The genetic basis for most patients with pustular skin disease remains elusive.

BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.

[Rituximab for the treatment of poly- and dermatomyositis : Results from the GRAID-2 registry]. / Rituximab zur Behandlung von Poly- und Dermatomyositis : Die Ergebnisse des GRAID-2-Registers.

INTRODUCTION: In the treatment of poly- and dermatomyositis, only a limited number of treatment modalities are established. OBJECTIVE: The goal of the GRAID-2 registry was to study off-label use of biologic drugs for this indication in Germany. PATIENTS AND METHODS: Analysis of the data of the GRAID-2 registry for poly- and dermatomyositis. RESULTS: In 22 of the 23 patients in the GRAID-2 registry, rituximab (RIX) was administered, while 1 patient was given tocilizumab as off-label therapy. The 22 patients who received RIX treatment were analyzed. At the start of treatment, the following active manifestations were present: myositis (n = 18), lung involvement (mainly interstitial lung disease; n = 10), arthritis (n = 10), skin manifestation (n = 9), and Raynaud syndrome (n = 5). Nine of the patients were Jo-1-antibody positive. All patients had previous treatments with multiple conventional immunosuppressive drugs. Treatment with RIX was given as infusions of 1 g i. v., which were repeated after 2 weeks. Patients received a mean of 3.09 ± 2.27 infusions (equivalent to 1.5 cycles of 2 × 1 g, max. 5 cycles). Tolerability of RIX treatment was rated as very good in 16 of 22 patients (72%), good in 5 (23%), and moderate in 1 (5%). In all, 27 adverse events were documented, with the majority being infections, whereby 2 severe infections occurred (6.59 per 100 patient-years). Eighty six percent of the patients showed complete remission of their myositis and 79% of their arthritis. The mean value of creatinine kinase in plasma fell from 1505 ± 2534 U/l before the start of treatment to 39 ± 134 U/l at the last visit. Regarding lung involvement, 1 of 10 of the patients showed complete and 6 of 10 partial remissions. In 2 of 10 patients, lung disease was stable during treatment. CONCLUSION: RIX is the preferred off-label biologic drug for poly- and dermatomyositis in Germany. In spite of a strongly pretreated group of patients, the tolerability is acceptable, although the patient number in this investigation is small. Moreover, the results lead to the assumption that the majority of the patients had a good or even very good therapeutic response to RIX.

[Off-label biologic therapy of ANCA-associated and non-ANCA-associated small-vessel vasculitis : Efficacy and safety analysis of a national registry (GRAID2)]. / Off-label-Biologikatherapie von ANCA-assoziierten und nicht-ANCA-assoziierten Kleingefäßvaskulitiden : Wirksamkeits- und Sicherheitsanalyse eines nationalen Registers (GRAID2).

OBJECTIVE: To evaluate the clinical efficacy and safety of off-label biological therapies in patients with ANCA-associated vasculitis (AAV) and non-ANCA-associated small-vessel vasculitis (nAAV) in clinical practice. METHODS: The German Registry in Autoimmune Diseases 2 (GRAID2) is a national, retrospective, non-interventional, multicentre observational study (August 2006 until December 2013) on patients with autoimmune diseases refractory to standard immunosuppressive therapy treated with off-label biologicals. RESULTS: Data from 64 patients (20.6% of all GRAID2 patients) were collected: 54 patients (84.4%) had ANCA-associated vasculitis (AAV) and 10 patients (15.6%) had non-ANCA-associated small-vessel vasculitis (nAAV). Of the AAV patients, 96.3% were treated off-label with rituximab (RTX) and 3.7% with tumor necrosis factor alpha (TNFα)-inhibitors. Of patients with nAAV, 30% were treated with RTX, 60% with TNFα-inhibitors, and 10% with tocilizumab. The main reasons for off-label biological treatment in AAV patients were pulmonary, renal, or ear, nose, and throat involvement. These manifestations clearly improved in most patients after off-label biological therapy was initiated. Daily glucocorticoid dosage could be reduced. The off-label biological therapy was generally well tolerated. In AAV patients, 4.18 severe infections per 100 patient years were observed. There was one death in the nAAV group caused by fungal infection and ileus. A correlation between this fatality and RTX treatment was regarded as possible. CONCLUSION: Safety and efficacy of off-label RTX-treatment in AAV-patients could be assessed in the GRAID2 data. Results point to good efficacy and safety of RTX in this special patient cohort and support the approval of RTX for AAV induction therapy.

