A new FRAX model for Brazil.

Fracture probabilities derived from the original FRAX model for Brazil were compared to those from an updated model based on more recent regional estimates of the incidence of hip fracture. Fracture probabilities were consistently lower in the updated FRAX model. Despite large differences between models, differences in the rank order of fracture probabilities were minimal. OBJECTIVE: Recent epidemiological data indicate that the risk of hip fracture in Brazil is lower than that used to create the original FRAX model. This paper describes the epidemiology of hip fracture in Brazil and the synthesis of an updated FRAX model with the aim of comparing this new model with the original model. METHODS: Hip fracture rates from three cities in three regions were combined, weighted by the population of each region. For other major fractures, incidence rates for Brazil were estimated using Swedish ratios for hip to other major osteoporotic fracture (humerus, forearm or clinical vertebral fractures). Mortality estimates were taken from the UN. RESULTS: Compared to the original FRAX model, the updated model gave lower 10-year fracture probabilities in men and women at all ages. Notwithstanding, there was a very close correlation in fracture probabilities between the original and updated models (r > 0.99) so that the revisions had little impact on the rank order of risk. CONCLUSION: The disparities between the original and updated FRAX models indicate the importance of updating country-specific FRAX models with the advent of significant changes in fracture epidemiology.

Efficacy of teriparatide compared with risedronate on FRAX®-defined major osteoporotic fractures: results of the VERO clinical trial.

FRAX® calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX®-defined MOF compared with those treated with risedronate. INTRODUCTION: The VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX®-defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures. METHODS: In total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 µg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX®-defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval. RESULTS: After 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX®-defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23-0.68; p = 0.001). Clinical vertebral and radius fractures were the most frequent FRAX®-defined MOF sites. The largest difference in incidence rates of both FRAX®-defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed. CONCLUSION: In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX®-defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT01709110 EudraCT Number: 2012-000123-41.

Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group.

Upper limb fractures (including wrist, forearm, and humerus) represent a significant burden among postmenopausal women with osteoporosis. Up to 7 years of treatment with denosumab resulted in an increase in bone mineral density and decrease in fractures in upper limb sites. INTRODUCTION: Upper limb (wrist, forearm, and humerus) fractures are a significant burden in osteoporosis, associated with significant morbidity and mortality. Denosumab, a monoclonal antibody against RANK ligand, increases bone mineral density (BMD) and decreases vertebral, nonvertebral, and hip fractures. Here, we evaluated the long-term effect of denosumab treatment on upper limb fracture risk and BMD. METHODS: In the FREEDOM trial, subjects were randomized 1:1 to receive every-6-month denosumab 60 mg or placebo subcutaneously for 3 years, after which all subjects could receive denosumab for up to 7 years (Extension). Among placebo subjects who completed FREEDOM and enrolled in the Extension, wrist, forearm, humerus, and upper limb fracture rates and rate ratios between different time periods (FREEDOM years 1-3, Extension years 1-3, and Extension years 4-7) were computed. BMD at the ultradistal radius, 1/3 radius, and total radius was analyzed in a subset of subjects in a BMD substudy. RESULTS: This analysis included 2207 subjects (116 in the BMD substudy). Fracture rates decreased over the 7-year Extension; fracture rate ratios between Extension years 4-7 (denosumab) and FREEDOM years 1-3 (placebo) reduced significantly for the wrist (0.57), forearm (0.57), humerus (0.42), and upper limb (0.52; p < 0.05 for all). Percentage increase in BMD from Extension baseline at the ultradistal radius, 1/3 radius, and total radius was significant by Extension year 7 (p < 0.05 for all). CONCLUSIONS: Long-term treatment with denosumab decreases upper limb fracture risk and increases forearm BMD, suggesting beneficial effects on both cortical and trabecular bone accruing over time.

