Rheumatoid Arthritis: Paulus HE

Paulus HE, Brahn E. · No affiliation provided · J Rheumatol. · Pubmed #15124238 links to  free full text

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Paulus HE. · No affiliation provided · J Rheumatol. · Pubmed #14705208 links to  free full text

This publication has no abstract.

Ranganath VK, Khanna D, Paulus HE. · Division of Rheumatology, Department of Medicine, University of California, Los Angeles, California 90095-1670, USA. · Clin Exp Rheumatol. · Pubmed #17083757 No free full text.

Abstract: As additional DMARDs have been added to the armamentarium of rheumatologists over the last 60 years, the approach to the treatment of rheumatoid arthritis has changed. Many clinical studies now are geared toward evaluating the concept of eradicating inflammation as a method to seek the elusive goal of sustained remission in RA. One of the first descriptions of remission in 'RA' was by Short et al in 1948, when he documented the natural progression of the disease. Since that time, various criteria have been developed to define RA remission utilizing clinical, radiographic, and laboratory measures. The most stringent of criteria is the American College of Rheumatology Remission Criteria, developed in 1980, which consists of clinical symptoms and signs of inflammation including fatigue, joint pain, morning stiffness, joint tenderness, joint swelling, and erythrocyte sedimentation rate (ESR). Several reports have compared ACR remission criteria to Disease Activity Score (DAS) values to identify equivalent DAS remission values, and these have been extrapolated to modified versions of the DAS, the Simple Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). The ACR remission criteria and the response measures were not designed for use as the target or goal for the clinical management of individual RA patients in routine clinical practice. Nevertheless, rheumatologists yearn for the eradication of inflammation in all RA patients, and attaining remission may be achievable in the future.

Moreland LW, Russell AS, Paulus HE. · University of Alabama at Birmingham, 1717-6th Avenue South, SRC 068, Birmingham, AL 35294-7201, USA. · J Rheumatol. · Pubmed #11409142 No free full text.

Abstract: We review the historical highlights of the management of rheumatoid arthritis (RA). Studies of nonsteroidal antiinflammatory drugs, disease modifying antirheumatic drugs, and biological agents over 5 decades were evaluated and summarized. There is emphasis on drug therapy as it has developed and evolved from empirical relief of symptoms with salicylates to targeted intervention in the immunoinflammatory process with tumor necrosis factor inhibitors. A therapeutic paradigm has been proposed to rationalize the use of the available therapies. If one accepts the thesis that both the acute and chronic consequences of RA are due to persistent misdirected and inadequately controlled inflammation that causes tissue destruction and loss of function, then prolonged complete control of the abnormal inflammatory process is the fundamental first step in the management of all patients with RA. Unfortunately, even with the newest therapeutic options to treat RA, most patients achieve only partial suppression of inflammation and many lose therapeutic benefit after an initial good response. The management of persistent or recurrent rheumatoid inflammation and disability continues to be a challenge. It remains to be determined whether the future addition of more potent specific interventions in the immunoinflammatory process will be able to solve this problem without disarming host defenses against infections and tumors.

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

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Chiou CF, Sherbourne CD, Cornelio I, Lubeck DP, Paulus HE, Dylan M, Weisman M. · Cerner Health Insights, Beverly Hills, CA 90212, USA. · J Rheumatol. · Pubmed #16465655 No free full text.

Abstract: OBJECTIVE: To assess the psychometric characteristics of the original 33-item Cedars-Sinai Health-Related Quality of Life in Rheumatoid Arthritis Questionnaire (O-CSHQ-RA) and 11-item CSHQ-RA Short Form (SF) using a representative population of patients with rheumatoid arthritis (RA) from 55 sites across the United States. METHODS: Data were from a 24-week multicenter, open-label, single-arm study of 312 RA patients receiving anakinra. Cronbach's alpha coefficient was used to indicate the internal consistency. Test-retest reliability was assessed by establishing the intraclass correlation coefficient (ICC) for screening and baseline visit responses. Convergent validity was tested with the Pearson correlation coefficient. Analysis of variance was performed to determine discriminant validity. A Wilcoxon signed-rank test and analysis of covariance were used to assess the responsiveness. A discriminant function was generated to determine the clinically meaningful change. RESULTS: Test-retest reliability was demonstrated for both versions of the CSHQ-RA, with ICC ranging from 0.82 to 0.94. Cronbach's alpha coefficients were > or = 0.9, indicating good internal consistency. Pearson correlations between health-related quality of life instruments and CSHQ-RA measures ranged from -0.33 to -0.73 and 0.39 to 0.76, demonstrating good convergent validity. Scores on both versions of the CSHQ-RA differed significantly (p < 0.0001) for patients with different levels of physical disability as measured by the Stanford Health Assessment Questionnaire. Both instruments were responsive to differences in patient health as measured by the general health question (p < 0.0001). Clinically meaningful changes were calculated for all 5 domains of the O-CSHQ-RA (6.9-14.0) and the overall O-CSHQ-RA SF (12.7). CONCLUSION: These results support the validity and reliability of both the original CSHQ-RA and the 11-item CSHQ-RA SF when tested in a representative patient population.

