Rodrigo Valdes-Rodriguez

Chronic Pruritus in the Elderly: Pathophysiology, Diagnosis and Management

Chronic itch in the elderly is a common problem, with a significant impact on quality of life and sleep in elderly patients. Chronic itch may be attributable to several causes, including dry skin, immunosenescence and neural degeneration. Itch may also be caused by skin diseases, such as seborrhoeic dermatitis and stasis dermatitis; systemic conditions, such as end-stage renal disease and diabetes; and psychogenic conditions, such as depression and anxiety. The use of polypharmacy may also cause itch, with or without a rash. Specifically, thiazides and calcium channel blockers have been known to cause itch in elderly patients. Management should be tailored according to the underlying dermatological or systemic aetiology of itch. Topical treatment is the mainstay of therapy, providing special emphasis on skin hydration and barrier repair. In addition, topical and oral medications that target the nervous system and reduce neuronal hypersensitization, such as gabapentin and selective antidepressants, have a role in treating patients with severe chronic itch. Furthermore, management must account for changes in metabolism and pharmacokinetics of drugs in the aging population in order to prevent the occurrence of adverse effects.

Topical ketamine-amitriptyline-lidocaine for chronic pruritus: A retrospective study assessing efficacy and tolerability

To the Editor: Topical analgesics have been well studied in the management of neuropathic pain, however, limited data are present on their role in treating pruritus. Although noted improvement was seen with low concentrations of topical ketamineamitriptyline in the therapy of localized itch, there are no studies to our knowledge examining the combination of topical ketamine-amitriptylinelidocaine (TKAL) on chronic itch with validated tools. Its proposed mechanism of action is aimed at reducing hypersensitivity of peripheral nerve fibers through blockade of N-methyl-D-aspartate receptor and sodium channels. Our study was intended to retrospectively examine the clinical response and tolerability of TKAL in the setting of chronic itch. Patients who were prescribed TKAL from September 1, 2013, to June 30, 2016, with at least 1 telephone or office follow-up visit at the Department of Dermatology at Temple University Hospital were identified. A primary review of medical charts with supplemental evaluation of pharmacy records from Temple University Hospital and a private compounding pharmacy were performed. The change in numeric rating scale before and after use of TKAL was assessed as were any adverse events. In addition, rates of prescription refills as a measure of patient adherence were documented as TKAL was not covered by most insurance. Statistical analysis was completed using software (SPSS, 16.0, IBM Corp, Armonk, NY). This study was institutional review board approved. A total of 96 patients (68.8% female) with a mean age of 65 6 14.4 years were identified. Patients reported a mean duration of itch of 76.7 6 99.2 months with 38% having failed more than 3 previous treatments. TKAL was prescribed at a standardized concentration of 10% ketamine, 5% amitriptyline, and 5% lidocaine compounded in a lipoderm cream, except for 16 patients who were prescribed the combination with 5% ketamine. Patients were instructed to apply sparingly to areas that were the most severe, limiting to less than 30% of total body surface area up to 3 times daily. The most frequent indications were for neuropathic conditions (29%) and prurigo nodularis (19%). The average numeric rating scale was 8.63 6 1.62 before and 4.19 6 2.9 after treatment with an average reduction of 4.61 6 2.77. Although oral systemic medications were concomitantly prescribed, most commonly gabapentin (46%) and mirtazapine (22%), 63% of patients attributed relief directly to the use of TKAL alone with reduction in numeric rating scale seen in all pruritus subtypes (Table I). Refills were granted as needed and requested on average of 2.41 times (range 0-18) with an average of 43.67 days between refills (range 7-211). Review of a pharmacyadministered telephone survey that assessed medication tolerability and efficacy of 40 patients revealed that 23 patients (58%) had relief to a great extent and 14 (35%) to a moderate extent, experiencing itch relief within 4.18 6 3.39 minutes on average. Side effects reported by 16 subjects were primarily a mild localized burning sensation (7%) and redness (6%) at the application site (Table II). Although limited by its retrospective nature and use of concomitantly prescribed systemic oral medications, this study further supports the use of TKAL as an effective single or adjuvant therapy when treating various pruritic conditions. Of note, a case of encephalopathy was recently reported in an elderly patient with eczema after applying TKAL over his entire body. Thus, prospective investigation is necessary to further validate its safety and therapeutic potential, including the extent of body surface application.

