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. 2020 Jan 22;48(3):366–401. doi: 10.1111/ceo.13702

Table 3.

Outline of studies on local delivery of corticosteroids in clinical ophthalmology

Conditions Authors, (Year) Design No. of eyes/(patients) Treatment steroid Study aims and outcome measures Conclusions
Adnexal
TED

Bordaberry et al, (2009)31

RCT 21
  • Peribulbar TA
 To assess the efficacy of peribulbar TA to treat inflammatory signs of moderate to severe Graves' orbitopathy and associated optic neuropathy

  • Clinical activity score

  • Extraocular muscle size

 Peribulbar TA reduced inflammatory signs of moderate Graves' orbitopathy as measured by the clinical activity score

Ebner et al, (2004)32

Multi‐centre RCT 41
  • Peribulbar TA
 To assess the efficacy of peribulbar TA vs control to treat TED

  • Extraocular muscle size

  • Binocular diplopia

 Peribulbar TA is effective in reducing diplopia and extraocular muscle size in TED

Alkawas et al, (2010)226

RCT 12
  • Peribulbar TA
  • Oral Prednisolone
 To assess the efficacy of peribulbar TA vs oral prednisolone to treat TED

  • Modified clinical activity score

  • Signs/Exophthalmometry

  • Complications

 No statistical difference found in study sample between peribulbar TA and oral prednisolone in treating TED
Lee et al, (2013)35 Single‐blinded RCT (106)

  • Sub‐conjunctival TA

 To assess the efficacy of sub‐conjunctival TA in treatment of TED related lid retraction

  • Lid retraction

  • Lid swelling

  • Exophthalmos

  • Lagophthalmos

  • Clinical activity score

  • Total eye score

 Sub‐conjunctival TA was effective in treating TED related lid retraction and persisted through to 24 weeks of follow‐up
Nasolacrimal disease McNeill et al, (2005)44 RCT 11

  • Nasal beclomethasone

 To assess the efficacy of nasal corticosteroids in treating functional epiphoria in patients with rhinitis

  • Epiphoria symptom score

 Epiphoria secondary to rhinitis can be treated successfully with intranasal beclomethasone
Chalazia Goawalla and Lee, (2007)46 RCT 136

  • Intra‐lesional TA

  • Incision and curettage

  • Hot compresses

 To compare intra‐lesional TA, incision and curettage and hot compresses in the treatment of chalazia

  • Resolution rate

  • Pain/inconvenience score

  • Patient satisfaction score

 Resolution rates between intra‐lesional TA and incision and curettage were similar and both were significantly greater than conservative group. There was less pain and patient inconvenience with intra‐lesional TA compared to incision and curettage
Ben Simon et al, (2011)47 RCT 94

  • Intra‐lesional TA

  • Incision and curettage

 To compare intra‐lesional TA against incision and curettage for the treatment of chalazia

  • Resolution rate

  • Additional treatments

 Intra‐lesional TA was as effective as incision and curettage in primary chalazia
Anterior segment
Bacterial keratitis Srinivasan et al, (2012)60 Multi‐centre placebo‐controlled double‐blinded RCT

500 (3 mo)

399 (12 mo)

  • Topical prednisolone

  • Placebo

 To compare the benefit in clinical outcomes of adjunctive topical corticosteroids in the treatment of bacterial corneal ulcers

  • BCVA

  • Infiltrate/scar size

  • Re‐epithelialisation

  • Corneal perforation

No significant differences in clinical outcomes with topical prednisolone sodium phosphate 1% compared to placebo in non‐Nocardia species.

Ulcers caused by Nocardia may fare worse with topical steroids
HSK Wilhelmus et al, (1994)62 Multi‐centre placebo‐controlled double‐blinded RCT 106

  • Topical prednisolone

  • Placebo
To compare the benefit in clinical outcomes of adjunctive topical corticosteroids in the treatment of HSV keratitis
  • Clinical resolution
 Topical prednisolone phosphate was significantly better than placebo in reducing persistence or progression of stromal inflammation (by 68%)
Allergic eye disease Singh et al, (2001)69 Double‐blinded RCT 90 (45)

  • Supratarsal DM

  • Supratarsal TA

  • Supratarsal HC

 To compare three types of supratarsal steroid injections for the treatment of refractory VKC

  • Symptoms and signs (cobblestone papillae, lid oedema, conjunctival discharge, chemosis, Horner‐Tranta dots and shield ulcers)

