Victor Llorenç

Dexamethasone intravitreal implant for treatment of uveitic persistent cystoid macular edema in vitrectomized patients.

Purpose: To evaluate the safety and efficacy of Ozurdex (dexamethasone intravitreal implant) 0.7 mg in the treatment of uveitic macular edema in vitrectomized eyes. Methods: Data from 13 patients (17 eyes) with persistent uveitic cystoid macular edema and a history of pars plana vitrectomy in the study eyes that were treated with intravitreal injection of 0.7-mg dexamethasone implant were reviewed retrospectively. Main outcome measures were changes in central retinal thickness measured by optical coherence tomography and changes in best-corrected visual acuity. Results: The median age of patients was 61 years (range, 19–81 years). The median duration of uveitic macular edema was 12 months (range, 2–72 months). The mean baseline central retinal thickness (95% confidence interval) was 461.6 &mgr;m (403.8–519.4), decreased to 277.2 &mgr;m (244.6–309.8) at 4 weeks (P < 0.01), remained low at 349.9 &mgr;m (281.8–418.0) at 3 months (P = 0.01), and then reached 394.1 &mgr;m (328.3–459.8) at 6 months (P = 0.14). After 3 months, there was a median improvement of 2 lines of best-corrected visual acuity, with 52.9% of eyes gaining 2 lines or more (P < 0.01). At 6 months, there were 5 eyes that maintained the 2 lines gain and none had lost >1 line from baseline (P = 0.03). In 8 eyes (47.1%), reinjection of the implant was performed at a mean of 6.5 months. Ocular hypertension (47.1%), hypotony (11.8%), anterior chamber displacement of the implant (5.9%), and glaucoma, which required filtration surgery (5.9%), were the most common adverse events. Mean follow-up was 9.6 months (range, 6–17 months). Conclusion: In this small case series of eyes with limited follow-up, treatment with dexamethasone intravitreal implant injection for uveitic macular edema in vitrectomized eyes was associated with favorable visual outcomes and had an acceptable safety profile.

Epidemiology of uveitis in a Western urban multiethnic population. The challenge of globalization

To report the anatomical pattern and etiological spectrum of uveitis in an urban multi‐ethnic population from Barcelona, Spain. General and specific epidemiological data for the most prevalent aetiologies are also calculated.

A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy

Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 × 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 × 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.

Behçet Disease-associated Uveitis Successfully Treated with Golimumab

Abstract Over the past decade, the off-label use of biologic agents such as TNF-α antagonists, including infliximab and adalimumab, has improved the treatment armamentarium for refractory immune-mediated uveitis, with particular success in Behçet disease-associated uveitis. Golimumab is a novel fully human anti-TNF-α monoclonal antibody that has been approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, with very promising results. Herein, the authors present the use of GLM in a case of Behçet uveitis refractory to other TNF-α blockers. There are only two reports in the literature about the use of GLM in uveitis, describing four patients with JIA-associated uveitis and a case of idiopathic retinal vasculitis. To the authors’ knowledge, this is the first report about the use of GLM in Behçet uveitis.

Long-Term Effects of Tocilizumab Therapy for Refractory Uveitis-Related Macular Edema

OBJECTIVE To report the long-term efficacy and safety of the interleukin-6 receptor antagonist tocilizumab for refractory uveitis-related macular edema (ME). DESIGN Retrospective cohort study. PARTICIPANTS Eyes with uveitis seen at a single tertiary referral center for which ME was the principal cause of reduced visual acuity. METHODS Data were obtained by standardized chart review. MAIN OUTCOME MEASURES Central foveal thickness (CFT) measured by optical coherence tomography, degree of anterior and posterior chamber inflammation (Standardization of Uveitis Nomenclature Working Group criteria), and visual acuity (logarithm of the minimum angle of resolution [logMAR]) were recorded during tocilizumab therapy at months 1, 3, 6, and 12. RESULTS Eleven eyes from 7 patients (all women) were included. Mean age was 43.4 years. Mean duration of ME was 14.2 years. Mean follow-up with tocilizumab therapy was 15.2 months (range, 12-18 months). Before tocilizumab therapy, conventional immunosuppressive therapy and 1 or more biologic agents failed in all patients. Uveitis diagnoses were birdshot chorioretinopathy (n = 3), juvenile idiopathic arthritis-associated uveitis (n = 3), and idiopathic panuveitis (n = 1). Mean CFT was 550 ± 226 μm at baseline, 389 ± 112 μm at month 1 (P = 0.007), 317 ± 88 μm at month 3 (P = 0.01), 292 ± 79 μm at month 6 (P = 0.006), and 274 ± 56 μm at month 12 of follow-up (P = 0.002). Mean logMAR best-corrected visual acuity improved from 0.67 ± 0.53 at baseline to 0.4 ± 0.56 at month 12 (P = 0.008). Tocilizumab therapy was withdrawn in 2 patients because of sustained remission at month 12. In both patients, ME relapsed 3 months after tocilizumab withdrawal. Reinitiation of tocilizumab therapy led to good uveitis control and ME resolution. Tocilizumab generally was well tolerated and no serious adverse events were reported. CONCLUSIONS In this study, tocilizumab was effective in the treatment of refractory inflammatory ME. No serious adverse events were observed.

