Coriorretinopatia de Birdshot: relato de caso e perspectivas sobre o tratamento / Birdshot chorioretinopathy: a case report and perspectives on its treatment

RESUMO A coriorretinopatia de Birdshot é uma uveíte posterior bilateral crônica rara que acomete, preferencialmente, mulheres de meia-idade. O quadro clínico é composto de pouco ou nenhum processo inflamatório de segmento anterior, associado a vitreíte e lesões coriorretinianas ovoides branco-amareladas de característica hiperfluorescente na angiofluoresceinografia e hipofluorescente na angiografia com indocianina verde. O tratamento se dá por meio de corticoides e outras drogas imunossupressoras. Todavia, em alguns casos, a doença é refratária a tal terapêutica, sendo necessário lançar mão de outras drogas, como os agentes biológicos. O presente artigo busca relatar um caso de coriorretinopatia de Birdshot em ajuste de terapia imunossupressora que evoluiu com má resposta às drogas iniciais e bom controle após uso de imunobiológico e discutir as opções terapêuticas disponíveis atualmente.

ABSTRACT Birdshot chorioretinopathy is a rare chronic bilateral posterior uveitis that preferentially affects middle-aged women. The clinical picture is composed of little or no anterior segment inflammatory process, associated with vitritis and yellowish-white ovoid chorioretinal lesions with hyperfluorescent characteristics on fluorescein angiography and hypofluorescent characteristics on green indocyanine green angiography. Treatment is with corticosteroids and other immunosuppressive drugs. However, in some cases, the disease is refractory to such therapy, making it necessary to resort to other drugs such as biological agents. The present article seeks to report a case of Birdshot chorioretinopathy in an adjustment of immunosuppressive therapy that evolved with poor response to the initial drugs and good control after the use of immunobiologicals and discuss the currently available therapeutic options.

ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers.

Purpose: Birdshot chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers. Methods: We sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29-positive controls to determine genome-wide common and rare variant associations. We further typed the HLA alleles of cases and 45,386 HLA-A29 controls of European ancestry to identify HLA alleles that associate with BSCR risk. Results: Carrying a second allele that belongs to the HLA-Aw19 broad antigen family (including HLA-A29, -A30, -A31, and -A33) increases the risk for BSCR (odds ratio [OR] = 4.44; P = 2.2e-03). This result was validated by comparing allele frequencies to large HLA-A29-controlled cohorts (n = 45,386; OR > 2.5; P < 1.3e-06). We also confirm that ERAP1 and ERAP2 haplotypes modulate disease risk. A meta-analysis with an independent dataset confirmed that ERAP1 and ERAP2 haplotypes modulate the risk for disease at a genome-wide significant level: ERAP1-rs27432 (OR = 2.46; 95% confidence interval [CI], 1.85-3.26; P = 4.07e-10), an expression quantitative trait locus (eQTL) decreasing ERAP1 expression; and ERAP2-rs10044354 (OR = 1.95; 95% CI, 1.55-2.44; P = 6.2e-09), an eQTL increasing ERAP2 expression. Furthermore, ERAP2-rs2248374 that disrupts ERAP2 expression is protective (OR = 0.56; 95% CI, 0.45-0.70; P = 2.39e-07). BSCR risk is additively increased when combining ERAP1/ERAP2 risk genotypes with two copies of HLA-Aw19 alleles (OR = 13.53; 95% CI, 3.79-54.77; P = 1.17e-05). Conclusions: The genetic factors increasing BSCR risk demonstrate a pattern of increased processing, as well as increased presentation of ERAP2-specific peptides. This suggests a mechanism in which exceeding a peptide presentation threshold activates the immune response in choroids of A29 carriers.

Classification Criteria for Birdshot Chorioretinitis.

PURPOSE: To determine classification criteria for birdshot chorioretinitis. DESIGN: Machine learning of cases with birdshot chorioretinitis and 8 other posterior uveitides. METHODS: Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior uveitides / panuveitides. The resulting criteria were evaluated on the validation set. RESULTS: One thousand sixty-eight cases of posterior uveitides, including 207 cases of birdshot chorioretinitis, were evaluated by machine learning. Key criteria for birdshot chorioretinitis included a multifocal choroiditis with (1) the characteristic appearance of a bilateral multifocal choroiditis with cream-colored or yellow-orange, oval or round choroidal spots ("birdshot" spots); (2) absent to mild anterior chamber inflammation; and (3) absent to moderate vitreous inflammation; or multifocal choroiditis with positive HLA-A29 testing and either classic "birdshot spots" or characteristic imaging on indocyanine green angiography. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for birdshot chorioretinitis were 10% in the training set and 0% in the validation set. CONCLUSIONS: The criteria for birdshot chorioretinitis had a low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.

ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29.

Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labeled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU.

Not All That Flickers Is Snow.

ABSTRACT: A woman presented with bilateral visual disturbances that had been diagnosed as visual snow. Dilated ophthalmic examination and multimodal imaging were strongly suggestive of birdshot chorioretinopathy, meriting initiation of systemic immunomodulatory therapy. Visual snow requires a thorough ophthalmologic exam to exclude other ocular diseases.

Reproducibility of Full-field Electroretinogram Measurements in Birdshot Chorioretinopathy Patients: An Intra- and Inter-visit Analysis.

Purpose: Aims to determine the variability of ffERG measurements in patients with clinically stable birdshot chorioretinopathy (BCR).Methods: Repeatability coefficients (RC) of ffERG amplitudes and implicit times were calculated from 11 BCR patients. Jackknife resampling estimated 95% confidence intervals of each ERG parameter's RC and the percentage change explained by variability alone was calculated.Results: Intra-visit variability in ffERG parameters was lower than inter-visit. Intravisit RCs demonstrated that for intravisit ERG testing, there was less than 30% variation in ERG amplitude for most parameters. For inter-visit ERG testing, a greater than 40% reduction in ERG amplitude may be clinically meaningful for 6 of 8 ERG parameters. Photopic single flash responses have <2 msec of test-retest variability both within and across visits.Conclusions: A 40% reduction in ERG amplitude and/or a delay of >2 msec in the photopic single flash response may be suitable criteria for meaningful change in BCR patients.

Choroidal Structural Changes in Patients with Birdshot Chorioretinopathy.

Purpose: To assess the choroidal vascularity index (CVI) in birdshot chorioretinopathy (BSCR) patients.Methods: The CVI was calculated as the ratio of luminar area to the total subfoveal choroidal area on enhanced-depth imaging optical coherence tomography. Intraocular inflammation was defined by the presence of macular edema and/or vitritis and/or vasculitis and/or papillitis.Results: Eighty BSCR patients and 22 healthy controls were included. Foveal choroidal thickness was lower in the BSCR compared with the control group (p < 0.001). CVI was not different between the two groups. CVI was significantly higher in BSCR patients with inflammatory activity (p = 0.004). Using a multivariate linear regression model, longer disease duration was associated with lower CVI (p = 0.038), whereas the presence of papillitis was associated with a higher CVI (p = 0.003).Conclusions: The CVI was not different between the BSCR and the control group. However, the CVI may be used as a new tool for monitoring inflammatory activity in BSCR.

Characteristics, Upon Presentation, of a Cohort of Hispanic Patients with Birdshot Retinochoroidopathy.

OBJECTIVE: To describe the characteristics, upon presentation, of a cohort of Hispanic patients with birdshot retinochoroidopathy. METHODS: A retrospective chart review of Hispanic patients with birdshot retinochoroidopathy of was performed. The demographic and clinical characteristics were analyzed. RESULTS: Nine patients who met the research criteria for a diagnosis of birdshot retinochoroidopathy were identified and included in the analysis, all of whom were HLA-A29 positive. The median age of the cohort upon presentation was 52 years; 89% of the patients were female, and all were Hispanics. Ninety-four percent of the eyes had an initial visual acuity of 20/50 or better, while 72% had measured 20/25 or better. Sixty-one percent of the eyes had retinal vasculitis, which was bilateral in 83% of the cases. Thirty-three percent of the patients had, upon presentation, evidence of cystoid macular edema, which was always bilateral. All the eyes had the typical birdshot lesions, at presentation. CONCLUSION: Birdshot retinochoroidopathy can be found in Hispanic patients. Our study suggests that the characteristics upon presentation in Hispanics may be similar to those of Caucasian cohorts.

Peripheral Capillary Non-perfusion in Birdshot Retinochoroiditis: A Novel Finding on Ultra-widefield Fluorescein Angiography.

