Severe Pruritus Research Articles

Needle-Free Jet Injector-Assisted Triamcinolone Treatment of Keloids and Hypertrophic Scars is Effective and Well Tolerated in Children.

Keloids and hypertrophic scars can cause severe pain, pruritus, and psychological distress. Conventional intralesional corticosteroid treatment with needle injections remains challenging, especially in children with needle phobia. We aimed to evaluate the effectiveness, tolerability, and patient satisfaction of intralesional treatment with triamcinolone acetonide using a needle-free electronic pneumatic jet injector in children with keloids and hypertrophic scars. A retrospective study was performed in children with keloids and hypertrophic scars who received intralesional triamcinolone acetonide treatments using an electronic pneumatic jet injector. Effectiveness was evaluated using the Patient and Observer Scar Assessment Scale and Global Aesthetic Improvement Score at follow-up versus baseline. Tolerability was assessed with reported adverse effects and injection-related pain using a visual analog scale. Satisfaction questionnaires were used to evaluate treatment-related patient satisfaction. Six female patients and five male patients aged 5-17 years, with a total of >118 keloids or hypertrophic scars were included. Electronic pneumatic jet injector treatment led to a significant reduction in the total Patient and Observer Scar Assessment Scale observer and patient scores compared with baseline, with a median reduction of 28.9% and 23.8%, respectively (p = 0.005; p = 0.009). Median visual analog scale pain scores for electronic pneumatic jet injector treatment were significantly lower compared with needle injections, 3.0 versus 7.0, respectively (p = 0.027). No severe adverse effects were reported. Overall, 6 patients were 'satisfied' and five patients were 'very satisfied' with the treatment. Electronic pneumatic jet injector-assisted intralesional triamcinolone acetonide is an effective and well-tolerated treatment for keloids and hypertrophic scars in children. It should be considered as an alternative non-traumatic delivery method, especially in children with needle phobia or severe pain during previous needle injections.

Comparison of the ED50 of prophylactic butorphanol in preventing morphine-induced pruritus with or without palonosetron: a prospective, double-blinded, randomized dose–response trial using an up-down sequential allocation method

Background Butorphanol has been used to reduce the incidence and severity of neuraxial morphine-induced pruritus. Palonosetron is a commonly used antiemetic for the prevention of postoperative nausea and vomiting. The aim of our study was to compare the effective dose in 50% of subjects (ED50) of intravenous butorphanol infusion with or without a single intravenous bolus of palonosetron for preventing pruritus induced by epidural administration of morphine. Methods A total of 120 parturients were randomly assigned to receive an intravenous bolus injection of palonosetron plus continuous infusion of butorphanol (Group P + B) or an intravenous bolus of saline plus continuous infusion of butorphanol (Group B) after epidural administration of morphine. The antipruritic effect was graded as satisfactory (numerical rating scale (NRS) of pruritus ≤3) or unsatisfactory (NRS >3) within 48 h after morphine treatment. The first patient in each group received butorphanol infusion at a rate of 4 µg/kg/h. The infusion dose for each subsequent patient in the corresponding group was increased by 0.2 µg/kg/h after an unsatisfactory response or decreased by 0.2 µg/kg/h after a satisfactory response. The ED50 was calculated for each group and compared using up-down sequential analysis. Results The ED50 (mean [95% confidence interval (CI)]) of the dose of intravenous butorphanol infusion for preventing moderate to severe pruritus was lower in Group P + B (3.29 µg/kg/min [3.25–3.34 µg/kg/min]) than in Group B (3.57 µg/kg/min [3.47–3.67 µg/kg/min]) (p < 0.05). Conclusions Under the conditions of the present study, a prophylactic use of 0.25 mg palonosetron reduced the ED50 of prophylactic infusion of butorphanol by approximately 8% to achieve a satisfactory antipruritic effect after epidural morphine for post-caesarean analgesia.

