Efficacy of medical treatments for vernal keratoconjunctivitis: A systematic review and meta-analysis
Ines Roumeau, MD, a Adrien Coutu, MD,a Valentin Navel, MD,a,b Bruno Pereira, PhD,c Julien S. Baker, PhD,d Fred eric Chiambaretta, MD, PhD, a,b Dominique Bremond-Gignac, MD, PhD,e,f and Fred eric Dutheil, MD, PhD g,h,i
Abstract
Background: Vernal keratoconjunctivitis (VKC) is a severe type of allergic conjunctivitis for which treatment strategies are still under debate.
Objectives: This study sought to conduct a systematic review and meta-analysis to evaluate the efficacy of medical treatments for VKC.
Methods: The PubMed, Cochrane Library, Embase, and
ScienceDirect databases were searched to assess the efficacy of treatments for VKC. Random-effect meta-analyses on changes in clinical scores of symptoms and signs between baseline and after treatment, stratified on treatment classes, were computed. Meta-regressions were searched for potential influencing parameters.
Results: Included were 45 studies (27 randomized controlled trials and 18 prospective cohort studies), 1749 patients (78% were men; mean age, 11.2 years), and 12 different treatment classes. Mast cell stabilizers (MCSs; usually considered as firstline therapy), cyclosporine, and tacrolimus were the most studied drugs (in three-quarters of studies). Overall, all clinical scores improved. Total symptom and sign score decreased for MCSs (effect size, 23.19; 95% CI, –4.26 to 22.13), cyclosporine (effect size, 22.06; 95% CI, 22.72 to 21.40), and tacrolimus (effect size, 22.39; 95% CI, 23.36 to 21.43). No significant differences were shown depending on treatment classes, From athe Ophthalmology Department, Centre Hospitalier Universitaire Clermont-Ferrand, hthe Preventive and Occupational Medicine Department, WittyFit, Centre Hospitalier Universitaire Clermont-Ferrand, University Hospital of Clermont-Ferrand, Witty Fit, cthe Biostatistics Unit, Clinical Research and Innovation Direction, University Hospital of Clermont-Ferrand, bthe Translational Approach to Epithelial Injury and Repair Department, Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Genetique Reproduction et Developpement, and gthe Physiological and Psychosocial Stress Department, Laboratoire de Psychologie Sociale et Cognitive, Centre National de la Recherche Scientifique, Universite Clermont Auvergne, Clermont-Ferrand; dthe Hong Kong Baptist University, Centre for Health and Exercise Science Research, Physical Education and Health, Kowlon Tong; e the Ophthalmology Department, University Hospital Necker Enfants Malades, and fthe Sorbonne Paris Cite University, Institut National de la Sante et de la Recherche Medicale, Unite Mixte de Recherche S1138, Team 17, From Physiopathology of Ocular Diseases to Clinical Development, Cordeliers Search Centre, Paris; and ithe Faculty of Health, School of Exercise Science, Australian Catholic University, Melbourne. concentration, age, sex, baseline activity scores, and atopy.
Sensitivity analyses demonstrated similar results. Conclusions: This study confirms the efficacy of MCSs in the treatment of VKC. Efficacy of cyclosporine and tacrolimus did not differ, suggesting that tacrolimus is a good alternative to cyclosporine for severe cases of VKC. Further studies are needed to compare other drugs and their precise place in treatment strategy. (J Allergy Clin Immunol 2021;nnn:nnn-nnn.)
