BACKGROUND:The Barthel Index (BI) is a reliable tool for assessing the level of independence in activities of daily living (ADLs). Current risk stratification for chronic limb-threatening ischemia (CLTI) primarily focuses on anatomical severity and comorbidities, with less emphasis on functional status. Although several studies have examined its prognostic utility in patients with CLTI, the association between BI at admission and wound healing outcomes remains unclear, particularly in the context of multidisciplinary treatment strategies. METHODS:This retrospective single-center study included 187 patients (220 limbs) with CLTI and tissue loss who underwent endovascular treatment (EVT). Patients were stratified into 4 groups according to their BI at admission: total independence (TI, BI ≥ 85), partial independence (PI, BI: 61-84), partial assistance (PA, BI: 41-60), and total assistance (TA, BI: ≤ 40). The primary endpoint was wound healing rate, and secondary analyses examined major amputation and ADL recovery. RESULTS:Baseline disease severity and treatment characteristics were comparable among the 4 groups. Most patients showed functional improvement during hospitalization, except those with high baseline BI who already maintained good independence. However, patients in the TA group exhibited significantly lower 1-year wound healing rates compared with PA, PI, and TI groups. Major amputations were also more frequent in the TA group. Multivariable Cox regression analysis identified BI ≤ 40 at admission as an independent negative predictor of wound healing, suggesting limited responsiveness to standardized multidisciplinary care, including EVT and rehabilitation, in these patients. CONCLUSIONS:A lower BI at admission was associated with delayed wound healing and a higher risk of major amputation despite appropriate EVT. These findings highlight the clinical value of incorporating functional assessment into current risk stratification frameworks. Barthel Index assessment at admission is a simple and reliable prognostic indicator for patients with CLTI and may aid in early risk stratification and optimization of treatment strategies, including the consideration of the intensity of revascularization and rehabilitation efforts.Clinical ImpactThis study demonstrates that the Barthel Index, a simple and readily available measure of functional status, provides clinically meaningful prognostic information in patients with chronic limb-threatening ischemia beyond conventional assessments of disease severity. A low Barthel Index at admission identifies patients who remain at high risk for delayed wound healing and major amputation despite guideline-based multidisciplinary treatment, including endovascular revascularization. Incorporating the Barthel Index into the initial evaluation improves risk stratification, facilitates individualized treatment planning, optimizes rehabilitation and resource allocation, and supports shared decision-making.

Purpose: Clinical frailty increases the risk of adverse outcomes in older people. Patients with Chronic limb-threatening ischemia (CLTI) also had several clinical frailties. The aim of this study was to investigate the correlation between clinical frailty scales (CFS) at discharge and wound healing rate in patients with tissue loss. Methods: A total of 510 limbs in 431 CLTI patients who were undergone endovascular treatment (EVT) from January 2013 to November 2018 were enrolled in this study. Patients were categorized into 4-groups based on the CFS stages: CFS 1 to 4 (well), CFS 5 (mild), CFS 6 (moderate) and CFS ≥7 (severe). And the change in patient’s activities during hospitalize was classified into 3 groups based on CFS; improve, stable, worse. Primary endpoint was correlation between CFS at discharge and wound healing rate. Secondary endpoint was relationship between the changes in patient’s activities and wound healing rate. Results: A total of 365 limbs were obtained complete wound healing during this study period. Patient distribution into the 4 CFS groups was as follows: 13.3% (well), 21.8% (mild), 25.3% (moderate) and 39.6% (severe). Wound healing rate in severe CFS group was significantly lower than that in other CFS groups (p<0.0001). Wound healing rate in the patients who achieved improvement of activity was significantly higher than that in the other groups (p=0.008). Conclusions: CFS might be useful for risk stratification in patients with tissue loss. And improvement of activity during hospitalization might lead to increase the wound healing rate. Clinical Impact Although the association between clinical frailty and prognosis outcome of Chronic limb-threatening ischemia (CLTI) has been reported, the effect of clinical frailty on wound healing remains unclear. Clinical frailty scale is independently associated with wound healing and might be useful for risk stratification in patients with tissue loss. Improvement of activity during hospitalization might lead to increase the wound healing rate.

AIM:No flow-limiting dissection after drug-coated balloon (DCB) treatment for femoropopliteal (FP) lesions is considered as one of the endpoints, but it has not investigated the difference between each vessel dissection. This study aimed to clarify whether there is a difference between no dissection and type C dissection without flow-limiting dissection for 3 months by peak systolic velocity ratio (PSVR) based on duplex ultrasonography.METHODS:Between February 2020 and April 2021, 44 consecutive de novo FP diseases that underwent endovascular therapy (EVT) with DCB were enrolled in this study. 65.9% of the patients had intermittent claudication, and mean lesion lengths were 194±107 mm. The chronic total occlusion was 38.6%. After DCB treatment, vessel dissection pattern was categorized by angiography. The minimum lumen area (MLA) identified by intravascular ultrasound was serially evaluated with PSVRs at 1 day, 1 month, and 3 months after EVT.RESULT:All lesions were treated with DCB without provisional stents. The vessel dissection pattern after DCB treatment showed that types D, E, and F were not observed, 9% were no dissection, 27% were type A, 32% were type B, and 32% were type C. In all cases, the PSVR values of MLA site were less than 2.6 at 3 months, and there were no significant differences between no dissection and type C dissection.CONCLUSION:Up to dissection pattern "C" is considered acceptable as one of the endpoints to determine the need for provisional stenting after DCB treatment.

