Distinct SPINK5 and IL-31 polymorphisms are associated with atopic eczema and non-atopic hand dermatitis in Taiwanese nursing population

Abstract: The term ‘hand dermatitis’ describes inflammatory skin condition localized to the hands. Nurses working at hospital settings are prone to develop hand dermatitis. The current study aimed to evaluate whether certain genetic polymorphisms were associated with the development of atopic eczema or non‐atopic hand dermatitis in Taiwanese population. Nurses of Kaohsiung Medical University Hospital were recruited. Atopic eczema, non‐atopic hand dermatitis and normal control groups were identified. The serine protease inhibitor Kazal type 5 (SPINK5), filaggrin and interleukin‐31 (IL‐31) gene variants were compared between the diseased and control groups. Our results showed that rs2303070 T allele of SPINK5 (assuming recessive model; OR = 3.58, 95% CI 1.63–7.84; P = 0.0014) and rs7977932 G allele of IL‐31 (assuming recessive model; OR = 18.25, 95% CI = 3.27–101.94; P = 0.0009) were associated with increased risks of developing atopic eczema, while rs6892205 G allele of SPINK5 (assuming dominant model; OR = 3.79, 95% CI 1.55–9.28; P = 0.0036) was associated with the development of non‐atopic hand dermatitis. In summary, our results showed that distinct SPINK5 and IL‐31 gene variants were associated with the development of atopic eczema and non‐atopic hand dermatitis. The barrier function, particularly those regulated by SPINK5, may play an important role in the development of both atopic eczema and non‐atopic hand dermatitis.     

Filaggrin null mutations increase the risk and persistence of hand eczema in subjects with atopic dermatitis: results from a general population study

Summary Background Hand eczema is prevalent in the general population. It remains unclear whether or not filaggrin gene (FLG) null mutations increase the overall risk of hand eczema or only increase the risk of hand eczema in subjects with atopic dermatitis. Objectives To investigate the association between FLG null mutations and hand eczema. Methods A random sample of 3335 adults from the general population in Denmark was patch tested, FLG genotyped for R501X and 2282del4 null mutations and questioned about hand eczema. Results Participants with combined presence of atopic dermatitis and FLG null mutation status had a significantly higher prevalence of hand eczema, an earlier onset of hand eczema and a higher persistence of hand eczema compared with subjects with normal FLG status and absence of atopic dermatitis. Logistic regression analyses revealed positive associations between hand eczema within the past 12 months and FLG null mutation status in participants with a history of atopic dermatitis [odds ratio (OR) 2·98; 95% confidence interval (CI) 1·27–7·01], but not in subjects without atopic dermatitis (OR 0·82; 95% CI 0·41–1·67). Conclusions FLG null mutations were significantly associated with hand eczema (< 12 months) in subjects with atopic dermatitis. Combined atopic dermatitis and filaggrin null mutation status was strongly associated with early onset of hand eczema and hand eczema persistence.     

Combined occurrence of filaggrin mutations and IL-10 or IL-13 polymorphisms predisposes to atopic dermatitis

Background: Although filaggrin mutations are presently believed to play a key role in the development of atopic dermatitis (AD), obviously also immunological factors involved in acquired immune response are important for the development of allergic inflammation. Objective: To assess the frequency of FLG mutations and the polymorphisms 590 C/T in the IL‐4 gene, ‐1082A/G in the IL‐10 gene and ‐1055C/T in the IL‐13 gene in patients with AD and their correlations between severity of AD and asthma. Methods: R501X and 2282del4 FLG mutations and IL‐4, IL‐10 and IL‐13 polymorphisms were assayed in 163 patients with AD of Polish origin. Results: In the Polish patients with AD, the prevalence of FLG mutations was higher in patients with AD than in the controls and 2282del4 FLG mutation was more frequent than R501X, and it was associated with a 6‐fold higher risk for AD development (P < 0.001; OR: 5.76), moderate or severe disease course, early onset of asthma and palmar hyperlinearity. Significant interactions between the 2282del4 FLG mutation and the CT genotype for IL‐13 or GG genotype for IL‐10 and a higher risk for developing AD were demonstrated. Conclusion: FLG mutation, alone and in combination with certain IL‐10 or IL‐13 polymorphisms, enhances the risk for the development of AD in the Polish population.     

