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1. Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

Author

Kuiper, Jonas JW, van Setten, Jessica, Devall, Matthew, Cretu-Stancu, Mircea, Hiddingh, Sanne, Ophoff, Roel A, Missotten, Tom OAR, van Velthoven, Mirjam, Hollander, Anneke I Den, Hoyng, Carel B, James, Edward, Reeves, Emma, Cordero-Coma, Miguel, Fonollosa, Alejandro, Adán, Alfredo, Martín, Javier, Koeleman, Bobby PC, de Boer, Joke H, Pulit, Sara L, Márquez, Ana, and Radstake, Timothy RDJ

Subjects
Genetics, 2.1 Biological and endogenous factors, Aetiology, Aminopeptidases, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, HLA-A Antigens, Haplotypes, Humans, Male, Minor Histocompatibility Antigens, Minor Histocompatibility Loci, Polymorphism, Single Nucleotide, Uveitis, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed 'MHC-I (major histocompatibility complex class I)-opathy' family. Genetic studies have pinpointed the endoplasmic reticulum aminopeptidase (ERAP1) and (ERAP2) genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression. We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC-I-opathies. We show that the risk ERAP1 haplotype conferred significantly altered expression of ERAP1 isoforms in transcriptomic data (n = 360), resulting in lowered protein expression and distinct enzymatic activity. Both the association for rs10044354 (meta-analysis: odds ratio (OR) [95% CI]=2.07[1.58-2.71], P = 1.24 × 10(-7)) and rs2287987 (OR[95% CI]: =2.01[1.51-2.67], P = 1.41 × 10(-6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either variant alone [meta-analysis: P=3.9 × 10(-9)]. Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n = 3353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.

Published
2018

2. Long-Term Follow-Up of Patients with Scleritis After Rituximab Treatment Including B Cell Monitoring.

Author

van Bilsen, Kiki, Vergouwen, Daphne P. C., van Velthoven, Mirjam E. J., Missotten, Tom O. A. R., Rombach, Saskia M., van Zelm, Menno C., Berkowska, Magdalena A., van Hagen, P. Martin, Kuijpers, Robert W. A. M., and van Laar, Jan A. M.

Subjects
B cells, SCLERITIS, RITUXIMAB, REFRACTORY materials
Abstract

Purpose: We report the long-term effect of rituximab (RTX) in scleritis and determine the value of B-cell monitoring for the prediction of relapses. Methods: We retrospectively studied 10 patients with scleritis, who were treated with RTX. Clinical characteristics were collected, and blood B-cell counts were measured before the start of RTX, and at various time points after treatment. Results: Clinical activity of scleritis decreased after RTX treatment in all patients within a median time of 8 weeks (range 3–13), and all reached remission. The median follow-up was 101 months (range 9–138). Relapses occurred in 6 out of 10 patients. All relapses, where B-cell counts were measured (11 out of 19), were heralded by returning B cells. However, B cells also returned in patients with long-term remissions. Conclusions: RTX is a promising therapeutic option for scleritis. Recurrence of B cells after initial depletion does not always predict relapse of scleritis. [ABSTRACT FROM AUTHOR]

Published
2024
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4. A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy

Author

Kuiper, Jonas JW, Van Setten, Jessica, Ripke, Stephan, Van ‘T Slot, Ruben, Mulder, Flip, Missotten, Tom, Baarsma, G Seerp, Francioli, Laurent C, Pulit, Sara L, De Kovel, Carolien GF, Loon, Ninette Ten Dam-Van, Hollander, Anneke I Den, Veld, Paulien Huis in het, Hoyng, Carel B, Cordero-Coma, Miguel, Martín, Javier, Llorenç, Victor, Arya, Bharti, Thomas, Dhanes, Bakker, Steven C, Ophoff, Roel A, Rothova, Aniki, De Bakker, Paul IW, Mutis, Tuna, and Koeleman, Bobby PC

Subjects
Genetics, Prevention, Clinical Research, Autoimmune Disease, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Alleles, Aminopeptidases, Birdshot Chorioretinopathy, Case-Control Studies, Chorioretinitis, Female, Genome-Wide Association Study, HLA-A Antigens, Haplotypes, Humans, Male, Whites, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 × 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 × 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.