354 © 2022 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2022/2003 2 Happle R. Cockade nevus. Unusual variation of nevus cell nevus]. Hautarzt 1974; 25(12): 594–6. 3 Yazici AC, Ikizoǧlu G, Apa DD et al. The eclipse naevus and cockade naevus: are they two of a kind? Clin Exp Dermatol 2006; 31(4): 596–7. 4 Capella GL, Altomare G. Cockade nevi and spinal dysraphism. Int J Dermatol 2000; 39(4): 318–20. 5 Kessides MC, Puttgen KB, Cohen BA. No biopsy needed for eclipse and cockade nevi found on the scalps of children. Arch Dermatol Res 2009; 145(11): 1334–6. 6 Tcheung WJ, Bellet JS, Prose NS et al. Clinical and dermoscopic features of 88 scalp naevi in 39 children. Br J Dermatol 2011; 165(1): 137–43. 7 Warin AP. Cockarde naevus. Clin Exp Dermatol 1976; 1(3): 221–4. 8 Guzzo C, Johnson B, Honig P. Cockarde nevus: a case report and review of the literature. Pediatr Dermatol 1988; 5(4): 250–3. 9 James MP, Wells RS. Cockade naevus: an unusual variant of the benign cellular naevus. Acta Derm Venereol 1980; 60(4): 360–3.

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 20, Issue 3 p. 353-355 Clinical Letter Pseudoangiomatous stromal hyperplasia (PASH) arising in an axillary accessory breast Yuka Maya, Yuka Maya Department of Dermatology, Sapporo City General Hospital, Sapporo, JapanSearch for more papers by this authorYasuyuki Fujita, Corresponding Author Yasuyuki Fujita [email protected] orcid.org/0000-0001-7934-9261 Department of Dermatology, Sapporo City General Hospital, Sapporo, Japan Correspondence to Yasuyuki Fujita, MD, PhD Department of Dermatology Sapporo City General Hospital North 11 West 14, Chuo-ku Sapporo 060–8604, Japan E-mail: [email protected]Search for more papers by this authorKodai Miyamoto, Kodai Miyamoto Department of Dermatology, Sapporo City General Hospital, Sapporo, JapanSearch for more papers by this authorMachiko Nishimura, Machiko Nishimura Iwata Skin Clinic, Sapporo, JapanSearch for more papers by this authorSari Iwasaki, Sari Iwasaki Department of Pathology, Sapporo City General Hospital, Sapporo, JapanSearch for more papers by this authorSatoko Shimizu, Satoko Shimizu Department of Dermatology, Sapporo City General Hospital, Sapporo, JapanSearch for more papers by this author Yuka Maya, Yuka Maya Department of Dermatology, Sapporo City General Hospital, Sapporo, JapanSearch for more papers by this authorYasuyuki Fujita, Corresponding Author Yasuyuki Fujita [email protected] orcid.org/0000-0001-7934-9261 Department of Dermatology, Sapporo City General Hospital, Sapporo, Japan Correspondence to Yasuyuki Fujita, MD, PhD Department of Dermatology Sapporo City General Hospital North 11 West 14, Chuo-ku Sapporo 060–8604, Japan E-mail: [email protected]Search for more papers by this authorKodai Miyamoto, Kodai Miyamoto Department of Dermatology, Sapporo City General Hospital, Sapporo, JapanSearch for more papers by this authorMachiko Nishimura, Machiko Nishimura Iwata Skin Clinic, Sapporo, JapanSearch for more papers by this authorSari Iwasaki, Sari Iwasaki Department of Pathology, Sapporo City General Hospital, Sapporo, JapanSearch for more papers by this authorSatoko Shimizu, Satoko Shimizu Department of Dermatology, Sapporo City General Hospital, Sapporo, JapanSearch for more papers by this author First published: 15 February 2022 https://doi.org/10.1111/ddg.14710AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume20, Issue3March 2022Pages 353-355 RelatedInformation