Cholinergic induction of perspiration attenuates nonhistaminergic pruritus in the skin of patients with atopic dermatitis and healthy controls.

Dear Editor, Although dry skin and barrier impairment are key drivers for itch induction in atopic dermatitis (AD), many other factors can impact itch intensity. In particular, AD patients often report that autologous sweating aggravates their itch1. Indeed, AD lesions are characteristically distributed in regions where sweat glands are prominent, such as the neck, face, wrists, and cubital and popliteal fossae. Additionally, sweat is known to influence the pH of skin, which plays a crucial role in the pathogenesis of skin dermatoses such as AD2. The association between perspiration and pruritus is of great clinical importance, yet no experimental model has been developed to assess this relationship. To address this issue, we conducted a controlled-cohort study to evaluate the effects of localized, cholinergically induced perspiration on the intensity of non-histaminergic induced itch (see Supplement). In the baseline sweat condition, sweat was induced by pilocarpine iontophoresis on healthy (n=10) and AD (n=10) subjects’ forearms. Sweat was collected for 30 minutes, and activated sweat glands (ASG) were counted after sweat collection. In the baseline itch condition, itch was induced using cowhage, which activates PAR2 receptors3, which have been shown to play a role in the itch of AD4. Subjects rated itch intensity using a visual analogue scale (VAS) for the duration of the itch sensation. In the combined sweat and itch condition, itch was induced immediately following sweat induction. Sweat was collected and itch intensity was rated as before. We hypothesized that sweating would increase itch intensity in both AD and healthy subjects. The average VAS itch for the AD subjects for two weeks before the experiment was 5.5 ± 2.3, while the average Eczema Area and Severity Index score was 21.2 ± 20.1. AD subjects reported that the forearm and thigh areas itched most often and that their pruritus-related QOL was most affected by “temperature or seasonal changes,” with an average frequency score of 4.13 ± 0.38. Of note, 60% of subjects reported that sweat exacerbated their itch. In the baseline sweat condition, healthy and AD subjects produced statistically similar amounts of sweat (0.48 ± 0.2 g vs. 0.42 ± 0.15 g). AD subjects produced less sweat when itch and sweat were induced together (0.22 ± 0.03 g) compared to baseline sweat alone (p=0.02). Healthy subjects did not significantly differ in sweat production during the sweat and itch condition (0.36 ± 0.18 g) compared to baseline sweat. Furthermore, AD subjects produced significantly less sweat than healthy controls during the combined itch and sweat condition (p=0.04; Fig. 1A). Although some prior reports have shown a reduced sweat response in AD subjects upon cholinergic stimulation5–7, another study found no difference in the volume of sweat produced by AD and healthy subjects with either pilocarpine-induced sweat or emotional sweat8. The amount of sweat collected from AD subjects was significantly decreased during the combined itch and sweat condition compared to baseline sweat. However, ASG counts were statistically similar in all conditions (Fig. 1B–D), suggesting that they were not responsible for the change in sweat production. Figure 1 (a) The amount of sweat produced did not differ between healthy and AD subjects. However, AD subjects produced less sweat while itching compared to their sweat baseline and compared to healthy subjects during sweat and itch (*p<0.05). (b) Healthy ... During the baseline itch condition, the overall time course of itch intensity did not differ significantly between healthy and AD subjects. This result matches our previous observations for non-eczematous skin9. Contrary to our hypothesis, AD subjects showed no significant change in itch intensity during the combined sweat and itch condition compared to the itch baseline, while healthy subjects displayed a significant decrease in itch intensity (p=0.01; Fig. 1E). Additionally, when comparing the area under the curve (AUC), which represents the total itch perceived, both healthy (p=0.03) and AD (p=0.01) subjects had significantly less itch during the combined sweat and itch condition compared to the itch baseline (Fig. 1F). The AUC was lower in healthy subjects than in AD subjects during the combined sweat and itch condition (p=0.02), but not during the baseline itch condition. Interestingly, no statistical differences were found when comparing the results of AD subjects who reported sweat as an aggravating factor in their itch compared to those who did not. We also hypothesized that sweat pH may have a role in aggravating itch, so in a second study visit, we explored the effects of sweat pH on itch intensity using artificial sweat solutions with differing pH values (4.2, 5.2, and 7.2). These artificial solutions sweat were applied to the forearms after cowhage itch induction, and subjects rated their itch intensity as before. In both healthy and AD subjects, itch intensity did not differ during the application of any imitation sweat solution compared to the control application of water (Fig. 2A–B). A previous study found that skin surface pH was approximately 5.24 in healthy subjects, while AD patients displayed relatively elevated pH levels on non-lesional skin (pH 5.54)10. This change in pH has been associated with an increased perception of itch, possibly due to increased activity of pH-dependent serine proteases, which can alter the integrity and barrier function of the stratum corneum11. Our artificial sweat solutions may have been restricted in their capacity to change the overall skin pH and to alter itch perception in subjects. We did not measure subjects’ skin surface pH before or after application of the different artificial sweat preparations. Figure 2 The differing pH values (4.2, 5.2, and 7.2) of imitation sweat did not significantly affect the itch VAS intensities in healthy (a) or AD subjects (b) compared to a water (pH 7) control. In conclusion, the results of our sweat model did not mimic the clinical observations of sweat as a major exacerbating factor of itch in AD patients. A major limitation of this study is that our model of sweat induction is pharmacological and thus may not mimic authentic, natural sweat, which has additional components (such as heat, emotional stress, sympathetic reflex, and adrenergic signaling) that can aggravate chronic itch12–14. In addition, future studies should examine both eczematous and unaffected skin, as there have been noted differences in sweat volume, sweat latency, and skin surface pH in lesional versus non-lesional sites5,10. In an abnormal cutaneous barrier, sweat can penetrate more deeply, activate epidermal keratinocytes, and stimulate pro-inflammatory cytokine production15. Studies on the molecular makeup of sweat could also elucidate the relationship between sweat and itch.

