[Update on the treatment of chronic prurigo]. / Update zur Therapie der chronischen Prurigo.

Chronic prurigo is an inflammatory dermatosis defined by the presence of chronic pruritus and single to multiple symmetrically distributed pruriginous lesions such as nodules, papules, and plaques. Various dermatological, systemic, neurological, and/or psychiatric diseases are associated with chronic prurigo. The care of these patients is very complex due to the multifactorial character and also because of the sometimes very pronounced consequences such as an impairment of quality of life with sleep disorders. Furthermore, there are no approved therapies. The current guideline-based treatment recommendations include topical application of steroids, capsaicin, calcineurin inhibitors, phototherapy, and systemic use of gabapentinoids, µ­opioid receptor antagonists, immunosuppressants, or dupilumab. Results from randomized controlled trials and case series on new therapies including biologics (e.g., nemolizumab) and Janus kinase inhibitors are promising. This article provides an overview of currently available treatment options and discusses the latest data on the efficacy of future therapies.

Biological and psychosocial factors associated with the persistence of pruritus symptoms: protocol for a prospective, exploratory observational study in Germany (individual project of the Interdisciplinary SOMACROSS Research Unit [RU 5211]).

INTRODUCTION: Chronic pruritus (CP) is a symptom of dermatologic, neurologic, systemic and psychosomatic diseases. CP has a prevalence of ~20% in the general population and is therefore a significant burden on society, but the transition from acute pruritus to CP is not well understood. It probably involves interactions between biological and psychosocial factors and pruritus-specific risk factors as well as mechanisms shared with other persistent somatic symptoms addressed in other projects of the SOMACROSS Research Unit (RU). Here we aim to identify psychosocial and biological factors and their interactions which might be associated with the persistence of CP with and without immunologic/inflammatory origin, that is, atopic dermatitis and pruritus on non-inflamed skin. We expect that psychosocial factors relevant to the persistence of symptoms such as fatigue and pain may also show associations to CP. METHODS AND ANALYSIS: In this prospective, exploratory observational study situated in Germany, three cohorts of 40 patients each with acute exacerbation of atopic dermatitis and chronic atopic dermatitis and 40 CP patients with unaffected skin will be recruited for a comprehensive translational investigation including pruritus-specific and the shared psychosocial assessments of the RU SOMACROSS. Pruritus-specific measures will include questionnaires, quantitative sensory testing, cutaneous nerve fibre morphology, skin barrier morphology, epidermal metabolism and pruritogen blood levels. Within 1 year, patients and 80 age-matched and sex-matched healthy controls will be examined at three time points, allowing cross-sectional comparison and a longitudinal investigation of predictive outcome factors in patients under treatment according to existing guidelines. ETHICS AND DISSEMINATION: The study has been approved by the ethics committees of Hamburg (2020-10200-BO-ff) and Münster (2020-676 f-S), Germany. All participants are required to provide written informed consent. Findings will be disseminated through peer-reviewed publications, scientific conferences and involvement of relevant stakeholders, patients and the lay public. TRIAL REGISTRATION NUMBER: DRKS00026646.

Mechanisms and therapeutic targets for neuropathic itch.

Neuropathic pruritus conditions arise from structural and/or functional damage of the peripheral or central nervous system. Novel findings of pruritus specific mediators and pathways strengthen the specificity theory of pruritus transmission, however electrophysiological studies suggest that focal activation of nociceptors and distinct discharge patterns of primary afferents also contribute to the development of the sensation of pruritus. A complex interplay between excitatory and inhibitory interneurons at spinal level, non-neuronal cells and descending modulation from upper centers contributes to neuronal sensitization and clinically to the chronicity of pruritus, as well as accompanying phenomena such as alloknesis and hyperknesis. Several topical, systemic and non-pharmacological therapeutic approaches directed at distinct targets are currently available.

Cutaneous neuroimmune crosstalk in pruritus.

The underlying mechanisms of chronic pruritus (CP), which is often very debilitating for patients, are still not well understood. Over the past few years, peripheral and central mechanisms involving different classes of pruriceptive and nociceptive neuron (e.g., C- and Aδ-fibers), immune cells (e.g., eosinophils, basophils, Th1, Th2, and mast cells) and epithelial cells (e.g., keratinocytes) have been investigated. Based on these, numerous promising target-specific therapies are under development. In this review, we highlight the cells, key mediators, and receptors involved in itch perception and CP, and conclude by summarizing the therapies developed for these conditions.

