Executive summary: Japanese guidelines for allergic conjunctival diseases 2021.

Allergic conjunctival disease (ACD) is an inflammatory disease of the conjunctiva that is mainly caused by type I hypersensitivity response to allergens and accompanied by subjective symptoms and other findings induced by antigens. ACD is classified as allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. This article summarizes the third edition of the Japanese guidelines for allergic conjunctival diseases published in 2021 and outlines the diagnosis, pathogenesis, and treatment of ACD. Since the introduction of immunosuppressive eye drops, the treatment strategies for severe ACDs have significantly changed. To clarify the recommended standard treatment protocols for ACD, the advantages and disadvantages of these treatments were assessed using clinical questions, with a focus on the use of steroids and immunosuppressive drugs. This knowledge will assist healthcare providers and patients in taking an active role in medical decision making.

Japanese guidelines for allergic conjunctival diseases 2020.

The definition, classification, pathogenesis, test methods, clinical findings, criteria for diagnosis, and therapies of allergic conjunctival disease are summarized based on the Guidelines for Clinical Management of Allergic Conjunctival Disease 2019. Allergic conjunctival disease is defined as "a conjunctival inflammatory disease associated with a Type I allergy accompanied by some subjective or objective symptoms." Allergic conjunctival disease is classified into allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. Representative subjective symptoms include ocular itching, hyperemia, and lacrimation, whereas objective symptoms include conjunctival hyperemia, swelling, folliculosis, and papillae. Patients with vernal keratoconjunctivitis, which is characterized by conjunctival proliferative changes called giant papilla accompanied by varying extents of corneal lesion, such as corneal erosion and shield ulcer, complain of foreign body sensation, ocular pain, and photophobia. In the diagnosis of allergic conjunctival diseases, it is required that type I allergic diathesis is present, along with subjective and objective symptoms accompanying allergic inflammation. The diagnosis is ensured by proving a type I allergic reaction in the conjunctiva. Given that the first-line drug for the treatment of allergic conjunctival disease is an antiallergic eye drop, a steroid eye drop will be selected in accordance with the severity. In the treatment of vernal keratoconjunctivitis, an immunosuppressive eye drop will be concomitantly used with the abovementioned drugs.

Reduced steroid-induced intraocular pressure elevation in tacrolimus-treated refractory allergic ocular diseases.

PURPOSE: To determine whether topical tacrolimus can lessen steroid-induced intraocular pressure (IOP) elevation. STUDY DESIGN: Open cohort post hoc analysis study. METHODS: Five hundred eleven patients with vernal keratoconjunctivitis or atopic keratoconjunctivitis (mean age 17.0 ± 9.2 years) were studied. All 511 patients were treated with topical tacrolimus with or without topical steroids, and the changes in IOP were measured monthly for 3 months. The elevation in IOP induced by use of topical steroids was calculated using mixed linear regression analyses. The relationship between the elevation in IOP within 4 weeks and the use or nonuse of tacrolimus reported in published data was analyzed using metaregression analysis to estimate the effects of tacrolimus on the IOP in eyes treated with topical steroids. RESULTS: The mean topical steroid-induced IOP elevation in tacrolimus-treated eyes was lower, by 5.2 mmHg (P = 0.04), than that in earlier published data without tacrolimus as the control. In the tacrolimus-treated eyes, the mean betamethasone-induced IOP elevation was 1.3 mmHg without discontinuation of the steroid. Metaregression analysis indicated that glaucoma history and younger age had significant effects on topical steroid-induced IOP elevation, by 4.0 mmHg (P = 0.002) and 3.9 mmHg (P = 0.01), respectively. In tacrolimus-treated eyes, the most significant effect on the IOP was associated with glaucoma history or medication; however, its effect on the IOP was limited to 1.7 mmHg elevation (P = 0.006). CONCLUSIONS: Topical tacrolimus may lessen the steroid-induced elevation in IOP in younger individuals and may be a good adjunctive therapy to avoid IOP elevation in refractory cases.

Long-Term Safety and Effectiveness of Diquafosol for the Treatment of Dry Eye in a Real-World Setting: A Prospective Observational Study.

