Etsuko Takamura

Sodium hyaluronate eyedrops in the treatment of dry eyes.

BACKGROUND--Several studies in the past have attempted to demonstrate the efficacy of sodium hyaluronate in the treatment of dry eyes. However, results have been conflicting and a definite conclusion has not yet been reached. This study recruited a larger group of patients and has incorporated for the first time both fluorescein and rose bengal staining in the evaluation of the epithelium. METHODS--Eighteen albino rabbit corneas were used in a basic animal study to demonstrate the efficacy of sodium hyaluronate by comparing the effects on the rate of epithelial healing. The optimal concentration to be used in the clinical trial was determined from the results of the basic study. In the clinical study 104 patients with dry eye syndrome were enrolled in a double masked controlled clinical trial. Patients received sodium hyaluronate drops in one eye and control medication in the other eye for 4 weeks. Grading of subjective symptoms and clinical examinations were performed at 2 and 4 weeks. RESULTS--In the animal study sodium hyaluronate at concentrations of 0.1% and 0.5% significantly accelerated the recovery time of iodine vapour induced corneal erosions (p < 0.01). In the clinical study no statistical significance was observed in the improvement of subjective symptoms or rose bengal staining, while fluorescein scores significantly improved in eyes receiving sodium hyaluronate (p = 0.0001) at 4 weeks. CONCLUSION--Sodium hyaluronate drops applied in six daily doses could not be demonstrated to offer advantages over conventional tear supplies in the improvement of subjective symptoms, but may play a role in maintaining a healthy corneal epithelium.

A Randomized, Placebo-Controlled Clinical Trial of Tacrolimus Ophthalmic Suspension 0.1% in Severe Allergic Conjunctivitis

AIMS To examine the efficacy of tacrolimus ophthalmic suspension 0.1% in treating severe allergic conjunctivitis. METHODS This was a multicenter, randomized, double-masked, placebo-controlled clinical trial. Fifty-six patients with severe allergic conjunctivitis in whom topical antiallergic agents and corticosteroids had been ineffective were randomized to tacrolimus or placebo treatment. Patients were treated either with tacrolimus or placebo twice-daily for 4 weeks. Severity of objective signs in palpebral and bulbar conjunctiva, limbus, and corneal involvement was assessed using 4 grades. Seven subjective symptoms were evaluated by visual analog scale (VAS) assessment. The primary efficacy endpoint was change in the total score of objective signs at the end of treatment. The secondary efficacy endpoints included change in the score for each objective sign and change in the VAS for each subjective symptom. Safety was assessed based on the severity and the incidence of adverse events. RESULTS Mean change from baseline in total score for objective signs was significantly greater in the tacrolimus (-5.6 + or - 5.1) than in the placebo group (-0.1 + or - 4.5; P < 0.001). Tacrolimus significantly improved giant papillae (P = 0.001) and corneal involvement (P = 0.005). Five subjective symptoms (itching, discharge, hyperemia, lacrimation, and foreign body sensation) were significantly better in the tacrolimus than in the placebo group. The most frequent treatment-related adverse event in the tacrolimus group was mild ocular irritation upon topical instillation, which was well-tolerated. CONCLUSION Tacrolimus ophthalmic suspension 0.1% is effective in treating severe allergic conjunctivitis.

A randomised, double-masked comparison study of diquafosol versus sodium hyaluronate ophthalmic solutions in dry eye patients

Aims To compare the efficacy and safety of 3% diquafosol ophthalmic solution with those of 0.1% sodium hyaluronate ophthalmic solution in dry eye patients, using mean changes in fluorescein and rose bengal staining scores as endpoints. Trial design and methods In this multicenter, randomised, double-masked, parallel study of 286 dry eye patients with fluorescein and rose bengal staining scores of ≥3 were randomised to the treatment groups in a 1 : 1 ratio. Efficacy and safety were evaluated after drop-wise instillation of the study drug, six times daily for 4 weeks. Results After 4 weeks, the intergroup difference in the mean change from baseline in fluorescein staining score was −0.03; this verified the non-inferiority of diquafosol. The mean change from baseline in rose bengal staining score was significantly lower in the diquafosol group (p=0.010), thus verifying its superiority. The incidence of adverse events was 26.4% and 18.9% in the diquafosol and sodium hyaluronate groups, respectively, with no significant difference. Conclusions Diquafosol (3%) and sodium hyaluronate (0.1%) exhibit similar efficacy in improving fluorescein staining scores of dry eye patients, whereas, diquafosol exhibits superior efficacy in improving rose bengal staining scores. Diquafosol has high clinical efficacy and is well tolerated with a good safety profile.

