Search

Objective: To analyze the -2849 A/G interleukin-10 (IL-10) promoter polymorphism, which is associated with high (AG/GG) and low (AA) IL-10 production, in a cohort of rheumatoid arthritis (RA) patients and controls in order to gain a better understanding of its role in the incidence and progression of RA., Methods: Allele frequencies of the promoter polymorphism -2849 A/G and carriage rates were compared in 283 RA patients, 413 patients with other rheumatic diseases, and 1,220 healthy controls. The rate of joint damage and baseline levels of IgG and IgM rheumatoid factors and anti-citrullinated peptide antibodies were measured and were correlated with the IL-10 gene polymorphism. Furthermore, the correlation between the invasiveness of fibroblast-like synoviocytes (FLS) and the -2849 IL-10 genotype was tested., Results: The IL-10 genotype was not associated with the incidence of RA, but instead, correlated with disease progression, as determined by the extent of joint destruction. A higher rate of joint destruction was observed in patients with the genotype associated with high IL-10 production. Since FLS are thought to be involved in joint destruction, we analyzed IL-10 genotypes in conjunction with FLS invasiveness. Although adenoviral gene transfer of IL-10 to FLS inhibited their invasiveness, no differences were observed in vitro in the FLS from RA patients who were -2849 non-G carriers compared with those who were G carriers. Instead, patients with the -2849 AG/GG genotype, which is associated with high IL-10 production, had higher autoantibody titers at baseline., Conclusion: The -2849 IL-10 promoter polymorphism is associated with autoantibody production and subsequent joint damage in RA.

Objective: To determine the clinical features associated with histologically proven rheumatoid vasculitis (HRV) and the additional diagnostic value of serological markers in an inception cohort of 81 patients with rheumatoid arthritis (RA) suspected of RV., Methods: The presence and number of recently developed extra-articular manifestations (EAMs) and a weighted EAM score, as well as the levels of serological markers, were compared between 31 patients with RA with histologically proven vasculitis and 50 patients with RA in whom vasculitis could not be documented histologically. The following markers were evaluated: circulating immune complexes, complement components C3 and C4, class-specific rheumatoid factors (IgM RF, IgG RF, IgA RF), antineutrophil cytoplasmic antibodies, antinuclear antibodies, antiendothelial antibodies, circulating intercellular adhesion molecule-1 and -3, circulating vascular cell adhesion molecule and E-selectin, cellular fibronectin, von Willebrand factor antigen, and C reactive protein. The diagnostic value of these markers, in addition to the clinical features, was evaluated with logistic regression analysis., Results: Peripheral neuropathy or purpura/petechiae, or both, were the most important clinical features to discriminate patients with RA with and without histologically proven RV. The presence of a high number of EAMs and a higher weighted EAM score in patients with RA suspected of vasculitis were also associated with an increased probability of histologically proven RV. After adjustment for EAMs, only the combination of an increased serum IgA RF level and a decreased serum C3 level appeared to make an additional contribution to the diagnosis histologically proven RV. Evidence of systemic vasculitis was found in a muscle biopsy of the rectus femoris in 9/14 (64%) patients with vasculitis with neuropathy and in 3/11 (27%) patients with purpura/petechiae and vasculitis of the skin., Conclusions: In the diagnostic process of RV the presence of peripheral neuropathy and/or purpura/petechiae or a high weighted EAM score will increase the probability of histologically proven RV. Of the circulating factors previously suggested to be markers for RV only IgA RF and C3 further increase the probability of histologically proven RV and may be useful to guide diagnostic decisions.

Objective: In the present study, the effects of plasmin antagonist tranexamic acid (TEA) on urinary pyridinoline excretion rates were investigated in rheumatoid arthritis (RA) patients., Methods: The study was set up as a double-blind placebo-controlled pilot study. Ten patients received tranexamic acid and 9 received placebo for 12 weeks. Urinary excretion rates of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) were used as molecular markers of articular cartilage and bone degradation. In addition, clinical parameters of disease activity were assessed and CRP levels were measured., Results: Treatment with TEA did not reduce pyridinoline excretion, nor was any effect observed on clinical parameters of disease activity or on CRP levels., Conclusion: The results of the present pilot study show no beneficial effect of TEA as adjuvant therapy in RA patients with respect to joint destruction or disease activity.

Objectives: To develop and validate a questionnaire for measuring satisfaction with different forms of complex multidisciplinary care in patients with rheumatoid arthritis (RA)., Methods: The satisfaction questionnaire (score range 0-100) comprised 28 items covering 11 domains. Together with a visual analog scale (VAS, range 0-100) on overall satisfaction, the questionnaire was applied in 210 RA patients who participated in a randomized trial comparing 3 types of multidisciplinary care., Results: The questionnaire was returned by 174 patients (83%). The questionnaire and VAS scores in the total group were 75 (SD 12) and 83 (SD 20), respectively. Reliability analysis showed Cronbach's alpha of the questionnaire was 0.91. Spearman's correlation coefficient between the satisfaction questionnaire score and VAS score was 0.58 (P < 0.01). Mean total satisfaction questionnaire scores were 72 (SD 9), 76 (SD 14), and 78 (SD 11), in the nurse specialist, inpatient and day patient groups, respectively (nurse specialist versus day patient, P = 0.004). Significant differences between nurse specialist and day patients were seen in the following domains: waiting time during the treatment, autonomy, coordination, non-financial access, and quality of general information (all P < 0.05)., Conclusion: Overall, patients were highly satisfied with the multidisciplinary care they received. Major differences regarding the organization of care were reflected in the results of the questionnaire scores. The satisfaction questionnaire appears to be a useful instrument for measuring satisfaction with complex multidisciplinary care in RA patients.

According to several reports, the risk of active tuberculosis in patients who are latently infected with Mycobacterium tuberculosis is increased after treatment with tumour necrosis factor alpha (TNF)-blocking agents. These drugs have demonstrated effectiveness and are increasingly being used for treatment of several inflammatory diseases, including rheumatoid arthritis and Crohn's disease. Specialists prescribing TNF-blocking agents should be aware of the risk of tuberculosis and other infections, the unusual and severe clinical presentations and the available preventive measures. In this review, we will weigh currently available data on the risk of infection with intracellular pathogens and in particular tuberculosis in patients treated with TNF-blocking agents, discuss the role of TNF in the pathogenesis of tuberculosis and describe the risk profile of this complication. Awaiting further consensus protocols, a provisional flow chart is presented that is based on dinical parameters to provide a logical framework to reduce and minimise the risk of tuberculosis during TNF blockade.

Rheumatoid arthritis (RA) is a heterogeneous disease. We used cDNA microarray technology to subclassify RA patients and disclose disease pathways in rheumatoid synovium. Hierarchical clustering of gene expression data identified two main groups of tissues (RA-I and RA-II). A total of 121 genes were significantly higher expressed in the RA-I tissues, whereas 39 genes were overexpressed in the RA-II tissues. Among the 121 genes overexpressed in RA-I tissues, a relative majority of nine genes are located on chromosome 6p21.3. An interpretation of biological processes that take place revealed that the gene expression profile in RA-I tissues is indicative for an adaptive immune response. The RA-II group showed expression of genes suggestive for fibroblast dedifferentiation. Within the RA-I group, two subgroups could be distinguished; the RA-Ia group showed predominantly immune-related gene activity, while the RA-Ib group showed an additional higher activity of genes indicative for the classical pathway of complement activation. All tissues except the RA-Ia subgroup showed elevated expression of genes involved in tissue remodeling. These results confirm the heterogeneous nature of RA and suggest the existence of distinct pathogenic mechanisms that contribute to RA. The differences in expression profiles provide opportunities to stratify patients based on molecular criteria.