Chronic Prurigo: Similar Clinical Profile and Burden Across Clinical Phenotypes.

Chronic prurigo is a debilitating skin disease characterized by the presence of chronic pruritus and scratching-related pruriginous lesions. The pruriginous lesions can differ in their clinics what has recently been categorized into different clinical phenotypes. The most common one is chronic nodular prurigo (syn. prurigo nodularis); other phenotypes are papular, plaque, umbilicated, and linear prurigo. A comparison between these phenotypes regarding similarities and differences has not yet been performed. In this explorative analysis, itch characteristics, scratching behavior, and disease burden of the nodular, papular, plaque, and umbilicated prurigo were investigated in 1,128 patients. Patients with nodular and plaque prurigo were younger than patients with papular and umbilicated prurigo. The shortest duration of the underlying pruritus was found in papular and umbilicated prurigo, the longest in plaque prurigo. Itch intensity, impairment of sleep, mood and the quality of life did not differ. These findings confirm that the clinical phenotypes of chronic prurigo belong to a spectrum of one disease with similar disease characteristics and can be categorized under the umbrella term of chronic prurigo. Future clinical trials should include all phenotypes of chronic prurigo.

Neuropathic Itch: Routes to Clinical Diagnosis.

Neuropathic itch occurs due to damage of neurons of the peripheral or central nervous system. Several entities, including metabolic, neurodegenerative, orthopedic, infectious, autoimmune, malignant, and iatrogenic conditions, may affect the somatosensory system and induce neuropathic itch. Due to the complex nature of neuropathic itch, particularly concerning its clinical presentation and possible etiological factors, diagnostic work-up of this condition is challenging. A detailed medical history, especially in regard to the itch, and a comprehensive physical examination are relevant to detect characteristic signs and symptoms of neuropathic itch and to rule out other possible causes for chronic itch. Complementary diagnostic exams, especially laboratory tests, determination of the intraepidermal nerve fiber density via a skin biopsy and radiological examinations may be indicated to confirm the diagnosis of neuropathic itch and to identify underlying etiological factors. Functional assessments such as quantitative sensory testing, nerve conduction studies, evoked potentials, or microneurography may be considered in particular cases. This review article provides a comprehensive overview of the diagnostic work-up recommended for patients with neuropathic itch.

Pruritus in Autoimmune and Inflammatory Dermatoses.

Pruritus in autoimmune and inflammatory dermatoses is a common symptom that can be severe and affect the quality of life of patients. In some diseases, pruritus is related to disorders activity and severity or may occur independent of the disease. Despite the high prevalence, the symptom is still underrated and there are only a few trials investigating the efficacy of drugs for disease-specific pruritus. In this review, the characteristics and possible pathomechanisms of pruritus in various dermatoses like autoimmune bullous diseases, connective tissue diseases as well as autoimmune-associated dermatoses (atopic dermatitis, psoriasis vulgaris) is illustrated. Additionally, studies analyzing the antipruritic treatment are discussed. Summarizing, the prevalence of pruritus in these diseases demonstrates the importance for symptom recognition and the need for an efficient antipruritic therapy.

Influence of Climate on Google Internet Searches for Pruritus Across 16 German Cities: Retrospective Analysis.

BACKGROUND: The burden of pruritus is high, especially among patients with dermatologic diseases. Identifying trends in pruritus burden and people's medical needs is challenging, since not all affected people consult a physician. OBJECTIVE: The purpose of this study was to investigate pruritus search behavior trends in Germany and identify associations with weather factors. METHODS: Google AdWords Keyword Planner was used to quantify pruritus-related search queries in 16 German cities from August 2014 to July 2018. All identified keywords were qualitatively categorized and pruritus-related terms were descriptively analyzed. The number of search queries per 100,000 inhabitants of each city was compared to environmental factors such as temperature, humidity, particulate matter 10 micrometers or less in diameter (PM10), and sunshine duration to investigate potential correlations. RESULTS: We included 1150 pruritus-related keywords, which resulted in 2,851,290 queries. "Pruritus" (n=115,680) and "anal pruritus" (n=102,390) were the most-searched-for keywords. Nearly half of all queries were related to the category localization, with Berlin and Munich having a comparatively high proportion of people that searched for pruritus in the genital and anal areas. People searched more frequently for information on chronic compared to acute pruritus. The most populated cities had the lowest number of queries per 100,000 inhabitants (Berlin, n=13,641; Hamburg, n=18,303; and Munich, n=21,363), while smaller cities (Kiel, n=35,027; and Freiburg, n=39,501) had the highest. Temperature had a greater effect on search query number (beta -7.94, 95% CI -10.74 to -5.15) than did PM10 (beta -5.13, 95% CI -7.04 to -3.22), humidity (beta 4.73, 95% CI 2.70 to 6.75), or sunshine duration (beta 0.66, 95% CI 0.36 to 0.97). The highest relative number of search queries occurred during the winter (ie, December to February). CONCLUSIONS: By taking into account the study results, Google data analysis helps to examine people's search frequency, behavior, and interest across cities and regions. The results indicated a general increase in search queries during the winter as well as differences across cities located in the same region; for example, there was a decline in search volume in Saarbrucken, while there were increases in Cologne, Frankfurt, and Dortmund. In addition, the detected correlation between search volume and weather data seems to be valuable in predicting an increase in pruritus burden, since a significant association with rising humidity and sunshine duration, as well as declining temperature and PM10, was found. Accordingly, this is an unconventional and inexpensive method to identify search behavior trends and respective inhabitants' needs.

