Effectiveness profiles and dose dependent retention of traditional disease modifying antirheumatic drugs for rheumatoid arthritis. An observational study

OBJECTIVE: To determine the fate of traditional disease modifying antirheumatic drugs (DMARD) in the longer term, with special respect to dose related effects on drug retention rates, efficacy, and toxicity. METHODS: Historical analysis of DMARD therapies in 593 patients, comprising a total of 1319 courses of DMARD over a period of 2378 patient-years of therapy. DMARD dosages, treatment durations, and reasons for discontinuation, and measures of C-reactive protein and erythrocyte sedimentation rate were analyzed. Drug retention rates were estimated by Kaplan-Meier analysis. RESULTS: Methotrexate (MTX), chloroquine, and sulfasalazine (SSZ) emerged as the drugs most commonly applied during the past 15 years, whereas gold salts and D-penicillamine became less frequently used during the past decade. Therapies had to be terminated mostly for adverse events (42%) or inefficacy (37%). Patients taking high dose therapy had significantly longer median retention rates than those taking low doses (SSZ 34 vs 7 mo; MTX 73 vs 39 mo). Toxicity, ratherthan inefficacy, was the main reason for discontinuation of MTX and SSZ at low doses (p < 0.001). Median retention rates lasted < 24 mo for most DMARD, except for high dose MTX (> 36 mo). CONCLUSION: MTX, SSZ, and antimalarials have become the most commonly used traditional DMARD for rheumatoid arthritis. Their use is more often limited by toxicity than by inefficacy. If tolerated, they can be retained for long periods of time.     

Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflunomide compared with other DMARD

OBJECTIVE: To determine and compare the incidence of serious adverse events (AE) during treatment of rheumatoid arthritis (RA) with disease modifying antirheumatic drugs (DMARD), focusing on leflunomide (LEF). METHODS: A retrospective cohort study of a large US insurance claims database was performed. Study groups were patients with RA classified by DMARD exposure as either no-DMARD therapy, single-agent DMARD (monotherapy), or combination-DMARD therapy. Specific DMARD examined were leflunomide (LEF) and methotrexate (MTX), compared to other DMARD (penicillamine, hydroxychloroquine, sulfasalazine, gold, etanercept, infliximab) and no DMARD (nonsteroidal antiinflammatory drugs, COX-2 inhibitors). All AE reported were considered endpoints; primary endpoints included hepatic, dermatologic, hematologic, infectious, respiratory, hypertension, and pancreatitis AE. RESULTS: The 40,594 RA patients of the study period (September 1998 to December 2000) accumulated 83,143 person-years (PY) of followup. Followup for each of the groups was: DMARD-monotherapy, 46,054 PY (55% of total); combination-DMARD, 25,830 PY (14%); and no-DMARD, 11,259 PY (14%). The incidence rate of all AE combined was significantly lower for LEF monotherapy (94 events/1000 PY) than MTX (145 events/1000 PY), other DMARD (143 events/1000 PY), or no DMARD (383 events/1000 PY) (p < 0.001 for all comparisons). The "all-AE" rates during combination therapy with LEF + MTX (43/1000 PY) and LEF + other DMARD (59/1000 PY) were lower than the "all-AE" rate for DMARD + MTX (70/1000 PY; p = 0.002). LEF monotherapy had the lowest rate of hepatic events in the DMARD monotherapy groups. CONCLUSION: The rates of AE in the LEF group, alone and combined with MTX, were generally lower than or comparable to the AE rates seen with MTX and other agents.     

