Rheumatoid Arthritis: Michaud K

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, Wichita, KS 67214, USA. · Arthritis Rheum. · Pubmed #17469100 links to  free full text

Abstract: OBJECTIVE: To ascertain the relationship between anti-tumor necrosis factor (anti-TNF) therapy, methotrexate (MTX), and the risk of lymphoma in patients with rheumatoid arthritis (RA). This report updates our previous report during 29,314 person-years of followup. METHODS: Participants in the National Data Bank for Rheumatic Diseases (NDB) longitudinal study of long-term outcomes of RA completed semiannual questionnaires from 1998 through 2005, during 89,710 person-years of followup. Lymphoma reports were validated by medical records. The association between lymphoma and treatment was investigated using conditional logistic regression, adjusted for severity and demographic covariates. RESULTS: Of the 19,591 participants, 55.3% received biologic agents and 68.0% received MTX while enrolled in the NDB. The lymphoma incidence rate was 105.9 (95% confidence interval [95% CI] 86.6-129.5) per 100,000 person-years of exposure. Compared with the SEER (Surveillance, Epidemiology, and End-Results) lymphoma database, the standardized incidence ratio was 1.8 (95% CI 1.5-2.2). The odds ratio (OR) for lymphoma in patients who received anti-TNF therapy compared with patients who did not receive anti-TNF therapy was 1.0 (95% CI 0.6-1.8 [P = 0.875]). The OR for lymphoma in patients who received anti-TNF plus MTX therapy compared with patients who received MTX treatment alone was 1.1 (95% CI 0.6-2.0 [P = 0.710]). Infliximab and etanercept considered individually also were not associated with a risk of lymphoma. CONCLUSION: In a study of lymphoma in 19,591 RA patients over 89,710 person-years of followup, which included exposure to anti-TNF therapy in 10,815 patients, we did not observe evidence for an increase in the incidence of lymphoma among patients who received anti-TNF therapy.

Caplan L, Wolfe F, Russell AS, Michaud K. · University of Colorado at Denver and Health Science Center, Denver, USA. · J Rheumatol. · Pubmed #17299838 No free full text.

Abstract: OBJECTIVE:To determine the rate of current and lifetime use of corticosteroids, the degree of association between corticosteroids and rheumatoid arthritis (RA) activity and outcome, corticosteroid initiation and discontinuation rates, and the predictors associated with initiation and discontinuation. METHODS: A total of 12,749 patients with RA were evaluated semiannually as to corticosteroid use, RA activity measures, RA outcomes, and predictors of initiation and discontinuation of corticosteroids. RESULTS: Current corticosteroid use was 35.5% and lifetime use was 65.5%. Rheumatologists varied substantially in their use of corticosteroids. The primary patient-derived determinant of corticosteroid initiation, current use, and discontinuation was symptom severity, although 21-25% of patients in remission or with minimal disease activity continued taking corticosteroids. Within the pool of current users, 24.3% [95% confidence interval (CI) 23.2-25.3%] discontinued corticosteroids yearly, and among patients newly starting corticosteroids this rate was 56.9% (95% CI 53.4-60.7%). Corticosteroid initiation occurred at a rate of 8.9% (95% CI 8.4-9.3%) per year. Among corticosteroid users, persistent use (> 5 years) occurs in about one-third of patients. Corticosteroid use and duration of use is associated with severe outcomes for current and past users. For current users versus non-current users, covariate adjusted outcomes were: mortality 5.7% versus 2.6%, work disability 28.4% versus 17.2%, and total joint replacement 18.5% versus 13.0%. CONCLUSION: Corticosteroid use is dynamic and is associated with RA severity. Corticosteroid use is also associated with adverse longterm outcomes, but the ability to discern causal associations is severely limited by confounding by indication. The idea of "once on corticosteroids, always on corticosteroids" is incorrect and applies to only a minority of patients.

Michaud K, Wolfe F. · National Data Bank for Rheumatic Diseases, University of Kansas School of Medicine, Wichita, Kansas 67214, USA. · J Rheumatol. · Pubmed #17143978 No free full text.

Abstract: OBJECTIVE: To determine if rates of sinus disease are increased in patients with rheumatoid arthritis (RA) and whether RA treatment alters the risk of sinus disease. METHODS: As part of a longitudinal study of rheumatic disease outcomes, 7,243 patients with RA, 1,667 with osteoarthritis (OA), and 447 with fibromyalgia (FM) were evaluated for important sinus problems in 2003. We defined an important sinus problem as one that required a physician visit. RESULTS: The lifetime prevalence of sinus disorders among all patients was 42.9%. During the previous 6 months 22.3% of patients with RA, 23.9% with OA, and 25.1% with FM visited a physician for a sinus problem and 22.4%, 23.9%, and 25.1% , respectively, received a prescription medication for a sinus problem. After adjustment for age and sex, the rate of physician visits for a sinus problem was significantly lower for patients with RA (22.1%) compared to patients with OA (24.8%). The strongest predictor of sinus problems among all patients was a history of allergy or asthma. Sinus problems were more common among users of etanercept: odds ratio (OR) 1.2; 95% confidence interval (CI): 1.0-1.4 univariably, and OR 1.2; 95% CI: 1.0-1.4 multivariably. Sulfasalazine (OR 0.7; 95% CI: 0.5-0.9) and leflunomide (OR 0.8; 95% CI: 0.7-1.0) had a protective effect on sinus problems. CONCLUSIONS: Sinus problems are decreased in patients with RA compared to OA and FM. Slight protective effects on sinus problems are noted with sulfasalazine and leflunomide, and a slight increase in risk of sinus problems is noted with etanercept.

