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. 2022 Oct 21;10(10):CD015070.
doi: 10.1002/14651858.CD015070.pub2.

Topical corticosteroids for dry eye

Su-Hsun Liu  1 , Ian J Saldanha  2 , Alison G Abraham  3 , Thanitsara Rittiphairoj  1 , Scott Hauswirth  1 , Darren Gregory  1 , Cristos Ifantides  1 , Tianjing Li  1
Affiliations

Topical corticosteroids for dry eye

Su-Hsun Liu et al. Cochrane Database Syst Rev. .

Abstract

Background: Dry eye disease (DED), arising from various etiologic factors, leads to tear film instability, ocular surface damage, and neurosensory changes. DED causes symptoms such as ocular dryness, burning, itching, pain, and visual impairment. Given their well-established anti-inflammatory effects, topical steroid preparations have been widely used as a short-term treatment option for DED. Because of potential risks of ocular hypertension, cataracts, and infections associated with the long-term use of topical steroids, published trials comparing the efficacy and safety of topical steroids (versus placebo) have mostly been of short duration (three to eight weeks).

Objectives: To evaluate the effectiveness and safety of topical corticosteroids compared with no treatment, placebo, other steroidal or non-steroidal therapies, or a combination of therapies for DED.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 8); Ovid MEDLINE; Ovid Embase; Latin American and Caribbean Health Sciences database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), without restriction on language or year of publication. The date of the last search was 20 August 2021.

Selection criteria: We included randomized controlled trials (RCTs) in which topical corticosteroids, alone or in combination with tobramycin, were compared with no treatment, artificial tears (AT), vehicles, AT plus tobramycin, or cyclosporine A (CsA).

Data collection and analysis: We applied standard Cochrane methodology.

Main results: We identified 22 RCTs conducted in the USA, Italy, Spain, China, South Korea, and India. These RCTs reported outcome data from a total of 4169 participants with DED. Study characteristics and risk of bias All trials recruited adults aged 18 years or older, except one trial that enrolled children and adolescents aged between 3 and 14 years. Half of these trials involved predominantly female participants (median 79%, interquartile range [IQR] 76% to 80%). On average, each trial enrolled 86 participants (IQR 40 to 158). The treatment duration of topical steroids ranged between one week and three months; trial duration lasted between one week and six months. Eight trials were sponsored exclusively by industry, and four trials were co-sponsored by industry and institutional or governmental funds. We assessed the risk of bias of both subjective and objective outcomes using RoB 2, finding nearly half of the trials to be at high risk of bias associated with selective outcome reporting. Findings Of the 22 trials, 16 evaluated effects of topical steroids, alone or in combination with tobramycin, as compared with lubricants (AT, vehicle), AT plus tobramycin, or no treatment. Corticosteroids probably have a small to moderate effect on improving patient-reported symptoms by 0.29 standardized mean difference (SMD) (95% confidence interval [CI] 0.16 to 0.42) as compared with lubricants (moderate certainty evidence). Topical steroids also likely have a small to moderate effect on lowering corneal staining scores by 0.4 SMDs (95% CI 0.18 to 0.62) (moderate certainty evidence). However, steroids may increase tear film break-up time (TBUT) slightly (mean difference [MD] 0.70 s, 95% CI 0.06 to 1.34; low certainty evidence) but not tear osmolarity (MD 1.60 mOsm/kg, 95% CI -10.47 to 13.67; very low certainty evidence). Six trials examined topical steroids, either alone or in combination with CsA, against CsA alone. Low certainty evidence indicates that steroid-based interventions may have a small to moderate effect on improving participants' symptoms (SMD -0.33, 95% CI -0.51 to -0.15), but little to no effect on corneal staining scores (SMD 0.05, 95% CI -0.25 to 0.35) as compared with CsA. The effect of topical steroids compared to CsA alone on TBUT (MD 0.37 s, 95% CI -0.13 to 0.87) or tear osmolarity (MD 5.80 mOsm/kg, 95% CI -0.94 to 12.54; loteprednol etabonate alone) is uncertain because the certainty of the evidence is low or very low. None of the included trials reported on quality of life scores. Adverse effects The evidence for adverse ocular effects of topical corticosteroids is very uncertain. Topical corticosteroids may increase participants' risk of intraocular pressure (IOP) elevation (risk ratio [RR] 5.96, 95% CI 1.30 to 27.38) as compared with lubricants. However, when compared with CsA, steroids alone or combined with CsA may decrease or increase IOP elevation (RR 1.45, 95% CI 0.25 to 8.33). It is also uncertain whether topical steroids may increase risk of cataract formation when compared with lubricants (RR 0.34, 95% CI 0.01 to 8.22), given the short-term use and study duration (four weeks or less) to observe longer-term adverse effects. AUTHORS' CONCLUSIONS: Overall, the evidence for the specified review outcomes was of moderate to very low certainty, mostly due to high risk of bias associated with selective results reporting. For dry eye patients whose symptoms require anti-inflammatory control, topical corticosteroids probably provide small to moderate degrees of symptom relief beyond lubricants, and may provide small to moderate degrees of symptom relief beyond CsA. However, the current evidence is less certain about the effects of steroids on improved tear film quality or quantity. The available evidence is also very uncertain regarding the adverse effects of topical corticosteroids on IOP elevation or cataract formation or progression. Future trials should generate high certainty evidence to inform physicians and patients of the optimal treatment strategies with topical corticosteroids in terms of regimen (types, formulations, dosages), duration, and its time-dependent adverse profile.

