Ophthalmology·
`Retina
`
`Volume 2, Number 7, July 2018
`www.ophthalmologyrctina.org
`
`Real-world Outcomes of Anti Vascular
`Endothelial Growth Factor Therapy in
`Neovascular Age-Related Macular
`Degeneration in the United States
`Thonws A. Ciulla, MD, MBA, Forbes Huang, Keith Westby, MBA,
`DavidF. Williams, MD, MBA, Sandi Zave1i , RPh, SamirC. Patel, MD
`
`Purpose: Real-world visual outcomes of aoti-vascular eodo(cid:173)
`thelial growth factor (anti-VEGF) therapy for neovascular age(cid:173)
`related macular degeneration (oAMD) have been reported in
`cohorts outside of the Uoited States. This study sought to assess the
`relationship between presenting visual acuity (VA) and visual
`outcomes, as well as the potential impact of loss to follow-up, in
`real-world anti-VEGF-treated nAMD patients from the United
`States.
`Design: Retrospective study of aggregated, longitudinal elec(cid:173)
`tronic medical records obtained from a geographically diverse
`sample of US retina specialists and included in the Vestmm Health
`Retina Database.
`Participants: Inclusion criteria were a diagnosis of nAMD, no
`previous treatment, and _2:3 monthly anti-VEGF injections in the
`first 4 months from diagnosis in patients diagnosed between
`January 2011 and July 2013.
`Methods: To model loss to follow-up, mun1ally exclusive co(cid:173)
`horts of oAMD patients with loss to follow-up after specific time
`points of 6 and 12 mooths (i.e., oo follow-up beyood) were
`compared with a separate cohort of patieots who completed 24
`months of follow-up endiog prior to July 2015 (n = 2213).
`Main Outcome Measure: VA outcomes were assessed on each
`cohort as a whole, with additional stratification by baseline VA.
`Results: The 6-, 12-, and 24- month cohorts received means of
`5.4, 7.3, and 12.l injections and showed no change, no change,
`and a meao change of + 3.1 letters from baseline (95% confidence
`interval l.8-4.4 letters, P < 0.01), respectively. When stratified
`by baseline VA, nearly all groups lose VA at their respective
`follow-up periods, except for those with baseline VA of 20/200
`or worse.
`Conclusions: Real-world nAMD patients in the United States
`receive fewer anti-VEGF injections and experience worse visual
`outcomes compared with patients in randomized clinical trials,
`consisteot with ooo-US studies. Patients with better VA at pre(cid:173)
`seotatioo tend to be particularly vuloen1ble to visioo
`loss.
`Compared with other patients, those ultimately lost to follow-up
`have worse visual outcomes at, or prior to, their final visit,
`suggesting that loss to follow-up may lead to overestimation of
`visual outcomes in clinical studies of nAMD.
`Ophthalmology Retina 2018;2:645-653.
`
`1130
`
`Timing of Povidone Iodine Application to
`Reduce the Risk of Endophthalmitis after
`lntravitreal Injections
`Joshua D. Levimon, MD, Richard A. Garfinkel, MD, Daniel M.
`Berinstein, MD, Mic/1ael Flory, CRA, COT, Frank A Spellman , MD
`
`Purpose: To analyze comparatively the effect of different
`intravitreal injection (TV{) protocols oa the incidence of endopb(cid:173)
`thalmitis occurring after injection.
`Design: Retrospective case-control series.
`Participants: Twenty-seven retina specialists in a large vitre(cid:173)
`oretinal practice performed 37 646 fVIs.
`Methods: Multivariate analysis was used to ideatify risk factors
`for development of endopbthalmitis occurring after injectioa. Before
`all injections, a technician applied 5% povidoae-iodine (Pl) to the
`eyelids and conjunctiva. There were 4 distinct aseptic protocols with
`,regard to reapplication of PI by physicians: physicians who did not
`reapply Pl, reapplicatioo of Pl without the use of a lid speculum,
`reapplication of Pl before speculum placement, and reapplication of
`PI after speculum placemeot. Other analyzed variables included the
`use of gloves, a caliper to mark the injection site, and the class of
`medicatioo (steroid vs. anti-vascular endothelial growth factor).
`Main Outcome Measures: Cases of presumed infectious
`eadophthalmitis.
