Publications by authors named "Takaharu Ikeda"

31 Publications

Immune checkpoint molecule expression is altered in the skin and peripheral blood in vasculitis.

Sci Rep 2021 10 8;11(1):20019. Epub 2021 Oct 8.

Division of Dermatology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Dysfunction of immunoinhibitory signals and persistent T cell activation reportedly play important roles in the development of vasculitis. The skin is one of the most accessible organs, and it is suitable for the characterization of immune cell signatures. However, the inhibitory checkpoint molecules in the skin and their relevance to vasculitis have not been studied. Here, we investigated the profile of immune checkpoint molecules in the skin and peripheral blood of patients with vasculitis and healthy donors. We found that some of the inhibitory checkpoint molecules, including programmed cell death 1 receptor (PD-1), were elevated in T-cells in the blood of patients with systemic and cutaneous vasculitis. In addition, programmed death-ligand 1 (PD-L1) expression was elevated in the skin of patients with cutaneous vasculitis. Histologically, PD-L1 was highly expressed in the vessels in the skin along with CD4 and CD8 T-cell infiltration in patients with cutaneous vasculitis. Notably, plasma soluble PD-L1 levels were increased, and these correlated with C-reactive protein in patients with systemic vasculitis. Our findings suggest that inhibitory checkpoint molecules might be differentially modulated in the skin and peripheral blood of patients with vasculitis, and that the alteration of the PD-L1/PD-1 axis may be associated with the regulation of T-cell activation in vasculitis.
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http://dx.doi.org/10.1038/s41598-021-99558-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501116PMC
October 2021

Clinical characteristics of itch in cutaneous lupus erythematosus: A prospective, multicenter, multinational, cross-sectional study.

Lupus 2021 Aug 18;30(9):1385-1393. Epub 2021 May 18.

Department of Dermatology, University of Rzeszow, Rzeszow, Poland.

Objective: Pruritus is an important symptom frequently accompanying various inflammatory skin conditions and some recent data indicated that it may be associated with autoimmune connective tissue diseases. The aim of this study was to assess the frequency and clinical presentation of itch in CLE.

Methods: A multinational, prospective, cross-sectional study was performed to assess the prevalence, intensity and clinical characteristic of pruritus in various subtypes of CLE. A total of 153 patients with active CLE lesions were included. Their age ranged between 17 and 82 years (mean 49.8 ± 15.4 years), and 115 patients (75.2%) were women. The disease activity and damage were assessed according to the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Pruritus severity was assessed with Numeric Rating Scale (NRS) and the 12-Item Pruritus Severity Scale. Dermatology Life Quality Index and EQ-5D questionnaire were used to measure quality of life.

Results: Pruritus was present in 116 (76.8%) of patients of whom half had NRS scoring equal or above 4 points indicating moderate or severe pruritus. Most commonly itch was localized on the scalp, face (excluding ears and nose) and arms (40.5%, 36.2%, 31.9%, respectively). Sensations connected with pruritus were most frequently described as burning, tingling and like ants crawling feeling, but 31.9% patients described it as "pure itch". More than half of patients reported that pruritus was present every day, and it was most frequent during the evenings. The pruritus scoring and the CLASI activity score were significantly correlated (r = 0.42, p = 0.0001), while no correlation was found with the CLASI damage score (p = 0.16). Both the maximum and average itch intensity were correlated with systemic lupus erythematosus (SLE) activity measured with the Systemic Lupus Erythematosus Disease Activity Index.

Conclusions: Pruritus is a common, but frequently overlooked symptom of CLE. Its intensity correlates with the activity of CLE, but not with the skin damage. In more than a half of patients it occurs on a daily basis. The correlation between the intensity of pruritus and the activity of the skin lesions and the systemic involvement indicate that pruritus could be an individual indicator of both SLE and CLE activity.
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http://dx.doi.org/10.1177/09612033211016098DOI Listing
August 2021

Pityriasis lichenoides et varioliformis acuta associated with anti-Ku-positive refractory interstitial lung disease and dermatomyositis.

J Dermatol 2020 Nov 17;47(11):e403-e404. Epub 2020 Aug 17.

Divisions of, Division of, Dermatology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

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http://dx.doi.org/10.1111/1346-8138.15556DOI Listing
November 2020

Early add-on administration of mepolizumab and intravenous immunoglobulin effective in treating eosinophilic granulomatosis with polyangiitis.

J Dermatol 2021 Apr 10;48(4):529-532. Epub 2020 Dec 10.