Effectiveness of switching from baricitinib 4 mg to upadacitinib 30 mg in patients with moderate-to-severe atopic dermatitis: a real-world clinical practice in Japan

Background Atopic dermatitis (AD) is a chronic eczematous disease with severe pruritus. Janus kinase (JAK) inhibitors, upadacitinib, baricitinib, and abrocitinib, are systemic treatments for AD. The outcomes of switching from one JAK inhibitor to another have not been examined. Objectives We assessed the outcomes of switching from baricitinib 4 mg to upadacitinib 30 mg in Japanese patients with moderate-to-severe AD. Methods Twenty patients treated with baricitinib 4 mg, showing insufficient response or adverse events, were switched to treatment with upadacitinib 30 mg. We evaluated total eczema area and severity index (EASI), EASI at head and neck, trunk, upper, or lower limbs, EASI of erythema, edema/papulation, excoriation, or lichenification, and peak pruritus numerical-rating scale (PP-NRS) at baseline (start of baricitinib), weeks 0 (time of switching), and 4 and 12 after switching. Results Total EASI, EASI at each anatomical site, EASI of each clinical sign, and PP-NRS were markedly reduced at weeks 4 or 12 compared to week 0. Achievement rates of more than 75% or 90% reduction of EASI from baseline significantly improved after switching. Conclusions Switching from baricitinib 4 mg to upadacitinib 30 mg effectively improved rash and pruritus.

Higher-order sensorimotor circuit of the whole-brain functional network involved in pruritus regulation in atopic dermatitis.

Little is known about the neural mechanisms underlying pruritus regulation in Atopic dermatitis (AD). To investigate the functional changes of the resting-state whole brain network of AD participants and the mechanisms by which they were involved in pruritus regulation. Based on the functional magnetic resonance imaging data from 19 AD participants and 37 healthy controls (HC), a graph-theoretical measure of degree centrality (DC) conjoined with a voxel-level seed-based functional connectivity (FC) method was used to identify abnormal higher-order nodes and the functionally relevant circuit in AD participants compared to healthy controls (HC). Of 64 participants screened, 19 AD participants (12M/7F, median [IQR] age, 27 [14] years) and 36 HCs (13M/23F, median [IQR] age, 20 [1] years) were enrolled. DC values of the left superior frontal gyrus (LSFG) increased in AD participants and exhibited a negative correlation with the SCORAD score (r = -0.561, p = 0.012) compared with HC. In the FC analysis with LSFG as the seed, FC values of several sensory and motor regions increased in AD participants, highly overlapping with the anatomical distribution of the inferior fronto-occipital fascicle (IFOF). AD participants with severe pruritus exhibited lower levels of DC (T = -2.316, p = 0.033) and FC between the LSFG and left insula (T = -2.203, p = 0.042) than those with mild-to- moderate pruritus. LSFG was involved in pruritus regulation in AD by forming a high-order sensorimotor circuit through the IFOF, a white matter fascicle that proved to provide multimodal integration in motor control and sensory information processing. These results offer more mechanism-guided treatment targets for severe pruritus in AD.

A Rare Case of Rifampicin-induced Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome

ABSTRACT Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an idiosyncratic adverse drug reaction that can be lethal in up to 20% cases. The commonest culprit drug includes phenytoin, allopurinol, phenobarbital, sulfasalazine and lamotrigine. DRESS syndrome due to antitubercular medicines is rarely reported. In India despite the widespread use of antitubercular medicines, only few cases of DRESS syndrome have been reported. Here we report an interesting case of a 23 year old girl who presented to us with complaints of high grade fever, cough, GI discomfort, numbness, severe pruritus and burning skin sensation. She was receiving antitubercular medicines for tubercular pleural effusion for the last three weeks. She was hospitalised for a suspected adverse drug reaction which was diagnosed as DRESS syndrome on the basis of RegiSCAR criteria. On re-challenge testing the culprit drug was found to be rifampicin. In this case the severity of skin involvement was much higher as compared to organ involvement.

EE120 Cost-Effectiveness of Difelikefalin for the Treatment of Moderate to Severe Chronic Kidney Disease-Associated Pruritus (CKD-AP) in Adult Patients Receiving in-Centre Haemodialysis

EE120 Cost-Effectiveness of Difelikefalin for the Treatment of Moderate to Severe Chronic Kidney Disease-Associated Pruritus (CKD-AP) in Adult Patients Receiving in-Centre Haemodialysis

What's New in Cutaneous T-Cell Lymphoma-Associated Pruritus.