`Results: Thirty-three cases of presumed infectious endoph(cid:173)
`thalmitis occurred after 37 646 injectioas (0.088%). The method of
`PI application was fouad to be a statistically signilicaat predictor of
`the incidence of endophthalmitis (P = 0.031). When compared
`with the incidence of eodopbthalmitis for pbysiciaos who did not
`reapply PI (0.124% [20/16 155]), there w,.~ no statistical. difference
`for reapplicatioo of PI without the use of a speculum (0.110% [6/
`5472); P = 0.584) or reapplication before speculum insertion
`(0.122% [5/4067); P = 0.863). However, reapplication of PI after
`insertion of the lid speculum wa~ associated with a significantly
`decreased incidence of endophthalmitis (0.017% [2/11 952); P =
`0.004; odds ratio, 0.113). Use of gloves (P = 0.119) or a caliper to
`mark the injection site (P = 0.496) aad the cla~s of medication
`(P = 0.740) were not found to be statistically sigaificaat risk
`factors for endophthalmitis developmeat.
`Conclusions: The application of PI after placement of the lid
`speculum reduced the incidence of eadopbthalmilis occurring after
`injection approximately 7-fold compared with other aseptic pro(cid:173)
`tocols. Preventing the eyelid from contacting the injection site after
`the fiaal application of PI is an important step in improving the
`safety of iatmvitreal injections.
`Ophthalmology Rerina 2018;2:654-658.
`
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`

`Fluorescein Angiography Does Not Alter
`the Initial Clinical Management of Choroidal
`Neovascularization in Age-Related Macular
`Degeneration
`Pra.sham K. Parekh, MD, MBA, James C. Folk, MD, Priya Gu/)Ca,
`MD, PhD, SreJ>hen R. Ru.ssell, MD, Elliott H. Sohn, MD, Michael D.
`Abramoff, MD, PhD
`
`Purpose: Fundus fluorescein angiography (FFA) is the standard
`modality to diagnose and manage cboroidal neovascularization
`(CNV). However, FFA is costly and bas considerable morbidity
`from allergic reactions and a morraLity of J per 220 000. Since the
`advent of anti-vascular endothelial growth factor (VEGF) therapy
`for CNV, OCT bas been used extensively to manage CNV, but FFA
`is still widely used. One recent study found the sensitivity and
`specificity of OCT compared with FF A in diagnosis of CJ\TV were
`100% and 80.8%, respectively. We hypothesize that FFA does not
`affect the management of patients initially suspected of having CNV
`to a clinically significant degree.
`Design: Evaluation of diagnostic test using vignettes.
`Participants: A total of99 patients (99 eyes) who had an initial
`presentation of later confirmed CNV.
`Methods: We retrospectively exti:acted in de-identified form
`the FFA, OCT, and clinical histories of the subjects. Vignettes
`were created with a standard narrative cl.inical history, posterior(cid:173)
`pole color fundus image, central 8 -scan OCT of the initial visit,
`and early, mid, and late FFA of the affected eye. Four masked
`retinal specialists reviewed, in randomized order, these vignettes
`without FF A images (FF A- arn1) and answered a forced choice
`management question: observation, 3 consecutive anti-VEGF in(cid:173)
`jections, or other. After re-randomization, experts again reviewed
`the vignettes with the addition of the FFA images (FFA+ arm).
`Main Outcome Measures: Tntraobserver and interobserver
`concordance and reliability statistics within and between specialists.
`Results: Among our retina specialists, intraobserver concor(cid:173)
`dances were 89.7%, 88.7%, 88.7%, and 95.9% (average 90.7%,
`95% confidence interval [CI], 83.7-97.6). The avernge interob(cid:173)
`server concordance for the FFA- ann was 84.0% (95% CI,
`72.6-95.4), and for the FFA+ arm, 81.8% (95% CI, 68.5-95.2);
`paired t testing demonstrated no significant difference between the
`FFA- and FFA+ anns: t = 0.6, P = 0.55.
`Conclusions: Our data suggest a high degree of agreement in
`clinical decision making whether FF A was used or not. There was a
`similar level of agreement among specialists in the FFA- and FFA+
`groups, albeit at higher, not statistically significant, variabiLity. We
`believe these findings further support deferring the use of FF A in the
`initial management of CNV in AMD, except in treatment failures
`and nonstandard cases.
`Oph1halmology Re1ina 2018;2:659-666.
