A randomised double-blind placebo-controlled crossover trial of HUMira (adalimumab) for erosive hand OsteoaRthritis - the HUMOR trial.

OBJECTIVE: To assess the efficacy of adalimumab in patients with erosive hand osteoarthritis (OA). METHOD: Patients >50 years old, meeting the American College of Rheumatology (ACR) criteria for hand OA, with pain >50 on 100 mm visual analogue scale (VAS), morning stiffness >30 min and ≥1 erosive joint on X-ray with synovitis present on magnetic resonance imaging (MRI) were included in a randomised double-blind placebo-controlled crossover trial. Patients were randomised to adalimumab (40 mg subcutaneous injections every other week) or identical placebo injections for 12 weeks followed by an 8-week washout and then crossed over treatment groups for another 12 weeks. The primary outcome was change in VAS hand pain over 12 weeks. Secondary outcomes included change in Australian/Canadian Hand OA Index (AUSCAN) pain, function and stiffness subscales from baseline to 4, 8 and 12 weeks, change in MRI-detected synovitis and bone marrow lesions (BMLs) from baseline to 12 weeks and change in VAS from baseline to 4 and 8 weeks. RESULTS: We recruited 51 patients and 43 were randomised to either Group 1 (N = 18, active then placebo) or Group 2 (N = 25, placebo then active). At 12 weeks there was no difference between the groups on the primary outcome measure (mean decrease in VAS pain of 3.2 mm standard deviation (SD 16.7) for adalimumab vs 0.8 mm (SD 29.6) for placebo). The adjusted treatment effect was -0.7 mm (95% confidence interval (CI) -9.3 to 8.0), P = 0.87. No statistically significant differences were found for any secondary outcomes. CONCLUSION: Adalimumab did not show any effect on pain, synovitis or BMLs in patients with erosive hand OA with MRI-detected synovitis as compared to placebo after 12 weeks. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12612000791831.

Development, linguistic and clinimetric validation of the WOMAC VA3.01 Bangla for Bangladesh Index.

The aim of this study was to develop and to validate a Bengali version of the Western Ontario and McMaster Osteoarthritis (WOMAC) index in Bangladesh. The WOMAC was translated into the local language of Bangladesh (Bengali) and adapted in the local sociocultural context, following the standard guidelines by Beaton et al. Content validity of the preliminary Bengali version was assessed by using the index of content validity (ICV) and floor and ceiling effects. Patients were assessed at the Department of Rheumatology of Bangabandhu Sheikh Mujib Medical University and were diagnosed to have knee OA by American College of Rheumatology criteria and recruited according to the requirements of the validation study. Convergent and divergent validity were measured by comparing with Health Assessment Questionnaire (HAQ) and the Short Form-36 (SF-36), and internal consistency was assessed using Cronbach's alpha coefficient. The questionnaire was readministered to 40 patients within a week for assessing reliability by using intra-class correlation coefficient (ICC) and Spearman's rank correlation coefficient. In addition, factor analysis of Bengali WOMAC questionnaire was performed to examine the number of factors influencing a common set of items. A Bengali version was developed with changes in three items to suit local practices. The ICV of the content validity was 1 for all items. The Bengali WOMAC had similar construct validity when compared to the HAQ (ρ 0.74, n = 70) and SF-36 bodily pain and physical functioning. It had dissimilar construct validity to SF-36 mental health domain except WOMAC pain. Factor analysis revealed five factors with eigenvalues of more than 1.0. Cronbach's alpha and ICC exceeded 0.7 in all domains. In the test-retest reliability testing, Spearman's ρ for all items exceeded 0.4 (n = 40). This study has demonstrated that the Bengali version of WOMAC is a valid tool for assessing quality of life of patients with knee osteoarthritis in Bangladesh and is reliable.

Severity in irritable bowel syndrome: a Rome Foundation Working Team report.

OBJECTIVES: The concept of severity in irritable bowel syndrome (IBS) is clinically recognized and operative in diagnostic decision making and treatment planning. Yet, there is no consensus on its definition, and there are limited data on the prevalence of severity subgroups, its medical and psychosocial determinants, and its association with other health status measures. The aims of the Rome Foundation Working Team Committee were to summarize current research, to develop a consensus of understanding on this concept, and to make recommendations for its use in research and clinical care. METHODS: In 2006, a multinational committee of clinical investigators with expertise in IBS and/or psychometric research methods undertook a systematic review of the literature relating to severity in IBS. Owing to limited data, the Foundation commissioned three clinical studies to better characterize the concept of severity in IBS, and summary information and recommendations for future research and clinical care were developed. RESULTS: The main findings were: (i) severity in IBS is defined as a biopsychosocial composite of patient-reported gastrointestinal and extraintestinal symptoms, degree of disability, and illness-related perceptions and behaviors; (ii) both visceral and central nervous system physiological factors affect severity; as severity increases, the central nervous system provides a greater contribution; (iii) severity is related to and influences health-related quality of life and health behaviors and also guides diagnostic and therapeutic clinical decision making; (iv) severity can be subcategorized into clinically meaningful subgroups as mild (∼40%), moderate (∼35%), and severe (∼25%), and this provides a working model for use in future research and clinical care. CONCLUSIONS: Future work is required to understand more precisely the factors contributing to severity and to develop a valid patient-reported instrument to measure severity in IBS.

