Body mass index, HbA1c and serum C-reactive protein are predictors of secondary failure in infliximab continuance for Japanese psoriasis patients: A hospital-based retrospective case-control study.

Biologics has had a great impact on psoriasis treatment as well as the life of psoriasis patients. Infliximab (IFX), one of the biologics targeting tumor necrosis factor (TNF), is the first of the biologics introduced to Japanese psoriasis patients. Many patients had benefits of IFX from initial applications and sustained remission of skin lesions and arthritis. Some, however, fall into so-called secondary failure, in which patients become less responsive to IFX when the treatment is repeated. The mechanism of secondary failure and the background of patients with secondary failure have not been completely elucidated. To address this issue, we retrospectively evaluated psoriasis patients treated with IFX in our department. In this retrospective, single-center, case-control study based on the clinical record, a total of 34 patients were enrolled. We excluded 7 patients who discontinued IFX because of adverse events of IFX. We divided other 27 patients into two groups; 16 patients who kept using IFX (Continuance group); and 11 patients who switched to other treatments (Discontinuance group). Among various clinical features, body mass index (BMI), HbA1c, and serum CRP level were significantly higher in the Discontinuance group than the Continuance group. The results indicated that these three clinical features of BMI, HbA1c and serum CRP level before treatment are the predictors of successful IFX treatment and suggest that improvement of metabolic conditions contributes to avoiding secondary failure and discontinuance of IFX.

Instrumental evaluation sensitively detects subclinical skin changes by the epidermal growth factor receptor inhibitors and risk factors for severe acneiform eruption.

Epidermal growth factor receptor inhibitors (EGFRI), EGFR tyrosine kinase inhibitors (TKI) and anti-EGFR antibodies commonly develop skin toxicities including acneiform eruption (AfE). However, precise skin changes and risk factors for severe AfE are still unclear. The objective of the current study was elucidation of the useful parameters for early and sensitive detection of the skin changes by EGFRI. Transepidermal water loss (TEWL), skin surface hydration, skin surface lipid levels and erythema/melanin index were serially measured for 2 weeks in 19 EGFR-TKI afatinib/erlotinib-treated patients and for 8 weeks in 20 anti-EGFR antibody cetuximab-treated patients. The TEWL levels of the cheek in the patients who developed AfE of grade 2 and more (AfE ≥ Gr2) were already elevated at 7 days after the initiation of afatinib/erlotinib therapy compared with those before therapy as well as in patients with grade 1 or less (AfE ≤ Gr1). In patients treated with cetuximab, the skin surface hydration on the cheek in AfE ≥ Gr2 patients significantly decreased compared with that of AfE ≤ Gr1 patients at the 2nd and 6th week. Baseline skin surface lipid levels and erythema index on the cheek of patients with AfE ≥ Gr2 were significantly higher than those with AfE ≤ Gr1. The small sample size of the present study, especially for logistic regression analysis, is a limitation. In conclusion, instrumental evaluation declared rapid inflammatory changes of the skin by EGFRI and elucidated oily skin as a risk for severe AfE.

Cross-sectional survey on disease severity in Japanese patients with harlequin ichthyosis/ichthyosis: Syndromic forms and quality-of-life analysis in a subgroup.

BACKGROUND: Congenital ichthyoses (CIs) adversely affect quality of life (QOL) in patients. However, the effects of CIs on patient QOL have not been studied sufficiently. OBJECTIVE: To investigate the association between disease severity and QOL in patients with harlequin ichthyosis (HI) and ichthyosis: syndromic forms (ISFs) METHODS: Clinical information of patients with HI and ISFs from 2010 to 2015 were obtained from 100 dermatology departments/divisions of principal institutes/hospitals throughout Japan. We examined the relationship between disease severity and QOL in patients with HI and ISFs. Patients who were aged 8 years or older and participated in a multicenter retrospective questionnaire survey in Japan were assessed by dermatology life quality index (DLQI, range of 0-30) and clinical ichthyosis score (range of 0-100). RESULTS: Netherton syndrome patients had a significantly higher risk of allergy to food or environmental allergens than patients with other phenotypes. Keratitis-ichthyosis-deafness (KID) syndrome patients showed a significantly higher risk of skin infections than patients with other phenotypes. Complete data on DLQI were obtained from 13 patients, whose median age was 21 (8-71) years. Nine patients were male, and 4 were female. Systemic retinoids were administrated to 2 of the 3 HI patients. The Spearman's correlation coefficient between the clinical ichthyosis score and DLQI was 0.611 (P < 0.05). CONCLUSION: We confirmed that Netherton syndrome and KID syndrome patients have a higher risk of allergy to food or environmental allergens and of skin infections, respectively. QOL impairment correlates with disease severity in HI and ISFs patients.