Division of Dermatology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Treatment of eosinophilic granulomatosis with polyangiitis (EGPA) remains a challenge because currently available therapies, corticosteroids and immunomodulators, do not always control symptoms and are often associated with significant morbidity and relapse. Mepolizumab has been demonstrated to be an effective add-on therapy with steroid-sparing effect in cases of relapsing or refractory EGPA. Intravenous immunoglobulin (IVIG) therapy is effective against mononeuritis multiplex or heart failure in patients with EGPA who do not respond to corticosteroid-cyclophosphamide treatment. We present two cases of EGPA in which earlier add-on administration of adjunct mepolizumab and IVIG led to significant improvement in EGPA symptoms and prevention of flare-up of the disease. We suggested that earlier add-on combination administration of IVIG and mepolizumab might be a useful adjunct treatment to induce clinical remission of EGPA and improve the rate of remission, decrease relapse rate, and allow for reduced glucocorticoid use without any serious adverse drug effects.
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http://dx.doi.org/10.1111/1346-8138.15709DOI Listing
April 2021

Skin biopsies using dermoscopy for earlier diagnosis of intravascular large B-cell lymphoma.

J Dermatol 2020 Jul 10;47(7):e276-e278. Epub 2020 Apr 10.

Divisions of, Division of, Dermatology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

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http://dx.doi.org/10.1111/1346-8138.15350DOI Listing
July 2020

Survey of Japanese dermatological vasculitis specialists on cases of cutaneous arteritis (cutaneous polyarteritis nodosa).

J Dermatol 2020 May 24;47(5):534-537. Epub 2020 Feb 24.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

We developed a questionnaire to examine the findings of cutaneous arteritis among dermatological specialists experienced in vasculitis as certified by the Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. We sent a questionnaire to 12 dermatological facilities identified through the revised Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. Retrospective data obtained from 84 patients at the 12 dermatological facilities between 2012 January 2016 December were evaluated. The 84 patients were categorized into two groups, a systemic steroid treatment group (group 1, n = 52) and a no systemic steroid treatment group (group 2, n = 32). C-reactive protein in group 1 patients was significantly higher than that in group 2 patients. Frequency of fever, arthritis, myalgia- and peripheral neuropathy in group 1 was significantly higher than that in group 2. We propose that these symptoms could serve as early markers for the transfer from cutaneous arteritis to systemic polyarteritis nodosa. We further suggest that patients who are subsequently associated with cerebral hemorrhage and infarction, who are originally diagnosed as having cutaneous arteritis, could progress to systemic polyarteritis nodosa. The study demonstrated that it is important for dermatologists to detect these findings early in order to establish an accurate diagnosis and a timely treatment.
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http://dx.doi.org/10.1111/1346-8138.15273DOI Listing
May 2020

Relationship between lysosomal-associated membrane protein-2 and anti-phosphatidylserine/prothrombin complex antibody in the pathogenesis of cutaneous vasculitis.

Clin Exp Rheumatol 2020 Mar-Apr;38 Suppl 124(2):161-165. Epub 2020 Jan 27.

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

Objectives: We investigated the relationship between lysosomal-associated membrane protein-2 (LAMP-2) and anti-phosphatidylserine/prothrombin (PS/PT) antibody in the pathogenesis of cutaneous vasculitis.

Methods: Cell surface LAMP-2 expression of human neutrophils was measured using flow cytometry. Twenty inbred wild-type Wistar-King-Aptekman-Hokudai (WKAH) rats were divided into four groups: Group 1, rabbit IgG injection only as negative control (n=5); Group 2, both histone and rabbit IgG injection (n=5); Group 3, anti-LAMP-2 antibody injection only (n=5); and Group 4, both histone and anti-LAMP-2 antibody injection (n=5). Ten WKAH rats were divided into two groups: Group A, histone, anti-PS/PT antibody, and anti-LAMP-2 antibody injection (n=5), and Group B, histone, anti-PS/PT antibody, and rabbit IgG injection as control (n=5).

Results: LAMP-2 expression on human neutrophils was induced by cell-free histone exposure in a dose- and time-dependent manner. Histopathological examination revealed the recruitment of neutrophils in cutaneous small vessels in all Group 4 rats. These observations were not evident in systemic organs other than the skin. LAMP-2 expression on the surface of vascular endothelial cells was evident in Group 2, exclusively in the skin, but not in Group 1. Thrombi were detected in various organs in all Groups A and B rats. However, no apparent thrombi were observed in the skin.

Conclusions: Anti-PS/PT and anti-LAMP-2 antibodies are responsible for independent effector mechanisms in the rats given intravenous injection of cell-free histones. We considered that undetermined factors other than cell-free histones could be required for the induction of cutaneous vasculitis by anti-PS/PT and anti-LAMP-2 antibodies.
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September 2020

Psoriatic arthritis induced by anti-programmed death 1 antibody pembrolizumab.

J Dermatol 2019 Dec 2;46(12):e466-e467. Epub 2019 Aug 2.

Department of Dermatology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.

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http://dx.doi.org/10.1111/1346-8138.15040DOI Listing
December 2019

Peripheral blood eosinophilia is associated with the presence of skin ulcers in patients with systemic sclerosis.

J Dermatol 2019 Apr 4;46(4):334-337. Epub 2019 Feb 4.

Department of Dermatology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.

