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.     

Improved functional ability in patients with rheumatoid arthritis--longterm treatment with leflunomide versus sulfasalazine. European Leflunomide Study Group

OBJECTIVE: We previously reported that the new disease modifying antirheumatic drug leflunomide resulted in significant improvement in functional ability compared with placebo and sulfasalazine in a 6 month double blind, randomized, Phase III trial in rheumatoid arthritis (RA). The current study compared functional disability in cohorts of patients with RA from the initial study who volunteered to continue treatment with leflunomide or sulfasalazine. METHODS: The Health Assessment Questionnaire (HAQ) was used to assess functional ability in patients completing 6 months of therapy who chose to continue in double blinded 12 and 24 month extensions. Patients on active regimens continued taking leflunomide 20 mg/day or sulfasalazine 2 g/day; those taking placebo were switched at Month 6 to sulfasalazine. RESULTS: Leflunomide significantly improved patients' functional ability compared to placebo (p < or = 0.0001) and sulfasalazine (p < or = 0.01) at 6 months. These changes were seen as early as Month 1, and continued improvements were seen in 12 and 24 month cohorts. Mean HAQ scores were significantly improved with leflunomide compared with sulfasalazine at 24 months (-0.65 vs -0.36; p = 0.0149); corresponding changes in HAQ Disability Index (DI) were -0.73 vs -0.56 and were not statistically different. Leflunomide is safe and well tolerated and no unexpected adverse events were noted during the 2 year period; diarrhea, nausea, and alopecia were less frequent with continued treatment. CONCLUSION: These longterm data confirm leflunomide improves functional ability as shown by reductions in HAQ scores. The benefit of leflunomide is reflected in other efficacy criteria, such as global assessments and the American College of Rheumatology response rates, all of which showed significantly more improvement with leflunomide than sulfasalazine at 24 months.     

Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine

OBJECTIVE: Recent studies have demonstrated the short term efficacy of leflunomide. This study evaluates the efficacy and safety of leflunomide and sulfasalazine in rheumatoid arthritis over a two year follow up period. METHODS: 358 patients with rheumatoid arthritis in a double blind trial were randomly allocated to receive either leflunomide 20 mg/day, placebo, or sulfasalazine 2 g/day. Those completing six months of treatment (n=230) were given the option to continue in 12 (n=168) and 24 (n=146) month double blinded extensions; the placebo group switched to sulfasalazine. This report compares efficacy and safety of leflunomide with sulfasalazine in the 6, 12, and 24 month patient cohorts. RESULTS: The efficacy seen at six months was maintained at 12 and 24 months. Twenty four month cohorts on leflunomide showed significant improvement compared with sulfasalazine in doctor (-1.46 v -1.11, p=0.03) and patient (-1.61 v -1.04, p<0.001) global assessments, ACR20% response (82% v 60%, p<0.01), and functional ability (Deltamean HAQ -0.65 v -0.36, p=0.0149; DeltaHAQ disability index -0.89 v -0.60, p=0.059). Improvement in other variables was comparable for the two drugs, including slowing of disease progression. Improved HAQ scores in 6, 12, and 24 month leflunomide cohorts were seen in both non-responders (24%, 29%, 35%, respectively v sulfasalazine 8%, 10%, 27%) and ACR20% responders (leflunomide 63%, 62%, 66% v sulfasalazine 50%, 64%, 44%). Leflunomide is well tolerated at doses of 20 mg. No unexpected adverse events or late toxicity were noted during the two year period. Diarrhoea, nausea, and alopecia were less frequent with continued treatment. CONCLUSION: These long term data confirm that leflunomide is an efficacious and safe disease modifying antirheumatic drug.     

Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis

Objective. To assess the safety and effectiveness of leflunomide versus placebo in patients with active rheumatoid arthritis (RA) treated for 6 months. Methods. Four hundred two patients were randomly assigned to receive placebo or leflunomide at 5 mg, 10 mg, or 25 mg daily. A washout period of 6–12 weeks from prior second-line therapy was required. Results. Statistically significant improvement in primary and secondary outcome measures, as well as by responder analyses, occurred in the 10-mg and 25-mg dosage groups compared to placebo. Twenty-one patients (7.0%) in the active treatment groups withdrew due to adverse events (AEs). The incidence of AEs was higher with leflunomide than with placebo. Gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia were more common in the 10-mg and 25-mg dosage groups. The incidence of infections was similar between the treatment and placebo groupsno opportunistic infections were seen. Transient elevations in liver function studies were noted in a small number of patients. Conclusion. Leflunomide is effective in daily doses of 10 mg and 25-mg in patients with active RA. Improved efficacy at the 25-mg dose was associated with a higher incidence of AEs. Randomized, placebocontrolled trials using daily doses of 10 mg and 20 mg are under way in the US and Europe to confirm these positive results.     

Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial

OBJECTIVE: To evaluate the efficacy and safety of etoricoxib and indomethacin in the treatment of patients with acute gout. METHODS: A randomized, double-blind, active-comparator study was conducted at 42 sites. A total of 189 men and women (> or =18 years of age) who were experiencing an acute attack (< or =48 hours) of clinically diagnosed gout were treated for 8 days with etoricoxib, 120 mg/day (n = 103), or indomethacin, 50 mg 3 times a day (n = 86). The primary efficacy end point was the patient's assessment of pain in the study joint (0-4-point Likert scale) over days 2-5. Safety was assessed by adverse experiences (AEs) occurring during the trial. RESULTS: Etoricoxib demonstrated clinical efficacy comparable to that of indomethacin in terms of the patient's assessment of pain in the study joint. The difference in the mean change from baseline over days 2-5 was -0.08 (95% confidence interval -0.29, 0.13) (P = 0.46), which fell within the prespecified comparability bounds of -0.5 to 0.5. Secondary end points over the 8-day study, including the onset of efficacy, reduction in signs of inflammation, and patient's and investigator's global assessments of response to therapy, confirmed the comparable efficacy of the two treatments. The etoricoxib-treated patients had a numerically lower incidence of AEs (43.7%) than did the indomethacin-treated patients (57.0%) and a significantly lower incidence of drug-related AEs (16.5% versus 37.2%; P < 0.05). CONCLUSION: Etoricoxib at a dosage of 120 mg once daily was confirmed to be an effective treatment for acute gout. Etoricoxib was comparable in efficacy to indomethacin at a dosage of 50 mg 3 times daily, and it was generally safe and well tolerated.     

Validation of the Health Assessment Questionnaire disability index in patients with gout

OBJECTIVE: To assess the psychometric properties of the Health Assessment Questionnaire (HAQ) disability index (DI) in patients with gout. METHODS: This study was conducted in a multicenter cohort of patients with gout whose data were collected at baseline (time 0) and 6 months later (time 6). Reliability was assessed by test-retest reliability (intraclass correlation coefficient [ICC]) and internal consistency (Cronbach's alpha coefficient). Construct validity was assessed with convergent validity (HAQ DI correlation with Short Form 36 [SF-36]) and discriminative validity (HAQ DI correlation with clinical features). Sensitivity to change was determined by comparing HAQ DI time 0 versus HAQ DI time 6 (percentage of change, effect size, smallest real difference [SRD], and Guyatt's responsiveness index [GRI]). RESULTS: We included 206 patients (96.6% men, mean +/- SD age and disease duration 56.3 +/- 12.4 years and 9.3 +/- 8.5 years, respectively). Of these, 52.4% had joint pain, 22.8% swelling, 32.5% reduced joint mobility, and 36.9% tophi. The mean HAQ DI score was 0.59 +/- 0.77 (95% confidence interval [95% CI] 0.49-0.70). ICC (n = 36, evaluations at baseline and 5 days later) was 0.76. Cronbach's alphas were 0.91 (95% CI 0.88-0.92, P = 0.000) for the 20 HAQ DI items and 0.93 (95% CI 0.92-0.94, P = 0.000) for the 8 HAQ DI categories. The HAQ DI correlated in predictable ways with SF-36 subscales and clinical variables, and discriminated between subgroups with and without any joint pain, swelling, and tophi. Concerning sensitivity to change (n = 167), the difference between HAQ DI time 0 and HAQ DI time 6 was 0.31 +/- 0.58 (effect size 0.62, SRD 0.59, and GRI 1.91). DeltaHAQ DI correlated with Deltapain (r = 0.349, P = 0.000). CONCLUSION: The HAQ DI is a valid and reliable measure of functioning in patients with gout.     

