Neovascular age-related macular degeneration: intraocular inflammatory cytokines in the poor responder to ranibizumab treatment

Figures & data

Figure 1 Histogram of gamma distribution range and prediction values below LOD of VEGF-C.

Abbreviations: LOD, limit of detection; VEGF, vascular endothelial growth factor.

Table 1 Baseline demographic data

	Total (n=32)	Control (n=13)	PDT+ranibizumab (n=8)	Aflibercept (n=11)
Age (years)	79.79	79.99	77.63	77.93
Sex, male (%)	19 (59)	8 (61.5)	5 (62.5)	6 (54.5)
Ethnicity
Caucasian (%)	13 (41)	4 (31)	4 (50)	5 (45)
Asian (%)	19 (59)	9 (69)	4 (50)	6 (55)
Type of AMD
Occult (%)	21 (65.7)	8 (61.5)	4 (50)	9 (81.8)
Minimally classic (%)	4 (11.4)	0	2 (25)	2 (18.2)
Predominantly classic (%)	7 (21.9)	5 (28.5)	2 (25)	0
Baseline BCVA (logMar)	0.79	0.87	0.78	0.83
Baseline CST (μm)	287.75	232.46	335.75	318.18

Abbreviations: AMD, age-related macular degeneration; BCVA, best-corrected visual acuity; CST, central subfield thickness; PDT, photodynamic therapy.

Table 2 Mean changes in cytokines levels (pg/dL) from baseline to visit 3

Cytokine	Control				PDT				AF
	Mean change	L95	U95	P-value	Mean change	L95	U95	P-value	Mean change	L95	U95	P-value
PLGF	0.65	−2.42	3.73	0.67	−1.43	−5.86	2.98	0.52	−1.06	−4.98	2.85	0.59
VEGF-A	−41.06	−227.48	145.34	0.66	−173.05	−440.48	94.36	0.20	−72.6	−72.60	−309.80	0.55
VEGF-C	−8.17	−27.4	11.04	0.2	−2.6	−31.37	26.12	0.4	27.76	2.83	52.69	0.01*
Angiopoeitin-2	−26.53	−8.79	25.71	0.16	49.66	−28.47	127.81	0.1	76.76	8.99	144.5	0.01*
EGF	1.5	0.03	3.09	0.02*	−0.54	−2.82	1.73	0.32	−1.11	−3.09	0.86	0.13
Endothelin-1	−6.7	−13.12	−0.32	0.02*	7.98	−1.57	17.55	0.052	0.27	−6.01	10.57	0.29
Follistatin	6.6	−44.99	31.78	0.3	19.04	−38.36	76.46	0.25	7.95	−41.82	57.73	0.37
G-CSF	−41.84	−92.5	9.81	0.06	34.01	−36.56	104.58	0.17	−9.09	−87.07	67.25	0.4
HBEGF	0.27	−0.55	1.1	0.25	−0.26	−1.5	0.98	0.34	0.65	−0.42	1.73	0.11
HGF	−126.71	−445.8	192.36	0.21	18.56	−348.52	605.66	0.29	476.31	62.5	890.12	0.01*
Leptin	159.53	−138.39	457.47	0.14	−451.12	−896.73	−5.5	0.02*	−63.6	−449.98	322.77	0.37
ICAM	1,532.74	−11,935.9	15,001.39	0.41	−4,664.07	−24,128.8	14,800.66	0.31	−18,910.5	−36,558	−1,288.68	0.01*
IL-3	0.05	−7.22	7.33	0.49	5.69	−5.19	16.57	0.15	1.68	−7.75	11.12	0.36
IL-6	10.78	−170.33	191.9	0.45	−319.73	−589.22	−50.25	0.01*	−35.7	−270.59	199.18	0.38
IL-7	−0.23	−0.73	0.25	0.17	0.23	−0.5	0.98	0.26	0.69	0.04	1.33	0.01*
IL-8	−1.6	−4.92	1.71	0.17	−0.07	−5.03	4.88	0.48	5.39	1.08	9.69	<0.01*
IL-17	0.19	−0.09	0.84	0.09	−0.32	−0.75	0.1	0.06	−0.41	−0.79	−0.04	0.01*
MCP-1	−194.13	−1,136.29	748.02	0.3	−1,219.17	−2,627.66	189.32	0.046	365.61	−856.25	1,587.47	0.2
TNF-α	−0.05	−0.26	0.15	0.31	−0.03	−0.35	0.28	0.4	0.03	−0.24	0.38	0.4
PDGF-AA	−4.15	−13.13	4.18	0.18	−10.4	−23.83	3.02	0.06	5.68	−5.96	17.33	0.17

Note:

* Statistical significant is P<0.05.

