Author reply
2
TIMOTHY J. MCCULLEY, MD Johns Hopkins University, The Wilmer Eye Institute, Baltimore, Maryland References 1. Schallhorn J, Haug SJ, Yoon MK, et al. A national survey of practice patterns: temporal artery biopsy. Ophthalmology 2013;120:1930–4. 2. Pereira LS, Yoon MK, Hwang TN, et al. Giant cell arteritis in Asians: a comparative study. Br J Ophthalmol 2011;95:214–6. 3. Yoon MK, Horton JC, McCulley TJ. Facial nerve injury: a complication of superficial temporal artery biopsy. Am J Oph- thalmol 2011;152:251–5. Corneal Hysteresis and Glaucoma Progression Dear Editor: We read with interest the paper by Medeiros et al 1 entitled “Corneal Hysteresis as a Risk Factor for Glaucoma Progression: A Prospective Longitudinal Study.” Although we applaud the utilization of longitudinal visual field analysis within that study, we have concerns regarding other aspects of the study design. First, we were surprised that the authors incompletely accounted for factors known to affect corneal hysteresis (CH) measurement. Particularly, we noted that visual field severity was not included in their regression model despite studies that have shown that increasing glaucoma severity is associated with both decreasing CH 2-4 and increased risk for visual field progression. 5 Thus, it is conceivable that the primary outcome in this studydthe relationship between CH and increased risk for visual field progressiondmight be explained by a relationship between lower CH and glaucoma severity. We also noticed that the authors acquired CH data during just one visit, despite the well-known intervisit variability of this parameter. Thus, although visual fields were analyzed longitudi- nally, CH was obtained as a cross-sectional parameter. Whether this methodology impacted the study results in any meaningful way is unknown, but the possibility remains. We were also intrigued by the numerous upward visual field index slopes in Figure 2 that seem to be more prevalent in the higher CH cohort compared with the lower CH cohort. Because upward VFI slopes often represent learning effects, we wonder whether there was a visual field performance bias between subjects with higher versus lower CH. If such a bias was present, it could have led to an overestimation of the relationship between CH and visual field progression risk. Despite the limitations in this paper, we do appreciate the au- thors’ efforts and hope that the work spurs additional investigation in this important area. MICHAEL SULLIVAN-MEE, OD DENISE PENSYL, OD, MS KATHY HALVERSON, OD Department of Surgery, Albuquerque VA Medical Center, Albuquerque, New Mexico References 1. Medeiros FA, Meira-Freitas D, Lisboa R, et al. Corneal hysteresis as a risk factor for glaucoma progression: a prospective longitudinal study. Ophthalmology 2013;120: 1533–40. 2. Kaushik S, Pandav SS, Banger A, et al. Relationship between corneal biomechanical properties, central corneal thickness, and intraocular pressure across the spectrum of glaucoma. Am J Ophthalmol 2012;153:840–9. 3. Sullivan-Mee M, Katiyar S, Pensyl D, et al. Relative importance of factors affecting corneal hysteresis measurement. Optom Vis Sci 2012;89:803–11. 4. Mansouri K, Leite MT, Weinreb RN, et al. Association between corneal biomechanical properties and glaucoma severity. Am J Ophthalmol 2012;153:419–27. 5. Leske MC, Heijl A, Hussein M, et al. Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 2003;121:48–56. Author reply Dear Editor: Sullivan-Mee et al questioned whether our longitudinal results demonstrating a relationship between lower corneal hysteresis (CH) and faster progression in glaucoma could perhaps be confounded by a relationship between CH and disease severity. They suggest that the longitudinal, mixed-effects model presented in our study should have included an adjustment for disease severity as a baseline co- variate. As stated in our study, an unstructured covariance between random effects was assumed, allowing for correlation between random intercepts (baseline) and slopes. This was done exactly for the fact that rates of visual field loss may depend on disease severity. Whether or not baseline disease severity should addi- tionally be included as a fixed effect term in the mixed model is a very controversial issue in the statistics literature. A recent study by Glymour et al 1 suggests that baseline adjustment in analyses of change may induce spurious statistical associations with inflated regression coefficients. Beside