Missing data in randomised controlled trials of rheumatoid arthritis drug therapy are substantial and handled inappropriately.

OBJECTIVES: To analyse the amount, reporting and handling of missing data, approach to intention-to-treat (ITT) principle application and sensitivity analysis utilisation in randomised clinical trials (RCTs) of rheumatoid arthritis (RA). To assess the trend in such reporting 10 years apart (2006 and 2016). METHODS: Parallel group drug therapy RA RCTs with a clinical primary endpoint. RESULTS: 176 studies enrolling a median of 160 (IQR 62-339) patients were eligible. In terms of actual analysis: 81 (46%) RCTs conducted ITT, 42 (23.9%) conducted modified ITT while 53 (30.1%) conducted non-ITT analysis. Only 58 of 97 (59.8%) RCTs reporting an ITT analysis actually performed it. The median (IQR) numbers of participants completing the trial and included in analysis for primary outcome were 86% (74%-91%) and 100% (97.1%-100%), respectively. 53 (32.7%) and 65 (40.1%) RCTs had >20% and 10%-20% missing primary outcome data, respectively. Missing data handling was unreported by 58 of 171 (33.9%) RCTs. When reported, vast majority used simple imputation methods. No significant trend towards improved reporting was seen between 2006 and 2016. Sensitivity analysis numerically improved from 2006 to 2016 (14.7% vs 21.4%). CONCLUSIONS: There is significant discrepancy in the reported and the actual performed analysis in RA drug therapy RCTs. Nearly one-third of RCTs had >20% missing data. The reporting and methods of missing data handling remain inadequate with high usage of non-preferred simple imputation methods. Sensitivity analysis utilisation was low. No trend towards better missing data reporting and handling was seen.

Scientific productivity: An exploratory study of metrics and incentives.

Competitive pressure to maximize the current bibliometric measures of productivity is jeopardizing the integrity of the scientific literature. Efforts are underway to address the 'reproducibility crisis' by encouraging the use of more rigorous, confirmatory methods. However, as long as productivity continues to be defined by the number of discoveries scientists publish, the impact factor of the journals they publish in and the number of times their papers are cited, they will be reluctant to accept high quality methods and consistently conduct and publish confirmatory/replication studies. This exploratory study examined a sample of rigorous Phase II-IV clinical trials, including unpublished studies, to determine if more appropriate metrics and incentives can be developed. The results suggest that rigorous procedures will help reduce false positives, but to the extent that higher quality methods are accepted as the standard of practice, the current bibliometric incentives will discourage innovative studies and encourage scientists to shift their research to less informative studies of subjects that are already being more actively investigated. However, the results also suggest that it is possible to develop a more appropriate system of rewards. In contrast to the current bibliometric incentives, evaluations of the quality of the methods and reproducibility of the results, innovation and diversity of thought, and amount of information produced may serve as measures and incentives that maintain the integrity of the scientific literature and maximize scientific progress.

Financial conflicts of interest and their association with outcome and quality of fibromyalgia drug therapy randomized controlled trials.

AIMS: To evaluate the association of financial conflicts of interest (FCOI) with the characteristics, outcome and reported methodological quality of fibromyalgia drug therapy randomized controlled trials (FM-RCTs). METHODS: A cross-sectional study of original, parallel-group, drug therapy FM-RCTs published between 1997 and 2011 from Medline and Cochrane Central Register of Controlled Trials was conducted. Two reviewers independently assessed each RCT for funding source, authors' FCOI(s), study characteristics, reporting of methodological measures important for internal validity and outcome (positive [statistically significant result favoring experimental drug for the primary outcome] or non-positive). RESULTS: Forty-seven RCTs were eligible with funding source as: 26 (55.3%) industry; eight (17%) non-profit source(s); five (10.6%) mixed; and eight (17%) unspecified. Industry-funded RCTs were more likely to be multicenter and enroll greater number of patients. Reporting of key methodological measures was suboptimal; however, industry and non-profit funded RCTs did not differ in their reporting. Thirty (63.8%) RCTs had ≥ one author who disclosed an FCOI (receipt of research grant [21, 44.7%], industry sponsor employee [20, 42.6%], receipt of consultancy fee/honorarium [16, 34%] and stock ownership [11, 23.4%]). Although industry funding and certain authors' FCOIs (employment and receipt of consultancy fee/honorarium) were univariately associated with positive outcome, such association was not observed after adjusting for study sample size. CONCLUSIONS: The majority of FM-RCTs were industry-sponsored, and had at least one author with an FCOI. Reporting of key methodological measures was suboptimal. After adjusting for study sample size, no association of industry funding or author's FCOI with study outcome was seen.

