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V Strand

Publications and source records attributed to V Strand.

At least 19 recordsLinked to original sources
PubMed2006

Sustained benefit in rheumatoid arthritis following one course of rituximab: improvements in physical function over 2 years.

OBJECTIVES: To evaluate the long-term impact on physical function of a single course of rituximab in rheumatoid factor, seropositive patients with active rheumatoid arthritis (RA) despite ongoing methotrexate treatment. METHODS: A randomized, controlled trial comparing rituximab alone [1,000 mg intravenously (iv) on days 1 and 15, n= 40], or in combination with cyclophosphamide (750 mg iv on days 3 and 7, n= 41) or oral methotrexate (> or =10 mg/week, n= 40) with placebo + methotrexate (> or =10 mg/week, n= 40), resulted in significant reductions in disease activity at weeks 24 and 48. Sustained improvements in physical function and standard effect sizes (SES) for changes in components of ACR and EULAR criteria were evaluated over 2 yrs. RESULTS: More patients receiving rituximab + methotrexate completed a 2-yr follow-up without further treatment than those receiving placebo + methotrexate (45% vs 15%, respectively), rituximab alone (10%) or rituximab + cyclophosphamide (22%). This reflected a higher percentage of patients receiving rituximab + methotrexate reporting improvements in Health Assessment Questionnaire Disability Index > or = minimum clinically important difference at 1 and 2 yrs (68% and 30%, respectively) compared with placebo + methotrexate (28% and 15%), rituximab monotherapy (43% and 10%) or rituximab + cyclophosphamide (39% and 12%). SES were high in all rituximab groups and revealed differing patterns of response over time. CONCLUSION: A single course of rituximab with continuing methotrexate in patients with active RA provided clinically meaningful improvements in physical function over 2 yrs, with lower discontinuation rates and larger SES for improvements in ACR and EULAR criteria components.

Adult↗
PubMed2006

An integrated analysis of five double-blind, randomized controlled trials evaluating the safety and efficacy of a hyaluronan product for intra-articular injection in osteoarthritis of the knee.

OBJECTIVE: Five double-blind, randomized, saline-controlled trials (RCTs) were included in the United States marketing application for an intra-articular hyaluronan (IA-HA) product for the treatment of osteoarthritis (OA) of the knee. We report an integrated analysis of the primary Case Report Form (CRF) data from these trials. METHOD: Trials were similar in design, patient population and outcome measures - all included the Lequèsne Algofunctional Index (LI), a validated composite index of pain and function, evaluating treatment over 3 months. Individual patient data were pooled; a repeated measures analysis of covariance was performed in the intent-to-treat (ITT) population. Analyses utilized both fixed and random effects models. Safety data from the five RCTs were summarized. RESULTS: A total of 1155 patients with radiologically confirmed knee OA were enrolled: 619 received three or five IA-HA injections; 536 received "placebo" saline injections. In the active and control groups, mean ages were 61.8 and 61.4 years; 62.4% and 58.8% were women; baseline total Lequèsne scores 11.03 and 11.30, respectively. Integrated analysis of the pooled data set found a statistically significant reduction (P < 0.001) in total Lequèsne score with hyaluronan (HA) (-2.68) vs placebo (-2.00); estimated difference -0.68 (95% CI: -0.56 to -0.79), effect size 0.20. Additional modeling approaches confirmed robustness of the analyses. CONCLUSIONS: This integrated analysis demonstrates that multiple design factors influence the results of RCTs assessing efficacy of intra-articular (IA) therapies, and that integrated analyses based on primary data differ from meta-analyses using transformed data.

Aged↗
PubMed2006

Are American College of Rheumatology 50% response criteria superior to 20% criteria in distinguishing active aggressive treatment in rheumatoid arthritis clinical trials reported since 1997? A meta-analysis of discriminant capacities.

