Manfred Zierhut

Adalimumab in the therapy of uveitis in childhood

Purpose: Chronic anterior uveitis in children often takes a serious course. Despite various immunosuppressive drugs some children do not respond sufficiently and there is a high risk of them becoming seriously disabled. Anti-TNF alpha therapy has been shown by our group and others to be mostly ineffective (Etanercept) or partly effective (Infliximab) with the risk of anaphylactic reactions. Here we report on 18 young patients treated with Adalimumab (Humira®), a complete humanised anti-TNF alpha antibody. Methods: We retrospectively analysed 18 patients, who were treated with Adalimumab (20–40 mg, every 2 weeks, when ineffective every week); 17 had juvenile idiopathic arthritis, one was without detectable underlying disease. The age at onset of arthritis varied from 0.5–15 years and for uveitis from 2–19 years. Patients were included when the previous anti-inflammatory therapy had been ineffective. It consisted of systemic steroids (n = 18), Cyclosporin A (n = 18), Methotrexate (n = 18), Azathioprine (n = 12), Mycophenolate mofetil (n = 4), Cyclophosphamide (n = 2), Leflunomide (n = 3), Etanercept (n = 8) and Infliximab (n = 5). The grading for uveitis was: (a) effective: no relapse or more than two relapses less than before treatment, (b) mild: one relapse less than before treatment, (c) no response: no change in relapse rate and (d) worsening: more relapses under treatment than before. The grading for arthritis (depending on the clinical findings), using three out of six parameters of the ACR PED Criteria, was: effective, mild, no response, worsening. Results: For arthritis (n = 16) the response to Adalimumab was effective in 10 of 16 patients, mild in three patients, three did not respond. For uveitis (n = 18) Adalimumab was effective in 16, mild in one child, and one patient did not show any effect. After a very good response initially a shorter application time had to be used to maintain the good anti-inflammatory effect in one child. Additional immunosuppressive treatment was used in seven of the effectively treated children. Due to elevation of liver enzymes in one patient, who also took MTX, Adalimumab had to be discontinued. No anaphylactic reactions or increased frequency of infections since start of Adalimumab treatment was reported. Conclusions: For our group of children with long lasting disease our results show that Adalimumab was effective or mildly effective against the arthritis in 81%, but in uveitis in 88%. While these results regarding arthritis are comparable with other TNF-alpha blocking drugs (Etanercept), Adalimumab seems to be much more effective against uveitis than Etanercept. Anaphylactic reactions, found in a previous study from our group after Infliximab treatment, were not seen with Adalimumab. The necessary dosage and the treatment period, which probably have to be defined individually for each patient, remain unclear.

Human recombinant interferon alfa-2a for the treatment of Behçet's disease with sight threatening posterior or panuveitis

Background: Behçets disease is a multisystem vasculitis of unknown origin. Standard treatment mainly comprises systemic immunosuppressive agents. Ocular involvement, mostly posterior uveitis with retinal vasculitis, leads to blindness in 20–50% of the involved eyes within 5 years. The efficacy of interferon alfa-2a was studied in patients with sight threatening posterior uveitis or retinal vasculitis. Methods: 50 patients were included in this open, non-randomised, uncontrolled prospective study. Recombinant human interferon alfa-2a (rhIFNα-2a) was applied at a dose of 6 million units subcutaneously daily. Dose reduction was performed according to a decision tree until discontinuation. Disease activity was evaluated every 2 weeks by the Behçets disease activity scoring system and the uveitis scoring system. Results: Response rate of the ocular manifestations was 92% (three non-responder, one incomplete response). Mean visual acuity rose significantly from 0.56 to 0.84 at week 24 (p<0.0001). Posterior uveitis score of the affected eyes fell by 46% every week (p<0.001). Remission of retinal inflammation was achieved by week 24. Mean Behçets disease activity score fell from 5.8 to 3.3 at week 24 and further to 2.8 at week 52. After a mean observation period of 36.4 months (range 12–72), 20 patients (40%) are off treatment and disease free for 7–58 months (mean 29.5). In the other patients maintenance IFN dosage is three million units three times weekly. Conclusions: rhIFNα-2a is effective in ocular Behçets disease, leading to significant improvement of vision and complete remission of ocular vasculitis in the majority of the patients.