Key words: Chronic disease, immunomodulators, topical drugs, atopy, inflammation, pediatrics
Introduction
Vernal keratoconjunctivitis (VKC) is a severe type of allergic conjunctivitis affecting mostly male children, with atopic condition.1 The prevalence of VKC strongly depends on the geographical origin, varying from 3.2 per 10,000 inhabitants in Western Europe2 to 500 per 10,000 inhabitants in Central Africa.3 Three forms are described: limbal VKC, tarsal VKC, and mixed VKC.1 In most cases, this eye condition is characterized by perennial ocular symptoms and signs with seasonal exacerbations.4 The physiopathology of VKC involves both IgEmediated allergic factors as well as nonallergic ones.4 The treatment of this pathology is a critical issue due to its wellknown impact on quality of life as well as its sightthreatening complications (shield ulcers, keratoconus, limbal stem cell deficiency, irregular astigmatism).5 Despite some proposals,6,7 therapeutic strategies are under debate. Nondrug therapies are the basis of the treatment (eye washing, solar protection, eviction of allergens with proven sensitization). Medical treatment is often necessary with artificial tears, mast cell stabilizing eye drops, and/or antihistaminic drugs as first-line therapies. In case of crisis or noncontrolled VKC, corticosteroids eye drops are usually added. Their effect is powerful, but they have potential serious side effects (glaucoma, cataract), leading to the use of cyclosporine (a calcineurin inhibitor) in case of cortico-dependence or resistance.4 The place of other immunomodulator drugs, such as tacrolimus (another calcineurin inhibitor) remains to be clarified.8 Numerous clinical scores attesting the VKC severity are available but none is consensual.9 In daily clinical practice, scores assessing the most frequent symptoms (itching, photophobia, discharge, tearing, foreign body sensation) and signs (hyperemia, keratitis, tarsal papillae, limbal inflammation) are simple and easy to apply.
Therefore, the objectives of this study were to assess the efficacy of all available medical treatments on symptoms and signs of VKC and to compare conventional drugs with new therapies.
METHODS
Literature search
We reviewed all interventional prospective studies measuring the efficacy of any treatment for active VKC. The PubMed, Cochrane Library, ScienceDirect, and Embase databases were searched in November 2020 with the following key words: ‘‘vernal keratoconjunctivitis’’ OR VKC AND therapy OR treatment OR therapeutic* (see Appendix E1 in this article’s Online Repository at www.jacionline.org). The search was not limited in time. Articles needed to be written in English, French, Spanish, or Portuguese. The studies had to report our primary outcome, an activity score (symptoms and/or signs) of VKC before and after any medical treatment. Studies needed to be primary research. Studies assessing severe allergic conjunctivitis without specification orpoolingpatientswithVKCandthosewithatopickeratoconjunctivitis,retrospective studies, and animal studies were excluded. We also excluded articles with only patients in nonactive phase of VKC. We imposed no limitation on the sample size and the regional origin. In addition, reference lists of all publications meeting the inclusion criteria were manually searched to identify any further studiesthat were not found with the key wordssearch. Thesearch strategy is presented in Fig 1. One author conducted all literature searches and collated the abstracts. Two authors separately reviewed the abstracts and, based on the selection criteria, decided the suitability of the articles for inclusion. Another author was asked to review the articles where consensus on suitability was debated. All authors then reviewed the eligible articles. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (see Appendix E2 in this article’s Online Repository at www.jacionline.org).
Data collection
The data collected included first author’s name, publication year, country, study design, aims, outcomes of included articles, sample size, number of eyes, age,percentageofmales,drugs(type,galenic,concentration,posology),activity scores of VKC (symptoms, signs, and total), measurement time (baseline and at re-evaluation), presentation of VKC (onset, severity, refractory characteristics, forms— limbic, tarsal, mixed), previous treatment with or without washout period, and other putative explaining variables (atopy, ethnicity).
Quality of assessment
We usedthe SIGN (ScottishIntercollegiate GuidelinesNetwork)checklists to assess the methodological quality of randomized clinical trials (10 items) and cohort studies (14 items).10 Items assessed the main causes of bias. We calculated an overall quality score by quoting each item (yes 5 1; no, cannot say, or not applicable 5 0).
