Perimembrane Aurora-A Expression is a Significant Prognostic Factor in Correlation with Proliferative Activity in Non-Small-Cell Lung Cancer -LRB- NSCLC -RRB- Purpose Aurora-A , also known as STK15/BTAK , is a member of the protein serine/threonine kinase family , and experimental studies have revealed that Aurora-A plays critical roles in cell mitosis and in carcinogenesis . However , no clinical studies on Aurora-A expression in non-small-cell lung cancer -LRB- NSCLC -RRB- have been reported . Thus , the present study was conducted to assess the clinical significance of Aurora-A status . Primary lung cancer is the leading cause of cancer deaths in most industrialized countries , and non-small-cell lung cancer -LRB- NSCLC -RRB- accounts for 75 -- 80 % of primary lung cancer . Surgery is the most effective therapeutic modality for the cure , but the postoperative prognosis remains poor .1 -- 3 To improve the prognosis , establishment of biological markers other than tumor-node-metastasis -LRB- TNM -RRB- factors that determine prognosis and response to a particular treatment is essential . Although many possible biological markers such as mutations of p53 and k-ras genes have been reported , none of them has been established as a marker in decision-making of the treatment of NSCLC . In addition , most NSCLC patients present with advanced stages and are appropriate candidates for surgery . For inoperable patients , chemotherapy with or without radiotherapy may be given . Recently , tyrosine kinase inhibitors targeting epidermal growth factor receptor -LRB- EGFR -RRB- , gefitinib and erlotinib , have been introduced into the therapy of NSCLC , and experimental and clinical studies have revealed that these agents induce dramatic antitumor effects for tumors with activating mutations within the EGFR kinase domain .4,5 Thus , other molecular abnormalities in NSCLC should be revealed in the development of useful prognostic markers and in the development of effective molecular targeting agents . Aurora-A , also known as BTAK , STK15 , Aurora-2 , ARKI , or AIKI , is a member of the serine/threonine kinase family . As Aurora-A is involved in proper centrosome functions and chromosome segregation during normal cell mitosis ,6 -- 8 its abnormalities such as overexpression as well as gene amplification may contribute to development and progression of malignant tumors .9 -- 11 In clinical studies , Aurora-A abnormalities have been reported in a variety of malignant tumor including glioma ,12 medullobrastoma ,13 gastric cancer ,14 esophageal cancer ,15,16 pancreatic cancer ,17 ovarian cancer ,18 breast cancer ,19,20 bladder cancer ,21 and hepatocellular carcinoma .22 In all these clinical studies , Aurora-A gene was amplified or Aurora-A expression was upregulated in tumor tissues compared with normal tissues , which also support experimental results suggesting that Aurora-A abnormalities are involved in carcinogenesis . In addition , many studies showed that Aurora-A abnormalities were positively correlated with aggressive tumor behavior such as poorly differentiated tumor grade , invasion , and nodal metastasis ,15,16,19,20 -- 22 but some studies showed no correlation12 ,17 or an inverse correlation .18 Some studies also assessed a prognostic significance of Aurora-A status ; most studies showed that Aurora-A abnormalities were correlated with a significant poor prognosis ,13,16,21,22 but one study failed to show .20 These results may suggest that clinical significant of Aurora-A status in malignant tumors remains controversial . Moreover , no clinical study on Aurora-A status in NSCLC has been reported . Thus , we conducted a clinical study on Aurora-A expression in resected NSCLC and assessed its clinical significance in correlation with other biomarkers including proliferative activity . Patients and Methods Patients We retrospectively reviewed a total of 191 consecutive patients with pathologic -LRB- p -RRB- - stage I -- IIIA NSCLC who underwent complete tumor resection and nodal dissection without any preoperative therapy at the Department of Thoracic Surgery , Kyoto University , between January 1 , 1985 and December 31 , 1990 . The p-stage was reevaluated and determined according to the current tumor-node-metastasis -LRB- TNM -RRB- classification as revised in 1997.1 Histological type was also redetermined according to the classification by the World Health Organization -LRB- WHO -RRB- as revised in 2004 . Two patients who experienced operation-related death were excluded from the study . Thus , a total of 189 patients were finally evaluated in the present study . For all these patients , the inpatient medical records , chest x-ray films , whole-body computed tomography -LRB- CT -RRB- films , bone and gallium scanning data , and records of surgery were reviewed without knowledge of the results of immunohistochemical staining -LRB- IHS -RRB- or the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling -LRB- TUNEL -RRB- staining . Details of postoperative adjuvant therapy were described in previous studies .23,24 In brief , cisplatin-based chemotherapy , radiation , and oral administration of tegafur -LRB- a fluorouracil derivative drug -RRB- were prescribed postoperatively for 47 , 30 , and 49 patients , respectively . Intraoperative therapy was not performed on any patient . The day of thoracotomy was considered the starting day for counting postoperative survival days . The median and mean follow-up periods were 1697 and 1983 days , respectively -LRB- range , 50 -- 6381 days -RRB- . This study has been approved by the Ethics Committee of Faculty of Medicine , Kyoto University . Tissue Preparation All tumor specimens were fixed immediately in 10 vol % formalin , and then embedded in paraffin . Serial 4-μm sections were prepared from each sample and used for routine hematoxylin and eosin -LRB- HE -RRB- staining , the TUNEL staining to detect apoptotic cells , and IHS to determine Aurora-A expression status , p53 status , intratumoral microvessel density -LRB- IMVD -RRB- , and proliferative index -LRB- PI -RRB- . Immunohistochemistry Aurora-A expression was evaluated using a standard streptavidin-biotinylated horseradish peroxidase detection system . Dewaxed sections were incubated overnight with a rabbit polyclonal antibody -LRB- KR051 , Transgenic Co. Ltd. , Kumamoto , Japan ; it had been produced and its reliability had been confirmed by western blotting on a commercial basis -RRB- diluted at 1:100 . Diaminobenzidine-tetrahydrochloride -LRB- 0.03 % -RRB- containing 0.1 % hydrogen peroxide was used as a chromogen , and sections were counterstained with hematoxylin . For negative control slides , rabbit immunoglobulin G was used instead of the primary antibody . Colon cancer sections that are known to express Aurora-A were used as positive control slides . Aurora-A expression on tumor cells was first classified into negative or positive expression ; a slide was judged to be Aurora-A positive expression , regardless of the staining intensity . For slides with positive Aurora-A expression , the staining pattern was , then , classified