Estudio clínico e inmunológico de la acción de adalimumab en el tratamiento de las uveítis inmunomediadas refractarias

[ES] Objetivos Analizar los efectos clínicos (eficacia terapéutica) que el tratamiento con un agente anti-factor de necrosis tumoral-alpha (TNF-alpha) (adalimumab) produce al emplearse en el manejo de pacientes con diversos tipos de uveítis inmuno-mediada refractarias. Determinar y evaluar algunas de las vias de actuación, antiinflamatorias e inmunoreguladoras, utilizadas por adalimumab para generar los efectos clínicos observados. Para ello se estudiará el efecto de adalimumab sobre la respuesta inmune celular, así como el efecto sobre el perfil plasmático de las principales citoquinas, quimioquinas y reactantes de fase aguda implicadas en la inflamación intraocular. Además se estudiará la posible correlación entre los posibles efectos inmunomoduladores inducidos por adalimumab y la respuesta clínica del individuo a dicha terapia. Material y métodos Estudio prospectivo observacional no-randomizado de casos y controles de 6 meses de duración. Se incluyeron 22 pacientes con diversos subtipos de uveítis inmuno-mediadas que se asignaron a 2 grupos de tratamiento sistémico (adalimumab o esteroides).Se seleccionó además un grupo de 25 pacientes sanos con edades comparables para ser utilizados como controles. Adalimumab (Humira ®), anticuerpo monoclonal humano anti-TNF-alpha se seleccionó como terapia de rescate en uno de los grupos (12 pacientes) con uveítis refractarias a tratamiento inmunosupresor convencional. Todos ellos recibieron 40mg de adalimumab subcutáneo cada 14 días sin modificación de la pauta de tratamiento durante el periodo de estudio. En el grupo restante (10 pacientes), con historia de al menos 2 brotes de uveítis inmuno-mediada, se empleó prednisona a una dosis inicial de 1mg/Kg al día, que fue lentamente descendida en función de la actividad inflamatoria del cuadro ocular. Todos los pacientes fueron evaluados clínicamente en tres ocasiones (al menos) durante el estudio. Respecto a la evaluación inmunológica, se evaluaron 2 muestras en el grupo de pacientes con uveítis: Una obtenida inmediatamente antes de iniciar el tratamiento (t0), y otra obtenida al mes de iniciar el tratamiento (t1). En el grupo de pacientes tratados con adalimumab se obtuvo una tercera muestra a los 6 meses de iniciar el tratamiento (t2). Resultados Un 66% (8/12) de los pacientes tratados con adalimumab experimentaron un control de la inflamación (biomicroscópico, angiográfico y por OCT) a t1, que se extendió al resto de los pacientes tratados con este fármaco (12/12) a los tres meses de tratamiento. Tras 6 meses de seguimiento (t2), sólo un 25% (3/12) de los pacientes del grupo tratado con adalimumab sufrieron alguna recaída. El estudio inmunológico de los efectos del tratamiento sobre la respuesta inmune celular reveló una ausencia de cambios sobre los valores basales (que a su vez no diferían entre los pacientes asignados a los dos grupos de tratamiento) de las poblaciones de linfocitos T CD4 y CD8 y linfocitos B. Tras un mes de tratamiento con adalimumab (a t1), la mediana de los niveles de linfocitos T-reguladores (CD3+ CD4 + CD25+high FoxP3+ CD127-) se incrementó significativamente sobre los niveles basales (a t0, p=0.003), y permaneció elevada tras 6 meses de tratamiento (a t2, p=0.003). Sin embargo no se observó ningún efecto en los niveles de la población de T-regs en los pacientes del grupo tratado con esteroides (p=0.67). El estudio inmunológico sobre la respuesta inmune inflamatoria incluyó el estudio de diversos reactantes de fase aguda (amiloide sérico A, proteína C reactiva) así como numerosas citoquinas (IL-1ß, IL-6, IL-10, IL-12p70, IL-17A, TNF-alpha y VEGF) y quimioquinas (MIG, IP-10, MCP-1). Este estudio reveló niveles basales elevados de IL-1ß, IL-6, IL-10, TNF-alpha, IL-12 e IL-22 en el grupo de pacientes con uveítis (n=22) que no se observaban en los controles sanos (n=25). Tras 1 mes de tratamiento (a t1), y sólo en el grupo de adalimumab (efecto específico de este tratamiento), se produjo un descenso significativo en las medianas de los niveles séricos de IL-6, IL-12p70, IL-22 y VEGF. También se produjo un descenso significativo de MIG sólo en este grupo. No hubo cambios en el resto de citoquinas, quimioquinas ni en los reactantes de fase aguda.. Tras 6 meses de tratamiento (a t2), las medianas de niveles séricos de IL-22, IL-12p70, VEGF y MIG habían descendido aún más al compararlas con t1. Sin embargo, IL-6 permanecía a niveles similares al compararla con los niveles basales. Finalmente, la mediana de niveles séricos de IL-10 estaba ahora significativamente descendida al compararla con los niveles basales. No se observaron cambios significativos en las otras citoquinas (IL-1ß, IL-17A y TNF-alpha), quimioquinas ni en los reactantes de fase aguda. Conclusiones Adalimumab es una opción terapeútica aparentemente eficaz y segura en el tratamiento de uveítis inmuno-mediadas que han sido refractarias a otros tratamientos. El tratamiento con adalimumab induce, de una forma específica e independiente de la enfermedad de base, una regulación de la respuesta inmune a varios niveles (celular y humoral). En la respuesta inmune celular, adalimumab induce un aumento de T-regs que se correlaciona con la mejoría clínica y que persiste en el tiempo. El empeoramiento clínico de los pacientes tratados con adalimumab coincide con un descenso de T-regs. En la respuesta inmune inflamatoria, adalimumab induce un descenso de IL-22 que se correlaciona con la mejoría clínica y que persiste en el tiempo. También induce un descenso de VEGF que se correlaciona con la mejoría clínica en un 50% de los pacientes. El resto de cambios (descenso de los niveles de IL-6, IL-12, IL-10 y MIG) no correlaciona con la evolución clínica de la uveítis