OBJECTIVE: To carry out a meta-analysis designed to compare the discriminant capacities of American College of Rheumatology 50% (ACR50) with 20% (ACR20) responses in clinical trials on rheumatoid arthritis reported after 1997 and to analyse whether ACR50 can be as informative as ACR20 in distinguishing active from control treatments in more recent trials. METHODS: Clinical trials on rheumatoid arthritis reported since 1997 were identified, which included aggressive combinations of disease-modifying antirheumatic drugs and glucocorticoids, as well as powerful new agents-leflunomide, etanercept, infliximab, anakinra, adalimumab, abatacept, tacrolimus and rituximab. A meta-analysis of ACR20 compared with ACR50 responses for 21 clinical trials was carried out on differences in proportions of responders for active and control treatments and corresponding odds ratios (ORs). RESULTS: In all but one clinical trial on rheumatoid arthritis published since 1997 with data available on ACR20 and ACR50, more than 50% of patients who were ACR20 responders among those randomised to active treatment were also ACR50 responders. This phenomenon was seen for control groups in 38% of trials, many of which included treatment with methotrexate. A meta-analysis of the clinical trials indicated a slight advantage to ACR50 for quantifying treatment comparisons, not significant for differences in proportions but significant for ORs. CONCLUSION: ACR20 and ACR50 seem to be similar in distinguishing active from control treatments in clinical trials on rheumatoid arthritis reported since 1997. As ACR50 represents a considerably stronger clinical response, ACR50 may be a preferred end point for contemporary clinical trials on rheumatoid arthritis.

Antirheumatic Agents↗
PubMed2005

OMERACT 7 psoriatic arthritis workshop: synopsis.

Outcome Measures in Rheumatology (OMERACT) conferences have developed a process by which outcome measures to be included in clinical trials are identified by consensus. During OMERACT 7, held in Asilomar, CA, USA, in May 2004, a workshop on outcome measures in psoriatic arthritis was held. Information derived through a previous Delphi exercise and nominal group process was shared with the participants, as were the results from a study using completed clinical trials with biological therapies. On the basis of the evidence presented and discussions in breakout groups at the OMERACT conference, a set of domains to be included in clinical trials in psoriatic arthritis was developed and a research agenda for further studies in psoriatic arthritis proposed.

Arthritis, Psoriatic↗
PubMed2004

Patient-reported outcomes better discriminate active treatment from placebo in randomized controlled trials in rheumatoid arthritis.

BACKGROUND: Recent randomized controlled trials (RCTs) in rheumatoid arthritis (RA) have used patient- and physician-reported outcomes, ESR and/or CRP as components of ACR response criteria to assess efficacy. OBJECTIVES: Mean changes from baseline in patient- and physician-reported outcome measures, ESR and CRP were compared in two RCTs in patients with active RA. Comparisons between active and placebo treatment used mean percentage improvements and standard effect sizes (SESs). RESULTS: In both protocols, patient-reported assessments of disease activity, pain and physical function reflected little or no improvement with placebo, best discriminating between active and placebo therapy, as did ESR and CRP. CONCLUSION: Improvements in signs and symptoms of active RA in placebo RCTs appear to be best reflected by patient-reported measures of physical function, as long as reported changes in global assessments of disease activity and/or pain reflect similar benefit. Patient-reported outcome measures should be considered objective; treatment-associated changes are congruent with measures of inflammation, and appear less susceptible to the placebo response.

Antirheumatic Agents↗
PubMed2004

Efficacy and safety of leflunomide 10 mg versus 20 mg once daily in patients with active rheumatoid arthritis: multinational double-blind, randomized trial.

