Maria E. Suarez-Almazor

2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease‐modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis

The American College of Rheumatology (ACR) most recently published recommendations for use of disease modifying anti-rheumatic drugs (DMARDs) and biologics in the treatment of rheumatoid arthritis (RA) in 2008 (1). These recommendations covered indications for use, monitoring of side-effects, assessment of the clinical response to DMARDs and biologics, screening for tuberculosis (TB), and assessment of the roles of cost and patient preference in decision-making for biologic agents (1). Recognizing the rapidly evolving knowledge in RA management and the accumulation of new evidence regarding the safety and efficacy of existing and newer therapies, the ACR commissioned an update of the 2008 recommendations in select topic areas. The 2012 revision updates the 2008 ACR recommendations in the following areas: (1) indications for DMARDs and biologics; (2) switching between DMARD and biologic therapies; (3) use of biologics in high-risk patients (those with hepatitis, congestive heart failure, and malignancy); (4) screening for TB in patients starting or currently receiving biologics; and (5) vaccination in patients starting or currently receiving DMARDs or biologics (Table 1). Table 1 Overview Comparison of Topics and Medications Included in the 2008 and 2012 ACR RA Recommendations METHODS We utilized the same methodology as described in detail in the 2008 guidelines (1) to maintain consistency and to allow cumulative evidence to inform this 2012 recommendation update. These recommendations were developed by two expert panels: (1) a non-voting working group and Core Expert Panel (CEP) of clinicians and methodologists responsible for the selection of the relevant topic areas to be considered, the systematic literature review, and the evidence synthesis and creation of “clinical scenarios”; and (2) a Task Force Panel (TFP) of 11 internationally-recognized expert clinicians, patient representatives and methodologists with expertise in RA treatment, evidence-based medicine and patient preferences who were tasked with rating the scenarios created using an ordinal scale specified in the Research and Development/University of California at Los Angeles (RAND/UCLA) Appropriateness method (2–4). This method solicited formal input from a multi-disciplinary TFP panel to make recommendations informed by the evidence. The methods used to develop the updated ACR recommendations are described briefly below. Systematic Literature Review – Sources, Databases and Domains Literature searches for both DMARDs and biologics relied predominantly on PubMed searches) with medical subject headings (MeSH) and relevant keywords similar to those used for the 2008 ACR RA recommendations (see Appendices 1 and 2). We included randomized clinical trials (RCTs), controlled clinical trials (CCTs), quasi-experimental designs, cohort studies (prospective or retrospective), and case-control studies, with no restrictions on sample size. More details about inclusion criteria are listed below and in Appendix 3. The 2008 recommendations were based on a literature search that ended on February 14, 2007. The literature search end date for the 2012 Update was February 26, 2010 for the efficacy and safety studies and September 22, 2010 for additional qualitative reviews related to TB screening, immunization and hepatitis (similar to the 2008 methodology). Studies published subsequent to that date were not included. For biologics, we also reviewed the Cochrane systematic reviews and overviews (published and in press) in the Cochrane Database of Systematic Reviews to identify additional studies (5–8) and further supplemented by hand-checking the bibliographies of all included articles. Finally, the CEP and TFP confirmed that relevant literature was included for evidence synthesis. Unless they were identified by the literature search and met the article inclusion criteria (see Appendix 3), we did not review any unpublished data from product manufacturers, investigators, or the Food and Drug Administration (FDA) Adverse Event Reporting System. We searched the literature for the eight DMARDs and nine biologics most commonly used for the treatment of RA. Literature was searched for eight DMARDS including azathioprine, cyclosporine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds and sulfasalazine. As in 2008, azathioprine, cyclosporine and gold were not included in the recommendations based on infrequent use and lack of new data (Table 1). Literature was searched for nine biologics including abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab and tocilizumab; anakinra was not included in the recommendations due to infrequent use and lack of new data. Details of the bibliographic search strategy are listed in Appendix 1.

