Rheumatoid Arthritis: Wolfe F

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, 1035 N. Emporia, Suite 288, Wichita, KS 67214, USA. · J Rheumatol. · Pubmed #19040313 No free full text.

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) and their physicians often disagree as to the success of RA treatment or RA outcomes. However, guidelines (such as EULAR criteria for DAS scores) are heavily weighted toward joint counts and laboratory tests, and no guidelines exist for patient reported outcomes. Our aims were (1) to provide a patient-based definition of successful RA outcome or of treatment success and failure; (2) to describe the characteristics of patients meeting this definition; (3) to describe how external states such as disability and comorbidity influence definitions of health outcome; and (4) to derive surrogate-measure cutpoints for the definition. METHODS: A total of 20,268 patients with RA (5132 without comorbidity) were studied by recursive partitioning and regression methods to determine best dividing points between RA treatment and outcome success and non-success using 0-10 visual analog scales (VAS) for patient global assessment, pain, fatigue, and RA activity, and a Health Assessment Questionnaire (HAQ) scale. RESULTS: 14.5% of all patients and 22.9% of those without comorbidity were very satisfied with their health (success). Patient global at a level<or=1.25 best separated success from failure. Mean and median scores for those who were very satisfied were HAQ (0-3 scale) 0.36, 0.12; pain (0-10) 1.1, 0.5; global (0-10) 0.9, 0.5; and fatigue (0-10) 1.5, 1.0. VAS scores increased by approximately 0.5 units for each comorbid condition. CONCLUSION: Patient global at a level<or=1.25 best separates patients who are very satisfied with their health from those not very satisfied, regardless of the presence of comorbidity. All scores increase with increasing comorbidity, which must be accounted for when assessing individual patients. Values identified here suggest patients require better outcomes than are found in patients who are in Disease Activity Score-28 remission or OMERACT low disease activity states.

Wolfe F, Petri M, Alarcón GS, Goldman J, Chakravarty EF, Katz RS, Karlson EW. · National Data Bank for Rheumatic Diseases, 1035 N. Emporia, Suite 288, Wichita, KS 67214, USA. · J Rheumatol. · Pubmed #19004039 No free full text.

Abstract: OBJECTIVE: To determine if fibromyalgia (FM) or fibromyalgia-ness (the tendency to respond to illness and psychosocial stress with fatigue, widespread pain, general increase in symptoms, and similar factors) is increased in patients with compared to those without systemic lupus erythematosus (SLE); to determine whether FM or fibromyalgia-ness biases the SLE Activity Questionnaire (SLAQ); and to determine if the SLAQ is overly sensitive to FM symptoms. METHODS: We developed a 16-item SLE Symptom Scale (SLESS) modeled on the SLAQ and used that scale to investigate the relation between SLE symptoms and fibromyalgia-ness in 23,321 patients with rheumatic disease. FM was diagnosed by survey FM criteria, and fibromyalgia-ness was measured using the Symptom Intensity (SI) Scale. As comparison groups, we combined patients with rheumatoid arthritis and noninflammatory rheumatic disorders into an "arthritis" group and also utilized a physician-diagnosed group of patients with FM. RESULTS: FM was identified in 22.1% of SLE and 17.0% of those with arthritis. The SI scale was minimally increased in SLE. The correlation between SLAQ and SLESS was 0.738. SLESS/SLAQ scale items (Raynaud's phenomenon, rash, fever, easy bruising, hair loss) were significantly more associated with SLE than FM, while the reverse was true for headache, abdominal pain, paresthesias/stroke, fatigue, cognitive problems, and muscle pain or weakness. There was no evidence of disproportionate symptom-reporting associated with fibromyalgia-ness. Self-reported SLE was associated with an increased prevalence of FM that was unconfirmed by physicians, compared to SLE confirmed by physicians. CONCLUSION: The prevalence of FM in SLE is minimally increased compared with its prevalence in patients with arthritis. Fibromyalgia-ness does not bias the SLESS and should not bias SLE assessments, including the SLAQ.

Aletaha D, Landewe R, Karonitsch T, Bathon J, Boers M, Bombardier C, Bombardieri S, Choi H, Combe B, Dougados M, Emery P, Gomez-Reino J, Keystone E, Koch G, Kvien TK, Martin-Mola E, Matucci-Cerinic M, Michaud K, O'Dell J, Paulus H, Pincus T, Richards P, Simon L, Siegel J, Smolen JS, Sokka T, Strand V, Tugwell P, van der Heijde D, van Riel P, Vlad S, van Vollenhoven R, Ward M, Weinblatt M, Wells G, White B, Wolfe F, Zhang B, Zink A, Felson D. · Division of Rheumatology, Medical University of Vienna, Vienna, Austria. · Ann Rheum Dis. · Pubmed #18791055 No free full text.