The role of eosinophil in systemic sclerosis (SSc) is still controversial. In the present study, the relationship between skin ulcers and peripheral blood eosinophilia were analyzed in patients with SSc. We retrospectively investigated the clinical records of all patients who were diagnosed with SSc on the basis of American College of Rheumatology/European League Against Rheumatism 2013 criteria, and were followed up for more than 2 years at Wakayama Medical University. As a result, maximum eosinophil counts during the 2-year follow-up period were 20-983/mm (median, 270), whereas maximum eosinophil percentages were 0.5-14.1% (median, 5.3%) in peripheral blood of 47 SSc patients. On the other hand, patients with skin ulcers during the 2-year follow up showed significantly increased maximum eosinophil counts compared with those without (median, 520 vs 228/mm ; P = 0.0001). Maximum eosinophil percentage was also significantly higher in patients with skin ulcers (median, 9.7% vs 4.6%; P = 0.00001). To note, in four of the nine patients with skin ulcers, the timing of emerging of the maximum eosinophil counts was associated with the ulcer development during the 2-year follow up. These results suggest that eosinophils are involved in the pathogenesis of vascular dysfunction of SSc. Larger studies should be performed to clarify the exact mechanism of ulcer formation caused by eosinophilia in SSc patients in the future.
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http://dx.doi.org/10.1111/1346-8138.14774DOI Listing
April 2019

Prognostic factors of daily blood examination for advanced melanoma patients treated with nivolumab.

Biosci Trends 2018 Sep 29;12(4):412-418. Epub 2018 Aug 29.

Department of Dermatology, Wakayama Medical University.

Biomarkers to distinguish patients with advanced melanoma responsive to nivolumab are of great interest. Therefore, we examined the possibility that laboratory data of daily blood examination become novel biomarkers. Laboratory data of 16 melanoma patients who were treated with nivolumab were retrospectively analyzed. Patients were classified as responder group or non-responder group. Examined were: white blood cell count (WBC), absolute lymphocyte counts (ALC), absolute neutrophil count (ANC), absolute monocyte count (AMC), absolute eosinophil count (AEC), and absolute basophil count (ABC), as well as levels of lactate dehydrogenase (LDH), C-reactive protein (CRP), one hour value of erythrocyte sedimentation rate (ESR), and 5-S-cysteinydopa (5-S-CD). Responder group showed significantly higher baseline levels of ESR or CRP and significantly lower ALC level before nivolumab treatment. Additionally, nivolumab treatment decreased the levels of CRP, ESR, and ANC, while it increased ALC level in the responder group. CRP was the most effective in distinguishing responder group from non-responder group both before and during treatment, according to the receiver operating characteristic (ROC) curve. We firstly showed that ESR is also the baseline biomarker of the efficacy of nivolumab. Furthermore, we confirmed that CRP is useful to predict the efficacy both before and during the treatment, and suggested that CRP is the most effective biomarker among daily blood examination by using ROC curve analysis. There is a possibility that nivolumab treatment may be more effective for malignant melanoma with stronger inflammation.
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http://dx.doi.org/10.5582/bst.2018.01158DOI Listing
September 2018

Prevalence of Pruritus in Cutaneous Lupus Erythematosus: Brief Report of a Multicenter, Multinational Cross-Sectional Study.

Biomed Res Int 2018 25;2018:3491798. Epub 2018 Jul 25.

Department of Dermatology, University of Rzeszow, Rzeszow, Poland.

Pruritus is an important symptom frequently accompanying various inflammatory skin conditions. Some recent data have indicated that it may also be associated with autoimmune connective tissue diseases, including systemic sclerosis and dermatomyositis; however, studies on the prevalence and clinical characteristics of pruritus in CLE are limited. We have performed a multinational, prospective, cross-sectional study in order to assess the prevalence and intensity of pruritus in adult patients suffering from various subtypes of CLE. After developing a questionnaire assessing various aspects of pruritus, we have surveyed 567 patients with cutaneous involvement during the course of LE regarding the presence and intensity of pruritus. Pruritus was present in 425 of all patients (75.0%) and was most frequently reported by subjects with acute CLE (82.1%), followed by chronic CLE (78.8%), subacute CLE (65.9%), and intermittent CLE (55.6%) (p<0.001). Based on the Numerical Rating Scale, the severity of itch was mild, moderate, and severe in 264 (62.1%), 98 (23.1%), and 63 (14.8%) patients, respectively. The highest mean pruritus intensity was reported by subjects with hypertrophic LE (5.1 ± 3.0 points) followed by generalized discoid LE (3.6 ± 3.0 points), subacute CLE (3.0 ± 3.0 points), chilblain LE (3.0 ± 1.0 points), localized discoid LE (2.6 ± 2.0 points), intermittent CLE (2.6 ± 3.0 points), acute CLE (2.5 ± 1.2 points), and lupus erythematosus profundus (1.9 ± 2.7 points). In conclusion, pruritus is a frequent phenomenon in CLE; however, in most patients it is of mild severity. Further studies are needed to better characterize its clinical characteristics and influence on patients' well-being.
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http://dx.doi.org/10.1155/2018/3491798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083500PMC
January 2019

Outline of guidelines for the management of vasculitis and vascular disorders in Japan, 2016 revised edition.