Interleukin‐6 blockade in ocular inflammatory diseases

Interleukin‐6 (IL‐6) is a key cytokine featuring redundancy and pleiotropic activity. It plays a central role in host defence against environmental stress such as infection and injury. Dysregulated, persistent interleukin (IL)‐6 production has been implicated in the development of various autoimmune, chronic inflammatory diseases and even cancers. Significant elevation of IL‐6 has been found in ocular fluids derived from refractory/chronic uveitis patients. In experimental autoimmune uveitis models with IL‐6 knock‐out mice, IL‐6 has shown to be essential for inducing inflammation. IL‐6 blockade can suppress acute T helper type 17 (Th17) responses via its differentiation and, importantly, can ameliorate chronic inflammation. Tocilizumab, a recombinant humanized anti‐IL‐6 receptor antibody, has been shown to be effective in several autoimmune diseases, including uveitis. Herein, we discuss the basic biology of IL‐6 and its role in development of autoimmune conditions, focusing particularly on non‐infectious uveitis. It also provides an overview of efficacy and safety of tocilizumab therapy for ocular inflammatory diseases.

Indirect supportive evidence for diagnosis of tuberculosis-related uveitis: from the tuberculin skin test to the new interferon gamma release assays.

Purpose:  To evaluate clinical and paraclinical parameters for the indirect diagnosis of tuberculosis‐related uveitis (TRU).

Tocilizumab treatment for recalcitrant uveitic macular edema.

Dear Editor, Cystoid macular edema (CME) is the most frequent structural complication of uveitis, and is responsible for a significant amount of visual morbidity. Treatments for uveitic CME include corticosteroids, administered systemically, periocularly, or intravitreal, systemic immunosuppressive medications, anti-tumor necrosis factor alpha (TNF-α) drugs, and vitreous surgery. Despite these treatment options, a number of patients remain that do not respond to any of these treatment modalities. Tocilizumab (TCZ), a fully humanized antibody that binds both to soluble and membrane-bound IL-6 receptors, is currently approved for the treatment of rheumatoid arthritis refractory to one or more anti-TNF-α drugs [1]. Herein, we report one case of idiopathic panuveitis with severe CME refractory to systemic and local treatments who favourably responded to TCZ. A 56-year-old-woman diagnosed with idiopathic panuveitis had been treated with prednisone (7.5 mg daily) in combination with cyclosporine A (CsA) (150 mg bid) and methotrexate (MTX) (15 mg weekly) for 12 years. In 2001, a total three-port pars plana vitrectomy with lensectomy was performed in both eyes. In 2009, her inflammatory condition relapsed with severe bilateral CME, and intravenous infusion with 5 mg/kg of infliximab was given. She developed an hypersensitivity reaction and therapy was switched from infliximab to 40 mg every 2 weeks of adalimumab, trying to get her uveitis and macular edema under control. Nevertheless, CME remained in both eyes. In 2011, an intravitreal injection of dexamethasone implant was performed in her left eye, but the implant migrated into the anterior chamber and Descemet’s folds with corneal edema developed. In April 2012, anterior segment examination disclosed 2+ cells in anterior chamber, and on fundus biomicroscopy 1+ vitreous cells and CME were observed in her right eye. Central retinal thickness (CRT) measured by optic coherence tomography (OCT) was 896 μm in her right eye (Fig. 1). OCT was not performed in the left eye due to corneal edema. Her visual acuity was counting fingers at 1 m in the right eye and light perception in the left eye. We then initiated intravenous TCZ 8 mg/Kg monthly with oral prednisone at a daily dose of 7.5 mg. Adalimumab was stopped 4 weeks prior starting TCZ. After six infusions of TCZ the patient remained asymptomatic, and ophthalmic examination revealed no sign of active inflammation; the CRT decreased from 896 to 182 μm on the OCT (Fig. 2a, b). Visual acuity improved to 20/400 in the right eye. No remarkable side-effects after 6 months of follow-up have been reported. IL-6 is a pleiotropic, proinflammatory cytokine mainly produced by T cells and monocytes/macrophages, inducing proliferation and differentiation of T cells as well as the terminal differentiation of B cells. Antiinterleukin 6 receptor (anti-IL-6R) antibodies have been effective in experimental models of autoimmune arthritis, encephalomyelitis, and also uveitis [2]. IL-6 is present in the vitreous of patients with active intermediate A. Adán (*) :V. Llorenç :M. Mesquida : L. Pelegrín Department of Ophthalmology, Hospital Clinic of Barcelona, Calle Sabino de Arana, 1, 08036 Barcelona, Spain e-mail: amadan@clinic.ub.es

Certolizumab Pegol, a New Anti-TNF-α in the Armamentarium against Ocular Inflammation.