Lumiracoxib 400 mg once daily is comparable to indomethacin 50 mg three times daily for the treatment of acute flares of gout

OBJECTIVES: To demonstrate non-inferiority of lumiracoxib 400 mg once daily (o.d.) compared with indomethacin 50 mg three times daily (t.i.d.) in the treatment of acute gout, and to compare the safety and tolerability of these treatments. METHODS: In this 1-week, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study, patients with a clinical diagnosis of gout, an acute attack of gout in four or more joints within the 48 h prior to evaluation, and at least moderate pain intensity in the target joint were randomized to treatment with lumiracoxib 400 mg o.d. (n = 118) or indomethacin 50 mg t.i.d. (n = 117). The primary efficacy endpoint was the mean change in pain intensity from baseline over days 2-5, assessed on a 5-point Likert scale, where non-inferiority could be claimed if the lower limit of the confidence interval (CI) was greater than -0.5. The patient's and physician's global assessment of response to treatment, and physician's assessment of tenderness, swelling and erythema of the study joint were also assessed. RESULTS: The estimated difference between treatments for the change from baseline in pain intensity over days 2-5 was -0.004 (95% CI -0.207 to 0.199, P > 0.05), indicating that lumiracoxib 400 mg o.d. had comparable efficacy to indomethacin 50 mg t.i.d. for the primary efficacy variable. There was no significant difference between treatments in any of the secondary efficacy variables. Adverse events were reported by 10.2% of patients treated with lumiracoxib and 22.2% of those receiving indomethacin. CONCLUSIONS: Lumiracoxib is as effective as indomethacin for treatment of acute gout and may have a better safety and tolerability profile.     

The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year followup study

OBJECTIVE: To investigate the efficacy and safety of leflunomide beyond 2 years in a multinational, open-label extension of 2 phase III double-blind studies. METHODS: Patients with rheumatoid arthritis (RA) who received leflunomide (100 mg/day for 3 days, 10 mg/day or 20 mg/day thereafter) in the 2 phase III studies and who completed 2 years of treatment were offered inclusion in the open-label extension phase and were maintained on the same dosage of leflunomide. The American College of Rheumatology revised criteria for 20% improvement (ACR20), ACR50, and ACR70 response rates, the Stanford Health Assessment Questionnaire (HAQ) scores, and C-reactive protein (CRP) levels were assessed. Safety measures included monitoring of adverse events and laboratory values. RESULTS: A total of 214 patients (mean age 57 years) were treated with leflunomide for >2 years; 74.8% of the patients were female. The mean disease duration was 4.1 years (range 0.1-26.6 years), and in 44% of patients, RA was first diagnosed within 2 years of entry into the phase III studies. The mean duration of leflunomide treatment was 4.6 years (range 2.8-5.8 years), and 32% of patients had received no previous treatment with disease-modifying antirheumatic drugs. ACR20, ACR50, and ACR70 response rates and HAQ scores at 1 year were maintained through year 4 or until the end point. No new types of adverse events were observed, and liver function was normal at baseline and at the end point in the majority of patients. CONCLUSION: The improvements in both functional ability and physician-based efficacy measures seen with leflunomide after 1 year were maintained for up to 5 years (maximum treatment duration 5.8 years), demonstrating that the early efficacy of leflunomide in patients with RA is sustained long-term, and that the long-term safety profile of leflunomide is no different from that observed in phase III trials.     

The Disability Index of the Health Assessment Questionnaire is a predictor and correlate of outcome in the high-dose versus low-dose penicillamine in systemic sclerosis trial

