Arnd Heiligenhaus

Methotrexate for uveitis associated with juvenile idiopathic arthritis: Value and requirement for additional anti-inflammatory medication

Purpose To study the value of methotrexate (MTX) and the requirement for additional anti-inflammatory drugs for the treatment of severe chronic iridocyclitis associated with juvenile idiopathic arthritis (JIA). Methods Institutional study of 35 consecutive patients with JIA started on MTX as the single systemic immunosuppressive drug for the treatment of associated iridocyclitis. The clinical epidemiologic data, course of visual acuity (VA), development of complications, and the need for additional anti-inflammatory drugs were analyzed. Results Mean follow-up with MTX treatment was 27.6 months. Uveitic complications were present in 31 patients before MTX treatment. With MTX, quiescence of uveitis was obtained with (n=21) or without (n=4) additional topical steroids. Additional systemic immunosuppressive drugs were required in another 7 patients: cyclosporine A (n=4), azathioprine (n=1), infliximab (n=1), or etanercept (n=1). Three patients had active uveitis at the end of the follow-up period. During MTX therapy, uveitis first developed in the unaffected fellow eyes in 2 patients, and secondary glaucoma or ocular hypertension occurred in 7 patients. The VA deteriorated in 6, improved in 13, and was stable in the remaining eyes. Conclusions The data suggest that MTX is very effective in controlling inflammation of uveitis in patients with JIA. However, additional topical steroids or systemic immunosuppressive drugs are often required.

Adalimumab in Patients with Active Noninfectious Uveitis.

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 .).

Prognostic value of clinical and histopathological parameters in conjunctival melanomas: a retrospective study

Aim: To determine prognostic factors for recurrence of disease and tumour related mortality in patients with conjunctival melanoma. Methods: A retrospective analysis of clinical and histopathological data of 69 patients with histologically verified conjunctival melanoma. Results: As univariate analysis showed, significant risk factors for the development of recurrence were: irregular pigmentation (RR = 2.0, p = 0.0007), incomplete surgical excision (RR = 3.5, p = 0.008), tumour invasion deeper than in substantia propria (RR = 3.9, p = 0.008), and presence of epithelioid tumour cells (RR = 2.9, p = 0.05). For tumour related mortality a significantly increased risk was found for tumour location in palpebral conjunctiva, caruncle, plica, or fornices (RR = 5.9, p = 0.001), for tumour infiltration deeper than the substantia propria (RR = 5.5, p = 0.001), for incomplete surgical excision (RR = 4.4, p = 0.05), and for nodular or mixed (nodular and superficial) growth pattern of the tumours (RR = 1.2, p = 0.002). The use of an adjuvant therapy for the surgical excision of the melanomas had no statistically significant influence upon the development of recurrent disease nor upon the tumour related mortality. Conclusion: These data present similar clinical and histopathological risk factors for patients with conjunctival melanoma as reported previously. The present study also addresses the failure of retrospective studies on conjunctival melanoma to prove the efficacy of a supplementary therapy to surgical excision.

Intravitreal bevacizumab (avastin) as a treatment for refractory macular edema in patients with uveitis: a pilot study.

Purpose: Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) which has been successfully used for the treatment of age-related macular degeneration with choroidal neovascularization. As VEGF is involved in the pathomechanisms of inflammation and endothelial dysfunction the authors used bevacizumab as a last resort treatment in patients with persistent uveitic cystoid macular edema (CME). Patients and Methods: Persistent uveitic CME was defined by optical coherence tomography (OCT) measurements >250 &mgr;m despite previous treatments. The authors reviewed patients with persistent CME who subsequently had been treated with intravitreous bevacizumab 1.25 or 2.5 mg. Improvement was judged by visual acuity (VA) gain ≥2 lines and thickness reduction in OCT. Results: Eleven eyes of 10 patients were injected since February 2006. Median follow-up was 70 days. Reduction in central retinal thickness could be seen as early as 2 weeks with a mean foveal thickness reduction of 127.2 &mgr;m at 4 weeks. Concurrent improvement in VA was seen in 4 of 10 patients, and was unchanged in the others. Four patients received two injections and five patients received three injections. Except for progression of cataract in one eye no ocular or systemic adverse events were recorded. Conclusions: Intravitreal bevacizumab seems to be an effective and safe treatment in the management of refractory inflammatory CME. The effect is transient, and reinjections may be necessary, although the time until reinjection is needed differs individually.

