Topical Immunomodulators Improve Clinical Signs of Vernal Keratoconjunctivitis and Atopic Keratoconjunctivitis: A Meta-Analysis

doi:10.21203/rs.3.rs-1738134/v1

Objective: Topical immunomodulators cyclosporine A (CsA) and tacrolimus have been added in recent years to the armament to control severe chronic allergic ocular diseases such as atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). This meta-analysis summarizes the randomized controlled trials (RCTs) that utilized topical immunomodulators, to examine their effectiveness at decreasing clinical signs as assessed by clinicians in severe allergic eye disease.

Methods: A systematic search identified thirteen studies and a total of 445 patients for inclusion, making this the largest meta-analysis published on the subject.

Results: Thirteen RCTs were included. Eleven studies used Cyclosporine A as the treatment, and two used Tacrolimus. In total, 445 participants were included, 76.6% were male. The mean age of the participants was 14 years. All studies reported clinical signs as evaluated by an examining clinician. Signs were usually assessed by anatomical region, with the most common regions being the conjunctiva and the cornea, and the most common signs assessed were hyperemia and papillae. Three studies accounted for over 50% of the meta-analysis's weight. Effect size (d) ranged from -2.37 to -0.03, negative values favoring immunomodulators. Fixed Effect Meta-Analysis returned an SMD of -0.81 (95% CI: [-0.98, -0.65]). However, there was significant heterogeneity (I²=61%, Q_w=30.76) in the outcome measure (P=0.0021); therefore, a random-effect meta-analysis was also completed where the pooled SMD was -0.98 (95% CI: [-1.26, -0.69], τ² = 0.16).

Conclusions: This study affirms that immunomodulators effectively treat clinical signs, including blepharitis, conjunctival hyperemia, edema, papillae, and corneal damage in severe ocular allergic disease.

Immunomodulators

Keratoconjunctivitis

Allergic eye disease

Atopy

Vernal

Table 1. Outcomes and analytical characteristics of the twelve randomized controlled trials (RCTs).

From left to right: the head author and year of publication, the mean absolute change in clinical signs score defined by that study for the intervention arm and SD, intervention arm sample size, the mean absolute change in clinical signs score defined by that study for the placebo arm and SD, placebo arm sample size, the study's weight in the meta-analysis (derived from its SD and sample sizes), the study's calculated random effect size, and the effect size's 95% CI.

Note that mean absolute change is not comparable between studies due to the different clinical signs' grading scales. Thus an effect size in the form of an SMD is calculated to allow comparison.

SD: Standard Deviation, N: number (unitless), CI: Confidence Interval, SMD: Standardized Mean Difference.

	Immunomodulator		Placebo		Weight	Effect Size	Random 95% CI
Study	Mean Change (±SD)	N	Mean Change (±SD)	N	Weight	Effect Size	Random 95% CI
Akpek et al. (2004)	-5 (±2.48)	10	-1 (±2.48)	10	3%	-1.55	[-2.5, -0.59]
Bleik et al. (1991)	-12.18 (±7.21)	11	-0.11 (±5.86)	9	3%	-1.74	[-2.73, -0.75]
Daniell et al. (2006)	-2.92 (±2.96)	17	-2.83 (±2.96)	18	7%	-0.03	[-0.68, 0.62]
Gupta et al. (2001)	-3.42 (±1.44)	12	-1.75 (±0.97)	12	4%	-1.31	[-2.16, -0.46]
Hingorani et al. (1998)	-14 (±11.78)	12	-1.5 (±5.7)	9	4%	-1.24	[-2.14, -0.33]
Keklikci et al. (2014)	-3.06 (±2.48)	31	-0.46 (±2.48)	31	11%	-1.04	[-1.56, -0.51]
Kilic et al. (2006)	-4.3 (±4.95)	20	0.7 (±2.25)	20	7%	-1.27	[-1.94, -0.61]
Leonardi et al. (2018)	-2.06 (±1.49)	56	-1.34 (±1.26)	58	21%	-0.52	[-0.89, -0.15]
Leonardi et al. (2018)	-1.93 (±1.39)	54	-1.34 (±1.26)	58	21%	-0.44	[-0.82, -0.07]
Ohashi et al. (2010)	-5.6 (±5.1)	28	-0.1 (±4.5)	28	9%	-1.13	[-1.68, -0.57]
Pucci et al. (2002)	-3.6 (±4.68)	24	-1.1 (±1.43)	24	9%	-0.71	[-1.28, -0.14]
Secchi et al. (1990)	-3.22 (±0.67)	9	-0.33 (±1.5)	9	2%	-2.37	[-3.52, -1.22]
Zhang et al. (2014)	-9.19 (±5.30)	8	-3.0625 (±5.96)	8	3%	-1.03	[-2.01, -0.04]

Table 2. Treatment regimen characteristics of the twelve randomized controlled trials (RCTs)

From left to right: the head author and year of publication, the immunomodulatory drug (active ingredient) used for the intervention arm, the substance used to deliver the active ingredient (in case of a commercial product, the product's brand name was listed, in concordance with the publication), the active ingredient concentration in the applied treatment, the substance used as placebo (as listed in the published paper), the treatment regimen in terms of drop-applications-per-day, the study duration until final follow up (in days), and the type of grouping in terms of treatment ("by patient" means each patient was blindly assigned either to the treatment group or the placebo group and received the same treatment in both eyes, "eye-eye" means each patient has blindly received the placebo in one eye and the intervention in the other). CsA=Cyclosporine A. N/A=data not available.