Cutaneous T-cell lymphomas are a heterogenous group of lymphomas that cause various skin manifestations. Severe pruritus occurs frequently in cutaneous T-cell lymphoma and negatively impacts patients' quality of life. The pathophysiology of cutaneous T-cell lymphoma-associated itch is complex and involves various immune cells, inflammatory cytokines, and neuroimmune interactions. Treating cutaneous T-cell lymphoma pruritus can be challenging, and there have been few randomized controlled studies evaluating the use of antipruritic treatments in these patients. Systemic therapies targeting the disease have also beenshown to have some antipruritic effects. Furthermore, although biologic therapy has revolutionized the treatment of other pruritic skin conditions, the use of biologics in cutaneous T-cell lymphoma remains controversial.

Cutaneous lesions and clinical outcomes in five cats after frunevetmab injections.

This case series describes five cats with cutaneous adverse events after subcutaneous administration of frunevetmab, a felinised anti-nerve growth factor monoclonal antibody, including histopathological findings in one case. All cats displayed moderate to severe pruritus resulting in self-trauma to the neck and/or head, causing lesions ranging from superficial dermatitis to alopecia and ulcerations. There were no reactions at the injection sites. In one cat, clinical signs developed after the second frunevetmab dose the cat received, with no reaction noted after the first dose. For the remaining cats, clinical signs were observed after their first dose of frunevetmab. The onset of the first episode of pruritus and self-trauma was 3-18 days after the most recent frunevetmab injection. Three cats had one or more additional frunevetmab injections after the original adverse event and all had subsequent reactions. Subsequent reactions were either similar in time frame or occurred more rapidly, with similar or more severe pruritus compared with the original reactions. Treatments and outcomes varied between cases. Frunevetmab is a novel, monthly injectable monoclonal antibody for the management of pain associated with osteoarthritis in cats. This is the first published report detailing the nature of cutaneous adverse events associated with this treatment, and the first report of the histopathological findings.

Gabapentin and oral antidepressants for chronic pruritus: a prospective cohort study evaluating efficacy and side effects in daily dermatological practice

BackgroundChronic pruritus is frequently seen in daily dermatological practice and is associated with marked impact on quality of life. Research on the use of gabapentin and oral antidepressants in daily dermatological practice is scarce.ObjectiveTo evaluate the efficacy and safety of gabapentin and oral antidepressants in patients with chronic pruritus in daily clinical practice.MethodsA prospective observational single-center cohort study was conducted including adult patients with chronic pruritus and an indication for systemic treatment between June 2016 and May 2019.ResultsSystemic treatment with gabapentin and/or antidepressants was initiated in 31 patients with severe chronic pruritus (median average pruritus NRS score 7.0), in which most cases no underlying origin was identified (83.9%). In patients treated with gabapentin 900–1800 mg/day (N = 25), median average pruritus NRS decreased to 5.5 (IQR 3.0) after 4 weeks and remained stable up to 24 weeks of treatment. Efficacy of antidepressants was variable, with the highest response after initiation of amitriptyline, nortriptyline, and mirtazapine. Side effects were frequently observed in both gabapentin and antidepressant treatments; however, were mostly mild and temporary.LimitationsThis was a single-site observational study, with limited sample size.ConclusionTreatment with gabapentin and antidepressants should be considered in patients with chronic pruritus unresponsive to conventional treatment.

Immune pathogenesis and immune therapy of a sclerosing variant of vulvar lichen sclerosus: a prospective cohort study

