[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.

Summary of Research: An Anti-OX40 Antibody to Treat Moderate-to-Severe Atopic Dermatitis: A Multicentre, Double-Blind, Placebo-Controlled Phase 2b Study.

This is a summary of the original article "An Anti-OX40 Antibody to Treat Moderate-to-Severe Atopic Dermatitis: a Multicentre, Double-blind, Placebo-Controlled Phase 2b Study". Atopic dermatitis (AD) is an inflammatory skin disease caused by a complex interplay of genetic factors, alterations to the skin microenvironment, and immune dysregulation, including T cells that have become uncontrolled. Rocatinlimab is an investigational agent that blocks OX40, a receptor on activated T cells that has an important role in inflammatory conditions such as AD. This summary of research provides an overview of a previously published article on the results of a phase 2b study of patients with moderate-to-severe AD who were treated with different doses of rocatinlimab or placebo and followed for up to 56 weeks. Rocatinlimab significantly improved the symptoms of AD and was well tolerated. The most common adverse events were fever, nasopharyngitis, and chills. This study supports rocatinlimab as a potentially safe and effective treatment for moderate-to-severe AD.

Clinical features and morphology of collagen fibrils in patients with vascular Ehlers-Danlos based on electron microscopy.

Background: Vascular-type Ehlers-Danlos syndrome (vEDS) is caused by collagen III deficit resulting from heterogeneous mutations in COL3A1, which occasionally causes sudden death due to arterial/visceral rupture. However, it is difficult to conduct basic research on the pathophysiology of vEDS. Moreover, the number of patients with vEDS is small, limiting the number of available samples. Furthermore, the symptoms of vEDS may vary among family members, even if they share the same mutation. Accordingly, many aspects of the pathology of vEDS remain unknown. Therefore, we investigated the structural abnormalities in collagen fibrils and endoplasmic reticulum (ER) stress in skin samples using electron microscopy as well as their relationship with clinical symptoms in 30 patients with vEDS (vEDS group) and 48 patients without vEDS (disease-negative control group). Methods: Differences between the two groups were evaluated in terms of the sizes of collagen fibrils using coefficient of variation (COV). Results: COV was found to be significantly higher in the vEDS group than in the disease-negative control group, indicating irregularity in the size of collagen fibrils. However, in the vEDS group, some patients had low COV and seldom experienced serious complications and ER stress. Conclusion: ER stress might affect collagen fibril-composing proteins. Moreover, as this stress varies among people based on environmental factors and aging, it may be the underlying cause of varying vEDS symptoms.

A case of hypocomplementemic urticarial vasculitis syndrome complicated by eosinophilic pneumonia: a case report and review of the literature.

The primary symptom of urticarial vasculitis (UV), which is a histopathological leukocytoclastic vasculitis disease, is an eruption that resembles urticaria. Other organs may also experience accompanying symptoms. Lung lesions with UV are mostly obstructive pulmonary disease with smoking. However, the coexistence of eosinophilic pneumonia (EP) and complicated UV remains unclear. We report a man in his 70s with chronic obstructive pulmonary disease who attended our department with ring-shaped erythema, marginal edema, and pigmentation. Additionally, a skin histological analysis showed nuclear dust and perivascular neutrophil infiltration, while a blood sample showed a decrease in C3 and C1q concentrations. Administration of prednisone temporarily improved the eruption. However, he developed a cough and a new UV eruption 1 year later. Computed tomography revealed infiltration in the right upper lobe of the lungs, and a blood sample showed a high eosinophil count. He was finally diagnosed with hypocomplementemic urticarial vasculitis syndrome and idiopathic chronic EP. A previous study showed that serum C1q concentrations in patients with EP were lower when this disease was active. Whether a decline in C1q concentrations can cause EP is unclear. However, our case is unique owing to the co-onset of EP with low complement concentrations and recurrence of UV.

An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study.

