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Is methotrexate or mycophenolate mofetil more effective as first-line immunosuppressive treatment for patients with noninfectious intermediate uveitis, posterior uveitis, or panuveitis requiring corticosteroid-sparing therapy?
In this randomized clinical trial of 216 patients with active noninfectious intermediate uveitis, posterior uveitis, and panuveitis, 66.7% of patients in the methotrexate group achieved corticosteroid-sparing control of inflammation compared with 57.1% in the mycophenolate group, a difference that was not statistically significant.
Mycophenolate mofetil was not more effective than methotrexate in treating noninfectious uveitis.
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT01829295
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Accepted for Publication: August 2, 2019.
Corresponding Author: Nisha R. Acharya, MD, MS; F.I. Proctor Foundation, University of California, San Francisco, 513 Parnassus Ave, S309, San Francisco, CA 94143 (Nisha.Acharya@ucsf.edu).
Author Contributions: Dr Porco and Mr Kim had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Gonzales, Kanakath, Suhler, Al-Dhibi, Acharya.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Gonzales, Kanakath, Bala Murugan, Vedhanayaki, Al-Dhibi, Rao, Ebert, Nguyen, Porco, Acharya.
Critical revision of the manuscript for important intellectual content: Rathinam, Gonzales, Thundikandy, Kanakath, Bala Murugan, Lim, Suhler, Al-Dhibi, Doan, Keenan, Ebert, Nguyen, Kim, Acharya.
Statistical analysis: Gonzales, Ebert, Nguyen, Kim, Porco.
Obtained funding: Acharya.
Administrative, technical, or material support: Gonzales, Kanakath, Bala Murugan, Vedhanayaki, Lim, Suhler, Al-Dhibi, Keenan, Rao, Ebert, Nguyen, Acharya.
Supervision: Rathinam, Bala Murugan, Suhler, Al-Dhibi, Acharya.
Conflict of Interest Disclosures: Dr Rathinam reports receipt of grants from Aravind Eye Hospital during the conduct of the study. Dr Lim reports receipt of grants from the National Eye Institute (NEI) during the conduct of the study; personal fees from Allergan, Novartis, and Novotech; and grants and personal fees from AbbVie and Bayer outside the submitted work. Dr Al-Dhibi reports receipt of personal fees from AbbVie, Allergan, and Novartis (consultancies) outside the submitted work. Dr Porco reports receipt of grants from NEI during the conduct of the study. Dr Acharya reports receipt of grants from NEI during the conduct of the study and personal fees from Santen and AbbVie (consultancies for advisory board participation) outside the submitted work. Dr Suhler reports receipt of personal fees from AbbVie, Clearside, EyeGate, EyePoint, Gilead, Santen, and Eyevensys and grants from AbbVie, Aldeyra, Clearside, EyeGate, EyePoint, Genentech, and Gilead. Drs Gonzales, Doan, and Keenan report receipt of grant funding from the NEI. No other disclosures were reported.
Funding/Support: This study was supported by NEI cooperative agreement U10 EY021125 (to Dr Acharya, primary investigator). The University of California San Francisco pharmacy provided study drugs for all sites. The Department of Ophthalmology at UCSF is supported by an unrestricted grant from the Research to Prevent Blindness Foundation, a core grant (EY06190) from the NEI, and That Man May See Foundation.
Role of Funder/Sponsor: The National Institutes of Health (NIH) did not have any direct role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. The data and safety monitoring committee, appointed by the NIH, reviewed and approved submitting this manuscript for publication.