`
`The Systemic Safety of Ranibizumab in
`Patients 85 Years and Older with
`Neovascular Age-Related Macular
`Degeneration
`Pravin U. Dugel, MD, Nauisha Singh, PhannD, Steven Francom,
`PhD, Ronald A. Cantrell, PhD, Susanna M. Grzeschik, PhD, RPh,
`Anne E. Fung, MD
`
`Objective: Ranibizumab safety is well established for treatment
`of neovascular age-related macular degeneration (nAMD), but less
`is known about the risk of systemic serious adverse events (SAEs),
`specifically among patients with heightened baseline risk due to
`age (?::85 years). This analysis examines whether patients ?::85
`years of age versus those < 85 years experience an incre,L~ed risk of
`key systemic SAEs during intravitreal ,dllibizumab treatment for
`nAMD.
`Design: Retrospective, pooled analysis of safety data from 5
`pha~e ITI/fllb multicenter randomized clinical trials in patients with
`nAMD: ANCHOR, MARINA, PIER, SAILOR, and HARBOR.
`Participants: Patients with nAMD receiving rnnibizumab
`(n = 4347) or control (sbam/verteporfin pbotodynamic therapy,
`n = 441) treatment included in the safety-evaluable set of the
`5 trials.
`Methods: The incidence of nonocular SAEs was analyzed
`stratified by age ( < 85 years [n = 3795] vs ?::85 years [n = 993]),
`treatment (control, ranibizumab 0.3 mg, ranibizumab 0.5 mg,
`ranibizumab 2.0 mg), and injection frequency (monthly, as needed
`[PRN]).
`Main Outcome Measures: Incidence of key systemic SAEs,
`defined as total nonocular SAEs, deaths, cardiovascular events,
`cerebrovascular (CBV) events, and Antiplatelet Trialists' Collab(cid:173)
`orntion events.
`Results: The MARINA and ANCHOR trials bad greater rates
`of key SAEs for patients 2:85 years versus those < 85 years.
`Ranibizumab exposure did not increase the risk of most SAEs in
`elderly patients; for CBV events and death, the effect of ranibi(cid:173)
`zumab versus control treatment for age ?::85 years was not inter(cid:173)
`pretable due to small number of events (CBV: n = 2, 2, 5 for
`control, rdllibizumab 0.3 mg, and ranibizumab 0.5 mg, respec(cid:173)
`tively; death: n = 2, 4, 5, respectively). Across all 5 trials, an
`increased risk was found for age 2:85 years versus < 85 years for
`the marketed dose of ranibizumab 0.5 mg. In the HARBOR trial,
`increased rates of key SAEs (excluding total nonocular SAEs) for
`age 2:85 years versus < 85 years were observed with monthly
`dosing but not with PRN dosing; event rates were similar for 2.0
`mg versus 0.5 mg.
`Conclusions: Consistent with general trends, the risk of key
`systemic SAEs was associated with age 2:85 years versus < 85
`years, but not with ranibizumab dmg exposure. The difference
`between monthly versus PRN was inconclusive. There was no
`evidence of a dose effect. lnterpretation of this retrospective
`analysis is limited because it was not prospectively powered for
`statistically definitive conclusions.
`Ophlhalmology Retina 2018;2:667-675.
`
`Impact of Baseline Characteristics on
`Treatment Response to lntravitreal
`Aflibercept Injection for Wet Age-Related
`Macular Degeneration
`Allen C. Ho, MD, Namraw. Saroj, OD, Keirli Baker, MD, Robert
`Vitti, MD, Alyson]. Berliner, MD, PhD, Desmond ThomJ>son, PhD,
`Daniel B. Roth , MD
`
`Purpose: To determine whether wet age-related macular
`degeneration (AMO) treatment outcomes within prespeci.fied pa(cid:173)
`tient subgroups were consistent with overall study results.
`
`1131
`
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`Novartis Exhibit 2316.002
`Regeneron v. Novartis, IPR2021-00816
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`

`

`Additionally, this subanalysis investigated whether there were any
`relationships between baseline characteristics and evaluated treat(cid:173)
`ment outcomes.
`Design: Post hoc subanalysis of The VEGF Trap-Eye: Inves(cid:173)
`tigation of Efficacy and Safety in Wet AMO (VIEW) l and 2, 2
`similarly dei;igned prospective, multicenter, double-ma~ked,
`acti ve-controUed, parallel-group, randomized clinical trials.
`Participants: Two thousand four hundred twelve patients with
`an active subfoveal choroidal neovascularization (CNV) lesion of
`any subtype secondary to AMO.