FRAX-based intervention and assessment thresholds in seven Latin American countries

Age-specific intervention and assessment thresholds were developed for seven Latin American countries. The intervention threshold ranged from 1.2% (Ecuador) to 27.5% (Argentina) at the age of 50 and 90 years, respectively. In the Latin American countries, FRAX offers a substantial advance for the detection of subjects at high fracture risk.INTRODUCTION:Intervention thresholds are proposed using the Fracture Risk Assessment (FRAX) tool. We recommended their use to calculate the ten-year probability of fragility fracture (FF) in both, men and women with or without the inclusion of bone mineral density (BMD). The purpose of this study is to compute FRAX-based intervention and BMD assessment thresholds for seven Latin American countries in men and women ≥ 40 years.METHODS:The intervention threshold (IT) was set at a 10-year probability of a major osteoporotic fracture (MOF) equivalent to a woman with a prior FF and a body mass index (BMI) equal to 25.0 kg/m2 without BMD or other clinical risk factors. The lower assessment threshold was set at a 10-year probability of a MOF in women with BMI equal to 25.0 kg/m2, no previous fracture and no clinical risk factors. The upper assessment threshold was set at 1.2 times the IT.RESULTS:For the seven LA countries, the age-specific IT varied from 1.5 to 27.5% in Argentina, 3.8 to 25.2% in Brazil, 1.6 up to 20.0% in Chile, 0.6 to 10.2% in Colombia, 0.9 up to 13.6% in Ecuador, 2.6 to 20.0% in Mexico, and 0.7 up to 22.0% in Venezuela at the age of 40 and 90 years, respectively.CONCLUSIONS:In the LA countries, FRAX-based IT offers a substantial advance for the detection of men and women at high fracture risk, particularly in the elderly. The heterogeneity of IT between the LA countries indicates that country-specific FRAX models are appropriate rather than a global LA model (AU)

Correction to: Global dietary calcium intake among adults: a systematic review.

The original Electronic Supplementary Material file 3 contained an erroneous reference for Mali. A link to the corrected file is provided here.

FRAX-based intervention and assessment thresholds in seven Latin American countries.

Age-specific intervention and assessment thresholds were developed for seven Latin American countries. The intervention threshold ranged from 1.2% (Ecuador) to 27.5% (Argentina) at the age of 50 and 90 years, respectively. In the Latin American countries, FRAX offers a substantial advance for the detection of subjects at high fracture risk. INTRODUCTION: Intervention thresholds are proposed using the Fracture Risk Assessment (FRAX) tool. We recommended their use to calculate the ten-year probability of fragility fracture (FF) in both, men and women with or without the inclusion of bone mineral density (BMD). The purpose of this study is to compute FRAX-based intervention and BMD assessment thresholds for seven Latin American countries in men and women ≥ 40 years. METHODS: The intervention threshold (IT) was set at a 10-year probability of a major osteoporotic fracture (MOF) equivalent to a woman with a prior FF and a body mass index (BMI) equal to 25.0 kg/m2 without BMD or other clinical risk factors. The lower assessment threshold was set at a 10-year probability of a MOF in women with BMI equal to 25.0 kg/m2, no previous fracture and no clinical risk factors. The upper assessment threshold was set at 1.2 times the IT. RESULTS: For the seven LA countries, the age-specific IT varied from 1.5 to 27.5% in Argentina, 3.8 to 25.2% in Brazil, 1.6 up to 20.0% in Chile, 0.6 to 10.2% in Colombia, 0.9 up to 13.6% in Ecuador, 2.6 to 20.0% in Mexico, and 0.7 up to 22.0% in Venezuela at the age of 40 and 90 years, respectively. CONCLUSIONS: In the LA countries, FRAX-based IT offers a substantial advance for the detection of men and women at high fracture risk, particularly in the elderly. The heterogeneity of IT between the LA countries indicates that country-specific FRAX models are appropriate rather than a global LA model.

Global dietary calcium intake among adults: a systematic review.

Low calcium intake may adversely affect bone health in adults. Recognizing the presence of low calcium intake is necessary to develop national strategies to optimize intake. To highlight regions where calcium intake should be improved, we systematically searched for the most representative national dietary calcium intake data in adults from the general population in all countries. We searched 13 electronic databases and requested data from domain experts. Studies were double-screened for eligibility. Data were extracted into a standard form. We developed an interactive global map, categorizing countries based on average calcium intake and summarized differences in intake based on sex, age, and socioeconomic status. Searches yielded 9780 abstracts. Across the 74 countries with data, average national dietary calcium intake ranges from 175 to 1233 mg/day. Many countries in Asia have average dietary calcium intake less than 500 mg/day. Countries in Africa and South America mostly have low calcium intake between about 400 and 700 mg/day. Only Northern European countries have national calcium intake greater than 1000 mg/day. Survey data for three quarters of available countries were not nationally representative. Average calcium intake is generally lower in women than men, but there are no clear patterns across countries regarding relative calcium intake by age, sex, or socioeconomic status. The global calcium map reveals that many countries have low average calcium intake. But recent, nationally representative data are mostly lacking. This review draws attention to regions where measures to increase calcium intake are likely to have skeletal benefits.

Biologic therapies and bone loss in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown cause, characterized by a chronic, symmetric, and progressive inflammatory polyarthritis. One of the most deleterious effects induced by the chronic inflammation of RA is bone loss. During the last 15 years, the better knowledge of the cytokine network involved in RA allowed the development of potent inhibitors of the inflammatory process classified as biological DMARDs. These new drugs are very effective in the inhibition of inflammation, but there are only few studies regarding their role in bone protection. The principal aim of this review was to show the evidence of the principal biologic therapies and bone loss in RA, focusing on their effects on bone mineral density, bone turnover markers, and fragility fractures. METHODS: Using the PICOST methodology, two coauthors (PC, LM-S) conducted the search using the following MESH terms: rheumatoid arthritis, osteoporosis, clinical trials, TNF- antagonists, infliximab, adalimumab, etanercept, certolizumab, golimumab, IL-6 antagonists, IL-1 antagonists, abatacept, tocilizumab, rituximab, bone mineral density, bone markers, and fractures. The search was conducted electronically and manually from the following databases: Medline and Science Direct. The search period included articles from 2003 to 2015. The selection included only original adult human research written in English. Titles were retrieved and the same two authors independently selected the relevant studies for a full text. The retrieved selected studies were also reviewed completing the search for relevant articles. The first search included 904 titles from which 253 titles were selected. The agreement on the selection among researchers resulted in a Kappa statistic of 0.95 (p < 0.000). Only 248 abstracts evaluated were included in the acronym PICOST. The final selection included only 28 studies, derived from the systematic search. Additionally, a manual search in the bibliography of the selected articles was made and included into the text and into the section of "small molecules of new agents." CONCLUSION: Treatment with biologic drugs is associated with the decrease in bone loss. Studies with anti-TNF blocking agents show preservation or increase in spine and hip BMD and also a better profile of bone markers. Most of these studies were performed with infliximab. Only three epidemiological studies analyzed the effect on fractures after anti-TNF blocking agent's treatment. IL-6 blocking agents also showed improvement in localized bone loss not seen with anti-TNF agents. There are a few studies with rituximab and abatacept. Although several studies reported favorable actions of biologic therapies on bone protection, there are still unmet needs for studies regarding their actions on the risk of bone fractures.

Incidence of hip fracture in Brazil and the development of a FRAX model.

