Age-related macular degeneration and the complement system

Khandhadia, Samir; Cipriani, Valentina; Yates, John R.; Lotery, Andrew

doi:10.1016/j.imbio.2011.07.019

Cited by 152 publications

(119 citation statements)

References 209 publications

(267 reference statements)

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“…During the study, blood samples for pharmacokinetic and complement factor screening were drawn and analyzed in a masked fashion at baseline and at every planned visit at weeks 1, 2, 3, 4,6,8,10,12,14,16,18,20,22,24,26,28,38, and 52. Alexion Pharmaceuticals laboratory measured soluble C5b-9 and performed a hemolytic assay for C5 activity.…”

Section: Pharmacokinetic and Complement Factors Analysismentioning

confidence: 99%

“…5,17 While the pathogenesis of AMD is multifactorial, resulting from a combination of genetic and environmental risk factors, there is convincing evidence that the complement system plays an important role in causing AMD. 18 Even before the genetic studies showed an association between AMD and complement genes, evidence of complement activation in AMD was provided by the presence of complement components 3 (C3) and 5 (C5), complement factor H, and the membrane attack complex in drusen. [19][20][21][22] Genetic studies have implicated these same gene products as well as other genetic loci in the complement pathway as having a protective or risk-enhancing role for the development of AMD.…”

Section: Introductionmentioning

confidence: 99%

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Change in Drusen Volume as a Novel Clinical Trial Endpoint for the Study of Complement Inhibition in Age-related Macular Degeneration

Filho¹,

Yehoshua²,

Gregori³

et al. 2014

Ophthalmic Surg Lasers Imaging Retina

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BACKGROUND AND OBJECTIVE:To evaluate the change in drusen volume following treatment with eculizumab, a systemic inhibitor of complement component 5. PATIENTS AND METHODS:Single-center, prospective, randomized, double-masked clinical trial. Patients were randomized 2:1 to receive intravenous eculizumab or placebo over 26 weeks. Main outcome measure: decrease in drusen volume of at least 50% at 26-week follow-up. RESULTS:Mean drusen cube root volumes were 0.49 mm and 0.47 mm (P = .64) at baseline and 0.51 mm and 0.42 mm (P = .17) at 26 weeks in the eculizumab and placebo groups, respectively. In the placebo group, one eye had a decrease in drusen volume of at least 50% and two eyes developed neovascularization through 26 weeks. CONCLUSION:Systemic complement inhibition with eculizumab did not significantly reduce drusen volume. Drusen growth was dependent on the number of complement at-risk alleles. Future trials should consider the use of a composite clinical trial endpoint in which efficacy is defined by the treatment's ability to prevent drusen growth, neovascularization, and the formation of geographic atrophy over 1 year.

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Section: Pharmacokinetic and Complement Factors Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Change in Drusen Volume as a Novel Clinical Trial Endpoint for the Study of Complement Inhibition in Age-related Macular Degeneration

Filho¹,

Yehoshua²,

Gregori³

et al. 2014

Ophthalmic Surg Lasers Imaging Retina

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“…It affects the central region of the retina and choroid, which can result in loss of central vision 2 . AMD is a bilateral disorder; choroidal neovascular membranes develop in more than one fourth (26%) of fellow eyes that are initially free of exudative AMD over a 5-year period 3 .…”

Section: Introductionmentioning

confidence: 99%

“…AMD is also the leading cause of vision loss in the developed world, such as in Europe, the USA and Australia, among people older than 55/ 65 years old, accounting for up to 50% of all cases. Additionally, its prevalence is likely to increase as a consequence of increasing longevity [2][3][4][5][6] . The prevalence in adults is approximately 3% (ref.…”

Section: Introductionmentioning

confidence: 99%

Blood levels of antioxidants during age-related macular degeneration treatment by rheohaemapheresis