  • Disease recurrence

 All three drugs were equally effective with no statistically significant difference in the time of resolution. Recurrence was seen within six in all cases irrespective of the steroid used
Saini et al, (1999)70 Double‐blinded RCT 38 (19)

  • Supratarsal TA

  • Supratarsal DM

 To compare supratarsal TM vs supratarsal DM for the treatment of refractory VKC

  • Symptoms and signs (cobblestone papillae, lid oedema, shield ulcer, SPK)

  • Disease recurrence

 Both were equally effective in controlling symptoms and signs however supratarsal TM had a lower recurrence rate
KCS Pflugfelder et al, (2004)81 Multi‐centre double‐blinded RCT 128 (64)

  • Topical loteprednol etabonate 0.5%

  • Placebo

 To assess the efficacy of loteprednol etabonate 0.5% vs placebo for KCS

  • Symptom severity score

  • Corneal fluorescein staining

  • Conjunctival injection

 Topical loteprednol etabonate may be beneficial in KSC with moderate clinical inflammation
Sheppard et al, (2014)84 Multi‐centre double‐blinded RCT (119)

  • Topical loteprednol etabonate 0.5% + topical cyclosporine 0.05%

  • Topical cyclosporine 0.05% + artificial tears
To assess the efficacy of loteprednol etabonate 0.5% with topical cyclosporin 0.05% in dry eye disease
  • Ocular surface disease index (OSDI)
  • Likert scale
  • Lissamine green staining, fluorescein staining, Schirmer test
 Loteprednol showed greater efficacy in dry eye signs and symptoms than topical cyclosporin or artificial tears alone. It also provided rapid relief of dry eye disease
Lin and Gong, (2015)86 Multi‐centre double‐blinded RCT (41)

  • Topical FML 0.1%

  • Cyclosporine A 0.5%

 To compare topical FML vs cyclosporin A for the treatment of dry eye disease in Sjogren syndrome

  • Fluorescein staining

  • OSDI

  • Conjunctival goblet cell density

  • Severity of conjunctival congestion

  • Tear break up time (TBUT)/Schirmer test

 Both medications gave similar improvement from baseline, however topical FML provided faster improvement in symptoms of ocular dryness
Pinto‐Fraga et al, (2016)87 Double‐blinded RCT (42)

  • Topical FML 0.1%

  • Artificial tears

 To assess the efficacy of topical FML in dry eye disease when exposed to adverse environments

  • Corneal and conjunctival staining

  • Conjunctival hyperaemia

  • TBUT

  • Tear osmolarity

  • Symptom assessment in dry eye (SANDE)

 Topical FML was effective in alleviating dry eye disease but also especially in preventing exacerbation caused by exposure to a desiccating stress
GVHD Yin et al, (2018)89 Double‐blinded RCT 42

  • Topical loteprednol 0.5%

  • Artificial tears

 To assess the efficacy of topical loteprednol in dry eye disease associated with GVHD

  • OSDI

  • Corneal fluorescein staining

  • Conjunctival lissamine green staining

  • TBUT

  • Schirmer test

 Topical loteprednol had a less favourable response in treating dry eye disease in GVHD compared to those without GVHD
Chemical Injury Brodovsky et al, (2000)93 Retrospective series 177 (121)

  • Intensive Topical FML + treatment protocol

  • Conservative management

 To compare treatment outcomes of a standard protocol of intensive treatment vs conservative management in alkali‐burned corneas

  • Time to corneal re‐epithelialisation

  • Final BCVA

  • Time to visual recovery

  • Length of hospital stay

  • Complications

 Patients with intensive treatment had a trend for rapid healing and better final visual outcomes in grade 3 chemical burns but no difference in grade 4 burns
Anterior scleritis Sohn et al, (2011)13 Retrospective multi‐centre cohort 68 (53)

  • Sub‐conjunctival TA

 To assess the efficacy of sub‐conjunctival TA for non‐necrotising anterior scleritis

  • Resolution of symptoms and signs

  • Recurrence

  • Adverse effects

 After one injection sub‐conjunctival TA gave improvement of symptoms and signs in 97% and eyes remained recurrence‐free in 67.6% at 24 mo. Sub‐conjunctival TA is a useful adjuvant therapy that may reduce the burden of systemic medication
Glaucoma surgery
Glaucoma filtration surgery Araujo et al, (1995)100 RCT 46 (35)