Published
2014

5. ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder

Author

Williams, Lloyd B., Javed, Asif, Sabri, Amin, Morgan, Denise J., Huff, Chad D., Grigg, John R., Heng, Xiu Ting, Khng, Alexis J., Hollink, Iris H. I. M., Morrison, Margaux A., Owen, Leah A., Anderson, Katherine, Kinard, Krista, Greenlees, Rebecca, Novacic, Danica, Nida Sen, H., Zein, Wadih M., Rodgers, George M., Vitale, Albert T., Haider, Neena B., Hillmer, Axel M., Ng, Pauline C., Shankaracharya, Cheng, Anson, Zheng, Linda, Gillies, Mark C., van Slegtenhorst, Marjon, van Hagen, P. Martin, Missotten, Tom O. A. R., Farley, Gary L., Polo, Michael, Malatack, James, Curtin, Julie, Martin, Frank, Arbuckle, Susan, Alexander, Stephen I., Chircop, Megan, Davila, Sonia, Digre, Kathleen B., Jamieson, Robyn V., and DeAngelis, Margaret M.

Published
2019
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6. Long-Term Follow-Up of Patients with Scleritis After Rituximab Treatment Including B Cell Monitoring

Author

van Bilsen, Kiki, primary, Vergouwen, Daphne P. C., additional, van Velthoven, Mirjam E. J., additional, Missotten, Tom O. A. R., additional, Rombach, Saskia M., additional, van Zelm, Menno C., additional, Berkowska, Magdalena A., additional, van Hagen, P. Martin, additional, Kuijpers, Robert W. A. M., additional, and van Laar, Jan A. M., additional

Published
2023
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8. Long-Term Follow-Up of Patients with Scleritis After Rituximab Treatment Including B Cell Monitoring

Author

van Bilsen, Kiki, Vergouwen, Daphne P.C., van Velthoven, Mirjam E.J., Missotten, Tom O.A.R., Rombach, Saskia M., van Zelm, Menno C., Berkowska, Magdalena A., van Hagen, P. Martin, Kuijpers, Robert W.A.M., van Laar, Jan A.M., van Bilsen, Kiki, Vergouwen, Daphne P.C., van Velthoven, Mirjam E.J., Missotten, Tom O.A.R., Rombach, Saskia M., van Zelm, Menno C., Berkowska, Magdalena A., van Hagen, P. Martin, Kuijpers, Robert W.A.M., and van Laar, Jan A.M.

Abstract

Purpose: We report the long-term effect of rituximab (RTX) in scleritis and determine the value of B-cell monitoring for the prediction of relapses. Methods: We retrospectively studied 10 patients with scleritis, who were treated with RTX. Clinical characteristics were collected, and blood B-cell counts were measured before the start of RTX, and at various time points after treatment. Results:Clinical activity of scleritis decreased after RTX treatment in all patients within a median time of 8 weeks (range 3–13), and all reached remission. The median follow-up was 101 months (range 9–138). Relapses occurred in 6 out of 10 patients. All relapses, where B-cell counts were measured (11 out of 19), were heralded by returning B cells. However, B cells also returned in patients with long-term remissions.Conclusions: RTX is a promising therapeutic option for scleritis. Recurrence of B cells after initial depletion does not always predict relapse of scleritis.

Published
2023

11. Vitreous proteomics, a gateway to improved understanding and stratification of diverse uveitis aetiologies

Author

Schrijver, Benjamin, Kolijn, P. Martijn, ten Berge, Josianne C.E.M., Nagtzaam, Nicole M.A., van Rijswijk, Angelique L.C.T., Swagemakers, Sigrid M.A., van der Spek, Peter J., Missotten, Tom O.A.R., van Velthoven, Mirjam E.J., de Hoog, Joeri, van Hagen, P. Martin, Langerak, Anton W., Dik, Willem A., Schrijver, Benjamin, Kolijn, P. Martijn, ten Berge, Josianne C.E.M., Nagtzaam, Nicole M.A., van Rijswijk, Angelique L.C.T., Swagemakers, Sigrid M.A., van der Spek, Peter J., Missotten, Tom O.A.R., van Velthoven, Mirjam E.J., de Hoog, Joeri, van Hagen, P. Martin, Langerak, Anton W., and Dik, Willem A.

