To evaluate the outcome of treatment with methotrexate for noninfectious ocular inflammation.
Retrospective cohort study.
Patients with noninfectious ocular inflammation managed at 4 tertiary ocular ...inflammation clinics in the United States observed to add methotrexate as a single, noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007, inclusive.
Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage, route of administration of methotrexate, and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers.
Control of inflammation, corticosteroid-sparing effects, and incidence of and reason for discontinuation of therapy.
Among 384 patients (639 eyes) observed from the point of addition of methotrexate to an anti-inflammatory regimen, 32.8%, 9.9%, 21.4%, 14.6%, 15.1%, and 6.3%, respectively, had anterior uveitis, intermediate uveitis, posterior or panuveitis, scleritis, ocular mucous membrane pemphigoid, and other forms of ocular inflammation. In these groups, complete suppression of inflammation sustained for >or=28 days was achieved within 6 months in 55.6%, 47.4%, 38.6%, 56.4%, 39.5%, and 76.7%, respectively. Corticosteroid-sparing success (sustained suppression of inflammation with prednisone <or=10 mg/d) was achieved within 6 months among 46.1%, 41.3%, 20.7%, 37.3%, 36.5%, and 50.9%, respectively. Overall, success within 12 months was 66% and 58.4% for sustained control and corticosteroid sparing (<or=10 mg), respectively. Methotrexate was discontinued within 1 year by 42% of patients. It was discontinued owing to ineffectiveness in 50 patients (13%); 60 patients (16%) discontinued because of side effects, which typically were reversible with dose reduction or discontinuation. Remission was seen in 43 patients, with 7.7% remitting within 1 year of treatment.
Our data suggest that adding methotrexate to an anti-inflammatory regimen not involving other noncorticosteroid immunosuppressive drugs is moderately effective for management of inflammatory activity and for achieving corticosteroid-sparing objectives, although many months may be required for therapeutic success. Methotrexate was well tolerated by most patients, and seems to convey little risk of serious side effects during treatment.
This phase 3 trial showed that persons with noninfectious uveitis who received adalimumab were more likely to have serious adverse events and less likely to have ophthalmic inflammation, uveitic ...flare, or visual impairment than were those who received placebo.
Noninfectious uveitis is a group of vision-threatening diseases that are characterized by intraocular inflammation; it can occur as a syndrome isolated to the eye or in association with a systemic condition. Uveitis has an estimated incidence of 17 to 52 cases per 100,000 person-years
1
and is estimated to cause 10 to 15% of cases of blindness in Western countries.
2
,
3
Glucocorticoids remain the mainstay of therapy despite their well-known ocular and systemic adverse effects.
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–
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Thus, there is a large unmet medical need for and a great interest in identifying more effective, glucocorticoid-sparing therapies, ideally targeting specific mediators of the . . .
To evaluate safety and efficacy of adalimumab in patients with noninfectious intermediate, posterior, or panuveitis.
Phase 3, open-label, multicenter clinical trial extension (VISUAL III).
Adults ...meeting treatment failure (TF) criteria or who completed VISUAL I or II (phase 3, randomized, double-masked, placebo-controlled) without TF.
Patients received adalimumab 40 mg every other week. Interim follow-up data were described from VISUAL III weeks 0 through 78.
Disease quiescence, steroid-free quiescence, active inflammatory chorioretinal/retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, best-corrected visual acuity (BCVA), and corticosteroid dose. Binary data were reported using nonresponder imputation (NRI), continuous data using last observation carried forward and as-observed analysis, and corticosteroid dose using observed-case analysis. Adverse events (AEs) were reported from first adalimumab dose in VISUAL III through interim cutoff.
Of 424 patients enrolled, 371 were included in intent-to-treat analysis. At study entry, 242 of 371 (65%) patients had active uveitis; 60% (145/242, NRI) achieved quiescence at week 78, and 66% (95/143, as-observed) of those were corticosteroid free. At study entry, 129 of 371 (35%) patients had inactive uveitis; 74% (96/129, NRI) achieved quiescence at week 78, and 93% (89/96, as-observed) of those were corticosteroid free. Inflammatory lesions, anterior chamber grade, and vitreous haze grade showed initial improvement followed by decline in patients with active uveitis and remained stable in patients with inactive uveitis. BCVA improved in patients with active uveitis from weeks 0 to 78 (0.27 to 0.14 logMAR; left and right eyes; as-observed) and remained stable in patients with inactive uveitis. Mean corticosteroid dose decreased from 13.6 mg/day (week 0) to 2.6 mg/day (week 78) in patients with active uveitis and remained stable in those with inactive uveitis (1.5–1.2 mg/day). AEs (424 events/100 patient-years) and serious AEs (16.5 events/100 patient-years) were comparable with previous VISUAL trials.