	Immunomodulator			Placebo	Interventions/Day	Study Duration	Groupimg Type
Study	Type	Substance	Concentration	Substance
Akpek et al. (2004)	CsA	restasis	0.05%	preservative free artificial tears	6 for 2 weeks, 4 for 2 weeks	28	by patient
Bleik et al. (1991)	CsA	corn oil	2.00%	corn oil	4	42	by patient
Daniell et al. (2006)	CsA	restasis	0.05%	vehicle	4	112	by patient
Gupta et al. (2001)	CsA	olive oil	2.00%	olive oil	4	112	by patient
Hingorani et al. (1998)	CsA	maize oil	2.00%	maize oil	4	84	by patient
Keklikci et al. (2014)	CsA	restasis	0.05%	preservative free artificial tears	4	28	by patient
Kilic et al. (2006)	CsA	preservative free artificial tears	2.00%	preservative free artificial tears	5	14	eye-eye
Leonardi et al. (2018)	CsA	cationic emulsion (water-in-oil)	0.10%	cationic emulsion (water-in-oil)	4	112	by patient
Leonardi et al. (2018)	CsA	cationic emulsion (water-in-oil)	0.10%	cationic emulsion (water-in-oil)	2 (and 2 placebo)	112	by patient
Ohashi et al. (2010)	Tacrolimus	polyinyl alcohol and benzalkonium chloride	0.10%	ophthalmic solution	2	28	by patient
Pucci et al. (2002)	CsA	olive oil	2.00%	vehicle	4	14	eye-eye
Secchi et al. (1990)	CsA	castor oil	2.00%	castor oil	4	15	eye-eye
Zhang et al. (2014)	Tacrolimus	N/A	0.10%	Tacrolimus without active ingredient (base solution)	2	28	by patient

Table 3. Clinical signs measured in each study. The signs are divided into anatomical categories: eyelids, palpebral and bulbar conjunctiva, limbus, cornea, and miscellaneous. The scale of measurement used is listed under the "Scale" column, and the way the composite sign score was calculated for analysis purposes can be found in the "Composite Sign Score" column.

MGD: Meibomian Gland Dysfunction, CFS: Corneal Fluorescein Staining, t_i: the date at the i^th time of assessment, Score(t_i): the score at t_i

Study	Clinical Signs						Scale	Composite Sign Score
Study	Lids	Palpebral (tarsal) Conjunctiva	Bulbar Conjunctiva	Limbus	Cornea	Miscellaneous	Scale	Composite Sign Score
Akpek et al. (2004)	Blepharitis (by hyperemia, edema, and MGD)	Papillae Scarring	Hyperemia	-	Punctate keratitis Neovascularization	-	0, 1, 2, or 3 according to severity for each sign	Sum of each score
Bleik et al. (1991)	-	-	Hyperemia	Trantas' dots Edema	Punctate keratitis	-	0, 1, 2, or 3 according to severity for each sign for each eye	Manually calculated sum of scores
Daniell et al. (2006)	Dermatitis Margin thickening Margin distortion Margin hyperemia Ptosis	Infiltration Hyperemia Papillae Scarring	Hyperemia Edema	-	Tear film deficiency Epithelial disease Opacity Neovascularization Lipid deposition	-	Not reported	Shown graphically on chart
Gupta et al. (2001)	-	Vessels' congestion Hyperemia Papillae		Injection Hyperemia	Architecture Re-epithelization	-	Not Applicable	Clinical grade of 1-5 given by clinical for total improvement in signs
Hingorani et al. (1998)	Ptosis Dermatitis Margin hyperemia Margin thickening MGD	Hyperemia Papillae Infiltration Scarring	Hyperemia Edema	Limbitis	Tear film deficiency Epithelial disease Opacity Neovascularization Lipid deposition	-	0, 1, 2, 3, or 4 according to severity for each sign except MGD (0-3)	Sum of each score
Keklikci et al. (2014)	Blepharitis	Papillae Scarring	Hyperemia	-	Punctate keratitis Neovascularization	-	0, 1, 2, or 3 according to severity for each sign	Sum of each score
Kilic et al. (2006)	Blepharitis	Papillae Scarring	Hyperemia	-	Punctate keratitis Neovascularization	-	0, 1, 2, or 3 according to severity for each sign	Sum of each score
Leonardi et al. (2018)	-	-	-	-	Keratitis (assessed by CFS according to the Modified Oxford scale) Ulceration	Need for rescue medication	Modified Oxford scale by CFS Penalties of (-1) points for incidence of ulceration or rescue medication	Score(t_i) = CFS(t_baseline) – CFS(t_i) - penalties
Ohashi et al. (2010)	-	Hyperemia Edema Follicles Papillae Giant papillae (>1mm)	Hyperemia Edema	Trantas' dots Swelling	Punctate keratitis Ulceration Erosion	-	0, 1, 2, or 3 according to severity for each sign	Sum of each score
Pucci et al. (2002)	-	Hyperemia Papillae Giant papillae		Trantas' dots (as a measure for corneal infiltration)		-	0, 1, 2, or 3 according to severity for each sign	Sum of each score
Secchi et al. (1990)	-	Hyperemia (3 sections) Chemosis Follicles Papillae Giant papillae secretion		Infiltrates		-	0 or 1	Sum of each score
Zhang et al. (2014)	-	Hyperemia Swelling Follicles Papillae Giant Papillae	Hyperemia Edema	Trantas’ dots Swelling	Epithelium	-	0, 1, 2, or 3 according to severity for each sign	Sum of each score

(Not answered)

Topical Immunomodulators Improve Clinical Signs of Vernal Keratoconjunctivitis and Atopic Keratoconjunctivitis: A Meta-Analysis

Status:

Version 1

Abstract

Figures

Full Text

tables

Additional Declarations

Status:

Version 1