Patient, disease, and therapy-related factors that influence discontinuation of disease-modifying antirheumatic drugs: a population-based incidence cohort of patients with rheumatoid arthritis

OBJECTIVE: A major challenge in management of rheumatoid arthritis (RA) is prediction of longterm response to disease-modifying antirheumatic drug (DMARD) treatment. Our objective was to identify the predictors of DMARD discontinuation in an incidence cohort of patients with RA followed continuously from their incidence date. METHODS: Members of a population-based incidence cohort of Rochester, Minnesota, residents aged > or = 18 years diagnosed with RA (by 1987 American College of Rheumatology criteria) from January 1, 1955, to January 1, 1995, were followed longitudinally through their complete medical records until January 1, 2001. Detailed drug exposure data were collected on all DMARD and glucocorticoid regimens. Subjects were considered exposed to a DMARD if duration of use was > or = 30 days. Time to discontinuation of DMARD was estimated using survival analysis techniques. Andersen-Gill models with multiple events per patient were used to assess the influence of demographics, calendar time, comorbidities, disease characteristics [disease duration, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), joint counts, radiographic changes, nodules, RA complications], and therapy characteristics (DMARD use, singly or in combination, glucocorticoid use, first or subsequent regimen, effect of previous therapy) on time from DMARD initiation to discontinuation. RESULTS: The study population comprised 345 DMARD-treated patients (73% female) with mean age of 53.1 years and mean followup 15.4 years. Median time taking any DMARD was 16.0 months for the first, and 17.9 months for all regimens. Methotrexate (MTX) had the longest time to discontinuation, with a median of 30.3 months without folate, and 61.7 months with folate supplementation. Among the various disease characteristics examined, only higher ESR at DMARD initiation was significantly associated with a shorter time taking DMARD [hazard ratio (HR) 1.05 per 10 mm/h increase, 95% CI 1.02, 1.08]. In multivariable Andersen-Gill models considering all DMARD regimens, hydroxychloroquine use (HR 0.77, 95% CI 0.64, 0.92) and MTX use (HR with folate 0.39, 95% CI 0.30, 0.51; HR without folate 0.51, 95% CI 0.39, 0.67) were significantly associated with longer time to DMARD discontinuation, whereas prior MTX use (HR 1.96, 95% CI 1.57, 2.45) was associated with shorter time to DMARD discontinuation, after adjusting for age, sex, calendar year, Charlson comorbidity index, disease duration, and ESR at DMARD initiation. Disease duration was negatively associated with time to DMARD discontinuation; each 10 year increase in disease duration corresponded to a 14% decrease in the risk of discontinuation (HR 0.86, 95% CI 0.75, 0.98). CONCLUSION: Longer RA disease duration does not appear to increase the risk of DMARD discontinuation. However, high disease activity (as assessed by ESR) is associated with a higher likelihood of discontinuing DMARD. MTX failure may identify a subgroup of patients who are less likely to respond to other DMARD and therefore could be considered as candidates for biological therapies.     

Longterm methotrexate use in rheumatoid arthritis: 12 year followup of 460 patients treated in community practice

OBJECTIVE: To extend our observations on the longterm tolerability of methotrexate (MTX) and reasons for discontinuation in a cohort of 460 patients with rheumatoid arthritis (RA). METHODS: We studied all patients with RA who started MTX before June 1986 and attended the community based private practices of 6 rheumatologists in Melbourne. Information to at least April 1, 1995, or within one year of death was updated from the patient's medical records to include MTX discontinuation and reasons for discontinuation. Addition of disease modifying antirheumatic drugs (DMARD) concomitant with MTX was noted. Survival analyses based upon life table methods were used with MTX discontinuation as the observable endpoint. Three different definitions of MTX discontinuation were used (1) according to whether the patient was taking the drug at last followup irrespective of any periods of temporary discontinuation; (2) MTX discontinuation for > 3 months considered to be a treatment endpoint; and (3) addition of concomitant DMARD considered to be only partial success of MTX (as a need for additional therapy to meet treatment goals). RESULTS: At 12 years, 53% of patients were continuing to take MTX (irrespective of any periods of temporary discontinuation). If discontinuation of the drug for 3 or more months was considered a treatment termination then 38% were still taking the drug at 12 years, and if addition of concomitant DMARD was regarded as a treatment endpoint only 17% of patients were continuing MTX at 12 years. Withdrawal for gastrointestinal toxicity declined over time but the risk of other adverse effects appeared to persist over time. CONCLUSION: MTX in RA is well tolerated over the longer term, with > 50% of patients starting MTX in a community based rheumatology private practice continuing to take it 12 years later. However, a substantial number of patients had 2nd line therapies added over this time. Monitoring for toxicity should continue throughout the course of therapy.     