Background: This study evaluated the mechanism of decline in coronary pressure from the proximal to the distal part of the coronary arteries in the left anterior descending (LAD) versus the right coronary artery (RCA) from the insight of coronary hemodynamics using wave intensity analysis (WIA). Methods: Twelve patients with angiographically normal LAD and RCA were prospectively enrolled. Distal coronary pressure, mean aortic pressure, and average peak velocity were measured at 4 different positions: 9, 6, 3, and 0 cm distal from each coronary ostium. Results: The distal-to-proximal coronary pressure ratio during maximum hyperemia gradually decreased in proportion to the distance from the ostium (0.92 +/- 0.03 and 0.98 +/- 0.03 at 9 cm distal to the LAD and RCA ostium). WIA showed the dominant forward-traveling compression wave gradually decreased and the backward-traveling suction wave gradually decreased in proportion to the decrease in coronary pressure through the length of the non-diseased LAD but not the RCA. Conclusions: The pushing wave and suction wave intensities on WIA were diminished in proportion to the distance from the ostium of the LAD despite the wave intensity not changing across the length of the RCA, which may lead to gradual intracoronary pressure drop in the angiographically normal LAD. (c) 2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Purpose: To identify intravascular ultrasound (IVUS) findings that predict midterm stent patency in femoropopliteal (FP) lesions. Materials and Methods: A retrospective analysis was undertaken of 335 de novo FP lesions in 274 consecutive patients (mean age 72.4±8.2 years; 210 men) who had IVUS assessment before and after successful stent implantation. The mean lesion length was 13.2±9.8 cm. The primary outcome was primary patency at 24 months, defined as freedom from major adverse limb event (MALE) and in-stent restenosis (ISR). MALE was defined as major amputation or any target lesion revascularization (TLR). ISR was defined by a peak systolic velocity ratio >2.4 by duplex ultrasonography. Logistic regression analyses were performed to identify independent predictors of stent patency at 24 months; the results are presented as the odds ratio (OR) and 95% confidence interval (CI). Receiver operator characteristic (ROC) curve analysis was performed to determine the optimal threshold for prediction of stent patency at 24 months. Results: Over the 24-month follow-up, 18 (7%) patients died and 43 (15%) of 286 lesions were responsible for MALE (42 TLRs and 1 major amputation). Primary patency was estimated at 82.5% (95% CI 78.1% to 86.9%) at 12 months and 73.2% (95% CI 67.9% to 78.5%) at 24 months. Multivariable analysis revealed that longer lesion length (OR 0.89, 95% CI 0.82 to 0.97, p<0.01) was an independent predictor of declining patency, while cilostazol use (OR 3.45, 95% CI 1.10 to 10.78, p=0.03) and increasing distal reference external elastic membrane (EEM) area (OR 1.18, 95% CI 1.02 to 1.37, p=0.03) were associated with midterm stent patency. ROC curve analysis identified a distal reference EEM area of 29.0 mm2 as the optimal cut-point for prediction of 24-month stent patency (area under the ROC curve 0.764). Kaplan-Meier estimates of 24-month primary patency were 83.7% (95% CI 78.3% to 89.2%) in lesions with a distal EEM area >29.0 mm2 vs 53.1% (95% CI 42.9% to 63.3%) in those with a distal EEM area ≤29.0 mm2 (p<0.001). Conclusion: In FP lesions with a larger distal vessel area estimated with IVUS, stent implantation can be considered as a reasonable treatment option, with the likelihood of acceptable midterm results.

Aim: The aim of this study was to investigate the clinical effect of planned endovascular therapy (EVT) for critical limb ischemia (CLI) patients with tissue loss. Although several rounds of EVT for CLI patients are required for complete wound healing, time required for complete wound healing depends on the wound severity. We hypothesized that planned EVT might reduce the time to wound healing. Methods: A total of 89 limbs of 76 CLI patients with tissue loss, who had undergone more than at least two EVTs were included in this study. From January 2013 through December 2015 (Conventional-EVT-group, 52 limbs), indication of target lesion revascularization (TLR) was decided based on decreased skin perfusion pressure (SPP) values or delayed wound healing. From January 2016 through October 2016 (Planned-EVT-group, 37 limbs), TLR were done every two months regardless of the SPP values until complete wound healing was obtained. Time to wound healing and complete wound healing rates were compared between the two groups. Results: No significant differences existed in baseline patients and lesion characteristics between the two groups. There was no significant difference in total EVT numbers between the two groups (2.0; interquartile range, 2.0-3.0 versus 2.0; interquartile range, 2.0-3.0; P=0.9). Although complete wound healing rate was similar in both groups (71.2% versus 73.0%, p=1.0), time to wound healing was significantly shorter (95 days versus 143 days, p =0.025) in the Planned-EVT-group than in the Conventional-EVT-group. Conclusions: Planned-EVT is a useful strategy to shorten the time to wound healing for CLI patients with tissue loss.

BACKGROUND Coronary angioscopy (CAS) is used to comprehensively evaluate vascular responses after drug-eluting stent (DES) implantation. This study sought to evaluate the capability of CAS for evaluating DES strut coverage grade and color grade of the intima compared with histological images in coronary autopsy specimens. Methods and Results: A total of 23 DES extracted from 11 autopsy hearts were imaged by CAS. All stent segments were graded as white or yellow according to the luminal surface color, and thrombus was evaluated according to a previous report. Neointimal coverage over the DES was graded as 0 (stent struts fully visible) to grade 3 (stent struts fully embedded and invisible). Of 76 segments, neointimal coverage was graded as 0 in 35 (46%), 1 in 22 (29%), 2 in 8 (11%), and 3 in 11 (14%). The neointimal thickness increased significantly with increasing neointimal coverage grade on angioscopy. Neointimal color was graded as white in 40 (53%) and yellow in 36 segments (47%). Histological analysis revealed that yellow neointima contained fibroatheroma, foam cells accumulation or superficial calcium deposition. A thrombus was identified in 13 segments. Thrombi adherent around the stent strut were partly intimal erythrocyte accumulation around the strut. CONCLUSIONS In-stent yellow segment had atherosclerotic components. CAS could evaluate vascular status comprehensively after DES implantation.

This study evaluated the impact of optical coherence tomography (OCT)-derived low-backscattered tissue on mid-term coronary endothelial function after drug-eluting stent (DES) implantation. Although OCT enables detailed in vivo evaluation of neointimal tissue characterization after DES implantation, its association with physiological vascular healing response is unclear. Thirty-three stable angina pectoris patients underwent OCT examination and endothelial function testing with intracoronary infusion of incremental doses of acetylcholine 8-month after DES implantation in a single lesion of the left anterior descending artery. Neointimal tissue was classified into two patterns based on the predominant OCT light backscatter: high backscatter and low backscatter. Although the presence of uncovered or malapposed stent strut was not associated with the degree of vasoconstriction, the degree of vasoconstriction was significantly greater in the DES with low-backscattered neointima than in the DES without low-backscattered neointima (− 32.1 ± 25.7 vs. − 4.1 ± 20.1%, p = 0.003). Moreover, there was an inverse linear relationship between low backscatter tissue index and degree of vasoconstriction after acetylcholine infusion (r = 0.50 and p = 0.003). The endothelium-dependent vasomotor response after 8-month of DES was impaired in patients with low neointimal tissue backscatter on OCT imaging. OCT assessment of low-backscattered tissue may be used as surrogate markers for impairment of endothelial function after DES.

