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Biomedical subjects

U Müller-Ladner

Publications and source records attributed to U Müller-Ladner.

At least 37 records · Page 2Linked to original sources
PubMed2005

Predictive and potentially predictive factors in early arthritis: a multidisciplinary approach.

OBJECTIVES: Rheumatoid arthritis (RA) is characterized by variable degrees of joint inflammation, joint destruction, progressive disability and premature death. Destruction of joint cartilage and bone may occur early during disease, as was shown in longitudinal studies of RA, and there is increasing consent among rheumatologists that early diagnosis and early initiation of therapy with disease-modifying anti-rheumatic drugs (DMARDs) can limit the severity of RA. Unfortunately, the currently used diagnostic and predictive indicators (clinical, laboratory and radiological) are of limited value for making an early diagnosis and prognosis of the disease course at the individual level, thus reducing optimal benefit from present and emerging therapies. Therefore, this review focuses on the multidisciplinary aspects of neuroendocrine-immune changes in RA. METHODS: A Medline search was performed using the search terms 'androgens', 'estrogens', 'sympathetic nervous system', 'sensory nervous system', 'prognosis', 'early rheumatoid arthritis', 'arthritis' and 'studies' in various combinations. For the tabular overview, we only listed clinical studies focusing on endocrine and neuronal aspects. RESULTS: In addition to the currently used predictive indicators, there is an abundant body of literature describing changes of the neuronal, endocrine and immune parameters during inflammatory diseases. Unfortunately, no longitudinal studies concerning neuroendocrine aspects have been done up to now. CONCLUSION: Parameters of the neuroendocrine system should be included in anticipated longitudinal clinical studies to find their true predictive value in early RA.

Arthritis, Rheumatoid↗
PubMed2005

Successful treatment of psoriatic onycho-pachydermo periostitis (POPP) with adalimumab.

Psoriatic onycho-pachydermo periostitis (POPP) is recognized as a rare subset of psoriatic arthritis, characterized by psoriatic onychodystrophy, connective tissue thickening above the distal phalanx, and a periosteal reaction. Therapy for this rare disease is based on treatments used for psoriatic arthritis, but traditional disease-modifying antirheumatic drugs, such as sulfasalazine and methotrexate, have shown inconsistent and unsatisfactory results. We report herein a successful therapeutic approach for POPP using the fully human anti-tumor necrosis factor (TNF) antibody adalimumab in a 42-year-old male patient. After 4 months of anti-TNF treatment, a remarkable normalization of the clinical appearance was achieved and magnetic resonance imaging showed complete resolution of the initial inflammatory lesions. Therefore, we consider a TNF-blocking strategy as promising for treatment of POPP.

Adalimumab↗
PubMed2005

[Pathogenesis of RA: more than just immune cells].

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that primarily affects the joints and results in their progressive destruction. Research during past years has shown that in addition to inflammatory cells and their mediators, resident fibroblasts of the synovial membrane play an important role in the pathogenesis of the disease. These cells exhibit features of stable cellular activation that is maintained in the absence of continuous inflammatory stimuli. In contrast to normal synovial fibroblasts or fibroblasts from patients with osteoarthritis, RA synovial fibroblasts show an upregulation of proto-oncogenes and transcription factors, which in a self-perpetuating manner mediate the expression of adhesion molecules and matrix degrading enzymes, and result in alterations in apoptosis. As a consequence, these activated fibroblasts attach to cartilage and bone and progressively destroy articular structures. A better understanding of the molecular mechanisms that lead to the stable activation of synovial fibroblasts in RA is, therefore, of utmost importance for elucidating the pathogenesis of RA as well as for the development of novel therapeutic strategies aimed at inhibiting joint destruction.

Animals↗
PubMed2005

Caucasian patients with type 2 diabetes mellitus have elevated levels of monocyte chemoattractant protein-1 that are not influenced by the -2518 A-->G promoter polymorphism.

