Bone mineral density, kidney function and participant-reported outcome measures in women who switch from tenofovir disoproxil emtricitabine and a nonnucleoside reverse transcriptase inhibitor to abacavir, lamivudine and dolutegravir.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). The aim of the study was to evaluate changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG). METHODS: We conducted a randomized controlled trial in which women aged ≥ 40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. We analysed changes in BMD at the hip and lumbar spine from baseline to week 96 using linear regression, and markers of bone turnover and kidney function using repeated measures mixed effects models with multiple imputation for missing data. We conducted exploratory analyses of weight, mental health, sleep and symptoms attributed to HIV infection and antiretroviral therapy. RESULTS: Ninety-one women [mean (standard deviation) age 50.4 (6.6) years] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in BMD at the lumbar spine (but not the neck of the femur or the total hip), bone resorption markers and proteinuria (total protein, albumin and retinol-binding protein) and modest weight gain without changes in body mass index. Although mean anxiety, depression and sleep scores did not differ between the two study arms, anxiety, depression and sleep disturbance at baseline predicted ABC/3TC/DTG discontinuation for neuropsychiatric side effects [odds ratios (95% confidence intervals) 11.9 (2.0-71.6), 16.0 (2.6-97.9) and 10.0 (1.8-56.0), respectively]. CONCLUSIONS: Switching from TDF/FTC/NNRTI to ABC/3TC/DTG improved the BMD of the lumbar spine and kidney function. These benefits need to be balanced against modest weight gain and the need for antiretroviral therapy substitutions in a proportion of participants.

Correction of Defective T-Regulatory Cells From Patients With Crohn's Disease by Ex Vivo Ligation of Retinoic Acid Receptor-α.

BACKGROUND & AIMS: Crohn's disease (CD) is characterized by an imbalance of effector and regulatory T cells in the intestinal mucosa. The efficacy of anti-adhesion therapies led us to investigate whether impaired trafficking of T-regulatory (Treg) cells contributes to the pathogenesis of CD. We also investigated whether proper function could be restored to Treg cells by ex vivo expansion in the presence of factors that activate their regulatory activities. METHODS: We measured levels of the integrin α4ß7 on Treg cells isolated from peripheral blood or lamina propria of patients with CD and healthy individuals (controls). Treg cells were expanded ex vivo and incubated with rapamycin with or without agonists of the retinoic acid receptor-α (RARA), and their gene expression profiles were analyzed. We also studied the cells in cytokine challenge, suppression, and flow chamber assays and in SCID mice with human intestinal xenografts. RESULTS: We found that Treg cells from patients with CD express lower levels of the integrin α4ß7 than Treg cells from control patients. The pathway that regulates the expression of integrin subunit α is induced by retinoic acid (RA). Treg cells from patients with CD incubated with rapamycin and an agonist of RARA (RAR568) expressed high levels of integrin α4ß7, as well as CD62L and FOXP3, compared with cells incubated with rapamycin or rapamycin and all-trans retinoic acid. These Treg cells had increased suppressive activities in assays and migrated under conditions of shear flow; they did not produce inflammatory cytokines, and RAR568 had no effect on cell stability or lineage commitment. Fluorescently labeled Treg cells incubated with RAR568 were significantly more likely to traffic to intestinal xenografts than Treg cells expanded in control medium. CONCLUSIONS: Treg cells from patients with CD express lower levels of the integrin α4ß7 than Treg cells from control patients. Incubation of patients' ex vivo expanded Treg cells with rapamycin and an RARA agonist induced expression of α4ß7 and had suppressive and migratory activities in culture and in intestinal xenografts in mice. These cells might be developed for treatment of CD. ClinicalTrials.gov, Number: NCT03185000.

Neuropsychological function at first episode in treatment-resistant psychosis: findings from the ÆSOP-10 study.

