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.

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.

The genetic basis for most patients with pustular skin disease remains elusive.

BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.

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.

[Charcot foot masked by erysipelas and peripheral arterial disease]. / Charcot-Fuß coupiert durch Erysipel und periphere arterielle Verschlusskrankheit.

Charcot foot is also known as Charcot disease or Charcot arthropathy. The associated aseptic destruction of the bones and joints of the foot results due to peripheral neuropathy accompanied by impaired pain perception, impaired vasomotricity with increased vasodilation, and an unequal weight distribution. Because it is frequently diagnosed late and, thus, incorrectly treated, serious complications often result. An 86-year-old man in poor health was diagnosed with erysipelas of the right foot. The foot was glossy and edematously swollen, showing necrosis of the distal phalanx of the third toe. The patient experienced pain after a walking distance of approximately 20 m. In addition to erysipelas, confirmed neuropathic arthropathy and radiological indicators for Charcot foot established peripheral artery disease (PAD) as a third diagnosis. Despite multiple systemic antibiotic therapies, there was a progressive disease pattern marked by increasing inflammation parameters with an increasing decline of the patient's overall health. The patient suffered severe deterioration in spite of vascular surgical measures, ultimately leading to his death. In the present case, the indicators and respective confirmation of the three overlapping diagnoses erysipelas, Charcot foot and PAD are elaborated.

[Chronic pruritus : Care in daily practice]. / Chronischer Pruritus : Versorgung in der Praxis.

Chronic pruritus is a highly prevalent, multifactorial symptom requiring extensive diagnostics, treatment and consideration of accompanying symptoms (reduced quality of life, sleep disorders, psychic factors). Patient care is thus complex and requires consideration of individual treatment goals. Patients indicate their wish for a symptom-free life an explanation of the causes and a trustful physician-patient relationship. The targeted use of questionnaires is thus advisable in order to structurally survey the history, pruritus intensity, quality of life and treatment progression. Nevertheless, there are many administrative and economical hurdles in the health care system to overcome in order to provide patients with chronic pruritus the best possible care, also per the recommended guidelines. The development of specialized centers and training courses for medical practitioners is thus urgently needed.

[Nihil certum: historical development of the term prurigo]. / Nihil certum: Historische Entwicklung des Begriffs Prurigo.

The term prurigo is still used to designate primary dermatoses and secondary reaction patterns. A clear definition of the term is not available nor a clear clinical classification of diseases categorized under the term. Furthermore, there is no certainty about the entity it was primarily used to refer to, and whether it should always be considered in relation to pruritus. The concept appears already in very early medical treatises. From the very beginning, it was used in dermatology in a non-uniform way, and was alternately accorded and denied the status of an independent disease entity. Moreover, prurigo was subdivided into many different forms, but their descriptions are partly very similar, so that, for instance, it is quite difficult today to draw any conclusions about the clinical entities the frequently used terms prurigo mitis and prurigo formicans referred to. In contrast, the term prurigo nodularis is still commonly used. This article traces exemplarily the use of the term prurigo in the standard medical textbooks up to the definition of prurigo nodularis.

[Medical emergencies in daily dermatological practice]. / Allgemeine Notfälle in der täglichen dermatologischen Praxis.

Many patients and their companions who present daily in dermatological clinics and private practices may have numerous non-dermatological comorbidities, which can cause medical emergencies. Additionally several dermatologic diagnostic or therapeutic procedures which are commonly performed can cause life-threatening complications. Therefore dermatologists can be confronted with acute medical emergencies at any time. Mostly these are internal medicine emergencies. Therefore dermatologists must have the basic emergency medical knowledge; emergency situations should be practiced regularly and this training documented for quality control measures. Every practice must be able to deliver life-saving care until trained emergency medical personnel arrive. The general emergency procedures are presented below and the practical approach is illustrated at different cardinal symptoms such as impaired consciousness, respiratory disorders or cardiocirculatory disorders.

Analysis of quality of life data from a randomized, placebo-controlled heart-failure trial.

In a randomized, double-blind, placebo-controlled, 3-months trial involving 111 congestive heart failure patients, one non-validated and three validated Quality of Life (QL) instruments were administered. Two randomized treatment groups were evaluated, one with 62 patients who continued on standard therapy and the other with 49 patients whose standard therapy was replaced by placebo. The data from Patient's Self-rating Scale (a non-validated instrument) and Spitzer's QL index showed a significant difference between the two treatment groups for an overall effect. There were no significant differences between two treatment groups for Sickness Impact Profile (SIP) and Quality of Well-Being (QWB). For analyzing the multiple components in a QL instrument, the global statistics as suggested by O'Brien were applied to compare the two treatment groups. Univariate statistics complemented the global methods. The general use of global statistics in analyzing QL data is recommended.

[Topical interferon-beta: an additional treatment for ulcerated mycosis fungoides]. / Topisches Interferon-beta. Ein Vorschlag zur additiven Therapie der ulzerierten Mycosis fungoides : Ein Vorschlag zur additiven Therapie der ulzerierten Mycosis fungoides.