Background. Today, no unified clinical classification of vulvar lichen sclerosus is registered (is yet to be registered?). Isolation of pathogenetically and clinically different variants of its course enable new approaches to the treatment to be developed. Objective. To develop a pathogenetic therapy for the sclerosing variant of vulvar lichen sclerosus, taking into account its clinical and immunological characteristics. Methods. A prospective cohort study was conducted from 2018 to 2022 on the basis of Regional Clinical Hospital No. 2, Krasonodar, Russia. 292 patients aged 20 to 70 years were histologically diagnosed with vulvar lichen sclerosus. After a clinical examination using the scale for assessing subjective and objective clinical signs of vulvar lichen sclerosus, 154 patients with a sclerosing variant of the disease course were selected for the study. The control cohort consisted of 30 women of the same age category without vulvar lichen sclerosus, taking into account the exclusion criteria. The study involved a clinical assessment (in points) of objective and subjective criteria characteristic of this variant of vulvar lichen sclerosus, as well as an assessment of the level of cytokines (interleukin-20; interleukin-23; interleukin-10; tumor necrosis factor α, interferon γ) in peripheral blood of the patients from the main and control groups. One month after the immunotherapy with sodium deoxyribonucleate, the authors evaluated its clinical efficacy (using Numerical rating scale for pain (vulvodynia) and Vulvar pruritus severity scale) and immunological efficacy (repeated assessment of the level of the studied cytokines). Analysis and statistical processing of the obtained data were performed using Graph Pad Prism version 6.0 (GraphPad Software, Inc., San Diego, CA). Results. Depigmentation of the vulvar skin against the background of vulvar sclerosis and thickening features a sclerosing variant of vulvar lichen sclerosus compared to vulvar atrophy. Stenosis of the vaginal vestibule is either absent (51.3%) or predominantly corresponds to grade I, and is less specific than depigmentation and even skin atrophy. The subjective signs include a severe vulvar pruritus without or with moderately expressed (in 68.1%) vulvodynia. An immunological study showed a statistically significant increase in the level of interleukin-20 (p &lt; 0.0001), interleukin-23 (p &lt; 0.0001), interferon-γ (p &lt; 0.03), tumor necrosis factor α (p &lt; 0.009) in patients with maximal tissue sclerosis with respect to the control group, along with a statistically significant decrease in the level of anti-inflammatory interleukin-10 (p &lt; 0.01). The immunological efficacy of sodium deoxyribonucleate was confirmed by a statistically significant (compared to baseline) decrease in interleukin-20 (p &lt; 0.0001), interferon-γ and tumor necrosis factor α (p &lt; 0.002), interleukin-23 (p &lt; 0.012) without statistical differences with the control group (except for interleukin-23, the level of which decreased after therapy but remained statistically higher (p &lt; 0.01) than in the control group). Clinical efficacy of immunotherapy was confirmed by a statistically significant (p &lt; 0.001) reduction in vulvodynia and vulvar pruritus after the treatment. Conclusion. The obtained data demonstrate characteristic clinical features and immunological differences in relation to the norm in women with the sclerosing variant of vulvar lichen sclerosus, thereby justifying the use of sodium deoxyribonucleate in this variant with confirmed clinical and immunological efficacy.

Revealing the therapeutic potential of dupilumab: a case report on managing post-COVID-19 chronic pruritus in a geriatric patient

This case report describes a 73-year-old Caucasian male who contracted COVID-19 and struggled with chronic, severe pruritus after that. The patient's pruritus resisted numerous conventional and unconventional therapy modalities, highlighting the difficulty of treating post-COVID-19 dermatological symptoms. Pruritus in the patient was significantly alleviated due to therapy with Dupixent, a monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling. Treatment of the condition improved significantly with the use of Dupixent. The report describes the story of the patient's journey, from the first-time symptoms showed up after COVID-19 infection, through several treatments that was not effective, to when the patient's symptoms disappeared after starting Dupixent. The patient's recent SARS-CoV-2 infection may be connected to the immune-mediated process shown by the patient's histopathological results. Even though these results are based on a single instance, they highlight COVID-19's ability to cause chronic pruritus and recommend Dupixent as a possible treatment approach. More study is required to confirm these findings and investigate possible immunological connections between COVID-19 and chronic pruritus.

Difelikefalin for Hemodialysis Patients with Pruritus in Japan

BackgroundDifelikefalin, a peripherally specific selective agonist of kappa opioid receptors, has been approved for the treatment of pruritus in hemodialysis patients in the United States. However, there is limited evidence for postdialysis intravenous use in non-U.S. populations.MethodsIn this double-blind, placebo-controlled, phase 3 trial in Japan, patients with moderate to severe pruritus were randomly allocated 1:1 to receive either placebo or 0.5 μg/kg of difelikefalin three times per week intravenously for 6 weeks. The primary end point was change from baseline in the Worst Itching Intensity Numerical Rating Scale (NRS; 0 to 10; higher scores indicate more severe itching) score at week 4.ResultsA total of 230 patients were screened, of whom 178 were randomly assigned to receive placebo (n=89) or difelikefalin (n=89). The change from baseline in the weekly adjusted mean NRS score (95% confidence interval) at week 4 in the placebo and difelikefalin groups was −1.09 (−1.47 to −0.70) and −2.06 (−2.45 to −1.66), respectively. The difference between the groups was −0.97 (−1.52 to −0.42), demonstrating that difelikefalin was superior to placebo (P<0.001). Prespecified secondary quality-of-life end points showed consistent improvement associated with difelikefalin. The incidence of treatment-related adverse events in the placebo and difelikefalin groups was 3 of 89 patients (3%) and 13 of 89 patients (15%), respectively, of which the majority in the difelikefalin group were gastrointestinal (e.g., constipation and abdominal discomfort).ConclusionsIntravenous difelikefalin reduced itching and improved quality of life in patients with moderate to severe pruritus who were undergoing maintenance hemodialysis. (Funded by Kissei Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT04711603.)

