Systemic anti-inflammatory treatment of atopic dermatitis during conception, pregnancy and breastfeeding: Interdisciplinary expert consensus in Northern Europe.

Treating atopic dermatitis (AD) in pregnant or breastfeeding women, and in women and men with AD aspiring to be parents is difficult and characterized by uncertainty, as evidence to inform decision-making on systemic anti-inflammatory treatment is limited. This project mapped consensus across dermatologists, obstetricians and patients in Northwestern Europe to build practical advice for managing AD with systemic anti-inflammatory treatment in men and women of reproductive age. Twenty-one individuals (sixteen dermatologists, two obstetricians and three patients) participated in a two-round Delphi process. Full consensus was reached on 32 statements, partial consensus on four statements and no consensus on four statements. Cyclosporine A was the first-choice long-term systemic AD treatment for women preconception, during pregnancy and when breastfeeding, with short-course prednisolone for flare management. No consensus was reached on second-choice systemics preconception or during pregnancy, although during breastfeeding dupilumab and azathioprine were deemed suitable. It may be appropriate to discuss continuing an existing systemic AD medication with a woman if it provides good disease control and its benefits in pregnancy outweigh its risks. Janus kinase (JAK) inhibitors, methotrexate and mycophenolate mofetil should be avoided by women during preconception, pregnancy and breastfeeding, with medication-specific washout periods advised. For men preconception: cyclosporine A, azathioprine, dupilumab and corticosteroids are appropriate; a 3-month washout prior to conception is desirable for methotrexate and mycophenolate mofetil; there was no consensus on JAK inhibitors. Patient and clinician education on appropriate (and inappropriate) AD treatments for use in pregnancy is vital. A shared-care framework for interdisciplinary management of AD patients is advocated and outlined. This consensus provides interdisciplinary clinical guidance to clinicians who care for patients with AD before, during and after pregnancy. While systemic AD medications are used uncommonly in this patient group, considerations in this article may help patients with severe refractory AD.

EADV Task Force Pruritus White Paper on chronic pruritus and chronic prurigo: Current challenges and future solutions.

Chronic pruritus (CP) is frequent in general medicine and the most common complaint in general dermatology. The prevalence of CP is expected to rise in the future due to the ageing population. The clinical presentation, underlying aetiology and treatment strategy of CP are heterogeneous. Also, individual treatment aims and physical, psychic and economic burdens of patients might vary. Chronic prurigo (CPG) is the most severe disease in the chronic pruritus spectrum, being associated with long-standing scratch-induced skin lesions and a therapy refractory itch-scratch-cycle. It is thus important to raise disease awareness for CP and CPG in the general public and among decision-makers in the health system. Further, there is a need to support a rational clinical framework to optimize both diagnostics and therapeutics. Currently, there is still a shortcoming regarding approved therapies and understanding CP/CPG as severe medical conditions. Therefore, the EADV Task Force Pruritus decided to publish this white paper based on several consensus meetings. The group consented on the following goals: (a) ensure that CP is recognized as a serious condition, (b) increase public awareness and understanding of CP and CPG as chronic and burdensome diseases that can greatly affect a person's quality of life, (c) clarify that in most cases CP and CPG are non-communicable and not caused by a psychiatric disease, (d) improve the support and treatment given to patients with CP to help them manage their disease and (e) publicize existing therapies including current guidelines. We aim to point to necessary improvements in access and quality of care directed to decision-makers in health policy, among payers and administrations as well as in practical care.

Google search trends for itch in Europe: a retrospective longitudinal study.