BACKGROUND: Neuropsychological investigations can help untangle the aetiological and phenomenological heterogeneity of schizophrenia but have scarcely been employed in the context of treatment-resistant (TR) schizophrenia. No population-based study has examined neuropsychological function in the first-episode of TR psychosis. METHODS: We report baseline neuropsychological findings from a longitudinal, population-based study of first-episode psychosis, which followed up cases from index admission to 10 years. At the 10-year follow up patients were classified as treatment responsive or TR after reconstructing their entire case histories. Of 145 cases with neuropsychological data at baseline, 113 were classified as treatment responsive, and 32 as TR at the 10-year follow-up. RESULTS: Compared with 257 community controls, both case groups showed baseline deficits in three composite neuropsychological scores, derived from principal component analysis: verbal intelligence and fluency, visuospatial ability and executive function, and verbal memory and learning (p values⩽0.001). Compared with treatment responders, TR cases showed deficits in verbal intelligence and fluency, both in the extended psychosis sample (t = -2.32; p = 0.022) and in the schizophrenia diagnostic subgroup (t = -2.49; p = 0.017). Similar relative deficits in the TR cases emerged in sub-/sensitivity analyses excluding patients with delayed-onset treatment resistance (p values<0.01-0.001) and those born outside the UK (p values<0.05). CONCLUSIONS: Verbal intelligence and fluency are impaired in patients with TR psychosis compared with those who respond to treatment. This differential is already detectable - at a group level - at the first illness episode, supporting the conceptualisation of TR psychosis as a severe, pathogenically distinct variant, embedded in aberrant neurodevelopmental processes.

A Comparison of Different Approaches for Costing Medication Use in an Economic Evaluation.

BACKGROUND: Estimating individual-level medication costs in an economic evaluation can involve extensive data collection and handling. Implications of detailed versus general approaches are unclear. OBJECTIVES: To compare costing approaches in a trial-based economic evaluation. METHODS: We applied four costing approaches to prescribed medication data from the Tumour necrosis factor inhibitors Against Combination Intensive Therapy randomized controlled trial. A detailed micro-costing approach was used as a base case, against which other approaches were compared: costing medications used by at least 1.5% of patients; costing medications on the basis of only chemical name; applying a generic prescription charge rather than a medication-specific cost. We quantitatively examined resulting estimates of prescribed medication and total care costs, and qualitatively examined trial conclusions. RESULTS: Medication costs made up 6% of the total health and social care costs. There was good agreement in prescribed medication costs (concordance correlation coefficient [CCC] 0.815, 0.819, and 0.989) and excellent agreement in total costs (CCC 0.990, 0.995, and 0.995) between approaches 1 and 2. Approaches 3 and 4 had poor agreement with approach 1 on prescribed medication costs (CCC 0.246-0.700 and 0.033-0.333, respectively), but agreement on total care costs remained good (CCC 0.778-0.993 and 0.729-0.986, respectively). CONCLUSIONS: Because medication costs comprised only a small proportion of total costs, the less resource-intensive approaches had substantial impacts on medication cost estimates, but had little impact on total care costs and did not significantly impact the trial's cost-effectiveness conclusions. There is room for research efficiencies without detriment to an evaluation in which medication costs are likely to form a small proportion of total costs.

Variable impacts of different remission states on health-related quality of life in rheumatoid arthritis.

OBJECTIVES: Targeting remission in rheumatoid arthritis (RA) improves health-related quality of life (HRQoL) and disability. However, the impacts of different remission criteria and durations and their frequencies are uncertain. Our observational study assessed these factors. METHODS: We recruited RA patients with disease durations <10 years, stable suppressive therapies and stable disease activity scores for 28 joints using ESR (DAS28-ESR) ≤3.2. Intermittent and sustained remisisons were classified using DAS28ESR, simple disease activity index (SDAI) and ACR/EULAR Boolean criteria. HRQoL, measured using SF-36, fatigue, EuroQol and health assessment questionnaire (HAQ) was compared using time-integrated areas under the curve (AUC). RESULTS: 104 patients were enrolled and followed for 12 months. DAS28-ESR remissions were intermittent in 42%, sustained in 47% and absent in 11%. Boolean remissions were intermittent in 38%, sustained in 10% and absent in 52%. Baseline remissions by all criteria significantly improved HAQ, Euroqol, SF36 and fatigue scores compared with low disease activity (LDAS); AUCs showed significant benefits for all HRQoLs persisted over 12-months. Boolean remissions achieved most benefits. Over time all remission states gave significantly better HRQoL scores than LDAS. Sustained DAS28ESR and SDAI remissions improved HRQoL more than intermittent remissions. Sustained and intermittent Boolean remissions gave similar improvements. Analysis of SF-36 domains showed even sustained Boolean remissions failed to optimise pain and fatigue. CONCLUSIONS: All remissions improve HRQoL but different criteria have variable impacts. Boolean remission had most impact but occurred least. There are trade-off between optimising individual impacts (Boolean remissions) and achieving maximal overall impacts (DAS28-ESR remissions).

