[Current dermatology guidelines in Germany-selected recommendations from 2021 and 2022]. / Aktuelle dermatologische Leitlinien in Deutschland ­ Ausgewählte Empfehlungen aus den Jahren 2021 und 2022.

Guidelines are systematically developed decision-making aids to ensure appropriate clinical care for specific medical conditions. In Germany, dermatological guidelines are developed under the aegis of the German Dermatological Society (DDG) and the Professional Association of German Dermatologists (BVDD), while European and international guidelines are published by organisations such as the European Centre for Guidelines Development (EuroGuiDerm), founded by the European Dermatology Forum (EDF) in cooperation with the Division of Evidence-Based Medicine at Charité-Universitätsmedizin Berlin. In 2021 and 2022, the German guidelines were revised or developed on topics such as the management of anticoagulation during dermatological procedures, chronic pruritus, contact dermatitis, laser therapy of the skin, psoriasis vulgaris, rosacea, extracorporeal photopheresis, onychomycosis, mucous membrane pemphigoid and prevention of skin cancer. A selection of the most important recommendations and innovations in the guidelines is summarized here.

Is benzyl alcohol a significant contact sensitizer?

BACKGROUND: Benzyl alcohol is a widely used preservative, solvent and fragrance material. According to published data, it is a rare sensitizer in humans. OBJECTIVES: To identify characteristics and sensitization patterns of patients with positive patch test reactions to benzyl alcohol and to check the reliability of the patch test preparation benzyl alcohol 1% pet. PATIENTS AND METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2010-2019. RESULTS: Of 70 867 patients patch tested with benzyl alcohol 1% pet., 146 (0.21%) showed a positive reaction, most of them (89%) only weakly positive. The number of doubtful and irritant reactions significantly exceeded the number of positive reactions. Reproducibility of positive test reactions was low. Among benzyl alcohol-positive patients, compared to benzyl alcohol-negative patients, there were significantly more patients with leg dermatitis (17.8% vs. 8.6%), more patients aged 40 years or more (81.5% vs. 70.5%) and more patients who were tested because of a suspected intolerance reaction to topical medications (34.9% vs. 16.6%). Concomitant positive reactions were mainly seen to fragrances, preservatives and ointment bases. CONCLUSIONS: Sensitization to benzyl alcohol occurs very rarely, mainly in patients with stasis dermatitis. In view of our results, benzyl alcohol cannot be regarded as a significant contact allergen, and therefore marking it as skin sensitizer 1B and labelling it with H 317 is not helpful.

Cutaneous findings following COVID-19 vaccination: review of world literature and own experience.

There is growing evidence that not only the novel coronavirus disease (COVID-19) but also the COVID-19 vaccines can cause a variety of skin reactions. In this review article, we provide a brief overview on cutaneous findings that have been observed since the emerging mass COVID-19 vaccination campaigns all over the world. Unspecific injection-site reactions very early occurring after the vaccination are most frequent. Type I hypersensitivity reactions (e.g. urticaria, angio-oedema and anaphylaxis) likely due to allergy to ingredients may rarely occur but can be severe. Type IV hypersensitivity reactions may be observed, including delayed large local skin lesions ("COVID arm"), inflammatory reactions in dermal filler or previous radiation sites or even old BCG scars, and more commonly morbilliform and erythema multiforme-like rashes. Autoimmune-mediated skin findings after COVID-19 vaccination include leucocytoclastic vasculitis, lupus erythematosus and immune thrombocytopenia. Functional angiopathies (chilblain-like lesions, erythromelalgia) may also be observed. Pityriasis rosea-like rashes and reactivation of herpes zoster have also been reported after COVID-19 vaccination. In conclusion, there are numerous cutaneous reaction patterns that may occur following COVID-19 vaccination, whereby many of these skin findings are of immunological/autoimmunological nature. Importantly, molecular mimicry exists between SARS-CoV-2 (e.g. the spike-protein sequences used to design the vaccines) and human components and may thus explain some COVID-19 pathologies as well as adverse skin reactions to COVID-19 vaccinations.

[Exceptional occupational allergies due to food of animal origin]. / Außergewöhnliche Berufsallergien durch Nahrungsmittel tierischen Ursprungs.