  • No corticosteroids

  • Topical 1% prednisolone acetate

  • Topical 1% prednisolone acetate and oral prednisone

 To compare no adjunctive steroids vs topical prednisolone vs topical prednisolone and oral steroids in glaucoma filtration surgery after 10 y

  • Final IOP in follow‐up periods

  • Number of glaucoma medications used

  • Additional glaucoma filtration surgery

  • Visual acuity

  • Stabilization of glaucoma (disc photos, visual fields)

 Patients treated with steroids (groups 2 and 3) had significantly improved outcomes compared with patients without steroids (group 1). Group 1 had more additional procedures, higher IOPs, more additional glaucoma drops and lower rate of stabilized glaucoma
Yuki et al, (2009)102 RCT 53

  • Sub‐Tenon TA

  • Control (no TA)

 To assess the efficacy of intraoperative sub‐Tenon TA on the success rate of trabeculectomy in secondary glaucoma

  • IOP reduction

  • Success rate

  • Indiana Bleb Appearance Grading Scale

 Intraoperative sub‐Tenon TA neither increased intermediate‐term success nor decreased postoperative complications
Breusegem et al, (2010)227 RCT 54

  • Topical FML

  • Topical ketorolac

  • Placebo

 To compare preoperative treatment of topical ketorolac or FML vs placebo on trabeculectomy outcomes

  • Postoperative surgical or medical interventions (needling, suture lysis, needling revision, IOP‐lowering medication)

 Use of topical ketorolac or fluorometholone 1 mo prior to trabeculectomy was associated with less likelihood of postoperative needling and less need for IOP‐lowering medication
Yazdani et al, (2017)110 Triple‐blinded RCT 90

  • Sub‐Tenon TA

  • Placebo

 To compare intraoperative sub‐Tenon TA vs without in Ahmed glaucoma valve implantation

  • IOP

  • BCVA

  • Occurrence of hypertensive phase

  • Peak IOP

  • Number of glaucoma medications

  • Postoperative complications

 Sub‐Tenon IOP resulted in a lower mean IOP at the first mo and was 1.5 mmHg lower throughout the study period. Peak postoperative IOP was also lower. The rates of success, occurrence of hypertensive phase and complications were similar between the two groups
Posterior segment
DMO Gillies et al, (2006)115 Double‐blinded RCT 69 (43)

  • IVTA

  • Placebo

 To assess the efficacy of outcomes of IVTA in the treatment of refractory DMO

  • Improvement of BCVA

  • Central macular thickness

  • Adverse events

 IVTA had significantly greater proportion of patients (56%) achieving ≥15 letters of improvement in BCVA than placebo (26%). IVTA was also found to reduce central macular thickening however adverse events included cataract and glaucoma

Bressler et al, (2010)117

DRCR Protocol I

 Multi‐centre double‐blinded RCT 828

  • Ranibizumab + Prompt laser

  • Ranibizumab + deferred laser

  • Prompt laser + sham

  • IVTA + prompt laser

  • (Latter two groups allowed very deferred ranibizumab)

 To compare intravitreal ranibizumab plus prompt or deferred laser vs prompt laser or IVTA plus prompt laser in DMO

  • Improvement of BCVA

  • Central subfield thickness

  • Number of injections (5 y)

 Eyes receiving initial ranibizumab for centre‐involving DMO had better long‐term vision and reduced central subfield thickness

Boyer et al, (2014)118

MEAD study

 Two identical, parallel multi‐centre double‐blinded RCT (1048)
  • DII (0.7 mg)
  • DII (0.35 mg)
  • Sham
 To assess safety and efficacy of DII in the treatment of DMO

  • Improvement of BCVA

  • Central retinal thickness

  • Adverse events

 DII had significantly greater proportion of patients achieving ≥15‐letters of improvement in BCVA (22.2% for 0.7 mg, 18.4% for 0.35 mg and 12.0% for sham)

Fraser‐Bell et al, (2016)120

BEVORDEX study

 Multi‐centre single‐blinded RCT 88 (61)

  • DII

  • Bevacizumab

 To compare DII vs intravitreal bevacizumab for the treatment of DMO

  • Improvement of BCVA

  • CMT

  • Injection frequency

  • Adverse events

 DII achieved similar rates of BCVA improvement with bevacizumab and superior anatomic outcomes with fewer injections at 12 mo. At 24‐mo, there was no significant difference of improvement in BCVA but less burden of injections
Callanan et al, (2013)189 Double‐blinded multi‐centre RCT 253