UNLABELLED: The Brazilian FRAX model is described and used to determine intervention thresholds for the treatment of osteoporosis. INTRODUCTION: A FRAX model for Brazil was released May 1, 2013. This paper describes the data used to develop the Brazilian FRAX(®) model, illustrates its features and develops intervention thresholds. METHODS: Age- and sex-stratified hip fracture incidence rates were extracted from four regional estimates from the age of 40 years. For other major fractures, Brazilian incidence rates were estimated using Swedish ratios for hip to other major osteoporotic fracture (humerus, forearm or clinical vertebral fractures). Assessment and intervention thresholds were determined using the approach recommended by the National Osteoporosis Guideline Group (UK) applied to the Brazilian FRAX model. RESULTS: Fracture incidence rates increased with increasing age: for hip fracture, incidence rates were higher amongst younger men than women but with a female preponderance from the age of 50 years. Ten-year probability of hip or major fracture was increased in patients with a clinical risk factor, lower BMI, female gender, a higher age and a decreased BMD T-score. Of the clinical risk factors, prior fracture accounted for the greatest increase in 10-year fracture probability at younger ages while a parental hip fracture history was the strongest risk factor at ages 80-90 years. Age-dependent probability-based intervention thresholds were developed equivalent to women with a prior fragility fracture. CONCLUSIONS: The FRAX tool is the first to provide a country-specific fracture prediction model for Brazil. It is based on the original FRAX methodology, which has been externally validated in several independent cohorts. Despite some limitations, the strengths make the Brazilian FRAX tool a good candidate for implementation into clinical practice.

Correlation between 25-hydroxyvitamin D levels and latitude in Brazilian postmenopausal women: from the Arzoxifene Generations Trial.

SUMMARY: We investigated vitamin D status in Brazilian cities located at different latitudes. Insufficiency (<50 nmol/L) was common (17 %), even in those living in a tropical climate. Vitamin D insufficiency increased as a function of latitude. Mean 25-hydroxyvitamin D (25(OH)D) levels in each site and latitude correlation were very high (r = -0.88; p=0.02). [corrected]. INTRODUCTION: Inadequate vitamin D, determined by low levels of 25(OH)D, has become very common despite the availability of sunlight at some latitudes. National data from a country that spans a wide range of latitudes would help to determine to what extent latitude or other factors are responsible for vitamin D deficiency. We investigated vitamin D status in cities located at different latitudes in Brazil, a large continental country. METHODS: The source is the Brazilian database from the Generations Trial (1,933 osteopenic or osteoporotic postmenopausal women (60 to 85 years old) with 25(OH)D measurements). 25(OH)D below 25 nmol/L (10 ng/mL) was an exclusion criterion. Baseline values were between fall and winter. The sites included Recife, Salvador, Rio de Janeiro, São Paulo, Curitiba, and Porto Alegre. Mean and standard deviation of 25(OH)D, age, spine and femoral neck T-score, calcium, creatinine, and alkaline phosphatase were calculated for each city. Pearson correlation was used for 25(OH)D and latitude. RESULTS: Insufficiency (<50 or <20 ng/mL) was common (329 subjects, 17 %). Vitamin D insufficiency increased as a function of latitude, reaching 24.5 % in the southernmost city, Porto Alegre. The correlation between mean 25(OH)D levels in each site and latitude was very high (r = -0.88, p < 0.0001). CONCLUSION: There is a high percentage of individuals with vitamin D insufficiency in Brazil, even in cities near the equator, and this percentage progressively increases with more southern latitudes.

Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial.

OBJECTIVES: To determine the efficacy of CP-690,550 in improving pain, function and health status in patients with moderate to severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate or a tumour necrosis factor alpha inhibitor. METHODS: Patients were randomised equally to placebo, CP-690,550 5, 15 or 30 mg twice daily for 6 weeks, with 6 weeks' follow-up. The patient's assessment of arthritis pain (pain), patient's assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) and Short Form-36 (SF-36) were recorded. RESULTS: At week 6, significantly more patients in the CP-690,550 5, 15 and 30 mg twice-daily groups experienced a 50% improvement in pain compared with placebo (44%, 66%, 78% and 14%, respectively), clinically meaningful reductions in HAQ-DI (> or =0.3 units) (57%, 75%, 76% and 36%, respectively) and clinically meaningful improvements in SF-36 domains and physical and mental components. CONCLUSIONS: CP-690,550 was efficacious in improving the pain, function and health status of patients with RA, from week 1 to week 6.

Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy.