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Conflict of interest statement

  1. Su‐Hsun Liu: reports a grant from the National Eye Institute, National Institutes of Health, USA; payment to institution.

  2. Ian J Saldanha: reports grants and contracts, Cochrane Eyes and Vision, from National Eye Institute, National Institutes of Health, USA; payment to institution. Travel reimbursement for making a talk on outcomes related to dry eye in 2018 from Johns Hopkins Wilmer Eye Institute; personal payment.

  3. Alison G Abraham: declared that she has no conflicts of interest.

  4. Thanitsara Rittiphairoj: declared that she has no conflicts of interest.

  5. Scott Hauswirth: reports grants and contracts for paid investigator from TearSolutions and Sylentis (contract pending—study not yet underway as of 23 February 2021); paid to institution. Payments for presentations from Kala Pharmaceuticals, Dompe, Sun Pharmaceuticals, Takeda, and Avedro; personal payment. Support for INTREPID meeting (indirect) from Alcon/Novartis; personal payment. Stock shares in Oyster Point (paid for and owned individually, not as compensation), TearRestore (compensation for design and medical advisory work), and Horizon Pharma (paid for and owned individually, not as compensation); personal payment. Consulting fees for study design and analysis from Ocular Therapeutix (pending); personal payment. Advisory Board payments from Dompe, NuSight Medical, Kala Pharmaceuticals, Sun Pharmaceuticals, EyePoint Medical, EyeVance Pharma, Horizon Pharma, Avedro/Glaukos, Quidel, and Sight Sciences; personal payment. Writing assistance from Takeda (medical writer for review paper); personal payment. SH reports publishing opinions on topical immunomodulation in dry eye in the OSDocs Facebook group (moderator/co‐administrator role), and published 'When dry eye compromises corneal integrity' in Review of Optometry, Nov 2017 (contract pending—study not yet underway as of 23 February 2021). They report working as an Optometrist at the University of Colorado.

  6. Darren Gregory: reports working as an Ophthalmologist at the University of Colorado Eye Center. Their clinical work focuses on the treatment of dry eyes, which sometimes involves the use of topical corticosteroid medications.

  7. Cristos Ifantides: reports being an inventor with intellectual property assigned to their university. The design relates to dry eye, but does not relate to corticosteroid use for dry eye. It is a design for a new form of eyeglasses that can theoretically help with dry eye (patent application filed, University of Colorado), paid to institution. Ownership of stock in Pfizer. Their partner works for AbbVie, which makes medications related to dry eye. She does not work in the eye care space. CI reports working as a clinician at Denver Health and University of Colorado, where they are an attending physician.

