Effects of olopatadine hydrochloride, an antihistamine drug, on skin inflammation induced by repeated topical application of oxazolone in mice

BACKGROUND: Olopatadine hydrochloride (olopatadine) is one of the second-generation antihistamines, which is prescribed for allergic disorders such as rhinitis, urticaria and eczema dermatitis. OBJECTIVES: To investigate the possible anti-inflammatory effect of olopatadine on the chronic contact hypersensitivity response to repeated topical application of oxazolone in mice. METHODS: The preventive and therapeutic effects of oral olopatadine were quantified by measurements of ear swelling, cytokine protein and mRNA expression in the ear lesion, and were compared with those of topical betamethasone 17-valerate (betamethasone). RESULTS: The ear receiving repeated applications of oxazolone exhibited erythema, oedema and abrasion. Both preventive and therapeutic administration of olopatadine (10 mg kg(-1) day(-1)) significantly inhibited the ear swelling and the increased production of interleukin (IL)-4, IL-1beta, granulocyte-macrophage colony-stimulating factor (GM-CSF) and nerve growth factor. In the histopathological analysis, olopatadine ameliorated epidermal hyperplasia and infiltration of inflammatory cells. Consistent with these results, olopatadine significantly reduced the increased expression of interferon-gamma and IL-4 mRNA. Although betamethasone (0.012 mg ear(-1) day(-1)) showed similar activities to olopatadine against these responses, it caused atrophy of the ear skin. CONCLUSIONS: These results indicate that olopatadine is an antihistamine agent having inhibitory activities against chronic inflammatory dermatitis, possibly resulting from its diminishing effect on elevated cytokines.     

Importance of concomitant topical therapy in moderate‐to‐severe atopic dermatitis treated with cyclosporine

Cyclosporine (CS) is widely used in patients with refractory atopic dermatitis (AD). During CS treatment, many patients have a tendency to decrease their adherence to topical agents as their disease improves. Our aim was to compare the efficacy and relapse rate of CS treatment combined with topical therapy and CS monotherapy. This prospective, randomized, 6 month study involved 60 patients with moderate‐to‐severe AD who were randomly assigned to two groups, one receiving CS and topical agents and the other, CS only. Clinical outcomes were based on investigators’ global assessment (IGA) scores, eczema areas and severity index scores, and trans‐epidermal water loss. If a patient achieved treatment success (IGA score ≤2) during the study period, CS was stopped. Relapse rate and time to relapse were evaluated during the 3 months after discontinuation of CS. The treatment success rate was significantly higher in the combination group (p = 0.028). The combination group had a shorter median time to response (p = 0.040), a lower cumulative dose (p = 0.041), and a longer time to relapse (p < 0.01) than the monotherapy group. Although CS monotherapy is effective against AD, topical agents should be used concomitantly.     

The various effects of four H1-antagonists on serum substance P levels in patients with atopic dermatitis

Antiallergic drugs have various actions against allergy-associated cells and molecules as well as antihistamic properties. We studied the effects of antiallergics on the serum levels of substance P. Patients with atopic dermatitis were treated with one of four oral H1-antagonists for 14 days, and the serum level of substance P was measured before and after treatment in parallel with several atopic severity markers. Olopatadine significantly decreased the substance P level. This is in accordance with its known downmodulatory effect on tachykinin release. In contrast, cetiridine and fexofenadine unexpectedly increased the substance P level. In patients administered cetiridine, the blood severity markers for atopic dermatitis, including lactate dehydrogenase, eosinophil number, and the soluble forms of IL-2R, E-selectin, VCAM-1 and ICAM-1 were reduced after the treatment. Therefore, the elevation of SP was unrelated to the deterioration of atopic dermatitis but rather associated with improvement. Our study suggests that antiallergics can be divided into substance P-increasing and -decreasing types and raises the possibility that the increment of substance P by the former type is caused by the competitive occupation of substance P receptors.     

