The mind-skin connection: A narrative review exploring the link between inflammatory skin diseases and psychological stress.

Inflammatory skin diseases are known to negatively impact patient psychology, with individuals experiencing higher rates of stress and subsequent diminished quality of life, as well as mental health issues including anxiety and depression. Moreover, increased psychological stress has been found to exacerbate existing inflammatory skin diseases. The association between inflammatory skin diseases and psychological stress is a timely topic, and a framework to better understand the relationship between the two that integrates available literature is needed. In this narrative review article, we discuss potential neurobiological mechanisms behind psychological stress due to inflammatory skin diseases, focusing mainly on proinflammatory cytokines in the circulating system (the brain-gut-skin communications) and the default mode network in the brain. We also discuss potential descending pathways from the brain that lead to aggravation of inflammatory skin diseases due to psychological stress, including the central and peripheral hypothalamic-pituitary-adrenal axes, peripheral nerves and the skin barrier function.

Tropical parasitic itch in returned travellers and immigrants from endemic areas.

Itch is the most common skin symptom among tropical parasitic diseases (TPD), but there are limited data about its characteristics in these conditions. In dermatology practices and travellers' health clinics in the developed world, itch is a common complaint among travellers returning from endemic areas, as well among migrants arriving from endemic areas, where they may have been exposed to TPD. Studying aspects of pruritus among TPD may lead to improvements in prompt, accurate diagnosis and management of these conditions. This review examines the major itch-inducing TPDs, including schistosomiasis, echinococcosis, onchocerciasis, scabies, cutaneous larva migrans, larva currens, African trypanosomiasis, dracunculiasis and other causes of travel associated pruritus. We focus on the link between pruritus and other symptoms, aetiology, clinical staging and therapeutic options for these parasitic illnesses. Because some tropical parasitic diseases can present with significant pruritus, we attempt to identify aspects of the pruritus that are characteristic of-or unique to-specific conditions. These diagnostic insights may help clinicians create a rational and focused differential diagnosis and help determine optimal disease management pathways. In this sense, management involves treating the individual, seeking epidemiologically linked cases, preventing recurrences or relapses, and reducing spread of the disease.

Nemolizumab efficacy in prurigo nodularis: onset of action on itch and sleep disturbances.

BACKGROUND: Patients with prurigo nodularis (PN) have multiple itchy nodules, impaired quality of life and sleep deprivation. Prurigo nodularis patients have a high burden of disease, primarily due to the intensity of the itch. It is reasonable to expect that rapid relief of itch - and associated improvement of sleep - are highly valued clinical outcomes for patients. Nemolizumab is an IL-31A-receptor inhibitor that modulates the neuroimmune response with reported positive efficacy and safety data in a phase 2 study of PN. OBJECTIVES: To evaluate the onset of action of nemolizumab on itch and sleep disturbances. METHODS: Post hoc analysis of a phase 2 trial of nemolizumab 0.5 mg/kg SC vs. placebo in patients (n = 70) with moderate-to-severe PN (≥20 nodules) and severe pruritus (NRS ≥ 7). Time to significant reduction was assessed for peak pruritus (PP) and sleep disturbance (SD) using numerical rating scales (NRS), also assessed was scratching time during sleep. RESULTS: Nemolizumab significantly reduced itch vs. placebo within 48 h (PP NRS -19.5% vs. -5.8%, respectively, P = 0.014). Significant difference between nemolizumab and placebo in reducing itch by ≥4 on PP NRS was achieved at Day 3 (23.5% vs. 0%, P < 0.001). A significant difference in SD NRS was reported by Day 4 (-24.0% vs. -4.3% placebo, P = 0.012). In addition, there was a separation between groups in SD responders (decrease of ≥4 points) in favour of nemolizumab by Day 2 (8.8% vs. 0%, P = 0.037). Sleep continued improving through Week 4, when there was a -56.0% reduction in SD NRS vs. -22.9% placebo (P < 0.001). Actigraphy data showed improvement in scratch/sleep duration for nemolizumab vs. placebo, respectively, by Week 1 (-32.15 vs. +28.15 min/h, P = 0.001). CONCLUSION: Nemolizumab has a rapid and robust onset of action in PN with itch reduction and improvement of sleep within 48 h.