  8. Tianjing Li: reports a grant from the National Eye Institute, National Institutes of Health, USA; payment to institution.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias domain for each included trial that reported patient‐reported symptom scores.
3
3
Risk of bias summary: review authors' judgements about each risk of bias domain for each included trial reporting corneal fluorescein staining results.
4
4
Forest plot of comparison 1: Steroids versus lubricants, outcome: 1.1 Patient‐reported symptom scores. The analysis included data of the LE group in Qazi 2015.
5
5
Forest plot of comparison 1: Steroids versus lubricants, outcome: 1.5 Patient‐reported symptom scores, with subgroup analysis by etiology of dry eye. The analysis included data of the LE group in Qazi 2015.
6
6
Forest plot of comparison 1: Steroids versus lubricants, outcome: 1.13 Corneal fluorescein staining scores. The analysis included data of the LE group in Qazi 2015.
7
7
Forest plot of comparison 1: Steroids versus lubricants, outcome: 1.17 Corneal fluorescein staining scores, with subgroup analysis by etiology of dry eye. The analysis included data of the LE group in Qazi 2015.
8
8
Forest plot of comparison 2: Steroids versus cyclosporine A, outcome: 2.1 Patient‐reported symptom scores. The analysis included data of the LE group in Bausch 2013.
9
9
Forest plot of comparison 2: Steroids versus cyclosporine A, outcome: 2.9 Corneal fluorescein staining scores. The analysis included data of the LE group in Bausch 2013.
1.1
1.1. Analysis
Comparison 1: Steroids versus lubricants, Outcome 1: Patient‐reported symptom scores—Qazi: LE alone
1.2
1.2. Analysis
Comparison 1: Steroids versus lubricants, Outcome 2: Patient‐reported symptom scores—by questionnaire, Qazi: LE alone
1.3
1.3. Analysis
Comparison 1: Steroids versus lubricants, Outcome 3: Patient‐reported symptom scores—Qazi: LE + tobramycin
1.4
1.4. Analysis
Comparison 1: Steroids versus lubricants, Outcome 4: Patient‐reported symptom scores—by questionnaire, Qazi: LE + tobramycin
1.5
1.5. Analysis
Comparison 1: Steroids versus lubricants, Outcome 5: Patient‐reported symptom scores—by etiology
1.6
1.6. Analysis
Comparison 1: Steroids versus lubricants, Outcome 6: Patient‐reported symptom scores—by risk of bias
1.7
1.7. Analysis
Comparison 1: Steroids versus lubricants, Outcome 7: Patient‐reported symptom scores—by sponsorship
1.8
1.8. Analysis
Comparison 1: Steroids versus lubricants, Outcome 8: Patient‐reported symptom scores—by regimen and steroid type
1.9
1.9. Analysis
Comparison 1: Steroids versus lubricants, Outcome 9: Patient‐reported symptom scores—by steroid treatment duration
1.10
1.10. Analysis
Comparison 1: Steroids versus lubricants, Outcome 10: Tear film break‐up time—Qazin: LE alone
1.11
1.11. Analysis
Comparison 1: Steroids versus lubricants, Outcome 11: Tear film break‐up time—Qazi: LE + tobramycin
1.12
1.12. Analysis
Comparison 1: Steroids versus lubricants, Outcome 12: Tear film break‐up time—by steroid type
1.13
1.13. Analysis
Comparison 1: Steroids versus lubricants, Outcome 13: Corneal fluorescein staining scores—Qazi: LE alone
1.14
1.14. Analysis
Comparison 1: Steroids versus lubricants, Outcome 14: Corneal fluorescein staining score—by grading system, Qazi: LE alone
1.15
1.15. Analysis
Comparison 1: Steroids versus lubricants, Outcome 15: Corneal fluorescein staining score—Qazi: LE + tobramycin
1.16
1.16. Analysis
Comparison 1: Steroids versus lubricants, Outcome 16: Corneal fluorescein staining score—by grading system, Qazi: LE + tobramycin