`Methods: Primary and key secondary visual end points at week
`52 were examined to explore the consistency of effect among
`prespecified subgroups of 5 baseline characteristics: age, best(cid:173)
`corrected visual acuity (BCV A), lesion type, lesion size, and
`central retinal thickness (CRT). Additionally, within-group ana(cid:173)
`lyses were conducted to detenn ine whether lhe mean changes in
`BCV A and CRT al 52 weeks were associated positively or nega(cid:173)
`tively with tbe baseline cbarncteristics of interest.
`Main Outcome Measures: Consistency of treatment outcomes
`among prespecified subgroups of baseline characteristics.
`Results: For each baseline characteristic, tests for interaction
`within each prespecified subgroup and among the subgroups were
`not significant, suggesting that relative visual outcomes for each
`treatment arm were consistent with overall study outcomes.
`Within-group analysis revealed a significant association between
`baseline age, BCV A, and lesion size with BCV A outcomes at 52
`weeks; namely, older age, greater BCVA, and larger lesion size
`were ,L~sociated with lower mean BCV A gains at 52 weeks.
`Conclusions: Patients in all subgroups of baseline age, BCV A,
`lesion type, lesion size, and CRT experienced visual outcomes
`consistent with those of the overall study population. Additionally,
`baseline older age, better BCV A, and larger CNV lesion size were
`found to be associated independently with lower mean BCV A
`gains after 52 weeks of anti-vascular endothelial growth factor
`therapy. The influence of baseline age, BCVA, and Cl\TV lesion
`size on treatment outcomes is consistent with other reports from
`large, prospective trials in wet AMO.
`Ophthalmology Retina 2018;2:676-683.
`
`Joint Contribution of Genetic Susceptibility
`and Modifiable Factors to the Progression
`of Age-Related Macular Degeneration over
`10 Years: The Three Continent AMD
`Consortium Report
`Nichole]oadiim, BSc(Hons), PhD, Annetre Kiftey, MA/>/>Suu, PhD,
`Johanna Maria Colijn, MD, MSc, Kristine E. Lee, MS, Gabrielle
`H.S. Buicendijk, MD, MSc, Barbara E.K. Klein, MD, MPH,
`Chelsea Myers , MStat, StaC)' M. Meuer, BS, Ava G. Tan, MAIT,
`MPH, Victoria Flood, MPH, PhD, Josje D. Sd1oufour, PhD, Oscar
`H. Fmnco, PhD, ElizabethG. Holliday, PhD, Jo/111 Attia, MD, PhD,
`Gerald Liew, MD, PhD, Sudha K. Iyengar, PhD, Pau!tts T.V.M. de
`Jong, MD, PhD, Albert Hofman, MD, PhD, Johannes R. Vingerling,
`MD, PhD, Paul Mirchell, MD, PhD, Ronald Klein , MD, MPH,
`Caroline C.W. Klaver, MD, PhD, Jie Jin Wang, MMed, PhD
`
`Purpose: To assess joint effect~ of genetic and modifiable
`factors on the 10-year progression of age-related macular degen(cid:173)
`eration (AMD).
`
`I I 32
`
`Design: Individual and pooled data analyses of 2 population(cid:173)
`based cohorts.
`Participants: Blue Mountains Eye Study (BMES) and Rot(cid:173)
`terdam Study (RS) participants (n = 835).
`Methods: Participants of the BMES and RS were followed up
`over 10 years or more. Al b,L,eline and follow-up visits, interviews
`using questionnaires and eye examinations with retinal photog(cid:173)
`raphy we.re perfonned. Age-related macular degeneration was
`assessed by trained photographic graders and verified by retinal
`special.isl,. Genetic susceptibility to AM O meant carrying 2 or
`more risk alleles of the CFH or ARMS2 SNPs, or both (rsl061 l 70
`and rs10490924), relative to O or 1 risk allele. Discrete logistic
`regression models were used to investigate the joint associations of
`genetic susceptibility and either smoking, fish consumption, dietary
`intake of lutein-zeaxanthin, or combined environmental risk scores
`from the 3 modifiable factors with the risk of AMD progression.
`Odds rntios (ORs) with 95% confidence intervals (Cls) and synergy
`indexes are reported.
`Main Outcome Measure: Ten-year progression of AMD,
`categorized as any (?"..l step) or 2-step (?"..2 steps) progression on
`the Three Continent AMD Consortium 5-step severity scale.