Khanna D, Park GS, Paulus HE, Simpson KM, Elashoff D, Cohen SB, Emery P, Dorrier C, Furst DE. · Division of Immunology, Department of Medicine, University of Cincinnati and Veterans Affairs Medical Center, Cincinnati, Ohio 45267-0563, USA. · Arthritis Rheum. · Pubmed #16200612 links to  free full text

Abstract: OBJECTIVE: To examine the effect of folic acid on the efficacy of methotrexate (MTX) treatment in rheumatoid arthritis (RA) at 12 months in 2 phase III randomized controlled trials (RCTs) of leflunomide in which MTX was used as a comparator. METHODS: Analyses were restricted to patients randomized to receive MTX who had rheumatoid factor data. The US study recruited 482 patients with active RA; 179 received at least 1 dose of MTX, and all were mandated to receive 1 mg of oral folic acid once or twice daily. The multinational European study recruited 999 patients with active RA; 489 received at least 1 dose of MTX, and oral folic acid was not required, although 50 received folate after developing an adverse event. Because of similar entry criteria for both studies, the data for patients with available primary outcome data at week 52 were pooled (n = 668), and the patients were grouped by folic acid use (n = 225) and nonuse (n = 443). To account for the significant between-study differences in the MTX groups, baseline covariates were adjusted using propensity scores so that folic acid users could be matched with nonusers. This allowed for a comparison of differences in American College of Rheumatology (ACR) 20% improvement criteria at week 52. RESULTS: At study entry, non-folic acid users had a significantly lower mean body weight, shorter mean RA duration, and higher mean disease activity (measured by joint counts, patient's and physician's global assessments, and acute-phase reactant levels). The mean MTX dosage at week 52 was similar in the 2 RCTs. Using propensity score matching techniques, the proportion of patients achieving an ACR 20% response at week 52 averaged 17% higher in the non-folic acid group than in the folic acid group (range 15-21%). Similarly, the proportion of patients achieving ACR 50% and ACR 70% responses averaged 14% (range 12-16%) and 12% (range 9-14%) higher, respectively, in the non-folic acid group. Adverse events were reported in 93% of US study patients and 94% of the multinational study patients. Elevated liver transaminase levels (above the upper limit of normal) were reported in 29% of the US study patients (majority receiving folic acid) and 62% of the multinational study patients (majority not receiving folic acid). CONCLUSION: After using propensity scores to adjust for differences in the baseline characteristics of folic acid users and non-folic acid users, 9-21% fewer MTX-treated RA patients taking folic acid had ACR 20%, 50%, or 70% improvement at 52 weeks compared with those who did not receive folic acid in the 2 phase III RA clinical trials. As a post hoc analysis, the results of this data analysis should be considered "hypothesis generating" and an impetus for future studies regarding the effects of folic acid on the efficacy of MTX in RA.

Paulus HE, Di Primeo D, Sharp JT, Genant HK, Weissman BN, Weisman MH, Sanda M, Anonymous00404. · Division of Rheumatology, UCLA Medical Center, Los Angeles, California 90095, USA. · J Rheumatol. · Pubmed #14994390 No free full text.

Abstract: OBJECTIVE: To quantitate patient retention and radiographic progression rates in serial hand/wrist radiographs of patients with rheumatoid arthritis (RA) who were not being treated with disease modifying antirheumatic drugs (DMARD). METHODS: A total of 1433 RA patients with 1-7 years' disease duration entered a 3-year prospective randomized double-blind clinical trial comparing the nonsteroidal antiinflammatory drugs (NSAID) etodolac (300 or 1000 mg daily) and ibuprofen (2400 mg daily). Standardized hand/wrist radiographs were obtained yearly and at dropout if > 6 months after entry. DMARD were not permitted. Joint erosion, joint space narrowing (JSN), and total scores of 3 readers were averaged. RESULTS: At entry, mean duration of RA was 3.5 years (range 1-7); ages were 21-78 years; patients were 71% female, 84% Caucasian, 67% rheumatoid factor (RF) positive; tender joint count was 29, swollen joint count 22, Westergren erythrocyte sedimentation rate (ESR) 49, and C-reactive protein (CRP) 2.44. There were 824 (57.5%) patients who completed >or= 6 months and had paired radiographs; 46% completed 48 weeks; 31%, 98 weeks; and 19%, 147 weeks. Months between paired radiographs (time in study) averaged 23.1 (range 6-36). Mean progression rates for total, erosion, and JSN scores (5.08, 2.53, and 2.54 units per year, respectively) were significantly associated with time in study, baseline RF, ESR, CRP, swollen joint count, presence of erosions at entry, and with 20% and 50% composite clinical responses. Painful joint count and RA duration were weakly associated only with progression of erosions. Progression rates were not associated with age, sex, corticosteroid use, or prior DMARD use. Patients who completed the 3-year trial had less severe disease activity and radiographic progression than those who dropped out. CONCLUSION: In this 3-year prospective double-blind clinical trial that prohibited DMARD, retention rates (57.5%, 46%, 31%, and 19% at 0.5, 1, 2, and 3 years) were similar to those in the non-DMARD-treated placebo groups of recent published studies. Radiographic progression rates are reported for 824 non-DMARD-treated patients during RA of 1-10 years' duration. This information may be useful as background information in the interpretation of longterm clinical trials that evaluate joint radiographic outcomes.

Furst DE, Weisman M, Paulus HE, Bulpitt K, Weinblatt M, Polisson R, Zaug M, Kneer J, Van der Auwera P, Stevens RM. · Virginia Mason Research Center, Seattle, Washington, USA. · J Rheumatol. · Pubmed #14528504 No free full text.