BACKGROUND: OX40 is crucial for T-cell differentiation and memory induction. The anti-OX40 antibody, rocatinlimab inhibits the OX40 pathway. We evaluated the efficacy and safety of rocatinlimab in adults with moderate-to-severe atopic dermatitis. METHODS: This multicentre, double-blind, placebo-controlled phase 2b study was done at 65 secondary and tertiary sites in the USA, Canada, Japan, and Germany. Eligible patients were adults (aged 18 years or older) with confirmed atopic dermatitis (American Academy of Dermatology Consensus Criteria or local diagnostic criteria) with moderate-to-severe disease activity, as defined by an Eczema Area and Severity Index (EASI) score of 16 or more, validated Investigator's Global Assessment for Atopic Dermatitis score of 3 (moderate) or 4 (severe), and affected body surface area 10% or higher at both screening and baseline, with documented history (within 1 year) of inadequate response to topical medications or if topical treatments were medically inadvisable. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous rocatinlimab every 4 weeks (150 mg or 600 mg) or every 2 weeks (300 mg or 600 mg) or subcutaneous placebo up to week 18, with an 18-week active-treatment extension and 20-week follow-up. Percentage change from baseline in EASI score was assessed as the primary endpoint at week 16 and during the active extension and follow-up in all randomly assigned patients exposed to study drug with a post-baseline EASI score at week 16 or earlier according to the group they were randomly assigned to. Safety was assessed in all randomly assigned patients exposed to study drug; patients were analysed according to the group they were randomly assigned to. The study is registered with ClinicalTrials.gov, NCT03703102. FINDINGS: Between Oct 22, 2018, and Oct 21, 2019, 274 patients (114 [42%] women, 160 [58%] men; mean age 38·0 years [SD 14·5]) were randomly assigned to one of the rocatinlimab groups (217 [79%] patients) or to the placebo group (57 [21%] patients). Compared with placebo (-15·0 [95% CI -28·6 to -1·4]), significant least-squares mean percent reductions in EASI score at week 16 were observed in all rocatinlimab groups (rocatinlimab 150 mg every 4 weeks -48·3 [-62·2 to -34·0], p=0·0003; rocatinlimab 600 mg every 4 weeks -49·7 [-64·3 to -35·2], p=0·0002; rocatinlimab 300 mg every 2 weeks -61·1 [-75·2 to -47·0], p<0·0001; and rocatinlimab 600 mg every 2 weeks -57·4 [-71·3 to -43·4], p<0·0001). The most common adverse events during the double-blind period in patients receiving rocatinlimab (adverse events ≥5% of patients in the total rocatinlimab group and more common than the placebo group) were pyrexia (36 [17%] patients), nasopharyngitis (30 [14%] patients), chills (24 [11%] patients), headache (19 [9%] patients), aphthous ulcer (15 [7%] patients), and nausea (13 [6%] patients). There were no deaths. INTERPRETATION: Patients treated with rocatinlimab had progressive improvements in atopic dermatitis, which was maintained in most patients after treatment discontinuation. Treatment was well tolerated. FUNDING: Kyowa Kirin.

Case report: Mild phenotype of a patient with vascular Ehlers-Danlos syndrome and COL3A1 duplication mutation without alteration in the [Gly-X-Y] repeat sequence.

Background: Vascular-type Ehlers-Danlos syndrome (vEDS) is an autosomal dominant inherited disorder caused by a deficit in collagen III as a result of heterogeneous mutations in the α1 type III collagen gene (COL3A1). Patients with vEDS often experience the first major complications in their early 20s and >80% have at least one complication by their 40s, reducing their average life expectancy to 48 years. Most commonly, vEDS variants are heterozygous missense substitutions of a base-pair encoding a glycine (Gly) residue of the [Gly-X-Y] repeat of the COL3A1 protein. When a peptide chain derived from a mutant allele is present in the procollagen triple helical structure, the helical structure cannot be maintained. Therefore, typically, the mutated collagen peptide induces a dominant negative effect on procollagen production. We reported the case of a patient with vEDS and a unique novel duplication mutation without alteration in the [Gly-X-Y] triplet repeat sequence. Case presentation: A 58-year-old man developed a sudden disorder of consciousness and abdominal pain and was consequently taken to a nearby hospital, where an intra-abdominal aneurysm was found, in addition to mild small joint hypermobility and acrogeria. There has been no history of spontaneous pneumothorax, dislocation, or subcutaneous hematoma. The analysis of genomic DNA from a blood sample identified a likely pathogenic in-frame duplication mutation in the COL3A1 gene coding region. Interestingly, this mutation is not expected to alter the [Gly-X-Y] triplet repeat sequence. We verified the mutation's pathogenicity by performing an analysis of synthetic procollagen from cultured skin fibroblasts, electron microscopy, and mRNA expression analysis of unfolded protein response sensors for endoplasmic reticulum (ER) stress. Conclusion: Although the clinical findings of the case were mild, when compared to typical vEDS, decreased α1 collagen III levels and morphological abnormalities of the collagenous bundles were observed in the patient samples when compared with the normal control samples. Our evidence supports the conclusion that this variant is pathogenic. However, unlike the common vEDS, ER stress was not observed, and the mild phenotype presentation was suggested to be due to the unique mutation, allowing the triple helical structure to be maintained to a certain extent.