BACKGROUND: Itch is a common symptom in the general population. Affected individuals often do not seek medical consultation and rely on Internet searches to obtain information regarding their itch. OBJECTIVES: The aim of this study was to attain insights into common concerns of the general population regarding itch can by analysing itch-related Internet search behaviour. METHODS: Google AdWords Keyword Planner was used to assess search volumes for itch-related terms in 15 European countries between September 2014 and August 2018. All identified keywords were qualitatively categorized. Itch-related terms were descriptively analysed and are shown as number of searches/100 000 inhabitants. RESULTS: The search volume for the keyword 'itch' per 100 000 inhabitants was highest in Northern Europe, followed by Eastern, Central and Southern Europe. In 4/15 countries, itch was searched for more often in the autumn/winter months compared to in the spring/summer months. Most itch-related terms were related to dermatological conditions such as inflammatory skin diseases (e.g. psoriasis, atopic dermatitis), allergic or immunologic conditions (e.g. urticaria), and infectious diseases or infestations (e.g. scabies). In terms of body location, genitoanal itch dominated the searches. Symptoms and signs related to itch, possible non-dermatological aetiologies, and treatment options were also among the most searched terms. CONCLUSIONS: These analyses provided for the first time insights into the search behaviour patterns related to itch across Europe. People from Northern and Eastern Europe are more likely to seek online information regarding itch. Causes for the itch, especially dermatological conditions, and genitoanal itch are the most important concerns for Internet users. This unconventional and inexpensive method identifies medical needs of people beyond the medical setting, including people who do not seek medical consultation. Accordingly, the data could be used to guide public health interventions and manage respective inhabitants' medical needs.

European academy of dermatology and venereology European prurigo project: expert consensus on the definition, classification and terminology of chronic prurigo.

BACKGROUND: The term prurigo has been used for many decades in dermatology without clear definition, and currently used terminology of prurigo is inconsistent and confusing. Especially, itch-related prurigo remains unexplored regarding the epidemiology, clinical profile, natural course, underlying causes, available treatments and economic burden, although burdensome and difficult to treat. OBJECTIVE: To address these issues, the multicentre European Prurigo Project (EPP) was designed to increase knowledge on chronic prurigo (CPG). In the first step, European experts of the EADV Task Force Pruritus (TFP) aimed to achieve a consensus on the definition, classification and terminology of CPG. Additionally, procedures of the cross-sectional EPP were discussed and agreed upon. METHODS: Discussions and surveys between members of the TFP served as basis for a consensus conference. Using the Delphi method, consensus was defined as an agreement ≥75% among the present members. RESULTS: Twenty-four members of the TFP participated in the consensus conference. Experts consented that CPG should be used as an umbrella term for the range of clinical manifestations (e.g. papular, nodular, plaque or umbilicated types). CPG is considered a distinct disease defined by the presence of chronic pruritus for ≥6 weeks, history and/or signs of repeated scratching and multiple localized/generalized pruriginous skin lesions (whitish or pink papules, nodules and/or plaques). CPG occurs due to a neuronal sensitization to itch and the development of an itch-scratch cycle. CONCLUSION: This new definition and terminology of CPG should be implemented in dermatology to harmonize communication in the clinical routine, clinical trials and scientific literature. Acute/subacute forms of prurigo are separated entities, which need to be differentiated from CPG and will be discussed in a next step. In the near future, the cross-sectional EPP will provide relevant clinical data on various aspects of CPG leading to new directions in the scientific investigation of CGP.

Antipruritic effect of pretreatment with topical capsaicin 8% on histamine- and cowhage-evoked itch in healthy volunteers: a randomized, vehicle-controlled, proof-of-concept trial.

BACKGROUND: Chronic itch is difficult to treat. Low-concentration topical capsaicin (0·006-0·05%) has previously been applied in itch therapy but evidence on its efficacy is contradictory. OBJECTIVES: This vehicle-controlled, double-blinded study investigated the effect of topical capsaicin 8% after 1- and 24-h application on evoked itch, neurogenic inflammation and itch-associated dysaesthesia. METHODS: Sixteen healthy volunteers (aged 22 ± 0·5 years, nine female) were treated with capsaicin for 1 h and 24 h, and vehicle for 24 h on each volar forearm. Subsequently, histamine (1%, administered prick test lancets) and cowhage (40-45 spicules) were applied to the pretreated areas. Evoked itch and pain intensities were recorded for 10 min using a visual analogue scale (0-10 cm), while sensitivity to touch-evoked itch was evaluated using von Frey filaments before and after itch provocations. Neurogenic inflammation was assessed using perfusion imaging. RESULTS: In the vehicle areas peak itch responses to histamine and cowhage were 4·67 ± 0·58 and 5·15 ± 0·71, respectively. Capsaicin pretreatment reduced peak itch responses to histamine and cowhage after 24-h pretreatment to 1·41 ± 0·58 (P = 0·003) and 0·81 ± 0·18, (P < 0·001), respectively. Capsaicin pretreatment for 1 h reduced only cowhage-induced itch (P = 0·023). Furthermore, 24-h capsaicin pretreatment abolished punctuate hyperknesis and lowered histamine-induced neurogenic inflammation but did not affect weal reactions. CONCLUSIONS: Topical capsaicin 8% pretreatment for 24 h reduced histaminergic and nonhistaminergic itch by about 75%, while a significant reduction (≈60%) was achieved for only nonhistaminergic itch in a standard 1-h treatment. Further investigations are needed to elucidate the clinical potential of high-concentration capsaicin as an antipruritic.