Intensive therapy and remissions in rheumatoid arthritis: a systematic review.

BACKGROUND: We systematically reviewed the effectiveness of intensive treatment strategies in achieving remission in patients with both early and established Rheumatoid Arthritis (RA). METHODS: A systematic literature review and meta-analysis evaluated trials and comparative studies reporting remission in RA patients treated intensively with disease modifying anti-rheumatic drugs (DMARDs), biologics and Janus Kinase (JAK) inhibitors. Analysis used RevMan 5.3 to report relative risks (RR) in random effects models with 95% confidence intervals (CI). RESULTS: We identified 928 publications: 53 studies were included (48 superiority studies; 6 head-to-head trials). In the superiority studies 3013/11259 patients achieved remission with intensive treatment compared with 1211/8493 of controls. Analysis of the 53 comparisons showed a significant benefit for intensive treatment (RR 2.23; 95% CI 1.90, 2.61). Intensive treatment increased remissions in both early RA (23 comparisons; RR 1.56; 1.38, 1.76) and established RA (29 comparisons RR 4.21, 2.92, 6.07). All intensive strategies (combination DMARDs, biologics, JAK inhibitors) increased remissions. In the 6 head-to-head trials 317/787 patients achieved remission with biologics compared with 229/671 of patients receiving combination DMARD therapies and there was no difference between treatment strategies (RR 1.06; 0.93. 1.21). There were differences in the frequency of remissions between early and established RA. In early RA the frequency of remissions with active treatment was 49% compared with 34% in controls. In established RA the frequency of remissions with active treatment was 19% compared with 6% in controls. CONCLUSIONS: Intensive treatment with combination DMARDs, biologics or JAK inhibitors increases the frequency of remission compared to control non-intensive strategies. The benefits are seen in both early and established RA.

The relationship between social support and health-related quality of life in patients with antiphospholipid (hughes) syndrome.

OBJECTIVE: Antiphospholipid (Hughes) syndrome (APS) is recognised as a systemic autoimmune disease defined by recurrent thromboembolic events and/or pregnancy morbidity. Little is known about the psychological burden of this long-term condition. This study aims to explore the relationship between social support and health-related quality of life (HRQoL) in patients with APS. METHODS: A total of 270 patients with a clinical diagnosis of APS participated in a cross-sectional online questionnaire survey. Data included demographics, disease-related information, social support and HRQoL. RESULTS: Both perceived and ideal social support were associated with HRQoL in APS. Patients reported receiving insufficient social support. Perceived emotional support was related to physical functioning (B = 7.77, p = .006, 95% CI: 2.25, 13.29); perceived instrumental support was associated with bodily pain (B = 17.52, p <  .001, 95% CI: 11.15, 23.90) and perceived informational support with physical and social functioning (B = -6.30, p = .05, 95% CI: -12.52, -0.08; B = 8.06, p = .02, 95% CI: 1.17, 14.94). Ideal emotional support was related to physical and social functioning (B = 5.80, p = .04, 95% CI: 0.26, 11.34; B = 7.53, p = .04, 95% CI: 0.55, 14.51); ideal instrumental support was associated with mental health (B = 4.73, p = .03, 95% CI: 0.38, 9.07) and ideal informational support with vitality (B = 5.85, p = .01, 95% CI: 1.23, 10.46). CONCLUSION: Social support was linked to HRQoL in patients with APS. Insufficient social support was associated with limitations in various HRQoL domains. Increasing social support especially through provision of disease-specific education might contribute to improving HRQoL in patients with APS. Patient-tailored interventions addressing psychosocial aspects of living with APS are needed to improve patients' psychological and physical status.

Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis-a proof of principle and exploratory trial: is dose tapering practical in good responders?

Objectives: RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response. Methods: We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0-6) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6-12) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares (DAS28 increasing ⩾0.6 with at least one additional swollen joint) were the primary outcome. Results: Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0-6 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls (adjusted hazard ratio 2.81, 95% CI: 0.99, 7.94; P = 0.051). Analysing all tapered patients after controls were re-randomized (months 6-12) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare (adjusted hazard ratio 3.47, 95% CI: 1.26, 9.58; P = 0.016). Conclusion: Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states. Trail registration: EudraCT, https://www.clinicaltrialsregister.eu, 2010-020738-24; ISRCTN registry, https://www.isrctn.com, 28955701.

