Matthias Bräutigam

Background: The topical calcineurin inhibitors [TCIs] pimecrolimus and tacrolimus, offer an effective non-steroidal option for treating atopic dermatitis [AD], particularly in sensitive skin areas and for long-term use. There are several studies published on the effect of calcineurin inhibitors on the skin barrier but a comprehensive review on this topic is still missing. Summary: This review summarizes current evidence on the impact of TCIs on epidermal barrier structure and function. Clinical studies in patients with AD show that TCIs improve transepidermal water loss [TEWL], enhance stratum corneum [SC] hydration, and promote normalization of structural proteins such as filaggrin and loricrin. Unlike topical corticosteroids [TCS], TCIs do not induce skin atrophy and may even reverse steroid-induced epidermal thinning. Additionally, TCIs partially preserve antimicrobial peptide [AMP] expression in lesional AD skin, which may help reduce Staphylococcus aureus colonization and support microbial diversity. Positive effects on lipid lamellar organization and natural moisturizing factor [NMF] levels further support barrier restoration. Animal data suggesting impaired lipid synthesis under TCI treatment contrast with consistent positive findings in clinical studies. Importantly, emerging evidence indicates that TCIs may improve the skin microbiome in AD. Key Messages: TCIs exert their beneficial effects on skin inflammation through selective T-cell modulation without disrupting keratinocyte differentiation or dermal matrix components. For this reason, the general indirect positive effects on skin barrier associated with reduction of skin inflammation is not counterbalanced by intrinsic barrier damaging mechanisms as observed with topical steroids. Further studies are needed to evaluate long-term effects on skin structure, microbiome stability, and their integration into biologic treatment algorithms.

Background: In the treatment of atopic dermatitis, pimecrolimus has high antipruritic effects. Objective: To investigate the efficacy of 1% pimecrolimus cream in comparison to 1% hydrocortisone cream in non-atopic prurigo nodularis (PN). Methods: A randomized, controlled, double-blind study with intraindividual randomization was done in 30 patients (17 females, 13 males; mean age 58.5 years) with PN. Results: Pruritus intensity decreased significantly (p < 0.001) on both treated sides as early as after 10 days of treatment; scratch lesions improved (p < 0.001). Quality of life as assessed by the Dermatology Life Quality Index improved significantly. However, a significant advantage of pimecrolimus over hydrocortisone was not found. Conclusion: The results suggest that the non-steroid pimecrolimus is an effective alternative for PN treatment.

Summary: Background: Urticaria is a common and frequently debilitating disease. Nevertheless, there are only few studies examining the situation of urticaria patient care.Patients and Methods: In this cross‐sectional study, we surveyed dermatologists, pediatricians and general practitioners in the practice setting regarding the epidemiology, situation of care as well as the perception of their patients with chronic spontaneous urticaria.Results: 776 data sets were available. The results show a high frequency of consultations due to chronic spontaneous urticaria. Most of the patients were reported to suffer moderately to severely and to have had history of disease of well over one year. The pediatricians indicated fewer diseases and shorter courses. The majority of participants stated that the time and cost spent on care, as well as the frequency of follow‐up visits, are above average. In addition, chronic spontaneous urticaria patients were reported to be a group with a strong emotional burden and high expectations as well as a group that is difficult to satisfy and hard to guide. Only a small minority of physicians rated patient satisfaction with current treatment options and therapy success as high.Conclusions: Chronic spontaneous urticaria plays an important role in daily practice. Problems are reported on various areas of care. Resolving these problems presents a major challenge and is crucial for improving the quality of patient care.

Topical corticosteroids are widely used to treat atopic dermatitis (AD), but their anti‐inflammatory mode of action can be accompanied by several unwanted side effects including skin atrophy and telangiectasia. In this 8‐week, investigator‐blinded, intraindividual right‐left comparison study with patients with mild‐to‐moderate AD, hydrocortisone 1% cream (HCT) was applied twice daily for 4 weeks on one side of forehead skin without clinical signs of AD and pimecrolimus 1% cream (PIM) on the other. Epidermal and dermal thickness were assessed by optical coherence tomography (OCT) and high‐frequency ultrasound, respectively. Skin atrophy and telangiectasia were assessed by contact dermatoscopic photography (Dermaphot^®). Treatment with HCT leads to a significant decrease in epidermal thickness after only 2 weeks of treatment, while the decrease in PIM‐treated sites was less pronounced and was not statistically significant. By 4 weeks after the end of treatment, epidermal thickness returned to baseline values. No dermal thinning or development of telangiectasia could be observed by means of ultrasound or Dermaphot^®, respectively. In summary, this study indicates that a 2‐week single course of topical treatment with a mildly potent steroid can cause transient epidermal thinning, an effect not seen in the PIM group. The slight decrease with PIM – although not significant – could be due to normalization of the increased skin thickness caused by a subclinical inflammation in AD. This study suggests that PIM may be safer for treatment of AD in sensitive skin areas like the face, especially when repeated application is required.