Wolfe F, Michaud K, Chakravarty EF. · National Data Bank for Rheumatic Diseases, Arthritis Research Center Foundation, 1035 N. Emporia, Suite 230 Wichita, KS 67214, USA. · Rheumatology (Oxford). · Pubmed #17003175 links to  free full text

Abstract: OBJECTIVES: Herpes zoster (HZ) is a common disorder that causes substantial pain and morbidity. We examined its rate and predictors in rheumatoid arthritis (RA) and non-inflammatory musculoskeletal (MSK) disorders to determine if HZ was increased in RA and whether treatment contributed to the risk of HZ. METHODS: After excluding patients witzh prior HZ, we assessed 10 614 RA and 1721 MSK patients by semi-annual questionnaires during 33 825 patient-years of follow-up. Predictors of HZ were determined by Cox regression and expressed as hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: The annualized incidence rate per 1000 patient-years was 13.2 (95% CI 11.9-14.5) in RA and 14.6 (95% CI 11.2-18.1) in MSK, and did not differ significantly after adjustment for age and sex. HZ was predicted by impaired functional status, as measured by the Health Assessment Questionnaire (HAQ), [HR 1.3 (95% CI 1.1-1.5)] and by the use of COX-2-specific non-steroidal anti-inflammatory drugs (NSAIDs) [HR 1.3 (95% CI 1.1-1.6)] in RA and MSK. In multivariable analyses in patients with RA, cyclophosphamide HR 4.2 (95% CI 1.6-11.5), azathioprine HR 2.0 (1.2-3.3), prednisone HR 1.5 (1.2-1.8), leflunomide HR 1.4 (1.1-1.8) and COX-2 NSAIDs HR 1.3 (95% CI 1.1-1.6) were significant predictors of HZ. CONCLUSION: The incidence of HZ is increased in RA and MSK compared with population-based rates. However, the rate of HZ in RA is not increased compared with MSK. After adjustment for severity, various treatments, but not methotrexate or biologics, were risk factors for HZ.

Wolfe F, Michaud K, Li T. · National Data Bank for Rheumatic Diseases, University of Kansas School of Medicine, Wichita, Kansas 67214, USA. · J Rheumatol. · Pubmed #16960928 No free full text.

Abstract: OBJECTIVE: Except for some polysomnography studies, there have been no large quantitative studies of sleep disturbance (SD) in rheumatoid arthritis (RA). SD has taken on new importance with the observation that etanercept and infliximab reduce daytime sleepiness, and patient groups indicate that sleep is an important issue. METHODS: We evaluated 8676 patients with RA and a comparison group of 1364 subjects with non-fibromyalgia, noninflammatory disorders (NID) using the Medical Outcome Study (MOS) sleep questionnaire, including 2 MOS sleep problem indexes (SPI-I, SPI-II) and the MOS SD scale. In addition, patients completed a visual analog scale (VAS) sleep disturbance scale (SDS). RESULTS: The scales had similar mean values: SPI-I 35.4 (19.4), SPI-II 36.0 (19.1), SDS 35.0 (24.7), and VAS sleep 36.1 (29.7), and the values for the MOS scales exceeded population norms by 25% (VAS by 42%). In multivariable analyses SD was primarily determined by pain and mood. Patients receiving anti-tumor necrosis factor (TNF) did not have less abnormal sleep scores. SD was comparable in RA and NID. The VAS scale was more strongly associated with RA clinical variables than the MOS scales; however, the distributional characteristics of the scales differed, with the VAS scales capturing more extreme values. The standard error of the measurement (SEM), which is related to minimal (important) change, was SPI-I 9.0, SPI-II 7.3, SDS 9.6, and VAS sleep 10.4. CONCLUSION: SD is increased in RA, and 25% to 42% of SD can be attributed to RA. SD is linked to pain, mood, and disease activity. SD is slightly greater in women and is less with increasing age. All scales appear to be valid in RA, with minimal differences in SEM.

Wolfe F, Michaud K, Simon T. · National Data Bank for Rheumatic Diseases, and University of Kansas School of Medicine, Wichita, Kansas 67214, USA. · J Rheumatol. · Pubmed #16960927 No free full text.

Abstract: OBJECTIVE: Administrative data bases provide rapid access to data regarding treatment and morbidity of rheumatoid arthritis (RA). A serious limitation of administrative data bases is the lack of information regarding RA severity, as in the case of lymphoma, where RA severity may contribute to the cause of the adverse outcome. We examined whether treatment variables could predict RA severity. METHODS: We studied 7541 patients with RA who were participating in a longitudinal study of RA outcomes. Disease severity was determined by the Patient Activity Scale (PAS), which represents on a 0 to 10 scale the mean of 0-10 standardized values of pain (by visual analog scale), patient global severity, and the Health Assessment Questionnaire. We tested the ability of disease modifying antirheumatic drugs (DMARD) and biologic treatment variables and the lifetime number of these treatments to predict severity status. The receiver-operating characteristic (ROC) area under the curve (AUC) was used to describe the association between severity and treatment variables. RESULTS: There was little difference in PAS scores between various treatments and treatment groups, including scores of the 18.3% of patients receiving no DMARD or biologic therapy. The ROC AUC to distinguish PAS scores above and below the median was 0.64 (60.5% correctly classified) and was 0.70 (67.2% correctly classified) in distinguishing first compared to fourth quartiles PAS scores. CONCLUSION: Treatment variables do not accurately or usefully identify severity status. As a corollary, there is little difference in severity between patients receiving different treatment regimens, and actual measures of severity rather than treatment surrogates are required to assess RA severity.

