. 2022 May 5;100(8):844–860. doi: 10.1111/aos.15159

Table 1.

Changes in commonly measured clinical signs and symptoms with HA treatment compared to baseline, sorted by publication date.

First Author (year)	Design	Population	Setup	Duration	Symp.	TBUT	OSS	Schi.	Other outcomes
Brar S. (Brar et al. ²⁰²¹)	RCT	60 DED	0.1% HA x4/d	3 mo	↑	↑			↑ tear film osmolarity, ↑ TMH, ↑ MG loss, ↑ objective scatter index, ⟷ VA
Morya A. K. (Morya et al. ²⁰²¹)	SB RCT	384 mild‐to‐severe DED	0.1% HA x4/d	2 mo	↑	⟷	↑	⟷	⟷ TMH
Balestrazzi A. (Balestrazzi et al. ²⁰²⁰)	OL RCT	19 DED with gastric reflux	0.2% HA x3/d	3 mo	↑	⟷		⟷
Cai M. (Cai & Zhang ²⁰²⁰)	SB RCT	45 moderate‐to‐severe DED	HA x4/d	1mo	↑	⟷	↑	⟷
Laihia J. (Laihia et al. ²⁰²⁰)	DB RCT	52 moderate‐to‐severe DED	0.2% x3/d	1 mo	↑	⟷	⟷
Garcia‐Conca V. (García‐Conca et al. ²⁰¹⁹)	SB RCT	84 mild‐to‐severe ADDE	0.18% HA x6/d	1 mo	↑		⟷	⟷	⟷ tear osmolarity, ⟷ hyperemia, ⟷ VA, ⟷ CIC measures
Kim Y. (Kim et al. ²⁰¹⁹)	OL RCT	54 mild‐to‐moderate DED	0.15% HA x5‐6/d	3 mo	↑	⟷	↑
Essa L. (Essa et al. ²⁰¹⁸)	SB RCT XO	50 DED	0.15% and 0.4% HA x3/d	1 mo	↑	⟷	↑/⟷	⟷^r	↑ LIPCOF, ⟷ tear meniscus height,
Groß D. (Groß et al. ²⁰¹⁸)	SB RCT	80 moderate DED	0.1% HA x3/d	3 mo	↑	⟷	↑
Miháltz K. (Miháltz et al. ²⁰¹⁸)	SB RCT	25 mild‐to‐moderate DED	0.2% HA x4/d	3 mo	↑	↑	↑	↑
Postorino E. (Postorino et al. ²⁰¹⁸)	SB RCT	40 mild‐to‐moderate DED	0.15% HA x4/d	3 mo	↑	⟷	↑		⟷ MG assessment, ⟷ corneal sensitivity, ⟷ VA
Roberti G. (Roberti et al. ²⁰¹⁸)	SB RCT	39 DED using long term preserved glaucoma medication	0.2% HA x4/d	3 mo	⟷	⟷	⟷	⟷	⟷ goblet cell density by IVCM
Groß D. (Groß et al. ²⁰¹⁷)	SB RCT	60 moderate‐to‐severe DED	0.2% HA x3/d	3 mo	↑	⟷	↑
Groß D. (Groß et al. ²⁰¹⁷)	SB RCT	60 moderate‐to‐severe DED	0.18% HA x3/d	3 mo	↑	⟷	↑
Labetoulle M. (Labetoulle et al. ²⁰¹⁷)	SB RCT	80 moderate‐to‐severe DED	0.18% HA hypotonic x2‐6/d	3 mo	↑	⟷	↑	⟷
Lambiase A. (Lambiase et al. ²⁰¹⁷)	DB RCT	35 moderate DED	0.18% HA 2‐6/d	2 w	↑		↑
López‐de la Rosa A. (López‐de la Rosa et al. ²⁰¹⁷)	DB RCT XO	16 moderate‐to‐severe DED	0.3% HA hypotonic x3‐8/d	1 mo x 2	↑	↑	↑/⟷	⟷	↑ tarsal hyperemia, ⟷ bulbar hyperemia
Park Y. (Park et al. ²⁰¹⁷)	SB RCT	176 moderate‐to‐severe DED	0.1% HA x5‐6/d	3 mo	↑	↑	↑	⟷	⟷ MG parameters
			0.15% HA x5‐6/d		↑	↑	↑	↑
			0.3% HA x5‐6/d		↑	↑	↑	⟷
Pinto‐Fraga J. (Pinto‐Fraga et al. ²⁰¹⁷)	DB RCT XO	16 mild DED	0.2% HA x3‐8/d	1 mo x 2	↑	⟷	↑	⟷	↑ bulbar hyperemia, ⟷ tarsal hyperemia
Chiambaretta F. (Chiambaretta et al. ²⁰¹⁷)	SB RCT	105 moderate‐to‐severe DED	0.18% HA x3‐6/d	3 mo	↑	↑	↑	↑	↑ conjunctival hyperemia