OBJECTIVE: To explore the clinical implications of a score of > or =1.0 on the Disability Index of the Health Assessment Questionnaire (HAQ DI) at the first patient visit, and to examine the implications of improvement in HAQ DI score over 2 years in a cohort of systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma. METHODS: SSc skin and visceral involvement was assessed in 134 SSc patients with diffuse scleroderma (mean +/- SD disease duration of 10 +/- 4 months) when they entered a multicenter drug trial and again 2 years later. Mortality and the occurrence of scleroderma renal crisis were assessed for a mean +/- SD of 4.0 +/- 1.1 years. Logistic and linear regression analyses were used to examine the relationship of the baseline HAQ DI score to morbidity, mortality, and visceral involvement, as well as the relationship of changes in the HAQ DI score to changes in physical examination, laboratory, and functional variables over 2 years. RESULTS: A baseline HAQ DI score of > or =1.0 was predictive of mortality (odds ratio 3.22, 95% confidence interval 1.097-9.468) over 4 years. Multivariate linear regression demonstrated that a model which included the erythrocyte sedimentation rate at baseline (P = 0.005) and changes at 2 years in the swollen joint count (P = 0.002), total skin score (P = 0.005), and white blood cell count (P = 0.005) best explained the change in HAQ DI score over 2 years (R2 = 0.528). The HAQ DI score and total skin score at baseline were highly correlated (correlation coefficient 0.368), as were changes in the HAQ DI score and the total skin score over 2 years (correlation coefficient 0.492). Although the HAQ DI score was heavily influenced by hand dysfunction at baseline and at 2 years, improvement (reduction) in the HAQ DI score over 2 years was related to factors other than hand dysfunction. CONCLUSION: A baseline HAQ DI score of > or =1.0 predicted mortality over 4 years. Improvement in the HAQ DI score in these patients with diffuse scleroderma was associated with improvement in skin thickening, hand function, oral aperture, lung function, signs of arthritis, serum creatinine level, and the investigator's global assessment of improvement. The HAQ DI is a self-administered questionnaire that SSc patients can complete easily and rapidly and that gives the practicing physician important information about prognosis, patient status, and changes in disease course over time.     

Treatment of psoriatic arthritis and psoriasis vulgaris with the tumor necrosis factor inhibitor infliximab

OBJECTIVE: The aim was to evaluate the efficacy and safety of multiple infusions with achimeric, anti-tumor necrosis factor (TNF)alpha monoclonal antibody (infliximab) in patients with psoriatic arthritis (PsA) and psoriasis vulgaris. METHODS: Over 22 weeks, nine patients with both active psoriasis and PsA received five infusions of 3 mg/kg infliximab. The endpoints included changes in the swollen and tender joints counts, American College of Rheumatology (ACR) preliminary criteria for improvement response rates 20, 50, and 70, and improvement in the psoriasis area and severity index (PASI). RESULTS: The swollen count (SJC) and tender joint count (TJC) fell from means of 5.33+/-2.22 and 17.80+/-4.21 to 1.44+/-1.09 and 9.77+/-0.92, respectively, by week 2 ( P=0.02, P=0.02). This benefit was sustained through week 22 (2.00+/-1.12/7.77+/-3.68, P=0.05/ P=0.002). The ACR 20/50/70 response was achieved in 89%/56%/22% of cases. The mean PASI score improved from 19.04+/-5.41 to 4.91+/-2.51 ( P=0.002). CONCLUSION: Multiple infusions of infliximab were effective and well tolerated in patients with active psoriasis and PsA.     

Randomized, double-blind, comparative study of dexrabeprazole 10 mg versus rabeprazole 20 mg in the treatment of gastroesophageal reflux disease

AIM：TO compare the efficacy and safety of dexrabe-prazole 10 mg versus rabeprazole 20 mg in the treatment of gastroesophageal reflux disease （GERD）.
METHODS： This was a randomized, double-blind clinical study. Fifty patients with GERD were randomly assigned to receive dexrabeprazole 10 mg or rabeprazole 20 mg once daily. Efficacy was assessed by evaluating improvement in visual analog scale （VAS） scores of heart-burn and regurgitation and safety was assessed by recording incidence of any adverse drug reactions. Laboratory investigations and upper gastro-intestinal endoscopy was conducted at baseline and after 28 d of therapy.
RESULTS： A total of 50 patients （n = 25 in dexrabeprazole group and rabeprazole group each） completed the study. There were no significant differences in the baseline characteristics between the two groups. The VAS score （mean 4. SD） of heartburn and regurgitation in dexrabeprazole （64.8±5.1 and 64 ± 8.1, respectively） and rabeprazole （64.4 ± 8.7 and 57.6 ± 9.7, respectively） groups significantly reduced （P 〈 0.0001） to 30 ± 11.5, 24 ± 10 and 32 ± 9.5, 29.2±11.9, respectively on d 28. A significantly higher （P = 0.002） proportion of patients showed ≥ 50% improvement in regurgitation with dexrabeprazole 10 mg （96%） compared to rabeprazole 20 mg （60%）. Onset of symptom improvement was significantly earlier with dexrabeprazole than with rabeprazole （1.8 ± 0.8 d vs 2.6 ± 1.4 d; P 〈0.05）. The incidences of esophagitis in the dexrabeprazole group and rabeprazole group before therapy were 84% and 92%, respectively （P = 0.38）. The incidence of improvement/healing of esophagitis after therapy was more （P = 0,036） in the dexrabeprazole group （95.2%） compared to the rabeprazole group （65.2%）. No adverse drug reaction was seen in either group.
CONCLUSION： In the treatment of GERD, efficacy of dexrabeprazole 10 mg is better than rabeprazole 20 mg, with regards to improvement/healing of endoscopic lesions and relief fro     