Group Information for the FAST Research Group: Aravind Eye Hospital, Madurai, India: S. R. Rathinam, MD, PhD (director); Radhika Thundikandy, MD; R. Vedhanayaki, MD; A. L. Sivarama Subramanian, MPT; G. Jeyakohila, DONA; Gracy Evangelin, BA; A. M. Azhagupandi, HSC; C. V. Praba, HSC; S. Bharati, BSc; P. Gomathi, SSC; N. J. Nirmaladevi, HSC; Mohammed Siddiq; B. Vijayakumar; S. R. Devi. Aravind Eye Hospital, Coimbatore, India: Anuradha Kanakath, MD (director); V. R. Saravanan, MD; Upendra Babu, MD; R. Srija, MSc; S. Dhanalakshmi, BA; R. R. Sakthimari, COT; P. S. Keerthana, COT; A. M. Mallika, COT; C. Vasanthi, COT; P. B. Mariselvi, COT; P. Pandeeswari; S. M. Sudarvanitha, COT; S. Prema, COT. Aravind Eye Hospital, Pondicherry, India: S. Bala Murugan, MD (director); Prabu Baskaran, MD; V. G. Madanagopalan, MD; K. Chokkahalli; K. Nagesha, MD; R. Thilagavathi, MCom, E. S. Chitra, COT; S. M. Krishnakumari, COT; P. Irudhaya Raj, COT; S. Saravanan, BA; Grace Mary, COT; K. Nagarasi, COT; Kiruba Gnansi, COT. Asociación Para Evitar la Ceguera, Mexico City, Mexico: Lourdes Arellanes-Garcia, MD (director); Luz Elena Concha del Rio, MD; Rashel Cheja Kalb, MD; Nancy Fernández, MD; Yoko Burgoa, BS; Hilda Hernández; Roberto Fabela Cuello, OD; Lorenzo Agustín, OD; Martínez Garcia; Ricardo Montoya Rodríguez; Maria del Carmen Preciado, PhD; Andrea Arreola, MD. King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia: Hassan A. Al-Dhibi, MD (director); Donald Stone, MD; Mohammed Al-Shamrani, MD; Sara Al-Nuwaysir, BSc; Abdulrahman Al-Hommadi, BBA; Abdullah Al-Omran, BSc; Saleh Al-Nasser, BSc; Gahram Al-Zahrani, BSc; Eman Mashan, BSc; Mizher Al-Ghamdi, BSc; Ayshah Al-Tuwejri, BSc. Northwestern University, Chicago, Illinois: Debra A. Goldstein, MD (director); Anna Liza Castro-Malek, MS; Gemma Dela Rosa, COT; Marriner Skelly, BA, BS. Oregon Health and Science University, Portland: Eric Suhler, MD, MPH (director); James Rosenbaum, MD; Phoebe Lin, MD, PhD; Sherveen Salek, MD; Kristin Biggee, MD; Amde Shifera, MD, PhD; Laura Kopplin, MD, PhD; George Mount, MD; Tracy Giles, BS; Susan Nolte; Ann Lundquist, BA, CCRP; Teresa Liesegang, COT; Albert Romo; Chris Howell, BA; Scott Pickell, BS; Peter Steinkemp, MS; Dawn Ryan, CRA; Jordan Barth, AAS; Jocelyn Hui, BS; Chiedozie Ukachukwu, BS. Royal Victorian Eye and Ear Hospital, East Melbourne, Australia: Lyndell Lim, MD (director); Richard Stawell, MD; Robyn Troutbeck, MD; Cecilia Ling, MD; Xavier Fagan, MD; Julian Bosco, MD; Timothy Godfrey, MD; Tanya Pejnovic, BAppSc; Carly D’Sylva, MPH; Sutha Sanmugasundram, BSc; Tina-Marie van Tonder; Maria Kolic, BOOS. University of California, San Francisco: Nisha Acharya, MD, MS (director); John Gonzales, MD; Thuy Doan, MD, PhD; Sarah Lopez, OD; Maya Rao, MPH; Erica Browne, MS; Betty Hom, BS; Mary Lew, COT; Salena Lee, OD. The remaining acknowledgements list indviduals at FAST Research Group Resource Centers. Coordinating Center, University of California, San Francisco, CA: Nisha Acharya, MD, MS; Travis Porco, PhD, MPH; Thomas Lietman, MD; Jeremy Keenan, MD, MPH; Eric Kim, MA; Hieu Nguyen, MS; Caleb Ebert, MPH; former members: Maya Rao, MPH; Elyse Berlinberg, BS; Erica Browne, MS; Andrew Hirst, MS; Rachel Weinrib, MPH. Data and Safety Monitoring Committee Voting Members: Maureen G. Maguire, PhD (chair); William E. Barlow, PhD; Steven Yeh, MD; Albert T. Vitale, MD; Jaqueline J. Glover, PhD; Narsing A. Rao, MD; former member: Debra A. Goldstein, MD. NEI Program Office: Donald F. Everett, MA. University of South Florida Fundus Photograph and OCT Reading Center, Tampa, Florida: Peter R. Pavan, MD (director); JoAnn Leto; former director: Brian Madow, MD.
Additional Information: The data and safety monitoring committee monitored efficacy, safety, and overall study performance throughout the trial.
Data Sharing Statement: See Supplement 4.
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