Statistical considerations
Statistical analysis was conducted using Stata software (version 15; StataCorp, College Station, Tex).11-13 Baseline characteristics were reported for each study sample as number (percent) and as mean 6 SD for categorical and continuous variables, respectively. We conducted meta-analyses on effects of treatment at the most frequent time of re-evaluation for each study compared to baseline measures—or the closest time to the most frequent time. We described our results by calculating the effect size (ES; standardized mean differences). A positive ES denoted improved efficacy. A scale for ES has been suggested with 0.8 reflecting a large effect, 0.5 a moderate effect, and 0.2 a small effect.14 We conducted random-effect meta-analyses for each symptom (itching, photophobia, discharge, tearing, and foreign body sensation) and for each sign of VKC (hyperemia, keratitis, tarsal papillae, and limbal inflammation). When not available, we proportionally calculated a total subjective symptom score (TSSS), a total ocular sign score (TOSS), and a total symptom and sign score combining both scores—by computing the average of all individual scores transformed on a 0 to 100 scale. We conducted sensitivity analyses considering time of assessment, as well as on studies reporting the absence of concomitant treatments. We also computed meta-analyses on the effect of treatment versus a placebo in studies reporting the use of a placebo in the control group at re-evaluation time. For all aforementioned meta-analyses, we computed stratification on drugs and type of drugs (treatment class). When possible, meta-regressions were proposed to compare the benefits between drugs and type of drugs and to assess the influence of putative clinically relevant parameters such as concentration for the mostfrequentdrugs, ageof patients,sex, baselineactivityscores, or atopy. Results were expressed as regression coefficients and 95% CIs.
RESULTS
An initial search produced 1131 possibly corresponding articles (Fig 1). Removal of duplicates and the use of the selection criteria reduced the number of articles reporting the evaluation of treatment of VKC to 45 articles from 31 different journals,15-59 published between 197224 and 2019.9 All articles were written in English except 1 in French23 and 1 in Portuguese.29
Study designs
Twenty-seven studies were randomized controlled studies (14 placebo-controlled15,19,20,24-27,31,33,35,41,48,50,51 and 13 with another active treatment as comparator17,28,36,37,39,40,43,44,46,49,55,56,59), 2 were controlled studies,29,52 and 16 were single-group prospective cohort studies.16,18,21-23,30,32,34,38,42,45,47,53,54,57,58 All controlled studies were double masked except 4 that were single masked,17,29,46,55 and 3 that were not masked.33,40,52 Forty-two studies were monocentric,15-26,28-40,42-55,57-59 and 3 were multicentric.27,41,56 The majority of studies was carried out in the Middle East (n 5 17)15-19,21,25,28,32-35,42,46,47,54,59 and Europe (n 5 16),20,22-24,30,38-40,45,48-50,52,53,55,56 followed by Asia (n 5 6),31,36,37,51,57,58 South America (n 5 3)29,43,44 and North America (n5 2).26,27 Onestudywasheldin11countriesthroughoutEurope, Asia, Middle East, and North America.41
Quality of articles
Results of SIGN cohort studies criteria ranged from 66.6%32,34,38 to 100%45 for yes responses, with a mean score of 82.5 6 10.5%. Results of SIGN randomized controlled trials criteria ranged from 33.3%40 to 100%25,37,44,48,51 for yes responses, with a mean score of 80.2 6 15.5 (Fig 2, and see Appendix E3 in this article’s Online Repository at www. jacionline.org).