INTRODUCTION: Diquafosol is a P2Y2 receptor agonist that has been shown to be effective in the treatment of dry eye disease (DED) in short-term studies; however, its long-term safety and effectiveness have not been evaluated in a real-world setting. METHODS: This prospective, multicentre, open-label observational study was conducted in patients with DED over 12 months. Safety endpoints included the incidence of adverse drug reactions (ADRs) and serious ADRs. Effectiveness endpoints included change from baseline in keratoconjunctival staining score, tear film break-up time (BUT) and Dry Eye-related Quality of Life Score (DEQS). RESULTS: A total of 580 patients were included, most of whom were female (82.9%). The proportion of patients who completed 12 months of observation was 55.0%, the most common reason for discontinuation was patient decision (54.6%). The incidence of ADRs was 10.7% and was highest during the first month of treatment (5.5%); no serious ADRs were reported. Compared with baseline, significant improvements in all effectiveness outcomes, including keratoconjunctival fluorescein staining score, BUT and DEQS summary score, were observed at each evaluation during the treatment period (p < 0.001). CONCLUSION: The present, real-world study showed that diquafosol 3.0% ophthalmic solution was well tolerated and effective in the long-term treatment of DED.

Air pollution significantly associated with severe ocular allergic inflammatory diseases.

Ambient air pollution is a well-recognized risk for various diseases including asthma and heart diseases. However, it remains unclear whether air pollution may also be a risk of ocular allergic diseases. Using a web-based, nation-wide, cross-sectional study design, we examined whether the level of ambient air pollution is significantly associated with the prevalence of ocular allergic diseases. A web-based questionnaire was posted to invite the participants who are members of the Japan Ophthalmologist Association and their family members. The answers from 3004 respondents were used to determine whether there were significant associations between the level of the pollutants and the prevalence of ocular allergic diseases. The study period was between March to May 2017. The data of the air pollutants during 2012 to 2016 were obtained from the National Institute for Environmental Studies. The prevalence of allergic diseases was calculated by post stratification and examined for significant associations with the level of pollutants using multiple logistic regression analyses. The prevalence of seasonal allergic conjunctivitis, perennial allergic conjunctivitis, atopic keratoconjunctivitis (AKC), and vernal keratoconjunctivitis (VKC) in Japan was 45.4%, 14.0%, 5.3%, and 1.2%, respectively. The high prevalence of the severe forms of allergic conjunctivitis, including AKC and VKC, were significantly associated with the levels of the air pollutants. The prevalence of AKC was significantly associated with the levels of NO2 with an odds ratio (OR) of 1.23 (per quintile). The prevalence of VKC was significantly associated with the levels of NOx and PM10 with ORs of 1.72 and 1.54 respectively. The significant associations between the prevalence of AKC and VKC and the levels of air pollutants indicate that clinicians need to be aware that air pollutants may pose serious risks of vision threatening severe ocular allergy.

Topical Tacrolimus for Chronic Allergic Conjunctival Disease with and without Atopic Dermatitis.

Purpose/Aim: This study evaluated the efficacy of topical 0.1% tacrolimus ophthalmic suspension for treating chronic allergic conjunctival disease with and without atopic dermatitis. Materials and Methods: This study was conducted as a prospective observational post-market survey. Our large-scale study protocol was accepted by the Pharmaceuticals and Medical Devices Agency in Japan and included patients who were prescribed topical tacrolimus for the treatment of chronic allergic conjunctival disease from May 2008 to Aug 2010 in Japan. Topical tacrolimus was instilled 2 times daily for 6 months. The primary endpoint was the change from baseline in papillae-limbus-cornea clinical signs score (based on the presence of papillae, giant papillae, Trantas' dots, limbal swelling, and corneal epithelial signs). Remission rate following topical tacrolimus treatment was investigated using generalized estimating equations. Results: A total of 1821 subjects were included in the analyses. Six months into treatment, 83.0% and 87.7% of subjects with and without atopic dermatitis, respectively, were in remission (based on the papillae-limbus-cornea grading score). Topical tacrolimus treatment was equally effective in improving papillae-limbus-cornea grading scores from baseline in both study groups after 6 months of treatment. Additionally, the odds ratio for remission increased over time. The concomitant use of topical steroids improved papillae-limbus-cornea grading scores, including papillary signs with a statistically significant, but low odds ratio. Conclusion: Tacrolimus ophthalmic suspension is useful for treating chronic allergic conjunctival disease with and without atopic dermatitis. Clinical response to local tacrolimus therapy is dependent upon treatment duration.

Clinical practice guideline for Sjögren's syndrome 2017.