Progression of hand osteoarthritis over 2 years: a clinical and radiological follow-up study.

OBJECTIVES: To investigate the course of hand osteoarthritis over 2 years by currently available outcome measures. METHODS: 189 participants of the Genetics, Arthrosis and Progression (GARP) study with hand osteoarthritis were followed for 2 years. Self-reported hand pain and functional limitations were assessed with the Australian/Canadian osteoarthritis hand index (AUSCAN LK 3.0). Pain intensity upon lateral pressure in the interphalangeal and thumb base joints was graded on a four-point scale. Osteophytes (0-3) and joint space narrowing (JSN) (0-3) was scored at baseline and after 2 years in interphalangeal and thumb base joints. Standardised response means (SRM) were calculated. RESULTS: 172 (91%) patients completed the 2-year follow-up (mean age 60.5 years, 78.5% women). Statistically significant increases in self-reported pain and function scores, in pain intensity scores as well as in osteophyte and JSN total scores were seen over 2 years. SRM were 0.25, 0.23, 0.67, 0.34 and 0.35, respectively, for self-reported pain and function scores, pain intensity scores, osteophyte and JSN total scores. Radiological progression was not associated with changes in self-reported pain and function. Women in an early post-menopausal stage were especially at risk of progressing radiologically. CONCLUSIONS: Currently available outcome measures were able to assess progression over the relatively short time period of 2 years. Radiographic outcomes were more responsive than self-reported outcomes. Pain intensity upon lateral pressure seems to be a responsive measure but needs validation.

Coral gas: oxygen production in millepora on the great barrier reef.

Large volumes of a gas consisting of 69 percent molecular oxygen and 31 percent molecular nitrogen with trace amounts of carbon monoxide, carbon dioxide, and methane have been found trapped inside skeletons of the common hydrozoan Millepora. Volumes were low in the morning and reached a maximum by late afternoon. The oxygen was probably produced by the endolithic (boring) algae, with which the Millepora skeletons are very heavily infested. Oxygen production by endolithic algae in Millepora and in other substrates could influence estimates of reef productivity based on measurements of dissolved gases.

Electronic data capture (EDC) using cellular technology: implications for clinical trials and practice, and preliminary experience with the m-Womac Index in hip and knee OA patients.

AIM: The capture, analysis and utilisation of health status information are attended by logistic considerations and interpretation challenges. We report a preliminary evaluation of cellular technology in capturing WOMAC NRS 3.1 Index data. METHODS: A Java midlet for delivering the WOMAC NRS3.1 Index on Nokia-6300, Motorola-V3 and Samsung-A711 mobile phones was developed by Exco InTouch. Following task orientation, patients completed the paper-based WOMAC (p-WOMAC questionnaire, and then the three mobile phonebased WOMAC (m-WOMAC applications, in random order. RESULTS: All 12 patients (age range = 55-82 years) successfully completed the m-WOMAC Index on each of the three phones, and all were found acceptable by patients. With respect to m-WOMAC mean overall rank score, no significant difference was found between the 3 phones (Friedman's chi square (2 df) = 2.2, p = 0.34) however, Motorola V3 was favoured with the best mean rank. Pearson correlation between the average p-WOMAC and average m-WOMAC score was 0.996. CONCLUSIONS: Patient reported ratings indicated the m-WOMAC application performed well on all three phones. EDC provides unique opportunities for using quantitative measurement in both clinical practice and research.

Improvement in condition-specific and generic quality of life outcomes in patients with knee osteoarthritis following single-injection Synvisc: results from the LOBRAS study.

