[Improvement of medication safety by identification of genetically predisposed subjects. Personalized clinical strategies and regulatory advices]. / Erhöhung der Arzneimitteltherapiesicherheit durch Identifizierung genetisch prädisponierter Personen. Personalisierte klinische Ansätze und regulatorische Maßnahmen.

BACKGROUND: Because adverse drug events (ADEs) have a high socio-economic impact there is an urgent need for effective prevention. In addition to process-related avoidable errors personalised approaches for the prevention of ADEs should also focus on genetic polymorphisms as potential causative agents. AIM: Using five case reports as examples therapeutic modalities are described to illustrate the clinical impact of prospective testing aimed at estimating the individual risk of susceptible subjects. MATERIAL AND METHODS: The role of the HLA system, the cytochrome P450 family, other metabolic enzymes and transport proteins are described to illustrate the broad range of genetic susceptibility. It is shown, why, when and for whom pretherapeutic tests on genetic polymorphisms are recommended to reduce the risk of ADEs. RESULTS: The determination of genetic susceptibility is already implemented in clinical practice prior to (1) carbamazepine therapy in south-east Asians and (2) treatment with abacavir independent of ethnicity. Before prescribing carbamazepine or abacavir, it is recommended that therapeutic decisions be based on these test results. CONCLUSION: The broad application of personalised medicine used as an effective tool for minimizing ADE risks is limited by the evidence-based benefit for the patient on the one hand and the costs of the test on the other hand.

Does smoking have a significant impact on early irritant hand dermatitis in metal workers?

BACKGROUND: Although they know the long-term complications of smoking, many smokers require additional motivation for entering a smoking cessation programme. At the same time, smoking is considered a possible promoting factor for various skin diseases. OBJECTIVE: The present study assesses the impact of smoking on occupational hand dermatitis in a high-risk population. MATERIAL AND METHODS: 1,355 metal workers, 97.3% of them shift workers, took part in a standardized interview and a dermatological examination of their hands. A subgroup of 1,020 males was willing to be followed-up for 1 year. Of those, 78.3% could be included in the final assessment. RESULTS: Compared to the general German adult population the percentage of smokers was increased (41.7% at baseline). Probably due to self-selection bias and to a higher drop-out rate, the proportion of smokers was significantly lower at follow-up. Compared to nonsmokers, smokers had significantly higher score values for both erythematous lesions and vesicles. CONCLUSION: The present data might give additional support for occupational physicians or dermatologists to convince workers to quit smoking.

How to quantify skin impairment in primary and secondary prevention? HEROS: a proposal of a hand eczema score for occupational screenings.

BACKGROUND: Skin scoring systems have to meet specific demands depending on their particular settings and indications, e.g. occupational screenings vs. clinical examinations, evaluating progress of treatment or supervision of preventive strategies. Until now, most scoring systems have been developed for severe cases of hand eczema. A validated quantitative scoring system for early hand eczema is still missing. OBJECTIVES: The present cross-sectional study was aimed at assessing the practical value of a quantitative hand eczema score for occupational screenings (HEROS) at the workplace and its potential for identifying individuals at increased risk of work-related skin disease. METHODS: Both hands of 800 male metal workers were examined for characteristic morphological patterns of hand dermatitis and quantified with HEROS. The score was validated by testing inter- and intraobserver reliability in random samples. Results of validation were compared with three already validated skin scores for distinct hand eczema (Osnabrück hand eczema severity index, hand eczema severity index, Manuscore). RESULTS: The score values ranged from 0 to 82 (theoretical maximum 2260), reflecting the skin condition of healthy, fit-for-work subjects. Inter- and intraobserver reliability was good to excellent. Results for reliability of the HEROS were in line with all three validated scores for hand eczema. The predictive value for identifying persons at increased risk for developing hand eczema was low. CONCLUSIONS: The HEROS seems to be an adequate tool for observer near-independent assessment of early hand eczema, especially for quantifying minimal skin impairment. Therefore, we propose the implementation of this scoring system for quantifying early hand dermatitis in occupational screenings.

An overview of skin scores used for quantifying hand eczema: a critical update according to the criteria of evidence-based medicine.