the statistical limitations of the adjustment proposed by Sullivan-Mee et al, one would also believe that, if lower CH is associated with worse disease severity, this would actually support our findings that lower CH is actually related to disease progression. Sullivan-Mee et al also question the fact that we included only baseline CH rather than longitudinal CH measurements in our analyses. This was done in our study to facilitate comparisons with other studies evaluating baseline risk factors for glaucoma progression. Although, to the best of our knowledge, the long- term reproducibility of CH has not been investigated in the liter- ature, all subjects in our study had the same number of CH measurements at baseline and, therefore, there is little reason to suspect that the variability of CH would be related to the outcomes of the study. Finally, Sullivan-Mee et al were intrigued by the fact that upward slopes of visual field index seemed to be more common in the group with higher hysteresis versus lower hysteresis. Upward slopes are very common in the analysis of longitudinal visual field data in glaucoma patients and may represent learning effect. The fact that these slopes seem to be more common in the group of lower hysteresis actually reinforces our findings of an association between lower CH and progression, because the progressive visual field loss in this group would offset the learning effect. Sullivan-Mee et al argue about a possible “visual Correspondence e85
Transcript of Author reply
Correspondence
TIMOTHY J. MCCULLEY, MDJohns Hopkins University, The Wilmer Eye Institute, Baltimore,Maryland
References
1. Schallhorn J, Haug SJ, YoonMK, et al. A national survey of practicepatterns: temporal artery biopsy. Ophthalmology 2013;120:1930–4.
2. Pereira LS, Yoon MK, Hwang TN, et al. Giant cell arteritis inAsians: a comparative study. Br J Ophthalmol 2011;95:214–6.
3. Yoon MK, Horton JC, McCulley TJ. Facial nerve injury: acomplication of superficial temporal artery biopsy. Am J Oph-thalmol 2011;152:251–5.
Corneal Hysteresis and GlaucomaProgression
Dear Editor:We read with interest the paper by Medeiros et al1 entitled “CornealHysteresis as a Risk Factor for Glaucoma Progression: AProspective Longitudinal Study.” Although we applaud theutilization of longitudinal visual field analysis within that study,we have concerns regarding other aspects of the study design.
First, we were surprised that the authors incompletely accountedfor factors known to affect corneal hysteresis (CH) measurement.Particularly, we noted that visual field severity was not included intheir regressionmodel despite studies that have shown that increasingglaucoma severity is associated with both decreasing CH2-4 andincreased risk for visualfield progression.5 Thus, it is conceivable thatthe primary outcome in this studydthe relationship between CH andincreased risk for visual field progressiondmight be explained by arelationship between lower CH and glaucoma severity.
We also noticed that the authors acquired CH data during justone visit, despite the well-known intervisit variability of thisparameter. Thus, although visual fields were analyzed longitudi-nally, CH was obtained as a cross-sectional parameter. Whether thismethodology impacted the study results in any meaningful way isunknown, but the possibility remains.
We were also intrigued by the numerous upward visual field indexslopes in Figure 2 that seem to be more prevalent in the higher CHcohort comparedwith the lowerCHcohort.BecauseupwardVFI slopesoften represent learning effects, we wonder whether there was a visualfieldperformance bias between subjectswith higher versus lowerCH. Ifsuch a bias was present, it could have led to an overestimation of therelationship between CH and visual field progression risk.
Despite the limitations in this paper, we do appreciate the au-thors’ efforts and hope that the work spurs additional investigationin this important area.
MICHAEL SULLIVAN-MEE, ODDENISE PENSYL, OD, MSKATHY HALVERSON, ODDepartment of Surgery, Albuquerque VA Medical Center, Albuquerque,New Mexico
References
1. Medeiros FA, Meira-Freitas D, Lisboa R, et al. Cornealhysteresis as a risk factor for glaucoma progression: a
prospective longitudinal study. Ophthalmology 2013;120:1533–40.
2. Kaushik S, Pandav SS, Banger A, et al. Relationship betweencorneal biomechanical properties, central corneal thickness, andintraocular pressure across the spectrum of glaucoma. Am JOphthalmol 2012;153:840–9.