Interleukin-8 concentrations in conjunctival epithelium brush cytology samples correlate with neutrophil, eosinophil infiltration, and corneal damage.

Purpose. To evaluate whether interleukin-8 (IL-8) and RANTES (regulated on activation, normal T-cell expressed and secreted) concentrations in the supernatants of conjunctival epithelial samples from patients with vernal keratoconjunctivitis (VKC) correlate with the number of infiltrating eosinophils or neutrophils and with the severity of corneal lesions. Methods. Thirty-four patients with VKC, 5 patients with seasonal allergic conjunctivitis, and 10 volunteers without allergic diseases were enrolled in this study. Conjunctival epithelial cells were collected by brush cytology and the number of inflammatory cells was counted. The chemokine expression in the cells was investigated by immunocytochemistry and the chemokine concentrations of the cell suspensions were measured by enzyme-linked immunosorbent assay. Results. The percentages of eosinophils and neutrophils in cell suspensions from VKC patients with corneal erosion or ulcer were higher than those from subjects with clear corneas or superficial punctate keratopathy. IL-8 concentrations in the supernatant of samples correlated significantly with the percentages of neutrophils and eosinophils in paired cell suspensions. No correlation was observed between RANTES and the percentages of eosinophils. Positive staining for IL-8 was observed in the cytosol of conjunctival epithelial cells. Conclusion. IL-8 in the extracellular space of the conjunctival epithelium may play a role in the recruitment of neutrophils and possibly eosinophils and in the pathogenesis of corneal damage in severe allergic diseases.

A Large Prospective Observational Study of Novel Cyclosporine 0.1% Aqueous Ophthalmic Solution in the Treatment of Severe Allergic Conjunctivitis

PURPOSE To evaluate the effectiveness and safety of a novel cyclosporine 0.1% aqueous ophthalmic solution in a large population with vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC). METHODS A prospective observational postmarketing study was initiated in Japan. A total of 594 patients with VKC or AKC were started on this drug within 1 year after market launch (January 2006) and completed a 6-month follow-up. These patients were observed clinically, and subjective ocular symptoms (itching, discharge, tearing, photophobia, foreign body sensation, and pain), objective signs (hyperemia, swelling, follicle, papillae, and giant papillae for the tarsal conjunctiva; hyperemia and edema for the bulbar conjunctiva; Trantas dots and swelling for the limbus; and corneal involvement), and adverse events were recorded. RESULTS All scores for symptoms and signs significantly decreased from Month 1 through Month 6 of treatment in both VKC and AKC. Median total symptom scores at baseline, Month 1, and Month 6 were 6, 2, and 1, respectively, for VKC, and 7, 3, and 2, respectively, for AKC. Similarly, median total sign scores were 12, 7, and 5, respectively, for VKC, and 14, 10, and 7, respectively, for AKC. The percentage of patients able to complete topical cyclosporine 0.1% therapy within 6 months due to alleviation of symptoms was higher for VKC (44.4%) than for AKC (21.9%). In both VKC and AKC, approximately 30% of steroid users were able to discontinue topical steroids. Adverse drug reactions (ADRs) were found in 12.0% of patients, and the most common ADR was eye irritation (4.4%). Infectious corneal complications were observed in five AKC patients, including two cases of bacterial corneal ulcer and three cases of herpetic keratitis; all of these patients were concomitantly using topical steroids. CONCLUSIONS Topical cyclosporine 0.1% is an effective and safe treatment for VKC and AKC.

Detection by brush cytology of mast cells and eosinophils in allergic and vernal conjunctivitis

The presence of eosinophils in the conjunctival epithelium is indicative of allergies, and detection is currently performed by cotton swab scrapings. Although mast cells are thought to be chemotactic for eosinophils and thus presage their accumulation, the formers use as early indicators of allergy has heretofore been hindered by poor detection methods. The recent development of a special brush now makes it possible to collect many cells with less disturbance of the conjunctival epithelium. In the present study, we have used this brush for conjunctival scraping in 18 patients with vernal and allergic conjunctivitis, and 10 patients serving as controls. The superior and inferior tarsal conjunctiva in both eyes were examined, and the specimens were stained using Hansels method. Mast cells were observed in at least one of the tarsal conjunctivae in all cases of vernal and allergic conjunctivitis, whereas eosinophils were so observed in only eight cases (44.4%). Neither mast cells nor eosinophils were present in the conjunctivae of the normal group. Although treatment by mast cell stabilizers produced clinical remissions, they induced disappearance of mast cells in only 10 cases (55.6%), whereas in six cases (33.3%) the mast cells increased, and in two cases they were unchanged (11.1%). Six cases (33.3%) each showed disappearance of, increase in, and no change in eosinophils, reflecting even less of a response of these allergic cells to the treatment. The presence of mast cells and eosinophils, as determined by our cytologic method, was found to be correlated with the early detection, but not the clinical severity, of allergic conjunctivitis.

