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.

Altered resting-state functional connectivity of default mode network in brachioradial pruritus.

BACKGROUND: Patients with chronic pruritus (CP) have a low quality of life, thus it is important to gain a better understanding of the underlying processes. Previous functional magnetic resonance imaging studies at rest (rsfMRI) have shown that mainly areas associated with the default mode network (DMN), sensorimotor (SMN), frontoparietal (FPN) and salience networks (SN) are involved in the processing of itch in patients with chronic pruritus (CP), as well as the cortico-striatal circuit, which is involved in the motoric preparation of scratching. rsfMRI studies on functional connectivity (FC) patterns of resting-state networks (RSNs) in patients with inflammatory atopic dermatitis (AD) or with neuropathic brachioradial pruritus (BRP) compared with healthy controls (HC) are lacking. OBJECTIVES: The main goals of this study were to investigate whether functional connectivity within networks and areas associated with itch detection and processing are altered in patients with AD and BRP compared with matched healthy controls by rsfMRI, respectively. METHODS: Patients with AD (n = 28) and with BRP (n = 28) were compared with corresponding matched healthy controls by rsfMRI. Group-specific RSNs were identified by independent component analysis (ICA) and between-group differences in the RSNs were analysed by dual regression technique. Seed-based functional connectivity was analysed in several itch-related brain regions belonging to the DMN, SN and FPN, respectively. RESULTS: ICA and seed-based analyses revealed decreased functional connectivity in BRP compared with HC specially within the DMN including the precuneus and cingulate cortex. For AD patients in comparison with HC, as well as when BRP and AD patients were compared directly, no significant FC differences at rest were seen. CONCLUSIONS: Our findings point towards decreased FC particularly in the DMN at rest in patients with BRP. These results seem to indicate that central connectivity patterns at rest differentially encode itch in BRP and AD.

Prevalence, incidence and presence of comorbidities in patients with prurigo and pruritus in Germany: A population-based claims data analysis.

BACKGROUND: There are currently no published population-based data on prurigo and pruritus epidemiology in Germany. OBJECTIVES: We present the prevalence, incidence and comorbidity frequency of prurigo and pruritus in Germany. METHODS: This was a retrospective healthcare research study based on anonymized routine data from the German health insurance company DAK-Gesundheit. Evaluations were carried out for 2 006 003 adults who were insured as of 31 December 2010. Prurigo and pruritus diagnoses were based on International Classification of Diseases, Tenth Revision, German Modification (ICD-10-GM) codes. RESULTS: Prevalence was determined to be 0.21% (adjusted for sex and age 0.19%) for prurigo and 2.21% (adjusted 2.14%) for pruritus in 2010. The adjusted rates extrapolated to the total German population in 2010 show that 130 685 adults would have received a prurigo diagnosis and 1 461 024 a diagnosis of pruritus. In 2011, incidence of new prurigo and pruritus cases was 0.13% (adjusted 0.12%, extrapolated 77 263 cases) and 1.51% (adjusted 1.46%, extrapolated 978 885), respectively. Adults with prurigo suffered most frequently from hypertension (35.16%), hyperlipidaemia (24.95%) and depression (21.97%); all were reported more frequently in patients with prurigo compared with the general population (P < 0.001). Similarly, adults with pruritus suffered most frequently from hypertension (31.28%), hyperlipidaemia (23.52%) and depression (18.91%) compared with patients without pruritus (P < 0.001). CONCLUSIONS: Our data show that prurigo is a relatively rare but significant disease and that pruritus is frequent and very variable in appearance, and both have a high comorbidity burden.

Pruritus Intensity Scales across Europe: a prospective validation study.