Objective: To assess the relative cost effectiveness of clinical nurse specialist care, inpatient team care, and day patient team care., Methods: Incremental cost effectiveness analysis and cost utility analysis, alongside a prospective randomised controlled trial with two year follow up. Included were patients with rheumatoid arthritis (RA) with increasing difficulty in performing activities of daily living over the previous six weeks. Quality of life and utility were assessed by the Rheumatoid Arthritis Quality of Life questionnaire, the Short Form-6D, a transformed rating scale, and the time tradeoff. A cost-price analysis was conducted to estimate the costs of inpatient and day patient hospitalisations. Other healthcare and non-healthcare costs were estimated from cost questionnaires., Results: 210 patients with RA (75% female, median age 59 years) were included. Aggregated over the two year follow up period, no significant differences were found on the quality of life and utility instruments. The costs of the initial treatment were estimated at euro 200 for clinical nurse specialist care, euro 5000 for inpatient team care, and euro 4100 for day patient team care. Other healthcare costs and non-healthcare costs were not significantly different. The total societal costs did not differ significantly between inpatients and day patients, but were significantly lower for the clinical nurse specialist patients by at least euro 5400., Conclusions: Compared with inpatient and day patient team care, clinical nurse specialist care was shown to provide equivalent quality of life and utility, at lower costs. Therefore, for patients with health conditions that allow for any of the three types of care, the preferred treatment from a health-economic perspective is the care provided by the clinical nurse specialist.

Objective: The objective of this study was to verify the usefulness of a simple disease activity index (SDAI) for rheumatoid arthritis (RA)., Methods: The SDAI is the numerical sum of five outcome parameters: tender and swollen joint count (based on a 28-joint assessment), patient and physician global assessment of disease activity [visual analogue scale (VAS) 0-10 cm] and level of C-reactive protein (mg/dl, normal <1 mg/dl). Analysis initially focused on MN301, one of the three phase III clinical trials of leflunomide, in order to assess possible correlations between the SDAI and the Health Assessment Questionnaire (HAQ) and Disease Activity Score 28 (DAS 28). Results were then compared with the other two trials, MN302 and US301. A total of 1839 patients were evaluated. At baseline, 6 and 12 months, the SDAI, DAS 28, American College of Rheumatology (ACR) response criteria and mean HAQ scores were determined for each patient and compared by linear regression for significant correlation. The SDAI was compared qualitatively to the ACR 20% at 3, 6 and 12 months. The index was further validated by comparing the SDAI with survey results obtained from rheumatologists' evaluations of disease activity in test cases. The survey results included defining categorical changes in the SDAI indicating major, minor or no improvement in disease activity in response to treatment. Changes in total Sharp score at 6 and 12 months of treatment were determined for each of these categories of the SDAI and for comparable categories of the DAS 28., Results: The mean SDAI calculated for patients at baseline in study MN301 was 50.06 (range 25.10-96.10) and was, respectively, 50.55 (range 22.10-98.10) and 43.20 (range 12.90-78.20) in studies MN302 and US301. In all three trials, the SDAI was correlated with a high level of statistical significance to the DAS 28 and HAQ scores at baseline, endpoint and change at endpoint. Patients achieving the ACR 20, 50, 70 or 90% response showed proportionate changes in the SDAI. Analysis of surveyed physician responses showed a significant association between the perception of disease activity and the SDAI, as well as changes in the SDAI. Qualitative analysis of radiographic progression at 6 and 12 months for patients showing either major, minor or no improvement of the SDAI showed correspondingly larger increases of the total Sharp score at 12 months., Conclusion: The SDAI is a valid and sensitive assessment of disease activity and treatment response that is comparable with the DAS 28 and ACR response criteria; it is easy to calculate and therefore a viable tool for day-to-day clinical assessment of RA treatment. Overall results indicate that the SDAI has content, criterion and construct validity.

Matrix metalloproteinases (MMPs) are believed to be pivotal enzymes in the invasion of articular cartilage by synovial tissue in rheumatoid arthritis (RA). Here, we investigated the effects of gene transfer of tissue inhibitors of metalloproteinases (TIMPs) on the invasiveness of RA synovial fibroblasts (RASF) in vitro and in vivo. Adenoviral vectors (Ad) were used for gene transfer. The effects of AdTIMP-1 and AdTIMP-3 gene transfer on matrix invasion were investigated in vitro in a transwell system. Cartilage invasion in vivo was studied in the SCID mouse co-implantation model for 60 days. In addition, the effects of AdTIMP-1 and AdTIMP-3 on cell proliferation were investigated. A significant reduction in invasiveness was demonstrated in vitro as well as in vivo in both the AdTIMP-1- and AdTIMP-3-transduced RASF compared with untransduced SF or SF that were transduced with control vectors. in vitro, the number of invading cells was reduced to 25% (P<0.001) in the AdTIMP-1-transduced cells and to 13% (P<0.0001) in the AdTIMP-3-transduced cells (% of untransduced cells). Cell proliferation was significantly inhibited by AdTIMP-3 and, less, by AdTIMP-1. In conclusion, overexpression of TIMP-1 and TIMP-3 by Ad gene transfer results in a marked reduction of the invasiveness of RASF in vitro and in the SCID mouse model. Apart from the inhibition of MMPs, a reduction in proliferation rate may contribute to this effect. These results suggest that overexpression of TIMPs, particularly TIMP-3 at the invasive front of pannus tissue, may provide a novel therapeutic strategy for inhibiting joint destruction in RA.

The persistent presence of rheumatoid factors (RFs) in the circulation is a characteristic phenomenon in patients with rheumatoid arthritis (RA). Recent data indicate that RFs associated with seropositive RA are derived from terminally differentiated CD20-, CD38+ plasma cells (PCs) present in synovial fluids of the inflamed joints. These cells were shown to secrete RFs actively and are thought to originate from germinal centre (GC)-like structures present in the inflamed synovium. To obtain a representative image of the structural properties of IgM and IgG RFs associated with RA, phage antibody display libraries were constructed from CD38+ PCs isolated from the inflamed joints of RF-seropositive patients with RA. Subsequently, human IgG Fc-binding monoclonal phage antibodies were selected and analysed. The data suggest that RA-associated RFs are encoded by a diverse set of VL and a more restricted set of VH regions. VH gene family usage of PC-derived IgM- and IgG-RFs was found to be restricted to the VH1 and 3 gene families, with a preference for VH3, and many different VL genes were shown to contribute to RF specificity. Clonally related VH as well as VL sequences were identified, based on the presence of identical CDR3 regions and shared somatic mutations. In this B cell selection process base-pair substitutions as well as deletions of triplets in CDR regions, leaving the transcripts in frame, were involved. Together, these data provide further evidence for an Ag-driven immune response in the terminal differentiation into RF-producing PCs in patients with RA, including expansion of clonally related B cells, selection and isotype switching, all hallmarks of a GC reaction.