Step-up combination versus switching of non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: results from a retrospective observational study

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.     

Recommendations of Czech Rheumatological Society for the treatment of rheumatoid arthritis. Efficacy and treatment strategies

Rheumatoid arthritis (RA) is an autoimmune disease of unknown aetiology characterized by presence of chronic symmetric synovitis, which leads to the formation of joint erosions. Generally recommended method for activity assessment of RA is so called Disease Activity Score (DAS). In early RA when low disease activity is present with oligo- or monoarthritis antimalarials are drugs of choice, while sulfasalazine (SAS) is recommended in cases with medium activity without erosions. Initial treatment with methotrexate (MTX) or leflunomide (LEF) should be applied in a very active polyarthritis with a rapid development of erosions. MTX is often combined with other disease modifying drugs (DMARD) and the blockers of tumour necrosis factor alpha (TNF-alpha). LEF is to be administered to the patients in whom the other DMARD are contraindicated or not tolerated. In established RA with oligo- or monoarthritis with permanent low activity SAS is DMARD of choice. In cases with insufficient response and medium activity MTX is used and if it is inefficient LEF or combination of DMARD should be considered. In a very active disease with a rapid evolution of erosions high doses of MTX or LEF are recommended. When extraarticular symptoms of RA are present azathioprine is to be applied and in case of involvement of vital organs cyclophosphamide should be used. When DMARD are failing or contraindicated TNF-alpha blockers are to be applied. When one TNF-alpha blocker is inefficient it should by replaced by another one from the same group or another biological should be used. For indication of biologicals the activity limit is DAS28 5.1 and the decrease of DAS28 more than 1.2 is an efficacy criterion. Nonsteroidal antirheumatic drugs are an important part in the management of RA, and also corticosteroids are often of used in oral or parenteral form. To the complex therapy of RA nonpharmacological means are usually implemented--different physical procedures and various surgeries.     

Survival and effectiveness of leflunomide compared with methotrexate and sulfasalazine in rheumatoid arthritis: a matched observational study

OBJECTIVE: To determine the survival and clinical effectiveness of leflunomide (LEF) compared with methotrexate (MTX) and sulfasalazine (SSZ) for RA in an observational study. METHODS: An observational database of 1088 patients and 5141 patient years of DMARD treatment (2680 courses) from two academic hospitals was filtered for treatment with LEF, MTX, and SSZ. LEF treatment groups were matched for patients' age, baseline ESR, number of previous DMARDs, and hospital cohort with MTX and SSZ treatment groups. For these treatments, Kaplan-Meier analyses of time until the drug was discontinued (drug "survival"), and the effectiveness and safety of continuation of treatment, were performed. The change in disease activity markers (CRP, ESR) was compared between the groups. RESULTS: The median dose during the study increased from 10 to 15 mg MTX/week and from 1.5 to 2.0 g SSZ/day. Matched survival analysis showed better retention rates for MTX (mean (SEM) survival 28 (1) months) than for LEF (20 (1) months; p=0.001), whereas retention rates of SSZ (23 (1) months) were similar to those of LEF (p=NS). Treatments were stopped earlier because of adverse events (AEs, 3 months) than because of ineffectiveness (IE, 10 months; p<0.001). LEF and MTX were less likely to be stopped because of AEs than SSZ. LEF courses were stopped earlier for AEs (p<0.001) than MTX. CONCLUSIONS: Current dosing strategies should be re-evaluated, and coping strategies for common AEs should be investigated. This will be necessary to achieve better drug retention of LEF. At present, MTX continues to be the most effective drug in clinical practice.     

Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group

OBJECTIVE: To determine whether treatment with leflunomide (LEF), methotrexate (MTX), or sulfasalazine (SSZ) for 6-12 months retards progression of radiographic damage and to identify clinical variables that correlate with radiographic progression. METHODS: Radiographs of the hands and feet were performed at baseline and at the end of study or early exit in 3 randomized controlled trials. Protocol US301 was a 12-month controlled trial of LEF or MTX treatment compared with placebo in 482 patients randomized in a 3:3:2 ratio. Protocol MN301 compared 6 months of LEF or SSZ treatment with placebo in 358 patients, randomized in a 3:3:2 ratio, with continued blinded treatment in the active control arms for 12 months. Protocol MN302 compared 12 months of LEF treatment with MTX in 999 patients. Radiographs were blinded for sequence and treatment and were scored for erosions and joint space narrowing. All analyses were by intent-to-treat. Sensitivity analyses were performed to account for missing data. RESULTS: LEF, MTX, and SSZ treatment resulted in statistically significantly less radiographic progression compared with placebo at 6 and 12 months: for protocol US301, LEF versus placebo P = 0.0007 and MTX versus placebo P = 0.0196; for protocol MN301, LEF versus placebo P = 0.0004 and SSZ versus placebo P = 0.0484. The effect of LEF treatment was similar to that of MTX and SSZ. CONCLUSION: These are the first 6- and 12-month randomized placebo- and active drug-controlled trials to demonstrate retardation of radiographic progression by a new disease-modifying antirheumatic drug (DMARD), LEF, as well as 2 commonly used DMARDs, MTX and SSZ.     

Leflunomide in rheumatoid arthritis in daily practice: treatment discontinuation rates in comparison with other DMARDs

OBJECTIVE: To evaluate the treatment discontinuation rate of leflunomide in rheumatoid arthritis (RA) in comparison with the discontinuation of other disease modifying anti-rheumatic drugs (DMARDs), in daily practice, in a single center and during the same period of time. METHODS: Study design: 3-year, retrospective, monocenter. Patients: RA patients for whom leflunomide or another DMARD was initiated between 1998 and 2001 (several DMARDs could be initiated for a given patient during this period). Collected data: For each patient, demographic and disease data. For each treatment course, date of initiation, if relevant date of discontinuation and reason for discontinuation. Analysis: Percentage of patients discontinuing treatment over time (life table method; Kaplan-Meier), comparison between leflunomide and the "any other DMARD" or methotrexate groups using the Log-Rank test. RESULTS: During the study period, 515 DMARDs were initiated in 285 patients. Leflunomide was initiated in 161 patients who were older and had a longer disease duration than the other treated patients (59 +/- 13 years and 14 +/- 9 years versus 54 +/- 15 years and 11 +/- 10 years in the leflunomide group and other DMARDs group respectively). Discontinuation rate of leflunomide after 1 year was 56.7%, mainly because of adverse drug reactions (41.6%). The discontinuation rate whatever the reason and for toxicity was higher for leflunomide than for other DMARDs studied. However discontinuation for inefficacy was similar in both groups. CONCLUSION: This study conducted in conditions of daily practice when leflunomide was first available suggests a higher discontinuation rate of leflunomide because of adverse events when compared to other DMARDs.     

Comparison of combination therapies in the treatment of rheumatoid arthritis: leflunomide-anti-TNF-alpha versus methotrexate-anti-TNF-alpha

To compare the efficacy and safety of leflunomide (LEF)-anti-TNF-alpha combination therapy to methotrexate (MTX)-anti-TNF-alpha combination therapy in a group of patients with active rheumatoid arthritis (RA). We have recruited 120 patients with RA with a high disease activity despite being treated with MTX (15 mg/week) or LEF (20 mg/die) for 3 months, without side effects. In each of these patients, therapy with either MTX or LEF was continued and randomly combined with an anti-TNF-alpha drug: etanercept, infliximab, or adalimumab. Patients were assessed at study entry and at 4, 12, and at 24 weeks. The efficacy endpoints included variations in the DAS28-ESR and the ACR20, ACR50, and ACR70 responses. At each visit, any side-effect was recorded. There were no statistically significant differences in the DAS28 variations and in the ACR responses between the two groups or among the six subgroups. The number of discontinuation due to the appearance of serious side effects was higher, but not statistically significant, in the LEF-anti-TNF-alpha group than in the MTX-anti-TNF-alpha group. Other adverse events that did not necessitate the discontinuation of therapy occurred much more frequently in patients treated with MTX than in those treated with LEF. Anti-TNF-alpha drugs can be used in combination not only with MTX, but also with LEF, with the same probability of achieving significant clinical improvement in RA patients and without a significantly greater risk of serious adverse events. In contrast, it seems that combination therapy with LEF-anti-TNF-alpha is more readily tolerated than combination therapy with MTX-anti-TNF-alpha.     

