Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs.
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OBJECTIVE: To summarize the evidence on treatment withdrawal rates reported in observational studies and randomized controlled trials (RCTs) of methotrexate (MTX), parenteral gold (GST), sulphasalazine (SSZ) and hydroxychloroquine (HCQ) among patients with rheumatoid arthritis (RA). METHODS: Two independent Medline searches were used to retrieve relevant studies published between 1966 and 1997. Those which disclosed information on the number of patients withdrawing from the drug were retained. Cumulative probabilities of survival on treatment were then computed using actuarial survival estimates, and differences were tested using log-rank, Wilcoxon and Cox proportional hazards tests. RESULTS: A total of 159 studies provided withdrawal information, and the numbers of patients who withdrew, in general or because of inefficacy or toxicity, could be abstracted from 110 studies contributing 142 treatment arms (MTX, 48; GST, 56; SSZ, 22; HCQ, 16). Data for HCQ were available only up to 24 months, but combined percentages of patients estimated to have continued MTX, GST or SSZ, respectively, for 60 months were 36, 23 and 22% when all failures were considered, 75, 73 and 53% when withdrawals due to lack of efficacy alone were considered, and 65, 36 and 48% when only withdrawals due to toxicity were taken into account. The Cox proportional hazards test performed on all withdrawals, after adjusting for year of publication and type of study, revealed that patients remained on MTX significantly longer than they did on the other three agents; however, the patients stayed significantly longer on GST than MTX when withdrawals for inefficacy were analysed separately. No significant differences in withdrawal rates were noted between observational studies and RCTs. CONCLUSION: Patients with RA stay significantly longer on MTX than on other disease-modifying anti-rheumatic drugs. Higher withdrawal rates among those given GST are mainly due to high toxicity, whereas the majority of withdrawals from SSZ and HCQ result from lack of efficacy. Withdrawal rates in observational studies are similar to those reported in RCTs. (+info)
Neonatal induction of tolerance to T(h)2-mediated autoimmunity in rats.
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Brown-Norway (BN) rats are highly susceptible to drug-induced immune dysregulations and when injected with mercuric chloride (HgCl(2)) or sodium aurothiopropanolsulfonate (ATPS), they develop a syndrome characterized by a polyclonal B cell activation depending upon CD4(+) T(h)2 cells that recognize self-MHC class II molecules. Since peripheral tolerance of T(h)2 cells might be crucial in the prevention of immunological manifestations such as allergy, establishing conditions for inducing tolerance to HgCl(2)- or ATPS-mediated immune manifestations appeared to be of large interest. We report here that BN rats neonatally injected with HgCl(2): (i) do not develop the mercury disease, (ii) remain resistant to HgCl(2)-induced autoimmunity at 8 weeks of age and later, provided they are regularly exposed to HgCl(2), (iii) are still susceptible to ATPS-induced immune manifestations, and (iv) exhibit spleen cells that adoptively transfer tolerance to HgCl(2)-induced autoimmunity in naive, slightly irradiated, syngeneic recipients. These findings demonstrate that dominant specific tolerance can be neonatally induced using a chemical otherwise responsible for T(h)2-mediated autoimmunity. (+info)
Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis.
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OBJECTIVE: To evaluate the toxicity of slow-acting anti-rheumatic drugs (SAARDs) and non-steroidal anti-inflammatory drugs (NSAIDs) in early rheumatoid arthritis. METHODS: Patients were randomized to receive a SAARD-hydroxychloroquine (HCQ; n=120), i.m. gold (n=114) or methotrexate (MTX; n=118)-or a NSAID only (n=67). Patients in the three SAARD groups were allowed to take NSAIDs. Follow-up included 545 patient-years (p-yr). Adverse effects were attributed to specific medications using the Naranjo scoring method. RESULTS: Fifty-five per cent of the patients suffered from adverse effect(s). Adverse effects were most common during i.m. gold therapy (87 per 100 p-yr), which led to permanent discontinuation of this treatment in 31 cases. The incidences of adverse effects that were probably attributable to NSAIDs in patients treated simultaneously with a SAARD were similar for the three SAARD groups. The mean period until the first adverse effect was longer in the MTX group (39 weeks) than in the HCQ group (27 weeks). Baseline clinical and sociodemographic parameters were not predictive of the occurrence of adverse effects. CONCLUSION: No adverse effect could be classified as definitely related to either SAARDs or NSAIDs by the Naranjo scoring method. The incidence of possible adverse effects of NSAIDs and SAARDs was 72 per 100 p-yr, and adverse effects led to permanent discontinuation of the therapy in 56 cases (13%) (31 patients receiving i.m. gold, 12 receiving MTX, 10 receiving HCQ and three receiving NSAID only). (+info)
The balance between CD45RChigh and CD45RClow CD4 T cells in rats is intrinsic to bone marrow-derived cells and is genetically controlled.