Aim: To compare the long-term effectiveness of care delivered by a clinical nurse specialist (CNS) with inpatient team care and day patient team care in patients with rheumatoid arthritis and increasing functional limitations. Background. The role of CNSs in the management of patients with rheumatoid arthritis (RA) is evolving, and their effectiveness in comparison with care provided by a rheumatologist alone has been established. However, long-term controlled studies showing how the effectiveness of CNSs compares with that of other forms of co-ordinated care, such as multidisciplinary team care, are lacking., Methods: Two hundred and ten patients rheumatoid arthritis patients were randomized to care delivered by a CNS in a rheumatology outpatient clinic (12 weeks), inpatient team care (2 weeks) and day patient team care (3 weeks). Clinical assessments recorded on study entry, weeks 12, 26, 52, 78 and 104 comprised the health assessment questionnaire (HAQ) and MacMaster Toronto Arthritis (MACTAR) patient preference interview as primary outcome measures. Grip strength, walk test, RAND-36, Rheumatoid Arthritis Quality of Life questionnaire and disease activity score (DAS) were applied as secondary outcome measures., Results: No significant differences in medical treatment, use of services of other health professionals, introduction of adaptive equipment or number of hospitalizations were observed between the three treatment groups during 2 year follow-up, except that visits to nurse specialists were more frequent and home help was less frequent in the CNS group. A comparison of clinical outcomes among the three groups and a comparison between the nurse specialist and inpatient and day patient care groups together did not show any significant differences. Within all three groups functional status, quality of life and disease activity improved significantly (P < 0.05). In general, the results obtained after 12 weeks remained stable until 104 weeks after the start of the study., Conclusion: Care provided by a CNS in an outpatient rheumatology clinic has a similar long-term clinical outcome to inpatient and day patient team care in patients with rheumatoid arthritis. A CNS intervention appears to be an effective innovation in the care for patients with rheumatoid arthritis.

Recent data indicate that rheumatoid factors (RFs) that occur in patients with rheumatoid arthritis (RA) are derived from Ig-producing terminally differentiated CD20-, CD38+ plasma cells present in synovial fluids (SFs). Phage antibody display libraries were constructed using CD38+ plasma cells isolated from SFs of two RF-seropositive RA patients. The libraries were enriched for phage antibodies (Phabs) binding to human IgG (HuIgG) Fc fragments and the sequences of their V genes were analysed. These data provided further evidence for an Ag-driven immune response in patients with RA, including expansion of clonally related B cells, selection and isotype switching, all hallmarks of a germinal center reaction. In the present study, the functional characteristics of these HuIgG Fc-binding monoclonal (mo) Phabs were further analysed in order to provide more insight into the specificity of HuIgG Fc-binding Phabs. Remarkably, all HuIgG Fc-binding moPhabs tested (n=48; derived from four different libraries) displayed polyreactivity. Structural analysis of the CDR3 regions revealed characteristic features of polyreactive Igs. Most H chain CDR3 regions harboured tryptophan/tyrosine-rich parts and approximately 60% of the L chain CDR3 regions of both RA patients displayed an identical stretch of amino acids (W/Y-D-S-S). Supportive for a dominant role of VH in specificity, exchange of VL regions with a single VH region yielded moPhabs with similar specificities. All together, the data suggest the presence of an Ag-driven process in the joints of patients with RA, including somatic mutation and clonal selection entailing isotype switching, resulting in the differentiation of B cells into polyreactive RF-secreting plasma cells.

Background: Matrix metalloproteinases (MMPs) have a pivotal role in the destruction of cartilage in rheumatoid arthritis (RA), which is mediated by the fibroblast-like synoviocytes (FLS)., Objective: To examine the in vitro invasiveness of synoviocytes obtained from inflamed joints of patients with arthritis in relation to the expression of MMP 1-14, 17, 19, cathepsin-K, the tissue inhibitors of matrix metalloproteinases TIMP-1 and TIMP-2 by FLS., Methods: FLS were derived from 56 patients (30 with RA, 17 with osteoarthritis (OA), and nine with avascular necrosis (AVN)). Invasive growth of FLS through an artificial matrix (Matrigel) was measured in a transwell system. The number of cells that migrated through the matrix were counted. Proliferation rate was determined by counting the FLS after seven days of culturing. Expression of MMPs, cathepsin-K and TIMPs was investigated with reverse transcriptase-polymerase chain reaction and related to the expression of a household gene, beta-actin., Results: FLS from RA showed greater invasive growth than FLS from OA and AVN. The median number of cells that grew through the matrix membrane was 4788 for RA, significantly higher than the number for OA, 1875 (p<0.001) and for AVN, 1530 (p=0.014). The median rate of proliferation of RA FLS was 0.27 per day compared with OA 0.22 per day (p= 0.012) and AVN 0.25 per day, but there was no correlation between the rate of proliferation and invasive growth in vitro. FLS from RA and OA that expressed MMP-1, MMP-3, or MMP-10 were significantly more invasive (median number of invasive cells: 3835, 4248, 4990, respectively) than cells that did not express these MMPs (1605, p=0.03; 1970, p=0.004; 2360, p=0.012, respectively). There was also a significant relationship between the expression of MMP-1 and MMP-9 and the diagnosis RA (both p=0.013). The expression levels of mRNA for MMP-1 and MMP-2 correlated with the protein levels produced by the synoviocytes as measured by an enzyme linked immunosorbent assay (ELISA)., Conclusion: FLS of RA invade more aggressively in a Matrigel matrix than OA and AVN FLS; this is not because of a higher rate of proliferation of RA FLS. The significant correlation between the expression of MMP-1, MMP-3, and MMP-10 and invasive growth in a Matrigel transwell system suggests that these MMPs play a part in the invasive growth of FLS obtained from patients with RA.

Objective: To determine the cellular origin of synovial microparticles, their procoagulant properties, and their relationship to local hypercoagulation., Methods: Microparticles in synovial fluid and plasma from patients with rheumatoid arthritis (RA; n = 10) and patients with other forms of arthritis (non-RA; n = 10) and in plasma from healthy subjects (n = 20) were isolated by centrifugation. Microparticles were identified by flow cytometry. The ability of microparticles to support coagulation was determined in normal plasma. Concentrations of prothrombin fragment F(1+2) (by enzyme-linked immunosorbent assay [ELISA]) and thrombin-antithrombin (TAT) complexes (by ELISA) were determined as estimates of the coagulation activation status in vivo., Results: Plasma from patients and healthy controls contained comparable numbers of microparticles, which originated from platelets and erythrocytes. Synovial microparticles from RA patients and non-RA patients originated mainly from monocytes and granulocytes; few originated from platelets and erythrocytes. Synovial microparticles bound less annexin V (which binds to negatively charged phospholipids) than did plasma microparticles, exposed tissue factor, and supported thrombin generation via factor VII. F(1+2) (median 66 nM) and TAT complex (median 710 microg/liter) concentrations were elevated in synovial fluid compared with plasma from the patients (1.6 nM and 7.0 microg/liter, respectively) as well as the controls (1.0 nM and 2.9 microg/liter, respectively)., Conclusion: Synovial fluid contains high numbers of microparticles derived from leukocytes that are strongly coagulant via the factor VII-dependent pathway. We propose that these microparticles contribute to the local hypercoagulation and fibrin deposition in inflamed joints of patients with RA and other arthritic disorders.

Objectives: To compare in a randomized, controlled trial the clinical effectiveness of care delivered by a clinical nurse specialist, inpatient team care, and day patient team care in patients with rheumatoid arthritis (RA) who have increasing functional limitations., Methods: Between December 1996 and January 1999, 210 patients with RA were recruited in the outpatient clinic of the rheumatology department of 6 academic and nonacademic hospitals. Clinical assessments recorded on study entry and weeks 6, 12, 26, and 52 included the Health Assessment Questionnaire (HAQ) and the McMaster Toronto Arthritis Patient Preference Disability Questionnaire as primary outcome measures, and the RAND-36 Item Health Survey, the Rheumatoid Arthritis Quality of Life questionnaire, the Health Utility Rating Scale, and the Disease Activity Score as secondary outcome measures. Patient satisfaction with care was measured on a visual analog scale in week 6 in all 3 groups and again in week 12 in the nurse specialist group., Results: Within all 3 groups, functional status, quality of life, health utility, and disease activity improved significantly over time (P < 0.05). However, a comparison of clinical outcome among the 3 groups and a comparison between the nurse specialist group and the inpatient and day patient care groups together did not show any sustained significant differences. Subgroup analysis showed that age had a significant impact on differences between the 3 treatment groups with respect to functional outcome as measured with the HAQ (P < 0.001). With increasing age, the most favorable outcome shifted from care provided by a clinical nurse specialist and inpatient care to day patient care. Patients' satisfaction with care was significantly lower in the nurse specialist group than in the inpatient and day patient care groups (P < 0.001)., Conclusion: Care provided by a clinical nurse specialist appears to have a similar clinical outcome in comparison with inpatient and day patient team care. Although all patients were highly satisfied with multidisciplinary care, patients who received care provided by a clinical nurse specialist were slightly less satisfied than those who received inpatient or day patient team care. Age appeared to be the only factor related to differences in functional outcome between the 3 treatment groups. The choice of management strategy may, apart from age, further be dependent on the availability of facilities, the preferences of patients and health care providers, and economic considerations.

Objective: Results of an earlier open-label pilot study showed that 4162W94 was a relatively non-depleting anti-CD4 monoclonal antibody that induced >80% down-modulation of CD4 molecules from the surface of T lymphocytes. This placebo-controlled repeat-cycle study was conducted in active rheumatoid arthritis (RA) patients to determine the duration of CD4 blockade required to achieve lasting clinical benefit., Methods: Following DMARD washout, 48 patients (i.e. three cohorts of 16 patients) with ACR-defined RA were to be dosed with 1 (cohort 1), 2 (cohort 2) or 3 (cohort 3) cycles of 5x300 mg 4162W94 or placebo (12 and 4 patients per cohort respectively) at monthly intervals. There was at least 3 months of follow-up after dosing. Clinical outcome was assessed in evaluable patients (receiving at least 80% of each dose course) using ACR20 criteria (required on two consecutive visits). CD4 lymphocyte counts and adverse events were also monitored., Results: Sixteen patients were dosed in each of the first two cohorts; however, the dose was reduced in cohort 3 after five patients had received up to two dose cycles due to accumulating evidence of a high frequency of skin rash. These patients were analysed according to the number of cycles received. A further eight patients received 5x100 mg for one to three cycles prior to stopping the study for administrative reasons. Four of 13 (P=0.119 vs placebo) and 7/13 (P=0.015 vs placebo) in cohorts 1 and 2 respectively achieved ACR20 response on at least two consecutive occasions. No patient receiving 5x100 mg/day or placebo achieved ACR20. Four patients were still responding at the end of the 3-month follow-up period. CD4 lymphocyte suppression (<0.2x10(9)/l on at least two successive occasions) occurred in 11/34 patients who received 4162W94 vs none on placebo. Rash occurred in 21/34 monoclonal antibody-treated patients, including one case of biopsy-confirmed cutaneous vasculitis and 1/11 placebo patients., Conclusion: 4162W94 demonstrated significant clinical efficacy in this study. However, because of unacceptable CD4 lymphopenia and rash, the original hypothesis that prolonged CD4 blockade would give lasting clinical benefit was not tested.

A new treatment approach, involving intense immunosuppression and autologous hematopoietic stem cell transplantation (SCT), has emerged in recent years for the treatment of severe, refractory rheumatic autoimmune diseases including rheumatoid arthritis (RA). The rationale of this strategy is based on the concept of immunoablation by intense immunosuppression with subsequent regeneration of naïve T lymphocytes derived from reinfused hematopoietic progenitor cells. Patients with a therapy-refractory, progressively erosive disease who are at risk of functional disability and early mortality are considered eligible for treatment with autologous SCT. The goal is long-term improvement of disease activity and quality of life. However, when offering SCT to RA patients these benefits should be balanced against toxicities and treatment-related mortality. In several patients with intractable RA, long-term remissions were observed with this strategy, but failures have been reported as well. Only small numbers of RA patients have been treated thus far. Although different treatment protocols have been used, high dose chemotherapy as a means to achieve immunoablation has been invariably used in all studies. In this review we discuss background, clinical results, protocols, and future prospects of high dose chemotherapy and autologous SCT for RA.

Objectives: To predict the long-term outcome of rheumatoid arthritis (RA) with respect to radiographic damage, disability, and disease course using baseline variables, and to construct decision trees identifying patients on an individual level at the extremes of the outcome spectrum of these 3 dimensions., Methods: The 12-year outcome of 112 female RA patients from a prospective inception cohort was assessed by measuring the tertiles of radiographic damage (measured by the modified Sharp/van der Heijde method, SHS), disability (measured by the Health Assessment Questionnaire, HAQ), and severe disease course as defined by patients with either the 33% highest cumulative disease activity (area under the curve of all observed disease activity scores) or the highest tertile of radiographic damage. Patients in the lowest (mild) and highest tertile (severe) of each outcome measure were identified. All baseline parameters known to be associated with each outcome (demographic and socioeconomic parameters; disease duration; disease activity measures; laboratory measures including rheumatoid factor, HLA typing, percentage agalactosyl IgG, functional and radiographic measures) were entered into cross-validated stepwise logistic regression models to find the best predictive combination of baseline parameters for each of the outcomes. Using the results of the logistic regression models, simple decision trees were constructed to categorize patients at an individual level in a particular prognostic group., Results: After 12 years, the lowest and highest tertiles were, respectively, 42.3 and 189 for the SHS and 0.37 and 1.25 for the HAQ. Fifty-five patients had a severe disease course. Mild and severe radiographic damage could be predicted with an accuracy of 90% and 85%, respectively. Mild and severe HAQ could be predicted with an accuracy of 90% and 84%, respectively, and severe disease course with an accuracy of 81%. The baseline variables found to be predictive of all 3 outcome measures were very similar and consisted of combinations of the following baseline parameters: swollen joint count (SJC), Ritchie score, rheumatoid factor (RF), the presence of erosions, and the HAQ score. Additional knowledge of the HLA typing hardly improved the accuracy of the prediction. To predict outcome at the individual level, simple decision trees were constructed using the RF, HAQ, SJC, and presence of erosions at baseline., Conclusion: The present study shows that prediction of outcome in long-term RA is possible and can be done using widely available baseline parameters.

Objectives: (a) To describe the clinical characteristics of acute sarcoid arthritis and the diagnostic value of its presenting clinical features; (b) to evaluate whether disease onset is seasonal; and (c) to evaluate whether smoking behaviour or the presence of HLA class II alleles is a risk factor for the disease., Methods: 579 consecutive patients with recent onset arthritis who had been newly referred to a rheumatology outpatient clinic were included in a prospective cohort study. The presenting clinical features, the smoking behaviour, and the results of HLA-DQ and HLA-DR DNA typing of 55 patients with sarcoid arthritis, 524 patients with other arthritides of recent onset, and samples of the normal population were compared., Results: In all cases the disease showed a self limiting arthritis and overall good prognosis. The diagnostic ability of a combination of four clinical features--symmetrical ankle arthritis, symptoms of less than two months, age below 40 years, and erythema nodosum--was exceptionally high. When test positivity is defined as the presence of at least three of four criteria the set rendered a sensitivity of 93%, a specificity of 99%, a positive predictive value of 75%, and a negative predictive value of 99.7%. The disease clustered in the months March-July. The disease was negatively associated with smoking (odds ratio (OR) 0.09; 95% confidence interval (95% CI) 0.02 to 0.37) and positively associated with the presence of the DQ2 (DQB1*0201)-DR3 (DRB1*0301) haplotype (OR 12.33; 95% CI 5.97 to 25.48)., Conclusion: The disease entity acute sarcoid arthritis has highly diagnostic clinical features. The seasonal clustering, the protective effect of smoking, and the association with specific HLA class II antigens support the hypothesis that it results from exposure of susceptible hosts to environmental agents through the lungs.

Background: Oral contraceptives (OC) and pregnancy are known to have an influence on the risk of onset of rheumatoid arthritis (RA). Pregnancy itself has beneficial effects on the activity of the disease, with relapses post partum. It is not known, however, whether OC and pregnancies influence the ultimate outcome of RA., Objectives: To explore whether OC use and pregnancies influence the 12 year outcome in RA as measured by radiological damage and disability., Methods: In a prospective inception cohort of 132 female patients with recent RA according to the 1987 American College of Rheumatology criteria-a cohort initially gathered to study the association between hormonal factors and the onset of RA-outcome was assessed in a follow up after 12 years. The outcome was evaluated in 112 (85%) women by the radiological damage of hands and feet as measured with the Sharp score modification van der Heijde (SHS), the damage of the large joints measured with the Larsen score (LS) of large joints (0-60), and the disability measured with the Health Assessment Questionnaire (HAQ). The median values of each outcome variable were calculated for several subgroups of patients stratified for OC use and pregnancies before and after onset of the disease and the tertiles of the total number of months of OC use and of pregnancies. The association of OC use and pregnancies before and after onset of the disease with the outcome variables was calculated using Spearman's rank correlation (r(s)). The combined influence of OC use and pregnancies on the SHS, LS, and HAQ at 12 years was estimated using ordinal polytomous logistic regression., Results: The median values of the SHS, LS, and HAQ showed a trend towards less radiological joint damage and less disability in women with long term OC use and multiple pregnancies. This difference, however, was not significant, except for the HAQ score in women with three or more pregnancies in life. There was no association between pregnancies, however defined, and any parameter of RA outcome after 12 years (maximum r(s)=-0.10). The only significant correlation was found between OC use before symptom onset and the LS (r(s)=-0.22, p<0.05). The combination of hormonal variables explained no more than a maximum of 3% of the variance of the 12 year outcome as measured by the SHS., Conclusion: OC use and pregnancy do not significantly influence outcome in long term RA. There is, however, a trend for patients with multiple pregnancies and long term OC use to have less radiographic joint damage and a better functional level.

Background: Effective treatment of active rheumatoid arthritis (RA) requires early diagnosis and early disease modifying antirheumatic drug (DMARD) treatment to have an impact on long term morbidity and mortality. Clinical criteria would facilitate early referral of the patient with suspected RA to a rheumatologist for definitive diagnosis and initiation of DMARD treatment at that point in the disease most likely to have an impact on the long term outcome., Objective: To develop a referral recommendation that may serve as a clinical guide for primary care doctors, enabling them to identify patients with suspected RA during the early inflammatory stages., Methods: Key points of the referral criteria were formed based on a thorough literature review targeting early RA, early arthritis clinics, DMARD treatment for early RA, prognostic factors of disease progression, early RA clinical trials, and quality of life. Evidence was graded using the methods defined by Shekelle et al. A draft version of the criterion was circulated among the authors for critical evaluation. A consensus integrated these comments., Results: Clinical evidence strongly supports the observations that structural damage occurs early in active RA and that early DMARD treatment improves the long term outcome of the disease. The observations indicate that rapid referral to a rheumatologist is advised when RA is suspected. This may be supported by the presence of any of the following: >or=3 swollen joints, metatarsophalangeal/metacarpophalangeal involvement, and morning stiffness of >or=30 minutes., Conclusion: The proposed early referral recommendation is a viable tool for primary care doctors to identify potential patients with active RA early in the disease. Early referral to a rheumatologist for definitive diagnosis and early DMARD treatment should improve the long term outcome of RA.

Objective: The presence of certain HLA class II antigens is strongly associated with the progression of joint destruction in rheumatoid arthritis (RA). Such antigens may be more effective than other class II antigens in inducing the formation of autoreactive T cells after presentation of (auto)antigens. We investigated whether early and aggressive treatment with disease-modifying antirheumatic drugs could modify this relationship., Methods: We analyzed data from 2 studies of patients with early RA treated according to different strategies. The first study consisted of 2 cohorts, one (n = 109; median disease duration before treatment 4 months) was treated according to the pyramid strategy (initial nonsteroidal antiinflammatory drugs, followed by chloroquine [CQ] or sulfasalazine [SSZ] when necessary), and the other (n = 97; median disease duration before treatment 2 weeks) was immediately treated with CQ or SSZ. The second study comprised 155 patients (median disease duration 4 months) from the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial, in which patients were randomly assigned to combination treatment with step-down prednisolone, methotrexate (MTX), and SSZ (n = 76) or with SSZ alone (n = 79). Prednisolone and MTX dosages were tapered and stopped after 28 and 40 weeks, respectively. The extent of joint damage was measured by the modified Sharp method., Results: In the pyramid treatment cohort, the median increase in Sharp score after 2 years was 12 in patients positive for the shared epitope (SE) and 1 in SE- patients. In the immediate treatment cohort, the median increase was 3 in SE+ patients and 2 in SE- patients. In the SSZ group of the COBRA study, the median increase in Sharp score after 1 year was 11 in DR4+ patients and 3 in DR4- patients. In the combination treatment group, the median increase was 4 in DR4+ patients and 2 in DR4- patients. Significance was confirmed by multiple regression using log-transformed scores., Conclusion: Early and aggressive antirheumatic drug treatment affects the association of HLA class II alleles with progression of joint damage in RA.

We investigated whether 5 to 20mg per week oral methotrexate could slow down disease progression in 44 patients with inclusion body myositis in a randomized double-blind placebo-controlled study over 48 weeks. Mean change of quantitative muscle strength testing sum scores was the primary study outcome measure. Quantitative muscle strength testing sum scores declined in both treatment groups, -0.2% for methotrexate and -3.4% for placebo (95% confidence interval = -2.5% to +9.1% for difference). There were also no differences in manual muscle testing sum scores, activity scale scores and patients' own assessments after 48 weeks of treatment. Serum creatine kinase activity decreased significantly in the methotrexate group. We conclude that oral methotrexate did not slow down progression of muscle weakness but decreased serum creatine kinase activity.

Interleukin-1 (IL-1) has been implicated in the pathogenesis of rheumatoid arthritis (RA). We investigated whether IotaL-1 gene locus polymorphisms are associated with susceptibility to or severity of RA. Genotyping for IL-1alpha, IL-1beta and IL-1Ra single nucleotide polymorphisms (SNPs) performed in a cross-sectional group of 312 consecutive RA patients (RA-group 1) and a cohort of 94 incident female RA patients (RA-group 2) revealed that the rare IL-1RN + 2017 C allele was significantly increased in RA compared to controls (n = 245). A retrospective analysis in RA-group 1 showed no significant associations between IL-1 genotypes and disease severity. A prospective study in RA-group 2 demonstrated that the extent of joint destruction over 12 years was higher in patients genotyped heterozygous for the IL-1 A + 4845, IL-1B + 3953 and IL-1RN + 5111 SNPs compared to homozygous wildtype patients, although differences did not reach statistical significance. These data indicate that the IL-1RN + 2017 polymorphism is associated with susceptibility to RA.

Objective: To develop a clinical model for the prediction, at the first visit, of 3 forms of arthritis outcome: self-limiting, persistent nonerosive, and persistent erosive arthritis., Methods: A standardized diagnostic evaluation was performed on 524 consecutive, newly referred patients with early arthritis. Potentially diagnostic determinants obtained at the first visit from the patient's history, physical examination, and blood and imaging testing were entered in a logistic regression analysis. Arthritis outcome was recorded at 2 years' followup. The discriminative ability of the model was expressed as a receiver operating characteristic (ROC) area under the curve (AUC)., Results: The developed prediction model consisted of 7 variables: symptom duration at first visit, morning stiffness for > or =1 hour, arthritis in > or =3 joints, bilateral compression pain in the metatarsophalangeal joints, rheumatoid factor positivity, anti-cyclic citrullinated peptide antibody positivity, and the presence of erosions (hands/feet). Application of the model to an individual patient resulted in 3 clinically relevant predictive values: one for self-limiting arthritis, one for persistent nonerosive arthritis, and one for persistent erosive arthritis. The ROC AUC of the model was 0.84 (SE 0.02) for discrimination between self-limiting and persistent arthritis, and 0.91 (SE 0.02) for discrimination between persistent nonerosive and persistent erosive arthritis, whereas the discriminative ability of the American College of Rheumatology 1987 classification criteria for rheumatoid arthritis was significantly lower, with ROC AUC values of 0.78 (SE 0.02) and 0.79 (SE 0.03), respectively., Conclusion: A clinical prediction model was developed with an excellent ability to discriminate, at the first visit, between 3 forms of arthritis outcome. Validation in other early arthritis clinics is necessary.

Objective: Ethical constraints on the conduct of placebo-controlled trials evaluating new therapies for serious chronic diseases, such as rheumatoid arthritis (RA), indicate the need for discerning methods to assess treatment effect in active-controlled clinical trials. Dynamic gadolinium-enhanced magnetic resonance imaging (DEMRI) is a sensitive technique for the detection of synovial inflammation in RA. Therefore, this investigation was undertaken to evaluate DEMRI as an efficacy assessment tool for differentiating treatment effect in a randomized, active-controlled trial comparing leflunomide and methotrexate., Methods: Patients with active RA (n = 39) were randomized in a 2-center, prospective, double-blind clinical trial to receive either leflunomide (n = 18) or methotrexate (n = 21) therapy for 4 months. DEMRI scans were obtained at baseline and at 4 months, and the initial rate of enhancement (IRE) and the maximal signal intensity (SI) enhancement (ME) were calculated from the SI curves. Clinical improvement was assessed by conventional outcome measures., Results: Thirty-four patients (17 treated with leflunomide and 17 with methotrexate) had usable baseline and end point DEMRI scans. Leflunomide treatment was associated with a significantly greater improvement in IRE compared with methotrexate treatment (P < 0.05). Average values of ME indicated reduction of inflammation with both leflunomide and methotrexate. The improvement in clinical signs and symptoms, as measured by traditional assessments, was comparable for both active treatments., Conclusion: Results of this study validate the sensitivity of DEMRI in detecting inflammatory changes in active RA in response to treatment. Improvement in synovial inflammation as measured by IRE was significantly better with leflunomide than with methotrexate over 4 months of therapy.

Our aim was to examine, using microsatellite (ms) markers, the contribution of the telomeric part of the HLA region to rheumatoid arthritis (RA) predisposition in the Spanish population. We have looked at the distribution of DQB1, DRBI and five ms loci (D6S1014, D6S273, D6STNFa, MIB and C1-2-5) within the HLA region in 147 Spanish RA patients and 202 control subjects. A total of 19 conserved ms configurations were observed, twelve of them in linkage disequilibrium with particular DQB1-DRB1 haplotypes. Interestingly, haplotype c1 (DQB1*0201-DRB1*0301-D6S1014*143-D6S273*139-D6STNFa*99-MIB*350-C1-2-5*196) was significantly associated with RA predisposition. As part of this haplotype, the MIB*350 allele was found to be a risk factor independently of the RA-predisposing haplotypes. The present results along with data from others prove the existence of a second predisposing locus located inside the MHC region, and suggest that might be located within the TNFa-HLA-B region.

The integral membrane protein linker for activation of T cells (LAT) is a central adapter protein in the T-cell receptor (TCR)-mediated signaling pathways. The cellular localization of LAT is extremely sensitive to intracellular redox balance alterations. Reduced intracellular levels of the antioxidant glutathione (GSH), a hallmark of chronic oxidative stress, resulted in the membrane displacement of LAT, abrogated TCR-mediated signaling and consequently hyporesponsiveness of T lymphocytes. The membrane displacement of LAT is accompanied by a considerable difference in the mobility of LAT upon native and nonreducing denaturing polyacrylamide gel electrophoresis analysis, a finding indicative of a conformational change. Targeted mutation of redox-sensitive cysteine residues within LAT created LAT mutants which remain membrane anchored under conditions of chronic oxidative stress. The expression of redox-insensitive LAT mutants allows for restoration of TCR-mediated signal transduction, whereas CD28-mediated signaling pathways remained impaired. These results are indicative that the membrane displacement of LAT as a result of redox balance alterations is a consequence of a conformational change interfering with the insertion of LAT into the plasma membrane. Conclusively, the data suggest a role for LAT as a crucial intermediate in the sensitivity of TCR signaling and hence T lymphocytes toward chronic oxidative stress.

