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1.  Leflunomide in the treatment of patients with early rheumatoid arthritis—results of a prospective non-interventional study 
Clinical Rheumatology  2010;29(8):913-920.
Leflunomide is effective and well tolerated in the treatment of rheumatoid arthritis (RA), however, data on its use in early RA are scarce. This study seeks to evaluate effectiveness and safety of leflunomide in the treatment of early RA in daily practice. This prospective, open-label, non-interventional, multi-center study was carried out over 24 weeks including adults with early RA (≤1 year since diagnosis). Leflunomide treatment was according to label instructions. Three hundred thirty-four patients were included. Disease activity score in 28 joints (DAS28) response (reduction in DAS28 of >1.2 or reduction of >0.6 and a DAS28 of ≤5.1) was 71.9% at week 12 and 84.6% at week 24. 25.0% of patients achieved clinical remission (DAS28 ≤ 2.6). Most frequently reported adverse drug reactions (ADR) were diarrhea (3.0%), nausea (2.4%), hypertension (1.8%), and headache (1.5%). Serious ADR were reported in four patients (1.2%). Leflunomide showed the effectiveness which was to be expected from controlled studies without revealing any new or hitherto unknown side effects. Onset of action was quick and significant improvement of disease was seen after 12 weeks of therapy and at even higher rates after 24 weeks irrespective of the use of a loading dose. Interestingly, the DAS28-remission rate achieved was similar to the rate seen with methotrexate or biologic therapy in other studies.
PMCID: PMC2895904  PMID: 20496042
Daily practice; DAS28 response; Early rheumatoid arthritis; Leflunomide
2.  Normative Reference Values of Joint Space Width Estimated by Computer-aided Joint Space Analysis (CAJSA): The Distal Interphalangeal Joint 
Journal of Digital Imaging  2007;21(Suppl 1):104-112.
The study introduces reference data for a computer-aided analysis. The semiautomated computer-aided diagnostic system provides the estimation of joint space width at the distal interphalangeal joints, considering gender-specific and age-related changes.
Patients and methods
869 subjects (351 female/518 male) with hand x-rays were included and underwent measurements of joint space distances at the distal interphalangeal articulation (JSD-DIP) of the second to the fifth finger using computer-aided joint space analysis (CAJSA).
Data showed a notable age-related decrease of CAJSA parameters, and an accentuated age-related joint space narrowing in women. Males showed a significantly wider JSD-DIP (+ 16.7%) compared to the female cohort for all age groups. Both men and women revealed an accentuated decrease of JSD-DIP (total) in the age group from 10 to 15 years (for men −10.5% and for women −17.6%). After the age of 21 years a continuous decline of the JSD-DIP (total) is observed.
Our data present gender-specific and age-related normative reference data for computer-aided joint space analysis, which provide a valid and reliable differentiation between disease-related joint space narrowing and age-related joint space narrowing, particularly in patients with osteoarthritis of the fingers.
PMCID: PMC3043877  PMID: 17384977
Computer-aided diagnosis; distal interphalangeal joint; joint space distance; normative reference value; osteoarthritis; rheumatoid arthritis
3.  Advanced glycation end products induce cell cycle arrest and proinflammatory changes in osteoarthritic fibroblast-like synovial cells 
Arthritis Research & Therapy  2009;11(5):R136.
Advanced glycation end products (AGEs) have been introduced to be involved in the pathogenesis of osteoarthritis (OA). The influence of AGEs on osteoarthritic fibroblast-like synovial cells (FLS) has been incompletely understood as yet. The present study investigates a potential influence of AGE-modified bovine serum albumin (AGE-BSA) on cell growth, and on the expression of proinflammatory and osteoclastogenic markers in cultured FLS.
FLS were established from OA joints and stimulated with AGE-BSA. The mRNA expression of p27Kip1, RAGE (receptor for AGEs), nuclear factor kappa B subunit p65 (NFκB p65), tumor necrosis factor alpha (TNF-α, interleukin-6 (IL-6), receptor activator of NFκB ligand (RANKL) and osteoprotegerin was measured by real-time PCR. The respective protein expression was evaluated by western blot analysis or ELISA. NFκB activation was investigated by luciferase assay and electrophoretic mobility shift assay (EMSA). Cell cycle analysis, cell proliferation and markers of necrosis and early apoptosis were assessed. The specificity of the response was tested in the presence of an anti-RAGE antibody.
AGE-BSA was actively taken up into the cells as determined by immunohistochemistry and western blots. AGE-induced p27Kip1 mRNA and protein expression was associated with cell cycle arrest and an increase in necrotic, but not apoptotic cells. NFκB activation was confirmed by EMSAs including supershift experiments. Anti-RAGE antibodies attenuated all AGE-BSA induced responses. The increased expression of RAGE, IL-6 and TNF-α together with NFκB activation indicates AGE-mediated inflammation. The decreased expression of RANKL and osteoprotegerin may reflect a diminished osteoclastogenic potential.
The present study demonstrates that AGEs modulate growth and expression of genes involved in the pathophysiological process of OA. This may lead to functional and structural impairment of the joints.