Golimumab as rescue therapy for refractory immune-mediated uveitis: a three-center experience

OBJECTIVE: To evaluate, in three Spanish tertiary referral centres, the short-term safety and efficacy of golimumab (GLM) for treatment of immune-mediated uveitis resistant to previous immunosuppressive therapy. METHODS: Nonrandomized retrospective interventional case series. Thirteen patients with different types of uveitis that were resistant to treatment with at least 2 previous immunosuppressors were included in this study. All included patients were treated with GLM (50 mg every four weeks) during at least 6 months. Clinical evaluation and treatment-related side effects were assessed at least four times in all included patients. RESULTS: Eight men and 5 women (22 affected eyes) with a median age of 30 years (range 20-38) and active immune-mediated uveitides were studied. GLM was used in combination with conventional immunosuppressors in 7 patients (53.8%). GLM therapy achieved complete control of inflammation in 12/13 patients (92.3%) after six months of treatment. There was a statistically significant improvement in mean BCVA (0.60 versus 0.68, P = 0.009) and mean 1 mm central retinal thickness (317 versus 261.2 µ, P = 0.05) at the six-month endpoint when compared to basal values. No major systemic adverse effects associated with GLM therapy were observed. CONCLUSIONS: GLM is a new and promising therapeutic option for patients with severe and refractory uveitis

Golimumab in refractory uveitis related to spondyloarthritis. Multicenter study of 15 patients

Objective: To assess the efficacy of golimumab (GLM) in refractory uveitis associated to spondyloarthritis (SpA). Methods: Multicenter study of SpA-related uveitis refractory to at least one immunosuppressive drug. The main outcome variables were degree of anterior and posterior chamber inflammation, visual acuity, and macular thickness. Results: Fifteen patients (13 men/2 women; 18 affected eyes; mean age 39±6 years) were evaluated. The underlying SpA subtypes were ankylosing spondylitis (n=8), psoriatic arthritis (n=6) and non-radiographic axial SpA (n=1). The ocular involvement patterns were recurrent anterior uveitis in 8 patients and chronic anterior uveitis in 7. Before GLM they have received methotrexate (n=13), sulfasalazine (n=6), pulses of methylprednisolone (n=4), azathioprine (n=3), leflunomide (n=2) and cyclosporine (n=1). Ten of them had also been treated with TNF-? blockers; etanercept (n=7), adalimumab (n=7), infliximab (n=6), and certolizumab (n=1). GLM was given at the standard dose (50 mg/sc/monthly) as monotherapy (n=7) or in combination with conventional immunosuppressive drugs (n=8), mainly methotrexate. Most patients had rapid and progressive improvement of intraocular inflammation parameters. The median number of cells in the anterior chamber at 2 years (0 [0-0]) was significantly reduced compared to baseline findings (1 [0-3]); p=0.04). The mean best corrected visual acuity value also improved (0.84±0.3 at 2 years versus 0.62±0.3 at baseline; p=0.03). Only minor side effects were observed after a mean follow-up of 23±7 months. Conclusions: Our results indicate that GLM may be a useful therapeutic option in refractory SpA-related uveitis