OBJECTIVE: To compare the efficacy and safety profile of two daily maintenance doses of leflunomide, 10 mg and 20 mg, for the treatment of active rheumatoid arthritis (RA). METHODS: In this multinational, randomized, double-blind, parallel-group study, 402 RA patients were randomized equally to receive daily doses of 10 mg leflunomide (n = 202; loading dose on day 3, 100 mg) or 20 mg leflunomide (n = 200; loading dose on day 1-3, 100 mg) for 24 weeks. The study was designed to demonstrate non-inferiority of the efficacy of 10 mg compared with 20 mg by calculating 95% confidence intervals for differences in changes in tender joint count (TJC), swollen joint count (SJC) and Health Assessment Questionnaire Disability Index (HAQ DI), comparing these confidence intervals with predefined bounds. RESULTS: In the intent-to-treat population, mean improvements at the end-point in the 10 and 20 mg groups respectively were: TJC, -7.57 and -8.89 (P = 0.061); SJC, -6.38 and -6.96 (P = 0.304); and HAQ DI, 0-0.37 and 0-0.49 (P = 0.095). By American College of Rheumatology (ACR) > or =20% criteria, response rates were 49.8 and 56.6% respectively (P = 0.1724). Adverse events (AEs) resulting in treatment withdrawal were higher in the 10 mg (15.3%) than in the 20 mg treatment group (12.0%), as were serious adverse events (SAEs): 12.9 vs 10.0%. CONCLUSIONS: This study rejected the hypothesis of non-inferiority of 10 mg compared with 20 mg daily maintenance doses of leflunomide. More AEs resulting in treatment discontinuation and SAEs in patients receiving 10 mg leflunomide daily also support a better efficacy profile for the 20 mg daily dose.

Adrenal Cortex Hormones↗
PubMed2004

Patient- versus physician-reported outcomes in rheumatoid arthritis patients treated with recombinant interleukin-1 receptor antagonist (anakinra) therapy.

OBJECTIVES: To determine whether patient-reported outcomes may differentiate treatment response better than physician-reported outcomes for rheumatoid arthritis (RA) patients being treated with anakinra. METHODS: A meta-analysis was conducted using data obtained from three separate randomized controlled clinical trials (RCTs) (n = 1007). Outcomes from 6-month assessments were grouped into four categories: American College of Rheumatology (ACR) response criteria, patient-reported measures (patient-reported pain, patient global assessment, and assessment of physical function using the Health Assessment Questionnaire), physician-reported measures (tender and swollen joint counts and physician global assessment), and laboratory tests (C-reactive protein and erythrocyte sedimentation rate). Effect sizes were calculated using changes from baseline and pooled standard deviations for each of these types of outcome. RESULTS: Active treatment with anakinra was superior to placebo by ACR(20) responses in all three RCTs. Effect sizes for patient-reported outcomes were greater than for physician-reported outcomes, and also greater than ACR(20) in three of five anakinra cohorts. Across the RCTs, placebo responses were greater with physician-reported than with patient-reported outcomes. In the two studies evaluating patients with longer-standing disease, differences between pooled effect sizes for patient-reported and physician-reported outcomes were even more pronounced. CONCLUSIONS: In three pivotal RCTs, active treatment with anakinra resulted in greater improvements in patient-reported than physician-reported outcomes compared with placebo. These observations confirm those previously reported from RCTs evaluating conventional DMARDs, demonstrating better discrimination of treatment effect with patient-reported outcomes.

Adult↗
PubMed2004

OMERACT-OARSI initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited.

BACKGROUND: The OARSI Standing Committee for Clinical Trials Response Criteria Initiative had developed two sets of responder criteria to present the results of changes after treatment in three symptomatic domains (pain, function, and patient's global assessment) as a single variable for clinical trials (1). For each domain, a response was defined by both a relative and an absolute change, with different cut-offs with regard to the drug, the route of administration and the OA localization. OBJECTIVE: To propose a simplified set of responder criteria with a similar cut-off, whatever the drug, the route or the OA localization. METHODS: Data driven approach: (1) Two databases were considered: the "elaboration" database with which the formal OARSI sets of responder criteria were elaborated, and the "revisit" database. (2) Six different scenarios were evaluated: The two formal OARSI sets of criteria; Four proposed scenarios of simplified sets of criteria. Data from clinical randomized blinded placebo controlled trials were used to evaluate the performances of the two formal scenarios with two different databases ("elaboration" versus "revisit") and those of the four proposed simplified scenarios within the "revisit" database. The placebo effect, active effect, treatment effect, and the required sample arm size to obtain the placebo effect and the active treatment effect observed were the performances evaluated for each of the six scenarios. Experts' opinion approach: Results were discussed among the participants of the OMERACT VI meeting, who voted to select the definite OMERACT-OARSI set of criteria (one of the six evaluated scenarios). RESULTS: Data driven approach: Fourteen trials totaling 1886 OA patients and fifteen studies involving 8164 OA patients were evaluated in the "elaboration"and the "revisit" databases respectively. The variability of the performances observed in the "revisit" database when using the different simplified scenarios was similar to that observed between the two databases ("elaboration" versus "revisit") when using the formal scenarios. The treatment effect and the required sample arm size were similar for each set of criteria. Experts' opinion approach: According to the experts, these two previous performances were the most important of an optimal set of responder criteria. They chose the set of criteria considering both pain and function as evaluation domain and requiring an absolute change and a relative change from baseline to define a response, with similar cut-offs whatever the drug, the route of administration or the OA localization. CONCLUSION: This data driven and experts' opinion approach is the basis for proposing an optimal simplified set of responder criteria for OA clinical trials. Other studies, using other sets of OA patients, are required in order to further validate this proposed OMERACT-OARSI set of criteria.