OBJECTIVES: The objective of this study is to develop clinical practice guideline (CPG) for Sjögren's syndrome (SS) based on recently available clinical and therapeutic evidences. METHODS: The CPG committee for SS was organized by the Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW), Japan. The committee completed a systematic review of evidences for several clinical questions and developed CPG for SS 2017 according to the procedure proposed by the Medical Information Network Distribution Service (Minds). The recommendations and their strength were checked by the modified Delphi method. The CPG for SS 2017 has been officially approved by both Japan College of Rheumatology and the Japanese Society for SS. RESULTS: The CPG committee set 38 clinical questions for clinical symptoms, signs, treatment, and management of SS in pediatric, adult and pregnant patients, using the PICO (P: patients, problem, population, I: interventions, C: comparisons, controls, comparators, O: outcomes) format. A summary of evidence, development of recommendation, recommendation, and strength for these 38 clinical questions are presented in the CPG. CONCLUSION: The CPG for SS 2017 should contribute to improvement and standardization of diagnosis and treatment of SS.

Comparison of performance of the 2016 ACR-EULAR classification criteria for primary Sjögren's syndrome with other sets of criteria in Japanese patients.

OBJECTIVES: To compare the performance of the new 2016 American College of Rheumatology (ACR)-European League Against Rheumatism (EULAR) classification criteria for primary Sjögren's syndrome (SS) with 1999 revised Japanese Ministry of Health criteria for diagnosis of SS (JPN), 2002 American-European Consensus Group classification criteria for SS (AECG) and 2012 ACR classification criteria for SS (ACR) in Japanese patients. METHODS: The study subjects were 499 patients with primary SS (pSS) or suspected pSS who were followed up in June 2012 at 10 hospitals in Japan. All patients had been assessed for all four criteria of JPN (pathology, oral, ocular, anti-SS-A/SS-B antibodies). The clinical diagnosis by the physician in charge was set as the 'gold standard'. RESULTS: pSS was diagnosed in 302 patients and ruled out in 197 patients by the physician in charge. The sensitivity of the ACR-EULAR criteria in the diagnosis of pSS (95.4%) was higher than those of the JPN, AECG and ACR (82.1%, 89.4% and 79.1%, respectively), while the specificity of the ACR-EULAR (72.1%) was lower than those of the three sets (90.9%, 84.3% and 84.8%, respectively). The differences of sensitivities and specificities between the ACR-EULAR and other three sets of criteria were statistically significant (p<0.001). Eight out of 302 patients with pSS and 11 cases out of 197 non-pSS cases satisfied only the ACR-EULAR criteria, compared with none of the other three sets. CONCLUSIONS: The ACR-EULAR criteria had significantly higher sensitivity and lower specificity in diagnosis of pSS, compared with the currently available three sets of criteria.

Japanese guidelines for allergic conjunctival diseases 2017.

The definition, classification, pathogenesis, test methods, clinical findings, criteria for diagnosis, and therapies of allergic conjunctival disease are summarized based on the Guidelines for Clinical Management of Allergic Conjunctival Disease (Second Edition) revised in 2010. Allergic conjunctival disease is defined as "a conjunctival inflammatory disease associated with a Type I allergy accompanied by some subjective or objective symptoms." Allergic conjunctival disease is classified into allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. Representative subjective symptoms include ocular itching, hyperemia, and lacrimation, whereas objective symptoms include conjunctival hyperemia, swelling, folliculosis, and papillae. Patients with vernal keratoconjunctivitis, which is characterized by conjunctival proliferative changes called giant papilla accompanied by varying extents of corneal lesion, such as corneal erosion and shield ulcer, complain of foreign body sensation, ocular pain, and photophobia. In the diagnosis of allergic conjunctival diseases, it is required that type I allergic diathesis is present, along with subjective and objective symptoms accompanying allergic inflammation. The diagnosis is ensured by proving a type I allergic reaction in the conjunctiva. Given that the first-line drug for the treatment of allergic conjunctival disease is an antiallergic eye drop, a steroid eye drop will be selected in accordance with the severity. In the treatment of vernal keratoconjunctivitis, an immunosuppressive eye drop will be concomitantly used with the abovementioned drugs.

Steroid-Sparing Effect of 0.1% Tacrolimus Eye Drop for Treatment of Shield Ulcer and Corneal Epitheliopathy in Refractory Allergic Ocular Diseases.