Is tocilizumab an effective option for treatment of refractory uveitis associated with juvenile idiopathic arthritis

To the Editor: Anti-interleukin 6 receptor (anti-IL-6R) antibodies have been effective in experimental models of autoimmune arthritis, encephalomyelitis, and also uveitis1,2. Tocilizumab (TCZ; RoActemra®, Hoffmann-La Roche, Basel, Switzerland), a fully humanized anti-IL-6R antibody, has been approved for the treatment of rheumatoid arthritis. Efficacy has also been shown for systemic-onset juvenile idiopathic arthritis (JIA)3 and vasculitis4. To date, however, no reports have appeared concerning its efficacy in JIA-associated uveitis. In about one-third of JIA patients with uveitis, eye inflammation runs a severe course and vision-threatening complications develop, and immunosuppressive treatment is required5. Because some patients do not respond properly to the widely used disease-modifying antirheumatic drugs (DMARD), including tumor necrosis factor-α (TNF-α) inhibitors, there is a significant need … Address correspondence to Dr. A. Heiligenhaus, Department of Ophthalmology and Ophtha Lab, St. Franziskus Hospital, Hohenzollernring 74, 48145 Munster, Germany. E-mail: arnd.heiligenhaus{at}uveitis-zentrum.de

Long-term results of pars plana vitrectomy in the management of complicated uveitis.

This retrospective study evaluates the long term efficacy of pars plana vitrectomy on the preservation of vision in complicated chronic uveitis, including endogenous intermediate uveitis and other entities. Combined vitrectomy-lensectomy was performed in 10 eyes with complicated cataracts, and 18 vitrectomies were done without lensectomies. The mean follow up was 45 months. Additional retinal surgery (for example, scleral buckling) was performed in five eyes. Visual acuity improved in 23 eyes (82.8%) following surgery, with 16 eyes (57%) achieving a vision better than 6/24. The main causes for vision less than 6/24 were persistent cystoid macular oedema (three eyes), macular puckers (one eye), retinal vascular obliterations (four eyes), optic atrophy (five eyes), and chorioretinal scars (seven eyes). Postoperative complications were cataract formation (seven eyes), cystoid macular oedema (one eye), and tractional retinal detachments (three eyes). The surgical intervention resulted in a remarkable reduction of the severity of inflammation or frequency of exacerbations, and allowed significant tapering (11 eyes) or withdrawal (11 eyes) of the topical steroids, or oral corticosteroids (10 cases). Pre-existent cystoid macular oedema resolved in three eyes. Pars plana vitrectomy, eventually combined with lensectomy, may visually rehabilitate eyes with chronic uveitis and media opacities, and may reduce the activity of disease postoperatively.

Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and adolescents. Immunomodulatory drugs are used frequently in its treatment. Using the nominal group technique (NGT) and Delphi method, we created a multidisciplinary, evidence- and consensus-based treatment guideline for JIA based on a systematic literature analysis and three consensus conferences. Conferences were headed by a professional moderator and were attended by representatives who had been nominated by their scientific societies or organizations. 15 statements regarding drug therapy, symptomatic and surgical management were generated. It is recommended that initially JIA is treated with NSAID followed by local glucocorticoids and/or methotrexate if unresponsive. Complementing literature evidence with long-standing experience of caregivers allows creating guidelines that may potentially improve the quality of care for children and adolescents with JIA.