Inclusion criteria
Inclusion criteria were VKC without precision,20-22,25,28,29,42,47,50,51 18,24,27,30,36,37,39,40,44,46,55,56 active VKC, active severe VKC or refractory to medical treatment15,16, 18,19,23,25,31-35,41,43,45,48,49,52-54,57-59 48 (especially first-line drugs, resistance or dependency to corticoids,15,19,23,34,43,58,59 and resistance to cyclosporine16,49,54,57). Only 4 studies had age criteria with age required over 3,45 4,41,55 or 6 years old59 and under 16,45 17,55 or 18 years old.41,59 One study required the association of VKC and asthma.38
Exclusion criteria
The main exclusion criteria were related to concomitant or previous specific ocular disease such as uveitis,16,19,36,37,45,58 glaucoma,19,36,37,45 local infection (acute conjunctivitis, history of herpes),16,19,25,30,36,37,40,41,43,44,46,58,59 corneal diseases,16,19, 22,30,31,36,37,45,49,58 45,46 16,46 blepharitis, conjunctival pathologies, history of dry eye syndrome,46,51 cataract,19,45 or nonspecific ocular disease.15,20,21,25,27-29,31,36,37,40,41,45,55,59 Some studies also excluded patients with previous ocular surgery,16,21,30,40,41,45,46,58 concomitant systemic disease,15,28,31,36,37,40,45,49,55,59 or those using systemic corticosteroids, nonsteroidal anti-inflammatory drugs, antihistamines, immunosuppressive therapy medications,15,19,20,27,35,38,41,44,49,58,59 or any systemic therapy.30,31,45,46,55 Some studies excluded patients using any ophthalmic therapy for other pathologies29,41,45,46,55 or previous ocular therapy for VKC.21 Other criteria were cited, such as contact lens use,16,20,25,27,29,30,45,46,55,56 pregnancy, possible risk of pregnancy, or breastfeeding.21,28,29,46,55,56,59 Fifteen studies had no exclusion criteria.17,18,23,24,26,32,33,39,42,47,48,50,52-54,57
Population
Sample size. A total of 1749 patients diagnosed with VKC representing3496eyeswereincluded:1440patientsreceivedactive treatmentinbotheyes,107weretreatedwithactivetreatmentinone eye and placebo treatment in the other, 202 were treated with only a placebo in both eyes. Population sizes ranged from 7 patients30 to 197 patients53 with a mean of 39 6 40 patients per study.
Sex. The mean proportion of men was 78% (95% CI, 76% to 80%), varying from 30%21 to 95.8%,37 one study did not specify the proportion of men.50
Age. The mean age of VKC patients was 11.2 years (95% CI, 10.2 to 12.1 years), ranging from 3 years25,45 to 38 years.15,34,51 The minimal mean age in the included studies was 7.1 6 1.6 years36 and the maximal mean age was 26.6 6 16 years.21 Three studies didnot specify the mean age.52,53,58 All patients were children in 19 studies,17,23,29,30,32,35-37,41,42,44,45,47-49,52,53,55,59 whereas 22 studies evaluated both adults and children.15,16, 18-22,24-28,31,33,34,43,46,50,51,54,56,58
Four studies did not report the age range of patients and therefore whether some adults were included or not.38-40,57
Clinical form. Twenty-one studies22,23,26,27,29,33,36,37,41-49, 51,53,54,58 specified the proportion of limbal, tarsal, and mixed form of VKC. In these studies, VKC’s tarsal form was the most common (56.1%), followed by limbal (24.3%) and mixed form (19.6%).
Duration of disease. Twenty-two studies mentioned the mean duration of disease,15-17,19,22,25,27,31,34-37,41,42,45,46,49,54,55,57-59 ranging from 1.1 years36,58 to 12.6 years.46 Atopy. There was an overall percentage of 53% of patients who were atopic (95% CI, 49% to 57%) within the 20 studies reporting atopy,19,21,23,25-27,32,36-38,41,45-49,52,53,55,57 20% of patients with asthma (95% CI, 16% to 23%) within 11 studies,23,26,27,32,36-38,41,47,48,57 9% of patients with atopic dermatitis (95% CI, 7% to 12%) within 10 studies,23,25-27,32,36,37,45-47 and 33% of patients with allergic rhinitis (95% CI, 28% to 37%) within 9 studies.23,26,27,32,36,37,45,48,57 Other atopic factors retrieved were multiple allergic diseases, positive prick test, biological stigmas such as elevated serum total and specific IgE, eosinophil count, and eosinophil cationic protein level.