PMCID: PMC2787298  PMID: 19735566
4.  Increased Frequency of EBV-Specific Effector Memory CD8+ T Cells Correlates with Higher Viral Load in Rheumatoid Arthritis1 
EBV is a candidate trigger of rheumatoid arthritis (RA). We determined both EBV-specific T cell and B cell responses and cell-associated EBV DNA copies in patients with RA and demographically matched healthy virus carriers. Patients with RA showed increased and broadened IgG responses to lytic and latent EBV-encoded Ags and 7-fold higher levels of EBV copy numbers in circulating blood cells. Additionally, patients with RA exhibited substantial expansions of CD8+ T cells specific for pooled EBV Ags expressed during both B cell transformation and productive viral replication and the frequency of CD8+ T cells specific for these Ags correlated with cellular EBV copy numbers. In contrast, CD4+ T cell responses to EBV and T cell responses to human CMV Ags were unchanged, altogether arguing against a defective control of latent EBV infection in RA. Our data show that the regulation of EBV infection is perturbed in RA and suggest that increased EBV-specific effector T cell and Ab responses are driven by an elevated EBV load in RA.
PMCID: PMC2570434  PMID: 18606650
5.  Patients with rheumatoid arthritis have an altered circulatory aggrecan profile 
Rheumatoid arthritis (RA) is a chronic auto-immune disease with extensive articular cartilage destruction. Aggrecan depletion, mediated by aggrecanases is one of the first signs of early cartilage erosion. We investigated, whether measurement of aggrecan and fragments thereof in serum, could be used as biomarkers for joint-disease in RA patients and furthermore characterized the fragments found in the circulation.
The study consisted of 38 patients, 12 males (62.2 ± 16.0 years) and 26 females (59.8 ± 20.7 years) diagnosed with RA: 41.5 ± 27.5 mm/h erythrocyte sedimentation rate (ESR), 38.4 ± 34.7 mg/ml C-reactive protein (CRP) and 4.8 ± 1.7 disease activity score (DAS) and 108 healthy age-matched controls. Aggrecan levels were measured using two immunoassays, i.e. the 374ARGSVI-G2 sandwich ELISA measuring aggrecanase-mediated aggrecan degradation and the G1/G2 sandwich assay, detecting aggrecan molecules containing G1 and/or G2 (total aggrecan) We further characterized serum samples by western blots, by using monoclonal antibodies F-78, binding to G1 and G2, or by BC-3, detecting the aggrecanase-generated N-terminal 374ARGSVI neo-epitope.
Total aggrecan levels in RA patients were significantly decreased from 824.8 ± 31 ng/ml in healthy controls to 570.5 ± 30 ng/ml (31% decrease, P < 0.0001), as measured by the G1/G2 ELISA. Western blot analysis with F-78 showed one strong band at 10 kDa, and weaker bands at 25 and 45 kDa in both healthy controls and RA patients. In contrast, staining for aggrecanase-activity revealed only one strong band in RA patients of 45 kDa.
This is the first study, which characterizes different aggrecan fragments in human serum. The data strongly suggests that total aggrecan levels, i.e. aggrecan molecules containing G1 and/or G2 are lower in RA patients, and that RA patients have at least one specific subpopulation of aggrecan fragments, namely aggrecanse generated 374ARGSVI fragments. Further clinical studies are needed to investigate the potential of G1/G2 as a structure-related biochemical marker in destructive joint-diseases.
PMCID: PMC2426686  PMID: 18507823
6.  Computerized Digital Imaging Techniques Provided by Digital X-ray Radiogrammetry as New Diagnostic Tool in Rheumatoid Arthritis 
Journal of Digital Imaging  2006;19(3):279-288.
Our study evaluates digital x-ray radiogrammetry (DXR) and Radiogrammetry Kit (RK) as a new diagnostic method for the measurement of disease-related osteoporosis including quantification of joint space narrowing dependent on the severity of rheumatoid arthritis (RA).
Materials and Methods
A total of 172 unselected patients with RA underwent computerized measurements of bone mineral density (BMD) and metacarpal index (MCI) by DXR, as well as a semiautomated measurement of joint space distances at the metacarpal–phalangeal articulation (JSD-MCP 2–5), both were analyzed from plain radiographs of the nondominant hand.
Correlations between DXR-BMD and DXR-MCI vs. parameters of RK were all significant (0.34 < R < 0.61; p < 0.01). An expected negative association was observed between RK parameters and the different scoring methods (−0.27 < R < −0.59). The maximum relative decrease in BMD vs. MCI as measured by DXR between the highest and lowest RA severity group was −27.7% vs. −27.5% (p < 0.01) for the modified Larsen Score, whereas the minimal value of relative DXR-BMD and DXR-MCI reduction could be documented for the Sharp Erosion Score (−20.8% vs. −26.8%; p < 0.01). The relative reduction of mean JSD-MCP using RK significantly varied from −25.0% (Sharp Erosion Score) to −41.2% (modified Larsen Score). In addition, an excellent reproducibility of DXR and RK could be verified.
DXR in combination with RK could be a promising, widely available diagnostic tool to supplement the different scoring methods of RA with quantitative data, allowing an earlier and improved diagnosis and more precision in determining disease progression.