OBJECTIVE: To determine the efficacy and safety of pamapimod in adult patients with active rheumatoid arthritis (RA) who had an inadequate clinical response to methotrexate (MTX). METHODS: Patients receiving stable doses of MTX were randomised to one of six dose groups and received 12 weeks of double-blind pamapimod (up to 300 mg once daily) or matching placebo. The primary efficacy measure was the proportion of patients with > or =20% improvement in RA based on the American College of Rheumatology criteria (ACR20) at 12 weeks. Secondary measures were ACR50, Disease Activity Score (DAS)/European League Against Rheumatism (EULAR) responses and the individual ACR core set of parameters. Safety measures included adverse events (AEs), laboratory testing and immunology assessments. RESULTS: On a background of MTX, the percentage of patients with an ACR20 response at week 12 in the pamapimod groups (31% to 43%) was not significantly different from placebo (34%). Secondary efficacy end points showed a similar pattern. AEs were typically mild and included infections, gastrointestinal disturbances, dizziness and rashes; AEs resulting in discontinuation of study drug were primarily attributed to infections. CONCLUSION: In patients with active RA receiving stable doses of MTX, pamapimod showed non-significant improvement in efficacy outcomes compared to placebo.

Dietary habits, ethanol and tobacco consumption as predictive factors in the development of esophageal carcinoma in patients with head and neck neoplasms.

Patients with primary head and neck cancers have a higher risk of developing esophageal cancer. The aim of this study was to investigate esophageal cancer prevalence, its risk factors (ethanol and tobacco consumption) and dietary habits in patients with head and neck cancer. Three hundred and twenty-six adults with primary head and neck cancer were followed by a retrospective observational study in a general university hospital in Sao Paulo, Brazil. Flexible videoendoscopy with lugol chromoscopy was the method used to investigate esophageal cancer prevalence. All subjects were interviewed face-to-face, revealing detailed information about their tobacco and alcohol use, as well as their dietary habits. Thirty-six patients with esophageal cancer were diagnosed and the overall prevalence rate was 11.04%. Patients who developed second esophageal tumors had the following characteristics: earlier age of initial ethanol consumption (P < 0.05), longer duration period of ethanol consumption (P < 0.05) and higher weekly consumption rate (P < 0.05). There was an increased risk of esophageal carcinoma in those patients who both smoked and drank (P < 0.05). There was no association between carcinoma of the esophagus and dietary habits in patients who developed esophageal neoplasms, compared with those who did not. Prevalence rate of esophageal neoplasms was 11.04% in patients with head and neck carcinoma, whose ethanol consumption was associated with esophageal cancer. There was an increased risk between ethanol and tobacco consumption and esophageal carcinoma development. On the other hand, there was no association regarding dietary habits between patients who developed esophageal cancer and those who did not.

Economic effects of exposure to bovine viral diarrhea virus on dairy herds in New Zealand.

The economic loss to dairy farmers associated with bovine viral diarrhea virus (BVDV) is believed to be high in New Zealand, but no estimates are yet available. The aim was therefore to estimate the economic loss associated with BVDV in dairy herds in New Zealand. Bulk tank milk (BTM) from a random sample of 590 herds from the Northland, Bay of Plenty, and Waikato regions was tested for antibody against BVDV. The inhibition percentage (sample to positive ratio), based on a threshold validated in an earlier study, was used to indicate herd-level infection. Herd reproductive indices, herd lactation-average somatic cell counts, and herd average production of milk solids were regressed on BTM inhibition percentage. Herd averages of the overall annual culling rate, the rate of culling because of failure to conceive, the proportion of physiological inter-service intervals, the first-service conception rate, the pregnancy rate at the end of mating, and somatic cell counts were not associated with BVDV antibody in BTM. Abortion rates, rates of calving induction, the time from calving to conception, and the number of services per conception increased, however, whereas milk production decreased with increasing BVDV antibody in BTM. The results indicated significant reproductive and production loss associated with the amount of BVDV antibody in BTM. Total loss attributable to infection with BVDV was similar to reports from other countries and estimated as NZ$87 per cow and year in affected herds, and NZ$44.5 million per year for the New Zealand dairy industry based on an estimated 14.6% affected herds. The loss estimate excludes added cost and negative consequences with respect to animal welfare attributable to increased induction rates, and a greater incidence of production disease because of BVD-induced immune suppression.