AIM: To investigate the association of serum levels and the -2518 A-->G promoter polymorphism of the gene for chemokine monocyte chemoattractant protein-1 (MCP-1), a major chemoattractant of monocytes and activated lymphocytes, with metabolic parameters as well as insulin, leptin and the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in 534 Caucasian patients with type 2 diabetes mellitus. METHODS: MCP-1 concentrations were measured by enzyme-linked immunosorbent assay. MCP-1 genotyping was performed by RFLP analysis in a subset of 426 patients. RESULTS: Two hundred and thirty-one (54.2%) patients were homozygous for the wildtype allele (AA), 156 (36.6%) were heterozygous (AG) and 39 (9.2%) were homozygous for the mutated allele (GG). Allelic frequency was similar to non-diabetic populations (wildtype allele A: 0.73; mutated allele G: 0.27). MCP-1 mean concentrations and percentiles were substantially higher in non-diabetic populations but were not influenced by the genotype (AA: 662.0 +/- 323.0 pg/ml; AG: 730.6 +/- 491.4 pg/ml; GG: 641.2 +/- 323.8 pg/ml). MCP-1 serum levels and genotypes were only marginally related to hormones (insulin and leptin) and cytokines (TNF-alpha and IL-6). CONCLUSIONS: This is the first study providing MCP-1 levels, percentiles and genotype frequency in a large and representative cohort of patients with type 2 diabetes mellitus. Compared to the literature, MCP-1 levels were found to be substantially higher in patients with type 2 diabetes mellitus. In contrast, genotype frequencies were similar compared to those in non-diabetic patients and were not related to MCP-1 levels. The mechanisms behind these elevated MCP-1 serum levels in type 2 diabetes are not to be explained by simple associations with hormones, cytokines or genotypes.

Aged↗
PubMed2004

Treatment of active psoriatic arthritis with the PPARgamma ligand pioglitazone: an open-label pilot study.

OBJECTIVES: Psoriatic arthritis (PsA) is an inflammatory joint disease, in which early neovascularization of affected skin and synovial tissue represents an important pathogenetic step in the disease process. Activation of the peroxisome proliferator activated receptor gamma (PPARgamma) showed anti-inflammatory effects in several in vitro and in vivo models (e.g. collagen-induced arthritis) by inhibition of angiogenesis and suppression of proinflammatory cytokines. Therefore, we studied the use of pioglitazone, a PPARgamma agonist originally developed for the treatment of diabetes, in patients with PsA. METHODS: Ten patients with active PsA, seven males and three females, who showed at least two tender and two swollen joints despite stable treatment with an NSAID, were enrolled in this open-label study. All patients received a daily dose of 60 mg pioglitazone while continuing their current NSAID therapy. The primary endpoint was the PsARC (Psoriatic Arthritis Response Criterion); the secondary endpoints included the ACR20 response and improvement in the Psoriasis Area and Severity Index (PASI) in patients with more than 2% skin involvement. Patients were evaluated for endpoints at baseline and after 12 weeks. RESULTS: After 12 weeks, six of 10 patients met the PsARC. The ACR20 response was achieved in five patients. The mean percentage reduction in PASI was 38%, with a clinically meaningful PASI 50 response in two of six patients. Median tender joint count (interquartile range) decreased from 12.0 (8.0-18.0) to 4.0 (2.0-10.0), and the median swollen joint count from 5.0 (4.0-8.0) to 2.0 (1.0-7.0) (P<0.05 for both). Median Health Assessment Questionnaire score changed from 1.0 (0.375-1.375) to 0.75 (0.375-1.0) (P<0.05). Three patients had to be withdrawn from the study due to inefficacy and side-effects. Major side-effects were oedema of the lower extremities and increase in weight. CONCLUSIONS: Treatment with a PPARgamma agonist appears to be a promising therapeutic principle in PsA, but the use of PPARgamma ligands might be limited by side-effects such as increase in weight and fluid retention.

Adult↗
PubMed2004

Albumin-coupled methotrexate (MTX-HSA) is a new anti-arthritic drug which acts synergistically to MTX.