`Results: Older age, the presence of AMD genetic susceptibility,
`and baseline AMO status were associated strongly with AMO
`progression (P < 0.0001). In analyses of pooled data, each addi(cid:173)
`tional score from the combined environmental risk scores was
`associated with an increased risk of 2-step progression over 10
`years (OR, 1.26; 95% Cl, 1.02-1.56). The copresence of AMO
`genetic susceptibility and combined risk score of 3 or more was
`associated with a substantially higher risk of 2-step progression
`compared with the presence of either factor alone. There wa~ a
`significant synergistic effect (OR, 4.14; 95% CI, 1.07-15.95) and
`interaction (P = 0.025) between genetic susceptibility and envi(cid:173)
`ronmental risk score of 3 or more.
`Conclusions : Among persons with AMD genetic susceptibility
`and pre-existing early AMO lesions, presenting with high environ(cid:173)
`mental risk scores from 3 modifiable factors (smoking, infrequent
`consumption of fish, low lutein-zeaxanthin intake) were associated
`with an increa,ed risk of2-step progression over JO years.
`Ophthalmology Retina 2018;2:684-693.
`
`Suspended Scattering Particles in Motion: A
`Novel Feature of OCT Angiography in
`Exudative Maculopathies
`Amir H. Kashani, MD, PhD, Kyle M. Green, BA, Julie Kwon, MD,
`Zhongdi Chu, MS, Qinqin Zhang, PhD, Ruikang K. Wang, PhD,
`Sean Garrity, MD, David Sarra[, MD, Ca1·l B. Rebhun, BA, Nadia
`K. Waheed, MD, MPH, Karen B. Schaal, MD, Ma1"ion R. Munk,
`MD, PhD, Sarra Gauoussi, MD, K. Bailey Freund, MD, Fang
`Zheng, MD, Guanghui Liu, PhD, Philip J. Rosenfeld, MD, PhD
`
`Objective: To characterize features of extravascular OCT
`angiography (OCTA) signals corresponding to hyperreflective
`intraretinal fluid across various exudative maculopathies.
`Design: Multicenter, retrospective, observational study.
`Participants: Patients whose eyes had various fonns of
`exudative maculopathy,
`including diabetic retinopathy (DR),
`retinal vein occlusion (RVO), and neov,L,cular age-related macular
`degeneration (nvAMD).
`
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`
`Novartis Exhibit 2316.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Methods: Patients with extravascular OCTA signal identified
`on en face OCTA images were included in this study. This signal
`was readily distinguishable from projection artifact~. The regions
`with the extravascular motion signal on OCTA were named
`"suspended scattering particles in motion" (SSPiM). Depth(cid:173)
`encoded, color en face OCTA images (3 mm x 3 mm) centered
`on the fovea and their corresponding structural OCT scans were
`used to quantify features of SSPiM and the corresponding hyper(cid:173)
`reflective fluid. Longitudinal data were collected when available.
`Main Outcome Measures: Anatomic location, the association
`with hyperreflective material, changes in location and appearance
`of SSPiM over time, and replication of SSPiM OCT A signal in an
`in vitro phantom.
`Results: Seventy-six eyes in 62 patients with various forms of
`exudative maculopathy were evaluated (60 eyes with DR, 9 eyes
`with RVO, and 5 eyes ovAMD, l eye with macroaneurysm, and 1
`eye with radiation retioopathy). lntraretioal accumulations of fluid
`with increased OCT signal intensity corresponded to regions of
`SSPiM in several exudative maculopathies. Ao in vitro phantom
`model demonstrates that particulate matter in suspension can
`generate a similar OCT A signal. SSPiM showed an anatomic
`preference for vascular-avascular junctions. The hyperreflective
`fluid corresponding to SSPiM appeared more frequently in the
`Henle fiber layer (HFL) than the inner nuclear layer (INL) and was
`highly associated with hyperreflective material (HRM) found
`bordering the fluid. In 5 of 8 longitudinal cases, the resolution of
`SSPiM resulted in the fonnatioo of confluent HRM. Clinically, this
`appeared as bard exudate on ti.mduscopic images.
`Conclusions: Clinical data suggest that SSPiM is a novel
`imaging feature of retinal vascular diseases that was not appre(cid:173)
`ciated before the use of OCTA. We characterized several novel
`features of SSPiM and demonstr<1ted that at least in some cases it
`resolves with residual hard exudate.
`Ophthalmology Retina 2018;2:694-702.
