Treatment With Upadacitinib in Refractory Prurigo Nodularis: A Prospective Cohort Study.

Prurigo nodularis (PN) is a chronic neuroinflammatory dermatosis with severe pruritus that has limited efficacy in various conventional treatments. This study investigated the outcomes of upadacitinib treatment in patients with refractory PN. A prospective study was conducted to screen for potential chronic infections prior to treatment. Upadacitinib was administered at a daily dose of 15 mg for 24 weeks, and the treatment response was assessed using the itch Numeric Rating Scale (NRS), investigator's Global Assessment (IGA), and Dermatology Life Quality Index (DLQI). Adverse events were monitored at each visit. Ten patients, with an average age of 48.8 years, were included in the study. All participants were treated with systemic cyclosporine before receiving upadacitinib, which yielded limited responses. At baseline, the mean prurigo severity scores assessed using the IGA, DLQI, and itch NRS were 3.4, 17.8, and 8.1, respectively; after 24 weeks of treatment, these scores significantly reduced to 1.0, 0.6, and 0.8, respectively. No severe adverse effects were observed. In conclusion, upadacitinib could be considered an alternative therapeutic option with good tolerability for refractory PN.

The role of blood purification therapies in the treatment of chronic kidney disease-associated pruritus: a systematic review.

Chronic kidney disease-associated pruritus (CKD-aP) is a common complication in dialysis patients which is not fully addressed by pharmacological and dialytic therapy. The objective was to review the literature on the effects of extracorporeal blood purification modalities on CKD-aP. The population comprised patients aged ≥18 years on chronic dialysis. PubMed, Embase, and Medline were systematically searched until February 2024 for clinical studies comparing the effect of different dialysis modalities on pruritus intensity. Two reviewers extracted data independently. Risk of bias for randomized controlled trials (RCTs) was assessed using the Cochrane tool. Any extracorporeal blood purification therapy for the treatment of CKD-aP was included. Outcome was quantitative change in pruritus intensity on a validated itching scale. This review included eight RCTs examining five different dialysis modalities, three observational studies examining three dialysis modalities, and six prospective clinical trials assessing four dialysis modalities. These treatments included peritoneal dialysis, low-flux and high-flux dialysis, hemodiafiltration, expanded hemodialysis, hemadsorption, hemodiafiltration with endogenous reinfusion and dialysis with polymethylmethacrylate membrane. Risk of bias was high in most studies. The largest body of evidence was found for the efficacy of hemadsorption. Limitations of evidence included heterogeneity in diagnostic tools and treatment, risk of selection bias, small sample sizes and short follow-up durations that made it challenging to perform a robust systematic review and meta-analysis. Despite the high prevalence of pruritus among dialysis patients, current evidence for efficacy of standard dialytic treatment is weak. The only technique that appears to be effective is hemoadsorption alone or coupled with hemodialysis. More high-quality studies are needed to confirm the long-term benefits.

Current clinical practice of prurigo nodularis in Japan: A cross-sectional web-survey among dermatologists.

Prurigo nodularis (PN) is a chronic inflammatory skin disease associated with intense pruritic nodules. The unclear patho-etiological mechanisms of PN cause difficulty in disease management; and there is a paucity of information on the current diagnosis and treatment options for PN in Japan. To describe the current management from a dermatologists' perspective we conducted a web-based survey (UMIN Clinical Trial Registry UMIN000047643) in 2022 among dermatologists from a Japanese commercially available physician panel, who had seen at least one patient with PN within the last 3 months. The survey included 117 dermatologists. The dermatologists diagnosed PN mainly by confirming clinical signs and patient interviews, while to assess the severity of PN, the number of pruritic nodules and the degree of itching were primarily utilized. Topical corticosteroids and antihistamines were the most used drugs, as recommended in the current guidelines on the diagnosis and treatment of prurigo. Dermatologists' treatment satisfaction decreased with increasing assumed severity of PN; almost 65% dermatologists were not satisfied with the treatment of severe PN. These results suggest the need of more effective medications and diagnostic tools for better management of PN in Japan.

Intrahepatic cholestasis of pregnancy: Introduction and overview 2024.

