Pruritus bei systemischen Erkrankungen

Chronic pruritus is a symptom of various internal disorders. In contrast to dermatological diseases, pruritus does not present with primary skin alterations in these patients. However, intense scratching may cause secondary skin changes such as abrasion, excoriation, prurigo nodularis, or in rare cases even scaring. The most common internal medicine causes for chronic pruritus are chronic kidney disease, hepatobiliary and hematological disorders as well as adverse drug reactions. Pruritus is less commonly seen in patients with endocrine or metabolic diseases, malabsorption syndromes, infectious diseases and solid tumors. The pathogenesis of pruritus in these disorders remains largely elusive, albeit preliminary insights have been gained for uremic and cholestatic pruritus. Antipruritic treatment is therefore symptomatic in most cases and may represent a clinical challenge. The calcium channel blockers gabapentin and pregabalin have the best proven efficacy in chronic kidney disease-associated pruritus. In Japan nalfurafine, a κ-opioid receptor agonist, has been licensed for this indication. UVB light may also attenuate uremic symptoms. In patients suffering from hepatobiliary disorders the sequestrant cholestyramine and the enzyme inducer rifampicin are effective. Furthermore, μ?opioid receptor antagonists and sertraline may be used to ameliorate cholestatic pruritus. So far, no randomized controlled trials have been performed for chronic itch in other internal medicine disorders. Antipruritic treatment is mainly based on effective therapy of the underlying disease.     

Causes,pathophysiology, and treatment of pruritus in the mature patient

Chronic itch is a common and debilitating health condition in the elderly. There are several common causes of itch in the mature population, such as skin xerosis, immunosenescence, and neuropathic changes. In addition, skin diseases, such as seborrheic dermatitis and stasis dermatitis, systemic conditions (end-stage renal disease and diabetes), or psychogenic derailments, such as depression, anxiety, and dementia, can all serve as triggers of pruritus. Polypharmacy, a common occurrence among the elderly population, may also serve as a cause of itch that may or may not be accompanied by dermatitis. Such medications as μ opioids and calcium channel blockers have been found to have a connection with pruritus in the advanced aging population.Determining the exact trigger for pruritus in the elderly may be especially challenging, because itch can be idiopathic in many cases. The role of treatments should not only take into account elimination of various underlying cutaneous, systemic, or psychogenic conditions associated with itch but also focus on the skin changes that are characteristic of the aging process. Development of such treatment options can be guided by elucidation of the mechanisms underlying the pathophysiology of itch in the geriatric population.     

The antipruritic effect of a 5-HT3 receptor antagonist (tropisetron) is dependent on mast cell depletion – an experimental study

The background of this study is that 5-HT3 receptor antagonists are reported to have an antipruritic effect in uremic and cholestatic pruritus. Recently, we could not confirm such an effect in healthy subjects under experimental conditions. Therefore, it was the aim of the present study to further evaluate a possible antipruritic effect of a 5-HT3 receptor antagonist (tropisetron) on serotonin- and histamine-induced itch before and after skin mast cell depletion in 10 healthy subjects. The results were compared to serotonin and histamine iontophoresis in non-pretreated and pretreated skin with an orally applied antihistamine (cetirizine). Skin mast cell depletion was performed by iontophoretical application of compound 48/80. Wheals and flares were planimetrically evaluated. Itching and burning sensations were rated on an analog scale over a 24-min period. The test protocol also comprised alloknesis, defined as induction of perifocal itch sensations by a mechanical stimulus. When serotonin was iontophoretically applied after mast cells had been depleted before, oral tropisetron resulted not only in significantly lower whealing, itching and alloknesis but also reduced flares. In contrast, after oral pretreatment with tropisetron histamine-induced reactions before and after mast cell depletion did not significantly change. Our study demonstrates that in this model, tropisetron as a 5-HT3 receptor antagonist does not effect histamine-induced itch but has a measurable effect in serotonin-induced reactions when mast cells were depleted before. From these data evidence now exists why tropisetron is to some extent effective in certain types of pruritus such as uremic pruritus, known for increased histamine liberation and increased serotonin levels as well as degranulated and diffusely spread mast cells in the skin.     

Some methods for evaluating clinical itch and their application for studying pathophysiological mechanisms.

Research on itch has been hampered by difficulties in measuring the itch sensation. A microcomputer-based system, where the patients themselves record their symptoms on portable data loggers can be used for quantitative measurements of clinical itch and for the detection of antipruritic effects of drugs. By using this system we have found that itch in atopic dermatitis is not inhibited by antihistamines but by cyclosporin A, a drug inhibiting cytokine production. Thus histamine is not a major pruritogen in atopic dermatitis. A hypothesis is proposed that cytokines are involved in itch in atopic dermatitis.     

