Prevalence, pathophysiology and management of itch in epidermolysis bullosa*

Papanikolaou, Maria; Onoufriadis, Alexandros; Mellerio, Jemima E.; Nattkemper, Leigh; Yosipovitch, Gil; Steinhoff, Martin; McGrath, John A.

doi:10.1111/bjd.19496

Cited by 52 publications

(70 citation statements)

References 105 publications

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“…Pain in severe generalized RDEB is often very severe in that it does not respond well to potent opioid analgesics, and its intensity was shown to be greater than in postherpetic neuralgia (39). RDEB also causes severe pruritus that is thought to be associated with cutaneous inflammation secondary to barrier disruption, wound healing processes, and dysregulated activity of epidermal nerve fibers (38).…”

Section: Discussionmentioning

confidence: 99%

Intravenous allogeneic umbilical cord blood–derived mesenchymal stem cell therapy in recessive dystrophic epidermolysis bullosa patients

Lee¹,

Lee²,

Kim³

et al. 2021

JCI Insight

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BACKGROUND Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease that causes severe mucocutaneous fragility due to mutations in COL7A1 (encoding type VII collagen [C7]). In this phase I/IIa trial, we evaluated the safety and possible clinical efficacy of intravenous infusion of allogeneic human umbilical cord blood–derived mesenchymal stem cells (hUCB-MSCs) in patients with RDEB. METHODS Four adult and two pediatric patients with RDEB were treated with 3 intravenous injections of hUCB-MSCs (1 × 10 6 to 3 × 10 6 cells/kg) every 2 weeks and followed up for 8–24 months after treatment. The primary endpoint was safety. Secondary endpoints related to efficacy included clinical parameters, such as disease severity score, wound assessment, itch and pain score, and quality of life. C7 expression levels and inflammatory infiltrates in the skin, as well as serum levels of inflammatory markers and neuropeptides, were also assessed. RESULTS Intravenous hUCB-MSC infusions were well tolerated, without serious adverse events. Improvements in the Birmingham Epidermolysis Bullosa Severity Score, body surface area involvement, blister counts, pain, pruritus, and quality of life were observed with maximal effects at 56–112 days after treatment. hUCB-MSC administration induced M2 macrophage polarization and reduced mast cell infiltration in RDEB skin. Serum levels of substance P were decreased after therapy. Increased C7 expression was observed at the dermoepidermal junction in 1 of 6 patients at day 56. CONCLUSION To the best of our knowledge, this is the first clinical trial of systemic administration of allogeneic hUCB-MSCs in patients with RDEB, demonstrating safety and transient clinical benefits. TRIAL REGISTRATION ClinicalTrials.gov NCT04520022. FUNDING This work was supported by Daewoong Pharmaceutical Co. Ltd. and Kangstem Biotech Co. Ltd.

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Section: Discussionmentioning

confidence: 99%

Intravenous allogeneic umbilical cord blood–derived mesenchymal stem cell therapy in recessive dystrophic epidermolysis bullosa patients

Lee¹,

Lee²,

Kim³

et al. 2021

JCI Insight

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“…The observed decrease in disease activity was reflected by alleviations of pruritus and pain (Figure 5A, B; Supplemental Figure 2A, B), which represent two of the most distressing symptoms creating physical, psychological and social burdens on the everyday lives of RDEB patients (53)(54)(55)(56)(57)(58). It may seem striking that the median reduction in both scores was greatest at day 35, which might be attributed to the shorter interval between the day-35 visit and the preceding (second) cell infusion (18 days) as compared to the week-12 visit and the preceding (third) cell infusion (49 days).…”

