Article Date: 3/1/2011

Recent Noteworthy Studies to Stimulate Discussion and Debate
JOURNAL CLUB

Recent Noteworthy Studies to Stimulate Discussion and Debate

Three's a charm. Allergan's Ozurdex dexamethasone implant recently received FDA approval for the treatment of posterior uveitis, in addition to its already approved status for RVO. Archives of Ophthalmology has published online a phase 3 study further documenting its efficacy and elucidating its role in clinical practice. The article also includes phase 2 data on the use of Ozurdex in noninfectious intermediate uveitis. The paper, by the Ozurdex HURON Study Group, reports six-month data from that trial.

Two hundred twenty-nine patients at 18 study sites in North and South America were randomized into three treatment groups: a group receiving the 700-µg implant, a group receiving the 350-µg implant, and a control group receiving neither. All patients had diagnoses of noninfectious intermediate or posterior uveitis. The primary outcome measurement was four-point vitreous haze scale.

At eight weeks, 47% of the patients in the higher-dose group and 36% of the patients in the lower-dose group had vitreous haze scores of zero, and these scores remained at zero over the course of the six months of the study. Improvements in best-corrected visual acuity and central macular thickness were similarly impressive, with the treatment cohorts having a statistically significant number of patients with 15 ETDRS letters or more of improvement in BCVA from their baseline measurements.

Adverse effects of treatment with Ozurdex were mainly cataract and increased intraocular pressure. The percentages of patients experiencing IOP ≥25 mm Hg maxed out at 7.1%, 8.7% and 4.2% for the high-dose, low-dose, and control groups, respectively. Cataract rates were 15%, 12% and 7%, respectively, for the same groups, though the study group concedes that, because cataracts typically take more than six months to form, these rates may ultimately prove higher. Nevertheless, it is likely that more phase 3 testing of Ozurdex in intermediate uveitis will follow soon.

Speaking of uveitis. An article in the February 2011 issue of the British Journal of Ophthalmology features a systematic review of the use of anti-VEGF agents in uveitis, which finds that more attention needs to be paid to underlying causes of uveitis.

The authors of the review, who are on the faculty at the Mount Sinai School of Medicine in New York, found that only nine reports have been published regarding the use of bevacizumab or ranibizumab for cystoid macular edema consequent to uveitis. Of these, only three were prospective case series; others were retrospective studies or case studies featuring as few as one case. All but one study had used bevacizumab.

The other articles the authors reviewed were studies in which anti-VEGF agents were used to address either retinal or choroidal neovascularization in cases of uveitis. In both of these investigations, the number of articles was again very small, and, according to the GRADE scale, all three categories would be rated as having “very low” quality regarding the available research.

With regard to the cases of CNV or CME with uveitis, the authors strongly suggest that the primary focus should be on treating the underlying disease that has led to uveitis. In the case of retinal neovascularization, however, while they also urge treatment of underlying disease first and foremost, they suggest that, if inflammation persists, bevacizumab might be a useful adjunct.

Avastin in combo. The rush to find an effective combination therapy regimen for wet AMD that will reduce the number and frequency of intravitreal injections of anti-VEGF agents continues. A team of retinal physicians affiliated with the Beth Israel Deaconess Hospital in Boston conducted a retrospective study of a triple combination consisting of intravitreal injections of bevacizumab, sub-Tenon's injections of triamcinolone acetonide, and low-fluence verteporfin/photodynamic therapy (Visudyne, Novartis). They report their results in the March 2011 issue of Retina.

The authors identified 31 eyes treated for wet AMD with triple therapy between June 2004 and November 2008. Of that number, 26 were treatment-naïve, and the other five had received previous treatment, but not combination therapy. Outcomes evaluated included visual acuity, retinal thickness as measured by optical coherence tomography, and time to retreatment.

At the three- and six-month marks, there were improvements in logMAR visual acuity of 0.140±0.273 and 0.182±0.383, respectively. Mean central retinal thickness decreased at these same time points, as well as at the final, one-year follow-up, when it decreased by 101.6±103.3 µm. Half the patients in the study required retreatment before the year-long period of examination ended. The only side effects reported were three cases of increased IOP.

