fundus autofluroescence (FAF), which document the location and extent of involvement of the choroid and retinal pigment epithelium (RPE), respectively, provide generally less direct determinants of therapy and, therefore, were not recommended routinely once the diagnosis of BU was established. Spectral Domain-Optical Coherence Tomography (SD-OCT), in contrast, provides highly relevant information regarding macular anatomy, including the location and extent of vitreomacular traction, the presence or absence or subretinal or intraretinal fluid, the development of a macular hole or atrophy, and the integrity of both photoreceptors and middle and inner retinal nuclear and plexiform layers – changes which may help identify and distinguish reversible from irreversible causes of vision loss. Optical coherence tomography is used most frequently for the identification and management of cystoid macular edema (CME), for documentation of non-glaucomatous retinal nerve fiber layer (RNFL) defects associated with inner retinal atrophy following focal infarcts, and, through automated comparison to reference standards, for screening of glaucomatous or non-glaucomatous optic atrophy.³⁰ As with ICGA, SD-OCT-based visualization of the choroid with enhanced depth imaging (EDI) approaches can show changes associated with disease activity, but provides less routine clinical utility. While OCT angiography (OCTA) was not addressed in the review by Tugal-Tutkun et al.¹⁶ Khairallah et al. recently published their experience 44 eyes of 25 patients with clinically active BU with posterior segment involvement.³¹ The authors found that OCTA was clearly superior to FA at identifying perifoveal microvascular abnormalities, including enlargement or disruption of the foveal avascular zone (FAZ) and an overall increase in the size and extent of retinal capillary abnormalities, such as vascular telangiectasis, dilation, or shunting and flow voids consistent with non-/hypo-perfusion. While both the superficial and deep retinal capillary plexuses were affected frequently, the deep retinal capillaries, those on either side of the inner nuclear layer, showed alterations most often – in over 80% of eyes. Of note, the degree of perifoveal capillary arcade disruption and of capillary vascular abnormalities in both the superficial and deep capillary networks were correlated with best-corrected vision. The authors concluded that OCTA is superior to FA for visualizing, characterizing, and quantifying perifoveal microvascular alterations in BU, but emphasized that FA remains the method of choice for revealing retinal vascular and optic disc leakage, and is indispensable for detecting leakage, non-perfusion, and neovascularization in the mid- to far-periphery.

Moon et al.¹⁷ studied inter-observer agreement in applying a previously described 40-point integrated scoring system for grading signs of posterior segment inflammation^32,33 in patients with BU seen in a referral unit in Korea. In brief, the semi-quantitative grading developed by the Angiography Scoring for Uveitis Working Group (ASUWOG) was used to evaluate late hyperfluorescence/leakage of the macular, the disc, the retinal vascular and the retinal capillaries; early and late hypofluorecence/non-perfusion of the macula, posterior pole and periphery; early and late hyperfluorescence/neovascularization of the disc and retina; and the presence and extent of subretinal pooling. Both FA and UWFA were tested in 21 eyes of 21 patients with active retinal vasculitis. Correlations were high with both imaging modalities, at 0.87 for FA and 0.93 for UWFA, and as noted above UWFA was more sensitive at detecting both leakage and non-perfusion in the periphery. As described by others^28,29 and by this same group previously,³⁴ diffuse retinal vascular leakage was noted in roughly three-quarters of eyes with active BU. The authors concluded that the ASUWOG system for grading posterior segment inflammation is a reliable method for monitoring disease activity in patients with BU.

Accorinti et al.¹⁸ investigated demographic and clinical trends of their cohort of 385 patients with BU seen over 44 years in a referral unit at Sapienza University in Rome. The cohort was divided into 174 patients seen over the first 25 years, beginning in 1968 and ending in 1992 (cohort 1), and 211 patients seen from 1993 to 2011 (cohort 2). A total of 138 (79.3%) of patients in cohort 1 and 135 (70.0%) of those in cohort 2 were followed for more than a year. While systemic and regional corticosteroids were used throughout the entire study, and 30.0% of patients in cohort 1 and 14.1% of those in cohort 2 were treated with corticosteroids alone, the choice and use of non-corticosteroid immunosuppressive agents varied over time. Comparing the two cohorts, the authors noted a significant, albeit modest, increase in the proportion of women (25.9%–36.5%) and a similarly significant, yet modest, decrease in the proportion of patients with all four major criteria as described in Japanese classification,³¹ including oral ulcer, genital ulcers, skin lesions, and ocular inflammation (63.8% vs 48.3%). While panuveitis was the most common presentation in both cohorts 1 (75.3%) and 2 (66.8%), cohort 2 had a higher proportion of patients with isolate anterior uveitis (1.7% vs 11.4%), and patients with isolated anterior uveitis tended to have better outcomes. Hypopyon, once considered a hallmark of the disease, was seen less frequently in cohort 2 (17.2% vs 9%; p = 0.024). Virtually all complications were higher in the earlier cohort, including optic atrophy (42.5% vs 13.7%; p < 0.0001), maculopathy (28.7% vs 15.2%; p = 0.002, retinal neovascularization (8.0% vs 2.4%; p = 0.02), and retinal detachment (6.3% vs 1.4%; p = 0.02). The rates of cataract (32.7% vs 29.8%; p = 0.61) and ocular hypertension/glaucoma (11.5% vs 14.2%; p = 0.52) were similar in the two cohorts. Not unexpectedly, mean vision at final visit was higher in cohort 2 (0.79 ± 0.35 [~20/25] vs 0.54 ± 0.44 [20/40]), with vision ≤20/200 in at least one eye decreasing roughly three-fold (39.1% vs 13.0%). Although the reason was unclear, men tended to present slightly younger, and to have more complete disease, more frequent complications, and worse vision over time than woman. The authors suggested that the decreased rates of ocular complications and better vision outcomes over time may have been due to improved treatment, including patterns in the use of non-corticosteroid immunosuppressive agents.

