Rheumatoid Arthritis: Strand V

Aletaha D, Landewe R, Karonitsch T, Bathon J, Boers M, Bombardier C, Bombardieri S, Choi H, Combe B, Dougados M, Emery P, Gomez-Reino J, Keystone E, Koch G, Kvien TK, Martin-Mola E, Matucci-Cerinic M, Michaud K, O'Dell J, Paulus H, Pincus T, Richards P, Simon L, Siegel J, Smolen JS, Sokka T, Strand V, Tugwell P, van der Heijde D, van Riel P, Vlad S, van Vollenhoven R, Ward M, Weinblatt M, Wells G, White B, Wolfe F, Zhang B, Zink A, Felson D, Anonymous00358, Anonymous00359. · Medical University of Vienna, Vienna, Austria. · Arthritis Rheum. · Pubmed #18821648 No free full text.

Abstract: OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. CONCLUSION: These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Strand V. · No affiliation provided · Semin Arthritis Rheum. · Pubmed #16461066 No free full text.

This publication has no abstract.

Lipani JA, Strand V, Woodworth T, Furst D, Singh G, Johnson K, Day R, Brooks P. · No affiliation provided · J Rheumatol. · Pubmed #10782801 No free full text.

This publication has no abstract.

Strand V, Singh JA. · Division of Immunology/ Rheumatology,Stanford University School of Medicine, 306 Ramona Rd, Portola Valley, CA 94028, USA. · Am J Manag Care. · Pubmed #18415967 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the articular synovium, resulting in bony erosions, deformity, and, ultimately, joint destruction. With associated comorbid conditions,especially cardiovascular, it can result in significant morbidity as well as early mortality. Patients with RA report impairments in health-related quality of life (HRQOL) in comparison with age- and sex-matched populations without arthritis. These decreases in HRQOL are attributed to the pain, impairment in physical function, and fatigue associated with this disease. The introduction of new disease-modifying antirheumatic drugs has revolutionized the treatment of RA, particularly the biologic agents: etanercept, infliximab,adalimumab, abatacept, and rituximab.Importantly, administration of these agents has resulted in statistically significant and clinically meaningful improvements in physical function and HRQOL. Many clinical studies confirm that with these therapies, RA patients report improvements in HRQOL, reflected by improved physical function, less fatigue, and better emotional and mental function.Maintenance of physical function is no longer the only treatment goal for RA but also to improve, restore, and preserve HRQOL. Results from pivotal clinical trials are analyzed in this article and the relevance of the data derived from the clinical studies to day-to-day clinical practice are also discussed.

Strand V, Singh JA. · Division of Immunology/Rheumatology, Stanford University School of Medicine, 306 Ramona Rd, Portola Valley, CA 94028, USA. · Am J Manag Care. · Pubmed #18095787 links to  free full text

Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the articular synovium, resulting in bony erosions, deformity, and, ultimately, joint destruction. With associated comorbid conditions, especially cardiovascular, it can result in significant morbidity as well as early mortality. Patients with RA report impairments in health-related quality of life (HRQOL) in comparison with age- and sex-matched populations without arthritis. These decreases in HRQOL are attributed to the pain, impairment in physical function, and fatigue associated with this disease. The introduction of new disease-modifying antirheumatic drugs has revolutionized the treatment of RA, particularly the biologic agents: etanercept, infliximab, adalimumab, abatacept, and rituximab. Importantly, administration of these agents has resulted in statistically significant and clinically meaningful improvements in physical function and HRQOL. Many clinical studies confirm that with these therapies, RA patients report improvements in HRQOL, reflected by improved physical function, less fatigue, and better emotional and mental function. Maintenance of physical function is no longer the only treatment goal for RA but also to improve, restore, and preserve HRQOL. Results from pivotal clinical trials are analyzed in this article and the relevance of the data derived from the clinical studies to day-to-day clinical practice are also discussed.

Strand V, Yazici Y. · Division of Immunology, Stanford University School of Medicine, Palo Alto, California, USA. · Bull NYU Hosp Jt Dis. · Pubmed #17708741 links to  free full text

Abstract: Tocilizumab, humanized monoclonal antibody to sIL-6R, is a promising new agent for the treatment of rheumatoid arthritis. Safety data from randomized controlled trials (RCT) to date have been overall reassuring with no evidence of increased opportunistic infections or malignancies, and some signals for elevated liver function tests and changed lipid profiles. The true implications of these signals in RCTs must be addressed in larger numbers of RA patients with longer term exposure before firm conclusions are reached.