Abstract

Purpose: The vitreous proteome might provide an attractive gateway to discriminate between various uveitis aetiologies and gain novel insights into the underlying pathophysiological processes. Here, we investigated 180 vitreous proteins to discover novel biomarkers and broaden disease insights by comparing (1). primary vitreoretinal lymphoma ((P)VRL) versus other aetiologies, (2). sarcoid uveitis versus tuberculosis (TB)-associated uveitis and (3). granulomatous (sarcoid and TB) uveitis versus other aetiologies. Methods: Vitreous protein levels were determined by proximity extension assay in 47 patients with intraocular inflammation and a prestudy diagnosis (cohort 1; training) and 22 patients with a blinded diagnosis (cohort 2; validation). Differentially expressed proteins identified by t-tests on cohort 1 were used to calculate Youden’s indices. Pathway and network analysis was performed by ingenuity pathway analysis. A random forest classifier was trained to predict the diagnosis of blinded patients. Results: For (P)VRL stratification, the previously reported combined diagnostic value of IL-10 and IL-6 was confirmed. Additionally, CD70 was identified as potential novel marker for (P)VRL. However, the classifier trained on the entire cohort (cohort 1 and 2) relied primarily on the interleukin score for intraocular lymphoma diagnosis (ISOLD) or IL-10/IL-6 ratio and only showed a supportive role for CD70. Furthermore, sarcoid uveitis displayed increased levels of vitreous CCL17 as compared to TB-associated uveitis. Conclusion: We underline the previously reported value of the ISOLD and the IL-10/IL-6 ratio for (P)VRL identification and present CD70 as a potentially valuable target for (P)VRL stratification. Finally, we also show that increased CCL17 levels might help to distinguish sarcoid uveitis from TB-associated uveitis.

Published
2022

12. Long-Term Follow-up of Patients With Uveitis Treated With Adalimumab:Response Rates and Reasons for Discontinuation of Therapy

Author

Eurelings, Laura E.M., Missotten, Tom O.A.R., van Velthoven, Mirjam E.J., van Daele, Paul L.A., van Laar, Jan A.M., van Hagen, P. Martin, Thiadens, Alberta A.H.J., Rombach, Saskia M., Eurelings, Laura E.M., Missotten, Tom O.A.R., van Velthoven, Mirjam E.J., van Daele, Paul L.A., van Laar, Jan A.M., van Hagen, P. Martin, Thiadens, Alberta A.H.J., and Rombach, Saskia M.

Abstract

PURPOSE: To evaluate the effectiveness and reasons for discontinuation including the side effect profiles of adalimumab in a real-world setting. DESIGN: Retrospective clinical cohort study. METHODS: A medical chart review of clinical practice in 2 tertiary eye care services in Rotterdam, the Netherlands, was performed Data were collected from May 1, 2004, through September 1, 2020. Patients with noninfectious uveitis treated with adalimumab (n = 341; 633 affected eyes) were included. The primary outcome was the effectiveness of adalimumab, measured by the number of patients achieving inactive disease, remission, and relapse-free survival. The secondary outcomes were the reasons for discontinuation, including side effects, and the number of patients who developed antibodies. RESULTS: In total, 341 patients were treated with adalimumab between May 2004 and September 2020. The uveitis recurrence-free survival interval was 3.4 years (range, 0-13 years). Adalimumab had an acceptable side effect profile. A total of 178 patients achieved inactive disease while continuing adalimumab, and 51 patients maintained remission after discontinuing adalimumab. Reasons for discontinuation of adalimumab were no response, relapse, or reasons unrelated to the effectiveness of treatment. Adalimumab antibodies were present in 40 of 115 patients (35%). Antibodies were associated with lower adalimumab levels, and antibodies were observed more often in patients on adalimumab monotherapy (P < .01). CONCLUSIONS: Adalimumab is effective for patients with noninfectious uveitis, with an acceptable side effect profile. Although relapses can occur, the majority of the patients achieved inactive disease or remission after cessation of adalimumab, without other systemic immunosuppressive medication.