New insights into the genetic component of non-infectious uveitis through an Immunochip strategy

Background: Large-scale genetic studies have reported several loci associated with specific disorders involving uveitis. Our aim was to identify genetic risk factors that might predispose to uveitis per se, independent of the clinical diagnosis, by performing a dense genotyping of immune-related loci. Methods: 613 cases and 3693 unaffected controls from three European case/control sets were genotyped using the Immunochip array. Only patients with non-infectious non-anterior uveitis and without systemic features were selected. To perform a more comprehensive analysis of the human leucocyte antigen (HLA) region, SNPs, classical alleles and polymorphic amino acid variants were obtained via imputation. A meta-analysis combining the three case/control sets was conducted by the inverse variance method. Results: The highest peak belonged to the HLA region. A more detailed analysis of this signal evidenced a strong association between the classical allele HLA-A*2902 and birdshot chorioretinopathy (p=3.21E-35, OR=50.95). An omnibus test yielded HLA-A 62 and 63 as relevant amino acid positions for this disease. In patients with intermediate and posterior uveitis, the strongest associations belonged to the rs7197 polymorphism, within HLA-DRA (p=2.07E-11, OR=1.99), and the HLA-DR15 haplotype (DRB1*1501: p=1.16E-10, OR=2.08; DQA1*0102: p=4.37E-09, OR=1.77; DQB1*0602: p=7.26E-10, OR=2.02). Outside the HLA region, the MAP4K4/IL1R2 locus reached statistical significance (rs7608679: p=8.38E-07, OR=1.42). Suggestive associations were found at five other loci. Conclusions: We have further interrogated the association between the HLA region and non-infectious non-anterior uveitis. In addition, we have identified a new non-HLA susceptibility factor and proposed additional risk loci with putative roles in this complex condition

Comparative Study of Infliximab Versus Adalimumab in Refractory Uveitis Due to Behçet's Disease: National Multicenter Study of 177 Cases

Objective: To compare the efficacy of infliximab (IFX) versus adalimumab (ADA) as a first-line biologic drug over 1 year of treatment in a large series of patients with refractory uveitis due to Behçet's disease (BD). Methods: We conducted an open-label multicenter study of IFX versus ADA for BD-related uveitis refractory to conventional nonbiologic treatment. IFX or ADA was chosen as the first-line biologic agent based on physician and patient agreement. Patients received 3-5 mg/kg intravenous IFX at 0, 2, and 6 weeks and every 4-8 weeks thereafter, or 40 mg subcutaneous ADA every other week without a loading dose. Ocular parameters were compared between the 2 groups. Results: The study included 177 patients (316 affected eyes), of whom 103 received IFX and 74 received ADA. There were no significant baseline differences between treatment groups in main demographic features, previous therapy, or ocular sign severity. After 1 year of therapy, we observed an improvement in all ocular parameters in both groups. However, patients receiving ADA had significantly better outcomes in some parameters, including improvement in anterior chamber inflammation (92.31% versus 78.18% for IFX; P = 0.06), improvement in vitritis (93.33% versus 78.95% for IFX; P = 0.04), and best-corrected visual acuity (mean ± SD 0.81 ± 0.26 versus 0.67 ± 0.34 for IFX; P = 0.001). A nonsignificant difference was seen for macular thickness (mean ± SD 250.62 ± 36.85 for ADA versus 264.89 ± 59.74 for IFX; P = 0.15), and improvement in retinal vasculitis was similar between the 2 groups (95% for ADA versus 97% for IFX; P = 0.28). The drug retention rate was higher in the ADA group (95.24% versus 84.95% for IFX; P = 0.042). Conclusion: Although both IFX and ADA are efficacious in refractory BD-related uveitis, ADA appears to be associated with better outcomes than IFX after 1 year of follow-up

Two functional variants of IRF5 influence the development of macular edema in patients with non-anterior uveitis.