Abstract: OBJECTIVE: To determine the optimal dose regimen of intravenous (IV) Ro 45-2081 (lenercept), a tumor necrosis factor receptor p55-Fc IgG1 fusion protein, in patients with active rheumatoid arthritis (RA) METHODS: In a double-blind, placebo-controlled, parallel-group, multicenter trial, adult patients with long-standing active RA stabilized on conventional therapy were randomly assigned to receive 3 IV infusions, one every 4 weeks, of one of the following: (a) placebo, (b) lenercept 0.01 mg/kg (maximum 1 mg), (c) lenercept 0.05 mg/kg (maximum 5 mg), (d) lenercept 0.2 mg/kg (maximum 20 mg), or (e) lenercept 0.5 mg/kg (maximum 50 mg). The material utilized in the study had a lower relative bioavailability [lower area under the time-concentration curve (AUC) per mg infused] than that used in a recent similar trial. Efficacy variables included change from baseline in number of swollen joints and tender joints, scores on physician and patient assessments of disease activity, and patient assessment of pain. RESULTS: Patients treated with lenercept exhibited improvement as early as one day after the first IV infusion. The treatment benefit, however, was modest, maximized by 2 weeks and then diminished or vanished as non-neutralizing anti-lenercept antibody concentrations increased. The majority of adverse experiences were mild or moderate and not considered related to study drug. CONCLUSION: Our results showed that lenercept administered by IV infusion every 4 weeks is well tolerated, but only transiently effective in patients with long-standing RA, likely due to both the low relative bioavailability of the material used in the study and the formation of non-neutralizing anti-lenercept antibodies.

Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, Paulus HE, Teoh LS, Velagapudi RB, Noertersheuser PA, Granneman GR, Fischkoff SA, Chartash EK. · Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Clin Ther. · Pubmed #12860493 No free full text.

Abstract: BACKGROUND: Because traditional therapies for rheumatoid arthritis (RA) such as methotrexate (MTX) do not produce an adequate response in many patients, newer therapies that block the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are increasingly being used in combination with MTX. OBJECTIVE: This study evaluated the efficacy, pharmacokinetics, and safety profile of adalimumab, a fully human anti-TNF alpha monoclonal antibody, when added to continuing MTX therapy. METHODS: This Phase I, randomized, dose-titration study consisted of a 4-week, double-blind, placebo-controlled treatment phase and a 26-month, open-label continuation phase. Patients with RA who had been taking stable doses of MTX (mean dose, 17 mg/wk) for > or =3 months before enrollment with an inadequate response were randomly assigned to receive 2 single doses of either adalimumab 0.25, 0.5, 1, 3, or 5 mg/kg i.v. or placebo in the double-blind phase. In the open-label phase, patients received treatment with 1 of the doses of adalimumab every other week or monthly for 18 months; patients were then switched to adalimumab 40 mg i.v. or SC every other week or monthly. The main efficacy end point was 20% improvement in American College of Rheumatology response criteria (ACR20). Other efficacy end points included 50% (ACR50) and 70% improvements in ACR response criteria. Pharmacokinetic parameters were analyzed for adalimumab and MTX during both phases of the study. Serum adalimumab concentrations were analyzed using a validated enzyme-linked immunosorbent assay relying on the double-antigen principle. Peak and trough concentrations were determined from observed concentration-time data, and a modeling approach was used to estimate total serum clearance, mean apparent terminal half-life, apparent volume of distribution at steady state, and area under the concentration-time curve. RESULTS: Sixty patients entered the double-blind phase, 45 receiving adalimumab and 15 receiving placebo; 1 placebo recipient chose not to continue into the open-label phase. Overall, the study population included 47 (78.3%) women and 13 (21.7%) men. The mean age was 52.9 years (range, 24-73 years), and the mean body weight was 69.7 kg (range, 43-98 kg). ACR20 and ACR50 responses were achieved on at least 1 assessment during the 4-week double-blind phase by a respective 29 (64.4%) and 11 (24.4%) of 45 patients receiving active treatment and by 4 (26.7%) and none of the 15 patients receiving placebo. Responses to adalimumab were rapid, with 10 (22.2%) of 45 patients achieving an ACR20 response within 24 hours of dosing. Of 29 adalimumab recipients who had an ACR20 response, 18 (62.1%) had a duration of response (time from first occurrence of a response to first occurrence of a nonresponse) of 1 to 2 weeks, and 11 (37.9%) had a duration of response of 3 to 13 weeks. The pharmacokinetic properties of adalimumab appeared to be linear. The mean apparent terminal half-life after a single intravenous dose of adalimumab ranged from 15 to 19 days in the 5 dose groups. Repeated administration of adalimumab had no statistically significant effect on the pharmacokinetics of MTX, indicating that dose adjustment of MTX is not necessary. Adalimumab was well tolerated, and there were no dose-related adverse events. CONCLUSIONS: Among patients with active RA who had not had an adequate response to MTX, addition of adalimumab to MTX achieved statistically significant, long-term improvement compared with placebo plus MTX (P < or = 0.05), as indicated by ACR responses at 26 months. The combination was well tolerated. Adalimumab exhibited linear pharmacokinetics. In this selected patient population, adalimumab's long half-life of 15 to 19 days supports every-other-week dosing. Coadministration of adalimumab did not alter serum levels of MTX.