as follows : diffuse cytoplasmic staining -LRB- Fig. 1B -RRB- , perimembrane staining -LRB- Fig. 1C -RRB- . Slides were evaluated by two pathologists -LRB- E.O. and Y.T. -RRB- independently , without knowledge of any patient characteristic . Fig. 1.Aurora-A expression in non-small-cell carcinoma -LRB- NSCLC -RRB- as detected with imuunohistochemical staining . A Negative staining . B diffuse cytoplasmic staining . C Peri-membrane staining . PI , IMVD , and p53 status were also determined with IHS as described previously .23,25 Briefly , an anti-PCNA monoclonal antibody -LRB- PC-10 , mouse immunogloblin G -LSB- IgG -RSB- 2a , kappa ; DAKO Japan , Kyoto , Japan -RRB- diluted at 1:50 was used as the primary antibody to determine PI ; 23 PI was defined as the percentage of PCNA-positive staining tumor cells . IMVD was determined with an anti-CD34 monoclonal antibody QBEnd10 -LRB- mouse IgG1 , kappa ; DAKO Japan -RRB- diluted at 1:50 ; the 10 most vascular areas within a section were selected for evaluation of angiogenesis , and the average counts of CD34-positive vessels were recorded as IMVD in each case .25 An antihuman p53 monoclonal antibody DO-7 -LRB- mouse IgG2b , kappa , 250 μg/mL , DAKO Japan -RRB- was used to determine p53 status . When the percentage of positive-staining cells exceeded 5 % , the slide was judged to exhibit aberrant expression of p53 .23 Detection of Apoptosis The TUNEL staining was performed using the In Situ Death Detection Kit , POD -LRB- Boehringer Manheim , Manheim , Germany -RRB- following the manufacture 's protocol as described previously .23 The specificity of the TUNEL staining of apoptotic cells was confirmed by making the negative and the positive control slides at every staining . As negative control slides , sections incubated with the TUNEL reaction mixture without TdT were used . Sections treated with DNase I -LRB- Stratagene , La Jolla , CA -RRB- before the TUNEL reaction were used as positive control slides . Apoptotic cells were determined with careful observation of TUNEL-staining sections and serial HE-staining sections , and TUNEL-positive staining cells , if they represented the histological features of necrosis in HE-staining sections , were not considered to be apoptotic cells . In each case , a total of 10,000 tumor cells , consisting of 1000 tumor cells each in 10 different fields , were evaluated at high magnification -LRB- 400 × -RRB- . The apoptotic index -LRB- AI -RRB- was defined as the number of apoptotic cells per 1000 tumor cells . Statistical Analysis Counts were compared by the chi-square test . Continuous data were compared using the t test if the distribution of the samples was normal , or using the Mann-Whitney U test if the sample distribution was asymmetrical . The postoperative survival rate was analyzed by the Kaplan-Meier method , and differences in the survival rates were assessed by the log-rank test . Death from any cause was included in calculation of postoperative survival . Multivariate analysis of the prognostic factors was performed using Cox 's proportional hazard model . Differences were considered significant when the P value was less than .05 . All statistical manipulations were performed using the SPSS ver .10 for the Windows software system -LRB- SPSS Inc. , Chicago , IL -RRB- . Results Expression of Aurora-A in NSCLC Expression of Aurora-A was not observed in normal adjacent lung tissues in any patient . Expression of Aurora-A in tumor cells was negative in 31 patients -LRB- 16.4 % -RRB- and positive in the other158 patients . Among Aurora-A positive patients , 124 patients showed diffuse cytoplasmic staining , 6 patients showed pure perimembrane staining , and 28 patients showed both diffuse cytoplasmic staining and perimembrane staining -LRB- mixed staining -RRB- . Because the number of patients showing pure perimembrane staining was very small -LRB- n = 6 -RRB- , both patients with pure perimembrane staining and patients with mixed staining were classified into perimembrane patients . Thus , there were 31 negative patients -LRB- 16.4 % -RRB- , 124 diffuse cytoplasmic patients -LRB- 65.6 % -RRB- , and 34 perimembrane patients -LRB- 18.0 % -RRB- -LRB- Table 1 -RRB- . Table 1 . Characteristics of patients and Aurora expressionNo . of patients -LRB- % -RRB- MAGE-D4 expressionP valueNegativePositiveDiffuse cytoplasmicPerimembraneAll patients189 -LRB- 100 -RRB- 31 -LRB- 16.4 % -RRB- 124 -LRB- 65.6 % -RRB- 34 -LRB- 18.0 % -RRB- Age -LRB- mean ± SD -RRB- 62.4 ± 9.660.5 ± 10.262.3 ± 9.264.3 ± 9.10.256 Sex .137 Male133 -LRB- 70.4 -RRB- 26 -LRB- 19.5 % -RRB- 86 -LRB- 64.7 % -RRB- 21 -LRB- 15.8 % -RRB- Female56 -LRB- 29.6 -RRB- 5 -LRB- 8.9 % -RRB- 38 -LRB- 67.9 % -RRB- 13 -LRB- 23.2 % -RRB- Performance status -LRB- PS -RRB- .353 0164 -LRB- 86.8 -RRB- 28 -LRB- 17.1 % -RRB- 109 -LRB- 66.5 % -RRB- 27 -LRB- 16.5 % -RRB- 1 -- 225 -LRB- 13.2 -RRB- 3 -LRB- 12.0 % -RRB- 15 -LRB- 60.0 % -RRB- 7 -LRB- 28.0 % -RRB- Histologic type .302 -LRB- Sq vs Ad -RRB- Squamous cell -LRB- Sq -RRB- 64 -LRB- 33.9 -RRB- 8 -LRB- 12.5 % -RRB- 41 -LRB- 64.1 % -RRB- 15 -LRB- 23.4 % -RRB- Adeno -LRB- Ad -RRB- 108 -LRB- 57.1 -RRB- 19 -LRB- 17.6 % -RRB- 73 -LRB- 67.6 % -RRB- 16 -LRB- 14.8 % -RRB- Large cell -LRB- La -RRB- 10 -LRB- 5.3 -RRB- 4 -LRB- 40.0 % -RRB- 4 -LRB- 40.0 % -RRB- 2 -LRB- 20.0 % -RRB- Others7 -LRB- 3.7 -RRB- 0 -LRB- 0.0 % -RRB- 5 -LRB- 85.7 % -RRB- 1 -LRB- 14.3 % -RRB- Tumor differentiation * .393 Well68 -LRB- 37.4 -RRB- 9 -LRB- 13.2 % -RRB- 49 -LRB- 72.1 % -RRB- 10 -LRB- 14.7 % -RRB- Moderately67 -LRB- 36.8 -RRB- 13 -LRB- 19.4 % -RRB- 43 -LRB- 64.2 % -RRB- 11 -LRB- 16.4 % -RRB- Poorly47 -LRB- 25.8 -RRB- 9 -LRB- 19.1 % -RRB- 26 -LRB- 55.3 % -RRB- 12 -LRB- 25.5 % -RRB- Pathologic -LRB- p - -RRB- stage .007 -LRB- for all p-stage -RRB- I104 -LRB- 55.0 -RRB- 12 -LRB- 11.5 % -RRB- 80 -LRB- 76.9 % -RRB- 12 -LRB- 11.5 % -RRB- II22 -LRB- 11.6 -RRB- 4 -LRB- 18.2 % -RRB- 11 -LRB- 50.0 % -RRB- 7 -LRB- 31.8 % -RRB- IIIA63 -LRB- 33.3 -RRB- 15 -LRB- 23.8 % -RRB- 33 -LRB- 52.4 % -RRB- 15 -LRB- 23.8 % -RRB- * Other histologic types were excluded in the analyses . The incidence of perimembrane staining was significantly higher in higher p-stages ; perimembrane staining was seen in only 11.5 % -LRB- 12 of 104 -RRB- of p-stage I patients , but seen in as high as 25.8 % -LRB- 22 of 85 -RRB- of p-stage II -- IIIA patients -LRB- Table 1 -RRB- . There was no significant correlation between Aurora-A expression status and any other patients ' characteristic -LRB- Table 1 -RRB- . The mean PI for perimembrane Aurora-A expression patients high tumor was significantly higher than that for Aurora-A negative or that for diffuse cytoplasmic Aurora-A expression patients -LRB- PIs : 63.5 , 49.2 , and 41.7 , respectively ; P < .001 -RRB- -LRB- Table 2 -RRB- . There was no significant difference in the mean IMVD or in the mean AI according to the status of Aurora-A expression ; there was no significant correlation between Aurora-A expression status and p53 status -LRB- Table 2 -RRB- . Table 2 . Correlation between Aurora expression and other biomarkersAurora expressionP valueNegativePositiveDiffuse