[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

Prevalence and comorbidities in adults with psoriasis compared to atopic eczema.

BACKGROUND: Most data suggesting an association between psoriasis and cardiovascular disease (CVD) have come from specialized populations at either low or high risk of CVD. Atopic dermatitis (AD) has been associated with a number of modifiable risk factors, particularly obesity. There has been a recent controversy on the suggestion that associations with comorbidities in psoriasis may be due to overreporting or biased by disease severity and therefore not necessarily representative of the general psoriasis population. OBJECTIVES: To evaluate the prevalence of AD and psoriasis and to compare the prevalence rates of comorbidities based on a large sample of health insurance data. METHODS: Data were collected from a database of non-selected individuals from a German statutory health insurance organization that covers all geographic regions. Individuals identified by International Classification of Diseases (ICD)-10 codes applied to all outpatient and inpatient visits in the year 2009. Comorbidities were evaluated by ICD-10 diagnoses. RESULTS: The database consisted of 1 642 852 members of a German statutory health insurance. Of 1 349 671 data sets analyzed, 37 456 patients ≥18 years were diagnosed with psoriasis (prevalence 2.78%), and 48 140 patients ≥18 years of age were diagnosed with AD, equivalent to a prevalence of 3.67%. Patients with psoriasis showed increased rates of comorbidities in all age groups. Comorbidities related to the metabolic syndrome including arterial hypertension [prevalence ratio (PR), 1.94; 95% confidence interval (CI), 1.90-1.98], hyperlipidaemia (PR, 1.77; 95% CI, 1.73-1.81), obesity (PR, 1.74; 95% CI, 1.69-1.79) and diabetes mellitus (PR, 1.88; 95% CI, 1.83-1.94) were significantly more common among patients with psoriasis compared to AD. CONCLUSIONS: Diseases forming part of the metabolic syndrome showed significant lower prevalence rates in patients with AD than in patients with psoriasis. Within the limitations of secondary healthcare data, our study disproves the suggestion that associations with comorbidities in psoriasis may be biased by a higher degree of severity or overreporting.

Patient benefits in the treatment of psoriasis: long-term outcomes in German routine care 2007-2014.

BACKGROUND: Psoriasis is associated with significant patient burden. Few studies have specifically measured patient preferences and benefits. OBJECTIVES: Outcomes assessment using the Patient Benefit Index (PBI) in nationwide psoriasis surveys comparing health care in 2007 and 2014. METHODS: This was a non-interventional, cross-sectional survey conducted in 2007 and 2014 in randomly selected dermatological practices and clinics recording by a) physicians: comorbidity, clinical severity (PASI, GCA), and b) patients: quality of life (DLQI, EQ-5D), patient-relevant therapeutic benefits (PBI) and previous and curent treatments. RESULTS: In 2014, a total of n = 1265 patients (43.4% female, mean age 51.9 ± 14.3 years.; mean disease duration 21.6 ± 15.4 years.) were included. Overall PBI was 2.8 ± 1.1. A total of 91.6% of patients showed a more than minimum clinically relevant benefit (PBI>1). Patients treated with biologics and biologics combined with conventional systemics showed the highest benefit compared to patients with conventional systemic treatment and patients treated with topical steroids. In comparison with the 2007 survey (n = 2009), there was an increase in PBI from 2.5 ± 1.1 to 2.8 ± 1.1 and a gain of patients with high benefits (PBI ≥3) by 30% (38.5% vs. 49.4%). CONCLUSION: In German routine care, psoriasis patients have shown increased therapeutic benefits over time with highest benefits deriving from biologics combined with systemics.

