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Monthly Intravitreal Infliximab in Behçet's Disease Active Posterior Uveitis: A Long-Term Safety Study
Abstract
Purpose:
To study the safety of extended monthly intravitreal infliximab injections in patients with active posterior uveitis in Behcet's disease (APUBD).
Methods:
This is a prospective, interventional, noncomparative, open-label, pilot study of 9 monthly intravitreal infliximab injections (1mg/0.05ml) for twenty-two eyes of 16 patients with APUBD. Control of inflammation and visual outcomes were assessed, and ocular complications were monitored during the study period.
Results:
Successful treatment was achieved in 7 eyes (35%) and failure was encountered in 13 eyes (65%). Only seven eyes of 6 patients (35%) had completed the study and achieved complete resolution of inflammation with improved BCVA, and no complications. Failure was either due to inability to control the inflammation in 9 eyes (45%) or development of exacerbation of inflammation in 4 eyes (20%). Four eyes developed severe immunological reaction from the drug following first (n=1), second (n=2), and third (n=1) injections and had to discontinue the injections. Kaplan-Meier survival analysis showed that the mean estimated time to failure was 3.3±0.2 months and all failed eyes required revision of their systemic immunotherapy to control the ocular inflammation.
Conclusion:
Intravitreal infliximab for APUBD was associated with a high complication rate and failure to control inflammation in the majority of eyes. It should not be considered a substitute to systemic therapy.
... Intravitreal administration of IFX has been investigated as an alternative route of administration. However, it has not demonstrated significant superiority over systemic administration with possible adverse events associated with intravitreal IFX administration including mainly severe immunological reactions leading thus to treatment discontinuation [86,87]. ...
... At 18 weeks of follow-up, they observed statistically significant improvements in mean visual acuity, reductions in mean central macular thickness, and decreased mean vitreous haze scores. In contrast, an open-label study of monthly intravitreal IFX injections reported a high ocular complication rate and failure to control BD uveitis, leading the authors to advice against this approach [38]. Studies have discovered that excessively high IFX concentrations in the vitreous cavity may provoke uveitis because of immune response; therefore, this therapy is recommended as an alternative treatment for patients who cannot tolerate systemic IFX medication [36]. ...
Behçet's uveitis (BU), a vision-threatening manifestation of Behçet's disease, poses substantial management challenges due to its chronic, relapsing nature and potential for vision loss. This review explores the role of biologic therapies in the treatment of BU, providing a comprehensive overview of their effectiveness, drawbacks, and future possibilities. Traditionally, management has relied heavily on corticosteroids and conventional immunosuppressants. However, their long-term use is frequently associated with systemic side effects and insufficient control of ocular inflammation. Biologic therapies, particularly TNF-alpha inhibitors like infliximab and adalimumab, have emerged as effective alternatives, offering better disease control and a more favorable safety profile. We critically evaluated these agents, noting their clinical efficacy in reducing inflammatory flares and preserving visual acuity. Despite their benefits, several issues remain. Accessibility, cost, and lack of long-term safety data limit their widespread use. Additionally, individual variability in treatment response necessitates personalized therapeutic strategies. Recent research has shown promise in addressing these challenges, with the emergence of novel biologic agents and personalized medicine approaches. In summary, biologic therapies represent a paradigm shift in BU management, contributing to better patient outcomes. Yet, there are significant challenges to be overcome. As we move forward, continued research, development of novel biologic agents, and a precision medicine approach will shape the future landscape of BU treatment.
... However, conflicting results regarding its safety and efficacy have been published in a study of 16 patients. Four eyes developed a severe immunological reaction and failure to control inflammation was described in the majority of eyes [78]. Intravitreal adalimumab was not successful in chronic refractory cystoid macular edema [79]. ...
Uveitis in Behçet’s disease (BD) is frequent (40% of cases) and is a major cause of morbidity. The age of onset of uveitis is between 20 and 30 years. Ocular involvement includes anterior, posterior, or panuveitis. Uveitis may be the first sign of the disease in 20% of cases or it may appear 2 or 3 years after the first symptoms. Panuveitis is the most common presentation and is more commonly found in men. Bilateralization usually occurs on average 2 years after the first symptoms. The estimated risk of blindness at 5 years is 10–15%. BD uveitis has several ophthalmological features that distinguish it from other uveitis. The main goals in the management of patients are the rapid resolution of intraocular inflammation, the prevention of recurrent attacks, the achievement of complete remission, and the preservation of vision. Biologic therapies have changed the management of intraocular inflammation. The aim of this review is to provide an update to a previous article by our team on pathogenesis, diagnostic approaches, and the therapeutic strategy of BD uveitis.
... The reported improvement in clinical parameters places intravitreal IFX as a promising strategy in the treatment of ocular inflammation. However, previous results differ from recent findings of severe immunological reactions and a high percentage of therapeutic failure after intravitreal administration of IFX in patients with posterior uveitis associated with Behçet's disease [118]. Furthermore, evidence of an inflammatory reaction and a strong suggestion of retinotoxicity to intravitreal IFX were shown in a pilot safety study of patients with diabetic macular oedema or choroidal neovascularization secondary to age-related macular degeneration who failed conventional therapies [119]. ...
Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the most widely used anti-TNFα drugs, have led to greater clinical benefits, but a significant fraction of patients with NIU do not respond to these drugs. The therapeutic outcome is closely related to systemic drug levels, which are influenced by several factors such as immunogenicity, concomitant treatment with immunomodulators, and genetic factors. Therapeutic drug monitoring (TDM) of drug and anti-drug antibody (ADAbs) levels is emerging as a resource to optimise biologic therapy by personalising treatment to bring and maintain drug concentration within the therapeutic range, especially in those patients where a clinical response is less than expected. Furthermore, some studies have described different genetic polymorphisms that may act as predictors of response to treatment with anti-TNFα agents in immune-mediated diseases and could be useful in personalising biologic treatment selection. This review is a compilation of the published evidence in NIU and in other immune-mediated diseases that support the usefulness of TDM and pharmacogenetics as a tool to guide clinicians’ treatment decisions leading to better clinical outcomes. In addition, findings from preclinical and clinical studies, assessing the safety and efficacy of intravitreal administration of anti-TNFα agents in NIU are discussed.