cytoplasmicPerimembraneIntratumoral microvessel density -LRB- IMVD -RRB- * 191.2 ± 16.3174.7 ± 8.9167.6 ± 14.6.584 Proliferative index -LRB- PI -RRB- -LRB- % -RRB- 49.2 ± 4.841.7 ± 2.563.5 ± 3.8 < .001 Apoptotic index -LRB- AI -RRB- -LRB- / 1000 tumor cells -RRB- 13.5 ± 3.220.5 ± 2.015.9 ± 2.5.154p53-status : Aberrant expression -LRB- + -RRB- 12/31 -LRB- 38.7 % -RRB- 55/124 -LRB- 44.4 % -RRB- 15/34 -LRB- 44.1 % -RRB- .848 Values were shown as the mean ± standard error -LRB- SE -RRB- . * Evaluated with an anti-CD34 antibody . Expression of Aurora-A and Postoperative Survival For all 189 patients , 5-year survival rates of Aurora-A negative patients , diffuse cytoplasmic Aurora-A patients , and perimembrane Aurora-A patients were 67.8 % , 66.7 % , and 47.6 % , respectively ; perimembrane Aurora-A patients showed the poorest postoperative survival -LRB- P = .033 -RRB- -LRB- Table 3 and Fig. 2 -RRB- . Table 3 . Aurora expression and postoperative survival in non-small-cell lung cancer -LRB- NSCLC -RRB- patients5-year survival rate -LRB- % -RRB- P valueAURORA expressionNegativePositiveDiffuse cytoplasmicPerimembraneAll patients67 .8 % 66.7 % 47.6 % .033 Subset analysis , histologic type Squamous cell -LRB- Sq -RRB- 75.0 % 74.2 % 34.5 % .007 Adeno -LRB- Ad -RRB- 64.2 % 60.8 % 62.5 % .894 Pathologic -LRB- p - -RRB- stage I91 .7 % 72.9 % 58.3 % .098 II75 .0 % 68.6 % 57.1 % .579 IIIA50 .4 % 50.9 % 28.9 % .088 Fig. 2 . Survival curves of patients who underwent complete resection for pathologic -LRB- p - -RRB- stage I -- IIIA non-small-cell lung cancer . Comparison according to Aurora-A expression status . Subset analyses revealed that perimembrane Aurora-A expression was a significant factor to predict a poor prognosis in squamous cell carcinoma patients , not in adenocarcinoma patients -LRB- P = .007 and P = .894 , respectively -RRB- -LRB- Table 3 -RRB- . A multivariate analysis of prognosis factors using a Cox proportional hazard model confirmed that perimembrane Aurora-A expression was an independent and significant factor to predict a poor prognosis in NSCLC -LRB- Table 4 -RRB- . Table 4Multivariate analysis of prognostic factors -LRB- Cox 's proportional hazard model -RRB- FactorsBetaP valueHazard ratio -LRB- 95 % confidence interval -RRB- Gender -LRB- male/female -RRB- − 0.539.0960.583 -LRB- 0.309 -- 1.101 -RRB- Age0 .006.7141.006 -LRB- 0.977 -- 1.035 -RRB- Performance status -LRB- 0/1/2 -RRB- 0.183.5711.201 -LRB- 0.637 -- 2.264 -RRB- Histologic type -LRB- Nonadenocarcinoma/adenocarcinoma -RRB- − 0.050.1620.951 -LRB- 0.887 -- 1.020 -RRB- Pathologic stage -LRB- I/II/IIIa -RRB- 0.551.0011.734 -LRB- 1.311 -- 2.295 -RRB- Perimembrane Aurora expression -LRB- No/Yes -RRB- − 0.362.0320.343 -LRB- 0.169 -- 0.699 -RRB- Discussion The present study is the first clinical study on Aurora-A expression in NSCLC and has revealed the clinical significance as follows : -LRB- 1 -RRB- positive Aurora-A expression is exclusively observed in tumor cells , not in normal cells ; -LRB- 2 -RRB- there are two Aurora-A expression patterns , diffuse cytoplasmic staining and perimembrane staining ; -LRB- 3 -RRB- perimembrane staining is significantly correlated to higher p-stage and higher proliferative activity ; and -LRB- 4 -RRB- perimembrane staining is a significant and independent factor to predict a poor prognosis , especially in squamous cell carcinoma patients . As mentioned in the introduction section , previous experimental and clinical studies have demonstrated that Aurora-A is overexpressed and upregulated in tumor cells and/or tissues ,8 -- 20,22,26 which is also true in NSCLC as demonstrated in the present study . The centrosomes play important roles in the maintenance of genomic instability by establishing bipolar spindles during mitosis and by ensuring equal segregation of replicated chromosome into two daughter cells .27 Aurora-A is involved in normal centrosome functions , and its abnormalities such as gene amplification and overexpression may lead to centrosome function disorder , chromosomal instability , and carcinogenesis.26Aurora-A gene amplification usually contributes to overexpression of Aurora-A gene and Aurora-A protein , but also common is overexpression without gene amplification .22 These results may suggest that Aurora-A expression is regulated not only by gene amplification but also by other mechanisms .22 In the present study , only Aurora-A protein expression was assessed immunohistochemically , and comparative study of overexpression and amplification should be conducted in future . In previous clinical studies on Aurora-A expression assessed with IHS , Aurora-A expression was classified simply into negative or positive , and its clinical significance was examined .13,15 -- 18,20 Some studies showed a significantly positive correlation between Aurora-A overexpression and aggressive tumor behavior such as poor differentiation and nodal metastasis ,15,16,20 but others showed no17 or an inverse correlation .18 In addition , among three studies where prognostic significance of Aurora-A overexpression was assessed , two studies showed a significantly poor prognosis in patients with Aurora-A overexpression13 ,16 and one failed to show .20 These conflicting results on clinical significance of Aurora-A expression status might be partly due to the evaluation system . In fact , there was no difference in the proliferative activity as represented as PI or in the prognosis between negative Aurora-A tumors and diffuse cytoplasmic Aurora-A tumors in the present study -LRB- Tables 2 and 3 -RRB- ; when perimembrane Aurora-A expression was separated and analyzed , tumors with perimembrane Aurora-A expression showed an aggressive tumor phenotype correlated with a higher PI and a poor prognosis . The biochemical implication of perimembrane Aurora-A expression is unknown , staining patterns should be taken into consideration in evaluation of Aurora-A expression status in clinical samples . Another reason for conflicting results of clinical significance of Aurora-A expression status might be difference in the histologic type . Two clinical studies on esophageal squamous cell carcinoma showed that Aurora-A overexpression was significantly correlated with aggressive tumor behavior .15,16 In contrast , two clinical studies on adenocarcinoma , one on pancreatic cancer17 and one on breast cancer ,20 failed to show a significant correlation between Aurora-A status and tumor differentiation or prognosis . In fact , a subset analysis according to histologic types in the present study showed that perimembrane Aurora-A expression was a significant factor to predict a poor prognosis in lung squamous cell carcinoma , but not in lung adenocarcinoma -LRB- Table 3 -RRB- . These results may suggest that clinical impact of Aurora-A expression status is enhanced in squamous cell carcinoma and reduced in adenocarcinoma . Further clinical studies on a variety of malignant tumors will give some answers to the issue . We analyzed correlations between Aurora-A status and other biomarkers such as proliferative activity and p53 status . There has been no clinical