Injury downregulates the expression of the human cathelicidin protein hCAP18/LL‐37 in atopic dermatitis

Please cite this paper as: Injury downregulates the expression of the human cathelicidin protein hCAP18/LL‐37 in atopic dermatitis. Experimental Dermatology 2009; 19: 442–449. Abstract: Reduced production of antimicrobial peptides was proposed to contribute to susceptibility for skin infections in atopic dermatitis (AD). Focusing on the human cathelicidin protein, hCAP18, the aim of the present study was to explore whether reduced hCAP18 expression is a constitutive trait in AD and if established inducers affect the expression of hCAP18 in the skin of AD. First, we compared levels of hCAP18 mRNA between lesional skin in AD and psoriasis and verified significantly lower expression of hCAP18 mRNA in AD. In non‐lesional skin, however, there was no difference between AD, psoriasis and healthy, indicating that there is no constitutive defect in the production of hCAP18 in AD patients. In healthy skin, hCAP18 was reported to be rapidly induced following wounding and here we verified this pattern in healthy controls and in psoriasis. In AD lesions, however, the expression of hCAP18 mRNA was markedly suppressed following wounding. Obviously, the inflammation in AD lesions neutralizes the expected induction of hCAP18 and even induces suppression. Notably, the mechanism to upregulate hCAP18 following vitamin D treatment was functional in lesional as well as in non‐lesional AD indicating that the CAMP gene is normally regulated in this respect. In addition, cultured primary keratinocytes from non‐lesional skin of psoriasis, AD and healthy skin, upregulated hCAP18mRNA following treatment with vitamin D. Itching is a hallmark of AD and scratching inevitably injures the skin. Failure to upregulate hCAP18 in eczema following injury is likely to affect antimicrobial protection and tissue repair in AD.     

US Prescription trends of antihistamines for atopic dermatitis, 2011‐2016

Antihistamine use for primary treatment of atopic dermatitis (AD) is not recommended, but current guidelines state that sedating antihistamines are favored over non‐sedating antihistamines for relief of burdensome pruritus. We analyzed the National Ambulatory Medical Care Survey data to compare use of antihistamines between dermatologists and non‐dermatologists. Overall, dermatologists are more likely to prescribe sedating than non‐sedating antihistamines when compared to non‐dermatologists (P < .001, δ_abs = 0.45). Patients under 21 years old (P = .03, δ_abs = 0.10) and Black patients (P < .001, δ_abs = 0.19) were also more likely to receive sedating antihistamines than non‐sedating antihistamines. These findings highlight the differential prescribing practices for atopic dermatitis among physicians.     

Increased levels of serum IL‐31 in chronic spontaneous urticaria*

Please cite this paper as: Increased levels of serum IL‐31 in chronic spontaneous urticaria. Experimental Dermatology 2010; 19: 464–466. Abstract: IL‐31 represents a novel cytokine involved in pruritic skin diseases including atopic dermatitis (AD). We, therefore, aimed at investigating IL‐31 levels in chronic spontaneous urticaria (CU). We included 46 patients with CU, 26 non‐atopic skin healthy subjects as negative and 28 patients with AD as positive controls. IL‐31 serum levels were analysed using commercial ELISA kit. IL‐31 serum levels were higher in patients with CU compared to healthy controls (P < 0.001), but lower compared to patients with AD (P < 0.001). There was no difference in IL‐31 serum levels in autologous serum skin test positive or negative CU patients and patients with infectious trigger factors including helicobacter pylori infection. IL‐31 serum levels may play a role in the pathophysiology of CU. This is supported by the finding that not all patients with CU respond to antihistamine treatment but to the treatment with immunosuppressive drugs.     

