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Biomedical subjects

Vibeke Strand

Publications and source records attributed to Vibeke Strand.

At least 19 recordsLinked to original sources
PubMed2007

Biologic therapies in rheumatology: lessons learned, future directions.

During the past decade biologic therapies such as monoclonal antibodies and fusion proteins have revolutionized the management of rheumatic disease. By targeting key cytokines and immune cells biologics have provided more specific therapeutic interventions with less immunosuppression. Clinical use, however, has revealed that their theoretical simplicity hides a more complex reality. Efficacy, toxicity and even pharmacodynamic effects can deviate from those predicted, as poignantly illustrated by the catastrophic effects witnessed during the first-into-human administration of TGN1412. This review summarizes lessons gleaned from practical experience and discusses how these can inform future discovery and development of new biologic therapies for rheumatology.

Animals↗
PubMed2006

Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.

OBJECTIVE: Bisphosphonates have slowed the progression of osteoarthritis (OA) in animal models and have decreased pain in states of high bone turnover. The Knee OA Structural Arthritis (KOSTAR) study, which is the largest study to date investigating a potential structure-modifying OA drug, tested the efficacy of risedronate in providing symptom relief and slowing disease progression in patients with knee OA. METHODS: The study group comprised 2,483 patients with medial compartment knee OA and 2-4 mm of joint space width (JSW), as determined using fluoroscopically positioned, semiflexed-view radiography. Patients were enrolled in 2 parallel 2-year studies in North America and the European Union. These studies evaluated the efficacy of risedronate at dosages of 5 mg/day, 15 mg/day, 35 mg/week (in Europe), and 50 mg/week (in North America) compared with placebo in reducing signs and symptoms, as measured by the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and patient global assessment (PGA) scores, and in slowing radiographic progression. RESULTS: A reduction of approximately 20% in signs and symptoms, as measured by WOMAC subscales and PGA scores, was observed in all groups, with no treatment effect of risedronate demonstrated. Risedronate did not significantly reduce radiographic progression as measured by decreased JSW or using a dichotomous definition of progression (joint space loss of >or=0.6 mm). Thirteen percent of patients receiving placebo demonstrated significant disease progression over 2 years. A dose-dependent reduction in the level of C-terminal crosslinking telopeptide of type II collagen, a cartilage degradation marker associated with progressive OA, was seen in patients who received risedronate. No increase in the number of adverse events was demonstrated for risedronate compared with placebo. CONCLUSION: Although risedronate (compared with placebo) did not improve signs or symptoms of OA, nor did it alter progression of OA, a reduction in the level of a marker of cartilage degradation was observed. A sustained clinically relevant improvement in signs and symptoms was observed in all treatment and placebo groups.

Adult↗
PubMed2006

Monitoring disease activity of rheumatoid arthritis in clinical practice: contributions from clinical trials.

Rheumatoid arthritis is a heterogeneous and progressive autoimmune disease, and patients with this condition show varied responses to treatment. Practical, reliable, individually tailored measures of disease activity and treatment responses are needed. Outcome measures used in randomized, controlled trials, including American College of Rheumatology response criteria and Disease Activity Scores, identify when treatment should be initiated or changed, but can be time consuming and impractical in daily practice. Simplified disease activity indices, abbreviated joint counts and patient-report questionnaires are more-convenient ways to assess therapeutic responses in the clinic. Patient-reported measures of physical function, pain and global disease activity best differentiate the results of active treatment from those of placebo treatment in randomized, controlled trials. Improvements in physical function closely reflect changes in health-related quality of life. Recent trials have demonstrated limited correlations between clinical responses and radiographically demonstrated responses; both should be assessed on a regular basis. It is recommended that three domains be assessed in the clinic for therapeutic responses: patient-reported measures of physical function and/or global disease activity; physician assessment of disease activity; and imaging of the hands and/or feet on a biannual basis. Problematic joints and cervical spine involvement should be followed as clinically indicated. Measures of improvement for individually relevant physical activities need to be defined for each patient.