Scalp dysesthesia: a neuropathic phenomenon.

Scalp dysesthesia is an abnormal sensation of the scalp in the absence of cutaneous disease. It is characterized by a burning and/or itching sensation and can be related to a variety of neurogenic or psychogenic causes. This condition is extremely bothersome and is also common- especially among the geriatric population, in women, in patients with diabetes mellitus, and patients with psychiatric history. However, despite its prevalence in many populations, there are limited data about its causes and characteristics. Given its limited cutaneous manifestations, it is also easily misdiagnosed and an underrecognized cause of scalp pruritus in the dermatological community. Therefore, education on scalp dysesthesia is paramount to helping physicians identify and provide appropriate treatment for these patients. This review focuses predominantly on the neurogenic causes (with a brief review of psychogenic itch) of scalp dysesthesia and the therapeutics that have been found to be effective for this condition. Neurogenic causes of scalp dysesthesia occur with damage to the central or peripheral pathways of itch sensation, resulting in modification and heightened sensitivity of nerves that result in abnormal sensations in the absence of or out of proportion to external stimuli. A comprehensive review of etiologies is provided here, ranging from lesions to the central nervous system caused by cervical spine disease, trigeminal trophic syndrome, tumor, stroke, and multiple sclerosis, to small-fiber neuropathies caused by diabetes, brow lifts, keloid, and burn scarring. Recently, there have also been reports of scalp dysesthesias associated with post-infectious COVID-19. Treatment options tailored toward disease severity and different causes of disease will also be discussed. By elucidating the different mechanisms and therapeutic treatments of scalp dysesthesia, we hope to provide clinicians with the tools to identify and treat this condition as well as encourage further research into its etiologies and therapeutics.

A single-arm pilot of a web-based intervention to improve itch-related quality of life.

BACKGROUND: Many patients with chronic itch and atopic dermatitis (AD) or psoriasis do not receive/use available medical and psychosocial treatments properly due to system, provider and/or patient factors. OBJECTIVE: An educational website (ITCH-RELIEF) to improve itch-related quality of life (QoL) for adults with AD or psoriasis and chronic itch was developed and assessed. ITCH RELIEF stands for Interactive Toolbox of Comprehensive Health Resources to Enhance Living with Itch - Educational Facilitation (for Adults). METHODS: Single-arm pre- and post-test design with 1-month follow-up (N = 137 at baseline). RESULTS: There was statistically and clinically significant improvement in the primary outcome of itch-related QoL impairment as assessed by the ItchyQoL from baseline [M = 78.9, 95% confidence interval (CI) = 75.9, 81.9] to follow up (M = 75.4, CI = 72.4, 78.5), P = 0.007, as well as statistically significant improvement in several itch-related secondary outcomes (all Ps < 0.05). CONCLUSIONS: This study demonstrated initial effectiveness of an online intervention to improve itch-related QoL among individuals with AD or psoriasis and chronic itch. Future studies should address limitations by randomizing more heterogeneous participants, utilizing a longer follow-up and assessing medication use.

Patient-reported outcomes from the JADE COMPARE randomized phase 3 study of abrocitinib in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: In JADE COMPARE, abrocitinib improved severity of atopic dermatitis (AD) and demonstrated rapid itch relief. OBJECTIVES: We examined clinically meaningful improvements in selected patient-reported outcomes (PROs). METHODS: JADE COMPARE was a multicentre, phase 3 randomized, double-blind, placebo-controlled trial. Adults with moderate-to-severe AD were randomized 2:2:2:1 to receive 16 weeks of oral abrocitinib 200 or 100 mg once daily, dupilumab 300 mg subcutaneous injection every 2 weeks, or placebo, with background topical therapy. PROs included Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Night Time Itch Scale (NTIS), Pruritus and Symptoms Assessment for Atopic Dermatitis, Patient Global Assessment, SCORing Atopic Dermatitis, and Hospital Anxiety and Depression Scale. RESULTS: At week 16, the proportion of patients achieving POEM scores <3 was 21.3% and 11.7% for 200 and 100 mg abrocitinib, 12.4% for dupilumab, and 4.8% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.04). Proportion achieving ≥4-point improvement from baseline in NTIS severity was 64.3% and 52.4% for 200 and 100 mg abrocitinib, 54.0% for dupilumab, and 34.4% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.007). Proportion achieving ≥4-point improvement from baseline in DLQI was 85.0% and 74.4% for 200 and 100 mg abrocitinib, 83.4% for dupilumab, and 59.7% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.005). CONCLUSION: Significant improvements in PROs were demonstrated with both abrocitinib doses vs. placebo, and abrocitinib 200 mg provided numerically greater effects compared with dupilumab in patients with moderate-to-severe AD.