Purpose: To report a novel peripheral finding in patients with Birdshot retinochoroiditis (BRC) using ultra-widefield fluorescein angiography (UWFFA). Methods: UWFFA images from 90 patients diagnosed with BRC were reviewed. All images were evaluated for the presence of peripheral retinal ischemic changes and ischemia-related complications. Findings: Thirty-six eyes of 24 patients showed features of peripheral ischemia, including 18 eyes with peripheral capillary non-perfusion (CNP), 5 eyes with teleangectasias, with or without microaneurysms, and 13 eyes with both teleangectasias and CNP. None of the 36 eyes with peripheral ischemic changes developed retinal neovascularization following the diagnosis of peripheral ischemia. Conclusions: Peripheral ischemia may present in eyes with chronic inflammation as seen in BRC but does not seem to progress to neovascular complications. This is likely to be more common than suspected and has now become evident following the advent of UWFFA. Abbreviations: HLA-A29: Human leukocyte antigen - A29; FFA: Fundus fluorescein angiography; OCT: Optical coherence tomography; ICGA: Indocyanine green angiography; UWF: Ultra-wide field; UWFFA: Ultra-wide field fluorescein angiography; CNP: Capillary non-perfusion.

INCREASED PHOTORECEPTOR OUTER SEGMENT VOLUME FOLLOWING SYSTEMIC TREATMENT OF BIRDSHOT CHORIORETINOPATHY.

PURPOSE: Retinal degeneration in birdshot chorioretinopathy can be quantified using spectral domain optical coherence tomography by measuring the photoreceptor outer segment (PROS) volume. The purpose of this study was to determine if the PROS volume in BSCR responds to systemic immunomodulatory therapy (IMT). METHODS: Retrospective chart review with analysis of PROS volume derived from spectral domain optical coherence tomography. RESULTS: We identified a total of three patients who met our inclusion criteria. At baseline, all patients had abnormal PROS and/or ellipsoid layer findings on spectral domain optical coherence tomography. After systemic immunomodulatory therapy, these abnormalities improved, and PROS volume increased, in all patients (P < 0.05). CONCLUSION: PROS volume can increase after systemic treatment of birdshot chorioretinopathy. This SD-OCT parameter may serve as a useful marker of retinal degeneration in BSCR, and may be a useful outcome measure in monitoring treatment response in birdshot chorioretinopathy.

Long-term outcomes of systemic corticosteroid-sparing immunomodulatory therapy for Birdshot Retinochoroidopathy.

PURPOSE: To report the visual prognosis, electroretinography (ERG) and perimetry outcomes of systemic corticosteroid-sparing immunomodulatory treatment (IMT) for birdshot retinochoroidopathy (BSRC). METHODS: Retrospective non-comparative case series of 132 patients (264 eyes) with BSRC treated with IMT from Massachusetts Eye Research and Surgery Institution. RESULTS: The average follow-up time was 60.1 months. After one year on IMT, 39.4% showed no clinically active inflammation. After 5 years of IMT, 78.0% had no signs of clinical inflammation. No significant differences were observed on best-corrected visual acuity (BCVA), ERG parameters, and perimetry parameters between baseline and subsequent visits on IMT. CONCLUSION: Long-term systemic corticosteroid-sparing IMT was associated with a low rate of BSRC disease exacerbation. While differences were seen on testing parameters, they were not consistent trends and difference were attributed to variability of testing or fluctuation of inflammation that may be expected in the course of the disease.

EVALUATION OF PHOTORECEPTORS, RETINAL CAPILLARY PLEXUSES, AND CHORIOCAPILLARIS IN PATIENTS WITH BIRDSHOT CHORIORETINOPATHY.