OBJECTIVE: To evaluate the anti-arthritic effects of the new inflammation-targeted drug MTX-HSA and to investigate whether peripheral blood mononuclear cells (PBMC) are potential target cells for albumin-mediated drug delivery. METHODS: The murine model of collagen-induced arthritis (CIA) was used to measure the anti-arthritic effect of MTX, MTX-HSA or a combination of both (n = 30 to 35 per group). In addition, the uptake of fluorescence-labelled albumin (AFLc-HSA) in PBMC of 14 patients with RA was measured by fluorescence-activated cell sorting (FACS). RESULTS: In equivalent doses of 7.5 mg/kg intravenously (IV) twice a week, MTX-HSA is significantly (P<0.02) superior to MTX in inhibiting the development of CIA and reducing the joint count as well as the number of affected paws. When given in lower doses as combination therapy, both drugs act synergistically (P<0.03). A mean of 96, 72 and 64% of the CD14-, CD16- and CD20-positive cells from peripheral blood of rheumatoid arthritis (RA) patients showed an uptake of albumin after incubation with AFLc-HSA in vitro. This finding was not significantly different in comparison to healthy controls. In contrast, the number of CD3-positive cells taking up albumin is increased significantly in RA patients in comparison to controls (26.3 +/- 12.9% s.d. vs 11.6 +/- 7.3% s.d.; P = 0.005). CONCLUSION: The data show that the effectiveness of MTX-HSA in CIA is superior to MTX and that both drugs act synergistically. In addition, albumin appears to be taken up by peripheral blood cells, suggesting that they might be one of the potential target cells of this novel anti-arthritic treatment approach.

Animals↗
PubMed2004

[Diagnosis and therapy of rheumatoid arthritis].

In the past years, the substantially increased number of potent drugs for the therapy of rheumatoid arthritis has made the goal of an early, highly effective therapy more feasible. In addition, combination therapy trials including biologics revealed that joint protection and downregulation of inflammation can be achieved also in stages of active articular destruction, and the detection of novel markers such as antibodies against cyclic citrullinated peptides supports an earlier diagnosis of the disease. The price for these advances, however, are more complex, demanding and expensive therapeutic regimens that need to be handled carefully by the rheumatologist, especially with regard to a new field of side effects inherent with the use of TNF inhibiting agents. Finally, the current therapeutic standard includes also the ongoing clinical and scientific exchange with the orthopedic surgeon to optimize the long-term treatment for the individual patient.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Role of specificity protein-1, PPARgamma, and pituitary protein transcription factor-1 in transcriptional regulation of the murine CORS-26 promoter.

The collagenous repeat-containing sequence of 26-kDa protein (CORS-26) was recently described as a new gene that is induced during adipocyte differentiation. Since the transcription factors specificity protein-1 (SP-1) and PPARgamma have been demonstrated to modulate transcriptional activation of adipocytic genes, we investigated the putative role of SP-1 and PPARgamma in the regulation of the murine CORS-26 promoter. Computer-based sequence analysis revealed two putative SP-1 binding sites and binding sites for PPARgamma and Pit-1 within the TATA-box containing promoter. Electrophoretic mobility shift assays (EMSA) with nuclear extracts from 3T3-L1 adipocytes and appropriate promoter fragments demonstrated that SP-1 binds specifically to both SP-1 binding sites. Specificity was demonstrated by (i) the appearance of supershift bands, (ii) competition experiments and, (iii) by using oligonucleotides carrying mutated SP-1 binding sites. Functional promoter activity was analyzed by Luciferase reporter gene assays and SP-1 was shown to exert inhibitory effects on the transcriptional activation of the murine CORS-26 gene. Additionally, specific binding activity of PPARgamma and Pit-1 to the CORS-26 promoter was demonstrated. Taken together, the present data demonstrate the functionality of the proximal murine CORS-26 promoter, which is regulated specifically by two SP-1 binding sites via SP-3-independent repressive effects of SP-1 on transcriptional activation. Pit-1 and PPARgamma can bind specifically to the promoter and might play an additive functional role in gene regulation of murine CORS-26.

3T3-L1 Cells↗
PubMed2004

[33-year old patient with thoraco-abdominal pain and differences of blood pressure].

We report on a 33-year-old women with ulcerative colitis, who presented with inspiratory thoracic pain due to perimyocarditis. Furthermore, postprandial abdominal pain associated with diarrhea and different blood pressure values on both arms were recorded. Computed tomography revealed embolism of the pulmonal arteries and angiography demonstrated stenoses of the subclavian and renal arteries and the celiac trunc suggesting the diagnosis of Takayasu's arteritis. A coronary or infectious etiology could be excluded. Since a coincidence of Takayasu's arteritis and ulcerative colitis has been reported in the literature, abdominal pain and diarrhea can either be explained by the inflammatory bowel disease or by chronic ischemia due to intestinal vasculitis. Differential diagnosis will be facilitated by the future course of the disease.