Published
2022

15. Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium

Author

de Breuk, Anita, Acar, Ilhan E., Kersten, Eveline, Schijvenaars, Mascha M.V.A.P., Colijn, Johanna M., Haer-Wigman, Lonneke, Bakker, Bjorn, de Jong, Sarah, Meester-Smoor, Magda A., Verzijden, Timo, Missotten, Tom O.A.R., Monés, Jordi, Biarnés, Marc, Pauleikhoff, Daniel, Hense, Hans W., Silva, Rufino, Nunes, Sandrina, Melo, Joana B., Fauser, Sascha, Hoyng, Carel B., Ueffing, Marius, Coenen, Marieke J.H., Klaver, Caroline C.W., den Hollander, Anneke I., Ikram, A., Vingerling, Johannes, Ophthalmology, and Epidemiology

Subjects
genetic structures, sense organs, eye diseases
Abstract

Purpose: To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD. Design: Case-control study. Participants: Individuals (n = 4740) from 5 European cohorts. Methods: We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis. Main Outcome Measures: Genetic risk score, association of genetic variants with AMD, and genotype–phenotype correlations. Results: We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy. Conclusions: This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.

Published
2021

17. Treatment Strategies in Primary Vitreoretinal Lymphoma: A 17-Center European Collaborative Study

Author

Riemens, Anjo, Bromberg, Jacoline, Touitou, Valerie, Sobolewska, Bianka, Missotten, Tom, Baarsma, Seerp, Hoyng, Carel, Cordero-Coma, Miguel, Tomkins-Netzer, Oren, Rozalski, Anna, Tugal-Tutkun, Ilknur, Guex-Crosier, Yan, Los, Leonoor I., Bollemeijer, Jan Geert, Nolan, Andrew, Pawade, Joya, Willermain, Francois, Bodaghi, Bahram, ten Dam-van Loon, Ninette, Dick, Andrew, Zierhut, Manfred, Lightman, Susan, Mackensen, Friederike, Moulin, Alexandre, Erckens, Roel, Wensing, Barbara, le Hoang, Phuc, Lokhorst, Henk, and Rothova, Aniki

Published
2015
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19. Vitreous proteomics, a gateway to improved understanding and stratification of diverse uveitis aetiologies

Author

Schrijver, Benjamin, primary, Kolijn, P. Martijn, additional, Berge, Josianne C.E.M., additional, Nagtzaam, Nicole M.A., additional, Rijswijk, Angelique L.C.T., additional, Swagemakers, Sigrid M.A., additional, Spek, Peter J., additional, Missotten, Tom O.A.R., additional, Velthoven, Mirjam E.J., additional, Hoog, Joeri, additional, Hagen, P. Martin, additional, Langerak, Anton W., additional, and Dik, Willem A., additional

Published
2021
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20. Development of a Genotype Assay for Age-Related Macular Degeneration:The EYE-RISK Consortium

Author

de Breuk, Anita, Acar, Ilhan E., Kersten, Eveline, Schijvenaars, Mascha M.V.A.P., Colijn, Johanna M., Haer-Wigman, Lonneke, Bakker, Bjorn, de Jong, Sarah, Meester-Smoor, Magda A., Verzijden, Timo, Missotten, Tom O.A.R., Monés, Jordi, Biarnés, Marc, Pauleikhoff, Daniel, Hense, Hans W., Silva, Rufino, Nunes, Sandrina, Melo, Joana B., Fauser, Sascha, Hoyng, Carel B., Ueffing, Marius, Coenen, Marieke J.H., Klaver, Caroline C.W., den Hollander, Anneke I., Ikram, A., Vingerling, Johannes, de Breuk, Anita, Acar, Ilhan E., Kersten, Eveline, Schijvenaars, Mascha M.V.A.P., Colijn, Johanna M., Haer-Wigman, Lonneke, Bakker, Bjorn, de Jong, Sarah, Meester-Smoor, Magda A., Verzijden, Timo, Missotten, Tom O.A.R., Monés, Jordi, Biarnés, Marc, Pauleikhoff, Daniel, Hense, Hans W., Silva, Rufino, Nunes, Sandrina, Melo, Joana B., Fauser, Sascha, Hoyng, Carel B., Ueffing, Marius, Coenen, Marieke J.H., Klaver, Caroline C.W., den Hollander, Anneke I., Ikram, A., and Vingerling, Johannes