BACKGROUND: The food industry is a high-risk area for work-related allergic immediate skin reactions (contact urticaria, contact urticaria syndrome, protein contact dermatitis) with or without respiratory symptoms (allergic rhinitis, allergic asthma) due to proteins of animal origin. OBJECTIVES: The present work gives an overview of allergenic seafood and meat proteins and their clinical and occupational relevance in different work settings. METHODS: A review of current knowledge and a supplementary selective literature search were performed. RESULTS: Protein contact dermatitis is one of the more common occupational dermatoses in workers exposed to seafood and meat, after irritant hand eczema. Fishermen, cooks, and butchers are most commonly affected. Crustaceans and mollusks are more frequent triggers of food allergies than fish and can in individual cases also be life threatening. In contrast, primary meat allergy is rare. Beef among mammals and chicken among birds are the most common triggers. CONCLUSIONS: All employees with allergic immediate skin and/or respiratory reactions exposed to proteins of animal origin in the workplace should undergo a careful allergological workup at an early stage. Determination of the specific IgE plays a central role in confirming the diagnosis and it is of great importance in individual cases to include the suspected native material in the skin tests. The course of the disease is generally characterized by a poor prognosis and is commonly associated with a change in occupation.

Atopy patch testing with aeroallergens in a large clinical population of dermatitis patients in Germany and Switzerland, 2000-2015: a retrospective multicentre study.

BACKGROUND: The diagnostic significance of the atopy patch test for the management of dermatitis possibly triggered by aeroallergens is still controversial. However, sufficiently large studies with routinely tested standardized aeroallergen patch test preparations in dermatitis patients are lacking. OBJECTIVE: To evaluate the reaction frequency and the reaction profiles of 10 until mid-2015 commercially available, standardized aeroallergen patch test preparations of the 'Stallerpatch' test series (Stallergenes, Antony Cedex, France) in a large multicentre patient cohort. METHODS: A retrospective data analysis of patients with suspected aeroallergen-dependent eczematous skin lesions was performed, who were patch tested in 15 Information Network of Departments of Dermatology-associated clinics between 2000 and 2015. Patients were stratified according to their atopic dermatitis (AD) status. RESULTS: The study group included 3676 patients (median age 41 years, 34.8% males, 54.5% AD). The most common aeroallergens causing positive patch test reactions were Dermatophagoides pteronyssinus (19.6%), Dermatophagoides farinae (16.9%), birch (6.2%), timothy grass (6.0%), cat dander (5.4%), mugwort (4.9%) and dog dander (4.6%). Reactions to other pollen allergen preparations, that is 5 grasses (3.2%), cocksfoot (2.1%) and plantain (1.6%), were less common. Positive patch test reactions to aeroallergens were consistently more frequent in patients with AD. These patients showed proportionally less dubious, follicular, irritant and weak positive reactions. Independent of AD status, a patient history of past or present allergic rhinitis was associated with an increased chance of a positive aeroallergen patch test reaction to pollen allergens. CONCLUSION: The aeroallergen patch test is a useful add-on tool in clinical routine, especially in patients with AD and/or respiratory allergy. A patch test series comprising Dermatophagoides pteronyssinus, Dermatophagoides farinae, birch, timothy grass, cat dander and mugwort seems to be suitable. Controlled studies with specific provocation and elimination procedures are required to further evaluate the diagnostic significance of the proposed screening series.

[Diagnosis of contact allergy in practice using current guidelines]. / Leitliniengerechte Diagnostik der Kontaktallergie in der Praxis.

BACKGROUND: In the case of a contact allergy, there is only allergen avoidance instead of causal therapy. If the allergen is not identified, dermatitis persists, which is a major burden for patients. Patch testing is the diagnostic standard for detecting contact sensitization. Based on a systematic literature search, the German patch test guideline was updated and methodologically upgraded. OBJECTIVES: The most important practical aspects of patch testing with contact allergens and drugs are presented. MATERIALS AND METHODS: Current consensus guidelines for performing patch tests as well as the results of a supplementary selective literature search are summarized. RESULTS: According to the patch test guideline (AWMF registry no. 013-018, 2019), the baseline series, special series and, if necessary, test preparations prepared from the patient's own contact substances should be tested routinely. A new evidence-based recommendation is a late reading after 7-10 days, as otherwise numerous patch test reactions will be missed. Antihistamines may weaken the cellular reactions of the patch test and should be discontinued with a latency of 5 half-lives. Finally, if a false-negative patch test result is suspected, it is recommended to perform a strip patch test according to the validated protocol. CONCLUSIONS: All patients with a suspected contact allergy should receive a guideline-based patch test at an early stage. Targeted patch testing identifies clinically relevant allergens and provides suggestions for further systematic investigations.