Horie et al.¹⁹ performed a meta-analysis of 18 English language articles to examine the strength of the association between HLA-B51 expression and BU, an association first reported by Shigeaki Ohno in 1982.³⁵ When examined geographically, the authors found a strong association between HLA-B51 expression and ocular involvement in reports from the Middle (OR 1.87, p = 0.0045; Palestine, Israel, Turkey) and Far East (OR 2.40, p = 0.00030, Taiwan, Korea, Japan), but no association in reports from North Africa (OR 1.15, p = 0.77, Morocco, Tunisia) or Europe (OR1.29, p = 0.67; Ireland, Britain, Italy, Greece). While this analysis supported the role of genetics in the pathogenesis of both BD and BU, and suggested further that genetics may play a greater role in some populations than others, it is important to remember that regardless of region, HLA-B51 testing lacks the sensitivity and specificity to support its use as a routine screening tool in patient suspected of having BU.³⁶

Yalcindag et al.²⁰ retrospectively evaluated the association between intraocular inflammation and laser flare photometry measurements in 78 eyes of 45 patients with BU seen in a referral unit in Turkey. Among the 78 eyes with BU, 58 eyes had active inflammation and 20 were in remission. Fifty healthy adults served as controls. While p-values appear not to have been corrected for multiple testing, the authors found that flare values were higher in eyes with active BU (8.4 ph/ms) vs eyes in remission (4.85 ph/ms; nominal p = 0.006) or control eyes (2.8 ph/ms; nominal p < 0.01), and that flare values correlated with the degrees of both anterior chamber and vitreous inflammation (nominal p = 0.04), with angiographic scoring (nominal p < 0.001), and with presence of either optic atrophy or maculopathy (nominal p = 0.02). Similar flare findings have been reported by others.^37,38 The authors suggested that quantitative flare measures may provide a reliable, non-invasive technique for monitoring the activity of BU, perhaps decreasing the need for frequent FA.

Keino et al.²¹ reported their experience with the use of infliximab in 13 patients with refractory BU see over a six-year period seen in a referral unit in Tokyo, Japan. Six of the patients had BU for 18 months or less (short duration) vs seven who had BU for greater than 18 months (long duration). Overall, the authors found that the introduction of infliximab significantly decreased both the attack rate and the severity of attacks based on BD ocular attack score (BOS24) in the full cohort of patients over 24 months of follow up (nominal p-values < 0.007 at 6, 12, 18, and 24 months for all endpoints), and that the magnitudes of these decreases were similar in the two groups over time. While patient numbers in the two subgroups were small, the mean total vascular leakage score as assessed by FA tended to respond both faster and to a greater extent in patients with BU of shorter duration. The authors suggested that early treatment with infliximab may be more effective at limiting leakage from the retinal and optic disc vasculature and, ultimately, may result in better preservation of visual function.

Takeuchi et al.²² examined cytokine production by peripheral blood mononuclear cells (PBMC) obtained from eight patients with BU seen in a referral Unit in Japan before and after treatment with infliximab. Ten healthy adults served as controls. Fresh PBMCs were stimulated with interphotoreceptor retinoid binding protein (IRBP) and concentrations of IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L) and TNFα were measured. The cytokines were broadly grouped as pro-inflammatory (sCD40L, IL-1β, IL-6), Th1- (IFN-γ, TNFα), Th2- (IL-4, IL-10, IL-31), and Th17-related (IL-17A, IL-17F, IL-21, IL-22). Perhaps not unexpectedly, the results showed that concentrations of most cytokines tended to be higher in patients with both active and inactive BU as compared to control subjects, and that levels in both active and inactive BU were higher prior as compared to after treatment with infliximab. The authors suggested that antigen-induced release of selected cytokines from PBMCs taken from patients with BU may provide an in vitro means of assessing the efficacy of infliximab, but acknowledged that additional work would be required both to identify the best antigen and to optimize the cytokine profile for such testing.

