Miguel Cordero-Coma

Treatment of Refractory Uveitis with Adalimumab: A Prospective Multicenter Study of 131 Patients

OBJECTIVE To evaluate adalimumab therapy in refractory uveitis. DESIGN Prospective case series. PARTICIPANTS A total of 131 patients with refractory uveitis and intolerance or failure to respond to prednisone and at least 1 other systemic immunosuppressive drug participated. INTERVENTION Patients received a 40 mg adalimumab subcutaneous injection every other week for 6 months. The associated immunosuppressants were tapered after administering 3 adalimumab injections (week 6). MAIN OUTCOME MEASURES Degree of anterior and posterior chamber inflammation (Standardization of Uveitis Nomenclature Working Group criteria), immunosuppression load (as defined by Nussenblatt et al), visual acuity (logarithm of the minimal angle of resolution [logMAR]), and macular thickness (optical coherence tomography). RESULTS There were 61 men and 70 women (mean age, 27.3 years). The most common causes were juvenile idiopathic arthritis in 39 patients, pars planitis in 16 patients, and Behçets disease in 13 patients. Twenty-seven patients had uveitis of idiopathic origin. Inflammation in the anterior chamber was present in 82% of patients and in the vitreous cavity in 59% of patients. Anterior chamber inflammation and vitreous inflammation decreased significantly (P < 0.001) from a mean of 1.51 and 1.03 at baseline to 0.25 and 0.14, respectively, at 6 months. Macular thickness was 296 (102) μ at baseline versus 240 (36) μ at the 6-month visit (P < 0.001). Visual acuity improved by -0.3 logMAR in 32 of 150 eyes (21.3%) and worsened by +0.3 logMAR (-15 letters) in 5 eyes (3.3%). The dose of corticosteroids also decreased from 0.74 (3.50) to 0.20 (0.57) mg/kg/day (P < 0.001). Cystoid macular edema, which was present in 40 eyes at baseline, showed complete resolution in 28 eyes at 6 months. The mean suppression load decreased significantly (8.81 [5.05] vs 5.40 [4.43]; P < 0.001). Six months after the initiation of the study, 111 patients (85%) were able to reduce at least 50% of their baseline immunosuppression load. Only 9 patients (6.9%) had severe relapses during the 6 months of follow-up. CONCLUSIONS Adalimumab seems to be well tolerated and helpful in decreasing inflammatory activity in refractory uveitis and may reduce steroid requirement. Further controlled studies of adalimumab for uveitis are warranted.

Intravitreal triamcinolone acetonide injection for treatment of refractory diabetic macular edema: a systematic review

OBJECTIVE To compare intravitreal triamcinolone acetonide (IVTA) injection versus no treatment or sub-Tenon triamcinolone acetonide (STTA) injection in improving visual acuity (VA) of patients with refractory diabetic macular edema (DME; unresponsive to focal laser therapy). CLINICAL RELEVANCE Diabetic macular edema is the leading cause of visual loss in diabetic retinopathy. Laser therapy has been the standard of care for patients with persistent or progressive disease. More recently, it has been suggested that IVTA injection may improve VA. METHODS AND LITERATURE REVIEWED: The following databases were searched: Medline (1950-September Week 2 2008), The Cochrane Library (Issue 3, 2008), and the TRIP Database (up to September 1, 2008), using no language or other limits. Randomized controlled trials were included that consisted of patients with refractory DME, those comparing IVTA injection with no treatment or STTA injection, those reporting VA outcomes, and those having a minimum follow-up of 3 months. RESULTS In the 4 randomized clinical trials comparing IVTA injection with placebo or no treatment, IVTA injection demonstrated greater improvement in VA at 3 months, but the benefit was no longer significant at 6 months. Those who received IVTA injection had significantly higher IOP at 3 months and at 6 months. In the 2 randomized clinical trials comparing IVTA injection with STTA injection, IVTA injection demonstrated greater improvement in VA at 3 months, but not at 6 months. Intravitreal triamcinolone acetonide injection demonstrated no difference in IOP at 3 months or at 6 months. CONCLUSIONS Intravitreal triamcinolone acetonide injection is effective in improving VA in patients with refractory DME in the short-term, but the benefits do not seem to persist in the long-term. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Golimumab for uveitis.