... On the contrary, in a prospective open-label pilot study, monthly intravitreal infliximab injections (1 mg/0.05 mL) in patients with BD with active posterior uveitis were ineffective and associated with a high complication rate [152]. ...
Behçet’s disease is a rare and poorly understood vasculitis affecting blood vessels of all types and sizes. Uveitis and oral and genital ulcers represent the typical clinical triad. Populations along the ancient trading route connecting the Mediterranean basin with the Middle and Far East are most affected. Up to a quarter of the cases has a pediatric onset, typically around puberty. The aim of the treatment is early intervention to control inflammation, with symptom relief and prevention of relapses, damage, and complications. The heterogeneous clinical presentation often requires a multidisciplinary and tailored approach. Ocular, neurological, gastrointestinal, and vascular involvement is associated with a worse prognosis and needs more aggressive treatments. In young patients with expected prolonged disease, treatment should also focus on preventive measures and lifestyle advice. In recent years, the pharmacological armamentarium has grown progressively, although only a limited number of drugs are currently authorized for pediatric use. Most evidence for these drugs still derives from adult studies and experience; these are prescribed as off-label medications and are only available as adult formulations. Corticosteroids frequently represent the mainstay for the management of the initial acute phases, but their potential serious adverse effects limit their use to short periods. Different conventional disease-modifying anti-rheumatic drugs have long been used. Many other biologic drugs targeting different cytokines such as interleukin-1, interleukin-6, and interleukin-17 and treatments with small molecules including the phosphodiesterase 4 and Janus kinase inhibitors are emerging as novel promising therapeutic agents. In recent years, a growing interest has developed around anti-tumor necrosis factor agents that have often proven to be effective in severe cases, especially in those with a gastrointestinal and ocular involvement.
... In an open-label study of monthly intravitreal infliximab injections, the authors reported a high ocular complication rate and failure to control BD uveitis; therefore, such an approach was not recommended [55]. ...
Purpose of review:
Uveitis is a major manifestation of Behçet disease (BD) and potentially has a high morbidity. This article reviews recently published data on BD uveitis.
Recent findings:
A set of classification criteria and a diagnostic algorithm have been developed for BD uveitis. Recent reports have confirmed male predominance and posterior segment inflammation in the majority of BD uveitis patients. A high uveitis attack severity score, fluorescein angiographic leakage at the posterior pole, and disruption of outer retinal layers on optical coherence tomography (OCT) predict poor visual outcome. OCT-angiography studies have suggested subclinical changes of retinal capillaries in patients with or without ocular involvement. In a randomized controlled trial, interferon-α was superior to cyclosporine. Favorable outcomes were reported with earlier initiation, optimization, and withdrawal of infliximab after remission. Adalimumab as first-line was superior to conventional therapy.
Summary:
Classification criteria will be used to select a homogeneous group of patients for research and the diagnostic algorithm may help ophthalmologists predict the probability of BD uveitis based on ocular findings. Fluorescein angiography and OCT are the routine imaging modalities. Clinical relevance of OCT-angiography is unclear. Interferon-α, infliximab, and adalimumab have proven superior efficacy compared to conventional therapy.
... Current treatments for this kind of disease mainly rely on surgery and a variety of invasive techniques. However, the invasive routes of administration can be associated with complications such as ocular inflammation, subconjunctival hemorrhage, and other adverse reactions to the patients which lead to the poor compliance [11]. Topical administration is a convenient, self-administrable, and noninvasive way of drug delivery for the treatment of posterior diseases. ...
Nanomedicine and aptamer have excellent potential in giving play to passive and active targeting respectively, which are considered to be effective strategies in the retro-ocular drug delivery system. The presence of closely adjoined tissue structures in the eye makes it difficult to administer the drug in the posterior segment of the eye. The application of nanomedicine could represent a new avenue for the treatment, since it could improve penetration, achieve targeted release, and improve bioavailability. Additionally, a novel type of targeted molecule aptamer with identical objective was proposed. As an emerging molecule, aptamer shows the advantages of penetration, non-toxicity, and high biocompatibility, which make it suitable for ocular drug administration. The purpose of this paper is to summarize the recent studies on the effectiveness of nanoparticles as a drug delivery to the posterior segment of the eye. This paper also creatively looks forward to the possibility of the combined application of nanocarriers and aptamers as a new method of targeted drug delivery system in the field of post-ophthalmic therapy.
... However, contradictory results regarding its safety and efficacy have also been reported in a more recent study in 16 patients. Four eyes developed severe immunological reaction and failure to control inflammation was described in the majority of eyes [116]. Intravitreal adalimumab was not successful in chronic refractory cystoid macular edema, i.e., reduction of central retinal thickness and improvement of visual acuity [117]; no ocular or systemic adverse events were observed. ...
Behçet’s disease (BD) is a systemic vasculitis disease of unknown origin occurring in young people, which can be venous, arterial or both, classically occlusive. Ocular involvement is particularly frequent and severe; vascular occlusion secondary to retinal vasculitis may lead to rapid and severe loss of vision. Biologics have transformed the management of intraocular inflammation. However, the diagnosis of BD is still a major challenge. In the absence of a reliable biological marker, diagnosis is based on clinical diagnostic criteria and may be delayed after the appearance of the onset sign. However, therapeutic management of BD needs to be introduced early in order to control inflammation, to preserve visual function and to limit irreversible structural damage. The aim of this review is to provide current data on how innovations in clinical evaluation, investigations and treatments were able to improve the prognosis of uveitis associated with BD.
Panuveitis with retinal vasculitis is the main form of ocular involvement in Behçet’s disease. The disease course is marked by sudden-onset uveitis attacks and clinical remission periods between attacks. Hypopyon iridocyclitis, diffuse vitritis, retinal infiltrates, and occlusive retinal periphlebitis may be seen during uveitis attacks. Fundus fluorescein angiography may show diffuse retinal capillary leakage during quiescent periods which indicates a high risk of recurrent uveitis attacks. Increased frequency and severity of uveitis attacks as well as incidence of complications such as cystoid macular edema and foveal ischemia are associated with poor visual outcome. Fundus fluorescein angiography is the gold standard in monitoring Behçet’s disease uveitis. Complete angiographic remission should be achieved by adequate therapy in order to preserve visual function. Biologic agents should be used in high-risk cases because of their proven superiority to conventional immunosuppressive agents in the treatment of Behçet’s disease uveitis.
