Bora Eldem

Efficacy and Safety of Monthly versus Quarterly Ranibizumab Treatment in Neovascular Age-related Macular Degeneration: The EXCITE Study

OBJECTIVE To demonstrate noninferiority of a quarterly treatment regimen to a monthly regimen of ranibizumab in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN A 12-month, multicenter, randomized, double-masked, active-controlled, phase IIIb study. PARTICIPANTS Patients with primary or recurrent subfoveal CNV secondary to AMD (353 patients), with predominantly classic, minimally classic, or occult (no classic component) lesions. INTERVENTION Patients were randomized (1:1:1) to 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly doses of ranibizumab. Treatment comprised of a loading phase (3 consecutive monthly injections) followed by a 9-month maintenance phase (either monthly or quarterly injection). MAIN OUTCOME MEASURES Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline to month 12 and the incidence of adverse events (AEs). RESULTS In the per-protocol population (293 patients), BCVA, measured by Early Treatment Diabetic Retinopathy Study-like charts, increased from baseline to month 12 by 4.9, 3.8, and 8.3 letters in the 0.3 mg quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg monthly (101 patients) dosing groups, respectively. Similar results were observed in the intent-to-treat (ITT) population (353 patients). The mean decrease in CRT from baseline to month 12 in the ITT population was -96.0 μm in 0.3 mg quarterly, -105.6 μm in 0.5 mg quarterly, and -105.3 μm in 0.3 mg monthly group. The most frequent ocular AEs were conjunctival hemorrhage (17.6%, pooled quarterly groups; 10.4%, monthly group) and eye pain (15.1%, pooled quarterly groups; 20.9%, monthly group). There were 9 ocular serious AEs and 3 deaths; 1 death was suspected to be study related (cerebral hemorrhage; 0.5 mg quarterly group). The incidences of key arteriothromboembolic events were low. CONCLUSIONS After 3 initial monthly ranibizumab injections, both monthly (0.3 mg) and quarterly (0.3 mg/0.5 mg) ranibizumab treatments maintained BCVA in patients with CNV secondary to AMD. At month 12, BCVA gain in the monthly regimen was higher than that of the quarterly regimens. The noninferiority of a quarterly regimen was not achieved with reference to 5.0 letters. The safety profile was similar to that reported in prior ranibizumab studies.

Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)

Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. The disease has a profound effect on quality of life of affected individuals and represents a major socioeconomic challenge for societies due to the exponential increase in life expectancy and environmental risks. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies in medicine. The wide introduction of anti-VEGF therapy has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, the therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management. The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance. Simultaneously, ground-breaking innovations in diagnostic technologies, such as optical coherence tomography, allows unprecedented high-resolution visualisation of disease morphology and provides a promising horizon for early disease detection and efficient therapeutic follow-up. However, definite conclusions from morphologic parameters are still lacking, and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state-of-the-art care to their patients. Trial registration number NCT01318941.

Two-Year Safety and Efficacy of Ranibizumab 0.5 mg in Diabetic Macular Edema: Interim Analysis of the RESTORE Extension Study

OBJECTIVE To evaluate the 2-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema (DME). DESIGN Twenty-four-month, open-label, multicenter, Phase IIIb extension study. PARTICIPANTS Two hundred forty of 303 patients with visual impairment due to DME who completed the RESTORE core study and entered the extension. METHODS All patients were eligible to receive ranibizumab 0.5 mg pro re nata (PRN) from month 12 (end of core study) to month 36 based on best-corrected visual acuity (BCVA) stability and disease progression retreatment criteria. Patients were also eligible to receive laser PRN according to Early Treatment Diabetic Retinopathy Study guidelines. A preplanned interim analysis was performed at month 24, stratifying by treatment groups as in the RESTORE core study and referred to as prior ranibizumab, ranibizumab plus laser, or laser groups in the extension. MAIN OUTCOME MEASURES Incidence of ocular and nonocular adverse events (AEs) and mean change in BCVA. RESULTS Two hundred twenty patients (92%) completed the month 24 visit. Over 2 years, the most frequent ocular serious AE (SAE) and AE were cataract (2.1%) and eye pain (14.6%), respectively. The main nonocular AEs were nasopharyngitis (18.8%) and hypertension (10.4%). There were no cases of endophthalmitis, and the incidences of nonocular SAEs were low. Of the patients entering the extension, 4 deaths were reported in the second year, none of which were related to study drug or procedure. Mean BCVA gain, central retinal thickness (CRT) decrease, and National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite score observed at month 12 were maintained at month 24 (prior ranibizumab: +7.9 letters, -140.6 μm, and 5.6, respectively; prior ranibizumab plus laser: +6.7 letters, -133.0 μm, and 5.8, respectively), with an average of 3.9 (prior ranibizumab) and 3.5 ranibizumab injections (prior ranibizumab plus laser). In patients treated with laser alone in the core study, the mean BCVA, CRT, and NEI VFQ-25 composite score improved from month 12 to month 24 (+5.4 letters, -126.6 μm, and 4.3, respectively), with an average of 4.1 ranibizumab injections. CONCLUSIONS Ranibizumab 0.5 mg administered according to prespecified visual stability and disease progression criteria was well tolerated, with no new safety concerns identified over 2 years. Overall, an average of 3.8 ranibizumab injections was sufficient to maintain (prior ranibizumab) or improve (prior laser) BCVA, CRT, and NEI VFQ-25 outcomes through the second year. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behçet's disease: a randomised trial

