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

Abstract

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.

Fig. 1

Ophthalmological diagnoses in 489 patients with rheumatoid arthritis (RA). Within this group, 52% of their conditions were strictly related to the underlying RA. *Peripheral ulcerative keratitis progressed to perforation of the cornea in the left eye of one patient and to corneal melt syndrome in the left eye of another patient

Fig. 2

a Right eye of a 53-year-old male patient with rheumatoid arthritis (RA) and bilateral simple episcleritis who presented with redness of both eyes, lacrimation, photophobia, and mild discomfort. Note the congested and prominent blood vessels of the nasal episclera. He was initially treated with fluoromethalone 1% eye drops three times daily, and, because of only partial efficacy, with prednisolone acetate 1% plus oral indomethacin 100 mg daily for one week, which resulted in a gradual reduction of the inflammation. Following frequent recurrences, infliximab was added to these conventional synthetic disease-modifying antirheumatic drugs for the treatment of the underlying RA. b Anterior multinodular scleritis, prevalent in the left eye, complicating active RA in a 47-year-old female patient who complained of moderate ocular pain, often stabbing in character, and a fall in visual acuity. Discrete scleral nodules, displacement of the deep vessels over the nodules, and surrounding inflammation overlying the unaffected sclera can be seen. The patient received topical steroids and weekly subcutaneous injections of methotrexate (15 mg) plus a 6-week course of oral methylprednisolone (12 mg per day), followed by gradual tapering. Two months later, the multinodular scleritis had completely regressed. c Anterior uveitis with hypopyon in a 69-year-old female patient with severe long-standing RA under treatment with methotrexate (15 mg weekly) plus adalimumab (40 mg subcutaneously every 2 weeks). The patient initially complained of pain, decreased vision, tearing, photophobia, and eye redness without discharge. Anterior inflammation with hypopyon was detected in her left eye, and her visual acuity dropped to 4/200, but no pathogens were demonstrated in the intraocular fluid collected by vitrectomy. Following the discontinuation of methotrexate and adalimumab, the ocular inflammation gradually improved and eventually resolved with the daily oral use of amoxycillin (850 mg) plus clavulanic acid (125 mg) and prednisone (15 mg). d Slit-lamp photograph from a 55-year-old female patient with RA and recurrent episodes of sarcoid anterior uveitis with multiple granulomatous mutton-fat keratic precipitates. Intraocular pressure was 25 mmHg in each eye. The patient described bilateral photophobia and a fall in visual acuity beginning ~ 1 month prior to presentation. Treatment with systemic and topical steroids in addition to methotrexate resulted in a marked improvement and sustained remission