Purpose: To evaluate the outcomes of pars plana vitrectomy (PPV) for full thickness macular holes (FTMH) in ocular Behcet's disease. Methods: Eyes with FTMH as confirmed on optical coherence tomography in patients with active ocular Behcet's disease (AOBD) were included in this study. These eye had PPV, epiretinal membrane (ERM) removal, internal limiting membrane (ILM) peel, and a tamponade injection. Postoperative visual improvement and macular hole closure at 6 months was recorded. Results: Fifteen FTMHs in 14 patients with AOBD were included with a mean age of 29.3 years (25-38), and 13 were males. All patients presented best corrected visual acuity (BCVA) of 0.05 decimals or worse; mean 0.04±0.01(0.02-0.05). All eyes had PPV, 11 eyes needed phacoemulsification, and the ILM was not peeled in one eye. Three eyes had total retinal detachment (RD) and needed silicone oil as a tamponade, the rest received SF6. Macular hole closure was achieved in 14 eyes with a single intervention, and the failed eye had no ILM peel. In the 14 eyes with successful outcome a thick ERM and a thick ILM were noted and removed. All patients were followed up for at least six months; mean 13 months (6- 48). The mean BCVA improved to 0.15±0.02 decimals (0.1-0.4) in first 3 months in eyes with successful closure. All patients had recurrent activity in the follow up period and responded to systemic and regional treatment, but with visual loss due to macular ischemia, at 6 months BCVA was 0.06±0.03 decimals (0.03-0.07). Conclusion: FTMH can occur in AOBD and can progress to RD in the absence of myopia. PPV, ERM removal, ILM peel, and either gas or silicone oil injection gives excellent anatomical results with significant visual improvements. However, full visual recovery is frequently undermined by the associated retinal ischemia and recurrent inflammation.
Non-infectious uveitis (NIU) is one of the leading causes of sight impairment worldwide. Corticosteroids are the mainstay treatment for acute NIU, although their known systemic and ocular side effects limit their long-term use. The most common types of immunosuppressants used as steroid-sparing treatment are non-biologic drugs, particularly antimetabolites (methotrexate, mycophenolate mofetil, and azathioprine) and biologic drugs, mainly TNF-α inhibitors such as Adalimumab or Infliximab. Antimetabolites have shown their effectiveness in the treatment of NIU in individual and comparative studies, being methotrexate and mycophenolate mofetil usually preferred over azathioprine. The choice of which antimetabolite to use at first is not well defined, and decisions usually depend on the patient's characteristics and the physician's preferences. Treatment of NIU with biologic drugs, and particularly TNF-α inhibitors, has significantly increased in the last years and is considered an important alternative in patients not responding to first-line immunomodulators such as antimetabolites. However, data regarding how different immunomodulators or biologic drugs perform in different NIU is still limited, and little is known about the optimization of both biologic and non-biologic drugs when used in NIU. Further randomized clinical trials and comparative studies are required to achieve more understanding and better results when addressing complicated NIU. The purpose of this review is to provide a comprehensive overview of the use of non-biologic and biologic drugs in NIU, which may be useful for clinicians in their daily practice, and to address those aspects that are less known about these treatments as well as their weaknesses.
Millions of people worldwide have hereditary genetic disorders, trauma, infectious diseases, or cancer of the eyes, and many of these eye diseases lead to irreversible blindness, which is a major public health burden. The eye is a relatively small and immune-privileged organ. The use of nucleic acid-based drugs to manipulate malfunctioning genes that target the root of ocular diseases is regarded as a therapeutic approach with great promise. However, there are still some challenges for utilizing nucleic acid therapeutics in vivo because of certain unfavorable characteristics, such as instability, biological carrier-dependent cellular uptake, short pharmacokinetic profiles in vivo (RNA), and on-target and off-target side effects (DNA). The development of lipid nanoparticles (LNPs) as gene vehicles is revolutionary progress that has contributed the clinical application of nucleic acid therapeutics. LNPs have the capability to entrap and transport various genetic materials such as small interfering RNA, mRNA, DNA, and gene editing complexes. This opens up avenues for addressing ocular diseases through the suppression of pathogenic genes, the expression of therapeutic proteins, or the correction of genetic defects. Here, we delve into the cutting-edge LNP technology for ocular gene therapy, encompassing formulation designs, preclinical development, and clinical translation.
Objective:
To study the safety and efficacy of intravitreal infliximab administered at the conclusion of pars plana vitrectomy (PPV) in the treatment of proliferative vitreoretinopathy (PVR) associated with rhegmatogenous retinal detachment (RRD).
Design:
Randomized controlled phase II clinical trial.
Subjects:
Patients with primary RRD and grade C PVR, according to the updated Retina Society Classification.
Methods:
Sixty-six patients were randomized in a 1:1 ratio to undergo PPV and silicone oil (SO) injection with or without intravitreal injection of 1 mg/0.05 mL of infliximab in the air-filled globe before SO injection at PPV conclusion. Surgeons were masked to treatment allocation until PPV conclusion.
Main Outcome Measures
The primary outcome measure was anatomic success (defined as complete retinal reattachment without a tamponade at 6 months post SO removal). Secondary outcome measures were final best-corrected visual acuity (BCVA), single-operation success rate (SOSR), rate of recurrent detachment, central macular thickness (CMT) by macular OCT, macular function by multifocal electroretinogram, and macular vascular density (VD) by OCT angiography.
