To evaluate the clinical efficacy of an intense pulsed light (IPL)-augmented regimen for moderate-to-severe perennial allergic conjunctivitis (PAC) and to elucidate its potential mechanisms through tear inflammatory factor profiling and untargeted metabolomics.
Methods:
In this prospective, single-arm, interventional study, 18 patients underwent two IPL sessions at two-week intervals. Outcomes included symptom visual analog scale (VAS) scores and sign scores, bulbar redness index (BRI), tear breakup time (TBUT), and tear inflammatory factors, including immunoglobulin E (IgE), matrix metalloproteinase-9 (MMP-9), and lymphotoxin-alpha (LTA). Untargeted metabolomics of tear fluid was performed using LC–MS/MS to identify differential metabolites and pathways.
Results:
Symptom VAS [median difference: –25.0 (95% CI: –31.0, –21.0); p < 0.01] and sign [–4.0 (–6.0, –4.0); p < 0.01] scores improved significantly, with 79.4% symptom reduction, a shift from frequent to occasional itching, and large effect sizes (Cohen’s d: 2.18 symptoms, 2.70 signs). TBUT and BRI showed no significant changes. Tear IgE and MMP-9 tended to decrease and LTA to increase (nonsignificant). MMP-9 positively correlated with posttreatment BRI (r = 0.570, p < 0.05), while LTA negatively correlated with baseline BRI (r = –0.573, p < 0.05). Untargeted metabolomics identified 65 differential metabolites: purine-related compounds (e.g., adenine, guanine) and stearic acid were downregulated; oleic acid, 9-OxoODE, etc., were upregulated. Purine metabolism was significantly altered (Raw p = 0.0013, false discovery rate [FDR] = 0.104), while unsaturated fatty acid biosynthesis changes were not significant (Raw p = 0.49, FDR = 1). No serious adverse events occurred.
Conclusion:
An IPL-augmented regimen may alleviate moderate-to-severe PAC, which is consistent with the modulation of purine and unsaturated fatty acid metabolism. This modulation is characterized by suppressed purine activity and proinflammatory lipids while enhancing anti-inflammatory and antioxidant unsaturated fatty acids. These changes collectively dampen inflammation and promote immune homeostasis.
TariqF. Allergic conjunctivitis: Review of current types, treatments, and trends. Life (Basel), 2024; 14(6):650; doi: 10.3390/life14060650
2.
PawankarR, WangJ-Y, WangI-J, et al.Asia Pacific Association of Allergy Asthma and Clinical Immunology White Paper 2020 on climate change, air pollution, and biodiversity in Asia-Pacific and impact on allergic diseases. Asia Pac Allergy, 2020; 10(1):e11; doi: 10.5415/apallergy.2020.10.e11
3.
BieloryBP, O’BrienTP, BieloryL. Management of seasonal allergic conjunctivitis: Guide to therapy. Acta Ophthalmol, 2012; 90(5):399–407; doi: 10.1111/j.1755-3768.2011.02272.x
4.
ItoY, KatoT, YoshidaK, et al.Prevalence of allergic diseases across all ages in Japan: A nationwide cross-sectional study employing designated allergic disease medical hospital network. Jma J, 2023; 6(2):165–174; doi: 10.31662/jmaj.2022-0218
5.
BashirM, AlghamdiTA, AlzahraniAM, et al.Evaluation of allergic conjunctivitis prevalence and attitude toward prevention and control in Saudi Arabia. Cureus, 2024; 16(4):e57711; doi: 10.7759/cureus.57711
6.
TaoZ, LiuW, ChenQ, et al.Blocking Th2 signaling pathway alleviates the clinical symptoms and inflammation in allergic conjunctivitis. Invest Ophthalmol Vis Sci, 2023; 64(10):30; doi: 10.1167/iovs.64.10.30
7.
PaikB, TongL. Polymorphisms in Lymphotoxin-Alpha as the “Missing Link” in prognosticating favourable response to Omega-3 supplementation for dry eye disease: A narrative review. Int J Mol Sci, 2023; 24(4):4236; doi: 10.3390/ijms24044236
8.
LiC-R. Role of lymphotoxin alpha as a new molecular biomarker in revolutionizing tear diagnostic testing for dry eye disease. Int J Ophthalmol, 2023; 16(11):1883–1889; doi: 10.18240/ijo.2023.11.22
LeonardiA, QuintieriL, PresaIJ, et al.Allergic conjunctivitis management: Update on ophthalmic solutions. Curr Allergy Asthma Rep, 2024; 24(7):347–360; doi: 10.1007/s11882-024-01150-0
11.