J Dermatol 2018 Feb 6;45(2):122-127. Epub 2017 Oct 6.

Department of Dermatology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

The proposal by the 1994 International Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides (CHCC1994) and by the CHCC2012 markedly influenced the classification and way of considering cutaneous vasculitis. In the proposal by the CHCC1994, hypersensitivity angiitis was defined as an equivalent pathological condition to microscopic polyangiitis or cutaneous leukocytoclastic angiitis (CLA), and it was not adopted as a disease name. However, CLA which was positioned as a type of small-vessel vasculitis is only a pathological name. In the proposal by the CHCC2012, a new category of single-organ vasculitis included CLA and cutaneous arteritis. Vasculitis allergica cutis (Ruiter) corresponded to CLA and cutaneous polyarteritis nodosa corresponded to cutaneous arteritis. The Japanese Dermatological Association (JDA) prepared guidelines for the management of vasculitis and vascular disorders in 2008 based on the proposal by the CHCC1994 and their original viewpoint of dermatology. The JDA subsequently revised the 2008 edition guidelines in 2016 following publication of the proposal of the CHCC2012 in Japanese. We presented the outline of the 2016 edition guidelines and propose a treatment algorithm for primary vasculitides based on the evaluation of the cutaneous symptoms for cases suspected as primary cutaneous vasculitides, which integrates the 2008 JDA guideline and CHCC2012 classification. This is the secondary English version of the original Japanese manuscript for the guideline for management of vasculitis and vascular disorders published in the Japanese Journal of Dermatology 127(3); 299-415, 2017.
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http://dx.doi.org/10.1111/1346-8138.14086DOI Listing
February 2018

Clinically amyopathic dermatomyositis with rapidly progressive interstitial pneumonia: The relation between the disease activity and the serum interleukin-6 level.

J Dermatol 2017 Oct 23;44(10):1164-1167. Epub 2017 May 23.

Department of Dermatology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.

A 67-year-old woman exhibited chilblain-like erythema on the bilateral auricles, erythema with hyperkeratosis on the sides of fingers and the bilateral elbows, and erythema on the extensor/flexor sides of the finger joints and the iliac regions. Fine crackles were audible on the dorsal side of the bilateral lower lung regions. We diagnosed clinically amyopathic dermatomyositis accompanied by rapidly progressive interstitial pneumonia. While we initiated immunosuppressive therapy, the respiratory failure showed no responses. We performed endotoxin adsorption therapy using polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP). After the first PMX-DHP session, the respiratory condition was slightly improved but it soon deteriorated. At the second PMX-DHP session, subcutaneous and mediastinal emphysema was noted. The patient died, showing no improvement in the respiratory condition. We measured the levels of serum interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-10 before and after PMX-DHP and compared them with previously reported levels. The levels of TNF-α and IL-10 showed no or slight changes, but those of IL-6 at the beginning of the treatment were higher compared with previous reports. After the first PMX-DHP, the IL-6 level decreased with slight improvement in respiratory condition. However, after the second PMX-DHP, it increased markedly with exacerbation of the respiratory failure. The serum IL-6 level is considered to be effective for the evaluation of the disease activity and prognosis under the treatment by PMX-DHP.
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http://dx.doi.org/10.1111/1346-8138.13887DOI Listing
October 2017

A case of alopecia as IgG4-related skin disease.

Mod Rheumatol 2019 May 23;29(3):538-541. Epub 2016 Nov 23.

a Department of Dermatology , Wakayama Medical University, Graduate School of Medicine , Wakayama , Japan.

A 53-year-old man with autoimmune pancreatitis as IgG4-related disease presented alopecia. Immunostaining showed perifollicular infiltration of IgG4-positive cells and perifollicular/intrafollicular infiltration of predominantly CD4-positive cells, especially in the upper and lower parts. Alopecia areata is characterized by perifollicular/intrafollicular lymphocyte infiltration of the lower bulb and inflammation in the upper dermis. We determined the patient had IgG4-related skin disease, rather than alopecia areata. Alopecia as IgG4-related skin disease has not been reported previously.
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http://dx.doi.org/10.1080/14397595.2016.1233929DOI Listing
May 2019

A case of rheumatoid vasculitis with acquired reactive perforating collagenosis.

Mod Rheumatol 2019 May 23;29(3):547-550. Epub 2016 Nov 23.

b Department of Human Pathology , Wakayama Medical University Graduate School of Medicine , Wakayama , Japan.

A 55-year-old man with rheumatoid arthritis (RA) presented hyperkeratotic erythematous papules with crusts or blisters on his limbs and buttocks. A histological study showed acquired reactive perforating collagenosis. Soon, skin lesions changed to umbilicated lesions with black necrosis, and the scar from his skin biopsy ulcerated with induration due to rheumatoid vasculitis. Systemic corticosteroids and tacrolimus administration resolved the RA and skin lesions. Rheumatoid vasculitis with acquired reactive perforating collagenosis has not been reported previously.
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http://dx.doi.org/10.1080/14397595.2016.1245175DOI Listing
May 2019

The effect of hydroxychloroquine on lupus erythematosus-like skin lesions in MRL/lpr mice.

