Rheumatoid Arthritis: Pincus T

Pincus T, Kavanaugh A, Sokka T. · Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-4500, USA. · Clin Exp Rheumatol. · Pubmed #15552508 No free full text.

Abstract: Most physicians are familiar with the side effects or risks of drugs used to treat rheumatoid arthritis (RA), but relatively less familiar with the "side effects" or risks associated with RA itself RA is not thought to have the same potential severity as a cardiovascular or neoplastic disease by most physicians, the public, or even some rheumatologists, although relative rates of predicted mortality in some patients with RA are in the range of some people with coronary artery disease or Hodgkin's disease. Many reasons may be identified to explain why the risks of RA have been underestimated: RA does not lead to acute life-threatening situations; population-based data have suggested that most people who meet criteria for RA have a mild or self-limited process; acute attributed causes of death in people with RA are superficially similar to those in the general population; clinical trials have suggested many therapies that are efficacious over a period of 3-12 months; few long-term longitudinal studies were performed prior to the 1980s; medical recommendations made during the 1950s-1980s suggested that simple therapies were adequate for most patients; and quantitative information concerning patient status is generally not included in standard rheumatology care. As more information has emerged concerning severe long-term outcomes in the "natural history" of RA (as treated prior to the 1990s), new strategies of aggressive intervention have been developed. Furthermore, basic research has led to new therapies. It appears that the benefit/risk ratio of therapies for RA has increased substantially over the last two decades, and the outlook for patients with RA is much better at this time than in previous years.

Pincus T, Sokka T. · Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, 203 Oxford House, Box 5, Nashville, TN 37232-4500, USA. · Rheum Dis Clin North Am. · Pubmed #15488690 No free full text.

Abstract: Modern medical care has been advanced, in large part, by quantitative measures that provide single, easily-assessed end points for clinical trials, clinical research, or clinical care (eg, blood pressure, serum cholesterol). In rheumatoid arthritis, several types of quantitative measures are used to assess patient status, including formal joint counts; radiographic scores; laboratory tests; patient self-report questionnaire measures of physical function, pain, global status, morning stiffness, and fatigue; as well as physical measures of functional status. Each of these measures is effective to document changes of status with treatment in groups of patients; however, no single measure can serve as a "gold standard" to document changes in each individual patient. Therefore, the measures have been combined into pooled indices that can be applied to individual patients in clinical research and clinical care.

Pincus T, Sokka T. · Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, 203 Oxford House, Box 5, Nashville, TN 37232-4500, USA. · Rheum Dis Clin North Am. · Pubmed #15488689 No free full text.

Abstract: Randomized controlled clinical trials provide the best method to distinguish a drug from placebo without the inevitable selection biases that are seen in standard clinical care. This article reviews designs and limitations of clinical trials that are used in rheumatic diseases. The primary design in clinical trials is a parallel, in which patients are randomized in parallel to different therapies at different dosages or placebo. In recent years, other designs have been used increasingly, including "step-up," "step-down," and "cross-over" designs. Limitations of clinical trials in chronic diseases include a short time frame versus the long duration of disease, inclusion and exclusion criteria, use of surrogate markers that may not represent clinically relevant markers, statistical significance does not necessarily indicate clinical significance necessarily, and the fact that a control group does not assure the absence of bias. Therefore, long-term databases are needed to supplement clinical trials in analyzing results of therapy for rheumatoid arthritis.

Pincus T, Sokka T. · Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, 203 Oxford House, Box 5, Nashville, TN 37232-4500, USA. · Ann Rheum Dis. · Pubmed #15479869 links to  free full text

Abstract: The information used by rheumatologists when delivering care to patients with rheumatoid arthritis (RA) is derived mainly from two sources: randomised controlled clinical trials and experience in clinical care. However, these two sources differ significantly because (a) the extensive inclusion and exclusion criteria result in clinical trial participants being recruited from only a minority of patients seen in standard clinical care; (b) assessments in clinical trials are conducted according to standard quantitative measures and indices, while standard clinical care of most patients with RA is generally conducted empirically, without collection of any quantitative data other than laboratory tests to estimate prognosis and document change in status; and (c) although baseline databases of various clinical trials (and observational studies) are 60-90% identical in content, they are not standardised and therefore not amenable to direct comparisons. Strategies to promote similarities between clinical trials and standard clinical care in patients with RA may include: more generalised inclusion criteria; incorporation of quantitative measurement into standard care, easily accomplished by asking each patient to complete a simple questionnaire at each visit to a rheumatologist; and consensus among rheumatologists for databases with standard content and format in clinical care and research involving patients with RA.

