Burden of atopic dermatitis in Japanese adults: Analysis of data from the 2013 National Health and Wellness Survey

Atopic dermatitis is a chronic inflammatory skin disease. The objective of this study was to characterize the burden of atopic dermatitis in Japanese adult patients relative to the general population. Japanese adults (≥18 years) with a self‐reported diagnosis of atopic dermatitis and adult controls without atopic dermatitis/eczema/dermatitis were identified from the 2013 Japan National Health and Wellness Survey. Atopic dermatitis patients were propensity‐score matched with non‐atopic dermatitis controls (1:2 ratio) on demographic variables. Patient‐reported outcome data on comorbidities, mood and sleep disorders, health‐related quality of life, work productivity and activity impairment, and health‐care resource utilization were analyzed in atopic dermatitis patients and matched controls. A total of 638 Japanese adult patients with atopic dermatitis were identified, of whom 290 (45.5%) rated their disease as “moderate/severe” and 348 (54.5%) as “mild”. The analysis cohort comprised 634 atopic dermatitis patients and 1268 matched controls. Atopic dermatitis patients reported a significantly higher prevalence of arthritis, asthma, nasal allergies/hay fever, anxiety, depression and sleep disorders compared with controls (all P < 0.001). Atopic dermatitis patients also reported a significantly poorer health‐related quality of life, higher overall work and activity impairment, and higher health‐care resource utilization (all P < 0.001). Self‐rated disease severity was not associated with disease burden, except for a significantly higher overall work and activity impairment. In conclusion, Japanese adult patients with atopic dermatitis reported a substantial disease burden relative to adults without atopic dermatitis, suggesting an unmet need for effective strategies targeting disease management.     

Post‐marketing surveillance on treatment of 5,665 patients with atopic dermatitis using the calcineurin inhibitor pimecrolimus: Positive effects on major symptoms of atopic dermatitis and on quality of life

Background: Topical application of the calcineurin inhibitors pimecrolimus and tacrolimus is a current major advance in the therapy of atopic dermatitis. The aims of this post‐marketing surveillance were: a) to acquire data on the efficacy and tolerability of pimecrolimus ointment (Elidel^®) on a very large cohort of patients from outpatient clinics, and b) to assess changes in their quality of life, a parameter not often considered in previous studies. Patients and methods: Included were 5,665 patients with atopic dermatitis. During the observation period, data on efficacy and tolerability were obtained at the beginning of the study, 3 to 10 days after initiation of therapy and after 4 to 6 weeks. Evaluation of symptoms as well as assessment of efficacy and tolerability were based on linear scales and on the percentage of the body surface area (% BSA) involved. Quality of life was assessed by the German version of the “Dermatology Life Quality Index (DLQI)” or the “Children's Dermatology Life Quality Index (CDLQI)”. Results: In this largest post‐marketing surveillance hitherto performed in Germany, the efficacy of pimecrolimus was judged as “good” by 79.3 % of physicians and by 76.5 % of patients. Tolerability was assessed as “good” by 87.2 % of physicians and by 83.1 % of patients. Major symptoms of atopic dermatitis such as pruritus, erythema or lichenification showed marked reduction after just 3 to 10 days, signalling general improvement of the skin disease. In addition, application of pimecrolimus resulted in a significant improvement of the quality of life scores in both children and adults. Conclusion: The present study demonstrates that the good efficacy and tolerability of pimecrolimus ointment which had been shown in controlled trials: i) could also be demonstrated on a very large cohort of patients with atopic dermatitis when used in the outpatient setting, and ii) were paralleled by a significant improvement in the quality of life.     