Results:
Sixty eyes of 60 patients, 30 eyes in each group, completed the study. At baseline, there were no differences regarding age, gender, history of trauma, lens status, duration of RRD, BCVA, intraocular pressure (IOP), intraocular inflammation (IOI), detachment extent in clock hours, number/size of breaks, presence of vitreous hemorrhage, axial length, or grade/extent of PVR between both groups. For the outcome measures, 30 eyes in the infliximab group achieved anatomic success vs. 29 eyes in the control group. The SOSR was higher in the infliximab group (26) vs. the control (23), but this was not statistically significant (P = 0.317). Final logarithm of the minimum angle of resolution BCVA was better in the infliximab group (mean, 0.96; standard deviation [SD], 0.4; Snellen equivalent ≈ 20/180) vs. the control (mean, 1.14; SD, 0.4); Snellen equivalent ≈ 20/280; P = 0.044). There were no differences regarding IOP, IOI, time of SO removal, macular function, CMT, or VD.
Conclusions:
Pars plana vitrectomy with SO tamponade with or without intravitreal infliximab is effective in treating PVR-associated RRD. Infliximab may be associated with modest improvement in final visual outcomes but not anatomic outcomes.
Background and Objective
The study aimed to investigate the alterations of retinal and conjunctival vessels in patients with Behcet's disease (BD).
Patients and Methods
In this case-control study, 17 patients (34 eyes) diagnosed with BD and 17 healthy volunteers (34 eyes) matched by age, sex, blood pressure, and intraocular pressure were recruited. Optical coherence tomography angiography examinations were performed to calculate the vessel density of the retina and conjunctiva according to different sizes of vessels and different zones divided by three segmentation methods of the retina: hemispheric segmentation, Early Treatment Diabetic Retinopathy Study, and central annulus segmentation.
Results
The vessel densities of the superficial macrovascular ( P = 0.050), superficial microvascular ( P < 0.001), superficial total microvascular ( P < 0.001), deep total microvascular ( P < 0.001), and deep total microvascular ( P < 0.001) were significantly lower in the BD group. The conjunctival vessel density was significantly higher in the BD group ( P < 0.001). The receiver operating characteristic curve analysis showed that the area under the curve of vessel density of the superior right (0.993, 95% CI 0.980–1) and right zones (0.996, 95% CI 0.987–1) were the largest in the superficial and deep retina, respectively. Otherwise, the area under the curve of conjunctival vessel density was 0.728 (95% CI 0.607–0.848).
Conclusions
In patients with BD, retinal vessel density decreases, while conjunctival vessel density increases. Optical coherence tomography angiography provides a new noninvasive and quantitative assessment for retinal and conjunctival vessels.
[ Ophthalmic Surg Lasers Imaging Retina 2024;55:13–21.]
Characterised by intraocular inflammation, non‐infectious uveitis includes a large group of autoimmune and autoinflammatory diseases that either involve the eye alone or have both ocular and systemic manifestations. When non‐infectious uveitis involves the posterior segment of the eye, specifically the retina, there is substantial risk of vision loss, often linked to breakdown of the inner blood‐retinal barrier. This barrier is formed by non‐fenestrated retinal vascular endothelial cells, reinforced by supporting cells that include pericytes, Müller cells and astrocytes. Across the published literature, a group of inflammatory cytokines stand out as prominent mediators of intraocular inflammation, with effects on the retinal endothelium that may contribute to breakdown of the inner blood‐retinal barrier, namely tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, IL‐8, IL‐17 and chemokine C‐C motif ligand (CCL)2. This article reviews the function of each cytokine and discusses the evidence for their involvement in retinal endothelial barrier dysfunction in non‐infectious uveitis, including basic laboratory investigations, studies of ocular fluids collected from patients with non‐infectious uveitis, and results of clinical treatment trials. The review also outlines gaps in knowledge in this area. Understanding the disease processes at a molecular level can suggest treatment alternatives that are directed against appropriate biological targets to protect the posterior segment of eye and preserve vision in non‐infectious uveitis.
Introduction:
In the past several years, there have been numerous advances in pharmacotherapeutics for the management of uveitis and other ocular inflammatory diseases, including newer therapeutic agents and ocular drug delivery systems. One of the most attractive modes of drug delivery is the intravitreal route since it has proven to be safe and efficacious and prevents unwanted systemic adverse events related to the agent.
Areas covered:
In this review, intravitreal delivery of various pharmacotherapeutic agents for noninfectious uveitis has been described. An extensive review of the literature was performed using specific keywords on the PubMed database to identify clinical studies employing various pharmacotherapeutic agents with intravitreal drug delivery for noninfectious uveitis. The mode of action, safety, efficacy, and tolerability of these drugs have also been elucidated.
Expert opinion:
Several agents, including biologic response modifier agents, have been found to be safe and efficacious for various indications of uveitis, such as cystoid macular edema, active uveitis, and other conditions such as retinal vasculitis and vitreous haze. The use of intravitreal biological therapies, especially infliximab, has been fraught with potential safety signals such as photoreceptor toxicity. However, pharmacotherapeutic agents such as corticosteroids and anti-vascular endothelial growth factor agents are now widely used in the clinical management of uveitis and its complications.
Uveitis in Behçet's disease (BD) is frequent (40% of cases) and is a major cause of morbidity. The age of onset of uveitis is between 20 and 30 years. Ocular involvement includes anterior, posterior or panuveitis. It is non-granulomatous. Uveitis may be the first sign of the disease in 20% of cases or it may appear 2 or 3 years after the first symptoms. Panuveitis is the most common presentation and is more commonly found in men. Bilateralisation usually occurs on average 2 years after the first symptoms. The estimated risk of blindness at 5 years is 10-15%. BD uveitis has several ophthalmological features that distinguish it from other uveitis. The main goals in the management of patients are the rapid resolution of intraocular inflammation, prevention of recurrent attacks, achievement of complete remission, and preservation of vision. Biologic therapies have changed the management of intraocular inflammation. The aim of this review is to provide an update previous article by our team on pathogenesis, diagnostic approaches, identification of factors associated with relapse and the therapeutic strategy of BD uveitis.