Objective Interferon (IFN) signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5), a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated IRF5 genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes. Methods Three IRF5 polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin. Results A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (PFDR=5.07E-03, OR=1.48, CI 95%=1.14-1.92 and PFDR=3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively). Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: P=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: P=0.030, OR=0.67, CI 95%=0.47-0.96), thus suggesting that both IRF5 genetic variants are specifically associated with the lack of macular edema in uveitis patients. Conclusion Our results clearly showed for the first time that two functional genetic variants of IRF5 may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies

Development of an activity disease score in patients with uveitis (UVEDAI)

To develop a disease activity index for patients with uveitis (UVEDAI) encompassing the relevant domains of disease activity considered important among experts in this field. The steps for designing UVEDAI were: (a) Defining the construct and establishing the domains through a formal judgment of experts, (b) A two-round Delphi study with a panel of 15 experts to determine the relevant items, (c) Selection of items: A logistic regression model was developed that set ocular inflammatory activity as the dependent variable. The construct "uveitis inflammatory activity" was defined as any intraocular inflammation that included external structures (cornea) in addition to uvea. Seven domains and 15 items were identified: best-corrected visual acuity, inflammation of the anterior chamber (anterior chamber cells, hypopyon, the presence of fibrin, active posterior keratic precipitates and iris nodules), intraocular pressure, inflammation of the vitreous cavity (vitreous haze, snowballs and snowbanks), central macular edema, inflammation of the posterior pole (the presence and number of choroidal/retinal lesions, vascular inflammation and papillitis), and global assessment from both (patient and physician). From all the variables studied in the multivariate model, anterior chamber cell grade, vitreous haze, central macular edema, inflammatory vessel sheathing, papillitis, choroidal/retinal lesions and patient evaluation were included in UVEDAI. UVEDAI is an index designed to assess the global ocular inflammatory activity in patients with uveitis. It might prove worthwhile to motorize the activity of this extraarticular manifestation of some rheumatic diseases

Guidance on Noncorticosteroid Systemic Immunomodulatory Therapy in Noninfectious Uveitis : Fundamentals Of Care for UveitiS (FOCUS) Initiative

Supplemental material available at www.aaojournal.org. Supported by AbbVie, Inc., and the Fundamentals of Care for Uveitis Initiative National Faculty. This manuscript was developed subsequent to an AbbVie-sponsored literature review of noninfectious, nonanterior uveitis. The meeting was conducted to understand the available literature regarding the management of patients with noninfectious, nonanterior uveitis. The program involved a total of 139 experts from 28 countries, who were selected for participation by AbbVie. However, AbbVie was not involved in the development of the manuscript. The authors maintained complete control over the content and this manuscript reflects the opinions of the authors. AbbVie selected the discussion participants and reviewed the final manuscript draft for scientific accuracy, but the authors determined the final content. All authors made substantial contributions to the article or critically revised it for important intellectual content and approved the final manuscript. AbbVie provided funding to invited participants, including honoraria for their attendance at the meetings. Travel to and from the meetings was reimbursed. No payments were made to the authors for the development of this manuscript. Dhinakaran Sambandan, PhD, and Shula Sarner, PhD, of Lucid Partners, Burleighfield House, Buckinghamshire, United Kingdom, provided medical writing and editorial support to the authors in the development of this manuscript; financial support for these services was provided by AbbVie. AbbVie reviewed the manuscript, but was not involved in the methodology, data collection and analysis, or completion of this manuscript.Peer reviewedPublisher PD

Long-term follow-up of certolizumab pegol in uveitis due to immune-mediated inflammatory diseases: multicentre study of 80 patients

Objectives: To evaluate effectiveness and safety of certolizumab pegol (CZP) in uveitis due to immune-mediated inflammatory diseases (IMID). Methods: Multicentre study of CZP-treated patients with IMID uveitis refractory to conventional immunosuppressant. Effectiveness was assessed through the following ocular parameters: best-corrected visual acuity, anterior chamber cells, vitritis, macular thickness and retinal vasculitis. These variables were compared between the baseline, and first week, first, third, sixth months, first and second year. Results: We studied 80 (33 men/47 women) patients (111 affected eyes) with a mean age of 41.6±11.7 years. The IMID included were: spondyloarthritis (n=43), Behçet's disease (n=10), psoriatic arthritis (n=8), Crohn's disease (n=4), sarcoidosis (n=2), juvenile idiopathic arthritis (n=1), reactive arthritis (n=1), rheumatoid arthritis (n=1), relapsing polychondritis (n=1), CONCLUSIONS: CZP seems to be effective and safe in uveitis related to different IMID, even in patients refractory to previous biological drugs.Funding: This work was also partially supported by RETICS Programmes, RD08/0075 (RIER) and RD12/0009/0013 from 'Instituto de Salud Carlos III' (ISCIII) (Spain)