Racial and ethnic disparities in the use of health services: Bias, preferences, or poor communication?

African Americans and Latinos use services that require a doctor’s order at lower rates than do whites. Racial bias and patient preferences contribute to disparities, but their effects appear small. Communication during the medical interaction plays a central role in decision making about subsequent interventions and health behaviors. Research has shown that doctors have poorer communication with minority patients than with others, but problems in doctor-patient communication have received little attention as a potential cause, a remediable one, of health disparities. We evaluate the evidence that poor communication is a cause of disparities and propose some remedies drawn from the communication sciences.

Survival prediction in terminal cancer patients: a systematic review of the medical literature.

The clinical significance of studies on survival predictors in terminal cancer patients is hindered by both methodological limitations and the difficulty of finding common predictors for all final events in cancer related deaths. To evaluate the published medical literature concerned with the survival of patients with terminal cancer and identify potential prognostic factors, major electronic databases including MEDLINE (1966–), CANCERLIT (1983–) and EMBASE (1988–) were searched up to September 1999. Studies were included in our review if published in English, were cohort studies, addressed the identification of clinical prognostic factors for survival and looked at samples with median survival of [.lessequal]3 months. Data extracted from selected papers included: sample size, median survival, type of study, sampling frame, cohort type, type of statistical analysis (univariate or multivariate), choice of models and underlying assumptions, predictors examined and their reported level of statistical significance. A total of 24 studies were found and reviewed. On the basis of these studies, performance status and the presence of cognitive failure, weight loss, dysphagia, anorexia and dyspnoea appear to be independent survival predictors in this population. Clinical estimation of survival by the treating physician appeared independently associated with survival but the magnitude of the association generally appeared small. Clinical predictions should be considered as one of many criteria, rather than as a unique criterion by which to choose therapeutic interventions or health care programmes for terminally ill cancer patients. The use of convenient samples as opposed to more representative inception cohorts, the inclusion of different variables in the statistical analyses and inappropriate statistical methods appear to be major limitations of the reviewed literature. Methodological improvements in the design and conduction of future studies may reduce the prognostic uncertainty in this population.

Understanding the pain experience in hip and knee osteoarthritis – an OARSI/OMERACT initiative

OBJECTIVE To examine the pain experience of people with hip or knee osteoarthritis (OA), particularly changes over time and most distressing features. METHOD Focus groups in individuals aged 40+ years with painful hip or knee OA obtained detailed descriptions of OA pain from early to late disease. A modified Patient Generated Index (PGI) was used to assess the features of OA pain that participants found most distressing. Content analysis was performed to examine response patterns; descriptive statistics were used to summarize PGI responses. RESULTS Mean age of the 143 participants (52 hip OA; 91 knee OA) was 69.5 years (47-92 years); 60.8% were female and 93.7% Caucasian. Participants described two distinct types of pain - a dull, aching pain, which became more constant over time, punctuated increasingly with short episodes of a more intense, often unpredictable, emotionally draining pain. The latter, but not the former, resulted in significant avoidance of social and recreational activities. From PGI responses, distressing pain features were: the pain itself (particularly intense and unpredictable pain) and the pains impact on mobility, mood and sleep. CONCLUSIONS Two distinct pain types were identified. Intermittent intense pain, particularly when unpredictable, had the greatest impact on quality of life.