Described as early as Hippocrates in his “Third Book of Endemic Diseases,” Behçet's Disease (BD), also known as “The Silk Road Disease” following its initial demographics, consists of a triad of recurrent oro-genital ulcers and associated uveitis. Current demographics and rising percentages of patients seen far beyond the Silk Road in Ocular Inflammatory Disease and Uveitis Clinics list BD uveitis as one of the frontliners of non-infectious autoinflammatory eye diseases. Clinical features of BD and juvenile-onset BD are detailed alongside various approaches in classification and suggested algorithms for diagnosis that are outlined in this review. With the ongoing Human Microbiome Project and studies such as the MAMBA study, the role of the human microbiome in BD is highlighted in the pathophysiology of BD to include the current research and literature perspective. Furthermore, with the advancement of recent diagnostic and investigative techniques, especially in the field of Optical Coherence Tomography (OCT), disease-related characteristics are updated to encompass SD, EDI and OCT-angiography characteristics of BD. Having entered the era of biologic therapy, the role of various specific cytokine-blocking biologic drugs, such as TNF-α inhibitors (e.g., adalimumab, infliximab), interferon α-2a inhibitors, IL-6 and IL-1 inhibitors are presented and contrasted alongside the conventional immunosuppressant drugs and the classic old gold standard: corticosteroids (systemic or local). Finally, with the ongoing SARS-CoV-2 pandemic, it was not possible to conclude the review without reviewing the latest evidence-based literature reporting BD morbidity in this era, the observed pattern and treatment recommendations as well as those related to reported post-vaccine complications and emergence of BD.
Several new treatment modalities with different mechanisms of action have been studied in patients with Behçet’s syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities.
Purpose:
To assess the safety and efficacy of intravitreal infliximab (1 mg/0.05 mL) in patients with refractory posterior uveitis in Behcet's disease.
Methods:
Twenty patients were included in this study. Best corrected visual acuity (BCVA), vitreous haze (graded 0-4), vasculitis, retinitis, and papillopathy (presence or absence) were assessed at baseline, Day 1 and Week 2, 4, 6, 8, 12, and 18. Optical coherence tomography (OCT) central foveal thickness, fluorescein angiography, and flash electroretinogram were done at baseline and 4, 12, and 18 weeks.
Results:
Mean baseline logMAR BCVA was 0.94 (20/160), had improved significantly by Week 2 to 0.6 (20/80) (P < 0.0001), and reached 0.36 (20/40) by Weeks 18 with three injections (P < 0.0001). Mean central foveal thickness OCT decreased significantly from baseline 361 μm to 180 μm at the end of follow-up (P < 0.0001). Profound decrease in mean vitreous haze gradings from two to 0.2 by the end follow-up (P < 0.05). There was a significant reduction in the number of patients with vasculitis (15 at baseline to 1 weeks at 18 weeks), retinitis (nine at baseline to none at 4 weeks), and papillitis (two at baseline to none at 4 weeks) (P < 0.05). No significant electrophysiological changes or ocular adverse inflammatory reactions were observed during the study period.
Conclusion:
Intravitreal infliximab appeared to be safe and effective in treating uveitis in Behcet's disease and should be considered as an alternative to systemic therapies.
Purpose:
To evaluate the short-term efficacy of intravitreal adalimumab (IVA) for the treatment of eyes with active noninfectious uveitis.
Methods:
Consecutive eyes with active noninfectious uveitis were injected with IVA at 0, 2, then every 4 weeks for total of 26 weeks.
Results:
Six out of 7 patients (12 of 13 eyes) completed 26 weeks of treatment. One patient (1 eye) failed treatment. Seven out of 12 eyes had improvement of ≥2 ETDRS lines. Three out of three eyes had resolution of anterior chamber cells. And 9 of 10 eyes with vitreous haze had zero haze at 26 weeks. Five out of 8 eyes with macular edema had complete resolution. Median fluorescein angiography score improved from 14 to 4 on last follow-up.
Conclusions:
IVA was effective in controlling the inflammation, decreasing the macular edema, and improving the best corrected visual acuity in the majority of eyes in this series.
Objective
Behcet's disease (BD) is a chronic, relapsing, inflammatory vascular disease with no pathognomonic test. Low sensitivity of the currently applied International Study Group (ISG) clinical diagnostic criteria led to their reassessment. Methods
An International Team for the Revision of the International Criteria for BD (from 27 countries) submitted data from 2556 clinically diagnosed BD patients and 1163 controls with BD-mimicking diseases or presenting at least one major BD sign. These were randomly divided into training and validation sets. Logistic regression, leave-one-country-out' cross-validation and clinical judgement were employed to develop new International Criteria for BD (ICBD) with the training data. Existing and new criteria were tested for their performance in the validation set. ResultsFor the ICBD, ocular lesions, oral aphthosis and genital aphthosis are each assigned 2 points, while skin lesions, central nervous system involvement and vascular manifestations 1 point each. The pathergy test, when used, was assigned 1 point. A patient scoring 4 points is classified as having BD. In the training set, 93.9% sensitivity and 92.1% specificity were assessed compared with 81.2% sensitivity and 95.9% specificity for the ISG criteria. In the validation set, ICBD demonstrated an unbiased estimate of sensitivity of 94.8% (95% CI: 93.4-95.9%), considerably higher than that of the ISG criteria (85.0%). Specificity (90.5%, 95% CI: 87.9-92.8%) was lower than that of the ISG-criteria (96.0%), yet still reasonably high. For countries with at least 90%-of-cases and controls having a pathergy test, adding 1 point for pathergy test increased the estimate of sensitivity from 95.5% to 98.5%, while barely reducing specificity from 92.1% to 91.6%. Conclusion
The new proposed criteria derived from multinational data exhibits much improved sensitivity over the ISG criteria while maintaining reasonable specificity. It is proposed that the ICBD criteria to be adopted both as a guide for diagnosis and classification of BD.