Association between smoking and hand dermatitis – a systematic review and meta‐analysis

Tobacco smoking is known to influence various inflammatory skin diseases. A systematic review with a meta‐analysis was conducted to analyse a possible association between the lifestyle factor tobacco smoking and hand dermatitis. We performed a systematic review using the MEDLINE, Embase and Cochrane Central Register databases. Our search was limited to English and German language, human‐subject studies published between January 1, 1980 and December 31, 2013. A total of 43 articles were identified from the initial search, and after taking into account exclusion criteria, only three studies remained investigating the risk factors for hand eczema in the general and in high‐risk populations (e.g. bakers, hairdressers, dental technicians). The extracted data were pooled and analysed by standard statistical methods. The studies meeting inclusion criteria consisted of one cohort study and two cross‐sectional studies based on a total of 4.113 subjects with hand dermatitis and 34.875 subjects without hand dermatitis. While one of the studies had reported a significant association between hand dermatitis and smoking, the meta‐analysis did not confirm this finding (OR 0.99; 95% CI 0.88–1.11). However, heterogeneity across studies was high (I² = 72%). Our meta‐analysis did not show tobacco smoking to be a risk factor for hand dermatitis. However, these results depend mainly on two large studies from one country. From present data, it cannot be excluded that smoking may influence the course of hand dermatitis. Even though smoking does not seem to be associated with hand dermatitis, it may still negatively influence the course of the disease.     

JAK-STAT信号通路及其抑制剂在特应性皮炎治疗中的应用

【摘要】 Janus激酶信号转导和转录激活因子（JAK-STAT）信号通路在特应性皮炎（AD）免疫学通路中起着重要作用，阻断JAK-STAT信号通路的药物，如经典的JAK抑制剂托法替尼、鲁索利替尼等，已逐步应用到AD治疗的临床试验中，并取得较好的疗效。其他对JAK-STAT信号通路有抑制作用的因子，如apamin、dupilumab等也在治疗AD上显示出一定效果。本文对近年来JAK-STAT信号通路及其相关抑制剂研究进行综述。     

JAK inhibitors for alopecia areata: a systematic review and meta‐analysis

There have been a number of case reports and small clinical trials reporting promising outcomes of Janus Kinase (JAK) inhibitors tofacitinib, ruxolitinib and baricitinib for alopecia areata (AA). The majority of the literature to date is based on small volume data, with a lack of definitive evidence or guidelines. To determine the expected response of AA to JAK inhibitor therapy and factors which influence response and recurrence rates. A systematic review and meta‐analysis was performed according to PRISMA guidelines. From 30 studies and 289 cases, there were 72.4% responders, good responders 45.7% and partial responders 21.4%. Mean time to initial hair growth was 2.2 ± 6.7 months, and time to complete hair regrowth was 6.7 ± 2.2 months. All 37 recurrences occurred when treatment was ceased after 2.7 months. Oral route was significantly associated with response to treatment compared to topical therapy. No difference was found between paediatric and adult cases in proportion of responses. There is promising low‐quality evidence regarding the effectiveness of JAK inhibitors in AA. Future large‐sized randomized studies are required to confirm findings.     

A novel JAK inhibitor JTE‐052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents

Janus kinases (JAKs) are required for several inflammatory cytokine signalling pathways and are implicated in the pathogenesis of chronic dermatitis, including atopic dermatitis and psoriasis. JAK inhibitors are therefore promising therapeutic candidates for chronic dermatitis. In this study, we evaluated the effects of the novel JAK inhibitor JTE‐052 on inflammatory responses associated with chronic dermatitis, and compared its profile with those of conventional therapeutic agents in rodent models of chronic dermatitis. JTE‐052 inhibited the Th1‐, Th2‐ and Th17‐type inflammatory responses of human T cells and mast cells in vitro. Oral administration of JTE‐052 inhibited skin inflammation in hapten‐induced chronic dermatitis in mice, associated with reduced levels of inflammatory cytokines in the skin and immunoglobulin (Ig) E in serum. In contrast, although ciclosporin partly inhibited skin inflammation, it did not reduce interleukin (IL)‐4 production in skin, and enhanced IgE production in serum. Oral administration of JTE‐052 also inhibited skin inflammation in mouse models of atopic dermatitis and psoriasis induced by a mite extract, thymic stromal lymphopoietin or IL‐23. The maximal efficacy of JTE‐052 in these dermatitis models was superior to the conventional therapeutic agents, ciclosporin and methotrexate. Topical application of JTE‐052 ointment ameliorated hapten‐induced chronic dermatitis in rats more effectively than tacrolimus ointment. Furthermore, JTE‐052 ointment did not cause the thinning of normal skin associated with topical corticosteroids. These results indicate that JTE‐052 is a promising candidate as an anti‐inflammatory drug for various types of chronic dermatitis, with a distinctly different profile from conventional therapy following either oral or topical application.     

