Pauline T. Merrill

Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial

BACKGROUND Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. METHODS We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10-35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov number NCT01124838. FINDINGS Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77-357) in the placebo group and 245 days (119-564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39-0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group). INTERPRETATION Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis. FUNDING AbbVie.

Use of intravitreal rituximab for treatment of vitreoretinal lymphoma

Aim Vitreoretinal lymphoma is a diffuse large B cell non-Hodgkin lymphoma. Targeting malignant cells with rituximab is being used increasingly as local chemotherapy, but information on this treatment is scant. We aimed to describe current therapeutic approaches, as well as responses to and complications of, intravitreal rituximab in patients with vitreoretinal lymphoma. Methods Clinical data were collected in a standardised manner retrospectively on patients with vitreoretinal lymphoma treated with intravitreal rituximab. Results 48 eyes (34 patients) with vitreoretinal lymphoma were treated with a median of 3.5 intravitreal injections of rituximab (1 mg/0.1 mL) for new diagnosis (68.8%), progressive disease (29.9%) and maintenance therapy (2.1%). Intravitreal rituximab±methotrexate was the sole treatment in 19 eyes (39.6%). 31 eyes (64.6%) eyes achieved complete remission, after a median of 3 injections; 7 of these eyes developed recurrent disease. 11 eyes (22.9%) achieved partial remission. Although rituximab may have contributed to complications reported in 12 eyes (25.0%), a 2-line loss of Snellen visual acuity occurred in only 2 of those eyes (4.2%). Conclusions Approaches in rituximab-based intravitreal chemotherapy vary widely, but our findings suggest that this treatment may be safe and effective in inducing remission in a majority of eyes with vitreoretinal lymphoma.

Hypotony in Patients with Uveitis: The Multicenter Uveitis Steroid Treatment (MUST) Trial

Purpose: To assess the prevalence of hypotony in patients with severe forms of uveitis. Methods: The Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized study, enrolled 255 patients. Patients with hypotony at the baseline visit were identified. Results: Twenty (8.3%) of 240 patients with sufficient data had hypotony. Hypotony was more common in patients with uveitis ≥5 years duration (odds ratio [OR] = 5.0; p < .01), and in eyes with a history of ocular surgery (vitrectomy vs. none, OR = 3.1; p = .03). Hypotony was less in patients with older age of uveitis onset (>51 years vs. <51 years, OR = 0.1; p = .02), in Caucasian patients (OR = 0.1; p < .01) compared to African American patients. Hypotonous eyes were more likely to have visual impairment (OR = 22.9; p < .01). Conclusions: Hypotony is an important complication of uveitis and more commonly affects African-American patients, those with uveitis onset at a younger age, and those with longer disease duration. It is associated with visual impairment.

Chronic central serous chorioretinopathy responsive to rifampin.

PURPOSE The purpose of this was to describe the clinical improvement of chronic central serous chorioretinopathy in a patient treated with rifampin for tuberculosis. METHODS A 54-year-old Hispanic man with a distant history of pulmonary tuberculosis presented with reduced vision in the right greater than left eye for over 1 year. He had diffuse chorioretinopathy in both eyes and a serous retinal detachment in his right eye. The findings were most consistent with chronic central serous chorioretinopathy, although tuberculosis -related choroiditis could not be excluded. Treatment with multidrug antituberculosis medications, including rifampin, resulted in the reduction in leakage and resolution of subretinal fluid. Fluid recurred on cessation of all medications and resolved again with retreatment. Monotherapy with rifampin maintained the absence of fluid. DISCUSSION This case represents the first report of chronic central serous chorioretinopathy responding to systemic therapy with rifampin. We hypothesize that the clinical response observed is secondary to induction of cytochrome P450 with increased hepatic metabolism of endogenous corticosteroids and a reduction in systemic cortisol levels.

Cytomegalovirus Acute Retinal Necrosis In An Immunocompetent Patient After Sub-tenon Triamcinolone Injection

PURPOSE To report a case of cytomegalovirus acute retinal necrosis after a sub-Tenon injection of triamcinolone acetonide in an immunocompetent patient. METHODS A 77-year-old man received a sub-Tenon injection of triamcinolone acetonide for treatment of iritis unresponsive to topical steroids. He subsequently developed unilateral acute retinal necrosis. RESULTS Vitreous biopsy with polymerase chain reaction analysis was positive for cytomegalovirus. Implantation of a sustained-release ganciclovir device resulted in disease stabilization. CONCLUSION Cytomegalovirus can be a causative agent of both anterior uveitis and acute retinal necrosis. A potential complication of a sub-Tenon steroid injection may be viral reactivation causing acute retinal necrosis secondary to localized immunosuppression.