Intermittent topical corticosteroid/tacrolimus sequential therapy improves lichenification and chronic papules more efficiently than intermittent topical corticosteroid/emollient sequential therapy in patients with atopic dermatitis

Atopic dermatitis (AD) is a common, chronic, relapsing, severely pruritic, eczematous skin disease. Topical steroids are the mainstay of treatment. However, the adverse effects of steroids on hormonal function are the major obstacle for their use as long-term topical therapy. Intermittent dosing with potent topical steroids and/or combination therapy with steroid and tacrolimus have been frequently used in the daily management of AD to overcome the problems accompanying the long term use of steroids. We compared the clinical effects of topical steroid/tacrolimus and steroid/emollient combination treatments in 17 patients with AD. An intermittent topical betamethasone butyrate propionate/tacrolimus sequential therapy improved lichenification and chronic papules of patients with AD more efficiently than an intermittent topical betamethasone butyrate propionate/emollient sequential therapy after four weeks of treatment. Only one out of 17 patients complained of a mild, but temporary, burning sensation after tacrolimus application. The intermittent topical steroid/tacrolimus sequential therapy may be a useful adjunctive treatment for AD.     

Olopatadine hydrochloride accelerates the recovery of skin barrier function in mice

BACKGROUND: The skin barrier function in patients with atopic dermatitis is disrupted and prolonged topical steroid therapy produces epidermal barrier disturbance. Olopatadine hydrochloride (olopatadine; Allelock; Kyowa Hakko Kogyo Co., Ltd, Shizuoka, Japan) is an antiallergic drug with histamine H(1) receptor antagonistic action. This drug alleviates skin inflammation and decreases the number of scratching episodes in a murine model of chronic contact dermatitis. OBJECTIVES: To investigate the effects of olopatadine and a steroid on the recovery of skin barrier function after barrier disruption in mice. METHODS: The skin barrier of the ears of mice was disrupted by tape stripping. The recovery of skin barrier function was monitored by measurement of transepidermal water loss (TEWL) after barrier disruption. Epidermal hyperplasia was induced by repeated tape stripping for 7 days. Olopatadine was administered orally once daily from 3 days before the first barrier disruption. Betamethasone 17-valerate (betamethasone) was applied topically once daily from 3 days before barrier disruption. RESULTS: Tape stripping led to a significant increase in TEWL. TEWL decreased with time after tape stripping and the skin barrier function recovered by over 60% within 9 h after tape stripping. The recovery of skin barrier in olopatadine-treated mice was significantly accelerated, compared with that in vehicle-treated mice. In contrast, the skin barrier recovery in mice treated with topical betamethasone was significantly delayed, compared with that in vehicle-treated mice. Combined treatment with olopatadine and betamethasone ameliorated the delay in barrier recovery induced by topical treatment with betamethasone. In addition, olopatadine significantly prevented the increase in epidermal thickness induced by prolonged barrier disruption. CONCLUSIONS: These results suggest that systemic administration of olopatadine accelerates the recovery of skin barrier function and ameliorates the adverse effects of topical steroids on skin barrier recovery.     

First experience of topical SDZ ASM 981 in children with atopic dermatitis

BACKGROUND: SDZ ASM 981 is a selective inhibitor of inflammatory cytokine release under development for the topical treatment of atopic dermatitis. OBJECTIVES: This first paediatric study was designed to measure the systemic exposure to SDZ ASM 981 in young children with atopic dermatitis treated on extensive skin areas. METHODS: Children 1-4 years of age referred to a tertiary care centre for their atopic dermatitis were treated twice daily for 3 weeks with 1% SDZ ASM 981 cream. SDZ ASM 981 blood concentrations were measured on day 4 and 22 (last day) of treatment, and 1 week after the last application, using a radioimmunoassay with a limit of quantification of 0.5 ng mL(-1). Efficacy was assessed by the Eczema Area Severity Index (EASI). RESULTS: The 10 patients included had 23-69% of their body surface area (BSA) affected at baseline. Of the 63 SDZ ASM 981 blood concentrations measured, 63% were < 0.5 ng mL(-1); the maximum value observed was 1.8 ng mL-1. No accumulation was evidenced between days 4 and 22. The first two patients experienced a flare of atopic dermatitis that was not controlled by the study medication. In the other patients, the EASI improved by 8-89% at 3 weeks of treatment. CONCLUSIONS: In these children 1-4 years of age, blood concentrations of SDZ ASM 981 during topical treatment with the 1% cream were consistently low even in the children with the most extensive areas treated (up to 69% of their BSA).     