Considerable progress has been made to explain the aetiology of intrahepatic cholestasis of pregnancy (ICP) and of the adverse pregnancy outcomes associated with high maternal total serum bile acids (TSBAs). The reported thresholds for non-fasting TSBA associated with the risk of stillbirth and spontaneous preterm birth can be used to identify pregnancies at risk of these adverse outcomes to decide on appropriate interventions and to give reassurance to women with lower concentrations of TSBA. Data also support the use of ursodeoxycholic acid to protect against the risk of spontaneous preterm birth. A previous history of ICP may be associated with higher rates of subsequent hepatobiliary disease: if there is a suspicion of underlying susceptibility, clinicians caring for women with ICP should screen for associated disorders or for genetic susceptibility and, where appropriate, refer for ongoing hepatology review.

Consenso sobre el algoritmo diagnóstico del prurigo crónico nodular.

Chronic nodular prurigo (CNP) is a chronic dermatological disease characterized by the presence of chronic pruritus and pruritic nodular lesions. The aim of this study was to reach consensus among a group of experts based on a non-systematic literature review and an algorithm for the clinical diagnosis of CNP. The resulting algorithm is structured in 3 blocks: 1) early identification of the patient with a possible diagnosis of CNP; 2) diagnosis and assessment of CNP; and 3) categorization of CNP (identification of the underlying causes or associated comorbidities).We believe that this clinical algorithm can facilitate the correct diagnosis of patients with CNP. Additionally, it raises awareness on the need for a multidisciplinary approach and specific treatment of CNP, steps of paramount importance to make better therapeutic decisions.

Exploring the Association Between Atopic Dermatitis and Malignancy: A Comprehensive Review with Therapeutic Strategies.

Atopic dermatitis (AD) is a prevalent dermatologic condition affecting both children and adults, and the debate surrounding its association as either a risk or protective factor for malignancies has garnered significant attention. Proposed mechanisms suggest that AD may act protectively against cancer formation through chronic immune system activation or create an inflammatory state conducive to cancer development. This review discusses the relationship between AD and various skin cancers, solid tumors, and hematologic malignancies. Additionally, the authors explore the impact of AD treatments, particularly novel biologic drugs targeting molecular pathways such as JAK-STAT, IL-4, and IL-13 in association with malignancies.

Progressive familial intrahepatic cholestasis type 4: a case report.

BACKGROUND: Progressive familial intrahepatic cholestasis is an autosomal recessive genetic disorder that manifests primarily with jaundice and pruritus and can progresses from persistent cholestasis to cirrhosis and late childhood liver failure. Classically, progressive familial intrahepatic cholestasis is classified into three subtypes: 1, 2, and 3 and results from a defect in a biliary protein responsible for bile formation and circulation in the liver. In the last decade and with the increased use of genetic testing, more types have been known. CASE PRESENTATION: A 6-month-old Afrocentric boy presented with progressive jaundice and pruritus that started since the age of 2 months. He was thoroughly investigated to be finally diagnosed as progressive familial intrahepatic cholestasis type 4. A low-fat diet, ursodeoxycholic acid, fat-soluble vitamins, and cholestyramine were started. He showed initial improvement then had refractory pruritus and impaired quality of life. He underwent surgical biliary diversion at the age of 1 year with marked improvement of manifestations. CONCLUSION: Owing to the increased technology of genetic testing, more clinical subtypes of progressive familial intrahepatic cholestasis were diagnosed other than the classical three types. Surgical management using biliary diversion could be beneficial and delays or may even obviate the need for liver transplantation.

Efficacy and Safety of Omega-3 Fatty Acids in Ameliorating Pruritus in Adult Patients With Chronic Kidney Disease: A Meta-Analysis of Randomized Controlled Trials.

Chronic kidney disease-associated pruritus (CKD-aP) represents a common distressing problem in patients with end-stage renal disease. This study aimed to assess the efficacy and safety of omega-3 supplementation in the treatment of CKD-aP. MEDLINE/PubMed, Cochrane Central Register of Controlled Trials, Web of Science, ProQuest, and Scopus databases were searched systematically for articles published from inception until May 21, 2024. Outcomes were pruritus severity at the end of the study or its change from baseline (primary) and intervention-related adverse effects (secondary). Results were pooled as standardized mean difference (SMD) and risk ratio (RR) for numeric and dichotomous outcomes, respectively, along with their 95% confidence intervals (CIs). Eight studies were included. Treatment with omega-3 fatty acids showed a significantly lower severity of CKD-aP at the end of treatment (pooled SMD (95% CI) = -1.03 (-1.85, -0.22), p = 0.024) and changed from baseline (pooled SMD (95% CI) = -0.93 (-1.57, -0.28), p = 0.014). Omega-3 supplementation reduced the risk of CKD-aP (pooled RR (95% CI) = 0.68 (0.12, 3.81), p = 0.661). Omega-3 fatty acid supplementation appears to be a promising effective and safe treatment for CKD-aP. However, the included studies had several limitations that warrant further high-quality studies to elucidate its effect and investigate the causes of non-response in patients who did not improve.