BACKGROUND: Chronic pruritus (CP) is a subjective symptom, and it is necessary to assess its intensity with validated patient-reported outcome tools in order to allow determination of the treatment course. OBJECTIVES: So far, the itch intensity scales were validated in small cohorts and in single languages. Here, we report the validation of the numerical rating scale, the verbal rating scale and the visual analogue scale for the worst and average pruritus intensity in the last 24h in several languages across Europe and across different pruritic dermatoses. METHODS: After professional translation, the intensity scales were digitized for use as a tablet computer application. Validation was performed in clinics for Dermatology in Austria, France, Germany, Italy, Poland, Russia, Spain, Switzerland and Turkey. RESULTS: A total of 547 patients with contact dermatitis, chronic nodular prurigo, psoriasis vulgaris, lichen planus or cutaneous T-cell lymphoma were included. The intensity scales showed a high level of reproducibility and inter-correlations with each other. The correlation with the Dermatology Life Quality Index was weak to strong in nearly all countries and dermatoses with the exception of France and patients with chronic nodular prurigo, for which no statistically significant correlations were found. CONCLUSIONS: The numerical rating scale, the verbal rating scale und the visual analogue scales are valid instruments with good reproducibility and internal consistency in German (Germany, Austria, Switzerland), French, Italian, Polish, Russian, Spanish and Turkish for different pruritic dermatoses. VAS worst was the best reproducible and consistent measuring instrument in all countries.

The burden in chronic prurigo: patients with chronic prurigo suffer more than patients with chronic pruritus on non-lesional skin: A comparative, retrospective, explorative statistical analysis of 4,484 patients in a real-world cohort.

BACKGROUND: Chronic prurigo (CPG) is known as a high burdensome disease characterized by severe pruritus and multiple pruriginous lesions. Interestingly, the disease-specific burden is not well established and there are no data which compare the impact of CPG with chronic pruritus (CP) on non-lesional skin (CP-NL). OBJECTIVES: To address this issue, we analysed datasets from 4484 patients with either CPG or CP-NL. METHODS: Demographic medical data and additional information collected by validated patient reported outcome tools were analysed. The visual analogue scale and numerical rating scale (NRS) were used for assessing the pruritus intensity, the ItchyQoL for patients' quality of life, the Hospital Anxiety and Depression Scale and the Patient Needs Questionnaire' as a part of Patient Benefit Index for Pruritus for measuring the importance of 27 patient needs in terms of treatment goals. The Neuroderm questionnaire was used to assess the history of pruritus characteristics and the impact on sleep. RESULTS: Patients with CPG suffered longer and with a higher intensity from pruritus [NRS worst the last 24 h, CPG 6.0 (4.0;8.0) vs. CP-NL 3.0 (5.0;7.0), P < 0.001]. In them, pruritus occurred more often and the whole day and night which led to more loss in sleeping hours [CPG 3.0 h (2.0;4.0) vs. CP-NL 2.0 h (1.0;4.0), P < 0.001]. Patients with CPG showed higher scores for depression [HADS-D, CPG 6.0 (3.0;10.0) vs. CP-NL 5.0 (2.0;8.0), P < 0.001], more impaired quality of life [ItchyQol; CPG: 72.6 (61.6;83.6) vs. CP-NL 59.4 (48.4;70.4), P < 0.001] and higher weighted needs in the predefined treatment goals. DISCUSSION: Not only the presence of severe pruritus and pruriginous lesions but also sleep disorders and other mental symptoms may contribute to a higher burden in patients with CPG when compared with patients with CP-NL.

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.

[Modern systemic therapy for pruritus]. / Moderne systemische Therapie des Pruritus.

Chronic pruritus (CP) is a highly prevalent, difficult to treat, and burdensome condition. Nowadays, multiple substances are available for the treatment of CP. Systemic therapies play a pivotal role in modern CP therapy, particularly in severe cases and those refractory to general antipruritic measures. Current guidelines recommend the use of a vast array of, mostly off-label, drugs with different mechanisms, including antihistamines, gabapentinoids, antidepressants, immunosuppressive drugs, and µ­opioid receptor antagonists. The choice of the right agent depends on the indication, safety profile of the drug, and patient-specific features, such as comorbidities and comedication. Owing to a deeper understanding of the pathophysiology of CP, novel drugs have been developed and have already shown anti-pruritic efficacy in clinical studies and case reports. Of note, monoclonal antibodies, neurokinin­1 receptor antagonists, Janus kinase inhibitors, and opioid receptor modulators are on the frontline of innovative CP treatment. Other promising targets include structures of the peripheral and central nervous system, e.g., histamine 4 receptors, which are involved in itch signaling. This review provides an overview of currently available systemic therapies for CP and their indications and discusses novel innovative agents and promising new targets in CP.