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

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, Wichita, Kansas, and University of Kansas School of Medicine, Wichita. · Arthritis Rheum. · Pubmed #18759273 No free full text.

Abstract: OBJECTIVE: To determine the risk of myocardial infarction (MI) in patients with rheumatoid arthritis (RA) compared with that in patients with noninflammatory rheumatic disorders and to determine risk factors for MI in RA, the relationship between cardiovascular risk factors and corticosteroid use, and the relationship between RA treatment and MI. METHODS: We conducted a cohort study of MI in 17,738 patients with RA and 3,001 patients with noninflammatory rheumatic disorders who were assessed at 6-month intervals between 1999 and July 2006. We evaluated treatment effect in a nested case-control study of RA participants who were matched by age, sex, study duration, and date of study entry. RESULTS: The covariate-adjusted risk of first MI in RA versus that in noninflammatory rheumatic disorders was 1.9 (95% confidence interval 1.2-2.9) (P = 0.005). In RA, MI was predicted by age, sex, education level, hypertension, smoking, exercise, prior MI, diabetes, a comorbidity index, use of low-dose aspirin and antilipemic agents, RA severity and treatment variables, and corticosteroid use. Except for obesity, predictors were of equal strength in RA and noninflammatory rheumatic disorders. The increased risk for MI in RA compared with that in noninflammatory rheumatic disorders lessened when corticosteroid users were excluded. Use of corticosteroids was associated with future development of diabetes and hypertension. CONCLUSION: MI in RA is associated with demographic and cardiovascular risk factors and corticosteroid use. Study data support the hypothesis that RA activity causes MI and that corticosteroids are primarily a marker of RA activity. However, corticosteroids increase the risk of diabetes and hypertension and contribute to the overall risk of MI.

Allaire S, Wolfe F, Niu J, Zhang Y, Zhang B, LaValley M. · Clinical Epidemiology Research and Training Unit, Boston University, 715 Albany Street, Boston, MA 02118, USA. · Arthritis Rheum. · Pubmed #18668597 No free full text.

Abstract: OBJECTIVE: To examine the role of anti-tumor necrosis factor (anti-TNF) agents in predicting work disability in subjects with rheumatoid arthritis (RA). METHODS: We studied 953 subjects with rheumatologist-diagnosed RA from a US cohort using a nested, matched, case-control approach. Subjects provided data on medication usage and employment every 6 months for 18 months, were employed at baseline, and were age <65 years at last followup. Cases were subjects who were not employed at followup (n = 231) and were matched approximately 3:1 by time of entry into the cohort to 722 controls who were employed at followup. Risk of any employment loss, or loss attributed to RA, at followup as predicted by use of an anti-TNF agent at baseline was computed using conditional logistic regression. Stratification on possible confounding factors and recursive partitioning analyses were also conducted. RESULTS: Subjects' mean age was 51 years, 82% were female, 92% were white, and 72% had more than a high school education. Nearly half (48%) used an anti-TNF agent at baseline; characteristics of anti-TNF agent users were similar to nonusers. In the main analyses, anti-TNF use did not protect against any or RA-attributed employment loss (odds ratio [95% confidence interval] 1.1 [0.7-1.6] versus 0.9 [0.5-1.5]). However, a protective effect was found for users with disease duration <11 years (odds ratio [95% confidence interval] 0.5 [0.2-0.9]). In recursive partitioning analyses, age, RA global severity, and functional limitation played a much greater role in determining employment loss than anti-TNF agent use. CONCLUSION: Anti-TNF agent use did not protect against work disability in the main analyses. In stratified analyses, their use was protective among subjects with shorter RA duration, whereas in nonparametric analyses, age and disease factors were the prominent predictors of work disability.

Nadareishvili Z, Michaud K, Hallenbeck JM, Wolfe F. · Georgetown University Hospital, Washington, DC, USA. · Arthritis Rheum. · Pubmed #18668583 No free full text.