The association of fatigue, comorbidity burden, disease activity, disability and gross domestic product in patients with rheumatoid arthritis. Results from 34 countries participating in the Quest-RA program.

OBJECTIVES: The aim is to assess the prevalence of comorbidities and to further analyse to which degree fatigue can be explained by comorbidity burden, disease activity, disability and gross domestic product (GDP) in patients with rheumatoid arthritis (RA). METHODS: Nine thousands eight hundred seventy-four patients from 34 countries, 16 with high GDP (>24.000 US dollars [USD] per capita) and 18 low-GDP countries (<24.000 USD) participated in the Quantitative Standard monitoring of Patients with RA (QUEST-RA) study. The prevalence of 31 comorbid conditions, fatigue (0-10 cm visual analogue scale [VAS] [10=worst]), disease activity in 28 joints (DAS28), and physical disability (Health Assessment Questionnaire score [HAQ]) were assessed. Univariate and multivariate linear regression analyses were performed to assess the association between fatigue and comorbidities, disease activity, disability and GDP. RESULTS: Overall, patients reported a median of 2 comorbid conditions of which hypertension (31.5%), osteoporosis (17.6%), osteoarthritis (15.5%) and hyperlipidaemia (14.2%) were the most prevalent. The majority of comorbidities were more common in high-GDP countries. The median fatigue score was 4.4 (4.8 in low-GDP countries and 3.8 in high-GDP countries, p<0.001). In low-GDP countries 25.4% of the patients had a high level of fatigue (>6.6) compared with 23.0% in high-GDP countries (p<0.001). In univariate analysis, fatigue increased with increasing number of comorbidities, disease activity and disability in both high- and low-GDP countries. In multivariate analysis of all countries, these 3 variables explained 29.4% of the variability, whereas GDP was not significant. CONCLUSIONS: Fatigue is a widespread problem associated with high comorbidity burden, disease activity and disability regardless of GDP.

Randomized controlled trials of rheumatoid arthritis registered at ClinicalTrials.gov: what gets published and when.

OBJECTIVE: To examine characteristics associated with the publication and timeliness of publication of randomized controlled trials (RCTs) of treatment of rheumatoid arthritis (RA). METHODS: RA RCTs (phases II-IV) registered at ClinicalTrials.gov and completed by December 31, 2009 were identified. A standardized strategy was used to determine publication status and outcome assessment. The association of RCT characteristics recorded at ClinicalTrials.gov and study outcome with publication and time to publication were assessed. RESULTS: A search conducted at least 30 months after trial completion revealed that among 143 eligible RCTs, 95 (64.4%) were published. The 48 unpublished RCTs had enrolled >10,000 patients. Efficacy outcomes could be ascertained for 127 of the RCTs. RCT publication was associated with positive outcome, with an adjusted odds ratio [OR] of 4.3 (95% confidence interval [95% CI] 1.8-10.2) (P = 0.001), and marginally with RCT registration before completion (adjusted OR 0.4 [95% CI 0.1-1.0], P = 0.06). The estimated median time to publication was 38 months. Positive outcome was associated with earlier publication (adjusted hazard ratio 1.9 [95% CI 1.2-2.9], P = 0.006). RCTs completed in 2006-2007 or 2008-2009 were likely to be published sooner than RCTs completed in or before 2005. Sensitivity analyses to assess the impact of 16 RCTs with unknown outcome did not alter these findings, except in the highly implausible scenario of all such trials being positive. CONCLUSION: Positive study outcome was associated with publication and timeliness of publication despite registration in a publicly available registry. A substantial minority of RA RCTs remained unpublished. Efforts to improve transparency in reporting of clinical trials need to continue.

Smoking cessation advice by rheumatologists: results of an international survey.

