Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
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| 18819772 | [Rheumatoid arthritis and pregnancy]. | 2008 Nov | During pregnancy, oestrogen and progesterone levels are increased. Consequently the initial predominant immune cellular response (Th1 type) is decreased, whereas humoral response (Th2 type) is increased. Due to this switch, a lot of Th2 anti-inflammatory cytokines IL-4 and IL-10 are synthesized. During the last months of pregnancy Treg lymphocytes level is elevated leading to overexpression of IL-4 and IL-10. Due to these mechanisms, reduce disease activity of rheumatoid arthritis (RA) occurred. Impaired fertility has not been demonstrated in women with RA. However, some studies suggest that polyarthritis could induced a reduced weight at birth and more frequent pregnancy and delivery complications. Methotrexate and biotherapies have demonstrated no effect on fertility; however these drugs must be stopped before conception for a period equal to seven fold of the half live of the molecule. No teratogenic effect are known for sulfazalasine and hydroxychloroquine; these drugs could be used during pregnancy. It is also the same for ciclosporine, which used is quite unfrequent in RA. Methotrexate is teratogenic in animal models and is forbidden during pregnancy. For leflunomide which is metabolised in A771726, highly teratogenic, a washout period of 3,5 months is necessary. All commercially available TNFalpha inhibitors are classified by the food and Drug Administration as pregnancy risk category B: no adverse pregnancy adverse effects have been observed in animal studies, but there have been insufficient controlled human studies. The published experiences with TNFalpha inhibition in pregnancy is limited to some case reports and ongoing registry. More recently some cases of Vater syndromes (polymalformations) were possibly related to TNFalpha blocking agents. Such treatment must be avoided during pregnancy. Only few case reports are published concerning rituximab use during pregnancy. No data have been found for abatacept. | |
| 15994280 | Clinical practice decision tree for the choice of the first disease modifying antirheumati | 2006 Jan | OBJECTIVE: To elaborate a clinical practice decision tree for the choice of the first disease modifying antirheumatic drug (DMARD) for untreated rheumatoid arthritis of less than six months' duration. METHODS: Four steps were employed: (1) review of published reports on DMARD efficacy against rheumatoid arthritis; (2) inventory of the information available to guide DMARD choice; (3) selection of the most pertinent information by 12 experts using a Delphi method; and (4) choice of DMARDs in 12 clinical situations defined by items selected in step 3 (28 joint disease activity score (DAS 28): < or =3.2; >3.2 and < or =5.1; >5.1; rheumatoid factor status (positive/negative); structural damage (with/without)-that is, 3 x 2 x 2). Thus, multiplied by all the possible treatment pairs, 180 scenarios were obtained and presented to 36 experts, who ranked treatment choices according to the Thurstone pairwise method. RESULTS: Among the 77 items identified, 41 were selected as pertinent to guide the DMARD choice. They were reorganised into five domains: rheumatoid arthritis activity, factors predictive of structural damage; patient characteristics; DMARD characteristics; physician characteristics. In the majority of situations, the two top ranking DMARD choices were methotrexate and leflunomide. Etanercept was an alternative for these agents when high disease activity was associated with poor structural prognosis and rheumatoid factor positivity. CONCLUSIONS: Starting with simple scenarios and using the pairwise method, a clinical decision tree could be devised for the choice of the first DMARD to treat very early rheumatoid arthritis. | |
| 17102944 | Durability of treatment with methotrexate in Venezuelan patients with rheumatoid arthritis | 2007 Apr | A multicenter, national, retrospective, and cross-sectional study of 219 hospital-based Venezuelan patients with rheumatoid arthritis (RA) was aimed to evaluate the probability of continuity of treatment with oral methotrexate (MTX). Treatment survival decreased from 92% at 12 months to 42% at 180 months, as assessed by life table analysis and the Kaplan-Meier method. Forty-seven patients stopped treatment and adverse effects (29.7%) and lack of continuous access to medication (19.1%) were the most common causes for withdrawal. MTX survival was decreased in the group with combined MTX plus leflunomide therapy, as shown by the log-rank test. Venezuelan patients with RA have a probability of continuing treatment with oral MTX comparable to non-Hispanic patient populations. However, concomitant use of leflunomide may increase the risk of interruption of MTX treatment in this RA population. | |