Current treatment strategies in refractory chronic pruritus.

Chronic pruritus is a highly prevalent, debilitating disease, which is often refractory to conventional therapies. A step-wise, guideline-driven approach should be adopted in the management of these patients. Emollients as well as topical corticosteroids if appropriate should be initiated whilst looking for the cause underlying the pruritus. If these measures fail, and the origin of the pruritus remains unknown, cannot be treated or does not respond to therapy, systemic therapies as for example gabapentinoids, antidepressants, mu-opioid-receptor antagonists or, in case of inflammatory conditions, immunosuppressive drugs should be recommended. Novel agents, especially systemic monoclonal antibodies, neurokinin-1 receptor antagonists and opioid receptor modulators, are promising in providing relief in refractory cases.

Assessment of severity and burden of pruritus.

Chronic pruritus is a complex multifactorial symptom associated with many different diseases that represents a diagnostic and therapeutic challenge for physicians. In order to better manage chronic pruritus, a detailed medical history, individualized diagnostic procedures and treatment approaches are necessary. Treatment should not only take itch into consideration, but also scratching-induced skin lesions and accompanying disorders such as anxiety, depression and insomnia. Various standardized questionnaires and scales have been developed to assist in the characterization and assessment of these parameters. Monodimensional scales (e.g. the visual analogue scale) represent a simple method for assessing pruritus intensity and are frequently used; however, they can easily be confounded and may indicate the level of satisfaction regarding the medical care provided rather than the itch course. The Dynamic Pruritus Score and Itch-Free Days questionnaire enable a closer assessment of patient responses to treatment. Because chronic pruritus has the potential to greatly impact the quality of life, it is important that physicians recognize it as a major issue. The Dermatology Quality of Life Index is an instrument that is used in a variety of dermatological conditions, but may be unsuitable for measuring pruritus of extracutaneous origin. The ItchyQol is a tool designed specifically for those suffering from pruritus. Additional tools, such as the Hospital Anxiety and Depression Scale, take psychiatric comorbidities into consideration. Recommendations from European (EADV-based Task Force Pruritus) and international (International Forum for the Study of Itch) expert groups focusing on assessment instruments for chronic pruritus are also provided in this article.

Itch Management: Treatments under Development.

Pruritus is a symptom arising from a plethora of dermatological, neurological, and systemic conditions. The pathophysiological mechanisms involved in the transmission of acute and chronic pruritus are of high complexity and not yet fully understood. Recent research has enhanced the understanding of these mechanisms, enabling the development of novel drugs. Specifically, new therapies for inflammatory dermatoses, uremic pruritus, cholestatic pruritus, cutaneous T-cell lymphoma, and prurigo nodularis are being tested in ongoing randomized clinical trials. Compounds in development include neurokinin 1 receptor antagonists, anti-interleukin-31 receptor A antibodies, nerve growth factor inhibitors, transient receptor potential cation channel V1 antagonists, as well as κ-opioid agonists, ileal bile acid transporter inhibitors, and bile acid sequestrants. Effective treatment options for the various forms of chronic pruritus are still insufficient. Basic research studying additional pathophysiological mechanisms involved in pruritus transmission is urgently needed, as well as clinical trials testing new compounds in patients with chronic pruritus. Moreover, clinical trials including specific patients groups, such as pregnant women or children, are of the utmost importance since only few treatment options are currently approved for these patients. The aim of this chapter is to provide an overview of the drugs under development, highlighting the pathophysiological mechanisms they target.

