Itch: an under‐recognized problem in psoriasis

Psoriasis has historically been considered a nonpruritic dermatosis, in contrast with atopic dermatitis. Thus, itch has often been underappreciated and overlooked in psoriasis. However, increasing evidence over the past decade has shown that itch can be one of the most prevalent and burdensome symptoms associated with psoriasis, affecting almost every patient to some degree. Itch can involve the entire body, although it predominantly affects the legs, hands, back, body and especially the scalp. Uncontrolled itch can significantly impact all aspects of the well‐being and quality of life of the patient. While there has been some progress in trying to better understand the pathophysiology of itch in psoriasis, more research effort and interest are needed. This under‐recognition of itch in psoriasis is clearly reflected in the dearth of treatment options targeting itch despite significant advancement in treating the lesions themselves. Recently, however, clinical studies have begun to include itch as a study outcome. The resulting data have demonstrated concomitant antipruritic benefits and improved Psoriasis Area and Severity Index (PASI) scores with mainstay treatments for psoriasis, such as topical corticosteroids and vitamin D analogs, phototherapies, and various systemics and biologics. This article takes a closer look at this debilitating symptom, reviewing the available epidemiology data for psoriatic itch, presenting the current understanding of psoriatic itch pathophysiology and highlighting important clinical data for various treatment options for itch. Practical considerations for increasing the recognition of itch as well as improving its management in psoriasis are also provided.     

Chronic pruritus: a paraneoplastic sign

Chronic itch could be a presenting sign of malignancy. Pruritus of lymphoma is the common prototype of paraneoplastic itch and can precede other clinical signs by weeks and months. Paraneoplastic pruritus has also been associated with solid tumors and is an important clinical symptom in paraneoplastic skin diseases such as erythroderma, Grovers disease, malignant acanthosis nigricans, generalized granuloma annulare, Bazex syndrome, and dermatomyositis. In any case with high index of suspicion a thorough work-up is required. This review highlights the association between itch and malignancy and presents new findings related to pathophysiological mechanisms and the treatment of itch associated with malignancy. Combinative therapies reducing itch sensitization and transmission using selective serotonin and neuroepinephrine reuptake inhibitors, Kappa opioids, and neuroleptics are of prime importance in reducing this bothersome symptom.     

Preclinical and human surrogate models of itch

Pruritus, or simply itch, is a debilitating symptom that significantly decreases the quality of life in a wide range of clinical conditions. While histamine remains the most studied mediator of itch in humans, treatment options for chronic itch, in particular antihistamine‐resistant itch, are limited. Relevant preclinical and human surrogate models of non‐histaminergic itch are needed to accelerate the development of novel antipruritics and diagnostic tools. Advances in basic itch research have facilitated the development of diverse models of itch and associated dysaesthesiae. While experimental itch in humans is induced over a short period of time and usually assessed psychophysically, the study of itch reactions in animals allows for both short‐term and long‐term studies but relies heavily on behavioural assessments. This review provides a background and a presentation of the established models of itch currently applied in animals and humans with emphasis on translatability.     

Cholestatischer Pruritus

Pruritus is a common symptom of hepatobiliary disorders and may considerably diminish quality of life. Cholestatic pruritus exerts a circadian rhythm and is typically most severe in the evening hours and early at night. Itching is reported often to be most intense at the palms and the soles, but may also be generalized. The pathophysiological mechanisms of cholestatic pruritus have not been completely clarified. In the past, bile salts, histamine, progesterone metabolites and opioids have been discussed as potential causal substances; a correlation with itch intensity could never be proven. The enzyme autotaxin, which releases lysophosphatidic acid, has recently been identified as potential cholestatic pruritogen. Treatment aims to bind pruritogens in the gut lumen by resins such as cholestyramine, to modulate pruritogen metabolism by rifampicin and to influence central itch signaling by μ-opioid antagonists and selective serotonin re-uptake inhibitors. In cases of refractory pruritus experimental treatment options such as UV-therapy, extracorporeal albumin dialysis and nasobiliary drainage may be considered.     