| 17307765 | Step-up combination versus switching of non-biological disease-modifying antirheumatic dru | 2007 Aug | BACKGROUND: In rheumatoid arthritis (RA), treatment with disease-modifying antirheumatic drugs (DMARDs) frequently needs to be changed because of insufficient effectiveness. AIM: To compare the clinical outcomes of two potential strategies for patients experiencing DMARD discontinuations related to ineffectiveness: switching to another DMARD or step-up combination therapy of the present DMARD with a new one. METHODS: In a large observational database of 4585 DMARD courses in 1214 patients with RA, all patients who had experienced a change in treatment regimen were identified, and retention, effectiveness and safety of these subsequent treatment courses between the two strategies (switching vs step-up combination). All analyses were stratified according to the type of the new DMARD into methotrexate (MTX), sulphasalazine (SSZ) or leflunomide (LEF); all other DMARDs were excluded. RESULTS: Kaplan-Meier analysis for MTX courses showed no significant difference in overall retention rates between the strategies of adding MTX and switching to MTX (p = 0.49 by log rank test). Likewise, switching or adding did not result in significantly different retention rates for SSZ and LEF (p = 0.61 and 0.74, respectively). This similarity between strategies remained after adjusting for several confounding variables. The frequencies of treatment terminations related to ineffectiveness or toxicity were likewise similar between the two strategies for the MTX, SSZ and LEF groups. This was also confirmed by the similarity of erythrocyte sedimentation rates that were reached at the end of the two therapeutic strategies for all three drugs, in adjusted analysis. CONCLUSION: Given all limitations of observational studies, the present data indicate that in situations of ineffective DMARD treatments, step-up combination therapy using traditional DMARDs, such as MTX, SSZ or LEF, bears no clear clinical advantage over switching to the new DMARD. Our results do not implicate any predication about step-up design including biologicals, where the benefit of combination therapy has been suggested convincingly. | |
| 18037627 | Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-m | 2008 Aug | OBJECTIVES: Everolimus, a proliferation signal inhibitor with disease-modifying properties, may be useful in treating rheumatoid arthritis (RA). This proof-of-concept study assessed efficacy and safety of everolimus in combination with methotrexate (MTX) in patients with refractory RA. METHODS: A multi-centre, randomised, double-blind, placebo-controlled trial was performed in 121 patients with active RA receiving MTX. Patients were randomised to receive everolimus (6 mg/day) or placebo. The primary endpoint was the American College of Rheumatology criteria for a 20% improvement in measures of disease activity (ACR20) at 12 weeks. RESULTS: There was a rapid onset of action and at 12 weeks the ACR20 response rate was significantly higher in the everolimus group (36.1%) than in the placebo group (16.7%; p = 0.022). Improvements from baseline in tender and swollen joint counts, patient's assessment of pain, and patient's and physician's global assessment of disease activity were significantly greater after treatment with everolimus. The most common adverse events (AEs) in the everolimus group were gastrointestinal (52.5% vs 31.7% in the placebo group), skin (29.5% vs 8.3%), and nervous system disorders (21.3% vs 10.0%); AEs leading to treatment discontinuation were reported for 16.4% and 10.0% of patients, respectively. Changes in haematological parameters, liver function tests, and lipid levels occurred more frequently with everolimus compared to placebo, but were mild and reversible. CONCLUSIONS: The study indicates that everolimus plus MTX provides clinical benefit with an acceptable safety and tolerability profile. It may offer a new treatment option in RA patients with inadequate response to MTX. | |
