Andrew Hassell

Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis

Objective: Treating early active rheumatoid arthritis (RA) with disease modifying antirheumatic drug (DMARD) monotherapy achieves incomplete outcomes and intensive treatment seems preferable. As the relative benefits of combining two DMARDs, one DMARD with glucocorticoids and two DMARDs with glucocorticoids are uncertain we defined them in a factorial trial. Methods: A 2-year randomised double-blind factorial trial in patients with RA within 2 years of diagnosis treated with methotrexate studied the benefits of added ciclosporin, 9 months intensive prednisolone or both (triple therapy). The primary outcome was the number of patients with new erosions. Secondary outcomes included Larsen’s x-ray scores, disability, quality of life and adverse events. Findings: 1391 patients were screened and 467 randomised. Over 2 years 132 (28%) changed therapy and 88 (19%) were lost to follow-up. The number of patients with new erosions was reduced by nearly half by adding ciclosporin or prednisolone (p = 0.01 and 0.03); both treatments reduced increases in Larsen’s x-ray scores by over 2 units (p = 0.008 and 0.003). A further reduction in erosive damage was seen with combined use of both treatments. Their effects on erosive damage appeared independent. Triple therapy reduced disability and improved quality of life compared with methotrexate; ciclosporin and prednisolone acted synergistically. More patients withdrew because of adverse events with triple therapy, without an increase in serious adverse effects. Conclusions: This study confirms the existence of a “window of opportunity” in early RA, when intensive combination therapy produces sustained benefits on damage and disability. Although methotrexate–prednisolone combinations reduce erosive damage, the synergistic effect of two DMARDs is needed to improve quality of life.

Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial

Objective To evaluate whether treating patients with very early inflammatory polyarthritis (IP) with a 3-week course of intramuscular (IM) methylprednisolone acetate may postpone the need for disease-modifying antirheumatic drugs (DMARDs) and prevent IP from evolving into rheumatoid arthritis (RA). Methods Patients with very early IP (4–10 weeks’ duration) were randomised to receive three injections of either 80 mg IM methylprednisolone acetate or placebo, given at weekly intervals. Assessments were monthly until 6 months after the first injection, and then concluded at 12 months. The primary outcome was the need to start DMARDs by the 6-month assessment. Secondary outcomes included disease activity and final clinical diagnosis by the rheumatologist at 12 months. Results Patients in the placebo group (76%) were more likely to need DMARDs during the first 6 months of the trial than patients in the glucocorticoid group (61%) (adjusted OR = 2.11, 95% CI 1.16 to 3.85, p = 0.015). Disease activity did not differ between the two groups at 12 months, probably because many patients in the placebo group started DMARDs early in the study. After 12 months, the arthritis had resolved without the need for DMARDs in 9.9% (11/111) of the patients in the placebo group and in 19.8% (22/111) in the glucocorticoid-treated group (adjusted OR = 0.42, 95% CI 0.18 to 0.99, p = 0.048). Conclusion Treatment of patients with very early IP with IM methylprednisolone acetate appears to postpone the prescription of DMARDs and prevent one in 10 patients from progressing into RA.

Association of polymorphism in glutathione S-transferase loci with susceptibility and outcome in rheumatoid arthritis: comparison with the shared epitope

OBJECTIVE To determine whether glutathione S-transferase GSTM1, GSTM3, GSTT1, and GSTP1 genotypes influence susceptibility or outcome in rheumatoid arthritis (RA). METHODS 277 RA patients were compared with 577 controls to examine any associations between GST genotypes and susceptibility to RA. The effect of genotypes on outcome (Larsen and functional scores) and time integrated acute phase responses (erythrocyte sedimentation rate and C reactive protein) was assessed in 122 patients with disease duration of 5–10 years. GST and HLA-DRB1 genotypes were determined using polymerase chain reaction based assays. Data were analysed using multiple regression analysis with correction for age, sex, disease duration, and the DRB1 associated shared epitope (SE) and rheumatoid factor (RF) positivity where appropriate. RESULTS TheGSTM1*A/*B genotype was less common in RA cases (3 of 276) than in controls (22 of 591) (exact p=0.047), though significance was lost when adjustment was made for multiple comparisons. The Larsen score was higher (p=0.039) in the GSTM1 null patients (89.9) than those with other GSTM1 genotypes (74.7), and this was independent of the SE. Again, correction for multiple testing resulted in loss of significance. The difference in Larsen scores between patients homozygous or negative for the SE (87.9v 74.3) was similar to that between GSTM1 null and non-null patients. No associations between GSTM3 or GSTT1 genotypes and disease markers were identified although the association between GSTP1*B/*B and Larsen score approached significance (p=0.096). CONCLUSION It is proposed that certain GSTs may influence susceptibility and radiological progression in RA and that this is independent of the effect of the HLA-DRB1 associated SE. The mechanism for this effect is presumed to be because of differences in the ability of various GST enzymes to utilise the cytotoxic products of oxidant stress. Although significance was lost after correction for multiple testing, the data indicate that further studies may be of value in RA to determine the influence of the GST and other genes involved in cellular protection against oxidative stress.