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, University of Kansas School of Medicine, Wichita, 67214, USA. · J Rheumatol. · Pubmed #16881108 No free full text.

Abstract: OBJECTIVE: Treatments are now available that can improve the anemia of chronic illnesses such as rheumatoid arthritis (RA). Despite recognition that anemia is common in RA and that renal function may be impaired and affect hemoglobin levels, there are almost no quantitative comparative data regarding the prevalence of anemia or decreased renal function in RA. METHODS: We studied a prospectively acquired clinical database of 2,120 patients with RA who had 26,221 hemoglobin determinations, and a control population of 7,124 patients with noninflammatory rheumatic disorders (NIRD) who had 12,086 determinations. RESULTS: Using the World Health Organization definition, anemia occurred in 31.5% of patients with RA, and followed a U-shaped distribution that had minimal prevalence around 60 years of age. Anemia prevalence in men was 30.4% and in women 32.0%. Anemia occurred in 11.1% at hemoglobin < 11 g/dl and 3.4% at hemoglobin < 10 g/dl. After erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) was the strongest predictor of anemia, followed by estimated creatinine clearance. Adjusted for age and sex, estimated creatinine clearance was 9.8 (95% CI 7.5 to 12.1) ml/min lower in patients with RA than in those with NIRD. CONCLUSION: Anemia occurs in 31.5% of RA patients, 3 times the rate in the general population. However, severe chronic anemia (hemoglobin < 10 g/dl) is rare (3.4%). In addition, renal function is impaired in patients with RA compared with NIRD. Renal function has a small effect on the anemia of RA, and ESR and CRP have slightly greater effects.

Allaire S, Wolfe F, Niu J, Baker N, Michaud K, LaValley M. · Clinical epidemiology Research and Training Unit A203, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA. · Arthritis Rheum. · Pubmed #16583427 links to  free full text

Abstract: OBJECTIVE: Occupational hand use is increasing due to increased computer use and could place persons with rheumatoid arthritis (RA) at risk for work disability. Although hand involvement in RA is typical, there is little information about occupational hand use in relation to RA. Study objectives were to describe the extent of occupational hand use by persons with RA; the types of jobs that require extensive hand use; the relationship between occupational hand use and joint pain; and the extent of occupational hand use among persons with shorter versus longer disease duration. METHODS: Cross-sectional survey data from 2,761 employed participants with RA from a US national cohort were used. Extent of occupational hand use was measured by the hand-use item from a job physical demand scale used in prior RA studies. Analyses included descriptive statistics and chi-square tests. RESULTS: The mean age was 50.6 years, 78.5% were women, 91.8% were white, and 68.8% had more than a high school education. Eighty-three percent of participants reported extensive occupational hand use. Large portions of participants in all types of jobs reported extensive hand use, 92% with administrative support jobs and 69% with operator/laborer jobs. Participants with extensive occupational hand use were more likely to have hand joint pain than those with moderate hand use (66% versus 58%; P = 0.004). Extensive hand use did not vary by disease duration (83% and 84% in participants with < or =15 and >15 years' duration, respectively). CONCLUSION: Extensive occupational hand use was ubiquitous among employed persons with RA and was associated with greater hand pain.

Garcia EB, Michaud K, Wolfe F. · Brigham and Women's Hospital, Boston, Massachusetts, USA. · J Rheumatol. · Pubmed #16511939 No free full text.

Abstract: OBJECTIVE: To determine rates of gastroprotective agent (GPA) use among patients with arthritis treated by rheumatologists, and to determine factors associated with GPA prescription. METHODS: In a longitudinal outcome study, 11,451 patients with rheumatoid arthritis (RA) and osteoarthritis (OA) reported all medication use, ulcer history, functional status, and sociodemographic characteristics. RESULTS: GPA were used in 21-24% of all patients with RA and OA and in about 35-40% of all high risk patients. In unadjusted analyses, GPA use was similar among NSAID users and non-users. In multivariable logistic regression analyses GPA use was associated with non-specific (NS) NSAID and COX-2 NSAID, prednisone, low dose aspirin, comorbidity, Health Assessment Questionnaire functional score, age < 65 years, increased income, not smoking, and being male. Despite numerous associations, the explanatory power for GPA use was poor (area under ROC curve = 0.680). CONCLUSION: GPA are used in 35% to 40% of patients with 4 risk factors for gastrointestinal ulceration. GPA use is not increased in NS NSAID users compared to COX-2 NSAID users, and was inversely associated with socioeconomic status. GPA use does not follow the model predicted by clinical trial results with respect to NS NSAID and age, reflecting a change in the pattern of NSAID use in patients with rheumatic disease. The major determinant of GPA use appears to be physician prescribing behavior.