| 16502118 | Risk factors for vertebral fracture in menopausal or postmenopausal Japanese women with rh | 2006 | The occurrence of vertebral fracture was examined cross-sectionally and longitudinally over a 4-year interval in 117 menopausal and postmenopausal Japanese women with rheumatoid arthritis (RA), whose ages ranged from 50 to 64 years. Patients treated with bisphosphonate were excluded. Vertebral fracture was diagnosed by lateral thoracic and lumbar spine radiography at the start and end of a 4-year period. Bone mineral density (BMD) at L2-L4 according to dual-energy X-ray absorptiometry (DXA), the administration of corticosteroids or methotrexate, and urinary excretion of N-telopeptide of type I collagen (NTx) were also recorded. In the cross-sectional study, the prevalence of vertebral fracture in the initial radiographs of RA patients was 21%, while it was 5% in healthy age-matched controls. Among RA patients treated with corticosteroids, 33% had vertebral fracture, which was a significantly higher prevalence than that in RA patients without steroid administration. In the longitudinal study, vertebral fracture prevalence was also increased in patients more than 60 years old. RA patients having steroid treatment and a BMD/YAM (young adult mean) ratio below 70% had higher risk of vertebral fracture than patients with a BMD/YAM ratio of 70%-80%, which in turn exceeded the risk with a BMD of 80% or more. No adverse effect of low-dose methotrexate on vertebral fracture was found. Urinary NTx was high in RA patients, as reported previously, and did not differ between patients with or without new fracture after 4 years. In conclusion, Japanese RA patients more than 60 years old who were treated with corticosteroid or had a BMD below 80% had high risk of vertebral fracture. | |
| 17907167 | Disease activity early in the course of treatment predicts response to therapy after one y | 2007 Oct | OBJECTIVE: To assess whether disease activity levels at treatment initiation or during the first 3 months of therapy predict disease activity at 1 year after treatment initiation. METHODS: Pooled patient data from early rheumatoid arthritis (RA) clinical trials (n = 1,342) of methotrexate (MTX), tumor necrosis factor (TNF) inhibitor monotherapy (adalimumab and etanercept), and the combination of the two (adalimumab or infliximab plus MTX) were used for the primary analyses. Pooled data from clinical trials of MTX and of TNF inhibitor plus MTX in late RA (n = 712) were used for validation of the results. Disease activity was primarily assessed using the Simplified Disease Activity Index (SDAI); in addition, we calculated the Disease Activity Score 28-joint assessment (DAS28) and the Clinical Disease Activity Index (CDAI). Associations of disease activity measures at baseline and at 1, 2, 3, and 6 months with disease activity values or disease activity states at 1 year were performed using Spearman's rank correlation, analysis of variance, and diagnostic testing procedures, including receiver operating characteristic (ROC) curve analyses, and probit analysis. RESULTS: Correlations with SDAI values at end point were significant (P < 0.0001) at baseline, and increased to r = approximately 0.6 at 3 months. The area under the ROC curve indicated a high diagnostic test yield with respect to the 1-year outcome (area under the ROC curve approximately 0.8). At all time points, including baseline, the group of patients who achieved remission at 1 year had lower average SDAI values than did those whose disease activity was high at 1 year. The groups achieving low or moderate disease activities at 1 year had SDAI values lying between. Baseline disease activity was less associated with disease activity at the end point for treatment with TNF inhibitor plus MTX, indicating its effectiveness over a broader range of baseline disease activity, but the association with end point disease activity was similar to that in the MTX treatment group at 1 month after treatment initiation. The data were similar when scores on the DAS28 and CDAI were used and were fully validated in the independent cohort of patients with late RA. CONCLUSION: The level of disease activity at baseline and especially during the first 3 months of treatment is significantly related to the level of disease activity at 1 year. Patients who reach a moderate or low disease activity status after 3-6 months of therapy may require switching to alternative therapies. Our findings indicate that intensive and dynamic treatment strategies that include a closer look at disease activity at 3 months in patients with early and late RA is warranted. | |