Chronic nodular prurigo: clinical profile and burden. A European cross-sectional study.

BACKGROUND: Chronic nodular prurigo (CNPG) is a condition characterized by chronic itch, a prolonged scratching behaviour and the presence of pruriginous nodules. A comprehensive understanding of this condition, especially regarding its clinical characteristics and impact on quality of life is still lacking. OBJECTIVES: Aim of this pan-European multicentre cross-sectional study was to establish the clinical profile of CNPG, including its associated burden. METHODS: Fifteen centres from 12 European countries recruited CNPG patients presenting at the centre or using the centres' own databases. Patients were asked to complete a questionnaire in paper or electronic format. Demography, current co-morbidities, underlying disease, itch intensity, additional sensory symptoms, quality of life, highest burden and emotional experience of itch were assessed. RESULTS: A total of 509 patients (210 male, median age: 64 years [52; 72]) were enrolled. Of these, 406 reported itch and CNPG lesions in the previous 7 days and qualified to complete the whole questionnaire. We recorded moderate to severe worst itch intensity scores in the previous 24 h. Scores were higher in patients with lower educational levels and those coming from Eastern or Southern Europe. Most patients experience itch often or always (71%) and report that their everyday life is negatively affected (53%). Itch intensity was considered to be the most burdensome aspect of the disease by 49% of the patients, followed by the visibility of skin lesions (21%) and bleeding of lesions (21%). The majority of patients was unaware of an underlying condition contributing to CNPG (64%), while psychiatric diseases were the conditions most often mentioned in association with CNPG (19%). CONCLUSIONS: This multicentre cross-sectional study shows that itch is the dominant symptom in CNPG and reveals that the profile of the disease is similar throughout Europe.

Generalized chronic itch induced by small-fibre neuropathy: clinical profile and proposed diagnostic criteria.

BACKGROUND: Small-fibre neuropathy (SFN) is a known cause for pain, however, it may be also associated with chronic itch. The clinical profile of chronic itch due to SFN is poorly defined and accordingly under-diagnosed in clinical care. OBJECTIVES: To establish the clinical profile of patients with SFN and to propose diagnostic criteria for this patient population. METHODS: Clinical data from patients diagnosed with SFN [chronic generalized itch and reduced intraepidermal nerve fibre density (IENFD)] were analysed retrospectively. RESULTS: A total of 142 patients (60 females, median age: 62.5 years) were included. Patients reported daily, moderate to severe itch intensity scores occurring mostly in attacks (62.5%). Only 11 patients experienced exclusively itch, while the remaining patients (92%) reported pruralgia (itch along with painful sensations). Burning (50%), a sensation like needle pricks (46%) and tingling (45%) were the sensory symptoms reported by most patients. Cold or ice application led to an alleviation of the symptoms. The IENFD did not correlate with itch intensity; however, patients with a severely reduced IENFD (<30% of the normative cut-off value) reported more frequently sharp, spiky and drilling sensations compared to the remaining patients. The quality of life was moderately impaired and correlated with itch intensity, whereas anxiety and depression scores were low. CONCLUSIONS: Onset of pruralgia on normal appearing skin, occurrence in attacks and symptomatic alleviation with cold/ice application should alert physicians for a possible neuropathic SFN-related origin of itch. A reduced IENFD can confirm the diagnosis of SFN.

Medical needs and major complaints related to pruritus in Germany: a 4-year retrospective analysis using Google AdWords Keyword Planner.

BACKGROUND: It is difficult to estimate the prevalence of acute and chronic pruritus in the population at large due to a lack of affected persons seeking medical assistance. OBJECTIVE: To discover the incidence of pruritus in Germany and determine what the most common related complaints are via an analysis of Google's search volume. METHODS: From June 2013 to April 2017, the Google AdWords Keyword Planner was utilized to select and critically assess relevant keywords for 'pruritus'. RESULTS: Among a total of 13 691 470 German language Google searches on the topic of pruritus, it was found that the most searched for terms included atopic eczema (24.3%) and the layman's term for psoriasis ('Schuppenflechte'; 17.8%), as well as just psoriasis (13.4%). 'Juckreiz', the German word for pruritus, was determined to be only the sixth most searched for term (2.9%). Anal pruritus and pruritus of the entire body comprised the most searched for localizations. The various factors that impact pruritus, particularly skin conditions and disorders, were established to be among the most searched for terms (72.6%). A decreased monthly search volume was associated with the changing seasons; the summertime had the lowest number of searches for pruritus. CONCLUSION: The Google search engine analysis provided insight for this study into the unexpectedly large number of unmet medical needs of those suffering from pruritus within Germany, especially that of specific localizations on the body.