Abstract Purpose: To compare the short-term visual and anatomic outcomes after intravitreal injections of 2 different tumor necrosis factor-α inhibitors to continued antivascular endothelial growth factor (VEGF) therapy in eyes with choroidal neovascularization (CNV) secondary to age-related macular degeneration that responded suboptimally to anti-VEGF agents. Methods: Retrospective comparative case series of 26 eyes. Eyes were injected intravitreally with 1 mg infliximab, 2 mg infliximab, 2 mg adalimumab, or 1.25 mg bevacizumab. The main outcomes measured were the best-corrected visual acuity (BCVA) and the central macular thickness (CMT) at 3 months of follow-up. Results: The mean log minimal angle of resolution BCVA changed from 1.04±0.23 at baseline to 1.06±0.51 at 3 months (P=0.9455) in the 1-mg infliximab group; 0.94±0.48 at baseline to 0.85±0.43 in the 2-mg infliximab group (P=0.2802); 1.58±0.50 at baseline to 1.38±0.43 in the adalimumab group (P=0.1116); and 1.08±0.1 at baseline to 1.03±0.16 in the bevacizumab group (P=0.9928). The mean CMT changed from 387±54 μm at baseline to 342±108 μm (P=0.1053) in the 1-mg infliximab group; 301±42 μm at baseline to 284±73 μm (P=0.4854) in the 2-mg infliximab group; remained unchanged at 348±106 μm (P=0.308) in the adalimumab group; and 362±66 μm to 340±27 μm in the bevacizumab group (P=0.4622). Adverse events included uveitis in 37.5% (6/16) of eyes injected with infliximab. Conclusion: Intravitreal infliximab and adalimumab do not appear to benefit eyes with CNV that responded suboptimally to anti-VEGF agents. Intravitreal injections of infliximab may elicit a severe intraocular inflammatory reaction.
To determine retinal and choroid toxicity levels of two and three infliximab intravitreous injections in albino rabbits by means of electroretinographic, histological and ophthalmological clinical tests.
12 albino rabbits were used in the study. Each eye was given two (n=10 eyes) or three (n=10 eyes) serial intravitreous 2 mg infliximab injections dissolved in 0.06 ml of saline, at monthly intervals. A separate group of rabbits (n=4 eyes) served as a control group. Ninety days after the study had begun, the rabbits underwent clinical and electroretinographic tests, and after being enucleated, the eyes were examined for histological changes.
Slit-lamp biomicroscopy and fundoscopic examination did not reveal any significant retinal abnormalities in the eyes injected with infliximab and control eyes or in pre- and post-treated eyes. The histological change that was noted was the presence of rare lymphocytes and eosinophils in the posterior vitreous of some of the rabbits subjected to two or three injections, but it was not considered clinically significant. A severe inflammatory reaction with vitreous exudates and ganglion cell edema in a single rabbit was clinically significant. The electroretinographic tests showed amplitudes that were on the average 12-13% smaller than those obtained before the treatment, however, there were no statistically significant differences when comparing the amplitude or the implicit time between pre- and post-treatment electroretinographic findings.
Two and three intravitreous 2 mg infliximab injections in rabbits at monthly intervals did not cause any changes after a 90-day follow-up, according to histological and electroretinographic tests and after clinical evaluation. Differently from prior studies that have investigated potential retinotoxicity effects after single administrations, this study investigated the possibility of retinotoxicity after multiple injections. Clinical studies in humans should be conducted to better evaluate the safety of this drug in the treatment of certain diseases affecting the retina and the choroid.
Many insights have been gained into cytokine-regulated control of inflammatory processes and host defence in recent years. Evidence has also gradually accumulated that cytokine cascades play a central role in events regulating cell death and differentiation. Further developments include an understanding that the biological effects of the tumor necrosis factor-alpha (TNF-alpha or TNFSF) cytokine may be regulated by soluble TNF receptor binding and that modulation of receptor levels may permit physiological inhibition of TNF action. There has been a gradual realisation of the value of TNF/TNFR ratios as predictors of disease outcome, and the discovery of functional regulatory polymorphisms of the TNF gene and mutations of TNFRSF1A (TNFR1 receptor) have led to conceptual breakthroughs in our understanding of the genetic control of inflammation. However the exact mechanisms by which TNFRSF1A mutations give rise to disease susceptibility are not yet well understood. Over the past 10 years these concepts have been used as the basis for successful anti-TNF therapy of autoimmune diseases like rheumatoid arthritis (RA) and Crohn's disease.
Purpose: To compare the efficacy of systemic and intravitreal infliximab treatments in an experimental endotoxin-induced uveitis (EIU) model.
Methods: Twenty-eight white New Zealand rabbits were equally divided into 4 groups. Group 1 received an intravitreal injection of 0.1 cc saline, group 2 received an intravitreal injection of 2 µg/0.1 cc lipopolysaccharide (LPS), group 3 received an intravitreal injection of 2 µg/0.1 cc LPS and 2 mg/0.1 cc infliximab, and group 4 received intravitreal injection of 2 µg/0.1 cc LPS and intravenous injection of 5 mg/kg infliximab. Clinical, biochemical (aqueous and vitreous humor protein levels and TNF-α concentrations), and histopathological evaluations were performed.
Results: The clinical examination score was lower in group 4 than in group 2 (p = 0.006); but there was no significant difference between groups 2 and 3 (Bonferroni correction, p = 0.016). No statistically significant difference was found among groups 2, 3, and 4 for aqueous humor protein levels (p > 0.05). Significantly higher aqueous humor concentrations of TNF-α was measured in group 3 comparing to both group 1 and 4 (p = 0.003 and p = 0.002, respectively). No significant difference was found in vitreous protein levels or TNF-α concentrations among all study groups (Bonferroni correction, p = 0.026 and p = 0.101, respectively). Histopathological evaluation of the uveal tissue and anterior chamber reaction revealed the highest inflammation in group 3 (p < 0.001). In group 4, histopathological evaluation of uveal tissue was lower than in groups 2 and 3 (p < 0.001 and p = 0.001, respectively); whereas there was no difference in anterior chamber inflammation between groups 2 and 4 (p = 1.00).
Conclusion: Intravitreal 2 mg0.1 cc infliximab injection exacerbated inflammation in an EIU model; whereas systemic infliximab treatment at a dose of 5 mg/kg suppressed inflammation effectively and rapidly.
Background
Patients with noninfectious uveitis are at risk for long-term complications of uncontrolled inflammation, as well as for the adverse effects of long-term glucocorticoid therapy. We conducted a trial to assess the efficacy and safety of adalimumab as a glucocorticoid-sparing agent for the treatment of noninfectious uveitis.
