[RECOMMENDATION FOR ITCH ASSESSMENT FROM THE ATOPIC ITCH CONSENSUS MEETING (AICOM)].

BACKGROUND: Itch is the most troublesome symptom of atopic dermatitis, and it is important to assess it appropriately for optimal treatment. We discussed issues regarding itch and the most appropriate methods of assessment at the Atopic Itch Consensus Meeting (AICOM), attended by physicians and researchers with expertise in itch treatment and research. METHODS: The AICOM participants prepared a draft consensus statement that addressed the most appropriate itch assessment methods for age groups <2 years, 2-6 years, 7-14 years, and ≥15 years. Consensus was defined as agreement by ≥80% of the participants. RESULTS: Votes were cast by 20 participants (8 dermatologists, 7 pediatricians, and 5 researchers), and a consensus on the best current methods of itch assessment was reached with 95% agreement. For infants and preschool children, because subjective evaluation is difficult, a checklist for itch assessment was developed for caregivers. CONCLUSION: For itch assessment, we recommend subjective evaluation by the patient using a rating scale. For infants and preschoolers, evaluation should be done by the caregiver using a checklist, combined with objective evaluation (of skin lesions, for example) by a physician. We anticipate that more objective itch assessment indices will be established in the future.

Monitoring Sleep and Scratch Improves Quality of Life in Patients with Atopic Dermatitis.

Atopic dermatitis itch may cause sleep disturbance and impair quality of life. For patients finding topical therapy difficult to continue, it is important to control itch and reduce scratching. This study developed algorithms to measure nocturnal sleep and scratch, using an actigraph device worn on the back of the hand, and assessed smartphone application feedback to improve adherence with therapy. In the first trial, actigraph measurements in 5 participants who wore the device were highly correlated with measurements by a sleep-monitoring device beneath the mattress. Total actigraph-measured scratching duration for each hour of sleep was highly correlated with measurements by a person rating infrared video-recording of the sleepers. In the second trial, 40 patients with atopic dermatitis were randomly allocated into an intervention group that used the actigraph and smartphone application, and a control group that did not. Both groups were instructed to use the same moisturizer. Dermatology Life Quality Index scores decreased significantly from baseline and were lower than those in the control group at week 8. It is suggested that the device and associated smartphone application reinforced therapy adherence, moisturizer use, and contributed to improved quality of life in patients with atopic dermatitis.

Difelikefalin for Hemodialysis Patients with Pruritus in Japan.

BACKGROUND: Difelikefalin, 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. METHODS: In 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. RESULTS: A 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). CONCLUSIONS: Intravenous 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.)

Prevalence of Pruritus in the Elderly with Dementia: A Multicenter Survey of Japanese Patients.

A total of 185 elderly Japanese patients with mild to severe dementia were surveyed on itch, using multiple methods of evaluation including self-evaluation of itch conducted by patients as well as evaluation of scratching behavior and scratching marks on the body surface conducted by others. As a result, 36.8% self-evaluated that they were suffering from itch, whereas 53.5% were found to scratch. Of those who by themselves denied the presence of itch, 31.4% were found to scratch. Dry skin was found in 74.1%, the severity of which was positively correlated to the rating of scratching behavior and marks. These results indicate a high prevalence of pruritus in patients with dementia, and suggest that one should not solely rely on self-evaluation but should refer to additional clinical information such as scratching for evaluation of pruritus in patients with dementia. Skin care with moisturizer may be important to control itch in patients with dementia.

Measurement of Nocturnal Scratching in Patients with Pruritus Using a Smartwatch: Initial Clinical Studies with the Itch Tracker App.

Three clinical studies were conducted to test a newly-developed app for smartwatches, which included an algorithm to measure nocturnal scratching using acceleration data. The first study in 5 patients with atopic dermatitis demonstrated high reliability of the app for measurement of scratching compared with video monitoring (positive predictive value 90.2 ± 6.6%, sensitivity 84.6 ± 10.2%, correlation of scratching duration per h r = 0.851-0.901, p < 0.001). The second study in 20 patients with atopic dermatitis and 10 healthy volunteers showed that total scratching duration in patients was significantly longer than in healthy volunteers and correlated positively with Eczema Area and Severity Index (EASI) scores. In the third study, conducted in an open-entry manner in which 201 evaluable participants measured nocturnal scratching, those who self-reported itch or pruritic diseases had a significantly longer duration of scratching than those who did not. In conclusion, this app has a high reliability and potential clinical usefulness for measurement of nocturnal scratching.