Predicting responses in patients with rheumatoid arthritis to disease-modifying agents using baseline clinical data.

OBJECTIVES: The optimal treatment for active rheumatoid arthritis (RA) is unresolved, particularly in early RA. We used data from an observational cohort to develop the simple predictor algorithm and evaluated its application in two completed clinical trials in early and established RA. We assessed whether using a simple algorithm can identify patients who have persisting active disease despite treatment with disease-modifying drugs (DMARDs). We also examined if patients who have lower likelihoods of persisting active RA are likely to benefit from intensive treatment. METHODS: We developed a simple predictive score for persisting disease activity using conventional clinical assessments in an observational cohort of patients with early RA (ERAN). It was tested in two trials in early (CARDERA) and established (TACIT) RA. Persistent disease activity was defined as disease activity score for 28 joints (DAS28) >3.2 at both 6 and 12 months. RESULTS: Regression modelling identified three main predictors of persisting active disease in ERAN; tender joint counts, health assessment questionnaire (HAQ) scores and ESR. We dichotomised these predictors (≥6 tender joint counts, ≥1.0 HAQ ≥20 mm/h ESR) in a four-point prediction score. This simple prediction score predicted persisting active disease in the ERAN cohort and both CARDERA and TACIT trials. Patients with high scores were more likely to have persistently active disease at 6 and 12 months. The relationship was weaker in TACIT because no patients were without any predictive factors. CONCLUSIONS: Combining tender joint counts, ESR and HAQ in a simple predictive score prospectively identifies patients with higher risks of persistent disease activity over the next 12 months. More patients with all three risk factors had persistent active disease than those with none or one risk factor.

A population study of the reported incidence of native joint septic arthritis in the United Kingdom between 1998 and 2013.

OBJECTIVES: Septic arthritis is a life-threatening condition with mortality rates of 10-15%. Previous studies in other countries have shown the incidence of septic arthritis may be changing. Our aim was investigate the incidence and pattern of native joint septic arthritis in the UK. METHODS: We performed an analysis using Hospital Episode Statistics to investigate the reported incidence of septic arthritis in the UK between 1998 and 2013. RESULTS: A total of 54 532 cases of septic arthritis were reported via Hospital Episode Statistics during the timeframe studied. There has been a 43% increase in the reported incidence of septic arthritis, with rates rising from 5.5/100 000 in 1998 to 7.8/100 000 in 2013. The rate increased most rapidly in those >75 years of age (15/100 000 in 1998 and 31/100 000 in 2013). Staphylococcal species were the most frequently reported, followed by Streptococcus Pneumococcus rates were relatively stable, with the exception of a 7-fold spike in reported incidence in 2011. DISCUSSION: This large population-based study demonstrates that the incidence of septic arthritis is increasing in the UK. Rates are increasing most rapidly in the >75 years age group, which is likely the result of increasing co-morbidities. The clustering of pneumococcal cases has potential public health implications.

A randomised trial evaluating anakinra in early active rheumatoid arthritis.

OBJECTIVES: The effectiveness of anakinra (interleukin-1 receptor antagonist) in early rheumatoid arthritis (RA) is unknown. We evaluated the efficacy of anakinra (combined with methotrexate) in a randomised clinical trial of early active RA patients. METHODS: The Combination Anti-Rheumatic Drugs in Early RA-2 (CARDERA-2) trial was a randomised trial of early (duration <1 year) active RA. Patients were randomised to 12 months of: (1) methotrexate or (2) anakinra-methotrexate. Follow-up lasted 2 years. The primary outcome was erosive progression (changes from baseline in modified Larsen scores). Secondary outcomes were changes from baseline in disease activity score on a 28-joint count (DAS28), health assessment questionnaire (HAQ), and quality of life (EQ-5D) scores alongside ACR responder rates. RESULTS: 154 patients received the allocated intervention (from 259 screened). Similar Larsen score progression was seen at 12 and 24 months in patients receiving anakinra-methotrexate (mean changes from baseline of 2.50 and 5.10, respectively) and methotrexate monotherapy (mean changes from baseline of 4.16 and 5.20, respectively). Lower improvements in DAS28 and HAQ scores were seen at all time-points in anakinra-methotrexate treated patients; these were significantly less at 24 months (DAS28 p=0.04; HAQ P=0.02). Significantly lower EQ-5D score increases were seen at 12 months with anakinra-methotrexate (p=0.03). Anakinra-methotrexate was associated with more serious adverse events compared with methotrexate monotherapy (11 vs. 6 patients), although this was not significant (p=0.59). CONCLUSIONS: Anakinra (combined with methotrexate) is not effective in early, active RA. It provided no clinical benefits beyond methotrexate monotherapy.