Leflunomide (Arava™) is a useful DMARD in Indian (Asian) patients: a clinic-based observational study of 1-year treatment

Several drug trials, predominantly of Caucasian patients, have demonstrated the therapeutic role of leflunomide (LEF) in the treatment of rheumatoid arthritis (RA). We report an Indian (Asian) experience from a prospective observational study. Two hundred thirty affording patients with moderately severe active RA (naïve for LEF), mostly failing methotrexate (MTX), were begun LEF (Arava?; 20 mg daily, post loading 100 mg od × 3 days) in a clinic setting and followed regularly in an open cohort as per standard of care practice guidelines. A priori, LEF was to be preferably used as a single-agent disease-modifying anti-rheumatic drug (DMARD). One hundred forty-three patients and 87 patients were clinically assigned to the LEF monotherapy and LEF + MTX combination, respectively; less than one third received prednisolone. We focus on 146 patients (64%) completing 1 year treatment. Patients improved significantly (p?相似文献   

Leflunomide in psoriatic arthritis: a retrospective study of discontinuation rate in daily clinical practice compared with methotrexate

OBJECTIVE: To assess the safety profile of leflunomide (LEF) in a two-year retrospective analysis of psoriatic arthritis (PsA) patients (pts) treated in daily clinical practice compared with methotrexate (MTX). PATIENTS: Fourty-two PsA patients with polyarticular involvement or asymmetrical oligoarticular arthritis, satisfying ESSG criteria for the spondyloarthropathies, treated with LEF monotherapy (10-20mg/die without loading dose) between September, 2004 and August, 2006 were reviewed. They were compared with MTX (7.5-15mg/week) users (44 cases). The adverse events (AEs) and the causes of withdrawal were evaluated. RESULTS: At 24 months, cumulative survival rate of pts remaining on drugs was 54.9% in LEF users and 57.0% in MTX users (p > 0.05). The discontinuation rate (DR) for toxicity was higher in LEF group (29.2%) than in MTX group (10.8%) (p = 0.07). The occurrence of AEs was more frequently registered in the first year in both groups. LEF monotherapy showed a significant higher crude incidence for any AEs (38.7 events x100 person-years) compared to MTX (14.3 events x100 person-years) (p < 0.001). The cumulative DR for inefficacy was greater but not statistically significant in MTX group than LEF (28.6% vs. 12.6% respectively; p = 0.056). Finally, DR for other causes accounted for 8.7% vs. 11.0% respectively (p > 0.05). CONCLUSIONS: Our data showed, in a setting of clinical practice, that the rate of PsA pts remaining on drug was comparable between LEF and MTX, and a manageable LEF safety profile during a 24 months of follow-up, even if a greater incidence of DR for AEs was registered than in MTX users.     

The time course of gastric methotrexate intolerance in patients with rheumatoid arthritis and psoriatic arthritis

Objectives

This study aimed to evaluate the incidence and the time course of methotrexate (MTX)-associated gastric intolerance in patients with rheumatoid arthritis and psoriatic arthritis.

Methods

Four hundred twenty subjects undergoing MTX treatment for rheumatoid arthritis (n = 346) and psoriatic arthritis (n = 74) were retrospectively assessed. The incidence and time course of gastric MTX intolerance resulting in treatment discontinuation were investigated. In addition, the relations between gastric intolerance and patient characteristics, including gender, age, diagnosis, and rheumatoid factor (RF) positivity, were examined.