MicroRNAs in cutaneous melanoma: Role as diagnostic and prognostic biomarkers

Melanoma is the leading cause of skin cancer deaths in the United States, and its incidence has been rising steadily for the past 30 years (Aftab, Dinger, & Perera, 2014). A more complete understanding of the molecular mechanisms that drive melanomagenesis is crucial to improve diagnosis, prognostication, and treatment of this disease. Given that melanoma survival rates are better when the disease is detected early, precise diagnostic tests for early melanoma detection would be extremely useful. In addition, as survival rates decrease drastically when the disease becomes metastatic, improved tools to more precisely identify high‐risk patients as well as to predict treatment response are necessary. The role of microRNAs (miRNAs) in melanoma biology could be the key. miRNA expression profiling has identified several miRNAs that play a crucial role in melanoma cell proliferation, migration, and invasion, as well as miRNAs involved in apoptosis and in the immune response. Here we review the most current data on the miRNAs involved in melanoma as well as their potential roles as diagnostic and prognostic biomarkers of this disease.

Chronic Pruritus and Connective Tissue Disorders: Review, Gaps, and Future Directions.

Chronic itch is a common skin manifestation in many connective tissue diseases. However, the cause of chronic itch in these diseases is still not fully understood. The complex, and in some cases incomplete understanding of, pathogenesis in each condition makes it difficult to target specific mediators of chronic itch. It is important to better understand the pathophysiology of chronic itch in these conditions, as this information might provide a fuller understanding of the pathogenesis of the diseases in general and lead to the development of more specific treatments for connective tissue diseases in patients with chronic itch. We present a review of the literature on what is known about the prevalence, possible pathophysiology, and effect on quality of life of chronic itch in patients with scleroderma, Sjögren’s syndrome, dermatomyositis, systemic lupus erythematosus, cutaneous lupus erythematosus, and mixed connective tissue 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.

