Effects of combinations of anti-rheumatic drugs on the production of vascular endothelial growth factor and basic fibroblast growth factor in cultured synoviocytes and patients with rheumatoid arthritis

OBJECTIVE: To examine whether different combinations of disease-modifying anti-rheumatic drugs (DMARDs), including bucillamine (BUC), gold sodium thiomalate (GST), methotrexate (MTX), salazosulphapyridine (SASP) and dexamethasone (DEX; a steroid), act by inhibiting the production of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in cultured synoviocytes, causing a decrease in their serum concentrations in patients with rheumatoid arthritis (RA). METHODS: The VEGF and bFGF concentrations in cultured synoviocytes and peripheral blood from patients with RA were measured by enzyme-linked immunosorbent assay and their serum concentrations were measured at two time points. RESULTS: BUC and GST inhibited VEGF production even when given alone, and a combination of BUC, GST and MTX with DEX also inhibited VEGF production. None of the DMARDs or DEX inhibited bFGF production when given alone, but a combination of SASP and GST inhibited the production of bFGF in cultured synoviocytes. Serum VEGF concentrations were significantly decreased 6 months after the commencement of medication compared with their concentrations before medication. CONCLUSION: Our results show that the effects of a combination of DEX with any two of BUC, GST, SASP and MTX on the production of VEGF and bFGF in cultured synoviocytes and on the serum concentrations of VEGF in patients with RA may be based on synergistic or additive effects of the drugs.     

Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components

OBJECTIVES: To investigate the potential clinical benefit of a combination therapy. METHODS: 205 patients fulfilling the ACR criteria for rheumatoid arthritis (RA), not treated with disease modifying antirheumatoid drugs previously, with an early (< or = 1 year duration), active (Disease Activity Score (DAS) > 3.0), rheumatoid factor and/or HLA DR 1/4 positive disease were randomised between sulphasalazine (SASP) 2000 (maximum 3000) mg daily (n = 68), or methotrexate (MTX) 7.5 (maximum 15) mg weekly (n = 69) or the combination (SASP + MTX) of both (n = 68). RESULTS: The mean changes in the DAS during the one year follow up of the study was -1.15, -0.87, -1.26 in the SASP, MTX, and SASP + MTX group respectively (p = 0.019). However, there was no statistically significant difference in terms of either EULAR good responders 34%, 38%, 38% or ACR criteria responders 59%, 59%, 65% in the SASP, MTX, and SASP + MTX group respectively. Radiological progression evaluated by the modified Sharp score was very modest in the three groups: mean changes in erosion score: +2.4, +2.4, +1.9, in narrowing score: +2.3, +2.1, +1.6 and in total damage score: +4.6, +4.5, +3.5, in the SASP, MTX, and SASP + MTX groups respectively. Adverse events occurred more frequently in the SASP + MTX group 91% versus 75% in the SASP and MTX group (p = 0.025). Nausea was the most frequent side effect: 32%, 23%, 49% in the SASP, MTX, and SASP + MTX groups respectively (p = 0.007). CONCLUSION: This study suggests that an early initiation therapy of disease modifying drug seems to be of benefit. However, this study was unable to demonstrate a clinically relevant superiority of the combination therapy although several outcomes were in favour of this observation. The tolerability of the three treatment modalities seems acceptable.     

Prediction of DAS28-ESR remission at 6 months by baseline variables in patients with rheumatoid arthritis treated with etanercept in Japanese population

Abstract

We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX.     

Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score

OBJECTIVES: To determine the efficacy of subsequent disease modifying antirheumatic drug (DMARD) therapies after initial methotrexate (MTX) failure in patients with recent onset rheumatoid arthritis (RA), treated according to the DAS for 2 years. METHODS: In groups 1 and 2 of the BeSt study, 244 RA patients were initially treated with MTX 15-25 mg/week. Patients who discontinued MTX because of insufficient clinical response (disease activity score, DAS >2.4) or toxicity were classified as "MTX failures." In group 1, these patients switched to sulfasalazine (SSA), then leflunomide and finally to MTX + infliximab (IFX). In group 2, "MTX failures" added SSA to MTX, then hydroxychloroquine (HCQ), then prednisone, and eventually switched to MTX + IFX. "MTX successes" were patients who achieved a DAS 相似文献   

The treatment of rheumatoid arthritis with low dose pulse methotrexate--comparative study with other disease modifying antirheumatic drugs]

Low dose pulse methotrexate (MTX, 5-7.5mg/week) was administered to fifty one patients with severe and active rheumatoid arthritis (RA) who did not respond to the various disease modifying antirheumatic drugs (DMARDs). The follow-up period ranged from 2 to 30 months. As to efficacy rate and probability of patients continuing therapy, the results of MTX were compared with those of the other DMARDs (131 cases of bucillamine (BU), 163 of D-penicillamine (DP), 98 of salazopyrin (SASP), 126 of auranofin (AF), 55 of lobenzarit (CCA)). The patients treated with MTX showed remarkable improvement within 1 or 2 months in Lansbury's index items, CRP, immunoglobulin levels and rheumatoid factor values. But OKT4/8 ratio remained unchanged throughout the study period. As to the adverse reactions due to MTX an elevation of serum transaminase occurred most frequently (41.2%). MTX treatment was, however, tolerable to the most cases with its transient discontinuance or its dose reduction. The efficacy rate of MTX (71.4%) was the best among above mentioned DMARDs at the end of 6 months treatment. After treatment of 24 months, the probability of still taking MTX (70.1%) proved to be about the same with that of DP and better than that of BU, SASP, AF and CCA. In conclusion low dose pulse MTX turned out to be effective in the treatment of severe and active rheumatoid arthritis.     

Adalimumab and methotrexate is more effective than adalimumab alone in patients with established rheumatoid arthritis: results from a 6-month longitudinal, observational, multicentre study

OBJECTIVES: To compare the effectiveness of adalimumab monotherapy and adalimumab and methotrexate (MTX) combination therapy in patients with established rheumatoid arthritis. METHODS: Data from an ongoing longitudinal observational study in Norway were used to compare response to treatment with two different adalimumab regimens (monotherapy, n = 84; combination with MTX, n = 99). Patients were assessed with measures of disease activity, health status and utility scores. Within-group changes were analysed from baseline to follow-up at 3 and 6 months and the changes were compared between groups after adjustment for the propensity score. The groups were also compared for the proportions of patients achieving European League Against Rheumatism (EULAR) good response, Disease Activity Score (DAS)28 remission and treatment terminations. RESULTS: The improvement from baseline was significant for all measures in the adalimumab and MTX group, but only for DAS28, joint counts, two Short-form Health Survey with 36 questions (SF-36) dimensions and patient's and investigator's global assessment in the monotherapy group. All between-group differences were numerically in favour of combination therapy and significant for C reactive protein, joint counts, DAS28, Modified Health Assessment Questionnaire, investigator's global assessment, four SF-36 dimensions and Short Form 6D at 6 months. More patients in the combination therapy group reached EULAR good response (p<0.001) and remission (p = 0.07). At 6 months, 80.8% of the patients in the combination therapy group and 59.5% in the monotherapy group remained on treatment (p = 0.002). More withdrawals in the monotherapy group were due to adverse events. CONCLUSIONS: Our results were consistent across several categories of end points and suggest that adalimumab combined with MTX is effective in patients with rheumatoid arthritis treated in daily clinical practice and is superior to adalimumab monotherapy.     

Prediction of DAS28-ESR remission at 6?months by baseline variables in patients with rheumatoid arthritis treated with etanercept in Japanese population

We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX.     