`
`Three-Year Results of Fluorescein
`Angiography Guided Standard
`Photodynamic Therapy with Multiple Spots
`for Central Serous Chorioretinopathy
`loannis D. Ladas, MD, Konstantinos D. Andreanos, MD, Dimirrios
`S. Ladas, MD, Ma1·ilita M. Mosc/10s, MD, Tr)fon Rocsos, MD,
`Athanasios I. Kotsolis , MD
`
`Purpose: To report the long-term results of fluorescein angi(cid:173)
`ography (FA)-guided standard photodyoamic therapy (PDT) for
`centrnl serous cborioretinopathy (CSCR) and its adverse effects.
`Design: Prospective, noncomparative, ioterventional study.
`Participants: Consecutive patients (N = 63 eyes) with acute
`(39 eyes) or chronic (24 eyes) CSCR.
`Methods: All eyes underwent FA-guided conventional PDT,
`using multiple spots in 1 session if appropriate, and were assessed
`before PDT, as well as at months 3, 6, and 12 after PDT, and every
`6 months thereafter until the end of the 3-year follow-up time.
`Main Outcome Measures: Primary outcome measures were
`the resolution of subretioal fluid (SRF) and the improvement of the
`Snellen best-corrected visual acuity (BCVA) to better than 20/100
`at the end of the study. Secondary outcomes were the changes
`in mean BCV A and centrnl foveal thickness (CFT) during the
`follow-up time.
`
`Results: All 63 eyes with acute or chronic CSCR demonstrated
`complete resolution of SRF at the end of the study. Of the studied
`eyes, 51 (80.95%) underwent a single PDT application. The mean
`CFT improved significantly at all time points in the acute CSCR
`group (P < 0.001) from 515.13± 110.5 ~Im to 297.75± 22.3 ~Im at
`3 years and in the chronic CSCR group from 484.12± 62.49 µm to
`293.81± 16.89 µm. At 3 years, a gain of more than 20/100 in
`Snellen BCVA was seen in 28 acute and 16 chronic CSCR PDT(cid:173)
`treated eyes (71.8% vs. 66.67%; P = 0.779). The mean logarithm
`of the minimum angle of resolution BCV A improved from
`0.349± 0.18 at baseline to 0.060± 0.06 at the end of the study
`(P < 0.001) for eyes with acute CSCR and from 0.502± 0.28
`to 0.198± 0.ll correspondingly for the eyes with chronic CSCR
`(P < 0.001). None of the study eyes demonstrated any serious
`systemic or ophthalmologic complication related to the use of the
`standard PDT with verteporfin.
`Conclusions: Fluorescein angiogrnpby-guided conventional
`PDT achieved outcomes for acute and cbrooic CSCR comparable
`with those reported with modified PDT techniques. We did not
`identify new safety concerns.
`Ophthalmology Retina 2018;2:703-711.
`
`Swept-Source OCT Angiography of
`Serpiginous Choroiditis
`Kaioon Pakzad-Vaezi, MD, Kosar Khaksari, PhD, Z/1ongdi Chu,
`MSc, Russell N. Van Gelder, MD, PhD, Ruikang K. Wang, PhD,
`Kathryn L. Pepple, MD, PhD
`
`Purpose: To examine and quantify choriocapillaris lesions in
`active and quiescent serpiginous choroiditis (SC) using swept(cid:173)
`source (SS) OCT angiography (OCTA) and en face image analysis.
`Design: Prospective, observational case series.
`Participants: Patients with a clinical diagnosis of SC.
`Methods: A SS-OCT A prototype was used to image active and
`quiescent serpiginous lesions longitudinally before and after anti(cid:173)
`inflammatory treatment. En face slabs of cboriocapillaris flow or
`outer nuclear layer structure were generated from OCfA and OCT
`data, respectively.
`Main Outcome Measures: Qualitative and quantitative ana(cid:173)
`lyses on lesion boundary and area using a semiautomated MAT(cid:173)
`LAB algorithm. Lesions also were compared with trnditional
`multimodal imaging.
`Results: Six eyes of 3 patients were imaged. Choroidal lesions
`were identified and analyzed in 4 of 6 eyes. Lesions with well(cid:173)
`defined boundaries were identified in the choriocapillaris slab in
`areas of both active and inactive cboroiditis. The cboriocapillaris
`slab lesion size and shape showed good correlation with lesions
`identified on indocyanine green angiogrnpby. The cboriocapillaris
`slab lesion area increased with disease activity and decreased with
`corticosteroid treatment. During active disease, the choriocapillaris
`slab lesion area was larger than both the outer nuclear layer (ONL)
`slab and fundus autofluorescence lesion areas. Active chorioca(cid:173)
`pillar:is slab lesions not associated with corresponding abnonnal
`autofluorescence resolved without clinical scarring after treatment.