study where Aurora-A status is assessed in correlation with proliferative activity . Considering experimental results that Aurora-A is a centrosome-associated kinase that contributes to regulation of cell mitosis ,8,26 Aurora-A expression status may be correlated with proliferative activity in clinical samples as shown in the present study -LRB- Table 2 -RRB- . However , it remains unknown why a specific Aurora-A expression pattern , the perimembrane expression , is correlated with higher proliferative activity . Experimental studies have also suggested an interaction between Aurora-A and p53 ,28 -- 30 suggesting that the p53 inhibit oncogenic activity of Aurora-A28 and that Aurora-A , especially when overexpressed , inactivate tumor-suppressor activity of p53 .29,30 One clinical study also documented that Aurora-A overexpression was significantly correlated with p53 mutation in hepatocellular carcinoma .22 These results strongly suggest that Aurora-A in concert with p53 contributes to the development and progression of malignant tumors . In the present study , we failed to show a significant correlation between Aurora-A expression status and p53 status as assessed with IHS . In a future study , p53 gene mutation status in correlation with Aurora-A expression should be examined . More recently , increasing studies on Aurora-A gene polymorphisms and risk of malignant tumors have been reported .31 -- 36 Two common single nucleotide polymorphisms in the coding regions are 91T - > A transversion and 169G - > A transversion , which result in phenylalanine/isoleucine substitution at amino acid 31 -LRB- F31I -RRB- and valine/isoleucine substitution at amino acid 57 -LRB- V57I -RRB- , respectively . Several studies have shown such polymorphisms are associated with increased risk of occurrence of a variety of malignant tumors including esophageal ,31,35 ovarian ,32 and breast33 ,34 cancers . In future , correlation between Aurora-A polymorphism and risk of development of primary lung cancer should be investigated . In conclusion , Aurora-A expression status was a significant prognostic factor in correlation with proliferative activity in NSCLC . To confirm the clinical significance , future prospective studies should be conducted .

O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O B I O B O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


German evidence-based guidelines for the treatment of Psoriasis vulgaris -LRB- short version -RRB- Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients . The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2 % . Despite the large variety of treatment options available , patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance . To optimize the treatment of psoriasis in Germany , the Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen -LRB- BVDD -RRB- have initiated a project to develop evidence-based guidelines for the management of psoriasis . The guidelines focus on induction therapy in cases of mild , moderate , and severe plaque-type psoriasis in adults . The short version of the guidelines reported here consist of a series of therapeutic recommendations that are based on a systematic literature search and subsequent discussion with experts in the field ; they have been approved by a team of dermatology experts . In addition to the therapeutic recommendations provided in this short version , the full version of the guidelines includes information on contraindications , adverse events , drug interactions , practicality , and costs as well as detailed information on how best to apply the treatments described -LRB- for full version , please see Nast et al. , JDDG , Suppl 2 : S1 -- S126 , 2006 ; or http://www.psoriasis-leitlinie.de -RRB- . Introduction The Deutsche Dermatologische Gesellschaft -LRB- DDG -RRB- and the Berufsverband Deutscher Dermatologen -LRB- BVDD -RRB- have initiated a project to develop evidence-based guidelines for the treatment of plaque psoriasis . The full version of the Guidelines has been published in the Journal der Deutschen Dermatologischen Gesellschaft -LRB- JDDG 2006 Suppl 2 -RRB- and is available at http://www.psoriasis-leitlinie.de -LSB- 149 -RSB- . This article summarizes the key points of the Guidelines . Background Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients . The incidence of psoriasis in Western industrialized countries is 1.5 -- 2 % -LSB- 2 -RSB- . Studies on the impairment of life quality have shown that , depending on the severity of the disease , a significant burden may exist in the form of a disability or psychosocial stigmatization -LSB- 3 -RSB- . Patient surveys have shown that the mental and physical impairment associated with psoriasis is comparable to that of other significant chronic conditions , such as type 2 diabetes or chronic respiratory diseases -LSB- 4 -RSB- . Patient surveys have shown that only 25 % of psoriasis patients are highly satisfied with the outcome of their treatment , another 50 % indicate moderate satisfaction , and approximately 20 % report low treatment satisfaction -LSB- 5 -RSB- . In addition , there is a high non-compliance rate in the intake of medication of up to 40 % -LSB- 1 -RSB- . Experience has shown that treatment selection for patients with psoriasis vulgaris is more commonly based on traditional concepts than on evidence-based data on the efficacy of various therapeutic options . In addition , it appears that systemic therapies are occasionally not applied in situations where they are needed due to the increased effort involved in monitoring the patients for unwanted side effects and possible interactions with other drugs . Goal of the Guidelines The overall objective of the Guidelines is to provide dermatologists in clinics and private practice with an accepted and evidence-based decision-making tool for the selection and implementation of a suitable and efficacious treatment for patients with psoriasis vulgaris . The focus of the Guidelines is on the induction therapy of mild , moderate , and severe plaque-type psoriasis in adults.Physicians ' personal experiences and traditional therapeutic concepts should be supplemented and , if necessary , replaced by an evidence-based assessment of the efficacy of individual therapies in psoriasis vulgaris.The guidelines provide in-depth explanations of the available systemic and topical treatments for psoriasis , including the different photo - and photochemical therapies , and provide detailed descriptions of the administration and safety aspects.By providing background information on the profile of the available drugs , including efficacy , safety , and aspects of practicality and costs , the Guidelines should facilitate the process of selecting an appropriate treatment for each individual patient . This should help increase compliance and optimize the benefit/risk ratio of psoriasis therapies . Methods A detailed description of the methodology employed in developing the Guidelines can be found in the Method Report on the Guidelines -LRB- http://www.psoriasis-leitlinie.de -RRB- . Basis of data A systematic search of the literature