OBJECTIVE: To evaluate the effectiveness of viscosupplementation with single-injection hylan G-F20 (Synvisc-One) in knee osteoarthritis (OA), during routine clinical care, in a 52 week observational study. RESEARCH DESIGN AND METHODS: The LOBRAS study involved a 1 year long, multi-center, quasi-experimental, repeated measures, observational study. Consenting patients in Australia fulfilling inclusion/exclusion criteria under the care of a medical specialist in routine clinical practice were enrolled. Prior to, and for 52 weeks following, intra-articular single-injection hylan G-F20, patients were repeatedly evaluated using the WOMAC NRS4.1 Index and the SF-36 questionnaire. The WOMAC NRS4.1 was administered by mobile phone (with paper back-up), and the SF-36 was administered on paper. Patients were monitored for adverse events. MAIN OUTCOME MEASURES: Western Ontario and McMaster (WOMAC) OA Index, and the Short Form 36 questionnaire (SF-36 v2). RESULTS: A total of 131 patients with knee OA were enrolled, of whom 119 provided both pre- and post-intervention WOMAC data. Statistically significant improvements (with a maximum of p ≤ .025) from baseline to Week 12, Month 6 and Week 52 were detected, by intention-to-treat (ITT) and per-protocol (PP) analyses, in WOMAC Pain, Stiffness, Function, PGA, and Total Score, SF-36 PCS, and WOMAC-derived HUI3. Adverse event (AE) monitoring detected treatment-related AEs in 5.3% of patients. CONCLUSIONS: The effectiveness of single-injection hylan G-F20 in routine clinical care is supported by the detection of statistically significant, clinically important improvements in WOMAC Pain, Stiffness, Function, Total, and PGA outcomes, and statistically significant improvements in SF-36 PCS and WOMAC-derived HUI3 outcomes at multiple time points. Limitations of this study include lack of a control group or blinding. No predictive indicators of the response to treatment were identified. In general single-injection hylan G-F20 was well tolerated with very few patients experiencing any treatment-related adverse events. Collectively, these observations attest to the effectiveness of single-injection hylan G-F20 and complement previous observations in routine clinical care.

Speed enforcement detection devices for preventing road traffic injuries.

BACKGROUND: It is estimated that by 2020, road traffic crashes will have moved from ninth to third in the world ranking of burden of disease, as measured in disability adjusted life years. The identification of effective strategies for the prevention of road traffic injuries is of global public health importance. Measures aimed at reducing traffic speed are considered essential to preventing road injuries; the use of speed enforcement detection devices (including speed cameras and radar and laser devices) is one such measure. OBJECTIVES: To assess whether the use of speed enforcement detection devices (SEDs) reduces the incidence of speeding, road traffic crashes, injuries and deaths. SEARCH STRATEGY: We searched the Cochrane Injuries Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, Science (and Social Science) Citation Index, TRANSPORT, PsycINFO, CINAHL, EconLit. We searched the websites of road safety and motoring associations, as well as general internet searches. We handsearched selected journals and conference proceedings, and contacted experts in the field. The searches were conducted during May to November 2004. SELECTION CRITERIA: Randomised controlled trials and controlled before-after studies that assessed the impact of speed enforcement detection devices on speeding, road crashes, injuries and deaths were eligible for inclusion. For studies involving co-interventions, SEDs had to be the major intervention focus of the study to be eligible. DATA COLLECTION AND ANALYSIS: We independently screened search results, assessed studies for inclusion, extracted data and assessed methodological quality. Due to variability between and within included studies, a pooled analysis was not appropriate. MAIN RESULTS: No randomised controlled trials were identified. Twenty-six studies met the inclusion criteria, of which 22 were controlled before-after trials incorporating a distinct control or comparison group(s) and four were interrupted time series designs with a comparison group(s). Fourteen studies reported speed and crash outcomes, seven reported crash outcomes only and five reported speed outcomes only. All but one study reported an absolute reduction in pre/post average speeds. A pre/post reduction in the proportion of speeding vehicles ranged across studies from 5% to 70% depending on the speed threshold set. Pre/post reductions of 50% to 65% were reported in the proportion of speeding vehicles travelling >15 km/h over the speed limit. Compared with controls, the relative improvement was from 1% to 15% for average speed and from 14% to 65% for percent speeding. All studies reporting crash outcomes reported an absolute pre/post reduction in all crashes and injury related crashes. In the vicinity of camera sites these pre/post reductions ranged from 14% to 72% for all crashes, 8% to 46% for injury crashes, and 40% to 45% for crashes resulting in fatalities or serious injuries. More generalised effects over wider areas showed an absolute pre/post crash reduction ranging from 9% to 35%, 7% to 30% for all injury crashes and 13% to 58% for crashes resulting in fatalities alone, or in combination with serious injuries. The studies of longer duration showed that these positive trends were either maintained or improved with time. Compared with controls, the relative improvement in pre/post crash numbers resulting in any type of injury ranged from 5% to 36%. AUTHORS' CONCLUSIONS: Despite the methodological limitations of the studies reviewed, the consistency of reported positive reductions in speed and crash outcomes across all studies suggest that SEDs are a promising intervention for reducing the number of road traffic injuries and deaths. More studies of a scientifically rigorous nature are necessary to provide a stronger evidence base that these interventions are worthwhile. There is a need for international harmonisation of data collection methods, including standards on how best to measure speeds and collect crash data, over lengthy intervention and follow-up periods, as well as some consensus as to the expression of outcomes in studies, so that studies can be compared.

