Disability outcomes and dose escalation with etanercept, adalimumab, and infliximab in rheumatoid arthritis patients: a US-based retrospective comparative effectiveness study.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic disease that if left untreated may substantially impair physical functioning. Etanercept, infliximab, and adalimumab are tumor necrosis factor (TNF) blockers whose FDA-approved indications in the US include moderate to severe RA. TNF-blocker dose escalation has been well documented in the literature; however, the comparative effectiveness of these agents remains uncertain. OBJECTIVE: To compare the effectiveness and dose escalation rates of etanercept, adalimumab, and infliximab in US community settings. We hypothesized that etanercept would be equivalent to infliximab and adalimumab in patient-reported disability 9-15 months after therapy initiation, and that fewer etanercept patients would experience dose escalation. METHODS: This is a retrospective analysis of the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS). Adult patients with no biologic use 6 months before TNF-blocker initiation (index) and with Health Assessment Questionnaire Disability Index (HAQ-DI) scores at index and 9-15 months after index were analyzed (218 etanercept, 93 infliximab, and 40 adalimumab). RESULTS: HAQ-DI change scores at 9-15 months did not differ by treatment (-0.12, -0.10, and -0.08 points for etanercept, infliximab, and adalimumab, respectively; p = 0.52). Dose increases were observed in 1.4% of etanercept, 10.8% of infliximab (p < 0.001), and 12.5% of adalimumab patients (p = 0.004). HAQ-DI change was associated with pre-index HAQ-DI score (p < 0.0001) and disease duration (p = 0.001). CONCLUSIONS: Fewer etanercept patients escalated dose than infliximab or adalimumab patients, but improvements in functional disability were similar. These differences may have been influenced by package labeling, mode of administration, or other factors. RA treatment with infliximab and adalimumab in community settings, characterized by dose escalation, did not yield greater disability improvements compared to etanercept, which remained at a relatively stable dose. Uncontrolled treatment selection in this observational design may have influenced outcomes, and prior methotrexate treatment may partly explain disability improvements smaller than typically observed in clinical trials.

Evaluation of a preliminary physical function item bank supported the expected advantages of the Patient-Reported Outcomes Measurement Information System (PROMIS).

OBJECTIVE: The Patient-Reported Outcomes Measurement Information System (PROMIS) was initiated to improve precision, reduce respondent burden, and enhance the comparability of health outcomes measures. We used item response theory (IRT) to construct and evaluate a preliminary item bank for physical function assuming four subdomains. STUDY DESIGN AND SETTING: Data from seven samples (N=17,726) using 136 items from nine questionnaires were evaluated. A generalized partial credit model was used to estimate item parameters, which were normed to a mean of 50 (SD=10) in the US population. Item bank properties were evaluated through Computerized Adaptive Test (CAT) simulations. RESULTS: IRT requirements were fulfilled by 70 items covering activities of daily living, lower extremity, and central body functions. The original item context partly affected parameter stability. Items on upper body function, and need for aid or devices did not fit the IRT model. In simulations, a 10-item CAT eliminated floor and decreased ceiling effects, achieving a small standard error (< 2.2) across scores from 20 to 50 (reliability >0.95 for a representative US sample). This precision was not achieved over a similar range by any comparable fixed length item sets. CONCLUSION: The methods of the PROMIS project are likely to substantially improve measures of physical function and to increase the efficiency of their administration using CAT.

More relevant, precise, and efficient items for assessment of physical function and disability: moving beyond the classic instruments.

OBJECTIVES: Patient reported outcomes (PROs) have become standard study endpoints. However, little attention has been given to using item improvement to advance PRO performance which could improve precision, clarity, patient relevance, and information content of "physical function/disability" items and thus the performance of resulting instruments. METHODS: The present study included 1860 physical function/disability items from 165 instruments. Item formulations were assessed by frequency of use, modified Delphi consensus, respondent judgement of clarity and importance, and item response theory (IRT). Data from 1100 rheumatoid arthritis, osteoarthritis, and normal ageing subjects, using qualitative item review, focus groups, cognitive interviews, and patient survey were used to achieve a unique item pool that was clear, reliable, sensitive to change, readily translatable, devoid of floor and ceiling limitations, contained unidimensional subdomains, and had maximal information content. RESULTS: A "present tense" time frame was used most frequently, better understood, more readily translated, and more directly estimated the latent trait of disability. Items in the "past tense" had 80-90% false negatives (p<0.001). The best items were brief, clear, and contained a single construct. Responses with four to five options were preferred by both experts and respondents. The term physical function may be preferable to the term disability because of fewer floor effects. IRT analyses of "disability" suggest four independent subdomains (mobility, dexterity, axial, and compound) with factor loadings of 0.81-0.99. CONCLUSIONS: Major improvement in performance of items and instruments is possible, and may have the effect of substantially reducing sample size requirements for clinical trials.