Effect of retinol palmitate as a treatment for dry eye: A cytological evaluation

Vitamin A is known to regulate the proliferation and differentiation of corneal epithelial cells and preserved conjunctival goblet cells and has been used in the treatment of disease of the eye such as dry eye and superior limbic keratoconjunctivitis for some time. This study was undertaken in order to evaluate the efficacy of retinol palmitate aqueous ophthalmic solution under development for the treatment of dry eye failing to respond to the conventional therapy with artificial tears or cornea-protective drugs. Retinol palmitate ophthalmic solution was applied repeatedly for 4 consecutive weeks. Before and after instillation therapy, brush cytology (Cytobrush-S) was performed and cytodiagnosis was made for keratinized cells, nonkeratinized cells, goblet cells and inflammatory cells on samples prepared using an automated smear apparatus (ThinPrep). In dry eye, an increase in goblet cells (1.3+/-2.6-->2.1+/-1.8 cells/slides), a decrease in keratinized cells (11.2+/-16.5-->5.2+/-10.9 cells/300 cells) and, hence, an increase in nonkeratinized cells (287.3+/-16.6-->293.4+/-11.4/300 cells) were found after treatment with retinol palmitate. As to inflammatory cells, there was no change from the pretreatment baseline (1.4+/-1.4-->1.4+/-1.3 cells/300 cells). These results demonstrate that brush cytology suggests the efficacy of retinol palmitate ophthalmic solution in dry eye treatment.

Tear IgE concentrations in allergic conjunctivitis.

Purpose Tear IgE has been considered to play an important role in allergic conjunctivitis and the measurement of tear IgE concentrations can help to diagnose this condition. Locally produced IgE levels have been shown to be the largest contributor to the severity of allergic conjunctivitis.Methods One hundred and thirteen allergic conjunctivitis patients (70 seasonal allergic conjunctivitis (SAC), 21 perennial allergic conjunctivitis (PAC), 22 vernal keratoconjunctivitis (VKC)), 14 bacterial conjunctivitis (BC) patients, 13 epidemic keratoconjunctivitis (EKC) patients and 18 normal controls were recruited. Tear samples were collected using the microcapillary method and tear IgE levels were measured using an immunoenzyme assay.Results Tear IgE concentrations showed significant increases in the VKC (322.2 ± 45.7 ng/ml), SAC (194.7 ± 21.7 ng/ml) and PAC (134.8 ± 23.1 ng/ml) groups when compared with controls (52.1 ± 9.7 ng/ml, p > 0.01). No significant difference was found between EKC (97.2 ± 11.7 ng/ml) and BC (92.6 ± 13.8 ng/ml) groups and controls (p = 0.1).Conclusions Tear IgE concentrations showed a significant increase in allergic conjunctivitis patients when compared with controls. Our results suggest that measuring tear IgE concentrations can help to diagnose allergic conjunctivitis.

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.

Primary and secondary surveys on epidemiology of Sjögren's syndrome in Japan

Abstract Objective. To characterize the epidemiology of Sjögrens syndrome (SS), including prevalence, disease type, extra-glandular involvement, satisfaction of diagnostic criteria sets, and treatment used in Japan. Methods. The Research Team for Autoimmune Diseases, the Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare conducted primary and secondary surveys on epidemiology of SS in 2011. The primary survey covered 4,729 out of 14,095 Japan-wide Hospital Departments to investigate the prevalence of SS. The secondary survey encompassed 214 Hospital Departments that agreed to the survey, to characterize disease type, extra-glandular involvement, satisfaction of diagnostic criteria sets, and treatments. Results. The number of patients with SS in Japan estimated by the primary survey was 68,483. The secondary survey involving data collected from 2,195 SS patients from 98 Hospital Departments showed that the mean age of patients was 60.8 ± 15.2 years, male/female ratio was 1/17.4, primary/secondary SS was about 60%/40% and glandular/extra-glandular form in primary SS was about 70%/25%. The satisfaction rate was 53.8% for the 1999 revised Japanese Ministry of Health criteria for the diagnosis of SS, 47.7% for the 2002 American–European Consensus Group classification criteria for SS and 49.6% for 2012 American College of Rheumatology classification criteria for SS. Corticosteroids were used by 752 of 2,195 patients (34%), immunosuppressants by 358 patients (16%), biologics by 68 patients (3%) and secretagogues by 695 patients (32%). Conclusion. The surveys provided valuable information on the epidemiology of SS including prevalence, disease type, extra-glandular involvement, satisfaction of diagnostic criteria sets and treatments used today in Japan.