Abstract: OBJECTIVE: To determine the risk of stroke in patients with rheumatoid arthritis (RA) and risk factors associated with stroke. METHODS: We performed nested case-control analyses within a longitudinal databank, matching up to 20 controls for age, sex, and time of cohort entry to each patient with stroke. Conditional logistic regression was performed as an estimate of the relative risk of stroke in RA patients compared with those with noninflammatory rheumatic disorders, and to examine severity and anti-tumor necrosis factor (anti-TNF) treatment effects in RA. RESULTS: We identified 269 patients with first-ever all-category strokes and 67 with ischemic stroke, including 41 in RA patients. The odds ratio (OR) for the risk of all-category stroke in RA was 1.64 (95% confidence interval [95% CI] 1.16-2.30, P = 0.005), and for ischemic stroke was 2.66 (95% CI 1.24-5.70, P = 0.012). Ischemic stroke was predicted by hypertension, myocardial infarction, low-dose aspirin, comorbidity score, Health Assessment Questionnaire score, and presence of total joint replacement, but not by diabetes, smoking, exercise, or body mass index. Adjusted for cardiovascular and RA risk factors, ischemic stroke was associated with rofecoxib (P = 0.060, OR 2.27 [95% CI 0.97-5.28]), and possibly with corticosteroid use. Anti-TNF therapy was not associated with ischemic stroke (P = 0.584, OR 0.80 [95% CI 0.34-1.82]). CONCLUSION: RA is associated with increased risk of stroke, particularly ischemic stroke. Stroke is predicted by RA severity, certain cardiovascular risk factors, and comorbidity. Except for rofecoxib, RA treatment does not appear to be associated with stroke, although the effect of corticosteroids remains uncertain.

Vera-Llonch M, Massarotti E, Wolfe F, Shadick N, Westhovens R, Sofrygin O, Maclean R, Li T, Oster G. · From Policy Analysis Inc., Brookline, MA 02445, USA. · J Rheumatol. · Pubmed #18634164 No free full text.

Abstract: OBJECTIVE: To assess cost-effectiveness of abatacept in patients with rheumatoid arthritis (RA) with inadequate response to tumor necrosis factor-alpha antagonists (anti-TNF). METHODS: We developed a simulation model to depict progression of disability [in terms of Health Assessment Questionnaire Disability Index (HAQ-DI)] in women aged 55-64 years with moderately to severely active RA and inadequate response to anti-TNF. At model entry, patients were assumed to receive either oral disease modifying antirheumatic drugs (DMARD) only or oral DMARD plus abatacept. Patients were then tracked from model entry until death. Future health-state utilities and medical-care costs (except study therapy) were estimated based on predicted values of the HAQ-DI. The model was estimated using data from a Phase III clinical trial of abatacept plus secondary sources. Cost-effectiveness was expressed in terms of incremental cost (2006 US$) per quality-adjusted life-year (QALY) gained alternatively over 10 years and a lifetime. Future costs and health effects were discounted at 3% annually. RESULTS: Over 10 years, abatacept would yield 1.0 additional QALY (undiscounted) per patient (4.0 vs 3.0 for oral DMARD) at an incremental (discounted) cost of $45,497 (100,648 vs $55,151) respectively; over a lifetime, corresponding figures were 1.6 QALY (5.8 vs 4.2) and $64,978 ($140,714 vs $82,489). Cost-effectiveness was [mean (95% CI)] $50,576 ($47,056, $54,944) per QALY gained over 10 years, and $45,979 ($42,678, $49,932) per QALY gained over a lifetime. Findings were robust in sensitivity analyses. CONCLUSION: Abatacept is cost-effective by current standards of medical practice in patients with moderately to severely active RA and inadequate response to an anti-TNF.

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, and University of Kansas School of Medicine, Wichita, KS 67214, USA. · Nat Clin Pract Rheumatol. · Pubmed #18628729 No free full text.

This publication has no abstract.

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, 1035 N. Emporia, Suite 288, Wichita, KS 67214, USA. · J Rheumatol. · Pubmed #18484696 No free full text.

Abstract: OBJECTIVE: To determine, primarily in rheumatoid arthritis (RA), the prevalence, relative risk, and risk factors for oral and ocular dryness. METHODS: We studied self-reported persistent ocular and oral dryness (PD) present in 2 consecutive observations, and sporadic dryness (SD) present in 1 of 2 consecutive observations, during semiannual assessments in 9921 patients with RA and in 2851 with a noninflammatory rheumatic disorder (NIRD) (not fibromyalgia; FM). We also evaluated prevalence in 2867 patients with FM. RESULTS: In RA, PD was noted in 11.6% and SD in 17.5%. Compared with NIRD, the age and sex adjusted relative risk (RR) for PD was 1.34 (95% CI 1.17-1.51) and the severity and treatment adjusted RR was 1.46 (95% CI 1.26-1.6). The adjusted RR for FM compared with RA and NIRD was 2.02 (95% CI 1.85-2.20). Dryness prevalence increased 10% to 13% every 10 years, and was associated with therapy. The treatment attributable risk was 27.5%. Fatigue and body pain (Symptom Intensity Scale) was more strongly associated with dryness than was any other clinical scale, including Health Assessment Questionnaire, pain, and Medical Outcomes Study Short Form-36 Health Survey. SD was associated with a covariate adjusted decrease in quality of life of 0.020 (95% CI 0.012-0.029) utility units. CONCLUSION: Dryness is increased in RA and is contributed to by severity and therapy. The combination of body pain and fatigue is the strongest clinical correlate of dryness, and is independent of diagnosis of FM. Any factor that increases illness severity or distress results in an increase in dryness.