OBJECTIVE: The aim of this study was to understand practices regarding smoking cessation among rheumatologists for patients with inflammatory rheumatic diseases. METHODS: A survey was sent to the rheumatologists participating in the multinational Quantitative Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST-RA) group. The survey inquired about the clinical practice characteristics and practices regarding smoking cessation (proportion of smokers with inflammatory rheumatic diseases given smoking cessation advice, specific protocols and written advice material, availability of dedicated smoking cessation clinic). RESULTS: Rheumatologists from 44 departments in 25 countries (16 European) completed the survey. The survey involved 395 rheumatologists, of whom 25 (6.3%) were smokers, and 199 nurses for patient education, of whom 44 (22.1%) were smokers. Eight departments (18.1 %) had a specific protocol for smoking cessation; 255 (64.5%) rheumatologists reported giving smoking cessation advice to all or almost all smokers with inflammatory diseases. In a regression model, early arthritis clinics (P = 0.01) and high gross domestic product countries (P = 0.001) were both independently associated with advice by the rheumatologist. Nurse gives advice to most patients in 11 of the 36 (30.5%) departments with nurses for patient education. CONCLUSION: Advice for smoking cessation within rheumatology departments is not homogeneous. In half of the departments, most doctors give advice to quit smoking to all or almost all patients with inflammatory diseases. However, only one in five departments have a specific protocol for smoking cessation. Our data highlight the need to improve awareness of the importance of and better practice implementation of smoking cessation advice for inflammatory rheumatic disease patients.

Diastolic dysfunction in rheumatoid arthritis: a meta-analysis and systematic review.

OBJECTIVE: To determine if the prevalence of diastolic dysfunction is increased in rheumatoid arthritis (RA) patients. METHODS: We conducted a time- and language-restricted literature search to identify studies conducted to compare echocardiographic parameters in patients with RA and controls. The mean difference for echocardiographic variables of interest was calculated using a random-effects model. A systematic review of the literature was performed. RESULTS: A total of 25 studies reporting on 5,836 subjects (1,614 with RA) were included. Results reflect mean differences, with positive values denoting higher values in RA patients. Patients with RA had larger mean left atrial dimension (mean difference 0.09 cm [95% confidence interval (95% CI) 0.01, 0.17]; P = 0.02), higher left ventricular mass index (mean difference 6.2 gm/m(2) [95% CI 1.08, 11.33]; P = 0.02), higher mean systolic pulmonary artery pressure (mean difference 5.87 mm Hg [95% CI 4.36, 7.38]; P < 0.00001), prolonged isovolumetric relaxation time (mean difference 9.67 msec [95% CI 5.78, 13.56]; P < 0.00001), and higher transmitral A wave velocity (mean difference 0.13 meters/second [95% CI 0.07, 0.18]; P < 0.00001) compared to controls. A subanalysis of 2,183 subjects excluding 2 large unmatched studies showed the same results, with the exception that patients with RA had a lower mitral E/A ratio (mean difference -0.17 [95% CI -0.25, -0.09]; P < 0.00001), suggestive of diastolic dysfunction. There were no differences in left ventricular ejection fraction (%), transmitral E wave velocity (meters/second), and mitral deceleration time (msec). CONCLUSION: Patients with RA were more likely to have echocardiographic parameters of diastolic dysfunction, and have higher systolic pulmonary artery pressures and larger left atrial sizes.

Body mass index and the rheumatoid arthritis swollen joint count: an observational study.

OBJECTIVE: Obesity is a prevalent condition and a serious health concern. The relationship between obesity and rheumatoid arthritis (RA) disease activity and severity has not been adequately examined, and there are concerns that periarticular adipose tissue may reduce the utility of the joint examination. METHODS: We used a cross-sectional study to compare the performance of swollen joint count (SJC) in subjects with RA across body mass index (BMI) strata. Specifically, regression techniques tested for associations of SJC and 7 RA disease activity/severity measures (including high-sensitivity C-reactive protein level, radiographic changes, and Multidimensional Health Assessment Questionnaire scores) within BMI quartiles. We also evaluated the association of BMI with radiographic evidence of RA in multivariate analyses and the association of BMI with SJC. Clinical and laboratory data from 980 Veterans Affairs Rheumatoid Arthritis registry participants were analyzed using linear and logistic regression. RESULTS: Associations were evident between SJC and 6 of the 7 examined RA disease activity/severity measures. SJC predicts RA disease activity/severity in more obese subjects at least as well as in subjects with lower BMIs, and there was a trend toward better performance in individuals with higher BMIs. Subjects with higher BMIs were marginally less likely to be characterized by radiographic changes (odds ratio 0.98, P = 0.051). We found no association between BMI and SJC. CONCLUSION: BMI does not obscure the relationship of SJC and objective disease activity measures. There is a borderline association of higher BMI and the likelihood of radiographic changes characteristic of RA after controlling for clinical characteristics.