With the introduction of new disease-modifying antirheumatic drugs (DMARDs) and other therapeutic agents, the management of rheumatoid arthritis (RA) has shifted toward earlier, more aggressive therapy. The ultimate goal is to prevent structural joint damage that leads to pain and functional disability. Early diagnosis of RA is therefore essential, and early DMARD treatment combined with nonsteroidal anti-inflammatory drugs is recommended. Combination DMARD regimens and new biologic agents (anti-tumor necrosis factor [TNF] therapies [infliximab, etanercept] and the interleukin [IL]-1 antagonist [anakinra]) have emerged as viable options for early treatment of RA patients. These new biologic agents and future nonbiologic agents that target proteins in signaling cascades are likely to change the landscape of RA treatments.

Conflicting data have been published on the value of the shared epitope (SE) hypothesis in predicting disease outcome in rheumatoid arthritis (RA). Recently we have proposed an alternative hypothesis, referred to as the RA protection (RAP) model. In this model, the HLA-DQ loci carry predisposition while HLA-DRB1 alleles encoding the motif DERAA provide protection against severe RA. In the present study, we have compared the respective values of the models in predicting both remission and erosions in early RA patients. We made use of an early arthritis clinic in which 158 RA patients and 138 patients with undifferentiated arthritis were enrolled. Patients were typed for HLA-DQ and -DR using high resolution DNA typing methods. Homozygosity for predisposing HLA-DQ alleles was associated with no remission and high erosion score. The presence of DERAA-bearing DRB1 alleles was negatively associated with erosions in otherwise predisposed individuals and increased the chance of being in remission. We found that the RAP model was significantly better than the SE model in predicting remission rate and erosion scores at one and two years in early RA patients. We conclude that HLA polymorphism does not only affect RA susceptibility, but also protects against severe disease at early stage.

TNF blocking agents have proved to be effective DMARDs and they have been a major advance in the treatment of RA. Their use is expanding to other rheumatic diseases. However, rare to uncommon and unexpected toxicities have been found and others may yet be found during their use. Studies in selected areas of efficacy, toxicity, and general use of TNF blocking agents are needed to help further define the most appropriate use of these agents. Use of these drugs will require doctors experienced in the diagnosis, treatment, and assessment of RA and other rheumatic diseases. These doctors will need to make long term observations of efficacy and toxicity. Further considerations which must be made when using TNF blocking agents in this disease include the cost and a recognition that data in subgroups are still being acquired. It is hoped that this statement, which is based upon the best evidence available at the time of its creation, and modified by expert opinion, will facilitate the optimal use of these agents for our patients with RA and other rheumatic diseases.

Purpose: To compare the effect of delayed and early treatment strategies on disease outcome in patients with rheumatoid arthritis., Subjects and Methods: Between 1993 and 1995, 109 patients diagnosed with probable or definite rheumatoid arthritis of recent onset were initially treated with analgesics; if they had persistent active disease, they were treated subsequently with the disease-modifying drugs chloroquine or salazopyrine (delayed treatment). Between 1996 and 1998, similar patients (n = 97) were promptly treated with either chloroquine or salazopyrine (early treatment)., Results: The median lag to the initiation of disease-modifying treatment was 15 days in the early treatment group and 123 days in the delayed treatment group. There was less radiologic joint damage after 2 years in the early treatment group (median Sharp score, 3.5; 95% confidence interval [CI]: 1 to 7) compared with the delayed treatment group (median Sharp score, 10; 95% CI: 5 to 15; P <0.05). The median area under the curve of the 2-year disease activity score was lower in the early treatment group (64 units; 95% CI: 59 to 69 units) compared with the delayed treatment group (73 units; 95% CI: 69 to 77 units; P = 0.002)., Conclusion: In this nonrandomized comparison, early introduction of disease-modifying antirheumatic drugs was associated with a better disease outcome after 2 years.

Ten patients with active, destructive rheumatoid arthritis refractory to antirheumatic therapy enrolled in a study to evaluate the effects of intensive immunosuppression followed by autologous stem cell transplantation. Intensive immunosuppression was achieved with high dose cyclophosphamide as part of the mobilization (4 g/m2) and conditioning (200 mg/kg) regimen. The autologous stem cell products were enriched for CD34+ cells to minimize the chance of reinfusing autoreactive lymphocytes. Eight patients completed all consecutive treatment steps, one patient withdrew after mobilization because of improvement, one patient was taken off study because of pulmonary embolism. The treatment appeared feasible and safe, and marked sustained clinical improvement was observed in 6 patients, 2 of whom were previously unresponsive to tumor necrosis factor blocking therapy. In 5 patients disease modifying antirheumatic drugs were successfully withdrawn after transplantation. The treatment induced significant lymphopenia, with low levels of naive CD4+ T cells in particular, without clinical sequelae. Titers of rheumatoid factor dropped but did not normalize.

The current pharmacotherapy of rheumatoid arthritis (RA) consists of non-steroidal anti inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) such as sulphasalazine, leflunomide and methotrexate. DMARDs can be given as monotherapy or in combination. However, not all patients show an adequate response due to toxicity or lack of efficacy. From animal studies and clinical studies in patients with RA, we know that tumour necrosis factor (TNF) is directly involved in the pathogenesis of RA. Two forms of TNF inhibition therapy have been extensively investigated in RA: anti-TNF monoclonal antibodies (infliximab) and TNF receptor-Fc fusion protein (etanercept). Both types of TNF inhibition induce a rapid improvement in multiple clinical measures of disease activity and patient functional status. Furthermore, a beneficial effect was demonstrated on radiographic progression of joint damage. Etanercept and the combination infliximab-methotrexate are generally well tolerated.

Objective: To provide a comprehensive understanding of the humoral immune response that takes place at the site of inflammation in rheumatoid arthritis (RA), we studied the functional properties of synovial B cells. In particular, the response to various modes of mitogen stimulation was investigated., Methods: Purified synovial fluid (SF) B cells were cultured in the presence of CD40 ligand (CD40L)-expressing fibroblasts and cytokines, activated T cells, or phorbol myristate acetate (PMA)/ionomycin. Proliferation was determined by 3H-thymidine incorporation. Release of intracellular calcium was studied by flow cytometry., Results: The inflamed joints of RA patients contained a population of CD20+,CD38- B cells with dramatically impaired mitogen responsiveness. Although the Ig-producing capacity was intact, these cells failed to proliferate in response to (a) CD40 in the presence of interleukin-2 (IL-2) and IL-10, (b) activated T cells, or (c) stimulation via the B cell receptor. Moreover, SF CD20+,CD38- B cells revealed a defective B cell receptor-induced Ca2+ influx, reminiscent of anergic B cells. Release of intracellular Ca2+ by ionomycin in the presence of the protein kinase C activator PMA did not restore the proliferative capacity. These findings indicate blockades in the proximal and distal intermediates involved in mitogen signaling., Conclusion: SF CD20+,CD38- B cells have functionally impaired proliferative responsiveness. The capacity of these cells to respond to activation by the production of Ig supports the notion that these cells might serve as Ig-producing effector cells and, as such, play a role in the pathophysiology of RA.

Objective: To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial., Methods: Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX., Results: Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively)., Conclusion: Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.