[Most important contact allergens in hand eczema]. / Wichtigste Kontaktallergene beim Handekzem.

The head and hands are the two most common locations for allergic contact dermatitis manifestation. In hand eczema, contact with a contact allergen is a frequent (co-)factor in the triggering and maintenance of eczema. For all hand eczemas lasting longer than 3 months, an allergological examination by means of patch testing is recommended. In patients with allergic contact dermatitis of the hands, nickel, MCI/MI, fragrance mix I, cobalt, thiuram mix, Balsam of Peru, chromium and fragrance mix II have been described in a multicenter European study as the most common contact allergens of the standard series. In the information network of dermatological clinics (IVDK) a total of 56,170 patients were patch-tested in the years 2014 to 2018. In all, 16,807 of these patients (29.9%) suffered from hand eczema, of which 7725 (46.0%) had occupational dermatosis (OD) and 6820 (40.6%) had no OD. For the remaining patients this was unknown. The top 30-list of allergens in hand eczema patients without and with OD included 22 common contact allergens, but with different reaction frequency. In hand eczema patients without OD, the following contact allergens also belong to this list: octyl gallate, sorbic acid, tert-butylhydroquinone, propylene glycol, mercury (II) amide chloride, tolubalsam, jasmine absolute, and sandalwood oil. For hand eczema patients with OD, these are instead: tetramethylthiurammonosulfide, tetramethylthiuramdisulfide, 1,3-diphenylguanidine, p­phenylenediamine, p­toluylenediamine, iodopropinylbutylcarbamate, glutaraldehyde, and monoethanolamine. In the case of OD of the hands, early involvement of the responsible statutory accident insurance by initiating the dermatologist procedure ("Hautarztverfahren") is necessary in order to work together towards successful allergen avoidance by means of substitution and optimizing personal protective equiment.

Fumaric acid ester-induced T-cell lymphopenia in the real-life treatment of psoriasis.

BACKGROUND: Fumaric acid esters (FAEs) are used to treat psoriasis and are known to cause lymphopenia in roughly 60% of the patients. Much remains to be elucidated about the biological effects of FAEs on lymphocytes. OBJECTIVE: To evaluate the influence of long-term FAE (Fumaderm® ) treatment on peripheral blood CD4+ and CD8+ T cells, CD19+ B cells and CD56+ natural killer (NK) cells in psoriasis. METHODS: In this single-centre retrospective observational subcohort study, we obtained leucocyte and lymphocyte subset counts before initiating FAE therapy in 371 psoriasis patients (mean age, 47.8 years; 63.3% males) and monitored them during treatment (mean treatment duration, 2.9 years). Multiparametric flow cytometry was used for immunophenotyping. RESULTS: FAEs significantly reduced the numbers of CD4+ T, CD8+ T, CD19+ B and CD56+ NK cells. Among lymphocyte subsets, the mean percentage reduction from baseline was always highest for CD8+ T cells, with a peak of 55.7% after 2 years of therapy. The risk of T-cell lymphopenia increased significantly with the age of the psoriasis patients at the time that FAE therapy was initiated. It was significantly decreased for the combination therapy with methotrexate and folic acid (vitamin B9) supplementation. Supporting evidence was found suggesting that T-cell lymphopenia enhances the effectiveness of FAE therapy. CONCLUSIONS: Monitoring distinct T-cell subsets rather than just absolute lymphocyte counts may provide more meaningful insights into both the FAE treatment safety and efficacy. We therefore suggest optimizing pharmacovigilance by additionally monitoring CD4+ and CD8+ T-cell counts at regular intervals, especially in patients of middle to older age. Thus, further prospective studies are needed to establish evidence-based recommendations to guide dermatologists in the management of psoriasis patients who are taking FAEs and who develop low absolute T-cell counts.