We recently reported the coronary thermodilution curve can be evaluated by analyzing the thermodilution curve obtained from a pressure sensor/thermistor-tipped guidewire, and presence of a bimodal-shaped thermodilution curve following primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction (STEMI) patients was associated with worse outcomes. This study evaluated whether the bimodal-shaped thermodilution curve predicts left ventricular (LV) remodeling after STEMI. The coronary thermodilution curve patterns were evaluated for 75 patients treated by pPCI for their first STEMI using a pressure sensor/thermistor-tipped guidewire, and classified into the three groups according to the thermodilution curve shape: narrow unimodal (n = 39), wide unimodal (n = 26), and bimodal pattern (n = 10). Echocardiography was performed at baseline and 6 months after STEMI. LV remodeling was defined as a >20 % increase in LV end-diastolic volumes (LVEDV). LVEDV at 6-month follow-up was greater in the bimodal group than in the other groups (p < 0.001). The prevalence of LV remodeling was highest in the bimodal group than in the narrow and wide unimodal groups (60, 12, and 15 %, respectively; p = 0.003). Multivariate analysis revealed a bimodal-shaped thermodilution curve as an independent predictor of the prevalence of LV remodeling. A bimodal-shaped thermodilution curve is associated with LV remodeling after STEMI. This easily assessable coronary thermodilution curve pattern is useful to predict mid-term LV remodeling for STEMI patients at the catheterization laboratory.

Plectin is a linker protein that interacts with intermediate filaments and 4 integrin in hemidesmosomes of the epidermal basement membrane zone (BMZ). Type XVII collagen (COL17) has been suggested as another candidate plectin binding partner in hemidesmosomes. Here, we demonstrate that plectin-COL17 binding helps to maintain epidermal BMZ organization. We identified an epidermolysis bullosa (EB) simplex patient as having markedly diminished expression of plectin and COL17 in skin. The patient is compound heterozygous for sequence variants in the plectin gene (PLEC); one is a truncation and the other is a small in-frame deletion sequence variant. The in-frame deletion is located in the putative COL17-binding domain of plectin and abolishes the plectin-COL17 interaction in vitro. These results imply that disrupted interaction between plectin and COL17 is involved in the development of EB. Our study suggests that protein-protein binding defects may underlie EB in patients with unidentified disease-causing sequence variants.

Mycosis fungoides (MF) is the majority of cutaneous T cell lymphoma (CTCL) cases, and is thought to originate from the clonal cell proliferation of CD4-positive helper T cells [ [1] Oslen E. Vonderheid E. Pimpinelli N. Willemze R. Kim Y. Knobler R. et al. Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007; 110: 1713-1722 Crossref PubMed Scopus (1084) Google Scholar ]. Patients with MF in the patch or plaque stages have good prognosis, whereas those in the tumor/erythrodermic stage have skin lesions that form painful ulcers, which lead to susceptibility to cutaneous infection. The treatment options for tumor-stage MF are limited; thus, a novel, pathogenesis-oriented therapeutic approach should be developed. Recently, investigations using whole-genome and whole-exon sequencing have revealed oncogenic mutations including JAK3, TP53, NOTCH2 [ [2] McGirt L.Y. Jia P. Baerenwald D.A. Duszynski R.J. Dahlman K.B. Zic J.A. et al. Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides. Blood. 2015; 126: 508-519 Crossref PubMed Scopus (154) Google Scholar ], TNFRSF1B, CTLA4-CD28 fusion [ [3] Ungewickell A. Bhaduri A. Rios E. Reuter J. Lee C.S. Mah A. et al. Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. Nat. Genet. 2015; 47: 1056-1060 Crossref PubMed Scopus (209) Google Scholar ], RB1, PTEN, DNMT3A, CDKN1B [ [4] da Silva Almeida A.C. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C.P. et al. The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome. Nat. Genet. 2015; 47: 1465-1470 Crossref PubMed Scopus (272) Google Scholar ], CARD11, CDKN2A, and CCR4 [ [5] Wang L. Ni X. Covington K.R. Yang B.Y. Shiu J. Zhang X. et al. Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat. Genet. 2015; 47: 1426-1434 Crossref PubMed Scopus (232) Google Scholar ] in CTCL. However, these mutations are not commonly observed in most MF cases, suggesting that they are not “driver” mutations. Furthermore, it has not been obvious whether reported mutations are associated with clinical severity/stage and patient prognosis. In light of the above, we performed mutation analysis targeting comprehensive cancer-associated genes (Supplemental Fig. 1).