Abdominal Pain↗
PubMed2004

[Are "biologics" in the treatment of rheumatoid arthritis really cost effective?].

Since the biologics have been introduced in clinical rheumatology, the landscape for medication of rheumatoid arthritis has changed substantially. A completely new family of drugs had to be evaluated for efficacy with regard to its impact on amelioration of disease activity but also with regard to long-term side effects and costs. This evaluation of effectiveness of biologics belongs to the most intensively discussed topics in rheumatology, and at present, only for the clinical side adequate answers can be obtained from the published data. On the other hand, more long-term observation and prospective studies are needed to be able to answer the question of real cost-effectiveness adequately. However, when all current data are summarized, the cost for a TNF-inhibitor in regard of one quality-adjusted life-year ranges below the internationally recommended critical amount of 40,000 euro.

Antirheumatic Agents↗
PubMed2004

[A synopsis of medication for degenerative osteoarthritis].

Drug treatment options should be used before starting operative procedures for degenerative osteoarthritis. The directed use of drugs helps to convert activate arthritis to the asymptomatic phase. This article summarizes guidelines and gives an overview of the effects and problems.

Adrenal Cortex Hormones↗
PubMed2004

Targeting cathepsin L (CL) by specific ribozymes decreases CL protein synthesis and cartilage destruction in rheumatoid arthritis.

The present study was undertaken to examine whether ribozymes cleaving specifically cathepsin L (CL) mRNA are able to decrease the synthesis of CL protease in rheumatoid arthritis synovial fibroblasts (RA-SF) and thereby reduce the invasiveness into cartilage both in vitro and in the SCID mouse coimplantation model of RA. Two different ribozymes that cleave CL mRNA specifically at positions 533 (RzCL533) and 790 (RzCL790) were generated. Using retroviral gene transfer, RA-SF were transduced with the ribozyme constructs or the empty vector. To examine the effect of the ribozymes on the mRNA level, quantitative analysis for CL mRNA was performed using real-time PCR. For evaluation on the protein level, ELISA using specific anti-CL antibodies was performed. In addition, transduced RA-SF were examined in vitro in a three-dimensional destruction assay evaluating their ability to degrade extracellular matrix produced by human chondrocytes. Matrix destruction was monitored by the release of soluble glycosaminoglycans (sGAG). Using the in vivo SCID mouse coimplantation model of RA, RzCL533-transduced RA-SF and control cells were coimplanted with human cartilage for 60 days. After being killed, invasion of RA-SF into the cartilage was evaluated by using a semiquantitative score. Transduction of RA-SF with RzCL533 and RzCL790 ribozymes decreased significantly the expression of CL mRNA to 44% (range 25-62%) and 20% (range 1-43%), respectively, when compared to mock-transduced cells. The protein concentration of CL in the cell culture supernatants of transduced RA-SF was decreased from 16.0 ng/ml in the mock constructs to 4.1 and 8.2 ng/ml (mean), respectively. Using the in vitro cartilage destruction assay, the release of sGAG decreased to 46 and 60%, respectively, after 14 days when compared to mock-transduced cells. In the SCID mouse coimplantation model of RA, RzCL533-transduced RA-SF revealed a significant lower cartilage invasion when compared to mock and untransduced cells. Using retroviral gene transfer, ribozymes cleaving CL mRNA inhibit specifically the synthesis of this matrix-degrading enzyme and reduce cartilage destruction in in vitro and in vivo models. Our study therefore suggests that ribozymes targeting CL could be a novel and efficient tool to inhibit joint destruction in RA.

Animals↗
PubMed2004

[Interdisciplinary management of pregnant women with connective tissue diseases].