Activity During Sleep Measured by a Sheet-Shaped Body Vibrometer and the Severity of Atopic Dermatitis in Adults: A Comparison With Wrist Actigraphy.

STUDY OBJECTIVES: To use a sheet-shaped body vibrometer (SBV) for measuring sleep in adult patients with atopic dermatitis (AD) of various severities and to compare the results with those measured by wrist actigraphy (WA). METHODS: Simultaneous measurements of activity during sleep by WA and the SBV were performed in 20 outpatients with AD for 5 to 10 days. The mean activity count per minute (ACT) and sleep efficiency (SE) were obtained using each device. The severity of AD was evaluated by the severity scoring of AD (SCORAD), serum thymus and activation-regulated chemokine (TARC) level, serum total immunoglobulin E level, and peripheral eosinophil count. RESULTS: The ACT measured by WA was correlated with SCORAD (Spearman correlation coefficient [rs] = .64, P = .002) and TARC (rs = .60, P = .005). The ACT obtained by the SBV was significantly correlated with TARC (rs = .58, P = .008) and ACT obtained by WA (rs = .63, P = .003). SE obtained by WA resulted in lower values compared with SE obtained by the SBV (69.7 ± 9.4% versus 82.9 ± 9.3%, P < .001), although SE obtained by WA was highly correlated with SE obtained by the SBV (rs = .82, P < .001). Bland-Altman plots revealed that SE measured by WA always had lower values in all the patients. CONCLUSIONS: Activity during sleep, presumably composed of scratching and other motions, is more vigorous in patients with severe adult AD. This was successfully demonstrated by the SBV and WA assessment. However, we consider that ACT measured by WA is more suited for the scratch evaluation and SE measured by the SBV is preferable for the sleep evaluation.

Drug-Induced Itch Management.

Drugs may cause itching as a concomitant symptom of drug-induced skin reactions or in the form of pruritus without skin lesions. Drug-induced itch is defined as generalized itching without skin lesions, caused by a drug. Itching associated with drug-induced cholestasis is among the common dermatologic adverse events (dAEs) that induce itching. Some drugs such as opioids, antimalarials, and hydroxyethyl starch are known to induce itching without skin lesions. The clinical features and underlying proposed mechanisms of itching caused by these drugs have been specifically investigated. The recent application of targeted anticancer drugs has increased the survival rate of cancer patients. These new agents cause significant dAEs such as acneiform rashes, dry skin, hand-foot syndrome, paronychia, and itching. Itching is a common side effect of epidermal growth factor receptor inhibitors. Though not life-threatening, these dAEs have a negative impact on a patient's quality of life, leading to dose reduction and possibly less effective cancer therapy. It is important to provide an effective supportive antipruritic treatment without interruption of the administration of these drugs. This chapter concludes by describing basic measures to be taken for diagnosis and treatment of drug-induced itch. The principle of treatment is discontinuation of suspected causative drugs in general except for anticancer medications. In case itching lasts long after drug withdrawal or the causative drug cannot be stopped, vigorous symptomatic antipruritic treatment and specific therapies for different types of drug-induced itch should be undertaken.

Antipruritic effects of the probiotic strain LKM512 in adults with atopic dermatitis.