It has been suggested that the increased rate of bacterial infection in atopic dermatitis (AD) may be caused by reduced antimicrobial protein (AMP) expression. We were interested whether common treatments in AD affect antimicrobial defense. We investigated the effects of topically applied corticosteroids betamethasone valerate (BV) and triamacinolone acetonide (TA) and those of the calcineurin inhibitor pimecrolimus for 3 weeks on AMP expression in AD. BV and TA treatment in AD led to a significant reduction in AMP expression; protein expression of human beta‐defensins (hBD)‐2 and hBD‐3, psoriasin, RNase 7 and cathelicidin LL‐37 was below the level in skin of healthy controls. After pimecrolimus treatment, AMP expression was also reduced but less compared to BV and TA; the expression levels of hBD‐2, psoriasin and RNase 7 still remained above the control levels. In essential fatty acid–deficient (EFAD) mice, a model of chronic skin barrier disease with inflammation, expression of the mouse beta‐defensins mBD‐1, mBD‐3 and mBD‐14 (orthologues for hBD‐1, hBD‐2 and hBD‐3, respectively), was reduced by both treatments, again more pronounced by BV compared to pimecrolimus. In summary, we found that treatment for AD with corticosteroids in human skin and EFAD mice caused a strong reduction in AMPs; reduction was less with pimecrolimus. This result may explain the clinical observation that prolonged treatment with topical corticosteroids sometimes leads to bacterial infection.

Background: Clinical efficacy of specific immunotherapy (SIT) with depigmented, polymerized allergen extracts is well documented in placebo-controlled trials, and safety data are encouraging although further data are required. Methods: We enrolled 768 patients (51% men; mean age, 31 years) in this prospective multicenter study on safety and clinical effects of Depigoid (Laboratorios LETI, S.L., Madrid, Spain). Immunotherapy consisted of four injections of increasing doses of Depigoid at weekly intervals followed by monthly maintenance injections. All adverse events were documented. Moreover, nose, eye, and lung symptoms were assessed at baseline after 3 and 6 months. Results were compared with the scores of the preceding season. Results: Rates for local and systemic reactions that might possibly be related to the study medication were 2.36 and 4.56/1000 injections, respectively. With 5923 injections given, 14 local reactions were reported (5 patients), and 27 systemic reactions were reported, including 20 of grade 1 (6 patients) and 7 of grade 2 (4 patients). The best safety profile was seen for patients vaccinated against house-dust mites. Reductions in nose, eye, and lung symptoms as well as in concomitant medication compared with either the preceding season (pollen-sensitized patients) or the baseline (house-dust mite–sensitized patients) were observed at the end of study. Conclusion: In this large multicenter study on 768 patients with allergic rhinoconjunctivitis and allergic asthma under daily practice conditions SIT with Depigoid was well tolerated with low rates of local and systemic reactions. Furthermore, SIT resulted in considerable reductions in symptoms and concomitant medication.

Summary: The skin's permeability barrier protects against extensive water loss and prevents the entry into the skin of harmful substances like irritants, allergens and microorganisms. The permeability barrier is mainly located in the stratum corneum and consists of corneocytes and a lipid‐enriched intercellular domain. The barrier is formed during epidermal differentiation. In atopic dermatitis the skin barrier is disturbed already in non‐lesional skin. The disturbed skin barrier allows the entry of environmental allergens from house dust mites, animal dander and grass pollen into the skin. In predisposed individuals these allergens may trigger via immunologic pathways the inflammation of atopy. The causes for the disturbed epidermal skin barrier are changes in skin lipids and in epidermal differentiation, in particular filaggrin mutations. Filaggrin mutations lead to a disturbed skin barrier and dry skin which are hallmarks in atopic dermatitis. Therapeutic agents influence the skin barrier differently; topical therapy with potent corticosteroids does not lead to the repair of the barrier in atopic dermatitis, whereas therapy with the calcineurin inhibitors and lipid‐containing emulsions support barrier repair.