Aggravation of atopic dermatitis‐like symptoms by consecutive low concentration of formaldehyde exposure in NC/Nga mice

Formaldehyde (FA) has been known to be associated with development of asthma (AS) and atopic dermatitis (AD). In this study, we investigated whether FA inhalation would affect the provocation or exacerbation of AD‐like symptoms. Atopic‐prone NC/Nga mice were exposed to low (0.2 ppm) and high (1.0 ppm) concentration of FA by inhalation. Combined exposure to low concentration of FA inhalation and topical house dust mite (HDM) stimulation significantly upregulated HDM‐induced total plasma IgE and IgG2a production, Th1‐, Th2‐, Th17‐related cytokine as well as COX‐2 mRNA expressions in the skin. Interestingly, independent FA inhalation, especially at low concentration (0.2 ppm), increased the skin mRNA expressions of IL‐13, IL‐17E/IL‐25 and COX‐2, even though it failed to induce AD‐like skin inflammation. In conclusion, we suggest that increased skin mRNA expressions of IL‐13, IL‐25/IL‐17E and COX‐2 by independent low concentration of FA exposure might be a key factor to exacerbate HDM‐mediated AD‐like skin inflammation.     

Calmodulin‐like skin protein level increases in the differentiated epidermal layers in atopic dermatitis

In atopic dermatitis (AD), the skin barrier is disturbed, and the expression of calcium‐dependent S100 proteins and the calcium gradient is also altered in the epidermis. The calmodulin‐like skin protein (CLSP), which is expressed in the differentiated epidermis, is believed to modulate the function of calcium‐dependent proteins involved in barrier formation and is significantly increased in the epidermis of psoriatic patients. We, therefore, investigated the CLSP level in skin biopsies taken from patients with acute exacerbated and non‐exacerbated AD as well as from healthy control subjects. Immunohistochemical, Western blot and ELISA analyses showed significant increases (P < 0.03) in CLSP level in the epidermis from patients with acute exacerbated AD as compared to that from patients with non‐exacerbated AD and from control subjects. Such increased expression of CLSP may help re‐establish a functional epidermal barrier in acute AD.     

Hand dermatitis among university hospital nursing staff with or without atopic eczema: assessment of risk factors

Background. Nurses are prone to develop hand dermatitis. Although an atopic constitution has been identified as a genetic risk factor, the behavioural risk factors associated with hand dermatitis in wet work conditions have not been fully explored. Objectives. This study aimed to clarify the impact of atopic eczema (fulfilling the diagnostic criteria during the past 1 year) on the occurrence of hand dermatitis and to identify the behavioural risk factors among non‐atopic nurses with hand dermatitis. Methods. From August 2007 to July 2009, nurses from Kaohsiung Medical University Hospital were recruited. The associations between different risk factors and hand dermatitis were documented. In addition, the behavioural risk factors among non‐atopic nurses were evaluated via observational study. Results. One thousand one hundred and thirty‐two nurses participated in the first part of the study, which revealed that individuals with atopic eczema had a 3.76‐fold increased risk for hand dermatitis. However, among 248 nurses with hand dermatitis, only 43 had atopic eczema. The observational study performed on 140 non‐atopic nurses identified frequency of hand washing as the behavioural risk factor associated with hand dermatitis. Conclusions. Although atopic eczema is the major risk factor for hand dermatitis, those with atopic eczema constitute only 17% of nurses with hand dermatitis. Decreasing hand washing frequency is the most effective strategy to reduce the occurrence of hand dermatitis among non‐atopic nurses.     

Topical application of rapamycin ointment ameliorates Dermatophagoides farina body extract‐induced atopic dermatitis in NC/Nga mice

Atopic dermatitis (AD), a chronic inflammatory skin disease characterized by relapsing eczema and intense prurigo, requires effective and safe pharmacological therapy. Recently, rapamycin, an mTOR (mammalian target of rapamycin) inhibitor, has been reported to play a critical role in immune responses and has emerged as an effective immunosuppressive drug. In this study, we assessed whether inhibition of mTOR signalling could suppress dermatitis in mice. Rapamycin was topically applied to inflamed skin in a murine AD model that was developed by repeated topical application of Dermatophagoides farina body (Dfb) extract antigen twice weekly for 7 weeks in NC/Nga mice. The efficacy of topical rapamycin treatment was evaluated immunologically and serologically. Topical application of rapamycin reduced inflammatory cell infiltration in the dermis, alleviated the increase of serum IgE levels and resulted in a significant reduction in clinical skin condition score and marked improvement of histological findings. In addition, increased mTOR phosphorylation in the lesional skin was observed in our murine AD model. Topical application of rapamycin ointment inhibited Dfb antigen‐induced dermatitis in NC/Nga mice, promising a new therapy for atopic dermatitis.     