PURPOSE: To assess the status of the cone photoreceptors using adaptive optics flood illumination ophthalmoscopy in patients with birdshot chorioretinopathy and to study their relationship with optical coherence tomography (OCT) angiography. METHODS: Seventeen patients with birdshot chorioretinopathy were studied using standard automated perimetry, color vision testing, fluorescein angiography, indocyanine green angiography, spectral domain OCT, enhanced depth imaging OCT, and adaptive optics flood illumination ophthalmoscopy (rtx1, Imagine Eyes, Orsay, France) in a 90 × 90-µm area at 1.5° temporal of the fovea and OCT angiography (Spectralis OCT2, Heidelberg Engineering, Heidelberg, Germany). For adaptive optics flood illumination ophthalmoscopy, spectral domain OCT, and OCT angiography, a control group of 12 healthy patients (12 eyes) matched for age, sex, and refractive error was included. RESULTS: After excluding low-quality adaptive optics flood illumination ophthalmoscopy images, 12 eyes (12 patients, 7 women, mean age 53.5 ± 10.8 years) were analyzed. Best-corrected visual acuity was 0.01 ± 0.03 LogMAR (20/25 Snellen equivalent), and foveal threshold at standard automated perimetry was 35.2 ± 3.0. Cone density at 1.5° of the fovea in the birdshot chorioretinopathy group (11,435.25 ± 4,342.9 cells/mm) was significantly smaller than in the control group (24,594.04 ± 4,764.3 cells/mm, P < 0.001). In the same area, birdshot chorioretinopathy eyes showed disruption of the ellipsoid/interdigitation zone and vascular abnormalities, such as capillary loops (58.3%), increased superficial intercapillary spaces (75%), increased deep intercapillary spaces (58.3%), capillary dilations (58.3%), telangiectatic vessels (66.6%), and absence of choriocapillary flow (58%). Cone density at 1.5° was associated with duration of the disease (Spearman's rho -0.8, P = 0.01), although it was not associated with OCT angiography abnormalities in the same area. CONCLUSION: Birdshot chorioretinopathy can result in a reduction in cone density and development of macular vascular abnormalities even in the presence of preserved visual function.

ADALIMUMAB THERAPY FOR REFRACTORY BIRDSHOT CHORIORETINOPATHY.

PURPOSE: To report the outcome of using adalimumab to treat birdshot chorioretinopathy. METHODS: Retrospective case series of 19 patients (38 eyes) with HLA-A29-positive birdshot chorioretinopathy who received adalimumab treatment. Patients had been refractory to previous standard systemic immunomodulatory therapy. They received biweekly subcutaneous injections of 40 mg of adalimumab. Outcome measures were change in visual acuity, fluorescein angiography, and optical coherence tomography features, the concomitant use of immunosuppressive drugs, and the occurrence of adverse effects between 1 year before, at baseline, and after 1 year of adalimumab treatment. RESULTS: Mean Snellen visual acuity at 1-year follow-up was 20/28, an improvement from 20/43 at the start of the treatment (P = 0.011) and equal to the visual acuity 1 year before the treatment (20/29). Only 2 of the 9 patients who had complete fluorescein angiography and optical coherence tomography results after the 1 year of treatment were completely free of inflammation signs at the end of the follow-up. Half (53%) of 17 patients were receiving adalimumab monotherapy after 1 year of treatment, an increase from 21% at the start of treatment (P = 0.047). Three of the 19 patients reported possible side effects; 2 discontinued treatment within 1 year. CONCLUSION: The results suggest that adalimumab is effective at improving visual acuity and at tapering concomitant immunomodulatory therapy, in patients with refractory birdshot chorioretinopathy. However, complete remission is rarely achieved.

PERIVASCULAR THICKENING ON OPTICAL COHERENCE TOMOGRAPHY AS A MARKER OF INFLAMMATION IN BIRDSHOT RETINOCHOROIDITIS.

PURPOSE: In this study, we hypothesized that thickening along the major arcade vessels is a noninvasive marker of inflammation in eyes with birdshot retinochoroiditis (BRC). METHODS: In this single-center retrospective study, patients with BRC were identified. Perivascular thickening was categorized as mild, moderate, or severe, based on a set of standard reference retinal thickness maps derived from representative spectral domain optical coherence tomography volume scans. The assigned perivascular severity thickness category was then compared with other inflammatory markers and optical coherence tomography measurements. These parameters were also examined in eyes with intermediate uveitis to assess the diagnostic specificity of perivascular thickening. RESULTS: In eyes with BRC, greater perivascular thickening was associated with increased vitreous haze (P = 0.009) and retinal vascular leakage on fluorescein angiography (P = 0.0001). Perivascular thickening was correlated with central subfield thickness and total macular volume on optical coherence tomography. Controlling for central subfield thickness and total macular volume, the odds of higher severity level of perivascular thickening were nine times greater in eyes with BRC than those with intermediate uveitis (P < 0.0001). Eyes with BRC and active inflammation were more likely to have moderate or severe perivascular thickening (P = 0.02). CONCLUSION: Perivascular thickening, determined by optical coherence tomography, may be a useful noninvasive biomarker of inflammation in eyes with BRC.

Low-grade "benign" birdshot retinochoroiditis: prevalence and characteristics.