Long-term real-life safety profile and effectiveness of fumaric acid esters in psoriasis patients: a single-centre, retrospective, observational study.

BACKGROUND: Fumaric acid esters (FAEs) are an established systemic treatment for moderate-to-severe psoriasis. However, the long-term clinical safety and effectiveness of continuous FAE monotherapy and combination therapy have not been established. OBJECTIVE: To examine the long-term safety and effectiveness of FAEs as monotherapy and in combination with phototherapy or methotrexate in patients with psoriasis treated at a single centre in Germany. METHODS: This monocentric, retrospective observational study, with a follow-up period of up to 32.5 years, included 859 patients: 626 received FAE monotherapy, 123 received FAEs with concomitant phototherapy and 110 received FAEs with methotrexate. RESULTS: Approximately half of patients (49.0%) reported adverse events (566 total events), most of which involved the gastrointestinal tract. Serious adverse events were reported in 2.3% of patients, but none were deemed to have a causal relationship with any of the treatment regimens. Adverse events leading to treatment discontinuation were observed in 12.9% of patients. A median duration of 1 year was observed in all three treatment subcohorts (P = 0.70) from initiation of FAE treatment to a 50% response rate, where response was defined as achieving a cumulative static Physician's Global Assessment (PGA) score of 'light' and at least a 2-point reduction in baseline PGA. A 50% response rate for the cumulative Psoriasis Area and Severity Index 75 was achieved in the FAE monotherapy subcohort after a median of 3 years of treatment, in the FAEs + phototherapy subcohort after 6.7 years and in the FAEs + methotrexate subcohort after 8.1 years (P = 0.001). CONCLUSION: According to our data, FAEs as monotherapy or in combination with phototherapy or methotrexate are safe and beneficial for long-term clinical use. However, multicentre, randomized controlled trials are required to establish the clinical value of monotherapy versus combination therapy and the optimal treatment duration.

Food-induced anaphylaxis and cofactors - data from the anaphylaxis registry.

Food allergens are frequent causes of anaphylaxis. In particular in children and adolescents they are the most frequent elicitors of severe allergic reactions, and in adults food allergens rank third behind insect venom and drugs. Since July 2006 severe allergic reactions from Germany, Austria, and Switzerland are collected in the anaphylaxis registry. Currently 78 hospitals and private practises are connected. From July 2006 until February 2009 1,156 severe allergic reactions were registered. Among children and adolescents (n = 187, age range from 3 months to 17 years) food allergens were the most frequent triggers, comprising 58% of cases. In the adult group (n = 968, 18 - 85 years) food allergens were in the third position (16.3%) behind insect venom and drugs. In children legumes (31%) and in particular peanuts were frequently responsible food allergens, followed by tree nuts (25%) with hazelnut being the most frequent elicitor. In adults fruits (13.4%) most often induced severe food-dependent anaphylaxis, but also animal products (12.2%); among these most frequently crustaceans and molluscs. Cofactors were often suspected in food-dependent anaphylaxis, namely in 39% of the adult group and in 14% of the pediatric group. In adults drugs (22%) and physical activity (10%) were reported to be the most frequent cofactors, in children physical activity was suspected in 8.7% and drugs in 2.6%. Concomitant diseases like atopic dermatitis, allergic asthma, or allergic rhinoconjunctivitis were reported in 78% of children and adolescents and in 67% of the adults. In conclusion, food-induced anaphylaxis, its cofactors and concomitant diseases are age-dependent. The data offers to identify risk factors of anaphylaxis.

[Should metal alloy discs be used for patch testing in suspected metal implant intolerance reaction?]. / DKG-Stellungnahme zur Epikutantestung von Metalllegierungsplättchen bei Verdacht auf Metallimplantat-Unverträglichkeit.

