Rituximab therapy for refractory scleritis: results of a phase I/II dose-ranging, randomized, clinical trial.

OBJECTIVE: To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory noninfectious scleritis. DESIGN: Prospective, dose-ranging, randomized, double-masked phase I/II clinical trial. PARTICIPANTS: Twelve patients with noninfectious scleritis refractory to systemic corticosteroid and ≥1 other systemic immunosuppressive agent were enrolled from January 2007 to March 2010. INTERVENTION: Subjects were randomly assigned to 500 (n = 5) or 1000 mg (n = 7) dosing arms of rituximab intravenous infusions (500 or 1000 mg), given at study days 1 and 15. Initial responders with breakthrough inflammation after study week 24 were offered treatment with an additional cycle of 2 open-label rituximab 1000 mg infusions. MAIN OUTCOME MEASURES: Primary outcomes were reduction of inflammation, as measured with a validated scleritis disease grading scale (SGS) and reduction in corticosteroid dose by ≥50%. Patients were characterized as responders to study therapy if ≥1 of these endpoints showed improvement and neither showed evidence of worsening. Secondary outcomes were improvement in visual acuity, reduction in pain, and improvement in patient and physician-reported global health assessment. RESULTS: Of 12 enrolled patients, 9 met the SGS endpoint at or before week 24, and 4 additionally were able to reduce corticosteroid dose by ≥50%. With regard to secondary outcome measures, 11 and 9 patients showed improvement in patient and physician global health scores, respectively, and 7 patients had reduction in pain. Of 9 initial responders, 7 experienced breakthrough inflammation after 24 weeks and were treated with a second cycle of rituximab infusions. Four patients had significant objective or subjective worsening within 8 weeks of receiving rituximab; this event was averted in subsequent patients by treatment with peri-infusional oral corticosteroid. No other significant adverse events were noted. No differences in efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms. CONCLUSIONS: Rituximab was effective treatment for 9 of 12 enrolled patients with refractory, noninfectious scleritis at 24 weeks, although 7 required reinfusion with rituximab to maintain inflammatory control. The treatment was well-tolerated, and peri-infusional inflammatory exacerbations were managed successfully with oral corticosteroids. Further long-term studies are warranted to determine the safety and efficacy of rituximab in treating noninfectious scleritis and other ocular inflammatory diseases.

Rituximab therapy for refractory orbital inflammation: results of a phase 1/2, dose-ranging, randomized clinical trial.

IMPORTANCE: Orbital inflammation is a potentially blinding and disfiguring disease process that is often treated with systemic corticosteroids and immunosuppression; better treatments are needed. OBJECTIVE: To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory orbital inflammation. DESIGN, SETTING, AND PARTICIPANTS: A dose-ranging, randomized, double-masked phase 1/2 clinical trial was conducted at a tertiary referral ophthalmology clinic. Ten individuals with orbital inflammation refractory to systemic corticosteroids and at least 1 other immunosuppressive agent were enrolled from January 2007 to March 2010. INTERVENTIONS: Rituximab infusions were administered on study days 1 and 15 at doses of either 500 mg or 1000 mg. Initial responders with recurrent inflammation after week 24 were permitted reinfusion with an additional cycle of 2 open-label 1000-mg rituximab infusions. MAIN OUTCOMES AND MEASURES: The primary outcomes were reduction of inflammation measured with a validated orbital disease grading scale and corticosteroid dose reduction by at least 50%. The secondary outcomes were visual acuity, reduction in pain, and participant- and physician-reported global health assessment. RESULTS: Of 10 enrolled patients, 7 demonstrated improvement on the orbital disease grading scale at the 24-week end point with rituximab therapy. Of these 7 individuals, 4 were receiving corticosteroids at study inception and all achieved successful dose reduction. For the secondary outcome measures in the 10 participants, 7 patients and 8 patients improved in self-rated and physician global health scores, respectively, and 7 patients had reduction in pain by 25% or more at 24 weeks. Four patients who were positive responders at the week 24 end point experienced breakthrough inflammation after week 24 and received reinfusions between 24 and 48 weeks. Vision remained stable in all participants. Three of 10 patients had short-term objective or subjective worsening 2 to 8 weeks after receiving rituximab infusions, which was averted in subsequent patients with oral corticosteroids administered during the infusion and did not affect the eventual positive treatment outcome. No significant differences with regard to efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms. CONCLUSIONS AND RELEVANCE: Rituximab was safe and effective in 7 of 10 patients with noninfectious orbital disease, although 4 required reinfusion with rituximab to maintain control of orbital inflammation. Substantial toxicity was not noted. Rituximab should be considered in the treatment of refractory orbital inflammation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00415506.

Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial.