Dosage and adverse effects of topical tacrolimus and steroids in daily management of atopic dermatitis

Since 1999, combination therapy with tacrolimus and topical steroids has been widely used for the treatment of adolescent/adult-type atopic dermatitis. In order to determine the clinical doses of topical tacrolimus and steroids for daily treatment of atopic dermatitis and to elucidate their beneficial and adverse effects, we analyzed the clinical data from 215 patients with atopic dermatitis who were more than 16 years old. Less than 70 g of tacrolimus and less than 15 g of steroids were applied to 90% of the patients on the face and neck, and less than 75.8 g of tacrolimus and less than 322 g of steroids were applied to 90% of the patients on the trunk and extremities during the six-month treatment period. Topical tacrolimus is much more frequently used on face and neck lesions (99.1%); in only 39.5% of cases was it used on the trunk and extremities. The majority of patients improved after six months of the combination topical therapy; however, atopic dermatitis was not controlled in 6% of the patients. The combination therapy did not seem to increase the risk of cutaneous infections; however, the incidence of herpes simplex infection on the face and neck was 2.8% at pre-treatment and slightly increased to 4.7% during the therapy. The incidence of all steroid-induced adverse effects was reduced both in frequency and intensity with a decrease in the dose of topical steroids through simultaneous tacrolimus application. Combination therapy with topical tacrolimus and steroids is useful for treating atopic dermatitis, but a small percentage of the patients still cannot be satisfactorily treated. For such patients, adjustments of the dose and rank of topical steroids and tacrolimus and other therapeutic adjuncts are necessary.     

Clinical dose and adverse effects of topical steroids in daily management of atopic dermatitis

BACKGROUND: Topical steroids are used as the first-line therapy for atopic dermatitis. OBJECTIVES: To determine the clinical doses of topical steroids for the daily treatment of atopic dermatitis in clinics and to elucidate their adverse effects. PATIENTS AND METHODS: A multicentre retrospective analysis of a series of 1271 patients (210 infants, 546 children, and 515 adolescents and adults) with atopic dermatitis. RESULTS: Less than 89.5 g, 135 g and 304 g of topical steroid were applied in 90% of the patients in the infant, childhood, and adolescent and adult AD groups, respectively, on the entire body during the 6-month treatment period. The majority of patients were controlled well; however, 7% of infant, 10% of childhood and 19% of adolescent and adult patients remained in a very severe or severe state or experienced exacerbation even though they applied larger amounts of topical steroids. With regard to adverse effects, the incidence of telangiectasia on cheeks tended to increase in patients who had a longer duration of disease and who applied more than 20 g to the face during the 6-month treatment period. The steroid-induced atrophy of the antecubital and popliteal fossae was more frequently observed in males than in females. CONCLUSIONS: Topical steroids are useful for treating atopic dermatitis, but a substantial percentage of patients cannot be satisfactorily treated with topical steroids. For such patients, adjustments of dose and rank of topical steroids and other therapeutic adjuncts are necessary.     