Behçet's disease: Ocular effects and treatment

Behçets disease (BD) is a systemic immune-mediated vasculitis of unclear origin. Major symptoms include oral aphthous ulcers, genital ulcerations, skin lesions, and ocular lesions. Eye involvement, which affects 60-80% of BD patients, is characterized by posterior or panuveitis with occlusive retinal vasculitis. The pathogenesis of BD remains unclear, but research of the last decades has shown a complex role of genetic factors (HLA-B51) predisposing to inflammation with involvement of the innate-immune system (neutrophils, NK cells), perpetuated by the adaptive immune response, most importantly T cells, against infectious- and/or auto-antigens. Despite aggressive immunosuppressive treatment, the visual prognosis of ocular BD was generally poor to date. Recently, novel biologic drugs, including interferon-alpha and tumour necrosis factor (TNF)-alpha-antagonists have been introduced in the treatment of ocular BD with very promising results and seem for the first time to improve the prognosis of the disease. This article will provide a current review of BD including recent developments in epidemiology, immunology, genetics, and treatment.

Understanding uveitis: the impact of research on visual outcomes.

The term uveitis encompasses a very diverse group of inflammatory ocular diseases that cause a significant burden of legal and economic blindness. Indeed, the socioeconomic impact of uveitis is at least as significant as that of diabetic retinopathy and, in the majority of cases, those affected are young individuals of working age. Significant progress has been made in our understanding of the mechanisms underlying the inflammatory process through the use of animal models, but correlation with human disease has proved elusive and many scientific approaches which appear highly effective in animal models prove to be less effective in patients. Nevertheless, effective, targeted treatments are needed in uveitis as current treatment is based on corticosteroids and immunosuppressive drugs whose usefulness is limited by their many side-effects. The aims of this review are to summarize the state of clinical research in uveitis, to identify gaps in our knowledge, and to propose new opportunities and methodologies for future developments in all aspects of uveitis research, including epidemiology, economic impact analysis, diagnosis, therapeutics, and clinical study design. Optimal patient management and efficient drug development depend on validated structured tools, such as those that have helped to drive a rapid acceleration in the means and methods available to assess and treat patients with rheumatoid arthritis and cancer. Uveitis care should witness a similar boom as the issues discussed are resolved.

Long‐term remission after cessation of interferon‐α treatment in patients with severe uveitis due to Behçet's disease

OBJECTIVE To retrospectively assess the development of visual acuity and the frequency and duration of relapse-free periods in patients who were treated with interferon-α (IFNα) for severe uveitis due to Behçets disease (BD) and who completed a followup period of ≥2 years. METHODS IFN alfa-2a was administered at an initial dosage of 6 million IU per day, then tapered to a maintenance dosage of 3 million IU twice per week, and finally discontinued, if possible. In case of a relapse, IFN treatment was repeated. Visual acuity at the end of followup was compared with visual acuity when ocular disease was in remission. RESULTS Of 53 patients (96 eyes), 52 (98.1%) responded to IFN. In 47 patients (88.7%), IFN could be discontinued when the disease was in remission. Twenty of these 47 (42.6%) needed a second treatment course during a median followup of 6.0 years (range 2.0-12.6 years). Visual acuity improved or remained unchanged in 91 eyes (94.8%). Ocular disease was still in remission in 50% of the patients 45.9 months after cessation of the first IFN course. The relapse rate tended to be lower in women than in men. The BD activity score decreased significantly during followup, but long-term remission of nonocular BD manifestations was not achieved. However, since local treatments were sufficient, no systemic treatment was administered. CONCLUSION Our findings indicate that IFNα induces long-lasting remission in patients with severe ocular BD, resulting in a notable improvement in visual prognosis.