Intolerance reactions to metal implants may be caused by metal allergy. However, prior to implantation, patch testing should not be done in a prophylactic-prophetic approach. Pre-implant patch testing should only be performed to verify or exclude metal allergy in patients with a reported respective history. In the case of implant-in particular arthroplasty-related complications like, for example, pain, effusion, skin changes, reduced range of motion, or loosening, orthopedic-surgical differential diagnostics should be performed first. Allergological workup of suspected metal implant allergy should be done with the DKG baseline series which contains nickel-, cobalt- and chromium-preparations. Various studies assessing the usefulness of metal alloy discs for patch testing proved that this approach does not give reliable information about metal allergy. Positive patch test reactions to the discs cannot be assigned to a specific metal within the disc alloy components. Furthermore, availability of such metal discs might be an invitation to uncritical testing. Accordingly, due to lack of benefit in comparison to patch testing with standardized metal salt preparations, we do not recommend patch testing with metal alloy discs.

Contact allergy induced by bisphenol A diglycidyl ether leachables from aluminium tubes for pharmaceutical use.

BACKGROUND: Aluminium tubes for pharmaceutical use are internally lacquered with epoxy resins (ER) based on bisphenol A diglycidyl ether (BADGE). Recently, it was shown that remnants of ER polymerization like BADGE are extractable from epoxy-based coatings of commercially available tubes and may leach into semi-solid drug preparations. We aimed to evaluate the safety of BADGE-contaminated macrogol ointments in individuals sensitized to ER based on BADGE by use tests. METHODS: Repeated open application testing (ROAT) in 11 patients sensitized to ER based on BADGE with BADGE in macrogol ointments (3 mg/kg; 30 mg/kg, equivalent to BADGE concentration determined in macrogol ointment after storage in a commercially available tube; 300 mg/kg). RESULTS: The 30 mg/kg BADGE ointment elicited reactions in three patients, and another three patients reacted to 300 mg/kg BADGE ointment. No reactions to the vehicle control and 3 mg/kg BADGE were observed. CONCLUSIONS: Elevated BADGE concentrations in ER-coated aluminium tubes pose a risk of developing contact dermatitis to patients sensitized to ER based on BADGE. Quality standards are deemed necessary for the production of ER-coated aluminium tubes intended for pharmaceutical use and should consider the results of the present ROAT study.

[Delayed anaphylaxis after ingestion of meat. Carbohydrate epitope galactose-α-1,3-galactose as cause of severe anaphylactic reactions]. / Verzögerte Anaphylaxie nach Fleischverzehr. Kohlenhydratepitop Galaktose-α-1,3-Galaktose als Auslöser schwerer anaphylaktischer Reaktionen.

The correlation between anaphylaxis after consumption of meat and the carbohydrate epitope galactose-α-1,3-galactose (α-Gal) was first described in oncologic patients treated with cetuximab. An association with tick bites and parasitosis is suspected. We report on a healthy patient who developed sudden anaphylactic reactions after the ingestion of meat. Serologic and skin tests confirmed sensitization to α-Gal. Avoiding the consumption of mammalian meat led to a complete absence of symptoms.

Add-on diagnostic tool for allergic contact dermatitis: the strip patch test.

The "conventional" patch test (PT) is considered to be the "gold standard" in diagnosing allergic contact dermatitis. However, the method of patch testing has repeatedly been criticized for its limited diagnostic accuracy and it is therefore by no means uniformly accepted as a reliable test method. Basic idea of the "strip" patch test (SPT), a modification by repeated tape stripping prior to patch testing, is to increase the quantity of allergen reaching the deeper epidermal cell layers and, thus, to increase the test sensitivity. The SPT according to our proposed standardized protocol is promising to improve diagnosis of allergic contact dermatitis which is demonstrated exemplary in the field of occupational contact dermatitis.

[Positive strip patch test reactions with coexistent negative patch test reactions. Relevance for the assessment practice of occupational skin disease]. / Positive Testreaktionen im Abrissepikutantest bei negativem Standardepikutantest. Bedeutung für die berufsdermatologische Begutachtung.

The strip patch test is recommended whenever a patch test is presumed to be false negative. The aim of this technique is to increase skin sensitivity to test substances by removing the upper layers of the stratum corneum prior to patch testing. We report on a 57-year-old former heavy-current electrical worker, who suffered from hyperkeratotic fissured hand eczema. Sensitization to nickel sulphate was demonstrated in both 2001 and 2009 with strip patch testing even though conventional patch testing was negative. To our knowledge, this is the first description of an allergy to nickel with a pension entitlement according to no. 5101 of the German ordinance on industrial disease based solely on positive strip patch tests.