Shaver TS, Anderson JD, Weidensaul DN, Shahouri SS, Busch RE, Mikuls TR, Michaud K, Wolfe F. · Arthritis and Rheumatology Clinics of Kansas, USA. · J Rheumatol. · Pubmed #18412311 No free full text.

Abstract: OBJECTIVE: To investigate the results and feasibility of available scales to measure minimal disease activity (MDA) and remission in rheumatoid arthritis (RA) in the clinic. METHODS: We studied 849 consecutive patients with RA seen in a community rheumatology practice for routine RA care by 4 rheumatologists, beginning in March 2007 and ending in August 2007. Patients and physicians completed a simple form at each visit. We calculated the Disease Activity Score 28 (DAS28), Clinical Disease Activity Index (CDAI), physician assessment of global activity, and the Patient Activity Scale (PAS-II). From these we calculated remission and MDA prevalence in this community practice. RESULTS: The DAS28 could not be determined in more than 50% of patients because of referring physician and insurance company restrictions. Remission prevalences differed by assessment method: DAS28 28.5%, CDAI 6.5%-8.1%, physician global 12.5%, PAS 13.7%. MDA was 26.9% using the American College of Rheumatology core set variables, 34.7% using the DAS28, and 26.8% using the PAS-II. The kappa statistic was only fair (0.2 to 0.4) for most comparisons between assessment methods. No significant differences were noted for remission and MDA according to biologic therapy. CONCLUSION: The CDAI and/or physician global and PAS-II are simple acceptable ways to measure RA activity in the clinic, but results differ strikingly according to method. Further standardization appears to be required for full implementation of the CDAI. Caution is urged before using these methods for regulatory purposes.

Allaire S, Wolfe F, Niu J, Lavalley MP. · Boston University, Boston, Massachusetts, USA. · Arthritis Rheum. · Pubmed #18383413 links to  free full text

Abstract: OBJECTIVE: To provide a contemporary estimate of the prevalence and incidence of rheumatoid arthritis (RA) work disability and examine its permanence over time. METHODS: Data were collected semiannually from 5,384 subjects with rheumatologist-diagnosed RA. We examined prevalence in subgroups formed by approximately 5-year disease duration intervals using data from subjects age < or =64 years who were employed at disease onset. Annual incidence was examined longitudinally among subjects who supplied data in 2003, 2004, or 2005, were employed at disease onset and in a year's first survey, and were age < or =63 years. For work disability permanence we used longitudinal data from all subjects who became work disabled and observed whether they later returned to work. RESULTS: Mean age of subjects was 52 years, 82% were female, 63% had more than a high school education, mean disease duration was 14 years, and mean Health Assessment Questionnaire score was 1.0. The prevalence of any premature work cessation was 23% in subjects with 1-3 years duration, 35% in those with 10 years, and 51% in those with > or =25 years RA duration. Arthritis-attributed work cessation was 14%, 29%, and 42%, respectively. Annual incidence of any premature work cessation was approximately 10% and arthritis-attributed work cessation incidence was approximately 6%. Thirty-nine percent of subjects who stopped working later returned to work. CONCLUSION: Work disability prevalence in this sample was high (35% within 10 years disease duration), but may represent a decline from the 50% prevalence reported in 1987. Annual incidence of work disability was higher than prior studies, but the return to work rate was also higher.