Paulus HE, Di Primeo D, Sanda M, Lynch JM, Schwartz BA, Sharp JT, Genant HK, Weissman BN. · Division of Rheumatology, UCLA Medical Center, Los Angeles, California, USA. · J Rheumatol. · Pubmed #10914843 No free full text.

Abstract: OBJECTIVE: The reported prevention of joint damage during treatment with prednisolone 7.5 mg daily in patients with early rheumatoid arthritis (RA)3 may have important implications for management of RA. We evaluated this observation in another patient population. METHODS: Radiographic progression rates in paired hand radiographs were analyzed in 824 patients with RA who participated in a 3 year prospective, randomized clinical trial comparing the nonsteroidal antiinflammatory drugs (NSAID) etodolac (150 or 500 mg bid) and ibuprofen (600 mg qid). Disease modifying antirheumatic drugs (DMARD) were not permitted. Prednisone < or=5 mg daily was continued by 197 patients (mean dose 4.37 mg daily) who had started prednisone therapy at least 6 mo before study entry, but new prednisone starts were not allowed. Standardized hand/wrist radiographs were done yearly and at dropout; joint erosion and narrowing scores of 3 readers were averaged and progression rates were compared. RESULTS: Mean duration of RA was 3.6 years (range 1-7); patients' ages were 21-78 years; 71% were women. Among the 824 patients, those taking prednisone were more likely to have had previous DMARD, and at study entry had higher radiographic scores for joint erosion and joint space narrowing and slightly higher swollen joint counts, C-reactive protein values, and rheumatoid factor titers than those not taking prednisone. However, for the subgroup of 252 patients with RA duration of 12-24 months, prestudy radiographic scores were not different in those taking or not taking prednisone. The mean (+/-SD) monthly rate of increase in erosion scores was 0.228 +/-0.37 for the prednisone patients and 0.206+/-0.35 for patients not taking prednisone (p = 0.994 by ANCOVA). The subgroup with 12 to 24 months' disease duration at entry also showed no significant effect of prednisone treatment on erosion progression. CONCLUSION: Clinically indicated low dose prednisone did not prevent progressive radiographic damage in 197 NSAID treated patients whose physicians had initiated < or =5 mg daily before study entry. The risk/benefit ratio of chronic low dose prednisone in early RA remains uncertain.

Amjadi SS, Maranian PM, Paulus HE, Kaplan RM, Ranganath VK, Furst DE, Khanna PP, Khanna D, Anonymous00069. · Division of Rheumatology, University of California Los Angeles School of Medicine, Department of Health Services, 1000 Veteran Avenue, Room 32-59, Rehabilitation Center, Los Angeles, CA 90095, USA. · J Rheumatol. · Pubmed #19369459 No free full text.

Abstract: OBJECTIVE: New methodologies allow the scores for the Health Assessment Questionnaire-Disability Index (HAQ-DI) to be translated into preferences/utility scores. We evaluated the construct validity of the HAQ-DI-derived Short Form-6D (SF-6D) score and assessed its responsiveness to change over 6- and 12-month followup periods in patients with early aggressive rheumatoid arthritis (RA). METHODS: Patients (n=277) participating in an RA observational study completed self-reported measures of symptoms and the HAQ-DI at baseline and at 6 and 12 months. Total Sharp scores, C-reactive protein, and erythrocyte sedimentation rate were assessed along with clinical data. Construct validity was assessed by examining the association between SF-6D score and patient-reported and clinical measures using Spearman correlation coefficients. The responsiveness of SF-6D to change was assessed using patient and physician assessments of the disease as clinical anchors. The magnitude of responsiveness was calculated using SF-6D effect size (ES). RESULT: Mean SF-6D scores were 0.690, 0.720, and 0.723 at baseline and 6 and 12-month followup, respectively. Baseline patient-reported measures had moderate to high correlations with baseline SF-6D (r=0.43 to 0.52); whereas clinical measures had negligible to low correlations with SF-6D (r=0.001 to 0.32). ES was moderate for the groups that were deemed to have improved (ES 0.63-0.75) but negligible to small for those that did not (ES 0.13-0.46). CONCLUSION: Our data support the validity and responsiveness of the HAQ-DI derived SF-6D score in an early RA cohort. These results support the use of the HAQ-DI derived SF-6D in RA cohorts and clinical trials lacking preference-based measures.

Ranganath VK, Paulus HE, Onofrei A, Khanna D, Reed G, Elashoff DA, Kremer JM, Furst DE. · Department of Medicine, Division of Rheumatology, UCLA Rehabilitation Center, University of California, Los Angeles, California 90095-1670, USA. · J Rheumatol. · Pubmed #18785317 No free full text.