A literature review of multi-source feedback systems within and without health services, leading to 10 tips for their successful design

Multi-source feedback (MSF) has become the accepted mechanism of ensuring the appropriate professional behaviour of doctors. It is part of the mandatory assessment of doctors in training and is to be utilized as part of the revalidation of trained doctors. There is significant variation in the models of MSF currently used within the National Health Service and new models of MSF are being designed by various specialties. No single model has been recognized as the ‘gold standard’. However, there is a large published literature concerning MSF, both in the context of health systems and, more extensively, within industry. This published literature is reviewed, drawing attention to aspects of MSF systems in which there is consensus on effective approaches as well as other aspects in which there is doubt about the optimum approach. In the light of the review 10 principles key in the development of effective MSF models have been produced. Practice points•Multi-source feedback has been used extensively in industry and the health sector.•Multi-source feedback is a valid way to measure professional behaviours in doctors.•Multi-source feedback can enhance team-working, productivity, good communication and trust.•Any desired behaviours you wish to assess should be described very clearly.•The assessment tool should be kept simple, with few items, and fit for purpose.

How does the Short Form 36 Health Questionnaire (SF-36) in Rheumatoid Arthritis (RA) Relate to RA Outcome Measures and SF-36 Population Values? A Cross-Sectional Study

Abstract: The aim of the study was to show that the SF-36 is a practical tool for use on outpatients with RA, to examine the relationship between the SF-36 and indices of outcome in RA, and to compare the results with population norms and other disease states. Eighty-six consecutive RA patients attending the Haywood Hospital in Stoke-on-Trent and starting or changing second-line therapy were enrolled. Disease outcome was assessed using the American College of Rheumatology core set and all subjects completed the SF-36 health questionnaire. The cohort had moderately active disease (median ESR 46) and appreciable disability (median HAQ 1.875). Impairment of health status was moderate to marked by the SF-36, with significant differences from population norms and chronic disease states such as low back pain. Good correlations were observed between HAQ and physical function (r>0.75, p<10–6) and HAQ and social function (r>0.61, p<10–6). In contrast, SF-36 scales for physical and emotional role showed no association with activity measures. We concluded that, SF-36 is a practical tool for use in patients with RA. HAQ is associated with its physical and social function scales. Other SF-36 scales, such as physical and emotional role, are not associated with activity core set measures; this suggests different information is involved. RA has a considerable impact on health status compared to other diseases.

Interaction between tumor necrosis factor microsatellite polymorphisms and the HLA-DRB1 shared epitope in rheumatoid arthritis: influence on disease outcome.

OBJECTIVE To investigate whether interactions between tumor necrosis factor (TNF) microsatellite polymorphisms and the HLA-DRB1 shared epitope (SE) are associated with disease severity in rheumatoid arthritis (RA), and to determine if such associations are the same in male and female patients. METHODS Genotyping for the TNFa microsatellite and HLA-DRB1 was carried out on 157 RA patients with established disease (duration >5 years). Disease severity measures included radiographic damage (the Larsen method), functional assessment by the Health Assessment Questionnaire, history of joint surgery, and global appraisal of outcome by means of a visual analog scale score. The association of severity measures with TNFa microsatellite polymorphisms stratified by SE status, and the interaction between TNFa and the SE, were investigated using stratified analyses and multiple or logistic regression analyses. RESULTS No significant associations were observed between any single TNFa microsatellite polymorphism and disease severity, although preliminary evidence for an interaction between TNFa6 and TNFa11 was obtained. In the presence of the SE, a significantly worse outcome was associated with individuals carrying TNFa6, and a significant interaction (P = 0.04-0.006) was found between these alleles for all the outcome measures examined except history of joint surgery. In the absence of the SE, the TNFa6 allele was associated with significantly better outcome scores. When examined by sex, significant associations between the TNFa6/SE haplotype and disease outcome measures were found only in females. No statistically significant interactions were found in males, although the TNFa6/SE haplotype was still associated with the worst outcome scores. CONCLUSION The association of the SE with disease severity in RA is influenced by an interaction with the TNFa6 microsatellite polymorphism. This interaction appears to be acting predominantly in female patients, although the trend is similar in the smaller percentage of males carrying the TNFa6/SE haplotype.

How ratings vary by staff group in multi-source feedback assessment of junior doctors.