[Translated article] Pruritus in Dermatology: Part 1—General Concepts and Pruritogens

Pruritus is the most common symptom of dermatologic and systemic diseases. The diagnosis of pruritus is clinical, although additional tests may be necessary to identify or confirm the cause. Translational medicine has led to the discovery of new mediators of itch, or pruritogens, as well as new receptors. Knowing how to properly recognize the main pathway that mediates itch in each patient is the key to successful treatment. Although the histaminergic pathway predominates in conditions like urticaria or drug-induced pruritus, it is the nonhistaminergic pathway that predominates in nearly all other skin diseases covered in this review. Part 1 of this 2-part review discusses the classification of pruritus, additional testing, the pathophysiology of itch and the pruritogens implicated (including cytokines and other molecules), and central sensitization to itch.     

Prurito en dermatología. Generalidades y pruritógenos. Parte 1

Pruritus is the most common symptom of dermatologic and systemic diseases. The diagnosis of pruritus is clinical, although additional tests may be necessary to identify or confirm the cause. Translational medicine has led to the discovery of new mediators of itch, or pruritogens, as well as new receptors. Knowing how to properly recognize the main pathway that mediates itch in each patient is the key to successful treatment. Although the histaminergic pathway predominates in conditions like urticaria or drug-induced pruritus, it is the nonhistaminergic pathway that predominates in nearly all other skin diseases covered in this review. Part 1 of this 2-part review discusses the classification of pruritus, additional testing, the pathophysiology of itch and the pruritogens implicated (including cytokines and other molecules), and central sensitization to itch.     

Pruritus – Pathophysiologie,Klinik und Therapie – Eine Übersicht

Pruritus is an unpleasant sensory perception of the skin associated with the desire to scratch. As a physiological nociception, pruritus leads to the removal of harmful agents such as parasites and plants from the skin surface. More often, pruritus occurs as a severe and therapy‐refractory symptom of various underlying dermatological and systemic diseases. Comparable to chronic pain, chronic pruritus worsens the general condition and may lead to physical and psychological exhaustion. Until the 1990s, pruritus had been regarded as an incomplete pain sensation. Only recently, itch was defined as a separate, pain‐independent sensation with its own mediators, spinal neurons and cortical areas. These observations led to the development of new therapeutic modalities. This paper gives an overview of itch pathophysiology, clinical types and therapies.     

Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis

Atopic dermatitis (AD) is a chronic skin disease occurring in about 5 to 10% of adults worldwide. It can cause intense and persistent itch. For almost two-thirds of patients with moderate-to-severe AD, the itching lasts at least 12 hours a day, and is severe to unbearable. In clinical trials that are looking at how effective a treatment for AD is, itch intensity must be measured. Given itch is subjective, its intensity is most accurately reported by patients themselves. In this study, investigators from the U.S.A. and Europe developed a scale of itch called the Peak Pruritus Numerical Rating Scale (NRS). The scale measures the worst itch (peak pruritus) during the past 24 hours by asking patients “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being ‘worst itch imaginable’, how would you rate your itch at the worst moment during the previous 24 hours?”. To ensure the scale is reliable and valid (i.e., appropriate for assessing itch in AD patients), patients were interviewed about their opinions of the scale. The scale was then implemented in three large clinical trials of adults with moderate-to-severe AD. Interviewed patients said that the scale provided a relevant, clear, and comprehensive assessment of itch severity. As hypothesized, scores from the Peak Pruritus NRS showed moderate-to-strong correlation with other measures of itch, and weak-to-moderate correlation with measures of AD signs (clinical symptoms). The investigators concluded that the Peak Pruritus NRS is a well-defined, reliable, sensitive, and valid scale for evaluating worst itch intensity in adults with moderate-to-severe AD.     