DAMP molecules S100A9 and S100A8 activated by IL‐17A and house‐dust mites are increased in atopic dermatitis

S100A9 and S100A8 are called damage‐associated molecular pattern (DAMP) molecules because of their pro‐inflammatory properties. Few studies have evaluated S100A9 and S100A8 function as DAMP molecules in atopic dermatitis (AD). We investigated how house‐dust mites affect S100A9 and S100A8 expression in Th2 cytokine‐ and Th17 cytokine‐treated keratinocytes, and how secretion of these molecules affects keratinocyte‐derived cytokines. Finally, we evaluated expression of these DAMP molecules in AD patients. S100A9 expression and S100A8 expression were strongly induced in IL‐17A‐ and Dermatophagoides (D.) farinae‐treated keratinocytes, respectively. Furthermore, co‐treatment with D. farinae and IL‐17A strongly increased expression of S100A9 and S100A8 compared with D. farinae‐Th2 cytokine co‐treatment. The IL‐33 mRNA level increased in a dose‐dependent manner in S100A9‐treated keratinocytes, but TSLP expression did not change. S100A8/A9 levels were also higher in the lesional skin and serum of AD patients, and correlated with disease severity. Taken together, S100A9 and S100A8 may be involved in inducing DAMP‐mediated inflammation in AD triggered by IL‐17A and house‐dust mites.     

Atopic dermatitis in older patients: particular points

We review the particular characteristics of atopic dermatitis (AD) in adult life, and compare findings with those of AD in childhood. AD affects 1–3% of adults world‐wide, and can present as adult‐onset AD, or as infantile/childhood AD that persists, or recurs after many years. Eczema in adults usually exists for years, compromising quality of life, sex life and occupational choices. The flexural areas, shoulders, head‐and‐neck, and hands are typically affected. In elderly adults, eczematous erythroderma is common. The intrinsic (non‐IgE‐allergic) eczema subtype affects 5–15% of cases. Classical food allergy has a low importance, although non‐IgE‐mediated and pseudoallergic reactions can cause eczema. Sensitivity to aeroallergens, especially dust mite, is demonstrated in the majority of adult AD patients, including elderly adults, by immunoglobulin E‐mediated tests and/or atopy patch tests. Occupational allergic and irritant contact dermatitis is increased. In adults, as in children, Staphylococcus aureus colonization is very high, whereas adult skin is more heavily colonized with Malassezia yeasts. Immediate and delayed sensitization to Malassezia sympodialis is specific for intrinsic and extrinsic AD, occurring especially in head‐and‐neck eczema. Concerning therapy, older patients are prone to certain adverse drug effects. In conclusion, differences exist between childhood and adult disease. As we should be seeing more adults with AD in the future, there is a need for more clinical and immunological studies in older patients.     

Effect of dupilumab on hand eczema in patients with atopic dermatitis: An observational study

Systemic treatment options for chronic hand eczema are limited. Dupilumab is used in atopic dermatitis (AD) but is not licensed for (isolated) hand eczema. In this observational prospective study we aimed to determine the response of hand eczema to dupilumab in patients with AD. Adult patients with hand eczema and AD received dupilumab s.c. at a 600 mg loading dose, followed by 300 mg every 2 weeks. Primary outcome was a minimum improvement of 75% on the Hand Eczema Severity Index after 16 weeks (HECSI‐75). Secondary outcomes were severity, measured using the Photographic guide; quality of life improvement as patient‐reported outcome, measured using the Dermatology Life Quality Index (DLQI); and AD severity, measured using the Eczema Area and Severity Index (EASI). Forty‐seven patients were included (32 males; mean age, 45 years). HECSI‐75 was achieved by 28 (60%). Mean HECSI score reduction was 49.2 points (range, 0–164; 95% within‐subject confidence interval, 46.4–52.0), which was already significantly decreased after 4 weeks (P < 0.001). DLQI score mean improvement was 8.8 points (standard deviation [SD], 6.0) or 70.0% decrease (SD, 26.4) (P < 0.001). Eighteen patients (38%) were classified as responders on the Photographic guide. There was no difference in response between chronic fissured and recurrent vesicular clinical subtypes. Similar percentages of patients achieving EASI‐75 and HECSI‐75 were seen after 16 weeks. In conclusion, this study shows a favorable response of hand eczema to dupilumab in patients with AD. This raises the question whether a response will also be seen in isolated hand eczema.     