BACKGROUND Sight-threatening eye involvement is a serious complication of Behçets disease. Extraocular complications such as arthritis, vascular occlusive disorders, mucocutaneous lesions, and central-nervous-system disease may lead to morbidity and even death. We designed a prospective study in newly diagnosed patients without previous eye disease to assess whether prevention of eye involvement and extraocular manifestations, and preservation of visual acuity are possible with combination treatments with and without interferon alfa-2b. METHODS Patients were randomly assigned 3 million units interferon alfa-2b subcutaneously every other day for the first 6 months plus 1.5 mg colchicine orally daily and 1.2 million units benzathine penicillin intramuscularly every 3 weeks (n=67), or colchicine and benzathine penicillin alone (n=68). The primary endpoint was visual-acuity loss. Analysis was by intention to treat. FINDINGS Significantly fewer patients who were treated with interferon had eye involvement than did patients who did not receive interferon (eight vs 27, relative risk 0.21 [95% CI 0.09-0.50], p<0.001). Ocular attack rate was 0.2 (SD 0.62) per year with interferon therapy and 1.02 (1.13) without interferon therapy (p=0.0001). Visual-acuity loss was significantly lower among patients treated with interferon than in those without interferon (two vs 13, relative risk 0.13 [95% CI 0.03-0.60], p=0.003). Arthritis episodes, vascular events, and mucocutaneous lesions were also less frequent in patients treated with interferon than in those not receiving interferon. No serious side-effects were reported. INTERPRETATION Therapy with interferon alfa-2b, colchicine, and benzathine penicillin seems to be an effective regimen in Behçets disease for the prevention of recurrent eye attacks and extraocular complications, and for the protection of vision.

The SECURE study:long-term safety of Ranibizumab 0.5 mg in neovascular age-related macular degeneration

OBJECTIVE To evaluate long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (nAMD). DESIGN Twenty-four-month, open-label, multicenter, phase IV extension study. PARTICIPANTS Two hundred thirty-four patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study. METHODS Ranibizumab 0.5 mg administered at the investigators discretion as per the European summary of product characteristics 2007 (SmPC, i.e., ranibizumab was administered if a patient experienced a best-corrected visual acuity [BCVA] loss of >5 Early Treatment Diabetic Retinopathy Study letters measured against the highest visual acuity [VA] value obtained in SECURE or previous studies [EXCITE and SUSTAIN], attributable to the presence or progression of active nAMD in the investigators opinion). MAIN OUTCOME MEASURES Incidence of ocular or nonocular adverse events (AEs) and serious AEs, mean change in BCVA from baseline over time, and the number of injections. RESULTS Of 234 enrolled patients, 210 (89.7%) completed the study. Patients received 6.1 (mean) ranibizumab injections over 24 months. Approximately 42% of patients had 7 or more visits at which ranibizumab was not administered, although they had experienced a VA loss of more than 5 letters, indicating either an undertreatment or that factors other than VA loss were considered for retreatment decision by the investigator. The most frequent ocular AEs (study eye) were retinal hemorrhage (12.8%; 1 event related to study drug), cataract (11.5%; 1 event related to treatment procedure), and increased intraocular pressure (6.4%; 1 event related to study drug). Cataract reported as serious due to hospitalization for cataract surgery occurred in 2.6% of patients; none was suspected to be related to study drug or procedure. Main nonocular AEs were hypertension and nasopharyngitis (9.0% each). Arterial thromboembolic events were reported in 5.6% of the patients. Five (2.1%) deaths occurred during the study, none related to the study drug or procedure. At month 24, mean BCVA declined by 4.3 letters from the SECURE baseline. CONCLUSIONS The SECURE study showed that ranibizumab administered as per a VA-guided flexible dosing regimen recommended in the European ranibizumab SmPC at the investigators discretion was well tolerated over 2 years. No new safety signals were identified in patients who received ranibizumab for a total of 3 years. On average, patients lost BCVA from the SECURE study baseline, which may be the result of disease progression or possible undertreatment. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Is elevated level of soluble endothelial protein C receptor a new risk factor for retinal vein occlusion

