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.

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.

Characterization of missing data patterns and mechanisms in longitudinal composite outcome trial in rheumatoid arthritis.

Background: Composite measures, like the Disease Activity Score for 28 joints (DAS28), are key primary outcomes in rheumatoid arthritis (RA) trials. DAS28 combines four different components in a continuous measure. When one or more of these components are missing the overall composite score is also missing at intermediate or trial endpoint assessments. Objectives: This study examined missing data patterns and mechanisms in a longitudinal RA trial to evaluate how best to handle missingness when analysing composite outcomes. Design: The Tumour-Necrosis-Factor Inhibitors against Combination Intensive Therapy (TACIT) trial was an open label, pragmatic randomized multicentre two arm non-inferiority study. Patients were followed up for 12 months, with monthly measurement of the composite outcome and its components. Active RA patients were randomized to conventional disease modifying drugs (cDMARDs) or Tumour Necrosis Factor-α inhibitors (TNFis). Methods: The TACIT trial was used to explore the extent of missing data in the composite outcome, DAS28. Patterns of missing data in components and the composite outcome were examined graphically. Longitudinal multivariable logistic regression analysis assessed missing data mechanisms during follow-up. Results: Two hundred and five patients were randomized: at 12 months 59/205 (29%) had unobserved composite outcome and 146/205 (71%) had an observed DAS28 outcome; however, 34/146 had one or more intermediate assessments missing. We observed mixed missing data patterns, especially for the missing composite outcome due to one component missing rather than patient not attending thier visit. Age and gender predicted missingness components, providing strong evidence the missing observations were unlikely to be Missing Completely at Random (MCAR). Conclusion: Researchers should undertake detailed evaluations of missing data patterns and mechanisms at the final and intermediate time points, whether or not the outcome variable is a composite outcome. In addition, the impact on treatment estimates in patients who only provide data at milestone assessments need to be assessed. Trial Registration ISRCTN Number: 37438295.

Defining the relationship between pain intensity and disease activity in patients with rheumatoid arthritis: a secondary analysis of six studies.

BACKGROUND: Pain is the main concern of patients with rheumatoid arthritis (RA) while reducing disease activity dominates specialist management. Disease activity assessments like the disease activity score for 28 joints with the erythrocyte sedimentation rate (DAS28-ESR) omit pain creating an apparent paradox between patients' concerns and specialists' treatment goals. We evaluated the relationship of pain intensity and disease activity in RA with three aims: defining associations between pain intensity and disease activity and its components, evaluating discordance between pain intensity and disease activity, and assessing temporal changes in pain intensity and disease activity. METHODS: We undertook secondary analyses of five trials and one observational study of RA patients followed for 12 months. The patients had early and established active disease or sustained low disease activity or remission. Pain was measured using 100-mm visual analogue scales. Individual patient data was pooled across all studies and by types of patients (early active, established active and established remission). Associations of pain intensity and disease activity were evaluated by correlations (Spearman's), linear regression methods and Bland-Altman plots. Discordance was assessed by Kappa statistics (for patients grouped into high and low pain intensity and disease activity). Temporal changes were assessed 6 monthly in different patient groups. RESULTS: A total of 1132 patients were studied: 490 had early active RA, 469 had established active RA and 173 were in remission/low disease activity. Our analyses showed, firstly, that pain intensity is associated with disease activity in general, and particularly with patient global assessments, across all patient groups. Patient global assessments were a reasonable proxy for pain intensity. Secondly, there was some discordance between pain intensity and disease activity across all disease activity levels, reflecting similar discrepancies in patient global assessments. Thirdly, there were strong temporal relationships between changes in disease activity and pain intensity. When mean disease activity fell, mean pain intensity scores also fell; when mean disease activity increased, there were comparable increases in pain intensity. CONCLUSIONS: These findings show pain intensity is an integral part of disease activity, though it is not measured directly in DAS28-ESR. Reducing disease activity is crucial for reducing pain intensity in RA.

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.

Baseline predictors of remission, pain and fatigue in rheumatoid arthritis: the TITRATE trial.