The present review gives an overview of the enormous variety of skin scores used for assessing severity in patients suffering from hand eczema. In order to evaluate the validity and practical relevance of different scoring systems according to the criteria of evidence-based medicine, in May 2009 we performed a systematic search of the literature using PubMed and the Cochrane Library. A total of 69 articles reporting on 45 different methods for quantifying hand eczema were identified. The panel of methods varied from pure subjective categories to more or less quantitative scoring systems. Furthermore, by focusing on skin scores used in clinical trials in which the results led to the licensing of a systemic or topical drug for treatment of hand eczema, a panel of different scoring systems was identified. In addition to morphological pattern, some scoring systems included subjective complaints, which might cause an individual bias by overestimation of self-reports. Inter- and intraobserver reliability was rarely reported except for three scores. Among these validated scores interobserver reliability was reported for three scores, but only one of the three included reliability within observers (repeatability). Advantages and disadvantages of the different scoring systems are critically discussed. Depending on different indications and particular settings (e.g. occupational screening vs. clinical examinations, evaluating progress of treatment in everyday clinical practice or for research purposes) scoring systems have to fulfil diverging demands. We draw the conclusion that a standardized diagnostic procedure for assessing the severity of hand eczema would facilitate the comparability of outcome of clinical trials. However, scoring systems used for occupational screening have to fulfil different demands compared with scoring systems used for licensing of drugs. This striking difference might be explained by the skin condition, which is generally supposed to be much better in subjects at medical check-ups at the workplace.

Effectiveness of skin protection measures in prevention of occupational hand eczema: results of a prospective randomized controlled trial over a follow-up period of 1 year.

BACKGROUND: We recently found a very low adherence to a generally recommended skin protection regimen in a sample of 1355 metalworkers. OBJECTIVES: The present study assessed the effectiveness of skin protection as presently recommended, especially the differential contribution of skin care and skin protection, to the prevention of occupational hand eczema. Methods Of 1355 metalworkers screened, 1020 male volunteers, all fit for work, were recruited for a prospective intervention study with four arms (skin care, skin protection, both combined, and control group, i.e. no recommendation). The study was performed from winter 2006/2007 to spring 2008, following each subject for up for 12 months. Both hands were examined using a quantitative skin score, and a standardized personal interview was performed three times. The change of the objective skin score from baseline to 12 months was used as primary outcome measure. RESULTS: After 12 months 800 subjects were included (78.4% of those recruited). The compliance to follow the randomized measure depended on the recommended measure and ranged from 73.7% to 88.7%. While in the control group a significant deterioration was found, the largest and significant improvement was noted in the group following the generally recommended skin protection programme (skin care + skin protection) followed by skin protection alone as second best. CONCLUSIONS: The generally recommended skin protection regimen seems to provide effective prevention of occupational skin disease. Therefore, the compliance to follow the skin protection regimen, especially the use of skin protection, should be enhanced.

Current acceptance and implementation of preventive strategies for occupational hand eczema in 1355 metalworkers in Germany.

BACKGROUND: The effectiveness of a skin care programme is based mainly on the effectiveness of the products used and the frequency and diligence of the application of skin care products. OBJECTIVES: The present cross-sectional study was aimed at evaluating the implementation and acceptance of generally recommended skin protective means at the workplace. METHODS: We included in our study 1355 metalworkers, employed in 19 factories, mainly of small or medium-size. The majority of participants were male (96.7%, n = 1310). The investigation included a standardized interview and a dermatological examination of the hands. RESULTS: More than half of all participants (52.4%) had suffered from skin problems of the hands at some time. Three hundred and ninety-six subjects (29%) indicated they followed the skin protection regimen as it was generally recommended, i.e. the use of barrier creams in combination with moisturizers. A similar number of participants (28%) denied any use of protective creams. In general, compliance in men was significantly poorer than in women. Participants with past or present history of hand eczema used both barrier creams and moisturizers significantly more often. The skin condition of the hands, examined using a quantitative score, did not differ significantly in the four subgroups defined by different skin protection measures. While acceptance of protective measures was limited, these were available in all factories. CONCLUSIONS: Although barrier creams and moisturizers are highly recommended as effective means to prevent irritant contact dermatitis in Germany, our data prove that the compliance of application in this group at special risk for hand eczema is extremely low.

[The three-step programme of skin protection. A useful instrument of primary prevention or more effective in secondary prevention?]. / Der dreistufige Hautschutzplan. Ein wirksames Instrument der Primärprävention oder eher geeignet für die Sekundärprävention?