Disease activity assessment and patient-reported outcomes in patients with early rheumatoid arthritis.

Quantitative assessment of disease activity and patient-reported outcomes are recognized as valuable in the management of rheumatoid arthritis (RA). Complexities of assessment of RA include challenges concerning measures themselves, as a gold standard measure for disease status does not exist. This article discusses the hurdles in the implementation of quantitative assessment of RA in usual clinical care and also provides an example to monitor patients with early RA.

Serum metabolomic profiles from patients with acute kidney injury: a pilot study.

Low sensitivity of current clinical markers (serum creatinine and blood urea nitrogen (BUN)) in early stages of the development of acute kidney injury (AKI) limits their utility. Rapid LC/MS-based metabolic profiling of serum demonstrated in a pilot study that metabolomics could provide novel indicators of AKI. Metabolic profiles of serum samples from seventeen hospitalized patients with newly diagnosed AKI were compared with the profiles of serum from age-matched subjects with normal kidney function. Increases in acylcarnitines and amino acids (methionine, homocysteine, pyroglutamate, asymmetric dimethylarginine (ADMA), and phenylalanine) and a reduction in serum levels of arginine and several lysophosphatidyl cholines were observed in patients with AKI compared to healthy subjects. Increases in homocysteine, ADMA and pyroglutamate have been recognized as biomarkers of cardiovascular and renal disease, and acylcarnitines represent biomarkers of defective fatty acid oxidation. The results of this pilot study demonstrate the utility of metabolomics in the discovery of novel serum biomarkers that can facilitate the diagnosis and determine prognosis of AKI in hospitalized patients.

Association of industry funding with the outcome and quality of randomized controlled trials of drug therapy for rheumatoid arthritis.

OBJECTIVE: To assess the association of industry funding with the characteristics, outcome, and reported quality of randomized controlled trials (RCTs) of drug therapy for rheumatoid arthritis (RA). METHODS: The Medline and Cochrane Central Register of Controlled Trials databases were searched to identify original RA drug therapy RCTs published in 2002-2003 and 2006-2007. Two reviewers independently assessed each RCT for the funding source, characteristics, outcome (positive [statistically significant result favoring experimental drug for the primary outcome] or not positive), and reporting of methodologic measures whose inadequate performance may have biased the assessment of treatment effect. RCTs that were registered at ClinicalTrials.gov and completed during the study years were assessed for publication bias. RESULTS: Of the 103 eligible RCTs identified, 58 (56.3%) were funded by industry, 19 (18.4%) were funded by nonprofit sources, 6 (5.8%) had mixed funding, and funding for 20 (19.4%) was not specified. Industry-funded RCTs had significantly more study centers and subjects, while nonprofit agency-funded RCTs had longer duration and were more likely to study different treatment strategies. Outcome could be assessed for 86 (83.5%) of the 103 RCTs studied. The funding source was not associated with a higher likelihood of positive outcomes favoring the sponsored experimental drug (75.5% of industry-funded RCTs had a positive outcome, compared with 68.8% of non-industry-funded RCTs, 40% of RCTs with mixed funding, and 81.2% of RCTs for which funding was not specified). Industry-funded RCTs showed a trend toward a higher likelihood of nonpublication (P=0.093). Industry-funded RCTs were more frequently associated with double-blinding, an adequate description of participant flow, and performance of an intent-to-treat analysis. CONCLUSION: Industry funding was not associated with a higher likelihood of positive outcomes of published RCTs of drug therapy for RA, and industry-funded RCTs performed significantly better than non-industry-funded RCTs in terms of reporting the use of some key methodologic quality measures.