Intraarticular corticosteroid for treatment of osteoarthritis of the knee.

BACKGROUND: Osteoarthritis (OA) is a common joint disorder. In the knee, injections of corticosteroids into the joint (intraarticular (IA)) may relieve inflammation, and reduce pain and disability. OBJECTIVES: To evaluate the efficacy and safety of IA corticosteroids in treatment of OA of the knee. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE (to January (week 1) 2006 for update), EMBASE, PREMEDLINE (all to July 2003), and Current Contents (Sept 2000). Specialised journals, trial reference lists and review articles were handsearched. SELECTION CRITERIA: Randomised controlled trials of IA corticosteroids for patients with OA of the knee: single/double blind, placebo-based/comparative studies, reporting at least one core OMERACT III outcome measure. DATA COLLECTION AND ANALYSIS: Methodological quality of trials was assessed, and data were extracted in duplicate. Fixed effect and random effects models, giving weighted mean differences (WMD), were used for continuous variables. Dichotomous outcomes were analysed by relative risk (RR). MAIN RESULTS: Twenty-eight trials (1973 participants) comparing IA corticosteroid against placebo, against IA hyaluronan/hylan (HA products), against joint lavage, and against other IA corticosteroids, were included.IA corticosteroid was more effective than IA placebo for pain reduction (WMD -21.91; 95% confidence interval (CI) -29.93 to -13.89) and patient global assessment (the RR was 1.44 (95% CI 1.13 to 1.82)) at one week post injection with an NNT of 3 to 4 for both, based on n=185 for pain on 100 mm visual analogue scale (VAS) and n=158 for patient global assessment. Data on function were sparse at one week post injection and neither statistically significant nor clinically important differences were detected. There was evidence of pain reduction between two weeks (the RR was 1.81 (95% CI 1.09 to 3.00)) to three weeks (the RR was 3.11 (95% CI 1.61 to 6.01), but a lack of evidence for efficacy in functional improvement. At four to 24 weeks post injection, there was lack of evidence of effect on pain and function (small studies showed benefits which did not reach statistical or clinical importance, i.e. less than 20% risk difference). For patient global, there were three studies which consistently showed lack of effect longer than one week post injection. However, all were fairly small sample sizes (less than 50 patients per group). This was supported by another study which did not find statistically significant differences, at any time point, on a continuous measure of patient global assessment (100 mm VAS).In comparisons of corticosteroids and HA products, no statistically significant differences were in general detected at one to four weeks post injection. Between five and 13 weeks post injection, HA products were more effective than corticosteroids for one or more of the following variables: WOMAC OA Index, Lequesne Index, pain, range of motion (flexion), and number of responders. One study showed a difference in function between 14 to 26 weeks, but no differences in efficacy were detected at 45 to 52 weeks. In general, the onset of effect was similar with IA corticosteroids, but was less durable than with HA products. Comparisons of IA corticosteroids showed triamcinolone hexacetonide was superior to betamethasone for number of patients reporting pain reduction up to four weeks post injection (the RR was 2.00 (95% CI 1.10 to 3.63). Comparisons between IA corticosteroid and joint lavage showed no differences in any of the efficacy or safety outcome measures. AUTHORS' CONCLUSIONS: The short-term benefit of IA corticosteroids in treatment of knee OA is well established, and few side effects have been reported. Longer term benefits have not been confirmed based on the RevMan analysis. The response to HA products appears more durable. In this review, some discrepancies were observed between the RevMan 4.2 analysis and the original publication. These are likely the result of using secondary rather than primary data and the statistical methods available in RevMan 4.2. Future trials should have standardised outcome measures and assessment times, run longer, investigate different patient subgroups, and clinical predictors of response (those associated with inflammation and structural damage).

Viscosupplementation for the treatment of osteoarthritis of the knee.