Clinical Trials as Topic↗
PubMed2004

The role of interleukin-1 in bone resorption in rheumatoid arthritis.

Bone loss in RA includes juxta-articular osteopenia, erosions and systemic osteoporosis. In each case, synthesis of new bone matrix is unable to balance osteoclast-mediated bone resorption, resulting in net bone loss. IL-1, TNF and other proinflammatory cytokines stimulate osteoclast differentiation and activation, resulting in bone loss. In addition, these proinflammatory cytokines stimulate synovial fibroblasts and chondrocytes to produce proteinases that degrade cartilage. In animal arthritis models, blocking IL-1 significantly reduces bone erosions and cartilage degradation, whereas blocking TNF decreases synovitis. In patients with active RA, treatment with the TNF blockers etanercept and infliximab, as well as with anakinra, a recombinant human IL-1 receptor antagonist, significantly reduced erosions and joint space narrowing. It remains to be determined, however, whether slowing radiographic progression with these biological therapies will significantly improve long-term outcomes in RA.

Antibodies, Monoclonal↗
PubMed2004

Long term evaluation of radiographic disease progression in a subset of patients with rheumatoid arthritis treated with leflunomide beyond 2 years.

OBJECTIVES: To assess the effect of long term (>2 years) leflunomide treatment on radiographic progression in patients with RA. METHODS: Patients treated with leflunomide for >2 years in one of three phase III trials and subsequent extensions, for whom paired, evaluable radiographs at baseline and study end point were available, were included. Radiographs of hands and feet were assessed according to the modified Sharp/van der Heijde scoring method, for erosion, joint space narrowing, and total score. Changes from baseline were assessed, and a predicted yearly progression rate estimated for each patient. RESULTS: 128 of the original 824 patients were included, with mean disease duration 5.1 years and mean leflunomide treatment duration 4.3 years until the final x ray examination. The mean change from baseline in total score was 8.6 with yearly adjusted rate 1.9, and the median change was 2 with yearly adjusted rate 0.5, compared with 7.9 and 4.9, respectively, before leflunomide treatment. After treatment, the rate improved in 92/128 (72%) patients and deteriorated in 21/128 (16%). In 42 (33%) patients who had a total score >0 at baseline, no radiographic progression occurred after leflunomide treatment. CONCLUSIONS: In a subset of patients who continued treatment long term, leflunomide treatment reduced the rate of radiographic damage.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Clinical trial design in systemic lupus erythematosus: lessons learned and future directions.