O’BrienTP. Allergic conjunctivitis: An update on diagnosis and management. Curr Opin Allergy Clin Immunol, 2013; 13(5):543–549; doi: 10.1097/ACI.0b013e328364ec3a
12.
McMonniesCW. Mechanisms of rubbing-related corneal trauma in keratoconus. Cornea, 2009; 28(6):607–615; doi: 10.1097/ICO.0b013e318198384f
13.
BabilasP, SchremlS, SzeimiesR-M, et al.Intense pulsed light (IPL): A review. Lasers Surg Med, 2010; 42(2):93–104; doi: 10.1002/lsm.20877
14.
GaoL, QuH, GaoN, et al.A retrospective analysis for facial telangiectasia treatment using pulsed dye laser and intense pulsed light configured with different wavelength bands. J Cosmet Dermatol, 2020; 19(1):88–92; doi: 10.1111/jocd.13179
15.
ToyosR, McGillW, BriscoeD. Intense pulsed light treatment for dry eye disease due to meibomian gland dysfunction; a 3-year retrospective study. Photomed Laser Surg, 2015; 33(1):41–46; doi: 10.1089/pho.2014.3819
16.
FishmanHA, PerimanLM, ShahAA. Real-Time video microscopy of in vitro demodex death by intense pulsed light. Photobiomodul Photomed Laser Surg, 2020; 38(8):472–476; doi: 10.1089/photob.2019.4737
17.
YinY, LiuN, GongL, et al.Changes in the meibomian gland after exposure to intense pulsed light in Meibomian Gland Dysfunction (MGD) patients. Curr Eye Res, 2018; 43(3):308–313; doi: 10.1080/02713683.2017.1406525
18.
ByunJY, ChoiHY, MyungKB, et al.Expression of IL-10, TGF-beta(1) and TNF-alpha in cultured Keratinocytes (HaCaT Cells) after IPL treatment or ALA-IPL photodynamic treatment. Ann Dermatol, 2009; 21(1):12–17; doi: 10.5021/ad.2009.21.1.12
19.
YuH, ZengW, ZhaoG, et al.Response of tear cytokines following intense pulsed light combined with meibomian gland expression for treating meibomian gland dysfunction-related dry eye. Front Endocrinol (Lausanne), 2022; 13:973962; doi: 10.3389/fendo.2022.973962
20.
FineideF, MagnøMS, KhanAZ, et al.Intense pulsed light treatment in meibomian gland dysfunction: Past, present, and future. Acta Ophthalmol, 2024; 102(4):e414–e442; doi: 10.1111/aos.15759
21.
LiD, LinS-B, ChengL-H-H, et al.Intense pulsed light treatment for itch associated with allergic keratoconjunctivitis: A retrospective study of 35 cases. Photobiomodul Photomed Laser Surg, 2021; 39(3):196–203; doi: 10.1089/photob.2020.4826
22.
JiangJ, YangX, DuF, et al.The therapeutic effect of IPL on children with refractory seasonal allergic conjunctivitis. BMC Ophthalmol, 2025; 25(1):217; doi: 10.1186/s12886-025-04058-z
ChenL, ZhouL, ChanECY, et al.Characterization of the human tear metabolome by LC-MS/MS. J Proteome Res, 2011; 10(10):4876–4882; doi: 10.1021/pr2004874
27.
BeckerS, KortzL, HelmschrodtC, et al.LC-MS-based metabolomics in the clinical laboratory. J Chromatogr B Analyt Technol Biomed Life Sci, 2012; 883–884:68–75; doi: 10.1016/j.jchromb.2011.10.018
28.
Expert Consensus Group for Allergic Conjunctivitis Diagnosis and Treatment. Expert consensus on the diagnosis and treatment of allergic conjunctivitis in China (2018). Chin J Ophthalmol, 2018; 54(6):409–414; doi: 10.3760/cma.j.issn.0412–4081.2018.06.003
29.
Expert Panel on Clinical Application of Intense Pulsed Light for Dry Eye, Dry Eye Rehabilitation Group of Visual Rehabilitation Committee of Chinese Rehabilitation Medical Association. Expert consensus on intense pulsed light for meibomian gland dysfunction and associated dry eye (2022). Chin J Exp Ophthalmol, 2022; 40(2):97–103; doi: 10.3760/cma.j.cn115989-20211015-00563
30.
OhashiY, EbiharaN, FujishimaH, et al.A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1% in severe allergic conjunctivitis. J Ocul Pharmacol Ther, 2010; 26(2):165–174; doi: 10.1089/jop.2009.0087
31.
LindenJ, Koch-NolteF, DahlG. Purine release, metabolism, and signaling in the inflammatory response. Annu Rev Immunol, 2019; 37:325–347; doi: 10.1146/annurev-immunol-051116-052406
32.