Dear Editor: The off-label use of biological response modifiers for the treatment of clinically relevant uveitides has widely increased over the past years. Anti-tumor necrosis factor alpha (TNF) drugs have shown a remarkable efficacy when prescribed for those uveitides associated with select immune-mediated diseases such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), plaque psoriasis, ankylosing spondylitis (AS), Crohn’s disease, and ulcerative colitis. Golimumab (GLM), a fully human anti-TNF monoclonal antibody, was approved by the US Food and Drug Administration in 2009 for the use with methotrexate (MTX) in adults with moderate to severe active RA, and with or without MTX or other biologic disease-modifying anti-rheumatic drugs in adults with active PsA or active AS. Subcutaneous injection of GLM is administered 50-mg once a month. We report 2 cases of uveitis refractory to other anti-TNF agents who favorably responded to GLM.

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.

Systematic Review of Anti-Tumor Necrosis Factor-alpha Therapy for Treatment of Immune-mediated Uveitis

Purpose: To establish evidence-based recommendations regarding the use of anti-Tumor Necrosis Factor alpha (TNF-α) agents for managing uveitis patients. Methods: Medline was searched via OVID (1950 – October Week 3, 2011) using a Cochrane highly sensitive search (phases 1 and 2). Additional literature searches were also conducted incuding the following databases: the Cochrane, LILACS and the TRIP Database. Results: A total of 54 studies met all of the inclusion criteria and were included in this review. A different level of recommendation and evidence is assigned to each anti-TNF-α agent. The overall rate of reported side effects with anti-TNF-α agents for the treatment of uvetis which required discontinuation of therapy was 2.2% (26/1147 patients). Conclusion: Based on the evidence gathered, infliximab and adalimumab seem to be effective in the management of immune-mediated uveitis. Further randomized studies evaluating the efficacy of these agents are warranted.

Adalimumab specifically induces CD3 + CD4 + CD25 high Foxp3 + CD127 − T-regulatory cells and decreases vascular endothelial growth factor plasma levels in refractory immuno-mediated uveitis: a non-randomized pilot intervention study

AimTo explore immunoregulatory and anti-inflammatory pathways specifically targeted by a subcutaneous anti-TNFαdrug—adalimumab—which might be relevant for controlling refractory uveitis.DesignNon-randomized pilot intervention study on the effects of adalimumab on Treg populations and plasma VEGF levels in refractory uveitis patients. Inflammatory and immunological parameters were measured in 12 patients before therapy, and 1 and 6 months after therapy, and analyzed in the context of ophthalmological outcomes. The results were compared with those obtained in 10 systemic prednisone-treated uveitis patients.ResultsAfter 1 month of treatment, all patients responded, with 67% of adalimumab group and 80% of the corticosteroid group achieving inactivity (P=0.5). Unlike steroid-treated patients, a significant increase in T-regulatory CD4+ CD25high Foxp3+ CD127− cells was observed in adalimumab patients after 1 month of treatment, and maintained after 6 months (P=0.003). A significant adalimumab-specific drop in plasma VEGF was observed after 1 and 6 months of treatment (P=0.019). In every single patient, Tregs but not VEGF correlated with disease activity.ConclusionsIn refractory uveitis patients treated with adalimumab, clinical efficacy may be mediated through upregulation of Tregs in addition to modulation of VEGF-mediated inflammatory pathways. These biological properties, which were not observed in patients treated with corticosteroids, may reflect the specificity of TNF-αtargeting.

Anti-tumor necrosis factor-α therapy in uveitis.

Since the first reported use in 2001 of an anti-tumor necrosis factor-alpha (TNF-α) agent, infliximab, for the treatment of uveitis, several new anti-TNF-α agents have emerged for the treatment of refractory noninfectious uveitides, although their use remains off-label in the US. These agents have demonstrated remarkable clinical antiinflammatory efficacy and a potential immunoregulatory role in selected uveitis patients, but it is currently unclear whether they can modify the natural history of disease. We review the rationale and clinical indications for this therapy, the differences between agents, how to manage dosing and intervals, and how to screen for and identify potential side effects. We also present a summary of the science behind the use of anti-TNF-α agents in ocular inflammation and the evidence for their efficacy.

