Objective Factors influencing the outcome of anti-VEGF treatment in neovascular AMD are still investigated. We analyzed the impact of a loading phase, the significance of an initial response for the long-term and the effect of the CFH polymorphism (p.His402Tyr) on treatment outcome. Methods Patients treated with ranibizumab for neovascular AMD were analyzed over a period of 24 months by assessing effects of loading phase, initial response and genotype of CFH rs1061170 (c.1204C>T, p.His402Tyr). Results 204 eyes were included. A change of +5.0 [？1;+11] letters and +1.5 [？5.5;+9.5] was observed with a median of 4 [3]; [7] and 10 [7]; [14] ranibizumab injections during 12 and 24 months, respectively. Loading phase was no significant predictor for treatment as VA outcome in eyes with and without loading phase was similar (p = 0.846 and p = 0.729) at 12 and 24 months. In contrast, initial response was a significant predictor for improving vision of 5 or more letters at 12 (p = 0.001; OR = 6.75) and 24 months (p = 0.01; OR = 4.66). Furthermore, the CT genotype at CFH rs1061170 was identified as a significant predictor for a favorable VA outcome at 12 and 24 months (OR = 6.75, p = 0.001 and OR = 4.66, p = 0.01). Conclusions Our data suggest that clinical decisions regarding treatment may be guided by observing patients’ initial response as well as their genotype of SNP rs1061170, while the criterion of loading phase may not bear the customary value.
References
[1]
Bressler NM (2004) Age-related macular degeneration is the leading cause of blindness. JAMA 291: 1900–1901.
[2]
Taylor HR, Keeffe JE, Vu HT, Wang JJ, Rochtchina E, et al. (2005) Vision loss in Australia. Med J Aust 182: 565–568.
[3]
VanNewkirk MR, Nanjan MB, Wang JJ, Mitchell P, Taylor HR, et al. (2000) The prevalence of age-related maculopathy: the visual impairment project. Ophthalmology 107: 1593–1600.
[4]
Wang JJ, Rochtchina E, Lee AJ, Chia EM, Smith W, et al. (2007) Ten-year incidence and progression of age-related maculopathy: the blue Mountains Eye Study. Ophthalmology 114: 92–98.
[5]
Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, et al. (1995) An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 39: 367–374.
[6]
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, et al. (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355: 1419–1431.
[7]
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, et al. (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355: 1432–1444.
[8]
Menghini M, Kurz-Levin MM, Amstutz C, Michels S, Windisch R, et al. (2010) Response to ranibizumab therapy in neovascular AMD - an evaluation of good and bad responders. Klin Monbl Augenheilkd 227: 244–248.
[9]
Lalwani GA, Rosenfeld PJ, Fung AE, Dubovy SR, Michels S, et al. (2009) A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 148: 43–58 e41.
[10]
Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, et al. (2008) Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 145: 239–248.
[11]
Mitchell P, Korobelnik JF, Lanzetta P, Holz FG, Prunte C, et al. (2010) Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol 94: 2–13.
[12]
Holz FG, Korobelnik JF, Lanzetta P, Mitchell P, Schmidt-Erfurth U, et al. (2010) The effects of a flexible visual acuity-driven ranibizumab treatment regimen in age-related macular degeneration: outcomes of a drug and disease model. Invest Ophthalmol Vis Sci 51: 405–412.
[13]
Gupta B, Adewoyin T, Patel SK, Sivaprasad S (2011) Comparison of two intravitreal ranibizumab treatment schedules for neovascular age-related macular degeneration. Br J Ophthalmol 3: 386–90.
[14]
Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, et al. (2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 364: 1897–1908.
[15]
Gerding H, Loukopoulos V, Riese J, Hefner L, Timmermann M (2011) Results of flexible ranibizumab treatment in age-related macular degeneration and search for parameters with impact on outcome. Graefes Arch Clin Exp Ophthalmol 249: 653–662.
[16]
Heimes B, Lommatzsch A, Zeimer M, Gutfleisch M, Spital G, et al. (2011) Long-term visual course after anti-VEGF therapy for exudative AMD in clinical practice evaluation of the German reinjection scheme. Graefes Arch Clin Exp Ophthalmol 249: 639–644.
[17]
Holz FG, Amoaku W, Donate J, Guymer RH, Kellner U, et al. (2011) Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology 118: 663–671.
[18]
Schmidt-Erfurth U, Eldem B, Guymer R, Korobelnik JF, Schlingemann RO, et al. (2011) Efficacy and Safety of Monthly versus Quarterly Ranibizumab Treatment in Neovascular Age-related Macular Degeneration: The EXCITE Study. Ophthalmology 118: 831–839.
[19]
Swaroop A, Branham KE, Chen W, Abecasis G (2007) Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Hum Mol Genet 16 Spec No. 2: R174–182.
[20]
Tuo J, Bojanowski CM, Chan CC (2004) Genetic factors of age-related macular degeneration. Prog Retin Eye Res 23: 229–249.
[21]
Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, et al. (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308: 419–421.
[22]
Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102: 7227–7232.
[23]
Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, et al. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308: 385–389.
[24]
Kloeckener-Gruissem B, Barthelmes D, Labs S, Schindler C, Kurz-Levin M, et al. (2011) Genetic association with response to intravitreal ranibizumab (Lucentis(R)) in neovascular AMD patients. Invest Ophthalmol Vis Sci 52: 4694–702.
[25]
McKibbin M, Ali M, Bansal S, Baxter PD, West K, et al. (2012) CFH, VEGF and HTRA1 promoter genotype may influence the response to intravitreal ranibizumab therapy for neovascular age-related macular degeneration. Br J Ophthalmol 96: 208–12.
[26]
Teper SJ, Nowinska A, Pilat J, Palucha A, Wylegala E (2010) Involvement of genetic factors in the response to a variable-dosing ranibizumab treatment regimen for age-related macular degeneration. Mol Vis 16: 2598–2604.
[27]
Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA Jr (2009) Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 93: 610–613.
[28]
Brantley MA Jr, Fang AM, King JM, Tewari A, Kymes SM, et al. (2007) Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology 114: 2168–2173.
[29]
Tsuchihashi T, Mori K, Horie-Inoue K, Gehlbach PL, Kabasawa S, et al. (2011) Complement factor H and high-temperature requirement A-1 genotypes and treatment response of age-related macular degeneration. Ophthalmology 118: 93–100.
[30]
Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T, et al. (2009) A Phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology 116: 1731–1739.
[31]
Ormsby RJ, Ranganathan S, Tong JC, Griggs KM, Dimasi DP, et al. (2008) Functional and structural implications of the complement factor H Y402H polymorphism associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 49: 1763–1770.
[32]
Laine M, Jarva H, Seitsonen S, Haapasalo K, Lehtinen MJ, et al. (2007) Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein. J Immunol 178: 3831–3836.
[33]
Bressler SB (2009) Introduction: Understanding the role of angiogenesis and antiangiogenic agents in age-related macular degeneration. Ophthalmology 116: S1–7.
[34]
Weismann D, Hartvigsen K, Lauer N, Bennett KL, Scholl HP, et al. (2011) Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478: 76–81.