BACKGROUND: Osteoarthritis (OA) is the most prevalent chronic joint disorder worldwide and is associated with significant pain and disability. OBJECTIVES: To assess the effects of viscosupplementation in the treatment of OA of the knee. The products were hyaluronan and hylan derivatives (Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease, Euflexxa, Nuflexxa), Durolane, Fermathron, Go-On, Hyalgan, Hylan G-F 20 (Synvisc Hylan G-F 20), Hyruan, NRD-101 (Suvenyl), Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel compositum). SEARCH STRATEGY: MEDLINE (up to January (week 1) 2006 for update), EMBASE, PREMEDLINE, Current Contents up to July 2003, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Specialised journals and reference lists of identified randomised controlled trials (RCTs) and pertinent review articles up to December 2005 were handsearched. SELECTION CRITERIA: RCTs of viscosupplementation for the treatment of people with a diagnosis of OA of the knee were eligible. Single and double-blinded studies, placebo-based and comparative studies were eligible. At least one of the four OMERACT III core set outcome measures had to be reported (Bellamy 1997). DATA COLLECTION AND ANALYSIS: Each trial was assessed independently by two reviewers for its methodological quality using a validated tool. All data were extracted by one reviewer and verified by a second reviewer . Continuous outcome measures were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). However, where different scales were used to measure the same outcome, standardized mean differences (SMD) were used. Dichotomous outcomes were analyzed by relative risk (RR). MAIN RESULTS: Seventy-six trials with a median quality score of 3 (range 1 to 5) were identified. Follow-up periods varied between day of last injection and eighteen months. Forty trials included comparisons of hyaluronan/hylan and placebo (saline or arthrocentesis), ten trials included comparisons of intra-articular (IA) corticosteroids, six trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs), three trials included comparisons of physical therapy, two trials included comparisons of exercise, two trials included comparisons of arthroscopy, two trials included comparisons of conventional treatment, and fifteen trials included comparisons of other hyaluronans/hylan. The pooled analyses of the effects of viscosupplements against 'placebo' controls generally supported the efficacy of this class of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 28 to 54% for pain and 9 to 32% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included in these analyses. AUTHORS' CONCLUSIONS: Based on the aforementioned analyses, viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period. It is of note that the magnitude of the clinical effect, as expressed by the WMD and standardised mean difference (SMD) from the RevMan 4.2 output, is different for different products, comparisons, timepoints, variables and trial designs. However, there are few randomised head-to-head comparisons of different viscosupplements and readers should be cautious, therefore, in drawing conclusions regarding the relative value of different products. The clinical effect for some products, against placebo, on some variables at some timepoints is in the moderate to large effect-size range. Readers should refer to relevant tables to review specific detail given the heterogeneity in effects across the product class and some discrepancies observed between the RevMan 4.2 analyses and the original publications. Overall, the analyses performed are positive for the HA class and particularly positive for some products with respect to certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks postinjection. In general, sample-size restrictions preclude any definitive comment on the safety of the HA class of products; however, within the constraints of the trial designs employed no major safety issues were detected. In some analyses viscosupplements were comparable in efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events. In other analyses HA products had more prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the use of the HA class of products in the treatment of knee OA.

The WOMAC Knee and Hip Osteoarthritis Indices: development, validation, globalization and influence on the development of the AUSCAN Hand Osteoarthritis Indices.

Clinical measurement in both clinical research and clinical practice requires tools and techniques that are valid, reliable and responsive. Patient-centred self-reported measures provide opportunity to evaluate consequences of osteoarthritis, that are important and relevant to patients with the condition. The WOMAC and AUSCAN Indices are health status measurement questionnaires that are valid, reliable and responsive, easy to complete, simple to score and available in multiple language forms and scaling formats. They provide opportunities to capture patient relevant information, relating to the impact of interventions, in clinical research and clinical practice environments. WOMAC data have also contributed to the development of proposed definitions for responder criteria and state-attainment criteria in osteoarthritis.

Viscosupplementation for the treatment of osteoarthritis of the knee.

BACKGROUND: Osteoarthritis (OA) is the most prevalent chronic joint disorder worldwide and is associated with significant pain and disability. OBJECTIVES: To assess the effects of viscosupplementation in the treatment of OA of the knee. The products were hyaluronan and hylan derivatives (Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease), Durolane, Fermathron, Go-On, Hyalgan, Hylan G-F 20 (Synvisc Hylan G-F 20), NRD-101, Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel compositum). SEARCH STRATEGY: MEDLINE, EMBASE, PREMEDLINE, Current Contents up to July 2003, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Specialised journals and reference lists of identified randomised controlled trials (RCTs) and pertinent review articles up to April 2004 were handsearched. SELECTION CRITERIA: RCTs of viscosupplementation for the treatment of people with a diagnosis of OA of the knee were eligible. Single and double-blinded studies, placebo-based and comparative studies were eligible. At least one of the four OMERACT III core set outcome measures had to be reported (Bellamy 1997). DATA COLLECTION AND ANALYSIS: Each trial was assessed independently by two reviewers (NB, JC) for its methodological quality using a validated tool. All data were extracted by one reviewer (JC) and verified by a second reviewer (VR). Continuous outcome measures were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). Dichotomous outcomes were analyzed by relative risk (RR). MAIN RESULTS: Sixty-three trials with a median quality score of 3 (range 1 to 5) were identified. Follow-up periods varied between day of last injection and one year. Thirty-seven trials included comparisons of hyaluronan/hylan and placebo, nine trials included comparisons of intra-articular (IA) corticosteroids, and five trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs). The pooled analyses of the effects of viscosupplements against 'placebo' controls generally supported the efficacy of this class of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 11 to 54% for pain and 9 to 15% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included in these analyses. AUTHORS' CONCLUSIONS: Based on the aforementioned analyses, viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period. It is of note that based on non-randomised groups, the magnitude of the clinical effect, as expressed by the WMD and standardised mean difference (SMD) from the RevMan 4.1 output, is different for different products, comparisons, timepoints, variables and trial designs. However, there are few randomised head-to-head comparisons of different viscosupplements and readers should be cautious, therefore, in drawing conclusions regarding the relative value of different products. The clinical effect for some products, against placebo, on some variables at some timepoints is in the moderate to large effect-size range. Readers should refer to relevant tables to review specific detail given the heterogeneity in effects across the product class and some discrepancies observed between the RevMan 4.1 analyses and the original publications. Overall, the analyses performed are positive for the HA class and particularly positive for some products with respect to certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks postinjection. In general, sample-size restrictions preclude any definitive comment on the safety of the HA class of products; however, within the constraints of the trial designs employed no major safety issues were detected. In some analyses viscosupplements were comparable in efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events. In other analyses HA products had more prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the use of the HA class of products in the treatment of knee OA.