Determinants of discordance in patients' and physicians' rating of rheumatoid arthritis disease activity.

OBJECTIVE: To assess the determinants of patients' (PTGL) and physicians' (MDGL) global assessment of rheumatoid arthritis (RA) activity and factors associated with discordance among them. METHODS: A total of 7,028 patients in the Quantitative Standard Monitoring of Patients with RA study had PTGL and MDGL assessed at the same clinic visit on a 0-10-cm visual analog scale (VAS). Three patient groups were defined: concordant rating group (PTGL and MDGL within ±2 cm), higher patient rating group (PTGL exceeding MDGL by >2 cm), and lower patient rating group (PTGL less than MDGL by >2 cm). Multivariable regression analysis was used to identify determinants of PTGL and MDGL and their discordance. RESULTS: The mean ± SD VAS scores for PTGL and MDGL were 4.01 ± 2.70 and 2.91 ± 2.37, respectively. Pain was overwhelmingly the single most important determinant of PTGL, followed by fatigue. In contrast, MDGL was most influenced by swollen joint count (SJC), followed by erythrocyte sedimentation rate (ESR) and tender joint count (TJC). A total of 4,454 (63.4%), 2,106 (30%), and 468 (6.6%) patients were in the concordant, higher, and lower patient rating groups, respectively. Odds of higher patient rating increased with higher pain, fatigue, psychological distress, age, and morning stiffness, and decreased with higher SJC, TJC, and ESR. Lower patient rating odds increased with higher SJC, TJC, and ESR, and decreased with lower fatigue levels. CONCLUSION: Nearly 36% of patients had discordance in RA activity assessment from their physicians. Sensitivity to the "disease experience" of patients, particularly pain and fatigue, is warranted for effective care of RA.

Declining needs for total joint replacements for rheumatoid arthritis.

This millennium brings new views to rheumatology. Total joint replacement surgery is needed less often as active treatment strategies combined with availability of new medications has led to more effective rheumatoid arthritis control. This was beautifully shown in a recent issue of Arthritis Research & Therapy by a Swedish study that uses data from national registers and compares incidence rates for total hip and knee arthroplasties before and after the establishment of biologic agents use for rheumatoid arthritis.

Reevaluation of the role of duration of morning stiffness in the assessment of rheumatoid arthritis activity.

OBJECTIVE: To evaluate the utility of the duration of morning stiffness (MS), as a patient-reported outcome (PRO), in assessing rheumatoid arthritis (RA) disease activity. METHODS: We acquired information on 5439 patients in QUEST-RA, an international database of patients with RA evaluated by a standard protocol. MS duration was assessed from time of waking to time of maximal improvement. Ability of MS duration to differentiate RA activity states, based on Disease Activity Score (DAS)28, was assessed by analysis of variance; and a receiver-operating characteristic (ROC) curve was plotted for discriminating clinically active (DAS28 > 3.2) from less active (DAS28 3.2). CONCLUSION: MS duration has a moderate correlation with RA disease activity. Assessment of MS duration may be clinically helpful in patients with low RAPID3 scores.

Clinical trials and public trust: the geographical shift to the Asia-Pacific region.

Multiple issues surrounding the publication of clinical trials and the conduct of clinical trials, especially those that are industry-sponsored, have raised doubts regarding the integrity of their results, and of the integrity of the medical profession. An appreciation of the historical and economic changes in the relationship between physicians and industry is crucial to the understanding of these issues. Increasingly, as healthcare professionals and centers in the Asia-Pacific region become involved in corporate-funded multi-center drug trials, these ethical issues similarly come into play. It is imperative for medical leaders to take actions ensuring rights of subjects participating in these clinical trials, and to ensure the integrity of physicians and authors of clinical trials from this region of the world.

Clinical profile and outcome of hospitalized patients during first outbreak of dengue in Makkah, Saudi Arabia.