OBJECTIVE: Tumour necrosis factor (TNF) blockers have been demonstrated to be effective in the treatment of systemic and ocular inflammatory diseases. We conducted a prospective, multicentre, open-label Phase II clinical trial to assess the effectiveness and safety of adalimumab, a fully human anti-TNF monoclonal antibody, in treating refractory uveitis. METHODS: Subjects with non-infectious uveitis refractory to corticosteroids and at least one other immunosuppressive medication were enrolled. Treatment outcome was ascertained by a composite endpoint comprised of visual acuity, intraocular inflammation, ability to taper immunosuppressives, and posterior segment imaging. Clinical response was defined by improvement in at least one parameter, worsening in none, and well controlled intraocular inflammation. Week 10 responders were permitted to continue receiving adalimumab for the study duration of 50 weeks. RESULTS: Twenty-one of 31 patients (68%) were characterised as clinical responders at 10 weeks, of whom 12 patients (39%) exhibited durable response after 50 weeks. The most common reason for study termination was primary or secondary inefficacy. No patients experienced treatment-limiting toxicity clearly related to study therapy. CONCLUSIONS: Adalimumab was safe and effective in 68% of refractory uveitis patients 10 weeks after study enrolment, and maintained in 39% after 1 year. Ongoing study is required to determine the place of adalimumab and other TNF blockers in the treatment of uveitis.

The use of vascular endothelial growth factor inhibitor for choroidal neovascularization complicating posterior uveitis in eyes with fluocinolone acetonide implants.

PURPOSE: To present a series of eyes with multifocal choroiditis and panuveitis (MFC) treated with fluocinolone acetonide intravitreal implants. All eyes developed recurrent choroidal neovascularization (CNV) and were treated with intravitreal bevacizumab or ranibizumab. METHODS: Retrospective chart review. Data collected included demographics, details of previous immunosuppressive therapy, preinjection Snellen visual acuity, and central macular thickness measured by optical coherence tomography, total injections administered, and postinjection central macular thickness and visual acuity. Patients were followed up for a minimum of 25 months from the first fluocinolone acetonide implant. Duration from implantation to first injection and complications, including development of cataracts, glaucoma, and recurrent inflammation, were followed. PATIENTS: Three patients treated for MFC at the Casey Eye Institute, a tertiary care referral center at Oregon Health & Science University, from 2005-2008 were studied. All three received fluocinolone acetonide implants and later underwent intravitreal anti-vascular endothelial growth factor (VEGF) therapy for CNV. RESULTS: Preinjection visual acuity in 3 patients was 1.2, 0.54, and 0.48 logarithm of minimal angle of resolution (mean 0.74). Postinjection visual acuity in 3 patients was 1.0, 0.40, and 0.0 logarithm of minimal angle of resolution (mean 0.47). Preinjection central macular thicknesses were 855 µm, 215 µm, and 276 µm (mean 449 µm). Postinjection central macular thicknesses were 220 µm, 190 µm, and 223 µm (mean 211 µm). Anti-VEGF injections did not reactivate inflammation. Advancing cataracts contributed to worsening visual acuity postinjection. The total number of anti-VEGF injections until resolution of intraretinal and subretinal fluid associated with CNV was 6 injections for case 1, 1 for case 2, and 8 for case 3 (mean 5, range 1-8). CONCLUSION: Intravitreal anti-VEGF therapy was successful in treating recurrent CNV in MFC patients with well-controlled inflammation after insertion of fluocinolone acetonide implants. Anti-VEGF therapy should be considered in treating active CNV in eyes with MFC and quiescent inflammatory disease.

The treatment of recurrent central serous chorioretinopathy with intravitreal bevacizumab.

PURPOSE: To study the effect of intravitreal bevacizumab injection in recurrent central serous chorioretinopathy (CSC). METHODS: Retrospective case series. Patients followed at the Yale Eye Center with a diagnosis of recurrent CSC who were treated with intravitreal bevacizumab from January 2007 to January 2009 were studied. Intravitreal injections of bevacizumab were given once every 4 weeks until sub-retinal fluid resolved. We collected preinjection visual acuity, optical coherence tomography (OCT), fluorescein angiography imaging, number of injections administered, OCT data after each injection, and visual acuity after each injection. Each patient was followed for a minimum of 6 months. RESULTS: Three patients met the inclusion criteria. All patients were men and aged from 39 to 46 years. All patients had recurrent disease. None had received prior treatment. Mean preinjection visual acuity was logMar 0.30, with a median of 0.30. Mean postbevacizumab visual acuity was 0.03, 0.07, and 0.03 at 1, 3, and 6 months, respectively. Median postbevacizumab acuity was 0, 0.10, and 0 at 1, 3, and 6 months, respectively. Baseline preinjection central macular thickness (CMT) by OCT imaging ranged from 320 to 500 µm, with a mean of 388 µm and a median of 344 µm. Mean CMT at month 1 was 248 µm, with a median of 190 µm. Mean CMT at month 3 was 252 µm, with a median of 281 µm. Mean CMT at month 6 was 273 µm, with a median of 187 µm. CONCLUSIONS: Bevacizumab may be an effective treatment option for patients with recurrent CSC. Although long-term efficacy is unknown, it is a relatively low-risk treatment option that may improve visual acuity and CMT.