For many years the three-step programme of skin protection, consisting of skin protection before work, cleaning and skin care after work, is one of the generally recommended measures to prevent occupational contact dermatitis. While protective creams are supposed to prevent skin damage caused by irritant contact, skin cleansing should mildly remove aggressive substances from the skin, whereas post-exposure skin care is intended to enhance epidermal barrier regeneration. This programme is strongly followed by most of the employees. But in spite of intensive preventive measurements the rate of reported occupational skin diseases according to BK 5101 is with a mean of 27.9% unchanged high since 1980. Occupational dermatologists even suggest that the reported cases mimic the top of an iceberg and that the incidence of occupational skin diseases might be much higher. These findings raise the question of how effective the actual recommended three-step programme really is in primary and secondary prevention of occupational contact dermatitis. This review is aimed to give an evaluation on the evidence of each single element of the three-step concept. Following results can be determined: In cases of impaired skin condition the therapeutic properties of skin protection (secondary prevention) is undoubted. The effectiveness of barrier creams in the primary prevention of hand eczema could not be proven. Beyond doubt is the fact that barrier creams facilitate the removal of sticky oils, greases, and resins from the skin, thus decreasing the need to wash with potentially irritating abrasives and waterless cleansers.

Trans-placental exposure of neonates to acrylamide--a pilot study.

OBJECTIVES: Acrylamide (AA) (CAS No 79-06-1) has most recently been identified as a food-borne toxicant generated during the heating process of starch-containing foods. It was the aim of the present study to investigate the trans-placental exposure of newborn infants to this possible human carcinogen by analysis of the specific haemoglobin adduct of AA ( N-2-carbamoylethylvaline, AAV) in the blood of mothers and the corresponding umbilical cord blood of neonates as a parameter of biochemical effects. METHODS: We investigated the blood of 11 women advanced in pregnancy (one smoker, ten non-smokers) and the corresponding umbilical cord blood of neonates for the N-terminal haemoglobin adducts of AA (AAV) and the smoking-specific adduct of acrylonitrile (CAS No 107-13-1) ( N-cyanoethylvaline, CEV). The limit of detection (LOD) was 5 pmol/g globin for AAV and 4 pmol/g globin for CEV. RESULTS: AAV could be determined in all blood samples of the mothers (median 21 pmol/g globin, range 18-104 pmol/g globin) as well as in the umbilical cord blood of neonates (median 10 pmol/g globin, range 6-43 pmol/g globin). The highest values were detected in the blood of the smoking mother and her child. CEV was detected only in the blood of the smoking mother (185 pmol/g globin) and the corresponding umbilical cord blood (69 pmol/g globin). DISCUSSION: AAV adduct levels in non-smoking mothers and neonates showed a good correlation (r=0.859). The concentration of AA adducts in the blood of neonates is approximately 50% of the adduct level found in the blood of the mother. In view of the shorter life span of neonatal erythrocytes and the lower body weight of newborn infants, the relative internal dose of AA in neonates (in microgrammes per kilogramme body weight) must be assumed to be at least equal to that of the mother. Because of the high cell-replication rates during foetal development, trans-placental exposure of neonates to AA might raise concerns. Neonates of smoking mothers take up much higher doses of AA than those of non-smoking mothers.

Evaluation of a dipstick test (Allergodip-Latex) for in vitro diagnosis of natural rubber latex allergy.

BACKGROUND: IgE-mediated hypersensitivity to latex has been recognized as an increasing health problem with far-reaching consequences for patients, regarding both their occupational situation and safety in medical care. Therefore, a correct diagnosis of natural rubber latex (NRL) allergy is essential. The purpose of the study was to evaluate sensitivity and specificity of several established diagnostic methods for NRL allergy (in vitro assays and skin prick test) in relation to a new semiquantitative dipstick test (Allergodip-Latex, Allergopharma) as a screening test for NRL allergy. METHODS: Data obtained with quantitative assays including Pharmacia CAP System(FEIA), DPC-AlaSTAT and Magic Lite were compared with the dipstick test results in latex-sensitized (n = 151) and nonsensitized persons (n = 232). In addition these in vitro findings were related to clinical symptoms after exposure to latex and skin prick test results with a panel of different latex allergen extracts. RESULTS: When comparing sensitivity and specificity of all in vitro assays relative to skin prick test results the Pharmacia CAP System (FEIA) had the highest sensitivity in the range of 90%. Sensitivity of the other in vitro assays was in the range of 73.7-74.9%, specificity varied from 85.3 to 89.8%. A diagnostic standard was defined in terms of at least three corresponding test results out of all diagnostic methods (in vitro assays and skin prick test). The sensitivity and specificity of each diagnostic test were determined relative to this diagnostic standard. Hereby the Allergodip test results showed a sensitivity of 91% and a specificity of 93%. CONCLUSION: The dipstick test results are in line with the data of the other in vitro assays. In contrast to other in vitro assays the dipstick test requires no further laboratory equipment and is easy to perform.