Aims and outcomes of included studies
All included studies, except 1,45 shared a similar main objective to evaluate the efficacy and safety of treatments for VKC based on clinical outcomes.15-22,24-26,28-40,42-44,46-55,57-59 Seven studies had an associated main objective of exploring the biological effects of treatments with a focus on changes in conjunctival impression cytology (in particular conjunctival immune cells and goblet cells),17,18,32 modifications of biological markers in tears (eosinophil cationic protein, cytokine levels, secretory mucins),39,40,47 and impacts on in vivo confocal microscopy images of dendritic cells.58 In 1 study, the main objective was the investigation of changes in biological markers after cyclosporine treatment in VKC.45
Characteristics of treatments
Type. A total of 20 different drugs grouped in 12 treatment classes were studied. All studies used local treatments except 2 assessing systemic treatments.38,42 Cyclosporine was assessed in 16 studies,18,19,23,32,33,35-37,41,45,47-50,52,53 mast cell stabilizers (MCSs) class in 11 studies (cromolyn sodium,17,24-27,39,44,55 lodoxamide,17,28,39,56 N-acetyl aspartyl glutamic acid [NAAGA],28,40 and nedocromil sodium25,55), and tacrolimus in 10 studies.16,34,36,37,43,44,49,57-59 Other drugs were used in fewer than 3 studies each: antihistaminic drugs (levocabastine);40,56 dual agents, MCS1 antihistaminic agents (olopatadine21,29 and ketotifen29); nonsteroidal anti-inflammatory drugs (topical ketorolac,51 topical diclofenac,22 oral aspirin42); corticosteroids46 (prednisolone, fluorometholone, loteprednol); mitomycinC;15,31 IFNa-2b;54,59 mipragoside;20 probiotic eye drop;30 and oral montelukast.38 Among the 14 studies using a placebo, the placebo was the vehicle in 8 studies,19,20,24,26,27,35,41,48 artificial tears or normal saline in 4 studies,15,31,33,51 and was not detailed in 2 studies.25,50
Meta-analyses on treatment efficacy compared to baseline
Overall meta-analyses showed that total symptoms and signs score improved globally (ES, 22.48; 95% CI, 22.88 to 22.09). Considering type of treatment, total symptoms and signs score decreased for MCSs (ES, 23.19; 95% CI, 24.26 to 22.13), cyclosporine (ES, 22.06; 95% CI, 22.72 to 21.40), and tacrolimus (ES, -2.39; 95% CI, 23.36 to 21.43). Antihistamines, dual agents, non-steroid anti-inflammatory drugs, IFNa-2b, mitomycin C, montelukast, probiotic eye drops, and mipragoside were seldom assessed, but all seemed to demonstrate improvement of total symptoms and signs score (Fig 3, and see Appendix E4 in this article’s Online Repository at www.jacionline.org). Meta-analysis on each symptom and sign demonstrated similar improvement for each treatment class (Fig 4 and see Appendixes E5 and E6 in this article’s Online Repository at www.jacionline.org). All symptoms were individually improved, with an ES <23 for itching (ES, 23.90; 95% CI, 24.67 to –3.13), foreign body sensation (ES, 23.05; 95% CI, 24.05 to 22.06), and TSSS (ES, 23.01; 95% CI, 23.47 to 22.55); an ES between 23 and 21.5 for tearing (ES, 22.29; ; 95% CI, 22.89 to 21.69) and discharge (ES, 21.99; 95% CI, 22.61 to 21.38); and an ES >21.5 for photophobia (ES, 21.39; 95% CI, 21.77 to 21.01) (Appendix E5). All signs were individually improved, with an ES <22 for limbal inflammation (ES, 22.81; 95% CI, 23.63 to 21.99), hyperemia (ES, 22.77; 95% CI, 23.43 to 22.12), and TOSS (ES, 22.26; 95% CI, 22.64 to 21.88); and an ES between 22 and 21 for tarsal papillae (ES, 21.28; 95% CI, 21.72 to 20.84) and keratitis (ES, 21.21; 95% CI, 21.61 to 20.8) (Appendix E6).
