SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis

BACKGROUND: SDZ ASM 981 is a selective inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro. It is the first ascomycin macrolactam derivative under development for the treatment of inflammatory skin diseases. OBJECTIVES: This study was designed to determine the safety and efficacy of SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6% and 1.0% in the treatment of patients with atopic dermatitis and to select the concentration to be used in phase III studies. METHODS: This was a double-blind, randomized, parallel-group, multicentre dose-finding study. A total of 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6%, or 1.0%, matching vehicle cream, or the internal control 0.1% betamethasone-17-valerate cream (BMV). Treatment was given twice daily for up to 3 weeks. RESULTS: A clear dose-response relationship for SDZ ASM 981 was evident, with 0.2%, 0.6% and 1.0% SDZ ASM 981 creams all being significantly more effective than vehicle (P = 0.041, 0.001 and 0.008, respectively) in terms of baseline to end-point changes in the Eczema Area Severity Index (EASI) and pruritus score. The 1.0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. It appears that the efficacy plateau was not reached with the SDZ ASM 981 creams within 3 weeks treatment. SDZ ASM 981 was well tolerated. Burning or a feeling of warmth were the only adverse events reported more frequently in the 0.6% and 1.0% SDZ ASM 981 treatment groups than in the vehicle treatment group (42.9%, 48.9% and 34.9%, respectively). Few systemic adverse events were reported during the study (headache was the most frequent systemic event reported by 15 of 252 patients) and none was considered to be related to treatment. The local tolerability profile of the 1.0% cream was similar to that of the lower concentrations. CONCLUSIONS: 1.0% SDZ ASM 981 cream, which was shown to be safe, well tolerated and the most effective concentration in this study, was selected as the concentration to be further developed in phase III studies.     

Treatment of paediatric atopic dermatitis with pimecrolimus (Elidel®, SDZ ASM 981): impact on quality of life and health-related quality of life

AIM: To report on quality of life (QoL) and health-related quality of life (HRQL) impacts of pimecrolimus (Elidel, Novartis A.G., Basel, Switzerland, SDZ ASM 981) 1% cream in the long-term treatment of paediatric atopic dermatitis. METHODS: QoL and HRQL data are presented from two 12-month international clinical trials evaluating the efficacy and safety of pimecrolimus 1% cream. Both trials were randomized and double blinded and compared two treatment strategies, one involving the use of emollients, pimecrolimus and topical corticosteroids, the other is 'usual care' (emollients plus topical corticosteroids) with a vehicle cream to maintain study blinding. The first trial (the infant trial) involved patients between ages 3 months and 2 years, whereas the children trial included patients aged 2-17 years. In both trials, QoL of the affected child's parent was evaluated with the parent's index of quality of life in atopic dermatitis (PIQoL-AD). HRQL was assessed in the children trial only with the children's dermatology life quality index (CDLQI). QoL and HRQL assessments were conducted at baseline, 6 weeks, 6 months and 12 months. RESULTS: Generalized linear modelling of PIQoL-AD scores at each post-baseline visit showed a greater impact on parent's QoL for pimecrolimus compared with control at all time-points in both trials. HRQL scores showed a greater improvement from baseline for children in the pimecrolimus group compared with those in the control group at all time-points. CONCLUSIONS: The results show a beneficial impact of pimecrolimus on parents' QoL in paediatric atopic dermatitis, confirming findings from earlier shorter term trials. There was also a clear benefit to the HRQL of the children treated.     

The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study

BACKGROUND: SDZ ASM 981 is a selective inhibitor of inflammatory cytokines released from T lymphocytes and mast cells, which has been developed for the treatment of inflammatory skin diseases. OBJECTIVES: In the present study, the atrophogenic potential of SDZ ASM 981 1% cream in humans was compared with that of medium and highly potent topical steroids, and vehicle. METHODS: Four different preparations, SDZ ASM 981 1% cream, the corresponding vehicle of SDZ ASM 981 1% cream, betamethasone-17-valerate 0.1% cream and triamcinolone acetonide 0.1% cream, were applied to the volar aspect of the forearms of 16 healthy volunteers, twice daily, 6 days a week, for 4 weeks. Skin thickness was evaluated by ultrasound examination, clinical signs of atrophy by stereomicroscopy, and epidermal thickness was assessed by histology. RESULTS: Both topical corticosteroids induced a significant reduction in skin thickness, as compared with SDZ ASM 981 1% cream and vehicle, which were shown to be equivalent. The difference in skin thickness (measured by ultrasound examination) between patients treated with SDZ ASM 981 1% cream and those receiving either of the two topical steroids was significant from day 8 onwards. Histological analysis performed at day 29 showed significant epidermal thinning with topical steroids compared with SDZ ASM 981 1% cream or the vehicle. Conclusion The lack of atrophogenic properties of SDZ ASM 981 1% cream in this short-term study demonstrates its potential as long-term treatment for inflammatory skin diseases, thus overcoming a major drawback of topical steroids. This may also be important for the treatment of children, and sensitive areas of skin, such as the face and skin-folds.     