3. Sullivan-Mee M, Katiyar S, Pensyl D, et al. Relative importanceof factors affecting corneal hysteresis measurement. Optom VisSci 2012;89:803–11.
4. Mansouri K, Leite MT, Weinreb RN, et al. Association betweencorneal biomechanical properties and glaucoma severity. Am JOphthalmol 2012;153:419–27.
5. Leske MC, Heijl A, Hussein M, et al. Early Manifest GlaucomaTrial Group. Factors for glaucoma progression and the effect oftreatment: the early manifest glaucoma trial. Arch Ophthalmol2003;121:48–56.
Author reply
Dear Editor:Sullivan-Mee et al questioned whether our longitudinal resultsdemonstrating a relationship between lower corneal hysteresis (CH)and faster progression in glaucoma could perhaps be confounded bya relationship between CH and disease severity. They suggest thatthe longitudinal, mixed-effects model presented in our study shouldhave included an adjustment for disease severity as a baseline co-variate. As stated in our study, an unstructured covariance betweenrandom effects was assumed, allowing for correlation betweenrandom intercepts (baseline) and slopes. This was done exactly forthe fact that rates of visual field loss may depend on diseaseseverity. Whether or not baseline disease severity should addi-tionally be included as a fixed effect term in the mixed model is avery controversial issue in the statistics literature. A recent study byGlymour et al1 suggests that baseline adjustment in analyses ofchange may induce spurious statistical associations with inflatedregression coefficients. Beside the statistical limitations of theadjustment proposed by Sullivan-Mee et al, one would alsobelieve that, if lower CH is associated with worse disease severity,this would actually support our findings that lower CH is actuallyrelated to disease progression.
Sullivan-Mee et al also question the fact that we included onlybaseline CH rather than longitudinal CH measurements in ouranalyses. This was done in our study to facilitate comparisonswith other studies evaluating baseline risk factors for glaucomaprogression. Although, to the best of our knowledge, the long-term reproducibility of CH has not been investigated in the liter-ature, all subjects in our study had the same number of CHmeasurements at baseline and, therefore, there is little reason tosuspect that the variability of CH would be related to the outcomesof the study.
Finally, Sullivan-Mee et al were intrigued by the fact thatupward slopes of visual field index seemed to be more commonin the group with higher hysteresis versus lower hysteresis.Upward slopes are very common in the analysis of longitudinalvisual field data in glaucoma patients and may represent learningeffect. The fact that these slopes seem to be more common in thegroup of lower hysteresis actually reinforces our findings of anassociation between lower CH and progression, because theprogressive visual field loss in this group would offset thelearning effect. Sullivan-Mee et al argue about a possible “visual
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field performance bias” between subjects with lower versushigher CH, but it is difficult to think about an association be-tween hysteresis and perimetric learning, rather than the simpleexplanation we give.
FELIPE A. MEDEIROS, MD, PhDDepartment of Ophthalmology, University of California, San Diego,California
Reference
1. Glymour MM, Weuve J, Berkman LF, et al. When is baselineadjustment useful in analyses of change? An example with edu-cation and cognitive change. Am J Epidemiol 2005;162:267–78.
Secukinumab in the Treatment ofNoninfectious Uveitis
Dear Editor:We read with interest the article by Dick et al1 on the efficacy andsafety of different doses of secukinumab in patients withnoninfectious uveitis in 3 multicenter, randomized, double-masked, placebo-controlled, dose-ranging, phase III studies in theUnited States. Although the study suggested secukinumab had abeneficial effect in reducing the use of concomitant immunosup-pressive medication, the researchers did not discover any differ-ences in uveitis recurrence between the secukinumab treatmentgroups and placebo groups. The studies’ authors believed that therelatively small sample size, the differences in the severity of thedisease in patients, the differences in the immune expression ofinterleukin (IL)-17 in individual patients, and the potentially con-founding effects of the concomitant immunosuppressive medicationmay have played roles in the lack of significant differences betweenthe experimental and placebo groups. Not mentioned, however,were 2 points that we believe are pertinent to exploring the efficacyand safety of different doses of secukinumab versus placebo intreating noninfectious uveitis, as well as relevant to the factors thatinfluence the results.