Boers M, Dijkmans B, Gabriel S, Maradit-Kremers H, O'Dell J, Pincus T. · Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #15188348 links to  free full text

This publication has no abstract.

Pincus T, Sokka T. · Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-4500, USA. · Clin Exp Rheumatol. · Pubmed #14989429 No free full text.

Abstract: Several reports concerning outcomes of rheumatoid arthritis (RA) document that measures of inflammatory activity [such as swollen joint count, tender joint count, and acute phase reactant, which are included in the Core Data Set or Disease Activity Score (DAS)] may be stable or improved over 5-10 years, while measures of damage (such as radiographic progression and joint deformity) may show contemporaneous progression. Therefore, studies which include only improvement in measures of disease activity cannot document overall improvement in patient status over 5-10 years. Studies designed to document favorable long-term effects of therapy in RA must include, at baseline and later follow-up evaluation, measures of damage, such as a radiograph, joint deformity, comorbidities, and extra-articular disease, in addition to measures of disease activity. The one prognostic measure which appears to detect both activity and damage in RA over short, intermediate, and long periods is a disability score on a patient questionnaire, which might be used by all rheumatologists at all patient encounters. The need for inclusion of accurate and relevant measures of damage appears of particular importance in the current era of biological drugs, in which the slowing or prevention of damage now appears a realistic goal in most patients with RA.

Pincus T, Yazici Y, Sokka T, Aletaha D, Smolen JS. · Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, 203 Oxford House, Box 5, Nashville, TN 37232-4500, USA. · Clin Exp Rheumatol. · Pubmed #14969073 No free full text.

Abstract: The two major advances over the 1990s in the treatment of rheumatoid arthritis (RA) were a shift in strategy from a "pyramid", in which disease modifying anti-rheumatic drugs (DMARDs) were deferred for several years, to the early aggressive use of DMARDs and widespread acceptance of methotrexate as the DMARD with the most long-term effectiveness and safety. Methotrexate courses are continued far longer than those of any other DMARD, an excellent indicator of greater effectiveness and safety. In one recent series, methotrexate was the first DMARD used in more than 80% of patients with RA. Studies which document the superiority of combinations of methotrexate with biological agents to methotrexate monotherapy select for only a minority of contemporary patients with RA who have severe disease activity and incomplete responses to methotrexate. In one locale, only 5% of patients met criteria for the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy (ATTRACT) trial and only 30% met the criteria for the Early Rheumatoid Arthritis (ERA) trial. In studies comparing methotrexate directly with biological agents, the biological agents have greater efficacy in patients with very severe disease, but the best results are seen in patients who take a combination of methotrexate and biologic agents. These data establish that methotrexate is the anchor drug and probably should be the first DMARD used in the majority of patients with RA at this time.

Sokka T, Willoughby J, Yazici Y, Pincus T. · Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Clin Exp Rheumatol. · Pubmed #14969067 No free full text.