Results

Overall, oral MTX discontinuation rate due to gastric intolerance was 28.6 %. The time to discontinuation for oral MTX was 8.1 ± 11.5 months on average, with more than half of the discontinuations occurring within the first three months of treatment. Discontinuation was not associated with gender, age, diagnosis, or RF positivity. More than half of the patients that switched to a parenteral treatment regimen (52.6 %, 20/38) could tolerate the agent.

Conclusions

Gastric MTX intolerance usually develops within the first year of treatment and presents a major obstacle to long-term treatment retention in patients with rheumatologic disease. However, parenteral MTX appears to be a good alternative for patients intolerant of oral MTX.     

Factors influencing length of time taking methotrexate in rheumatoid arthritis

OBJECTIVE: Duration of therapy has been suggested to represent a measure of effectiveness. Life table analyses of therapy with methotrexate (MTX) in rheumatoid arthritis (RA) have indicated a longer duration than with other drugs. However, individual patients continue taking MTX for different periods of time. We assessed the influence of patient variables at treatment onset upon subsequent duration of MTX therapy. METHODS: Patients with RA (n = 437) from 8 North American databank centers beginning MTX therapy after January 1, 1988, were followed prospectively. Age at onset of MTX treatment, sex, years of education, age at onset of disease, years with disease, number of comorbid conditions, number of disease modifying antirheumatic drugs (DMARD) and nonsteroidal antiinflammatory drugs (NSAID) taken just prior to MTX. disability level, pain, and global assessment prior to starting MTX were used in univariate Kaplan-Meier analyses to predict number of months taking MTX alone. An index that divided the patients into risk strata for predicting duration of therapy was constructed to be clinically useful. RESULTS: The median number of months continuing MTX without addition of other DMARD was 41 months and the median for the total course taking MTX was 52 months. The retention rate was lowest for patients with the most negative initial health state. High level of initial pain, long duration of disease, and not using a DMARD just prior to MTX were associated with low retention rate and can be used to predict expected durations of MTX treatment ranging from 17 to 52 months. For practical guidance in clinical decisions an index was computed based on the predictor variables: level of initial pain, duration of disease, and number of DMARD; this index identifies subgroups with very different durations taking MTX alone. Disease duration at baseline was strongly related to time taking MTX alone and could therefore also be used as a simplified rule in clinical work. CONCLUSION: Expected duration of MTX treatment is influenced by clinical variables, and these may suggest those patients likely to have more or less satisfactory experiences with MTX. The time taking drug alone (therapeutic segment) may be a more logical and sensitive indicator of effectiveness than the total course on the medication.     

Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis

BACKGROUND: Acquired drug resistance or gradual drug failure has been described with most disease modifying antirheumatic drugs (DMARDs) and is also starting to be recognised with anti-tumour necrosis factor (anti-TNF) agents. OBJECTIVE: To study acquired drug resistance to anti-TNF agents in rheumatoid arthritis (RA). METHODS: Swiss health authorities requested continuous monitoring of patients receiving biological agents. Intensification of co-therapy with traditional DMARDs, gradual dose escalation, and drug discontinuation rates in all patients receiving infliximab, etanercept, or adalimumab, adjusting for potential confounders, were analysed. Intensification of DMARD co-therapy and time to discontinuation of the three anti-TNF agents were analysed using a proportional hazards models. Dose escalation and evolution of RA disease activity (DAS28) were analysed using a longitudinal regression model. RESULTS: 1198 patients contributing 1450 patient-years of anti-TNF treatment met the inclusion criteria. The rate of intensification of traditional DMARD co-therapy over time was significantly higher with infliximab (hazards ratio = 1.73 (99% confidence interval (CI) 1.19 to 2.51)) than with the two other agents. Infliximab also showed significant dose escalation over time, with an average dose increase of +12% (99% CI 8% to 16%) after 1 year, and +18% (99% CI 11% to 25%) after 2 years. No significant differences in discontinuation rates were seen between the three anti-TNF agents (ANOVA, p = 0.67). Evolution of disease activity over time indicated a lower therapeutic response to infliximab (DAS28, p<0.001) compared with etanercept, after 6 months' treatment. CONCLUSIONS: In this population, infliximab was associated with a higher risk of requiring intensification of DMARD co-therapy than the other anti-TNF agents and a significant dose escalation over time. Analysis of RA disease activity indicated a reduced therapeutic response to infliximab after the first 6 months of treatment, suggestive of acquired drug resistance.     

