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OBJECTIVE: Current treatment options for psoriatic arthritis (PsA) are limited. Leflunomide, an oral pyrimidine synthesis inhibitor, is highly effective in the treatment of rheumatoid arthritis, and small studies have suggested similar efficacy in PsA. We undertook this double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of leflunomide in patients with PsA and psoriasis. METHODS: One hundred ninety patients with active PsA and psoriasis (at least 3% skin involvement) were randomized to receive leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally) or placebo for 24 weeks. The primary efficacy end point was the proportion of patients classified as responders by the Psoriatic Arthritis Response Criteria (PsARC). Additional efficacy (joint and skin involvement), safety, and quality-of-life assessments were performed. RESULTS: At 24 weeks, 56 of 95 leflunomide-treated patients (58.9%; 95% confidence interval [95% CI] 48.4-68.9) and 27 of 91 placebo-treated patients (29.7% [95% CI 20.6-40.2]) were classified as responders by the PsARC (P < 0.0001). Significant differences in favor of leflunomide were also observed in the proportions of patients achieving modified American College of Rheumatology 20% improvement criteria, improvement in the designated psoriasis target lesion, and mean changes from baseline in Psoriasis Area and Severity Index scores and quality-of-life assessments. Diarrhea and alanine aminotransferase increases occurred at higher rates in the leflunomide group. No cases of serious liver toxicity were observed. CONCLUSION: Leflunomide is an effective treatment for PsA and psoriasis, providing a safe and convenient alternative to current therapies. [ABSTRACT FROM AUTHOR]

Objective. This study compared the progression of joint damage in patients with early active severe rheumatoid arthritis (RA) treated with cyclosporin or parenteral gold. [ABSTRACT FROM PUBLISHER]

Objective: To determine the prevalence of and independent factors associated with joint involvement in a large population of patients with systemic sclerosis (SSc)., Methods: This study was cross-sectional, based on data collected on patients included in the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) registry. We queried this database to extract data regarding global evaluation of patients with SSc and the presence of any clinical articular involvement: synovitis (tender and swollen joints), tendon friction rubs (rubbing sensation detected as the tendon was moved), and joint contracture (stiffness of the joints that decreased their range of motion). Overall joint involvement was defined by the occurrence of synovitis and/or joint contracture and/or tendon friction rubs., Results: We recruited 7286 patients with SSc; their mean age was 56 +/- 14 years, disease duration 10 +/- 9 years, and 4210 (58%) had a limited cutaneous disease subset. Frequencies of synovitis, tendon friction rubs, and joint contractures were 16%, 11%, and 31%, respectively. Synovitis, tendon friction rubs, and joint contracture were more prevalent in patients with the diffuse cutaneous subset and were associated together and with severe vascular, muscular, renal, and interstitial lung involvement. Moreover, synovitis had the highest strength of association with elevated acute-phase reactants taken as the dependent variable., Conclusion: Our results highlight the striking level of articular involvement in SSc, as evaluated by systematic examination in a large cohort of patients with SSc. Our data also show that synovitis, joint contracture, and tendon friction rubs are associated with a more severe disease and with systemic inflammation.

We evaluated a combined physician and patient questionnaire designed for identifying early rheumatoid arthritis (RA) and spondyloarthritis (SpA) in a cohort of 220 patients supposed for admission to an early arthritis clinic (EAC). The documents including personal and basis demographic data, referral diagnosis, questions related to RA and SpA classification criteria, functional limitations and previous diagnostic and therapeutic attempts were fax-transmitted to referring practices and returned before first EAC appointment. 125 referrals before introduction of the questionnaire served as controls. We found that a functional impairment of the hands provided more accurate prediction of RA than reports on morning stiffness or joint swelling. No clinical data proved predictive for SpA. We observed an unintended increase in the prescription of analgesics/NSAID and corticosteroids. In conclusion, questionnaires as designed here may provide substantial information for diagnosis of RA, but also imply the risk of unmeant therapeutic attempts.

