Christoph Deuter

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.

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.

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.

Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome

OBJECTIVE Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive interleukin-1 (IL-1) release. It is characterized by severe fevers, rashes, arthralgia, and conjunctivitis, leading to sensorineural deafness and amyloidosis. The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1. The aim of this study was to determine the short- and long-term efficacy and safety of anakinra therapy in children and adults with severe MWS. METHODS A single-center observational study was performed. Standardized assessments included clinical features, the Disease Activity Score (DAS) for MWS, classic and novel markers of inflammation, and patient-derived measures of health status. The primary outcome was a score of <10 on the DAS for MWS at 2 weeks and at the last followup visit. Measures of MWS disease activity were investigated using descriptive statistics and paired comparative analysis. RESULTS A total of 12 patients with severe MWS (5 children and 7 adults) received anakinra for a median of 11 months (range 5-14 months). The median followup was 11 months (range 5-14 months). Disease activity was significantly lower in all patients at 2 weeks (P = 0.0005). Organ manifestations of MWS improved, as did all patient-derived measures of health status, markers of inflammation, and hearing loss in 2 of the patients. Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity. Treatment was well tolerated, and no serious adverse events were observed. CONCLUSION Anakinra was found to be a safe and effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well as long-term. Anakinra therapy should therefore be considered in children and adults with severe MWS disease requiring IL-1 blockade.

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.

Interferon alfa-2a: a new treatment option for long lasting refractory cystoid macular edema in uveitis? A pilot study.

Purpose: To perform a prospective pilot study to evaluate interferon alfa-2a (IFN alfa-2a) for the treatment of refractory cystoid macular edema (CME) in endogenous uveitis. Methods: IFN alfa-2a was administered at an initial dose of 3 or 6 million IU (depending on body weight) per day subcutaneously. Afterwards IFN alfa-2a was tapered slowly over 6 months and finally discontinued. If CME relapsed IFN alfa-2a was reinstituted and tapered slowly again to evaluate the lowest maintenance dose to keep remission. Results: A total of 15 eyes of 8 patients with refractory CME due to intermediate or posterior uveitis were included. Ineffective pretreatment consisted of systemic steroids and acetazolamide (all patients) and at least one additional immunosuppressant (6 patients). Six of 8 patients (11 eyes) responded well to IFN alfa-2a and CME resolved completely during 6 months treatment. One patient was lost to follow-up after IFN alfa-2a was stopped. In 1 patient (1 eye) even 19 months after cessation of IFN alfa-2a no recurrence of CME occurred. In 4 patients (8 eyes) IFN alfa-2a had to be reinstituted because CME relapsed. All 4 patients responded again. During a mean follow-up period of 16.4 months since restart of therapy we succeeded in all 4 patients to taper IFN alfa-2a to maintenance doses between 1.5 million IU every second and every sixth day without a recurrence of CME in any of the 8 eyes. Conclusion: IFN alfa-2a can be a treatment option for patients with otherwise treatment resistant uveitic CME.

Weak transient response of chronic uveitic macular edema to intravitreal bevacizumab (Avastin)