Safety and effectiveness of HSK21542 for hemodialysis patients: a multiple ascending dose study.

Background: HSK21542, a novel selective peripherally-restricted κ-opioid receptor agonist has been proven to be a safe and effective analgesic and antipruritic drug in both in vitro and in vivo studies. We aimed to evaluate its safety, pharmacokinetics and efficacy in hemodialysis patients over a 1-week treatment period, and to establish the optimal dosage for a further 12-week stage 2 trial. Methods: In this multiple ascending dose study, hemodialysis patients were randomly assigned to receive HSK21542 (0.05-0.80μg/kg), or a placebo three times within 2.5h at the end of each dialysis session for 1week. Safety evaluations included reports of treatment-emergent adverse events (TEAEs); pharmacokinetics and efficacy outcomes were also assessed. Results: Among the 44 screened patients, 41 were enrolled and completed the trial. The overall incidence of TEAEs was higher in the HSK21542 group compared to the placebo group, with an incidence of 75.0%, 50.0%, 75.0%, and 88.9% in the range of 0.05-0.80μg/kg. All TEAEs were grade 1 or 2 in severity. HSK21542 exhibited linear pharmacokinetics characteristics within the dose range 0.05-0.80μg/kg, without drug accumulation after multiple-doses. Compared to the placebo, a significant decrease of the weekly mean Worst Itching Intensity Numerical Rating Scale was found in the HSK21542-0.30μg/kg group (p = 0.046), but without significant improvement in the Skindex-16 score. Conclusion: HSK21542 was well tolerated in the dose range 0.05-0.80μg/kg in hemodialysis patients. HSK21542-0.3μg/kg exhibited promising efficacy in patients with moderate to severe pruritus and warrants a further Stage 2 trial. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04470154.

S104 The Devastating Impact of Severe Pruritus in Primary Biliary Cholangitis

S104 The Devastating Impact of Severe Pruritus in Primary Biliary Cholangitis

Retrospective Review of Intrathecal Hydromorphone Dose Range and Complications

BACKGROUND: Optimal intrathecal dosing regimens for hydromorphone are not well established for analgesia after abdominal surgery. OBJECTIVES: We reviewed intrathecal hydromorphone doses and complications because dosing variability has been observed among anesthesiologists. We hypothesized that increasing doses of intrathecal hydromorphone would be associated with improved postoperative analgesia, but with increased rates of opioid-related adverse events. STUDY DESIGN: Retrospective analysis. SETTING: A high-volume academic referral center in the United States. METHODS: A retrospective study was conducted of adults undergoing abdominal surgery under general anesthesia supplemented preoperatively with intrathecal hydromorphone for postoperative analgesia from May 5, 2018, through May 31, 2021. Patients were categorized into 3 hydromorphone dosing groups: low-dose (50-100 µg), middle-dose (101-199 µg), and high-dose (200-300 µg). Multivariable logistic regression models were used to assess rates of severe postoperative pain, severe opioid-related adverse events, oversedation, and pruritus in the postanesthesia care unit (PACU) and within 24 hours after PACU discharge. RESULTS: Of 1,846 patients identified, 1,235 (66.9%) were in the low-dose group; 321 (17.3%), middle-dose group; and 290 (15.7%), high-dose group. Patients receiving the 2 higher doses had more extensive procedures. An unadjusted analysis showed differing rates of severe pain in the PACU by group: 306 (24.8%) in the low-dose, 73 (22.7%) middle-dose, and 45 (15.5%) in the high-dose group (P = 0.003); these differences, however, were no longer significant after an adjusted analysis (P = 0.34). Ten severe opioid-related events occurred; all were recognized in the PACU. Five events each occurred in the low-dose and high-dose groups versus none in the middle-dose group (P = 0.02). No other differences were identified with adjusted analyses. LIMITATIONS: Limitations of our study include its retrospective design and its conduct at a single center, along with the apparent, but difficult to characterize, treatment biases in hydromorphone dosing. CONCLUSIONS: No dose response was observed between intrathecal hydromorphone dose and postoperative analgesia, a finding that may reflect treatment bias. Higher rates of severe opioid-related events were detected for patients receiving high-dose hydromorphone in the PACU, but all other safety outcomes were similar between dosing regimens. KEY WORDS: Drug-related side effects, opioid analgesics, outcome assessment, postoperative pain, spinal injections

Complex Hypersensitivity and Irritation Reaction (CHAIR) Phenomenon after Cyanoacrylate Closure of Varicose Vein.

