[Skip to Content]
[Skip to Content Landing]

Effect of Corticosteroid-Sparing Treatment With Mycophenolate Mofetil vs Methotrexate on Inflammation in Patients With UveitisA Randomized Clinical Trial

Educational Objective
To learn about the treatment of noninfectious uveitis.
1 Credit CME
Key Points

Question  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?

Findings  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.

Meaning  Mycophenolate mofetil was not more effective than methotrexate in treating noninfectious uveitis.


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

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

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.

Gritz  DC, Wong  IG.  Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study.  Ophthalmology. 2004;111(3):491-500. doi:10.1016/j.ophtha.2003.06.014PubMedGoogle ScholarCrossref
Suttorp-Schulten  MS, Rothova  A.  The possible impact of uveitis in blindness: a literature survey.  Br J Ophthalmol. 1996;80(9):844-848. doi:10.1136/bjo.80.9.844PubMedGoogle ScholarCrossref
Rosenbaum  JT, Dick  AD.  The eyes have it: a rheumatologist’s view of uveitis.  Arthritis Rheumatol. 2018;70(10):1533-1543. doi:10.1002/art.40568PubMedGoogle ScholarCrossref
Jabs  DA, Rosenbaum  JT, Foster  CS,  et al.  Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.  Am J Ophthalmol. 2000;130(4):492-513. doi:10.1016/S0002-9394(00)00659-0PubMedGoogle ScholarCrossref
Galor  A, Jabs  DA, Leder  HA,  et al.  Comparison of antimetabolite drugs as corticosteroid-sparing therapy for noninfectious ocular inflammation.  Ophthalmology. 2008;115(10):1826-1832. doi:10.1016/j.ophtha.2008.04.026PubMedGoogle ScholarCrossref
Jaffe  GJ, Dick  AD, Brézin  AP,  et al.  Adalimumab in patients with active noninfectious uveitis.  N Engl J Med. 2016;375(10):932-943. doi:10.1056/NEJMoa1509852PubMedGoogle ScholarCrossref
Dick  AD, Rosenbaum  JT, Al-Dhibi  HA,  et al; Fundamentals of Care for Uveitis International Consensus Group.  Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for Uveitis (FOCUS) initiative.  Ophthalmology. 2018;125(5):757-773. doi:10.1016/j.ophtha.2017.11.017PubMedGoogle ScholarCrossref
Teoh  SC, Hogan  AC, Dick  AD, Lee  RWJ.  Mycophenolate mofetil for the treatment of uveitis.  Am J Ophthalmol. 2008;146(5):752-760, 760.e1-760.e3. doi:10.1016/j.ajo.2008.03.004PubMedGoogle ScholarCrossref
Thorne  JE, Jabs  DA, Qazi  FA, Nguyen  QD, Kempen  JH, Dunn  JP.  Mycophenolate mofetil therapy for inflammatory eye disease.  Ophthalmology. 2005;112(8):1472-1477. doi:10.1016/j.ophtha.2005.02.020PubMedGoogle ScholarCrossref
Baltatzis  S, Tufail  F, Yu  EN, Vredeveld  CM, Foster  CS.  Mycophenolate mofetil as an immunomodulatory agent in the treatment of chronic ocular inflammatory disorders.  Ophthalmology. 2003;110(5):1061-1065. doi:10.1016/S0161-6420(03)00092-7PubMedGoogle ScholarCrossref
Gangaputra  S, Newcomb  CW, Liesegang  TL,  et al; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study.  Methotrexate for ocular inflammatory diseases.  Ophthalmology. 2009;116(11):2188-98.e1. doi:10.1016/j.ophtha.2009.04.020PubMedGoogle ScholarCrossref
Sobrin  L, Christen  W, Foster  CS.  Mycophenolate mofetil after methotrexate failure or intolerance in the treatment of scleritis and uveitis.  Ophthalmology. 2008;115(8):1416-1421, 1421.e1. doi:10.1016/j.ophtha.2007.12.011PubMedGoogle ScholarCrossref
National Institutes of Health.  NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research.https://grants.nih.gov/policy/inclusion/women-and-minorities/guidelines.htm. Accessed June 24, 2019.
US Food and Drug Administration (FDA).  Collection of race and ethnicity data in clinical trials. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/collection-race-and-ethnicity-data-clinical-trials?source=govdelivery&utm_medium=email&utm_source=govdelivery. Published 2016. Accessed June 24, 2019.