Nocturnal wrist movements are correlated with objective clinical scores and plasma chemokine levels in children with atopic dermatitis

BACKGROUND: Atopic dermatitis (AD) is a distressing disease associated with pruritus and sleep disturbance. Scratching due to pruritus is an important mechanism in the exacerbation of AD but is difficult to document in the home environment. OBJECTIVES: To evaluate whether nocturnal wrist activities, defined as average acceleration in the early hours of sleep, were correlated with components of the SCORing Atopic Dermatitis (SCORAD) index and various AD-associated chemokine markers. METHODS: Patients with AD aged under 18 years were recruited and the severity of eczema was assessed with the SCORAD index. Concentrations of plasma AD-associated chemokines [cutaneous T-cell attracting cytokine (CTACK); macrophage-derived chemokine (MDC); thymus and activation regulated chemokine (TARC)], interleukin (IL)-18, serum total IgE, and eosinophil counts were measured in these patients. Healthy children with noninflammatory and nonitchy skin conditions as well as healthy children of staff volunteers were recruited as controls. All children were instructed to wear the DigiTrac monitor on their dominant wrist before sleeping. The monitor was programmed to record limb motion between 22.00 and 08.00 h the following morning. RESULTS: Twenty-four Chinese children with AD (mean +/- SD age 12.6 +/- 3.7 years) and 15 normal children (mean +/- SD age 11.9 +/- 3.4 years) were recruited. The median (interquartile range) SCORAD was 54.8 (32.8-70.2). Plasma concentrations in pg mL(-1) of CTACK, MDC, TARC and IL-18 in the patients were 105 (92-172), 1648 (973-4214), 258 (100-850) and 415 (304-539), respectively. When compared with controls, most wrist activities occurred at frequencies between 1 and 3 Hz. These activities were most consistent over the first 3 h of sleeping and correlated significantly with disease severity, extent, intensity, and AD-associated chemokine markers CTACK, MDC and TARC. However, there was no significant correlation between wrist activities and the subjective symptom of pruritus or sleep loss. CONCLUSIONS: This is the first study to demonstrate that wrist activities, nonintrusively measured by the DigiTrac monitor at home, are closely correlated with the objective clinical scores and levels of peripheral blood chemokine markers for AD but not with the reported symptoms of pruritus or sleep loss. We propose that wrist activities between 1 and 3 Hz for the first 3 h are a good indicator of AD severity in children and should substitute for the pruritus and sleep-loss components of the SCORAD.     

Long-term safety and efficacy of delgocitinib ointment,a topical Janus kinase inhibitor,in adult patients with atopic dermatitis

Previous studies demonstrated that delgocitinib ointment, a novel topical Janus kinase inhibitor, rapidly improved clinical signs and symptoms of atopic dermatitis (AD) in Japanese adult patients. We sought to evaluate the long-term safety and efficacy of delgocitinib 0.5% ointment in a 52-week study (QBA4-2). Japanese patients aged 16 years or older with AD received delgocitinib 0.5% ointment b.i.d. for up to 52 weeks. Topical corticosteroids for the treatment of worsening of AD could be used at the investigators’ discretion during the treatment period. Safety end-points included the incidence and severity of adverse events (AEs). Pooled safety analyses included the data from the other long-term study (QBA4-1). Efficacy end-points included the percentage change from baseline in the modified Eczema Area and Severity Index (mEASI). A total of 506 patients were included in the pooled safety population. Overall, AEs were reported in 69.0% of patients; most AEs were mild and unrelated to delgocitinib ointment. The most common AE was nasopharyngitis, followed by contact dermatitis, acne, and application site folliculitis. No skin atrophy or telangiectasia was found at the application sites of delgocitinib ointment. Application site irritation symptoms were infrequent (<2%) and mild. The incidence of AEs did not increase over time, except for seasonal diseases. The improvement effects on AD as assessed by mEASI were maintained throughout the treatment period. Delgocitinib 0.5% ointment was well tolerated and effective when administrated to Japanese adult patients with AD for up to 52 weeks.     

ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of atopic dermatitis

Background The diagnosis of atopic dermatitis (AD) is made using evaluated clinical criteria. Management of AD must consider the symptomatic variability of the disease. Methods EADV eczema task force developed its guideline for atopic dermatitis diagnosis and treatment based on literature review and repeated consenting group discussions. Results and Discussion Basic therapy relies on hydrating topical treatment and avoidance of specific and unspecific provocation factors. Anti‐inflammatory treatment based on topical glucocorticosteroids and topical calcineurin antagonists is used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, but the topical calcineurin inhibitors, tacrolimus and pimecrolimus are preferred in certain locations. Systemic anti‐inflammatory treatment is an option for severe refractory cases. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial/antiseptic treatment. Systemic antihistamines (H1) can relieve pruritus, but do not have sufficient effect on eczema. Adjuvant therapy includes UV irradiation preferably of UVA1 wavelength or UVB 311 nm. Dietary recommendations should be specific and given only in diagnosed individual food allergy. Allergen‐specific immunotherapy to aeroallergens may be useful in selected cases. Stress‐induced exacerbations may make psychosomatic counselling recommendable. ‘Eczema school’ educational programmes have been proven to be helpful.     

Tacrolimus decreases the expression of eotaxin, CCR3, RANTES and interleukin-5 in atopic dermatitis

Background There is a lack of studies on the effect of tacrolimus on eosinophils and related molecules including eotaxin, CCR3, RANTES and interleukin (IL)‐5. Objectives To investigate the effects of tacrolimus on in vivo eosinophil counts and on the related molecules eotaxin, CCR3, RANTES and IL‐5 in patients with atopic dermatitis (AD). Methods Lesional skin specimens and sera were obtained from 15 patients with AD and from 15 normal controls. For 8 weeks, the patients with AD applied 0·03% tacrolimus ointment to all affected areas twice daily. Blood sampling and skin biopsies were then repeated. We evaluated serum eotaxin and IL‐5 levels, and tissue eotaxin, CCR3, RANTES and IL‐5 levels. Additionally, tissue levels of eotaxin and CCR3 mRNA were measured. Results After treatment with topical tacrolimus twice daily for 8 weeks, significant decreases were found in serum IL‐5 levels, immunoreactive cell counts of eotaxin, IL‐5, CCR3 and RANTES in AD skin, and tissue eosinophil counts. However, the change in the serum eosinophil count was not statistically significant, and mRNA levels of eotaxin and CCR3 were not decreased significantly after treatment. Conclusions Topical tacrolimus reduces the number of eosinophils in tissue and suppresses the expression of eotaxin, CCR3, RANTES and IL‐5 related to proliferation, recruitment, activation and survival of eosinophils.     

Substance P levels are decreased in lesional skin of atopic dermatitis

There is increasing evidence that neuropeptides (NP) such as substance P (SP) and vasoactive intestinal polypeptide (VIP) are involved in the pathogenesis of atopic dermatitis (AD). Vasoactive intestinal polypeptide levels were found to be significantly elevated in lesional skin of AD as compared to controls. We evaluated by radioimmunoassay the SP content in whole skin homogenates from chronic lichenified lesions of patients with AD. The levels of SP were significantly decreased in lesional skin from AD patients as compared to control skin (0.25 +/- 0.03 vs. 0.97 +/- 0.24 pmol/g tissue, p < 0.01). The diminished SP levels as opposed to increased VIP concentrations could be consistent with different roles of these NP as modulatory agents in the mechanisms associated with AD.     

Risk factors of admission in school children with severe atopic dermatitis

There are no data about risk factor of admission and long-term (>1 year) prognosis of proactive therapy using topical corticosteroids (TCSs) in school children. This study aims to identify the prognosis of school children over 3 years treated with proactive therapy after hospitalization due to atopic dermatitis (AD). This retrospective cohort study used electronic medical record data of schoolchildren (aged 5–19 years) with a long-term admission program for AD at the National Center for Child Health and Development from January 2008 to December 2013. Long-term prognosis at 1 and 3 years after discharge were retrospectively identified from their medical records. The most common exacerbation factor was poor adherence (51.8%). At 1 and 3 years after hospitalization, 87.3% and 74.3%, respectively, of the children used TCSs on their trunk and limbs less than twice a week. Investigator's Global Assessment of AD scores were ≤1 for 81.0%and 75.7% at 1 and 3 years after discharge, respectively. AD was well-controlled during follow-up. Rehospitalization due to AD was observed in 11.8% children. Poor adherence was biggest risk factor for admission. Children with severe AD could achieve well-controlled AD with a long-term admission AD program and home-based proactive therapy using TCSs for 3 years after discharge. Maintaining good adherence for AD treatment is required to prevent exacerbation and improve future prognosis in school children. However, we need to engage for the children who required rehospitalization.     