Methods
This multinational phase 3 trial involved adults who had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite having received prednisone treatment for 2 or more weeks. Investigators and patients were unaware of the study-group assignments. Patients were randomly assigned in a 1:1 ratio to receive adalimumab (a loading dose of 80 mg followed by a dose of 40 mg every 2 weeks) or matched placebo. All patients received a mandatory prednisone burst followed by tapering of prednisone over the course of 15 weeks. The primary efficacy end point was the time to treatment failure occurring at or after week 6. Treatment failure was a multicomponent outcome that was based on assessment of new inflammatory lesions, best corrected visual acuity, anterior chamber cell grade, and vitreous haze grade. Nine ranked secondary efficacy end points were assessed, and adverse events were reported.
Results
The median time to treatment failure was 24 weeks in the adalimumab group and 13 weeks in the placebo group. Among the 217 patients in the intention-to-treat population, those receiving adalimumab were less likely than those in the placebo group to have treatment failure (hazard ratio, 0.50; 95% confidence interval, 0.36 to 0.70; P<0.001). Outcomes with regard to three secondary end points (change in anterior chamber cell grade, change in vitreous haze grade, and change in best corrected visual acuity) were significantly better in the adalimumab group than in the placebo group. Adverse events and serious adverse events were reported more frequently among patients who received adalimumab (1052.4 vs. 971.7 adverse events and 28.8 vs. 13.6 serious adverse events per 100 person-years).
Conclusions
In our trial, adalimumab was found to be associated with a lower risk of uveitic flare or visual impairment and with more adverse events and serious adverse events than was placebo. (Funded by AbbVie; VISUAL I ClinicalTrials.gov number, NCT01138657.)
Abstract Purpose: This study aimed to evaluate the safety and long-term effects of infliximab on chronic noninfectious uveitis with measuring best corrected visual acuity (BCVA) and central macular thickness (CMT). Method: Ten eyes of 7 patients were included in this prospective case series. All the patients had noninfectious anterior and posterior uveitis that was unresponsive to conventional treatments for 3 months. About 1.5 mg of infliximab in 0.15 cc was injected intravitreally and the patients were followed for 6 months. BCVA was measured by Snellen chart and grading of vitritis was measured according to binocular indirect ophthalmoscope score before injection, 4 weeks, 3 months, and 6 months after the injection. CMT was measured 1 day before injection and compared with the same factors 4 weeks and 6 months after the injection. Results: Mean of LogMAR before injection was 1.37±0.43 that changed to 0.67±0.55 and 1.38±0.36 one month and 6 months after the injection, respectively. Mean CMT before injection was 673.2±338.39 that changed to 456.4±317.46 and 659.3±342.48, 4 weeks and 6 months after the injection, respectively. Mean vitreous haziness grade before injection, 4 weeks, 3 months, and 6 months after the injection was 2.7, 0.95, 2.3, and 2.6, respectively. Conclusions: Intravitreal Infliximab may be used in treatment of noninfectious uveitis. It probably improves the vision and decreases the macular edema but its effect is temporary and repeated injections may be needed to achieve the best therapeutic goal.
To assess the safety and to conduct a preliminary assessment of efficacy of intravitreal infliximab, an anti-tumor necrosis factor antibody, for sight-threatening relapsing uveitis in Behçet disease.
Prospective, noncomparative, interventional pilot study.
A single intravitreal injection of infliximab (1 mg/0.05 mL) was given to 15 patients with relapsing posterior uveitis at the onset of a unilateral attack. Best-corrected visual acuity, anterior chamber cells, vitreous haze, and posterior eye segment inflammation were assessed at baseline and at 1, 7, 14, and 30 days after treatment.
Ocular or extra-ocular side effects were not observed. Baseline best-corrected visual acuity (mean logarithm of minimal angle of resolution, 0.74; range, 0.15 to 1.7) improved significantly by day 7 and continued to improve through day 30 after infliximab (mean, 0.30; P < .0001). Profound decreases in anterior chamber cells and vitreous haze (both P < .0001), as well as beneficial effects in retinal vasculitis (P = .0001) and retinitis (P = .001) were evident through day 30. Cystoid macular edema persisted in 9 of 11 eyes affected, but central macular thickness decreased from a baseline mean of 434 to 309 mm at the end of follow-up (P < .0001). Lack of systemic treatment at baseline in 4 patients or background immunosuppressive medications, which remained unchanged during follow-up, did not influence significantly these responses; additional treatment was not required.
These findings suggest that intraocularly produced or acting tumor necrosis factor, or both, is crucial in Behçet disease-associated relapsing uveitis and that intravitreal infliximab should be considered when systemic administration is not feasible or contraindicated. Further studies may identify patients for whom intravitreal infliximab is preferable to systemic treatment.
To review the new data on the epidemiology, etiopathogenesis, clinicolaboratory spectrum, prognosis, and treatments of Behçet's disease (BD).
The information concerning the etiopathogenesis of the disease is divided into infection, immune, and genetic factors. The clinical features of the disease are discussed according to the organ or system involved. Treatment is described as general, local, and systemic.
BD is a multisystem vasculitis with recurrent symptoms. It affects mainly people living around the Mediterranean basin and in Japan. The mean age at onset is the third decade. Children are rarely affected, and few neonatal cases have been reported. In large series of patients, men predominate over women. Infectious agents, immune mechanisms, and genetic factors are implicated in the etiopathogenesis of the disease, which remains to be elucidated. The pathology of the lesions consists of widespread vasculitis. Eyes, skin, joints, the oral cavity, blood vessels, and central nervous system are usually involved, although less frequently the heart, lung, kidney, genital system, and gastrointestinal tract may be affected. The prognosis of the disease has been improved because of early diagnosis and suitable treatment. Local remedies and systemic administration of colchicine, corticosteroids, immunosuppressives, and other agents have been applied.
BD is a widespread vasculitis affecting young people and involving concurrently or consecutively nearly all organs and systems. Treatment results in better prognosis even when vital organs are involved.
Biologicals are selectively acting proteins that demonstrated high efficacy in the treatment of chronic disorders. In particular, biologicals blocking tumor necrosis factor α (TNF-α), an essential cytokine in chronic inflammatory diseases, have demonstrated great promise. Experimental and clinical data indicate that TNF-α plays an important role in intraocular inflammation. Neutralization of TNF-α might therefore be a promising strategy for prevention and treatment of uveitis. Here we review the principle effects, therapeutic value, and potential side effects of anti-TNF agents in uveitis.