Abstract: OBJECTIVE: We examined the relationships of rheumatoid arthritis (RA), disease duration (DD), number of previous disease modifying antirheumatic drugs (DMARD), and frequency of DMARD changes, with regard to changes in function in patients with RA evaluated by modified Health Assessment Questionnaire (mHAQ) after the start of a new DMARD. METHODS: In total, 889 patients with active RA from the CORRONA database [patients had mHAQ>or=0.5 and/or Disease Activity Score 28-joint count (DAS28)>or=1.6] started a new DMARD (baseline) and had at least one followup visit 6-12 mo later. Change in mHAQ from baseline to followup visit was modeled using univariate/multivariate linear regression analysis. Due to colinearity, separate multivariate regression models were performed including/excluding the predictors disease duration, number of prior DMARD, and frequency of DMARD changes. RESULTS: Baseline age, mHAQ, erythrocyte sedimentation rate (ESR), DAS28, and number of prior DMARD differed across DD groups. The univariate linear regression model showed that higher baseline values of mHAQ, DAS28, swollen joint count (SJC), tender joint count (TJC), Clinical Disease Activity Index (CDAI), ESR, physician global assessment, prednisone use, and subsequent addition/discontinuation of DMARD were associated with improvement of the mHAQ at followup (p=0.05). Multivariate linear regression models showed that mHAQ improvement was associated with shorter DD, higher baseline mHAQ, addition of subsequent DMARD, and the DMARD frequency index (no. previous DMARD/yrs of DD) (p<0.05). Number of DMARD patients used previously was not associated with change of mHAQ in either model. CONCLUSION: Our study demonstrates that in clinical rheumatologic practices, more frequent changes in DMARD are associated with greater improvement in function (by mHAQ). It does not support the idea that number of previous DMARD used predicts response. Indirectly, these data support the concept that DMARD should be changed if optimal responses are not achieved within a specified time.

Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, Elkins-Melton M, Outman R, Allison JJ, Suarez Almazor M, Bridges SL, Chatham WW, Hochberg M, MacLean C, Mikuls T, Moreland LW, O'Dell J, Turkiewicz AM, Furst DE, Anonymous00442. · University of Alabama, Birmingham, AL, USA. · Arthritis Rheum. · Pubmed #18512708 links to  free full text

This publication has no abstract.

Charles-Schoeman C, Khanna D, Furst DE, McMahon M, Reddy ST, Fogelman AM, Paulus HE, Park GS, Gong T, Ansell BJ. · Division of Rheumatology, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, California 90095-1670, USA. · J Rheumatol. · Pubmed #17552046 No free full text.

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) have a 2-3-fold increased risk of myocardial infarction. Recent work suggests that plasma high density lipoproteins (HDL) from patients with RA are more proinflammatory than HDL from controls. We examined the effects of atorvastatin 80 mg daily on the inflammatory properties of HDL and clinical disease activity in RA. METHODS: Twenty subjects with active RA (mean Disease Activity Score 5.13 +/- 0.92) without dyslipidemia and no history of coronary artery disease were randomized in a double-blind placebo-controlled trial to receive 80 mg of atorvastatin (A) or placebo (P) daily in addition to stable antirheumatic drug therapy. Disease activity variables were followed over 12 weeks and the anti-/proinflammatory properties of HDL were determined by a cell-free assay (CFA) that measures lipid oxidation products. RESULTS: After 12 weeks, subjects completing the A protocol had a mean reduction in CFA values of 14.8 +/- 21.7%, while subjects completing P protocol had a mean increase in CFA values of 7.1 +/- 13.2% (p = 0.026). There was a trend for a decrease in highly sensitive C-reactive protein (hs-CRP) over 12 weeks in the A group compared to an increase in hs-CRP in the P group (p > 0.05), but changes in measures of clinical disease activity and plasma cytokine/intercellular adhesion molecule-1 levels were not significantly different in the A and P groups. CONCLUSION: In patients with active RA, HDL was rendered more antiinflammatory by high-dose atorvastatin compared to placebo. Functional characterization of HDL may warrant further investigation as a method of cardiovascular risk assessment in RA patients without traditional coronary risk factors. (ClinicalTrials.gov number NCT00356473).

Kahn KL, Maclean CH, Wong AL, Rubenstein LZ, Liu H, Fitzpatrick DM, Harker JO, Chen WP, Traina SB, Mittman BS, Hahn BH, Paulus HE. · University of California at Los Angeles, California 90095-1736, USA. · Arthritis Rheum. · Pubmed #17530663 links to  free full text

Abstract: OBJECTIVE: To evaluate the American College of Rheumatology (ACR) starter set of quality measures for rheumatoid arthritis (RA) in an actual patient cohort that preceded publication of the quality measures. METHODS: We retrospectively applied the 2006 ACR quality criteria to a prospectively studied cohort of 568 patients with RA treated by 1,932 unique physicians including 255 different rheumatologists between the years 1999 and 2003. Data on performance were obtained from self-report surveys and medical record review within 12 months. RESULTS: At least 1 joint examination was performed in 98% of patients. Patient and physician global assessments were reported for 79% and 74% of patients, respectively. A total of 85% of patients received disease-modifying antirheumatic drugs (DMARDs). DMARD adjustments were made for 50% of patients in whom increasing disease activity was noted at least once and for 64% of patients in whom increasing disease activity was noted during 2 (of 4) 3-month periods within the year. Compared with self-report surveys, medical records substantially underreported performance on quality measures. CONCLUSION: The ACR-endorsed quality measures for RA can be assessed using available data sources. When both self-report and medical record data are used, adherence rates, designed to serve as minimum standards of care, were moderate or high for most measures. Prior to using indicators to compare quality across groups, specific strategies for operationalizing measures and for using accurate data sources to assess adherence to the measures should be defined.

Ranganath VK, Yoon J, Khanna D, Park GS, Furst DE, Elashoff DA, Jawaheer D, Sharp JT, Gold RH, Keystone EC, Paulus HE, Anonymous00172. · UCLA, Department of Medicine, Division of Rheumatology, Rehabilitation Center, Room 32-59, 1000 Veteran Avenue, Los Angeles, CA 90095-1670, USA. · Ann Rheum Dis. · Pubmed #17472996 No free full text.