[House dust mite-crustaceans-molluscs syndrome. A rare variant of food allergy in primary sensitization to inhaled allergens]. / Das Milben-Krustazeen-Mollusken-Syndrom. Eine seltenere Variante einer Nahrungsmittelallergie bei primärer Sensibilisierung auf ein Aeroallergen.

80% of all cases in food allergy in adults are preceded by a clinical or subclinical sensitisation to inhalative allergens. Food allergy is caused by cross-reactions between ingested food and inhaled particles. We report a patient suffering from the house-dust mite-crustaceans-molluscs-syndrome. Here, house-dust mite is the sensitising agent, therefore even first ingestion of invertebrates such as snails, shrimps, mussels or oysters can lead to severe anaphylaxis.

Natural rubber latex allergy: a problem of interdisciplinary concern in medicine.

In the past 10 years, IgE-mediated allergy to natural rubber latex has become a significant health problem in industrialized countries, especially among health care workers, patients with congenital malformations, and children with a history of multiple surgical interventions. Curative treatment inducing immunological tolerance in formerly sensitized patients is experimental and not yet generally available. Therefore, it is important to be aware of the seriousness of latex allergy and to understand the risk factors leading to this allergy. Preventive measures are needed to decrease the incidence of natural rubber latex sensitization. This article gives a brief review of the current state of knowledge concerning latex allergy, including a definition of latex, epidemiological data, identified allergens, the clinical spectrum, diagnostic procedures, cross-reactions, preventive measures, the legislative background, and economics.

Safety of a two-day ultrarush insect venom immunotherapy protocol in comparison with protocols of longer duration and involving a larger number of injections.

BACKGROUND: Insect venom immunotherapy (VIT) is initiated by a dose increase protocol administered usually over 7 to 9 days. Shorter protocols have the advantage of reducing the patient's stay in the hospital. Very few data are currently available on the safety of shorter VIT dose increase protocols. OBJECTIVE: The aim of this study was to investigate whether a reduction in the duration of the VIT dose increase protocol from 7 to 9 days to 2 days causes an increase in the incidence and severity of adverse reactions. METHODS: Between 1992 and 1997 we administered VIT to 1055 patients allergic to bee or wasp venom. We shortened the 7- to 9-day rush protocol stepwise to 2 days by reducing the number of injections and increasing the initial dose and compared the incidence and severity of adverse reactions. The patients were retrospectively divided into 3 cohorts: 20 injections over 7 to 9 days (cohort 1, 317 patients), 10 to 14 injections over 3 to 6 days (cohort 2, 335 patients), and 9 injections over 2 days (cohort 3, 403 patients). RESULTS: We observed no severe adverse reactions in any of the cohorts during VIT. Adverse reactions were treated in 7.1% of the patients by oral and in 2.9% by intravenous antihistamines and in 0.8% by systemic corticosteroids. The incidence of adverse reactions declined significantly from 22.4% in cohort 1 to 13.7% in cohort 2 and 10.7% in cohort 3 with reduced number of injections (P <.001). CONCLUSION: The incidence and severity of adverse reactions decline if the VIT dose increase protocol is shortened to 2 days.

[Specific skin infiltration of extracutaneous B-cell lymphoma in healing herpes simplex skin]. / Spezifische Hautinfiltrate eines extrakutanen B-Zell-Lymphoms in einem abheilenden Herpes simplex.

Both herpes simplex and herpes zoster are not uncommon in patients affected by malignant lymphoma or leukemia. Of particular interest, the herpetic lesions may be followed by specific cutaneous infiltrates. We report on a patient with a centrocytic-centroblastic non-Hodgkin lymphoma who showed primary skin infiltrates within the area affected by herpes simplex. After effective therapy with aciclovir, papules and plaques developed at the site of the herpetic scars. Histologic investigation confirmed dense B-lymphocytic infiltrates with immunoglobulin light chain restriction and a granulomatous reaction. Although the chemotherapeutical regiment was modified, the patient died one month later of a lethal blast crisis. The occurrence of so called isotopic skin reactions and their prognostic significance is discussed.