Arthritis, Rheumatoid↗
PubMed2006

Expectations from patients with rheumatoid arthritis regarding COX-2s: cutting to the heart of the matter.

Before the withdrawal of 2 COX-2 selective agents (COX-2s) from the market, many rheumatoid arthritis patients were using these products regularly, with disease-modifying antirheumatic agents. Clinical trials have shown benefit of COX-2s equivalent to nonselective nonsteroidal anti-inflammatory drugs (NS-NSAIDs) in rheumatoid arthritis. Better gastrointestinal (GI) safety has been demonstrated with COX-2s; numerical but not statistical benefit with concomitant use of cardiovascular (CV) doses of aspirin. COX-2 benefit may extend to lower GI blood loss against which proton pump inhibitors are not protective. COX-2s are associated with hypertension and edema of similar magnitude to NS-NSAIDs in predisposed individuals. Epidemiologic studies and clinical trials have confirmed the association of serious thromboembolic (CV) events and congestive heart failure with rofecoxib>25 mg daily, celecoxib, and NS-NSAIDs, although there is a paucity of long-term data. Important questions remain regarding relative GI and CV risks: is concomitant aspirin protective when coadministered with COX-2s? Does this abrogate their GI benefit? As identified many years ago with NS-NSAIDs, patients may respond to one and not another; COX-2s should be considered individually and not as a single "class." Patients deserve the opportunity to make a choice about the perceived benefit/risk assessment when using these therapies, with the collaboration of their physician.

Arthritis, Rheumatoid↗
PubMed2005

Leflunomide or methotrexate for juvenile rheumatoid arthritis.

BACKGROUND: We compared the safety and efficacy of leflunomide with that of methotrexate in the treatment of polyarticular juvenile rheumatoid arthritis in a multinational, randomized, controlled trial. METHODS: Patients 3 to 17 years of age received leflunomide or methotrexate for 16 weeks in a double-dummy, blinded fashion, followed by a 32-week blinded extension. The rates of American College of Rheumatology Pediatric 30 percent responses (ACR Pedi 30) and the Percent Improvement Index were assessed at baseline and every 4 weeks for 16 weeks and every 8 weeks during the 32-week extension study. RESULTS: Of 94 patients randomized, 86 completed 16 weeks of treatment, 70 of whom entered the extension study. At week 16, more patients in the methotrexate group than in the leflunomide group had an ACR Pedi 30 response (89 percent vs. 68 percent, P=0.02), whereas the values for the Percent Improvement Index did not differ significantly (-52.87 percent vs. -44.41 percent, P=0.18). In both groups, the improvements achieved at week 16 were maintained at week 48. The most common adverse events in both groups included gastrointestinal symptoms, headache, and nasopharyngeal symptoms. Aminotransferase elevations were more frequent with methotrexate than with leflunomide during the initial study and the extension study. CONCLUSIONS: In patients with polyarticular juvenile rheumatoid arthritis, methotrexate and leflunomide both resulted in high rates of clinical improvement, but the rate was slightly greater for methotrexate. At the doses used in this study, methotrexate was more effective than leflunomide.

Administration, Oral↗
PubMed2005

Long-term open-label preliminary study of the safety and efficacy of leflunomide in patients with polyarticular-course juvenile rheumatoid arthritis.