Aletaha D, Strand V, Smolen JS, Ward MM. · Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Austria. · Ann Rheum Dis. · Pubmed #17644550 No free full text.

Abstract: BACKGROUND: Physical function in rheumatoid arthritis (RA) has reversible and irreversible components, and is typically assessed by the Health Assessment Questionnaire Disability Index (HAQ). Since irreversible components are expected to increase with longer duration of RA and reduce the ability for improvement in physical function, we analysed responsiveness of HAQ scores in patient populations with differing RA durations in randomised controlled trials (RCTs). METHODS: Data from all RCTs published between 1980 and 2005 that reported changes from baseline in HAQ at 6 and/or 12 months were analysed. Treatments were grouped as "biologics", or "traditional" disease modifying antirheumatic drugs (DMARDs), and "placebo". We computed effect sizes of HAQ in each trial, and contrasted the association between these effects and duration of RA among treatment groups using regression models. RESULTS: We identified 42 RCTs with complete data for the statistical models. The models indicate that discrimination of functional improvement between active drug groups and placebo is reduced in patients with a longer duration of RA (p = 0.02 for the change in discrimination over time). The placebo-adjusted HAQ responses decreased on average by 0.37 per year of RA duration. CONCLUSION: Responsiveness in HAQ scores is inversely associated with mean disease duration in RA. This impacts assessment of physical function, a key outcome measure in RCTs and practice, and impacts the ability to discriminate active treatment from placebo.

Strand V. · Division of Immunology/ Rheumatology, Stanford University, Palo Alto, CA, USA. · Am J Orthop. · Pubmed #17491581 No free full text.

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Zatarain E, Strand V. · Division of Immunology and Rheumatology at Stanford University School of Medicine, Palo Alto, CA 94035, USA. · Nat Clin Pract Rheumatol. · Pubmed #17075600 No free full text.

Abstract: 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.

Chung CP, Thompson JL, Koch GG, Amara I, Strand V, Pincus T. · Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee 37232-4500, USA. · Ann Rheum Dis. · Pubmed #16504992 No free full text.

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

Strand V. · Division of Immunology/Rheumatology, Stanford University, 306 Ramona Road, Portola Valley, California 94028, USA. · Clin Exp Rheumatol. · Pubmed #15552516 No free full text.

Abstract: Evidence from randomized controlled trials with newly approved DMARD therapies have proven efficacy by American College of Rheumatology [ACR] response criteria, Disease Activity Scores [DAS] and radiographic measures of disease progression. Treatment over 2 years duration results in clinically meaningful improvements in physical function, by the Health Assessment Questionnaire [HAQ] and health related quality of life [HRQOL], using the medical outcomes short form 36 [SF-36]. Changes in HAQ are evident within one month, maximal at 3-6 months, and sustained over 24 months, reflected by improvements in social functioning, role emotional and the general health profile as well as physical domains of SF-36. Trials with the new DMARDs, as well as MTX, indicate that long term benefits in radiographic damage and physical function can be inferred from treatment data over 12 months. "Successful" patients who continue to do well will derive benefit from treatment for as long as 3 to 5 years. Recent RCTs indicate that combination therapy, initiated together, offers more improvement in radiographic progression and physical function than monotherapy, although the trial data cannot yet tell us which DMARD may be most beneficial in a given patient. Once treatment with any one agent--biologic or synthetic--is initiated, the addition of a second agent should occur rapidly, if for example active disease persists 8 or 12 weeks later, without waiting for documented treatment failure. If this treatment paradigm is followed, along with regular assessments of radiographic damage and physical function, then patients may more likely derive long term clinical benefit than with traditional approaches.

Strand V, Kavanaugh AF. · Division of Immunology, Stanford University, Stanford, CA, USA. · Rheumatology (Oxford). · Pubmed #15150427 links to  free full text

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

Strand V. · Stanford University, Portola Valley, CA, USA. · Arthritis Rheum. · Pubmed #15077319 links to  free full text

This publication has no abstract.

Strand V, Simon LS. · Division of Immunology and Rheumatology, Stanford University School of Medicine, 306 Ramona Road, Portola Valley, CA 94028, USA. · Clin Exp Rheumatol. · Pubmed #14969074 No free full text.