Matrix metalloproteinases (MMP-2 and 9) and tissue inhibitors of matrix metalloproteinases (TIMP-1 and 2) during the course of experimental necrotizing herpetic keratitis

To determine the distribution and activities of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) during the course of experimental herpes simplex virus (HSV) type-1 keratitis, BALB/c mice were corneally infected with 10(5) plaque-forming units (PFU) of HSV-1 (KOS strain) and then observed for the clinical signs of keratitis. Corneas were harvested at days 0, 2, 7 and 14 post-infection (p.i.). MMP-2, MMP-9, MMP-8, TIMP-1 and TIMP-2 were detected by immunohistochemistry and the Western blot technique. The enzymatic activities were analyzed by zymography. Epithelial HSV keratitis was present at day 2 after corneal infection and healed by day 5 p.i. While the expression and activity of MMP-2, MMP-8 and MMP-9 increased in the corneas at day 2 p.i., it was reduced at day 7 p.i. TIMP-1 and -2 were expressed in the corneas before and seven days after infection. Necrotizing stromal keratitis with corneal ulceration and dense polymorphonuclear leukocyte (PMN) infiltration was present at day 14 p.i. This correlated with increased expression of MMP-2, MMP-8 and MMP-9 in the corneas. MMP-8, MMP-9 and MMP-2 staining was particularly intense in the proximity of the ulcers and in areas of PMN infiltration. At day 14 p.i., MMP-2, -8 and -9 activities were upregulated, and TIMP-2 was expressed. These data suggest that MMPs produced by resident corneal cells and PMNs may possibly play a role in early epithelial keratitis and in the ulcerative process in the late phase after corneal HSV-1 infection. The ratio of MMPs to TIMPs may be important for the course of necrotizing HSV keratitis. TIMPs might participate in the repair process.

Review for Disease of the Year: Epidemiology of Juvenile Idiopathic Arthritis and its Associated Uveitis: The Probable Risk Factors

Abstract Juvenile idiopathic arthritis (JIA) is the most common systemic disease associated with uveitis in childhood. The frequency of JIA-associated uveitis (JIAU) varies geographically, and between ethnicities. Uveitis risk is high in JIA associated with oligoarthritis, young age at arthritis onset and ANA positivity. Gender alters risk for the incidence of JIA and the severity of JIAU. Familial cases support the possible role of genetic influences in the pathogenesis. Arthritis typically precedes the uveitis, but uveitis may occur up to seven years following the arthritis onset. Although complications still occur, the frequency of bilateral blindness has dropped, probably by both improved screening of high-risk patients with JIA, and the increased use of early immunosuppression. However, there is still continuing persistence of JIAU into adulthood. For improvement of epidemiological knowledge of this complicated disease, large, well-defined, long-term population-based registries are needed with the application of universally agreed case definitions and outcome measures.

Limited value of cyclosporine A for the treatment of patients with uveitis associated with juvenile idiopathic arthritis

AimsJuvenile idiopathic arthritis (JIA) is often associated with severe chronic anterior uveitis (CAU), and immunosuppressive therapy may be required. In this study, the value of cyclosporine A (CsA) as monotherapy or as combination therapy for treating uveitis was studied in a large cohort of JIA children.MethodsMulticentre retrospective study including 82 JIA children (girls n=60) suffering from unilateral or bilateral (n=55) CAU. The indication for CsA was active uveitis, although patients were on topical or systemic corticosteroids, MTX, or other immunosuppressive drugs.ResultsInactivity of uveitis during the entire treatment period (mean 3.9 years) was obtained with CsA monotherapy in 6 of 25 (24%) patients, but more often when CsA was combined with the immunosuppressives (35/72 patients; 48.6%, P=0.037), or MTX (18/37 patients, 48.6%, P=0.065), which had already been given. With CsA (mean dosage 2.9 mg/kg), systemic immunosuppressive drugs and steroids could be reduced by ⩾50% (n=19) or topical steroids reduced to ⩽2 drops/eye/day (n=40) in selected patients. Pre-existing cystoid macular oedema did not resolve under CsA treatment in any of the patients. In nine patients (11%), CsA was discontinued because of systemic hypertension (n=1), elevated creatinine levels (n=3), or other adverse effects (n=5).ConclusionsThese observations suggest that CsA has limited value as a second-line immunosuppressive drug for the treatment of JIA-associated CAU. The efficacy was better as the combination therapy in patients not responding to other immunosuppressives (eg, MTX) than the systemic monotherapy.