Cyanoacrylate glue is a non-thermal, non-tumescent agent used to treat saphenous reflux. It was introduced to overcome heat-related discomfort and complications. Multiple randomized controlled trials using this therapy have demonstrated excellent clinical outcomes at long-term follow-up. However, diffuse injection-site inflammation and systemic urticaria are worrisome complications. In preclinical studies, serial histopathological findings demonstrated acute inflammatory reaction, subacute vasculitis, chronic granulomatous foreign body reaction, fibrotic changes with partial vascular recanalization, and chronic foreign body-type inflammatory response. While the exact nature of this unique complication remains undefined, complex hypersensitivity and irritation reaction phenomena have been suggested based on reported clinical presentations. The incidence of this complication has been reported as ranging from 0.3%-25.4%. Typically, erythematous reactions can occur near treatment sites, with symptoms ranging from mild pruritus and/or erythema that resolves without treatment to recurrent severe inflammation and pruritus requiring nonsteroidal anti-inflammatory drugs, antihistamines, and/or corticosteroids. Surgical excision has been rarely reported in patients with severe intractable inflammation or treatment-site infections. Although several anecdotal studies reported on using antihistaminics or corticosteroids, no effective strategies have been established to prevent this complication.

Patient Perspectives on Living With Severe Prurigo Nodularis

Because of a paucity of qualitative research on prurigo nodularis (PN), the symptoms and impacts of PN that are most important to patients are poorly understood. To explore patients' perspectives on their PN symptoms and to understand the impacts of the condition. One-on-one qualitative telephone interviews were held with English-speaking US adults aged 18 years or older with a confirmed diagnosis of PN, severe pruritus, and moderate to severe sleep disturbance. Participants were recruited via patient associations, patient panels, and social media posts. Interviews took place between September 10, 2020, and March 16, 2021. The main symptoms of PN and their impacts on quality of life were identified by content analysis of deidentified interview transcripts. A total of 21 adults with PN (mean [SD] age, 53.1 [11.8] years; 15 [71%] female; 2 African American or Black patients [10%], 1 Asian patient [5%], and 18 White patients [86%]; of these, 1 patient [ 5%] had Hispanic or Latino ethnicity) participated in the interviews. All participants reported itch, pain associated with PN, bleeding or scabbing, and dry skin. Other frequently reported symptoms included lumps or bumps (95%), having a crust on the skin (95%), burning (90%), stinging (90%), lesions or sores (86%), skin discoloration (86%), and raw skin (81%). Of the 17 participants who indicated what their worst symptoms were, 15 (88%) identified itching as the worst or 1 of the worst symptoms. The most frequently reported impacts of PN for quality of life were changes in sleep (100%), daily life (100%), feelings or mood (95%), relationships (95%), social life (81%), and work or school (71%). Overall, the worst impact of PN was its association with impaired feelings or mood. This qualitative study suggests the importance of itching, sleep disturbance, and other symptoms and impacts of PN. This information can be used to guide end point selection in clinical trials and to inform patient-centric decision-making in clinical practice.

Mosaic BRAF Fusions Are a Recurrent Cause of Congenital Melanocytic Nevi Targetable by MAPK Pathway Inhibition

Among children with multiple congenital melanocytic naevi (CMN), 25% have no established genetic cause, of which many develop a hyperproliferative and severely pruritic phenotype resistant to treatment. Gene fusions have been reported in individual cases of CMN. Here, we study 169 CMN patients, 38 of whom were double wild-type for NRAS/BRAF mutations. Nineteen of these 38 patients had sufficient tissue to undergo RNAseq, which revealed mosaic BRAF fusions in 11/19 patients and mosaic RAF1 fusions in 1/19. Recurrently, fusions involved the loss of the 5' regulatory domain of BRAF or RAF1 but preserved the kinase domain. We validated all cases and detected the fusions in two separate naevi in 5/12 patients, confirming clonality. The absence of the fusion in blood in 8/12 patients indicated mosaicism. Primary culture of BRAF-fusion naevus cells from 3/12 patients demonstrated highly increased MAPK activation, despite only mildly increased BRAF expression, suggesting additional mechanisms of kinase activation. Trametinib quenched MAPK hyperactivation in vitro and treatment of two patients caused rapid improvement in bulk tissue, improving bodily movement, and reducing inflammation and severe pruritus. These findings offer a genetic diagnosis to an additional group of patients and trametinib as a treatment option for the severe associated phenotypes.