Conditioning pain stimulation does not affect itch induced by intra-epidermal histamine pricks but aggravates neurogenic inflammation in healthy volunteers.

This study investigated whether itch induced by intra-epidermal histamine is subjected to modulation by a standardized conditioned pain modulation (CPM) paradigm in 24 healthy volunteers. CPM was induced by computer-controlled cuff pressure algometry and histamine was introduced to the volar forearm by skin prick test punctures. Moreover, neurogenic inflammation and wheal reactions induced by histamine and autonomic nervous system responses (heart rate variability and skin conductance) were monitored. CPM did not modulate the intensity of histamine-induced itch suggesting that pruriceptive signaling is not inhibited by pain-recruited endogenous modulation, however, CPM was found to aggravate histamine-induced neurogenic inflammation, likely facilitated by efferent sympathetic fibers.

Mindfulness-based cognitive therapy to treat multiple chemical sensitivities: a randomized pilot trial.

Multiple chemical sensitivities (MCS) is a medically unexplained and socially disabling disorder characterized by negative health effects attributed to exposure to common airborne chemicals. Currently, there is no evidence-based treatment. The objectives of the study were to assess the feasibility of an 8-week mindfulness-based cognitive therapy program (MBCT) for adults with MCS and to evaluate possible effects on psychological distress and illness perception. The study design was a randomized clinical trial. The MBCT programme comprised 8 weekly sessions of 2½ hours. Forty-two adults were screened for eligibility and 37 were included. Mean age of the participants was 51.6 years, 35 (94.6%) were female and 21 (56.8%) were unemployed. Measures of psychological distress and illness perceptions were assessed at baseline, 4 weeks, 8 weeks and at 3 months follow-up. No significant differences in effect measures were found between the groups. However, those who completed the MBCT program generally reported benefiting in terms of improved coping strategies and sleep quality. The positive verbal feedback from the participants in the MBCT group suggests that a larger randomized clinical trial on the effect of MBCT for MCS could be considered.

Prevalence of self-reported hypersensitivity symptoms following intake of alcoholic drinks.

UNLABELLED: BACKGROUND; Although hypersensitivity symptoms following alcoholic drink consumption are common in asthmatics, the prevalence of such symptoms in the general population is not known. OBJECTIVE: To assess the prevalence of hypersensitivity symptoms following alcoholic drink consumption in an adult Northern European general population and the association of these symptoms with the prevalence of allergic rhinitis (AR) and asthma. METHODS: In 2006, a postal questionnaire was sent to a random sample of 18-69-year-olds living in Copenhagen, the capital of Denmark. The response rate was 70.7% (4242/6000). RESULTS: The prevalence of alcohol-induced symptoms from the upper airways, lower airways, and skin was 7.6% [95% confidence interval (CI): 6.8-8.4%], 3.2% (95% CI: 2.7-3.8%), and 7.2% (95% CI: 6.4-8.9%), respectively. A total of 13.9% (95% CI: 12.9-15.0%) had ever experienced alcohol-induced symptoms from at least one of the three regions (upper airways, lower airways, or skin), and 9.9% (95% CI: 9.0-10.8%) had experienced symptoms in the last 12 months. All types of beverages were commonly reported as triggers of hypersensitivity symptoms, red wine being the most common. Alcohol-induced hypersensitivity symptoms from the upper and lower airways were significantly more prevalent in persons with AR and asthma (odds ratios between 3.0 and 8.1, P-value <0.001 for all associations). CONCLUSIONS: In this Northern European general population, self-reported hypersensitivity symptoms following the intake of alcoholic drinks are common. These symptoms were markedly more prevalent in persons with AR and asthma. The underlying mechanisms and the clinical significance of these symptoms remain to be elucidated.