Wolfe F, Caplan L, Michaud K. · National Data Bank for Rheumatic Diseases and University of Kansas School of Medicine, Wichita, Kansas 67214, USA. · Arthritis Rheum. · Pubmed #16447241 links to  free full text

Abstract: OBJECTIVE: Pneumonia is a major cause of mortality and morbidity in rheumatoid arthritis (RA). This study was undertaken to determine the rate and predictors of hospitalization for pneumonia and the extent to which specific RA treatments increase pneumonia risk. METHODS: RA patients (n = 16,788) were assessed semiannually for 3.5 years. Pneumonia was confirmed by medical records or detailed patient interview. Covariates included RA severity measures, diabetes, pulmonary disease, and myocardial infarction. Cox proportional hazards regression was used to determine the multivariable risk associated with RA treatments. RESULTS: After adjustment for covariates, prednisone use increased the risk of pneumonia hospitalization (hazard ratio [HR] 1.7 [95% confidence interval 1.5-2.0]), including a dose-related increase in risk (< or = 5 mg/day HR 1.4 [95% confidence interval 1.1-1.6], > 5-10 mg/day HR 2.1 [95% confidence interval 1.7-2.7], > 10 mg/day HR 2.3 [95% confidence interval 1.6-3.2]). Leflunomide also increased the risk (HR 1.2 [95% confidence interval 1.0-1.5]). HRs for etanercept (0.8 [95% confidence interval 0.6-110]) and sulfasalazine (0.7 [95% confidence interval 0.5-1.0]) did not reflect an increased risk of pneumonia. HRs for infliximab, adalimumab, and methotrexate were not significantly different from zero. CONCLUSION: There is a dose-related relationship between prednisone use and pneumonia risk in RA. No increase in risk was found for anti-tumor necrosis factor therapy or methotrexate. These data call into question the belief that low-dose prednisone is safe. Because corticosteroid use is common in RA, the results of this study suggest that prednisone exposure may have important public health consequences.

Wolfe F, Katz RS, Michaud K. · National Data Bank for Rheumatic Diseases, University of Kansas School of Medicine, Wichita, Kansas 67214, USA. · J Rheumatol. · Pubmed #16331775 No free full text.

Abstract: OBJECTIVE. Jaw pain may occur in rheumatoid arthritis (RA), osteoarthritis (OA), and fibromyalgia (FM). We investigated the prevalence and correlates of jaw pain, and whether jaw pain is increased in RA, where intrinsic articular disease can be noted radiographically, or is a manifestation of a generalized pain problem. METHODS: We analyzed data from 22,720 patients participating in a longitudinal outcome study of rheumatic diseases, including 17,683 with RA, 4,011 with OA, and 1,026 with FM. Jaw pain was considered to be present if a patient indicated it in either the left or right jaw. In addition to standard rheumatic disease measures, we also obtained self-report assessments that included a count of painful nonarticular regions (the regional pain score, RPS), a joint count, and a count of symptoms. RESULTS: The age and sex adjusted rate of jaw pain was 18.7% in RA, 18.6% in OA, and 35.4% in FM. Jaw pain was best predicted by joint count, RPS, and a count of somatic symptoms in univariate analyses. In multivariate analyses jaw pain was predicted by joint count, RPS, symptom count, and fatigue. The ROC area under the curve for this model was 0.79, and 82.8% of patients were correctly classified. There was little difference in predictor variables for RA and OA patients. Covariate adjusted analyses controlling for age, sex, symptom count, fatigue, RPS, and joint count predicted jaw pain in 14.7% (95% CI 14.1 to 15.3) of RA and 11.6% (95% CI 10.6 to 12.7) of OA patients. This difference, 3.1%, may represent the increment in jaw pain attributable to RA. CONCLUSION: Jaw pain is present in about 19% of patients with RA and OA, and is primarily a marker for a general pain increase and symptom sensitivity problem. Patients who have jaw pain have worse outcomes manifested by decreased functional ability, lower household income, and decreased quality of life. Variables not usually formally measured in clinical practice best identify this problem: self-reported joint count, symptom count, count of painful regions (RPS), and a visual analog scale for fatigue.

Wolfe F, Michaud K, Pincus T. · National Data Bank for Rheumatic Diseases, University of Kansas School of Medicine, Wichita, Kansas 67214, USA. · J Rheumatol. · Pubmed #16331773 No free full text.

Abstract: OBJECTIVE: To develop and validate a composite patient self-report disease activity scale for use in clinical practice and in observational studies and clinical trials. METHODS: A total of 9078 patients with rheumatoid arthritis completed detailed questionnaires that included measure of quality of life in the form of utilities. We evaluated several disease activity scales by measuring their agreement with the utility scales, and also their assessed ability to predict mortality and prescription for anti-tumor necrosis factor therapy. RESULTS: A composite index composed of a visual analog scale (VAS) for pain, a patient global VAS, and the Health Assessment Questionnaire (HAQ) or the HAQ II formed the Patient Activity Scale (PAS) and PAS-II. These scales performed as well as or better than longer, more complex scales. CONCLUSION: A simple, useful clinical scale, the PAS or PAS-II, can be formed by the use of common clinical variables. It is well correlated with and relevant to a wide range of clinical variables. This scale should be useful for comparative studies, clinical care, and regulatory documentation.

Wolfe F, Michaud K, Pincus T, Furst D, Keystone E. · National Data Bank for Rheumatic Diseases, Wichita, Kansas 67214, USA. · Arthritis Rheum. · Pubmed #16320335 links to  free full text

Abstract: OBJECTIVE: The Disease Activity Score (DAS) is widely used in clinical trials. A DAS of 5.1 defines the level of severe rheumatoid arthritis (RA) and is the criterion for the initiation of anti-tumor necrosis factor therapy in the UK and The Netherlands. In North America, similar rules are sometimes imposed. However, it is not known how accurately the DAS characterizes RA activity. The present study was undertaken to determine the concordance between DAS scores and physicians' assessments of RA activity, to investigate factors relating to discrepancies, and to assess the suitability of using the DAS in individual patients. METHODS: Six hundred sixty-nine RA patients were assessed using the DAS and other clinical measures. A physician's global estimate of RA activity was performed using an 11-point predefined scale and a standard definition of disease activity. RESULTS: The DAS and physician global assessment had substantially different distributions of values. The level of agreement (Kendall's tau-a) between DAS scores and physician global assessments was 49% (95% confidence interval 45-53%), Lin's coefficient of concordance was 0.62, and the Bland-Altman 95% limits of agreement were -3.17 and 3.99. These results suggest poor-to-moderate concordance between the 2 measures of disease activity. CONCLUSION: The DAS and the physician's assessment of RA activity do not approach, value, and weight RA variables to the same extent, suggesting that RA activity is not evaluated similarly by North American physicians and with the DAS. The scales do not have acceptable levels of concordance. There is too much inherent variability in the DAS and other RA scales (e.g., the Health Assessment Questionnaire) to recommend them as sole determinants of RA activity for clinical or regulatory purposes.