Mod Rheumatol 2016 Sep 11;26(5):744-8. Epub 2016 Mar 11.

a Department of Dermatology , Wakayama Medical University , Wakayama , Japan .

Objectives: To evaluate the effect and safety of hydroxychloroquine (HCQ) on lupus erythematosus (LE)-like skin lesions in the MRL/lpr mouse, a model for systemic LE (SLE).

Methods: We divided the MRL/lpr mice into three groups that were given: (1) drinking water, (2) HCQ at a dose of 4 mg/kg/d, or (3) HCQ at a dose of 40 mg/kg/d. The HCQ was administered to examine the effect and safety of HCQ on skin lesions and the number of infiltrating cells including mast cells in the dermis.

Results: Six of 13 mice in the group given drinking water, 3 of 11 mice in the group administered low-dose HCQ (4 mg/kg/d), and 1 of 10 mice in the group administered high-dose HCQ (40 mg/kg/d) presented the skin lesions. The average number of mast cells was 81, 50, and 12 (magnification, ×100), the mortality rate was 24%, 8%, and 9% and the mean body weight gain was 4.6 g, 8.0 g and 5.1 g, respectively.

Conclusions: HCQ was demonstrated to decrease the appearance of LE-like lesions and the number of mast cells in the dermis. Furthermore, there were no obvious systemic adverse effects. This study provides evidence that suggests benefits in human patients.
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http://dx.doi.org/10.3109/14397595.2016.1140711DOI Listing
September 2016

Personal Authentication Analysis Using Finger-Vein Patterns in Patients with Connective Tissue Diseases--Possible Association with Vascular Disease and Seasonal Change.

PLoS One 2015 23;10(12):e0144952. Epub 2015 Dec 23.

Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Objective: To examine how connective tissue diseases affect finger-vein pattern authentication.

Methods: The finger-vein patterns of 68 patients with connective tissue diseases and 24 healthy volunteers were acquired. Captured as CCD (charge-coupled device) images by transmitting near-infrared light through fingers, they were followed up in once in each season for one year. The similarity of the follow-up patterns and the initial one was evaluated in terms of their normalized cross-correlation C.

Results: The mean C values calculated for patients tended to be lower than those calculated for healthy volunteers. In midwinter (February in Japan) they showed statistically significant reduction both as compared with patients in other seasons and as compared with season-matched healthy controls, whereas the values calculated for healthy controls showed no significant seasonal changes. Values calculated for patients with systemic sclerosis (SSc) or mixed connective tissue disease (MCTD) showed major reductions in November and, especially, February. Patients with rheumatoid arthritis (RA) and patients with dermatomyositis or polymyositis (DM/PM) did not show statistically significant seasonal changes in C values.

Conclusions: Finger-vein patterns can be used throughout the year to identify patients with connective tissue diseases, but some attention is needed for patients with advanced disease such as SSc.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144952PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689452PMC
June 2016

A patient with localized scleroderma successfully treated with etretinate.

Case Rep Dermatol 2014 Sep 3;6(3):200-6. Epub 2014 Sep 3.

Department of Dermatology, Wakayama Medical University, Wakayama, Japan.

There are several treatment methods for localized scleroderma, but treatment is difficult when the lesion is widely distributed. We encountered a case who was treated successfully with etretinate, a vitamin A derivative. The usefulness of this agent is discussed.
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http://dx.doi.org/10.1159/000367707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209276PMC
September 2014

Disseminated cryptococcosis-induced skin ulcers in a patient with autoimmune hepatitis.

Case Rep Dermatol 2014 Jan 20;6(1):98-102. Epub 2014 Mar 20.

Department of Dermatology, Wakayama Medical University, Wakayama, Japan.

We report the case of a 68-year-old woman with autoimmune hepatitis (AIH) who had leg ulcers induced by disseminated cryptococcosis. She had received prednisolone for her AIH at 20 mg/day for maintenance. On the initial visit, she complained of a painful ulcer that had round, shallow pockets with erythema and erythematous subcutaneous indurations on the right thigh. Several metacarpophalangeal joints and wrist joints were swollen, with tenderness and stiffness in the morning for over 3 h. Her serum rheumatoid factor was high. Since other autoimmune disorders such as rheumatoid arthritis can present with AIH, it was necessary to distinguish it from ulcers due to rheumatoid arthritis, although the characteristic features of these ulcers seemed to be different. A biopsy specimen from the erythematous skin showed globe-shaped organisms in the dermis and subcutaneous tissues; vasculitis and phlebostasis were not observed. The results from computed tomography scans and sputum culture led to the diagnosis of disseminated cryptococcosis. The administration of fluconazole, fosfluconazole, and voriconazole for about 2 months improved the cryptococcal pneumonia, but the size of the skin ulcer enlarged. The administration was changed to itraconazole, which reduced the size. Cryptococcal infections occur more commonly in immunocompromised hosts, including patients under immunosuppressive therapies such as corticosteroids. The possibility that the skin ulcers in immunocompromised hosts may be caused by cryptococcosis should be considered.
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http://dx.doi.org/10.1159/000360978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995400PMC
January 2014

Evaluation of facilitative supervision visits in primary health care service delivery in Northern Ghana.