Nail involvement as a predictor of concomitant psoriatic arthritis in patients with psoriasis.

BACKGROUND: Patients with psoriatic arthritis (PsA) suffer from increased burden of disease and impairments in quality of life. Early detection and treatment of PsA could contribute to the prevention of clinical and radiological progression. OBJECTIVES: To analyse the predictive value of clinical and patient-reported outcomes for concomitant PsA in a population-based cohort of patients with psoriasis. METHODS: We performed a retrospective analysis of data from three independent national cross-sectional studies on health care in psoriasis and PsA, conducted in Germany in the years 2005, 2007 and 2008. Patients with psoriasis were included in the study by dermatologists (n = 3520) and via the German patient advocacy group for psoriasis (n = 2449). In all studies, psoriasis history, clinical findings, PsA, nail involvement, health care and patient-reported outcomes were collected with standardized questionnaires. RESULTS: In the regression model on 4146 patients the strongest predictors for concomitant PsA were nail involvement [odds ratio (OR) 2·93, 95% confidence interval (CI) 2·51-3·42, P < 0·001] and inpatient hospital treatment (OR 1·63, 95% CI 1·38-1·93, P < 0·001). By contrast, scalp involvement was not a significant predictor. CONCLUSIONS: Patients with psoriasis seen by dermatologists and those in patient advocacy groups show clinical indicators of PsA, the most predictive being nail disease. In practice, a comprehensive assessment of clinical findings associated with PsA is needed.

[Rituximab for treatment of Felty's syndrome]. / Rituximab zur Therapie des Felty-Syndroms.

Felty's syndrome is a rare variant of severe seropositive rheumatoid arthritis with neutropenia and splenomegaly. It is difficult to treat and associated with a poor prognosis due to the substantial risk of infections. This article presents the case of a patient with refractory disease who responded to rituximab with permanent normalization of neutrophil counts. Repeated infusions were necessary to induce and maintain remission.

The 2009 influenza A (H1N1) pandemic. Management and vaccination strategies in The Netherlands.

Prior to 2009, The Netherlands had prepared itself extensively for a potential pandemic. Multidisciplinary guidelines had been drafted to control transmission and limit adverse outcomes for both a phase of early incidental introduction and for a phase with widespread transmission. The Ministry of Health had ensured a supply and distribution schedule for antivirals and negotiated a contract for vaccine purchases. During the pandemic, existing surveillance was expanded, the established infectious disease response structure was activated, and the previously prepared protocols for communication, diagnostics, use of antivirals, and vaccination implementation were operationalized and implemented. When the pandemic turned out to be less severe than many had anticipated, risk communication and rapid modification of guidelines and communication became a major challenge. Antivirals and pandemic vaccines were reserved for those at high risk for severe outcomes only. Overall, the impact of the pandemic was comparable to the impact of an average seasonal influenza epidemic, but with a shift in (severe) outcomes from the very young and elderly toward young adults. Established prepared protocols enabled timely coordinated responses. In preparing for the worst, sufficient attention must be given to preparing for a mild scenario as well.

[Interleukin-1-mediated diseases]. / Interleukin-1-vermittelte Erkrankungen.