Psoriatic arthritis (PsA) is a common unique form of inflammatory arthritis associated with psoriasis. Its exact prevalence is unknown but 5-30% of the 2-3% of subjects of the general population affected with psoriasis are developing PsA. Typically PsA presents as an oligoarticular asymmetrical arthritis with predominant distal finger joint pattern, presence of spinal involvement enthesitis and dactylitis. There is evidence that T-cells play a key role in the immunopathology of PsA as well as Psoriasis. Leflunomide, a selective pyrimidine synthesis inhibitor with the property to inhibit T-cell activation and proliferation has been shown to improve both joint and skin symptoms in patients with PsA. Significant response rates have been observed for Psoriatic Arthritis Response Criteria (PsARC), modified ACR20 and PASI 50 after 24 weeks of treatment with 20 mg/d Leflunomide orally in a randomised, placebo controlled multicenter trial (TOPAS Study). Leflunomide treatment also improved quality of life and showed a favourable safety profile. It is therefore concluded that Leflunomide offers an efficacious, well tolerated, safe, and relatively inexpensive therapeutic option for the treatment of actively inflamed joints and psoriatic skin lesions in patients with PsA.

Objectives: Regulatory T cells (Tregs) exert their anti-inflammatory activity predominantly by cell contact-dependent mechanisms. A study was undertaken to investigate the regulatory capacity of autologous peripheral blood Tregs in contact with synovial tissue cell cultures, and to evaluate their presence in peripheral blood, synovial tissue and synovial fluid of patients with rheumatoid arthritis (RA)., Methods: 44 patients with RA and 5 with osteoarthritis were included in the study. The frequency of interferon (IFN)gamma-secreting cells was quantified in synovial tissue cell cultures, CD3-depleted synovial tissue cell cultures, synovial tissue cultures co-cultured with autologous CD4+ and with CD4+CD25+ peripheral blood T cells by ELISPOT. Total CD3+, Th1 polarised and Tregs were quantified by real-time PCR for CD3epsilon, T-bet and FoxP3 mRNA, and by immunohistochemistry for FoxP3 protein., Results: RA synovial tissue cell cultures exhibited spontaneous expression of IFNgamma which was abrogated by depletion of CD3+ T cells and specifically reduced by co-culture with autologous peripheral blood Treg. The presence of Treg in RA synovitis was indicated by FoxP3 mRNA expression and confirmed by immunohistochemistry. The amount of FoxP3 transcripts, however, was lower in the synovial membrane than in peripheral blood or synovial fluid. The T-bet/FoxP3 ratio correlated with both a higher grade of synovial tissue lymphocyte infiltration and higher disease activity., Conclusion: This study has shown, for the first time in human RA, the efficacy of autologous Tregs in reducing the inflammatory activity of synovial tissue cell cultures ex vivo, while in the synovium FoxP3+ Tregs of patients with RA are reduced compared with peripheral blood and synovial fluid. This local imbalance of Th1 and Treg may be responsible for repeated rheumatic flares and thus will be of interest as a target for future treatments.

Background: Leflunomide has shown promise in the treatment of psoriasis., Objective: To provide an in-depth analysis of the effect of leflunomide on psoriasis in patients with psoriatic arthritis (PsA)., Methods: 190 patients with plaque psoriasis (at least 3% skin involvement) and active PsA were randomized to double-blind treatment with leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally) or placebo for 24 weeks., Results: As previously reported, leflunomide resulted in a significantly higher Psoriatic Arthritis Response Criteria response rate than placebo (58.9 vs. 29.7%; p < 0.0001). Significant differences in favor of leflunomide were also observed in the Psoriasis Area and Severity Index (PASI 50 in 30.4% of patients vs. 18.9% for placebo; p = 0.05), target lesion response (46.4 vs. 25.3%; p = 0.0048), combined skin and joint response (27.2 vs. 8.9%; p < 0.0001), Dermatology Life Quality Index (improvement of 1.9 points vs. 0.2; p = 0.0173) and certain SF-36 subdomains. Dermatological responses were observed at the earliest examination (4 weeks) and increased throughout the 24-week study., Conclusion: Once-daily oral leflunomide is an effective and convenient treatment for PsA and plaque psoriasis., (2006 S. Karger AG, Basel)

Leflunomide (Arava, Aventis Pharmaceuticals) is an oral pyrimidine synthesis inhibitor with immunomodulatory and anti-inflammatory activity. This agent has demonstrated significant efficacy in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis in randomised, double-blind, placebo-controlled trials. Both the efficacy and safety of leflunomide are maintained with long-term administration in patients with RA. Leflunomide compares favourably with other biological and non-biological agents used to treat RA in the incidence of adverse events and serious adverse events. Economic studies indicate that leflunomide is a cost-effective option in the treatment of RA. New investigations with leflunomide have focused mainly on combination regimens for the treatment of RA and the use of leflunomide in other inflammatory or autoimmune disorders.