Abstract: Several databases of patients with early rheumatoid arthritis (RA) have been established in the USA. The University of Tennessee at Memphis Cohort was organized in 1967-1971 to enroll 50 young adults (16-44 years) with symptom onset of < or = 6 months who met the 1958 American Rheumatism Association (ARA) criteria for at least probable RA. Two important observations from this database were that many patients seen within the first 6 months of meeting the criteria for probable RA have a self-limited rather than progressive disease, and that progressive disease is predicted by a high number of baseline swollen and tender joints. The National Institutes of Health (NIH) cohort of patients with peripheral synovitis for > or = 6 weeks but < 12 months in at least one peripheral joint was established in 1994. At the one-year follow-up, 45% of the patients met the RA criteria, 9% had reactive arthritis, 6% had psoriatic arthritis, 5% had other rheumatic diseases, and 35% had undifferentiated arthritis. The number of active joints, rather than meeting the criteria for RA, was the primary determinant of function and performance after one year. The Western Consortium of Practicing Rheumatologists (CPR) was established in 1993 to enroll patients with an RA duration < 1 year, positive rheumatoid factor, > or = 6 swollen and > or = 9 tender joints, and no previous treatment with disease modifying anti-rheumatic drugs (DMARDs). Data from this cohort indicated the validity of self-report joint counts. American College of Rheumatology 20% improvement (ACR20) responses were seen in 50% of patients at 6 months and in 57% of patients at 24 months, while antinuclear antibodies (ANA) were seen in 69% of patients prior to the availability of biologic agents. The North American Cohort of Patients with Early RA (SONORA), which included patients with symptoms for > 3 but < 12 months, indicated that methotrexate (MTX) was the most frequently prescribed DMARD, being taken by more than half the patients. The Consortium for the Longitudinal Evaluation of African-Americans with RA (CLEAR) registry and DNA repository has enrolled 123 African-American patients with early RA of less than 2 years' duration to analyze genetic and non-genetic factors associated with disease severity. The Early RA Treatment Evaluation Registry (ERATER) of patients with early RA (< 3 years) was established in 2001. In this registry, MTX was the first DMARD used in 83% of patients, and most patients would not meet the criteria for inclusion in recent clinical trials of biological agents. Further observation of recent cohorts of patients with early RA over the next decade should be informative regarding whether aggressive intervention strategies and new DMARDs and biologic agents lead to improved long-term outcomes.

Pincus T, Sokka T. · Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Clin Exp Rheumatol. · Pubmed #14969056 No free full text.

Abstract: Rheumatoid arthritis (RA) is not characterized by a single pathognomonic measure such as blood pressure in hypertension or cholesterol in hyperlipidemia, which can be used in the diagnosis, prognosis, and monitoring of patient status. Measures such as swollen joints and an elevated erythrocyte sedimentation rate are certainly valuable, but many individuals with abnormal values have conditions other than RA, and many people with RA may have favorable values for one or more of these measures. Therefore, the rheumatology community has developed indices of several measures, such as classification criteria, the disease activity score (DAS), and the ACR Core Data Set with 20%, 50% and 70% improvement (ACR 20, ACR 50, ACR 70) to classify and monitor patients with RA. While these indices have greatly advanced clinical research, databases for long-term observations, including those in early RA described in this Supplement, differ in 20-50% of included data, and the software platforms for these databases differ sufficiently to render it difficult to merge the data to compare one data set to another. It has been proposed that a uniform database for early arthritis clinical research could help advance clinical research in early arthritis. One example of such a database, termed a "standard protocol to evaluate rheumatoid arthritis" (SPERA), has been in use for almost two decades in one clinical site, and has proven valuable in a number of ways, including the demonstration of early radiographic damage, development of a 28-joint count, and documentation that patient questionnaire data are correlated significantly with laboratory, joint count and radiographic data, although questionnaire data are the strongest predictors of severe outcomes including work disability and premature mortality. The use of a uniform database in no way precludes the collection of additional data at particular centers including immunogenetic, serologic, or structural magnetic resonance imaging (MRI) data. However, the availability of an infrastructure of standard data in all RA databases would enhance clinical research in early RA.

Pincus T, Sokka T. · Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, 203 Oxford House, Box 5, Nashville, TN 37232-4500, USA. · Best Pract Res Clin Rheumatol. · Pubmed #12915156 No free full text.