Efficacy of etoricoxib 60 mg/day and diclofenac 150 mg/day in reduction of pain and disability in patients with chronic low back pain: results of a 4-week, multinational, randomized, double-blind study.

BACKGROUND AND METHODS: The efficacy and safety of etoricoxib 60 mg/day in patients with established chronic low back pain (CLBP) were compared with those of diclofenac 150 mg/day in a 4-week, multicentre, randomized, double-blind, parallel-group trial. Four hundred and forty-six adult patients with CLBP (Quebec Task Force on Spinal Disorders Class 1 or 2) and with worsening pain upon discontinuation of pre-study analgesic medication were enrolled in the study. The study primary efficacy endpoint was change from baseline in Low Back Pain Intensity Scale (LBP-IS) score over the 4-week treatment period. Secondary and other efficacy endpoints included: changes in Roland and Morris Disability Questionnaire (RMDQ), Patient Global Assessment of Response to Therapy (PGART) and Low Back Pain Bothersomeness Scale (LBP-BS) scores. Early efficacy was assessed using PGART and LBP-IS scores 4 h after the first dose on the mornings of Days 1, 2 and 3. The overall safety and tolerability of etoricoxib 60 mg/day during 4 weeks of treatment were also assessed. RESULTS: The least-squares mean time-weighted change from baseline LBP-IS score over 4 weeks was -32.94 mm (95% CI -36.25, -29.63) for etoricoxib, indicating substantial efficacy in relief of pain. The treatment difference for the primary outcome was 2.51 mm (95% CI -1.50, 6.51), fulfilling the prespecified equivalence criterion of 95% confidence interval wholly within +/- 10 mm. Etoricoxib improved all secondary and other efficacy outcomes. There were no statistically significant between-group differences in the proportion of patients with one or more clinical adverse events (AEs) (etoricoxib 35%, diclofenac 39%), or the proportion of patients who discontinued due to AEs (etoricoxib 7%, diclofenac 5%). CONCLUSIONS: The results of this study confirm that, for adult patients with CLBP, etoricoxib 60 mg once daily over 4 weeks is effective for relief of pain and improvement of physical function and comparable to high-dose diclofenac 150 mg daily.

When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide?

OBJECTIVE: To evaluate the efficacy and safety of adding sulfasalazine to leflunomide treatment compared with switching to sulfasalazine alone in patients with RA with an inadequate response to leflunomide monotherapy. METHODS: Patients with active RA ((DAS28) >3.2) who were enrolled in the first open label phase of the RELIEF study received leflunomide for 24 weeks. Inadequate responders then entered the double blind phase and received a further 24 weeks' treatment with leflunomide (20 mg once daily) plus sulfasalazine (final dose 2 g once daily), or placebo plus sulfasalazine (dose as above). The primary efficacy variable was the DAS28 response rate, and secondary efficacy outcomes were ACR 20%, 50%, and 70% response rates. Adverse events, including standard laboratory tests, were recorded. RESULTS: 106 inadequate responders entered the double blind phase; 56 received leflunomide plus sulfasalazine, and 50 placebo plus sulfasalazine. In the intention to treat population, more patients receiving leflunomide plus sulfasalazine (25/56 (45%)) achieved a DAS28 response than those receiving placebo plus sulfasalazine (17/50 (34%)) (p = 0.179). In week 24 completers, more patients receiving leflunomide plus sulfasalazine (17/56 (30%)) were DAS28 responders than those receiving placebo plus sulfasalazine (10/50 (20%)) (p = 0.081). Comparable numbers in each group were ACR 20% responders; the ACR 50% response rate was significantly higher in the leflunomide plus sulfasalazine group (8.9%) than in the placebo plus sulfasalazine group (0%) (p = 0.038). The safety profiles of both groups were comparable. CONCLUSION: Patient numbers are small and firm conclusions cannot be reached, but a non-significant benefit is indicated for combining leflunomide with sulfasalazine compared with switching to sulfasalazine alone in patients inadequately responding to leflunomide.