Abbreviations: AF, aflibercept; EGF, epidermal growth factor; G-CSF, granulocyte-colony stimulating factor; HBEGF, heparin-binding EGF-like growth factor; HGF, hepatocyte growth factor; ICAM, intercellular adhesion molecule; IL, interleukin; MCP, monocyte chemoattractant protein; PDGF, platelet-derived growth factor; PDT, photodynamic therapy; PLGF, placental growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

Table 3 Mean visual acuity of patient in each study group

Visual acuity (logMar)	Baseline	Visit 1		Visit 2		Visit 3
	Mean	Mean	P-value*	Mean	P-value*	Mean	P-value*
Control group	0.92	0.84	0.23	0.77	0.03	0.78	0.04
PDT group	0.7	0.72	0.78	0.59	0.37	0.68	0.97
AF group	0.75	0.68	0.48	0.77	0.43	0.82	0.76

Note:

* P-value determines the change from baseline.

Abbreviations: AF, aflibercept; PDT, photodynamic therapy.

Table S1 Mean and range of cytokine level (pg/dL) at baseline visit

Cytokine	Control		PDT		AF
	Mean (min, max)	SD	Mean (min, max)	SD	Mean (min, max)	SD
PLGF	2.5 (0.2, 10.6)	3.1	3.6 (0.1, 15.6)	5.7	1.7 (0.1, 4.0)	1.4
VEGF-A	78 (3.5, 664.8)	184	177.9 (1.7, 744.2)	269.6	86.8 (1.5, 386.3)	135.2
VEGF-C	66 (6.2, 233.6)	66.1	78.7 (0.9, 289.1)	101.8	84.5 (4.7, 236.6)	67.7
Angiopoeitin-2	344 (43.3, 996.2)	239.2	195.1 (11.1, 338.6)	98.5	289.2 (158.6, 517.1)	117.3
EGF	2.6 (0.6, 9.2)	2.1	2.8 (0.3, 5.7)	2.4	3.9 (0.3, 10.4)	3.4
Endothelin-1	20.3 (3.1, 36.7)	12.9	9.2 (0.1, 27.2)	11.0	18.2 (0.4, 43)	15.8
FGF-1	7.4 (1.4, 13.4)	3.9	5.8 (1.5, 11)	3.1	6.7 (1, 12.4)	4.5
FGF-2	42.6 (5.7, 112.3)	35.5	32.4 (1.7, 59.8)	24.3	37.7 (3.3, 98.3)	34.4
Follistatin	72.2 (7.7, 170.9)	60.5	74.3 (2.3, 206.2)	68.2	199.6 (2, 1,413.9)	407.6
G-CSF	79.2 (5.5, 210.8)	75.4	150.8 (4.7, 669.1)	226.9	53 (4.2, 152.7)	45.3
HBEGF	2.4 (0.2, 0.6)	3.3	3.6 (0.1, 9.9)	3.5	3.1 (0.1, 7.1)	3
HGF	1,909.9 (228.4, 2,353.1)	743.6	1,729.2 (183.5, 3,750.8)	1,022	2,044.2 (1,292.8, 3,314.6)	655.6
Leptin	528.6 (16.8, 4,579.4)	1,248.3	1,479.8 (14.3, 8,325.2)	2,836.5	338.1 (10.2, 2,009.8)	568.2
ICAM	2,047.2 (138.2, 12,424.8)	3,609.6	5,324.1 (69, 19,380.5)	7,024.4	12,928.5 (76, 115,354.1)	36,037.2
IL-1A	8.5 (1.6, 16.3)	4.2	5.4 (0.1, 11.1)	4.2	7.6 (0.9, 17.4)	5.7
IL-3	43 (25.8, 66.9)	11.8	38.4 (9, 76.3)	24.5	34.3 (14.2, 77.2)	21.1
IL-6	81.9 (1.1, 423.0)	140	458.6 (9.4, 1,186.5)	535	104.4 (0.5, 487.8)	169.0
IL-7	1.4 (0.3, 3.2)	1.0	0.8 (0.1, 2.5)	0.9	0.6 (0, 2.5)	0.7
IL-8	13.1 (1.5, 34.8)	9.9	13 (1.7, 43)	14.1	8.9 (0.3, 17.9)	5.5
IL12p70	1.3 (0.2, 3)	1.0	1.1 (0.2, 2.4)	0.8	1.2 (0.2, 2.7)	1.0
IL-17	0.7 (0.2, 1.9)	0.5	1.0 (0.2, 2.6)	0.9	0.8 (0, 1.7)	0.6
MCP-1	3,765 (1,554, 8,231.8)	2,145.5	4,914.1 (1,548, 9,421.6)	3,426.8	3,751.5 (1,740.6, 7,815.3)	2,082.7
TNF-α	0.6 (0.1, 1.3)	0.4	0.5 (0.2, 1.5)	0.4	0.5 (0, 1.3)	0.4
PDGF-AA	36.3 (10, 80.5)	19.5	53 (13.9, 115.3)	38.9	39.3 (14.5, 67.4)	19.7

Abbreviations: AF, aflibercept; EGF, epidermal growth factor; FGF, fibroblast growth factor; G-CSF, granulocyte-colony stimulating factor; HBEGF, heparin-binding EGF-like growth factor; HGF, hepatocyte growth factor; ICAM, intercellular adhesion molecule; IL, interleukin; MCP, monocyte chemoattractant protein; PDGF, platelet-derived growth factor; PDT, photodynamic therapy; PLGF, placental growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.