Abstract: There is no single 'gold standard' quantitative measure to assess and monitor the clinical status in patients with rheumatoid arthritis (RA). Therefore, a variety of measures have been used in clinical research and clinical care, including laboratory tests, radiographic scores, formal joint counts, physical measures of functional status, global measures and patient self-report questionnaires. These measures may address disease activity, joint damage, both activity and damage, or long-term outcomes. Measures of disease activity, such as joint swelling, are reversible and are emphasized in clinical trials. However, activity measures may be improved over 5 years while measures of damage, such as radiographic score, indicate disease progression. Two quantitative indices which are widely used in clinical trials are the (1) American College of Rheumatology (ACR) Core Data Set, which includes swollen joint count, tender joint count, physician assessment of global status, acute-phase reactant-erythrocyte sedimentation rate or C-reactive protein, functional status, pain, patient estimate of global status, a radiograph in studies over 1 year or longer, and (2) the disease activity score(DAs), which includes a swollen joint count, tender joint count, acute-phase reactant, and patient assessment of global status. Randomized controlled clinical trials provide the optimal method to evaluate new therapies, by comparing a therapy with a placebo or another therapy without selecting patients for specific therapies. However, randomized trials in chronic diseases have important limitations, including a relatively short observation period, patient selection for inclusion and exclusion criteria, inflexible dosage schedules, influence of the design on results despite a control group, emphasis on group data while ignoring individual variation in treatment responses, non-standardized interpretation of adverse effects, and others. Therefore, clinical trials in RA must be supplemented by long-term observational studies to assess results of therapy in regard to long-term outcomes such as work disability, joint replacement surgery and premature mortality. The most simple and effective method of collecting important long-term data from patients in routine clinical care is through patient self-report questionnaires.

Pincus T, Ferraccioli G, Sokka T, Larsen A, Rau R, Kushner I, Wolfe F. · Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University School of Medicine, 203 Oxford House, Nashville, TN 37232-4500, USA. · Rheumatology (Oxford). · Pubmed #12468813 links to  free full text

Abstract: Earlier reports, including a comprehensive 1983 review, had indicated that slowing of radiographic progression was relatively unusual in treatment of rheumatoid arthritis (RA) using traditional disease modifying anti-rheumatic drugs. However, in recent years, slowing of radiographic progression has been documented in a number of clinical trials, as well as long-term observational studies, with use of (in alphabetical order) adalimumab, anakinra, corticosteroids, cyclophosphamide, cyclosporin, etanercept, gold salts, infliximab, leflunomide, methotrexate and sulphasalazine. At this time, disease modification is a realistic goal in the clinical care of patients with RA. Documentation of improved long-term outcomes requires long-term observational data over 5-20 yr to supplement data from randomized controlled clinical trials over 6-24 months.

Braun J, Pincus T. · Rheumazentrum Ruhrgebiet, St. Josefs-Krankenhaus, Herne, Germany. · Clin Exp Rheumatol. · Pubmed #12463441 No free full text.

Abstract: Patients with ankylosing spondylitis (AS) have about a 50% increased risk of mortality on the basis of the limited amount of data available. There is some evidence that the progression of disease is strongest in the first 10 years of disease but it is also clear that the disease keeps on being active for further decades. The overall burden of disease is similar to rheumatoid arthritis but the overall disease duration of AS is longer. Prognostic factors have also not been studied extensively in AS but it seems clear that early hip involvement indicates a worse outcome. The same is true for early limitation of spinal mobility, laboratory evidence of ongoing disease activity (ESR, hypergammaglobulinemia), peripheral arthritis and dactylitis. The significance of organ involvement for the prognosis, especially in the kidney in the form of amyloidosis, and in the heart and lungs, is less clear. Radiation therapy of the spine, which had been performed quite extensively in former decades, has been associated with a mean radiation dose of about double that of atomic bomb survivors and an increased risk of leukemia and mortality. This therapy has been largely abandoned nowadays. Elder rheumatologists report however that the clinical improvement of irradiated patients has been partly impressive.

Pincus T. · Division of Rheumatology, Vanderbilt University Medical Center, 203 Oxford House, Box 5, Nashville, TN 37232-4500, USA. · Curr Rheumatol Rep. · Pubmed #11709116 No free full text.

Abstract: Osteoarthritis (OA) is not a simple consequence of "wear and tear" or aging--the presence of cytokines suggests a role for inflammation. OA is polyarticular in most patients, with metabolic and differential risk factors for prevalence and severity. Odds ratios for the prevalence of OA according to formal education levels are similar to those seen for dysregulatory diseases such as hypertension, diabetes, and rheumatoid arthritis. Clinical survey data indicate significant patient preference for nonsteroidal anti-inflammatory drugs (NSAIDs) compared with acetaminophen. A recent crossover clinical trial indicated significantly greater efficacy of the NSAID, diclofenac/misoprostol, versus acetaminophen for most patients with OA.

Pincus T, Sokka T. · Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-4500, USA. · J Rheumatol. · Pubmed #11469488 No free full text.