Secukinumab in the Treatment of Noninfectious Uveitis: Results of Three Randomized, Controlled Clinical Trials

PURPOSE To determine the efficacy and safety of different doses of secukinumab, a fully human monoclonal antibody for targeted interleukin-17A blockade, in patients with noninfectious uveitis. DESIGN Three multicenter, randomized, double-masked, placebo-controlled, dose-ranging phase III studies: SHIELD, INSURE, and ENDURE. PARTICIPANTS A total of 118 patients with Behçets uveitis (SHIELD study); 31 patients with active, noninfectious, non-Behçets uveitis (INSURE study); and 125 patients with quiescent, noninfectious, non-Behçets uveitis (ENDURE study) were enrolled. METHODS After an initial subcutaneous (s.c.) loading phase in each treatment arm, patients received s.c. maintenance therapy with secukinumab 300 mg every 2 weeks (q2w), secukinumab 300 mg monthly (q4w), or placebo in the SHIELD study; secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the INSURE study; or secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the ENDURE study. MAIN OUTCOME MEASURES Reduction of uveitis recurrence or vitreous haze score during withdrawal of concomitant immunosuppressive medication (ISM). Other end points included best-corrected visual acuity, ISM use (expressed as a standardized ISM score), and safety outcomes. RESULTS After completion or early termination of each trial, there were no statistically significant differences in uveitis recurrence between the secukinumab treatment groups and placebo groups in any study. Secukinumab was associated with a significant reduction in mean total post-baseline ISM score (P = 0.019; 300 mg q4w vs. placebo) in the SHIELD study. Likewise, secukinumab was associated with a greater median reduction in ISM score versus placebo in the INSURE study, although no statistical analysis of the difference was conducted because of the small sample size. Overall, there was no loss in visual acuity reported in any treatment group during follow-up in all 3 studies. According to descriptive safety statistics, the frequencies of ocular and nonocular adverse events seemed to be slightly higher among secukinumab groups versus placebo across the 3 studies. CONCLUSIONS The primary efficacy end points of the 3 studies were not met. The secondary efficacy data from these studies suggest a beneficial effect of secukinumab in reducing the use of concomitant ISM.

Treatment of ocular symptoms of Behçet’s disease with interferon α2a: a pilot study

AIM To study long term effects of interferon α2a (IFNα2a) on panuveitis in seven patients with Behçet’s disease in a prospective, open clinical trial. METHODS Seven patients were treated with IFNα2a for a mean of 23.6 months (14–37 months). They received an initial dose of IFNα2a of 6×106IU/day, followed by 3×106 IU/day after 1 month and 3×106 IU every other day after 3 months. Two patients received low dose prednisolone (between 0.2 and 0.4 mg/kg/body weight) additionally at the beginning of the therapy. Complete cessation of IFNα2a was possible in three patients (observation period 22, 6, and 4 months). RESULTS Marked improvement occurred in six patients who had ocular manifestations of Behçet’s disease for the first time or with minor damage during their course of chronic relapsing panuveitis. In one patient with advanced ocular Behçet’s disease, new relapses were prevented. Retinal infiltrates resolved within 2 weeks; vasculitis, macular oedema, infiltration of the anterior chamber and vitreous resolved within 4 weeks. Mean posterior uveitis score before treatment (nine affected eyes) was 6.6, 4 weeks after IFN it was reduced to 0.4. The mean observation period is 27.6 months, ranging from 14 to 42 months. CONCLUSION Treatment of ocular symptoms of Behçet’s disease with IFNα2a alone or in combination with low dose steroids led to complete remission of ocular vasculitis in all patients treated in this open, uncontrolled trial. Treatment with IFNα2a may prevent permanent retinal or optic nerve damage due to vascular occlusion. No severe side effects occurred. Controlled randomised studies are warranted in order to prove the efficacy of IFNα2a in ocular Behçet’s disease and to compare it with other, established treatments such as azathioprine or cyclosporin A.

