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The role of biologics in non-infectious uveitis
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Non-infectious uveitis (NIU) comprises a heterogeneous group of inflammatory diseases of the uvea and is commonly believed to result from an imune-mediated response to ocular antigens. Complications of uveitis can be sight-threatening, severely impairing quality of life (QoL). Hence, NIU brings a significant burden for both healthcare systems and affected patients, who tend to be young and professionally active. Regarding the treatment of NIU, the ultimate treatment goal is to reduce ocular inflammation, thus preventing damage to ocular structures and consequent vision loss. Although corticosteroids are the mainstay of therapy, such drugs are often incapable of proper inflammation control and have long-term systemic side effects. Therefore, systemic immunomodulatory treatment, including conventional synthetic (csDMARDs) and biological disease modifying anti-rheumatic drugs (bDMARDs), is currently considered in the therapeutic stepladder approach. Despite scarce evidence on the use of systemic immunomodulatory therapy in NIU, bDMARDs are placed at the top of the treatment algorithms, with evidence supporting its efficacy and safety.
Encompassed in bDMARDs, tumour necrosis factor-inhibitors (TNFi) are still used off-label for NIU, except adalimumab (ADA), which has recently been approved for adult non-infectious intermediate, posterior uveitis and panuveitis dependent on and/or resistant to corticosteroids and paediatric chronic NIU. However, some patients present incomplete response and/or intolerance to ADA. Also, most of the available evidence does not come from real-world conditions, and almost all published trials and/or case series focusing on the role of bDMARDs in NIU exclude anterior NIU, for which high-quality evidence is still lacking. Thus, a gap in the existing knowledge has been identified regarding the role of bDMARDs in
NIU.
In this dissertation, which includes four chapters (Introduction, Results, Integrated Discussion and Scientific and Personal Acknowledgements), we sought to provide novel multiapproach insights into the treatment of NIU with bDMARDs. Our specific aims were: i) to provide state-of-the-art evidence for the use of TNF inhibitors (TNFi) in current and future clinical practice (considering novel drug delivery routes), ii) to describe the bDMARDs’ positioning in the NIU treatment algorithm developed by Portuguese ophthalmologists and rheumatologists and generate national guidelines on the use of bDMARDs in this disease, iii) to present real-world evidence on the role of anti-TNF in NIU (first, by studying the currently only approved drug for NIU [ADA], and then, by exploring the role of another TNFi (golimumab, [GLM]) in the treatment and prevention of uveitis flares in an underlying systemic inflammatory disease, and iv) to develop a ground-breaking tool to pave the way for future research.
Encompassed by the first aim of this thesis, we described the state-of-the-art role of bDMARD therapy in NIU using systematic approaches. In the first systematic review and meta-analysis, we assessed the efficacy and safety of TNFi drugs for chronic adult NIU. We concluded that there is high-quality evidence demonstrating that ADA decreases the risk of worsening visual acuity (VA) in active and inactive NIU and very low-quality evidence that the risk of etanercept (ETN) worsening VA in inactive NIU is no different from placebo.
With regard to the risk of drug withdrawal, moderate quality evidence suggests that TNFi drugs are not different from placebo. The second approach included a systematic review investigating the role of a possible intravitreal administration of TNFi drugs in view of minimising patient morbidity and systemic adverse effects while maintaining therapeutic effectiveness. Since the available evidence is not sufficiently solid to draw a conclusion on the clinical effectivity of intravitreal TNFi in NIU, no recommendations can be made. The intravitreal injection of TNFi remains a possible treatment option to be explored through robust clinical investigation.
To unveil the national positioning of bDMARDs in the NIU treatment algorithm and to emanate valuable recommendations, the second aim of this thesis was built through collaborative multidisciplinary work. Applied to the case of juvenile idiopathic arthritis associated-uveitis (JIA-U), and through a systematic literature review, we performed a national ophthalmologists’ and paediatric rheumatologists’ consensus following a modified Delphi approach. This document, which represents a coordinated effort at a national level, delivers a comprehensive and easy-to-read systematic review on the topic and 26 guidelines focusing on the following topics: general management (3), screening and follow-up of uveitis (4), treatment (17) and health education in JIA-U among patients and families (2). These guidelines were designed to support the shared medical management of patients with JIA-U and to emphasise the imperative need for a multidisciplinary approach in Ophthalmology and Paediatric Rheumatology.
Two real-world studies addressed the third aim of this thesis. The first project, a retrospective study on the role of TNFi according to the European label in adults with NIU, used real-world data from the Manchester Uveitis Clinic, including efficacy, safety, ability to spare corticosteroids and predictors of response. To permit comparisons with published evidence, while acknowledging heterogeneity in the study cohorts, we used established composite treatment failure endpoints as the primary goal, as used in VISUAL studies. This study included 51 patients (102 eyes). Treatment failure occurred in 9/51 patients (10 eyes) after six months and 13/51 (20 eyes) patients after 12 months. The need for rescue treatment in the 12 months before ADA was significantly associated with treatment failure at 12 months (p<0.05). The mean prednisolone dosage was <10 mg/day at 6 and 12 months. There were no serious adverse events. Patients with NIU who received ADA therapy for 12 months were likely to achieve disease control, stabilise or improve VA, experience a reduction in immunosuppression and reduce corticosteroid dosage. The GO-VISION observational study (VISION-related quality of life in spondyloarthritis [SpA] patients with a history of acute anterior uveitis under treatment with GOlimumab) was also developed under the scope of the third aim of this thesis and assessed health-related QoL (HRQoL) outcomes for the first time as the primary endpoint of a prospective study in NIU.
The GO-VISION study was able to prospectively explore the efficacy of an additional TNFi drug (GLM) in acute anterior uveitis (AAU) recurrence in patients with SpA, including the description of the efficacy, safety and change in general HRQoL and vision-related QoL (VRQoL). By the time of this thesis completion, this study was still ongoing, and we herein present an interim analysis. During the first six months of GLM treatment, the AAU incidence rate was reduced from 1.54 to 0.11 per 100 patient-years (incidence rate-ratio 13.46, 95% CI 2.15–558.00; p < 0.01). At baseline and 24 weeks after GLM onset, the overall mean index National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) total score was 70.2 and 83.2, respectively; improvement in the NEI VFQ-25 total score was +13±18.2. Preliminary data from the GO-VISION study suggest that GLM is safe and effective in patients with SpA and history of AAU, reducing the AAU occurrence rate and potentially increasing QoL.
As a closure to our efforts and imbued with the hindrances we experienced in gathering data for the two observational studies, in the fourth aim, we created an innovative platform, called Uveite.pt, which enables follow-up of uveitis patients at a countrywide level. Working as a fully structured electronic medical record, the platform provides robust evidence in this infrequent disease. The usefulness of Uveite.pt was further confirmed in a proof-of concept paper, which included the description of our multidisciplinary clinic and demonstrated the added value of the tool in a dedicated, real-world NIU setting. This platform can be utilised for both clinical practice and future research.
In conclusion, not only does this thesis provide new evidence of the current challenges in NIU management, but it also unveils the blossoming future ofbDMARD therapy over the next few years, and hopefully nourishes future research with Uveite.pt.
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Palavras-chave
uveíte não infeciosa fármacos antirreumáticos modificadores da doença biológicos algoritmo de tratamento qualidade de vida registo clínico non-infectious uveitis biological disease-modifying antirheumatic drugs treatment algorithm quality of life clinical registry