1.17
1.17. Analysis
Comparison 1: Steroids versus lubricants, Outcome 17: Corneal fluorescein staining scores—by etiology
1.18
1.18. Analysis
Comparison 1: Steroids versus lubricants, Outcome 18: Corneal fluorescein staining score—by risk of bias
1.19
1.19. Analysis
Comparison 1: Steroids versus lubricants, Outcome 19: Corneal fluorescein staining score—by sponsorship
1.20
1.20. Analysis
Comparison 1: Steroids versus lubricants, Outcome 20: Corneal fluorescein staining score—by steroid treatment duration
1.21
1.21. Analysis
Comparison 1: Steroids versus lubricants, Outcome 21: Tear osmolarity
1.22
1.22. Analysis
Comparison 1: Steroids versus lubricants, Outcome 22: Schirmer's test—Qazi: LE alone
1.23
1.23. Analysis
Comparison 1: Steroids versus lubricants, Outcome 23: Schirmer's test—Qazi: LE + tobramycin
1.24
1.24. Analysis
Comparison 1: Steroids versus lubricants, Outcome 24: Schirmer test—by steroid type, Qazi: LE alone
1.25
1.25. Analysis
Comparison 1: Steroids versus lubricants, Outcome 25: Schirmer test—by steroid type, Qazi: LE + tobramycin
1.26
1.26. Analysis
Comparison 1: Steroids versus lubricants, Outcome 26: Proportion of participants with increased IOP—by steroid type
1.27
1.27. Analysis
Comparison 1: Steroids versus lubricants, Outcome 27: Proportion of participants with new cataract formation
1.28
1.28. Analysis
Comparison 1: Steroids versus lubricants, Outcome 28: Proportion of participants with serious adverse events (systemic or ocular)
2.1
2.1. Analysis
Comparison 2: Steroids versus CsA, Outcome 1: Patient‐reported symptom scores—Bausch: LE alone
2.2
2.2. Analysis
Comparison 2: Steroids versus CsA, Outcome 2: Patient‐reported symptom scores—Bausch: LE + CsA
2.3
2.3. Analysis
Comparison 2: Steroids versus CsA, Outcome 3: Patient‐reported symptom scores—by regimen
2.4
2.4. Analysis
Comparison 2: Steroids versus CsA, Outcome 4: Patient‐reported symptom scores—steroid treatment duration
2.5
2.5. Analysis
Comparison 2: Steroids versus CsA, Outcome 5: Tear film break‐up time—Bausch: LE alone
2.6
2.6. Analysis
Comparison 2: Steroids versus CsA, Outcome 6: Tear film break‐up time—Bausch: LE + CsA
2.7
2.7. Analysis
Comparison 2: Steroids versus CsA, Outcome 7: Tear film break‐up time—by regimen
2.8
2.8. Analysis
Comparison 2: Steroids versus CsA, Outcome 8: Tear film break‐up time—by steroid treatment duration
2.9
2.9. Analysis
Comparison 2: Steroids versus CsA, Outcome 9: Corneal fluorescein staining scores—Bausch: LE alone
2.10
2.10. Analysis
Comparison 2: Steroids versus CsA, Outcome 10: Corneal fluorescein staining score—Bausch: LE + CsA
2.11
2.11. Analysis
Comparison 2: Steroids versus CsA, Outcome 11: Corneal fluorescein staining score—by grading system
2.12
2.12. Analysis
Comparison 2: Steroids versus CsA, Outcome 12: Corneal fluorescein staining score—by regimen
2.13
2.13. Analysis
Comparison 2: Steroids versus CsA, Outcome 13: Corneal fluorescein staining score—by steroid treatment duration
2.14
2.14. Analysis
Comparison 2: Steroids versus CsA, Outcome 14: Tear osmolarity
2.15
2.15. Analysis
Comparison 2: Steroids versus CsA, Outcome 15: Schirmer's test
2.16
2.16. Analysis
Comparison 2: Steroids versus CsA, Outcome 16: Schirmer's test—by steroid type
2.17
2.17. Analysis
Comparison 2: Steroids versus CsA, Outcome 17: Proportion of participants with increased IOP
2.18
2.18. Analysis
Comparison 2: Steroids versus CsA, Outcome 18: Proportion of participants with any ocular complication
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD015070