Context  UK doctors‐in‐training undergo assessments of their professional behaviours. From an analysis of multi‐source feedback (MSF) data, we report how ratings of junior doctors (Foundation Programme [FP] doctors and senior house officers [SHOs]) differed by staff group.

Development of a behaviour change intervention: a case study on the practical application of theory

BackgroundUse of theory in implementation of complex interventions is widely recommended. A complex trial intervention, to enhance self-management support for people with osteoarthritis (OA) in primary care, needed to be implemented in the Managing Osteoarthritis in Consultations (MOSAICS) trial. One component of the trial intervention was delivery by general practitioners (GPs) of an enhanced consultation for patients with OA. The aim of our case study is to describe the systematic selection and use of theory to develop a behaviour change intervention to implement GP delivery of the enhanced consultation.MethodsThe development of the behaviour change intervention was guided by four theoretical models/frameworks: i) an implementation of change model to guide overall approach, ii) the Theoretical Domains Framework (TDF) to identify relevant determinants of change, iii) a model for the selection of behaviour change techniques to address identified determinants of behaviour change, and iv) the principles of adult learning. Methods and measures to evaluate impact of the behaviour change intervention were identified.ResultsThe behaviour change intervention presented the GPs with a well-defined proposal for change; addressed seven of the TDF domains (e.g., knowledge, skills, motivation and goals); incorporated ten behaviour change techniques (e.g., information provision, skills rehearsal, persuasive communication); and was delivered in workshops that valued the expertise and professional values of GPs. The workshops used a mixture of interactive and didactic sessions, were facilitated by opinion leaders, and utilised ‘context-bound communication skills training.’ Methods and measures selected to evaluate the behaviour change intervention included: appraisal of satisfaction with workshops, GP report of intention to practise and an assessment of video-recorded consultations of GPs with patients with OA.ConclusionsA stepped approach to the development of a behaviour change intervention, with the utilisation of theoretical frameworks to identify determinants of change matched with behaviour change techniques, has enabled a systematic and theory-driven development of an intervention designed to enhance consultations by GPs for patients with OA. The success of the behaviour change intervention in practice will be evaluated in the context of the MOSAICS trial as a whole, and will inform understanding of practice level and patient outcomes in the trial.

360 degree assessment (multisource feedback) of UK trainee doctors: Field testing of team assessment of behaviours (TAB)

Background: This study was to see if the team assessment of behaviours (TAB) 360 degree assessment tool was able to identify interpersonal behaviour problems in doctors in training, to see if feedback was useful, to gauge the value of the process by those involved, and to learn lessons about implementing the process for the future. Methods: TAB was administered to assess interpersonal behaviours of senior house officers in four hospitals in the West Midlands, UK. In addition, questionnaires were sent to all participants, some were interviewed about the whole process, and records kept of the time involved. Results: One hundred and seventyone SHO volunteers received 1378 assessments. The median number of ratings per SHO was 8 (mode 9). Sixtyfour percent of SHOs received ‘no concern’ ratings in all four behaviours (domains) assessed. Twentyone percent received one ‘some concern’ rating. Fifteen percent received more than one ‘concern’ rating. Conclusion: Assessors and trainees found the process practical, valuable and fair. Educational supervisors found it valuable, although only 23% learned something new about their trainees. Clinical tutors valued the system. Administrative staff found it time consuming. The TAB four-domain rating form with its single pass category identified specific concern about volunteer trainees’ professional behaviour. Not all trainees received skilled feedback.

Remission in Early Rheumatoid Arthritis: Predicting Treatment Response

Objective. Optimizing therapeutic strategies to induce remission requires an understanding of the initial features predicting remission. Currently no suitable model exists. We aim to develop a remission score using predictors of remission in early rheumatoid arthritis (RA). Methods. We used a dataset from a UK randomized controlled trial that evaluated intensive treatment with conventional combination therapy, to develop a predictive model for 24-month remission. We studied 378 patients in the trial who received 24 months’ treatment. Our model was validated using data from a UK observational cohort (Early RA Network, ERAN). A group of 194 patients was followed for 24 months. Remission was defined as 28-joint Disease Activity Score < 2.6. Logistic regression models were used to estimate the associations between remission and potential baseline predictors. Results. Multivariate logistic regression analyses showed age, sex, and tender joint count (TJC) were independently associated with 24-month remission. The multivariate remission score developed using the trial data correctly classified 80% of patients. These findings were replicated using ERAN. The remission score has high specificity (98%) but low sensitivity (13%). Combining data from the trial and ERAN, we also developed a simplified remission score that showed that younger men with a TJC of 5 or lower were most likely to achieve 24-month remission. Remission was least likely in older women with high TJC. Rheumatoid factor, rheumatoid nodules, and radiographic damage did not predict remission. Conclusion. Remission can be predicted using a score based on age, sex, and TJC. The score is relevant in clinical trial and routine practice settings.