Intraarticular corticosteroid for treatment of osteoarthritis of the knee.

BACKGROUND: Osteoarthritis (OA) is a common joint disorder. In the knee, injections of corticosteroids into the joint (intra-articular (IA)) may relieve inflammation, and reduce pain and disability. OBJECTIVES: To evaluate the efficacy and safety of IA corticosteroids in treatment of OA of the knee. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE, EMBASE, PREMEDLINE (all to July 2003), and Current Contents (Sept 2000). Specialised journals, trial reference lists and review articles were handsearched. SELECTION CRITERIA: Randomised controlled trials of IA corticosteroids for patients with OA of the knee: single/double blind, placebo-based/comparative studies, reporting at least one core OMERACT III outcome measure. DATA COLLECTION AND ANALYSIS: Methodological quality of trials was assessed, and data were extracted in duplicate. Fixed effect and random effects models, giving weighted mean differences (WMD), were used for continuous variables. Dichotomous outcomes were analysed by relative risk (RR). MAIN RESULTS: Twenty-six trials (1721 participants) comparing IA corticosteroid against placebo, against IA hyaluronan/hylan (HA products), against joint lavage, and against other IA corticosteroids, were included.IA corticosteroid was more effective than IA placebo for pain reduction (WMD -17.79; 95% confidence interval (CI) -25.02 to -10.55) and patient global assessment (the RR was 1.44 (95% CI 1.13 to 1.82)) at one week post injection with an NNT of 3 to 4 for both, based on n=185 for pain on 100 mm visual analogue scale (VAS) and n=158 for patient global assessment. Data on function were sparse at one week post injection and neither statistically significant nor clinically important differences were detected. There was evidence of pain reduction between two weeks (the RR was 1.81 (95% CI 1.09 to 3.00)) to three weeks (the RR was 3.11 (95% CI 1.61 to 6.01), but a lack of evidence for efficacy in functional improvement. At four to 24 weeks post injection, there was lack of evidence of effect on pain and function (small studies showed benefits which did not reach statistical or clinical importance, i.e. less than 20% risk difference). For patient global, there were three studies which consistently showed lack of effect longer than one week post injection. However, all were fairly small sample sizes (less than 50 patients per group). This was supported by another study which did not find statistically significant differences, at any time point, on a continuous measure of patient global assessment (100 mm VAS). In comparisons of corticosteroids and HA products, no statistically significant differences were in general detected at one to four weeks post injection. Between five and 13 weeks post injection, HA products were more effective than corticosteroids for one or more of the following variables: WOMAC OA Index, Lequesne Index, pain, range of motion (flexion), and number of responders. One study showed a difference in function between 14 to 26 weeks, but no differences in efficacy were detected at 45 to 52 weeks. In general, the onset of effect was similar with IA corticosteroids, but was less durable than with HA products. Comparisons of IA corticosteroids showed triamcinolone hexacetonide was superior to betamethasone for number of patients reporting pain reduction up to four weeks post injection (the RR was 2.00 (95% CI 1.10 to 3.63). Comparisons between IA corticosteroid and joint lavage showed no differences in any of the efficacy or safety outcome measures. AUTHORS' CONCLUSIONS: The short-term benefit of IA corticosteroids in treatment of knee OA is well established, and few side effects have been reported. Longer term benefits have not been confirmed based on the RevMan analysis. The response to HA products appears more durable. In this review, some discrepancies were observed between the RevMan 4.1 analysis and the original publication. These are likely the result of using secondary rather than primary data and the statistical methods available in RevMan 4.1. Future trials should have standardised outcome measures and assessment times, run longer, investigate different patient subgroups, and clinical predictors of response (those associated with inflammation and structural damage).