Interleukin-1 (IL-1)-mediated diseases are caused by an inappropriately high production and release of IL-1 beta which results in a multitude of symptoms, e.g. arthritis, exanthema, conjunctivitis, serositis, fever and loss of hearing. If IL-1-mediated diseases remain unrecognized or are recognized and treated too late, long-term complications, such as amyloidosis may occur. In recent years the diagnostic and therapeutic options with respect to IL-1-mediated diseases have drastically improved. These diseases often manifesting in childhood can now be treated with monoclonal antibodies against IL-1 or with IL-1 receptor antagonists. Increased IL-1 secretion does not only play a role in relatively rare hereditary diseases, such as cryopyrin-associated periodic fever syndromes or familial Mediterranean fever but also in widespread diseases, such as gout or type 2 diabetes. This article will focus on pathogenic, diagnostic and therapeutic aspects of IL-1-mediated inflammatory diseases.

Current state of evidence on 'off-label' therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland--a consensus report.

Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence.

Bullous cryothermic dermatitis artefacta induced by deodorant spray abuse.

BACKGROUND: Dermatitis artefacta belongs to a broad spectrum of factitious diseases of lesions usually self-induced by patients. Here we report a surprisingly effective induction of blisters and thermic dermatitis by excessive abuse of common deodorant sprays. OBJECTIVES: We evaluated the clinical course and outcome in three patients with dermatitis artefacta induced by deodorant spray. METHODS: A 12-year-old boy only admitted the abuse of deodorant spray after psychiatric intervention. Two adults (21-year-old and 37-year-old women) had borderline personality disorder and frankly reported the urge to induce pain by spraying for at least 100 s at a short distance. RESULTS: Bullous dermatitis was the acute presenting sign in all patients. The bullae were found on the extensor surfaces of the extremities, with a distribution of older lesions showing erosions and scarring and fresh lesions with intact bullae with a diameter of 3-15 cm. After searching for the causative agent and removal of the deodorant spray, clinical outcome showed a healing without and with scars. CONCLUSIONS: Cryo-damage by abuse of common deodorant sprays seems to become a popular mechanism by which an impressive bullous dermatitis can be artificially induced. Dermatologists and psychiatrist should be aware of this method of injury.

[Patient/rheumatologist evaluation of infusion treatment for rheumatoid arthritis]. / Bewertung einer Infusionbehandlung der rheumatoiden Arthritis durch Patienten und Rheumatologen.

OBJECTIVES: The various biologic agents currently available for the treatment of RA can be administered subcutaneously (s.c.) or via intravenous (i.v.) infusion with variable intervals depending on the drug. This investigation aims to identify the preferences and concerns of affected patients and their physicians. METHODS: We conducted a survey of 102 patients with RA currently receiving Rituximab (RTX) therapy. They were asked about different aspects of their current and previous RA therapy, including overall satisfaction, tolerability, mode of drug administration, as well as duration and intervals. In addition, 17 rheumatologists were asked about different aspects of s.c. or i.v. drug administration, their preference and the suspected preference of their patients. RESULTS: The mean age of our patients was 59 ± 11.2 years. Patients had failed ≥2 DMARD therapies and ≥ 1 biologic treatment. The impact of RTX infusions on planning different activities including job, hobbies or travelling was considered as low or very low in 76% of the respondents. Interestingly, 63.4% of patients would prefer an infusion every 6-9 months as RA therapy, whereas 21.5% would prefer tablets only; 12.9% of our patient cohort would prefer s.c. injections every second week, and only 2% would prefer an infusion every month. In all, 92% of patients questioned would choose RTX therapy again. In contrast, 88% of rheumatologists preferred s.c. injection and even 94% of them assumed that their patients would do so as well if they had the choice. The suggested reasons included greater flexibility, convenience and independence during s.c. therapy. CONCLUSION: Contrary to the assumption of rheumatologists, we have demonstrated a preference among RTX patients for i.v. drug administration every 6-9 months over other methods of administration.

[Screening questionnaire for documentation of medical history and diagnostic findings in dry eye disease]. / Erhebungsbogen zur Anamnese und Diagnostik des trockenen Auges.