References

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References to studies excluded from this review

Abud 2016 {published data only}
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Asbell 2011 {published data only}
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ChiCTR‐IPQ‐15006773 {published data only}
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Edward 2014 {published data only}
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EUCTR2006‐003391‐35‐NL {published data only}
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EUCTR2019‐000747‐27‐IT {published data only}
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Kallab 2020 {published data only}
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Lee 2006 {published data only}
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NCT03907865 {published data only}
    1. NCT03907865. Clinical efficacy of topical hydrocortisone 0.335% (Softacort®) in patients with chronic dry eye disease and associated ocular surface inflammation. clinicaltrials.gov/show/NCT03907865 (first received 9 April 2019).
Rolando 2008 {published data only}
    1. Rolando M, Solignani F, Valente C, Allavena F, Bertolotto M, Barabino S. Is there a role for a long term tapered small dose steroidal treatment for keratoconjunctivitis sicca? Investigative Ophthalmology & Vision Science 2008;49:ARVO E‐Abstract 97.
Ryu 2005 {published data only}
    1. Ryu I, Lee HK, Seo KR, Kim E. Change of nerve growth factor after 01% prednisolone instillation in dry eye syndrome patients and its correlation with clinical parameters. Investigative Ophthalmology & Vision Science 2005;46:ARVO E‐Abstract 2049.
Shen 2015 {published data only}
    1. Shen ZB, Li JL. Clinical effect of 1g/L fluorometholone drops combined with soft corneal contact lens for filamentary keratitis. International Eye Science 2015;15(9):1633‐5.
Sindhu 2015 {published data only}
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Wong 2021 {published data only}
    1. Wong S (Editor). Loteprednol 0.25% (Eysuvis) for dry eye disease. Medical Letter on Drugs and Therapeutics 2021;63(1624):75-7. - PubMed

References to studies awaiting assessment

ChiCTR‐IPR‐15007196 {published data only (unpublished sought but not used)}
    1. ChiCTR-IPR-15007196. Clinical trial of sodium bromide hydrate eye drops and Pranoprofen eye drops for dry eye. trialsearch.who.int/Trial2.aspx?TrialID=ChiCTR-IPR-15007196 (first received 9 October 2015).
Herman 2005 {published data only (unpublished sought but not used)}
    1. Herman JP, Korb DR, Greiner JV, Scaffidi RC, Blackie CA. Treatment of lid wiper epitheliopathy with a metastable lipid emulsion or a corticosteroid. Investigative Ophthalmology & Vision Science 2005;46:ARVO E‐Abstract 2017.
NCT00471419 {published data only (unpublished sought but not used)}
    1. NCT00471419. Phase II study of AL-2178 (FID 109980) in the treatment of dry eye. clinicaltrials.gov/show/NCT00471419 (first received 7 May 2007).
NCT00560638 {published data only (unpublished sought but not used)}
    1. NCT00560638. Loteprednol etabonate ophthalmic suspension for the treatment of dry eye. clinicaltrials.gov/ct2/show/NCT00560638 (first received 19 November 2007).
NCT01562795 {published data only (unpublished sought but not used)}
    1. NCT01562795. Efficacy of nonsteroidal anti-inflammatory drugs in treatment of moderate and severe dry eye disease. clinicaltrials.gov/ct2/show/NCT01562795 (first received 23 March 2012).
NCT03418727 {published data only (unpublished sought but not used)}
    1. NCT03418727. Dry eye disease study with brimonidine. clinicaltrials.gov/show/NCT03418727 (first received 1 February 2018).
NTR2291 {published data only (unpublished sought but not used)}
    1. NTR2291. Ocular inflammation and dry eye. trialsearch.who.int/?trialid=NTR2291 (first received 15 April 2010).

References to ongoing studies

CTRI/2021/02/031182 {published data only (unpublished sought but not used)}
    1. CTRI/2021/02/031182. Eye drops made of antibodies for dry eye disease patients. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2021/02/031182 (first received 10 February 2021).
ISRCTN16288419 {published data only (unpublished sought but not used)}
    1. ISRCTN16288419. Evaluation of the performance of new substitute tears in dry eye patients. trialsearch.who.int/?TrialID=ISRCTN16288419 (first received 8 May 2020).
NCT04734197 {published data only}
    1. NCT04734197. A Research Study To See How Well an Eye Drop, SURF-100 (A Mycophenolic Acid/Betamethasone Sodium Phosphate Combination), Works and What Side Effects There Are in Subjects With Dry Eye Disease. clinicaltrials.gov/show/NCT04734197 (first received 2 February 2021).
NCT04734210 {published data only}
    1. NCT04734210. A research study to see how well an eye drop, SURF-200 (0.02% and 0.04% Betamethasone Sodium Phosphate), works, what side effects there are, and to compare it with vehicle (placebo) in subjects diagnosed with dry eye disease and experiencing an episodic flare-up. clinicaltrials.gov/show/NCT04734210 (first received 2 February 2021).

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References to other published versions of this review

Liu 2021
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Publication types