PURPOSE: To establish the prevalence, morphologic and functional characteristics and evolution of mild birdshot retinochoroiditis (BRC). METHODS: Retrospective review of all BRC cases treated at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland, with at least 3 years of follow-up since the initial symptoms. Sub-Tenon's injection of triamcinolone was the first line of treatment if visual field changes were unilateral, with no additional treatment if visual field returned to normal. The percentage of patients who did not need systemic therapy was established, and the following parameters were evaluated: demographic characteristics, best-corrected visual acuity (BCVA), fundus photographs, fluorescein angiography (FA) and indocyanine green (ICGA) angiography frames and perimetry evaluation from initial visit to last follow-up. RESULTS: Twenty cases of BRC were included in this study. Three of these patients (15%) received only local periocular therapy and qualified as mild BRC, with a mean follow-up of 9.3 years. The BCVA was 0.89 ± 0.25 at presentation and 1.0 ± 0.39 at last follow-up. Average visual field mean defect was 5.05 ± 3.27 at presentation and 1.78 ± 0.95 at last follow-up. Depigmented fundus lesions remained stable from presentation to last follow-up. Choroidal inflammatory activity monitored by ICGA decreased from 11.66 ± 3.44 at presentation to 4.25 ± 2.87 at last follow-up. FA revealed mild retinal vasculitis (2.25 ± 3.20) which remained stable (2.00 ± 4.00). CONCLUSIONS: In our setting, 15% of BRC cases had a benign course, controlled with periocular treatment. It is important to identify such cases in order not to overtreat, exposing patients needlessly to potential side effects of aggressive and prolonged immunosuppressive treatment.

Outcomes of "Early" Withdrawal of Corticosteroid Sparing Immunomodulatory Therapy for Birdshot Retinochoroidopathy.

Purpose: To review early withdrawal of immunomodulatory therapy (IMT) for birdshot retinochoroidopathy (BSRC). Design: Retrospective case-series of sixteen patients with Human-leukocyte-antigen-A29-positive BSRC treated with IMT ≥ 1 year and discontinued prior to achieving durable remission, observed ≥ 6 months off IMT. Results: Mean duration on IMT was 42.4 months. At discontinuation, quiescence was achieved in 75.0% of eyes. Subjects off IMT for 6 months, 1 year, and 3 years showed quiescence in 75.0%, 77.8%, and 80.0% of eyes. No significantly decreased vision was found 6 or 12 months after discontinuation. One eye experienced significantly decreased vision following 3 years without IMT. Significantly decreased amplitude on electroretinography and worse deviation parameters in perimetry were found in patients 3 years after withdrawal that experienced early discontinuation when compared with those achieving durable remission on IMT > 2 years (p < 0.05). Conclusion: The possibility of electroretinography and perimetry results worsening after early IMT discontinuation remained if the patients couldn't achieve remission.

Five-Year Trends in Multifocal Electroretinogram for Patients With Birdshot Chorioretinopathy.

PURPOSE: The aim of this study is to investigate temporal trends in multifocal ERG (mfERG) parameters and analyze their relationships with anatomic and functional markers in patients with birdshot chorioretinopathy (BSCR). DESIGN: Prospective observational case series. METHODS: Sixteen BSCR patients were include and underwent 2 standardized follow-up (FU) visits within 5 years following a baseline examination, including mfERG, visual acuity (VA), visual field (VF), Lanthony desaturated panel D-15 test for color vision, quality of life (QoL), fluorescein and indocyanine green angiography, and optical coherence tomography (OCT). RESULTS: A significant trend toward a decrease in absolute N1 amplitude values was observed over the follow-up period (P < .001) while N1 implicit time remained unchanged. In contrast, P1 amplitude decreased (P < .001) and P1 implicit time increased (P < .001) over the same period. No significant temporal change was found for VA, color vision score, foveal threshold, mean deviation of VF, and QoL. After adjusting for time to FU, increasing N1 and P1 IT were both associated with decreasing values of logMAR, foveal threshold, and QoL and with increasing color vision score and mean deviation of VF. A significant relationship was observed between decreasing P1 amplitude values and increasing mean deviation of VF. Lower absolute values of N1 amplitude were associated with venous vasculitis, whereas lower P1 amplitude values correlated with alteration of the outer retina in OCT. CONCLUSIONS: Progressive deterioration in mfERG during a 5-year period is detected in BSCR, whereas classical functional test results were unchanged. This study suggests a better sensitivity of mfERG in monitoring the retinal function of BSCR patients.