Meta-regressions and sensitivity analyses
Considering improvement in total symptoms and signs score, meta-regressions comparing the efficacy of treatments did not show significant differences depending on age, sex, baseline activityscoresofVKC,atopy, typeoftreatment,and concentration fortacrolimusandcyclosporine(Fig5,andseeAppendixE7inthis article’s Online Repository at www.jacionline.org). Metaregressions comparing the efficacy of treatments depending on each symptom or sign could not be performed due to collinearity. For rigor, funnel plots of all aforementioned meta-analyses were used to search for potential publication bias (partly presented in Appendix E8 in this article’s Online Repository at www. jacionline.org). All aforementioned meta-analyses were reperformed after exclusion of studies not evenly distributed around themeta-funnels andgavesimilarresults(data notshown).Finally, we performed the following additional sensitivity analyses (only on total symptoms and signs score in order to keep a sufficient number of studies). Using different time of re-evaluation gave similar results. The meta-analysis comparing the treatment groups to the placebo groups also demonstrated similar findings (see Appendix E9 in this article’s Online Repository at www. jacionline.org). Also, we performed a meta-analysis of treatment efficacy in the subgroup of 23 studies specifying the absence of concomitant treatment,15,16,20-22,27,29-35,37,42-44,46-49,51,58 and results did not differ from the main analyses.
DISCUSSION
The main findings were that clinical symptoms and signs improved with all tested treatments. Although transposition of our results in clinical practice should be interpreted with caution because of heterogeneity of patients between studies, efficacy of drugs did not differ in our metaanalysis between usual first-line therapy (MCSs), and immunomodulators (cyclosporine and tacrolimus that could be a good alternative in severe VKC). Other drugs were seldom assessed precluding robust conclusions. Underlined re-evaluation times were those included in the main analyses.
Conventional drugs
We demonstrated that all clinical scores showed great improvement with all treatments. Although meta-regressions were not feasible, tarsal papillae seemed the most resistant sign to treatment, in accordance with literature.48,50,56,58 Similarly, photophobia seemed the most difficult symptom to treat although results in literature are more discordant.19,21,54 MCSs were the most studied conventional drugs, especially cromolyn sodium that was historically the first described MCS.60 Despite insufficient data that precluded further comparisons among the 4 main MCSs, some investigators found better efficacy of nedocromil sodium and lodoxamide compared to that of cromolyn sodium.4 In case of absence of efficacy, they also proposed to try other MCSs before switching for another class, because of the specificities of each drug.4 Although other drugs (antihistamines, dual agents, nonsteroidal anti-inflammatory drugs, corticosteroids) are conventional in allergic conjunctivitis, efficacy of these drugs cannot be fairly assessed in our meta-analysis due to insufficient data. Likewise, no study on ‘‘over-the-counter’’ vasoconstrictors and oral antihistamines were reported. However, these 2 treatments are rarely used in VKC due to tachyphylaxis and inducedconjunctivitis for the first and more delayed and less efficient action than with topical presentation for the second.7
Place of topical immunomodulators
Cyclosporine and tacrolimus were the most studied drugs. Both drugs are calcineurin inhibitors that inhibit T-lymphocyte activation and the release of inflammatory cytokines.61 Ophthalmic application in VKC has been studied since the 1990s for cyclosporine,50 whereas the interest in tacrolimus is more recent.57 In our meta-analysis, patients with VKC benefiting from cyclosporine and tacrolimus often had a severe or refractory disease. We demonstrated similar benefits for both drugs, confirming that tacrolimus is a good alternative to cyclosporine for severe corticosteroid-dependent VKC, in line with literature.36,37,49 Efficacy also did not differ depending on concentration of cyclosporine or tacrolimus, for a similar number of applications per day, suggesting that low dose could be sufficient. It is particularly interesting considering that local tolerance of these otherwise well-tolerated drugs seems to be concentration-dependent.62 Initially, cyclosporine was only available as hospital-compound preparations at varying concentrations63 and now has commercialized forms at low dose (0.05% with only a marketing authorization in dry eye disease, and 0.1% concentrations, which is the only commercialized form with a marketing authorization for severe VKC). Several studies were in favor of 0.1% concentration.41,64 Similarly, tacrolimus is still mostly hospital-delivered, but is starting to be marketed in some countries.62 Tacrolimus 0.1% suspension received marketing authorization since 2008, only in Japan, with the indication: ‘‘Vernal conjunctivitis (in patients with inadequate response to anti-allergic agents)” and with the recommendation to use in patients with severe giant papillae. No other studies for marketing authorization have been conducted. The patients who may benefit the most from tacrolimus should be further investigated.
