银屑病患者皮损局部朗格汉斯细胞数量异常机制的研究

目的：探讨银屑病患者皮损局部朗格汉斯细胞(LCs)数量异常的原因。方法：培养银屑病患者皮损处角质形成细胞，通过微孔小室实验检测其上清液对单核细胞的趋化功能；通过酶联免疫吸附法(ELISA)检测上清液中单核细胞趋化蛋白—1(MCP-1)的表达。结果：银屑病患者皮损处角质形成细胞分泌上清液对单核细胞的趋化能力明显强于正常对照组；其分泌的MCP-1水平也高于正常人。结论：银屑病角质形成细胞表达的趋化因子趋化了更多数量的单核细胞至皮损局部，因此，银屑病患者皮损局部LCs的数量理应是增多的。但由于银屑病角质形成细胞表达的其它一些因子也促使了单核细胞衍生的LCs的活化，活化的LCs会迁移至淋巴结或活化后凋亡，又导致其数量减少。因此，银屑病患者皮损局部朗格汉斯细胞数量是一动态变化过程。     

Evaluation of the efficacy and safety of infliximab on psoriatic nails: an unblinded, nonrandomized, open-label study

Background  Despite advances in the treatment of skin psoriasis during the last years, therapy of psoriatic nails remains a challenge.
Objectives  The objective of this unblended, nonrandomized, open-label study was to evaluate the efficacy and safety of infliximab on nail psoriasis.
Patients/Methods  Eighteen psoriatic patients with nail involvement, consecutively selected among patients scheduled to start infliximab infusions were included in the study. Thirteen of these patients had psoriatic arthritis and five had severe plaque type psoriasis. Outcome measures were assessed at baseline and at weeks 14, 22, 30 and 38 using the nail psoriasis severity index (NAPSI). Patients also filled in a Greek translation of the international onychomycosis-specific questionnaire to assess improvement in quality of life after improvement of psoriatic nail signs.
Results  All 18 patients completed the study. Significant improvement was noted in most patients after the third infusion as shown by the reduction of mean NAPSI (NAPSIm) from 55·8 at baseline to 29·8 at week 14. Evaluation after six infusions, at week 38, showed an almost complete resolution of psoriatic nail involvement (NAPSIm: 3·3). No adverse event was observed. All patients reported satisfaction with the results and significant improvement in their quality of life with reduction of the score of the international quality of life questionnaire from 66·3 at baseline to 19·1 at week 38.
Conclusions  Αlthough there is no control group, this data suggests that infliximab is effective for psoriatic nail disease in the context of severe skin and joint involvement.     

Infliximab improves health-related quality of life in the presence of comorbidities among patients with moderate-to-severe psoriasis

Background  Psoriasis affects patients both physically and psychologically.
Objectives  To investigate the effect of comorbidities on health-related quality of life (HRQoL) and to determine whether infliximab improved HRQoL in the presence of these conditions.
Methods  In this multicentre, double-blind study, 835 patients with moderate-to-severe plaque psoriasis were randomized to receive infliximab 3 or 5 mg kg⁻¹ or placebo at weeks 0, 2 and 6. Infliximab-treated patients were re-randomized at week 14 to receive the same treatment every 8 weeks or as needed through week 46; placebo patients crossed over to infliximab 5 mg kg⁻¹ at week 16. Disease severity (Psoriasis Area and Severity Index, PASI) and HRQoL (Dermatology Life Quality Index, DLQI; 36-item Short-Form Health Survey, SF-36) were measured at various time points. The effect of patient comorbidities on baseline HRQoL was assessed using multiple regression models. The impact of key comorbidities on infliximab treatment effect was also assessed.
Results  Disease severity (PASI), depression and psoriatic arthritis (PsA) were predictors of poor baseline HRQoL. At week 10, infliximab 3 and 5 mg kg⁻¹ significantly improved physical and mental health dimensions of the SF-36 and the DLQI (all P  < 0·001). Consistent improvement in HRQoL with infliximab treatment was observed regardless of baseline patient characteristics or comorbidities. Through week 50, HRQoL and PASI scores were most improved with infliximab 5 mg kg⁻¹ administered every 8 weeks.
Conclusions  Disease severity, depression and PsA were significant predictors of poor HRQoL. Infliximab significantly improved HRQoL, regardless of these characteristics.     