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, Arthritis Research Center Foundation, Wichita, KS 67214, USA. · Rheumatology (Oxford). · Pubmed #16306476 links to  free full text

Abstract: The results and outcomes of randomized clinical trials of leflunomide and anti-TNF therapy are much better than are seen in rheumatoid arthritis patients in the community. This appears to be an effect of the clinical trial system. The consequence of deriving effectiveness estimates from clinical trials is to overestimate the effectiveness and thereby the cost-effectiveness of rheumatoid arthritis treatments.

Chakravarty EF, Michaud K, Wolfe F. · Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, California, USA. · J Rheumatol. · Pubmed #16265690 No free full text.

Abstract: OBJECTIVE: To determine the rates of reported non-melanoma skin cancer (NMSC) in a large cohort of patients with rheumatoid arthritis (RA) in comparison to patients with osteoarthritis (OA) and to determine risk factors for the development of NMSC in patients with RA. METHODS: Self-reported information from 15,789 patients with RA and 3,639 patients with OA were collected through semi-annual questionnaires since 1999. Survival analyses were used to determine incidence rates for NMSC among patients with RA and OA. Multivariate Cox proportional hazard models were used to estimate hazard ratios (HR) for the development of NMSC. Separate analyses were performed for patients with RA to explore associations between use of immunosuppressive medication and development of NMSC. RESULTS: The crude (unadjusted) incidence rate for reported NMSC among patients with RA and OA were 18.1 and 20.4 per 1000 patient years, respectively. OA patients were older, more likely to be Caucasian, and had higher past incidence of NMSC. Age, male sex, Caucasian race, and history of NMSC prior to entry into the database were associated with an increased risk of NMSC in multivariate Cox proportional hazard models. After adjustment for covariates, RA was associated with an increased risk of NMSC (HR 1.19, p = 0.042). Among RA patients, the development of NMSC was associated with use of prednisone (HR 1.28, p = 0.014) and tumor necrosis factor (TNF) inhibitors alone or with concomitant methotrexate (HR 1.24, p = 0.89 and HR 1.97, p = 0.001, respectively) in addition to established risk factors including fair skin, age, male sex, and previous history of NMSC. No association was found between use of methotrexate or leflunomide and development of NMSC (HR 1.12, p = 0.471, HR 0.83, p = 0.173, respectively). CONCLUSION: In this large, national cohort, RA was associated with an increased risk for development of NMSC. Among patients with RA, use of TNF inhibitors and prednisone were associated with an increased risk of NMSC.

Wells GA, Boers M, Shea B, Brooks PM, Simon LS, Strand CV, Aletaha D, Anderson JJ, Bombardier C, Dougados M, Emery P, Felson DT, Fransen J, Furst DE, Hazes JM, Johnson KR, Kirwan JR, Landewé RB, Lassere MN, Michaud K, Suarez-Almazor M, Silman AJ, Smolen JS, Van der Heijde DM, van Riel PL, Wolfe F, Tugwell PS. · Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada. · J Rheumatol. · Pubmed #16206362 No free full text.

Abstract: Agreement on response criteria in rheumatoid arthritis (RA) has allowed better standardization and interpretation of clinical trial reports. With recent advances in therapy, the proportion of patients achieving a satisfactory state of minimal disease activity (MDA) is becoming a more important measure with which to compare different treatment strategies. The threshold for MDA is between high disease activity and remission and, by definition, anyone in remission will also be in MDA. True remission is still rare in RA; in addition, the American College of Rheumatology definition is difficult to apply in the context of trials. Participants at OMERACT 6 in 2002 agreed on a conceptual definition of minimal disease activity (MDA): "that state of disease activity deemed a useful target of treatment by both the patient and the physician, given current treatment possibilities and limitations." To prepare for a preliminary operational definition of MDA for use in clinical trials, we asked rheumatologists to assess 60 patient profiles describing real RA patients seen in routine clinical practice. Based on their responses, several candidate definitions for MDA were designed and discussed at the OMERACT 7 in 2004. Feedback from participants and additional on-site analyses in a cross-sectional database allowed the formulation of 2 preliminary, equivalent definitions of MDA: one based on the Disease Activity Score 28 (DAS28) index, and one based on meeting cutpoints in 5 out the 7 WHO/ILAR core set measures. Researchers applying these definitions first need to choose whether to use the DAS28 or the core set definition, because although each selects a similar proportion in a population, these are not always the same patients. In both MDA definitions, an initial decision node places all patients in MDA who have a tender joint count of 0 and a swollen joint count of 0, and an erythrocyte sedimentation rate (ESR) no greater than 10 mm. If this condition is not met: * The DAS28 definition places patients in MDA when DAS28 < or = 2.85; * The core set definition places patients in MDA when they meet 5 of 7 criteria: (1) Pain (0-10) < or = 2; (2) Swollen joint count (0-28) < or = 1; (3) Tender joint count (0-28) < or = 1; (4) Health Assessment Questionnaire (HAQ, 0-3) < or = 0.5; (5) Physician global assessment of disease activity (0-10) < or = 1.5; (6) Patient global assessment of disease activity (0-10) < or = 2; (7) ESR < or = 20. This set of 2 definitions gained approval of 73% of the attendees. These (and other) definitions will now be subject to further validation in other databases.