  • DII + laser

  • Laser

 To compare DII combined with laser photocoagulation compared with laser alone for treatment of diffuse DMO

  • BCVA

  • Vessel leakage

  • Adverse events

 DII combined with laser resulted in significantly greater mean improvement in BCVA at all time points through month 9. Combination treatment also reduced areas of diffuse vascular leakage on angiography. At 12 mo, there was no significant difference between the two groups

Campochiaro et al, (2011)121

FAME A and B

 Two identical parallel, multi‐centre double‐blinded RCT 392

  • IVFA implant (0.2 μg/d)

  • IVFA implant (0.5 μg/d)

  • Sham
To compare efficacy and safety of IVFA implants for treatment of DMO
  • Improvement of BCVA
  • Foveal thickness
  • Adverse events
 Low‐dose and high‐dose IVFA implant groups had greater percentage of patients with ≥15 letters of improvement in BCVA at 24 mo (28.7% and 28.6%) compared with sham (16.2%). There was also more improvement in foveal thickness compared to sham. A significant percentage (7.6%) of the high‐dose group required incisional glaucoma surgery
CMO in RVO

Ip et al, (2009)22

SCORE‐CRVO

 Multi‐centre RCT 271

  • IVTA 1 mg

  • IVTA 4 mg

  • Standard of care (observation)

 To assess the efficacy and safety of IVTA for treatment of macular oedema secondary to central retinal vein occlusion

  • Improvement of BCVA

  • Centre point thickness

  • Vessel leakage, capillary non‐perfusion

  • Adverse events

 IVTA had significantly greater proportion of patients with ≥15 letter improvement in BCVA (27% for 1 mg, 26% for 4 mg and 7% for sham). Superior safety profile of 1 mg dose compared with 4 mg dose IVTA with respect to glaucoma and cataract
Scott et al, (2009)23 SCORE‐BRVO Multi‐centre RCT 411

  • IVTA 1 mg

  • IVTA 4 mg

  • Standard of care (grid laser)

 To assess the efficacy and safety of IVTA for treatment of macular oedema secondary to branch retinal vein occlusion

  • Improvement of BCVA

  • Centre point thickness

  • Vessel leakage, capillary non‐perfusion

  • Adverse events

 Treatment with IVTA with 1 mg or 4 mg or standard of care did not demonstrate a significant difference in visual acuity outcomes in macular oedema secondary to branch retinal vein occlusion

Haller et al, (2010)123

GENEVA

 Two identical, parallel multi‐centre double‐blinded RCT 1267

  • DII

  • Sham

 To assess the efficacy for DII for treatment of macular oedema secondary to CRVO or BRVO

  • Improvement of BCVA

  • Central retinal thickness

  • Adverse events

 DII had significantly greater proportion of patients with ≥15 letter improvement in BCVA, mean BCVA and less proportion of patients losing ≥15 letters in BCVA
Posterior non‐infectious uveitis

Sen et al, (2014)140

SITE

 Retrospective review of multi‐centre cohort 1192 (914) Periocular corticosteroid (including sub‐Tenon and orbital floor) To assess the efficacy and safety of periocular corticosteroid injections in uveitis

  • Improvement of BCVA

  • Improvement of macular oedema affecting BCVA

  • Intraocular inflammation

  • Systemic medications

  • Adverse events

 Over 50% of eyes demonstrated improved VA at some point within 6 mo of receiving periocular steroid. Periocular corticosteroids were also effective in treating acute inflammation or macular oedema

Kempen et al, (2015)141

MUST study

 Multi‐centre RCT 479 (255)

  • IVFA implant (Retisert)

  • Systemic therapy

 To compare IV FA implant with systemic immunosuppression in the treatment of posterior non‐infectious uveitis

  • BCVA

  • Visual field mean deviation

  • Activity of uveitis

  • Presence of macular oedema

 No significant difference in BCVA at 2 and 5 y. Systemic immunosuppression had better BCVA outcome at 7 y
Jaffe et al, (2019)30 Multi‐centre, double‐blinded sham‐controlled RCT 129

  • IVFA implant (Yutiq)

  • Sham

 To assess efficacy and safety of IVFA implant on recurrence rates in chronic posterior non‐infectious uveitis

  • Improvement of BCVA

  • Recurrence of uveitis

  • Macular oedema

  • Adverse events

 IVFA provided a greater proportion of patients with ≥15 letter improvement as well as effective management of intraocular inflammation and lower recurrence rates during the first 12 mo