Gong L. (Gong et al. ²⁰¹⁵)	SB RCT	489 moderate DED	0.1% HA x6/d	1 mo	↑	↑	↑
Lanzini M. (Lanzini et al. ²⁰¹⁵)	PL	24 DED	0.2% HA x4/d	3 mo		⟷	↑	⟷	↑ IVCM, ⟷ CIC measures
Liu X. (Liu et al. ²⁰¹⁵)	SB RCT	58 severe DED + glaucoma	0.3% HA x3/d	3 mo	↑	↑	↑	↑	↑ goblet cell density by CIC
Hwang H. S. (Hwang et al. ²⁰¹⁴)	OL RCT	128 moderate ADDE	0.1% HA x4/d	3 mo	↑	↑	↑	↑	↑ goblet cell density and CIC grade
Lee H. S. (Lee et al. ^2014a)	PL	30 mild DED	0.1% HA isotonic x4/d	3 mo	⟷	⟷	⟷	⟷
Lee H. S. (Lee et al. ^2014a)	PL	30 mild DED	0.18% HA hypotonic x4/d	3 mo	⟷	⟷	↑	↑
Lee J. E. (Lee et al. ^2014b)	OL RCT	86 moderate DED	0.1% HA x5/d	1 mo	↑	↑	⟷	⟷	↑/⟷ tear osmolarity
Aragona P. (Aragona et al. ²⁰¹³)	DB RCT	40 moderate‐to‐severe DED, SS	0.15% HA x5/d	3 mo	↑	↑	⟷	⟷	↑ morphometric analysis by IVCM
Kinoshita S. (Kinoshita et al. ²⁰¹³)	SB RCT	182 moderate DED	0.1% HA x6/d	1 mo	↑	↑	↑	↑	70% of patients reported symptomatic improvement with HA
Saeed N. (Saeed et al. ²⁰¹³)	OL PL	240 DED	HA x2‐4/d	2 mo	↑	↑		↑
Baeyens V. (Baeyens et al. ²⁰¹²)	DB RCT	303 mild‐to‐moderate DED	0.18% HA x2‐4/d	3 mo	↑	↑	↑	↑	Evaluated as moderately‐very effective by >60% of evaluators and participants
Liu X. (Liu et al. ²⁰¹²)	DB RCT	60 moderate‐to‐severe DED	0.1% HA x4/d	1 mo	⟷	⟷	⟷	⟷	⟷ CIC measures
McCann L. C. (McCann et al. ²⁰¹²)	SB RCT	73 mild‐to‐moderate DED	0.15% HA x4/d	3 mo	↑	↑	⟷		↑ evaporation, ↑ tear film stability by interferometry, ⟷ osmolarity
Takamura E. (Takamura et al. ²⁰¹²)	DB RCT	286 moderate DED	0.1% HA x6/d	1 mo		↑	↑
Lee J. H. (Lee et al. ²⁰¹¹)	SB RCT	65 mild‐to‐moderate DED	0.1% HA x6/d	2 mo	↑	↑	↑
Monaco G. (Monaco et al. ²⁰¹¹)	DB RCT XO	20 glaucoma patients with dry eye symptoms	0.2% HA x4/d	2 w x2	⟷		⟷
Sanchez M. (Sanchez et al. ²⁰¹⁰)	SB RCT	15 mild‐to‐moderate DED	0.15% HA x4/d	1 mo		⟷	⟷	⟷	↑ HLA‐DR by CIC flow cytometry
Vogel R. (Vogel et al. ²⁰¹⁰)	DB RCT	436 moderate DED	0.18% HA hypotonic x3‐6/d	2 w	↑		↑
Johnson M. E. (Johnson et al. ²⁰⁰⁸)	DB RCT	65 moderate DED	0.18% HA x2/d	1 mo	↑	⟷	↑
Troiano P. (Troiano & Monaco ²⁰⁰⁸)	SB RCT XO	28 moderate DED	0.4% HA hypotonic x4/d	1 w x 2	↑↑		↑↑		↑ conjunctival hyperemia, 61% preferred hypotonic over isotonic drops
Troiano P. (Troiano & Monaco ²⁰⁰⁸)	SB RCT XO	28 moderate DED	0.4% HA isotonic x4/d	1 w x 2	↑		↑		↑ conjunctival hyperemia
Rolando M. (Rolando & Valente ²⁰⁰⁷)	OL RCT	30 mild‐to‐moderate DED	0.2% HA x3‐4/d	3 mo	↑	↑	↑
Lee H. K. (Lee et al. ²⁰⁰⁶)	DB RCT	41 DED (severity NG)	0.1% HA x3/d	1 mo	↑	↑		⟷	⟷ NFG/TP, ⟷ CIC measures
Benitez‐del‐Castillo J. M. (Benitez‐del‐Castillo et al. ²⁰⁰²)	PL	6 moderate‐to‐severe DED	0.18% HA x4/d	2 w			↑^s