was carried out in May 2005 with the objective of assessing the effectiveness of individual therapeutic options . This search yielded 6,224 publications of which 142 studies fulfilled the inclusion criteria for the Guidelines -LRB- see Box 1 -RRB- and were therefore included in the assessment of the effectiveness of the relevant treatment . Various other aspects were evaluated on the basis of information presented in available literature , without a systematic analysis , and the years of personal experience of the experts . Evidence assessment The efficacy and effectiveness of each intervention was evaluated using evidence-based criteria . The methodological quality of each individual study was assessed using the following grades of evidence -LRB- GE -RRB- : A1Meta-analysis that includes at least one randomized study with grade A2 evidence . In addition , the results of the different studies included in the meta-analysis must be consistent with one another.A2A high-quality -LRB- e.g. sample-size calculation , flow chart , intention-to-treat -LRB- ITT -RRB- analysis , sufficient size -RRB- randomized , double-blind comparative clinical study.BRandomized clinical study of lesser quality or other comparative study -LRB- non-randomized , cohort , or case-control study -RRB- . CNon-comparative study.DExpert opinion.Individual interventions -LRB- i.e. , as monotherapy -RRB- were rated according to the following levels of evidence -LRB- LE -RRB- : Intervention is supported by studies with grade A1 evidence or studies with grade A2 evidence whose results are predominantly consistent with one another.Intervention is supported by studies with grade A2 evidence or studies with grade B evidence whose results are predominantly consistent with one another.Intervention is supported by studies with grade B evidence or studies with grade C evidence whose results are predominantly consistent with one another.Little or no systematic empirical evidence Therapeutic recommendation A distinct rating of the therapeutic options or a strict clinical algorithm can not be defined for the treatment of psoriasis vulgaris . The criteria for selecting a particular therapy are complex . The decision for a specific treatment should be based on the profile of the available drugs and the characteristics of a given patient . The decision for or against a therapy remains a case-by-case decision . These Guidelines provide a reasonable form of assistance in deciding on a suitable therapy and are an instrument for optimizing the required therapeutic process . The recommendations formulated in the text are supported graphically in selected key recommendations by the following indications of the strength of the therapeutic recommendation : ↑ ↑ Measure is highly recommended ↑ Measure is recommended → Neutral ↓ Measure is not recommended ↓ ↓ Measure is highly inadvisableThe strength of the recommendation reflects both a treatment 's efficacy and the level of evidence supporting it as well as aspects of safety , practicality , and the cost/benefit ratio . A consensus on the strength of the recommendation was reached during the Consensus Conference . Results Therapeutic options are named and discussed in alphabetical order . Therapeutic strategies Fig. 1 Overview of the therapeutic options evaluated for chronic plaque psoriasis -LRB- the therapeutic options are listed alphabetically and do not represent a ranking -RRB- Evaluation of topical and systemic therapies in tabular form These tables are intended to provide a rough orientation for evaluating the therapeutic options . Cumulative calculations of the individual aspects for the overall evaluation of the therapeutic options are not possible and can not be drawn upon for the final analysis of a therapeutic option . The product assessment for each individual patient may deviate greatly . A direct comparison between systemic and topical therapies is not possible because of the different severity of the psoriasis lesions of patients treated with topical or systemic treatments . The evaluations reported here were made on the basis of data extracted from the literature and expert opinions . For further details refer to the Methods Report at www.psoriasis-leitlinie.de Topical monotherapy Phototherapy and systemic monotherapy -LRB- a -RRB- Efficacy The evaluation of the efficacy column reflects the percentage of patients who achieved a reduction in the baseline Psoriasis Area and Severity Index -LRB- PASI -RRB- of ≥ 75 % . ScaleSystemic therapyTopical therapy + + + + Approx. 90 % Approx. 60 % + + + Approx. 70 % Approx. 45 % + + Approx. 50 % Approx. 30 % + Approx. 30 % Approx. 15 % + / − Approx. 10 % Approx. 5 % -- Not definedNot defined The evidence level applies only to the estimate of efficacy . -LRB- b -RRB- Safety/tolerance in induction therapy or maintenance therapy This refers to the risk of occurrence of severe adverse drug reactions or the probability of adverse drug reactions that would result in the discontinuation of therapy . -LRB- c -RRB- Practicality -LRB- Patient -RRB- This evaluation analyzes the effort involved in handling and administrating the treatment regimen by the patient . -LRB- d -RRB- Practicality -LRB- Physician -RRB- This aspect considers the amount of work -LRB- documentation , explanation , monitoring -RRB- , personnel and equipment needs , time for physician/patient interaction , remuneration of therapeutic measures , invoicing difficulties/risk of recourse claims from the health insurance companies . -LRB- e -RRB- Cost/benefit Consideration of the costs of an induction therapy or a maintenance therapy . The evaluations of safety/tolerance in induction therapy or maintenance therapy as well as practicality for the physician or patient and the cost/benefit were performed using a scale ranging from poor -LRB- -- -RRB- to good -LRB- + + + + -RRB- . The gradation between these two extremes was made based on expert opinion and unsystematic literature search . A level of evidence was not given for these evaluations since no systematic literature review was performed . Evaluation of topical therapies Calcineurin inhibitors Table 1 Tabular summary Calcineurin inhibitors First approved in Germany Pimecrolimus -LRB- Elidel ® -RRB- 2002 -LRB- Atopic dermatitis , not approved for psoriasis vulgaris -RRB- Tacrolimus -LRB- Protopic ® -RRB- 2002 -LRB- Atopic dermatitis , not approved for psoriasis vulgaris -RRB- Recommended initial dosage Pimecrolimus cream : 1 × to 2 × dailyTacrolimus : 1 × to 2 × daily -LRB- application on the face : Begin with 0.03 % salve ; increase later dosage to 0.1 % salve -RRB- Recommended maintenance dosage Individual therapeutic adjustment Expected beginning of clinical effect After approximately 2 weeks Response rate No data available Important contraindications Pregnancy and nursing -LRB- due to lack of experience -RRB- skin infections , immune suppression Important adverse drug reactions -LRB- ADRs -RRB- Burning sensation on skin , skin infections Important drug interactions None known Other Cave : Do not combine with phototherapy ! Photoprotection ! Corticosteroids Table 2 Tabular