Diagnostic and therapeutic challenges. Acute retinal necrosis syndrom.

A 73-year-old Hispanic man presented with a gradual decrease in visual acuity in the left eye over 3 weeks time. He had longstanding type 2 diabetes mellitus, proliferative diabetic retinopathy, and clinically significant diabetic macular edema for which he has had both panretinal photocoagulation and focal macular laser. Cataract surgery had been performed in both eyes 4 years earlier. Severe diabetic nephropathy led to a dual renal transplant 5 years ago. Other notable medical history includes a history of hypertension, chicken pox as a child, and HIV with recent CD4 count of 166 and viral load of 75. His medications included Sustiva, abacavir, Bactrim, CellCept, Prograf, prednisone, Norvasc, Lotensin, and Epogen. Examination revealed best-corrected visual acuity of 20/25 in the right eye and 20/200 in the left eye. There was no afferent pupillary defect. Intraocular pressures were 16 mmHg in the right eye and 14 mmHg in the left eye. External examination was normal. Slit lamp examination of the right eye was unremarkable. The left eye revealed 1 conjunctival injection with 2 cell and 3 flare anterior chamber reaction with granulomatous keratic precipitates (KP) on the endothelium accompanied by 2 corneal edema (Figure 1A). Each eye contained a well-centered acrylic posterior chamber intraocular lens in both eyes. Fundus examination of the right eye revealed no vitreous cells, an epiretinal membrane in the macula, sclerotic arteries, and panretinal photocoagulation scars. Examination of the left fundus revealed 2 vitreous cells, sclerotic arteries, and physiologic optic nerve head. Panretinal photocoagulation scars were present with a confluent area of retinitis inferior and peripheral to the laser scars with a paucity of intraretinal hemorrhages (Figure 1, B and C). Laboratory testing revealed an angiotensin converting enzyme (ACE) level of 9. Toxoplasmosis titers, fluorescent treponemal antibody testing, and purified protein derivative (PPD) with control were all negative. Cytomegalovirus (CMV) and herpes simplex virus 1 and 2 were positive by serologic assay for IgG. A presumed diagnosis of viral acute retinal necrosis was made. The patient was started on acyclovir 700 mg IV three times daily for 1 week. Two days later oral prednisone was begun at 60 mg. Intraocular inflammation and retinitis decreased, and he was converted to oral Acyclovir 800 mg 5 times daily. The patient did well, though he continued to have a modicum of vitreous inflammation as the prednisone was slowly tapered to 30 mg. At the 4-month visit the vision in the right eye had dropped to 20/50 and the left eye vision was hand motions. Intraocular pressures were now 45 mmHg in the right eye and 23 mmHg in the left eye. There was 1 cell and flare with fine KP in the right eye and 4 mutton fat KP and profound corneal edema in the left eye making visualization of retinal details very difficult. The fundus examination of the right eye revealed 1 vitreous cell and a patch of new retinitis in the superior periphery. The patient stated compliance with the acyclovir treatment. The CD4 count had also now dropped to 68 possibly due to chronic oral prednisone, and his internist requested the steroid be tapered. In light of these new findings the patient was switched to oral valganciclovir 450 mg twice daily for possible cytomegalovirus (CMV) retinitis. His steroids were tapered and his CD4 count responded with an increase to 157 over the following month. The retinitis and inflammation resolved in both eyes. We asked several experts for their opinions concerning this case.

HLA-A29-Positive Birdshot Chorioretinopathy in An African American Patient

PURPOSE To report the first documented case of HLA-A29-positive birdshot chorioretinopathy in an African American patient. METHODS A 51-year-old African American woman presented with a 10-year history of photopsia, progressive decrease in visual acuity, metamorphopsia, and new nyctalopia. Both fundi showed evidence of periphlebitis, arterial attenuation, macular edema, and diffuse chorioretinal atrophy. RESULTS Fluorescein angiography revealed diffuse vascular leakage, and indocyanine green showed evenly distributed and symmetrical hypofluorescent spots, which were difficult to appreciate on fundoscopy. Workup revealed a positive HLA-A29 and was negative for sarcoid, tuberculosis, and syphilis. CONCLUSION Birdshot chorioretinopathy overwhelmingly affects non-Hispanic Caucasians, but there have been rare reported cases in other ethnicities including Hispanics and African Americans. This patients ethnicity may have contributed to the 10-year delay in diagnosis. To our knowledge, this is the first documented HLA-A29 positive case of birdshot chorioretinopathy in an African American. HLA-A29 may be a useful supportive test in cases with classic clinical presentation in non-Caucasian patients to enable the correct diagnose in a timely manner.