BACKGROUND: Evidence suggests that intestinal microbiota play an important role in the pathogenesis of atopic dermatitis (AD) through induction of immunosuppression and immune tolerance; however, the exact underlying mechanism is unclear. Few studies to date have examined the effects of probiotics on adult-type AD. OBJECTIVE: To examine the effects of the probiotic Bifidobacterium animalis subsp lactis LKM512 on adult-type AD and the expression of metabolites that are known to be influenced by gut microbiota in fecal samples. METHODS: Forty-four patients were randomly assigned to receive LKM512 or a placebo and underwent medical examinations. Fecal microbiota were analyzed with real-time polymerase chain reaction. Metabolomic analysis was conducted to search for antipruritic metabolites produced by intestinal bacteria using feces derived from 3 patients whose itch scores had improved using capillary electrophoresis with time-of-flight mass spectrometry. Antipruritic effects of kynurenic acid were observed using AD-induced NC/Nga mice. RESULTS: LKM512 administration alleviated itch in AD patients compared with controls and improved the dermatology-specific quality-of-life scores when compared with the controls. Administration of LKM512 also increased the expression of the antipruritic and antinociceptive metabolite kynurenic acid (KYNA) in patients whose itch score had improved after LKM512 treatment. In mouse experiments, scratching behavior counts tended to be decreased by KYNA injection when compared with no treatment. CONCLUSION: LKM512 administration may exert antipruritic effects by increasing KYNA production. LKM512 could therefore be a potentially effective therapeutic candidate for the reduction of pruritus. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000005695.

Pruritus assessment in clinical trials: consensus recommendations from the International Forum for the Study of Itch (IFSI) Special Interest Group Scoring Itch in Clinical Trials.

Chronic pruritus is a common symptom and there is an urgent need to test new anti-pruritic substances in high-quality clinical trials. However, no widely accepted standardized and validated method for objectively measuring pruritus is yet available. A special interest group of the International Forum for the Study of Itch has been established to assess scoring methods and questionnaires for use in clinical trials. This paper presents our current recommendations. The set of measures we recommend includes pruritus intensity scales, instruments for assessment of scratch lesions, chronic pruritus course, quality of life and patient benefits.

Efficacy and safety of a novel ĸ-agonist for managing intractable pruritus in dialysis patients.

BACKGROUND: Our previous placebo-controlled, prospective, double-blind study demonstrated that a new opioid ĸ-receptor agonist, nalfurafine hydrochloride, effectively reduced treatment-resistant pruritus in 337 hemodialysis patients. Thus, we designed this study to evaluate prospectively the efficacy, safety, addiction liability, and pharmacokinetics of nalfurafine given orally for 1 year. METHODS: This open-label study examined the effects and adverse drug reactions (ADRs) of 52-week oral administration of nalfurafine hydrochloride (5 µg/day) in 211 hemodialysis patients with a treatment-resistant itch. RESULTS: Of 211 patients, 145 completed the study as scheduled. The mean pruritus value assessed by the visual analogue scale was 75.2 mm during the pre-observation period, which decreased significantly to 50.9 and 30.9 mm in week 2 and 52, respectively, indicating a long-lasting efficacy. ADRs occurred in 103 patients (48.8%). Frequent ADRs were insomnia (sleep disturbance, 19.4%), constipation (7.1%) and increased blood prolactin (3.3%), similar to previous reports. Regarding addiction liability, it appeared unlikely that nalfurafine hydrochloride was abused. After the start of treatment, plasma drug levels reached a steady state in week 2 with no apparent tendency of systemic accumulation. CONCLUSIONS: Nalfurafine hydrochloride, orally administered at 5 µg/day for 52 weeks to hemodialysis patients, produced a long-term suppression of pruritus without significant safety problems.

Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus.

The most commonly used tool for self-report of pruritus intensity is the visual analogue scale (VAS). Similar tools are the numerical rating scale (NRS) and verbal rating scale (VRS). In the present study, initiated by the International Forum for the Study of Itch assessing reliability of these tools, 471 randomly selected patients with chronic itch (200 males, 271 females, mean age 58.44 years) recorded their pruritus intensity on VAS (100-mm line), NRS (0-10) and VRS (four-point) scales. Re-test reliability was analysed in a subgroup of 250 patients after one hour. Statistical analysis showed a high reliability and concurrent validity (r>0.8; p<0.01) for all tools. Mean values of all scales showed a high correlation. In conclusion, high reliability and concurrent validity was found for VAS, NRS and VRS. On re-test, higher correlation and less missing values were observed. A training session before starting a clinical trial is recommended.

Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a Phase III, randomized, double-blind, placebo-controlled study.