summary Corticosteroids First approved in Germany 1956 -LRB- Psoriasis vulgaris -RRB- Recommended control parameters None Recommended initial dosage One to two times daily Recommended maintenance dosage Gradual reduction following onset of effect Expected beginning of clinical effect After 1 -- 2 weeks Response rate Betamethasone dipropionate , two times daily : marked improvement or clearance of the skin lesions in 46 -- 56 % patients after 4 weeks -LRB- LE 1 -RRB- Important contraindications Skin infections , rosacea , perioral dermatitis Important ADRs Skin infections , perioral dermatitis , skin atrophy , hypertrichosis , striae Important drug interactions None Other -- Coal tar Table 3 Tabular summary Coal tar First approved in Germany Listed active ingredient since 2000 -LRB- DAC on page 170 -RRB- , historical application , various tar-containing externals are licensed as drugs , application of tar as anti-psoriatic following publication by Goeckermann in 1925 Recommended control parameters After long-term application/application on large areas : if needed clinical controls for potential development of skin carcinoma Recommended initial dosage 5 -- 20 % salve preparations or gels for local therapy , 1 × daily Recommended maintenance dosage No long-term application -LRB- max . 4 weeks , DAC 2000 -RRB- Expected beginning of clinical effect After 4 -- 8 weeks , efficacy improves in combination with UV application Response rate There is insufficient data available on the response rate as a monotherapy -LRB- LE 4 -RRB- Important contraindications Pregnancy and nursing Important ADRs Color , odor , carcinogenic risk , phototoxicity -- which is part of the desired effect Important drug interactions Not known with topical use Other DAC 2000 -LRB- on page 170 -RRB- , Hazardous Goods Directive Appendix 4 No. 13 Dithranol Table 4 Tabular summary Dithranol First approved in Germany Psoralon 1983 -LRB- Psoriasis vulgaris -RRB- Psoradexan 1994 -LRB- Psoriasis vulgaris -RRB- Micanol 1997 -LRB- Psoriasis vulgaris -RRB- Recommended control parameters Intensity of irritation Recommended initial dosage Begin with 0.5 % preparation for long-term therapy or 1 % for short-contact therapy , then increase if tolerated Recommended maintenance dosage Not recommended for maintenance therapy Expected beginning of clinical effect After 2 -- 3 weeks Response rate Marked improvement or clearance of skin lesions in 30 -- 50 % of the patients -LRB- LE 2 -RRB- Important contraindications Acute , erythrodermic forms of psoriasis vulgaris ; pustular psoriasis Important ADRs Burning and reddening of the skin in > 10 % Important drug interactions -- Other -- Tazarotene Table 5 Tabular summary Tazarotene First approved in Germany 1997 -LRB- psoriasis vulgaris -RRB- Recommended control parameters Check development of skin irritations Recommended initial dosage Begin with one treatment daily of tazarotene gel 0.05 % in the evening for approximately 1 -- 2 weeks Recommended maintenance dosage If necessary continue for 1 -- 2 weeks with tazarotene gel 0.1 % Expected beginning of clinical effect After 1 -- 2 weeks Response rate After 12 weeks therapy with 0.1 % tazarotene gel improved findings of at least 50 % in approximately 50 % of the patients -LRB- LE 2 -RRB- Important contraindications Pregnancy , nursing Important ADRs Pruritus , burning sensation of skin , erythema , irritation Important drug interactions Avoid concomitant use of preparations with irritating and drying properties Other -- Vitamin D3 and analogues Table 6 Tabular summary Vitamin D3 and analogues First approved in Germany Calcipotriol 1992 -LRB- Psoriasis vulgaris -RRB- Tacalcitol 1994 -LRB- Psoriasis vulgaris -RRB- Calcitriol 1999 -LRB- Psoriasis vulgaris -RRB- Calcipotriol/Betamethasone 2002 -LRB- Psoriasis vulgaris -RRB- Recommended control parameters Monitor for skin irritations Recommended initial dosage Calcipotriol : 1 × to 2 × daily to affected locations , up to a maximum of 30 % of the body surface Tacalcitol : 1 × daily to affected locations , up to a maximum of 20 % of the body surface Calcitriol : 2 × daily to affected locations , up to a maximum of 35 % of the body surface Recommended maintenance dosage Calcipotriol : 1 × to 2 × daily , up to 100 g/week for up to 1 year Tacalcitol : 1 × daily for 8 weeks , for up to 18 months , on a maximum of 15 % of the body surface with up to 3.5 g daily Calcitriol : insufficient experience with the application for more than 6 weeks Expected beginning of clinical effect After 1 -- 2 weeks Response rate Between 30 and 50 % of the patients demonstrated a marked improvement or clearance of the lesions after 4 -- 6 weeks -LRB- LE 1 -RRB- Important contraindications Diseases with abnormal calcium metabolism , severe liver and renal diseases Important ADRs Skin irritation -LRB- reddening , itching , burning -RRB- Important drug interactions Drugs which elevate the calcium levels , -LRB- e.g. thiazide diuretics -RRB- , no concomitant application of topical salicylic acid preparations -LRB- inactivation -RRB- Other Exposure to UV light results in inactivation of the vitamin D3-analogues Phototherapy Table 7 Tabular summary Phototherapy First approved in Germany Clinical experience , depending on the modality for > 50 years Recommended control parameters Regular skin inspection -LRB- UV erythema -RRB- Recommended initial dosage Individual dose depends on skin type ; options : • UVB : 70 % of minimum erythema dose -LRB- MED -RRB- • Oral PUVA -LRB- photochemotherapy -RRB- : 75 % of the minimum phototoxic dose -LRB- MPD -RRB- • Bath/cream PUVA : 20 -- 30 % of MPD Recommended maintenance dosage Increase according to degree of UV erythema Expected beginning of clinical effect After 1 -- 2 weeks Response rate In > 75 % of the patients PASI , 75 after 4 -- 6 weeks -LRB- LE 2 -RRB- Important contraindications Photo-dermatoses/photosensitive diseases , skin malignancies , immunosuppressionOnly PUVA : pregnancy and nursing Important ADRs Erythema , itching , blistering , malignanciesOnly oral PUVA : nausea Important drug interactions Drugs causing phototoxicity or photoallergy Other Combination with topical preparations acts synergistically , PUVA may not be combined with cyclosporine Evaluation of systemic therapies Efalizumab Table 8 Tabular summary Efalizumab First approved in Germany September 2004 -LRB- psoriasis vulgaris -RRB- Recommended control parameters Prior to therapy exclusion of significant infections , complete blood count , liver values Recommended initial dosage 0.7 mg/kg body weight -LRB- BW -RRB- per week Recommended maintenance dosage 1 mg/kg BW per week Expected beginning of clinical effect After 4 -- 8 weeks Response rate PASI 75 for approximately 30 % of the patients after 12 weeks -LRB- LE 1 -RRB- Important contraindications -LRB- limited selection -RRB- Chronic or acute infections , pregnancy , malignant diseases , immune deficiencies , no vaccinations before or during treatment Important ADRs -LRB- limited selection -RRB- Flu-like injection reactions , leukocytosis and lymphocytosis , rebound , exacerbation and arthralgia , thrombocytopenia Important drug interactions Not known Other Stop therapy due to the risk of exacerbation and rebound if a PASI reduction of 50 % is not achieved after 12 weeks Table 9 Laboratory controls during treatment with efalizumab aHb -LRB- hemoglobin -RRB- , HCT -LRB- hematocrit -RRB- , erythrocytes , leukocytes , differential blood count , platelets bALT alanine aminotransferase , AST aspartate aminotransferase Etanercept Table 10 Tabular summary Etanercept First approved in Germany 2002 -LRB- Psoriasis arthritis -RRB- / 2004 -LRB- psoriasis vulgaris -RRB- Recommended control parameters Prior to therapy exclusion of tuberculosis , complete blood count , liver and renal values , urinanalysis Recommended initial dosage Twice 25 mg per week or 2 × 50 mg/week Recommended maintenance dosage Twice 25 mg per week Expected beginning of clinical effect After 4 -- 8 weeks , at the latest after 12 weeks Response rate PASI 75 in 34 % -LRB- 2 × 25 mg -RRB- or 49 % -LRB- 2 × 50 mg -RRB- of the patients at the end of the induction phase -LRB- 12 weeks -RRB- -LRB- LE 1 -RRB- Important contraindications -LRB- limited selection -RRB- Infections , pregnancy , nursing , heart failure NYHA III -- IV Important ADRs -LRB- limited selection -RRB- Local reactions , infections Important drug interactions -LRB- limited selection -RRB- Anakinra -LRB- IL-1 receptor antagonist -RRB- Other -- Table 11 Laboratory controls during treatment with etanercept Infliximab Table 12 Tabular summary Infliximab First approved in Germany 2004 -LRB- Psoriasis arthritis -RRB- / 2005 -LRB- psoriasis vulgaris -RRB- Recommended control parameters Prior to therapy exclusion of tuberculosis , during therapy : leukocyte and platelet counts , liver value controls , signs of clinical infection Recommended initial dosage 5 mg/kg BW at week 0 , 2 , 6 Recommended maintenance dosage 5 mg/kg BW in dosage intervals of 8 weeks Expected beginning of clinical effect After 1 -- 2 weeks Response rate PASI 75 in ≥ 80 % of the patients with moderate to severe psoriasis vulgaris -LRB- LE 1 -RRB- Important contraindications -LRB- limited selection -RRB- Acute or chronic infections , tuberculosis , cardiac failure NYHA III -- IV , pregnancy and nursing Important ADRs -LRB- limited selection -RRB- Infusion reactions , severe infections , progression of heart failure NYHA III -- IV , very rare liver failure , autoimmune phenomena Important drug interactions -LRB- limited selection -RRB- Anakinra -LRB- IL-1 receptor antagonist -RRB- Other -- Table 13 Laboratory controls during treatment with infliximab aHb , HCT , erythrocytes , leukocytes , differential blood count , platelets Cyclosporine Table 14 Tabular summary Cyclosporine First approved in Germany 1983 -LRB- Transplantation medicine -RRB- 1993 -LRB- Psoriasis vulgaris -RRB- Recommended control parameters Interview/examination : • Status of skin and mucous membranes • Signs of infection • Neurological , gastrointestinal symptoms • Blood pressure Laboratory controls : see Table 14 Recommended initial dosage 2.5 -- 3 -LRB- max . 5 -RRB- mg/kg BW Recommended maintenance dosage Interval therapy -LRB- between 8 and 16 weeks -RRB- with dosage reduction at the end of the induction therapy -LRB- e.g. , 0.5 mg/kg BW every 14 days -RRB- or Continuous long-term therapy with dosage reduction -LRB- e.g. by 50 mg every 4 weeks after week 12 -RRB- and a dosage increase by 50 mg with relapse Maximum total duration of therapy : 2 years Expected beginning of clinical effect After approximately 4 weeks Response rate Dose-dependent : after 8 -- 16 weeks with 3 mg/kg BW ; PASI 90 in approximately 30 -- 50 % of patient and PASI 75 in approximately 50 -- 70 % of patients -LRB- LE 1 -RRB- Important contraindications -LRB- limited selection -RRB- Absolute : Reduced renal function , insufficiently controlled arterial hypertension , uncontrolled infections , relevant malignancies -LRB- current or previous , in particular hematologic diseases and cutaneous malignancies with the exception of basal cell carcinoma -RRB- Relative : Relevant hepatic dysfunction , pregnancy and nursing , concomitant use of substance which interacts with cyclosporine , concomitant UV-therapy or prior PUVA-pre-therapy with cumulative dosage > 1000 J/cm ² , concomitant application of other immunosuppressives , retinoids or long-term prior-therapy with methotrexate -LRB- MTX -RRB- Important ADRs -LRB- limited selection -RRB- Renal failure , increase of blood pressure , liver failure , nausea , anorexia , vomiting , diarrhea , hypertrichosis , gingival hyperplasia , tremor , weariness , parasthesia , hyperlipidemia Important drug interactions -LRB- limited selection -RRB- Increase of the cyclosporine level -LRB- CYP3A inhibition -RRB- through : Allopurinol , calcium antagonists , amiodarone , antibiotics -LRB- macrolides , clarithromycin , josamycin , ponsinomycin , pristinamycin , doxycycline , gentamicin , tobramycin , ticarcillin , quinolones -RRB- , ketoconazole , oral contraceptives , methylprednisolone -LRB- high dosages -RRB- , ranitidine , cimetidine , grapefruit juice Decrease of the cyclosporine level -LRB- CYP3A induction -RRB- through : Carbamazepine , phenytoin , barbiturates , metamizole , St. John 's wort Possible reinforcement of nephrotoxic adverse drug reactions through : Aminoglycosides , amphotericin B , ciprofloxacin , acyclovir , non-steroidal antiphlogistics Specific interactions : Potassium-saving substances : increased risk of hyperpotassemia Reduced clearance of : Digoxin , colchicine , prednisolone , HMG-CoA reductase inhibitors -LRB- e.g. lovastatin -RRB- , diclofenac Other Increased risk of lympho-proliferative diseases in transplant patients . Increased risk of squamous cell carcinoma in psoriasis patients following excessive phototherapy . Only moderately effective in and not approved for psoriatic arthritis Also used successfully in the therapy of chronic-inflammatory diseases in children Table 15 Laboratory controls during treatment with cyclosporine aErythrocytes , leukocytes , platelets bALT , AST , AP -LRB- alkaline phosphatase -RRB- , γGT -LRB- gamma glutamyl transpeptidase -RRB- , bilirubin cSodium , potassium dRecommended twice -LRB- fasting -RRB- and week-2 and 0 eOnly with indication -LRB- e.g. muscle cramps -RRB- Fumaric acid esters Table 16 Tabular summary Fumaric acid esters First approved in Germany 1995 -LRB- Psoriasis vulgaris -RRB- Recommended control parameters Serum creatinine , transaminases/γGT , complete blood count including differential blood count , urinanalysis Recommended initial dosage According to recommended dosage regimen see Table 17 Recommended maintenance dosage Individually adapted dosage Expected beginning of clinical effect After approximately 6 weeks Response rate PASI 75 in 50 -- 70 % of the patients at the end of the induction phase after 16 weeks -LRB- LE 2 -RRB- Important contraindications -LRB- limited selection -RRB- Chronic diseases of the gastrointestinal tract and/or the kidneys and chronic diseases , which are accompanied by an impairment of the leukocyte count or functions , malignant diseases , pregnancy and