Abstract: Predictors of longterm mortality in rheumatoid arthritis (RA) include patient questionnaire measures, grip strength, walk time, physician and patient assessment of global status, joint examination abnormalities, erythrocyte sedimentation rate (ESR), and morning stiffness. In the rheumatology literature, these measures have been analyzed primarily according to mean values in groups or regression analyses, which are valuable to recognize that mortality in RA is predicted by more severe disease, but do not provide the clinician with specific goals of therapy. Goals for therapeutic intervention are often expressed either as complete remission or as statistically significant differences versus a placebo, as in a 20% or even 50% response of a measure such as the American College of Rheumatology Core Data Set. Remission may be too stringent, while statistically significant efficacy of a drug compared to placebo may not necessarily indicate effectiveness to control longterm damage. An alternative approach might be to identify possible target values for therapeutic efficacy that markers of a poor prognosis be "near normal" rather than necessarily at normal or remission levels, as has been explored in management of hypertension and diabetes. However, it remains uncertain whether the goal of therapy should be a "near normal" or entirely normal values for a clinical marker. Better control of quantitative markers that predict early mortality could provide a valuable approach to improving outcomes in RA.

Sokka T, Pincus T. · Jyvaskyla Central Hospital, Department of Medicine, Finland. · J Rheumatol. · Pubmed #11469487 No free full text.

Abstract: Work disability is common in rheumatoid arthritis (RA), and accounts for a large fraction of its costs. People with RA who are work disabled have more joint involvement, radiographic damage, and/or laboratory abnormalities than people who are working. However, analysis of predictive and associative markers in 15 studies of work disability indicate that the demographic variables, such as age, occupation, level of education, and duration of disease, as well as functional status in activities of daily living (ADL) identified on a patient questionnaire, appear to identify work status more than physiological variables. Work disability results from complex interactions of a medical disease, demographic variables, social conditions, and government policies. Some patients with RA are work disabled before they see a rheumatologist. Improved work disability outcomes in RA will require attention to social, economic, and political issues, and wider physician and public education concerning RA, in addition to improved medical management of disease.

Wolfe F, O'Dell JR, Kavanaugh A, Wilske K, Pincus T. · National Data Bank for Rheumatic Diseases, Arthritis Research Center Foundation, Inc. and University of Kansas School of Medicine, Wichita, Kansas, USA. · J Rheumatol. · Pubmed #11409143 No free full text.

Abstract: There is general agreement regarding the most appropriate examinations and methods to use to evaluate change in status in randomized controlled trials (RCT). However, no guidelines exist to aid in determining and evaluating actual status rather than change in status, particularly when applied to individual patients with rheumatoid arthritis (RA). In addition, methods appropriate for clinical trials may not be useful in evaluating individual patients because of time constraints. This report reviews current methods of evaluation and develops modified methods, based on data bank research that will be useful in clinical practice and in the evaluation of RCT and observational studies. Using data from longitudinal observational data banks, further reduction in the number of joints examined is evaluated to reconcile the time constraints of clinical practice with the need to maintain reliability and validity. Percentile methods to determine severity status are applied to the variables used in RCT and extended further to observational studies and routine clinical practice. Shortened joint counts, based on modifications of the Ritchie method, are identified that allow for examination of groups of 18 (clinical-18) and 16 (clinical-16) joints, the clinical-16 omitting the metatarsophalangeal joints. Using percentile charts, actual severity valuations are given to the variables evaluated in the clinic as well as in RCT. Disease activity status of clinic patients can be determined quantitatively thus allowing clinicians further insight into the status and prognosis of their patients. By quantifying disease activity severity, clinicians and 3rd party payers can better evaluate the appropriateness of and response to disease modifying antirheumatic drugs and biologic therapies. Further, RCT can be evaluated as to severity status of patients participating, and the generalizability of RCT can be better evaluated.

Wolfe F, Cush JJ, O'Dell JR, Kavanaugh A, Kremer JM, Lane NE, Moreland LW, Paulus HE, Pincus T, Russell AS, Wilskie KR. · National Data Bank for Rheumatic Diseases-Arthritis Research Center Foundation, Inc. and University of Kansas School of Medicine, Wichita, Kansas, USA. · J Rheumatol. · Pubmed #11409141 No free full text.

This publication has no abstract.