| 16947774 | Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthriti | 2006 Sep | OBJECTIVE: Concerns persist about a possible association between tumor necrosis factor alpha (TNFalpha) antagonist treatment and development of cancers in patients with rheumatoid arthritis (RA). This study was undertaken to estimate the association between treatment with biologic disease-modifying antirheumatic drugs (DMARDs) and development of cancer in patients with RA. METHODS: We conducted a cohort study pooling administrative databases from 2 US states and 1 Canadian province. A cohort of patients who had received a diagnosis of RA on > or =1 occasion and had been prescribed DMARDs was identified. We categorized patients with a prescription for a biologic DMARD as biologic DMARD users, and those with a prescription for methotrexate (MTX) but no biologic DMARD as MTX users. We used time-varying propensity scores to adjust for the large number of possible confounders and stratified proportional hazards regression to estimate the effects of biologic DMARDs on cancer. The primary end points were hematologic malignancies (lymphoma, multiple myeloma, and leukemia) and common solid tumors (colorectal, lung, stomach, breast, prostate, uterine, ovarian, urinary tract/bladder, and melanoma). RESULTS: The pooled cohort included 1,152 biologic DMARD users and 7,306 MTX users. We identified 11 hematologic malignancies and 46 solid tumors during 2,940 person-years of biologic DMARD use, and 88 hematologic malignancies and 558 solid tumors during 30,300 person-years of MTX use. Comparing biologic DMARD users with MTX users, the propensity score-adjusted pooled hazard ratio was 1.37 (95% confidence interval 0.71-2.65) for hematologic malignancies and 0.91 (95% confidence interval 0.65-1.26) for solid tumors. CONCLUSION: Our results indicate that users of biologic agents are unlikely to have a substantial increase in the risk of hematologic malignancies and solid tumors as compared with MTX users. Despite the use of large combined data sets, studying the effect of an infrequent exposure (biologic DMARDs) on rare diseases (hematologic malignancies) remains a challenge. | |
| 18388156 | Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an i | 2009 Feb | OBJECTIVE: To determine if treatment with a B cell-targeted therapy can inhibit the progression of structural joint damage in patients with rheumatoid arthritis (RA), exhibiting an inadequate response to tumour necrosis factor (TNF) inhibitors. METHODS: In this phase III study, patients with an inadequate response to a TNF inhibitor and receiving methotrexate were randomised to rituximab or placebo. Radiographs were obtained at baseline, week 24 and week 56 after randomisation. Patients with an inadequate response to their randomised therapy could receive rescue medication from week 16. From week 24, eligible patients from both treatment arms could receive open-label rituximab. Patients were analysed according to their original treatment group. Radiographs were scored using the Genant-modified Sharp method. The primary radiographic endpoint was change in total Genant-modified Sharp score at week 56. RESULTS: Rituximab treatment caused significant reduction in joint damage progression compared with placebo. The mean change from baseline in the total Genant-modified Sharp score at week 56 was significantly lower for patients treated with rituximab than for patients treated with placebo (1.00 vs 2.31; p = 0.005), and was supported by changes in erosion score (0.59 and 1.32 for rituximab plus methotrexate vs placebo plus methotrexate, respectively; p = 0.011) and joint space narrowing score (0.41 and 0.99, respectively; p<0.001). CONCLUSIONS: This study provides the first evidence that a B cell-targeted therapy-rituximab-can significantly inhibit the progression of structural joint damage in patients with RA with long-standing, active and treatment-resistant disease. | |