Anemia of chronic disease (ACD) is a frequent complication of chronic inflammation in rheumatoid arthritis (RA). Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting ACD, although with a variable rate of nonresponders. The first aim of this trial was to improve the response to rHuEpo by parenteral iron supplementation in cases of iron-deficient erythropoiesis (IDE). An additional goal was the evaluation of the zinc protoporphyrin content of erythrocytes (ZnPP), the soluble transferrin receptor (sTrfR) serum concentration, and the hemoglobin (Hb) content of reticulocytes (CHr) in stimulated erythropoiesis as diagnostic and prognostic parameters. Thirty RA patients with ACD were treated with subcutaneous 150 IU rHuEpo/kg body weight twice weekly. Intravenous iron supplementation (200 mg iron sucrose once weekly) was added in cases of IDE (n=23), which was defined by the presence of two of three criteria: saturation of transferrin (TrfS) < or =15%, hypochromic erythrocytes (HypoE) > or =10%, and a serum ferritin (Fn) concentration < or =50 microg/l. All 28 completers met the treatment goal, with an increase of the median Hb concentration from 10.3 g/dl to 13.3 g/dl. Epo treatment and iron supplementation was safe and well tolerated in all patients. Monitoring of Fn, TrfS, and HypoE every other week allowed a successful correction of anemia. Retrospective analysis of the evaluable parameters (CHr, sTrfR, and ZnPP) revealed no additional benefit for predicting or monitoring IDE in this setting, although the one or other may be advantageous in other therapeutic situations.

Objective: To investigate expression of the endogenous antagonist of interleukin 18 (IL-18) bioactivity, IL-18 binding protein isoform a (IL-18BPa), in fibroblast-like synoviocytes (FLS)., Methods: Long-term cultured FLS from rheumatoid arthritis (RA), osteoarthritis (OA) and spondylarthropathy patients were analysed for spontaneous and cytokine-induced IL-18BPa expression. Messenger RNA and release of IL-18BPa were assessed by semi-quantitative and quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) as well as immunoblot analysis, respectively., Results: All investigated FLS cultures expressed low amounts of IL-18BPa transcripts. However, there was no detectable release of IL-18BPa from unstimulated synoviocytes. Of the investigated cytokines, only interferon (IFN)-gamma markedly up-regulated IL-18BPa mRNA levels. Induction was accompanied by release of IL-18BPa immunoreactivity from FLS. Conditioned media from IFN-gamma-stimulated FLS cultures reduced IL-12/IL-18-dependent IFN- production by peripheral blood mononuclear cells., Conclusion: The present data imply that IFN--activated synoviocytes mediate a negative feedback loop via IL-18BPa, which may limit IL-18 biological activity in arthritis.

Immunosuppression with antithymocyte globulin, (methyl)prednisolone, and cyclosporin A is considered the treatment of choice for the patient with aplastic anemia without a donor for standard-risk stem cell transplantation. This consensus is supported by the results of several series, including a randomized German trial. Here we report 11-year results of the latter trial. With stringent response criteria and 4 months as the time to evaluate responses, this analysis confirms the superiority of the cyclosporine regimen regarding the response rate in all patients treated (70% vs 41%, with or without cyclosporine; P =.015) and in patients with severe aplastic anemia (65% vs 31%; P =.011). Patients responded more rapidly after treatment with cyclosporine (median, 60 vs 82 days; P =.019). Most patients treated with cyclosporine needed only one course of immunosuppression, whereas many patients treated without cyclosporine required repeated immunosuppressive treatment. Because of the efficacy of salvage treatment, overall survival was not different between the 2 treatment groups. However, failure-free survival favored the cyclosporine regimen (39% vs 24%; P =.04). The relapse rate, projected at 38% after 11.3 years, was similar between the 2 treatment groups. Remissions were cyclosporine dependent in 26% of the patients responding to a regimen that included cyclosporine. Clonal or malignant diseases developed in 25% of the patients. These data demonstrate that antithymocyte globulin, methylprednisolone, and cyclosporin A are an effective regimen for the treatment of aplastic anemia. However, remissions are unstable, and secondary diseases are common. In contrast to the results of stem cell transplantation, most patients are not cured.

Continuing medical education is essential to improve the quality of health care delivery. The efficacy of postgraduate medical education generally improves when participants feel that their specific needs are met by a particular educational activity. Audit circles of general practitioners allow for a discussion of relevant issues. The present paper describes a novel concept for delivering knowledge and skills in arthritis and rheumatic conditions to general practitioners. A well-designed paper case was used for discussion in established audit circles of general practitioners, and a specially trained expert rheumatologist participated as an external expert to answer all those questions that could not be solved by the other participants. The participation of such as an expert-on-demand was found extremely helpful, as an evaluation during pilot sessions in 6 pre-existing audit circles of general practitioners revealed.

The goal of this study was to obtain data for prescription habits, tolerability for patients at high risk, and clinical effectiveness of meloxicam administered at 7.5 mg and 15 mg for various rheumatic diseases under real world prescribing conditions. This was a 3-month large-scale prospective observational cohort study in 4000 medical practices throughout Germany shortly after the introduction of meloxicam. To be eligible, patients had to have a diagnosis of acute or chronic active rheumatic disease for which nonsteroidal antiinflammatory drug (NSAID) therapy was required according to the prescribing information. In this study, 13,307 patients receiving meloxicam prescriptions (7.5 mg in 65% and 15 mg in 33%) were observed. The diagnoses of these patients included osteoarthritis (61%), rheumatoid arthritis (24%), ankylosing spondylitis (1.6%), and other rheumatic conditions (28%). A substantial proportion of high risk patients were enrolled: 12% with a previous history of a perforation, ulceration, and bleeding (PUB), 24% with at least one concomitant cardiovascular disorder, and 26% receiving concomitant antihypertensive medication. Many of the patients (58%) had received NSAIDs before meloxicam, including patients with insufficient prior treatment effectiveness (43%) and those with NSAID-related adverse drug reactions (21%). In 85% and 94% of the patients, respectively, effectiveness and tolerability were rated as good or very good. Quality of life and daily functions improved in 64% to 84% of the patients. Only 0.8% of the patients reported gastrointestinal (GI) adverse drug reactions. Four uncomplicated cases of gastric ulceration, one serious perforated gastric ulcer, and one serious ileus complication were reported after incorrect use or overdosing of meloxicam. Treatment with the selective cyclooxygenase-2 (COX-2) inhibitor meloxicam in doses of 7.5 mg and 15 mg resulted in meaningful treatment responses under real life conditions, despite inclusion of a substantial number of patients with insufficient effectiveness of previous use of non-COX-2 selective NSAIDs. All major GI toxicity (PUB) observed was owing to the fact that prescribing conditions were not respected appropriately. Despite a selection of high risk patients overall, GI, cardiovascular, and renal tolerability was favorable.

Objective: To search for RA specific processes among T cell accumulation, T cell activation, or cytokine expression in CD4+ and CD8+ synovial fluid (SF) T cells., Methods: Flow cytometry of CD4+, CD8+, CD45RA+, CD45RO+, CD69 double or triple stained peripheral blood (PB) and SF T cells. IL-2, IL-10, and IFN-gamma expression was determined in PMA + ionomycin stimulated T cells on the single cell level. Concentrations of secreted IL-2, IL-4, IL-10, and IFN-gamma were quantified in the sera and synovial fluids by enzyme linked immunosorbent assay (ELISA)., Results: A preferential recruitment of CD45RO+ memory T cells was found for CD4+ helper T cells, and in similar also for CD8+ suppressor T cells. An elevated CD69 expression was detected in memory, but also in CD45RA+ naive CD4+ and CD8+ SF T cells, whilst IL-2 expression was only demonstrable in a minor proportion of T cells populations. Preferential recruitment of memory T cells, but incomplete activation of naive and memory, CD4+ and CD8+ T cells were in similar found in RA and control patients. In RA but not in the control patients, a relevant proportion of CD4+ and CD8+ PB and SF T cells expressed IL-10 and IFN-gamma. High concentrations of IL-10, that were correlated with the amounts of secreted TNF-alpha, were only detected in RA joints., Conclusion: Memory and naive T cell state of CD4+ and CD8+ T cell accumulates in the joints, and early T cell activation occur in similar patterns in RA and control patients. High IL-10 SF concentrations in contrast, and elevated percentages of IFN-gamma and IL-10 expressing CD4+ and CD8+ T cells in the PB and SF were characteristic for RA. Here, CD8+ T cells may contribute to high IL-10 concentrations in RA joints.

Objective: Interleukin (IL)-18 is involved in host defense mechanisms and inflammatory diseases, among them rheumatoid arthritis (RA). High levels of IL-18 expression in RA joints are contrasted by reduced IL-18 expression in RA peripheral blood mononuclear cells (PBMC). Here, we investigated a putative IL-18 regulating role of corticosteroids., Methods: IL-18 transcript and protein levels in PBMC from untreated and prednisolone treated RA patients, and from healthy donors were assessed by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting. IL-18 regulation was determined in PBMC and U937 cells upon exposure to prednisolone in vitro by RT-PCR and Northern Blot analysis, by ELISA in cell culture supernatants, and in transiently transfected THP-1 cells by IL-18 promoter activity luciferase assays., Results: In RA PBMC, IL-18 transcript levels were dose dependently restored, in parallel with administered prednisolone treatment, to subnormal levels. The corresponding intracellular IL-18 deposits in contrast were depleted. In cultured PBMC and promonocytic cell lines, prednisolone up-regulated IL-18 transcription in parallel with increasing the IL- 18 protein release into cell culture supernatants., Conclusion: Prednisolone increases IL-18 expression and release in PBMC and monocytic cell lines.

Objective: The anti-inflammatory action of low-dose methoxetrate (MTX) in the treatment of rheumatoid arthritis (RA) appears to be partially impaired by folate supplementation. Here we investigated whether a folate excess impairs monocyte differentiation, a putative anti-inflammatory action of low-dose MTX., Methods: Monocyte differentiation of U937 promonocytic cells was assessed by CD11b and CD14 immunostaining and fluorescent absorbent cell sorting (FACS) analysis. Cell proliferation and viability were determined by cell counts and trypan-blue staining, respectively. Nuclear apoptosis was assessed by 7-actinomycin staining. Cells were treated with 10(-10)-10(-6) M MTX in the presence or absence of folinic acid. Exposure to 1,25-OH-vitamine D(3) and TGF-beta served as a positive control of monocyte differentiation in U937 cells., Results: Low-dose MTX-induced monocyte differentiation was marginal when compared with 1,25-OH-D(3) + TGF-beta treatment. Low-dose MTX inhibited cell proliferation, induced apoptosis, and reduced cell viability. All the antiproliferative, cytotoxic, and monocyte differentiating effects of MTX were completely reversed by folinic acid., Conclusions: Monocyte differentiation is part of the folate-dependent MTX actions.

This study is aimed to demonstrate the feasibility of stable isotopes for the assessment of reliable data on fractional intestinal absorption of trace metals in healthy humans. Among the various methods available, the double isotope technique, i.e. one isotope given orally together with the test substance to be investigated and another isotope injected intravenously to correct for retention and endogenous excretion of the particular trace metal, provides quantitative figures of intestinal absorption at reasonable expenses with regard to costs for materials and number of samples to be evaluated. The trace metals exemplarily included in this study, i.e. iron, cobalt and molybdenum show diverging relations between absorbed fractions and amounts administered which are indicative for different regulatory mechanisms of their body content. Food ligands influence the fractional absorption significantly so that the uptake from a composite meal cannot be derived from results on uptake from particular foodstuffs. Therefore, validated data on the behaviour of intestinal absorption will significantly contribute to a better understanding of human trace metal metabolism.

Unlabelled: Synovial fluid (SF) analysis was a mandatory investigation in rheumatological practice. In recent time, synovial fluid analysis lost importance predominantly due to unclear defined guidelines for the practical use., Objective: To evaluate the clinical value of the determination of the complement components C'3c and C'4 and immunoglobulines IgG, IgA and IgM synovial fluid concentrations with regard to pathophysiology and currently used RA and SpA classification criteria., Methods: Synovial fluid samples were obtained from 22 patients fulfilling ACR criteria for rheumatoid arthritis (RA), and 18 patients suffering from seronegative spondyloarthropathy (SpA) according to the ESSG criteria. Sixteen osteoarthritis (OA) SF samples were used as controls. IgG, IgA, IgM, C'3c and C'4 in SF and sera were determined by nephelometry. Comparison of the diseases, and linear as well as stepwise logistic regression analyses were performed in order to determine the interrelation of the determined parameters and a ranking of their diagnostic value for the identification of RA or SpA synovial fluids., Results: SF-IgA, SF-IgG and SF-IgM concentrations were closely correlated with their corresponding serum levels (p < 0.01), while SF-C'3c and SF-C'4 depended on articular factors (p < 0.01). Determination of SF-C'3c (accuracy = 80.4%, improved chi 2 = 22.02, p < 0.001) and SF-C'4 (accuracy = 75.0%, improved chi 2 = 21.81, p < 0.001) both provided a good predictive value for the diagnosis of SpA when exceeding the cut off level of about 40 mg/dl (C'3c) or 15 mg/dl (C'4), respectively. Calculation of the C'-SF/S ratios did not provide an additional diagnostic benefit. SF-IgG, IgA and IgM as well as the calculated SF/S ratios were within the same range in RA and SpA fluids., Conclusions: SF concentration of complement components primarily depends on local articular factors. Significant differences of SF complement concentrations in established RA and SpA give reason for prospective analysis of these parameters in early undifferentiated oligoarthritis and evaluation in large studies, e.g. when re-evaluating the preliminary criteria for spondyloarthropathy.

An excess of the proinflammatory substance IL-18 is present in joints of patients with rheumatoid arthritis (RA), and expression of IL-18 receptor (IL-18R) regulates IL-18 bioactivity in various cell types. We examined the expression of IL-18R alpha-chain and beta-chain and the biologic effects of IL-18 in fibroblast-like synoviocytes (FLS) after long-term culture. The presence of both IL-18R chains was a prerequisite for IL-18 signal transduction in FLS. However, all FLS cultures studied were either resistant or barely responsive to IL-18 stimulation as regards cell proliferation, expression of adhesion molecules ICAM-1 and vascular cell adhesion molecule (VCAM)-1, and the release of interstitial collagenase and stromelysin, IL-6 and IL-8, prostaglandin E2, or nitric oxide. We conclude that the presence of macrophages or IL-18R+ T cells that can respond directly to IL-18 is essential for the proinflammatory effects of IL-18 in synovitis in RA.

Objective: To investigate whether treatment of anemia of chronic disease (ACD) in patients with rheumatoid arthritis (RA) with recombinant human erythropoietin (rHu-Epo) in combination with intravenous (i.v.) iron influences health related quality of life (HRQoL) and clinical outcome including disease activity., Methods: Thirty patients with ACD and RA were treated with 150 IU/kg rHu-Epo twice weekly for 12 weeks. As well, in case of functional iron deficiency 200 mg of iron-sucrose per week was given intravenously. Vitality and fatigue as dimensions of HRQoL were evaluated by the vitality subscale of the Short Form-36 (SF-36-VT) and the Multidimensional Assessment of Fatigue (MAF). Muscle strength was measured by the Muscle Strength Index., Results: All 28 patients completing the study responded to treatment; 23/28 patients developed functional iron deficiency and received i.v. iron (mean absolute dose 710 +/- 560 mg). Average hemoglobin concentration increased from 10.7 +/- 1.1 to 13.2 +/- 1.0 g/dl after a mean treatment period of 8.7 +/- 2.3 weeks. Muscle strength increased from 43.5 +/- 11.2 to 49.1 +/- 12.9 and SF-36-VT from 28.2% +/- 14.3% to 47.1% +/- 20.8%. while fatigue decreased (MAF from 34.7 +/- 9.3 to 25.0 +/- 11.3). Among the disease activity variables the number of swollen/tender joints, erythrocyte sedimentation rate, Disease Activity Score, and RA Disease Activity Index improved significantly during treatment., Conclusion: Treatment of ACD in RA patients with rHu-Epo and i.v. iron is safe and effective in correction of anemia, increases muscle strength. improves vitality, and lowers fatigue. In addition we observed a reduction of disease activity.

Experimental studies in transgenic mice have suggested that HLA-DQ predisposes to rheumatoid arthritis (RA), but could also modulate disease severity by presenting peptides derived from self-DR molecules. In particular, a short amino acid sequence, (70)DERAA(74), in the third hypervariable region of HLA-DRB1 confers protection for the disease, while particular HLA-DQ [DQB1*0501/DQA1*01 (DQ5) and DQB1*03/DQA1*03 (DQ3)] molecules predispose to the disease. We have therefore analyzed the allelic distribution of HLA-DRB1, DQA1, and DQB1 and the presence of rheumatoid factor and nodules among 199 German RA patients and 196 healthy controls. Our results show that HLA-DQB1*03/DQA1*03 (or DRB1*04) predisposes to RA more than HLA-DQB1*0501/DQA1*01 (i.e., DRB1*01 and DRB1*10). Homozygosity for DQ3 confers the strongest genetic risk for RA (OR = 19.79 compared to OR = 10.05 for two doses of shared epitope (SE) positive HLA-DRB1 alleles). Furthermore, patients carrying both predisposing DQ and (70)DERAA(74)-positive HLA-DRB1 alleles are more often rheumatoid factor (RF) negative than patients carrying predisposing DQ alleles alone. Only one out of 14 patients (7%) with a protective combination (DQ3/(70)DERAA(74) and DQ5/(70)DERAA(74)) had rheumatoid nodules compared to 67 out of 144 patients (46.5%) with predisposing DQ alleles alone (OR = 0.12, 95% CI: 0.02-0.72, p = 0.004). These results demonstrate a protective role of (70)DERAA(74)-positive DRB1 alleles against disease severity among RA patients.