Designing successful randomized controlled trials (RCTs) in systemic lupus erythematosus (SLE) poses many challenges. It remains difficult to correlate alterations in biologic markers with clinical outcome, especially when signs and symptoms are intermittent and broadly variable between patients. Disease activity indices were not designed specifically as outcome measures in RCTs, as they were developed in the context of longitudinal observational studies. Although all disease activity indices have been validated against each other and demonstrated to show change, organ system manifestations are variably weighted; fatigue and autoantibody titers are scored in some and not in others. Due to the variability of the underlying disease course an assessment of disease activity may most accurately be portrayed as change over time, such as an area under the curve analysis. Another lesson learned is that 'responder indices' proposed in the absence of prospective validation in RCTs do not function well. The argument can always be made that any response criteria will work if the treatment is effective; but without the precedent of a product specifically approved for use in SLE, this is hard to prove. The ACR/Systemic Lupus International Cooperating Clinics (SLICC) damage index was designed to score irreversible manifestations of disease or consequences of its treatment, provided they had been present for at least six months. The damage index may best be utilized to stratify patients or balance randomization at baseline. It may also be incorporated into an endpoint analysis, to ensure that treatment or disease associated deterioration in organ system function (that may be overlooked in scoring disease activity alone) has not occurred. Patient cohort data have demonstrated that the medical outcomes survey short form-36 (SF-36) reflected the effects of SLE better than other patient reported measures. Worsening SF-36 domain scores best correlate with higher disease activity, increased glucocorticoid doses and use of cytotoxic agents. It has been shown sensitive to change in RCTs and observational cohorts, and reflects the impact of treatment with high dose glucocorticoids and immunosuppressive agents, as well as end stage renal disease. There is now a body of data derived from RCTs in SLE. Albeit limited, yet to result in an approved therapy, evidence is accumulating that indicate 'early markers' of response can be defined which may correlate with longer term clinical outcomes. This should inform us in our ongoing efforts to clinically test a broad variety of promising interventions.

Clinical Trials as Topic↗
PubMed2003

Leflunomide for treating rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. Leflunomide, as an inhibitor of pyrimidine synthesis, has a different mechanism of action than other existing disease modifying anti-rheumatic drugs (DMARD). OBJECTIVES: To determine the efficacy and toxicity of leflunomide compared to placebo or other DMARDs in the treatment of RA. SEARCH STRATEGY: We conducted a search in MEDLINE, EMBASE, Current Contents and the Cochrane Controlled Trial Register for trials up to December 2001. We also hand-searched reference lists and consulted content experts. SELECTION CRITERIA: Two independent reviewers selected the trials that met predetermined inclusion criteria. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data and assessed methodologic quality using standardized forms. MAIN RESULTS: Six trials were included in this review. Using the ACR20 improvement criteria, there was an absolute difference in improvement of 28% (95% confidence interval: 21 - 35%) favouring leflunomide (232 out of 413 leflunomide treated patients compared to 89 out of 311 placebo patients met the criteria). There was no difference in ACR20 response rate between the patients treated with leflunomide and SSZ or MTX at 6 and 12 months. Other clinical outcomes were improved significantly in the leflunomide group compared to placebo but not different from SSZ or MTX. Withdrawals due to adverse events with leflunomide were 10% greater than placebo (70 out of 416 compared to 18 out of 311 respectively). Important adverse events included gastrointestinal symptoms, elevated liver function tests, alopecia, and infections. Overall adverse events and withdrawals in the leflunomide group were not significantly different from SSZ or MTX. REVIEWER'S CONCLUSIONS: Leflunomide appears to improve all clinical outcomes and delay radiologic progression at both 6 and 12 months of treatment compared to placebo. Its efficacy and adverse events at 2 years of treatment are comparable to SSZ and MTX. Long-term efficacy and toxicity remains to be established.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

An index of the three core data set patient questionnaire measures distinguishes efficacy of active treatment from that of placebo as effectively as the American College of Rheumatology 20% response criteria (ACR20) or the Disease Activity Score (DAS) in a rheumatoid arthritis clinical trial.