Effects of Local Use of Insulin on Wound Healing in Non-diabetic Patients:

Background: Clinical trials have shown the positive effects of local insulin therapy in the formation of new vessels and fibrosis in acute and chronic diabetic wounds without major adverse effects. Objective: The aim of this study was to investigate the effects of local insulin use on wound healing in non-diabetic patients. Methods: A randomized, split-plot, double-blind, placebo-controlled trial was conducted. Ten non-diabetic patients with full-thickness acute wounds were recruited (5 due to trauma, 3 to burns, and 2 to pressure). All wounds received standard bedside treatment. Each wound was divided into 2 zones. One side received a standard care plus insulin, while the other received standard care plus injection of saline solution. A biopsy specimen was taken from both sites on days 0 and 14. The amount of blood vessel growth and the percentage of fibrosis were evaluated. Results: A significant difference in the number of new vessels was observed on the insulin-treated site (70.6 [29.21]) compared to saline only (26.5 [34.3]; P < .04). The percentage of fibrosis (insulin 34.7 [28.02] vs saline 27.8 [29.9]) showed no significant difference. No adverse events related to the study occurred. The clinical implications of this study are considerable in terms of the formation of blood vessels but not fibrosis. Conclusion: We suggest that local insulin administration is a safe therapeutic option for angiogenesis in wounds of non-diabetic patients.

Paraneoplastic pemphigus mimicking toxic epidermal necrolysis: An underdiagnosed entity?

CLL: chronic lymphocytic leukemia DSG: desmoglein ELISA: enzyme-linked immunosorbent assay EP: envoplakin PNP: paraneoplastic pemphigus IIF: indirect immunofluorescence PP: periplakin SJS: Stevens-Johnson syndrome TEN: toxic epidermal necrolysis INTRODUCTION Paraneoplastic pemphigus (PNP) is an autoimmune blistering syndrome with 5 well-described clinicopathologic phenotypes. Nguyen et al categorized these subtypes as pemphigus-like, pemphigoid-like, erythema multiforme-like, graftvs-host-diseaseelike, and lichen planuselike. However, there is increasing recognition of PNP simulating Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Herein, we propose SJS/TEN-like PNP as a distinct subtype of PNP. We present 2 new cases of SJS/TEN-like PNP and review the previously reported cases of this subtype. Clinicopathologic factors that merit consideration for PNP in this context include a history of associated underlying neoplasia, the absence of a new drug, and histopathology indicative of chronicity or acantholysis. In patients with these features and clinical morphology typical of SJS/TEN, serologic evaluation for IgG autoantibodies against envoplakin (EP), desmoglein (DSG) 1, and DSG3 should be considered in order to exclude SJS/TEN-like PNP.

Prurigo pigmentosa: Case series and differentiation from confluent and reticulated papillomatosis

CARP: confluent and reticulated papillomatosis PP: prurigo pigmentosa INTRODUCTION Prurigo pigmentosa (PP) is an uncommon, acquired inflammatory disorder with a predilection for young adults of Asian descent. This condition is manifested by highly pruritic, reticulated, and erythematous papules that resolve with hyperpigmentation. Multiple cases of PP have been reported since its initial description in 1971 by Nagashima et al; however, this dermatosis is still underdiagnosed or misdiagnosed. The most significant challenge limiting the identification of PP is successful distinction from confluent and reticulated papillomatosis (CARP). Herein, 2 patientswith PP are described, with a focus on differentiating features from CARP.

Experiences with the First Eczema School in the United States

Patient education programs are beneficial in the treatment of chronic diseases. In Germany, France, and other countries worldwide, educating children, adolescents, and adults plus the parents of children with atopic dermatitis (AD) leads to better coping with the skin disease, as well as to a reduction in the severity of the skin symptoms and signs. The results in Europe led to the idea to also establish an eczema school in the United States. In the style of the German eczema school, an eczema school was founded in 2014 at Temple University, Philadelphia, PA. Since then, a team consisting of a dermatologist, psychologist, nutritionist, and nurse practitioner has offered an eczema school to interested patients with AD and their families three times a year. This patient education program consists of three weekly 2-hour sessions, which address proper skin care, the itch-scratch cycle, healthy nutrition, and the role of stress in AD. The current review summarizes the first experiences with the education program in the United States.