Abstract

Purpose: To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD. Design: Case-control study. Participants: Individuals (n = 4740) from 5 European cohorts. Methods: We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis. Main Outcome Measures: Genetic risk score, association of genetic variants with AMD, and genotype–phenotype correlations. Results: We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy. Conclusions: This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at interm

Published
2021

26. Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium

Author

Breuk, Anita de, Acar, Ilhan E., Kersten, Eveline, Schijvenaars, Mascha M. V. A. P., Colijn, Johanna M., Haer-Wigman, Lonneke, Bakker, Bjorn, Jong, Sarah de, Meester-Smoor, Magda, Verzijden, Timo, Missotten, Tom O. A. R., Monés, Jordi, Biarnés, Marc, Pauleikhoff, Daniel, Hense, Hans W., Silva, Rufino, Nunes, Sandrina, Melo, Joana B., Fauser, Sascha, Hoyng, Carel B., Ueffing, Marius, Coenen, Marieke J. H., Klaver, Caroline C. W., and Hollander, Anneke I. den

Subjects
Genetic testing, Age-related macular degeneration, Genetics, eye diseases, Genetic counseling
Abstract

The EYE-RISK Consortium: Université Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France: Soufiane Ajana, Audrey Cougnard-Grégoire, Cécile Delcourt, Bénédicte M. J. Merle; Institute for Ophthalmic Research, Eberhard Karls University Tübingen, University Clinic Tübingen, Tübingen, Germany: Blanca Arango-Gonzalez, Sascha Dammeier, Sigrid Diether, Sabina Honisch, Ellen Kilger, Marius Ueffing; AYOXXA Biosystems GmbH, Cologne, Germany: Tanja Endermann, Markus Zumbansen; Pro-Retina Deutschland, Aachen, Germany: Franz Badura; Department of Regeneration and Cell Therapy, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, Spain: Berta De la Cerda; Barcelona Macula Foundation, Barcelona, Spain: Marc Biarnés, Anna Borrell, Lucia L. Ferraro, Míriam Garcia, Jordi Monés, Eduardo Rodríguez; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands: Johanna M. Colijn, A. Ikram, Caroline C. W. Klaver, Magda Meester-Smoor, Timo Verzijden, Johannes Vingerling; Radboud University Medical Center, Nijmegen, The Netherlands: Anneke I. den Hollander, Thomas J. Heesterbeek, Caroline C. W. Klaver, Eveline Kersten, Eiko K. de Jong, I. Erkin Acar, Anita de Breuk; Centre for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom: Eszter Emri, Imre Lengyel; Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland: Hanno Langen, Everson Nogoceke; Centre for Public Health, Queen’s University Belfast, Belfast, United Kingdom: Tunde Peto; Institute of Ophthalmology, University College London, London, United Kingdom: Phil Luthert, Frances M. Pool., Purpose To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD. Design Case-control study. Participants Individuals (n = 4740) from 5 European cohorts. Methods We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis. Main Outcome Measures Genetic risk score, association of genetic variants with AMD, and genotype–phenotype correlations. Results We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy. Conclusions This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.