`In inactive scars, the areas of retinal and choriocapillaris lesions
`were si1ni.lar and d id not change over time.
`Conclusions: En face analysis of SS-OCTA cboriocapi.llaris
`flow voids provide a noninvasive method for the detection of
`lesions in patients with SC. The presence of lesions in the
`
`I 133
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`Regeneron v. Novartis, IPR2021-00816
`
`

`

`choriocapillaris in the absence of retinal pigment epithelium
`and outer retinal abnormalities supports the hypothesis that
`choriocapillaris is the primary site of pathologic features in
`SC and may be a sensitive early sign of disease activity. We
`propose a simple grading system of SC lesions based on SS(cid:173)
`OCTA and fundus autofluorescence findings. Swept-source
`OCTA is a promising noninvasive method for monitoring
`patients with SC.
`Ophthalmology Retina 2018;2:712-719.
`
`Characteristics of Retinal Breaks and
`Surgical Outcomes in Rhegmatogenous
`Retinal Detachment in Familial Exudative
`Vitreoretinopathy
`Satoshi Katagiri, MD, PhD, Tad.as/ii Yokoi, MD, PhD, Tomo:yo
`Yoshida,Uemura, MD, Sachiko Nishina, MD, PhD, Noriyuki Azuma,
`MD, PliD
`
`Purpose: To determine the characteristics of retinal breaks and
`surgical outcomes in eyes with a rhegmatogenous retinal detach(cid:173)
`ment (RRD) with f,unilial exudative vitreoretinopathy (FEVR).
`Design: Retrospective, noncomparntive case series.
`Participants: Thirty-seven patients (46 eyes) with a RRD in
`FEVR.
`Methods: The medical records were reviewed and tbe types,
`directions, and positions of the retinal breaks and surgical out(cid:173)
`comes were analyzed.
`Main Outcome Measures: Fundus examinations, including
`opbthalmoscopy, fiuorescein angiography, and RetCam imaging
`(Natus Medical Incorporated, Pleasanton, CA).
`Results: The retinal breaks were identified as tears in 12 eyes,
`atrophic boles in 24 eyes, tears and atrophic holes in 2 eyes,
`dialysis-related in l eye, a retinal break in the ora sem1ta in 1 eye,
`and unidentified in 6 eyes. Most retinal breaks (86.1 %) were
`identified only in the temporal retina. Most tears (85.7%) were
`observed on the demarcation line, whereas atrophic holes were
`identified both on the demarcation line (53.8%) and the avascular
`retina (42.3%). The representative tears were almond-shaped,
`which differs from the typical horseshoe-shaped tears. Sciera!
`buckling was performed as the initial surgery in 37 eyes and
`resulted in reattachment in 35 eyes (94.6%). Vitrectomy with or
`without scleral buck.le was perfonned for eyes with more complex
`RRD in FEVR and resulted in reattachment in 5 of 9 eyes (55 .6% ).
`In total, reattachment was achieved in 40 of 46 eyes (87 .0 % ). There
`was a history of stage l A or 2A FEVR in 45 eyes and a history of
`stage 28 FEVR in l eye.
`Conclusions: Our data clarified the types, directions, and
`positions of the retinal breaks and the effectiveness of sclernl
`buck.ling as the first surgical choice for treating RRDs in FEVR.
`Ophthalmology Retina 2018;2:720-725.
`
`Number of Hyperreflective Foci in the Outer
`Retina Correlates with Inflammation and
`Photoreceptor Degeneration in Retinitis
`Pigmentosa
`Yosuke Nagasaka, MD, Yasuki lr.o, MD, Shinji Ueno, MD, Himko
`Terasaki, MD
`
`1134
`
`Purpose: Hyperreflective foci (HRF) in the outer retina are
`associated with the progression of multiple retinal diseases, but
`their pathogenic significance in retinitis pigmentosa (RP) remains
`obscure. We studied outer retinal HRF number and distribution in
`RP using spectral-domain (SD) OCT and assessed associations
`with visual field loss, retinal inflammation, and photoreceptor
`degenerntion.
`Design: Retrospective cross-sectional study.