Pincus T, Sokka T. · Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, 203 Oxford House, Nashville, TN 37232, USA. · Best Pract Res Clin Rheumatol. · Pubmed #11358420 No free full text.

Abstract: The long-term natural history of rheumatoid arthritis includes early radiographic damage and progression, severe functional declines, work disability and increased mortality rates. Emerging evidence suggests that this natural history may be favourably affected by disease-modifying anti-rheumatic drugs (DMARDs), which slow the radiographic progression and functional decline. It is necessary to document both the efficacy of these drugs in randomized controlled clinical trials and their long-term effectiveness in clinical observational studies. Although a 20% improvement in inflammatory measures in the American College of Rheumatology Core Data Set (ACR20) distinguishes DMARDs from placebo in clinical trials, it is not clear that a control of inflammation at this level, or even at 50%, is sufficient to prevent long-term damage. There is limited financial support for long-term observational studies, which depend on data from the clinical experience of rheumatologists. Quantitative databases from clinical care, can be developed to document long-term outcomes in patients with early rheumatoid arthritis to include additional physical, radiographic, laboratory and patient questionnaire quantitative data. Patient self-report questionnaires appear to provide the least expensive and most effective measures toward this goal.

Hawley DJ, Wolfe F, Pincus T. · National Data Bank for Rheumatic Diseases, Wichita, Kansas 67214, USA. · Clin Exp Rheumatol. · Pubmed #10589363 No free full text.

Abstract: AIMS: To describe the utilization of combination therapy in the treatment of rheumatoid arthritis (RA). METHODS: Review of published articles and abstracts, and patient/physician questionnaire data. RESULTS: Combination therapy was rarely used in the early 1980s and is now (1999) used for about 25% of RA patients in the US. Physician and patient surveys indicate that methotrexate plus hydroxychloroquine is the most commonly used combination in North America, and physician surveys indicate that methotrexate plus sulfasalazine is the most commonly used combination in Europe. Patient questionnaire data indicate that 13.4% of patients in the US take methotrexate and hydroxychloroquine, and between 11% and 15% of patients with recent onset of RA receive treatment with disease-modifying antirheumatic drug (DMARD) combinations. CONCLUSIONS: Combination therapy with agents such as hydroxychloroquine and methotrexate is used in up to 25% of RA patients in the US, but the use of "aggressive combination therapy" is unusual. Whether combination therapy as currently practiced is beneficial remains to be determined.

Pincus T, Breedveld FC, Emery P. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-4500, USA. · Clin Exp Rheumatol. · Pubmed #10589350 No free full text.

This publication has no abstract.

Pincus T, O'Dell JR, Kremer JM. · Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Ann Intern Med. · Pubmed #10577301 links to  free full text

Abstract: The traditional "pyramid" or sequential approach to treatment of patients with rheumatoid arthritis involved use of a nonsteroidal anti-inflammatory drug for months to years while seeking to avoid use of second-line antirheumatic drugs until evidence of joint damage was seen. This approach led to short-term reduction of inflammation and a few remissions. However, long-term remissions were rare, and most patients experienced poor long-term outcomes, including joint destruction, severe functional declines, considerable economic losses, work disability, and premature mortality. At this time, a "preventive" strategy is evolving in which early aggressive treatment with disease-modifying antirheumatic drugs is used, seeking to minimize long-term joint damage. When residual inflammation remains after maximum doses of single agents, as is usually the case, combinations of disease-modifying antirheumatic drugs appear to be a reasonable consideration for many patients. Methotrexate is the most commonly used "anchor drug" in combination therapy. Evidence from randomized, controlled clinical trials and observational studies have indicated increased efficacy and acceptable (and often lower) toxicity for combinations of methotrexate plus cyclosporine, hydroxychloroquine, sulfasalazine, leflunomide, etanercept, and infliximab. Further studies lasting 5 years or more are needed to determine the long-term effectiveness, toxicities, and optimal clinical use of disease-modifying antirheumatic drug combinations. At this time, such combinations are taken by at least some patients under care of almost all rheumatologists, and it appears likely that they will be used increasingly in the coming decades.

Stein CM, Pincus T. · Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA. · Lancet. · Pubmed #9950461 No free full text.

This publication has no abstract.