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The level of CD45RC expression differentiates rat CD4 T cells in two subpopulations, CD45RC(high) and CD45RC(low), that have different cytokine profiles and functions. Interestingly, Lewis (LEW) and Brown Norway (BN) rats, two strains that differ in their ability to mount type 1 and type 2 immune responses and in their susceptibility to autoimmune diseases, exhibit distinct CD45RC(high)/CD45RC(low) CD4 T cell ratios. The CD45RC(high) subpopulation predominates in LEW rats, and the CD45RC(low) subpopulation in BN rats. In this study, we found that the antiinflammatory cytokines, IL-4, IL-10, and IL-13, are exclusively produced by the CD45RC(low) CD4 T cells. Using bone marrow chimeras, we showed that the difference in the CD45RC(high)/CD45RC(low) CD4 T cell ratio between naive LEW and BN rats is intrinsic to hemopoietic cells. Furthermore, a genome-wide search for loci controlling the balance between T cell subpopulations was conducted in a (LEW x BN) F(2) intercross. Genome scanning identified one quantitative trait locus on chromosome 9 (approximately 17 centiMorgan (cM); log of the odds ratio (LOD) score 3.9). In addition, two regions on chromosomes 10 (approximately 28 cM; LOD score 3.1) and 20 (approximately 40 cM; LOD ratio score 3) that contain, respectively, a cytokine gene cluster and the MHC region were suggestive for linkage. Interestingly, overlapping regions on these chromosomes have been implicated in the susceptibility to various immune-mediated disorders. The identification and functional characterization of genes in these regions controlling the CD45RC(high)/CD45RC(low) Th cell subpopulations may shed light on key regulatory mechanisms of pathogenic immune responses. (+info)
The rheumatoid arthritis patient in the clinic: comparing more than 1,300 consecutive DMARD courses.
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BACKGROUND: Therapy of rheumatoid arthritis (RA) is typically characterized by the sequential use of disease-modifying anti-rheumatic drugs (DMARDs). This study aimed to reveal treatment patterns with traditional DMARDs and their changes during the two decades before the recent introduction of new DMARDs. METHODS: A total of 593 RA patients were followed from their first presentation to our clinic throughout the course of their disease; 222 patients received their first DMARD therapy while under our care. More than 2,300 patient years of therapy were analysed for the efficacy [using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as surrogates] and duration of drug therapy of consecutive DMARDs. RESULTS: Before 1985, 65-90% of initial DMARDs were gold compounds, but their use decreased continuously thereafter. Antimalarial (AM) drugs were important initial DMARDs in new patients at all times, whereas sulphasalazine (SSZ) and methotrexate (MTX) gained increasing significance after 1985 (the first DMARD was MTX in up to 29% of new patients). Penicillamine (DPA), azathioprine (AZP), cyclosporin (CyA) and combination therapies were not usually employed initially, but were reserved for the later course of the disease. Gender, age and rheumatoid factor were not different between patients receiving different DMARDs. The baseline acute-phase response was higher in patients treated with MTX (mean CRP 3.5 mg/dl) than in those treated with SSZ (CRP 2.4 mg/dl; P < 0.05) or AM (CRP 2.1 mg/dl; P < 0.05), suggesting that MTX was used preferentially in patients with high disease activity. On the other hand, once AM or SSZ had been discontinued, MTX was the most common subsequent DMARD (in 31 and 56% respectively). Comparison of first DMARDs with subsequent ones revealed that first DMARDs were more effective: the acute-phase response decreased most prominently during first therapies (CRP reduction was 1.28 mg/dl during first courses and 0.35 mg/dl during fourth or later courses; P < 0.01); and retention rates were significantly longer for first compared with subsequent therapies (median of 24.5 months for first and 18.6 months for fourth or subsequent therapies; P < 0.001). CONCLUSION: MTX was the most commonly employed DMARD therapy for RA and was used increasingly as first therapy in newly diagnosed RA. Patients with high disease activity were given MTX therapy more often than other DMARDs, while those with low activity were more likely to receive SSZ or AM, and MTX on failure of these drugs. First DMARDs in new patients were retained longer than subsequent DMARDs, apparently because they are more effective. (+info)
Five-year followup of rheumatoid arthritis patients after early treatment with disease-modifying antirheumatic drugs versus treatment according to the pyramid approach in the first year.