In addition to plaque rupture (PR), calcified nodule (CN) may also have the potential to develop into arterial thrombus in the peripheral arteries. This study evaluated the distribution of plaque ruptures and calcified nodules in the peripheral arteries and their impact on the outcome of endovascular therapy (EVT). Consecutive 159 patients who underwent EVT with intravascular ultrasound guidance were enrolled. The position of CNs and PRs were assigned to any of common iliac artery, external iliac artery, common femoral artery, and superficial femoral artery. Forty-six (29%) patients had calcified nodule and twenty-eight (18%) patients had plaque rupture somewhere in the lower limb arteries. Although calcified nodules were evenly distributed throughout the length of the arteries plaque ruptures were predominantly located in the proximal segment of the iliofemoral arteries. Stent expansion ratio was significantly smaller in the target arteries with calcified nodules than in those with plaque rupture. Multivariate logistic regression analysis identified hemodialysis as an independent clinical predictor of calcified nodule (odds ratio 8.15, 95% confidence interval 1.73–38.3; P = 0.008). CN definitely affects incomplete stent deployment in the peripheral artery contributing to adverse events, on the other hand, PR has more acceptable outcomes after stent implantation. In the clinical setting, it is important that we realize the features of peripheral artery disease and its patient characteristics which having CNs and PRs to make a strategy for revascularization.

Bullous pemphigoid (BP) is a common autoimmune bullous disease which is mainly caused by autoantibodies to the 180-kDa bullous pemphigoid antigen (BP180) [1]. BP is characterized by generalized bullous lesions and itchy oedematous erythemas, although some localized forms have been reported [2]. Herein, we report a case of BP presenting with an unusual feature of severe oedema of the hands during recurrence.A 69-year-old Japanese man presented with itchy erythemas and tense blisters on the trunk, [...]

Pyoderma gangrenosum is a chronic non-infectious neutrophilic dermatosis that causes undermining ulcers. Topical therapies for the deep ulcers of pyoderma gangrenosum have not been established. To investigate whether negative-pressure wound therapy is effective for a pyoderma gangrenosum ulcer, we used the PICO single use negative-pressure wound therapy system (Smith & Nephew, London, UK) for two pyoderma gangrenosum patients. In these cases, the ulcers decreased in size and necrolytic tissue was removed notably. Moreover, there were no secondary infections nor was there Koebner phenomena. Our cases suggest that portable negative-pressure wound therapy can be a treatment option for deep, intractable ulcers caused by pyoderma gangrenosum. Because portable negative-pressure wound therapy devices afford increased mobility to patients, they can give the patient a better quality of life than standard negative-pressure wound therapy systems do.

The Journal of DermatologyVolume 44, Issue 10 p. e242-e243 Letter to the Editor Chemiluminescent enzyme immunoassay failed to detect anti-desmoglein 3 antibodies in a case of pemphigus vulgaris Yosuke Mai, Yosuke Mai orcid.org/0000-0001-6356-7192 Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorHideyuki Ujiie, Corresponding Author Hideyuki Ujiie h-ujiie@med.hokudai.ac.jp Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoCorrespondence: Hideyuki Ujiie, M.D., Ph.D., Department of Dermatology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan. Email: h-ujiie@med.hokudai.ac.jpSearch for more papers by this authorMachiko Nishimura, Machiko Nishimura Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorHiroshi Koga, Hiroshi Koga Department of Dermatology, Kurume University School of Medicine, FukuokaSearch for more papers by this authorYuka Maya, Yuka Maya orcid.org/0000-0002-5649-8499 Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorKeiko Shiba-Tokuchi, Keiko Shiba-Tokuchi orcid.org/0000-0001-9085-1922 Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorYasuyuki Fujita, Yasuyuki Fujita Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorHiroaki Iwata, Hiroaki Iwata Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorYohei Mikawa, Yohei Mikawa Department of Oral Pathological Science, Hokkaido University Graduate School of Dental Medicine, Sapporo, JapanSearch for more papers by this authorHiroshi Shimizu, Hiroshi Shimizu Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this author Yosuke Mai, Yosuke Mai orcid.org/0000-0001-6356-7192 Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorHideyuki Ujiie, Corresponding Author Hideyuki Ujiie h-ujiie@med.hokudai.ac.jp Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoCorrespondence: Hideyuki Ujiie, M.D., Ph.D., Department of Dermatology, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan. Email: h-ujiie@med.hokudai.ac.jpSearch for more papers by this authorMachiko Nishimura, Machiko Nishimura Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorHiroshi Koga, Hiroshi Koga Department of Dermatology, Kurume University School of Medicine, FukuokaSearch for more papers by this authorYuka Maya, Yuka Maya orcid.org/0000-0002-5649-8499 Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorKeiko Shiba-Tokuchi, Keiko Shiba-Tokuchi orcid.org/0000-0001-9085-1922 Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorYasuyuki Fujita, Yasuyuki Fujita Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorHiroaki Iwata, Hiroaki Iwata Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this authorYohei Mikawa, Yohei Mikawa Department of Oral Pathological Science, Hokkaido University Graduate School of Dental Medicine, Sapporo, JapanSearch for more papers by this authorHiroshi Shimizu, Hiroshi Shimizu Department of Dermatology, Hokkaido University Graduate School of Medicine, SapporoSearch for more papers by this author First published: 17 June 2017 https://doi.org/10.1111/1346-8138.13932Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume44, Issue10October 2017Pages e242-e243 RelatedInformation