OBJECTIVE: To obtain preliminary data regarding the efficacy and long-term safety of leflunomide in patients with refractory polyarticular-course juvenile rheumatoid arthritis (JRA). METHODS: Twenty-seven patients were entered into the initial 26-week open-label study of leflunomide therapy; 17 entered the extension phase (maximum 107 weeks). Mean disease duration at study entry was 7.0 years. All patients had >or=5 joints with active arthritis and had received methotrexate for a mean of 36.0 months. Following a loading dose, patients initially received leflunomide at a dosage of 10 mg/1.73 m(2)/day, which could be increased to 20 mg/1.73 m(2)/day (maximum 20 mg/day) beginning at week 8. The primary efficacy outcome was the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement. Last observation carried forward (LOCF) analysis was used, and all patients were entered into an intent-to-treat analysis. Intraarticular corticosteroids (maximum of 2 in the initial 26 weeks) were allowed, but no new disease-modifying antirheumatic drug or change in nonsteroidal antiinflammatory drug was allowed throughout the study. RESULTS: Seventeen of the 27 patients (63%) completed the initial 26-week study. Fourteen patients (52%) met the ACR Pedi 30 response criteria at week 26. Seventeen patients entered into the extension phase (13 who met response criteria and 4 who failed to meet response criteria but decided to continue). Nine of the 17 patients (53%) who entered the extension phase either completed all 30 months of study or the study ended prior to the month 30 visit. Five patients withdrew because of failure to maintain efficacy, 2 withdrew their consent, and 1 withdrew because of an adverse event. Using LOCF analysis, 65% of patients met ACR Pedi 30 response criteria at 1 year and 2 years (weeks 50 and 106, respectively) and 53% at the end of the study. Good response rates were also seen using ACR Pedi 50 and ACR Pedi 70 criteria (47% and 24% at week 106, respectively). CONCLUSION: In this open-label study of JRA patients who either failed to respond to, or were intolerant of, methotrexate, the majority met the ACR Pedi 30 response criteria at week 26. The response was durable, since 53% of patients who entered into the extension phase (maximum 30 months) responded at the end of this phase. Our findings support the further study of the role of leflunomide in the treatment of polyarticular-course JRA.

Adolescent↗
PubMed2005

Relationship between anti-double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus.

OBJECTIVE: To examine the relationship between changes in anti-double-stranded DNA (anti-dsDNA) antibody levels and the risk of renal flare in patients with systemic lupus erythematosus (SLE), using data from 2 randomized, controlled trials. METHODS: Analyses were based on 487 patients with SLE and a history of lupus nephritis who had an anti-dsDNA antibody titer >/=15 IU/ml at baseline, as measured by Farr assay. Results are presented for the combined population of patients, the placebo arms, and the drug treatment arms in which a dsDNA-based bioconjugate (abetimus sodium; LJP 394) was used. RESULTS: Changes in anti-dsDNA antibody levels were inversely correlated with changes in the C3 level (P < 0.0001 in both trials). Cox proportional hazards regression models showed that changes in anti-dsDNA antibody levels correlated with the risk of renal flare. The models predicted that a point estimate of a 50% reduction in anti-dsDNA antibody levels is associated with a 52% reduction (95% confidence interval [95% CI] 26-68%, nominal P = 0.0007) and a 53% reduction (95% CI 33-69%, nominal P < 0.0001) in the risk of renal flare in the 2 trials, respectively. In the 2 trials, the incidence of renal flare was lower in patients with sustained reductions in anti-dsDNA antibodies (3.0% and 4.1%, respectively) than in patients with stable or increasing antibody levels (21.3% and 20.3%, respectively). CONCLUSION: Changes in anti-dsDNA antibody levels were directly correlated with the risk of renal flare and inversely correlated with changes in the C3 level. Reducing anti-dsDNA antibody levels may represent a therapeutic objective in SLE patients with lupus nephritis, because it is associated with a reduced risk of renal flare.

Adjuvants, Immunologic↗
PubMed2005

Expanding the definition of clinical differences: from minimally clinically important differences to really important differences. Analyses in 8931 patients with rheumatoid arthritis.