The purpose of this study was to determine the efficacy and safety of intravitreal infliximab in the treatment of choroidal neovascularization secondary to age-related macular degeneration in patients who are nonresponders to antivascular endothelial growth factor therapy.
Prospective, noncomparative, interventional case series. The primary inclusion criteria for patients consisted of previous treatment with five or more intravitreal injections of bevacizumab and/or ranibizumab, visual loss, angiographic leakage, and intraretinal and/or subretinal fluid on spectral domain optical coherence tomography. At Day 0, a single intravitreal injection of infliximab (2 mg/0.05 mL) was administered. Best-corrected visual acuity testing measured with Early Treatment Diabetic Retinopathy Study charts and spectral domain optical coherence tomography scans were performed on Days 0, 3, 7, 30, 60, and 90. Fluorescein angiography was performed at days 0 and 90. The development of systemic antibodies against infliximab (human antichimeric antibodies) was not sought. Main outcome measures were changes in best-corrected visual acuity, foveal thickness, and lesion size.
We included four patients. At Day 90, the best-corrected visual acuity change was -18, +3, +4, and -4 letters, respectively. Intraretinal and/or subretinal fluid on spectral domain optical coherence tomography scans was not significantly reduced in any case. Lesion size was not reduced in any case. Two patients developed intraocular inflammation with high intraocular pressure 3 and 5 weeks after the infliximab injection, respectively. One case was controlled with topical medication, and one case required posterior vitrectomy.
Intravitreal infliximab showed no significant visual or anatomical benefit for the treatment of choroidal neovascularization secondary to age-related macular degeneration in patients who were nonresponders to antivascular endothelial growth factor therapy. In addition, half of the cases developed intraocular inflammation.
Despite a lack of robust evidence, anti-TNF therapies are in wide use for the treatment of noninfectious ocular inflammatory diseases. There is a clear rationale, based on mechanistic and preclinical efficacy data, for their use in posterior segment intraocular inflammation. However, their increasing use for other indications has been largely extrapolated from the benefit observed in autoinflammatory and autoimmune systemic diseases. Given their cost and the potential for significant adverse events, this review highlights the evidence for their continued use, possibilities for switching anti-TNF agents, and ways of reducing the risk of therapy.
To determine the tolerability of intravitreal infliximab (Remicade) in patients with refractory diabetic macular edema or choroidal neovascularization secondary to age-related macular degeneration.
This is a prospective, interventional, noncomparative, open-label, 12-week pilot study of intravitreal infliximab in four patients who failed conventional therapies. Two had diabetic macular edema and two had choroidal neovascularization secondary to age-related macular degeneration. All patients received 0.5 mg/0.05 mL intravitreal infliximab and were eligible for a second injection at 6 weeks if reinjection criteria were met. Outcome measures were best-corrected visual acuity using standard Early Treatment Diabetic Retinopathy Study refraction, central retinal thickness on optical coherence tomography, fluorescein angiography, standard electroretinography, and microperimetry. Patients were evaluated at Days 0 and 1 and Weeks 2, 6, and 12. Six months after study completion, all patients were tested for human antimouse and human antichimeric antibodies.
At Week 12, visual acuity scores had declined in three patients. All patients had persistence of cystoid macular edema on optical coherence tomography, although two had a decrease in central retinal thickness. Three patients had an overall worsened appearance on angiography. On the final electroretinography, all patients had a decrease in maximal combined responses, from 7% to 24% from baseline, which may have been within expected variability of electroretinography data. To photopic flicker stimulus, three patients had slower latency of response, and all had decreased amplitudes. All patients declined on microperimetry. The first patient entered in the study met the criteria for a second injection because of improved standard electroretinography and microperimetry at Week 6. However, 2 weeks after the second injection, he developed panuveitis. Two other patients, after one injection only, had evidence of inflammation (vitritis or panuveitis) on examination at Week 6. Three patients developed systemic antibodies against infliximab (human antichimeric antibodies).
Low-dose intravitreal infliximab was not well tolerated in this small group of patients and was both immunogenic and probably retinotoxic.
We aimed to describe the demographic and clinical features, ocular manifestations, complications, visual prognosis, and treatment in a large population of Turkish patients with Behçet uveitis. We also aimed to compare visual prognosis between male and female sex and between patients who presented before and after 1990.
Observational case series.
A retrospective study of 880 consecutive patients (1,567 eyes) with Behçet uveitis seen at the Uveitis Service, Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, from 1980 to 1998. All patients met the classification criteria of the International Study Group for Behçet's Disease. Information on the patient's sex, age at onset of uveitis, ocular features, ocular complications, visual acuity, and systemic treatment was collected.
Five hundred ninety-nine patients (68%) were male and 281 (32%) were female. The mean age at onset of uveitis was 28.5 years in male and 30 years in female patients. Ocular involvement was bilateral in 78.1% and unilateral in 21.9% of the patients. Panuveitis was the most common form in both sexes. Fundus lesions as well as sight-threatening complications were more common in males. At the beginning of the follow-up, potential visual acuity was 0.1 or less in 30.9% of eyes in males and 24.2% of eyes in females. Kaplan-Meier survival analysis estimated the risks of losing useful vision (>0.1) at 5 and 10 years for males and females as 21% vs 10% and 30% vs 17%, respectively. Male patients who presented in the 1990s had a significantly lower risk of losing vision compared with male patients who presented in the 1980s.
Behçet uveitis starts frequently around the end of the third decade and has a male predominance. The disease is more severe and the risk of losing useful vision is higher in males than in females. However, this risk has been significantly reduced in the 1990s.
International Team for the Revision of the International Criteria for Behçet's Disease (ITR-ICBD)
- F Davatchi
- S Assaad-Khalil
- K T Calamia
International Team for the Revision of the International Criteria for Behçet's Disease (ITR-ICBD), Davatchi F, Assaad-Khalil S, Calamia KT, et al. The International Criteria for Behçet's
Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop
Standardization of Uveitis Nomenclature (SUN) Working
Group. Standardization of uveitis nomenclature for reporting
clinical data. Results of the First International Workshop. Am J
Ophthalmol 2005;140:509-516.
Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop