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.

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.

Pathophysiology and management of sensitive skin: position paper from the special interest group on sensitive skin of the International Forum for the Study of Itch (IFSI).

The special interest group on sensitive skin of the International Forum for the Study of Itch previously defined sensitive skin as a syndrome defined by the occurrence of unpleasant sensations (stinging, burning, pain, pruritus and tingling sensations) in response to stimuli that normally should not provoke such sensations. This additional paper focuses on the pathophysiology and the management of sensitive skin. Sensitive skin is not an immunological disorder but is related to alterations of the skin nervous system. Skin barrier abnormalities are frequently associated, but there is no cause and direct relationship. Further studies are needed to better understand the pathophysiology of sensitive skin - as well as the inducing factors. Avoidance of possible triggering factors and the use of well-tolerated cosmetics, especially those containing inhibitors of unpleasant sensations, might be suggested for patients with sensitive skin. The role of psychosocial factors, such as stress or negative expectations, might be relevant for subgroups of patients. To date, there is no clinical trial supporting the use of topical or systemic drugs in sensitive skin. The published data are not sufficient to reach a consensus on sensitive skin management. In general, patients with sensitive skin require a personalized approach, taking into account various biomedical, neural and psychosocial factors affecting sensitive skin.

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.

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.

European EADV network on assessment of severity and burden of Pruritus (PruNet): first meeting on outcome tools.

BACKGROUND: Chronic pruritus is a frequently occurring symptom of various dermatoses that causes a high burden and impaired quality of life. An effective anti pruritic therapy is important for the patient, but its effectiveness is difficult to evaluate. Diverse methods and interpretations of pruritic metrics are utilized in clinical trials and the daily clinical practice in different countries, resulting in difficulties comparing collected data. METHODS: We founded a European Network on Assessment of Severity and Burden of Pruritus (PruNet) that is supported by the EADV. PruNet consists of 28 experts from 15 EU countries (21 dermatologists, 5 medical informaticists, 2 psychologists) and aims to unify the assessment of itch in routine dermatological care. Following a preliminary survey, a consensus conference was held in order to agree upon the prioritization of patient-reported outcome tools. RESULTS: Through utilizing the Delphi method, it was agreed that tools for measuring itch intensity (ex. the visual analogue scale) and quality of life (ex. ItchyQoL) are of primary importance and should urgently be foremost validated. CONCLUSION: The validation and harmonization of standards are needed for the improvement of quality care for patients suffering from pruritic dermatoses. This summer, the first validation studies in several EADV member countries already began.

Therapeutic and experimental therapeutic studies on acupuncture and itch: review of the literature.

Itch accompanies most inflammatory skin diseases but may occur as a solitary sensation in otherwise normal skin. Chronic itch often requires combined treatments but some cases remain therapy resistant. Complementary medicine is becoming increasingly popular among patients. Acupuncture is the oldest and most well-studied alternative option with evidence-based effect on pain. This article summarizes the rational for the use of acupuncture in treatment of itch and reviews therapeutic and experimental therapeutic studies on acupuncture and itch.

Cutaneous innervation before and after one treatment period of acupuncture.

BACKGROUND: The effect of acupuncture on nociceptive pain is well documented, but effects on nociceptive itch have been contradictory. OBJECTIVES: To evaluate possible effects of acupuncture on the occurrence, distribution and function of sensory nerve fibres in human skin. METHODS: Ten subjects were treated by inserting 10 acupuncture needles subcutaneously at the upper lateral aspect of one buttock. The subjects were recruited from an acupuncture clinic and were undergoing specific acupuncture treatment for their disorders. The needles were stimulated (rotated to and fro) twice during the twice-weekly 25-min sessions over 5 weeks. Skin biopsies, diameter 3 mm, were taken before and 3-6 days after local acupuncture. Antibodies to the pan-neuronal marker protein gene product 9.5 (PGP 9.5), calcitonin gene-related peptide (CGRP), vanilloid receptor 1 (VR1) and mu- and delta-opioid receptors were employed to study sensory unmyelinated nerve fibres that transmit nociceptive pain and itch. A histamine prick test using planimetry was used to record experimental itch after acupuncture on the treated area and on the corresponding control skin, and a visual analogue scale was used to evaluate itch. RESULTS: The mean +/- SEM number of CGRP-immunoreactive nerve fibres per biopsy section was reduced from 36.0 +/- 3.3 to 21.3 +/- 4.0 (P = 0.05) after the treatment. PGP 9.5-immunoreactive nerve fibres were found both in the epidermis and in the subpapillary dermis. The mean +/- SEM total number of PGP 9.5-immunoreactive nerve fibres decreased from 249.8 +/- 16.7 to 211.8 +/- 12.0 (P = 0.03). The PGP 9.5-immunoreactive nerve fibres occurring in the dermis appeared more fragmented after the acupuncture compared with pretreatment. VR1 immunoreactivity was found both in the free nerve fibres and in kite-like formations, possibly mast cells, throughout the dermis, sometimes occurring around hair follicles. The mean +/- SEM number of VR1-immunoreactive elements was not significantly influenced by acupuncture, at 33.5 +/- 4.6 vs. 43.0 +/- 4.4 (P = 0.09). No immunoreactivity was found in the skin against mu- and delta-opioid receptors with the antibodies used in this study. Neither histamine-induced itch nor cutaneous responses were influenced by acupuncture. CONCLUSIONS: The present data indicate an effect of acupuncture on neuropathic itch but not histamine-mediated itch. Our findings support the opinion that the pain-relieving effects of acupuncture partly depend on its effect on the peripheral innervation.

Circulating eosinophils in asthma, allergic rhinitis, and atopic dermatitis lack morphological signs of degranulation.

BACKGROUND: In allergic diseases, eosinophils in affected tissues release granule proteins with cytotoxic, immunoregulatory, and remodelling-promoting properties. From recent observations, it may be assumed that eosinophils degranulate already in circulating blood. If degranulation occurs in the circulation, this could contribute to widespread systemic effects and provide an important marker of disease. OBJECTIVE: To determine the degranulation status of circulating eosinophils in common allergic diseases. METHODS: Using a novel approach of whole blood fixation and leucocyte preparation, the granule morphology of blood eosinophils from healthy subjects, non-symptomatic patients, symptomatic patients with asthma, asthma and Churg-Strauss syndrome, allergic rhinitis, and atopic dermatitis was evaluated by transmission electron microscopy (TEM) and eosinophil peroxidase (TEM) histochemistry. Plasma and serum levels of eosinophil cationic protein were measured by fluoroenzymeimmunoassay. Selected tissue biopsies were examined by TEM. RESULTS: Regardless of symptoms, circulating eosinophils from allergic patients showed the same granule morphology as cells from healthy subjects. The majority of eosinophil-specific granules had preserved intact electron-density (96%; range: 89-98%), while the remaining granules typically exhibited marginal coarsening or mild lucency of the matrix structure. Abnormalities of the crystalline granule core were rarely detected. Furthermore, granule matrix alterations were not associated with any re-localization of intracellular EPO or increase in plasma eosinophil cationic protein. By contrast, eosinophils in diseased tissues exhibited cytolysis (granule release through membrane rupture) and piecemeal degranulation (loss of granule matrix and core structures). CONCLUSION: In symptomatic eosinophilic diseases, circulating blood eosinophils retain their granule contents until they have reached their target organ.

Familial brachioradial pruritus.

BACKGROUND: The cause of brachioradial pruritus (a localized itching on the arms or shoulders) is controversial. A hereditary form of this condition has not been reported. OBJECTIVES: To describe the occurrence of brachioradial pruritus in several members of one family. PATIENTS AND METHODS: The pedigree of the three generations and the history of brachioradial pruritus was outlined. Four sisters were investigated by radiography of the cervical spine. RESULTS: Five sisters and one brother, together with five of their daughters suffered from recurring brachioradial pruritus. The sisters had had occupations requiring heavy lifting, spent much time outdoors and exposed themselves extensively to the sun. Several complained of neck pain and cervical radiographs of four of them indicated arthrosis. CONCLUSIONS: Spinal disease alone cannot explain the symptoms of brachioradial pruritus, which in our patients was characterized by symptom-free periods broken off by relapse late in the summer each year. The pedigree suggests this hereditary form of brachioradial pruritus to be dominant and possibly X-linked.

Cutaneous field stimulation of sensory nerve fibers reduces itch without affecting contact dermatitis.

BACKGROUND: A new technique, cutaneous field stimulation (CFS), which activates electrically unmyelinated C-fibers, is used to treat localized itch. Its action is similar to that of capsaicin, the pungent agent in hot peppers, which enhances delayed allergic reactions. The aim of the study was to investigate how experimental contact dermatitis responds to CFS. METHODS: Twelve patients with contact dermatitis in response to nickel were treated by CFS for 1 h each for four consecutive days. A flexible plate containing electrodes was applied to a test area on the upper arm and was stimulated by a constant current (0.8 mA). On the fifth day, patients were provoked by epicutaneous application of nickel sulfate (allergic contact dermatitis) and benzalkonium chloride (irritant contact dermatitis), and by intradermal tuberculin (delayed immunologic reaction). Twelve other patients with IgE-mediated allergy were treated by CFS on the lower arm for 1 h and were then pricked with histamine and allergen extracts (wheal volume was measured) and were tested using benzoic acid (nonimmunologic contact urticaria; closed test). Ten of these patients were also treated by CFS for four days, and experiments were performed on the fifth day. RESULTS: Test reactions to nickel, benzalkonium, and tuberculin were found to be unaffected by CFS treatment. Although allergic prick test reactions were enhanced (by 28%) after a single CFS treatment, the associated itch was significantly reduced both after single and repeated CFS treatments (by 65% and 38%, respectively). CONCLUSIONS: Repeated use of CFS to reduce itch has no adverse effects on contact dermatitis.