Dipeptidyl peptidase-4 inhibitor (DPP-4i) has been widely used to treat type 2 diabetes. DPP-4 inactivates incretins by catalyzing the cleavage of those proteins to inactive forms (Drucker, 2007Drucker D.J. The role of gut hormones in glucose homeostasis.J Clin Invest. 2007; 117: 24-32Crossref PubMed Scopus (487) Google Scholar). DPP-4i works by inhibiting the action of this enzyme and improves glycemic control (Aschner and Kipnes, 2006Aschner P. Kipnes M. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes.Diabetes Metab. 2006; 29: 2632-2637Google Scholar). DPP-4i has been known as a safe drug; however, an increased risk of bullous pemphigoid (BP) during DPP-4i exposure has been reported in diabetic patients administered DPP-4i (Béné et al., 2016Béné J. Moulis G. Bennani I. Auffret M. Coupe P. Babai S. et al.Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case-noncase study in the French Pharmacovigilance Database.Br J Dermatol. 2016; 175: 296-301Crossref PubMed Scopus (125) Google Scholar). BP is the most common autoimmune blistering disorder, and it is characterized by itchy edematous erythema and tense blisters on the whole body. It is mainly caused by autoantibodies to a major hemidesmosomal component at the dermal-epidermal junction of the skin, type XVII collagen (COL17 or BP180). The noncollagenous 16A (NC16A) domain of COL17 contains a major pathogenic epitope (Giudice et al., 1993Giudice G.J. Emery D.J. Zelickson B.D. Anhalt G.J. Liu Z. Diaz L a Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain.J Immunol. 1993; 151: 5742-5750PubMed Google Scholar). Although several factors have been reported as triggers of BP, the etiology of BP remains largely unknown. The exact mechanism behind the association of DPP-4i exposure and BP has yet to be elucidated. Because several studies have reported an association between HLAs and drug-induced reactions (Chung et al., 2004Chung W.-H. Hung S.-I. Hong H.-S. Hsih M. Yang L.-C. Ho H.-C. et al.Medical genetics: a marker for Stevens-Johnson syndrome.Nature. 2004; 428: 486Crossref PubMed Scopus (1362) Google Scholar, Wang et al., 2013Wang H. Yan L. Zhang G. Chen X. Yang J. Li M. et al.Association between HLA-B*1301 and Dapsone-Induced Hypersensitivity Reactions among Leprosy Patients in China.J Invest Dermatol. 2013; 133: 2642-2644Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), we examined HLA alleles in Japanese patients with BP who had been taking DPP-4i for type 2 diabetes for at least 3 months before BP onset (DPP-4i-BP). We recently reported that DPP-4i-BP tends to show a noninflammatory phenotype with few erythematous lesions, in sharp contrast to conventional BP unrelated to DPP-4i intake (Izumi et al., 2016Izumi K. Nishie W. Mai Y. Wada M. Natsuga K. Ujiie H. et al.Autoantibody profile differentiates between inflammatory and noninflammatory bullous pemphigoid.J Invest Dermatol. 2016; 136: 2201-2210Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). We encountered 30 patients with DPP-4i-BP in the last 3 years and found that most patients (21/30) showed the noninflammatory phenotype (Figure 1a). Based on the scores for erythema/urticaria in the bullous pemphigoid disease area index (BPDAI) (Murrell et al., 2012Murrell D.F. Daniel B.S. Joly P. Borradori L. Amagai M. Hashimoto T. et al.Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.J Am Acad Dermatol. 2012; 66: 479-485Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar), DPP-4i-BP was clearly divided into two groups, inflammatory (BPDAI: erythema/urticaria ≥ 10) and noninflammatory (BPDAI: erythema/urticaria < 10) (Figure 1b), and the clinical appearance of the patients with noninflammatory disease was distinct from that of those with conventional BP (Figure 1a). BPDAI scores for erosions/blisters showed no significant difference between DPP-4i-BP and conventional BP patients (Figure 1c). The antibody titers to full-length COL17 were similar between the two groups (Figure 1d), whereas those to the NC16A domain of COL17 were significantly lower in the noniflammatory DPP-4i-BP patients (Figure 1e). Histologically, eosinophil counts in the upper dermis of periblister lesions were significantly lower in noninflammatory DPP-4i-BP than in inflammatory DPP-4i-BP (Figure 1f). From these findings, we considered this unique noninflammatory subgroup to be distinct from inflammatory DPP-4i-BP and conventional BP, and this study focuses on this subgroup (Figure 1b red square [blue dots], and see Supplementary Tables S1 and S2 online). The collection of human samples was approved by the local ethics committee and the institutional review board of Hokkaido University and Keio University and by the research ethics committee of RIKEN. Written informed patient consent was obtained from the patients. Surprisingly, 86% (18/21) of noninflammatory DPP-4i-BP patients in our sample carry HLA-DQB1*03:01 (Table 1). The frequencies of carriers of alleles HLA-DQB1*03:01, -DQA1*05:05, -DRB1*11:01, and -DRB1*12:01 were significantly higher, and those of carriers of alleles HLA-DQA1*01:03 and -DQB1*06:01 were significantly lower, in DPP-4i-BP than in Japanese general population control individuals (Table 1, and see Supplementary Tables S3–S9 online). We also compared the six HLA alleles in conventional BP patients with those in Japanese general population control individuals and found that none of those alleles was significantly different (Table 1). We next compared the six alleles in DPP-4i-BP with those in DPP-4i–tolerant patients with type 2 diabetes who were exposed to DPP-4i for at least 2 years (see Supplementary Table S10 online) and found that the frequencies of carriers of alleles HLA-DQB1*03:01 and -DRB1*12:01 were significantly higher in DPP-4i-BP (Table 1). These findings clearly show that the two alleles are significantly associated with DPP-4i-BP but not with conventional BP nor with type 2 diabetes. HLA-DQB1*03:01 was present in 19 (31%) of the 61 DPP-4i–tolerant control individuals, suggesting that this allele has 86% sensitivity and 69% specificity when we apply HLA-DQB1*03:01 as a risk predictor for noninflammatory DPP-4i-BP in the Japanese population. In addition to the allele frequencies, the two- or three-locus haplotype frequencies for HLA-DQA1, -DQB1 and -DRB1 were compared between DPP-4i-BP and control groups. HLA-DRB1*12:01-DQB1*03:01 