LeT-TT, BergNK, HartingMT, et al.Purinergic signaling in pulmonary inflammation. Front Immunol, 2019; 10:1633; doi: 10.3389/fimmu.2019.01633
33.
BortolottiM, PolitoL, BattelliMG, et al.Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biol, 2021; 41:101882; doi: 10.1016/j.redox.2021.101882
34.
SalminenA, HyttinenJMT, KaarnirantaK. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: Impact on healthspan and lifespan. J Mol Med (Berl), 2011; 89(7):667–676; doi: 10.1007/s00109-011-0748-0
35.
SavioLEB, Leite-AguiarR, AlvesVS, et al.Purinergic signaling in the modulation of redox biology. Redox Biol, 2021; 47:102137; doi: 10.1016/j.redox.2021.102137
36.
AydinE, CallahanDL, ChongL, et al.The plight of the metabolite: Oxidative stress and tear film destabilisation evident in ocular allergy sufferers across seasons in Victoria, Australia. Int J Mol Sci, 2024; 25(7):4019; doi: 10.3390/ijms25074019
37.
ZicariAM, BrindisiG, De CastroG, et al.Is oxidative stress involved in vernal keratoconjunctivitis? Results from a pilot study in children. Pediatr Allergy Immunol, 2020; 31(Suppl 26):52–56; doi: 10.1111/pai.13382
38.
Santa-MaríaC, López-EnríquezS, Montserrat-de la PazS, et al.Update on anti-inflammatory molecular mechanisms induced by oleic acid. Nutrients, 2023; 15(1):224; doi: 10.3390/nu15010224
39.
Andres ContrerasG, De KosterJ, de SouzaJ, et al.Lipolysis modulates the biosynthesis of inflammatory lipid mediators derived from linoleic acid in adipose tissue of periparturient dairy cows. J Dairy Sci, 2020; 103(2):1944–1955; doi: 10.3168/jds.2019-17256
40.
AltinozMA, OzpinarA. PPAR-δ and erucic acid in multiple sclerosis and Alzheimer’s Disease. Likely benefits in terms of immunity and metabolism. Int Immunopharmacol, 2019; 69:245–256; doi: 10.1016/j.intimp.2019.01.057
41.
ZengJ, ZhangY, HaoJ, et al.Stearic acid induces CD11c expression in proinflammatory macrophages via epidermal fatty acid binding protein. J Immunol, 2018; 200(10):3407–3419; doi: 10.4049/jimmunol.1701416
42.
KochumonS, ArefanianH, AzimR, et al.Stearic acid and TNF-α Co-Operatively potentiate MIP-1α production in monocytic cells via MyD88 independent TLR4/TBK/IRF3 signaling pathway. Biomedicines, 2020; 8(10):403; doi: 10.3390/biomedicines8100403
43.
AritaR, FukuokaS, MorishigeN. Therapeutic efficacy of intense pulsed light in patients with refractory meibomian gland dysfunction. Ocul Surf, 2019; 17(1):104–110; doi: 10.1016/j.jtos.2018.11.004
44.
LiD, LuJ, HuZ, et al.Intense pulsed light therapy to inhibit meibomian gland inflammation: Untargeted metabolomics analysis of Meibomian gland secretions. Photobiomodul Photomed Laser Surg, 2022; 40(10):715–727; doi: 10.1089/photob.2022.0058
45.
Barbosa RibeiroB, MartaA, Ponces RamalhãoJ, et al.Pulsed light therapy in the management of dry eye disease: Current perspectives. Clin Ophthalmol, 2022; 16:3883–3893; doi: 10.2147/OPTH.S349596
46.
LamSM, TongL, DuanX, et al.Longitudinal changes in tear fluid lipidome brought about by eyelid-warming treatment in a cohort of meibomian gland dysfunction. J Lipid Res, 2014; 55(9):1959–1969; doi: 10.1194/jlr.P051185
47.
AhmedSA, TaherIME, GhoneimDF, et al.Effect of intense pulsed light therapy on tear proteins and lipids in meibomian gland dysfunction. J Ophthalmic Vis Res, 2019; 14(1):3–10; doi: 10.4103/jovr.jovr_12_18
48.
KateA, ShanbhagSS, GattuJ, et al.Allergen testing: A review of the indications, procedures, and limitations in ocular allergy. Clin Rev Allergy Immunol, 2024; 67(1–3):1–20; doi: 10.1007/s12016-024–09002-5
49.