BMC Health Serv Res 2013 Sep 24;13:358. Epub 2013 Sep 24.

School of Public Health, College of Health Sciences, University of Ghana, Legon, Accra, Ghana.

Background: In Ghana's health delivery services, facilitative supervisory visit (FSV) as a system of management is new. This paper presents the standard evaluation results of FSV, which formed an integral part of the community-based health planning services (CHPS) initiative.

Methods: The study was conducted in the Upper West Region of Ghana. The Project developed guidelines and tools for FSV for four different health system levels--regional, district, sub-district and community levels. Electronic data from all four levels representing quarterly results were compiled into their annual equivalents, and summarized graphically for comparison.

Results: The data show that all the nine districts embraced the FSV concept even though they differed markedly with regard to the degree of adherence to some set benchmarks. Three DHMTs (Wa Municipal, Lawra and Jirapa) were graded as good while the remaining six DHMTs were adjudged as fair in relation to management of supplies, transport and equipment, information, meeting, and technical support.

Conclusions: The data further suggest that there is much to gain both individually and institutionally from FSVs. Generally, FSVs are crucial to the delivery of primary health care services in especially rural areas.
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http://dx.doi.org/10.1186/1472-6963-13-358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850550PMC
September 2013

Response to hydroxychloroquine in Japanese patients with lupus-related skin disease using the cutaneous lupus erythematosus disease area and severity index (CLASI).

Mod Rheumatol 2013 Mar 12;23(2):318-22. Epub 2012 May 12.

Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo 183-8524, Japan.

Background: Hydroxychloroquine (HCQ) is not available in Japan. To design a clinical trial of HCQ, we evaluated the response to HCQ in Japanese patients with lupus-related skin disease using the cutaneous lupus erythematosus disease area and severity index (CLASI).

Methods: Twenty-seven patients with lupus-related skin disease who started HCQ at four hospitals were included. Patients were categorized into responders by the CLASI response criteria. The points and the rate of improvement in the CLASI activity score after 16 weeks of treatment were analyzed, focusing on six parameters: systemic lupus erythematosus (SLE), skin manifestations, disease duration, prednisolone, smoking, and severity.

Results: Twenty-seven patients, including 17 with SLE (6 with SLE/Sjögren's syndrome), were analyzed retrospectively. Twenty-three patients (85 %) were categorized as responders. The mean CLASI activity score improved from 10.1 to 4.5 (p < 0.0001). The improvement rate did not differ in these parameters except for that of annular erythema (81.6 versus 34.3 %, p = 0.036). On multivariate analysis, the baseline CLASI activity score (CLASI ≥9) correlated with the greatest decrease in CLASI activity score (F = 69.7, p < 0.0001).

Conclusions: CLASI is a reliable indicator to evaluate the efficacy of the drug, and HCQ is an effective treatment for Japanese patients with lupus-related skin disease.
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http://dx.doi.org/10.1007/s10165-012-0656-3DOI Listing
March 2013

Comparison of polytetrafluoroethylene flat-sheet membranes with different pore sizes in application to submerged membrane bioreactor.

Membranes (Basel) 2012 Jun 1;2(2):228-36. Epub 2012 Jun 1.

Corporate Research Division, Nippon Valqua Industries, Ltd., 2-2-2 Oyamagaoka, Machida, Tokyo 194-0215, Japan.

This study focused on phase separation of activated sludge mixed liquor by flat-sheet membranes of polytetrafluoroethylene (PTFE). A 20 liter working volume lab-scale MBR incorporating immersed PTFE flat-sheet membrane modules with different pore sizes (0.3, 0.5 and 1.0 μm) was operated for 19 days treating a synthetic wastewater. The experiment was interrupted twice at days 5 and 13 when the modules were removed and cleaned physically and chemically in sequence. The pure water permeate flux of each membrane module was measured before and after each cleaning step to calculate membrane resistances. Results showed that fouling of membrane modules with 0.3 μm pore size was more rapid than other membrane modules with different pore sizes (0.5 and 1.0 μm). On the other hand, it was not clear whether fouling of the 0.5 μm membrane module was more severe than that of the 1.0 μm membrane module. This was partly because of the membrane condition after chemical cleaning, which seemed to determine the fouling of those modules over the next period. When irreversible resistance (Ri) i.e., differences in membrane resistance before use and after chemical cleaning was high, the transmembrane pressure increased quickly during the next period irrespective of membrane pore size.
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http://dx.doi.org/10.3390/membranes2020228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021889PMC
June 2012

Hydroxychloroquine administration for Japanese lupus erythematosus in Wakayama: a pilot study.

J Dermatol 2012 Jun 14;39(6):531-5. Epub 2011 Dec 14.