Anti-pruritic effect of nemolizumab in hemodialysis patients with uremic pruritus: a phase II, randomized, double-blind, placebo-controlled clinical study.

BACKGROUND: The pathophysiology of uremic pruritus (UP), which is characterized by systemic and intractable itching, remains unclear. As interleukin (IL)-31 may be involved, we conducted a phase II, randomized, controlled study to evaluate nemolizumab (anti-IL-31 receptor A antibody) in Japanese hemodialysis patients with UP. METHODS: Patients were randomly assigned (1:1:1:1:1) to one of four double-blind groups (receiving a single subcutaneous injection of nemolizumab 0.125, 0.5, or 2.0 mg/kg, or placebo on Day 1) or an open-label reference group (receiving oral nalfurafine hydrochloride 2.5-5 µg once daily for 12 weeks). The primary endpoint was the difference in the absolute change in pruritus visual analog scale (VAS) at Week 4 between placebo and each nemolizumab group. RESULTS: The primary efficacy endpoint was not met. The mean change from baseline with all three nemolizumab doses at Week 1, and with 0.5 mg/kg at Week 4, was greater than with placebo. Least square mean differences (95% confidence intervals) in the absolute changes between the placebo arm and each nemolizumab arm were - 2.4 (- 19.7, 14.9) for 0.125 mg/kg, - 8.7 (- 26.6, 9.2) for 0.5 mg/kg, and 0.4 (- 17.0, 17.8) for 2.0 mg/kg. Secondary efficacy parameters including the Shiratori severity score and 5-D itch score failed to show between-group differences. Patients with higher serum IL-31 levels at screening tended to have greater pruritus VAS reductions following nemolizumab treatment. CONCLUSIONS: In this phase II study in patients with UP, the primary efficacy parameter was not met. Nemolizumab was generally well tolerated with no clinically significant safety concerns. CLINICAL TRIAL REGISTRATION: JAPIC: JapicCTI-152961, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-152961 .

Endoplasmic reticulum stress and collagenous formation anomalies in vascular-type Ehlers-Danlos syndrome via electron microscopy.

Vascular-type Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant inherited disorder caused by a deficit in collagen III. It results from heterogeneous mutations in the α1 collagen III gene (COL3A1) and is associated with life-threatening complications, even in younger patients. However, the details of the pathogenesis underlying the COL3A1 mutation causing vEDS remain unclear. Here, we focus on anomalies in collagen fiber size and the endoplasmic reticulum (ER) stress response in patients with vEDS using electron microscopy (EM). We discovered that although the infants did not have vEDS, collagenous formations were similar to their samples in vEDS. Moreover, we examined the expression of activating transcription factor 6 (ATF6) as an ER stress marker and cartilage oligomeric matrix protein (COMP) as a binding partner protein for collagen fibrils in the dermis and COL3A1. The expression levels of ATF6 in the vEDS group were significantly higher than in infants and controls; COMP and COL3A1 levels were significantly lower. The fragile collagen fibrils in vEDS might form as a result of ER stress and that small, newly formed collagen fibrils may appear. This research revealed a novel prospect regarding an issue that has been unclear for a long time, which is the reason for the abnormal sizes of collagenous fibrils in vEDS.