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Two cytokines from fluid in the anterior chamber of the eye help predict response to the anti–vascular endothelial growth factor drug ranibizumab (Lucentis, Genentech) in patients with diabetic macular edema (DME), new research suggests.

If validated, the biomarkers could spare patients repeated injections with an ineffective agent, but one expert expressed concern about the invasiveness of the test.

“The prospect of ongoing injections in the eye is daunting for patients,” senior author Rajeev Muni, MD, a vitreoretinal surgeon at St. Michael’s Hospital, Toronto, Ontario, Canada, said in a statement. “The fact that we can now measure a protein in the eye that allows us to predict which patients are less likely to respond to treatment could lead to more personalized and tailored medicine and fewer injections. This could alleviate the treatment burden on patients and the healthcare system,” he added.

The study was published online March 8 in JAMA Ophthalmology.

A total of 48 patients with either type 1 or type 2 diabetes with center-involving DME participated in the study. To be eligible, patients had to have central subfield thickness (CST) of at least 310 µm in the study eye, as determined with spectral-domain optical coherence tomography (SD-OCT). At baseline, the mean best-corrected visual acuity was 20/80, the mean SD-OCT was 495 μm, and the mean SD-OCT macular volume (MV) was 13.0 mm³. The mean diameter of focal avascular zone (FAZ) was 847.3 μm.

All patients received a monthly intravitreal injection of ranibizumab, 0.5 mg, at baseline and again at month 1 and month 2.

“Aqueous fluid (0.2mL) for cytokine analysis was obtained at baseline and repeated at the 2-month visit, immediately before the third intravitreal ranibizumab injection,” Roxane Hillier, MD, University of Toronto, Ontario, Canada, and colleagues write.

One month after the third and final study injection, the investigators recorded a number of changes in the aqueous cytokines tested, most notably in intercellular adhesion molecule 1 (ICAM-1) and in vascular endothelial growth factor (VEGF) levels, as well as in placental growth factor (PlGF), interleukin 6 (IL-6), and monocyte chemoattractant protein 1 (MCP = 1).

Table. Median Changes in Aqueous Cytokines at Month 2 From Baseline

	Baseline		Medium Change From Baseline to Month 2
ICAM-1	1489.54 pg/mL	1021.57 pg/mL	-190.88 pg/mL	P < .001
VEGF	752.79 pg/mL	14.65 pg/mL	-639.45 pg/mL	P < .001
PlGF	3.67 pg/mL	1.56 pg/mL	-1.31 pg/mL	P < .001
IL-6	80.84 pg/mL	34.14 pg/mL	-38.61 pg/mL	P < .001
MCP-1	1395.96 pg/mL	1210.18 pg/mL	-90.13 pg/mL	P = .01

 

Favorable Anatomic Response

Overall, 30 (62.5%) patients responded to the treatment when response was defined as an improvement in CST, as did 23 (47.9%) when response was defined by MV change.

After adjusting for age, FAZ size, and lens status, the investigators found that higher baseline levels of ICAM-1 were associated with a 27% greater likelihood of an MV response (odds ratio [OR], 1.270; 95% confidence interval [CI], 1.064 – 1.515), whereas higher VEGF levels were associated with a 21% lower likelihood (OR, .793; 95% CI, .658 – .955).

Specifically, each additional 100 pg/mL of ICAM-1 at baseline was associated with a 0.0379 mm³ reduction in MV after treatment (p =.01). In the case of VEGF, every additional 100 pg/mL increase of the cytokine at baseline was associated with a .0731 mm³ increase in MV at (P = .02).

“No other baseline cytokine or any other variable was associated with SD-OCT MV anatomic response,” the authors note.

Increasing levels of VEGF at baseline were associated with a poorer anatomic response to treatment, as assessed by SD-OCT CST (P = .03), although the association only became significant after adjusting for FAZ size. The odds of achieving a CST response dropped by 13.2% for every 100-pg/mL increase in baseline VEGF(OR, .868; 95% CI, .755 – .998).

There was no association between baseline ICAM-1 and CST response.

“The key finding of this study is that not only are aqueous ICAM-1 levels reduced in response to intravitreal ranibizumab therapy, but increasing aqueous ICAM-1 at baseline is associated with a subsequent favorable anatomic response to ranibizumab therapy at month 3, in terms of SD-OCT MV, in patients with DME,” the investigators affirm.

“Conversely, increasing aqueous VEGF at baseline is associated with a less favorable anatomic response to ranibizumab at month 3,” they add.

The authors speculate that the variable response to the agents used to treat DME might be attributable to varying degrees of ICAM-1 suppression brought about by the different agents. It was recently reported that patients who respond poorly to three intravitreal injections of ranibizumab are unlikely to respond to continued treatment.

Great Patient Burden

Asked by Medscape Medical News to comment on the findings, Albert Augustin, MD, from the Staedtisches Klinikum Karlsruhe in Germany, said physicians absolutely need a prediction tool in this setting. Otherwise, it can take 8 to 9 months of injections to tell whether or not a patient is responding to treatment.

“Not only is this a great burden to the patient but also to payers and relatives, so that is why we need parameters which help us to predict response earlier, ideally after three injections,” Augustin said.

However, in his view, the use of cytokines from the anterior chamber of the eye probably won’t be useful as a routine predictive tool because cytokine measurement involves an invasive procedure — “so I don’t believe this can be done on a routine basis because it is too invasive,” he suggested. What would work better is the use of central rental thickness (CRT), as measured by optical coherence tomography.

Augustin was himself involved in a post hoc analysis. “We nicely showed that we could predict responsiveness in DME patients after only three injections,” he noted. As was previously reported by Medscape Medical News, the study showed that a strong early CRT response to ranibizumab was associated with greater long-term improvement in best-corrected visual acuity in patients with DME. CRT was measured by optical coherence tomography at 12 weeks, and changes in CRT were measured from baseline.

Thus, if CRT drops by at least 20% after three injections of ranibizumab, most patients with DME will do well over the long term, Augustin reaffirmed.

The study was funded by Novartis Pharmaceuticals Canada Inc and the Retina Foundation of Canada. Dr Hillier has received personal fees from Novartis Inc and Alimera Sciences Ltd. Dr Muni has received personal fees from Bayer and Novartis and grants from Novartis. Other investigators have disclosed relevant financial relationships. Dr Augustin has received speaker honoraria, travel support, and study grants from Allergan.

JAMA Ophthalmol. Published online March 8, 2018. Full text

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