Etanercept in combination with conventional disease-modifying antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis patients intolerant to methotrexate

Although etanercept (ETN) is effective when used in monotherapy for the treatment of rheumatoid arthritis (RA), ETN/methotrexate (MTX) combination therapy is more efficacious. However, some patients show MTX intolerance; these patients may develop adverse events (AEs) or have risk factors for AEs. There is limited published information regarding the efficacy of combination therapy involving ETN and disease-modifying antirheumatic drugs other than MTX. Therefore, we evaluated the effects of combination therapy with ETN and salazosulfapyridine (SASP) and/or bucillamine (Bc), a d-penicillamine analogue, in MTX-intolerant RA patients. Indices of RA activity, including disease activity score in 28 joints (DAS28), were retrospectively analyzed over a 48-week period in 66 patients treated with ETN. Treatment efficacy was compared in the following 4 major treatment groups: ETN monotherapy, ETN + MTX, ETN + SASP, and ETN + SASP + Bc. Although intergroup differences in the percent change of DAS were not statistically significant, ETN + SASP + Bc seemed to be more effective than ETN monotherapy, and the efficacy of ETN + SASP + Bc was comparable to that of ETN + MTX according to the European League Against Rheumatism (EULAR) improvement ratings. These results suggest that ETN + SASP + Bc combination therapy may be a viable option for RA treatment in patients in whom MTX cannot be used.     

Leflunomide addition in patients with articular manifestations of psoriatic arthritis resistant to methotrexate

In contrast to rheumatoid arthritis, in psoriatic arthritis (PsA), the efficacy of disease-modifying antirheumatic drugs (DMARDs) combination has not been documented. We conducted a retrospective study to evaluate the effectiveness of leflunomide (LEF) addition in 11 PsA patients with articular manifestations that failed to respond to methotrexate (MTX) monotherapy [disease activity score in 28 joints (DAS28) > 3.2)]. Eight of them, all with moderate disease activity (DAS28 < 5.1) at baseline, tolerated the combination. A statistically significant improvement of the mean DAS28, based on erythrocyte sedimentation rate (ESR), and its variables, and C-reactive protein (CRP) at 12–16 weeks after LEF addition was observed. Mean change of DAS28 in patients with polyarticular disease did not differ compared with those with oligoarticular. Based on the European League Against Rheumatism (EULAR) response criteria, none of our patients achieved a good response, seven had a moderate response, and one was a non-responder. The two patients with the lower DAS28 at baseline attained low disease activity (LDA, DAS28 ≤ 3.2), while none reached remission (DAS28 ≤ 2.6). Achievement of clinical remission or at least LDA has been recently proposed as the goal of treatment in PsA. Our results imply that LEF addition may serve as an alternative therapeutic modality for patients with moderately active PsA and, as lower as possible, residual disease activity after the initial therapy with MTX alone.     

Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: the ADORE study

OBJECTIVE: To evaluate the efficacy and safety of etanercept (ETN) monotherapy compared with combination ETN and methotrexate (MTX) treatment in patients with rheumatoid arthritis who had an inadequate response to MTX monotherapy. (The response was defined by the presence of Disease Activity Score-28 joint count (DAS28) >or=3.2 or a combination of >or=5 swollen joints, >or=5 painful joints and erythrocyte sedimentation rate >or=10 mm/h.) METHODS: Patients with active rheumatoid arthritis taking MTX >or=12.5 mg/week for >or=3 months were included in this 16 week, randomised, open-label study. Patients were randomly assigned to either ETN (25 mg subcutaneous injection twice weekly) added to the baseline dose of MTX or ETN monotherapy. RESULTS: 315 patients were randomised to ETN (n = 160) or ETN plus MTX (n = 155). The primary end point, DAS28 (4) improvement of >1.2 units, was achieved by 72.8% and 75.2% of patients treated with ETN and those treated with ETN plus MTX, respectively, with no significant difference (p = 0.658) between the two groups. The European League Against Rheumatism response criteria of good or moderate response was attained by 80.0% of patients in the ETN group and by 82.4% of patients in the ETN plus MTX group. American College of Rheumatology 20%, 50% and 70% response rates achieved by both groups were also similar: 71.0% v 67.1%, 41.9% v 40.1% and 17.4% v 18.4%, respectively. The rates of adverse and serious adverse events were similar between the treatment groups. CONCLUSION: Both the addition of ETN to MTX and the substitution of ETN for MTX in patients with rheumatoid arthritis who had an inadequate response to MTX resulted in substantial improvements in clinical signs and symptoms and were generally well-tolerated treatment strategies for improving clinical signs and symptoms of rheumatoid arthritis.     

Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis

OBJECTIVE: The response to single disease modifying antirheumatic drug (DMARD) is often suboptimal in patients with rheumatoid arthritis (RA). Thus, despite the limited data on the therapeutic efficacy of combination therapies, many patients are currently treated with a combination of DMARDs. METHODS: We studied prospectively the efficacy of combination therapy with DMARDs. The study was designed as a randomized trial and a single DMARD or two or three DMARD combinations were administered to 180 consecutive, age- and sex-matched patients with active RA, each of whom was followed up for a period of 2 years under treatment. Patients were divided into 3 groups which did not differ with regard to demographic, clinical and laboratory parameters. Patients in group I were treated with a single DMARD [methotrexate (MTX) 7.5-15 mg/week or sulfasalazine (SSZ) 1-2 g/day or hydroxychloroquine (HCQ) 200 mg/day], group II with MTX + SSZ or MTX + HCQ, and group III with a combination of all three drugs. Patients were re-evaluated at regular intervals by means of clinical and biochemical tests designed to detect specific rheumatic activity. Radiological assessments were also performed and scored according to Larsen by the same radiologist who was blinded to the treatment groups. RESULTS: At the end of the trial there were significant improvements in the clinical and laboratory parameters in all 3 groups. However, improvements were greater and much more significant in the patients who were given combination therapies. The combination of MTX + SSZ + HCQ was more effective than both monotherapy and the two-drug combinations. CONCLUSION: In conclusion, we suggest that patients with RA should be treated with combinations of DMARDs.     

Rescue of combination therapy failures using infliximab,while maintaining the combination or monotherapy with methotrexate: results of an open trial

OBJECTIVE: To assess the possible clinical and biological rescue of rheumatoid arthritis (RA) in 16 patients who were still active despite intensive combination therapy after receiving infliximab following the Anti-Tumour necrosis factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) schedule. METHODS: Sixteen patients who were still active despite combination therapy with optimal doses of methotrexate (MTX 15-17.5 mg/week) and cyclosporin A (CsA 2.5-3.5 mg/day) received infliximab. Ten received their combination plus infliximab (Combi), and six received infliximab plus MTX alone (Mono). The follow-up was carried out for 30 weeks in all patients and for 46 weeks in eight. Efficacy and safety were examined. RESULTS: At entry, the mean disease activity score (DAS) was 5.6 (all patients had a DAS >3.7). After therapy, eight of 10 patients in Combi and four out of six in Mono showed an improvement of >50% in the initial swollen joint count, yet only one patient reached 50% improvement in the initial DAS after 30 weeks, and one patient had a DAS <2.4 (low disease activity). Of the eight patients who reached 46 weeks of follow-up, three showed an improvement in DAS of 50% and two had a DAS <2.4. When considering the change over time, the difference between DAS at entry and at week 30 was statistically significant only in patients receiving MTX plus CsA, while it was not significant in those receiving MTX only. Two patients developed recurrent febrile upper respiratory infections in the Combi therapy group, while two had a single febrile infection in the MTX alone group. Two patients became strongly anti-cardiolipin positive (IgM >40 MPL) and one developed a coronary syndrome. CONCLUSION: Infliximab can be added incrementally to MTX plus CsA, with favourable results in terms of efficacy and safety over time in severe rapidly aggressive and progressive RA. Finally, minor evidence emerged for a stronger efficacy of the Combi treatment compared with Mono.     