An Italian shared dermatological and rheumatological proposal for the use of biological agents in psoriatic disease

Background As psoriatic disease (PD) is a condition characterized by the combination of inflammatory skin (psoriasis) and osteo‐articular manifestations (psoriatic arthritis), its treatment should cover both its clinical components. Objective The objective of this study was to propose a flexible framework for the use of biological agents in PD. Methods The proposal was drawn up by a group of dermatologists and rheumatologist expert in PD and was based on existing evidence and personal opinion. Results The three TNF‐α inhibitors (adalimumab, etanercept, infliximab) are effective in all of the psoriatic manifestations and should be used in the case of moderate/severe disease refractory to systemic treatment with non‐biological drugs. We propose the following definitions of moderate/severe disease: PASI > 10 or BSA > 10 or DLQI > 10 for plaque‐psoriasis; BSA ≥ 10 or DLQI ≥ 10 for the other psoriatic skin lesions; DLQI ≥ 10 or meaningful values of the NAPSI or mNAPSI for psoriatic nail involvement; ≥ 1 inflamed joint + patient global VAS³4 + physician's judgement or arthritic joint deformities or radiographic joint damage plus ≥ 5 inflamed small joints or ≥ 1 large joints for peripheral joint involvement; ≥ 1 digit with dactylitis and ≥ 1 enthesitic sites + patient global VAS³4 + physician's judgement for dactylitis and enthesitis. BASDAI ≥ 4 + physician's judgement for spondylitis; recurrent flares or risk of developing irreversible damage for uveitis. Other assessment instruments can be used if the physician is more familiar with them and if they have been validated. Conclusion We provide a shared dermatological and rheumatological proposal for the use of biological agents in PD.     

银屑病皮损中c-myc和c-jun的检测

目的:为了探索c-myc及c-jun与银屑病的关系。方法:运用免疫组化SP法对22例寻常型银屑病患者及15例正常人皮肤c-myc及c-jun的表达进行观察。结果:c-myc、c-jun在银屑病皮损中过度表达,而在正常皮肤不表达或弱表达,结论:c-myc、c-jun可能与银屑病的表皮细胞过度增殖、分化异常有关。     

Infliximab for the treatment of psoriasis in Greece: 4 years of clinical experience at a single centre

Background Infliximab, a chimeric monoclonal antibody, has been shown to be effective for moderate to severe psoriasis. Clinical experience with long‐term infliximab therapy for psoriasis is accumulating, and it is therefore important to share our experience with its use in real‐life clinical practice. Objectives To report our experience with infliximab (Remicade^®; Schering Plough, Kenilworth, NJ, U.S.A.) for the treatment of moderate to severe plaque psoriasis (and/or arthritis) from a single clinic in Greece. Patients and methods Between August 2004 and March 2008, 62 patients presenting to our clinic with moderate to severe psoriasis were treated with infliximab. Disease phenotype, clinical course, disease severity and adverse events were assessed throughout the treatment period. Results Infliximab resulted in a reduction of median Psoriasis Area and Severity Index (PASI) of 70% at week 6 and 84·4% at week 14. Nineteen patients who have completed 1 year on infliximab treatment experienced sustained efficacy with a median PASI improvement of 92·16% and a Physician’s Global Assessment (PGA) of ‘clear’ or ‘almost clear’, while nine patients have reached approximately 20 months of continuous therapy. All patients with psoriatic arthritis showed marked improvement in their clinical symptoms following the first infusion. Eight patients (12·9%) experienced adverse events that required discontinuation of treatment. There were no statistically significant differences in PASI and Dermatology Life Quality Index (DLQI) scores between patients with arthritis and those with only skin lesions, or between those who received methotrexate, either from the beginning or during infliximab therapy, and those who did not receive methotrexate at all. Selected patients of interest are discussed. Conclusions The above data confirm previous reports that treatment with infliximab is an efficacious and safe option for patients with moderate to severe plaque psoriasis (and/or arthritis). Long‐term follow‐up, continued pharmacovigilance, and controlled comparative studies will be required to fully evaluate its use in the treatment of psoriasis.     