The promise of PROMIS: using item response theory to improve assessment of patient-reported outcomes.

PROMIS (Patient-Reported-Outcomes Measurement Information System) is an NIH Roadmap network project intended to improve the reliability, validity, and precision of PROs and to provide definitive new instruments that will exceed the capabilities of classic instruments and enable improved outcome measurement for clinical research across all NIH institutes. Item response theory (IRT) measurement models now permit us to transition conventional health status assessment into an era of item banking and computerized adaptive testing (CAT). Item banking uses IRT measurement models and methods to develop item banks from large pools of items from many available questionnaires. IRT allows the reduction and improvement of items and assembles domains of items which are unidimensional and not excessively redundant. CAT provides a model-driven algorithm and software to iteratively select the most informative remaining item in a domain until a desired degree of precision is obtained. Through these approaches the number of patients required for a clinical trial may be reduced while holding statistical power constant. PROMIS tools, expected to improve precision and enable assessment at the individual patient level which should broaden the appeal of PROs, will begin to be available to the general medical community in 2008.

The Health Assessment Questionnaire (HAQ).

Patient-reported outcomes (PROs) provide intrinsic knowledge about a patient's health, functional status, symptoms, treatment preferences, satisfaction, and quality of life. They have become an established approach for assessing health outcomes. The Health Assessment Questionnaire (HAQ), introduced in 1980, is among the first PRO instruments designed to represent a model of patient-oriented outcome assessment. The HAQ is based on five patient-centered dimensions: disability, pain, medication effects, costs of care, and mortality. It has been validated by mail, in the office, by telephone, and by comparison with paraprofessional and physician judgments as a reliable instrument, and has been significantly correlated with other PRO instruments. Typically, one of two HAQ versions is used: the Full HAQ, which assesses all five dimensions, and the Short or 2-page HAQ, which contains only the HAQ disability index (HAQ-DI) and the HAQ's patient global and pain visual analog scales (VAS). The HAQ-DI and the global and pain VAS (i.e., the short HAQ) have essentially retained their original content since their inception, while the Full HAQ undergoes periodic revision to address issues of contemporary scientific interest. The HAQ-DI has been translated or culturally adapted into more than 60 different languages or dialects and has become part of the National Institutes of Health "Road-map" Project, the Patient-Reported Outcomes Measurement Information System (PROMIS).

The Arthritis, Rheumatism and Aging Medical Information System (ARAMIS): still young at 30 years.

Chronic diseases such as atherosclerosis, arthritis, diabetes, and cancer are among major public health concerns. To understand their cumulative risk factors and antecedents, a chronic disease databank consisting of time-oriented, multidisciplinary longitudinal data, prospectively collected on consecutive patients and describing their clinical courses, provides a systematic anthology of patient reported outcome (PRO) data. ARAMIS, which began in the mid-1970s, was the first large-scale chronic disease data bank system. Outcomes data are collected using the Health Assessment Questionnaire (HAQ), a well established PRO instrument that collects patient-centered data in the areas of disability, pain and other symptoms, adverse effects of treatment, economic impact, and mortality. More than 900 peer-reviewed studies have emanated from ARAMIS since its inception. In the earlier days, and even today, ARAMIS had to invent its own tools for the study of these new sciences. ARAMIS has made dominant contributions to the understanding of PROs and to helping improve treatment and health outcomes in rheumatoid arthritis (RA), osteoarthritis (OA), scleroderma, lupus, aging, and drug side effects. It continues to traverse terrain with participation in the NIH "Roadmap" project, the Patient Reported Outcome Measurement Information System (PROMIS). PROMIS is designed to provide improved assessment of health status across all chronic illnesses as part of an improved infrastructure for clinical research. As initiator of the rich history of chronic disease data banks with "rolling" consecutive open patient cohorts, ARAMIS has enabled the study of real-world PROs in rheumatology, with a wealth of resultant improved approaches to treatment, outcome, cost effectiveness, and quality of life.

Aging, cumulative disability, and the compression of morbidity.

The Compression of Morbidity paradigm emphasizes reduction in cumulative disability by postponing chronic infirmity. This article describes the model, reviews data suggesting morbidity compression over time, establishes associations between health risks and subsequent disability, and describes risk reduction interventions.