Renal itch

Renal itch is localized or generalized itch, affecting patients with chronic renal failure, where there is no primary skin disease and no systemic or psychological dysfunction that might cause pruritus. It does not result from raised serum urea levels. The prevalence of renal itch has increased with the growing population in chronic renal failure and is a considerable cause of morbidity. The prevalence of itch increases with deteriorating renal function but does not improve significantly with dialysis. The pruritus is independent of duration of dialysis or cause of renal failure. The aetiology of renal itch is unclear. There is little evidence of a major role for histamine and antihistamines are rarely beneficial. Hyperparathyroidism, abnormal cutaneous innervation and endogenous opioids have been postulated as contributory factors. Treatment of renal itch is difficult. Naltrexone, oral activated charcoal, UVB phototherapy and ondansetron have been shown to be effective. Topical capsaicin may be of benefit in patients with localized pruritus. The definitive treatment for renal itch remains renal transplantation.     

Antipruritic effects of pimecrolimus and tacrolimus

The development of topical calcineurin inhibitors resulted in a significant improvement in the treatment of inflammatory skin diseases such as atopic dermatitis. In addition, an excellent amelioration of pruritus could be observed. Other itchy dermatoses such as chronic irritative hand dermatitis, rosacea, graft-versus-host-disease, renal pruritus, lichen sclerosus, prurigo simplex, prurigo nodularis, scrotal eczema, and inverse psoriasis also have been treated successfully with pimecrolimus and tacrolimus. The antipruritic effect currently is believed to be related to the inhibition of inflammatory cytokines. Furthermore, recent investigations indicate a release of neuropeptides from sensory nerve fibers and degranulation of mast cells mediated by pimecrolimus and tacrolimus. Similar effects have been observed during capsaicin treatment. These findings may provide a possible explanation for initially observed calcineurin inhibitors related side-effects such as burning and pruritus. Moreover, the antipruritic potency may be related to a direct effect on nerve fibers leading to suppression of itch mediated by unknown mechanisms.     

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.     

A review of pruritus

This article reviews the neurophysiology of pruritus and presents evidence that itch is a separate modality from pain, rather than a submodality of pain. The numerous suggested pruritogens are reviewed, and evidence supporting each one is critically examined. The systemic causes of generalized pruritus are reviewed, with detailed review of the literature on uremic pruritus, cholestatic pruritus, and the pruritus associated with polycythemia vera. The specific treatments used for each of these conditions are reviewed, as well as the use of antihistamines in generalized pruritus. An approach to the workup of a patient with pruritus is suggested.     

Pain and Pruritus: a study of their similarities and differences

Pruritus is one of the most common dermatologic complaints and, as the most common dermatologic symptom, is a major contributor to frequent dermatology visits. Chronic pruritus mirrors another major medical condition faced by millions of Americans each year - chronic pain. In older literature, pain and pruritus were thought to have been conveyed by the same C fiber, and the proportion contributing to pruritus was just a small subset of this general fiber. Overall, pain and pruritus share many integral similarities. Although these sensations both initiate the body’s awareness to injury, pain and itch may have evolved for sensing different damages such as a burrowing parasite or a noxious stimulus, respectively. This seems to have been validated through analyses of their pathophysiology, acute and chronic conditions, and treatment modalities. However, their symptoms and intrinsic mechanisms vary considerably. It is important to view pruritus in more of an overall, whole body experience, rather than just the sensory aspect. Future studies should investigate the psychological treatment of chronic pruritus, considering the immense similarities with its chronic pain counterpart.     

Itch and psyche: psychiatric aspects of pruritus

Itch, also referred to as pruritus, is an unpleasant cutaneous sensation provoking the desire to scratch. It is often an uncomfortable, subjective sensation responsible for decreased quality of life in a variety of psychodermatological conditions. Comorbid psychiatric conditions, including depression and anxiety, are frequently associated with itch and scratch cycle. The reciprocal and intricate relationship between the psyche and itch has been widely studied. The neurobiology of itch involves the complexity of specific mediators, itch-related neuronal pathways, and central processing of itch. The connection between itch and the psyche can be grouped under three headings: pruritic diseases with psychosocial sequelae, pruritic diseases aggravated by psychosocial factors, and psychiatric disorders causing pruritus. Itch and pain modulation go together in most circumstances and involve various substances including histamine, interleukins, protease-activated receptors, transient receptor potential receptors, opioids, and cannabinoids. The close interaction between keratinocytes and nerve endings modulating pain and itch also play a major role. Management of itch associated with its psychosomatic components is directed at an underlying cause and adopting a holistic approach to address not only dermatologic and somatosensory aspects, but also the cognitive, emotional, and psychosocial components. An integrated multidisciplinary team consisting of a dermatologist, psychiatrist, psychologist, and social worker is vital in addressing the multifaceted aspects of pruritus.     