Connective tissue diseases affect frequently women during the childbearing period. As fertility is not considerably reduced in these patients, monitoring and treatment of a pregnant patient is a complex clinical setting that requires an intensive cooperation between gynecologists, rheumatologists and pediatricians. In this article, a 4-point-program for the clinical management of these patients is presented that addresses specifically the problems inherent with the identification of patients with connective tissue diseases, preconceptional diagnostics as well as monitoring and treatment during pregnancy and the postpartal period. Clinical aspects that are intensively discussed include immunosuppressive therapy during pregnancy, the management of antiphospholipid antibody-dependent problems and the prophylaxis and treatment options for congenital heart block.

Antiphospholipid Syndrome↗
PubMed2004

Identification of influencing variables on adiponectin serum levels in diabetes mellitus type 1 and type 2.

BACKGROUND: Adiponectin represents an adipocyte-specific secretory protein that has been discussed recently as candidate gene and promising new drug target to restore insulin sensitivity in diabetes mellitus type 2. AIM: The aim of the present study was to define influencing variables on adiponectin serum levels in a large cohort of caucasian patients with type 1/type 2 diabetes and healthy controls. Additionally, adiponectin gene polymorphisms (Tyr111His and Gly15Gly) were investigated for possible associations with adiponectin serum levels. METHODS: Adiponectin serum concentrations were measured in a metabolically well characterized cohort of 892 caucasian patients (556 with type 2 diabetes, 118 with type 1 diabetes, 218 controls) by ELISA. Gene polymorphisms were determined by PCR-based RFLP. RESULTS: 1) Adiponectin values are dependent on gender with higher levels in diabetic females than in diabetic males. This gender-specific effect was only restricted to patients with diabetes and cannot be observed in controls. 2) In contrast to previous studies, the presence of diabetes does not influence adiponectin serum levels after correction for BMI. In addition, age has no influence on adiponectin levels. 3) Adiponectin levels are dependent on renal function at a creatinine clearance < 45 ml/min. 4) Regression analysis showed a significant, but only weak correlation between BMI and adiponectin in patients with diabetes mellitus type 2 (r = 0.47) and type 1 (r = 0.57). 5) Adiponectin gene polymorphisms (Tyr111His and Gly15Gly) do not influence adiponectin levels. CONCLUSIONS: Adiponectin serum concentrations can only be interpreted after careful correction for gender and renal function, whereas the genetic variants Tyr11His and Gly15Gly do not seem to play a role. The correlation between BMI and adiponectin was weaker than expected in diabetic patients.

Adiponectin↗
PubMed2004

Identification of variables influencing resistin serum levels in patients with type 1 and type 2 diabetes mellitus.

BACKGROUND: Resistin, a peptide hormone, has been discussed controversially as a missing link between obesity and insulin resistance. In contrast to resistin mRNA expression in adipose tissue, data on human serum levels in obesity and diabetes mellitus is scarce. The physiological range of serum resistin levels, reference values or adjusted percentiles have not yet been determined, making the interpretation of serum resistin concentrations quite difficult. METHODS: Resistin serum concentrations were measured systematically by ELISA in 216 healthy controls, 555 patients with type 2 diabetes and 114 patients with type 1 diabetes. Mean values, median, and range were determined, and BMI-, gender-, and disease-adapted percentiles were calculated for all subgroups. RESULTS: Age and gender did not have any influence on resistin levels. BMI and resistin levels were positively correlated in healthy controls (p = 0.02), albeit with a weak correlation coefficient. This correlation was absent in patients with type 1 and type 2 diabetes. In both genders, healthy controls had significantly higher resistin levels than patients with type 1 and type 2 diabetes (7.9 +/- 0.2 ng/ml vs. 5.7 +/- 0.2 ng/ml and 5.5 +/- 0.1 ng/ml, respectively; p < 0.0001). There was no correlation between resistin levels and occurrence of diabetic retinopathy or nephropathy. CONCLUSIONS: Serum resistin levels can be measured by ELISA over a broad range from 0.6 ng/ml up to 27.7 ng/ml, suggesting that percentiles might be helpful in the interpretation of an individuals resistin value. While age and gender do not influence resistin levels, BMI and occurrence of diabetes have to be considered.

Adolescent↗
PubMed2004

Differential adherence of osteoarthritis and rheumatoid arthritis synovial fibroblasts to cartilage and bone matrix proteins and its implication for osteoarthritis pathogenesis.