Other therapeutic options
Alongside these well-known treatments, some drugs were only reported in 1 (montelukast, mipragoside, probiotic eye drop) or 2 studies (IFNa-2b, mitomycin C) per drug in our meta-analyses, precluding robust conclusions and warranting further studies. There are also new emerging strategies of treatment of VKC. Atopic condition is an important risk factor of VKC, though not all patients with VKC present this condition—53% in our meta- analysis, which is in linewithliterature.65,66 Atopy couldalso be a prognostic factor for the severity of VKC.23 For patients who are atopic, specific therapies can be used, such as omalizumab or allergen immunotherapy. Omalizumab is an IgE-blocking agent commercialized for severe allergic asthma that could be an encouraging lead in VKC.67-69 Allergen immunotherapy, in case of proven sensitization, may as well be very promising,70,71 with even better results than with first-line topical medications.72 Subgroups of atopic patients in VKC should be considered, as some studies did.27,38 In addition to the atopy challenge, there may be a renewed interest in corticosteroids in VKC, although they are usually used sparingly because of their long-term side effects. Indeed, low-penetrating low-dose corticosteroids such as hydrocortisone, clobetasone, loteprednol, or fluorometholone in eye drops may warrant further studies in the treatment of VKC.1,46.
Quality of evidence and potential biases
Our study has some limitations. Even if our population of 1749 patients may not seem important considering the frequency of VKC in some countries,3 it is a considerable sample compared to existing literature in which 50% of included studies have fewer than 50 patients. It is also a huge step forward compared to the previous meta-analysis on VKC treatment that included 245 patients from 10 studies of which the most recent was from 2002 and which included few drugs.73 We updated the knowledge with all the new treatments. However, our meta-analysis is mainly salient in the evaluation of cyclosporine, tacrolimus, and MCSs, because other drugs were seldomly reported. Though there were similarities between patients, inclusion criteria were not identical between studies. In particular, even if severity assessment of VKC is not consensual6 and was not reported in most studies, a major limitation is heterogeneity in VKC severity across studies. It may have altered the comparison between classical first- and second-line medications—the latter mostly used in severe or refractory VKC. Severity assessment was also based on a subjectiveevaluation,limitingthequality ofthereported data. Similarly, the differential diagnosis of atopic keratoconjunctivitis could be questionable in studies reporting a mean age older than 20 years old,18,31,43,53 inducing a selection bias as both diseases could have specific treatment needs.74,75 There is also heterogeneity between studies regarding concomitant treatments. However, this corresponds to real life, and sensitivity analysis revealed similar results. Seasonal influence was not controlled in most studies. Moreover, symptoms and signs varied between studies, also inducing heterogeneity in total scores (total symptoms and signs score, TSSS, and TOSS). Even if we took the re-evaluation time closest to 1 month for each study, it varied across studies, limiting comparability. Not all of the included studies were randomized controlled studies, which may have induced heterogeneity in our results; however, we followed a rigorous methodology and computed sensitivity analyses by only keeping studies with the best studies designs. There was only 1 study for each stratification, thus the weight of studies did not require further ponderings. Anotherlimitationofourmeta-analysis isthelack ofdataoncharacteristics of patients such as history of previous treatments or duration of VKC, precluding further analyses. Finally, studies were mostly monocentric although all continents and all ethnicities were represented, favoring generalizability of our results.
Conclusions
We showed an overall improvement in clinical symptoms and signs with all treatments. The most frequent drugs were MCSs (usually considered as first-line therapy), cyclosporine, and tacrolimus. Efficacy of drugs did not differ, indicating that tacrolimus is a good alternative to cyclosporine for cases of severe VKC and promoting the possibility of using smaller doses for a similar effect in order to enhance local tolerance. Other drugs were seldom assessed and their places in VKC treatment strategy remain unclear.
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