Wolfe F, Michaud K, Choi HK, Williams R. · Arthritis Research Center Foundation, University of Kansas School of Medicine, Wichita, KS 67214, USA. · J Rheumatol. · Pubmed #16206340 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) causes disability and reduced productivity. There are no large quantitative studies of earnings and productivity losses in patients with clinical RA, and no studies of household income losses. We describe methods for obtaining earnings and household income losses that are applicable to working as well as nonworking RA patients, and we perform such studies using these methods. METHODS: We estimated cross-sectional expected annual earnings and household income losses in 6,649 persons with RA from Current Populations Survey (CPS) and O*NET (Occupational Information Network) data, and we estimated expected household income and earnings losses based on demographic characteristics after adjustment to Medical Outcomes Study Short-Form 36 (SF-36) population norms (internal method). Workplace productivity was measured by the Work Limitations Questionnaire (WLQ). RESULTS: 27.9% of patients aged < or = 65 years considered themselves disabled after 14.6 years of RA, and 8.8% received disability benefits. Annual earnings losses ranged between USD 2,319 and USD 3,407 by the CPS and internal method (preferred), with losses of 9.3% and 10.9%. A 0.25 difference in Health Assessment Questionnaire (HAQ) score was associated with a $1,095 difference in annual earnings. Productivity losses were 6% based on work limitations identified by the WLQ. Household income loss (percentage loss) including transfer payments was USD 6,287 (11.8%) for all patients, USD 4,247 (6.9%) for employed patients, and USD 7,374 (14.8%) for nonworking patients. Among nonworking nondisabled patients aged < or = 65 years, income loss was 14.1%. CONCLUSION: As measured by annual household income loss, the overall impact of RA is USD 6,287 (11.8%). Earnings and household income are dependent on functional status, education, age, ethnicity, and marital status. Income loss is predicted by the HAQ, HAQ-II, Modified HAQ, and SF-36.

Allaire S, Wolfe F, Niu J, Lavalley M, Michaud K. · Boston University, Boston, Massachusetts, USA. · Arthritis Rheum. · Pubmed #16082625 links to  free full text

Abstract: OBJECTIVE: To examine the extent and financial impact of work disability among older workers with rheumatoid arthritis (RA). METHODS: Year 2002 data from 5,419 subjects with RA < 65 years of age in the National Data Bank for Rheumatic Diseases were used, along with US population data. Measures of work disability were employment status, part-time work, sick day use, and limitation in work demands; the latter was assessed by the Work Limitations Questionnaire (WLQ). Measures of financial status were median household income and poverty level income. Statistical procedures included logistic and linear regression, Wilcoxon's rank sum test, and chi-square test. RESULTS: Despite being better educated, subjects with RA ages 55-64 years had lower employment rates than individuals of the same age in the US (women 40% versus 53% and men 54% versus 66%). These older subjects with RA had stopped working more often than younger subjects with RA, and more worked part time (40% versus 34%; P < 0.01). However, the older subjects used sick time less often than younger subjects (35% versus 41%; P < 0.01) and were similarly limited in job demands, e.g., physical demands (mean WLQ subscale score 27.0 versus 26.6; P = 0.65). Median household income of older employed subjects was 20,000 dollars greater than that of retired subjects; 56% of retired subjects had incomes lower than US median income versus 32% of employed subjects, and 11% had income below the poverty level. CONCLUSION: Premature work cessation in persons with RA ages 55-64 years is a serious problem that needs to be addressed.

Walker N, Michaud K, Wolfe F. · Rheumatology Division, Department of Medicine, University of Massachusetts, Worcester, Massachusett, USA. · J Rheumatol. · Pubmed #15940759 No free full text.

Abstract: OBJECTIVE: To describe workplace limitations and the validity and reliability of the Work Limitations Questionnaire (WLQ) in persons with rheumatoid arthritis (RA). METHODS: A total of 836 employed persons with RA reported clinical and work related measures and completed the WLQ, a 25 item questionnaire that assesses the impact of chronic health conditions on job performance and productivity. Limitations are categorized into 4 domains: physical demands (PDS), mental demands (MDS), time management demands (TMS), and output demands (ODS), which are then used to calculate the WLQ index. RESULTS: Of the 836 completed WLQ, about 10% (85) could not be scored, as more than half the items in each domain were not applicable to the patient's job. Demographic and clinical variables were associated with missing WLQ scores including older age (OR 1.7, 95% CI 1.3-2.1), male sex (OR 1.9, 95% CI 1.2-3.0), and Health Assessment Questionnaire (HAQ) scores (OR 1.4, 95% CI 1.0-2.0). Work limitations were present in all work domains: PDS (27.5%), MDS (15.7%), ODS (19.4%), and TMS (28.6%), resulting in a mean WLQ index of 5.9 (SD 5.6), which corresponds to a 4.9% decrease in productivity and a 5.1% increase in work hours to compensate for productivity loss. The WLQ index was inversely associated with Medical Outcomes Study Short Form 36 (SF-36) Mental Component Score (MCS; r = -0.60) and Physical Component Score (PCS; r = -0.49). Fatigue (0.5), pain (0.46), and HAQ (0.56) were also significantly associated with the WLQ index. Weaker associations were seen with days unable to perform (0.29), days activities cut down (0.38), and annual income (-0.10). CONCLUSION: The WLQ is a reliable tool for assessing work productivity. However, persons with RA tend to select jobs that they can do with their RA limitations, with the result that the WLQ does not detect functional limitations as well as the HAQ and SF-36. The WLQ provides special information that is not available using conventional measures of assessment, and can provide helpful knowledge about individual patient problems in the workplace. Whether this information will have greater predictive ability and clinical relevance compared with surrogate measures such as the HAQ and SF-36 has not been determined, but should be the subject of future studies.