Itch in atopic dermatitis - pathophysiology and treatment

Pruritus is an essential feature of atopic dermatitis with a high impact on the quality of life. Although the pathophysiology of atopic dermatitis itch is not fully understood, recent studies have demonstrated that a variety of mechanisms contribute to the induction and maintenance of the symptom. For example, an increased number of cutaneous nerve fibers and neuropeptides were identified in atopic dermatitis skin. Histamine and histamine 4 receptor as well as interleukin 31 are novel key players identified in itch induction, in addition to inflammatory cells such as mast cells, eosinophils and lymphocytes. The new findings suggest that target-specific therapies are most likely to control atopic dermatitis itch. To date, only few therapies are available and controlled studies are pending.     

British Association of Dermatologists’ guidelines for the investigation and management of generalized pruritus in adults without an underlying dermatosis, 2018

Pruritus (or itch) is a common and distressing symptom of many skin diseases, systemic illnesses and psychological disorders. Itch is perhaps the commonest presenting symptom of skin disorders. In any two week period, 8 to 9% of the population suffer from significant pruritus. The focus of this guideline is not itchy rashes, but rather the situation where itch is present without rash. The guidelines also do not cover itch in children, in pregnancy, nor do they detail the science of the cause of itch. The study group consist mostly of dermatologists (skin specialists) from a number of hospitals in the U.K., but a number of other hospital doctors, a nurse and a general practitioner (GP) are also part of the team. There may be an underlying cause of pruritus, such as blood disorders, iron deficiency or excess, kidney problems, liver problems, cancer, infections, medications, behavioural factors, dry skin or any combination of these with old age. This can be significant in 20 to 30% of cases of itchy skin without rash. There remain a small number of individuals with itch and no apparent underlying cause or rash. It is always important to look for an underlying causative condition, as the most effective management of pruritus without rash depends on the treatment of any underlying disease. The management of itch appears to be very situation specific, even if the underlying cause cannot be treated. The management of true pruritus of unknown cause is different again.     

Treatment of pruritus of reactive perforating collagenosis using transcutaneous electrical nerve stimulation

Reactive perforating collagenosis is a form of perforating dermatosis due to transepithelial elimination of collagen and characterized by itchy papulonodular eruptions frequently seen in patients with diabetes mellitus and end stage renal failure. Pruritus is often severe and treatment is difficult. Two adult Chinese diabetic patients with acquired reactive perforating collagenosis unresponsive to topical therapies and oral antihistamines, were treated with transcutaneous electrical nerve stimulation. There was a significant reduction of itch followed by gradual resolution of the skin lesions.     

Pruritus ani and its management—a study and reappraisal*

In a survey of 3000 patients, forty-seven (1.6%) had pruritus ani as the major (thirty-eight) or a minor (nine) symptom. Pruritus ani may be either constitutional or secondary, but there is often a tenuous line separating these two groups. Management of this common symptom is discussed.     

Pathophysiology of pruritus in atopic dermatitis: an overview

Pruritus is an essential feature of atopic dermatitis (AD) and the diagnosis of active AD cannot be made without the history of itching. Because of the high impact on life quality, most of the patients measure the severity of eczema by the intensity of pruritus rather than appearance of skin lesions. However, although pruritus is a cardinal symptom of AD, its mechanism and association with the cutaneous nervous system is not completely understood. Recently, a considerable progress has been achieved in clarifying the complex pathophysiology of pruritus in AD. As a cutaneous sensory perception, itch requires excitation of neuropeptide-containing free nerve endings of unmyelinated nociceptor fibers. It is well known that histamine and acetylcholine provoke itch by direct binding to 'itch receptors' and several mediators such as neuropeptides, proteases or cytokines indirectly via histamine release. Interestingly, some variations of these complex mechanisms could be demonstrated in patients with AD. This review highlights the recent knowledge of different mechanisms which may be involved in regulating pruritus in patients with AD potentially leading to new therapeutic applications for the treatment of itch in AD.     