Nonhistaminergic and mechanical itch sensitization in atopic dermatitis.

Chronic or episodic severe itch is recurrent in atopic dermatitis (AD). Nonhistaminergic itch pathways are suggested to dominate in AD itch, contributing to an "itch-scratch-itch cycle" that prolongs and worsens itch, pain, and skin lesions. We hypothesized that nonhistaminergic neuronal sensitization contributes to itch in AD. Hence, we compared sensitivity with thermal, mechanical, and chemical pruritic stimuli in patients with AD and controls. The study comprised 25 patients with AD with chronic itch and 25 healthy controls. Questionnaires on itch characteristics were administered, and sensory tests were conducted intralesionally, extralesionally, and in homologous areas of controls. Thermal and mechanical quantitative sensory testing (QST) as well as histamine and cowhage provocations were performed. Subsequently, hyperknesis and vasomotor reactivity were assessed. Average itch and associated pain among patients with AD were 60.7 ± 4.3 and 39.7 ± 5.2 (VAS0-100), respectively. Patients experienced significantly higher itch from cowhage both intralesionally and extralesionally compared with controls, whereas histamine-evoked itch intensity was not significantly different between groups. No group differences were found for thermal quantitative sensory testings or pain evoked by itch provocations. Patients had decreased mechanical detection thresholds intralesionally and increased mechanical pain sensitivity intralesionally and extralesionally. Lastly, patients exhibited intralesional and extralesional hyperknesis before chemical itch provocations and augmented hyperknesis after itch provocations. Increased itch in response to cowhage (but not histamine) suggests nonhistaminergic pathway-specific itch sensitization in AD, whereas increased susceptibility to mechanically evoked itch and pain, particularly intralesionally suggests sensitization of mechanosensitive circuitry not normally associated with itch. Drugs targeting the nonhistaminergic (PAR2/TRPA1) itch pathway and itch sensitization are promising for treating AD itch.

Histaminergic and non-histaminergic elicited itch is attenuated in capsaicin-evoked areas of allodynia and hyperalgesia: A healthy volunteer study.

BACKGROUND: Chronic pain patients with sensitization may exhibit decreased sensitivity to normally pruritogenic sensory stimuli and moreover occasionally perceive these as painful. This study explored the relationship between itch and pain, by evaluating histaminergic and non-histaminergic itch evoked in capsaicin-induced allodynic and hyperalgesic areas. METHODS: In 28 healthy volunteers, capsaicin (100 µg/0.1 mL) was injected intradermally in the volar forearm to establish secondary dysesthesias. After the capsaicin-induced pain subsided, the areas of allodynia and hyperalgesia were mapped and itch was provoked inside these areas by histamine (10 mg/mL) and cowhage (25-40 spicules). The evoked itch and pain were recorded on a visual analogue scale (VAS 0-10 cm). Contralateral injection of 0.1 mL isotonic saline served as a control. RESULTS: Histaminergic and non-histaminergic evoked itch were significantly decreased when provoked in allodynic skin (p < 0.05). The area-under-the-curve of the evoked itch was reduced -43% from 18.0 ± 2.6 cm10 min in normal skin to 10.3 ± 1.8 cm10 min in allodynic skin (p < 0.01) for cowhage and -56% from 20.0 ± 3.5 cm10 min in normal skin to 8.8 ± 2.3 cm10 min allodynic skin (p < 0.001) for histamine. The pain responses to the pruritogens were not significantly altered between the areas of allodynia and normal skin (p > 0.1). An additional experiment showed that pinprick hyperalgesia in the absence of allodynia was sufficient to evoke the observed reduced sensitivity to itch stimuli. CONCLUSIONS: Cutaneous sensitization (secondary allodynia and hyperalgesia) reduced itch responses regardless of the type of itch model applied and without attenuation of the associated pruritogen-induced pain responses. This could explain the decreased sensitivity to itch provocations previously observed in patients with chronic pain. SIGNIFICANCE: This study shows that the neuronal sensitization processes underlying the development secondary hyperalgesia involve significant gating of histaminergic as well as non-histaminergic pruriceptive transmission. Because these itch provocations normally target specific subpopulations of C-nociceptors they could be of relevance for exploratory purposes in pain patients.

Beta-substituted cysteines as sequestering agents for ethanol-derived acetaldehyde in vivo.