Osteoarthritis: new insights. Part 2: treatment approaches.

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors, such as genetics, diet, estrogen use, and bone density, and local biomechanical factors, such as muscle weakness, obesity, and joint laxity. These risk factors are particularly important in the weight-bearing joints, and modifying them may help prevent osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 2 of a two-part summary of a National Institutes of Health conference that brought together experts in osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 2 focuses on treatment approaches; evidence for the efficacy of commonly used oral therapies is reviewed and information on alternative therapies, including nutriceuticals and acupuncture, is presented. Biomechanical interventions, such as exercise and bracing, and behavioral interventions directed toward enhancing self-management are reviewed. Current surgical approaches are described and probable future biotechnology-oriented approaches to treatment are suggested.

Osteoarthritis: new insights. Part 1: the disease and its risk factors.

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors (such as genetics, dietary intake, estrogen use, and bone density) and of local biomechanical factors (such as muscle weakness, obesity, and joint laxity). These risk factors are particularly important in weight-bearing joints, and modifying them may present opportunities for prevention of osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 1 of a two-part summary of a National Institutes of Health conference. The conference brought together experts on osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 1 focuses on a new understanding of what osteoarthritis is and on risk factors that predispose to disease occurrence. It concludes with a discussion of the impact of osteoarthritis on disability.

Current treatment paradigms in rheumatoid arthritis.

Rheumatoid arthritis (RA) has traditionally been treated using the pyramid approach, in which non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment and disease-modifying anti-rheumatic drugs (DMARDs) are introduced relatively late in the disease. This approach is no longer valid. Previously regarded as a benign disease, RA is now recognized as causing substantial morbidity and mortality, as do the NSAIDs used in treatment. DMARDs are more effective in controlling the pain and disability of RA than NSAIDs, and are often no more toxic. The current treatment paradigm emphasizes early, consistent use of DMARDs. A 'sawtooth' strategy of DMARD use has been proposed, in which a rising but low level of disability triggers a change in therapy. Determining the most clinically useful DMARD combinations and the optimal sequence of DMARD use requires effectiveness studies, Bayesian approaches and analyses of long-term outcomes. Such approaches will allow optimization of multiple drug therapies in RA, and should substantially improve the long-term outcome for many patients.

Factors influencing length of time taking methotrexate in rheumatoid arthritis.

OBJECTIVE: Duration of therapy has been suggested to represent a measure of effectiveness. Life table analyses of therapy with methotrexate (MTX) in rheumatoid arthritis (RA) have indicated a longer duration than with other drugs. However, individual patients continue taking MTX for different periods of time. We assessed the influence of patient variables at treatment onset upon subsequent duration of MTX therapy. METHODS: Patients with RA (n = 437) from 8 North American databank centers beginning MTX therapy after January 1, 1988, were followed prospectively. Age at onset of MTX treatment, sex, years of education, age at onset of disease, years with disease, number of comorbid conditions, number of disease modifying antirheumatic drugs (DMARD) and nonsteroidal antiinflammatory drugs (NSAID) taken just prior to MTX. disability level, pain, and global assessment prior to starting MTX were used in univariate Kaplan-Meier analyses to predict number of months taking MTX alone. An index that divided the patients into risk strata for predicting duration of therapy was constructed to be clinically useful. RESULTS: The median number of months continuing MTX without addition of other DMARD was 41 months and the median for the total course taking MTX was 52 months. The retention rate was lowest for patients with the most negative initial health state. High level of initial pain, long duration of disease, and not using a DMARD just prior to MTX were associated with low retention rate and can be used to predict expected durations of MTX treatment ranging from 17 to 52 months. For practical guidance in clinical decisions an index was computed based on the predictor variables: level of initial pain, duration of disease, and number of DMARD; this index identifies subgroups with very different durations taking MTX alone. Disease duration at baseline was strongly related to time taking MTX alone and could therefore also be used as a simplified rule in clinical work. CONCLUSION: Expected duration of MTX treatment is influenced by clinical variables, and these may suggest those patients likely to have more or less satisfactory experiences with MTX. The time taking drug alone (therapeutic segment) may be a more logical and sensitive indicator of effectiveness than the total course on the medication.

Modeling therapeutic strategies in rheumatoid arthritis: use of decision analysis and Markov models.