Dear Editor: We want to report on our experiences with bevacizumab (Avastin; Genentech, Inc., San Francisco, CA, USA) in chronic cystoid macular edema (CME), which is the most common cause of irreversible visual loss in chronic uveitis [1, 2]. Anti-VEGF treatment has been reported to be a powerful treatment modality in reducing macular edema of different origin [3, 4]. Additionally, there is a rationale that VEGF-antagonists may also have anti-inflammatory capabilities. VEGF can induce chemotaxis and migration of monocytes [5]. Other pro-inflammatory effects are the induction of Band Tlymphocytes [6, 7]. Therefore, VEGF-inhibitors have also been considered to be effective in inflammatory autoimmune disorders such as rheumatoid arthritis. Intraocular administration of triamcinolone acetonide frequently causes a harmful increase in intraocular pressure—especially in uveitis [8]. Limited efficacy of other topical agents in otherwise systemically controlled inflammation led us to think about the use of bevacizumab in chronic CME. Six patients with chronic macular edema due to uveitis were treated with an intravitreal injection of bevacizumab 1.25 mg in 0.05 ml. Extensive evaluation had previously been performed to determine the cause of the uveitis. Offlabel bevacizumab therapy was only considered if inflammatory activity was judged completely quiet for more than 6 months, steroid-induced increase in IOP was in the history, or no response was seen to other immunosuppressive agents. All patients underwent Snellen chart visual acuity testing, ophthalmoscopic examination, flare measurement (FC-2000, Kowa Co. Ltd, Tokyo, Japan) and ocular coherence tomography at baseline, 1-week and 4-week intervals. The subjects opted for the injection, signing for informed consent after being given detailed information about the limited experience and the “off-label” nature of the treatment in compliance with IRB approval. Two patients showed a marked, but temporary decrease in the height of the edema and experienced transient improvement of visual acuity at the 1-week examination. One month after the injection, none of the patients had either significant improvement in visual acuity or decrease in central retinal thickness (CRT, Table 1). Apart from the rupture of a retinal cyst, no other adverse events were observed in any patient up to 12 months after the injection. Non-parametric Fisher–Pitman test (small sample procedure) revealed no significant difference in flare (p=0.369). CRT after 4 weeks did not differ significantly from the baseline (Wilcoxon matched pairs test, p=0.599). Thus, in this group of severe, chronic uveitis-associated CME, resistant to established therapies, bevacizumab has shown only minor and transient effects, but good tolerability. The full-length antibody was well-tolerated in the vitreous, in spite of present autoimmune disorders. The disrupted boundary of an intraretinal cyst could be explained by a coincidental and spontaneous event. However, with respect to pigment epithelium tears seen after anti-VEGF treatment [9] mechanical stress has also been thought to occur in desiccating CME. Graefe’s Arch Clin Exp Ophthalmol (2007) 245:917–918 DOI 10.1007/s00417-006-0512-2

High frequency of MYD88 mutations in vitreoretinal B-cell lymphoma: a valuable tool to improve diagnostic yield of vitreous aspirates

Vitreoretinal diffuse large B-cell lymphoma is a rare disorder, occurring as primary ocular disease or as secondary involvement by primary central nervous system lymphoma. It is usually diagnosed by cytologic, immunocytochemical, and molecular examination of vitreous aspirates. However, distinguishing vitreoretinal diffuse large B-cell lymphoma from uveitis remains difficult, and clonality analysis may be either unsuccessful or misleading. Diffuse large B-cell lymphoma arising in immune-privileged sites (eg, the central nervous system) shows a high frequency of MYD88 mutations. Therefore, we retrospectively assessed the frequency of MYD88 mutations in vitreoretinal lymphoma (VRL) and their diagnostic potential in 75 vitrectomy samples of 69 patients, and validated our results in a separate cohort (n = 21). MYD88 mutations were identified in 20 of 29 (69%) clinically, histologically, and molecularly confirmed VRL, including 6 cases of the test cohort initially diagnosed as reactive (3/6) or suspicious (3/6) for lymphoma. MYD88 mutations, especially L265P, are very frequent in VRL and their detection significantly improves the diagnostic yield of vitrectomy specimens.

Uveitis in Children

Uveitis in children is less frequent compared to adults. It is estimated that the population-based incidence and prevalence of uveitis in children is 5to 10-fold lower than in adults. Children constitute only about 5% to 10% of patients with uveitis in most tertiary uveitis clinics. Moreover, forms and causes of uveitis in children differ somewhat from those in adults. Whereas in adult patients anterior uveitis accounts for 50%, intermediate uveitis for 30%, and posterior uveitis for 20%, Cunningham found that posterior uveitis was slightly more common than anterior uveitis in a review of 9 large series: anterior uveitis accounted for 30% to 40% of cases, posterior uveitis for 40% to 50%, intermediate uveitis for 10% to 20%, and panuveitis for 5% to 10%. Most of these series have been reported from tertiary care facilities. The distribution of the different types of uveitis varies with age and between reported series, in part because of a different spectrum of diseases seen in different geographic areas. But recent population-based studies suggest that the majority of children with uveitis