Outcome measurement in scleroderma clinical trials.

Clinical trials in scleroderma were reviewed to assess the clinimetric properties of frequently used outcome measures. Twenty-seven controlled intervention studies were found in the English literature; nine demonstrated effective therapy. The outcome measures used included skin involvement, functional status, physical performance (grip strength, oral aperture), and internal organ involvement (pulmonary, gastrointestinal, renal, and cardiac). Very few outcome measures detected between- or within-group differences even when an active drug was compared with a placebo. Skin measures were found to yield statistical differences in seven studies, patient global assessment in three, and physician global assessments in four. Internal organ measures detected differences between groups only rarely; the pulmonary diffusing capacity was statistically different twice. Physical performance measures (eg, grip strength and oral aperture) never yielded statistical differences, and in only one of five trials did a functional assessment detect statistical differences. To show drug efficacy in future trials in scleroderma, better outcome measures need to be developed and a consensus obtained on which outcomes to use so that potentially effective therapies can be tested in a standardized fashion against a placebo or current therapy. Currently, because of a lack of clinimetric data on outcome measures, therapeutic inefficacy cannot be differentiated from a lack of sensitivity in the outcome measures used. In the future, outcome measures should be chosen on the basis of the adequacy of their reliability, construct, and content validity and be sensitive to change. Ideally, outcome measures also should have criterion validity, ie, show a strong association between the measure (such as a skin score) and an irrefutable gold standard (such as skin pathology).

The lack of associations between rheumatoid arthritis and both nulliparity and infertility.

OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease that occurs more commonly in women and frequently onsets in women of childbearing age. Pregnancy often causes disease remission, with a subsequent flare postpartum. Nulliparity may be a risk factor for RA, but the literature does not consistently report this finding. There may be a production of antibodies in women with RA that could lead to infertility, and subsequent nulliparity, but this has not been proved. We wanted to determine whether there was a relationship between nulliparity, infertility, oral contraceptive use, and adverse pregnancy outcome in women with newly diagnosed RA. METHODS: Through a case control study, using a mailed questionnaire, we compared the fertility and pregnancy outcome histories of 34 women between the ages of 19 and 44 years with recent-onset RA with 68 healthy controls matched for age and marital status. The response rate was 97%. A review of the literature also was performed to study the associations between RA and infertility and nulliparity, using Medline searching key references. RESULTS: We found no association between infertility and the onset of RA. Seventy-one percent of women with RA and 68% of controls had been pregnant. There was a trend toward increased nulliparity in these patients, but the result was not statistically significant (odds ratio [OR], 1.4; P<.6). There were no differences in the number of children (2.6 v. 2.7; P<.6) and parity outcomes in the two groups. Age at first pregnancy was younger in the women with RA (22.6 v. 25.5 years; P<.008), but the education level was higher in the controls (P<.0001), which may explain these differences. Oral contraceptive use was lower in the RA women, but more RA women had long-term use (greater than or equal to 5 years), and neither result was statistically significant. Literature review shows that at best, there are weak negative associations between current estrogen use and RA, and no association with nulliparity and infertility. CONCLUSIONS: It appears that infertility, the number of pregnancies, and pregnancy outcome are not strongly associated with the risk of developing RA in women of childbearing age. However, in this study there may have been selection biases in the women with RA and the controls that differentially could have affected their reproductive outcomes. Thus, a true association could have been missed. Most other published studies find no association between nulliparity and RA.

A standardized protocol for measurement of range of movement of the shoulder using the Plurimeter-V inclinometer and assessment of its intrarater and interrater reliability.

OBJECTIVE: To develop a standardized protocol for measurement of shoulder movements using a gravity inclinometer designed for use in clinical trials, and to assess its intra- and interrater reliability in a group of manipulative physiotherapists. METHODS: After instruction, 6 manipulative physiotherapists independently assessed 8 movements of the shoulder, including total and glenohumeral flexion (TF, GHF), total and glenohumeral abduction (TA, GHA), external rotation in neutral (ERN) and abduction (ERA), internal rotation in abduction (IRA), and hand behind back (HBB), in random order in 6 patients with shoulder pain and stiffness according to a 6 x 6 Latin square design using the standardized protocol. The assessments were then repeated. Analysis of variance was used to partition total variability into components of variance in order to calculate intraclass correlation coefficients (ICCs). RESULTS: The intra- and interrater reliability of the different movements varied widely. Reliability was higher for TF and TA than for the corresponding glenohumeral movements (e.g., intrarater ICCs: TF = 0.80, GHF = 0.65, TA = 0.75, GHA = 0.62). Interrater reliability was higher in the second round suggesting a practice effect (e.g., round 1, 2 interrater ICCs TF = 0.62, 0.82; TA = 0.62, 0.88; ERN = 0.85, 0.95). CONCLUSION: The measurement of the active range of TF, TA, ERN, and HBB, measured by manipulative physiotherapists following the standardized protocol, has intra- and interrater reliability acceptable for use as an outcome measure in clinical trials assessing interventions for shoulder pain.