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.     

Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed

OBJECTIVE: To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed. METHODS: In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was > or =20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI). RESULTS: After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p< or =0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p< or =0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p< or =0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p< or =0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (-0.29, -0.39, -0.38, -0.49 v -0.07; p< or =0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p< or =0.05). CONCLUSION: Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated.     

Disease activity score 28 as an instrument to measure disease activity in patients with early rheumatoid arthritis

OBJECTIVE: To examine the influence of components of the Disease Activity Score 28 (DAS28) [tender joint count (TJC), swollen joint count (SJC), patient's general health (GH), and erythrocyte sedimentation rate (ESR)] on the total DAS28 score, and overlapping of the 4 individual components in rheumatoid arthritis (RA) patients with low, moderate, or high disease activity. METHODS: The effect of each component was studied in the FIN-RACo trial patients at 6 months and in a "theoretical model," where each component of the DAS28 ranged as follows: TJC and SJC from 0 to 28, GH from 0 to 100, and ESR from 1 to 100, while the other 3 components were 0 (ESR1). Overlapping of the components was studied in the FIN-RACo trial patients at 6 months with low (DAS28 < or = 3.2), moderate (DAS28 > 3.2 and < or = 5.1), and high (DAS28 > 5.1) disease activity. The higher limit for overlapping was defined as the highest SJC in the low disease activity group, and the lower limit as the lowest SJC in the high disease activity group; the percentage of patients who fall between these limits represent overlapping in SJC. Overlapping was calculated similarly concerning TJC, ESR, and GH. RESULTS: ESR had the greatest effect on DAS28, followed by TJC, GH, and SJC, while in the "theoretical model" TJC had the greatest effect on the DAS28, followed by ESR, SJC, and GH. At 6 months, overlapping was present in 54%, 45%, 49%, and 31% of patients in SJC, TJC, GH, and ESR, respectively. CONCLUSION: In real-life patients, ESR had the greatest effect of the 4 components of DAS28 on the total DAS28 score. The values of the individual components of DAS28 overlap considerably among the 3 disease activity groups.     

Rupatadine 10 mg and cetirizine 10 mg in seasonal allergic rhinitis: a randomised, double-blind parallel study.

This randomised, double-blind, parallel-group, multicentre clinical trial evaluated the efficacy and safety of rupatadine, a new antihistamine with antiplatelet-activating factor (PAF) activity, and cetirizine in the treatment of patients with seasonal allergic rhinitis (SAR). A total 249 patients were randomised to receive rupatadine 10 mg once daily (127 patients) or cetirizine 10 mg (122 patients) for two weeks. The main efficacy variable was the mean total daily symptom score (mTDSS) and was based on the daily subjective assessment of the severity of each rhinitis symptom--nasal (runny nose, sneezing, nasal itching and nasal obstruction) and non-nasal (conjunctival itching, tearing, and pharyngeal itching)--recorded by patients in their diaries. The mTDSS was 0.7 for both treatment groups (intention to treat analysis). In the investigator's global evaluation of efficacy at the seventh day, 93.3% and 83.7% patients in the rupatadine and cetirizine groups, respectively, showed some or great improvement (p = 0.022). In the per protocol analysis (n = 181), runny nose at the seventh day of treatment was absent or mild in 81.1% of patients in the rupatadine group and in 68.6% of patients in the cetirizine group (p = 0.029). In any case statistical significance was not maintained at the second week. Overall, all treatments were well tolerated. Adverse events (AEs) were similar in both treatment groups, i.e. headache, somnolence and fatigue/asthenia as the most often reported. Somnolence was reported in 9.6% and 8.5% of patients treated with rupatadine or cetirizine, respectively. The most reported AEs (67%) were mild in intensity. Our results suggest that rupatadine 10 mg may be a valuable and safe alternative for the symptomatic treatment of SAR.     