Chung CP, Oeser A, Avalos I, Gebretsadik T, Shintani A, Raggi P, Sokka T, Pincus T, Stein CM. · Department of Medicine, Vanderbilt University School of Medicine, 1161 21st Ave, Nashville, TN 37232, USA. · Arthritis Res Ther. · Pubmed #17169159 links to  free full text

Abstract: The prevalence of ischemic heart disease and atherosclerosis is increased in patients with rheumatoid arthritis (RA). In the general population, but not in patients with systemic lupus erythematosus, the Framingham risk score identifies patients at increased cardiovascular risk and helps determine the need for preventive interventions. We examined the hypothesis that the Framingham score is increased and associated with coronary-artery atherosclerosis in patients with RA. The Framingham score and the 10-year cardiovascular risk were compared among 155 patients with RA (89 with early disease, 66 with long-standing disease) and 85 control subjects. The presence of coronary-artery calcification was determined by electron-beam computed tomography. The Framingham score was compared in patients with RA and control subjects, and the association between the risk score and coronary-artery calcification was examined in patients. Patients with long-standing RA had a higher Framingham score (14 [11 to 18]) (median [interquartile range]) compared to patients with early RA (11 [8 to 14]) or control subjects (12 [7 to 14], P < 0.001). This remained significant after adjustment for age and gender (P = 0.015). Seventy-six patients with RA had coronary calcification; their Framingham risk score was higher (14 [12 to 17]) than that of 79 patients without calcification (10 [5 to 14]) (P < 0.001). Furthermore, a higher Framingham score was associated with a higher calcium score (odds ratio [OR] = 1.20, 95% confidence interval [CI] 1.12 to 1.29, P < 0.001), and the association remained significant after adjustment for age and gender (OR = 1.15, 95% CI 1.02 to 1.29, P = 0.03). In conclusion, a higher Framingham risk score is independently associated with the presence of coronary calcification in patients with RA.

Wolfe F, Michaud K, Pincus T. · Arthritis Research Center Foundation, University of Kansas School of Medicine, Wichita, KS 67214, USA. · J Rheumatol. · Pubmed #15996062 No free full text.

Abstract: OBJECTIVE: Key outcomes in rheumatoid arthritis (RA) are evaluated with multi-item ratings scales such as the Health Assessment Questionnaire (HAQ) and visual analog scales (VAS) such as pain and patient and physician global. As VAS scales are easy to use and particularly effective in research and patient care, we studied the characteristics, association, and psychometric properties of a VAS function scale (VAS-F) to determine if it could be used in RA studies and clinical practice. METHODS: A total of 394 patients with RA completed the HAQ, the HAQ-II, and a VAS functional scale. In addition, they completed standard assessments of pain, global, fatigue, sleep problems, joint count, and the Medical Outcome Study Short-Form 36 (SF-36) physical component summary score (PCS) and vitality and total pain scores. RESULTS: The HAQ-II was correlated with VAS-F at 0.76, but distributional characteristics of the HAQ and VAS-F differed, as the VAS-F scale results contained more higher scores as well as more lower scores compared with the HAQ-II and HAQ. Kendall's tau concordance analyses indicated that VAS scales were more concordant with other VAS than with non-VAS scales. Concordance of VAS-F was greatest with VAS global and was similar overall with VAS pain, sleep disturbance, fatigue, and quality of life. By contrast, the PCS, a multi-item scale, was more concordant with HAQ-II and HAQ. There was little to no difference between the VAS-F and the 2 HAQ with regard to concordance with the multi-item joint count, SF-36 vitality, and SF-36 total pain. CONCLUSION: The distribution differences between HAQ and HAQ-II and the VAS-F suggest that patients do not see minor limitations as problematic, but rate major limitations as being particularly limiting and worthy of high ratings. A VAS functional scale represents a patient-weighted functional assessment in which additional interpretation is given to the meaning of the limitations by the patient. VAS-F scales may be suitable for use in the clinic and in research. However, studies to assess sensitivity to change are required to determine the appropriate role of this scale.

Pincus T, Strand V, Koch G, Amara I, Crawford B, Wolfe F, Cohen S, Felson D. · Division of Rheumatology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. · Arthritis Rheum. · Pubmed #12632413 links to  free full text

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