OBJECTIVE: The management of patients with rheumatoid arthritis (RA) is controversial, with a number of different proposed treatment strategies based on different conceptions of the natural history of the disease and different interpretations of the efficacy and effectiveness of the drugs used for treatment. We attempted to develop a theoretical framework to assess the effectiveness of different treatment regimens for RA. METHODS: We used decision analysis to structure the problem of comparing sequential monotherapy to a combination strategy. Subsequently, we used 3 different estimates of drug effectiveness: one from expert rheumatologists; a metaanalysis; and a recent nationwide survey of American rheumatologists, in a Markov model. Last, we utilized published duration of therapy data to model drug treatment over time. RESULTS: Estimates of drug effectiveness differed substantially among rheumatologists, but regardless of the estimates and the treatment strategy used, the model predicted over 90% of patients improved by the 3rd drug trial. Over time, treatment patterns in our model resemble the "sawtooth" pattern previously observed. CONCLUSION: Treatment strategies in RA are difficult to model because of uncertainty in both the structure of the model and the data needed to perform the analysis. These models tend to overestimate the effectiveness of drug sequences because of nonindependence between therapies, probably due to sequence effects, a change in responsiveness over time, or resistant subgroups. Our preliminary analysis suggests that the most effective agent, possibly methotrexate, should be used first if the objective is to get as many patients into remission as quickly as possible.

Compression of morbidity in the elderly.

The Compression of morbidity paradigm envisions reduction in cumulative lifetime morbidity through primary prevention by postponing the age of onset of morbidity to a greater amount than life expectancy is increased, largely by reducing the lifestyle health risks which cause morbidity and disability. Recent data document slowly improving age-specific health status for seniors, indicate that postponement of the onset of disability by at least 10 years is feasible, and prove effectiveness of some lifestyle interventions by randomized controlled trials. Human aging is increasingly represented by frailty, with declining reserve function of many organ systems, including the immune system. Enhancement of immune function in this setting raises medical, ethical, and social issues which are sometimes in conflict.

How may quality of life for rheumatoid arthritis patients be enhanced by current and future treatments?

Health-related quality of life is best thought of simply as 'health'. Life quality in patients with rheumatoid arthritis (RA) is affected, for good or ill, by treatment effects. Health status now is readily and validly measurable, using the Health Assessment Questionnaire or other instruments. Disability and pain are reduced by disease-modifying anti-rheumatic drugs (DMARDs) much more than by non-steroidal anti-inflammatory drugs (NSAIDs). Toxicity considerations vary among individual drugs but are roughly comparable between NSAIDs and DMARDs, mandating DMARD-based treatment strategies. Future therapies must accentuate the positives (reduction in pain and disability) while reducing the negatives (unwanted effects) if the health of RA patients is to be improved.

Reducing need and demand for medical services in high-risk persons. A health education approach.

We undertook this study to identify persons with high medical use to target them for health promotion and self-management interventions specific to their problems. We compared the reductions in cost and health risk of a health education program aimed at high-risk persons with a similar program addressed to all risk levels. We compared health risk and use in 2,586 high-risk persons with those of employee (N = 50,576) and senior (N = 39,076) groups and contrasted results in specific high-risk disease or behavior categories (modules)--arthritis, back pain, high blood pressure, diabetes mellitus, heart disease, smoking, and obesity--against each other, using validated self-report measures, over a 6-month period. Interventions were a standard generic health education program and a similar program directed at high risk individuals (Healthtrac). Health risk scores improved by 11% in the overall high-risk group compared with 9% in the employee group and 6% in the senior group. Physician use decreased by 0.8 visits per 6 months in the high-risk group compared with 0.05 and 0.15 visits, respectively, per 6 months in the employee and senior groups. Hospital stays decreased by 0.2 days per 6 months in the high-risk group compared with 0.05 days in the comparison groups. The duration of illness or confinement to home decreased by 0.9 days per 6 months in the high-risk group and 0.15 and 0.25, respectively, in the employee and senior groups. Using imputed costs of $130 per physician visit, $1,000 per hospital day, and $200 per sick day, previous year costs were $1,138 in direct costs for the high-risk groups compared with $352 and $995 in the employee and senior groups, respectively. At 6 months, direct costs were reduced by $304 in the high-risk group compared with $57 and $70 in the comparison groups. Total costs were reduced $484 in the high-risk groups compared with $87 in the employee group and $120 in the senior group. The return on investment was about 6:1 in the high-risk group compared with 4:1 in the comparison groups. Effective health education programs can result in larger changes in use and costs in high-risk persons than in unscreened persons, justifying more intensive educational interventions in high-risk groups.