The pruritus of cholestasis

The pruritus of cholestasis is a difficult clinical problem to manage. The pathogenesis of this symptom is unknown. All conventional therapies have been unsuccessful in isolating a particular group of substances that could be implicated as direct or indirect causative agents. It should be emphasized that nonspecific treatment modalities that lower the plasma concentrations of a variety of substances (such as cholestyramine, colestipol, charcoal hemoperfusion, plasmapheresis, partial external diversion of bile, and drugs that induce hepatic enzymes), can potentially ameliorate the pruritus of cholestasis by lowering the circulating levels of an undefined pruritogen or a factor responsible for inducing the primary mechanism of the pruritus. The encouraging results reported by the use of antibiotic therapy for this condition merits investigation. Increased opioidergic neurotransmission is part of the syndrome of cholestasis and it contributes, at least in part, to the pruritus associated with it. Opiate antagonists seem to be an effective alternative therapy for some patients. Recent preliminary reports suggest that other neurotransmitter systems, eg, serotoninergic, may be involved in the pruritus of cholestasis.^84,85

The need for quantitation of scratching activity cannot be over emphasized. The use of quantitative methodology offers the opportunity to facilitate the study of scratching behavior that is a biological phenomenon secondary to liver disease.     

瘙痒介质及其受体的研究进展

瘙痒的产生是一个复杂的多因素作用的结果,其具体机制尚不完全清楚.研究已证实,瘙痒具有特异的神经传导通路,多种内源性物质与瘙痒的发病密切相关.近年来的研究表明,组胺4型受体、蛋白酶活化受体-2、白介素-31受体、神经激肽受体-1在皮肤无髓C神经纤维的表达可能介导瘙痒的发生,而神经营养素和神经生长因子及其受体则可能作为一种瘙痒敏感剂,促进瘙痒的形成与发展.这些化学介质及其受体在瘙痒发生的病理生理机制中并不是孤立地起作用,而是与神经细胞、免疫细胞及皮肤细胞紧密联系.     

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.     

What are new treatment concepts in systemic itch?

Chronic pruritus is a relevant symptom burden in various systemic diseases. It is most commonly observed in patients with chronic kidney disease, hepatobiliary and hematological disorders as well as adverse drug reaction. Recent basic research has unravelled novel treatment targets which are currently in preclinical phases, clinical trials or have already been licensed. While µ‐opioid receptor antagonists have been used since decades mainly in cholestatic pruritus, the k‐opioid receptor agonist nalfurafine has been licensed in Japan for chronic kidney disease‐associated pruritus (CKDaP) as well as cholestatic pruritus. Further κ‐opioid receptor agonists are currently investigated in various clinical trials including CKDaP. In recent years, the calcium channel blockers gabapentin and pregabalin have also been recognized as effective anti‐pruritus therapy in several internal diseases with the best evidence in chronic kidney disease‐associated pruritus. Neurokinin‐1 receptor antagonists have been investigated with variable benefit in CKDaP, solid tumors and lymphoproliferative disorders such as cutaneous T‐cell lymphoma, Sézary syndrome. Inhibitors of the ileal bile acid transporter (IBAT) represent a selective interruption of the enterohepatic circulation and are currently investigated in various hepatobiliary disorders associated with pruritus. The current development and testing of novel drugs in clinical trials offers hope to struggling physicians and suffering patients.     

A practical review and update on the management of pruritus sine materia

Pruritus can be divided into several categories: pruritoceptive, neurogenic, neuropathic, and psychogenic. Neuropathic itch is caused by lesions of afferent neural pathways. Psychogenic itch is secondary to primary psychiatric disorders. Both of these types of pruritus present with no evidence of primary cutaneous lesions. The presentation of both conditions can be confusing and patients with no primary cutaneous lesions can be prematurely diagnosed as having a psychiatric disorder. Treatment of neuropathic and psychogenic pruritus can be divided into pharmacologic and nonpharmacologic therapies. Medications used include topical capsaicin and anesthetic agents, antiepileptic agents, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and atypical antipsychotic agents. Nonpharmacologic therapies such as psychotherapy and hypnosis have been beneficial. Further studies are needed, as most reports of efficacy are not evidence based.     