Safety and efficacy of total dose infusion of 1,020 mg of ferumoxytol administered over 15 min

For the majority of patients with iron deficiency anemia (IDA), a full course of intravenous (IV) iron is 1 g. Most IV irons require 5–10 administrations of 100–300 mg. We have successfully employed 1 g low molecular weight iron dextran over 1 hr. For further convenience for patients and physicians, we explored the administration of 1.02 g of ferumoxytol over 15 min instead of the approved 2 × 510 mg injections. Sixty patients with IDA, (hemoglobin <11 g/dL, transferrin saturation [TSAT] ≤20%, and ferritin <100 ng/mL) with an inadequate response or intolerance to oral iron, received 1020 mg ferumoxytol over 15 min. Vital signs were measured for 1 hr. Adverse events (AEs) were collected via telephone at 1, 2, and 7 days. Follow‐up visits occurred at 4 and 8 weeks for efficacy assessments. The primary endpoint was safety and tolerability. Secondary efficacy endpoints included mean change in hemoglobin, TSAT, and red cell distribution width. No serious adverse events (SAEs) occurred. Fifty‐eight patients received the planned dose. Twenty‐six out of sixty (43.3%) patients reported AEs of which 13 were mild and transient during infusion. All resolved within minutes. Fourteen patients reported self‐limited arthralgias, myalgias, and/or headache within 24–48 hr. At Baseline, the mean hemoglobin was 9.4 g/dL. The mean increments at Week 4 and 8 were 2.1 and 2.6 g/dL, respectively. Ferumoxytol, administered as 1.02 g infusion over 15 min was well tolerated with no SAEs and demonstrated excellent efficacy. If corroborated in future studies this represents an improved method of treating IDA. Am. J. Heamtol. 88:944–947, 2013. © 2013 Wiley Periodicals, Inc.     

Efficacy of ezetimibe/simvastatin 10/20 and 10/40 mg compared with atorvastatin 20 mg in patients with type 2 diabetes mellitus

AIM: This randomized, double-blind study evaluated the efficacy of switching from atorvastatin (ATV) 10 mg to ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg, EZE/SIMVA 10/40 mg or doubling the dose of ATV from 10 to 20 mg in patients with type 2 diabetes (T2D). METHODS: Eligible patients had haemoglobin A(1C)< or =10%, were aged > or =18 years and were on ATV 10 mg for > or =6 weeks before study entry. After a 4-week open-label ATV 10 mg run-in, patients were randomized to EZE/SIMVA 10/20 mg (n = 220), EZE/SIMVA 10/40 mg (n = 222) or ATV 20 g (n = 219) daily for 6 weeks. RESULTS: Greater (p < or = 0.001) reductions in low-density lipoprotein cholesterol (LDL-C) (the primary end-point) were achieved by switching to EZE/SIMVA 10/20 mg (26.2%) or 10/40 mg (30.1%) than by doubling the dose of ATV to 20 mg (8.5%). EZE/SIMVA 10/20 mg and 10/40 mg produced greater (p < or = 0.001) reductions in total cholesterol, non-high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B relative to ATV 20 mg. A reduction (p < or = 0.050) in C-reactive protein was observed with EZE/SIMVA 10/40 mg vs. ATV 20 mg. Similar reductions in triglycerides were observed across the three groups, and none of the treatments produced a significant change in HDL-C. A greater (p < or = 0.001) proportion of patients achieved LDL-C <2.5 mmol/l with EZE/SIMVA 10/20 mg (90.5%) and 10/40 mg (87.0%) than with ATV 20 mg (70.4%). Both EZE/SIMVA doses were generally well tolerated, with an overall safety profile similar to ATV 20 mg. CONCLUSIONS: EZE/SIMVA 10/20 and 10/40 mg provided greater lipid-altering efficacy than doubling the dose of ATV from 10 to 20 mg and were well tolerated in patients with T2D.     