showed the lowest P-value in 243 haplotypes (P = 2.16 × 10–8), which was greater than that of HLA-DQB1*03:01 alone (P = 5.86 × 10–11), indicating that HLA-DQB1*03:01 will be the more useful biomarker in predicting DPP-4i-BP before administration to Japanese patients (Table 1).Table 1Frequency of HLA alleles and haplotypes in cases and controlsHLA AlleleDPP-4i-BP (Noninflammatory), n (%)(n = 21)Conventional BP, n (%)(n = 72)Japanese General Population Control Individuals, n (%)(n = 873)DPP-4i–Tolerant Diabetes Patients, n (%)(n = 61)DPP-4i-BP (Noninflammatory) Patients VersusGeneral Population Control IndividualsConventional BP Patients VersusGeneral Population Control IndividualsDPP-4i-BP (Noninflammatory) Versus Tolerant Control IndividualsOR (95% CI)P-Value1All values in this column are significant after Bonferroni correction: P < 1.27 × 10–4 (0.05/152 HLA-A, -B, -C, -DRB1, -DPB1, -DQA, -DQB1 alleles; 76 DRB1-DQA1-DQB1 haplotypes; 52 DRB1-DQA1 haplotypes; 68 DRB1-DQB1 haplotypes; and 47 DQA1-DQB1 haplotypes).OR (95% CI)P-ValueOR (95% CI)P-Value2Boldface values in this column are significant after Bonferroni correction: P < 5.56 × 10–3 (0.05/6 HLA alleles, 1 DRB1-DQB1 haplotype, and 2 DQA1-DQB1 haplotypes).DQB1*03:0118 (86)19 (26)156 (18)19 (31)27.6 (8.0–94.8)5.86 × 10–111.6 (0.9–2.9)8.24 × 10–213.3 (3.5–50.5)2.13 × 10–5DQA1*05:0510 (48)10 (14)60 (7)11 (18)12.3 (5.0–30.2)8.11 × 10–72.2 (1.1–4.5)5.58 × 10–24.1 (1.4–12.1)1.79 × 10–2DRB1*12:0110 (48)8 (11)68 (8)7 (11)10.8 (4.4–26.2)2.34 × 10–61.5 (0.7–3.2)3.63 × 10–17.0 (2.2–22.4)1.08 × 10–3DQA1*01:030 (0)18 (25)368 (42)18 (30)0.0 (0.0–0.5)1.52 × 10–50.5 (0.3–0.8)4.07 × 10–30.1 (0.0–0.9)4.31 × 10–3DRB1*11:017 (33)6 (8)37 (4)9 (15)11.3 (4.3–29.7)2.99 × 10–52.1 (0.8–5.0)1.32 × 10–12.9 (0.9–9.1)1.07 × 10–1DQB1*06:010 (0)18 (25)359 (41)18 (30)0.0 (0.0–0.6)3.67 × 10–50.4 (0.3–0.8)3.45 × 10–20.1 (0.0–0.9)4.31 × 10–3DRB1*12:01-DQB1*03:0110 (48)6 (8)39 (4)1 (0)19.4 (7.8–48.5)2.16 × 10–81.9 (0.8–4.8)1.46 × 10–154.5 (6.3–470.1)1.56 × 10–6DQA1*05:05-DQB1*03:0110 (48)8 (11)58 (7)11 (18)12.8 (5.2–31.3)6.09 × 10–71.8 (0.8–3.8)1.51 × 10–14.1 (1.4–12.1)1.79 × 10–2DQA1*01:03-DQB1*06:010 (0)16 (22)357 (41)18 (30)0.0 (0.0–0.6)3.65 × 10–50.4 (0.2–0.7)1.62 × 10–30.0 (0.0–0.9)4.31 × 10–3Abbreviations: BP, bullous pemphigoid; CI, confidence interval; DPP-4i, dipeptidyl peptidase-4 inhibitor; HLA, human leukocyte antigen; OR, odds ratio.1 All values in this column are significant after Bonferroni correction: P < 1.27 × 10–4 (0.05/152 HLA-A, -B, -C, -DRB1, -DPB1, -DQA, -DQB1 alleles; 76 DRB1-DQA1-DQB1 haplotypes; 52 DRB1-DQA1 haplotypes; 68 DRB1-DQB1 haplotypes; and 47 DQA1-DQB1 haplotypes).2 Boldface values in this column are significant after Bonferroni correction: P < 5.56 × 10–3 (0.05/6 HLA alleles, 1 DRB1-DQB1 haplotype, and 2 DQA1-DQB1 haplotypes). Open table in a new tab Abbreviations: BP, bullous pemphigoid; CI, confidence interval; DPP-4i, dipeptidyl peptidase-4 inhibitor; HLA, human leukocyte antigen; OR, odds ratio. Six patients with conventional BP suffered from type 2 diabetes at the onset of BP. We found that BPDAI scores for erosions/blisters were similar in those with DPP-4i-BP and conventional BP with diabetes, whereas scores for erythema/urticaria were significantly higher in those with conventional BP with diabetes (see Supplementary Figure S1 online), suggesting that the noninflammatory phenotype in DPP-4i-BP correlates with the intake of DPP-4i rather than with the existence of type 2 diabetes. Furthermore, none of the patients with conventional BP with diabetes carried HLA-DQB1*03:01. Eight patients with conventional BP had noninflammatory disease, and 37.5% (3/8) of those patients carried HLA-DQB1*03:01. This frequency is similar to that for patients with inflammatory conventional BP (16/64 [25%]) and inflammatory DPP-4i-BP (4/9 [44%]) and lower than that for those with noninflammatory DPP-4i-BP (18/21 [86%]), suggesting that HLA-DQB1*03:01 is associated with noninflammatory DPP-4i-BP rather than with noninflammatory conventional BP or inflammatory DPP-4i-BP. To our knowledge, the association of HLA-DQB1*03:01 with noninflammatory DPP-4i-BP is the strongest association that has been described between a class II HLA and a drug-related autoimmune disease. HLA-DQB1*03:01, also reported to be associated with mucous membrane pemphigoid in Caucasian patients (Ahmed et al., 1991Ahmed A.R. Foster S. Zaltas M. Notani G. Awdeh Z. Alper C.A. et al.Association of DQw7 (DQB1*0301) with ocular cicatricial pemphigoid.Proc Natl Acad Sci USA. 1991; 88: 11579-11582Crossref PubMed Scopus (89) Google Scholar, Delgado et al., 1996Delgado J.C. Turbay D. Yunis E.J. Yunis J.J. Morton E.D. Bhol K. et al.A common major histocompatibility complex class II allele HLA-DQB1* 0301 is present in clinical variants of pemphigoid.Proc Natl Acad Sci USA. 1996; 93: 8569-8571Crossref PubMed Scopus (173) Google Scholar), seems to be a risk factor for DPP-4i-BP in Japanese. To confirm this, the incidence of DPP-4i-BP among diabetic patients carrying HLA-DQB1*03:01 should be investigated. In addition, to determine whether the noninflammatory phenotype is a distinctive feature of DPP-4i-BP or just a mild form of BP, further investigations are required. The findings of this study give us important clues about the breakdown of self-tolerance that results from the interaction of genetic background and drug intake. The authors state no conflict of interest. We thank Jun Yamagami and Yuichi Kurihara of the Keio University Department of Dermatology for collecting the DPP-4i-BP samples and Shingo Yanagiya and Yuka Kameda of the Hokkaido University Department of Rheumatology, Endocrinology, and Nephrology for collecting the DPP-4i–tolerant control samples. We also thank Miyuki Kasegai of the Hokkaido University Hospital Clinical Research and Medical Innovation Center for technical assistance. This work was supported by the Research on Measures for Intractable Diseases Project: Matching Fund Subsidy (H26-069 to HS) from the Ministry of Health, Labor, and Welfare of Japan and the Tailor-Made Medical Treatment Program (BioBank Japan Project) funded by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. We thank the Midosuji Rotary Clubs and other Rotary Clubs for cooperation in this study. Download .pdf (.37 MB) Help with pdf files Supplementary Data