Abstract Purpose: To study the efficacy and tolerance of certolizumab pegol (CZP) in active uveitis. Methods: Retrospective case series at 4 referral centers. Patients treated with CZP for active uveitis during at least 6 months were eligible. Inflammation by SUN scores, visual acuity (VA) (logMAR), and central macular thickness (CMT) were compared from baseline until final follow-up. Quiescence was defined as 0+ to 0.5+ in anterior chamber and vitreous haze scores and no CMT increase. Results: Four males and 3 females (14 eyes) were included, mean age 42.4 ± 8.8 years. All were long-lasting chronic-relapsing uveitis with prior failure to other anti-TNF-α. After a mean follow-up of 10.4 ± 4.8 months, 5/7 patients (71.4%) achieved quiescence with CZP. VA improved significantly from +0.52 ± 0.68 to +0.45 ± 0.68 (p = 0.032) at 1 month and to +0.44 ± 0.64 (p = 0.035) at 6 months. No adverse events were found. Conclusion: CZP can be an effective alternative in refractory uveitis.

Tocilizumab for retinal vasoproliferative tumor secondary to juvenile idiopathic arthritis-associated uveitis: a case report

Dear Editor, Retinal vasoproliferative tumors (VPRTs) are highly vascularised masses of the neuro-sensory retina. These benign tumours have been classified as idiopathic or secondary. This secondary type has been associated with predisposing lesions such as pars planitis or other inflammatory events [1]. In some cases, visual acuity may be profoundly impaired owing to progressive exudation involving the macular region with macular exudation or cystoid macular edema. Interleukin (IL)-6 receptor blockade using tocilizumab (TCZ) proved effective for many autoimmune or inflammatory diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis (JIA), and large-vessel vasculitides [2]. Here, we present a case of intractable case of VPRT secondary to JIA-associated uveitis who favourably responded to TCZ. A 29-year-old female with a history of JIA-associated uveitis was referred with bilateral visual loss. She gave a history of extended oligo-arthritis since the age of 5 years, and JIAassociated uveitis. She underwent pars plana vitrectomy and lensectomy in both eyes in 1993. Glaucoma surgery was performed in her left eye in 2008. She was previously treated with oral prednisone and methotrexate for 12 years, infliximab for 1 year, and adalimumab for 2 years. With all these drugs the uveitis became refractory or the patient presented side effects and the drug needed to be stopped. Hypotonic maculopathy, with an intraocular pressure (IOP) of 3 mmHg, was diagnosed in her right eye. Despite adalimumab treatment, her left vision had continued to deteriorate over the last 3 months, from 0.2 to counting fingers at 50 cm due to severe intraocular inflammation and recalcitrant macular edema. Ocular examination disclosed 1+ cells in the anterior chamber and 1+ vitreous haze. Wide-field fundus photography using Optomap scanning laser ophthalmoscope (Optos, Marlborough, MA) was performed and showed an elevated pink mass located in the inferotemporal region near the ora serrata of the left eye associated with subretinal exudation (Fig. 1a). Spectraldomain optical coherence tomography (OCT; Cirrus, Carl Zeiss Meditec, Germany) revealed an oedematous macula in her left eye, with a central subfoveal thickness (CST) of 775 μm (Fig. 1b). We then initiated intravenous TCZ 8 mg/Kg monthly; adalimumab was stopped prior starting TCZ. Written informed consent was obtained from the patient for off-label use of TCZ. After 12 injections of TCZ the ophthalmic examination revealed a distinct regression in exudation and the CST decreased from 775 to 264 μm on the OCT (Fig. 1c,d). Visual acuity improved to 20/80 in her left eye. No changes were observed in the right eye. No remarkable side effects after 12 month follow-up time have been reported. JIA-associated uveitis carries significant ocular morbidity that lasts well into adulthood despite treatment with immunosuppressive agents and anti-TNF-α drugs [3]. VPRT was not previously reported in JIAassociated uveitis . In our patient, VPRT and macular edema was intractable despite maximum systemic treatment. Management of VPRT includes observation, laser photocoagulation or cryotherapy for the treatment of small tumours. Larger tumours are, however, difficult to treat with cryotherapy because freezing of lesions can lead to an increase in associated exudative changes and, possibly, complete exudative retinal detachment [4]. In consequence, the treatment of VPTR is still a challenge, and A. Adán (*) :M. Mesquida :V. Llorenç Department of Ophthalmology, Hospital Clínic of Barcelona, University of Barcelona, Barcelona, Spain e-mail: amadan@clinic.ub.es