Reduced Dose Methotrexate and Mycophenolate Mofetil in Noninfectious Uveitis: A Sub-Analysis from the First-Line Antimetabolites as Steroid Sparing Therapy (FAST) Trial.

PURPOSE: Some patients taking methotrexate (MTX) or mycophenolate mofetil (MMF) experience intolerable side effects at full doses. We evaluated whether dose reduction affected treatment outcomes in uveitis patients. METHODS: Subanalysis of the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial. Patients were randomized to receive MTX (25 mg weekly) or MMF (3 g daily). A pre-specified dose reduction protocol could be employed for intolerable side effects. Primary analysis was performed at 6 months. RESULTS: 43/194 patients (22%) required dose reduction. 88/151 patients (58%) on maximum doses and 32/43 patients (74%) on reduced doses were deemed treatment successes at 6 months. The odds ratio point estimate (1.60, 95% CI 0.72-3.74) favored dose-reduction but this was not significant. Following reduction, adverse events improved at the subsequent study visit (79 events reduced to 63 events). CONCLUSION: Dose reduction of antimetabolites was not associated with worse outcomes in this subanalysis of a uveitis trial

A Bayesian Analysis of a Randomized Clinical Trial Comparing Antimetabolite Therapies for Non-Infectious Uveitis

PurposeTo conduct a Bayesian analysis of a randomized clinical trial (RCT) for non-infectious uveitis using expert opinion as a subjective prior belief.MethodsA RCT was conducted to determine which antimetabolite, methotrexate or mycophenolate mofetil, is more effective as an initial corticosteroid-sparing agent for the treatment of intermediate, posterior, and pan-uveitis. Before the release of trial results, expert opinion on the relative effectiveness of these two medications was collected via online survey. Members of the American Uveitis Society executive committee were invited to provide an estimate for the relative decrease in efficacy with a 95% credible interval (CrI). A prior probability distribution was created from experts' estimates. A Bayesian analysis was performed using the constructed expert prior probability distribution and the trial's primary outcome.ResultsA total of 11 of the 12 invited uveitis specialists provided estimates. Eight of 11 experts (73%) believed mycophenolate mofetil is more effective. The group prior belief was that the odds of treatment success for patients taking mycophenolate mofetil were 1.4-fold the odds of those taking methotrexate (95% CrI 0.03-45.0). The odds of treatment success with mycophenolate mofetil compared to methotrexate was 0.4 from the RCT (95% confidence interval 0.1-1.2) and 0.7 (95% CrI 0.2-1.7) from the Bayesian analysis.ConclusionsA Bayesian analysis combining expert belief with the trial's result did not indicate preference for one drug. However, the wide credible interval leaves open the possibility of a substantial treatment effect. This suggests clinical equipoise necessary to allow a larger, more definitive RCT

Quality-of-Life Outcomes From a Randomized Clinical Trial Comparing Antimetabolites for Intermediate, Posterior, and Panuveitis.

PurposeTo evaluate the changes in quality of life in noninfectious uveitis patients treated with 2 of the most commonly prescribed antimetabolite treatments.DesignSecondary analysis of a multicenter, block-randomized clinical trial.MethodsEighty patients at Aravind Eye Hospitals in Madurai and Coimbatore, India, with noninfectious intermediate, posterior, or panuveitis were randomized to receive oral methotrexate, 25 mg weekly, or oral mycophenolate mofetil, 1 g twice daily, and were followed up monthly for 6 months. Best-corrected visual acuity, Indian Vision Function Questionnaire (IND-VFQ), and Medical Outcomes Study 36-item Short Form Survey (SF-36) were obtained at enrollment and at 6 months (or prior, in the event of early treatment failure).ResultsIND-VFQ scores, on average, increased by 9.2 points from trial enrollment to 6 months (95% confidence interval [CI]: 4.9, 13.5, P = .0001). Although the SF-36 physical component summary score did not significantly differ over the course of the trial, the mental component summary score decreased by 2.3 points (95% CI: -4.4, -0.1, P = .04) and the vitality subscale decreased by 3.5 points (95% CI: -5.6, -1.4, P = .001). Quality-of-life scores did not differ between treatment arms. Linear regression modeling showed a 3.2-point improvement in IND-VFQ score for every 5-letter improvement in visual acuity (95% CI: 1.9, 4.3; P < .001).ConclusionsAlthough uveitis treatment was associated with increased vision and vision-related quality of life, patient-reported physical health did not change after 6 months of treatment, and mental health decreased. Despite improved visual outcomes, uveitis patients receiving systemic immunosuppressive therapy may experience a deterioration in mental health-related quality of life

A Randomized Clinical Trial Comparing Methotrexate and Mycophenolate Mofetil for Noninfectious Uveitis