Changing pattern of agitated impaired mental status in patients with advanced cancer: Association with cognitive monitoring, hydration, and opioid rotation

In late 1990, it became standard practice at the palliative care unit of the Edmonton General Hospital to regularly administer the Mini-Mental State Questionnaire (MMSQ) and to undertake opioid rotation and hydration upon detection of cognitive failure. We retrospectively reviewed the charts of 117 and 162 patients admitted in 1988-1989 and 1991-1992, respectively, to assess the impact of these maneuvers on the prevalence of agitated impaired mental status (IMS). All patients underwent regular cognitive assessment in 1991-1992 versus none in 1988-1989. Seventy-three percent of patients received hydration in the second period versus 32% in the first (P < 0.01). The frequency of opioid rotation was also greater in the second period (41% versus 21%, P < 0.001). The incidence of agitated IMS decreased from 26% in 1988-1989 to 10% in 1991-1992 (P < 0.001). This was reflected by a lower mean dose of the major drug used to treat this condition, haloperidol (3.6 +/- 2.4 versus 5.6 +/- 3.8 mg/day, P < 0.01), and less frequent use of other neuroleptics and benzodiazepines (0.12 versus 0.38 prescriptions per patient, P < 0.01) in the second period. Our data suggest that routine cognitive monitoring, opioid rotation, and hydration may reduce the incidence of agitated IMS in terminal cancer patients.

A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview

Background: We sought to compare the benefits and safety of 6 biologics (abatacept, adalimumab, anakinra, etanercept, infliximab and rituximab) in patients with rheumatoid arthritis. Methods: In this network meta-analysis, we included all completed and updated Cochrane reviews on biologics for rheumatoid arthritis. We included data from all placebo-controlled trials that used standard dosing regimens. The major outcomes were benefit (defined as a 50% improvement in patient- and physician-reported criteria of the American College of Rheumatology [ACR50]) and safety (determined by the number of withdrawals related to adverse events). We used mixed-effects logistic regression to carry out an indirect comparison of the treatment effects between biologics. Results: Compared with placebo, biologics were associated with a clinically important higher ACR50 rate (odds ratio [OR] 3.35, 95% confidence interval [CI] 2.62–4.29) and a number needed to treat for benefit of 4 (95% CI 4–6). However, biologics were associated with more withdrawals related to adverse events (OR 1.39, 95% CI 1.13–1.71), with a number needed to treat for harm of 52 (95% CI 29–152). Anakinra was less effective than all of the other biologics, although this difference was statistically significant only for the comparison with adalimumab (OR 0.45, 95% CI 0.21–0.99) and etanercept (OR 0.34, 95% CI 0.14–0.81). Adalimumab, anakinra and infliximab were more likely than etanercept to lead to withdrawals related to adverse events (adalimumab OR 1.89, 95% CI 1.18–3.04; anakinra OR 2.05, 95% CI 1.27–3.29; and infliximab OR 2.70, 95% CI 1.43–5.26). Interpretation: Given the limitations of indirect comparisons, anakinra was less effective than adalimumab and etanercept, and etanercept was safer than adalimumab, anakinra and infliximab. This summary of the evidence will help physicians and patients to make evidence-based choices about biologics for the treatment of rheumatoid arthritis.

Mortality and Institutionalization Following Hip Fracture

OBJECTIVES: To identify determinants of mortality and institutionalization after hip fracture and to identify those older hip fracture patients at high risk of death or institutionalization after hip fracture.

Development and preliminary psychometric testing of a new OA pain measure – an OARSI/OMERACT initiative

OBJECTIVE To evaluate the measurement properties of a new osteoarthritis (OA) pain measure. METHODS The new tool, comprised of 12 questions on constant vs intermittent pain was administered by phone to 100 subjects aged 40+ years with hip or knee OA, followed by three global hip/knee questions, the Western Ontario and McMaster Universities (WOMAC) pain subscale, the symptom subscales of the Hip Disability and OA Outcome Score (HOOS) or Knee Injury and OA Outcome Score (KOOS), and the limitation dimension of the Late Life Function and Disability Instrument (LLFDI). Test-retest reliability was assessed by re-administration after 48-96h. Item response distributions, inter-item correlations, item-total correlations and Cronbachs alpha were assessed. Principle component analysis was performed and test-retest reliability was assessed by intra-class correlation coefficient (ICC). RESULTS There was good distribution of response options across all items. The mean intensity was higher for intermittent vs constant pain, indicating subjects could distinguish the two concepts. Inter-item correlations ranged from 0.37 to 0.76 indicating no item redundancy. One item, predictability of pain, was removed from subsequent analyses as correlations with other items and item-total correlations were low. The 11-item scale had a corrected inter-item correlation range of 0.54-0.81 with Cronbachs alpha of 0.93 for the combined sample. Principle components analysis demonstrated factorial complexity. As such, scoring was based on the summing of individual items. Test-retest reliability was excellent (ICC 0.85). The measure was significantly correlated with each of the other measures [Spearman correlations -0.60 (KOOS symptoms) to 0.81 (WOMAC pain scale)], except the LLFDI, where correlations were low. CONCLUSIONS Preliminary psychometric testing suggests this OA pain measure is reliable and valid.