| 16572441 | Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumat | 2006 Apr | OBJECTIVE: To evaluate the efficacy, including radiographic changes, and safety of etanercept and methotrexate (MTX), used in combination and alone, in patients with rheumatoid arthritis (RA) in whom previous treatment with a disease-modifying antirheumatic drug other than MTX had failed. METHODS: Patients with RA were treated with etanercept (25 mg subcutaneously twice weekly), oral MTX (up to 20 mg weekly), or combination therapy with etanercept plus MTX through a second year, in a double-blinded manner. Clinical response was assessed using American College of Rheumatology (ACR) criteria and the Disease Activity Score (DAS), in a modified intent-to-treat analysis with the last observation carried forward (LOCF) and in a population of completers. Radiographs of the hands, wrists, and forefeet were scored for erosions and joint space narrowing at annual intervals. RESULTS: A total of 503 of 686 patients continued into year 2 of the study. During the 2 years, significantly fewer patients receiving combination therapy withdrew from the study (29% of the combination therapy group, 39% of the etanercept group, and 48% of the MTX group). Both the LOCF and the completer analyses yielded similar results. The ACR 20% improvement (ACR20), ACR50, and ACR70 responses and the remission rates (based on a DAS of <1.6) were significantly higher with combination therapy than with either monotherapy (P<0.01). Similarly, improvement in disability (based on the Health Assessment Questionnaire) was greater with combination therapy (P<0.01). The combination therapy group showed significantly less radiographic progression than did either group receiving monotherapy (P<0.05); moreover, radiographic progression was significantly lower in the etanercept group compared with the MTX group (P<0.05). For the second consecutive year, overall disease progression in the combination therapy group was negative, with the 95% confidence interval less than zero. Adverse events were similar in the 3 treatment groups. CONCLUSION: Etanercept in combination with MTX reduced disease activity, slowed radiographic progression, and improved function more effectively than did either monotherapy over a 2-year period. No increase in toxicity was associated with combination treatment with etanercept plus MTX. | |
| 17181924 | ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis pati | 2006 Sep | OBJECTIVE: Methotrexate (MTX) is most widely used for the treatment of rheumatoid arthritis (RA). However, it has certain drawbacks with regard to individual differences in its therapeutic effects as well as the differences in the patients' response to MTX therapy. We investigated whether multi-drug resistance-1 (ABCB1) C3435T, reduced folate carrier-1 (RFC1) G80A, 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) C347G and a 6bp-deletion polymorphism in the 3'-untranslated region of the thymidylase synthase (TYMS) gene are predictive of MTX sensitivity and its adverse effects. METHODS: Patients whose last maintenance dosage of MTX was |
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| 16947782 | Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist | 2006 Sep | OBJECTIVE: To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti-interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA). METHODS: The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo. RESULTS: A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX. CONCLUSION: These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA. | |
| 18050385 | Improved health-related quality of life for patients with active rheumatoid arthritis rece | 2008 Jan | OBJECTIVE: To evaluate the effect of rituximab treatment on health-related quality of life (HRQOL) in patients with active rheumatoid arthritis (RA), who have had an inadequate response to disease-modifying antirheumatic drugs, including biologic agents. METHODS: A randomized, multicenter, double-blind, placebo-controlled clinical trial involving 367 rheumatoid factor-positive patients was conducted. Patients received 2 infusions 2 weeks apart of placebo (n = 122), rituximab 500 mg (n = 123), or rituximab 1000 mg (n = 122), with or without glucocorticoids. All patients received stable doses of methotrexate (10 25 mg/wk). Measures included SF-36, assessed at baseline and at 24 weeks, as well as the HAQ and FACIT-Fatigue scale assessed at baseline and monthly for 24 weeks. Patients exceeding prespecified minimal clinically important differences (MCID) were examined. Clinical efficacy measurements (ACR20/50/70 and EULAR responses) were compared with HRQOL outcomes. RESULTS: At 24 weeks, the rituximab 500 mg and 1000 mg groups both reported statistically significantly greater improvements on the SF-36 physical component summary (4.37 