Keratoconjunctivitis sicca is one of the most common ocular diseases world-wide. These patients suffer from severe symptoms which lead to an extremely reduced quality of life. Dry eye syndrome constitutes a major diagnostic and therapeutic challenge to all ophthalmologists because there is often a discrepancy between objective ocular signs and subjective symptoms of the patients. Furthermore, there exist only few causal therapeutic options. The physician-patient relationship plays an outstanding role in this condition. For the treatment of moderate to severe dry eye syndrome, special dry eye clinics have proved to be extremely useful. For follow-up measurements as well as the realisation of evidence-based medicine and quality control, it is a fundamental necessity to document symptoms, signs and therapy of these patients in order to optimise therapeutic strategies. For this purpose, we have developed special forms and standardised questionnaires for the individual documentation of medical history and diagnostic findings. To objectively assess the patient's complaints we use the "ocular surface disease index" (OSDI score). Only the establishment of standardised diagnostic and therapeutic algorithms with the help of special forms and questionnaires can help in the long run to improve the treatment of these severely affected patients.

Human autoantibody to defensin: disease association with hyperreactive onchocerciasis (sowda).

Chronic hyperreactive onchodermatitis (sowda) is a severe form of onchocerciasis observed in a subset of individuals infected with the filarial nematode Onchocerca volvulus. SDS-PAGE and immunoblot analyses of O. volvulus adult worm extracts were used to characterize the antigens of the marked antibody response of sowda patients. One 2.5-kD antigen was recognized by sera from all 35(100%) sowda patients that were studied. In comparison, only 7 of 44 (16%) patients with generalized onchocerciasis and 11 of 21 (52%) of exposed individuals with no microfilariae in skin snips and no signs of disease showed reactivity to this antigen. Microfilaricidal treatment of sowda patients with improvement of the clinical status was associated with a decrease or disappearance of antibodies to the 2.5-kD antigen. Amino acid sequencing of the antigen indicated identity to human defensins 1-3 of neutrophils. Defensin was demonstrated by immunohistochemical staining in onchocercal nodules on the surface of adult filariae and in the surrounding tissue. A similar staining pattern was observed for other proteins present in neutrophils such as myeloperoxidase, elastase, and the L-1 protein complex (MRP 8/MRP 14), indicating that neutrophils, macrophages, and their proteins predominate in the environment adjacent to the worms. These results demonstrate an association between the presence of autoantibodies to defensins and an infectious disease of known etiology. The association with a particular form of onchocerciasis, sowda, suggests a link between formation of autoantibodies to defensin and enhanced immune reactivity towards the parasite.

HLA-DRhigh/CD27high plasmablasts indicate active disease in patients with systemic lupus erythematosus.

OBJECTIVES: Monitoring of peripheral B-cell subsets in patients with systemic lupus erythematosus (SLE) revealed an activity-related expansion of CD27(++)CD20(-)CD19(dim) Ig-secreting cells. A similar subset has also been identified 6-8 days after tetanus/diphtheria vaccination in normal individuals and in patients with infectious disease. METHODS: This subset was analysed further focussing on the HLA-DR surface expression in a cohort of 25 patients with SLE. RESULTS: This study revealed that 86% (range 59-97%) of CD27(++)CD20(-)CD19(dim) cells express high levels of HLA-DR, are also expanded in the bone marrow, and represent plasmablasts enriched with anti-dsDNA secreting cells. The remaining CD27(++)CD20(-)CD19(dim) cells were HLA-DR(low) and represent mature plasma cells. Importantly, HLA-DR(high) plasmablasts showed a closer correlation with lupus activity and anti-dsDNA levels than the previously identified CD27(++)CD20(-)CD19(dim) cells. CONCLUSION: HLA-DR(high)CD27(++)CD20(-)CD19(dim) plasmablasts represent a more precise indicator of lupus activity and suggest that there is an overproduction or lack of negative selection of these cells in SLE.

Expression pattern differences between osteoarthritic chondrocytes and mesenchymal stem cells during chondrogenic differentiation.