Efficacy of oral cholecalciferol on rhododendrol-induced vitiligo: A blinded randomized clinical trial.

Rhododendrol (RD), 4-(4-hydroxyphenyl)-2-butanol, inhibits melanin synthesis and has been used for skin-whitening cosmetic products. RD has been very effective in lightening skin pigmentation, but some persons have developed so-called RD vitiligo, in which vitiligo starts on the face, neck and hands where topical RD has been applied and even extended over skin areas where RD has not been applied. RD vitiligo lesions in some patients have lasted for years and have been resistant to conventional vitiligo treatments. We examined the effects of cholecalciferol on RD vitiligo in a blinded randomized clinical trial. Forty-eight female RD vitiligo patients were recruited for the trial and were randomized into two groups: the vitamin D (VD)-intervention group that received daily 5000 IU cholecalciferol for 5 months and the control group. Three blinded investigators scored vitiligo improvement by comparing photographic images of baseline and at 5-month observation. Serum 25(OH)D3 of RD vitiligo patients was not significantly different from age-matched healthy volunteers. Twenty-two in the VD-intervention group and 23 in the control group completed the 5-month observation. Serum 25(OH)D3 levels were significantly increased after the 5-month VD intervention, while the control group did not change. The improvement scores were significantly higher in the VD-intervention group than the control group. The improvement scores were positively correlated with the serum 25(OH)D3 levels after the 5-month intervention period but not before the treatment. This blinded randomized clinical trial showed favor in administrating 5000 IU cholecalciferol daily to RD vitiligo patients.

Epidermal iron metabolism for iron salvage.

BACKGROUND: The epidermis shows a reverse iron gradient from the basal layer to the stratum corneum and consequently, little epidermal intracellular iron is lost by desquamation. OBJECTIVE: To clarify the underlying mechanism of iron salvage. METHODS: We first used immunohistochemistry and mRNA quantification to demonstrate the distinctive expression pattern of iron metabolism molecules. The obtained results were confirmed using normal human epidermal keratinocytes (NHEKs) during in vitro differentiation. We next examined the effects of reducing ferroportin expression in vitro by ferroportin-specific siRNAs or hepcidin on the intracellular iron content of cultured NHEKs. Finally, we compared epidermal and systemic iron metabolism between FpnEpi-KO mice and control mice. RESULTS: The results of both mRNA and protein expression analysis showed that most molecules participating in iron import and storage were expressed in the lower epidermis, while those involved in iron release from heme or iron transport were expressed in the upper epidermis. Consistent with their expression, keratinocyte differentiation reduced intracellular iron content. We next demonstrated that reducing ferroportin expression in vitro by ferroportin-specific siRNAs or hepcidin significantly increased the intracellular iron content. Finally, we showed that the iron content of the epidermis and squames was significantly greater in FpnEpi-KO mice than in control mice, and that FpnEpi-KO exhibited a more rapid decrease in blood hemoglobin concentration than control mice on a low iron diet. CONCLUSION: These studies demonstrated that the epidermis is equipped with a machinery by which intracellular iron in differentiated keratinocytes is excreted to the extracellular space before reaching the stratum corneum.

Plexiform Fibrohistiocytic Tumor on the Ear: Case Report and Immunohistochemical Investigation of Stromal Factor.

Plexiform fibrohistiocytic tumor (PFT) is a rare mesenchymal neoplasm of intermediate malignant potential with a high local recurrence rate. In this report, we describe a case of PFT on the ear, which showed a dense deposition of periostin (POSTN) in the stromal areas of the tumor. In addition, dense infiltration of CD163+CD206- tumor-associated macrophages (TAMs) was detected in the same areas as POSTN. Since POSTN was previously reported to possess immunomodulatory effects on TAMs, our present report suggested the significance of the POSTN/TAMs axis in the progression of PFT.

Tumor-associated M2 macrophages in mycosis fungoides acquire immunomodulatory function by interferon alpha and interferon gamma.

BACKGROUND: Tumor-associated M2 macrophages (TAMs) produce chemokines that affect the formation of cutaneous T-cell lymphoma (CTCL) by stromal factors. Since IFNs are an effective treatment for advanced-stage mycosis fungoides (MF), we hypothesized that IFNs might modulate M2 macrophages. OBJECTIVE: To prove our hypothesis, we stimulated monocyte-derived M2 macrophages with IFN-α2a or IFN-γ and examined the mRNA expression of chemokines. METHODS: By using a microarray, we selected a series of chemokines and MMPs that were strongly connected with the IL-4 stimulation. Then, we investigated the effects of IFN-α2a and IFN-γ on these chemokines. RESULTS: IFN-α2a and IFN-γ decreased the expression and production of CCL17 and CCL18 and increased those of CXCL10 and CXCL11. Moreover, the subcutaneous administration of IFN-α2a increased the CXCL11-producing cells in the lesional skin of patients with advanced MF. CONCLUSION: Our data suggest one possible mechanism of the therapeutic effects of IFNs through TAMs for the treatment of advanced-stage MF.