Wailoo AJ, Bansback N, Brennan A, Michaud K, Nixon RM, Wolfe F. · Health Economics and Decision Science, ScHARR, University of Sheffield, Sheffield, UK. · Arthritis Rheum. · Pubmed #18383356 links to  free full text

Abstract: OBJECTIVE: Since the introduction of the Medicare Prescription Drug Improvement and Modernization Act and its associated demonstration project, coverage of selected biologic drugs has been expanded for Medicare beneficiaries. For rheumatoid arthritis, coverage was extended to etanercept, adalimumab, and anakinra in addition to the previously covered infliximab. We undertook to develop a model to compare the costs and quality-adjusted life years (QALYs) generated by each of the 4 biologic agents. METHODS: Data were drawn from meta-analysis of randomized controlled trials and from a large longitudinal outcomes databank. Uncertainty was addressed using probabilistic and one-way sensitivity analyses. A lifetime horizon and Medicare viewpoint were adopted. RESULTS: In the base case analysis, anakinra was the least effective and least costly strategy. Etanercept, adalimumab, and infliximab were similar in terms of effectiveness, but infliximab was more costly. If decision makers are willing to pay a maximum of $50,000/QALY, the probability that infliximab is cost-effective is <1%. Findings were robust to a range of sensitivity analyses. Only if the dose of infliximab remains constant over time is this likely to be a cost-effective strategy. CONCLUSION: Infliximab is unlikely to be cost-effective in the Medicare population compared with either etanercept or adalimumab. Anakinra is substantially less costly but is also less effective than the 3 tumor necrosis factor alpha inhibitors.

Cannon GW, Pincus SH, Emkey RD, Denes A, Cohen SA, Wolfe F, Saway PA, Jaffer AM, Weaver AL, Cogen L, Schindler JD. · Division of Rheumatology, University of Utah, Salt Lake City, UT 84132, USA. · Arthritis Rheum. · Pubmed #18240222 links to  free full text

Abstract: One hundred five patients were enrolled in a 12-week, randomized, prospective, double-blind, placebo-controlled trial of recombinant human gamma-interferon (rHu gamma-IFN) for the treatment of rheumatoid arthritis. Fifty-four patients received rHu gamma-IFN and 51 received placebo. Forty-two patients in each group completed the 12-week trial. Some clinical improvement occurred in both groups of patients. Although the improvement with rHu gamma-IFN was greater than that with placebo, the differences were generally not statistically significant.

Wolfe F, Allaire S, Michaud K. · National Data Bank for Rheumatic Diseases, 1035 N. Emporia, Wichita, KS 67214, USA. · J Rheumatol. · Pubmed #17787043 No free full text.

Abstract: OBJECTIVE: To determine the prevalence and incidence rates of work disability in rheumatoid arthritis (RA), and to determine the effect of anti-tumor necrosis factor (TNF) therapy on work disability. METHODS: Participants with RA who were employed when RA was diagnosed (N = 8082) were evaluated for up to 5.5 years. Work disability incidence rates were determined in a subset (N = 4155) of those who stated they were currently employed, and the effect of anti-TNF therapy was determined by conditional logistic regression, after adjustment for covariates. RESULTS: At a median of 12.8 years after RA onset, 56.2% were still employed and 43.8% were not working. Of those not working, 22.7% considered themselves disabled. In addition, 30.5% had stopped work over their lifetimes for health reasons and 20.6% were currently receiving Social Security disability benefits. The annualized incidence rate for self-reported disability was 2.5% and for Social Security disability 1.9%. The incidence rate for persons who stopped working and did not resume employment was 4.0%. Anti-TNF therapy was not associated with Social Security disability, but was associated with an increased risk of self-reported disability (odds ratio 1.6) after adjustment for covariates. CONCLUSION: Rates of self-reported disability were lower than noted in previous studies, perhaps reflecting overall improvement in RA therapy. We could not discern a positive effect of anti-TNF therapy on the risk of work disability.

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases and University of Kansas School of Medicine, Wichita, KS 67214, USA. · Arthritis Rheum. · Pubmed #17729297 links to  free full text

Abstract: OBJECTIVE: Induction of malignancy is a major concern when rheumatoid arthritis (RA) is treated with biologic therapy. A meta-analysis of RA biologic clinical trials found a general increased risk of malignancy, but this risk was not found in a large observational study. We undertook this study to assess the risk of malignancy among biologic-treated patients in a large US observational database. METHODS: We studied incident cases of cancer among 13,001 patients during approximately 49,000 patient-years of observation in the years 1998-2005. Cancer rates were compared with population rates using the US National Cancer Institute SEER (Surveillance, Epidemiology, and End-Results) database. Assessment of the risk of biologic therapy utilized conditional logistic regression to calculate odds ratios (ORs) as estimates of the relative risk, further adjusted for 6 confounders: age, sex, education level, smoking history, RA severity, and prednisone use. RESULTS: Biologic exposure was 49%. There were 623 incident cases of nonmelanotic skin cancer and 537 other cancers. The standardized incidence ratios and 95% confidence intervals (95% CIs) compared with SEER data were as follows: all cancers 1.0 (1.0-1.1), breast 0.8 (0.6-0.9), colon 0.5 (0.4-0.6), lung 1.2 (1.0-1.4), lymphoma 1.7 (1.3-2.2). Biologics were associated with an increased risk of nonmelanotic skin cancer (OR 1.5, 95% CI 1.2-1.8) and melanoma (OR 2.3, 95% CI 0.9-5.4). No other malignancy was associated with biologic use; the OR (overall risk) of any cancer was 1.0 (95% CI 0.8-1.2). CONCLUSION: Biologic therapy is associated with increased risk for skin cancers, but not for solid tumors or lymphoproliferative malignancies. These associations were consistent across different biologic therapies.