Abstract: OBJECTIVE: To evaluate concordance and agreement of the original DAS44/ESR-4 item composite disease activity status measure with nine simpler derivatives when classifying patient responses by European League of Associations for Rheumatology (EULAR) criteria, using an early rheumatoid factor positive (RF+) rheumatoid arthritis (RA) patient cohort. METHODS: Disease-modifying anti-rheumatic drug-naïve RF+ patients (n = 223; mean duration of symptoms, 6 months) were categorised as ACR none/20/50/70 responders. One-way analysis of variance and two-sample t tests were used to investigate the relationship between the ACR response groups and each composite measure. EULAR reached/change cut-point scores were calculated for each composite measure. EULAR (good/moderate/none) responses for each composite measure and the degree of agreement with the DAS44/ESR-4 item were calculated for 203 patients. RESULTS: Patients were mostly female (78%) with moderate to high disease activity. A centile-based nomogram compared equivalent composite measure scores. Changes from baseline in the composite measures in patients with ACRnone were significantly less than those of ACR20/50/70 responders, and those for ACR50 were significantly different from those for ACR70. EULAR reached/change cut-point scores for our cohort were similar to published cut-points. When compared with the DAS44/ESR-4 item, EULAR (good/moderate/none) percentage agreements were 92 with the DAS44/ESR-3 item, 74 with the Clinical Disease Activity Index, and 80 with the DAS28/ESR-4 item, the DAS28/CRP-4 item and the Simplified Disease Activity Index. CONCLUSION: The relationships of nine different RA composite measures against the DAS44/ESR-4 item when applied to a cohort of seropositive patients with early RA are described. Each of these simplified status and response measures could be useful in assessing patients with RA, but the specific measure selected should be pre-specified and described for each study.

Weisman MH, Paulus HE, Burch FX, Kivitz AJ, Fierer J, Dunn M, Kerr DR, Tsuji W, Baumgartner SW. · Division of Rheumatology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. · Rheumatology (Oxford). · Pubmed #17470434 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety of etanercept in patients with rheumatoid arthritis (RA) and concomitant comorbidities. METHODS: The safety of etanercept (25 mg twice weekly) in RA patients with at least one comorbidity (i.e. diabetes mellitus, chronic pulmonary disease, recent pneumonia, recurrent infections) was evaluated in a 16-week placebo-controlled, randomized, double-blinded study. The primary endpoint was the incidence of medically important infections (MIIs; defined as those resulting in hospitalization or treatment with intravenous antibiotics). RESULTS: Data from 535 patients were analysed; the study was terminated early because of slow enrolment and lower than predicted incidence of infections. Serious adverse events (5.9% placebo, 8.6% etanercept) were most commonly observed in the cardiovascular system. Six patients (1 placebo; 5 etanercept) died during the study; four deaths were attributed to cardiovascular events. The numerically higher mortality in the etanercept group was not statistically significant [relative risk (95% CI) = 5.06 (0.59, 42.99)] but remains unexplained. No etanercept-related increase in the incidence of MIIs (3.7% placebo, 3.0% etanercept) or overall infections was observed in the total study population or in subgroups of patients who were > or = 65 yrs of age, had diabetes or had chronic pulmonary disease. CONCLUSIONS: Etanercept was generally well tolerated by RA patients with comorbidities. Serious adverse events and deaths occurred more frequently in the etanercept group but event numbers were small and CIs were broad, preventing reliable conclusions from being drawn. Although the study had limited statistical power, the incidence of MIIs in these patients was not increased by etanercept treatment.

Khanna D, Oh M, Furst DE, Ranganath V, Gold RH, Sharp JT, Park GS, Keystone EC, Paulus HE, Anonymous00313. · Division of Immunology, Department of Medicine, University of Cincinnati and the Veterans Affairs Medical Center, Cincinnati, Ohio 45267-0563, USA. · Arthritis Rheum. · Pubmed #17394230 links to  free full text

Abstract: OBJECTIVE: To evaluate published proposed definitions of minimal disease activity (MDA) and remission in patients with early rheumatoid arthritis (RA). METHODS: The cohort comprised disease-modifying antirheumatic drug (DMARD)-naive patients with early seropositive active RA (n = 200) treated with traditional DMARDs in the prebiologic era. MDA definitions included Disease Activity Score in 28 joints (DAS28) <or=2.85, or achieving 5 of 7 World Health Organization (WHO)/International League of Associations for Rheumatology (ILAR) core set measure thresholds as proposed by the Outcome Measures in Rheumatology Clinical Trials. Other MDA definitions included Simplified Disease Activity Index (SDAI) score <or=11 and Clinical Disease Activity Index (CDAI) score <or=10. Remission definitions included American College of Rheumatology (ACR) remission, DAS28 <2.6, DAS28 <2.4, achieving all 7 WHO/ILAR core set measure thresholds, SDAI <or=3.3, and CDAI <or=2.8. Physical function was assessed using the Health Assessment Questionnaire (HAQ) disability index (DI) and radiographic progression was assessed using the Sharp score. RESULTS: At baseline, no patients were in MDA or remission. Depending on the MDA definition, 20-32%, 27-32%, and 30-48% were in MDA at 6, 12, and 24 months, respectively. Depending on the remission definition, 0.7-15%, 0-24%, and 0-33% were in remission at 6, 12, and 24 months, respectively. For example, at 6 months, lowest (highest) responses for MDA were seen with DAS28 <or=2.85 (SDAI <or=11) and for remission with ACR remission criteria (DAS28 <2.6). Patients who achieved either MDA or remission had lower HAQ DI and radiographic scores compared with patients who achieved neither. CONCLUSION: Our study demonstrated that different proportions of patients were classified as MDA or remission depending on the definition used. This has implications in predefining MDA or remission for a clinical trial or to establish goals for optimum management of RA in clinical practice.