Cynomolgus monkey model of interleukin‐31‐induced scratching depicts blockade of human interleukin‐31 receptor A by a humanized monoclonal antibody

Scratching is an important factor exacerbating skin lesions through the so‐called itch‐scratch cycle in atopic dermatitis (AD). In mice, interleukin (IL)‐31 and its receptor IL‐31 receptor A (IL‐31RA) are known to play a critical role in pruritus and the pathogenesis of AD; however, study of their precise roles in primates is hindered by the low sequence homologies between primates and mice and the lack of direct evidence of itch sensation by IL‐31 in primates. We showed that administration of cynomolgus IL‐31 induces transient scratching behaviour in cynomolgus monkeys and by that were able to establish a monkey model of scratching. We then showed that a single subcutaneous injection of 1 mg/kg nemolizumab, a humanized anti‐human IL‐31RA monoclonal antibody that also neutralizes cynomolgus IL‐31 signalling and shows a good pharmacokinetic profile in cynomolgus monkeys, suppressed the IL‐31‐induced scratching for about 2 months. These results suggest that the IL‐31 axis and IL‐31RA axis play as critical a role in the induction of scratching in primates as in mice and that the blockade of IL‐31 signalling by an anti‐human IL‐31RA antibody is a promising therapeutic approach for treatment of AD. Nemolizumab is currently under investigation in clinical trials.     

Consequences of occupational food‐related hand dermatoses with a focus on protein contact dermatitis

Background. Protein contact dermatitis is a frequent disorder among hand eczema patients who have occupational food contact. Knowledge about the consequences of having protein contact dermatitis is lacking. Objectives. To investigate the consequences of having occupational skin disease on the hands resulting from food handling, with a focus on protein contact dermatitis. Material and methods. One hundred and seventy‐eight patients who were identified as having skin disease related to occupational food exposure and who answered a questionnaire concerning the consequences of their skin disease were included in the study. The patients were consecutively examined at Gentofte Hospital, Denmark between 2001 and 2010. Results. Seventy‐five per cent of patients with protein contact dermatitis had to wear gloves at work, and 62.5% reported sick leave lasting for >3 weeks, as compared with 60.2% and 30%, respectively, of the patients with other occupational food‐related hand dermatoses (p = 0.02). Sixty‐two per cent and 43%, respectively, had to change job because of skin problems (p = 0.02). Atopic dermatitis was equally common in the two groups. Conclusion. We found that the patients with protein contact dermatitis experienced more severe and frequent consequences than patients with other food‐related hand dermatoses.     

The crucial role of IL‐22 and its receptor in thymus and activation regulated chemokine production and T‐cell migration by house dust mite extract

House dust mite (HDM) is known as one of the factors that causes atopic dermatitis (AD). Interleukin (IL)‐22 and thymus and activation regulated chemokine (TARC) are related to skin inflammatory disease and highly expressed in AD lesions. However, the effects of HDM on IL‐22 production in T cells and on TARC production and IL‐22Rα receptor expression in keratinocytes are unknown. To identify the role of HDM in keratinocytes and T cells, we investigated IL‐22Rα expression and TARC production in the human keratinocyte cell line HaCaT and IL‐22 production in T cells treated with HDM extract as well as their roles in HDM‐induced skin inflammation. HDM extract not only increased IL‐22Rα expression and TARC production in HaCaT but also enhanced IL‐22, tumor necrosis factor (TNF)‐α and interferon (IFN)‐γ production in T cells. The HDM extract‐induced IL‐22 from T cells significantly increased the production of IL‐1α, IL‐6 and TARC in HaCaT cells. In addition, we found that TARC produced in HDM extract‐treated HaCaT induced T‐cell recruitment. These results suggest that there is a direct involvement of HDM extract‐induced IL‐22 in TARC production and T‐cell migration. Taken together, TARC production in HaCaT through the interaction between IL‐22 and IL‐22Rα facilitates T‐cell migration. These data show one of the reasons for inflammation in the skin lesions of AD patients.     