ObjectiveTo compare the relative effectiveness of methotrexate and mycophenolate mofetil for noninfectious intermediate uveitis, posterior uveitis, or panuveitis.DesignMulticenter, block-randomized, observer-masked clinical trial.ParticipantsEighty patients with noninfectious intermediate, posterior, or panuveitis requiring corticosteroid-sparing therapy at Aravind Eye Hospitals in Madurai and Coimbatore, India.InterventionPatients were randomized to receive 25 mg weekly oral methotrexate or 1 g twice daily oral mycophenolate mofetil and were monitored monthly for 6 months. Oral prednisone and topical corticosteroids were tapered.Main outcome measuresMasked examiners assessed the primary outcome of treatment success, defined by achieving the following at 5 and 6 months: (1) ≤0.5+ anterior chamber cells, ≤0.5+ vitreous cells, ≤0.5+ vitreous haze and no active retinal/choroidal lesions in both eyes, (2) ≤10 mg of prednisone and ≤2 drops of prednisolone acetate 1% a day, and (3) no declaration of treatment failure because of intolerability or safety. Additional outcomes included time to sustained corticosteroid-sparing control of inflammation, change in best spectacle-corrected visual acuity, resolution of macular edema, adverse events, subgroup analysis by anatomic location, and medication adherence.ResultsForty-one patients were randomized to methotrexate and 39 to mycophenolate mofetil. A total of 67 patients (35 methotrexate, 32 mycophenolate mofetil) contributed to the primary outcome. Sixty-nine percent of patients achieved treatment success with methotrexate and 47% with mycophenolate mofetil (P = 0.09). Treatment failure from adverse events or tolerability was not different by treatment arm (P = 0.99). There were no differences between treatment groups in time to corticosteroid-sparing control of inflammation (P = 0.44), change in best spectacle-corrected visual acuity (P = 0.68), or resolution of macular edema (P = 0.31).ConclusionsThere was no statistically significant difference in corticosteroid-sparing control of inflammation between patients receiving methotrexate or mycophenolate mofetil. However, there was a 22% difference in treatment success favoring methotrexate

Comparison of CD4 Counts with Mycophenolate Mofetil versus Methotrexate from the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial

PurposeSub-analysis of the FAST Trial comparing change in CD4 (∆CD4) from baseline through 12 months in uveitis patients treated with mycophenolate mofetil (MMF) and methotrexate (MTX).MethodsPatients were randomly allocated to 1.5 g twice daily MMF or 25 mg weekly MTX. Individuals with CD4 counts at baseline, 6 months (or treatment failure prior), and 12 months (or treatment failure between 6 and 12 months) were included. The association between treatment and ∆CD4 (cells/μL) was analyzed using multivariable linear regression.ResultsThere was no significant difference in ∆CD4 between MMF and MTX at 6 months (-31.7 cells/μL for MMF compared to MTX; 95% CI: -358.2 to 294.8, P = .85) and 12 months (-78.3 cells/μL for MMF compared to MTX; 95% CI: -468.0 to 311.3; P = .69).ConclusionThere was no significant difference in ∆CD4 between MMF and MTX from baseline to 12 months, suggesting that MMF does not confer additional risk of CD4 lymphopenia in uveitic patients.ClinicalTrials.gov Identifier: NCT01829295

Risk of failing both methotrexate and mycophenolate mofetil from the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial.

BackgroundThe antimetabolites methotrexate (MTX) and mycophenolate mofetil (MMF) are commonly used as initial corticosteroid-sparing treatment for uveitis. There is little data examining risk factors for failing both MTX and MMF. The objective of this study is to determine risk factors for failing both MTX and MMF in patients with non-infectious uveitis.Main bodyThis is a sub-analysis of the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial, which was an international, multicenter, block-randomized, observer-masked, comparative effectiveness trial comparing MTX and MMF as initial treatments for non-infectious uveitis. This study was undertaken at multiple referral centers in India, the United States, Australia, Saudi Arabia and Mexico between 2013 and 2017. A total of 137 patients who completed all 12 months of follow-up from the FAST trial, were included in this study. The primary outcome was failing both antimetabolites over the 12 months of the trial. Potential predictors included: age, sex, bilateral involvement, anatomic location of the uveitis, presence of cystoid macular edema (CME) and retinal vasculitis at baseline visit, uveitis duration, and country/study sites as risk factors for failing both MTX and MMF. The presence of retinal vasculitis posterior to the equator on fluorescein angiogram was associated with failing both MTX and MMF.ConclusionRetinal vasculitis may be a risk factor for failing multiple antimetabolites. Clinicians could consider more quickly advancing these patients to other medication classes, such as biologics

Effect of Corticosteroid-Sparing Treatment With Mycophenolate Mofetil vs Methotrexate on Inflammation in Patients With Uveitis: A Randomized Clinical Trial.