Patients with active uveitis at study entry who received adalimumab therapy were likely to achieve quiescence, improve visual acuity, and reduce their daily uveitis-related systemic corticosteroid use. Most patients with inactive uveitis at study entry sustained quiescence without a systemic corticosteroid dose increase. No new safety signals were identified.
The future of uveitis treatment Lin, Phoebe; Suhler, Eric B; Rosenbaum, James T
Ophthalmology,
01/2014, Volume:
121, Issue:
1
Journal Article
Peer reviewed
Open access
Uveitis is a heterogeneous collection of diseases with polygenic and environmental influences. This heterogeneity presents challenges in trial design and selection of end points. Despite the ...multitude of causes, therapeutics targeting common inflammatory pathways are effective in treating diverse forms of uveitis. These treatments, including corticosteroids and immunomodulatory agents, although often effective, can have untoward side effects, limiting their utility. The search for drugs with equal or improved efficacy that are safe is therefore paramount. A mechanism-based approach is most likely to yield the future breakthroughs in the treatment of uveitis. We review the literature and provide examples of the nuances of immune regulation and dysregulation that can be targeted for therapeutic benefit. As our understanding of the causes of uveitis grows we will learn how to better apply antibodies designed to block interaction between inflammatory cytokines and their receptors. T-lymphocyte activation can be targeted by blocking co-stimulatory pathways or inhibiting major histocompatibility complex protein interactions. Furthermore, intracellular downstream molecules from cytokine or other pathways can be inhibited using small molecule inhibitors, which have the benefit of being orally bioavailable. An emerging field is the lipid-mediated inflammatory and regulatory pathways. Alternatively, anti-inflammatory cytokines can be provided by administering recombinant protein, and intracellular "brakes" of inflammatory pathways can be introduced potentially by gene therapy. Novel approaches of delivering a therapeutic substance include, but are not limited to, the use of small interfering RNA, viral and nonviral gene therapy, and microparticle or viscous gel sustained-release drug-delivery platforms.
To describe the incidence of and risk factors for visual acuity (VA) loss and ocular complications in patients with juvenile idiopathic arthritis (JIA)-associated uveitis.
Multicenter retrospective ...cohort study.
A total of 327 patients (596 affected eyes) with JIA-associated uveitis managed at 5 tertiary uveitis clinics in the United States.
Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) cohort study. Demographic and clinical characteristics were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers.
Loss of VA to 20/50 or to 20/200 or worse thresholds and the development of ocular complications.
At presentation, 240 eyes (40.3%) had a VA of ≤20/50, 144 eyes (24.2%) had a VA of ≤20/200, and 359 eyes (60.2%) had at least 1 ocular complication. The incidences of VA loss to the ≤20/50 and ≤20/200 thresholds were 0.18 and 0.09 per eye-year (EY), respectively; the incidence of developing at least 1 new ocular complication over follow-up was 0.15/EY (95% confidence interval CI, 0.13-0.17). However, among eyes with uveitis that had no complications at presentation, the rate of developing at least 1 ocular complication during follow-up was lower (0.04/EY; 95% CI, 0.02-0.06). Posterior synechiae, active uveitis, and prior intraocular surgery were statistically significantly associated with VA to the ≤20/50 and ≤20/200 thresholds both at presentation and during follow-up. Increasing (time-updated) anterior chamber cell grade was associated with increased rates of visual loss in a dose-dependent fashion. Use of immunosuppressive drugs was associated with a reduced risk of visual loss, particularly for the ≤20/50 outcome (hazard ratio, 0.40; 95% CI, 0.21-0.75; P<0.01).