Abstract: The use of glucocorticoid therapy in the treatment of rheumatoid arthritis [RA] remains controversial. There has been much data accumulated over the years describing both the risks and benefits of acute and chronic glucocorticoid therapy. Initially there was significant enthusiasm for this type of therapy given the extent of the anti-inflammatory effects. However, use was then modified as chronic therapy with higher doses was associated with frequent reports of important safety concerns. More recently low dose glucocorticoid therapy (e.g. < or = 5 mg prednisone per day) is being reconsidered in particular for patients with early disease. This paper will review the historical experience with higher dose therapy along with the evolving evidence of an improved benefit to risk ratio with the advent of concomitant therapies to minimize some of the more problematic adverse events associated with chronic use of even low dose glucocorticoid therapy. It is suggested that with appropriate monitoring and careful concomitant prophylactic therapy to prevent osteoporosis, adjunctive therapy using low dose glucocorticoids along with the appropriate disease modifying anti-rheumatic drug may be a reasonable treatment plan for select patients.

Wells G, Anderson J, Boers M, Felson D, Heiberg T, Hewlett S, Johnson K, Kirwan J, Lassere M, Robinson V, Shea B, Simon L, Strand V, van Riel P, Tugwell P. · Department of Clinical Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada. · J Rheumatol. · Pubmed #12734920 No free full text.

Abstract: The OMERACT 6 Minimal Clinically Important Difference/Low Disease Activity Workshop was organized with the aim of meeting the many challenges that exist in determining a low disease activity in rheumatoid arthritis (RA). This article presents an overview of that workshop, including results of the voting, a summary of associated discussions, recommendations, and a proposed research agenda.

Wells G, Boers M, Shea B, Anderson J, Felson D, Johnson K, Kirwan J, Lassere M, Robinson V, Simon L, Strand V, van Riel P, Tugwell P. · Department of Clinical Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada. · J Rheumatol. · Pubmed #12734918 No free full text.

Abstract: The MCID (minimal clinically important difference) module of OMERACT 5 developed a research agenda that led to the conclusion that a state of low disease activity for rheumatoid arthritis (RA) would need to be defined. To develop such a definition the various concepts and terminologies, the process for developing an operational definition, and the availability and design of longitudinal datasets for validation needed to be considered. This article describes the process of the MCID/Low Disease Activity State Workshop at OMERACT 6 to develop such a definition.

Van Der Heijde D, Sharp JT, Rau R, Strand V, Anonymous00465. · University Hospital Maastricht, Maastricht, The Netherlands. · J Rheumatol. · Pubmed #12734917 No free full text.

Abstract: This article describes the process and results of a workshop aimed at reviewing data on repair of structural damage collected by the OMERACT Subcommittee on Healing of Erosions and at defining a priority list for the subsequent research agenda.

Osiri M, Shea B, Robinson V, Suarez-Almazor M, Strand V, Tugwell P, Wells G. · Medicine, Chulalongkorn University Hospital, Division of Rheumatology, Department of Medicine, Chulalongkorn University Hospital, Rama IV Road, Pathumwan, Bangkok, Thailand, 10330. · Cochrane Database Syst Rev. · Pubmed #12535423 No free full text.

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

Strand V, Sharp JT. · Stanford University, Palo Alto, CA, USA. · Arthritis Rheum. · Pubmed #12528100 links to  free full text

This publication has no abstract.

Strand V, Landéwé R, van der Heijde D. · Stanford University, Division of Immunology, Palo Alto, CA, USA. · Ann Rheum Dis. · Pubmed #12379626 links to  free full text

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Haraoui B, Strand V, Keystone E. · Université de Montreal, Rheumatic Disease Unit, CHUM, Canada. · Curr Pharm Biotechnol. · Pubmed #11469381 No free full text.