Position Statement: Linear prurigo is a subtype of chronic prurigo.

BACKGROUND: Chronic prurigo (CPG) is a distinct disease characterized by chronic pruritus, history and/or signs of prolonged scratching and multiple pruriginous lesions. It may present with various clinical manifestations, including papules, nodules, plaques or umbilicated lesions. Some patients with chronic pruritus show pruriginous linear and scaring scratch lesions (LSSL) and it is unclear whether these lesions belong to the spectrum of CPG. OBJECTIVE: To achieve a consensus on the classification of pruriginous LSSL and establish criteria to differentiate them from similar appearing conditions of different nature. METHODS: Members of the Task Force Pruritus (TFP) of the European Academy of Dermatology and Venereology participated in the consensus conference, discussing representative clinical cases. Using the Delphi method, consensus was reached when ≥75% of members agreed on a statement. RESULTS: Twenty-one members of the TFP with voting rights participated in the meeting. It was consented that LSSL occurs due to chronic pruritus and prolonged scratching, and share common pathophysiological mechanisms with CPG. LSSL were thus considered as belonging to the spectrum of CPG and the term 'linear prurigo' was chosen to describe this manifestation. CONCLUSION: Considering linear prurigo as belonging to the spectrum of CPG has important clinical implications, since both the diagnostic and therapeutic approach of these patients should be performed as recommended for CPG. Importantly, linear prurigo should be differentiated from self-inflicted skin lesions as factitious disorders or skin picking syndromes. In the latter, artificial manipulation rather than pruritus itself leads to the development of cutaneous lesions, which can show clinical similarities to linear prurigo.

Cadmium tolerance of Typha domingensis Pers. (Typhaceae) as related to growth and leaf morphophysiology / A tolerância ao cádmio por Typha domingensis Pers. (Typhaceae) correlacionada com o crescimento e a morfofisiologia foliar

Abstract Typha domingensis (cattail) is a native macrophyte known by its capacity to tolerate several heavy metals effects and the potential use for phytoremediation. However, in despite that cadmium (Cd) is one of the most toxic pollutants; its effects in T. domingensis biology remain uninvestigated. Thus, the objective of this study was to study the tolerance of T. domingensis to cadmium contamination by evaluating its growth, Cd uptake, leaf anatomy and gas exchange. The experiment was designed using three cadmium concentrations (0, 10 and 50 µM) and ten replicates for 90 days. The cadmium uptake, growth, gas exchange, chlorophyll content and leaf anatomy were evaluated. Data was submitted to ANOVA and Scott-Knott test for P<0.05. Typha domingensis accumulates Cd proportionally to its concentration on the solution and the content of this metal was higher in roots as compared to shoots. Plants showed no significant modifications on growth parameters such as the biomass production, number of leaves, number of clones and the biomass allocation to organs. The photosynthesis, transpiration and chlorophyll content were not modified by Cd. Most anatomical traits evaluated were not modified by the metal but the stomatal density and the proportion of vascular tissues were reduced under 50 µM of Cd. In despite, the leaf anatomy showed no toxicity evidences for any Cd level. The absence of growth reduction and the stability of anatomical and physiological traits give insight about the Cd tolerance of this species. Therefore, T. domingensis is able to overcome Cd toxicity and shows potential for phytoremediation.