The possible interaction between periostin expressed by cancer stroma and tumor-associated macrophages in developing mycosis fungoides.

Mycosis fungoides (MF) starts as an indolent disease, progresses from a patch stage to confluent plaques and ultimately develops skin tumors. Tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment in MF. The purpose of this study was to elucidate the involvement of TAMs in the lesional skin of different stages of MF. First, we immunohistologically examined the percentage of CD163+ macrophages and CD206+ cells, as well as the levels of periostin and IL-4 in cancer stroma. The percentage of CD206+ cells increased in parallel with tumor progression, while there was no significant difference in the percentage of CD163+ cells. Periostin was prominent in the stromal area at the patch and plaque stages but decreased at the tumor stage. In contrast, IL-4 was prominently stained at both plaque and tumor stages. To further elucidate the molecular mechanisms of the effects of these stromal factors on TAMs, we examined their effects on mRNA expression in monocyte-derived macrophages in vitro. Based on microarray analysis and gene ontology, we examined a series of chemokines and MMPs whose expression was strongly connected with periostin stimulation. The DNA microarray results were verified in M2 macrophages using real-time PCR. We further examined the mRNA expression of these chemokines and MMPs in the presence of periostin and IL-4 to simulate the advanced stages of MF and validated their protein expression by ELISA. Our present report suggests possible roles of periostin on TAMs in establishing the tumor microenvironment in MF.

Alarmin function of cathelicidin antimicrobial peptide LL37 through IL-36γ induction in human epidermal keratinocytes.

Several dermatoses, including psoriasis, atopic dermatitis, and rosacea, alter the expression of the innate immune effector human cathelicidin antimicrobial peptide (CAMP). To elucidate the roles of aberrant CAMP in dermatoses, we performed cDNA array analysis in CAMP-stimulated human epidermal keratinocytes, the primary cells responding to innate immune stimuli and a major source of CAMP LL37 in skin. Among LL37-inducible genes, IL-1 cluster genes, particularly IL36G, are of interest because we observed coordinate increases in CAMP and IL-36γ in the lesional skin of psoriasis, whereas virtually no CAMP or IL-36γ was observed in nonlesional skin and normal skin. The production and release of IL-36γ were up to 20-30 ng/ml in differentiated keratinocytes cultured in high-calcium media. G-protein inhibitor pertussis toxin and p38 inhibitor suppressed IL-36γ induction by LL37. As an alarmin, LL37 induces chemokines, including CXCL1, CXCL8/IL8, CXCL10/IP-10, and CCL20/MIP3a, and IL-36 (10-100 ng/ml) augments the production of these chemokines by LL37. Pretreatment with small interfering RNA against IL36γ and IL-36R IL36R/IL1RL2 and IL1RAP suppressed LL37-dependent IL8, CXCL1, CXCL10/IP10, and CCL20 production in keratinocytes, suggesting that the alarmin function of LL37 was partially dependent on IL-36γ and its receptors. Counting on CAMP induction in innate stimuli, such as in infection and wounding, IL-36γ induction by cathelicidin would explain the mechanism of initiation of skin inflammation and occasional exacerbations of psoriasis and skin diseases by general infection.

Effect of pharmacokinetic profile on the pancreatic toxicity and efficacy of tacrolimus in rats.

The aim of this study is to investigate the effect of the pharmacokinetic profile of tacrolimus on its pancreatic toxicity and efficacy in rats. For toxicity evaluation, doses of 0.03, 0.1, or 0.3 mg/kg/day were given once daily for 8 days in the bolus intravenous injection groups. In the continuous intravenous infusion groups, tacrolimus was infused using an Alzet osmotic mini-pump for 9 days at the same doses. Pancreatic insulin content decreased dose-dependently in both the bolus intravenous injection and continuous intravenous infusion groups, and there was no significant difference between the decreases caused by the two dosing regimens. At 0.03 mg/kg, continuous intravenous infusion did not cause glucose intolerance, but bolus intravenous injection induced significant and dose-dependent glucose intolerance. The pharmacokinetic data indicated that continuous intravenous infusion resulted in a sustained blood drug concentration with an area under the curve (AUC) similar to that obtained with the bolus administration at the same dose. For efficacy evaluation, donor ear grafts were transplanted to the lateral thoraxes of recipients. Tacrolimus doses of 0.01, 0.1, or 1 mg/kg/day were administered from day 0 to day 13. Both bolus intramuscular administration and continuous intravenous infusion prolonged skin allograft survival dose-dependently, and there was no significant difference between the median survival times of groups given the same doses. To summarize, the sustained-release of tacrolimus resulted in a steady blood drug concentration with an AUC similar to that of the bolus administration. In rats, it was better tolerated and just as efficacious as the bolus administration without producing a higher maximal blood concentration (Cmax). These results indicate that the sustained-release formulation has the potential to improve the safety of tacrolimus.