Abstract: Advances in the understanding of the pathogenesis of rheumatoid arthritis (RA) as well as improved biotechnology has enabled selective targeting of the pathogenic elements of disease. Targeting cell recruitment through adhesion molecules has been shown to be successful in pre-clinical murine models. Results of studies of an anti-ICAM-1 monoclonal antibody and anti-sense oligonucleotides have been encouraging. An alternate approach to inhibiting recruitment has been the targeting of chemoattractant molecules ie. chemokines. Important advances have been made in cytokine directed therapy targeting TNFalpha and IL-1. TNF antagonists (anti-TNF monoclonal antibody/soluble TNF receptor Fc fusion protein) have resulted in rapid and substantial improvement in signs and symptoms of disease as well as disease modification, shown by slowing of radiological progression. IL-1 receptor antagonist protein appears to have a significant effect on radiological progression despite a modest effect on symptoms and signs. Studies using anti-inflammatory cytokines such as IL-10 are in progress. A more recent therapeutic approach has been to target T-cell activation by interfering with co-stimulatory complexes such as CD40L/CD40 and CD28/CD80 and CD86. Both pre-clinical and preliminary clinical studies in human subjects support the concept. Another approach involving T-cell receptor peptide vaccination with VB peptides over-utilized in RA synovium has shown to be beneficial. Targeting the cytokines driving T-cells in the RA synovium ie. IL-12 & IL-15 has also proven beneficial in animal studies. Recent attention has also been directed toward the invading synovial fibroblast using Fas-FasL mediated apoptosis. Pre-clinical studies in which angiogenesis and osteoclast activation are targeted have been encouraging. In conclusion, the proof of principle has been established that selective targeting of pathogenic elements of disease results in substantial improvement in signs and symptoms as well as disease progression. Improved efficacy is expected with more aggressive targeting of the pathogenic elements.

Strand V. · Division of Immunology, Stanford University School of Medicine, 306 Ramona Road, Portola Valley, CA 94028, USA. · Springer Semin Immunopathol. · Pubmed #11455860 No free full text.

This publication has no abstract.

Lipani JA, Strand V, Johnson K, Woodworth T, Furst D, Singh G, Day R, Brooks P, Anonymous00241. · Department of Medicine, Standford Universiity, Palo Alto, CA, USA. · J Rheumatol. · Pubmed #11361208 No free full text.

Abstract: This paper proposes the creation of an objectively acquired reference database to more accurately characterize the incidence and longterm risk of relatively infrequent, but serious, adverse events. Such a database would be maintained longitudinally to provide for ongoing comparison with new rheumatologic drug safety databases collecting the occurrences and treatments of rare events. We propose the establishment of product-specific registries to prospectively follow a cohort of patients with rheumatoid arthritis (RA) who receive newly approved therapies. In addition, a database is required of a much larger cohort of RA patients treated with multiple second line agents of sufficient size to enable case-controlled determinations of the relative incidence of rare but serious events in the treated (registry) versus the larger disease population. The number of patients necessary for agent-specific registries and a larger patient population adequate to supply a matched case-control cohort will depend upon estimates of the detectability of an increased incidence over background. We suggest a system to carry out this proposal that will involve an umbrella organization, responsible for establishment of this large patient cohort, envisioned to be drawn from around the world.

Strand V, Lassere M, van der Heijde D, Johnson K, Boers M. · Division of Immunology, Stanford University, San Francisco, CA 94028, USA. · J Rheumatol. · Pubmed #11327271 No free full text.

Abstract: Recent randomized controlled trials of traditional and newly developed therapies provide evidence that we have interventions that potentially slow or prevent structural damage in active rheumatoid arthritis, as measured using radiography. These trials also provide a unique opportunity for exploratory data analysis to generate hypotheses apropos the pathogenesis and determinants of radiographic progression and functional disability; they also facilitate further study of the methodological issues regarding imaging measurement.

Wolfe F, Strand V. · Arthritis Research Center Foundation, 1035 N. Emporia, Suite 230, Wichita, KS 67214, USA. · Curr Rheumatol Rep. · Pubmed #11177770 No free full text.

Abstract: Recent clinical development programs for new therapeutic agents in rheumatoid arthritis have included assessment of radiographic progression comparing changes with treatment to placebo and active controls. Studies now use reliable methods of assessment and sufficient study length to detect radiographic changes. Although patient populations and characteristics differ, and radiographic scoring methods vary, the direction of a series of studies appears to indicate that leflunomide (LEF), methotrexate (MTX), sulfasalazine (SSZ), etanercept, infliximab, and IL-1ra are all effective in retarding radiographic progression, as measured by erosions and joint space narrowing. Interpretation of radiograph data in future trials will be aided by utilization of common reading methods and by continuing comparison across differing rheumatoid arthritis protocol populations.