FC03.3Identification of subjects with atopic dermatitis in questionnaire studies

The performances of three different questions from The Nordic Occupational Skin Questionnaire (NOSQ‐2002) were compared with respect to their ability to identify subjects with atopic dermatitis. NOSQ‐2002 was used in an intervention study on the prevention of work related skin diseases among gut cleaners. The questions were: “Have you ever had an itchy rash that has been coming and going for at least 6 months, and at sometime has affected skin creases?”(A1), “Have you ever had eczema on the fronts of the elbow or behind the knees?”(S5a), and “Have you ever had “childhood” eczema?”(S5b). Question A1 is the single UK‐working party question on atopic dermatitis; questions S5a & S5b are national atopic dermatitis questions previously used in different Nordic studies. A total of 255 of 622 (41%) gut cleaners answered “yes” to question A1. Questions S5a and S5b gave rise to 14% and 5% positive answers, respectively. The high frequency of positive answers to question A1 could be due to the occupational exposure of gut cleaners. Their working environment is wet and often involves both forearms and hands, hence often leading to eczema of elbow creases. In conclusion, compared to other Danish studies the UK question seems to lead to over‐reporting. Question S5a seems to give a reliable frequency of atopic dermatitis in adult populations at risk for work‐related skin diseases.     

Efficacy and safety of topical JTE‐052, a Janus kinase inhibitor,in Japanese adult patients with moderate‐to‐severe atopic dermatitis: a phase II,multicentre randomized,vehicle‐controlled clinical study

Atopic dermatitis (eczema) is a chronic, and sometimes debilitating, inflammatory skin disease which causes itching and damaged skin barrier function. Current treatments include topical (applied to the skin) corticosteroids and calcineurin inhibitors such as tacrolimus; unfortunately long‐term use of topical corticosteroids may cause thinning of the skin and tacrolimus can be irritant. Kinases are enzymes that are important to many roles of cells within the body, and the Janus Kinase (JAK) pathway plays a role in inflammation. In recent years, medicines that inhibit this pathway have been developed, with potential benefit in inflammatory skin diseases such as eczema or psoriasis. The authors, based in Tokyo and Hokkaido, Japan, studied the effect of different concentrations (0.5‐3%) of a topical JAK inhibitor, JTE‐052, in adults with moderate to severe atopic dermatitis, compared with the vehicle on its own (the ointment to which the medicine is added), and with 0.1% tacrolimus ointment. They used a modified Eczema Area and Severity Score before and after 4 weeks of treatment to allow them to see how well each of the treatments was working. In the patients using the 3% concentration there was 73% improvement in the score, compared with 12% using the placebo (vehicle) ointment. There was a 62% improvement in the patients using tacrolimus. Even the 3% concentration of JTE‐052 was very well tolerated, without the irritancy and burning seen with tacrolimus, and the patients using JTE‐052 noticed a reduction in itching within a day of starting treatment. The authors conclude that topical use of this JAK inhibitor is effective in the treatment of atopic dermatitis.     

Biologic and targeted therapeutics in vitiligo

Background

Vitiligo is a long-standing progressive autoimmune disease with depigmented macules/patches with significant psychological morbidity to the patients. From being one of the most poorly understood diseases in the past, there has been a rampant advance in determining the molecular and genetic factors influencing the disease process. More light has been shed on the complex intracellular environment and interplay between innate and adaptive immunity. Numerous cytokines and signaling pathways have been associated with disease pathogenesis in the recent past.

Objective

The aim of this review the efficacy of biologic and targeted therapeutics in vitiligo.