OBJECTIVE: Minimally clinically important differences (MCID) have become an important way to interpret data of randomized clinical trials (RCT), but do not reflect the degree of improvement consistent with a "really important difference" (RID). To define RID, we compared mean and/or least desirable clinical states with best and/or most desirable states. METHODS: In total, 8931 patients with rheumatoid arthritis (RA) < 65 years of age completed the Health Assessment Questionnaire (HAQ) and Medical Outcomes Survey Short Form 36 Physical Component Score (PCS). Definitions of RID were based on values for HAQ and PCS corresponding with the best and worst category of the following conditions: disabled vs not disabled: joint replacement vs no joint replacement; < poverty level vs > poverty level; very satisfied with health vs not; and independent in participation activities vs not. RESULTS: In contrast to published MCID values for the HAQ of approximately 0.22, RID was as high as 0.76 using objective reference conditions and 0.87 using the subjective measure of dependence vs independence. The HAQ score of independent RA patients was 0.38 (SD 0.45), and was 0.42 (SD 0.53) for those very satisfied with their health. The difference in HAQ scores between disabled and working patients was approximately 0.75. PCS differences were similarly increased. CONCLUSION: RID values are 3 to 4 times greater than MCID values. Although MCID are meaningful statistics for RCT, the RID percentage achieved [(actual improvement/RID) 100%] is a simple way to put the results of RCT in a broader perspective that gives an idea of how much additional treatment effect is needed.

Arthritis, Rheumatoid↗
PubMed2005

Physical function and health related quality of life: analysis of 2-year data from randomized, controlled studies of leflunomide, sulfasalazine, or methotrexate in patients with active rheumatoid arthritis.

OBJECTIVE: To determine whether improvements in physical function and health related quality of life (HRQOL) are sustained over 2 years of blinded treatment with leflunomide (LEF), methotrexate (MTX), or sulfasalazine (SSZ) in patients with active rheumatoid arthritis (RA). METHODS: Three phase III randomized, controlled trials compared LEF, MTX, and SSZ in patients with active RA. Improvements in physical function were assessed by Health Assessment Questionnaire Disability Index (HAQ-DI) and Modified Health Assessment Questionnaire (MHAQ); monthly MHAQ and mean HAQ scores were used to calculate American College of Rheumatology responses; HAQ-DI was assessed at baseline and 6-month intervals. In US301, the Medical Outcomes Study 36-Item Short-Form questionnaire (SF-36) assessed treatment-associated changes in HRQOL at baseline and 6-month intervals. RESULTS: Mean and median improvements in HAQ-DI after 12 and 24 months of active treatment in all phase III protocols significantly exceeded -0.22 or a minimum clinically important difference (MCID). These improvements closely reflected positive changes in SF-36 that met or exceeded MCID in all domains with LEF and MTX treatment. Problem Elicitation Technique Top 5 scores reflected improvements in performance of physical activities most important to patients. CONCLUSION: Improvements in physical function were sustained over 24 months of successful treatment with LEF, MTX, and SSZ, and reflected improvements in mental as well as physical domains of HRQOL.

Antirheumatic Agents↗
PubMed2004

Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus.

OBJECTIVE: To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms. METHODS: Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (</=10 mg/day), antimalarials, and immunosuppressive agents; dosages were required to be stable for >/=6 weeks prior to enrollment and remain unchanged during protocol treatment. Responders were patients who experienced no clinical deterioration and had improvement or stabilization over the duration of the study in 2 disease activity measures (the SLE Disease Activity Index [SLEDAI] and the Systemic Lupus Activity Measure) and 2 quality of life measures (patient's global assessment and the Krupp Fatigue Severity Scale). RESULTS: A total of 381 women with SLE were enrolled. Among patients with clinically active disease at baseline (SLEDAI score >2), 86 of 147 in the prasterone group (58.5%) demonstrated improvement or stabilization without clinical deterioration, as compared with 65 of 146 in the placebo group (44.5%) (P = 0.017). Acne and hirsutism were reported in 33% and 16%, respectively, of the prasterone group and in 14% and 2%, respectively, of the placebo group (P < 0.05 for both comparisons). However, most cases of acne and hirsutism were mild and did not require withdrawal from therapy. Myalgias and oral stomatitis were reported less frequently in the prasterone group (22% and 15%, respectively) than in the placebo group (36% and 23%, respectively) (P < 0.05 for both comparisons). Serum levels of high-density lipoprotein cholesterol, triglycerides, and C3 complement significantly decreased, while levels of testosterone and, to a lesser extent, estradiol increased in the prasterone group. CONCLUSION: In adult women with active SLE, administration of prasterone at a dosage of 200 mg/day improved or stabilized signs and symptoms of disease and was generally well tolerated.