The Association of Uremic Pruritus with Blood Lead Level in Prevalent Hemodialysis Patients through Systemic Inflammation

Abstract Back ground and objective Pruritus is a common and often distressing symptom in patients with chronic kidney disease. Though the pathogenesis of uremic pruritus remains poorly understood, however systemic inflammation is one of the possible pathogenesis of uremic pruritus, and blood lead level has been noted to be associated with inflammation and nutritional status in long-term hemodialysis patients. There might be an interaction or association, therefore, between blood lead level and uremic pruritus through systemic inflammation. Blood lead level in hemodialysis patients might increase the intensity or have an additive role of pruritus caused by other more common risk factors. This study aims to further verify or deny the relation between blood lead level and uremic pruritus. Design, setting, participants, &amp; measurements The present study is a cross sectional study that investigates the relation between blood lead levels and pruritus in patients with end stage renal disease receiving hemodialysis. 50 patients were enrolled in this study, all were on regular hemodialysis 3 times a week, patients with primary skin diseases (psoriasis, erythroderma, etc), HCV positive patients, patients with chronic liver disease and patients with malignancies were excluded. Patients with PTH levels over 300 pg/dl And those with corrected calcium and phosphorus levels over 10.2 and 5.5 mg/dl Were excluded from the study. We divided the patients into 2 groups, group 1 (n = 10) with no pruritus and group 2 (n = 40) with varying degrees of pruritus. Results There was a significant difference in serum lead levels and ferritin levels between group 1 and 2. Group 2 was further divided according to intensity of Pruritus by VAS score into mild (n = 10), moderate (n = 20) and severe pruritus (n = 10) There was also a statistically significant difference in serum lead levels in different groups of intensity of pruritus, having higher serum lead levels in patients who exhibited severe pruritus. And there was a significant correlation between blood lead and duration of dialysis Conclusion Uremic pruritus is a multi-factorial phenomenon, our study showed that Blood lead level in HD patients might increase the intensity and have an additive role in the pathogenesis of pruritus in dialysis patients hence Blood lead level is positively correlated with Uremic Pruritus. We were able to demonstrate that both blood lead and duration of dialysis together are the most sensitive predictors for pruritus, the best cut off value for blood lead is 6 together with duration above 10 with high sensitivity, specificity and efficacy.

Pemphigoid diseases in older adults

Pemphigoid diseases are agroup of bullous autoimmune diseases characterized by autoantibodies against structural proteins of the dermal-epidermal junction. With asteadily growing aging population, pemphigoid diseases are emerging as asignificant medical challenge, because they occur primarily in older individuals. The by far most common disease is bullous pemphigoid, which is clinically characterized by tense blisters, erosions, erythema or urticarial plaques, while severe pruritus is the leading subjective symptom. Mucous membrane pemphigoid predominantly affects surface-close mucous membranes with painful erosions and blisters as well as frequently scarring usually in the mouth, nose, and eyes. Anti-p200 pemphigoid clinically resembles bullous pemphigoid but is much less common. Diagnosis of these diseases involves the combination of clinical evaluation, lesional histopathology, direct immunofluorescence microscopy of aperilesional biopsy and serology. Topical and systemic corticosteroids are the mainstay of pemphigoid diseases treatment. Depending on the severity of the disease, various potentially corticosteroid-sparing therapies, such as dapsone, doxycycline, methotrexate, azathioprine and mycophenolate may be used. In severe courses, treatment with rituximab, cyclophosphamide, intravenous immunoglobulins or immunoadsorption are second- or third-line treatment options. Patients are best managed in centers experience with the management of pemphigoid diseases. Updated national and international guidelines for the diagnosis and treatment of bullous pemphigoid and mucous membrane pemphigoid have recently been published.