Methods

A detailed literature search was conducted on databases like PubMed, COCHRANE Central, EMBASE and Google Scholar using keywords—“biologics,” “vitiligo,” “treatment,” “repigmentation,” “JAK inhibitors,”, “TNF-ꭤ inhibitors,” and “IL17/23 inhibitors,” Relevant studies and review articles in English were analyzed in detail and report was written. This article aimed at a comprehensive review of all the biologicals and newer targeted therapeutics tried in vitiligo and their efficacy with an insight into the potential complications arising as a result of the therapy.

Results

Most conventional vitiligo treatment modalities are restricted to generalized nonspecific immunosuppressants like topical and oral corticosteroids, calcineurin inhibitors, phototherapy, and surgical modalities. There have been reports and studies on the usage of biologicals in treating vitiligo. JAK inhibitors have shown good efficacy in vitiligo; however, it lacks substantial evidence in the form of randomized control trials. Similarly, the use of targeted therapeutics in treating vitiligo is substantiated by limited evidence and requires more randomized trials for further evidence.

Conclusion

JAK inhibitors have shown promising results and good tolerability; Adjuvant phototherapy can achieve a superior response compared to monotherapy. Though TNF-ꭤ has been tried in a few cases, it is best used if vitiligo is present in association with other chronic autoimmune diseases for which it is indicated. More in vitro studies and clinical research are required to understand the pathogenesis clearly, and therapy has to be targeted at specific pathways for a better approach toward vitiligo. Treatment aimed at induction and differentiation of melanocytes may be added to achieve faster repigmentation.     

Phenotypic Differences between Human Blood Monocyte Subpopulations in Psoriasis and Atopic Dermatitis

Peripheral blood monocytes seem to be of importance in the initiation and maintenance of cutaneous inflammatory disorders such as psoriasis and atopic dermatitis. Functional abnormalities of monocytes have been observed in both diseases. We sought to determine whether these abnormalities are reflected by an altered phenotypic expression of functionally active surface molecules. Peripheral blood monocyte subsets varying in cellular density and cell size from patients with psoriasis and atopic dermatitis were investigated using FACS analysis employing a panel of monoclonal antibodies (CD14, CD16, HLA-DR, HLA-DQ, Fc?RII, IL-2R, ICAM-1, CR3). Furthermore, the modulation of expression by interferon-γ in monocyte subsets from patients was compared to normal controls. The results show that HLA-DR and -DQ expression on monocyte subsets in psoriatic patients was significantly decreased; “large” monocytes expressed significantly less HLA-DR than “small” monocyte subpopulations. Decreased HLA-DR and -DQ expression could be upregulated by incubation of psoriatic monocytes with IFNγ. In atopic dermatitis, a different phenotype pattern of monocyte subsets was demonstrated: HLA-DR expression and HLA-DQ expression were both decreased in both “large” and “small” monocytes as compared to normal controls. However, there were no significant differences in HLA-DR and HLA-DQ expression between “large” and “small” monocyte subpopulations in atopic dermatitis. Moreover, the ICAM-1 and IL-2R expression of “large” and “small” monocyte subpopulations was significantly decreased in atopic patients from levels in normal controls and psoriatic patients. The altered expression of HLA-DR, -DQ, ICAM-1 and IL-2R could be upregulated by incubation of atopic monocytes with IFNγ. In addition, there was a significant increase in the percentage of monocytes in the differential count of patients with psoriasis or atopic dermatitis. We conclude that the differential phenotype pattern of surface molecules on monocytes in psoriasis and atopic dermatitis may reflect an abnormal monocyte maturation/differentiation state. This may explain the functional abnormalities of monocytes observed in patients with psoriasis and atopic dermatitis.     