Published
2020

39. Diagnosis and treatment of uveitis; not restricted to the ophthalmologist

Author

van Laar, Jan A M, Rothova, Aniki, Missotten, Tom, Kuijpers, Robert W A M, van Hagen, P Martin, van Velthoven, Mirjam E J, and Surgical clinical sciences

Subjects
Medicine(all), ethiology, uveitis, immunosuppressive therapy, multidisciplinary management, Review, anti-TNF
Abstract

Uveitis is associated with a wide range of underlying causes. Familiarity with its clinical manifestations, referral indications, and treatment strategies are required for the optimal use of current therapeutic options. Uveitis can be caused by infectious and non-infectious factors, resulting in differing prognoses and treatments. The treatment of chronic, non-infectious uveitis has profoundly changed in the last years due to the advent of biologicals, but also of intraocular therapies. In severe uveitis, treatment of the underlying cause, whether ocular or systemic, is required to prevent severe loss of vision. For these purposes, a multidisciplinary clinical approach is important, which is addressed in this review. Relevance for patients: A broad understanding of the different causes of uveitis and the implementation of disease-tailored, multidisciplinary management of uveitis is expected to improve treatment outcomes for patients with different types of uveitis.

Published
2015

40. Clinical characteristics and long-term visual outcome of severe phenotypes of chronic central serous chorioretinopathy

Author

Mohabati,Danial, van Rijssen,Thomas J, van Dijk,Elon, Luyten,Gregorius, Missotten,Tom O, Hoyng,Carel, Yzer,Suzanne, Boon,Camiel, Mohabati,Danial, van Rijssen,Thomas J, van Dijk,Elon, Luyten,Gregorius, Missotten,Tom O, Hoyng,Carel, Yzer,Suzanne, and Boon,Camiel

Abstract

Danial Mohabati,1,2 Thomas J van Rijssen,1 Elon HC van Dijk,1 Gregorius PM Luyten,1 Tom O Missotten,3 Carel B Hoyng,4 Suzanne Yzer,3 Camiel JF Boon1,5 1Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands; 2Department of Ophthalmology, Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands; 3Department of Ophthalmology, The Rotterdam Eye Hospital, Rotterdam, the Netherlands; 4Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; 5Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Purpose: The aim of this study was to investigate disease onset and disease progression in patients with severe chronic central serous chorioretinopathy (cCSC). Patients and methods: The medical records of 143 cCSC patients (199 eyes) were reviewed. All cases had visual complaints for >6 months and showed signs of a severe disease phenotype on optical coherence tomography (OCT) and fluorescein angiography (FA). Clinical presentation at onset was evaluated, together with disease progression on multimodal imaging and final treatment outcome. Results: Twenty-eight cases (14%) had a documented history of an acute episode of CSC, whereas 145 cases (73%) showed pre-existing features of chronicity already at first presentation. The first clinical presentation could not be evaluated in 13% of cases. Best-corrected visual acuity (BCVA) was 70 ± 18 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters at onset and 70 ± 22 ETDRS letters at final visit (p = 0.770). Among all studied cases, 173 eyes (87%) were treated, which resulted in complete resolution of subretinal fluid (SRF) in 76% of eyes at final visit. In eyes with fluorescein angiographic follow-up, the area of diffuse atrophic retinal pigment epithelium (RPE) abnormalities (diffuse atrophic RPE alterations [DARA]) h

Published
2018

43. Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

Author

Kuiper, Jonas J.W., primary, van Setten, Jessica, additional, Devall, Matthew, additional, Cretu-Stancu, Mircea, additional, Hiddingh, Sanne, additional, Ophoff, Roel A., additional, Missotten, Tom O.A.R., additional, van Velthoven, Mirjam, additional, Den Hollander, Anneke I, additional, Hoyng, Carel B, additional, James, Edward, additional, Reeves, Emma, additional, Cordero-Coma, Miguel, additional, Fonollosa, Alejandro, additional, Adán, Alfredo, additional, Martín, Javier, additional, Koeleman, Bobby P.C., additional, de Boer, Joke H., additional, Pulit, Sara L., additional, Márquez, Ana, additional, and Radstake, Timothy R. D. J., additional

Published
2018
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45. Aberrant leukocyte telomere length in Birdshot Uveitis