Safety and immunogenicity of a tetravalent live-attenuated dengue vaccine in flavivirus-naive infants

A Phase I/II observer-blind, randomized, controlled trial evaluated the safety and immunogenicity of a dengue virus (DENV) vaccine candidate in healthy Thai infants (aged 12-15 months) without measurable pre-vaccination neutralizing antibodies to DENV and Japanese encephalitis virus. Fifty-one subjects received two doses of either DENV (N = 34; four received 1/10th dose) or control vaccine (N = 17; dose 1, live varicella; dose 2, Haemophilus influenzae type b). After each vaccine dose, adverse events (AEs) were solicited for 21 days, and non-serious AEs were solicited for 30 days; serious AEs (SAEs) were recorded throughout the study. Laboratory safety assessments were performed at 10 and 30 days; neutralizing antibodies were measured at 30 days. The DENV vaccine was well-tolerated without any related SAEs. After the second dose, 85.7% of full-dose DENV vaccinees developed at least trivalent and 53.6% developed tetravalent neutralizing antibodies ≥ 1:10 to DENV (control group = 0%). This vaccine candidate, therefore, warrants continued development in this age group (NCT00322049; clinicaltrials.gov).     

Esomeprazole 40 mg provides improved intragastric acid control as compared with lansoprazole 30 mg and rabeprazole 20 mg in healthy volunteers

AIM: To compare the effects of standard-dose esomeprazole with those of standard doses of lansoprazole and rabeprazole on intragastric pH during repeated daily oral dosing in healthy volunteers. METHODS: In two standardized, randomized crossover studies, Helicobacter pylori negative healthy volunteers (study A: 19 males, 5 females; study B: 13 males, 10 females) received esomeprazole 40 mg and either lansoprazole 30 mg (study A) or rabeprazole 20 mg (study B) orally once daily in the morning for 5 days. Continuous 24-hour intragastric pH recording was performed on day 5. RESULTS: The intragastric pH was maintained >4 for 65% (95% CI 59.5-71.3) of the 24-hour period with esomeprazole and for 53% of the time (95% CI 47.0-58.9) with lansoprazole in study A (p < 0.001). In study B, the proportion of time with pH >4 was 61% (95% CI 53.6-68.3) with esomeprazole versus 45% (95% CI 37.7-52.5) with rabeprazole (p = 0.005). The 24-hour median pH and the proportion of volunteers with intragastric pH >4 for > or =12 h and > or =16 h were significantly higher with esomeprazole than with either lansoprazole or rabeprazole. CONCLUSION: Esomeprazole 40 mg provides significantly more effective and more sustained gastric acid control than lansoprazole 30 mg or rabeprazole 20 mg in healthy volunteers.     

Sources of discrepancy in patient and physician global assessments of rheumatoid arthritis disease activity

OBJECTIVE: To investigate discrepancy in the perception of rheumatoid arthritis (RA) disease activity between patient and physician, and its possible sources. METHODS: Eighty patients with RA rated their level of disease activity on a visual analog scale (VAS). Physician global assessment (MDGA) of disease activity was performed blinded to the patient evaluation except for the results of laboratory tests. A discrepancy score (DS) was calculated by subtracting MDGA from patient global assessment (PTGA), leading to definition of 3 groups of patients: (1) no discrepancy when PTGA and MDGA were within 1.0 or 3.0 cm of each other; (2) negative discrepancy when PTGA was under-rated relative to the physician; and (3) positive discrepancy when PTGA was over-rated relative to the physician. Age, sex, disease duration, education, income, residence area, employment, use of antirheumatic drugs, comorbidity, pain score, Health Assessment Questionnaire (HAQ) rating, tender (TJC) and swollen (SJC) joint count, and Disease Activity Score (DAS28) were recorded. RESULTS: Negative discrepancy was found in 27.5% (VAS 1 cm) and 8.7% (VAS 3 cm) of patients, positive discrepancy in 43.7% (VAS 1 cm) and 23.7% (VAS 3 cm), and no discrepancy in 28.7% (VAS 1 cm) and 67.5% (VAS 3 cm). Patients were predominantly older (mean age near 50 yrs), female, with long disease duration and low income. The negative discrepancy group had a lower level of education and higher C-reactive protein (p < 0.05). The positive discrepancy group presented a higher pain score, HAQ score, and TJC (p < 0.0001). The no-discrepancy group had lower SJC (p < 0.05). CONCLUSION: Our results indicate that for disease activity in patients with RA assessed on pain score, HAQ, and TJC, the only important feature that determined perception of their RA disease activity was education.