nursing Important ADRs -LRB- limited selection -RRB- Gastrointestinal complaints , flush , lymphopenia , eosinophilia Important drug interactions None known Other -- Table 17 Dosage regimen for Fumaderm therapy Fumaderm initial Fumaderm Week 1 1-0-0 Week 2 1-0-1 Week 3 1-1-1 Week 4 1-0-0 Week 5 1-0-1 Week 6 1-1-1 Week 7 2-1-1 Week 8 2-1-2 Week 9 2-2-2 Table 18 Laboratory controls during treatment with fumaric acid esters aLeukocytes , platelets , erythrocytes , differential blood count Methotrexate Table 19 Tabular summary Methotrexate First approved in Germany Lantarel ® 1991 -LRB- Psoriasis vulgaris -RRB- Metex ® 7.5 / 10 mg 1992 -LRB- Psoriasis vulgaris -RRB- Metex ® 2.5 mg 2004 -LRB- Psoriasis vulgaris -RRB- Recommended control parameters Complete blood count -LRB- Hb , HCT , differential blood count , platelets -RRB- , renal function -LRB- serum creatinine , urea , urine sediment -RRB- , liver values -LRB- serum transaminases -RRB- , III-procollagen amino terminal propeptides Recommended initial dosage 5 -- 15 mg per week Recommended maintenance dosage 5 -- 22.5 mg per week depending on effect Expected beginning of clinical effect After 4 -- 8 weeks Response rate PASI 75 in approximately 60 % of the patients at the end of the induction phase of 16 weeks -LRB- LE 3 -RRB- Important contraindications -LRB- limited selection -RRB- Absolute contraindications : Desire to have children -LRB- for both men and women -RRB- , pregnancy and nursing , inadequate contraception , drug consumption , alcoholism , known sensitivity to active ingredient methotrexate -LRB- e.g. pulmonary toxicity -RRB- , bone marrow dysfunction , severe liver disease , severe infections , immunodeficiency , active peptic ulcers , hematologic changes -LRB- leucopenia , thrombocytopenia , anemia -RRB- , renal failure Relative contraindications : Kidney disorders , liver disorders , history of arsenic consumption , chronic congestive cardio-myopathy , adiposity , old age , diabetes mellitus , history of hepatitis , lack of patient compliance , ulcerative colitis , diarrhea , NSAID use , gastritis Important ADRs -LRB- limited selection -RRB- Liver fibrosis/cirrhosis , pneumonia/alveolitis , bone marrow depression , renal damage , alopecia -LRB- reversible -RRB- , nausea , weariness , vomiting , elevated transaminases , infection , gastrointestinal ulcerations , nephrotoxicity Important drug interactions -LRB- limited selection -RRB- Cyclosporine , salicylates , sulfonamides , probenecide , penicillin , colchicin , NSAIDs -LRB- naproxene , ibuprofene , etc. -RRB- , ethanol , co-trimoxazole , pyrimethamine , chloramphenicol , sulfonamides , prostaglandin synthesis inhibitors , cytostatics , probenecide , barbiturates , phenytoin , retinoids , sulfonamides , sulfonylurea , tetracyclines , co-trimoxazol , chloramphenicol , dipyridamole , retinoids , ethanol , leflunomide Other Consistent avoidance of alcohol , X-ray of the lungs prior to beginning therapy Table 20 Laboratory controls during treatment with MTX -LSB- 137 -RSB- aHb , HCT , erythrocytes , leukocytes , differential blood count , platelets bALT , AST , AP , γGT , albumin , bilirubin , lactate dehydrogenase -LRB- LDH -RRB- cLiver biopsy instead of a liver sonography in risk groups Retinoids Table 21 Tabular summary Acitretin First approved in Germany 1992 -LRB- Psoriasis vulgaris -RRB- Recommended control parameters Erythrocyte sedimentation rate -LRB- ESR -RRB- , complete blood count , liver values , renal values , blood lipid values , pregnancy test , x-ray control of the bones in case of long-term therapy Recommended initial dosage 0.3 -- 0.5 mg/kg BW per day for approximately 4 weeks , then 0.5 -- 0.8 mg/kg BW Recommended maintenance dosage Individual dosaging dependent on the results and tolerance Expected beginning of clinical effect After 4 -- 8 weeks Response rate Widely variable and dose-dependent , no definite statement possible , partial remission -LRB- PASI 75 -RRB- in 25 -- 75 % of the patients -LRB- 30 -- 40 mg per day -RRB- -LRB- LE 3 -RRB- in studies Important contraindications -LRB- limited selection -RRB- Renal and liver damage , desire to have children in female patients of child-bearing age , pregnancy , nursing , alcohol abuse , manifest diabetes mellitus , wearing of contact lenses , history of pancreatitis , hyperlipidemia requiring drug treatment Important ADRs -LRB- limited selection -RRB- Hypervitaminosis A -LRB- e.g. , cheilitis , xerosis , nose-bleeding , alopecia , increased skin fragility -RRB- Important drug interactions -LRB- limited selection -RRB- Phenytoin , tetracyclines , methotrexate , alcohol , mini-pill Other Contraception up to 2 years after discontinuation in female patients of child-bearing age aDouble contraception is recommended -LRB- e.g. , condom + pill ; IUD/Nuva-Ring + pill ; cave : no low-dosed progesterone preparations/mini-pills -RRB- during and up to 2 years after the end of therapy ; effectiveness is reduced by acitretin Table 22 Laboratory controls during treatment with Acitretin aHb , HCT , leukocytes , platelets bPreferably assayed twice -LRB- week-2 and 0 -RRB- ; HDL , high-density lipidoprotein Other therapies Climate/balneotherapy Table 23 Tabular summary Climate/balneotherapy First approved in Germany Clinical experience with balneotherapy has existed for more than 200 years Recommended control parameters Regular skin inspection Recommended initial dosage Therapy regimens vary depending on the institution/location Recommended maintenance dosage Therapy regimens vary depending on the institution/location Expected beginning of clinical effect Varies greatly Response rate Varies greatly -LRB- LE 4 -RRB- Important contraindications Dependent on modality selected Important ADRs Dependent on modality selected Important drug interactions Not applicable Other Balneotherapy and climate therapy are frequently combined Psychosocial therapy Notes on the use of the Guidelines The presentation of the therapies deliberately focused on those aspects deemed particularly relevant by a panel of experts . Aspects which are not of specific importance for a certain intervention , but which are part of the physician 's general obligations to the patient , such as the investigation of intolerance and allergies toward certain drugs or the exclusion of contraindications , are not individually listed , but it is nevertheless taken for granted that these are part of the physician 's duty to provide care . It is recommended that each and every user carefully reads and follows the product information and compare it with the recommendations in the Guidelines on dosaging , contraindications , and drug interactions for completeness and currentness . Every dose or application is administered at the user 's own risk . The authors and the publishers kindly request that users inform them of any inaccuracies that they might notice . The users are requested to keep themselves constantly informed of any new findings subsequent to the publication of the Guidelines .

O O O O O B O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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