Background: Systemic sclerosis (SSc, scleroderma) in either its diffuse or limited skin forms has a high mortality when vital organs are affected. No treatment has been shown to influence the outcome or significantly affect the skin score, though many forms of immunosuppression have been tried. Recent developments in haemopoietic stem cell transplantation (HSCT) have allowed the application of profound immunosuppression followed by HSCT, or rescue, to autoimmune diseases such as SSc., Methods: Results for 41 patients included in continuing multicentre open phase I/II studies using HSCT in the treatment of poor prognosis SSc are reported. Thirty seven patients had a predominantly diffuse skin form of the disease and four the limited form, with some clinical overlap. Median age was 41 years with a 5:1 female to male ratio. The skin score was >50% of maximum in 20/33 (61%) patients, with some lung disease attributable to SSc in 28/37 (76%), the forced vital capacity being <70% of the predicted value in 18/36 (50%). Pulmonary hypertension was described in 7/37 (19%) patients and renal disease in 5/37 (14%). The Scl-70 antibody was positive in 18/32 (56%) and the anticentromere antibody in 10% of evaluable patients. Peripheral blood stem cell mobilisation was performed with cyclophosphamide or granulocyte colony stimulating factor, alone or in combination. Thirty eight patients had ex vivo CD34 stem cell selection, with additional T cell depletion in seven. Seven conditioning regimens were used, but six of these used haemoimmunoablative doses of cyclophosphamide +/- anti-thymocyte globulin +/- total body irradiation. The median duration of follow up was 12 months (3-55)., Results: An improvement in skin score of >25% after transplantation occurred in 20/29 (69%) evaluable patients, and deterioration in 2/29 (7%). Lung function did not change significantly after transplantation. One of five renal cases deteriorated but with no new occurrences of renal disease after HSCT, and the pulmonary hypertension did not progress in the evaluable cases. Disease progression was seen in 7/37 (19%) patients after HSCT with a median period of 67 (range 49-255) days. Eleven (27%) patients had died at census and seven (17%) deaths were considered to be related to the procedure (direct organ toxicity in four, haemorrhage in two, and infection/neutropenic fever in one). The cumulative probability of survival at one year was 73% (95% CI 58 to 88) by Kaplan-Meier analysis., Conclusion: Despite a higher procedure related mortality rate from HSCT in SSc compared with patients with breast cancer and non-Hodgkin's lymphoma, the marked impact on skin score, a surrogate marker of mortality, the trend towards stabilisation of lung involvement, and lack of other treatment alternatives justify further carefully designed studies. If future trials incorporate inclusion and exclusion criteria based on this preliminary experience, the predicted procedure related mortality should be around 10%.

Severe adult rheumatoid arthritis is a cause of progressive disability and increased mortality across Europe. A cure for the disease remains elusive, but control of symptoms and maintenance of individual independence is possible. Anti-cytokine therapies offer a new approach to disease management. They are effective after the failure of full doses of methotrexate, and are at least as effective as methotrexate in retarding the progression of radiological changes. Until more is known about the long-term safety and efficacy of these drugs they should be reserved for patients with severe disease who are progressing despite adequate doses of methotrexate or other disease-modifying anti-rheumatic drugs. They should be continued until therapeutic failure or intolerance. A comprehensive health economic evaluation is needed to optimally direct the use of these drugs. This should be undertaken when long-term safety and efficacy studies are completed.

It has become clear that early suppression of rheumatoid arthritis disease activity is important in preventing progressive joint destruction and functional decline. To achieve this goal, many rheumatologists today advocate a more aggressive approach, using combinations of classic disease-modifying antirheumatic drugs-often including methotrexate-or new drugs. During the last 2 years, the combination of methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone has been demonstrated to be more beneficial than monotherapy in patients with early rheumatoid arthritis. In addition, the superior efficacy of the combination of new tumor necrosis factor-alpha blocking agents plus methotrexate to methotrexate alone in patients with chronic disease is very promising. Most studies of combination therapy focus on the efficacy of a combination compared with monotherapy, rather than on the efficacy of a treatment strategy. Although these studies of combination therapy provide useful information about the possible synergistic action of combinations of drugs, many questions remain unanswered, and studies evaluating different treatment strategies are needed before a new approach can be suggested.

Interindividual variation in the expression of tumor necrosis factor alpha (TNF) suggests the existence of functionally distinct TNF alleles that could play a role in susceptibility to TNF associated diseases such as rheumatoid arthritis (RA). To determine whether differential expression of TNF alleles exists, the relative contribution of TNF alleles in total TNF RNA production in peripheral blood mononuclear cells (PBMC) of healthy individuals and synovial tissue of RA patients was analyzed. By using a Tai I restriction fragment length polymorphism (RFLP) located at position +489 in the first intron of the gene, the relative contribution of each allele in precursor transcript production in heterozygous individuals could be measured. By means of this method we studied whether differences exist between TNF alleles in TNF pre-mRNA production. The relative contribution of TNF alleles to the non-spliced RNA pool was measured in PBMC of healthy individuals which were stimulated with LPS, PMA and anti-CD3 and anti-CD28 monoclonal antibodies for different time periods. Moreover, synovial biopsy material of RA patients was analyzed. The results of this study do not reveal a difference in the contribution of distinct TNF alleles in TNF pre-mRNA production upon in vitro and physiological stimulation conditions in healthy individuals and RA patients. Since some of the individuals whose PBMC were tested were also heterozygous for either -308, -1031, -863, -857 TNF promoter/enhancer single nucleotide polymorphisms (SNPs), the data argue against functional relevance of these TNF promoter/enhancer SNPs in the regulation of transcription. In conclusion, the data do not provide evidence for the existence of transcriptionally distinct TNF alleles to explain interindividual variation in TNF expression.

Predisposition to rheumatoid arthritis (RA) is thought to be associated with HLA-DR1, -DR4, and -DR10. However, many epidemiological observations are better explained by a model in which the DQ alleles that are linked to these DR alleles, i.e., DQ5, DQ7, and DQ8, predispose to RA, while certain DR alleles have a dominant protective effect. All protective DRB1 alleles, e.g., *0402, *1301, and *1302, encode a unique motif, (70)DERAA(74). The protection may be explained by the presentation of DRB1-derived peptides by DQ to immunoregulatory T cells, because it was demonstrated in various autoimmune disease models that T cell responses to certain self-Ags can be involved in disease suppression. The aim of this study was to analyze whether peptides carrying the DERAA motif are naturally processed by human APC and presented in the context of the RA-predisposing DQ. Using a synthetic peptide carrying the DRB1*0402-derived sequence (65)KDILEDERAAVDTYC(79), we generated DERAA peptide-specific DQ-restricted T cell clones (TCC) from a DQ8 homozygous individual carrying DERAA-negative DR4 alleles. By analyzing the proliferation of these TCC, we demonstrated natural processing and presentation of the DERAA sequence by the APC of all the individuals (n = 12) carrying a DERAA-positive DRB1 allele and either DQ8 or the DQ8-related DQ7. Using a panel of truncated synthetic peptides, we identified the sequence (67)(I)LEDERAAVD(TY)(78) as the minimal determinant for binding to DQ8 and for recognition by the TCC. These findings support a model in which self-MHC-derived peptide can modulate predisposition to autoimmune disease in humans.