An approach to the treatment of anogenital pruritus

The anogenital area is a common location for pruritic complaints. Specific terms for chronic itch in this location have included pruritus vulvae, pruritus ani, lichen simplex chronicus, and neurodermatitis. A male counterpart to pruritus vulvae, pruritus scroti, is less common. Acute anogenital pruritus is usually caused by infections or contact dermatitis. In chronic pruritus, inflammatory dermatoses and malignancies must be ruled out. In idiopathic anogenital pruritus or neurodermatitis, the skin findings should be limited to lichenification and excoriations. Skin findings may be entirely absent. When treating anogenital pruritus, topic irritants and potential sensitizers must be eliminated. Cleansing and toilet habits must be addressed. A short course of a high-potency topical steroid should bring moderate to complete relief. Sedating antihistamines may limit nighttime symptoms. In some patients, psychotropic agents are required to achieve adequate sedation. Antidepressants may be required in patients refractory to treatment or with underlying psychiatric disorders.     

Cholestatic pruritus: a knowledge update

This review is focused on updating knowledge about cholestatic pruritus. It summarizes clinical-epidemiological characteristics, pathophysiology, diagnostic approach, and evidence-based therapeutic recommendations regarding this form of pruritus. Pruritus is a frequent symptom that accompanies several liver diseases, particularly cholestatic ones. The symptom may be mild and tolerable, but it can also dramatically reduce the quality of life. Although the exact pathophysiology of this form of pruritus remains unclear, current evidence supports a mixed origin. It is extremely important for dermatologists to have knowledge about cholestatic pruritus since they are usually the first physicians to be sought by the patient when they experience the symptom. In the absence of specific dermatological alterations, cholestasis must always be considered as a possible cause of pruritus. In addition to allowing an adequate diagnosis, a better pathophysiological understanding of hepatic pruritus provides the identification of new therapeutic targets and, consequently, optimization of the approach in patients with this condition.     

Inflammatory mediators causing cutaneous chronic itch in some diseases via transient receptor potential channel subfamily V member 1 and subfamily A member 1

Chronic itch with an itch–scratch vicious circle is a significant problem in a large amount of diseases. Some of these diseases, such as psoriasis, atopic dermatitis, prurigo nodularis, Sézary syndrome, uremic pruritus, diabetes and jaundice, are common. For a very long time, chronic itch has been a thorny problem with few effective treatments. Because of this, itch researchers and dermatologists seek to find the mechanisms among chronic itch, inflammatory cytokines and neurons. As an immediate area of research focus, we are going to find the peripheral cross‐talk between neurons and skin cells. Two receptors, named transient receptor potential channel vanilloid 1 and transient receptor potential channel ankyrin transmembrane protein 1, have been shown to play important roles in chronic itch. Many advances have been made so far this decade. This review talks about the updated mechanism of itch‐related inflammatory cytokines via transient receptor potential channels in cutaneous chronic itch and corresponding diseases. The search for itch‐related inflammatory mediators and the structure of transient receptor potential channels this decade could deepen our understanding of the mechanism of itch and help us find more treatments of chronic itch in the future.     

Pruritus secondary to primary biliary cholangitis: a review of the pathophysiology and management with phototherapy

Primary biliary cholangitis (PBC) is a long-term disease affecting 35 in every 100,000 people in the United Kingdom (UK) and United States. It is driven by the immune system and causes inflammation of bile ducts (tubes carrying bile from the liver to the gut), leading to bile duct destruction and eventual scarring of the liver. For unclear reasons, PBC causes persistent itch (cholestatic itch) that is difficult to suppress with conventional treatments. Several case studies have shown that phototherapy (treatment of the skin with UV light) can be used to reduce cholestatic itch, although the processes behind this treatment remain poorly understood. This review article, written by researchers in the UK, summarises the evidence behind the use of phototherapy to treat cholestatic itch and explores potential reasons (mechanisms) for how it works. Fifty articles were included in this review, alongside the authors’ own expertise. Key theories about potential mechanisms include the effect of phototherapy on bile salt components, enzyme activity and the expression of receptors involved in cholestatic itch pathways. This paper has developed several testable hypotheses (theories) that can be trialled to increase knowledge on this important subject and to aid the development of effective treatments.     

Neuropathic and psychogenic itch

ABSTRACT:  Neuropathic and psychogenic itch are two entities that have not been well studied. Neuropathic itch is related to pathology located at any point along the afferent pathway of the nervous system. It could be related to damage to the peripheral nervous system, such as in postherpetic neuropathy, brachioradial pruritus, notalgia paresthetica, and in central nervous system damage as a result of spinal cord tumors and demyelinization diseases such as multiple sclerosis. It has many clinical features similar to neuropathic pain. Patients complain of itch, which coincides with burning sensation, aching, and stinging. Psychogenic itch is related to psychologic abnormalities e.g., itch in obsessive compulsive disorders, depression, and delusions of parasitosis. Although no controlled studies have been conducted for treatment of neuropathic and psychogenic itch, medications that are part of the treatment armentarium for neuropathic pain, depression, and anxiety seem to be effective.