[Localized reticulate hyperpigmentation]. / Umschriebene retikuläre Hyperpigmentierungen--ein weites klinisches Spektrum.

34 year-old pregnant woman presented with reticulate pigmentation of the flexures, the dorsum of the hands and the genitoperianal region. She was in good health and her family history was unremarkable. Histologic examination of the hyperpigmented patches revealed pigmented filiform downgrowths of the interfollicular epidermis and follicular infundibula, as well as small epithelial cysts. Upon immunohistochemical and ultrastructural studies, the number of melanocytes appeared normal. The elongated dendritic processes of the melanocytes contained many mature melanosomes. In the adjacent keratinocytes large melanosomes did not aggregate into complexes. The diagnosis of localized reticulate pigmentary disorder was established. The knowledge of the broad clinical spectrum of localized reticulate hyperpigmentations with its favorable prognosis is of practical importance. Genital or flexural pigmented lesions have to be differentiated from melanosis of the vulva or acanthosis nigricans. The presented case gives further evidence that many of the proposed entities characterized clinically by reticulate pigmented macules and hyperkeratotic follicular lesions are different phenotypic expressions of the same autosomal dominant genodermatosis.

Borrelia burgdorferi-associated primary cutaneous B cell lymphoma: complete clearing of skin lesions after antibiotic pulse therapy or intralesional injection of interferon alfa-2a.

We report two patients with low-grade malignant primary cutaneous B cell lymphoma in association with Borrelia burgdorferi infection. Extracutaneous manifestations were ruled out by standard staging procedures. Infection with Borrelia burgdorferi was confirmed by cultivation from lesional skin in both patients. In the first patient skin lesions cleared completely after pulse therapy with cefotaxime, whereas in the second patient antibiotic treatment failed. In this patient, however, skin lesions completely cleared after intralesional injection of interferon alfa-2a. Antibiotic treatment or intralesional injection of interferon alfa-2a should be considered as a first-line treatment of Borrelia burgdorferi-associated primary cutaneous B cell lymphoma before more aggressive conventional therapeutic modalities (e.g., radiation therapy) are applied.

Mycosis fungoides presenting as an acquired ichthyosis.

A 25-year-old patient with an acquired ichthyosis-like condition is described. Histologic and molecular biologic examination of the fine, whitish, scaling skin lesions suggested the diagnosis of mycosis fungoides. Typical lesions of mycosis fungoides, such as patches, plaques, or tumors, were not present. To the best of our knowledge, this is the first case of mycosis fungoides presenting solely with the clinical features of acquired ichthyosis. The sudden appearance of ichthyosiform skin changes in adults must be taken seriously and the underlying cause must be evaluated. A skin biopsy should be performed in all cases of acquired ichthyosis to rule out mycosis fungoides.

[Rare variants of cutaneous T-cell lymphomas]. / Seltene Varianten kutaner T-Zell-Lymphome.

Besides the classical forms of cutaneous T-cell lymphoma (C-CTCL), such as mycosis fungoides and Sézary's syndrome, unique variants may be encountered. The classification of these rare cutaneous T cell lymphomas is problematic and controversial. Newer classifications of lymphoma in general, such as the Revised European-American Lymphoma (REAL) Classification, emphasize well-established clinico-pathological entities. It seems appropriate to attempt to bring greater clarity to the classification of cutaneous T-cell lymphomas using the same principles. In this review, we list and characterize the rare variants of cutaneous T-cell lymphoma, such as (1) clinical, histological and immunological variants of mycosis fungoides; (2) progressive cutaneous T-cell lymphoma (P-CTCL) including transformed classical cutaneous T-cell lymphoma (TC-CTCL) and primary progressive cutaneous T-cell lymphoma (PP-CTCL); (3) angiocentric and angioimmunoblastic cutaneous T-cell lymphomas; (4) large cell anaplastic, CD30+ cutaneous T-cell lymphoma; (5) HTLV-I-associated adult T-cell leukemia/lymphoma (ATLL); (6) cutaneous manifestations of primary extracutaneous T-cell neoplasias; (7) unclassifiable cutaneous T-cell lymphoma.