RasmussenMLR, D’SouzaM, TopalDG, et al.Prevalence of allergic sensitization with vernal keratoconjunctivitis: A systematic review with meta-analyses. Acta Ophthalmol, 2023; 101(1):9–21; doi: 10.1111/aos.15212
50.
WangR, DaiX, ChenW, et al.Matrix metalloproteinase 9 plays a crucial role in inflammation and itch in allergic contact dermatitis by regulating toll-like receptor 2/1 signaling. J Invest Dermatol, 2024; 144(8):1893–1897.e6; doi: 10.1016/j.jid.2024.01.013
51.
KishimotoT, IshidaW, NakajimaI, et al.Promotion of conjunctival fibroblast-mediated collagen gel contraction by mast cells through up-regulation of matrix metalloproteinase release and activation. Exp Eye Res, 2022; 218:108980; doi: 10.1016/j.exer.2022.108980
52.
AbelM, VliagoftisH. Mast cell-fibroblast interactions induce matrix metalloproteinase-9 release from fibroblasts: Role for IgE-mediated mast cell activation. J Immunol, 2008; 180(5):3543–3550; doi: 10.4049/jimmunol.180.5.3543
53.
ManuelD-L, Dolores1P-DM, LoretoD-G, et al.Seawater solution on inflammation of the ocular surface in matrix metalloproteinase mmp-9-positive allergic conjunctivitis patients. Int J Ophthalmol Opt, 2025; 7(1):1–7; doi: 10.33545/26648547.2025.v7.i1a.36
54.
BolstadAI, Le HellardS, KristjansdottirG, et al.Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjogren’s syndrome in Scandinavian samples. Ann Rheum Dis, 2012; 71(6):981–988; doi: 10.1136/annrheumdis-2011-200446
55.
FangX, LanG, LinY, et al.Inflammation due to ocular surface homeostasis imbalance caused by pterygia: Tear lymphotoxin-alpha study and a literature review. J Ophthalmic Inflamm Infect, 2024; 14(1):28; doi: 10.1186/s12348-024-00413-1
56.
BuhrmannC, ShayanP, AggarwalBB, et al.Evidence that TNF-β (lymphotoxin α) can activate the inflammatory environment in human chondrocytes. Arthritis Res Ther, 2013; 15(6):R202; doi: 10.1186/ar4393
57.
JiaoX, GaoN, WangD, et al.Differential expression of tear Lymphotoxin-Α, Immunoglobulin E, and matrix Metalloproteinase-9 in allergic conjunctivitis-associated dry eye. Curr Eye Res, 2025:1–8; doi: 10.1080/02713683.2025.2549298
58.
SchlatterA, PalkovitsS, Amir-AsgariS, et al.Safety and efficacy of a novel intense pulsed light system in patients with meibomian gland dysfunction: A randomized, double-masked, intra-individual controlled study. Int Ophthalmol, 2025; 45(1):246; doi: 10.1007/s10792-025-03622-2
59.
ToyosR, DesaiNR, ToyosM, et al.Intense pulsed light improves signs and symptoms of dry eye disease due to meibomian gland dysfunction: A randomized controlled study. PLoS One, 2022; 17(6):e0270268; doi: 10.1371/journal.pone.0270268
60.
SongY, YuS, HeX, et al.Tear film interferometry assessment after intense pulsed light in dry eye disease: A randomized, single masked, sham-controlled study. Cont Lens Anterior Eye, 2022; 45(4):101499; doi: 10.1016/j.clae.2021.101499
61.
ComstockTL, DeCoryHH. Advances in corticosteroid therapy for ocular inflammation: Loteprednol Etabonate. Int J Inflam, 2012; 2012:789623; doi: 10.1155/2012/789623
62.
WuMMS, YauGSK, LeeJWY, et al.Retrospective review on the use of topical Cyclosporin A 0.05% for paediatric allergic conjunctivitis in Hong Kong Chinese. ScientificWorldJournal, 2014; 2014:396987; doi: 10.1155/2014/396987
63.
HazarikaAK, SinghPK. Efficacy of topical application of 0.03% tacrolimus eye ointment in the management of allergic conjunctivitis. J Nat Sci Biol Med, 2015; 6(Suppl 1):S10–S12; doi: 10.4103/0976–9668.166051
64.
VillegasBV, Benitez-del-CastilloJM. Current knowledge in allergic conjunctivitis. Turk J Ophthalmol, 2021; 51(1):45–54; doi: 10.4274/tjo.galenos.2020.11456
65.
AnesiSD, TauberJ, NguyenQD, et al.Lirentelimab for severe and chronic forms of allergic conjunctivitis. J Allergy Clin Immunol, 2022; 150(3):631–639; doi: 10.1016/j.jaci.2022.03.021