Biomarkers and patient-related factors associated with clinical outcomes in dupilumab-treated atopic dermatitis.

Background: Atopic dermatitis (AD) is a common chronic eczematous skin disease with severe pruritus. Several new therapeutic agents for AD such as dupilumab, an anti-IL-4Rα antibody, have been developed in recent years. We need to predict which agent is the best choice for each patient, but this remains difficult. Objective: Our aim was to examine clinical background factors and baseline biomarkers that could predict the achievement of improved clinical outcomes in patients with AD treated with dupilumab. Methods: A multicenter, prospective observational study was conducted on 110 patients with AD. The Eczema Area and Severity Index was used as an objective assessment, and the Patient-Oriented Eczema Measure and Numerical Rating Scale for Pruritus were used as patient-reported outcomes. In addition, some clinical background factors were evaluated. Results: The achievement of an absolute Eczema Area and Severity Index of 7 or less was negatively associated with current comorbidity of food allergy and baseline serum lactate dehydrogenase (LDH) levels. There were negative associations between achievement of a Patient-Oriented Eczema Measure score of 7 or less and duration of severe AD and between achievement of an itching Numerical Rating Scale for Pruritus score of 1 or less and current comorbidity of allergic conjunctivitis or baseline serum periostin level. Furthermore, signal detection analysis showed that a baseline serum LDH level less than 328 U/L could potentially be used as a cutoff value for predicting the efficacy of dupilumab. Conclusion: Baseline biomarkers such as LDH and periostin and clinical background factors such as current comorbidity of food allergy and a long period of severe disease may be useful indicators when choosing dupilumab for systemic treatment for AD, as they can predict the efficacy of dupilumab.

Cannabis-Containing Cream for CKD-Associated Pruritus: A Double-Blind, Placebo Controlled Trial.

Rationale & Objective: This study aims to compare the efficacy of a cannabis cream and a placebo in the treatment of chronic kidney disease (CKD)-associated pruritus. Study Design: A double-blind randomized controlled study. Setting & Participants: Sixty hemodialysis patients with the worst itching intensity numerical rating scale (WI-NRS) ≥3. Exposure: Patients received cannabis cream or placebo. Outcomes: The primary endpoint was the WI-NRS score at week 4. The secondary endpoints included the WI-NRS at week 2, the Skindex-10 score at weeks 2 and 4, and the mean difference score between baseline and week 4 for the WI-NRS and the Skindex-10 score. Analytical Approach: We used unpaired t tests or Mann Whitney U tests, along with χ2 or Fisher exact tests as appropriate. The adjusted mean differences were determined using ANCOVA, adjusting for baseline scores. Results: Among 60 participants, the mean age was 61.6 ± 14.4 years and the mean baseline WI-NRS was 6.7 ± 1.7. The placebo and cannabis cream groups were similar at baseline, although more individuals in the placebo group had diabetes. At 4 weeks, the WI-NRS dropped to 2.6 in the cannabis group and 3.6 in the placebo group (the mean difference after adjustment for baseline scores:-1.1, 95% CI, -2.1 to -0.2; P = 0.02). Skindex-10 scores at week 4 were also lower in the cannabis group, but after adjustment for baseline scores, statistical significance was not maintained. No side effects were observed in either group. Limitations: A single study with a small sample size restricts its generalizability. Variances in participants' diabetes statuses might have affected the itch outcomes. The absence of cannabinoid level assessment in blood prevents conclusive determination of the potential systemic impacts. A 4-week follow-up period inadequately captures long-term effect. Conclusions: In CKD-associated pruritus, the topical cream containing cannabis significantly reduced the severity of itching symptoms compared to the placebo. Trial Registration: clinicaltrials.gov Identifier: NCT06159686.

