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1.  The effectiveness of anti-TNF-α therapies when used sequentially in rheumatoid arthritis patients: a systematic review and meta-analysis 
Rheumatology (Oxford, England)  2010;49(12):2313-2321.
Objectives. To systematically review and meta-analyse evidence on the effectiveness of the TNF-α inhibitors when used sequentially.
Methods. Systematic review of comparative and single-arm observational studies. Data were synthesized using random-effects meta-analysis. Treatment effects were estimated using four outcome measures from the included studies: European League Against Rheumatism (EULAR) and ACR20 response rates and mean improvement in disease activity score-28 (DAS-20) and HAQ. The effect of other factors was explored via meta-regression and sub-group analyses.
Results. Twenty studies comprising 2705 patients were included in the analysis. All studies were observational and most had no control group. Therefore, our primary analysis considered patient changes from baseline. The mean percentage of ACR20 responders was 60.8% (95% CI 53.8, 67.4), EULAR responders 70.5% (95% CI 63.7, 76.6), mean overall improvement in DAS-28 scores was 1.53 (95% CI 1.25, 1.80) and in HAQ scores was 0.25 (95% CI 0.11, 0.40). Four studies made comparisons with patients who received TNF-α inhibitors for the first time. Response rates associated with sequential TNF-α inhibitor treatment were lower than for first-time use.
Conclusions. Sequential TNF-α inhibitor use is likely to lead to treatment benefit in terms of the signs and symptoms of disease and physical function. There is also some evidence to suggest that the probability of achieving a response is lower, and the average magnitude of response is lower than the first use. Further evidence from randomized controlled trials is required to confirm and further quantify the role specific anti-TNF-α agents have when used sequentially.
PMCID: PMC2982750  PMID: 20566736
Rheumatoid arthritis; Systematic review; Meta-analysis; TNF-α inhibitors; Sequential
2.  Health Assessment Questionnaire disability progression in early rheumatoid arthritis: Systematic review and analysis of two inception cohorts 
The Health Assessment Questionnaire is widely used for patients with inflammatory polyarthritis (IP) and its subset, rheumatoid arthritis (RA). In this study, we evaluated the progression of HAQ scores in RA (i) by systematically reviewing the published literature on the methods used to assess changes in functional disability over time and (ii) to study in detail HAQ progression in two large prospective observational studies from the UK.
Data from two large inception cohorts, ERAS and NOAR, were studied to determine trajectories of HAQ progression over time by applying latent class growth models (LCGMs) to each dataset separately. Age, sex, baseline DAS28, symptom duration, rheumatoid factor, fulfilment of the 1987 ACR criteria and socio-economic status (SES) were included as potential predictors of HAQ trajectory subgroup membership.
The literature search identified 49 studies showing that HAQ progression has mainly been based on average changes in the total study population. In the HAQ progression study, a LCGM with four HAQ trajectory subgroups was selected as providing the best fit in both cohorts. In both the cohorts, older age, female sex, longer symptom duration, fulfilment of the 1987 ACR criteria, higher DAS28 and lower SES were associated with increased likelihood of membership of subgroups with worse HAQ progression.
Four distinct HAQ trajectory subgroups were derived from the ERAS and NOAR cohorts. The fact that the subgroups identified were nearly identical supports their validity. Identifying distinct groups of patients who are at risk of poor functional outcome may help to target therapy to those who are most likely to benefit.
PMCID: PMC4282305  PMID: 24925692
Systematic review; Latent class growth model; Health Assessment Questionnaire; Rheumatoid arthritis; Inflammatory polyarthritis; Predictors
3.  The HubBLe trial: haemorrhoidal artery ligation (HAL) versus rubber band ligation (RBL) for haemorrhoids 
BMC Gastroenterology  2012;12:153.
Haemorrhoids (piles) are a very common condition seen in surgical clinics. After exclusion of more sinister causes of haemorrhoidal symptoms (rectal bleeding, perianal irritation and prolapse), the best option for treatment depends upon persistence and severity of the symptoms. Minor symptoms often respond to conservative treatment such as dietary fibre and reassurance. For more severe symptoms treatment such as rubber band ligation may be therapeutic and is a very commonly performed procedure in the surgical outpatient setting. Surgery is usually reserved for those who have more severe symptoms, as well as those who do not respond to non-operative therapy; surgical techniques include haemorrhoidectomy and haemorrhoidopexy. More recently, haemorrhoidal artery ligation has been introduced as a minimally invasive, non destructive surgical option.
There are substantial data in the literature concerning efficacy and safety of 'rubber band ligation including multiple comparisons with other interventions, though there are no studies comparing it to haemorrhoidal artery ligation. A recent overview has been carried out by the National Institute for Health and Clinical Excellence which concludes that current evidence shows haemorrhoidal artery ligation to be a safe alternative to haemorrhoidectomy and haemorrhoidopexy though it also highlights the lack of good quality data as evidence for the advantages of the technique.
The aim of this study is to establish the clinical effectiveness and cost effectiveness of haemorrhoidal artery ligation compared with conventional rubber band ligation in the treatment of people with symptomatic second or third degree (Grade II or Grade III) haemorrhoids.
Design: A multi-centre, parallel group randomised controlled trial.
Outcomes: The primary outcome is patient-reported symptom recurrence twelve months following the intervention. Secondary outcome measures relate to symptoms, complications, health resource use, health related quality of life and cost effectiveness following the intervention.
Participants: 350 patients with grade II or grade III haemorrhoids will be recruited in surgical departments in up to 14 NHS hospitals.
Randomisation: A multi-centre, parallel group randomised controlled trial. Block randomisation by centre will be used, with 175 participants randomised to each group.
The results of the research will help inform future practice for the treatment of grade II and III haemorrhoids.
Trial Registration
PMCID: PMC3503770  PMID: 23098097
Haemorrhoids; Rubber band ligation; Haemorrhoidal artery ligation; Surgical randomised controlled trial
4.  Assessing methods for dealing with treatment switching in randomised controlled trials: a simulation study 
We investigate methods used to analyse the results of clinical trials with survival outcomes in which some patients switch from their allocated treatment to another trial treatment. These included simple methods which are commonly used in medical literature and may be subject to selection bias if patients switching are not typical of the population as a whole. Methods which attempt to adjust the estimated treatment effect, either through adjustment to the hazard ratio or via accelerated failure time models, were also considered. A simulation study was conducted to assess the performance of each method in a number of different scenarios.
16 different scenarios were identified which differed by the proportion of patients switching, underlying prognosis of switchers and the size of true treatment effect. 1000 datasets were simulated for each of these and all methods applied. Selection bias was observed in simple methods when the difference in survival between switchers and non-switchers were large. A number of methods, particularly the AFT method of Branson and Whitehead were found to give less biased estimates of the true treatment effect in these situations.
Simple methods are often not appropriate to deal with treatment switching. Alternative approaches such as the Branson & Whitehead method to adjust for switching should be considered.
PMCID: PMC3024998  PMID: 21223539

Results 1-4 (4)