BACKGROUND: Pruritus in haemodialysis patients is an intractable disease and substantially impairs their quality of life. Based on the results of our earlier clinical study, we hypothesized that the micro-(mu) opioid system is itch-inducible, whereas the kappa (kappa) system is itch-suppressive. METHODS: The efficacy and safety of nalfurafine hydrochloride (a novel kappa-receptor agonist) were prospectively investigated by randomly (1:1:1) administering 5 or 2.5 microg of the drug or a placebo orally for 14 days using a double-blind design in 337 haemodialysis patients with itch that was resistant to currently available treatments, such as antihistamines. RESULTS: The mean decrease in the visual analogue scale (VAS) from baseline, the study's primary endpoint, was significantly larger in the 5-microg nalfurafine hydrochloride group (n = 114) than in the placebo group (n = 111, P = 0.0002, one-sided test at 2.5% significance level). The decrease in the VAS in the 2.5-microg group (n = 112) was also significantly larger than that in the placebo group (P = 0.0001). The incidence of adverse drug reactions (ADRs) was 35.1% in the 5-microg group, 25.0% in the 2.5-microg group and 16.2% in the placebo group. Moderate to severe ADRs were observed in 10 of the 226 patients. The most common ADR was insomnia (sleep disturbance), seen in 24 of the 226 nalfurafine patients. CONCLUSIONS: This Phase III, randomized, double-blind, placebo-controlled, parallel-group, prospective study based on VAS evaluations clearly showed that orally taken nalfurafine hydrochloride effectively reduced itches that were otherwise refractory to currently available treatments in maintenance haemodialysis patients, with few significant ADRs. This novel drug was officially approved for clinical use in January 2009 by the Ministry of Health, Labour and Welfare of Japan.

Tuberculous gumma associated with idiopathic thrombocytopenic purpura: report of a Japanese female patient.

Our patient was a 77-year-old Japanese woman, who was under treatment for idiopathic thrombocytopenic purpura (ITP) and chronic renal failure. She had warm nodules and cord-like induration on her left knee that appeared similar to Bazin's erythema induratum. A chest X-ray examination revealed miliary tuberculosis; after anti-mycobacterial therapy, the warm nodules and cord-like induration were transformed into a cold, non-tender abscess that drained. Histopathological findings showed caseation necrosis in the subcutaneous tissue, however, mycobacteria were directly detected by Ziehl-Neelsen staining from cutaneous lesions, and cultures from the same lesion also grew Mycobacterium tuberculosis. Tuberculous gumma demonstrated multiple, cold, painless abscesses and thrombosis were also seen. This is a rare and unusual clinical form of cutaneous tuberculosis, and the result of hematogenous dissemination from a primary focus during periods of lowered resistance.

Skin permeation of lidocaine from crystal suspended oily formulations.

In vitro permeation of lidocaine (lidocaine base, LID) through excised rat skin was investigated using several LID-suspended oily formulations. The first skin permeation of LID from an LID-suspended oily solution such as liquid paraffin (LP), isopropyl myristate (IPM), polyoxyethylene (2) oleylether (BO-2), and diethyl sebacate (DES) was evaluated and compared with that from polyethylene glycol 400 (PEG400) solution, a hydrophilic base. The obtained permeation rate of LID, Japp, from PEG400, LP, IPM, BO-2, and DES was in the order of DES>BO-2=IPM>LP>PEG400, and increased with LID solubility in the oily solvents, although LID crystals were dispersed in all solvents. Subsequently, oily formulations that consisted of different ratios of the first oily solvent (IPM, BO-2, or DES) (each 0-20%), the second oily solvent (LP) and an oily mixture of microcrystalline wax/white petrolatum/paraffin (1/5/4) were evaluated. BO-2 groups at a concentration of 5% and 10% had the highest Japp among the oily formulations, although a higher BO-2 resulted in lower skin permeation. In addition, pretreatment with BO-2 increased the skin permeation of LID. These results suggest that the penetration enhancing effect by the system may be related to the skin penetration of BO-2 itself. Finally, mathematical analysis was done to evaluate the effect of BO-2, and it was shown that BO-2 improved the LID solubility in stratum corneum lipids to efficiently enhance the LID permeation through skin.