A series of beta-mono- and beta,beta-disubstituted cysteines were evaluated in rats as sequestering agents for metabolically generated acetaldehyde (AcH) during the oxidation of ethanol in vivo and compared against D-(-)-penicillamine. Both threo- (5) and erythro-beta-phenyl-DL-cysteine (6) reduced ethanol-derived blood AcH by ca. 40% and 60%, respectively, whereas the corresponding beta-methyl-DL-cysteines (3 and 4) and the alpha-substituted alpha-methyl-DL-cysteine (8) had no effect. beta,beta-Tetramethylene-DL-cysteine (7), however, was as effective as D-(-)-penicillamine in sequestering AcH in vivo, reducing blood AcH after ethanol to 20% of maximal values. Thus, bulky beta-substitution or, better, beta,beta-disubstitution on cysteine is required for such activity. 14C-Labeled 2(RS),5,5-trimethylthiazolidine-4(S)-carboxylic acid (1) prepared by the condensation of D-(-)-penicillamine with [1,2-14C]acetaldehyde was found to be relatively stable in vivo, giving rise to less than 6% 14CO2 excretion in the expired air and the recovery of 65.5% of the administered dose in the urine as unchanged 1.

Latent inhibitors of aldehyde dehydrogenase as alcohol deterrent agents.

A series of compounds structurally related to pargyline (N-methyl-N-propargylbenzylamine, 4) were synthesized with the propargyl group replaced by a cyclopropyl, allyl, or 2,2,2-trichloroethyl group and, additionally in several cases, with the methyl group replaced by H. The rationale for their preparation was based on the expectation that, like pargyline, which gives rise to propiolaldehyde, oxidative metabolism of the above compounds by the hepatic cytochrome P-450 enzymes would lead to the generation in vivo of the aldehyde dehydrogenase (AlDH) inhibitors, cyclopropanone, acrolein, or chloral. These compounds were evaluated for inhibition of liver AlDH in vivo by measuring the elevation of ethanol-derived blood acetaldehyde in rats and in vitro by the rate of oxidation of acetaldehyde by intact and osmotically disrupted liver mitochondria. Administration of N-methyl-N-cyclopropylbenzylamine (5) and its nor-methyl analogue (8) to rats raised blood acetaldehyde levels significantly over controls at 2 h. This effect was more pronounced at 9 h, with blood acetaldehyde levels reaching 19 to 27 times control values and approaching the values induced by pargyline. Other compounds elicited significant elevations in ethanol-derived blood acetaldehyde only at 9 h. We suggest that latent inhibitors of AlDH such as 5 or 8 might be useful as alcohol deterrent agents.

N1-hydroxylated derivatives of chlorpropamide and its analogs as inhibitors of aldehyde dehydrogenase in vivo.

Certain (arylsulfonyl)urea hypoglycemic drugs exemplified by chlorpropamide (CP) are known to interact pharmacologically with alcohol (ethanol) to elicit a chlorpropamide-alcohol flushing (CPAF) reaction that is reminiscent of the disulfiram-ethanol reaction (DER). In the present structure-activity study, designed to elucidate the mechanism of inhibition of aldehyde dehydrogenase (AlDH) by CP, we discovered that the N1-methoxy derivative of CP 2a was a potent inhibitor of AlDH in vivo similar in activity to that of the N1-ethyl derivative 2b. Both 2a and 2b can release n-propyl isocyanate, a known inhibitor of AlDH, nonenzymatically. However, (arylsulfonyl)carbamates that are structurally analogous to 2a were also active inhibitors of AlDH, whereas the corresponding (arylsulfonyl)carbamate analogs of 2b were uniformly without activity. We propose a mechanism of bioactivation of 2a and its analogs that involves initial O-demethylation followed by disproportionation and solvolysis of the intermediate formed to release nitroxyl, the putative inhibitor of AlDH.

Structural requirements for the sequestration of metabolically generated acetaldehyde.