银屑病测皮损中c-myc和c-jun的检测

目的：为了探索c—myc及c—jun与银屑病的关系。方法：运用免疫组化SP法对22例寻常型银屑病患者及15例正常人皮肤c—myc及c—jun的表达进行观察。结果：c—myc、c—jun在银屑病皮损中过度表达，而在正常皮肤不表达或弱表达，结论：c—myc、c—jun可能与银屑病的表皮细胞过度增殖、分化异常有关。     

Use of biological drugs in patients with psoriasis and psoriatic arthritis in Italy: Results from the PSONG survey

This Italian multicenter retrospective study compared the drug survival and efficacy of different anti‐TNF agents in psoriasis (PsO) and psoriatic arthritis (PsA) patients. A database of PsO/PsA patients treated with adalimumab, etanercept, and infliximab from May 2013 to May 2014 was analyzed. PASI 75, 90, and 100 was calculated at each time point to evaluate efficacy. Drug survival rate and probability of maintaining PASI response were evaluated. The impact of dependent variables on probability of PASI 75 loss was evaluated by logistic regression. 1,235 patients were included, 577 with PsO and 658 with PsA. Highest survival rates were observed with adalimumab followed by etanercept and infliximab in PsO and PsA patients. The probability of maintaining PASI response was significantly higher for adalimumab followed by infliximab. For PsO patients, the odds of losing PASI 75 was higher in etanercept‐treated patients (OR: 8.1; 95% CI: 4.2–15.6, p < .001) or infliximab (OR: 6.6; 95% CI: 2.6–16.3, p < .001) vs. adalimumab. Likewise, for PsA patients the odds of losing PASI 75 was higher in etanercept‐treated patients (OR: 2.3; 95% CI: 1.4–3.8, p = .01) or infliximab (OR: 2.2; 95% CI: 1.1–4.1, p = .018) vs. adalimumab. Adalimumab could be the best therapeutic option over other anti‐TNF agents for the treatment of PsO and PsA patients.     

Trappin-2在银屑病患者血清及皮损中的检测及临床意义

目的：检测trappin-2蛋白在银屑病患者血清及皮损中的表达。方法：用双抗体夹心ELISA法,检测50例寻常性银屑病患者和16例脓疱性银屑病患者外周血,以及32例寻常性银屑病患者和10例局限性脓疱性银屑病患者皮损负压吸疱液中trappin-2蛋白表达水平。结果：寻常性银屑病患者外周血及皮损组织液中trappin-2蛋白表达水平显著高于对照组（P值均〈0．01）,其中进行期和稳定期寻常性银屑病患者外周血trappin-2蛋白的表达差异有统计学意义（P〈0．05）,且与患者相应的银屑病皮损面积和严重度指数（PASI）呈正相关。局限性和泛发性脓疱性银屑病患者外周血及皮损组织液中trappin-2蛋白的表达水平与对照组相比,差异亦有统计学意义（P〈0．05）,与寻常性银屑病患者比较差异无统计学意义,且与病情活动指数无线性相关。结论：trappin-2蛋白在寻常性银屑病和脓疱性银屑病发病机制中可能起重要作用。     

Perforin expression is upregulated in the epidermis of psoriatic lesions

BACKGROUND: There are currently very few data regarding the role of cell-mediated cytotoxicity in psoriasis. Both cytotoxic T lymphocytes and natural killer (NK) cells mediate cytotoxicity reactions, mainly by two distinct pathways, the perforin/granzyme and the Fas/Fas ligand pathway. OBJECTIVES: To study the expression and distribution of perforin, T- and NK-cell subsets in psoriatic lesional and nonlesional skin. METHODS: Skin biopsy specimens from both lesional and nonlesional skin of 11 patients with chronic plaque psoriasis and eight healthy controls were analysed by immunohistochemistry. RESULTS: We found a significant increase in CD4+ and CD8+ cells in psoriatic lesions compared with nonlesional and healthy skin. The expression of CD16+ NK cells was significantly lower in lesions compared with healthy skin. Perforin expression was significantly enhanced in the epidermis of psoriatic lesions. CONCLUSIONS: Perforin expression is upregulated in the epidermis of psoriatic lesions, suggesting a potential role for perforin in the creation of the psoriatic plaque.     