Wolfe F, Rasker JJ, Boers M, Wells GA, Michaud K. · National Data Bank for Rheumatic Diseases, Wichita, Kansas 67214, USA. · Arthritis Rheum. · Pubmed #17665487 links to  free full text

Abstract: OBJECTIVE: To determine the prevalence of minimal disease activity (MDA) and remission in patients with rheumatoid arthritis (RA), to assess the effect of anti-tumor necrosis factor (anti-TNF) therapy on MDA, and to determine the extent to which MDA status improves long-term outcomes. METHODS: Using the Patient Activity Scale (PAS) as a surrogate, we assessed the prevalence of MDA and remission in 18,062 patients with RA using the newly developed Outcome Measures in Rheumatology Clinical Trials (OMERACT) criteria for MDA. RESULTS: MDA was noted in 20.2% of 18,062 patients and persistent MDA, operationally defined as having MDA during >or=2 consecutive 6-month observation periods, occurred in 13.5% of 7,433 patients followed longitudinally. Disease activity at remission levels was noted in 7%. Among patients with MDA, 82% received disease-modifying antirheumatic drugs or biologic agents. Following anti-TNF initiation, the cumulative probability of achieving MDA at 2 and 6 years was 4.1% and 7.6%, respectively, and persistent MDA probabilities were 2.7% and 4.5%, respectively. Regardless of RA duration, patients with MDA had substantially better outcomes, including a 10-fold reduction in work disability and an approximately 2-fold reduction in total joint replacement and mortality. CONCLUSION: Remission remains uncommon in RA, and the prevalence of new remission in community practice is substantially lower than noted in published trials of biologic therapy. On average, persons with MDA appear to have persistently mild RA. This might be the effect of milder RA and/or more effective treatment in early RA. The PAS had satisfactory levels of agreement with the full MDA criteria and appears suitable for use in clinical and epidemiologic research.

Wolfe F, Caplan L, Michaud K. · National Data Bank for Rheumatic Diseases, Arthritis Research Center Foundation, Wichita, KS 67214, USA. · Scand J Rheumatol. · Pubmed #17657669 No free full text.

Abstract: OBJECTIVES: Interstitial lung disease (ILD) is an important complication of rheumatoid arthritis (RA) or its treatment, and is associated with substantially increased mortality. Reports have suggested that infliximab with or without azathioprine might lead to rapidly progressive or fatal ILD. We used an RA data bank to assess the associations of treatments for RA and severe ILD. METHODS: ILD was identified in hospitalisations and death records in 100 of 17,598 RA patients and studied in relation to RA therapy with Cox regression analyses. RESULTS: The incidence of hospitalisation for ILD (HILD) was 260 per 100,000 patient years. Among those hospitalised for ILD, 27.0% died. In multivariable models of current and past RA treatment, the only current treatment associated with HILD was prednisone: hazard ratio (HR) 2.5 [95% confidence interval (CI) 1.5-4.1]. Among past therapies, prednisone (HR 3.0, 95% CI 1.0-8.9), infliximab (HR 2.1, 95% CI 1.1-3.8), etanercept (HR 1.7, 95% CI 1.0-3.0), and cyclophosphamide (HR 3.7, 95% CI 0.9-15.5) were associated with HILD. Pre-existing lung problems were identified in 67% of HILD. Only one case of HILD in the 100 hospitalisations suggested a possible temporal relationship between infliximab and HILD. CONCLUSIONS: Associations between RA treatment and HILD are confounded by the prescription of treatments for ILD such as prednisone, infliximab, etanercept, and cyclophosphamide. There is no clear pattern of causal association of treatment and ILD, and there is no clear evidence to support a causal relationship between infliximab, azathioprine, and HILD.

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, Arthritis Research Center Foundation, Wichita, Kansas 67214, USA. · J Rheumatol. · Pubmed #17611989 No free full text.