Aragona P. Aug. 2002 (Aragona et al. ^2002a)	SB RCT	40 severe DED with SS	0.4% HA hypotonic x6/d	3 mo	↑	↑↑	↑↑	⟷	↑↑ CIC measures
Aragona P. Aug. 2002 (Aragona et al. ^2002a)	SB RCT	40 severe DED with SS	0.4% HA isotonic x6/d	3 mo	↑	↑	↑	⟷	↑ CIC measures
McDonald C. C. (McDonald et al. ²⁰⁰²)	DB RCT XO	32 severe DED with SS	0.1% HA x3‐4/d	2 mo	↑/⟷
Milafzzo G. (Milafzzo et al. ²⁰⁰²)	DB RCT XO	139 moderate KCS	HA hypotonic	1 mo x 2	↑	↑↑	↑	↑
Milafzzo G. (Milafzzo et al. ²⁰⁰²)	DB RCT XO	139 moderate KCS	HA isotonic	1 mo x 2	↑	↑	↑	↑
Papa V. (Papa et al. ²⁰⁰¹)	DB RCT XO	139 moderate DED	HA hypotonic up to x 6/d	1 mo x 2	↑	↑↑	↑	↑	↑ conjunctival hyperemia
Papa V. (Papa et al. ²⁰⁰¹)	DB RCT XO	139 moderate DED	HA isotonic up to x 6/d	1 mo x 2	↑	↑	↑	↑	↑ conjunctival hyperemia
Iester M. (Iester et al. ²⁰⁰⁰)	OL RCT	113 moderate‐to‐severe DED	0.4% HA hypotonic x6/d	3 mo	↑	↑	↑	↑	↑ tear osmolarity, ↑ CIC score
Condon P. I. (Condon et al. ¹⁹⁹⁹)	DB RCT XO	70 KCS, SS	0.1% HA x3‐4/d	1 mo x2	↑		↑	↑
Yokoi N. (Yokoi et al. ¹⁹⁹⁷)	PL	7 SS + 4 moderate KCS	0.1% HA x5/d	1 mo			↑
Nelson J. D. (Nelson & Farris ¹⁹⁸⁸)	DB RCT	35 moderate KCS	0.1% HA x8/d	2 mo	↑	↑	⟷	⟷	↑ tear film osmolality, ↑ conjunctival hyperemia, ↑/⟷ CIC measures
DeLuise V. P. (DeLuise & Peterson ¹⁹⁸⁴)	PL	28 severe DED, SS	0.1% HA x4/d	2 mo	↑	↑	↑	⟷	↑ mucus strand formation, ⟷ TMH

⟷ = no statistically significant difference at p > 0.05 compared to baseline, ↑ = statistically significant improvement at p < 0.05 compared to baseline, ↑/⟷ = statistically significant improvement at p < 0.05 in some parameters and no difference in others compared to baseline, ↑↑ = statistically significant improvement at p > 0.05 compared to baseline and compared to other hyaluronic acid treatment arm (empty cell) = not described, ADDE = Aqueous‐deficient dry eye, CIC = conjunctival impression cytology, DB = double‐blinded, DED = dry eye disease/syndrome, IVCM = in vivo confocal microscopy, KCS = keratoconjunctivitis sicca, LIPCOF = lid parallel conjunctival folds, MG = meibomian gland, mo = month(s), NFG/TP = Nerve Growth Factor/total protein ratio, OL = open label, OSS = ocular surface staining, PL = prospective longitudinal study, ^r = phenol red test, RCT = randomized controlled trial, ^s = stromal fluorescein uptake by fluorophotometer, SB = single‐blinded, Schi. = Schirmer's test, SS = Sjögren's syndrome, Symp. = subjective symptoms, TBUT = tear film break‐up time, TMH = tear meniscus height, VA = visual acuity, w = weeks, XO = cross‐over design.