Standardized tape stripping: a practical and reproducible protocol to uniformly reduce the stratum corneum.

The basic idea of the strip patch test (SPT), a modification of the conventional patch test (PT), is to increase the bioavailability of a test substance in the deeper epidermal cell layers by defined tape stripping of the test area on the back prior to a PT. In a prospective, investigator-blinded clinical study, we evaluated the variability and the interrater agreement of our proposed SPT protocol. The relative stratum corneum (SC) reduction after tape stripping was measured on 75 subjects for variability and in a subgroup of 18 subjects for interrater agreement, by performing in vivo confocal laser scanning microscopy. We found good reproducibility with an SC reduction of 31%, with 95% of the values lying between 22 and 40%, and good interrater agreement. As a result, our SPT protocol yields a clinically adequate standardization of the SC reduction and the SPT may therefore be recommended for performance in daily clinical routine.

Para-phenylenediamine and allergic sensitization: risk modification by N-acetyltransferase 1 and 2 genotypes.

BACKGROUND: Para-phenylenediamine (PPD) is a common contact sensitizer causing allergic contact dermatitis, a major skin problem. As PPD may need activation to become immunogenic, the balance between activation and/or detoxification processes may influence an individual's susceptibility. PPD is acetylated and the metabolites do not activate dendritic-like cells and T cells of PPD-sensitized individuals. OBJECTIVES: To investigate whether PPD can be acetylated in vitro by the two N-acetyltransferases 1 (NAT1) and 2 (NAT2). Based on the assumption that N-acetylation by NAT1 or NAT2 is a detoxification reaction with respect to sensitization, we examined whether NAT1 and NAT2 genotypes are different between PPD-sensitized individuals and matched controls. METHODS: Genotyping for NAT1 and NAT2 polymorphisms was performed in 147 PPD-sensitized individuals and 200 age- and gender-matched controls. Results Both PPD and monoacetyl-PPD were N-acetylated in vitro by recombinant human NAT1 and to a lesser extent by NAT2. Genotyping for NAT1*3, NAT1*4, NAT1*10, NAT1*11 and NAT1*14 showed that genotypes containing the rapid acetylator NAT1*10 allele were under-represented in PPD-sensitized cases (adjusted odds ratio 0.72, 95% confidence interval 0.45-1.16). For NAT2, NAT2*4, NAT2*5AB, NAT2*5C, NAT2*6A and NAT2*7B alleles were genotyped. Individuals homozygous for the rapid acetylator allele NAT2*4 were under-represented in cases compared with controls (4.3% vs. 9.4%), but this trend was not significant. CONCLUSIONS: With respect to data indicating that NAT1 but not NAT2 is present in human skin, we conclude that NAT1 genotypes containing the rapid acetylator NAT1*10 allele are potentially associated with reduced susceptibility to PPD sensitization.

Strip patch test vs. conventional patch test: investigation of dose-dependent test sensitivities in nickel- and chromium-sensitive subjects.

BACKGROUND: Tape stripping the skin prior to patch testing (strip patch test, SPT) may enhance percutaneous penetration of test substances and increase skin reactivity to test substances. OBJECTIVE: To evaluate the test sensitivity of SPT in compliance with our recently presented practical method vs. conventional patch test (PT) in nickel- and dichromate-sensitive subjects. METHODS: Thirty subjects participated in the prospective, randomized, controlled, investigator-blind study. Serial dilution tests of nickel sulphate (10,000-50 ppm aq.) and potassium dichromate (1000-5 ppm aq.) were used. Tests were applied in duplicate to both sides of the upper back of the subject, where one, randomly chosen side was tape stripped. RESULTS: According to the estimated test sensitivities, SPT is more sensitive than PT in nickel- and dichromate-sensitive subjects, regardless of the interindividual different numbers of tape strips. The superiority of the SPT grows with diminishing concentrations of the allergens. CONCLUSION: Test sensitivity of SPT vs. PT is increased. If no positive results are obtained by PT, the SPT could help to detect hidden allergens in case of weak sensitization or low concentration and poor percutaneous penetration of the test substances.