The combination of systemic interferon-alpha and systemic photochemotherapy is one of the most effective and most frequently administered treatment regimens for mycosis fungoides. Two patients with mycosis fungoides stage IIb with ulcerated tumors were treated with this regimen. While the plaques responded favorably to the combination therapy, the ulcerated tumors were quite resistant despite treatment for several weeks. When topical interferon-beta in a gel base was added to the regimen, a rapid resolution of the tumors was noticed. This observation suggests topical interferon-beta may be an effective adjuvant strategy to be combined with systemic therapy.

Topical pimecrolimus and tacrolimus transiently induce neuropeptide release and mast cell degranulation in murine skin.

BACKGROUND: The topical calcineurin inhibitors pimecrolimus and tacrolimus have been demonstrated to be an effective new anti-inflammatory therapy. The only clinically relevant side-effect reported is transient application site burning and stinging itch at the beginning of topical therapy. OBJECTIVES: In order to understand the underlying mechanism of this effect, we examined whether or not the compounds are able to stimulate neuropeptide release in normal murine skin as well as in a mouse model of experimentally induced irritant contact dermatitis. METHODS: Balb/c mice were treated with 1% pimecrolimus cream or 0.1% tacrolimus ointment. Untreated and corresponding vehicle-treated mice served as controls. Skin specimens were investigated by light, immunofluorescence and electron microscopy as well as enzyme-linked immunosorbent assay and polymerase chain reaction. RESULTS: Topical application of pimecrolimus and tacrolimus was followed by an initial release of substance P and calcitonin gene-related peptide from primary afferent nerve fibres in murine skin during the early inflammatory response. The release of the neuropeptides and their binding to mast cells (MCs) led to MC degranulation. Mediators of MCs such as histamine and tryptase may induce pruritus and burning by binding to the corresponding receptors (histamine receptor 1, proteinase-activated receptor 2) on sensory nerve fibres, which explains the initial side-effects during therapy with calcineurin inhibitors. CONCLUSIONS: It may be speculated that calcineurin inhibitors directly stimulate intracellular signalling pathways or bind to ion channels such as transient receptor potential vanilloid 1 or receptors involved in nociception.

[Anaphylactoid reaction in occult systemic mastocytosis. A rare dermatologic emergency ]. / Anaphylaktoide Reaktionen bei okkulter systemischer Mastozytose Ein seltener dermatologischer Notfall.

With the occurrence of unclear consciousness conditions primarily internal or neurological causes are considered. Of a systemic mastocytosis one thinks only rarely, which can accompany without or with slight clinically visible skin changes. In the following we report on a patient who has repeated unclear shock conditions and required resuscitation several times without a recognizable cause, with whom a systemic mastocytosis could be proven. Clinically very discrete lesions of mastocytosis were recognizable from the skin. Only an increased tryptase level referred to being present an occult systemic mastocytosis. The diagnostics, potential triggers and therapy of this disease are to be discussed on the basis the available case.

UVA rush hardening for the treatment of solar urticaria.

Induction of tolerance by subsequent UV exposures is the most effective therapy for solar urticaria; however, it is time-consuming and takes a long time until protection is achieved. Three patients with solar urticaria were exposed to multiple UVA irradiations at 1-hour intervals per day. With this rush hardening regimen, protection was achieved within 3 days.

[Incidence of fungal involvement in nail psoriasis]. / Häufigkeit des Pilzbefalles bei Nagelpsoriasis.

BACKGROUND AND OBJECTIVE: Because it is clinically so similar, onychomycosis is one of the most important differential diagnostic considerations in psoriatic nail changes. We determined the frequency of fungal involvement in nails of psoriatic patients. PATIENTS/METHODS: Fungal colonization of the nails of psoriatic patients with and without clinically obvious nail changes was investigated in a collective of 250 patients compared to a group of 102 non-psoriatic persons. RESULTS: There was no significant difference in the frequency of nail colonization with dermatophytes and moulds between healthy persons and psoriatics. Yeasts were more commonly found in psoriatic nails. CONCLUSIONS: Nail changes in psoriatic patients are mostly caused by psoriasis. However secondary colonization by yeasts is more common in psoriatic nails than in the general population. It remains to be clarified why dermatophytes are not more common in psoriatic nails.

Application of new two-sample tests to data from a randomized placebo-controlled heart-failure trial.

In a randomized placebo-controlled double-blind trial of 230 congestive heart failure patients, four treatments were evaluated for efficacy, with exercise tolerance time (ETT) as the primary outcome. Various two-sample tests were applied to the analysis of ETT data. It is shown in this paper that the conventional two-sample tests (t and rank-sum) are insensitive to situations where the effect of the experimental therapy is not consistent across a patient population. Tests recommended by O'Brien are more appropriate for these data. It is also shown that the application of the O'Brien tests led to the identification of sub-groups where the observed effect of the experimental therapy was most pronounced.