OBJECTIVE: To evaluate the capacity of a pooled index of only the 3 patient self-report questionnaire measures among the 7 American College of Rheumatology (ACR) core data set (Core Data Set) measures to distinguish efficacy of active treatment of rheumatoid arthritis (RA) with leflunomide or methotrexate versus placebo in a randomized, controlled clinical trial, and to compare the results with those obtained using the ACR 20% response criteria (ACR20), Disease Activity Score (DAS), and other pooled indices. METHODS: The 7 ACR Core Data Set measures of 1) joint swelling, 2) joint tenderness, 3) physician global assessment, 4) erythrocyte sedimentation rate (ESR), 5) functional disability, 6) pain, and 7) patient global assessment were combined into the following 5 pooled indices: "All Core Data Set" (all 7 measures), "Assessor Only" (measures 1-3), "Assessor + ESR" (measures 1-4), "Patient Only" (measures 5-7), and "Patient + ESR" (measures 4-7). The capacity of each of these 5 indices to detect differences between active treatment and placebo treatment was compared with that of the ACR20 and the DAS using 4 different analytic methods, each of which presented advantages and limitations. Agreement of the indices with one another and with the ACR20 and the DAS was analyzed according to pairwise kappa statistics and Z scores in multivariate logistic regression models. RESULTS: Each of the 5 indices, including "Patient Only," had a similar capacity to detect greater efficacy of leflunomide and methotrexate versus placebo in this clinical trial, according to each of 4 methods, at similar levels of statistical and clinical significance. CONCLUSION: A pooled index of patient self-report questionnaire Core Data Set measures appears to be as informative as ACR20 responses, DAS scores, and pooled indices of all and assessor-derived Core Data Set measures for distinguishing between active treatment and placebo treatment in this RA clinical trial.

Antirheumatic Agents↗
PubMed2003

Improvement in health-related quality of life in systemic lupus erythematosus patients enrolled in a randomized clinical trial comparing LJP 394 treatment with placebo.

In a 76-week, randomized controlled trial, patients received 100 mg LJP 394 or placebo weekly for 16 weeks followed by three 12-week treatment cycles of 50 mg LJP 394 or placebo weekly each separated by eight-week periods when no therapy was administered. Health-related quality of life (HRQOL) was assessed using SF-36 at baseline, 16 weeks and every 12 weeks thereafter. Analyses populations included intent to treat (ITT) (n = 179) and patients with high-affinity anti-dsDNA antibody binding (HA): 157/179; 85% active, 90% placebo. In the ITT population, there were improvements in role emotional (RE) (+7.3 versus -8.2), social functioning (SF) (+4.3 versus +0.7), and role physical (RP) (+11.3 versus +6.0) domains in the active treatment group when compared with placebo, with similar changes observed in the HA population. In 37 patients with data pre- and post-renal flares, those receiving LJP 394 reported stabilization or improvement in all but one domain compared with deterioration in all domains with placebo. Changes in RE domain scores following a flare differed by 22.7 points between the two treatment groups, favouring LJP 394 treatment. Patients receiving LJP 394 reported stable or improved HRQOL with active treatment following renal flares compared with deterioration in placebo. Differences between treatment groups in RE and SF domains are clinically important and were replicated irrespective of the protocol population analysed.

Double-Blind Method↗
PubMed2002

Ambient level of NO2 augments the inflammatory response to inhaled allergen in asthmatics.

Air pollution constitutes an important factor for asthma aggravation, and there is increased concern about respiratory health effects of common air pollutants. The purpose of this study was to examine how exposure to a high ambient concentration nitrogen dioxide (NO2) prior to a bronchial allergen challenge modulated the inflammatory response in the bronchi. Thirteen subjects with mild asthma and allergy were exposed at rest to either purified air or 500 microg x m 3 NO2 for 30 min, followed 4 h later by an allergen inhalation challenge. The exposures (NO2 or air) were performed in random order and at least 4 weeks apart. Lung function during NO2/air exposure and allergen challenge was measured by plethysmography, and then hourly by portable spirometry after exposures. Subjective symptoms were recorded during and after exposure. Bronchoscopy with bronchial wash (BW) and bronchoalveolar lavage (BAL) was performed 19 h after allergen challenge. NO2+allergen enhanced the percentage of neutrophils in both BW and BAL compared to air+allergen (BW 19 vs. 11, P=0.05; BAL 3 vs. 1, P=0.02 median values). The levels of eosinophil cationic protein (ECP) in BW was higher after NO2+allergen compared to air+allergen (90 vs. 3.6 microg/l; P=0.02, median values). There was no NO2-associated effect on symptoms or pulmonary function. These data suggest that ambient NO2 can enhance allergic inflammatory reaction in the airways without causing symptoms or pulmonary dysfunction.