Safety profiles and efficacy of infliximab therapy in Japanese patients with plaque psoriasis with or without psoriatic arthritis,pustular psoriasis or psoriatic erythroderma: Results from the prospective post‐marketing surveillance

A large‐scale prospective post‐marketing surveillance was conducted to evaluate the safety and efficacy of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. This study was conducted in all psoriasis patients treated with infliximab after its Japanese regulatory approval. Infliximab was administrated at 5 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter. Patients were serially enrolled and observed for 6 months to evaluate the safety and efficacy. The safety and efficacy were evaluated in 764 and 746 patients, respectively. Incidences of any and serious adverse drug reactions were 22.51% and 6.94%, respectively, and those of any and serious infusion reactions were 6.15% and 1.31%, respectively, which were comparable with the results in the post‐marketing surveillance with 5000 rheumatoid arthritis patients in Japan. Major adverse drug reactions during the follow‐up period were infections (5.10%) including pneumonia, cellulitis and herpes zoster, however, no tuberculosis was observed. The safety profiles were equivalent, regardless of the psoriasis types. No new safety problems were identified. The response rates on global improvement and median improvement rate of Psoriasis Area and Severity Index in all patients were 88.0% and 85.0%, respectively. Of note, the efficacy was equivalent for each psoriasis type as well as for each body region. Infliximab was also effective in pustular psoriasis symptoms, joint symptoms and nail psoriasis, as well as improvement of quality of life. Infliximab was confirmed to be highly effective and well tolerated in treating refractory psoriasis, including pustular psoriasis and psoriatic erythroderma.     

Long-term study of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma

The efficacy and safety of infliximab in patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis (excluding localized type) and psoriatic erythroderma were assessed in clinical practice. Without washout of the existing treatment of psoriasis, treatment was switched to infliximab, which was given at a dose of 5 mg/kg at weeks 0, 2 and 6 and then every 8 weeks up to week 46. The primary end-points were 75% improvement in Psoriasis Area and Severity Index score (PASI 75 response rate) for plaque psoriasis, 20% improvement in American College of Rheumatology criteria (ACR 20 response rate) for psoriatic arthritis, and global improvement in pustular psoriasis and psoriatic erythroderma. The PASI 75 response rate in plaque psoriasis was 72.2% at week 10 and 53.6% at week 50. The ACR 20 response rate in psoriatic arthritis was 66.7% at week 14 and 80.0% at week 46. The response defined as global improvement in pustular psoriasis was between 66.7% and 100.0% during the 2–50-week period. The response defined as global improvement in psoriatic erythroderma was between 75.0% and 100.0% during the week-2–50 period. There were 14 discontinued patients. The most frequently reported reason for discontinuation was the development of adverse events. However, there were no serious respiratory diseases, infections or infusion reactions. In patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma, infliximab was well tolerated, regardless of prior treatment, and also showed superior efficacy over a period of approximately 1 year.     

Autoradiographic and planimetric analyses of the inflammatory infiltrate in psoriatic lesions under PUVA-therapy

Summary The effects of oral 8-methoxypsoralen-photochemotherapy (PUVA-therapy) on the inflammatory infiltrate in 14 psoriatic skinlesions and on normal skin of 7 controls were investigated by means of autoradiography and planimetry. Under PUVA-therapy, one finds a significant decrease in dermal cells per millimeter lesion in psoriasis. Percentage of ³H-TdR-labeled dermal cells in the lesions and total number of dermal cells in the control group do not change significantly. The relative decrease of dermal cells per millimeter lesion in psoriasis is far less significant than the reduction of ³H-TdR-labeled epidermal cells under PUVA-therapy.Lecture held at VII^th Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung (ADF), Innsbruck, Austria, November 16–18, 1979     