and 4.89 points higher, respectively, vs placebo; p < 0.001). SF-36 physical function, bodily pain, vitality, social function, and role-physical subscale scores also statistically significantly improved vs placebo. At 24 weeks, 62.6% and 67.2% of the rituximab 500 mg and 1000 mg groups, respectively, exceeded the MCID of 0.22 in HAQ (p < 0.001). For FACIT-Fatigue, 55.3% and 65.6% of patients exceeded the MCID of 3.5 points compared with 35.2% of placebo over 24 weeks (p < 0.001). ACR20/50/70 and EULAR responders demonstrated greater improvements in mean baseline to 24 week changes in SF-36 and FACIT-Fatigue scores compared with nonresponders (p < 0.05). CONCLUSION: Both rituximab doses in combination with methotrexate were effective in improving all HRQOL outcomes in patients with active RA consistent with clinical efficacy. | |
| 16438485 | Genetics of rheumatoid arthritis. | 2006 Jan | Rheumatoid arthritis (RA) is a heterogeneous autoimmune disorder of unknown cause with variable clinical expression. About 70% of patients are women. Genetic factors play an important role and likely account for about 60% of disease susceptibility and expression. The association with the HLA-DRB1 gene is the best understood, although several non-HLA loci have been linked to RA, including the 18q21 region of the TNFRSR11A gene, which encodes the receptor activator of nuclear factor kappaB, important in bone resorption in RA. Genetic factors are also important in the treatment of RA because the activity of enzymes relevant in the metabolism of drugs such as methotrexate and azathioprine, including methylenetetrahydrofolate reductase and thiopurine methyltransferase, are in part genetically determined. | |
| 18808212 | Discontinuation of methotrexate therapy in older patients with newly diagnosed rheumatoid | 2008 | BACKGROUND: Rheumatoid arthritis (RA) is a potentially devastating form of chronic arthritis. Methotrexate is the cornerstone of drug therapy of the disorder, and may slow or prevent joint damage. Unfortunately, this agent is not without adverse effects. Furthermore, increasing age has been been invoked as a predictor of greater toxicity and drug discontinuation by some, but not all, investigators. OBJECTIVE: To assess the effect of age and other covariates on methotrexate discontinuation in a population-based sample of older patients with newly diagnosed RA. METHODS: We studied the health administrative databases covering residents of the province of Québec, Canada. In these databases, we identified 246 individuals aged>or=65 years with newly diagnosed RA who had been started on methotrexate. We assessed discontinuation of methotrexate therapy using Cox proportional hazards regression models, with potential predictors of discontinuation being age, sex, co-morbidity, methotrexate dose and route (oral vs intramuscular), folic acid coadministration and disease severity. RESULTS: Five patients died or were lost to follow-up in the database at 6 months, and there were ten such patients at 1 year. Six months after the initial prescription of methotrexate therapy, about 80% (n=192) of remaining subjects continued to be prescribed the drug. By 1 year, 161 of 236 (68.2%) subjects continued to be prescribed the drug; by 2 years, only 108 of 217 (49.8%) subjects continued to receive the drug. Increasing age was associated with a greater risk of methotrexate discontinuation. CONCLUSION: Our population-based data indicate that increasing age is associated with a greater tendency for methotrexate discontinuation in patients with newly diagnosed RA. These results emphasize the need to ensure that older patients with RA are provided with effective therapy to minimize the effects of this chronic, potentially disabling disease. | |
| 17673491 | A single tumour necrosis factor haplotype influences the response to adalimumab in rheumat | 2008 Apr | OBJECTIVE: To determine whether tumour necrosis factor (TNF) gene polymorphisms and/or the shared epitope are genetic predictors of the response to adalimumab (ADA) in rheumatoid arthritis (RA). METHODS: This ancillary study to the Research in Active Rheumatoid Arthritis (ReAct) Phase IIIb study included a large cohort of Caucasian patients with RA from France (n = 388) treated with ADA plus methotrexate (MTX) (n = 182), ADA plus any other DMARD (n = 98) or ADA alone (n = 108). The primary outcome was ACR50 at 12 weeks. Patients underwent genotyping for HLA-DRB1 and three TNF gene polymorphisms (-238A/G,-308A/G and-857C/T). Extended haplotypes involving HLA-DRB1 and TNF loci were reconstructed using the PHASE program. RESULTS: A total of 151 patients (40%) had an ACR50 response at week 12. Neither the number of HLA-DRB1 shared epitope copies nor presence of the three TNF polymorphisms tested separately was significantly associated with ACR50 response at week 12. However, haplotype reconstruction of the TNF locus revealed that the GGC haplotype (-238G/-308G/-857C) in a homozygous form (i.e. present in more than half of the patients) was significantly associated with a lower ACR50 response to ADA at 12 weeks (34% vs. 50% in patients without the haplotype) (p = 0.003; pa = 0.015). This effect was more important in the subgroup of patients concomitantly treated with MTX. CONCLUSION: This large pharmacogenetic study provides preliminary data indicating that a single TNF locus haplotype (-238G/-308G/-857C), present on both chromosomes is associated with a lower response to ADA, mainly in patients treated with ADA and MTX. | |
| 16926184 | Combination therapy with sulfasalazine and methotrexate is more effective than either drug | 2007 Feb | BACKGROUND: Optimal use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis is vital if progression of disease is to be reduced. Methotrexate (MTX) and sulfasalazine (SASP) are widely used inexpensive DMARDs, recently often combined despite no firm evidence of benefit from previous studies. AIM: To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP. METHODS: A randomised controlled study of step-up DMARD treatment in early rheumatoid arthritis. In phase I, 687 patients received SASP for 6 months. Those with a disease activity score (DAS) > or =2.4 were offered additional treatment in phase II (SASP alone, MTX alone or a combination of the two). The primary outcome measure was change in DAS. RESULTS: At 6 months, 191 (28%) patients had a DAS <2.4, 123 (18%) were eligible but did not wish to enter phase II, 130 (19%) stopped SASP because of reversible adverse events and 165 (24%) entered phase II. DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX: monotherapy arms did not differ. Improvement in European League Against Rheumatism and American College of Rheumatology 20, 50 and 70 scores favoured combination therapy. CONCLUSIONS: In this "true-to-life" study, an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP. There was no increase in toxicity. These results provide an evidence base for the use of this combination as a component of tight control strategies. | |
| 16641044 | Factors associated with hyperhomocysteinaemia in Mexican patients with rheumatoid arthriti | 2006 Mar | BACKGROUND: Hyperhomocysteinaemia is a factor related to the development of atherosclerosis in rheumatoid arthritis (RA). However, Hispanics with RA develop high rates of coronary disease; there are no studies about the frequency and factors related to high levels of homocysteine in Mexican patients. OBJECTIVE: To evaluate the prevalence and characteristics associated with hyperhomocysteinaemia in Mexican patients with RA. METHODS: One hundred and fifty-two patients with RA were compared with 153 controls. The assessment in RA included clinical characteristics, disease activity (RADAR), functioning (HAQ-Di and global functional status), comorbidity, and radiological damage. Laboratory determinations included total serum homocysteine (tHcy), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and lipid profile. RESULTS: Median levels of homocysteine were higher in RA compared with controls (11.3 vs. 9.3, p<0.001). Twenty per cent of the patients with RA had hyperhomocysteinaemia (>15 micromol/L) compared with 6% in controls (p<0.001). There was statistical association between hyperhomocysteinaemia in RA with male gender (p<0.001), impairment in the global functional status (p = 0.004), higher radiological damage (p = 0.001), and CRP (p = 0.04). There was no association with RADAR, HAQ-Di, or RF, methotrexate dose or duration of use. In the adjusted multivariate model, the two variables associated with higher risk for hyperhomocysteinaemia were male gender (OR = 4.2, 95% CI 2 to 12, p = 0.006) and higher radiological damage (III-IV) (OR = 3.4, 95% CI 1.3 to 9, p = 0.01). CONCLUSIONS: Our data show a high prevalence of hyperhomocysteinaemia in Mexican patients with RA. More effort is required to evaluate and treat earlier this coronary risk factor. | |