Preliminary evaluation in rheumatoid arthritis activity in patients treated with TNF-α blocker plus methotrexate versus methotrexate or leflunomide alone

Methotrexate (MTX) is a first-line disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA). Leflunomide (LEF) and the biologic agents entered the arsenal of DMARDs in 1998. Therapeutic properties of new drugs are still under survey. The purpose of this study was to evaluate and compare the efficacy of MTX, LEF and a biologic agent (TNF-α blocker) combined with MTX in reducing disease activity in RA. Seventy-eight patients with active RA underwent a 24-week treatment with MTX 15 mg/week (30 pts), LEF 20 mg/day (30 pts) or a TNF-α blocker (etanercept 25 mg 2× weekly or infliximab 3 mg/kg in the week 0, 2, 6 and every 8 weeks thereafter) plus MTX 15 mg/week (18 pts). Only patients with RA resistant to MTX were included in groups receiving LEF or a biologic agent. During follow-up, patients’ characteristics, disease characteristics, and clinical and laboratory data were registered. RA activity was evaluated using the ESR, tender and swollen joint counts, the duration of morning stiffness, disease activity score-28 (DAS 28), visual analogue scale (VAS) and health assessment questionnaire (HAQ). Treatment efficacy was demonstrated with ACR 20, 50 and 70 criteria. All groups revealed statistically significant improvement in all disease activity parameters measured. The percentage improvements were similar in groups treated with MTX and LEF and—except for VAS—significantly greater in the group treated with a biologic agent. Disease activity assessed by DAS 28 decreased significantly in all groups: the results were comparable in groups treated with MTX and LEF and significantly more prominent in the group treated with a TNF-α blocker. The ACR 20, 50 and 70 improvements amounted, respectively: 100, 50 and 7% in MTX group 87, 60 and 13% in LEF group and 100, 83 and 50% in a biologic agent group. The study revealed equal effectiveness of MTX and LEF in reducing disease activity in rheumatoid arthritis. The efficacy of a TNF-α blocker combined with MTX was higher than that of each conventional DMARDs, especially with regard to ACR 70 criteria (considerable improvement after treatment). LEF was equally effective as MTX in patients unable to continue MTX treatment due to the drug’s ineffectiveness.     

Eight versus 16-week re-evaluation period in rheumatoid arthritis patients treated with leflunomide or methotrexate accompanied by moderate dose prednisone

In a step-up approach of DMARD treatment of RA a fast response and an early DMARD switch in the case of non-response is important. Therefore, we performed an open trial in which we compared an 8-week and a 16-week observation period during treatment of RA with MTX or LEF, both given in intensified starting doses and accompanied by moderate dose prednisone. MTX and LEF naïve patients with RA (mean time since diagnosis: 2.3 years) were randomised to receive either LEF in a 3-day-loading dose of 100 mg/day followed by 20 mg/day (n = 19) or MTX intramuscularly in a dose of 25 mg once weekly (n = 21). All patients received concomitant treatment with oral prednisone in an initial dose of 20 mg/day with weekly dose reductions of 5 mg/day. The disease activity was re-evaluated 8 and 16 weeks after the start of the treatment. Mean DAS28 before the start of treatment was 5.36 ± 0.8 for the MTX-group and 5.46 ± 0.8 for the LEF-group. After 8 weeks of treatment the DAS28 in the MTX-group was 2.59 ± 1.0 and 3.16 ± 0.8 in the LEF group (difference not significant). The mean DAS28 at re-evaluation 16 weeks after the starting of treatment (2.58 ± 1.5 for the MTX-group and 3.25 ± 1.16 for the LEF-group) was significantly different neither in between the both treatment groups nor in comparison to the week 8 evaluation. Efficiency of RA treatment with MTX or LEF in intensified doses and in combination with moderate dose prednisone can be sufficiently judged 8 weeks after its initiation.