Objectives: To investigate the expression of and monokine induction by interleukin 18 (IL-18; also called interferon-gamma inducing factor, IGIF), in peripheral blood mononuclear cells (PBMC) and cultured synoviocytes from rheumatoid arthritis (RA) patients., Methods: We carried out IL-18 Western blotting and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) of cytokines in PBMC [IL-18, IL-1beta and tumour necrosis factor alpha (TNF-alpha)] and long-term cultured fibroblast-like synoviocytes (FLS) [IL-18, IL-1beta, TNF-alpha, IL-6, interferon gamma (INF-gamma) and [granulocyte-macrophage colony stimulating factor (GM-CSF)] from RA patients and controls. FLS were isolated from RA synovial membranes (FLS(SM)) and RA synovial fluids (FLS(SF)), osteoarthritis (OA) FLS(SM) and FLS(SF) from spondyloarthropathy patients. FLS were characterized by fluorescence-activated cell sorting of the FLS. PBMC and FLS from RA patients and control subjects were stimulated with recombinant human IL-18 and IL-1beta (rHuIL-18/rHuIL-1beta), and TNF-alpha, IL-1beta and MMP-1 were measured by ELISA in supernatants., Results: Constitutive expression of IL-18 mRNA was significantly reduced whereas that of TNF-alpha was enhanced in RA PBMC. Persistent low expression of IL-18, TNF-alpha, GM-CSF and IL-1beta was observed in RA and OA FLS(SM) as well as spondyloarthropathy FLS(SF). In contrast, high constitutive expression of IL-18 in FLS (CD90/Thy-1- and CD54-positive, CD14- and CD86-negative), accompanied by persistent high levels of TNF-alpha, GM-CSF and IL-1beta expression, was restricted to synovial fluid-derived FLS obtained from RA patients. IFN-gamma was not detectable in any culture, but IL-6 mRNA was equally expressed in all FLS cultures. rHuIL-18 was effective in stimulating TNF-alpha and IL-1beta secretion in PBMC from healthy controls, but failed to stimulate TNF-alpha and IL-1beta secretion from PBMC in 11 of 12 RA patients, and all FLS cultures. rHu-IL-1beta, but not rHu-IL-18, induced interstitial collagenase (MMP-1) in FLS., Conclusions: Persistent high production of proinflammatory cytokines in RA-FLS(SF) may be relevant for chronic progression in RA synovitis. Levels of TNF-alpha and IL-1beta expression are increased in RA-FLS(SF), but are independent of IL-18. The pathological function of enhanced IL-18 expression in RA-FLS(SF) remains to be further elucidated.

Gene variations of HFE, a HLA-class I like molecule, are highly associated with hereditary haemochromatosis (HH). Functional as well as molecular studies of the HFE protein have indicated that the molecule is involved in iron metabolism and that the HFE gene variations observed among HH patients affect its interaction with the transferrin receptor (TfR). In the present study, we have therefore analysed the relationship between the HFE gene variants, C282Y and H63D, and body iron status among 85 German HH patients. In addition, two TfR gene polymorphism, TfR-Hin6I and TfR-BanI, were typed that have been reported to define ethnically distinct haplotypes. As controls we used 251/159 healthy German blood donors. Seventy-eight (92%) patients were C292Y homozygous, the H63D mutation was present in five (6%) patients with none of the patients being H63D homozygous. Serum transferrin, transferrin saturation and liver iron content were determined prior to therapeutic intervention. Among C282Y homozygous patients serum ferritin levels (2294 +/- 3174 vs. 463 +/- 224 microg L-1, P < 0.0001) and transferrin saturation (86 +/- 18% vs. 62 +/- 25%, P = 0.048) were elevated significantly compared with C282Y and/or H63D heterozygous patients. In addition, the liver iron content (291 +/- 165 vs. 138 +/- 95 micromol g-1, P = 0.028) and liver iron index (6.4 +/- 2.8 vs. 3.2 +/- 2.3, P = 0.019) were increased among C282Y homozygotes compared with C282Y heterozygotes. In contrast, no difference was observed between patients and controls regarding the distribution of TfR-Hin6I and TfR-BanI alleles. These data indicate that the iron intake is higher among C282Y homozygous patients compared with C282Y heterozygous or C282Y/H63D compound heterozygous individuals and supports the functional role of the HFE protein in iron metabolism whereas the TfR gene variants seem to have no influence on iron uptake.