Harris  PA, Taylor  R, Thielke  R, Payne  J, Gonzalez  N, Conde  JG.  Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support.  J Biomed Inform. 2009;42(2):377-381. doi:10.1016/j.jbi.2008.08.010PubMedGoogle ScholarCrossref
Jabs  DA, Nussenblatt  RB, Rosenbaum  JT; Standardization of Uveitis Nomenclature (SUN) Working Group.  Standardization of uveitis nomenclature for reporting clinical data: results of the first international workshop.  Am J Ophthalmol. 2005;140(3):509-516. doi:10.1016/j.ajo.2005.03.057PubMedGoogle ScholarCrossref
Daniel  E, Thorne  JE, Newcomb  CW,  et al.  Mycophenolate mofetil for ocular inflammation.  Am J Ophthalmol. 2010;149(3):423-32.e1, 2. doi:10.1016/j.ajo.2009.09.026PubMedGoogle ScholarCrossref
Fleiss  JL, Levin  B, Paik  MC. 6.9 Standard errors for measures of association. In: Balding  DJ, Cressie  NAC, Fisher  NI,  et al, eds.  Statistical Methods for Rates and Proportions. 3rd ed. Hoboken, NJ: John Wiley & Sons; 2003.
Rathinam  SR, Babu  M, Thundikandy  R,  et al.  A randomized clinical trial comparing methotrexate and mycophenolate mofetil for noninfectious uveitis.  Ophthalmology. 2014;121(10):1863-1870. doi:10.1016/j.ophtha.2014.04.023PubMedGoogle ScholarCrossref
Kempen  JH, Van Natta  ML, Altaweel  MM,  et al; Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group.  Factors predicting visual acuity outcome in intermediate, posterior, and panuveitis: the Multicenter Uveitis Steroid Treatment (MUST) trial.  Am J Ophthalmol. 2015;160(6):1133-1141.e9. doi:10.1016/j.ajo.2015.09.017PubMedGoogle ScholarCrossref
Jabs  DA.  Immunosuppression for the uveitides.  Ophthalmology. 2018;125(2):193-202. doi:10.1016/j.ophtha.2017.08.007PubMedGoogle ScholarCrossref
Foeldvari  I, Wierk  A.  Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis.  J Rheumatol. 2005;32(2):362-365.PubMedGoogle Scholar
Bom  S, Zamiri  P, Lightman  S.  Use of methotrexate in the management of sight-threatening uveitis.  Ocul Immunol Inflamm. 2001;9(1):35-40. doi:10.1076/ocii. ScholarCrossref
Dev  S, McCallum  RM, Jaffe  GJ.  Methotrexate treatment for sarcoid-associated panuveitis.  Ophthalmology. 1999;106(1):111-118. doi:10.1016/S0161-6420(99)90011-8PubMedGoogle ScholarCrossref
Holz  FG, Krastel  H, Breitbart  A, Schwarz-Eywill  M, Pezzutto  A, Völcker  HE.  Low-dose methotrexate treatment in noninfectious uveitis resistant to corticosteroids.  Ger J Ophthalmol. 1992;1(3-4):142-144.PubMedGoogle Scholar
Shah  SS, Lowder  CY, Schmitt  MA, Wilke  WS, Kosmorsky  GS, Meisler  DM.  Low-dose methotrexate therapy for ocular inflammatory disease.  Ophthalmology. 1992;99(9):1419-1423. doi:10.1016/S0161-6420(92)31790-7PubMedGoogle ScholarCrossref
Schiff  MH, Jaffe  JS, Freundlich  B.  Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration.  Ann Rheum Dis. 2014;73(8):1549-1551. doi:10.1136/annrheumdis-2014-205228PubMedGoogle ScholarCrossref
Dooley  MA, Jayne  D, Ginzler  EM,  et al; ALMS Group.  Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.  N Engl J Med. 2011;365(20):1886-1895. doi:10.1056/NEJMoa1014460PubMedGoogle ScholarCrossref
Smolen  JS, Landewé  R, Bijlsma  J,  et al.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.  Ann Rheum Dis. 2017;76(6):960-977. doi:10.1136/annrheumdis-2016-210715PubMedGoogle ScholarCrossref
Singh  JA, Saag  KG, Bridges  SL  Jr,  et al; American College of Rheumatology.  2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis.  Arthritis Care Res (Hoboken). 2016;68(1):1-25. doi:10.1002/acr.22783PubMedGoogle ScholarCrossref
Kempen  JH, Ganesh  SK, Sangwan  VS, Rathinam  SR.  Interobserver agreement in grading activity and site of inflammation in eyes of patients with uveitis.  Am J Ophthalmol. 2008;146(6):813-8.e1. doi:10.1016/j.ajo.2008.06.004PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity



My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right