Serum measurement of interleukin‐31 (IL‐31) in paediatric atopic dermatitis: elevated levels correlate with severity scoring

Background Interleukin‐31 (IL‐31) is a novel T‐helper‐lymphocyte‐derived cytokine that plays an important role in human T‐cell‐mediated skin diseases. When overexpressed in transgenic mice, IL‐31 induces severe pruritus resembling eczema in humans. Serum IL‐31 was previously found overexpressed in adults with atopic dermatitis (AD). The novelty of this study is the use of a pediatric patient group as well as comparison of IL‐31 levels during flare and quiescence. Objective This case‐controlled longitudinal study was designed to determine the levels of IL‐31 in serum of AD children and its associations in relation to disease activity and severity. Methods Sera were obtained from 50 AD children and 40 healthy volunteers. IL‐31 levels were measured using a sandwich ELISA. All AD patients were followed up and re‐sampled for serum IL‐31 after clinical remission. Serum IL‐31 levels were correlated with AD disease activity and severity variables. Results Serum IL‐31 levels were significantly higher whether during AD flare [median, 1600; mean (SD) = 1457.8 ± 770.4 pg/mL] or quiescence (1040; 958.7 ± 419.5 pg/mL), than those in controls (220; 197.3 ± 91.9 pg/mL). Serum IL‐31 levels were significantly higher in the high disease severity group compared with the moderate or low severity group. Moreover, serum IL‐31 levels correlated positively with the calculated severity scores (LSS, SSS and SCORAD index). Conclusion The results of this study confirm the importance of IL‐31 in AD pathophysiology. Serum IL‐31 level is an objective reliable marker of AD severity in children. It may represent a novel target for antipruritic drug development.     

Healthy worker effect in hairdressing apprentices

Background. Hairdressers and hairdressing apprentices have a high incidence of occupational hand eczema, owing to excessive wet work and exposure to chemical substances. Hairdressing apprentices, in particular, seem to be at high risk of developing hand eczema. Previous hand eczema and atopic dermatitis are known risk factors for the development of hand eczema in wet work occupations. Objectives. To estimate the prevalence of hand eczema, eczema on wrists or forearms and atopic dermatitis in a cohort of hairdressing apprentices at the start of their education, and subsequently evaluate any potential healthy worker effect. Methods. During the first 2 weeks of training, 382 hairdressing apprentices were enrolled in this study. All apprentices completed a self‐administered questionnaire, including previously validated questions regarding, for example, previous and present hand eczema, eczema on the wrists or forearms, and atopic dermatitis. For comparison, the questionnaire was sent to a control group matched for age, gender and city code from the general population (n = 1870). Results. Response rates were 99.7% for the hairdressing apprentices (mean age 17.5 years, range 15–39 years, 96.3% females) and 68.3% for the control group (mean age 17.4 years, range 15–39 years, 96.8% females). Previous or present hand eczema were reported by 8.0% of hairdressing apprentices and by 12.5% of the matched control group (p = 0.009), and eczema on the wrists or forearms was reported by 5.3% of the apprentices and by 11.9% of the controls (p < 0.001). We classified 21.4% of the hairdressing apprentices as having atopic dermatitis versus 29.8% of the matched control group (p = 0.001). Conclusions. These results indicate a healthy worker effect, as there was a lower reported incidence of hand eczema and eczema on wrists or forearms, and there were fewer cases classified as having atopic dermatitis, among hairdressing apprentices than in a matched control group from the general population.