Section: Discussionmentioning

confidence: 99%

Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa

Kiritsi¹,

Dieter²,

Niebergall-Roth³

et al. 2021

JCI Insight

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Background. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and life-threatening inherited skin fragility disorder due to a lack of functional type VII collagen, for which no effective therapy exists. ABCB5-positive dermal mesenchymal stem cells (ABCB5 + MSCs) possess immunomodulatory, inflammation-dampening and tissue-healing capacities. In a Col7a1 -/mouse model of RDEB, treatment with ABCB5 + MSCs markedly extended the animals' lifespans.Methods. In this international, multicentric, single-arm, phase I/IIa clinical trial, 16 patients (aged 4-36 years) enrolled into four age cohorts received three intravenous infusions of 2×10 6 ABCB5 + MSCs/kg on days 0, 17 and 35. Patients were followed up for 12 weeks regarding efficacy and 12 months regarding safety. Results. At 12 weeks, statistically significant median (IQR) reductions in the EpidermolysisBullosa Disease Activity and Scarring Index activity (EBDASI activity) score of 13.0%(2.9%-30%; p=0.049) and the Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa clinician (iscorEB-c) score of 18.2% (1.9%-39.8%; p=0.037) were observed. Reductions in itch and pain numerical rating scale scores were greatest on day 35, amounting to 37.5% (0.0%-42.9%; p=0.033) and 25.0% (-8.4%-46.4%; p=0.168), respectively. Three adverse events were considered related to the cell product, one mild lymphadenopathy and two hypersensitivity reactions. The latter two were serious but resolved without sequelae shortly after withdrawal of treatment. Conclusion.This trial demonstrates good tolerability, manageable safety and potential efficacy of intravenous ABCB5 + MSCs as a readily available disease-modifying therapy for RDEB and provides a rationale for further clinical evaluation.

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“…Epidermolysis bullosa (EB) is a group of diverse, rare, inherited skin disorders, resulting from mutations in genes encoding, for example, for laminin, keratin and collagen [70]. Pruritus is one of the common symptoms across all EB subtypes and is considered to be the most distressing of disease-related symptoms and when chronic, can cause major morbidities [70]. A Phase II, randomised clinical trial to assess safety and efficacy of serlopitant in treating moderate-to-severe pruritus in EB, reported potential itch reduction [71].…”

Section: Serlopitantmentioning

confidence: 99%

Neurokinin 1 Receptor Antagonists for Pruritus

Alam

Buddenkotte

Faried

et al. 2021

Drugs

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Pruritus, commonly known as itch, is a very common symptom in numerous dermatological disorders and systemic diseases. It can manifest as acute, or when lasting longer than 6 weeks, it is considered chronic and can lead to significant distress and reduced quality-of-life of those suffering. Current therapeutics are limited and are lacking in efficacy, and the development of more effective treatments is needed. The neurokinin 1 receptor (NK1R) antagonists are a novel class of drugs that possess several properties such as antidepressant, anxiolytic and antiemetic activities. Recently, several studies have described the antipruritic activity of NK1R antagonists for treating chronic pruritus. In this review we outline the pathogenesis of chronic pruritus, the mechanism by which the neuropeptide substance P (SP) and its receptor NK1R may be targeted to inhibit pruritic activity, and the efficacy and tolerability of NK1R antagonists, which have been, or are currently being investigated for treating conditions where chronic pruritus is a major symptom. Increasing evidence from ongoing and completed studies demonstrates the importance of SP and NK1R signalling in mediating pruritic activity. Several NK1R antagonists have shown significant antipruritic activity and thus targeting the SP-NK1R pathway may provide a therapeutic option for treating chronic pruritus of certain origin/s in the foreseeable future.

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Prevalence, pathophysiology and management of itch in epidermolysis bullosa*

Cited by 52 publications

References 105 publications

Intravenous allogeneic umbilical cord blood–derived mesenchymal stem cell therapy in recessive dystrophic epidermolysis bullosa patients

Intravenous allogeneic umbilical cord blood–derived mesenchymal stem cell therapy in recessive dystrophic epidermolysis bullosa patients

Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa

Neurokinin 1 Receptor Antagonists for Pruritus

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