Impact of biologic therapies on risk of major adverse cardiovascular events in patients with psoriasis: systematic review and meta‐analysis of randomized controlled trials

Concerns have been raised regarding an increased risk of major adverse cardiovascular events (MACEs) (myocardial infarction, cerebrovascular accident or cardiovascular death) in patients treated with anti‐interleukin (IL)‐12/23 agents for moderate‐to‐severe psoriasis. We aimed to examine the risk of MACEs in adult patients with plaque psoriasis that are exposed to biologic therapies via a meta‐analysis of randomized controlled trials (RCTs). Data were obtained from systematic searches in the Cochrane Library, MEDLINE and Embase, U.S. Food and Drug Administration, European Medicines Agency, individual pharmaceutical companies online search platforms and five trials registers (up to 31 March 2016). We selected RCTs reporting adverse events in adults with plaque psoriasis receiving at least one licensed dose of biologic therapy, conventional systematic therapy or placebo. We calculated Peto odds ratios (ORs) with 95% confidence intervals (CIs) and calculated I² statistics to assess heterogeneity. Overall, 38 RCTs involving 18 024 patients were included. No MACEs were observed in 29 studies, while nine RCTs reported 10 patients experiencing MACEs. There was no statistically significant difference in risk of MACEs associated with the use of biologic therapies overall (OR 1·45, 95% CI 0·34–6·24); tumour necrosis factor‐α inhibitors (adalimumab, etanercept and infliximab) (OR 0·67, 95% CI 0·10–4·63); anti‐IL‐17A agents (secukinumab and ixekizumab) (OR 1·00, 95% CI 0·09–11·09) or ustekinumab (OR 4·48, 95% CI 0·24–84·77). No heterogeneity was observed in these comparisons. In conclusion, the limited existing evidence suggests that licensed biologic therapies are not associated with MACEs during the short randomized controlled periods in clinical trials.     

Janus kinase inhibitors: An innovative treatment for alopecia areata

Alopecia areata (AA) is a relatively common disease, but no satisfactory treatment has yet been developed. Recently, research progress has been made in the pathogenesis of AA, revealing that autoreactive cytotoxic T cells are important and that the Janus kinase (JAK) pathway is involved. Therefore, the potential of JAK inhibitors as therapeutic agents for AA is attracting attention. Several single‐arm clinical trials and retrospective studies demonstrated that oral JAK inhibitors are effective and tolerable treatments for moderate to severe AA. Although JAK inhibitors are emerging as an innovative treatment for AA, further placebo‐controlled clinical trials are required to confirm their efficacy and long‐term safety.     

A real-world Australian experience of upadacitinib for the treatment of severe atopic dermatitis

Upadacitinib is a selective Janus kinase-1 (JAK-1) inhibitor that has been shown in clinical trials to be effective for the treatment of moderate-to-severe atopic dermatitis (AD). This study aimed to evaluate the real-world experience of patients with AD treated with upadacitinib in a single-centre Australian cohort. Our study revealed a higher propensity for herpetic infections compared with previous randomised controlled trials (RCTs).     

Upadacitinib treatment in patients with moderate to severe atopic dermatitis: A retrospective single-centre Australian review of 14 patients post phase 3 clinical trial

Recent phase 2b and phase 3 clinical trials support the safety and efficacy of the selective Janus kinase (JAK)-1 inhibitor upadacitinib (UPA) in the treatment of moderate to severe atopic dermatitis (AD). However, to date, there is little experience with UPA therapy for AD in Australia. We report findings from a retrospective study to better understand the therapeutic response and side effects noted in a single-centre Australian cohort.     

Innovación en dermatitis atópica: de la patogenia a la terapéutica

Atopic dermatitis is the most common inflammatory skin disease and up to 20% of cases can be classified as moderate to severe. Our understanding of the pathogenesis of this disease has improved in recent years. The process is primarily driven by the Th2 pathway, but with significant contributions from the Th22 pathway, the Th1 and Th17 axes, epidermal barrier dysfunction, pruritus, and JAK/STAT signaling. Advances in our understanding of the pathogenesis of atopic dermatitis have led to the development of new systemic treatments. Of particular note are biologic agents targeting IL-4 and IL-13 (e. g., dupilumab, tralokinumab, and lebrikizumab) and small molecules, such as JAK inhibitors (e. g., baricitinib, upadacitinib, and abrocitinib). Novel topical treatments include phosphodiesterase 4 and JAK/STAT inhibitors. In this article, we review the main advances in the treatment of atopic dermatitis. Characterization of clinical and molecular phenotypes with a key pathogenic role is essential for driving these advances.