Evaluation of epidermal nerve density and opioid receptor levels in psoriatic itch

Background Psoriasis is a complex, multifactorial inflammatory skin disease with genetic and environmental interactions. Patients with psoriasis exhibit erythematous plaques with itch, but the mechanisms of psoriatic itch are poorly understood. Objectives This study was performed to investigate epidermal nerve density and opioid receptor levels in psoriatic skin with or without itch. Methods Twenty‐four patients with psoriasis aged between 39 and 82 years were included in this study. The number of epidermal nerve fibres, the levels of semaphorin 3A (Sema3A) and the expression patterns of μ‐ and κ‐opioid systems were examined immunohistologically in skin biopsies from psoriatic patients with or without itch and healthy volunteers as controls. Results The number of epidermal nerve fibres tended to increase in approximately 40% of psoriatic patients with itch compared with healthy controls, while such intraepidermal nerves were not observed in other itchy patients. In comparison with healthy controls, Sema3A levels also tended to decrease in the epidermis of psoriatic patients with itch. However, no relationship was found between nerve density and Sema3A levels in the epidermis of psoriatic patients with itch. The levels of μ‐opioid receptor and β‐endorphin in the epidermis were the same in healthy controls and psoriatic patients with or without itch. The levels of κ‐opioid receptor and dynorphin A were significantly decreased in the epidermis of psoriatic patients with itch compared with healthy controls. Conclusions Based on Sema3A levels in the epidermis, epidermal opioid systems, rather than hyperinnervation, may be involved in the pathogenesis of psoriatic itch.     

银屑病瘙痒机制及治疗研究进展

瘙痒是银屑病患者的一种常见症状,严重影响患者的生活质量.但其瘙痒的机制尚不清楚,许多常规治疗瘙痒的药物并不能有效缓解银屑病的瘙痒.目前认为,银屑病皮损中神经分布异常增多和敏感性增加,炎症细胞在病灶中聚集、活化并释放炎症介质是银屑病瘙痒的主要原因.抗组胺药不能有效控制银屑病瘙痒,而神经肽受体拮抗剂、免疫抑制剂及光疗等为治疗银屑病瘙痒的有效方法.

Abstract：

Pruritus is an important symptom of psoriasis.It seriously affects the quality of life of psoriatic patients,but its pathogenesis remains unanswered.Many routine treatments cannot relieve the pruritus in psoriasis effectively.It has been demonstrated that the pruritus in psoriasis is mainly attributed to the abnormally increased innervation and sensitivity of sensory nerves,as well as the aggregation,activation of and release of inflammatory mediators by inflammatory cells.Antihistamine drugs are usually ineffective for the treatment of pruritus in psoriasis,while antagonists of neuropeptide receptors,immunosuppressants and phototherapy have shown favorable efficacy.     

银屑病患者瘙痒特征及其对生活质量的影响

目的:确定银屑病患者的瘙痒特征并评价其生活质量。方法:采用问卷调查的方法,评价银屑病患者的瘙痒特征和生活质量。结果:131例银屑病患者中有89.31%伴有不同程度的瘙痒,其中87.18%的患者因瘙痒影响心情,62.39%因瘙痒影响睡眠;相关分析显示,瘙痒强度、频率、持续时间与银屑病严重程度和皮损红斑、浸润、脱屑呈正相关(P0.05)。结论:大多数银屑病患者有不同程度的瘙痒,且对患者的生活质量产生的负面影响。     

Pruritus measurement and treatment

Pruritus measurement is problematic, because of its subjective nature and poor localization. Ratio scales enhance the usefulness of the visual analogue scale (VAS) by reducing variation; other scales such as the generalized labelled magnitude scale may also be useful. Pruritus neuroanatomy includes peripheral receptors, peripheral and central nerves, ascending and descending spinal pathways, and several brain regions. Pruritus receptors include Merkel discs and free nerve endings, and itch receptors have fast or slow adaptation. In this review, we discuss the pathophysiology of pruritus in atopic dermatitis, psoriasis and scabies. Pruritus treatment is reviewed for topical agents and antihistamines. Future research directions are suggested.