Adjuvants, Immunologic↗
PubMed2004

Outcome measures in osteoarthritis: randomized controlled trials.

Accepted outcome measures in randomized controlled trials (RCTs) in osteoarthritis (OA) include patient-reported assessments of physical function and health-related quality of life (HRQOL). Available data can inform treatment decisions when statistically significant changes are viewed in terms of clinically important improvements. Patient-reported outcomes validated in OA include global assessments of pain, disease activity, and disease-specific and generic measures of physical function and HRQOL. Definitions of minimum clinically important differences (MCID) have been derived from RCTs with physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 selective agents. Definitions of MCID should serve only as guidelines based on mean changes in a treatment group, and do not necessarily reflect clinically meaningful improvements for an individual patient. They help to interpret data across treatments and patient populations. Definitions of MCID may differ for the type of intervention assessed; additional methodologic issues must be addressed when evaluating nonpharmacologic treatments. Based on RCTs in OA evaluating physical therapy, cyclooxygenase-2 agents, and NSAIDs, the Western Ontario and McMaster Osteoarthritis Index is valid, reliable, sensitive to change, and correlates closely with the generic Medical Outcomes Survey Short-Form 36 measure of HRQOL. When evaluating RCT data, understanding derivation and MCID values of outcome measures facilitates informed therapeutic decisions regarding therapeutic interventions.

Acupuncture↗
PubMed2004

Variability of precision in scoring radiographic abnormalities in rheumatoid arthritis by experienced readers.

OBJECTIVE: To determine the extent of precision and sources of variability among experts on scoring radiographic abnormalities in rheumatoid arthritis. METHODS: Radiographic scores from 6 datasets in which 2 or more readers had scored film sets were analyzed. Datasets included scores by 11 different readers, 6 of whom scored films by both the Larsen (global) and Sharp (composite) methods. Scores of each possible combination of 2 readers were compared in calculating the smallest detectable difference (SDD) on raw scores and on scores normalized for each individual reader (nSDD). Intraclass correlation (ICC), Pearson's r, and the correlation between differences in score and their mean scores were determined. Agreement on progression of radiographic damage scores was also examined. RESULTS: Variability among readers was greater than previous studies suggested. Agreement was better for intra- than interreader comparisons; average intrareader SDD was 24.4 for the composite method and 9.0 for the global. The larger SDD for the composite method reflect their greater range of possible scores. When normalized scores were used to adjust for the range difference, there was minimal difference in the SDD; nSDD was 10.1 for the composite method, 8.0 for the global. Interreader variability was larger: SDD of 53.7 for the composite method and 23.3 for the global; nSDD 12.9 and 14.4, respectively. ICC varied between 0.465 and 0.999, with all but one value below 0.925 occurring in composite scores with a range below 100. Differences in repeated scores were frequently associated with the mean of those scores and this was greater for inter- than for intrareader comparisons. Agreement between progression scores showed a similar pattern. The SDD was better for intrareader comparisons and smaller for global scores: compare 13.7 (composite, intrareader) and 5.4 (global, intrareader) to 18.1 (composite, interreader) and 8.7 (global, interreader). The ICC was lower for progression scores than for raw scores, averaging between 0.661 and 0.885. CONCLUSION: The variability in scoring radiographic abnormalities is considerable among this group of 11 expert readers. This has important implications for power calculations in comparison studies such as therapeutic trials and for cross-trial comparisons. The correlation between the difference in repeated scores and their means indicates systematic error (bias), which, if corrected, may improve the detection of treatment effects when using a responder-type analysis. These and other design and analysis issues are discussed.

Arthritis, Rheumatoid↗
PubMed2004

Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial.

OBJECTIVE: To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA). METHODS: Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained. RESULTS: For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose. CONCLUSION: Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.

Antirheumatic Agents↗