A large two-centre study in to rates of influenza and pneumococcal vaccination and infection burden in rheumatoid arthritis in the UK.

BACKGROUND: Infections are a common complication of RA with associated morbidity and mortality. The aetiology of increased risk is complex and multifactorial. Despite this, strategies to mitigate against risk of infection including vaccination are not always addressed in primary or secondary care with wide variation in practice from multiple small single centre audits. This study was a large two-centre survey of vaccine uptake in routine clinical practice and evaluated the relationship between vaccination and the burden of infection in RA patients. METHODS: A patient questionnaire was devised and disseminated through postal, clinic and phone survey at 2 UK rheumatology centres, detailing past vaccination history, reasons for non-vaccination, and history of recent infection. In a subset of patients, primary care vaccination data were also obtained. RESULTS: In total 929 patients responded to the survey. Over 85 % of patients were vaccinated against influenza, however only 44 % were vaccinated against pneumococcus. The vast majority of vaccination was undertaken in primary care. In the 12 months prior to the survey, 7.7 % of subjects recalled at least one episode of severe infection requiring admission, and nearly 40 % reported receiving at least one course of antibiotics. CONCLUSIONS: Infections are common in RA and Rheumatologists need to be adept at recognising at risk patients and managing them appropriately. Influenza vaccination uptake is good whilst pneumococcal vaccination rates are comparatively poor. Collaborative approaches between primary and secondary care are required to maximise vaccine uptake, which is safe and recommended in RA patients.

Changing clinical patterns in rheumatoid arthritis management over two decades: sequential observational studies.

BACKGROUND: Rheumatoid arthritis (RA) treatment paradigms have shifted over the last two decades. There has been increasing emphasis on combination disease modifying anti-rheumatic drug (DMARD) therapy, newer biologic therapies have become available and there is a greater focus on achieving remission. We have evaluated the impact of treatment changes on disease activity scores for 28 joints (DAS28) and disability measured by the health assessment questionnaire scores (HAQ). METHODS: Four cross-sectional surveys between 1996 and 2014 in two adjacent secondary care rheumatology departments in London evaluated changes in drug therapy, DAS28 and its component parts and HAQ scores (in three surveys). Descriptive statistics used means and standard deviations (SD) or medians and interquartile ranges (IQR) to summarise changes. Spearman's correlations assessed relationships between assessments. RESULTS: 1324 patients were studied. Gender ratios, age and mean disease duration were similar across all cohorts. There were temporal increases in the use of any DMARDs (rising from 61% to 87% of patients from 1996-2014), combination DMARDs (1% to 41%) and biologic (0 to 32%). Mean DAS28 fell (5.2 to 3.7), active disease (DAS28 > 5.1) declined (50% to 18%) and DAS28 remission (DAS28 < 2.6) increased (8% to 28%). In contrast HAQ scores were unchanged (1.30 to 1.32) and correlations between DAS28 and HAQ weakened (Spearman's rho fell from 0.56 to 0.44). CONCLUSIONS: Treatment intensity has increased over time, disease activity has fallen and there are more remissions. However, these improvements in controlling synovitis have not resulted in comparable reductions in disability measured by HAQ. As a consequence the relationship between DAS28 and HAQ has become weaker over time. Although the reasons for this divergence between disease activity and disability are uncertain, focussing treatment entirely in suppressing synovitis may be insufficient.

Second-line agents in myositis: 1-year factorial trial of additional immunosuppression in patients who have partially responded to steroids.