`Participants: Medical records of 128 eyes of 66 RP patients
`(mean age, 45.7± 16.l years; range, 10-85 years).
`Methods: All participants underwent high-resolution SD-OCT.
`Outer retinal HRF were counted on vertical and horizontal SD-OCT
`images centered at the fovea of 55 eyes of 29 patients. In addition,
`SD-OCT macular volume scans of 92 eyes of 48 patients were
`reviewed and compared with fundus autofluorescence images of the
`same area to investigate outer retinal HRF distri.bution and the spatial
`relations to areas of low autofluorescence and photoreceptor inner
`segment and outer segment junction (IS/OS) preservation.
`Main Outcome Measures: The number and distribution of
`outer retinal HRF, aqueous flare value, thickness of outer layen;,
`visual field area, and fundus autofluorescence.
`Results: In the HRF counting analysis, the mean number of
`outer retinal HRF per scan was 24.0± 18.6, mean aqueous flare
`value was 7.7±3.2 photon count/ms, visual field area was
`25.2± 26.6%, and thickness of the outer layers was 95.2± 39.6 µm.
`Generalized estimating equations revealed that the number of outer
`retinal l{Rf was associated positively with aqueous flare value
`(P = 0.01) and associated negatively with visual field area and
`outer layer thickness (P = 0.016 and P < 0.001, respectively). In
`the distribution analysis, macular areas exhibiting outer retinal
`HRF (HRF areas) spatially overlapped with areas of low auto(cid:173)
`fluorescence. In contrast, HRF areas did not overlap with areas
`showing preserved IS/OS.
`Conclusions: Outer retinal HRF number is a%ociated with
`intraocular inflammation and photoreceptor degeneration in RP.
`Their distribution in areas with IS/OS dismption and low auto(cid:173)
`fluorescence suggests that outer retina.I HRF reflect defects in the
`retinal pigment epithelium (RPE) layer caused by RPE cell or
`microgl.ial migration in response to photoreceptor degeneration.
`Ophthalmology Retina 2018;2:726-734.
`
`Ultra-Widefield Fundus Autofluorescence
`Imaging of Patients with Retinitis
`Pigmentosa: A Standardized Grading
`System in Different Genotypes
`Amir H. Hariri, MD, \Vei Gui, MD, Ghazala A. Dawo O'Keefe,
`MD, Michael S. Ip, MD, SriniVas R. SIJllda, MD, Michael 8. Gorin,
`MD, PhD
`
`Purpose: To report a genotype-phenotype correlation study of
`patients with retinitis pigmentosa (RP) b,t~ed on ultra-widefield
`(lJWF) fundus autofluorescence (FAF) imaging.
`Design: Case series.
`Participants: Thirty-four patients with RP.
`Methods: This retrospective study included RP patients with
`confirmed causative genetic variants and UWF FAF imaging data.
`Qualitative grading criteria including the pattern of macular
`abnormal autofluorescence, decreased autofluorescence (DAF), and
`
`REGITC01 118691
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`Novartis Exhibit 2316.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`its extent and distribution were applied to evaluate the genotype(cid:173)
`phenotype correlation.
`Main Outcome Measures: The main parameters measured
`patterns
`and
`extent of
`increased or decrea~ed
`were
`autofluorescence.
`Results: Thirty-four unrelated patients 38± 19 years of age
`(nmge, 9-82 yean;) were enrolled. Mutations in 17 different genes
`were detected in patients, including 7 patients having mutations in
`USH2A, 4 in DHDDS, 4 in RPGR, 3 in PRPFJJ, and 3 in RPI.
`Patients with nummular OAF and widespread DAF were signifi(cid:173)
`cantly older (59± 14 yean; and 56± 19 years, respectively). All 3
`
`patients with PRPFJJ mutations showed an abnonnal macular ring
`hypernutofluorescence and a circular pattern of coarse DAF
`distributed in Early Treatment Diabetic Retinopathy Study fields 1,
`2, and 3 with sparing of the far periphery. In other genotypes, no
`specific DAF or macular abnormal autofluorescence pattern could
`be discerned.
`Conclusions: Specific lJWF FAF cbarncteristics in RP patients
`were correlated strongly with patient age and stage of the disease.
`Particular lJWF FAF characteristics were found to be more promi(cid:173)
`nent in a unique genotype.
`Ophthalmology Rerina 2018;2:735-745.
`
`I 135
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`REGITC01118692
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`Novartis Exhibit 2316.006
`Regeneron v. Novartis, IPR