Natural and iatrogenic ocular manifestations of rheumatoid arthritis: a systematic review

Int Ophthalmol. 2022 Feb;42(2):689-711. doi: 10.1007/s10792-021-02058-8. Epub 2021 Nov 21.


Purpose: To provide an overview of the ocular features of rheumatoid arthritis (RA) and of the ophthalmic adverse drug reactions (ADRs) that may be associated with the administration of antirheumatic drugs.

Methods: A systematic literature search was performed using the PubMed, MEDLINE, and EMBASE databases. In addition, a cohort of 489 RA patients who attended the Authors' departments were examined.

Results: Keratoconjunctivitis sicca, episcleritis, scleritis, peripheral ulcerative keratitis (PUK), and anterior uveitis were diagnosed in 29%, 6%, 5%, 2%, and 10%, respectively, of the mentioned cohort. Ocular ADRs to non-steroidal anti-inflammatory drugs are rarely reported and include subconjunctival hemorrhages and hemorrhagic retinopathy. In patients taking indomethacin, whorl-like corneal deposits and pigmentary retinopathy have been observed. Glucocorticoids are frequently responsible for posterior subcapsular cataracts and open-angle glaucoma. Methotrexate, the prototype of disease-modifying antirheumatic drugs (DMARDs), has been associated with the onset of ischemic optic neuropathy, retinal cotton-wool spots, and orbital non-Hodgkin's lymphoma. Mild cystoid macular edema and punctate keratitis in patients treated with leflunomide have been occasionally reported. The most frequently occurring ADR of hydroxychloroquine is vortex keratopathy, which may progress to "bull's eye" maculopathy. Patients taking tofacitinib, a synthetic DMARD, more frequently suffer herpes zoster virus (HZV) reactivation, including ophthalmic HZ. Tumor necrosis factor inhibitors have been associated with the paradoxical onset or recurrence of uveitis or sarcoidosis, as well as optic neuritis, demyelinating optic neuropathy, chiasmopathy, and oculomotor palsy. Recurrent episodes of PUK, multiple cotton-wool spots, and retinal hemorrhages have occasionally been reported in patients given tocilizumab, that may also be associated with HZV reactivation, possibly involving the eye. Finally, rituximab, an anti-CD20 monoclonal antibody, has rarely been associated with necrotizing scleritis, macular edema, and visual impairment.

Conclusion: The level of evidence for most of the drug reactions described herein is restricted to the "likely" or "possible" rather than to the "certain" category. However, the lack of biomarkers indicative of the potential risk of ocular ADRs hinders their prevention and emphasizes the need for an accurate risk vs. benefit assessment of these therapies for each patient.

Keywords: Causality in adverse drug reactions; Disease-modifying antirheumatic drugs; Non-steroidal anti-inflammatory drugs; Ocular adverse drug reactions; Rheumatoid arthritis; Tumor necrosis factor inhibitors.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Antirheumatic Agents* / adverse effects
  • Arthritis, Rheumatoid* / complications
  • Arthritis, Rheumatoid* / diagnosis
  • Arthritis, Rheumatoid* / drug therapy
  • Glaucoma, Open-Angle* / complications
  • Humans
  • Iatrogenic Disease
  • Rituximab


  • Antirheumatic Agents
  • Rituximab