Chronic kidney disease (CKD)-associated pruritus presents a significant burden to hemodialysis patients, with current medications often falling short in alleviating symptoms. Cannabinoids, with their anti-inflammatory, antioxidative, and peripheral nerve activation reduction properties, hold promise in treating CKD-associated pruritus. Especially when applied topically, cannabinoids could provide moisturized skin along with their other effects. We analyzed the efficacy of cannabis cream compared to a placebo, demonstrating that the cannabis cream could improve the severity of itch, as reported by the WI-NRS score at the end of the fourth week of treatment. This innovative therapeutic approach has the potential to pave the way for new drugs aimed at effectively treating CKD-associated pruritus, ultimately reducing symptom severity, and potentially enhancing patients' quality of life.

Integrative Treatment Approaches with Mind-Body Therapies in the Management of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex pathophysiology characterized by intense pruritus, often associated with psychological stress and atopic and non-atopic comorbidities that significantly reduce quality of life. The psychological aspects of AD and the interaction between the mind and body via the skin-brain axis have led to an interest in mind-body therapies (MBT). The aim of this article is, therefore, to reinforce the importance of psychodermatological care in AD. We performed a focused literature review on holistic practices or integrative MBT in AD, including education, cognitive behavioral therapy, habit reversal, meditation, mindfulness, hypnotherapy, eye movement desensitization and reprocessing, biofeedback, progressive muscle relaxation, autonomous sensory meridian response, music therapy, massage, and touch therapy. A multidisciplinary holistic approach with MBT, in addition to conventional pharmacologic antipruritic therapies, to break the itch-scratch cycle may improve AD outcomes and psychological well-being. Although there is a paucity of rigorously designed trials, evidence shows the potential benefits of an integrative approach on pruritus, pain, psychological stress, anxiety, depressive symptoms, and sleep quality. Relaxation and various behavioral interventions, such as habit reversal therapy for replacing harmful scratching with massaging with emollient 'plus', may reduce the urge to scratch, while education may improve adherence to conventional therapies.

A case of chronic spontaneous urticaria with wheals lasting for more than a week.

Urticaria is characterized by the development of wheals which usually disappear within a day, and are not present beyond a few days. A 58-year-old man began to develop edematous, partially ring-shaped erythematous lesions accompanied by severe body itching without any particular cause, approximately 2 months before his first visit to our hospital. Each rash emerged as being about 5 mm in diameter, gradually enlarging over several days, and disappeared in up to 10 days. Despite oral treatment with several antihistamines and 10 mg of prednisolone, there was no improvement. Most eruptions disappeared without a trace, but the erythema that appeared on the palms left desquamation. The patient had a history of shellfish allergy, but otherwise no atopic diseases. Drug eruption was ruled out due to a lack of regular taking other medications. Histopathological findings of the skin lesions showed moderate lymphocytic and few eosinophilic infiltrates with edema, but no evidence of vasculitis. Despite the concomitant use of two second-generation antihistamines and montelukast, the rash did not improve. The symptoms began to improve following oral intake of 1.5 mg of betamethasone, which was tapered off with the addition of 150 mg of cyclosporin. The use of all medications was stopped at 4 months from the first visit without recurrence. Wheals of chronic spontaneous urticaria may last for longer than a week without apparent histopathological findings of vasculitis.

Mouse Models of Itch.

Murine models are vital preclinical and biological tools for studying itch. In this paper, we explore how these models have enhanced our understanding of the mechanisms underlying itch through both acute and chronic itch models. We provide detailed protocols and recommend experimental setups for specific models to guide researchers in conducting itch research. We distinguish between what constitutes a bona fide pruritogen versus a stimulus that causes pruritogen release, an acute itch model versus a chronic itch model, and how murine models can capture aspects of pruritus in human disease. Finally, we highlight how mouse models of itch have transformed our understanding and development of therapeutics for chronic pruritus in patients.

Activation of NPY2R-expressing amygdala neurons inhibits itch behavior in mice without lateralization.

The central amygdala (CeA) is a crucial hub in the processing of affective itch, containing a diverse array of neuronal populations. Among these components, Neuropeptide Y (NPY) and its receptors, such as NPY2R, affect various physiological and psychological processes. Despite this broad impact, the precise role of NPY2R+ CeA neurons in itch modulation remains unknown, particularly concerning any potential lateralization effects. To address this, we employed optogenetics to selectively stimulate NPY2R+ CeA neurons in mice, investigating their impact on itch modulation. Optogenetic activation of NPY2R+ CeA neurons reduced scratching behavior elicited by pruritogens without exhibiting any lateralization effects. Electrophysiological recordings confirmed increased neuronal activity upon stimulation. However, this modulation did not affect thermal sensitivity, mechanical sensitivity, or formalin-induced hyperalgesia. Additionally, no alterations in anxiety-like behaviors or locomotion were observed upon stimulation. Projection tracing revealed connections of NPY2R+ CeA neurons to brain regions implicated in itch processing. Overall, this comprehensive study highlights the role of NPY2R+ CeA neurons in itch regulation without any lateralization effects.