A randomized controlled trial of pimecrolimus cream 1% in adolescents and adults with head and neck atopic dermatitis and intolerant of, or dependent on, topical corticosteroids

BACKGROUND: There is a need for alternative treatments for atopic dermatitis (AD) of the face and neck as long-term use of topical corticosteroids (TCS) is associated with skin atrophy and telangiectasia and some patients develop allergy, intolerance or other side-effects. OBJECTIVES: This study was designed to assess the efficacy and safety of pimecrolimus cream 1% in patients with AD of the face and neck who are either dependent on, or intolerant of, TCS. METHODS: A 12-week study comprising a 6-week, double-blind, randomized, vehicle-controlled phase was conducted, followed by a 6-week, open-label phase. Two hundred patients aged 12 years or over with mild to moderate head and neck AD, intolerant of, or dependent on, TCS were randomized to either pimecrolimus cream or vehicle cream. The primary efficacy criterion was the facial investigator's global assessment score at 6 weeks. Secondary efficacy criteria were head and neck Eczema Area and Severity Index (EASI), pruritus score and eyelid dermatitis. Facial skin atrophy and telangiectasia were assessed with dermatoscopy. RESULTS: A significantly higher percentage of patients treated with pimecrolimus was cleared or almost cleared of facial AD compared with vehicle (47% vs. 16%, respectively). A statistically significant difference was also seen on head and neck EASI and pruritus score. Significantly more pimecrolimus-treated patients than vehicle-treated patients achieved clearance of eyelid dermatitis (45% vs. 19%, respectively). Among the 77 patients with skin atrophy at baseline, treatment with pimecrolimus was associated with a reversal in skin thinning. Of the 112 patients with telangiectasia at baseline, no statistically significant difference was seen between treatment groups. Adverse events occurred with similar frequency in both groups. CONCLUSION: Pimecrolimus cream 1% is effective in patients with head and neck dermatitis intolerant of, or dependent on, TCS. Reversion of skin atrophy may occur during TCS-free intervals.     

Non‐corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis

Topical corticosteroid phobia is an important problem in the treatment of atopic dermatitis as it can affect the ability to control disease severity and itch by reducing treatment adherence. Topical corticosteroid phobia often ends up even non‐corticosteroid adherence. As such, non‐corticosteroid adherence, disease severity and itch are likely to be associated with each other, but their relationship has yet to be thoroughly investigated. Thus, the purpose of this study is to investigate it in atopic dermatitis. Using data from 1190 participants in an Internet survey, we identified 255 non‐corticosteroid users and 225 with moderate to severe itch who were defined as non‐corticosteroid adherents. Corticosteroid users with the same itch categories (n = 878) served as controls. We also examined how itch severity affects the perception of itch in atopic dermatitis. Unexpectedly, non‐corticosteroid adherents were less sensitive to the conditions to elicit itch such as perspiring, commuting homeward, drinking alcohol and wearing woolen clothes compared with the control. We also found that patients with severer itch were more sensitive to itch during/after bathing, when lying in bed, commuting homeward, studying/working, drinking alcohol, undressing, getting up in the morning, after a meal, ingesting piquant foods and when they were unoccupied, angry, busy, nervous, sad or enjoying themselves. In conclusion, we found that non‐corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis and discuss possible mechanisms underlying these results. The information obtained in this study may be useful for communication with and education of atopic dermatitis patients and their treatment in outpatient clinics.