Lowder et al, (2011)146

HURON study

 Parallel‐group, multi‐centre, blinded RCT 229

  • DII (0.7 mg)

  • DII (0.35 mg)

  • Sham

 Efficacy of DII on treating inflammation and CMO in non‐infectious posterior uveitis or panuveitis

  • Vitreous haze

  • BCVA

  • Central macular thickness

  • Adverse events

 Both doses of DII showed a significant reduction of posterior inflammation and CMO compared to sham which persisted through week 25. The proportion of patients with ≥15 letter improvement of BCVA was also significantly higher in the DII groups compared to sham

Thorne et al, (2019)228

POINT trial

 Multi‐centre, parallel‐treatment comparative RCT 235

  • Periocular TA

  • IVTA

  • DII

 To compare the efficacy of periocular TA, IVTA and OZURDEX for treatment of uveitic macular oedema

  • Central subfield thickness

  • Resolution macular oedema

  • BCVA

  • IOP events

 Improvements of CMT were seen in all three groups, periocular TA (23%), IVTA (39%), OZURDEX (46%). Greater improvements in BCVA were also seen with IVTA and OZURDEX. No significant differences between IVTA and OZURDEX in central subfield thickness or BCVA
Das et al, (1999)151 RCT 63

  • IVDM + intravitreal antibiotics

  • Intravitreal antibiotics alone

 To compare adjunctive IVDM vs intravitreal antibiotics‐only during vitrectomy for suspected postoperative or post‐traumatic bacterial endophthalmitis

  • Inflammation scoring

  • BCVA

 A reduction of inflammation was observed in the IV DM group at 1 week and 1 mo (although topical corticosteroids were not given in the intravitreal antibiotic‐only group). Final visual outcomes at 3 mo were not significantly different
Gan et al, (2005)152 RCT 29

  • IVDM + intravitreal antibiotics

  • Intravitreal antibiotics alone
To compare adjunctive IVDM vs intravitreal antibiotics alone in postoperative endophthalmitis
  • BCVA
 No statistically significant difference on visual acuity at 3 and 12 mo between the two groups. Trial terminated prematurely due to the study drug (dexamethasone sodium diphosphate was no longer available)
Albrecht et al, (2011)153 Double‐masked RCT 62

  • IVDM + intravitreal antibiotics

  • Intravitreal antibiotics alone

 To compare adjunctive IV DM vs intravitreal antibiotics alone in presumed bacterial endophthalmitis

  • BCVA

 No statistically significant difference in visual outcomes in short‐term (2 weeks) or intermediate‐term (2–4 mo post‐treatment) between the two groups
Manning et al, (2018)154 Multi‐centre RCT 167

  • IVDM + intravitreal antibiotics

  • Intravitreal antibiotics alone

 To compare adjunctive IVDM vs intravitreal antibiotics alone in patients with suspected bacterial endophthalmitis post‐cataract surgery

  • BCVA

 No statistically significant difference in final visual outcomes between IVDM and placebo group
Postoperative CMO Konstantopoulos et al, (2008)158 Retrospective case series 21 (20)

  • IVTA (4 mg)

 To assess efficacy and safety of IVTA in postoperative CMO

  • Improvement of BCVA

  • Adverse events

 All patients had significantly improved BCVA from baseline which was maintained at 6 mo
Thach et al, (1997)229 Retrospective review 49 (48)

  • Retrobulbar TA (40 mg)

  • Posterior sub‐Tenon TA (40 mg)

 To compare the retrobulbar TA vs posterior sub‐Tenon's TA for pseudophakic CMO refractory to topical medications

  • BCVA

  • Resolution of CMO

  • IOP

 There was significant improvement in BCVA compared to baseline for both groups but no statistically significant difference was found between the two groups

Abbreviations: CMO, cystoid macular oedema; DM, dexamethasone; DMO, diabetic macular oedema; FML, fluoromethalone; HC, hydrocortisone; HSK, herpes simples keratitis; IV, intravitreal; JXH, Juvenile xanthogranuloma; KCS, keratoconjunctivits sicca; LCH, Langerhan's cell histiocytosis; MP, methylprednisolone; PA, prednisolone acetate; RCT, Randomized Controlled Clinical Trial; RVO, retinal vein occlusion; TA, triamcinolone; TED, thyroid eye disease; VKC, vernal keratoconjunctivitis.