Comparison of the responsiveness and relative effect size of the western Ontario and McMaster Universities Osteoarthritis Index and the short-form Medical Outcomes Study Survey in a randomized, clinical trial of osteoarthritis patients.

OBJECTIVE: This study compares the responsiveness and relative effect sizes of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) with the Medical Outcomes Study Short Form Health Survey (SF-36) in a randomized clinical trial for treatment of osteoarthritis (OA). METHODS: Patients with OA of the knee or hip were randomized to receive either placebo or 2,400 mg/day of ibuprofen for 28 days. Patients completed the WOMAC and SF-36 at baseline and days 7, 14, and 28 of the trial. RESULTS: Patients receiving ibuprofen showed significant improvement in WOMAC pain, physical functioning, and the total score, while improvement was detected only for bodily pain on the SF-36. The WOMAC detected significant differences between ibuprofen and placebo for pain and physical functioning, whereas the SF-36 detected differences for the bodily pain subscale. CONCLUSION: These results suggest the WOMAC has greater power to detect treatment differences than the SF-36, with respect to pain and physical functioning, in OA clinical trials.

Comparative study of self-rating pain scales in osteoarthritis patients.

Although progress has been made in the clinical metrology of pain in osteoarthritis, much further work remains. The preferred methods of measurement remain debatable. In this longitudinal, open study, a comparison of eight self-rating pain scales has been conducted. A total of 333 patients entered the four-week study after completing a 3-7 day NSAID-free washout period. Patients were assigned to treatment with oxaprozin 1200 mg p.o. once daily with titration permitted between 600 mg and 1800 mg. Rescue analgesia with acetaminophen (paracetamol) 325 mg (maximum 2600 mg) was allowed. At the end of the washout and the treatment period, patients completed eight self-administered pain scales. All pain measures detected clinically important and statistically significant improvements in pain. The pain scales differed in their degree of responsiveness. The Likert and visual analogue scales and their primary variations (continuous chromatic analogue and numerical scales) were more responsive than more complex measures. A positive correlation between initial pain rating and subsequent pain relief was confirmed in this study. We conclude that, while pain is a subjective sensory phenomenon, its perceived severity can be evaluated using a variety of self-administered pain scales, all of which are capable of detecting improvements in health status following effective pharmacological intervention.

Comparative study of self-rating pain scales in rheumatoid arthritis patients.

Although progress has been made in the clinical metrology of pain in rheumatoid arthritis, much further work remains. The preferred methods of measurement remain debatable. In this longitudinal, open study, a comparison of eight self-rating pain scales has been conducted. A total of 124 patients entered the four-week study after completing a 3-7-day NSAID-free washout period. Patients were assigned to treatment with oxaprozin 1200 mg p.o. once daily with titration permitted between 600 mg and 1800 mg. Rescue analgesia with acetaminophen (paracetamol) 325 mg (maximum 2600 mg) was permitted. At the end of the washout and treatment period, patients completed eight self-administered pain rating scales. All pain measures detected clinically important and statistically significant improvements in pain. The pain scales differed in their degree of responsiveness. The Likert and visual analogue scales and their primary variations (continuous chromatic analogue and numerical scales) were more responsive than more complex measures. A positive correlation between initial pain rating and subsequent pain response was confirmed in this study. We conclude that, while pain is a subjective sensory phenomenon, its perceived severity can be evaluated using a variety of self-administered pain scales, all of which are capable of detecting improvements in health status following effective pharmacological intervention.

Controlled, double-blind, randomized trial of amitriptyline in relieving articular pain and tenderness in patients with rheumatoid arthritis.

Thirty-six patients with definite or classical rheumatoid arthritis participated in a double-blind, randomized, placebo-controlled trial to assess the effectiveness of adding amitriptyline to the treatment regimen for the relief of pain not adequately controlled by non-steroidal anti-inflammatory drugs. Dosage of amitriptyline was increased gradually up to 25 mg 3-times daily and patients were followed up for 12 weeks. Assessments were made of joint pain and tenderness every 4 weeks. The results showed no difference between the amitriptyline and placebo-treated patients for either parameter.