In this study, the authors enrolled patients with several types ofnoninfectious uveitis, including those with Behçet’s disease withposterior uveitis, and patients without Behçet’s disease with activeand quiescent noninfectious uveitis. It would have been better ifthey had taken into account the exact causes of uveitis in the finalanalysis of how effective the treatment with secukinumab was. Aswe know, noninfectious uveitis includes Fuchs’ heterochromiciridocyclitis, HLA-B27erelated uveitis, tubulointerstitialnephritis, and uveitis syndrome, as well as systemic disordersassociated with uveitis, such as ankylosing spondylitis, Behçet’sdisease, juvenile rheumatoid arthritis, and sarcoidosis. Severalrecent publications reported the application of secukinumab inimmune-mediated diseases, but the exact interplay between IL-17and different kinds of uveitis is unknown. Rich et al2 found thatblockade of IL-17 showed a marked alleviation of diseaseseverity in psoriasis. In addition, the reduction of the symptoms ofrheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis
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has been observed in secukinumab-treated patients, with no overtwarning signs.3 Dysregulation of T helper (Th17) cells may notexist in all autoimmune uveitis. Those who have uveitis withincreased numbers of Th17 cells tend to respond tosecukinumab treatment.
A significant advantage of using secukinumab to treat autoim-mune uveitis is that it is effective in patients with noninfectiousuveitis refractory to conventional therapy using local or oral cor-ticosteroids.4 In addition, secukinumab also improves visual acuity,ameliorates ocular inflammation, and causes a decrease in the useddose of corticosteroids therapy for these patients. Uveitis istypically treated with glucocorticoid steroids in the form oftopical eye drops or oral therapy. In clinical practice, the therapyof noninfectious uveitis has progressed ever since corticoid-sparing immunosuppressive agents begun to be used. Althoughthese drugs have decreased corticosteroid-related complications inpatients, many cases remain refractory, which has prompted theneed for immunosuppressive therapies. The authors also found thatsecukinumab had the beneficial effect of reducing the use ofimmunosuppressive medications. We believe further research iswarranted to identify the efficiency of secukinumab in managingnoninfectious uveitis patients who are refractory to routine immu-nosuppressive medications.
JIAXU HONG, MD1,2,3
ZUGUO LIU, MD2
XINGHUAI SUN, MD1
JIANJIANG XU, MD1
1Department of Ophthalmology, and Visual Science, Eye, and ENTHospital, Shanghai Medical College, Fudan University, Shanghai,China; 2Eye Institute of Xiamen University, Fujian Provincial KeyLaboratory of Ophthalmology and Visual Science, Xiamen, China;3Health Communication Institute, Fudan University, Shanghai, China
Financial Disclosures: The authors were supported by grants from theKey Clinic Medicine Research Program, the Ministry of Health, China(2010e2012); National Science and Technology Research Program, theMinistry of Science and Technology, China (2012BAI08B01); NationalNatural Science Foundation of China (81170817, 81200658); ScientificResearch Program, Science and Technology Commission of ShanghaiMunicipality, Shanghai. The sponsor or funding organization had norole in the design or conduct of this research.The authors of the original article declined to respond.
References
1. Dick AD, Tugal-Tutkun I, Foster S, et al. Secukinumab in thetreatment of noninfectious uveitis: results of three randomized,controlled clinical trials. Ophthalmology 2013;120:777–87.
2. Rich P, Sigurgeirsson B, Thaci D, et al. Secukinumab inductionand maintenance therapy in moderate-to-severe plaque psoriasis:a randomized, double-blind, placebo-controlled, phase IIregimen-finding study. Br J Dermatol 2013;168:402–11.
3. Patel DD, Lee DM, Kolbinger F, Antoni C. Effect of IL-17Ablockade with secukinumab in autoimmune diseases. AnnRheum Dis 2013;72(Suppl 2):116–23.
4. Hueber W, Patel DD, Dryja T, et al. Effects of AIN457, a fullyhuman antibody to interleukin-17A, on psoriasis, rheumatoidarthritis, and uveitis. Sci Transl Med 2010;2:52ra72.