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OBJECTIVE: To evaluate whether the clinical advantages observed after 1 year in a randomized controlled clinical trial, in which 2 treatment strategies were compared (the early disease-modifying antirheumatic drug [DMARD] approach versus the pyramid approach), persist after 5 years. METHODS: In this study, 238 patients with recently diagnosed rheumatoid arthritis (RA) were randomized to either the pyramid group (n = 56) or the early DMARD group (n = 182). Patients assigned to the pyramid group received nonsteroidal antiinflammatory drugs for at least 1 year after inclusion (the mean +/- SD lag time until first prescription of a DMARD was 14 +/- 9 months). Patients in the early DMARD group were treated with a DMARD immediately after inclusion. RESULTS: After 5 years, data were available for 44 patients in the pyramid group (79%) and 145 patients in the early DMARD group (80%). No prolongation of the clinical advantages in favor of the early DMARD group, as observed after the first year, was demonstrated. Nevertheless, a significantly shorter delay time until complete response and a higher number of patients with overall clinically relevant improvement at several assessment points were observed in the early DMARD group compared with the pyramid group. CONCLUSION: The clinical results in favor of the early DMARD group, as observed after the first year, were not as evident after 5 years. This indicates that a more aggressive treatment approach in early RA is required, and that treatment should be continued for a prolonged period of time, in order to maintain the advantages obtained in the first year. (+info)
Patient preferences for treatment of rheumatoid arthritis.
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OBJECTIVE: To elicit treatment preferences of patients with rheumatoid arthritis (RA) for disease modifying antirheumatic drugs (DMARDs) with varying risk profiles. METHODS: Patient values for 16 DMARD characteristics were ascertained using published data about side effects, effectiveness, and cost. Patient preferences were determined by Adaptive Conjoint Analysis, an interactive computer program that predicts preferences by asking patients to make trade-offs between specific treatment characteristics. Simulations were run to derive preferences for four drugs: methotrexate, gold, leflunomide, and etanercept, under different risk-benefit scenarios. Infliximab was not included because it is given with methotrexate, and we did not include preferences for combination therapy. Based on each patient's expressed preferences, and the characteristics of the treatments available at the time of the study, the option that best fitted each patient's perspective was identified. RESULTS: 120 patients (mean age 70 years) were interviewed. For the base case scenario (which assumed the maximum benefits reported in the literature, a low probability of adverse effects, and low equal monthly "co-pays" (out of pocket costs)), 95% of the respondents preferred etanercept over the other treatment options. When all four options were described as being equally effective, 88% continued to prefer etanercept owing to its safer short term adverse effect profile. Increasing etanercept's co-pay to $30.00 decreased the percentage of patients preferring this option to 80%. CONCLUSIONS: In this study, older patients with RA, when asked to consider trade-offs between specific risk and benefits, preferred etanercept over other treatment options. Preference for etanercept is explained by older patients' risk aversion for drug toxicity. (+info)
Studies of congenic lines in the Brown Norway rat model of Th2-mediated immunopathological disorders show that the aurothiopropanol sulfonate-induced immunological disorder (Aiid3) locus on chromosome 9 plays a major role compared to Aiid2 on chromosome 10.
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Brown Norway (BN) rats treated with aurothiopropanol-sulfonate (Atps) constitute a model of Th2-mediated immunological disorders associated with elevated IgE responses and renal IgG deposits. Using F(2) offspring between Atps-susceptible BN and Atps-resistant Lewis rats, we had previously mapped three quantitative trait loci on chromosomes 9, 10, and 20 for which BN alleles increased susceptibility to Atps-induced immunological disorders (Aiid). In this study we have used congenic lines for the latter two quantitative trait loci, formerly called Atps2 and Atps3 and now named Aiid2 (chromosome 10) and Aiid3 (chromosome 9), for fine mapping and characterization of their impact on Atps-triggered reactions. In Aiid2 congenic lines, the gene(s) controlling part of the IgE response to Atps was mapped to an approximately 7-cM region, which includes the IL-4 cytokine gene cluster. Two congenic lines in which the introgressed segments shared only a portion of this 7-cM region, showed an intermediate IgE response, indicating the involvement of several genes within this region. Results from BN rats congenic for the Lewis Aiid3 locus, which we mapped to a 1.2-cM interval, showed a stronger effect of this region. In this congenic line, the Atps-triggered IgE response was 10-fold lower than in the BN parental strain, and glomerular IgG deposits were either absent or dramatically reduced. Further genetic and functional dissections of these loci should provide insights into pathways that lead to Th2-adverse reactions. (+info)