PMCID: PMC3045148  PMID: 16628388
Digital x-ray radiogrammetry; rheumatoid arthritis; joint space width; bone mineral density; metacarpal index; Larsen Score; Sharp Score
7.  Metacarpal Index Estimated by Digital X-ray Radiogrammetry as a Tool for Differentiating Rheumatoid Arthritis Related Periarticular Osteopenia 
To investigate Metacarpal Index (MCI) and Bone Mineral Density (BMD) estimated by Digital X-ray Radiogrammetry (DXR) with respect to its ability to quantify severity-dependent variations of bone mineralisation in patients with early rheumatoid arthritis compared to Dual Energy X-ray Absorptiometry (DXA), 122 patients underwent a prospective analysis of BMD and MCI by DXR, whereas both DXR-parameters were estimated from plain radiographs of the non-dominant hand. In comparison DXA measured BMD on total femur and lumbar spine (L2-L4). Additionally Steinbrocker Stage was assessed to differentiate the severity of rheumatoid arthritis (RA). Disease activity of RA was estimated by C-reactive Protein (CRP; in mg/l), Erythrocyte Sedimentation Rate (ESR in mm/1st hour) and by the disease activity score with 28-joint count (DAS 28). In consequence, The DXR-parameters, in particular DXR-MCI, revealed significant associations to age, Body Mass Index, CRP, DAS 28 and Steinbrocker graduation; no significant associations could be verified between DXA-parameters and all characteristics of disease activity and severity of RA. The highest correlation was found between DXR-MCI and DXR-BMD with R=0.89 (independent from severity of RA). In all patients DXR-MCI significantly decreased (-14.3%) from 0.42 ± 0.09 (stage 1) to 0.36 ± 0.07 (stage 2) dependent on severity of RA. The comparable relative reduction of DXR-BMD was -11.1%. The group of patients with minor disease activity (DAS 28>5.1) showed a significant flattened reduction (-11.4%) for DXR-MCI from 0.44 ± 0.08 (stage 1) to 0.39 ± 0.08 (stage 2). For accentuated disease activity (DAS 28>5.1) the DXR-MCI revealed a pronounced reduction (-23.1 %). No significant declines were observed for DXA-BMD of the lumbar spine and total femur in all patients as well as dependent on disease activity. Conclusion: DXR can exactly quantify cortical thinning of the metacarpal bones and can identify cortical demineralisation in patients suffering from early rheumatoid arthritis surpassing DXA-measurements at axial bone sites. In this context DXR-MCI seems to be the most sensitive parameter for differentiation of patients with minor or accentuated disease activity following severity-dependent cortical bone loss.
PMCID: PMC3614609  PMID: 23674987
digital X-ray radiogrammetry; dual energy X-ray absorptiometry; metacarpal index; bone mineral density; rheumatoid arthritis; steinbrocker stage
8.  Mosaic chromosomal aberrations in synovial fibroblasts of patients with rheumatoid arthritis, osteoarthritis, and other inflammatory joint diseases 
Arthritis Research  2001;3(5):319-330.
Chromosomal aberrations were comparatively assessed in nuclei extracted from synovial tissue, primary-culture (P-0) synovial cells, and early-passage synovial fibroblasts (SFB; 98% enrichment; P-1, P-4 [passage 1, passage 4]) from patients with rheumatoid arthritis (RA; n = 21), osteoarthritis (OA; n = 24), and other rheumatic diseases. Peripheral blood lymphocytes (PBL) and skin fibroblasts (FB) (P-1, P-4) from the same patients, as well as SFB from normal joints and patients with joint trauma (JT) (n = 4), were used as controls. Analyses proceeded by standard GTG-banding and interphase centromere fluorescence in situ hybridization. Structural chromosomal aberrations were observed in SFB (P-1 or P-4) from 4 of 21 RA patients (19%), with involvement of chromosome 1 [e.g. del(1)(q12)] in 3 of 4 cases. In 10 of the 21 RA cases (48%), polysomy 7 was observed in P-1 SFB. In addition, aneusomies of chromosomes 4, 6, 8, 9, 12, 18, and Y were present. The percentage of polysomies was increased in P-4. Similar chromosomal aberrations were detected in SFB of OA and spondylarthropathy patients. No aberrations were detected in i) PBL or skin FB from the same patients (except for one OA patient with a karyotype 45,X[10]/46,XX[17] in PBL and variable polysomies in long-term culture skin FB); or ii) synovial tissue and/or P-1 SFB of normal joints or of patients with joint trauma. In conclusion, qualitatively comparable chromosomal aberrations were observed in synovial tissue and early-passage SFB of patients with RA, OA, and other inflammatory joint diseases. Thus, although of possible functional relevance for the pathologic role of SFB in RA, these alterations probably reflect a common response to chronic inflammatory stress in rheumatic diseases.
PMCID: PMC64845  PMID: 11549374
osteoarthritis; rheumatoid arthritis; spondylarthropathy; synovial fibroblasts; trisomy/polysomy 7

Results 1-8 (8)