BackgroundThe optimal sizing of self-expanding paclitaxel-eluting stents (PES) in the treatment for superficial femoral artery (SFA) lesions is unclear. This study sought to investigate the influence of PES diameter on stent patency in SFA lesions using optical frequency domain imaging (OFDI).MethodsA total of 20 de novo SFA lesions were randomized 1:1 to receive either self-expanding PES with a nominal diameter of 6 mm or 8 mm. Follow-up angiography and OFDI was scheduled six months after stent implantation, and volumetric OFDI analysis was performed to evaluate vascular response to the stents. Volume index (VI) was defined as the volume divided by the stent length. The primary end point was lumen VI at the 6-month follow-up. Secondary end point was minimum lumen diameter (MLD) by quantitative vascular angiography (QVA) at the follow-up.ResultsStent length was 78.0 ± 23.9 mm in the 6-mm group and 70.0 ± 23.6 mm in the 8-mm group (p = 0.46). Baseline QVA data were also similar between the two groups. MLD immediately after stent implantation was similar between the two groups (4.2 ± 0.5 mm in the 6-mm group and 3.9 ± 0.5 mm in the 8-mm group, p = NS). At the 6-month follow-up, MLD was greater in the 8-mm group compared to the 6-mm group (4.0 ± 1.0 mm vs. 3.2 ± 0.4 mm, p < 0.05). Stent VI was larger in the 8-mm group (28.4 ± 6.7 mm3/mm vs. 22.2 ± 1.2 mm3/mm, p = 0.01). Neointimal VI was similar between the two groups (5.8 ± 2.9 mm3/mm vs. 5.2 ± 2.6 mm3/mm, p = 0.68). Lumen VI was greater in the 8-mm group (23.2 ± 7.6 mm3/mm vs. 17.3 ± 2.6 mm3/mm, p = 0.04).ConclusionsChronic stent enlargement resulted in greater lumen area after implantation of self-expanding PES with a large diameter at the mid-term follow-up. Stent diameter might be important for stent patency in procedure with PES for SFA lesions.