PURPOSE: To evaluate the effects of 0.1% topical tacrolimus alone or in combination with steroids for the treatment of shield ulcers and corneal epitheliopathy in patients with refractory allergic ocular diseases. DESIGN: Open cohort study. PARTICIPANTS: Patients with refractory allergic conjunctivitis epitheliopathy, shield ulcers, or corneal plaques (N = 791). METHODS: The 791 patients were treated with topical tacrolimus alone or in combination with topical or oral steroids. The effectiveness of the treatments was determined by a corneal epitheliopathy score during the 3-month follow-up period. The clinical signs were rated on a 4-grade scale. Corneal epitheliopathy with no corneal staining was graded as 0, and shield ulcers or plaques were graded as 3, the highest grade. The effects of tacrolimus with and without topical steroids on the epitheliopathy scores were assessed after adjustments for the severity of the clinical signs and characteristics. MAIN OUTCOME MEASURES: Changes in the corneal epitheliopathy score. RESULTS: Adjusted mean epitheliopathy score at the baseline was 1.73 (95% confidence interval [CI], 1.65-1.81) for patients treated with tacrolimus alone, and this was significantly reduced by -0.93 at 1 month. The reduction of the score by topical and oral steroids was -0.02 for fluorometholone, 0.02 for betamethasone, and -0.02 for oral steroids, and these reductions were not significant compared with the reduction effect of topical tacrolimus alone at -0.93. The 238 patients with shield ulcer (score 3) were analyzed with adjustments, and the mean epitheliopathy score at 1 month was reduced to 1.38 with tacrolimus alone (95% CI, 1.24-1.51), 1.41 (95% CI, 1.26-1.56) with adjuvant fluorometholone, and 1.46 (95% CI, 1.32-1.61) with adjuvant betamethasone. No significant difference was observed in the adjunctive topical steroids. The presence of severe palpebral conjunctival symptoms, including giant papillae, was a significant resisting factor for topical tacrolimus. CONCLUSIONS: The significant effects of topical tacrolimus alone on shield ulcers and corneal epitheliopathy suggest that it may be used without the need for steroids.

A diagnostic method for herpes simplex keratitis by simultaneous measurement of viral DNA and virus-specific secretory IgA in tears: an evaluation.

PURPOSE: We performed simultaneous measurement of herpes simplex virus (HSV) DNA by real-time polymerase chain reaction (real-time PCR) and of HSV-specific secretory IgA antibody (HSV-sIgA) by enzyme-linked immunosorbent assay (ELISA) in tears obtained using Schirmer strips in order to investigate its diagnostic efficacy for herpes simplex keratitis (HSK). METHODS: A total of 59 affected eyes from 59 patients with clinically suspected HSK (HSK group) and 23 eyes from 23 healthy volunteers (control group) were enrolled in this study. The HSK group was divided into five subgroups: dendritic/geographic keratitis, disciform keratitis, necrotizing keratitis, atypical keratitis, and others. The tear samples were taken using Schirmer strips to determine the HSV DNA and HSV-sIgA levels. RESULTS: The overall sensitivity and specificity were 55.8 and 100 % for HSV DNA and 49.2 and 82.6 % for HSV-sIgA. The HSV DNA levels in the disciform keratitis subgroup (median, 3.1 × 10(2) copies/sample) were significantly lower than those in the dendritic/geographic keratitis subgroup (median, 2.3 × 10(4) copies/sample) (P < 0.05, Mann-Whitney test). The HSV-sIgA levels in the disciform keratitis subgroup (median, 50.0 NU/ml) were significantly higher than those in the control group (median, 18.0 NU/ml) (P < 0.05, Steel test). The positive and negative predictive values obtained by simultaneous measurement of HSV DNA and sIgA were 90.9 and 61.3 %, respectively. CONCLUSION: The combination of laboratory detection of HSV DNA by real-time PCR and of HSV-sIgA by ELISA using tear samples enables higher reliability in diagnosing the subgroups of HSK, although the HSV DNA value is relatively lower in disciform HSK than in dendritic/geographic HSK.

Real-world assessment of diquafosol in dry eye patients with risk factors such as contact lens, meibomian gland dysfunction, and conjunctivochalasis: subgroup analysis from a prospective observational study.

PURPOSE: To evaluate the efficacy and safety of diquafosol (DQS) ophthalmic solution in dry eye (DE) patients wearing contact lenses (CLs) or with concomitant meibomian gland dysfunction (MGD) or conjunctivochalasis in a real-world setting. PATIENTS AND METHODS: From a cohort of patients enrolled in a prospective observational study, DE patients who met the Japanese diagnostic criteria and who received DQS as a monotherapy were extracted and stratified according to the presence or absence of CL use, MGD, and conjunctivochalasis. Corneal and conjunctival fluorescein staining score, tear film break-up time, total symptom score (12 DE-related subjective symptoms), patient-reported outcomes, and adverse reactions were investigated. RESULTS: DQS treatment resulted in significant improvement in total symptom score, corneal and conjunctival fluorescein staining score, and tear film break-up time without significant differences between patient subgroups with versus without CL use, MGD, or conjunctivochalasis. Comparable proportions of patients perceived symptomatic improvements in all subgroups. There were no adverse reactions specifically associated with the CL use or any comorbidity of MGD or conjunctivochalasis. CONCLUSION: DQS can be used effectively and safely as a monotherapy for the treatment of DE patients wearing CLs or with concomitant MGD or conjunctivochalasis.