Aufartová¹,

Bláha²,

Kasalová³

et al. 2015

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Aims. Rheohaemapheresis treatment influences rheological markers and most likely improves metabolism in affected retinal areas, resulting not only in absorption of soft drusen but also reduction or complete disappearance of drusenoid retinal pigment epithelium detachments. However, the character of the treatment process has raised suspicion that there is a decrease not only in cholesterol but also in antioxidants, such as vitamin E and vitamin A. Methods. Twenty-three patients with the progressive dry form of age-related macular degeneration were each treated with 8 procedures of rheohaemapheresis. We measured levels of vitamin E (α-tocopherol), the vitamin E/cholesterol ratio in serum and lipoproteins (VLDL, LDL, HDL). Vitamin E in erythrocyte membrane and serum vitamin A (retinol) were also measured. These parameters were determined before and after rheohaemapheresis. Erythrocyte superoxide dismutase, erythrocyte glutathione peroxidase and serum malondialdehyde were analysed as markers of antioxidant activity and lipid peroxidation, respectively. Results. In serum, the VLDL and LDL fraction ratios of vitamin E/cholesterol increased significantly. Additionally, the HDL fraction ratio showed an increase but this was not statistically significant. The patients showed no clinical signs of vitamin E deficiency, and their serum concentrations of vitamin E did not differ from normal values. The results show that rheohaemapheresis in addition to causing a significant reduction in atherogenic LDL cholesterol, may have favourable additive anti-atherogenic effects due to a relative increase in the content of vitamin E in the lipoprotein fractions.

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“…It is a complex, degenerative and progressive disease, which involves multiple genetic and environmental factors (Fine et al 2000;Bok 2005), such as ageing and cigarette smoking (Smith et al 2001; Thornton et al 2005). The molecular mechanisms causing AMD remain unknown although inflammatory processes have been implicated as evidenced by the identification of susceptibility genes encoding complement factors (Tuo et al 2004;Klein et al 2005;Chen et al 2010;Khandhadia et al 2012) and the presence of complement proteins in drusen (Hageman et al 2001). These findings were supported by studies showing an increase in the level of various complement activation products in the circulation of AMD patients (Donoso et al 2006;Scholl et al 2008;Reynolds et al 2009;Hecker et al 2010) and provided further evidence for a systemic inflammatory component to the disease pathogenesis (Parmeggiani et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Lutein supplementation leads to decreased soluble complement membrane attack complex sC5b‐9 plasma levels

Tian

Kijlstra

Veen

et al. 2014

Acta Ophthalmologica

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ABSTRACT.Purpose: The purpose of this study was to investigate the effect of lutein on systemic complement activation in elderly individuals. Methods: Seventy patients with signs of early age-related macular degeneration (AMD) were included in this study. All subjects were randomly assigned to receive a 10 mg daily dose of lutein or a placebo for a time period of 1 year. EDTA blood was collected before and at various time-points during the study (0, 4, 8 and 12 months). The plasma level of the soluble complement membrane attack complex sC5b-9 was measured by ELISA. Results: We found a significant 1.1 ng/ml monthly decrease in the plasma sC5b-9 concentration in the lutein group (p < 0.001), resulting in a decrease from 60.3 ng/ml at baseline to 46.3 ng/ml at 12 months. For the placebo group, we found a significant 0.6 ng/ml monthly increase in plasma sC5b-9 concentration (p = 0.001), resulting in an increase from 51.6 ng/ml at baseline to 58.4 ng/ml at 12 months. Conclusions: Lutein supplementation inhibits the systemic activation of the complement system, which provides further functional evidence for the reported beneficial effects of this carotenoid in the management of AMD.

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Age-related macular degeneration and the complement system

Cited by 152 publications

References 209 publications

Change in Drusen Volume as a Novel Clinical Trial Endpoint for the Study of Complement Inhibition in Age-related Macular Degeneration

Change in Drusen Volume as a Novel Clinical Trial Endpoint for the Study of Complement Inhibition in Age-related Macular Degeneration

Blood levels of antioxidants during age-related macular degeneration treatment by rheohaemapheresis

Lutein supplementation leads to decreased soluble complement membrane attack complex sC5b‐9 plasma levels

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