Department of Dermatology, Wakayama Medical University, Wakayama, Japan.

Hydroxychloroquine (HCQ) is used as the first-line systemic treatment for severe, widespread or refractory cutaneous lupus erythematosus (CLE) in many countries. However HCQ is not an approved drug in Japan. For the establishment of HCQ therapy as the alternative treatment for CLE in Japan, we conducted a pilot study in Japanese patients with refractory CLE by administrating HCQ, and evaluated the improvements in the skin lesions using the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). We administrated HCQ to seven CLE cases, including four systemic lupus erythematosus (SLE) cases. The skin lesions of the four cases improved dramatically, and their mean CLASI activity index decreased significantly following HCQ treatment. Arthralgia improved in all three cases with arthralgia and general malaise also improved in two of the three cases who had complained. In three cases who discontinued HCQ therapy after 16 weeks of treatment, their skin lesions and general malaise worsened soon, and after the resumption of HCQ therapy these symptoms improved again. The mean serum triglyceride and total cholesterol levels also decreased significantly at the end of this study. Our results suggest that HCQ might be effective for Japanese SLE skin lesions and CLE, and support the studies which reported that HCQ prevented clinical flare ups of SLE. An additional effect to improve lipid profiles was also observed in our Japanese cases. It is necessary to confirm that these effects are reproducible when Japanese lupus erythematosus cases are given HCQ.
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http://dx.doi.org/10.1111/j.1346-8138.2011.01448.xDOI Listing
June 2012

Effects of sarpogrelate hydrochloride on skin ulcers and quality of life in patients with systemic sclerosis.

J Dermatol 2012 Jun 14;39(6):536-40. Epub 2011 Nov 14.

Department of Dermatology, Arida Municipal Hospital, Arida, Japan.

5-Hydroxytryptamine 2A serotonin receptor (5-HT(2A) ) is associated with the contraction of vascular smooth muscle, platelet aggregation and thrombus formation and coronary artery spasms. Sarpogrelate hydrochloride (sarpogrelate) is a selective 5-HT(2A) antagonist and was supposed to be effective for Raynaud's phenomenon with collagen disease. Sarpogrelate has not been investigated regarding the effects, safety and quality of life (QOL) in patient with skin ulcers of collagen disease. Eleven patients with skin ulcers and systemic sclerosis (SSc) were administrated sarpogrelate p.o. three times a day for 3-6 months. The area (mean ± standard error) of skin ulcer at the pretreatment, and after 3 and 6 months of sarpogrelate intake was 2.1 ± 0.8, 0.2 ± 0.1 and 0.1 ± 0.1 mm(2), respectively. The reduction of skin ulcer area was significant after 3 months of sarpogrelate intake. In assessment of QOL, scores of symptoms and emotions but not of functioning were significantly improved after sarpogrelate intake. The global score (mean ± SE) of Skindex-16 at pretreatment, and after 3 and 6 months of sarpogrelate intake was 31.8 ± 8.7, 23.7 ± 8.3 and 10.9 ± 4.6, respectively. The score was significantly improved after 6 months of sarpogrelate intake. There were no obvious side-effects during this study. Sarpogrelate was considered to be a useful drug to improve skin ulcers and QOL in patients with SSc.
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http://dx.doi.org/10.1111/j.1346-8138.2011.01432.xDOI Listing
June 2012

Recent advances in cytokines in cutaneous and systemic lupus erythematosus.

J Dermatol 2011 Sep 18;38(9):839-49. Epub 2011 Jul 18.

Department of Dermatology, Wakayama Medical University, Wakayama Department of Dermatology, Hashimoto Municipal Hospital, Hashimoto, Japan.

Lupus erythematosus (LE) includes a broad spectrum of diseases from a cutaneous-limited type to a systemic type. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease which affects multiple organs. Cutaneous lupus erythematosus (CLE) includes skin symptoms seen in SLE and cutaneous-limited LE. Although immune abnormalities, as well as heritable, hormonal and environmental factors, are involved in the pathology of LE, the actual pathogenesis is still unclear. Recently, the involvement of various cytokines has been shown in the pathogenesis of LE. Moreover, some trials with biological agents targeted specific cytokines are also ongoing for SLE. In this article, we review the contributions of major cytokines such as interferon, tumor necrosis factor-α and interleukin-18 to LE, especially SLE and CLE.
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http://dx.doi.org/10.1111/j.1346-8138.2011.01237.xDOI Listing
September 2011

The protective effects of ultraviolet A1 irradiation on spontaneous lupus erythematosus-like skin lesions in MRL/lpr mice.

Clin Dev Immunol 2009 26;2009:673952. Epub 2009 Apr 26.

Department of Dermatology, Wakayama Medical University, Wakayama, Japan.