OBJECTIVE: The use of mesenchymal stem cells (MSCs) for cartilage regeneration is hampered by lack of knowledge about the underlying molecular differences between chondrogenically stimulated chondrocytes and MSCs. The aim of this study was to evaluate differences in phenotype and gene expression between primary human chondrocytes and MSCs during chondrogenic differentiation in three-dimensional (3D) pellet culture (PC). MATERIALS AND METHODS: Chondrocytes isolated from cartilage samples obtained during total knee alloarthroplastic procedure (N=8) and MSCs, purified from bone marrow aspirates of healthy donors (N=8), were cultivated in PC under chondrogenic conditions. Immunohistology and quantitative reverse transcribing PCR (RT-PCR) were performed for chondrogenic-specific markers (i.e., Sox9, Collagen II). Global gene expression of the so-cultivated chondrocytes and MSCs was assessed by a novel approach of microarray-based pathway analysis. Refinement of data was done by hypothesis-driven gene expression omnibus (GEO) dataset comparison. Validation was performed with separate samples in transforming growth factor (TGF)ß+ or TGFß- conditions by use of quantitative real-time RT-PCR. RESULTS/CONCLUSIONS: Chondrogenic commitment of both cell types was observed. Interestingly, chondrocytes demonstrated an upregulated fatty acid/cholesterol metabolism which may give hints for future optimization of culture conditions. The novel microarray-based pathway analysis applied in this study seems suitable for the evaluation of whole-genome based array datasets in case when hypotheses can be backed with already existing GEO datasets. Future experiments should further explore the different metabolic behaviour of chondrocytes and MSC.

Cancer-associated fibroblasts of the prostate promote a compliant and more invasive phenotype in benign prostate epithelial cells.

Reciprocal interactions between prostate epithelial cells and their adjacent stromal microenvironment not only are essential for tissue homeostasis but also play a key role in tumor development and progression. Malignant transformation is associated with the formation of a reactive stroma where cancer-associated fibroblasts (CAFs) induce matrix remodeling and thereby provide atypical biochemical and biomechanical signals to epithelial cells. Previous work has been focused on the cellular and molecular phenotype as well as on matrix stiffness and remodeling, providing potential targets for cancer therapeutics. So far, biomechanical changes in CAFs and adjacent epithelial cells of the prostate have not been explored. Here, we compared the mechanical properties of primary prostatic CAFs and patient-matched non-malignant prostate tissue fibroblasts (NPFs) using atomic force microscopy (AFM) and real-time deformability cytometry (RT-FDC). It was found that CAFs exhibit an increased apparent Young's modulus, coinciding with an altered architecture of the cytoskeleton compared with NPFs. In contrast, co-cultures of benign prostate epithelial (BPH-1) cells with CAFs resulted in a decreased stiffness of the epithelial cells, as well as an elongated morphological phenotype, when compared with co-cultures with NPFs. Moreover, the presence of CAFs increased proliferation and invasion of epithelial cells, features typically associated with tumor progression. Altogether, this study provides novel insights into the mechanical interactions between epithelial cells with the malignant prostate microenvironment, which could potentially be explored for new diagnostic approaches.

[Systemic lupus erythematosus. Target criteria for treatment]. / Systemischer Lupus erythematodes. Zielkriterien der Behandlung.

Systemic lupus erythematosus (SLE) is a chronic systemic intermittent autoimmune disease, which can affect nearly all organ systems. The disease is characterized by the detection of more than 100 different auto-antibodies. For the clinical practice as well as in controlled clinical studies it is absolutely necessary to define target criteria which allow the evaluation of the effectiveness of therapy. Many instruments are available for measuring the activity of the disease, the quality of life, the extent of irreversible damage and the individual manifestation in organs. There are also now various biomarkers to characterize the pathophysiologic aspects, clinical activity, therapeutic effectiveness and prognosis.