In osteoarthritis (OA), cartilage and bone fragments have been described within the synovial tissue which are surrounded by synovial cells (i.e. detritus synovitis). These cells appear to attach actively to the cartilage and bone fragments. In rheumatoid arthritis (RA), on the other hand, synovial fibroblasts (SF) have also been shown to be localized at sites of invasion into cartilage and bone and to degrade extracellular matrix (ECM) by secreting proteolytic enzymes. One prerequisite for exerting their aggressive properties is the attachment to cartilage and bone ECM. This attachment appears to be mediated by the expression of different adhesion molecules for which corresponding binding sites on ECM components are known. As it has not been addressed to which ECM proteins SF adhere and with which affinity this process takes place, we investigated the adherence of SF from patients with OA and RA to different cartilage and bone matrix proteins. Synovial tissue samples were obtained during synovectomy or arthroplastic surgery and used for isolating and culturing SF. Synovial cells attaching to cartilage/bone fragments were characterized using immunohistochemistry. The adherence of SF to ECM proteins was examined using an adhesion assay with the following proteins coated on 96-well plates: aggrecan (AGG), bone sialoprotein (BSP), cartilage oligomeric matrix protein (COMP), collagen type I, II and VI, proline arginine-rich, end leucine-rich repeat protein (PRELP), osteopontin (OPN) and recombinant chondroadherin (CHAD). Bovine serum albumin was used as negative control. In addition, adhering fibroblasts were photographed using a phase-contrast microscope. As compared with RA-SF, significantly higher numbers of OA-SF adhering to collagen type II, OPN and CHAD could be detected (P < 0.05). In contrast, RA-SF showed increased attachment to collagen type II, OPN and BSP. Adhesion to AGG, COMP and PRELP appeared not to be significantly increased and differed widely among the SF samples, and, apart from one exception (BSP), OA-SF adhered in higher numbers to the matrix proteins than did RA-SF. Using immunohistochemistry, synovial cells attached to cartilage/bone fragments could be shown to predominantly express CD68 (>/=50%). The CD68-negative population was of the fibroblast phenotype (AS02 positive). The study demonstrates that the binding pattern of OA-SF and RA-SF to ECM proteins differs considerably and therefore provides novel insights into the difficult pathophysiology of OA and RA. In general, it appeared that SF adhere primarily to ECM proteins that contain known binding sites for adhesion molecules (e.g. integrins: collagen/integrin alpha(2)beta(1)) and that higher numbers of OA-SF adhered to the cartilage and bone matrix proteins than did RA-SF.

Arthritis, Rheumatoid↗
PubMed2004

Discrepancy between mRNA and protein expression of tumour suppressor maspin in synovial tissue may contribute to synovial hyperplasia in rheumatoid arthritis.

OBJECTIVE: To investigate the expression of maspin in RA synovial tissue and compare it with the expression in osteoarthritis (OA) and normal synovial tissue (NS). METHODS: Using specific primers for maspin, a 237 bp fragment was amplified from cDNA obtained from cultured RA, OA, and normal synovial fibroblasts (SF) by RT-PCR. Additionally, mRNA expression levels were determined quantitatively by real time PCR. mRNA expression of maspin was investigated on snap frozen and paraffin embedded synovial tissue sections by in situ hybridisation. Immunohistochemistry was used to identify the cell type expressing maspin. SDS-PAGE and western blotting were performed to evaluate the protein expression in cultured SF. To confirm protein synthesis in situ, immunohistochemistry with specific anti-maspin antibodies was performed in synovial tissue sections of patients with RA. RESULTS: RT-PCR showed expression of maspin in all cDNA samples from cultured SF. Maspin mRNA was found to be decreased in RA SF twofold and 70-fold compared with OA SF and NS SF, respectively. Maspin mRNA was expressed in RA, OA, and normal synovial tissue. Importantly, maspin transcripts were also found at sites of invasion into cartilage and bone. At the protein level, maspin could be detected in RA and, less prominently, OA SF. In RA synovial tissue, maspin protein was detected in only a few synovial lining cells. CONCLUSION: Maspin is expressed intensively in RA SF at the mRNA level, but only slightly at the protein level, possibly owing to down regulation of maspin; this may contribute to the hyperplasia of synovial tissue in RA.

Adult↗