We investigated the effects of ultraviolet A1 (UVA1) irradiation on spontaneous lupus erythematosus- (LE-) like skin lesions of MRL/lpr mice, using a disease prevention model. UVA1 irradiation significantly inhibited the development of LE-like skin lesions, without obvious changes of the disease including renal disease and serum antinuclear antibody levels. Besides the massive infiltration of mast cells in the LE-like skin lesions, in the nonlesional skins, more mast cells infiltrated in the UVA1-irradiated group compared with the nonirradiated group. Although apoptotic cells were remarkably seen in the dermis of UVA1-irradiated mice, those cells were hardly detectable in the dermis of the nonirradiated mice without skin lesions. Further analysis showed that some of those apoptotic cells were mast cells. Thus, UVA1 might exert its effects, at least in part, through the induction of the apoptosis of pathogenic mast cells. Our results supported the clinical efficacy of UVA1 irradiation for skin lesions of lupus patients.
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http://dx.doi.org/10.1155/2009/673952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673515PMC
July 2009

Cutaneous polyarteritis nodosa: revisiting its definition and diagnostic criteria.

Arch Dermatol Res 2009 Jan 19;301(1):117-21. Epub 2008 Sep 19.

Department of Dermatology, School of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama 641-0012, Japan.

Polyarteritis nodosa (PN) is a classical collagen disease with poor prognosis that demonstrates systemic necrotizing vasculitis of small and medium-sized arteries. Cutaneous symptoms are observed in 25-60% of PN patients. On other hand, cutaneous polyarteritis nodosa (CPN) is designated for the cutaneous limited form of PN and demonstrates benign prognosis. However, there has been much debate on whether or not CPN can progress to PN. Although CPN lesions are fundamentally limited to skin, some CPN cases show extracutaneous symptoms such as peripheral neuropathy and myalgia. According to PN diagnostic criteria, which were established by the Ministry of Health, Labour and Welfare of Japan, a disease with both cutaneous and at least one extracutaneous symptom with appropriate histopathological findings can be diagnosed as PN. The same is true according to diagnostic criteria established by the American College of Rheumatology. In addition, there are no specific diagnostic criteria for CPN. In this study, CPN cases were retrospectively collected from multiple Japanese clinics, and analyzed for detailed clinical and histopathological manifestations, in order to redefine the clinical entity of CPN and to propose appropriate diagnostic criteria for CPN and PN. According to the CPN description in Rook's Textbook of Dermatology, we collected 22 cases with appropriate histopathological findings. Of the 22 cases, none progressed to PN or death during the follow-up period, 32% had peripheral neuropathy and 27% had myalgia. Regarding extracutaneous symptoms with CPN, 17 dermatological specialists in vasculitis sustained the opinion that CPN can be accompanied by peripheral neuropathy and myalgia but these symptoms are limited to the same area as skin lesions. Based on these results, we devised new drafts for CPN and PN diagnostic criteria. Our study shows the efficacy of these criteria and most dermatologists recognized that our new diagnostic criteria for CPN and PN are appropriate at the present time. In conclusion, this study suggests that CPN does not progress to PN, and introduces new drafts for CPN and PN diagnostic criteria.
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http://dx.doi.org/10.1007/s00403-008-0898-2DOI Listing
January 2009

Endotoxin shock due to Vibrio vulnificus infection.

Eur J Dermatol 2006 Jul-Aug;16(4):423-7

Department of Dermatology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan.

A 54-year-old man with hepatitis C fell into shock with symptoms similar to enterocolitis after ingesting an undercooked barbecued mackerel. Most of his eruptions developed into annular erythema with small vesicles. He had taken high dose corticosteroids with intravenous cefotiam. His eruptions improved, but his shock state was exacerbated on Day 2. Treatment for endotoxin shock was initiated using piperacillin, intravenous immunoglobulin (IVIg), and hemoperfusion with Polymyxin B immobilized fiber (PMX-F), which resulted in shock reversal. The serum IL-6 value was 118,000 pg/mL on admission, and decreased to 2040 pg/mL on Day 3. On Day 6, the results from the culture of skin biopsy specimens showed the diagnosis as Vibrio vulnificus septic shock. Debridement was not needed, which is thought to be essential to Vibrio vulnificus sepsis. The changes in the serum IL-6 levels demonstrated that hemoperfusion with PMX-F and IVIg therapy was practical for Vibrio vulnificus septic shock.
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March 2007

A case of symmetrical leukemia cutis on the eyelids complicated by B-cell chronic lymphocytic lymphoma.

J Dermatol 2004 Jul;31(7):560-3

Department of Dermatology, Wakayama Medical University, Wakayama, Japan.

We describe herein a case of symmetrical bilateral leukemia cutis on the eyelids, especially on the lower lids, in a patient with B-cell chronic lymphocytic leukemia (CLL). The patient was a 63-year-old Japanese man who had been diagnosed with CLL. Eyelid swelling is well known to result from local skin or systemic diseases including tumors, hyperthyroidism, nephritic syndrome, and hypoalbuminemia. To our knowledge, symmetrical, bilateral, flesh-colored leukemia cutis on the eyelids has not been previously reported.
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http://dx.doi.org/10.1111/j.1346-8138.2004.tb00555.xDOI Listing
July 2004
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