Objective: To compare the clinical efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis (RA)., Methods: In this multicentre, double-blind trial, 999 subjects with active RA were randomized to leflunomide (n = 501; loading dose 100 mg/day for 3 days, maintenance dose 20 mg/day) or methotrexate (n = 498; 10-15 mg/week) for 52 weeks. After 1 yr the subjects could choose to stay for a second year of double-blind treatment. The primary end-points were tender and swollen joint counts and overall physician and patient assessments. Analyses were of the intent-to-treat group., Results: After 1 yr, the mean changes in the leflunomide and methotrexate groups, respectively, were -8.3 and -9.7 for tender joint count; -6.8 and -9.0 for swollen joint count; -0.9 and -1.2 for physician global assessment; -0.9 and -1.2 for patient global assessment; -14.4 and -28.2 for erythrocyte sedimentation rate. Improvements seen with methotrexate were significantly greater than those with leflunomide. No further improvement occurred after the second year of treatment and the distinction between the two treatments in terms of tender joint count and patient global assessment was lost. During the first year of treatment, a small and equivalent degree of radiographically assessed disease progression was seen with both drugs. After 2 yr, disease progression was significantly less with methotrexate. The most common treatment-related adverse events in both groups were diarrhoea, nausea, alopecia, rash, headache, and elevated plasma liver enzyme levels. Over 2 yr, 21 subjects receiving methotrexate were withdrawn due to elevated plasma liver enzymes vs eight subjects taking leflunomide. Two drug-related deaths from pulmonary causes were recorded with methotrexate vs no drug-related deaths among the subjects receiving leflunomide., Conclusions: Both leflunomide and methotrexate are efficacious for prolonged treatment of RA. At the doses used, some clinical benefit of methotrexate over leflunomide was observed in the first year of treatment. This benefit must be weighed against the potential toxicity of this drug when used without folate supplementation.

Patients with rheumatic diseases are commonly treated as an outpatient in their local environment or are referred to specialized centers. Two recently founded day-patient clinics in Berlin and Frankfurt/Rhein-Main (Germany) for patients suffering from rheumatic diseases will be evaluated for their medical outcome and cost-effectiveness of comprehensive treatment of RA patients in stages of high inflammatory activity and progressive disability. The study design will be prospective, controlled, and randomized to compare outpatient and day-patient treatment. The case-control study design with matched pairs within the network of collaborative arthritis centers will be used to compare day-patient and inpatient treatment. The paper contains a review of studies published in English or German language dealing with day-patient treatment of RA patients.

In this study TIBC and serum-transferrin concentrations were determined by immunochemical turbidimetry, immunochemical nephelometry and radial immunodiffusion under normal and pathological clinical conditions. A total of 246 (123 male/123 female) patients were included [iron deficiency: 60 (18/42), iron overload: 56 (39/17), chronic inflammation: 47 (23/24), undefined diseases: 35 (16/19), healthy volunteers 48 (27/21)]. The data show that determination of TIBC from conversion of transferrin values using a constant factor results in significantly higher values compared to conversion with a function of first degree. For clinical practice the influence of different diseases is negligible. This study indicates that it is not possible to develop a universal algorithm for the conversion of transferrin values into TIBC.

Objective: We have shown that HLA-DRB1 alleles influence inflammatory activity in patients with early active and severe rheumatoid arthritis (RA). Therefore, we analyzed the effect of HLA-DRB1 alleles on disease progression in patients with early RA during a clinical followup period of 18 months., Methods: Disease progression was defined by the Larsen Score, the Ritchie Index (RI), and the Health Assessment Questionnaire (HAQ) score., Results: Patients carrying arthritogenic HLA-DRB1 alleles on one or both haplotypes are characterized by increased radiological joint destruction (Larsen Score). Further, (Q)R/KRAA homozygous patients were characterized by worse overall disease course (higher RI and HAQ). However, analysis of changes in joint effects (delta-RI) and personal disability (delta-HAQ) did not reveal significant differences between patients with or without disease associated HLA-DRB1 alleles., Conclusion: The predisposing genetic pattern with disease associated HLA-DRB1 alleles did not profoundly influence the therapeutic outcome. Our data support the role of the HLA-DRB1 gene locus in disease modulation of RA. The genetic predisposition due to HLA-DRB1, however, may have only a limited influence on the therapeutic outcome in clinically severe cases of RA.