ImportanceMethotrexate 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.ObjectiveTo compare the effect of methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis.Design, setting, and participantsThe 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.InterventionsPatients were randomized to receive oral methotrexate, 25 mg weekly (n = 107), or oral mycophenolate mofetil, 3 g daily (n = 109).Main outcomes and measuresThe 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.ResultsAmong 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 relevanceAmong 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 registrationClinicalTrials.gov Identifier: NCT01829295

A Randomized Clinical Trial Comparing Methotrexate and Mycophenolate Mofetil for Noninfectious Uveitis

OBJECTIVE: To compare the relative effectiveness of methotrexate and mycophenolate mofetil for non-infectious intermediate uveitis, posterior uveitis, or panuveitis. DESIGN: Multicenter, block-randomized, observer-masked clinical trial PARTICIPANTS: Eighty patients with non-infectious intermediate, posterior or panuveitis requiring corticosteroid-sparing therapy at Aravind Eye Hospitals in Madurai and Coimbatore, India. INTERVENTION: Patients were randomized to receive 25mg weekly oral methotrexate or 1g twice daily oral mycophenolate mofetil and were monitored monthly for 6 months. Oral prednisone and topical corticosteroids were tapered. MAIN OUTCOME MEASURES: Masked examiners assessed the primary outcome of treatment success, defined by achieving the following at 5 and 6 months: (1) ≤0.5+ anterior chamber cells, ≤0.5+ vitreous cells, ≤0.5+ vitreous haze and no active retinal/choroidal lesions in both eyes, (2) ≤ 10 mg of prednisone and ≤ 2 drops of prednisolone acetate 1% a day and (3) no declaration of treatment failure due to intolerability or safety. Additional outcomes included time to sustained corticosteroid-sparing control of inflammation, change in best spectacle-corrected visual acuity, resolution of macular edema, adverse events, subgroup analysis by anatomic location, and medication adherence. RESULTS: Forty-one patients were randomized to methotrexate and 39 to mycophenolate mofetil. A total of 67 patients (35 methotrexate, 32 mycophenolate mofetil) contributed to the primary outcome. Sixty-nine percent of patients achieved treatment success with methotrexate and 47% with mycophenolate mofetil (p=0.09). Treatment failure due to adverse events or tolerability was not significantly different by treatment arm (p=0.99). There were no statistically significant differences between treatment groups in time to corticosteroid-sparing control of inflammation (p=0.44), change in best spectacle-corrected visual acuity (p=0.68), and resolution of macular edema (p=0.31). CONCLUSIONS: There was no statistically significant difference in corticosteroid-sparing control of inflammation between patients receiving methotrexate or mycophenolate mofetil. However, there was a 22% difference in treatment success favoring methotrexate

Outcomes of Vogt-Koyanagi-Harada Disease: A Subanalysis From a Randomized Clinical Trial of Antimetabolite Therapies

PURPOSE: To report outcomes of Vogt-Koyanagi-Harada (VKH) disease from a clinical trial of antimetabolite therapies. DESIGN: Subanalysis from an observer-masked randomized clinical trial for non-infectious intermediate, posterior, and pan- uveitis. METHODS: SETTING: clinical practice at Aravind Eye Hospitals, India PATIENT POPULATION: Forty-three of 80 patients enrolled (54%) diagnosed with VKH. INTERVENTION: Patients were randomized to either 25mg oral methotrexate weekly or 1g mycophenolate mofetil twice daily, with a corticosteroid taper. MAIN OUTCOME MEASURES: Primary outcome was corticosteroid-sparing control of inflammation at 5 and 6 months. Secondary outcomes included visual acuity, central subfield thickness, and adverse events. Patients were categorized as acute (diagnosis ≤3 months prior to enrollment) or chronic (diagnosis >3 months prior to enrollment). RESULTS: Twenty-seven patients were randomized to methotrexate and 16 to mycophenolate mofetil; 30 had acute VKH. The odds of achieving corticosteroid-sparing control of inflammation with methotrexate were 2.5 times (95% CI: 0.6, 9.8; P=0.20) the odds with mycophenolate mofetil, a difference which was not statistically significant. The average improvement in visual acuity was 12.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. On average, visual acuity for patients with acute VKH improved by 14 more ETDRS letters than those with chronic VKH (P<0.001), but there was no difference in corticosteroid-sparing control of inflammation (P=0.99). All 26 eyes with a serous retinal detachment at baseline resolved, and 88% achieved corticosteroid-sparing control of inflammation. CONCLUSIONS: The majority of patients treated with antimetabolites and corticosteroids were able to achieve corticosteroid-sparing control of inflammation by 6 months. Although patients with acute VKH gained more visual improvement than those with chronic VKH, this did not correspond with a higher rate of controlled inflammation