Efficacy and safety of oral nalbuphine extended release in prurigo nodularis: results of a phase 2 randomized controlled trial with an open-label extension phase.

BACKGROUND: Treatment of prurigo nodularis (PN) is challenging and new treatment options are needed. OBJECTIVE: To evaluate the efficacy and safety of two oral doses of the kappa opioid agonist and mu opioid antagonist nalbuphine extended release (NAL-ER) tablets in a phase 2, multicentre, randomized, double-blind, placebo-controlled trial with an open-label, 50-week extension phase. METHODS: Subjects with moderate-to-severe PN were randomized to NAL-ER 81 mg (NAL-ER81) or 162 mg (NAL-ER162) tablets twice-daily or placebo for 8 weeks of stable dosing following a 2-week titration period. Subjects completing Week 10 with a Worst Itch Numerical Rating Scale (WI-NRS) score ≥5 at the time of rollover (or during the observation period) were eligible for open-label treatment. RESULTS: Of 63 randomized subjects, 62 were treated and comprised the modified intent-to-treat population (MITT), 50 completed 10 weeks of treatment. In the MITT analysis, 8 subjects (44.4%) treated with NAL-ER162 (P = 0.32) and 6 (27.3%) treated with NAL-ER81 (P = 0.78) achieved ≥30% reduction from baseline in 7-day WI-NRS at Week 10 (primary efficacy endpoint) vs. 8 (36.4%) in the placebo group. Itch reduction was significant among 8/12 (66.7%) subjects completing Week 10 treated with NAL-ER162 vs. placebo (8/20, 40.0%; P = 0.03). Additionally, 6 subjects (33.3%) treated with NAL-ER162 and 3 (13.6%) treated with NAL-ER81 achieved ≥50% reduction from baseline in 7-day WI-NRS at Week 10 (coprimary endpoint). Extended open-label treatment was associated with further improvements in itch reduction and favourable changes in PN lesion activity as assessed by Prurigo Activity Score. Adverse events occurred predominantly during dose titration and were of mild-to-moderate severity. The safety profile did not change with extended open-label treatment. CONCLUSION: In adult subjects with PN, oral treatment with NAL-ER 162 mg twice daily provided measurable anti-pruritic efficacy in subjects completing ≥10 weeks of treatment and was well tolerated (ClinicalTrials.gov: NCT02174419).

Scabies itch: an update on neuroimmune interactions and novel targets.

Frequently described as 'the worst itch' one can ever experience scabies itch is the hallmark of Sarcoptes scabiei mite infestation. Notably, the itchiness often persists for weeks despite scabicides therapy. The mechanism of scabies itch is not yet fully understood, and effective treatment modalities are still missing which can severely affect the quality of life. The aim of this review is to provide an overview of the scope of itch in scabies and highlight candidate mechanisms underlying this itch. We herein discuss scabies itch, with a focus on the nature, candidate underlying mechanisms and treatment options. We also synthesize this information with current understanding of the mechanisms contributing to non-histaminergic itch in other conditions. Itch is a major problem in scabies and can lead to grave consequences. We provide the latest insights on host-mite interaction, secondary microbial infection and neural sensitization with special emphasis on keratinocytes and mast cells to better understand the mechanism of itch in scabies. Also, the most relevant current modalities remaining under investigation that possess promising perspectives for scabies itch (i.e. protease-activated receptor-2 (PAR-2) inhibitor, Mas-related G protein-coupled receptor X2 (MRGPRX2) antagonist) are discussed. Greater understanding of these diverse mechanisms may provide a rational basis for the development of improved and targeted approaches to control itch in individuals with scabies.

Fixed-dose combination calcipotriol/betamethasone dipropionate foam provides a rapid onset of action, effective itch relief and improves patient quality of life.