Resumo A espécie Typha domingensis (taboa) é uma macrófita nativa conhecida por sua tolerância a vários metais pesados e potencial uso na fitorremediação. Contudo, apesar de que o Cd é um dos poluentes mais tóxicos; Seus efeitos em T. domingensis ainda não foram investigados. Assim, o objetivo desse estudo foi avaliar a tolerância de T. domingensis ao cádmio, avaliando o crescimento, absorção de Cd, anatomia foliar e trocas gasosas. O experimento foi conduzido utilizando três concentrações de Cd (0, 10 e 50 µM) e dez repetições por 90 dias.. O crescimento, trocas gasosas e o teor de clorofila e anatomia foliar foram avaliados. Os dados foram submetidos à ANOVA e ao teste de Scott-Knott para P<0,05. A absorção de cádmio, crescimento, trocas gasosas, teor de clorofila e anatomia foliar foram analisados. As plantas de T. domingensis podem acumular Cd proporcionalmente à sua concentração na solução e o teor deste metal foi maior nas raízes em comparação com a parte aérea. As plantas não apresentam modificações significativas nos parâmetros de crescimento como produção de biomassa, número de folhas, número de clones produzidos e alocação de biomassa nos órgãos. A fotossíntese, transpiração e conteúdo de clorofila não foram afetados de forma significativa pelo Cd. A maioria das características anatômicas avaliadas não apresentou diferenças, mas houve redução na densidade estomática e na proporção de tecidos vasculares na concentração de 50 µM de Cd. A anatomia foliar não mostrou evidências de toxicidade em nenhum dos níveis de Cd. A ausência de redução de crescimento e estabilidade das características anatômicas e fisiológicas caracteriza alta tolerância da espécie ao Cd. Portanto, T. domingensis é capaz de superar a toxicidade do Cd e demostra potencial para fitorremediação.

Cadmium tolerance of Typha domingensis Pers. (Typhaceae) as related to growth and leaf morphophysiology.

Typha domingensis (cattail) is a native macrophyte known by its capacity to tolerate several heavy metals effects and the potential use for phytoremediation. However, in despite that cadmium (Cd) is one of the most toxic pollutants; its effects in T. domingensis biology remain uninvestigated. Thus, the objective of this study was to study the tolerance of T. domingensis to cadmium contamination by evaluating its growth, Cd uptake, leaf anatomy and gas exchange. The experiment was designed using three cadmium concentrations (0, 10 and 50 µM) and ten replicates for 90 days. The cadmium uptake, growth, gas exchange, chlorophyll content and leaf anatomy were evaluated. Data was submitted to ANOVA and Scott-Knott test for P<0.05. Typha domingensis accumulates Cd proportionally to its concentration on the solution and the content of this metal was higher in roots as compared to shoots. Plants showed no significant modifications on growth parameters such as the biomass production, number of leaves, number of clones and the biomass allocation to organs. The photosynthesis, transpiration and chlorophyll content were not modified by Cd. Most anatomical traits evaluated were not modified by the metal but the stomatal density and the proportion of vascular tissues were reduced under 50 µM of Cd. In despite, the leaf anatomy showed no toxicity evidences for any Cd level. The absence of growth reduction and the stability of anatomical and physiological traits give insight about the Cd tolerance of this species. Therefore, T. domingensis is able to overcome Cd toxicity and shows potential for phytoremediation.

[New findings regarding the neurobiology of pruritus]. / Aktuelles zur Neurobiologie von Pruritus.

Chronic pruritus may arise from different conditions, including dermatological, systemic, neurologic, psychiatric, and psychosomatic diseases, leading to a substantial decrease in the quality of life of affected patients. The neurobiological mechanisms involved in chronic pruritus are not yet fully understood. However, in recent years important achievements have been made in this regard. This article aims to provide an overview of the current understanding of these mechanisms. The complex network of neurons, keratinocytes, inflammatory cells, cytokines, and neurotrophic factors which play a role in the development and maintenance of chronic pruritus are highlighted, as well as the pruritogens involved in pruritic diseases in humans. Additionally, the importance of neuropathy and scratch-induced changes for the pathophysiology of chronic pruritus are discussed. The new findings on the neurobiological mechanisms underlying chronic pruritus have already led to the development of novel therapies, e. g., monoclonal antibodies against specific interleukins, which are important for pruritus transmission. A deeper understanding of the neurobiological mechanisms is necessary in order to develop specifically targeted therapeutic options and thus provide better care for affected patients.