Discovery of the first non-peptide full agonists for the human bradykinin B(2) receptor incorporating 4-(2-picolyloxy)quinoline and 1-(2-picolyl)benzimidazole frameworks.

In the course of our studies on non-peptide bradykinin (BK) B(2) receptor ligands, it was suggested that the 4-substituent of the quinoline ring may play a critical role in determining binding affinities for human and guinea pig B(2) receptors, as well as agonist/antagonist properties. We carried out an extensive investigation to elucidate the structure-activity relationships (SAR) for this key pharmacophore. Introduction of lower alkoxy groups to the 4-position of the quinoline ring of 3 led to the identification of 4-ethoxy derivative 22b as a unique partial agonist. This compound significantly stimulated inositol phosphates (IPs) formation in Chinese hamster ovary cells expressing the cloned human B(2) receptor at concentrations greater than 10 nM and displayed one-tenth of the intrinsic activity of BK. The agonist activity of 22b was selective for the B(2) receptor and was inhibited by selective peptide and non-peptide B(2) antagonists. On the other hand, 22b strongly suppressed BK-induced IPs formation through the cloned human B(2) receptor. Further studies on the key pharmacophore led to identification of a 2-picolyloxy moiety as a powerful agonist switch, leading to the discovery of a potent and efficacious non-peptide B(2) agonist, 19a. Successive optimization of the acyl side chain afforded 38, which exhibited full agonist activity on stimulation of IPs formation. Furthermore, this strategy could be applied successfully to the benzimidazole series. The representative 1-(2-picolyl)benzimidazole derivative 47c increased PGE(2) production at a 1 microM concentration to the same level as the maximum effect of BK. Thus, we have established the medicinal chemistry modifications required to convert our highly potent non-peptide B(2) antagonists to agonists with potent efficacy.

A new class of nonpeptide bradykinin B(2) receptor ligand, incorporating a 4-aminoquinoline framework. Identification of a key pharmacophore to determine species difference and agonist/antagonist profile.

Introduction of various aliphatic amino groups at the 4-position of the quinoline moiety of our nonpeptide bradykinin (BK) B(2) receptor antagonists afforded highly potent ligands for human B(2) receptor with various affinities for guinea pig B(2) receptor, indicating remarkable species difference. A representative 4-dimethyamino derivative 40a exhibited subnanomolar and nanomolar binding affinities for human and guinea pig B(2) receptors, respectively, and significantly inhibited BK-induced bronchoconstriction in guinea pigs at 10 microg/kg by intravenous administration. Further chemical modification led us to discover unique partial agonists for the human B(2) receptor that increase inositol phosphates (IPs) production by themselves in Chinese hamster ovary (CHO) cells expressing the cloned human B(2) receptor. Although their potency and efficacy were much lower than those of BK, we identified them as screening leads for nonpeptide B(2) agonists. In these studies it was revealed the 4-substituent of the quinoline moiety is the key pharmacophore to determine species difference and agonist/antagonist profiles.

A new series of highly potent non-peptide bradykinin B2 receptor antagonists incorporating the 4-heteroarylquinoline framework. Improvement of aqueous solubility and new insights into species difference.

Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B(2) receptor antagonists resulted in enhancing binding affinities for the human B(2) receptor and reducing binding affinities for the guinea pig one, providing new structural insights into species difference. A CoMFA study focused on the diversity of the quinoline moiety afforded correlative and predictive QSAR models of binding for the human B(2) receptor but not for the guinea pig one. A series of 4-(1-imidazolyl)quinoline derivatives could be dissolved in a 5% aqueous solution of citric acid up to a concentration of 10 mg/mL. A representative compound 48a inhibited the specific binding of [(3)H]BK to the cloned human B(2) receptor expressed in Chinese hamster ovary cells with an IC(50) value of 0.26 nM and significantly inhibited BK-induced bronchoconstriction in guinea pigs even at 1 microg/kg by intravenous administration.