Author

Vazirpanah, Nadia, Verhagen, Fleurieke H, Rothova, Anna, Missotten, Tom O A R, van Velthoven, Mirjam, Den Hollander, Anneke I, Hoyng, Carel B, Radstake, Timothy R D J, Broen, Jasper C A, Kuiper, Jonas J W, Vazirpanah, Nadia, Verhagen, Fleurieke H, Rothova, Anna, Missotten, Tom O A R, van Velthoven, Mirjam, Den Hollander, Anneke I, Hoyng, Carel B, Radstake, Timothy R D J, Broen, Jasper C A, and Kuiper, Jonas J W

Published
2017

46. Aberrant leukocyte telomere length in Birdshot Uveitis

Author

Translationele immunologie, Infection & Immunity, Oogheelkunde Onderzoek, Unit Opleiding Reumat./Klin. Immunologie, MS Oogheelkunde, Other research (not in main researchprogram), Vazirpanah, Nadia, Verhagen, Fleurieke H, Rothova, Anna, Missotten, Tom O A R, van Velthoven, Mirjam, Den Hollander, Anneke I, Hoyng, Carel B, Radstake, Timothy R D J, Broen, Jasper C A, Kuiper, Jonas J W, Translationele immunologie, Infection & Immunity, Oogheelkunde Onderzoek, Unit Opleiding Reumat./Klin. Immunologie, MS Oogheelkunde, Other research (not in main researchprogram), Vazirpanah, Nadia, Verhagen, Fleurieke H, Rothova, Anna, Missotten, Tom O A R, van Velthoven, Mirjam, Den Hollander, Anneke I, Hoyng, Carel B, Radstake, Timothy R D J, Broen, Jasper C A, and Kuiper, Jonas J W

Published
2017

47. Aberrant leukocyte telomere length in Birdshot Uveitis

Author

Vazirpanah, Nadia, primary, Verhagen, Fleurieke H., additional, Rothova, Anna, additional, Missotten, Tom O. A. R., additional, van Velthoven, Mirjam, additional, Den Hollander, Anneke I., additional, Hoyng, Carel B., additional, Radstake, Timothy.R. D. J., additional, Broen, Jasper C. A., additional, and Kuiper, Jonas J. W., additional

Published
2017
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50. Treatment Effects in Retinal Angiomatous Proliferation Imaged with OCT Angiography.

Author

de Jong, Jan H., Braaf, Boy, Amarakoon, Sankha, Gräfe, Maximilian, Yzer, Suzanne, Vermeer, Koenraad A., Missotten, Tom, de Boer, Johannes F., and van Velthoven, Mirjam E.J.

Subjects
ANGIOGRAPHY, BLOOD flow, COHERENCE (Optics), PHOTODYNAMIC therapy, PATIENT monitoring
Abstract

Purpose: This prospective case series is aimed at exploring optical coherence tomographic angiography (OCT-A) as a treatment monitoring tool in patients treated for retinal angiomatous proliferation (RAP). Methods: Twelve treatment-naïve RAP patients were included, with a median age of 79 years (range 65–90). Patients were imaged with an experimental 1,040-nm swept-source phase-resolved OCT-A instrument before and after treatment. Treatment consisted of either intravitreal bevacizumab or triamcinolone injections with or without photodynamic therapy (PDT). Abnormal blood flow after treatment was graded as increased, unchanged, decreased, or resolved. Results: OCT-A images before and after treatment could be obtained in 9 patients. The median follow-up period was 10 weeks (range 5–19). After various treatments, the RAP lesion resolved in 7 patients, in 1 patient the OCT-A depicted decreased flow in the lesion, and 1 patient showed unchanged abnormal blood flow. Monotherapy with intravitreal bevacizumab injections resolved RAP in 1 out of 2 patients. Combined therapy of bevacizumab with PDT resolved RAP in 6 out of 7 patients. Conclusions: OCT-A visualized resolution of abnormal blood flow in 7 out of 9 RAP patients after various short-term treatment sequences. OCT-A may become an important noninvasive monitoring tool for optimizing treatment strategies in RAP patients. [ABSTRACT FROM AUTHOR]

Published
2019
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