Abstract: OBJECTIVE: To compare a visual analog pain scale (VAS) with the Medical Outcomes Study Short Form-36 Health Survey (SF-36) bodily pain; to define the minimal clinically important change (MCIC) for pain in observational studies; to define clinically useful cutpoints for pain; to quantify the predictors of pain; and to estimate the effect of anti-tumor necrosis factor (TNF) therapy on pain. METHODS: Over 6 years we studied 12,090 patients with rheumatoid arthritis (RA). Pain was assessed by VAS and SF-36 pain scales. RESULTS: Compared with the SF-36 scale, the 0-10 VAS pain scale was better correlated with all clinical variables. The mean VAS score was 3.4 (standard deviation 2.8), and the best cutpoint for an "acceptable" level of pain was <or=2.0. The MCIC for pain was approximately 0.5 units by one measure and 1.1 by another. Pain increased slightly with the duration of RA, 0.03 (95% confidence interval 0.02-0.03) and decreased with age, 0.01 (95% CI 0.01-1.02) units per year. Pain was greater in ethnic minorities [0.78 (95% CI 0.63-0.93)] and women [0.31 (95% CI 0.23-0.39)] and was lower in college graduates [-0.88 (95% CI -1.00 to -0.76)]. Self-reported joint and nonarticular pain at 16 bilateral sites explained 44% of VAS pain scores. Anti-TNF therapy reduced pain by 0.59 to 0.53 units and EuroQol utility by 0.02 (95% CI 0.02-0.02) units. CONCLUSION: Anti-TNF therapy improved pain by 0.53 to 0.70 units. The MCIC for improvement and worsening of pain is about 0.5 to 1.1 units. Pain levels are almost constant over RA duration, and are increased in women, ethnic minorities, smokers, and those with less education.

Wolfe F, Michaud K. · National Data Bank for Rheumatic Diseases, Wichita, Kansas 67214, USA. · Arthritis Rheum. · Pubmed #17599730 links to  free full text

Abstract: OBJECTIVE: Despite advances in rheumatoid arthritis (RA) treatment, patients' decisions regarding therapy often deviate from expert recommendation. This study was undertaken to investigate patients' acceptance and satisfaction with therapy, willingness to change therapy, and reasons for not changing. METHODS: Participants (n = 6,135) completed an 11-item questionnaire concerning treatment preferences. Eight questions assessed reasons for not wanting to change therapy. The contribution of individual predictors was determined by logistic regression analysis. RESULTS: Questionnaire responses showed that 63.8% of the patients would not want to change therapy as long as their condition didn't get worse; 77.3% were satisfied with their medications, while 9.4% were dissatisfied. These assessments were weakly related to RA activity and functional status. Side effects had occurred in 22.4% of the patients during the previous 6 months, and in 65.5% at some period during their lifetime. Predictors of unwillingness to change therapy were satisfaction with RA control, which had an odds ratio (OR) of 6.8 (95% confidence interval [95% CI] 5.8-8.0), risk of side effects (OR 4.4 [95% CI 3.8-5.2]), physician opinion (OR 1.9 [95% CI 1.6-2.2]), fear of loss of control (OR 1.8 [95% CI 1.6-2.1]), lack of better medications (OR 1.4 [95% CI 1.2-1.6]), and costs (OR 1.3 [95% CI 1.1-1.6]). There was little difference in results between patients who were receiving biologic agents and those who were not. CONCLUSION: There is substantial discrepancy between declared satisfaction with therapy and measured RA activity and functional status. Most RA patients are satisfied with their therapy, even many with abnormal scores. Fear of loss of control of RA and fear of side effects are major patient concerns. Maintenance of current status, rather than future improvement, appears to be a high priority for patients.

Lee HS, Irigoyen P, Kern M, Lee A, Batliwalla F, Khalili H, Wolfe F, Lum RF, Massarotti E, Weisman M, Bombardier C, Karlson EW, Criswell LA, Vlietinck R, Gregersen PK. · Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA. · Arthritis Rheum. · Pubmed #17530703 links to  free full text