Park GS, Wong WK, Oh M, Khanna D, Gold RH, Sharp JT, Paulus HE. · Department of Biostatistics, School of Public Health, University of California, Los Angeles, CA 90095-1772, USA. · Stat Methods Med Res. · Pubmed #17338292 No free full text.

Abstract: Various methods are used to measure radiographic joint damage in patients with rheumatoid arthritis (RA), but determining proportions of responsive patients is difficult. A key problem in observational studies when assessing damage outcomes is incorporating time to treatment initialization and adjusting for observed baseline differences. We examined five different definitions to select an appropriate index to classify radiographic damage in RA patients as progressive or nonprogressive. In addition, we compared different times from symptom onset to treatment and their effects on patient radiographic categorization. Propensity scores to adjust for baseline differences, including time since symptom onset, were used to match those treated early with those treated later using the stratification, radius, nearest neighbor and kernel methods. The mean effect of treatment on the treated was computed for each matching method. Observational data were analyzed for 185 early RA patients from the Western Consortium study followed six to sixty months (mean thirty-one months). For the selected index, 75 patients were categorized as nonprogressors; they had significantly lower disease activity, more clinical improvement and were treated earlier than the progressors. Of those treated within three months of symptom onset, 57% were classified as radiographically progressive versus 35% of those treated later (P = 0.0058). However, after propensity score adjustment for baseline differences, we noticed nonsignificant (P > 0.05) nonprogression in patients given earlier treatment. We conclude that propensity score analysis reduced but did not remove all bias.

Kahn KL, MacLean CH, Liu H, Rubenstein LZ, Wong AL, Harker JO, Chen WP, Fitzpatrick DM, Bulpitt KJ, Traina SB, Mittman BS, Hahn BH, Paulus HE. · University of California at Los Angeles, Greater Los Angeles VA Healthcare System, Los Angeles, California 90095-1736, USA. · Med Care. · Pubmed #17279021 No free full text.

Abstract: BACKGROUND: Patients with rheumatoid arthritis (RA) provide an important opportunity for understanding care of patients with a serious chronic condition. OBJECTIVES: We sought to characterize the complexity of care for patients with RA, including metrics describing the patient, the disease, and use of the health care system across time and place. METHODS: We undertook a prospective cohort study of 568 community-dwelling patients with RA by using observational data from clinically detailed telephone interviews at baseline and 2 years later in addition to medical record abstraction. Health status, comorbidity, use of disease-modifying antirheumatic drugs, visits, providers, provider types, encounter settings, and the discontinuity between patients and providers were studied. RESULTS: Within a 12-month window, 568 patients had 8686 outpatient encounters with the health care system with a mean of 3.41 unique providers per patient associated with a mean of 5 primary care and 6 rheumatologist visits. Half did not see a primary care physician, and 20% did not see a rheumatologist during 6-month periods despite their use of potentially toxic drugs, a mean of 4 comorbidities and progressive RA. Over the course of 24 months, 29% of patients changed their primary care provider, and 15% changed their rheumatologist. Patients were moderately impaired with mean SF-12 physical component score 37 (SD, 9). CONCLUSION: Patients with RA have frequent encounters with multiple providers and also frequent discontinuity of care. Recognizing the complexity of the care of patients with a chronic disease across multiple dimensions provides an opportunity to better understand challenges and opportunities in delivering high quality care.

Kahn KL, MacLean CH, Liu H, Rubenstein LZ, Wong AL, Harker JO, Chen WP, Fitzpatrick DM, Bulpitt KJ, Traina SB, Mittman BS, Hahn BH, Paulus HE. · Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1736, USA. · Arthritis Rheum. · Pubmed #17139665 links to  free full text

Abstract: OBJECTIVE: To construct quality measures with measurement validity and meaning for clinicians. METHODS: We conducted a prospective cohort study of rates of change in disease-modifying antirheumatic drug (DMARD) and/or systemic corticosteroid drug or dose for 568 patients with rheumatoid arthritis (RA) across 6,159 clinical encounters within 12 months to examine how changes in clinical specifications change adherence. RESULTS: Rates of DMARD change were sensitive to specifications regarding the intensity of disease activity (severe or moderate), duration of specified disease activity, and length of the observation period. Over 12 months, the proportions of 377 patients with severe disease activity observed for 1-month, 2-month, and 3-month time blocks who had a change in DMARD drug or dose were 36%, 57%, and 74%, respectively. Over 12 months, a change in DMARD drug or dose was observed for 44%, 50%, and 68% of 377 patients with severe disease within 3 months, 6 months, and 12 months, respectively, of the patient meeting criteria for severe disease activity. A change in DMARD drug or dose was observed for 21%, 23%, and 34% of 149 patients with moderate disease activity within 3, 6, and 12 months, respectively, of the patient meeting criteria for moderate disease activity. CONCLUSION: Rates of pharmacologic interventions for patients with moderate and severe RA disease activity vary substantially by intensity and duration of disease activity and by duration of period for observing change. Lack of precision in explicit process criteria could substantially mislead comparisons of quality of care across comparison groups.