角蛋白K6、K16在寻常性银屑病皮损中的表达及其临床意义

目的：探讨角蛋白K6、K16在银屑病发病机制中的地位。方法：用免疫组化法，检测30例银屑病患者皮损处和10例正常对照者皮肤角质形成细胞中角蛋白K6和K16的表达水平。结果：①银屑病组患者皮损处表皮角质形成细胞中K6、K16的表达水平与正常对照组相比，差异具有显著性，其中，病例组棘细胞层K6、K16的表达与对照组相比，差异具有极显著性；②角蛋白K6、K16在银屑病进行期和稳定期的表达差异无显著性，但分别与消退期银屑病相比差异均具有显著性；③角蛋白K6、K16的表达在急性点滴状和慢性斑块状银屑病间差异无显著性。结论：角蛋白K6、K16在银屑病发病机制中可能起重要作用，这两个指标有望作为监测银屑病活动性的指标。     

寻常型银屑病皮损肥大细胞密度及IL-8表达的研究

目的：探讨肥大细胞和IL-8在寻常型银屑病中的作用。方法：采用免疫组化技术(SABC法)观察寻常型银屑病皮损处MC分布和IL-8在表皮中的表达情况。结果：寻常型银屑病皮损处MC密度明显高于皮肤血管炎组和健康对照组；寻常型银屑病皮损处KC中IL-8的表达明显高于两对照组。结论：结果提示MC和IL-8参与寻常型银屑病的致病过程，并且两者之间存在相关性。     

Alterations in the desquamation-related proteolytic cleavage of corneodesmosin and other corneodesmosomal proteins in psoriatic lesional epidermis

Background  Desquamation occurs after proteolysis of corneodesmosomal proteins, including corneodesmosin (CDSN), by proteases of the kallikrein family, particularly KLK7. Impaired desquamation is one of the features of psoriasis, and psoriasis-associated single nucleotide polymorphisms of the CDSN gene may potentially modify the proteolysis of the encoded protein.
Objectives  To test whether the proteolysis of CDSN and other corneodesmosomal components is altered in psoriatic epidermis.
Methods  Total protein extracts obtained by tape-stripping of nonlesional and lesional skin from 11 patients were compared by immunoblotting experiments.
Results  An almost intact form of CDSN that has never been observed previously in the normal upper stratum corneum was detected in the lesional skin extracts, showing an altered proteolytic processing of the protein. This form was also observed in the nonlesional skin extracts, but in lower amounts. For most patients, increased amounts of desmoglein 1, plakoglobin and of high molecular weight fragments of desmocollin 1 were detected in the lesional skin. For most of them, similar amounts of KLK7 were immunodetected in both nonlesional and lesional skin extracts. No particular differences were observed related to the psoriasis type, the HLA-Cw6 status of the patients or any particular CDSN polymorphisms.
Conclusions  We detected a near full-length form of CDSN that has not been previously observed in normal stratum corneum. The results suggest a reduced degradation of all corneodesmosomal proteins in psoriatic lesions which probably reflects the persistence of corneodesmosomes.     

Cyclin D1, B and A expression and cell turnover in psoriatic skin lesions before and after cyclosporin treatment

BACKGROUND: Cyclosporin induces a dramatic reversal to normality in psoriatic lesions, with a reduction of inflammatory infiltrate and epidermal proliferation. It is known that the cell cycle and cell proliferation are regulated by the sequential activation of cyclin-dependent kinase/cyclin complexes. AIM: We evaluated epidermal cell turnover and thickness, as well as the expression of cyclins D1, B and A in psoriatic skin before and after therapy with cyclosporin. METHODS: Epidermal thickness, mitotic and apoptotic indices (MI, AI), as well as the percentages of epidermal cell nuclei positive for Ki-67 and cyclins D1, B and A were calculated. Cytoplasmic positivity to cyclin B was also evaluated. RESULTS: After 6 weeks of therapy, we observed a clinical improvement of the disease and normalization of the epidermis. Epidermal thickness and Ki-67-, cyclins B- and A-positive nuclei percentage were significantly higher before therapy than after (0.52 +/- 0.05 mm vs. 0.21 +/- 0.03 mm, P < 0.001; 19 vs. 2.6, 19 vs. 3, and 12 vs. 1, respectively; P < 0.0005); cytoplasmic positivity to cyclin B was slightly higher before therapy (score 3 vs. 2-3). Cyclin D1 was negative or expressed in a low percentage of nuclei in psoriasis before therapy (0.78), whereas it was always negative after therapy. MI was 0.15 before therapy, whereas mitoses were almost absent afterwards. Apoptoses were undetectable before therapy, whereas a few apoptoses were observed after treatment (AI = 0.4). CONCLUSIONS: Overexpression of cyclins B and A, rather than D1 seems to characterize psoriasis. Their evaluation could provide further insights in understanding the development of this disorder and could be used to verify the efficacy of currently used therapies as well as future ones.     