Association between atopic dermatitis and prurigo nodularis: a systematic review and meta-analysis.

Atopic dermatitis (AD) and prurigo nodularis (PN) are chronic dermatological conditions marked by severe itching and the presence of eczematous lesions such as papules and nodules. Both diseases can pose significant physical and psychological harm, leading to poor quality of life. Notably, AD and PN were clinically linked in the past, with suggestions by researchers that PN might be a distinct clinical phenotype of AD. However, the extent of their relationship had not been fully quantified until our recent investigations. Through a meticulous systematic review and meta-analysis adhering to the PRISMA guidelines, we extensively searched databases, including PubMed, EMBASE, Scopus, and the Cochrane Library, up to February 18, 2024. Our random effects meta-analysis presented a strikingly increased risk of AD in patients suffering from PN as opposed to control groups (pooled unadjusted odds ratio [OR], 16.85; 95% confidence interval [CI], 6.13-46.31; I2 = 100%). Correspondingly, an elevated prevalence of PN was identified in subjects with AD (2.00%; 95% CI, 1.62-2.37%). These findings underscore the close association between AD and PN, suggesting a multifaceted overlap and potential bi-directionality in developing these skin conditions. However, further comprehensive studies are essential to validate these associations and understand their precise clinical implications, with the ultimate goal of refining patient management strategies.

Interleukin-31: The Inflammatory Cytokine Connecting Pruritus and Cancer.

Interleukin 31 (IL-31) is a proinflammatory cytokine, mainly secreted by Type II helper T cells. It signals through a heterodimeric receptor complex composed of IL-31 receptor α and oncostatin-M receptor ß chain. The hallmark feature of IL-31, in its pathological role, is its ability to induce pruritus in mammals. Pruritus is a common symptom and major reason of morbidity in cancer patients, compromising their quality of life. Although, IL-31 is differentially expressed in different tumor types and could promote or inhibit cancer progression, high expression of IL-31 is a contributing factor to advanced stage tumor and severity of pruritus. The simultaneous existence of pruritus and cancer could either result from the aberrations in common proteins that co-exist in both cancer and pruritus or the therapeutic treatment of cancer could indirectly induce pruritus. Although the biology of IL-31 has predominantly been described in skin diseases such as atopic dermatitis and other inflammatory diseases, the precise role of IL-31 in the tumor biology of different cancer types remains elusive. Herein, we summarize the current understanding on the role of this cytokine in the pathogenesis of different cancers.

Rationale for the topical use of a combination of diphenhydramine hydrochloride and lidocaine hydrochloride in the symptomatic treatment of histamine-dependent allergic and inflammatory skin reactions, accompanied by pruritus.

Introduction: Allergic reactions caused by external factors are treated with medicinal products containing antihistamines, therefore their action is delayed in time. Combination of antihistamines and fast-acting analgesics may help to reduce discomfort associated with cutaneous reactions. Aim: To evaluate efficacy and safety of the combination topical gel containing diphenhydramine hydrochloride 20 mg/g and lidocaine hydrochloride 10 mg/g over placebo in the treatment of local skin inflammatory and allergic reactions. Material and methods: A study was a single-centre, single-dose, randomized, double-blind, two-treatment, two-period, two-sequence cross-over clinical trial (n = 44) in healthy subjects. Local skin inflammatory and allergic lesions were induced by the provocative test with histamine in healthy subjects. For all parameters recorded with the Visual Analogue Scale (VAS), the area under the curve (AUC) was calculated and the peak itch intensity was noted for every subject in response to the skin prick test. The primary endpoint of the study was the difference in AUC calculated from the intensity of itch for test product A (diphenhydramine hydrochloride 20 mg/g and lidocaine hydrochloride 10 mg/g, gel) and placebo product B. Results: The results revealed that itching intensity AUC was significantly greater for product B than for product A, on average by 2.05 points. A decrease in itching intensity was observed from the second minute after application of the test product. Conclusions: The study provided evidence for differences in efficacy between the product tested and placebo.