Tugal-Tutkun et al.²³ reported the results of a seven-center, open label, randomized, phase 2 trial of the safety and efficacy of three doses of gevokizumab, a recombinant, humanized, allosteric, monoclonal antibody that binds to IL-1β, in 21 patients either with (17) or at risk of developing (4) acute BU (17), and who were already receiving a stable regimen of immunosuppressive drugs. No drug-related adverse events were noted. Three of the 17 patients with active BU withdrew prematurely and so were not included in the efficacy analysis. Inflammation improved in the remaining 14 patients within 21 days, including one patient by day one, six additional patients by day four, three additional patients by day seven, and three additional by day 14. While such rapid efficacy responses to systemic gevokizumab appeared to support the results of a single-center, open-label, pilot study,³⁹ a robust therapeutic benefit was not borne out in a much larger, randomized and controlled phase three trial.⁴⁰

Hasanreisoglu et al.²⁴ reported their results from a referral unit in Turkey using interferon alpha-2a (IFNα2a) in 16 patients with BU refractory to combination therapy with azathioprine and cyclosporine. Clinical response and relapse rates in this cohort before and after switching to IFNα2a were compared to a group of 23 patients with BU who were treated with a combination of azathioprine and cyclosporine. Patients initially received IFNα2a at a dose of 4.5 MU at bedtime each day. Once the uveitis was controlled, the dose was reduced to 4.5 million units (MU) three times weekly, and then as possible to 3 MU on this same dosing interval. The authors noted that changing from combination therapy to IFNα2a in patients with frequent recurrences decreased the annual relapse rate from 2.4 ± 1.8 to 1.3 ± 2.0, a rate similar to the 0.8+/1.6 rate observed in the combination therapy group. The authors also noted that there was no statistically significant difference in the use of periocular corticosteroid injections or the mean time to first attack in the two comparison cohorts. Other than fever and a flu-like syndrome in all patients on IFNα2a, no difference in adverse events was noted. While such retrospective, clinic-based comparisons are susceptible to referral, selection, and treatment bias, the authors concluded that IFNα2a is a viable alternative for patients with BU who are incompletely responsive to combination therapy with azathioprine and cyclosporine.

Diwo et al.²⁵ retrospectively assessed the annual relapse rate, relapse type, time from discontinuation of treatment to relapse, and rate of long-term, drug-free remission in 26 patients with severe BU treated with either IFNα2α or IFNα2b over 9.5 years in a referral unit in Paris, France. Time from first ocular manifestation of BD to treatment with IFNα ranged from 2 months to 19 years (mean 3.2 years), and treatment time with IFNα ranged from 6 to 191 months (mean 53.8 months). Most patients were treated with 3 MU three times a week. In those who responded incompletely, the dose was increased to 6 MU at the same dosing interval. Three patients received a combination of IFNα and azathioprine. Overall, 31 of 36 (86.1%) patients responded to IFNα treatment. Prior to treatment with IFNα, the annual relapse rate for the cohort was 1.39, and following initiation of IFNα the annual rate fell to 0.050 (p = 1.82 × 10⁻¹⁰), a nearly 30-fold reduction. Discontinuation of IFNα was possible in 58% of patients and following discontinuation of IFNα, 81.0% of patients never relapsed during a mean follow up of 5.1 years. Of the remaining 19.0% who did relapse, all were controlled promptly upon retreatment with IFNα. Common side effects with IFNα treatment included a flu-like syndrome (48.5%), hematologic abnormalities (27.3%) and depression (9.1%). As supported by others,^1,10-,13,41 the authors concluded that IFNα provides a valuable, second-line adjunct in the treatment of severe BU.

Together, these studies highlight the often serious, vision-threatening nature of BU, and emphasize the need for both close monitoring with state-of-the-art imaging technologies and prompt treatment with corticosteroids followed by long-term non-corticosteroid immunomodulatory therapy in most patients. While sustained suppression of BU can be achieved with various immunomodulatory agents and selection of any given agent depends upon regional availability, physician experience, and patient specific consideration, the high rates of control achieved with both anti-TNF and IFNα therapy supports earlier and more frequent consideration of these targeted biologics in the management of BU.

FINANCIAL CONFLICTS

The authors have no financial conflicts.

FUNDING

This work was supported in part by The Pacific Vision Foundation (ETC) and The San Francisco Retina Foundation (ETC).