Identifying clinical trials in the medical literature with electronic databases : MEDLINE alone is not enough

The objective of this study was to compare the performance of MEDLINE and EMBASE for the identification of articles regarding controlled clinical trials (CCTs) published in English and related to selected topics: rheumatoid arthritis (RA), osteoporosis (OP), and low back pain (LBP). MEDLINE and EMBASE were searched for literature published in 1988 and 1994. The initial selection of papers was then reviewed to confirm that the articles were about CCTs and to assess the quality of the studies. Selected journals were also hand searched to identify CCTs not retrieved by either database. Overall, 4111 different references were retrieved (2253 for RA, 978 for OP, and 880 for LBP); 3418 (83%) of the papers were in English. EMBASE retrieved 78% more references than MEDLINE (2895 versus 1625). Overall, 1217 (30%) of the papers were retrieved by both databases. Two hundred forty-three papers were about CCTs. Two-thirds of these were retrieved by both databases, and one-third by only one. An additional 16 CCTs not retrieved by either database were identified through hand searching. Taking these into account, EMBASE retrieved 16% more CCTs than MEDLINE (220 versus 188); the EMBASE search identified 85% of the CCTs compared to 73% by MEDLINE. No significant differences were observed in the mean quality scores and sample size of the CCTs missed by MEDLINE compared to those missed by EMBASE. Our findings suggest that the use of MEDLINE alone to identify CCTs is inadequate. The use of two or more databases and hand searching of selected journals are needed to perform a comprehensive search.

Variation in the Estimation of Quality-adjusted Life-years by Different Preference-based Instruments

Objectives. To assess the interchangeability of preference‐based health‐related quality of life tools and compare the potential gains in quality‐adjusted life years (QALYs) in patients with musculoskeletal disease. Methods. Consecutive patients visiting a rheumatology clinic completed health‐related quality of life assessments at baseline and 3, 6, and 12 months with the EuroQol (EQ‐5D), Health Utilities Index (HUI3), and Short‐Form 6D (SF‐6D). Patients rated their health changes retrospectively and responses were categorized into three groups: better, same, and worse. Correlations and repeated measures analysis of variance with post hoc contrasts and a Bonferroni correction were used to assess interchangeability of tools. Results. Results were based on 161 cases with complete baseline data and 98 cases with data at baseline and 12 months. Correlations ranged from 0.66 to 0.79. An interaction effect showed that for the better group, the EQ‐5D showed a significantly greater mean improvement (0.15) than the HUI3 (0.07) or the SF‐6D (0.05). For the worse group, the EQ‐5D showed a significantly greater mean decrease (0.19) than either the HUI3 (0.05) or the SF‐6D (0.03). QALYs differences between the better and worse groups were significantly greater (0.23) with the EQ‐5D than with the HUI3 (0.11) or the SF‐6D (0.09). Conclusions. Although results moderately support the idea that the three tools are measuring a similar underlying construct, the tools are not interchangeable because they are scaled differently and produce varying results. These findings have potential implications for the interpretation and comparability of health outcome studies and economic analyses. Possible approaches are sensitivity analysis or standardization of scores before calculation of QALYs.