Key component of inflammasome,NLRC4, was identified in the lesional epidermis of psoriatic patients

Inflammasomes are multimolecular complexes that control the inflammatory response. The function of inflammasomes in the pathogenesis of psoriasis is still unclear. To clarify the relationship between inflammasomes and the pathophysiology of psoriasis, and in particular, to identify molecules interacting with caspase‐1, a crucial component of inflammasomes, scale extracts obtained from patients with psoriasis were immunoprecipitated with anti‐caspase‐1 antibody and analyzed by liquid chromatography coupled with electrospray tandem mass spectrometry (LC‐MS/MS). The expression of the inflammasome component was assessed by immunohistochemical analysis and an in vitro assay. We identified several candidates for caspase‐1‐interacting proteins from the psoriatic scale extracts by immunoprecipitation and LC‐MS/MS. Nucleotide‐binding oligomerization domain‐containing protein‐like receptor family CARD domain‐containing protein 4 (NLRC4) was the only inflammasome component among the candidates; thus, the protein is considered to be a key factor of inflammasomes in psoriasis. No inflammasome component was found in the extracts of atopic dermatitis or normal skin by LC‐MS/MS. Immunohistochemical analysis demonstrated upregulation of NLRC4 in the lesional epidermis of some psoriatic patients whereas weak expression of NLRC4 was detected in the normal and non‐lesional epidermis. The mRNA expression of the NLRC4 gene increased in keratinocytes at confluency, 48 h after air exposure and after the addition of 1.5 mmol/L calcium chloride. Our findings suggest that NLRC4 may be involved in the exacerbation or modification of psoriatic lesions.     

Mesenchymal stem cells in psoriatic lesions affect the skin microenvironment through circular RNA

Psoriasis is an autoimmune skin disease. Our previous studies revealed abnormal immune regulation of skin mesenchymal stem cells (S‐MSCs) in psoriatic lesions. Circular RNA (circRNA) molecules were recently discovered as a new class of non‐coding regulatory RNAs. Their role in the pathogenesis of psoriasis has not yet been studied. To explore potential circRNA‐mediated mechanisms of S‐MSCs in the pathogenesis of psoriasis, we sequenced mRNAs and circRNAs of MSCs from normal skin and psoriatic lesions, followed by functional prediction and interaction analyses. In total, 129 circRNAs were differentially expressed, including 123 up‐regulated and 6 down‐regulated circRNAs, in MSCs from psoriatic lesions. Pathway analysis showed that the genes significantly down‐regulated in psoriatic as compared to normal S‐MSCs were mainly involved in JAK‐STAT signalling. According to a circRNA‐miRNA‐mRNA interaction network, the expression of circRNAs associated with these mRNAs was also down‐regulated in MSCs of psoriatic skin lesions. Knockdown of the circRNA gene chr2:206992521|206994966 reduced the capacity of S‐MSCs to inhibit T‐cell proliferation upon co‐culture in normal as well as lesion‐derived S‐MSCs. Secreted‐cytokine profiles (IL‐6, IL‐11 and hepatocyte growth factor) were also similar in normal and lesion‐derived S‐MSCs after circRNA knockdown. Thus, the circRNA chr2:206992521|206994966 in S‐MSCs from psoriatic lesions affects the activity of T lymphocytes in local lesions by influencing their cytokine secretion. Taken together, our findings indicate that circRNA mediates the role of S‐MSCs in the pathogenesis of psoriasis.