This study is significant both because of the use of a sub-Tenon's injection of triamcinolone, as well as the use of bevacizumab, which has tended to have a longer efficacy than ranibizumab, albeit while being used off-label. Whether the particular combination used in this study will have a long-term effect on treatment of wet AMD will require prospective clinical trials.

Complement in AMD. A new study carried out by scientists at Oxford University in the United Kingdom and Johns Hopkins University in Baltimore discusses the role of the complement system in the pathogenesis and possibly the treatment of AMD by examining the available evidence in a meta-analysis. Their article, which appears in the February 2011 issue of Graefe's Archive for Clinical and Experimental Ophthalmology, also suggests that inhibition of growth factors should be done in such a manner that does not compromise the innate immune system of the eye.

The study first looks at the complement system itself and the arguments in favor of this system playing a role in AMD pathogenesis. In particular, complement factor H has been identified in several papers as playing a key role in the development of the disease. From there, the study addresses systemic complement activation and the identification of genetic variants and mutations that have been identified in twin and family studies.

Then the authors review the AREDS data with regard to the complement system and review several treatments under investigation that address this system, including eculizumab, a monoclonal antibody (the same family of drug as bevacizumab and ranibizumab) approved by the FDA to treat hemoglobinuria and currently in a phase 2 trial for the treatment of AMD.

In the conclusion, there is an emphasis on the balancing act that must be performed by doctors treating long-term disease processes such as AMD, wherein the use of agents involving the immune system over a long period of time may have the undesired effect of rendering less than effective against infection of that very system. They urge adequate disease monitoring during clinical trials to help address this concern.

STDs and eye disease. Based on the resurgence of syphilis, which can cause blindness, in the wake of the advent of AIDS, doctors in Liverpool, United Kingdom, and Sydney, Australia, have collaborated on a small retrospective case series investigating syphilitic retinitis and uveitis in HIV-positive adult patients. They draw conclusions about differential diagnosis in their article published in the December 2010 issue of Clinical & Experimental Ophthalmology.

The cases of 13 men, all of whom had been diagnosed with syphilis and six of whom had tested positive for HIV, were examined. The authors found that peripheral retinitis with panuveitis was the most common ocular manifestation of syphilis in the group, with seven of the 13 men being diagnosed. These patients were treated with foscarnet (Foscavir, Clinigen) in the event that the cases were viral rather than syphilis-associated, and they were also subjected to vitreous tap. Retinitis, it turned out, was present in 100% of the HIV-positive patients, but only one of the six patients who were HIV-negative. There were also cases of anterior uveitis, vitritis, multifocal choroiditis, scleritis and papillitis in the group of patients. All 13 patients were treated successfully with penicillin.

The study authors express concern that patients who are treated for syphilitic retinitis will not be given HIV tests, and this will result in under-reporting of and, thus, spreading of HIV infection. Conversely, in an environment where HIV infections are increasingly common but survival rates are much better, patients presenting with retinitis should also be screened for syphilis, particularly if they are already HIV-positive.

Microperimetry news. BMC Ophthalmology has posted online the results of a London-based trial of a modified perimeter to measure scotopic function in patients with inherited retinal dystrophies. The study authors adapted a Nidek MP-1 microperimeter by adding a 1 log unit neutral density filter and a 530 nm shortpass filter, thereby shielding against stray light. The modified instrument was then tested in 10 volunteers.

The authors found that the adapted perimeter not only was comparable to the Humphrey field analyzer (HFA), but the mean time that it took the new device to locate a foveal scotoma was seven seconds less than for the HFA. The study team will likely undertake further comparative study of the instrument to determine its overall usefulness in retinal medicine.

Telemedicine in DR. What role does telemedicine have to play in the treatment of diabetic retinopathy? Doctors from the Harvard Medical School say that it has a large role to play, and they make their case in the February 2011 issue of Archives of Ophthalmology.

Because of the sheer number of patients who may need to be treated in the coming decades and the fact that many of these patients will lack either the monetary or logistic ability to see a retinal specialist in person, the authors argue telemedicine may help in assisting these patients. While the authors are realistic in knowing that the technology has yet to reach the level where this kind of treatment could replace an office visit, they note that the same technologies could ultimately lead to a far more rapid sharing of the results of clinical research, which may help patients regardless of where they are treated. RP



Retinal Physician, Issue: March 2011