Background:  To evaluate the systemic and thrombophilic risk factors for retinal vein occlusion (RVO) and to determine whether the elevated level of soluble endothelial protein C receptor (sEPCR) is a risk factor for thrombosis.

Cataract surgery in patients with Behçet’s disease

Purpose: To evaluate the outcomes and complications of cataract surgery in patients with Behçets disease. Setting: Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey. Methods: Thirty‐three eyes of 26 patients with Behçets disease that had extracapsular cataract surgery between January 1993 and July 1999 were analyzed retrospectively. The mean age of the patients was 38.9 years (range 20 to 54 years). The mean postoperative follow‐up was 22.9 months (range 6 to 66 months). Results: Extracapsular cataract extraction (ECCE) was performed in 22 eyes with and in 6 eyes without intraocular lens (IOL) implantation. Phacoemulsification with IOL implantation was performed in 5 eyes. Postoperatively, the visual acuity was better in 29 eyes (87.8%) and was 0.5 or better in 14 eyes (42.4%). Posterior segment complications of Behçets disease, mainly optic atrophy and macular alterations from preoperative inflammatory episodes, restricted final acuity. No significant difference was detected in postoperative inflammation among the types of surgery; that is, ECCE, ECCE with IOL implantation, and phacoemulsification with IOL implantation. A neodymium:YAG laser posterior capsulotomy was performed in 3 cases. Conclusions: In patients with Behçets disease, inflammation after extracapsular surgery was mild when surgery was performed after at least 3 months of no inflammatory signs. The results show that the outcomes of extracapsular cataract surgery mainly depend on the degree of preoperative posterior segment involvement.

PARANEOPLASTIC RETINOPATHY ASSOCIATED WITH METASTATIC CUTANEOUS MELANOMA OF UNKNOWN PRIMARY SITE

Purpose: To describe further the clinical and immunological features of cutaneous melanoma-associated retinopathy, which is an infrequent form of paraneoplastic syndrome.Methods: We studied the salient clinical and immuno-logical aspects of a 66-year-old man with metastatic cutaneous melanoma to lymph nodes of unknown primary site who developed melanoma-associated retinopathy.Results: There was gradual loss of vision in the left eye. Colour vision and night vision were not affected. Visual fields showed arcuate defects. A full-field electroretinogram demonstrated attenuation of the b-wave amplitude in the left eye. The a-wave was intact. Indirect immunofluorescence techniques showed that the antibody reactions took place mainly in the outer plexiform layer of the retina.Conclusions: Bipolar cells seem to be the target in melanoma-associated retinopathy. Contrary to previous reports, night blindness may not be a universal finding.

Management of Moderate to Advanced Coats’ Disease

Sixteen patients (16 eyes) with Coats’ disease who had either total bullous exudative retinal detachment or macular involvement and/or at least two quadrants of exudative retinal detachment were followed for a mean period of 60.6 months. Three patients with no light perception received no treatment. Ten eyes received cryotherapy on one or more occasions and two had laser photocoagulation. One eye underwent subretinal fluid drainage, intraocular infusion and cryotherapy. In those patients who could be tested, all the treated eyes retained their initial visual acuities. All 16 eyes had an acceptable cosmesis and none progressed to painful neovascular glaucoma or phthisis bulbi. Patients with late onset disease had a more benign course.

Panuveitis associated with multiple sclerosis complicated by cerebral venous thrombosis.

Purpose: To report cerebral venous thrombosis as a complication of intravenous corticosteroid treatment in a patient with multiple sclerosis. Method: A case report. A 44-year-old woman with a previous diagnosis of multiple sclerosis presented with panuveitis and retinal perivasculitis. Intravenous pulse corticosteroid therapy was given for three days. Results: The panuveitis and retinal periphlebitis began to resolve within one week; however, ten days after the last corticosteroid dose, the patient was hospitalized with the diagnosis of cerebral venous thrombosis. Conclusion: Although intravenous corticosteroid treatment for uveitis associated with multiple sclerosis can be very helpful, the patient should be monitored closely for systemic side effects.