Wolfe F, Michaud K, Strand V. · Arthritis Research Center Foundation and the University of Kansas School of Medicine, Wichita, Kansas 67214, USA. · J Rheumatol. · Pubmed #15801011 No free full text.

Abstract: 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.

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, Arthritis Research Foundation, Wichita, KS 67214, USA. · Arthritis Rheum. · Pubmed #15188349 links to  free full text

Abstract: OBJECTIVE: The risk of lymphoma is increased in patients with rheumatoid arthritis (RA), and spontaneous reporting suggests that methotrexate (MTX) and anti-tumor necrosis factor (anti-TNF) therapy might be associated independently with an increased risk of lymphoma. However, data from clinical trials and clinical practice do not provide sufficient evidence concerning these issues because of small sample sizes and selected study populations. The objective of this study was to determine the rate of and standardized incidence ratio (SIR) for lymphoma in patients with RA and in RA patient subsets by treatment group. Additionally, we sought to determine predictors of lymphoma in RA. METHODS: We prospectively studied 18,572 patients with RA who were enrolled in the National Data Bank for Rheumatic Diseases (NDB). Patients were surveyed biannually, and potential lymphoma cases received detailed followup. The SEER (Survey, Epidemiology, and End Results) cancer data resource was used to derive the expected number of cases of lymphoma in a cohort that was comparable in age and sex with the RA cohort. RESULTS: The overall SIR for lymphoma was 1.9 (95% confidence interval [95% CI] 1.3-2.7). The SIR for biologic use was 2.9 (95% CI 1.7-4.9) and for the use of infliximab (with or without etanercept) was 2.6 (95% CI 1.4-4.5). For etanercept, with or without infliximab, the SIR was 3.8 (95% CI 1.9-7.5). The SIR for MTX was 1.7 (95% CI 0.9-3.2), and was 1.0 (95% CI 0.4-2.5) for those not receiving MTX or biologics. Lymphoma was associated with increasing age, male sex, and education. CONCLUSION: Lymphomas are increased in RA. Although the SIR is greatest for anti-TNF therapies, differences between therapies are slight, and confidence intervals for treatment groups overlap. The increased lymphoma rates observed with anti-TNF therapy may reflect channeling bias, whereby patients with the highest risk of lymphoma preferentially receive anti-TNF therapy. Current data are insufficient to establish a causal relationship between RA treatments and the development of lymphoma.

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, Arthritis Research Center Foundation, University of Kansas School of Medicine, Wichita, Kansas 67214, USA. · J Rheumatol. · Pubmed #15088293 No free full text.

Abstract: OBJECTIVE: Fibromyalgia (FM) is a controversial construct. Recently suggested survey criteria identify persons with FM characteristics without physical examination or clinical diagnosis, thereby obviating many of the objections to FM. Little is known about FM among patients with rheumatoid arthritis (RAF). We used the survey definition to characterize persons with RAF and to obtain insight into possible pathogenic mechanisms. METHODS: A total of 11,866 patients with RA completed the Regional Pain Scale (RPS) and a 0-10 visual analog scale (VAS) for fatigue. FM was diagnosed in patients with an RPS score > or = 8 and a VAS fatigue score > or = 6. RESULTS: Altogether 1731 (17.1%) patients with RA fulfilled the criteria. Fewer RAF patients were married (64.9% vs 69.8%) and more were divorced (14.8% vs 10.4%); fewer were college graduates (19.7% vs 28.1%) and more did not finish high school (15.0% vs 8.9%). We found 35.8% of patients with FM but only 21.5% of those without FM had incomes less than 185% of the US poverty guidelines. Patients with RAF had higher validated hospitalization rates for major comorbid conditions and received treatment for comorbid conditions more often (expressed as odds ratios and 95% confidence interval): hypertension (1.5, 1.4-1.7), cardiovascular (1.8, 1.6-2.0), diabetes (1.9, 1.6-2.3), and depression (2.7, 1.8-4.2). RAF were 3.3 (3.0-3.7) times more likely to have been work-disabled (54.5% vs 26.4%) or to have total joint replacement (14.0% vs 11.2%; OR 1.3, 1.1-1.5), and incurred greater direct 6-month medical costs (6477 vs 4687 US dollars). RAF patients had more severe symptoms across all scales, including the Health Assessment Questionnaire (1.8 vs 1.0), pain (6.7 vs 3.4), Medical Outcomes Study Short Form-36 (SF-36) physical component score (23.5 vs 33.5), SF-36 mental component score (29.5 vs 46.1), and quality of life assessed by EuroQol mapped utilities (0.33 vs 0.65). CONCLUSION: FM exists in a substantial number of patients with RA (17.1%), who have more severe RA by subjective and objective measures, greater medical costs, worse outcomes, more comorbidities, sociodemographic disadvantage, and substantially worse quality of life. We hypothesize that illness severity and sociodemographic disadvantage both play a role in producing the clinical picture of FM.