Abstract: OBJECTIVE: Recently, Swedish members of the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) provided evidence that smoking may trigger RA-specific immune reactions to citrullinated protein in carriers of HLA-DR shared epitope alleles. In an effort to confirm this interaction between smoking and shared epitope alleles, we performed a case-only analysis of 3 North American RA cohorts. METHODS: A total of 2,476 white patients with RA were studied, 1,105 from the North American Rheumatoid Arthritis Consortium (NARAC) family collection, 753 from the National Inception Cohort of Rheumatoid Arthritis Patients (Inception Cohort), and 618 from the Study of New Onset Rheumatoid Arthritis (SONORA). All patients were HLA-DRB1 typed, and tested for anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor. Information about smoking history was obtained by questionnaire. RESULTS: A significant association was found between smoking and the presence of anti-CCP in the NARAC and the Inception Cohort, but not in the SONORA. The shared epitope alleles consistently correlated with anti-CCP in all 3 populations. Using multiple logistic regression analyses, shared epitope alleles were still the most significant risk factor for anti-CCP positivity. Weak evidence of gene-environment interaction between smoking and shared epitope alleles for anti-CCP formation was found only in the NARAC. CONCLUSION: Unlike the EIRA data, we could not confirm a major gene-environment interaction for anti-CCP formation between shared epitope alleles and smoking in 3 North American RA cohorts. Our data indicate a need for further studies to address the full range of environmental factors other than smoking that may be associated with citrullination and RA.

Marra CA, Marion SA, Guh DP, Najafzadeh M, Wolfe F, Esdaile JM, Clarke AE, Gignac MA, Anis AH. · Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. · J Clin Epidemiol. · Pubmed #17493521 No free full text.

Abstract: BACKGROUND: There is evidence that utility elicitation methods used in the calculation of quality-adjusted life years (QALYs) yield different results. It is not clear how these differences impact economic evaluations. METHODS: Using a mathematical model incorporating data on efficacy, costs, and utility values, we simulated the experiences of 100,000 hypothetical rheumatoid arthritis patients over 10 years (50,000 exposed to infliximab plus methotrexate [MTX] and 50,000 exposed to MTX alone). QALYs, were derived from the Health Utilities Index 2 and 3 (HUI2 and HUI3), the Short Form 6-D (SF-6D), and the Euroqol 5-D (EQ-5D). Incremental cost-utility ratios were determined using each instrument to calculate QALYs and the results were compared using cost-effectiveness acceptability curves. RESULTS: Using the different utility measurement methods, the mean difference in QALYs between the infliximab plus MTX and MTX groups ranged from a high of 1.95 QALYs (95% CI=1.93-1.97) using the HUI3 to 0.89 QALYs (95% CI=0.88-0.91) using the SF-6D. Adopting the commonly cited value of society's willingness to pay for a QALY of $50,000, 91% of the simulations favored the cost utility of infliximab plus MTX when using the HUI3 to calculate QALYs. However, when using the EQ-5D, HUI2, or the SF-6D utility values to calculate QALYS, the proportion of simulations that favored the cost utility of infliximab were 63%, 45%, and 12%, respectively. CONCLUSION: Depending on the method for determining utility values used in the calculation of QALYs, very different incremental cost-utility ratios are generated.

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.

Dessein PH, Norton GR, Woodiwiss AJ, Joffe BI, Wolfe F. · Department of Rheumatology, Johannesburg Hospital and Milpark Hospital, Parktown, University of Witwatersrand, Johannesburg, South Africa. · J Rheumatol. · Pubmed #17444592 No free full text.

Abstract: OBJECTIVE: To determine whether nontraditional risk factors increase the accuracy of predicting the presence of carotid artery plaque based on traditional cardiovascular risk factors only in patients with rheumatoid arthritis (RA). METHODS: We identified risk factors that were independently associated with ultrasonographically located plaque. In predicting carotid artery plaque, the area under the curve (AUC) of the receiver-operating characteristic (ROC) curve for the combination of traditional and nontraditional risk factors was compared to the AUC of the ROC curve for traditional risk factors and nontraditional risk factors considered separately in 91 patients with RA. RESULTS: Thirty-one (34%) patients had carotid artery plaque. The 3 traditional risk factors of age > 55 years, hypertension, and ever-smoking, and the 3 nontraditional risk factors of a disease duration > 8 years, polymorphonuclear cell count > 4.5 x 10(6)/l, and hypothyroidism were each independently associated with the presence of plaque (odds ratios 2.08-8.78; p = 0.001-0.02). The percentage of patients with plaque was 0, 10%, 50%, and 83% in patients with 0-1, 2, 3, and 4-6 of these risk factors, respectively. In predicting plaque, the AUC of the ROC curve for the combination of traditional and nontraditional risk factors (0.90 +/- 0.03) was greater than that for either traditional (0.80 +/- 0.05; p = 0.006) or nontraditional (0.80 +/- 0.04; p = 0.005) risk factors considered separately. CONCLUSION: The combination of disease duration, polymorphonuclear cell counts, and thyroid status increased the accuracy of predicting subclinical atheroma in patients with RA. We believe that our findings merit external validation.

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.