Adult↗
PubMed2002

The effects of disease-modifying anti-rheumatic drugs on the Health Assessment Questionnaire score. Lessons from the leflunomide clinical trials database.

OBJECTIVE: A primary therapeutic goal in rheumatoid arthritis (RA) is to reduce functional disability. The recent introduction of several new drugs for RA creates a need for readily assessing the effectiveness of therapy. Because the consistent use of disease-modifying anti-rheumatic drugs (DMARDs) reduces long-term disability, we analysed the large database of 1817 RA patients from leflunomide trials to assess if changes in the Health Assessment Questionnaire (HAQ) can measure the effectiveness of RA therapy. METHODS: Data from three randomized double-blind RA trials were evaluated. The patients had received 100 mg leflunomide (then 20 mg/day in 807 cases), methotrexate (15-20 mg/day in 669 cases), sulphasalazine (2 g/day in 132 cases) and placebo (in 209 cases). HAQ scores and outcomes were assessed using the American College of Rheumatology core data set. Detailed statistical analyses were made of changes in outcome variables at 1 and 6 months, changes in HAQ scores at 1-12 months, and effect sizes for outcome variables at 6 and 12 months. Multiple regression models of changes in HAQ scores were evaluated using backwards stepwise linear regression. RESULTS: Mean HAQ scores declined progressively with treatment with all three DMARDs. Changes occurred rapidly, and at month 1 were most pronounced with leflunomide. HAQ scores correlated closely with clinical response, as seen in changes in non-responders and ACR 20% and 50% responders. Regression analysis indicated that pain intensity and global assessments were significant determinants of HAQ. CONCLUSION: HAQ scores are sensitive measures of effective DMARD therapy. HAQ may be especially useful early in the treatment process to assess patients' responses to DMARDs that show rapid onset of action, such as leflunomide.

Antirheumatic Agents↗
PubMed2001

Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group.

OBJECTIVE: Three 6-12-month, double-blind, randomized, controlled trials have shown leflunomide (LEF; 20 mg/day, loading dose 100 mg x 3 days) to be effective and safe for the treatment of rheumatoid arthritis (RA). This analysis of the North American trial assessed whether the clinical benefit evident at month 12 was sustained over 24 months of treatment with LEF as compared with the efficacy and safety of methotrexate (MTX), an equivalent disease-modifying antirheumatic drug, at 24 months. METHODS: The year-2 cohort, comprising patients continuing into the second year of treatment with > or = 1 dose of study medication and > or = 1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/- SD) maintenance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 12.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) approach. Statistical comparisons of the active treatments only were prospectively defined in the protocol. RESULTS: In total, 85% and 79% of LEF and MTX patients, respectively, who entered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of > or = 20% (LEF 79% versus MTX 67%; P = 0.049), > or = 50% (LEF 56% versus MTX 43%; P = 0.053), and > or = 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the active treatment groups. The mean change in total Sharp radiologic damage scores at year 2 compared with year 1 and baseline (LEF 1.6 versus MTX 1.2) showed statistically equivalent sustained retardation of radiographic progression in the active treatment groups. Maximal improvements evident at 6 months in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) and the physical component score of the Medical Outcomes Survey 36-item short form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF4(-0.60) was statistically significantly superior to that with MTX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, serious treatment-related adverse events were reported in 1.6% of the LEF-treated patients and 3.7% of the MTX-treated patients. Frequently reported adverse events included upper respiratory tract infections, diarrhea, nausea and vomiting, rash, reversible alopecia, and transient liver enzyme elevations. CONCLUSION: The safety and efficacy of LEF and MTX were maintained over the second year of this 2-year trial. Both active treatments retarded radiographic progression over 24 months. LEF was statistically significantly superior to MTX in improving physical function as measured by the HAQ DI over 24 months of treatment. Results indicate that LEF is a safe and effective initial treatment for active RA, with clinical benefit sustained over 2 years of treatment without evidence of new or increased toxicity.

Adult↗