Effect of a high-dose target-controlled naloxone infusion on pain and hyperalgesia in patients following groin hernia repair: study protocol for a randomized controlled trial.

BACKGROUND: Central sensitization is modulated by the endogenous opioid system and plays a major role in the development and maintenance of pain. Recent animal studies performed following resolution of inflammatory pain showed reinstatement of tactile hypersensitivity induced by administration of a mu-opioid-antagonist, suggesting latent sensitization is mediated by endogenous opioids. In a recent crossover study in healthy volunteers, following resolution of a first-degree burn, 4 out of 12 volunteers developed large secondary areas of hyperalgesia areas after a naloxone infusion, while no volunteer developed significant secondary hyperalgesia after the placebo infusion. In order to consistently demonstrate latent sensitization in humans, a pain model inducing deep tissue inflammation, as used in animal studies, might be necessary. The aim of the present study is to examine whether a high-dose target-controlled naloxone infusion can reinstate pain and hyperalgesia following recovery from open groin hernia repair and thus consistently demonstrate opioid-mediated latent sensitization in humans. METHODS/DESIGN: Patients submitted to unilateral, primary, open groin hernia repair will be included in this randomized, placebo-controlled, double-blind, crossover study. The experimental days take place 6-8 weeks after surgery, time-points at which patients are expected to be almost pain- free. Prior to administration of naloxone or placebo, the primary outcome (a summated measure of pain: at rest, during transition from supine to standing position, and evoked by pressure algometry) and the secondary outcomes (secondary hyperalgesia/allodynia, pressure pain thresholds, assessed at the surgical site and at the mirror-site in the contralateral groin, and, opioid withdrawal symptoms) will be assessed. These assessments will be repeated at each step of the target-controlled infusion of placebo or naloxone at estimated median (95 % CI) plasma concentrations of 344 ng/ml (130;567), 1059 ng/ml (400;1752) and 3196 ng/ml (1205;5276). DISCUSSION: We aim to demonstrate opioid-mediated latent sensitization in a post-surgical setting, using pain as a clinical relevant variable. Impairment of the protective endogenous opioid system may play an important role in the transition from acute to chronic pain. In order to sufficiently block the endogenous opioid system, a high-dose target-controlled naloxone-infusion is used, in accordance with recent findings in animal studies. EUDRACT: 2015-000793-36 (Registration date: 16 February 2015) Clinicaltrials.gov: NCT01992146 (Registration date: 12 December 2014).

Secondary hyperalgesia phenotypes exhibit differences in brain activation during noxious stimulation.

Noxious stimulation of the skin with either chemical, electrical or heat stimuli leads to the development of primary hyperalgesia at the site of injury, and to secondary hyperalgesia in normal skin surrounding the injury. Secondary hyperalgesia is inducible in most individuals and is attributed to central neuronal sensitization. Some individuals develop large areas of secondary hyperalgesia (high-sensitization responders), while others develop small areas (low-sensitization responders). The magnitude of each area is reproducible within individuals, and can be regarded as a phenotypic characteristic. To study differences in the propensity to develop central sensitization we examined differences in brain activity and anatomy according to individual phenotypical expression of secondary hyperalgesia by magnetic resonance imaging. Forty healthy volunteers received a first-degree burn-injury (47 °C, 7 min, 9 cm(2)) on the non-dominant lower-leg. Areas of secondary hyperalgesia were assessed 100 min after the injury. We measured neuronal activation by recording blood-oxygen-level-dependent-signals (BOLD-signals) during mechanical noxious stimulation before burn injury and in both primary and secondary hyperalgesia areas after burn-injury. In addition, T1-weighted images were used to measure differences in gray-matter density in cortical and subcortical regions of the brain. We found significant differences in neuronal activity between high- and low-sensitization responders at baseline (before application of the burn-injury) (p < 0.05). After the burn-injury, we found significant differences between responders during noxious stimulation of both primary (p < 0.01) and secondary hyperalgesia (p ≤ 0.04) skin areas. A decreased volume of the right (p = 0.001) and left caudate nucleus (p = 0.01) was detected in high-sensitization responders in comparison to low-sensitization responders. These findings suggest that brain-structure and neuronal activation to noxious stimulation differs according to secondary hyperalgesia phenotype. This indicates differences in central sensitization according to phenotype, which may have predictive value on the susceptibility to development of high-intensity acute and persistent pain.