Ocular complications and vision loss were common in our cohort. Increasing uveitis activity was associated with increased risk of vision loss, and use of immunosuppressive drugs was associated with reduced risk of vision loss, suggesting that control of inflammation and use of immunosuppression may be critical aspects in improving the outcomes of patients with JIA-related uveitis.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
IMPORTANCE: Methotrexate and mycophenolate mofetil are commonly used immunomodulatory therapies for achieving corticosteroid-sparing control of noninfectious uveitis, but there is uncertainty about ...which drug is more effective. OBJECTIVE: To compare the effect of methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. DESIGN, SETTING, AND PARTICIPANTS: The First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial screened 265 adults with noninfectious uveitis requiring corticosteroid-sparing immunosuppressive therapy from 9 referral eye centers in India, the United States, Australia, Saudi Arabia, and Mexico between August 22, 2013, and August 16, 2017. Follow-up ended on August 20, 2018. INTERVENTIONS: Patients were randomized to receive oral methotrexate, 25 mg weekly (n = 107), or oral mycophenolate mofetil, 3 g daily (n = 109). MAIN OUTCOMES AND MEASURES: The primary outcome was treatment success at 6 months, which was defined as having control of inflammation in both eyes, no more than 7.5 mg prednisone daily and less than or equal to 2 drops of prednisolone acetate 1%, and no treatment failure due to safety or intolerability. Patients underwent follow-up to 12 months while receiving the same treatment or switched to the other antimetabolite, depending on their 6-month outcome. RESULTS: Among 216 patients who were randomized (median age, 38 years; 135 (62.5%) women), 194 (89.8%) completed follow-up through 6 months. Treatment success occurred in 64 (66.7%) patients in the methotrexate group vs 56 (57.1%) in the mycophenolate group (difference, 9.5% 95% CI, −5.3% to 21.8%; odds ratio OR, 1.50 95% CI, 0.81 to 2.81; P = .20). Among patients with posterior uveitis or panuveitis, treatment success was achieved in 58 (74.4%) in the methotrexate group vs 42 (55.3%) in the mycophenolate group (difference, 19.1% 95% CI, 3.6% to 30.6%; OR, 2.35 95% CI, 1.16 to 4.90; P = .02); whereas among patients with intermediate uveitis treatment success occurred in 6 (33.3%) in the methotrexate group vs 14 (63.6%) in the mycophenolate group (difference, −30.3% 95% CI, −51.6% to 1.1%; OR, 0.29 95% CI, 0.08 to 1.05; P = .07; P for interaction = .004). Elevated liver enzymes were the most common nonserious laboratory adverse event, occurring in 14 patients (13.0%) in the methotrexate group and 8 patients (7.4%) in the mycophenolate group. CONCLUSIONS AND RELEVANCE: Among adults with noninfectious uveitis, the use of mycophenolate mofetil compared with methotrexate as first-line corticosteroid-sparing treatment did not result in superior control of inflammation. Further research is needed to determine if either drug is more effective based on the anatomical subtype of uveitis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01829295
Gordonia bronchialis is an aerobic actinomycetes that rarely causes infections in humans. Few reports describe Gordonia spp. causing eye-related infections. We report a case of chronic infectious ...endophthalmitis in Oregon, USA, associated with infection by G. bronchialis.
Purpose To ascertain the frequency of uveitis in Veterans Affairs (VA) patients in the Pacific Northwest and to compare disease rates with those in previously published epidemiologic studies. Design ...Cross-sectional, population based-study. Methods The medical records of 152,267 patients seen at six VA Medical Centers in Oregon and Washington during fiscal year 2004 were searched for uveitis-related Internation Classification of Diseases 9th edition codes. Cases were reviewed and classified anatomically, by associated systemic disease, and as incident or prevalent. Only definite cases were used for disease rate calculations. Results This study found a crude incidence of 25.6 cases/100,000 person-years and a crude prevalence of 69 cases/100,000 persons. The most common anatomic location for uveitis was anterior. Approximately half of cases were idiopathic, with human leukocyte antigen-B27–related diseases being the most common identified cause. There was no statistical evidence of increased or decreased incidence with age, although uveitis seemed to be more prevalent in the younger age groups. Conclusions Our data are consistent with those of most published population-based studies on the epidemiologic features of uveitis, but we detected significantly lower incidence and prevalence than those reported in a recently published study from Kaiser Permanente. The significance of and possible explanations for the differences between our data and that published by the Kaiser group are discussed.
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.
To evaluate the clinical outcomes of cyclosporine treatment for noninfectious ocular inflammation.
Retrospective cohort study.
A total of 373 patients with noninfectious ocular inflammation managed ...at 4 tertiary ocular inflammation clinics in the United States observed to use cyclosporine as a single noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007 inclusive.
Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage of cyclosporine and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers.
Control of inflammation, sustained control after reducing corticosteroid dosages, and discontinuation of therapy because of toxicity.
Of the 373 patients (681 eyes) initiating cyclosporine monotherapy, 33.4% by 6 months and 51.9% by 1 year gained sustained, complete control of inflammation over at least 2 visits spanning at least 28 days. Approximately 25% more improved to a level of slight inflammatory activity by each of these time points. Corticosteroid-sparing success (completely controlled inflammation for at least 28 days with prednisone < or = 10 mg/day) was achieved by 22.1% by 6 months and 36.1% within 1 year. Toxicity led to discontinuation of therapy within 1 year by 10.7% of the population. Patients aged more than 55 years were more than 3-fold more likely to discontinue therapy because of toxicity than patients aged 18 to 39 years. Doses of 151 to 250 mg/day tended to be more successful than lower doses and were not associated with a higher discontinuation for toxicity rate; higher doses did not seem to offer a therapeutic advantage.
Cyclosporine, with corticosteroid therapy as indicated, was modestly effective for controlling ocular inflammation. Our data support a preference for cyclosporine adult dosing between 151 and 250 mg/day. Although cyclosporine was tolerated by the majority of patients, toxicity was more frequent with increasing age; alternative agents may be preferred for patients aged more than 55 years.
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