Evaluation of an Intravitreal Fluocinolone Acetonide Implant versus Standard Systemic Therapy in Noninfectious Posterior Uveitis

PURPOSE To evaluate the safety and efficacy of an intravitreal fluocinolone acetonide (FA) implant compared with standard therapy in subjects with noninfectious posterior uveitis (NIPU). DESIGN Randomized, controlled, phase 2b/3, open-label, multicenter superiority trial. PARTICIPANTS Subjects with unilateral or bilateral NIPU. METHODS One hundred forty subjects received either a 0.59-mg FA intravitreal implant (n = 66) or standard of care (SOC; n = 74) with either systemic prednisolone or equivalent corticosteroid as monotherapy (> or =0.2 mg/kg daily) or, if judged necessary by the investigator, combination therapy with an immunosuppressive agent plus a lower dose of prednisolone or equivalent corticosteroid (> or =0.1 mg/kg daily). MAIN OUTCOME MEASURES Time to first recurrence of uveitis. RESULTS Eyes that received the FA intravitreal implant experienced delayed onset of observed recurrence of uveitis (P<0.01) and a lower rate of recurrence of uveitis (18.2% vs. 63.5%; P< or =0.01) compared with SOC study eyes. Adverse events frequently observed in implanted eyes included elevated intraocular pressure (IOP) requiring IOP-lowering surgery (occurring in 21.2% of implanted eyes) and cataracts requiring extraction (occurring in 87.8% of phakic implanted eyes). No treatment-related nonocular adverse events were observed in the implant group, whereas such events occurred in 25.7% of subjects in the SOC group. CONCLUSIONS The FA intravitreal implant provided better control of inflammation in patients with uveitis compared with systemic therapy. Intraocular pressure and lens clarity of implanted eyes need close monitoring in patients receiving the FA intravitreal implant.

Mycophenolate mofetil in the treatment of uveitis in children

Background: Mycophenolate mofetil (MMF) is a new immunosuppressive agent that effectively controls the intraocular inflammation in adults. Purpose: To assess the efficacy of MMF in uveitis in children and to analyse the possible side effects. Participants and methods: A retrospective analysis was carried out on 17 children (32 eyes) with intraocular inflammation treated with MMF and followed up at the University Eye Hospital Tuebingen, Tuebingen, Germany, between 2000 and 2005. All children had chronic non-infectious uveitis and received MMF for at least 6 months. All patients were given steroids or other immunosuppressive agents before initiating treatment with MMF. Results: 17 children (10 boys and 7 girls) with a mean age of 8 (range 2–13) years at the onset of uveitis were examined. The average duration of follow-up after initiation of MMF was 3 (range 2–5) years. A steroid-sparing effect was achieved in 88% of the patients. The oral prednisolone was successfully discontinued in 41% children and reduced to a daily dose of ⩽5 mg in 47% of the children. 24% of the patients remained relapse-free during the treatment, but a reduction in the relapse rate was observed in all other patients except one. Visual acuity was increased or maintained in 13 children (76%). Mild side effects (headache, rash, gastrointestinal discomfort) occurred in 7 patients (41%) and were the cause of discontinuation of MMF in 1 patient. Conclusion: The results of our study are encouraging and suggest that MMF is an effective agent also in the treatment for uveitis in children, with marked steroid-sparing potential and an acceptable side effect profile.

Efficacy and tolerability of interferon alpha treatment in patients with chronic cystoid macular oedema due to non-infectious uveitis

Aim: To assess the efficacy and tolerability of interferon (IFN) alpha in chronic cystoid macular oedema (CMO) due to non-infectious uveitis. Methods: Retrospective analysis of an interventional case series. IFN alpha-2a was administered at an initial dose of 3 or 6 million IU per day subcutaneously and tapered afterwards to the lowest possible dose to maintain the absence of CMO. Treatment efficacy was assessed by optical coherence tomography. Results: Twenty-four patients with chronic CMO (median duration 36.0 months) due to non-infectious anterior (n = 2), intermediate (n = 18) or posterior (n = 4) uveitis have been analysed. Ineffective pretreatment included systemic corticosteroids (all patients), acetazolamide (22 patients) and at least one immunosuppressive drug (18 patients). IFN therapy was shown to be effective ( = complete resolution of CMO within 3 months, able to taper IFN) in 15 patients (62.5%), partly effective ( = incomplete resolution of CMO, unable to taper IFN) in six patients (25.0%) and not effective ( = no response or recurrence of CMO) in three patients (12.5%). IFN treatment was generally well tolerated. Common side effects including flu-like symptoms, fatigue or increased liver enzymes were dose-dependent and led to discontinuation of IFN in only one patient. Conclusion: The data demonstrate IFN alpha to be an effective and well-tolerated therapy for chronic refractory uveitic CMO.