Combined therapy of cyclosporine A and mycophenolate mofetil for the treatment of birdshot retinochoroidopathy: a 12-month follow-up

Purpose To retrospectively report a 12-month follow up for combined therapy with systemic cyclosporine A (CSA) and mycophenolate mofetil (MM) in treatment of patients with birdshot retinochoroidopathy (BSRC). Participants Ninety-eight eyes of patients who received CSA and MM for the treatment of BSRC were included in the study. Methods All patients were followed for at least five visits during the study, or until treatment failure, or loss of follow-up. Clinical data were analysed using a Student paired t-test, Wilcoxon signed-rank test, McNemars test, and Kaplan -Meier survival curve. Side effects related to therapy were also recorded. Main outcome measures included best-corrected logarithm of the minimum angle of resolution visual acuity, vitreous inflammation, fluorescein angiography pathologic features, and electroretinogram recordings. Results Vitreous inflammation scores at baseline and at 1 year were statistically significantly reduced in both eyes (p<0.001; p=0.001). The presence of angiographic leakage at the 1-year follow-up was significantly reduced (p=0.004). However, the presence of cystoid macular oedema (p=0.32) and comparison of electroretinogram 30-Hz amplitude revealed no significant reduction between baseline and 1-year values for either eye (p=0.61, p=0.87); nonetheless, 30-Hz implicit times were statistically significantly shorter at the end of follow-up for both eyes (p<0.001, p=0.035). Thirty-one patients (67.4%) achieved inflammation control at the 1-year endpoint. Side effects were transient, and resolved after lowering or withholding IMT for a few weeks in the majority of patients. Conclusions These results suggest that combined IMT with CSA and MM for BSRC is well tolerated and associated with long-term control of inflammation.

Systemic Immunomodulatory Therapy in Severe Dry Eye Secondary to Inflammation

Purpose: To report four patients with unusually severe acute keratitis sicca secondary to lacrimal tissue and ocular surface inflammation who eventually required systemic immunosuppressive therapy. Methods: Observational case series of four patients with extremely severe acute dry eye syndrome who were profoundly disabled by pain and photophobia (to the extent of staying in dark rooms) despite aggressive conventional therapy. Clinical data including visual acuities, other treatments administered for dry eye, systemic medical conditions, Schirmer and rose bengal staining results, degree of conjunctival injection, and medications were recorded. All four patients were treated with systemic immunomodulatory therapy. Results: All four patients were female with a mean age at presentation of 40 years (range 22–58 years), and all had systemic autoimmune diseases: systemic lupus erythematosus (SLE) and Sjogrens syndrome (n = 2), Sjogrens syndrome (n = 1), rheumatoid arthritis (RA) and psoriasis (n = 1). Schirmer test values at onset ranged from 0 to 2 mm. All patients had failed aggressive lubrication, topical cyclosporine, lid care, and punctual plugs. In two patients, serum tears and hyphrecation punctal occlusion were tried without success. Various systemic immunosuppressive agents were used to control inflammation of the lacrimal glands: methotrexate and cyclosporine A (patient 1), cyclosporine A (patient 2), prednisone (patient 3), and methotrexate and infliximab (patient 4). Treatment with systemic immunomodulatory agents resulted in resolution of the acute inflammatory assault on the lacrimal glands and control of signs and symptoms of keratoconjunctivitis sicca in all four patients, and visual acuities improved in all of them. Post-treatment Schirmer values ranged from 7 to 10 mm. Conclusion: Systemic immunosuppressive agents may be required in the treatment of recalcitrant primary and secondary Sjogrens syndrome caused by systemic autoimmune conditions. We show that systemic immunomodulatory therapy leads to significantly improved tear production and resolution of the keratoconjunctivitis in these rare but severe cases.

Usefulness of Adalimumab in the Treatment of Refractory Uveitis Associated with Juvenile Idiopathic Arthritis

Purpose. To assess the efficacy and safety of adalimumab in patients with juvenile idiopathic arthritis (JIA) and associated refractory uveitis. Design. Multicenter, prospective case series. Methods. Thirty-nine patients (mean [SD] age of 11.5 [7.9] years) with JIA-associated uveitis who were either not responsive to standard immunosuppressive therapy or intolerant to it were enrolled. Patients aged 13–17 years were treated with 40 mg of adalimumab every other week for 6 months and those aged 4–12 years received 24 mg/m2 body surface. Results. Inflammation of the anterior chamber (2.02 [1.16] versus 0.42 [0.62]) and of the posterior segment (2.38 [2.97] versus 0.35 [0.71] decreased significantly between baseline and the final visit (P < 0.001). The mean (SD) macular thickness at baseline was 304.54 (125.03) μ and at the end of follow-up was 230.87 (31.12) μ (P < 0.014). Baseline immunosuppression load was 8.10 (3.99) as compared with 5.08 (3.76) at the final visit (P < 0.001). The mean dose of corticosteroids also decreased from 0.25 (0.43) to 0 (0.02) mg (P < 0.001). No significant side effects requiring discontinuation of therapy were observed. Conclusion. Adalimumab seems to be an effective and safe treatment for JIA-associated refractory uveitis and may reduce steroid requirement.