Of a series of polyfunctional compounds containing amino, hydroxyl, or mercapto groups in conjunction with the carboxyl group, only the 1,2- or 1,3-disubstituted aminothiols, namely, D-(-)-penicillamine (1), L-cysteine (2), L-cysteinyl-L-valine (3), mercaptoethylglycine (4), and DL-homocysteine (12), showed any propensity to sequester acetaldehyde (AcH) when tested in vitro in a buffered system at pH 7.5. In vivo, however, only D-(-)-penicillamine (1) was effective in lowering ethanol-derived blood AcH in rats that had been treated with disulfiram and ethanol. These results suggest that, in addition to the functionality in the molecule, pharmacokinetic and metabolic factors must also be considered when designing AcH-sequestering agents for use in vivo.

Potential inhibitors of collagen biosynthesis. 5,5-Difluoro-DL-lysine and 5,5-dimethyl-DL-lysine and their activation by lysyl-tRNA ligase.

The synthesis of lysine analogues wherein blocking groups are substituted at position 5, the site of hydroxylation by peptidyl lysine hydroxylase, is described. Thus, 5,5-difluorolysine (1) and 5,5-dimethylysine (2) were synthesized via a four- and six-step sequence, respectively, starting from ketone precursors. The propensity for these lysine analogues to be incorporated into procollagen protein in vivo was assessed by their ability to stimulate the lysine-dependent ATP-PPi exchange reaction in the presence of lysyl-tRNA ligase in vitro. The difluoro analogue 1 stimulated exchange, but at a Km (1.3 X 10(-3) M) 1000 times greater than that for lysine itself. The dimethyl analogue 2 did not stimulate exchange, but at high concentrations was a competitive inhibitor of lysine, with an apparent Ki of 1.6 X 10(-2) M. Thus, electronegative and/or bulky substituents at the 5 position of lysine cannot be tolerated by lysyl-tRNA ligase, and this position must be kept free in lysine analogues specifically designed to block collagen biosynthesis.

Potential latentiation forms of biologically active compounds based on action of leucine aminopeptidase. Dipeptide derivatives of the tricycloaliphatic alpha-amino acid, adamantanine.

Some glycine, leucine and phenylalanine dipeptide derivatives of the transport inhibitory, tricycloaliphatic alpha-amino acid, adamantanine (1), have been synthesized using classical methods of peptide synthesis with the aim of improving the latter's bioavailability. Although test doses of glycyladamantanine and L-leucyladamantanine appeared to be absorbed in vivo as evidenced by its appearance in the uring following intraperitoneal administration, they were not hydrolyzed by a purified preparation of leucine aminopeptidase in vitro. Indeed, they were inhibitors of this enzyme. Adamantanylglycine, adamantanyl-L-leucine, and adamantanyl-L-phenylalanine were also not hydrolyzed by leucine aminopeptidase.

N1-alkyl-substituted derivatives of chlorpropamide as inhibitors of aldehyde dehydrogenase.

On the basis of an earlier observation that the N1-ethyl derivative of the hypoglycemic agent chlorpropamide (CP) inhibited aldehyde dehydrogenase (AlDH) in rats without producing hypoglycemia, we undertook a structure-activity study to assess the effect of altering the alkyl substituents at N1 and N3, as well as substituting O for N at the latter position, and evaluated these analogues for their effect on AlDH in vivo and in vitro. Our results suggest that only those CP analogues that can release alkyl isocyanates nonenzymatically inhibited AlDH. Increasing the steric bulk of the N1-alkyl substituent enhanced isocyanate formation and AlDH inhibition. CP analogues that lacked the NH group at N3 or were otherwise incapable of alkyl isocyanate release were inactive.

Prodrugs of nitroxyl as inhibitors of aldehyde dehydrogenase.

In the preceding paper, analogs of chlorpropamide with an OMe substituent on the sulfonamide nitrogen were shown to inhibit aldehyde dehydrogenase (AlDH), and it was postulated that these compounds were bioactivated by O-demethylation to release nitroxyl (HN = O, nitrosyl hydride), which is an inhibitor of AlDH. Further evidence for the production of nitroxyl from compounds with O-acyl instead of OMe on the sulfonamide nitrogen is now presented. Thus, nitrous oxide (N2O), the end product of nitroxyl dimerization and disproportionation, was found to be generated on alkaline or enzymatic hydrolysis of N,O-diacylated N-hydroxyarylsulfonamides. Since the latter compounds strongly inhibit yeast AlDH in vitro after bioactivation by an esterase intrinsic to this enzyme, nitroxyl generated from these compounds must be the common intermediate that inhibits AlDH.