| 18634159 | Predictors of discontinuation of tumor necrosis factor inhibitors in patients with rheumat | 2008 Sep | OBJECTIVE: Tumor necrosis factor-alpha (TNF) inhibitors have transformed management of rheumatoid arthritis (RA); however, many patients discontinue TNF inhibitors. Our goal was to determine the discontinuation rate of TNF inhibitors and identify predictors associated with discontinuation. METHODS: Enrollees in the Brigham RA Sequential Study (BRASS) formed the eligible cohort. Patients reporting use of a TNF inhibitor with at least 6 months of followup were followed until reporting TNF inhibitor discontinuation or their last study visit if they continued therapy. Potential predictor variables, including demographic and clinical data assessed at baseline and 6 months prior to study endpoint, were identified using a Cox proportional regression. RESULTS: Among 961 patients in BRASS, 503 were using a TNF inhibitor with at least 6 months of followup in BRASS (mean length of followup 39 mo, SD 13). Two hundred ten patients (42%) reported discontinuation of TNF inhibitor. Higher physician global scores (hazard ratio 1.27, 95% CI 1.18-1.38) and RA Disease Activity Index scores (HR 1.13, 95% CI 1.05-1.22) 6 months prior to stopping the TNF inhibitor and higher number of TNF inhibitors used previously (HR 1.30, 95% CI 1.03-1.66) were associated with discontinuation of TNF inhibitor. Prior use of synthetic disease modifying antirheumatic drugs (HR 0.50, 95% CI 0.34-0.72) and more years of cumulative methotrexate use (HR 0.24, 95% CI 0.12-0.47) were inversely associated with discontinuation of TNF inhibitor. CONCLUSION: These data demonstrate that a significant number of patients with RA discontinue TNF inhibitors. Several easily characterized clinical variables have a modest predictive association with reduced probability of TNF inhibitor discontinuation. | |
| 18179735 | The incidence and prevalence of extra-articular and systemic manifestations in a cohort of | 2008 Feb | OBJECTIVE: To evaluate the incidence and prevalence of extra-articular (ExRA) and systemic (SysM) manifestations in a cohort of newly-diagnosed patients with rheumatoid arthritis (RA) in the United States. PATIENTS AND METHODS: Retrospective analysis using inpatient, outpatient, and pharmacy claims data contained in the Thomson Healthcare MarketScan research databases. Patients >or= 18 years of age with a diagnosis of RA (ICD-9-CM 714.0x) on three non-diagnostic claims on different days between January 1, 1999 and September 30, 2006, and at least 12 months of continuous enrollment prior to, and at least 2 years following diagnosis were included in the analysis. Thirty ExRA/SysM, classified into six groups (cardiovascular, blood, mucosa, pulmonary, other, and non-specific), were evaluated. Patients were followed until in-hospital death, disenrollment, or study end. RESULTS: A total of 16,752 patients were included (mean age 59.8 +/- 13.5 years; 72.0% female), and were followed up for a mean of 3.9 +/- 1.4 years. ExRA/SysM were experienced by 47.5% of patients, with cardiovascular (27.2%) the most common. The most frequent individual ExRA/SysM was 'other CVD' (17.2%). Female sex was associated with a reduced risk of cardiovascular ExRA/SysM (HR, 0.66; 95% CI, 0.61-0.72), and an increase in mucosa ExRA/SysM (HR, 2.55; 95% CI, 2.03-3.19). Prior treatment with methotrexate (MTX) was associated with significantly reduced risks of cardiovascular (HR 0.65; 95% CI, 0.59-0.72) and blood system (HR 0.71; 95% CI, 0.61-0.82) ExRA/SysM. Other significant associations were also evident: age, comorbidity as measured by CCI and CDS, and geographic region were associated with increased risks for some ExRA/SysM, while prior NSAID treatment and the presence of diabetes were associated with a lower risk for some ExRA/SysM. CONCLUSION: ExRA/SysM develop in approximately 47% of patients with RA within a few years of diagnosis. Prior treatment with some therapies used in RA management were associated with a reduced risk of developing some ExRA/SysM, while several demographic factors and the presence of comorbidities also affected the risk of developing ExRA/SysM. This analysis was restricted to patients with employer- or government-funded health insurance, while several potential predictors of ExRA/SysM could not be controlled for in the multivariate analysis, as they could not be measured using claims data. Hence, these results may not be generalizable to other groups of patients with RA. |