OBJECTIVE: Ciclosporin and MTX are used in idiopathic inflammatory myopathies (DM and PM) when patients incompletely respond to glucocorticoids. Their effectiveness is unproved in randomized controlled trials (RCTs). We evaluated their benefits in a placebo-controlled factorial RCT. METHODS: A 56-week multicentre factorial-design double-blind placebo-controlled RCT compared steroids alone, MTX (15-25 mg weekly) plus steroids, ciclosporin (1-5 mg/kg/day) plus steroids and all three treatments. It enrolled adults with myositis (by Bohan and Peter criteria) with active disease receiving corticosteroids. RESULTS: A total of 359 patients were screened and 58 randomized. Of the latter, 37 patients completed 12 months of treatment, 7 were lost to follow-up and 14 discontinued treatment. Patients completing 12 months of treatment showed significant improvement (P < 0.001 on paired t-tests) in manual muscle testing (14% change), walking time (22% change) and function (9% change). Intention to treat and completer analyses indicated that ciclosporin monotherapy, MTX monotherapy and ciclosporin/MTX combination therapy showed no significant treatment effects in comparison with placebo. CONCLUSION: Neither MTX nor ciclosporin (by themselves or in combination) improved clinical features in myositis patients who had incompletely responded to glucocorticoids. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register; http://www.controlled-trials.com/; ISRCTN40085050.

Expectations of new treatment in rheumatoid arthritis: developing a patient-generated questionnaire.

BACKGROUND: Service-user partnerships in research exist in mental health, but there have been few advances in other disciplines, apart from cancer. OBJECTIVES: To develop a patient-generated expectancy measure for new treatments in rheumatoid arthritis (RA), using a participatory method. METHOD: Stage 1: three repeated focus groups and two expert panels with patients with RA conducted by a patient researcher to generate items for the draft questionnaire. Stage 2: feasibility study of draft scale with consecutive outpatient attendees. RESULTS: Patients identified 21 dimensions of new treatment expectations, grouped into (i) physical, (ii) psycho-social and (iii) expectations relating to the impact of treatment. This resulted in a draft instrument assessed in a feasibility study. DISCUSSION AND CONCLUSION: The participatory research method was useful in involving patients actively in research and to produce collaboratively a feasible, valid and acceptable measure in RA. The scale will be included in a longitudinal observational study, with newly diagnosed patients, to assess (i) whether the new scale demonstrates sensitivity to change for expectations when receiving new treatment and (ii) participants' completion rate of the new scale compared with five instruments included in the future study.

Psychometric properties of a new treatment expectation scale in rheumatoid arthritis: an application of item response theory.

BACKGROUND: Patient-generated health outcome measures are important in the assessment of long-term treatment goals for Rheumatoid Arthritis (RA), but few psychometrically sound measures are available. The MAPLe-RA (Measuring Actual Patient-Led expectations in RA) is a new questionnaire and its psychometric properties are not investigated. This study aims to examine these properties for each of the items using Item Response Theory (IRT) . METHODS: Participants were included if they completed the scale (MAPLe-RA). A one parameter (Rasch) model and a two parameter logistic (2PL) model were applied to these data using M-plus software. RESULTS: One hundred thirty-eight patients with RA were included in the analysis. MAPLe-RA scale comprised of 21 items, the mean score was 71 (20.28) ranging from 0 to 105. Most items operated in the high expectations part of the items characteristics curves (ICC). Item discrimination varied widely, items with the highest discrimination capacity from the three domains were: pain (physical domain); control of my RA (self-management) and maintaining social role (psycho-social domain); feeling better overall and involvement in treatment decision making (impact of new treatment domain). CONCLUSION: RA patients' expectations of treatment are higher in the physical and psycho-social domains and less so in the impact of new treatment domain.

Cost-effectiveness of treatment strategies using combination disease-modifying anti-rheumatic drugs and glucocorticoids in early rheumatoid arthritis.

OBJECTIVE: The aim of this study was to estimate the cost-effectiveness of combination DMARDs with short-term glucocorticoids in early active RA using data from the 2-year Combination of Anti-Rheumatic Drugs in Early RA (CARDERA) trial. METHODS: CARDERA enrolled 467 patients with active RA of <24-months duration. All patients received MTX; half received step-down prednisolone and half ciclosporin in a placebo-controlled factorial design. Differences in mean costs and quality-adjusted life-years (QALYs) over 24-months follow-up were estimated using patient-level data from a UK health service perspective and 2011-12 costs. RESULTS: Two-year costs for each treatment strategy showed primary care costs were negligible across all groups. Drug costs were lowest with MTX/ciclosporin and triple therapy. Hospital costs were lowest with MTX/prednisolone and triple therapy. Triple therapy was least costly and most effective; it dominated all other strategies. At positive values for a QALY in the typical UK range (£20 000-30 000) the probability that triple therapy was the most cost-effective strategy was 0.9. Results were robust to methods used to impute missing data. CONCLUSION: Intensive treatment of early RA with triple therapy (two DMARDs and short-term glucocorticoids) is both clinically effective and cost effective.

Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study.

OBJECTIVES: To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent. METHODS: In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18. RESULTS: 53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): -1.03 (-1.66 to -0.40) vs -0.58 (-1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement. CONCLUSIONS: Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA. TRIAL REGISTRATION NUMBER: NCT04991753.

Late HIV diagnosis is a major risk factor for intensive care unit admission in HIV-positive patients: a single centre observational cohort study.

BACKGROUND: HIV positive patients are at risk of infectious and non-infectious complications that may necessitate intensive care unit (ICU) admission. While the characteristics of patients requiring ICU admission have been described previously, these studies did not include information on the denominator population from which these cases arose. METHODS: We conducted an observational cohort study of ICU admissions among 2751 HIV positive patients attending King's College Hospital, South London, UK. Poisson regression models were used to identify factors associated with ICU admission. RESULTS: The overall incidence rate of ICU admission was 1.0 [95% CI 0.8, 1.2] per 100 person-years of follow up, and particularly high early (during the first 3 months) following HIV diagnosis (12.4 [8.7, 17.3] per 100 person-years compared to 0.37 [0.27, 0.50] per 100 person-years thereafter; incidence rate ratio 33.5 [23.4, 48.1], p < 0.001). In time-updated analyses, AIDS and current CD4 cell counts of less than 200 cells/mm3 were associated with an increased incidence of ICU admission while receipt of combination antiretroviral therapy (cART) was associated with a reduced incidence of ICU admission. Late HIV diagnosis (initial CD4 cell count <350 or AIDS within 3 months of HIV diagnosis) applied to 81% of patients who were first diagnosed HIV positive during the study period and who required ICU admission. Late HIV diagnosis was significantly associated with ICU admission in the first 3 months following HIV diagnosis (adjusted incidence rate ratio 8.72, 95% CI 2.76, 27.5). CONCLUSIONS: Late HIV diagnosis was a major risk factor for early ICU admission in our cohort. Earlier HIV diagnosis allowing cART initiation at CD4 cell counts of 350 cells/mm3 is likely to have a significant impact on the need for ICU care.

Heterogeneity of treatment responses in rheumatoid arthritis using group based trajectory models: secondary analysis of clinical trial data.

BACKGROUND: Traditionally rheumatoid arthritis (RA) trials classify patients as responders and non-responders; they ignore the potential range of treatment responses. Group Based Trajectory Models (GBTMs) provide a more refined approach. They identify patient subgroups with similar outcome trajectories. We used GBTMs to classify patients into subgroups of varying responses and explore factors associated with different responses to intensive treatment in a secondary analysis of intensive treatment in the TITRATE clinical trial. METHODS: The TITRATE trial enrolled 335 patients with RA: 168 patients were randomised to receive intensive management, which comprised monthly assessments including measures of the disease activity score for 28 joints (DAS28), treatment escalation when patients were not responding sufficiently and psychosocial support; 163 of these patients completed the trial. We applied GBTMs to monthly DAS28 scores over one year to these patients who had received intensive management. The control group had standard care and were assessed every 6 months; they had too few DAS28 scores for applying GBTMs. RESULTS: GBTMs identified three distinct trajectories in the patients receiving intensive management: good (n = 40), moderate (n = 76) and poor (n = 47) responders. Baseline body mass index (BMI), disability, fatigue and depression levels were significantly different between trajectory groups. Few (10%) good responders were obese, compared to 38% of moderate, and 43% of poor responders (P = 0.002). Few (8%) good responders had depression, compared to 14% moderate responders, and 38% poor responders (P < 0.001). The key difference in treatments was using high-cost biologics, used in only 5% of good responders but 30% of moderate and 51% of poor responders (P < 0.001). Most good responders had endpoint remissions and low disability, pain, and fatigue scores; few poor responders achieved any favourable outcomes. CONCLUSION: GBTMs identified three trajectories of disease activity progression in patients receiving intensive management for moderately active RA. Baseline variables like obesity and depression predicted different treatment responses. Few good responders needed biologic drugs; they responded to conventional DMARDs alone. GBTMs have the potential to facilitate precision medicine enabling patient-oriented treatment strategies based on key characteristics. REGISTRATION: TITRATE Trial ISRCTN 70160382.