OBJECTIVE: To describe clinical profile of patients with dengue virus infection hospitalized at a single center during the first outbreak of dengue in Makkah, Saudi Arabia from April to July 2004. METHODS: Clinical information and laboratory abnormalities of patients with suspected dengue infection were collected by a standardized data collection sheet and review of medical records. Dengue virus infection was confirmed by a positive IgM capture ELISA or RT-PCR. RESULTS: Of the 160 clinically suspected patients, 91 were confirmed (64 by IgM ELISA, 14 by RT-PCR and 13 by both) to have dengue virus infection. Dengue serotypes 2 and 3 were identified in 19 and 4 patients respectively. Most patients were young adults with median age of 26 (range=6-94) years and male:female ratio of 1.5:1. The common symptoms were fever (100%), malaise (83%), musculoskeletal pain (81%), headache (75%), nausea (69%), vomiting (65%) and abdominal pain (48%). According to World Health Organization (WHO) classification (10 patients were excluded due to lack of serial hematocrits), 75 (93%) had dengue fever (DF) and 6 (7%) had dengue hemorrhagic fever (DHF). Only one patient with DHF was in pediatric age group. Twenty-one patients (5 with DHF and 16 with DF) developed one or more clinical complications that included bleeding (14), shock (4), seizures (3), acute renal failure (2), meningo-encephalitis (1), and secondary bacterial infection (1). Only one patient with shock had dengue shock syndrome (DSS) by WHO classification. Development of clinical complications was significantly associated with absence of musculoskeletal pain (p-value=0.03), lower platelet counts (p-value=0.03) and higher serum aspartate aminotransferase levels (p-value=0.04). The median duration of symptoms and hospitalization was 8 days (range=3-18) and 4 days (range=1-10) respectively. No mortality was noted. CONCLUSION: Occurrence of dengue virus infection in Makkah, Saudi Arabia is documented. Continued surveillance and effective vector control programs are warranted due to unique population dynamics of Makkah that receives millions of pilgrims annually from all over the world.

Pattern of medical diseases and determinants of prognosis of hospitalization during 2005 Muslim pilgrimage Hajj in a tertiary care hospital. A prospective cohort study.

OBJECTIVE: To document the pattern of medical diseases necessitating admission in a tertiary care hospital during Muslim pilgrimage (Hajj). To assess the risk factors associated with mortality during hospitalization. METHODS: The study was conducted at Al Noor Specialist Hospital, a 550-bed tertiary care teaching hospital, in Makkah, KSA. The participants included all Hajj patients admitted in the Department of Medicine in a 5-week period (January 3 to February 6, 2005) during the 2005 (1425 AH) Hajj. Information about demographics; past medical history; pre-Hajj functional status; presence of language barrier and translator availability; diagnosis for admission and complications during hospitalization including mortality was obtained prospectively using a standardized form. RESULTS: Six hundred and eighty-nine patients, belonging to 49 countries, with mean age of 62 years and male:female ratio of 1.8:1 were admitted. Two hundred-twenty (31.9%) had diabetes mellitus, 256 (37.2%) had hypertension, 219 (31.8%) had cardiac disease, and 103 (14.9%) patients had chronic lung disease. Of the 449 (65.2%) patients assessed, 284 (63.2%) patients had language barrier, and translator was not available for 152 (53.5%) of them. Pre-Hajj functional status assessment of 240 patients showed that 20 (8.3%) required assistance in performing activities of daily living (ADL), and 40 (16.7%) could not walk for half kilometer without difficulty. Common causes of morbidity were: 235 (34.1%) cardiovascular, 137 (19.9%) infectious and 85 (12.3%) neurological diseases. One hundered and fourteen (16.5%) patients died, with the common causes being pneumonia (28 patients), acute coronary syndrome (21), and stroke (20). The risk factors associated with higher mortality were older age (65 +/- 1 versus 61 +/- 0.6 years, p=0.008), prior history of chronic lung disease (crude odds ratio, 1.81, p=0.034), dependence in any ADLs (4.90, p=0.025), inability to ambulate for half kilometer without difficulty (4.17, p=0.017) and non-availability of translator for patients with language barrier (5.51, p<0.0001). CONCLUSION: Most patients were elderly with high prevalence of chronic medical disorders. Non-infectious diseases accounted for most morbidity and mortality. Pre-Hajj functional assessment should be carried out to identify patients at high risk of mortality. Provision of translator services for patients with language barrier is essential to improve future outcomes.