Comparison of tocilizumab as monotherapy or with add-on disease-modifying antirheumatic drugs in patients with rheumatoid arthritis and inadequate responses to previous treatments: an open-label study close to clinical practice

This was an exploratory analysis comparing the safety and efficacy of tocilizumab monotherapy with those of tocilizumab in combination with disease-modifying anti-rheumatic drugs (DMARDs). Data were from a single-arm, nonrandomized, open-label, 24-week study in patients with rheumatoid arthritis in which patients with inadequate responses to DMARDs or tumor necrosis factor-α inhibitors received tocilizumab 8 mg/kg intravenously every 4 weeks plus methotrexate/other DMARD(s) combination therapy. If they were intolerant of methotrexate/other DMARD, patients received tocilizumab monotherapy. Effectiveness endpoints included American College of Rheumatology (ACR) responses (ACR20/50/70/90) and disease activity score using 28 joints (DAS28). Of 1,681 patients, 239 received tocilizumab monotherapy, and 1,442 received combination therapy. Methotrexate was the most common DMARD (79 %) used in combination therapy. The frequency of adverse events (AEs), serious AEs, and AEs leading to withdrawal were similar between tocilizumab monotherapy (82.4, 7.9, and 5.4 %, respectively) and combination therapy (76.6, 7.8, and 5.1 %, respectively). No differences in ACR20/50/70/90 responses were observed between treatment groups (66.9 %/43.5 %/23.8 %/10.0 % vs 66.9 %/47.2 %/26.8 %/8.5 %, respectively; p > 0.12 for all individual comparisons, including ACR50 propensity score analyses). The decrease in DAS28 was also similar between treatment groups (mean ± standard deviation: −3.41 ± 1.49 for tocilizumab monotherapy vs −3.43 ± 1.43 for combination therapy; p > 0.33 all analyses, including propensity score analyses). Tocilizumab had a comparable safety profile, and was similarly effective, when used as monotherapy or in combination with DMARDs in a broad population of patients with rheumatoid arthritis.

     

Infliximab and methotrexate as induction therapy in patients with early rheumatoid arthritis

OBJECTIVE: To evaluate the efficacy of infliximab plus methotrexate (MTX) as induction therapy in patients with early rheumatoid arthritis (RA). METHODS: Disease-modifying antirheumatic drug (DMARD)-naive patients with active, early RA who were included as group 4 of the BeSt study were initially treated with infliximab (3 mg/kg) in combination with MTX (25 mg/week). The Disease Activity Score (DAS) was measured every 3 months. In patients with persistent low disease activity (DAS 2.4, the infliximab dosage was increased (maximum 10 mg/kg), and they were subsequently switched to another DMARD. Except for intraarticular administration, corticosteroids were not permitted. Functional ability and the modified Sharp/van der Heijde score were determined after 2 years of therapy. RESULTS: Of the 120 patients, 67 responders (56%) had persistent low disease activity and discontinued infliximab after a median of 9.9 months, with a median MTX dosage of 10 mg/week after 2 years. Ten other patients experienced a disease flare after discontinuation and resumed infliximab after a median of 3.7 months. Thirteen patients did not achieve persistent low disease activity and received infliximab at various dosages. Treatment was unsuccessful in 30 patients. In the 67 responders, the progression of joint damage was lower than in the 30 patients in whom treatment failed. CONCLUSION: Fifty-six percent of patients with active early RA, initially treated with infliximab plus MTX, could discontinue infliximab after achieving a DAS of 相似文献   

METHOTREXATE AND SULPHASALAZINE AS COMBINATION THERAPY IN RHEUMATOID ARTHRITIS

Sulphasalazine (SASP) and methotrexate (MTX) are well-establishedtreatments for RA but the use of these drugs in combinationhas been avoided as both have antifolate activity. In this paperwe report our experience with 32 patients treated with the combinationMTX/SASP and compare the toxicity and tolerability of the combinationwith 63 patients treated with MTX alone. The median durationof exposure to the combination was 23 months. Nineteen patientshave continued this regime for over 18 months. Five patientson MTX/SASP combination discontinued MTX, in four cases dueto toxicity and in one because MTX/SASP was ineffective. In17 patients on MTX alone, the drug was withdrawn permanently.In seven cases the cause was toxicity including two patientswith severe reactions. In patients known to tolerate SASP alone,the combination of MTX/SASP is also well tolerated. In our experienceof 48 patient-years of such combination therapy, there is noincrease in toxicity compared to therapy with MTX alone in RA. KEY WORDS: Methotrexate, Sulphasalazine, Combination therapy, Toxicity, Rheumatoid arthritis     

Comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another disease-modifying antirheumatic drug in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register

OBJECTIVE: To compare outcome at 6 months in unselected "real-world" patients with rheumatoid arthritis treated with etanercept or infliximab as either monotherapy, cotherapy with methotrexate (MTX), or cotherapy with another disease-modifying antirheumatic drug (DMARD). METHODS: A total of 2,711 subjects starting treatment with their first biologic agent (1,453 infliximab and 1,258 etanercept) were followed up for 6 months. Outcome was assessed using the European League Against Rheumatism (EULAR) response criteria. Ordinal regression was used to model the response in the MTX and other DMARD cotherapy groups relative to the monotherapy group separately for the 2 anti-tumor necrosis factor alpha agents, after adjusting for baseline differences. RESULTS: Etanercept-treated patients had an increased likelihood of achieving a higher EULAR response category with cotherapy with MTX (odds ratio [OR] 2.0, 95% confidence interval [95% CI] 1.5-2.7) and with another DMARD (OR 1.2, 95% CI 0.9-1.6) as compared with monotherapy. For infliximab-treated patients, the likelihoods were 1.4 (95% CI 0.9-2.0) for MTX and 1.3 (95% CI 0.8-2.1) for other DMARDs versus monotherapy. Cotherapy with MTX or another DMARD produced significantly higher rates of remission with etanercept (12% and 11%, respectively) as compared with etanercept monotherapy (5%). Infliximab-treated patients showed similar remission rates in the MTX and other DMARD cotherapy groups (8% and 5%, respectively) as in the monotherapy group (7%). CONCLUSION: In this study of real-world patients, the use of MTX and, to a lesser extent, other DMARDs as cotherapy with etanercept was associated with a higher likelihood of response. Although the infliximab guidelines suggest that MTX be used as cotherapy, in clinical practice, both monotherapy and cotherapy with DMARDs other than MTX are used. These data suggest that either of the latter strategies may be useful in patients who are intolerant to MTX.     

The ability of disease modifying antirheumatic drugs to induce and maintain improvement in patients with rheumatoid arthritis. epidemiology of DMARDs treatment in Japan

OBJECTIVE: The effectiveness of the disease-modifying antirheumatic drugs (DMARDs) methotrexate (MTX), bucillamine (BUC), salazosulphapyridine (SASP) and gold sodium thiomalate (GST) over two courses of treatment with a follow-up period of at least 12 months was evaluated in 425 patients with rheumatoid arthritis. METHODS: Clinical efficacy was evaluated on the basis of the numbers of painful and swollen joints, morning stiffness, grip strength, erythrocyte sedimentation rate, C-reactive protein and rheumatoid factor levels before and after treatment. Results were evaluated on the basis of the survival rate (Kaplan-Meier method) and the incidence and types of adverse drug reactions (ADR) following single and combined therapies. RESULTS: In the first course of treatment, the survival rates for MTX, GST, BUC and SASP were 52.3%, 40.4%, 33.0% and 24.8%, respectively. The rates of development of ADR were 22.9%, 23.5%, 26.3% and 30.0% for BUC, SASP, GST and MTX, respectively. In the second course, the survival rates for MTX, BUC and SASP were 36.6%, 14.1% and 10%, respectively. CONCLUSION: DMARDs used in the first course of treatment improved the clinical parameters until the 6th month after initiation of treatment. Combination treatments showed some effectiveness, but because of the high incidence of ADR the survival rate was low. DMARDs used in the second course of treatment were not efficacious and there was no improvement in the survival rate compared to the first course of treatment.     

Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis

OBJECTIVE: To study genetic polymorphisms in the folate pathway, a site of action of methotrexate (MTX) and sulfasalazine (SSZ), as predictors of efficacy of combination disease modifying antirheumatic drug (DMARD) regimens containing MTX and SSZ in early rheumatoid arthritis (RA). METHODS: Ninety-eight Caucasian patients with early RA received MTX with SSZ, hydroxychloroquine, and folate according to a standardized protocol. Efficacy was evaluated using the Disease Activity Score (DAS28) and European League Against Rheumatism response criteria at 12 months. Nine polymorphisms in 7 genes of the folate pathway were studied. RESULTS: Response to therapy was associated with SLC19A1, MTR, and TYMS polymorphisms. Two favorable allele combinations associated with responder status at 12 months were identified: the MTR 2756A allele in combination with either the SLC19A1 80A allele or the TYMS 3R-del6 haplotype (multivariate analysis, p = 0.0002, p = 0.009 respectively). Seventy of the 72 patients with these allele combinations responded compared to 12/24 patients without [odds ratio (OR) 35.0, 95% confidence interval (CI) 6.9-176, p < 0.0001]. An association with remission (DAS28 < 2.6) was also observed (OR 3.4, 95% CI 1.1-10.0, p = 0.04). When analyzed over 3 years, both the change in DAS score from baseline and the final DAS scores were significantly higher and lower, respectively, with the favorable genotype group (p < 0.0001, p < 0.0001). CONCLUSION: Polymorphic variations in the MTR, SLC19A1, and TYMS genes were associated with better clinical response to combination DMARD regimens containing MTX and SSZ. Allele combinations of these genes may predict response to combination DMARD and assist in treatment decisions in patients with early RA.     

Cyclosporin and sulfasalazine combination in the treatment of early rheumatoid arthritis.

The aim of the study was to assess the efficacy of a new formulation of cyclosporin-A (CyA) and sulfasalazine (SASP) combination treatment in preventing disability and reducing inflammatory disease activity in patients with early rheumatoid arthritis, as well as to assess the tolerability, safety, and suitability for long-term treatment. Forty five patients with early, active rheumatoid arthritis, (RA) were treated with CyA and SASP combination therapy for 12 months. The patients were evaluated by disease activity and radiologic measurements. The combined CyA and SASP therapy seems to be effective. Disease activity parameters improved within 3 months. The individual treatment response rate according to EULAR response criteria was 78% after a one year treatment period. Five patients were withdrawn due to gastrointestinal side effect and two patients because of lack of efficacy. CyA and SASP combination treatment seems to be effective in early severe RA, and with careful monitoring, side effects can be kept under control.     

Daily practice effectiveness of a step-down treatment in comparison with a tight step-up for early rheumatoid arthritis

OBJECTIVE: To study prospectively the daily practice effectiveness of a step-down early rheumatoid arthritis (RA) treatment strategy. METHODS: Patients with severe RA and no contra-indications were proposed step-down therapy, the others step-up. Step-down patients received a modified combination therapy in early RA (COBRA) regimen: sulphasalazine (SPS), 2 g daily, and methotrexate (MTX), 15 mg weekly, combined with step-down oral prednisolone (start 60 mg daily, fast tapering to 7.5 mg over 6 weeks, discontinuation from week 28). At week 40, patients were randomized to maintenance therapy with either SPS or MTX if disease activity score-28 (DAS28) was acceptably low. The step-up group started disease-modifying anti-rheumatic drug (DMARD) monotherapy. In both groups, treatment was adjusted at follow-up, based on DAS28. DAS28, functionality Health Assessment Questionnaire (HAQ), adverse events, DMARD changes and steroid use were registered 4-monthly for 2 yrs. RESULTS: Nineteen patients received step-down and 52 step-up treatment. More patients completed the first year without unplanned DMARD changes and without dosage adjustment and fewer had DMARD changes due to side effects or inefficacy in the step-down group compared with step-up, whereas the number of adverse events was comparable. MTX proved to be the most effective maintenance therapy after step-down. The DAS response, proportion of patients in remission, HAQ response and proportion of patients without disability at 4 months was higher in the step-down group. CONCLUSIONS: In daily practice, a step-down treatment strategy for early RA is more effective than a step-up approach.