Chiou CF, Sherbourne CD, Cornelio I, Lubeck DP, Paulus HE, Dylan M, Chang CH, Weisman MH. · Cerner LifeSciences, Beverly Hills, California, USA. · Arthritis Rheum. · Pubmed #17139661 links to  free full text

Abstract: OBJECTIVE: To improve accuracy and content coverage of the original 33-item Cedars-Sinai Health-Related Quality of Life for Rheumatoid Arthritis Instrument (CSHQ-RA). METHODS: A total of 312 RA patients from 55 sites were screened in a 24-week trial. Patients completed an expanded 48-item version of the CSHQ-RA, Medical Outcomes Study Short Form 36 (MOS SF-36), and Stanford Health Assessment Questionnaire (HAQ) Disability Index at 5 visits. The revised CSHQ-RA was created based on response frequencies and distributions, item-to-item correlation, factor and Rasch analysis, and input from experts. Psychometric evaluation included internal consistency, test-retest reliability, convergent and discriminant validity, and responsiveness. Minimum clinically important difference (MCID) was also measured. RESULTS: Response rates were 93% at baseline and 71% at 12 weeks. Eighty-one percent of respondents at baseline were women, mean +/- SD age was 52 +/- 12 years, and mean +/- SD duration of RA was 10.8 +/- 10.4 years. The revised CSHQ-RA included 36 items measuring 7 domains (4 original and 3 new). All Cronbach's alpha coefficients were >0.8, indicating good internal consistency. Test-retest reliability measured intraclass correlation coefficients, which ranged from 0.86 to 0.95. All 7 domains correlated significantly with the MOS SF-36 and HAQ, indicating good convergent validity. Analysis of variance of disability group scores showed good discriminant validity (P < 0.0001). The MCIDs ranged from 6.2 for social well-being to 14.8 for pain/discomfort. CONCLUSION: The revised CSHQ-RA was validated using a broader RA patient population. It captures 3 additional domains (social well-being, pain/discomfort, and fatigue), which allow for measuring all important aspects of health-related quality of life.

Cole JC, Khanna D, Clements PJ, Seibold JR, Tashkin DP, Paulus HE, Irwin MR, Motivala SJ, Furst DE. · Consulting Measurement Group, Huntington Beach, CA 91403, USA. · Qual Life Res. · Pubmed #16826439 No free full text.

Abstract: OBJECTIVE: Structural validity for the Health Assessment Questionnaire-Disability Index (HAQ-DI) has recently been provided for patients with rheumatoid arthritis (RA). The goal of the current study was to examine the structural validity of the HAQ-DI in patients with systemic sclerosis (SSc, scleroderma) and to compare its performance with that in patients with RA. METHODS: The HAQ-DI structural validity was first assessed in a sample of 100 scleroderma patients using confirmatory factor analysis. Second, the similarity of factor structures between SSc patients (n = 291) and RA patients (n = 278) was tested using a multigroup structural validity model to assure that comparison of scores between these two diagnostic groups is appropriate. RESULTS: Results yielded a single-factor HAQ-DI score which favored the current scoring system of the HAQ-DI (model fit was CFI = 0.99 and RMSEA = 0.04). Moreover, even the most stringent model of multigroup structural validity affirmed the similarity between SSc and RA patients on the HAQ-DI (model fit was CFI = 0.99 and RMSEA = 0.04) nor was it different from a model without any demands on group similarity: CFI difference = 0.007; chi(2) = 4.29, df = 26, p=0.99. CONCLUSION: The current results indicate that a single-factor HAQ-DI is appropriate for future clinical trials in scleroderma and, in addition, HAQ-DI scores among patients with SSc and early RA can be compared legitimately with one another.

Ang DC, Paulus HE, Louie JS. · Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5100, USA. · J Rheumatol. · Pubmed #16652419 No free full text.

Abstract: OBJECTIVE: Biological agents have revolutionized the treatment of rheumatoid arthritis (RA). Given the previously documented ethnic disparity in the health service literature, we sought to determine if ethnic difference exists in the lag time between the diagnosis of RA and use of first biological agent. METHODS: RADIUS 1 and 2 are observational studies designed to document how rheumatologists treat RA across the United States. The sample analyzed here included early patients with RA who entered RADIUS with the initiation of the first biological agent. Ethnic status was categorized as White (W), African American (AA), and Hispanic (H). Lag time (months from RA diagnosis to initiation of the first biological agent) was the principal outcome variable. RESULTS: Compared to W (n=1616), AA (n=147) and H (n=116) were more likely to be female, younger, and have less than a high school education. Despite similar swollen and tender joint counts, AA and H had more active disease on the basis of Health Assessment Questionnaire and patient global assessments. Almost 97% of patients had some type of insurance coverage. On multivariable analysis, ethnic affiliation was not associated with lag time (14.5 months W vs 14.9 AA vs 14.3 H; p=NS). Similarly, there were also no significant ethnic differences in time to first DMARD (e.g., methotrexate) initiation. CONCLUSION: In a national sample of patients with RA, most of whom were insured, the length of time from diagnosis of RA to initiation of the first biological agent was not significantly different among Whites, African Americans, and Hispanics.