The physical symptoms of psoriasis vulgaris (chronic plaque psoriasis), such as itch and itch-related sleep loss, and the psychological impact of visible plaques on the body, all contribute to significantly reduced health-related quality of life (HRQoL) in patients with psoriasis. In fact, the deterioration of HRQoL in patients with psoriasis is similar to patients with other chronic conditions, such as cancer and cardiovascular diseases. Rapid and effective improvements in HRQoL and itch-related outcomes would therefore be highly valued by patients and may even improve adherence to treatment. In this article, we summarise previously published data assessing the impact of fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) on itch relief, quality of sleep, onset of action and HRQoL. Findings across multiple analyses indicate that Cal/BD foam provides significant improvements in itch, itch-related sleep loss and HRQoL compared with vehicle foam or Cal/BD gel comparators. Additionally, the benefits of Cal/BD foam were recorded earlier than these comparators, often within 1 week of treatment, indicating a rapid onset of action. With the published data to hand, it is clear that Cal/BD foam provides significant improvements in the outcomes that matter most to patients and should be considered an effective topical treatment for psoriasis.

Genodermatoses with itch as a prominent feature.

A number of inherited conditions cause chronic itch as a part of the recognized phenotype. Advances in the understanding of the genetic factors that cause these diseases elucidate the molecular underpinning of itch as a symptom. Our knowledge of the causes of chronic itch has also advanced, providing an opportunity to integrate the genetic pathophysiology with the molecular landscape of chronic itch mediators. This article reviews select genodermatoses that have itch as a predominant feature with a focus on the pathophysiology of the disease, how it may lead to itch and potential therapeutic targets.

Prevalence, pathophysiology and management of itch in epidermolysis bullosa.

Epidermolysis bullosa (EB) is a highly diverse group of inherited skin disorders, resulting from mutations in genes encoding proteins of the dermoepidermal junction. Itch (pruritus) is one of the most common symptoms across all EB subtypes. It occurs in blistered or wounded sites, or manifests as a generalized phenomenon, thereby affecting both intact skin and healing wounds. The mechanism of pruritus in EB is unclear. It is likely that skin inflammation secondary to barrier disruption, wound healing cascades and dysregulated activation of epidermal sensory nerve endings are all involved in its pathophysiology on the molecular and cellular level. Understanding these mechanisms in depth is crucial in developing optimized treatments for people with EB and improving quality of life. This review summarizes current evidence on the prevalence, mechanisms and management of itch in EB.

The treatment of Kyrle's disease: a systematic review.

Kyrle's disease (KD) is a cutaneous disease that develops in individuals with underlying systemic disease, particularly chronic renal failure and diabetes mellitus (DM), and is associated with a high burden of disease linked to itch. The intensely pruritic, hyperkeratotic papulonodular rash seen in KD dramatically impairs patients' quality of life and increases their risk of mortality. Unfortunately, no guidelines or evidence-based regimens have been specifically developed for KD, making the treatment of this disease particularly challenging for physicians. This article aims to provide the first comprehensive, up-to-date overview and analysis of treatment options employed for KD. A search of the PubMed/MEDLINE and Scopus databases was performed for articles regarding the treatment of KD, published in English between 1990 and 2019. Seventy-three articles were identified, of which eighteen met the inclusion criteria. We discovered that a wide variety of treatment regimens for KD have been reported in the literature, including oral antibiotics, immunosuppressants, phototherapy, topical/systemic retinoids, topical keratolytics and various combination therapies, which include some of the aforementioned treatments, in conjunction with oral/topical/injectable steroids, emollients and/or antihistamines. The use of a combination regimen is the most commonly practiced therapeutic approach to KD. Topical corticosteroids and depot corticosteroid injections repeatedly appeared in many of the regimens encountered during our search. While no definitive recommendations can be made based on existing literature, this article provides physicians with a summative outline that can help guide management and be referenced when other treatment efforts fail. The increasing prevalence of renal disease, DM and other chronic diseases will inevitably lead to rising rates of KD in the upcoming years. While randomized controlled trials are greatly needed, novel antipruritic immunomodulatory drugs targeting specific interleukin receptors (IL-4/13/31) and intracellular signalling (e.g. Janus kinase) pathways may have a potential role in the treatment of this disease.