Wolfe F, Michaud K. · Arthritis Research Center Foundation, University of Kansas School of Medicine, Wichita 67214, USA. · Am J Med. · Pubmed #14984815 No free full text.

Abstract: PURPOSE: We sought to determine the frequency of heart failure in patients with rheumatoid arthritis, and to determine its predictors, particularly the use of anti-tumor necrosis factor (TNF) therapy. METHODS: Rheumatoid arthritis (n = 13,171) and osteoarthritis (n = 2568) patients were studied during a 2-year period ending in June 2002. The diagnosis of heart failure was based on self-report or review of medical records. Propensity scores were used to adjust for the risk of anti-TNF (infliximab and etanercept) prescription. RESULTS: Heart failure was more common among patients with rheumatoid arthritis (3.9% [n = 461]) than in those with osteoarthritis (2.3% [n = 87]), after adjusting for differences in demographic characteristics. Patients with rheumatoid arthritis had similar risk factors for heart failure (e.g., hypertension, prior myocardial infarction, diabetes, advanced age) as persons in population-based studies. Heart failure was significantly (P <0.05) less common in anti-TNF-treated patients (3.1% [180/5832]) than in the remaining patients (3.8% [281/7339]), even after adjusting for baseline differences. In the absence of pre-existing cardiovascular disease, the risk of heart failure was low (0.4% [24/6251]) and was not related to anti-TNF therapy. CONCLUSION: Our results suggest that rheumatoid arthritis increases the risk of heart failure, which may be ameliorated by anti-TNF therapies.

Wolfe F, Michaud K, Anderson J, Urbansky K. · National Data Bank for Rheumatic Diseases, Wichita, Kansas, and University of Kansas School of Medicine, Wichita, Kansas 67214, USA. · Arthritis Rheum. · Pubmed #14872478 links to  free full text

Abstract: OBJECTIVE: According to the Centers for Disease Control and Prevention, the 1999 and 2000 incidence rates for tuberculosis (TB) in the US population were 6.4 and 5.8, respectively, per 100,000 persons. Recently, reports of TB following infliximab administration have raised questions regarding the rate of TB in patients with rheumatoid arthritis (RA) generally and in those treated with infliximab in clinical practice. We undertook this study to determine the baseline rate of TB in RA prior to the introduction of infliximab and to determine the rate of TB among those currently receiving infliximab. METHODS: We surveyed patients with questionnaires, followed by detailed validation from medical records and physician reports. In study 1, we evaluated 10,782 RA patients in 1998-1999 prior to the widespread use of infliximab. In study 2, we evaluated 6,460 infliximab-treated patients in 2000-2002. RESULTS: In study 1, the lifetime rate of TB was 696 per 100,000 patients (95% confidence interval [95% CI] 547-872). Of these cases, 76.8% occurred prior to the onset of RA. During the period of prospective followup, 1 case of TB developed during 16,173 patient-years of followup, yielding a rate of 6.2 cases (95% CI 1.6-34.4) per 100,000 patients. In study 2, the TB incidence rate among infliximab-treated patients was 52.5 cases (95% CI 14.3-134.4) per 100,000 patient-years of exposure. Three of the 4 cases occurred in patients with a history of TB exposure, and no cases occurred in persons with recent TB skin tests or prophylaxis. CONCLUSION: The rate of TB is not increased in RA patients generally. Among infliximab-treated patients, the rate is 52.5 cases (95% CI 14.3-134.4) per 100,000 patient-years of exposure. A thorough medical history regarding TB, as well as tuberculin testing and radiographic examination (if indicated), should be an essential component of anti-tumor necrosis factor therapy.

Wolfe F, Michaud K, Burke TA, Zhao SZ. · National Data Bank for Rheumatic Diseases-Arthritis Research Center Foundation, Wichita, Kansas 67214, USA. · J Rheumatol. · Pubmed #14760808 No free full text.

Abstract: OBJECTIVE: To compare COX-2-specific inhibitor therapy with conventional nonspecific nonsteroidal antiinflammatory drugs (NS NSAID), and investigate the effect of demographic and disease factors on NSAID duration of use. METHODS: A total of 3639 patients with rheumatoid arthritis (RA), osteoarthritis, and fibromyalgia starting therapy of celecoxib, rofecoxib, naproxen, or ibuprofen were surveyed at 6-month intervals for up to 2.5 years. Detailed demographic and disease severity variables were also measured. Time to discontinuation, discontinuation rates, and effect of covariates were determined by Weibull parametric survival analyses, controlling for a wide variety of demographic and disease severity factors. RESULTS: The median duration of use for celecoxib, rofecoxib, naproxen, and ibuprofen was 15, 13, 10, and 10 months, respectively. Duration of use of celecoxib and rofecoxib, as measured by survival times, was significantly longer than those of naproxen and ibuprofen. The celecoxib survival time was significantly longer than the rofecoxib survival time (p = 0.005). Disease severity was not associated with survival times, but survival was related to younger age and male sex. In addition, ulcer diagnosis was a strong predictor of early termination. After adjustment for severity, survival times for RA and non-RA patients were the same. CONCLUSION: COX-2-specific inhibitors have a longer duration of use than NS NSAID. Among the COX-2-specific inhibitors, celecoxib has a longer survival time than rofecoxib. In addition, COX-2-specific inhibitors also have longer survival times than noted in the literature of NS NSAID in RA community practice. Duration of use can be an indicator of treatment effectiveness and/or drug acceptability, and provides additional interpretation beyond the results of clinical trials.