Clinical usefulness of diquafosol for real-world dry eye patients: a prospective, open-label, non-interventional, observational study.

INTRODUCTION: This study was designed to evaluate the efficacy and safety of 3% diquafosol ophthalmic solution in dry eye patients in clinical practice. METHODS: Subjects were dry eye patients who had never used diquafosol, and observation was conducted prospectively over 2 months. The corneal and conjunctival fluorescein staining score, tear film break-up time, 12 dry eye-related subjective symptoms, patient-reported outcomes, and adverse events were investigated. RESULTS: Data were collected from 465 medical institutions for 3,196 patients. Diquafosol led to significant improvement in all subjective symptoms and objective findings (P < 0.001, paired t test). Diquafosol was effective regardless of the degree of severity according to the corneal and conjunctival fluorescein staining score or therapeutic pattern. Overall, 76.0% patients responded that their condition had improved. Adverse reactions were observed in 6.3% of patients. The major adverse reactions were eye discharge, eye irritation, and eye pain. CONCLUSION: Diquafosol was effective for various dry eye patients in clinical practice, and no significant safety-related problems occurred.

Efficacy of epinastine hydrochloride ophthalmic solution in allergic conjunctivitis by conjunctival cedar pollen allergen challenge.

BACKGROUND: Epinastine hydrochloride is a selective histamine H1 receptor antagonist that also inhibits IgE receptor-mediated histamine release from mast cells. OBJECTIVE: To show the superiority of epinastine 0.05% ophthalmic solution (epinastine) to placebo ophthalmic solution (placebo) and noninferiority to olopatadine 0.1% ophthalmic solution (olopatadine) for cedar pollen antigen-induced ocular itching and conjunctival hyperemia. METHODS: The study was conducted in ophthalmologically asymptomatic adult volunteers with seasonal allergic conjunctivitis using a conjunctival allergen challenge test. Subjects were randomized into 3 groups (n = 87) to evaluate superiority to placebo (visits 4 to 6) and 2 groups (n = 86) to evaluate noninferiority to olopatadine (visit 7). At each visit, a single administration of the study medication was instilled at 15 minutes (visit 4), 4 hours (visit 5), 8 hours (visit 6), and 4 hours (visit 7) before the conjunctival allergen challenge test. Ocular itching and conjunctival hyperemia of allergic conjunctivitis were assessed after the conjunctival allergen challenge test. RESULTS: For the primary end point, epinastine showed superiority to placebo for the inhibition of ocular itching and conjunctival hyperemia induced at 4 hours after the dose (equivalent to 4-times-daily dosing). For the secondary end points, epinastine significantly inhibited itching and conjunctival hyperemia induced at 15 minutes and 8 hours after the dose (equivalent to 2-times-daily dosing) compared with placebo. In addition, epinastine demonstrated noninferiority to olopatadine for ocular itching and conjunctival hyperemia. No adverse drug reactions or serious adverse events were reported throughout the study, indicating that epinastine has a good safety profile. CONCLUSION: Epinastine is effective and safe for the treatment of allergic conjunctivitis. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01363700.

Therapeutic effects of 0.1% tacrolimus eye drops for refractory allergic ocular diseases with proliferative lesion or corneal involvement.

BACKGROUND: The objective of this study was to investigate the efficacy of topical 0.1% tacrolimus in treating refractory allergic conjunctivitis with proliferative lesions and/or corneal involvement. METHODS: This prospective observational study included 1436 patients with refractory allergic conjunctivitis whose condition had responded poorly to conventional antiallergic drugs and/or topical steroids and/or topical cyclosporine. All patients received tacrolimus eye drops twice daily during the study period. Ten clinical signs and six clinical symptoms were rated on a four-grade scale. The primary endpoint was the change from baseline in total clinical signs and symptoms score at the last observation or following 6 months of treatment. RESULTS: Total signs and symptoms score significantly decreased after 1 month of treatment (p<0.001). Giant papillae and corneal lesions were also reduced by tacrolimus eye drop use (p<0.001). The drug proved effective in patients whose condition did not respond well to topical cyclosporine therapy. About 50% of all patients using topical steroids were weaned. The most common adverse reaction was a transient burning sensation (3.20%). CONCLUSIONS: Tacrolimus eye drops are highly effective in treating refractory allergic conjunctivitis with proliferative lesions and/or corneal involvement, and may reduce or replace topical steroid use. TRIAL REGISTRATION NUMBER: UMIN 000008640.