SPOTTED FEVER GROUP RICKETTSIA RETINITIS IN A TRAVELER TO AFRICA.

PURPOSE To describe a case of rickettsial retinitis in a traveler returning from Africa. METHOD Case description. RESULTS A 67-year-old woman returning from an excursion in the jungles of Africa presented with a 2-day history of floaters and decreased vision in the right eye. In the two preceding weeks, she had experienced fever, malaise, a black eschar on the right elbow, and a rash on her extremities. Examination revealed panuveitis with a solitary, white retinal lesion adjacent to a retinal vessel in the posterior pole of each eye. Extensive diagnostic workup revealed a positive serology for rickettsial antibodies. Her treatment consisted of a course of oral doxycycline. CONCLUSION Rickettsial retinitis is an emerging ocular infection in several endemic areas. This case description constitutes the first report of spotted fever group rickettsial retinitis in a traveler to Africa.

Surgical Management of Macular Edema Associated with Uveitis

Uveitis is a significant cause of vision loss in the working-age population in the developed world. The most common cause of vision loss in uveitis patients is macular edema (ME). In some cases, maximum-tolerated medical therapy may be inadequate, and compliance with medical regimens may also be an issue. Surgical approaches may provide an alternative or adjunctive means of controlling uveitis and uveitic ME.

FRI0618 Adalimumab in non-infectious uveitis – efficacy across different etiologies in the visual i and visual ii trials

Background There is increasing interest in understanding the efficacy of adalimumab across different etiologies of uveitis. No prospective analysis has been conducted to date to determine the efficacy of adalimumab among non-infectious uveitis patients with different etiologies. Objectives To assess adalimumab (ADA) efficacy in active and inactive, non-infectious uveitis across different etiologies in patients who were recruited as part of the VISUAL program. Methods Exploratory data analyses from two global phase 3, double-masked trials: VISUAL I (patients with active uveitis despite ≥2 weeks of prednisone 10–60 mg/day) and VISUAL II (patients with inactive disease dependent on 10–35 mg/day of prednisone to maintain inactivity) were performed. Patients received placebo (PBO) or ADA subcutaneously (80 mg week 0, followed by 40 mg every other week from week 1 up to 80 weeks). In VISUAL I, all patients received a prednisone burst followed by taper to 0 mg by week 15. In VISUAL II, prednisone taper to 0 mg was mandatory by week 19. The primary endpoint was time to treatment failure (TF) at or after week 6 for VISUAL I; and at or after week 2 for VISUAL II1,2. For this analysis, patients were categorized into different uveitis etiologies which they presented at study entry. Hazard ratios (HR) for time to TF were obtained for each uveitis etiology. Results The efficacy of ADA was significantly greater than PBO in the largest subgroup of patients with Idiopathic/other uveitis (VISUAL I: 103 and VISUAL II: 90) etiology in both VISUAL I1 and VISUAL II trials. All other subgroups showed a trend in favor of ADA, except for Sarcoidosis subgroup in the VISUAL II trial (Figure). Overall safety for both trials has been previously reported 1,2. Conclusions These exploratory analyses from the VISUAL I and VISUAL II trials show significantly higher efficacy in ADA-treated patients over PBO in “idiopathic/other” diagnoses of patients with both active and inactive non-infectious uveitis. Furthermore, across different uveitis etiologies, these analyses suggest that ADA-treated patients had a prolonged time to treatment failure compared to PBO. References Jaffe GJ, Dick AD, Brezin AP, et al. N Engl J Med (2016); 375:932–43. Nguyen QD, Merrill PT, Jaffe GJ, et al. The Lancet (2016); 388(10050): 1183–92. Acknowledgements AbbVie funded the VISUAL I and VISUAL II studies and provided writing support. All authors contributed to the development of the content. The authors and AbbVie reviewed and approved the abstract. The authors maintained control over the final content. Medical writing assistance was provided by Gaurav Patki, PhD of AbbVie Inc. Disclosure of Interest P. T. Merrill Consultant for: Santen, AbbVie, A. Vitale Consultant for: ACIONT, M. Zierhut Consultant for: AbbVie and Santen, E. Forton Consultant for: AbbVie, Alcon and Allergan, H. Goto Consultant for: AbbVie, M. Kron Shareholder of: AbbVie, Employee of: AbbVie, S. Tari Shareholder of: AbbVie, Employee of: AbbVie, S. Pathai Shareholder of: AbbVie, Employee of: AbbVie