Blood concentrations, tolerability and efficacy of pimecrolimus cream 1% in Japanese infants and children with atopic dermatitis

Pimecrolimus cream 1% is a topical calcineurin inhibitor for the treatment of atopic dermatitis. Minimal systemic exposure to pimecrolimus has been previously observed in Caucasian pediatric patients treated with the cream twice daily for up to 1 year. The objective of this open-label, non-comparative, multicenter study was to assess the systemic exposure, tolerability and efficacy of pimecrolimus cream 1% when used twice daily for 3 weeks in pediatric patients of Japanese background. The patient cohort consisted of 17 Japanese infants and children (age range, 3.6 months to 11.6 years) with atopic dermatitis of at least mild severity affecting >or=10% of the total body surface area (range, 10-48%). Pimecrolimus cream 1% was applied twice daily for 3 weeks. Blood levels of pimecrolimus were determined on days 1, 10 and 22. Safety and tolerability were evaluated by monitoring adverse events, laboratory parameters, physical condition and vital signs. Efficacy parameters included the Eczema Area and Severity Index, the Investigators' Global Assessment and the pruritus score. The median exposure to pimecrolimus cream 1% was 22 treatment days (range, 9-29 treatment days). Pimecrolimus blood concentrations were <0.5 ng/mL in 94% of samples on day 1, in 93% of samples on day 10 and in 100% of samples on day 22, with no indication of an increase with increasing body surface area treated (up to 48% of the total body surface area). No drug-related systemic adverse events or serious adverse events were reported. Treatment was effective according to all efficacy parameters. The findings of this study indicate that the use of pimecrolimus cream 1% results in minimal systemic absorption of the active ingredient in pediatric patients of Japanese background with extensive disease.     

Atopic dermatitis-like symptoms in hypomagnesaemic hairless rats are prevented and inhibited by systemic or topical SDZ ASM 981

Magnesium deficiency in hairless rats results in a transient erythematous rash within several days, the pathogenetic mechanisms of which are not yet well defined. However, the extremely pruritic rash closely mimics the acute clinical features of atopic dermatitis. Owing to the similarity of clinical signs between hypomagnesaemic rats and patients with atopic dermatitis, this rodent skin condition holds promise as a model for the in vivo evaluation of new treatment modalities against pruritic inflammatory skin conditions. The efficacy of the new ascomycin macrolactam derivative SDZ ASM 981 was tested in hypomagnesaemic rats by systemic or topical administration using prophylactic or therapeutic treatment regimens. Oral treatment of diseased rats with SDZ ASM 981 (12.5 mg kg-1 daily) inhibited the erythematous pruritic rash within 1 day after the start of treatment. This was associated with a clear reduction in histaminaemia, leucocytosis, eosinophilia and serum nitric oxide levels. The same daily oral dose of SDZ ASM 981 administered before the onset of the rash proved to be an efficacious prophylactic treatment regimen to prevent signs. Topical treatment of the ears with 0.4% SDZ ASM 981 locally inhibited and prevented inflammatory changes in a therapeutic and prophylactic treatment regimen, respectively. The histo- and immunopathological skin changes, as well as the numbers of degranulated mast cells in the dermis, were reversed towards normal after oral and topical administration. The pharmacological activity of SDZ ASM 981 reported here corresponds well to its anti-inflammatory and antipruritic activity observed in atopic dermatitis patients, confirming the usefulness of this rat model in drug evaluations.     

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.     

213例儿童特应性皮炎临床及病理特点分析

本研究对213例AD儿童患者临床及组织病理学特点进行分析,患儿平均发病年龄为0.88±1.73岁,约85.9%的患者表现为慢性皮炎;约78.9%的患者有个人或家族遗传过敏史。组织病理学示角化过度、微水疱形成、棘层肥厚、海绵水肿、浅层血管周围炎症及嗜酸性粒细胞浸润。     

Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis

Background  Systemic exposure to tacrolimus following topical application of tacrolimus ointment is minimal. There are, however, no data on the distribution of tacrolimus in the skin.
Objectives  To assess the distribution of tacrolimus in the skin and the systemic pharmacokinetics of tacrolimus in adults with moderate to severe atopic dermatitis after first and repeated application of tacrolimus ointment.
Methods  We investigated skin distribution of topically applied tacrolimus and systemic pharmacokinetics of percutaneously absorbed tacrolimus in adults with atopic dermatitis after topical application of tacrolimus 0·1% ointment twice daily for 2 weeks. Tacrolimus concentrations were assessed in full-thickness skin biopsies and blood samples.
Results  Of 14 patients, 11 completed treatment and were analysed. Mean ± SD tacrolimus concentrations in the skin at 24 h after first and last ointment applications were 94 ± 20 and 595 ± 98 ng cm⁻³, respectively. At 168 h after stopping treatment, values were 97% lower than at 24 h after last application. Tacrolimus concentration decreased with increasing skin depth. Systemic tacrolimus exposure after ointment application was low and highly variable, with 31% of samples below the limit of quantification (0·025 ng mL⁻¹) and 94% below 1 ng mL⁻¹. Blood concentrations at 24 h after the first and last ointment applications were 750 and 1800 times lower, respectively, than those in skin. Physicians' assessments showed that tacrolimus ointment was effective and well tolerated.
Conclusions  Tacrolimus was primarily partitioned in the skin, with minimal systemic absorption after topical application, in patients with atopic dermatitis.     

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.     

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.     

Severity scores, itch scores and plasma substance P levels in atopic dermatitis treated with standard topical therapy with oral olopatadine hydrochloride

Atopic dermatitis (AD) is a common chronic or chronically relapsing, severely pruritic, eczematous skin disease. Recently, substance P (SP) has been demonstrated to be one of the important neuropeptides for mediating itch–scratch and stress–scratch cycles. In this study, we examined the severity scores, itch scores and plasma SP levels in 19 patients with AD treated with standard topical therapy with or without an oral antihistamine, olopatadine hydrochloride, for 4 weeks. The standard therapy decreased SCORAD scores, itch behavioral rating scores and plasma SP levels at post-treatment in the mass, but the topical therapy with olopatadine was more effective than the topical therapy alone, suggesting a potential additive effect.     

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.     

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.