Cutaneous field stimulation in the treatment of severe itch.

OBJECTIVE: To evaluate the efficacy of cutaneous field stimulation of C fibers for the treatment of itchy skin and its effect on peripheral nerve fibers as shown in skin biopsy specimens. DESIGN: We conducted an open-label uncontrolled study of 19 patients with itching. Each patient applied a flexible plate containing electrodes to the itchy area for 20 minutes at a time once daily for 5 weeks to stimulate nerve fibers with a constant current (0.8 mA). Skin biopsy specimens were collected before treatment and at the end of treatment and were immunostained for calcitonin gene-related peptide and protein gene product 9.5. SETTING: University hospital in Lund, Sweden. PATIENTS: Sixteen patients with nostalgia paresthetica or brachioradial pruritus and 3 with generalized itch. INTERVENTIONS: Cutaneous field stimulation and punch biopsies of the itchy skin. MAIN OUTCOME MEASURES: Visual analog scale for assessment of itching and counting the immunoreactive nerve fibers in 3-mm biopsy specimens. RESULTS: Patients with localized itching experienced a reduction in mean values on the visual analog scale (from 78% before treatment to 42% by the end of the fifth week). The number of protein gene product 9.5- immunoreactive nerve fibers in the epidermis was reduced by 40% by the end of treatment compared with baseline values. CONCLUSIONS: Cutaneous field stimulation is an effective alternative for the treatment of localized itching. The reduction in itching is accompanied by degeneration of the epidermal nerve fibers, as evidenced by the loss of protein gene product 9.5 immunoreactivity.

Nitric oxide participates in prick test and irritant patch test reactions in human skin.

The aim of this study was to investigate the involvement of nitric oxide (NO) in the modulation of immediate and delayed immunological and nonimmunological reactions in human skin. The NO donor nitroglycerin, 0.1 microgram, and the NO synthase inhibitor, NG-nitro-L-arginine (L-NAME), 0.1 microgram, were injected intracutaneously prior to provocation tests. The following provocation tests were carried out: 8 patients with pollen allergy to birch were provoked by a prick test with the allergen and the volume of the weals was measured; 20 patients with allergy to nickel were provoked with nickel sulfate epicutaneously; and 26 healthy volunteers were provoked with tuberculin (causing delayed immunologic reaction), benzalkonium chloride (irritant contact dermatitis), UV radiation or benzoic acid (nonimmunological contact urticaria). The test reactions were evaluated by planimetry. L-NAME inhibited irritant contact dermatitis (P = 0.020) but augmented immediate immunological reactions (prick test) (P = 0.016). The other test reactions remained unchanged. Nitroglycerin did not affect any of the reactions significantly. The results suggest that NO is involved in immediate immunological reactions and irritant contact dermatitis.

Dual effects of CGRP-antagonist on allergic contact dermatitis in human skin.

There is increasing evidence of an interaction between the nervous and the immune systems. The aim of this study was to investigate the rôle of calcitonin gene-related peptide (CGRP) in the modulation of the elicitation of immediate and delayed, immunological and non-immunological reactions in human skin. CGRP (13 pmol and 39 pmol), and the CGRP-antagonist, CGRP/8-37/, (50 pmol and 500 pmol) were injected intracutaneously prior to provocation tests. Patients with allergy to nickel were provoked with nickel sulfate epicutaneously, and the reactions were evaluated by a clinical scoring system (guidelines of the International Contact Dermatitis Research Group). Patients with allergy to birch pollen were provoked by a prick test with the allergen, and the volume of the weals was measured. The patients were also provoked with tuberculin (delayed immunologic reaction), benzalkonium chloride (irritant contact dermatitis), UV-light and benzoic acid (non-immunologic contact urticaria). The test reactions were estimated by planimetry. CGRP/8-37/ exerted dual effects on allergic contact dermatitis, causing potentiation at a dose of 500 pmol (p= 0.004) and inhibition at a dose of 50 pmol (p=0.012). Other reactions were not significantly affected by the pretreatments. The results suggest that CGRP participates in delayed inflammatory reactions, but is not involved in immediate immunologic reactions.