BACKGROUND: Clinical trials show intensive treatment to induce remission is effective in patients with highly active rheumatoid arthritis (RA). The TITRATE trial showed that the benefits of intensive treatment also extend to moderately active RA. However, many patients failed to achieve remission or show improvements in pain and fatigue. We investigated whether baseline predictors could identify treatment non-responders. METHODS: The impact of obesity, depression, anxiety and illness perception on RA outcomes, including disease activity, remission, pain and fatigue were determined using a pre-planned secondary analysis of the TITRATE trial data. RESULTS: Body mass index was associated with disease activity levels and remission: obese patients had a higher overall disease activity and fewer obese patients achieved remission. Intensive management was not associated with increased remission in these patients. Obesity was also associated with increased overall pain and fatigue. Anxiety, depression and health perceptions had no discernible impact on disease activity but were associated with high levels of pain and fatigue. There was a strong association between anxiety and high pain scores; and between depression and high fatigue scores; and health perception was strongly related to both. None of the predictors had an important impact on pain and fatigue reduction in cross-sectional analysis. CONCLUSIONS: Disease activity is higher in obese patients and they have fewer remissions over 12 months. Anxiety, depression and health perceptions were associated with higher pain and fatigue scores. Intensive management strategies need to account for these baseline features as they impact significantly on clinical and psychological outcomes. TRIAL REGISTRATION: ISRCTN 70160382 ; date registered 16 January 2014.

Similar risk of cardiovascular events in idiopathic inflammatory myopathy and rheumatoid arthritis in the first 5 years after diagnosis.

OBJECTIVES: To estimate the incidence of cardiovascular (CV) events in idiopathic inflammatory myopathy (IIM) compared to patients with rheumatoid arthritis (RA) and the general population. To explore the contribution of traditional CV risk factors to any difference observed. METHODS: A retrospective matched population-based cohort study was conducted using UK Clinical Practice Research Datalink (CPRD) from 1987 to 2013. The incidence of CV events was calculated for each cohort over time and compared using Cox proportional hazards models. Multivariable analyses were used to adjust for traditional CV risk factors. RESULTS: A total of 603 patients with IIM 4047 RA and 4061 healthy controls were included. The rate of CV events in IIM was significantly greater than healthy controls [hazard ratio (HR) 1.47 (95% confidence interval (CI) 1.18-1.83)] and remained significant after adjustment for CV risk factors [HR 1.38 (95% CI 1.11-1.72)]. Risk was similar between IIM and RA [HR 1.01 (95% CI 0.78-1.31)]. The rate of myocardial infarction [HR 1.61 (95% CI 1.27-2.04)] but not stroke [HR 0.92 (95% CI 0.59-1.44)] was significantly greater in IIM compared to healthy controls. After the first 5 years, the rate of CV events for RA remained significantly greater compared to the control group, but appeared to return to that of the healthy controls in the IIM group. CONCLUSION: IIM is associated with an increased risk of CV events in the first 5 years after diagnosis similar to that of RA. Beyond 5 years, the risk appears to return to that of the general population in IIM but not RA. Key Points • The excess risk of cardiovascular events in IIM is similar to that found in RA. • The excess risk of cardiovascular events is greatest in the first 5 years after diagnosis.

The clinical effectiveness of intensive management in moderate established rheumatoid arthritis: The titrate trial.

OBJECTIVES: Many trials have shown that intensive management is effective in patients with early active rheumatoid arthritis (RA). But its benefits are unproven for the large number of RA patients seen in routine care who have established, moderately active RA and are already taking conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). The TITRATE trial studied whether these patients also benefit from intensive management and, in particular, achieve more remissions. METHODS: A 12-month multicentre individually randomised trial compared standard care with monthly intensive management appointments which was delivered by specially trained healthcare professionals and incorporated monthly clinical assessments, medication titration and psychosocial support. The primary outcome was 12-month remission assessed using the Disease Activity Score for 28 joints using ESR (DAS28-ESR). Secondary outcomes included fatigue, disability, harms and healthcare costs. Intention-to-treat multivariable logistic- and linear regression analyses compared treatment arms with multiple imputation used for missing data. RESULTS: 459 patients were screened and 335 were randomised (168 intensive management; 167 standard care); 303 (90%) patients provided 12-month outcomes. Intensive management increased DAS28-ESR 12-month remissions compared to standard care (32% vs 18%, p = 0.004). Intensive management also significantly increased remissions using a range of alternative remission criteria and increased patients with DAS28-ESR low disease activity scores. (48% vs 32%, p = 0.005). In addition it substantially reduced fatigue (mean difference -18; 95% CI: -24, -11, p<0.001). There was no evidence that serious adverse events (intensive management =15 vs standard care =11) or other adverse events (114 vs 151) significantly increase with intensive management. INTERPRETATION: The trial shows that intensive management incorporating psychosocial support delivered by specially trained healthcare professions is effective in moderately active established RA. More patients achieve remissions, there were greater improvements in fatigue, and there were no more harms.

Cost-Effectiveness of Combination Disease-Modifying Antirheumatic Drugs Versus Tumor Necrosis Factor Inhibitors in Active Rheumatoid Arthritis: A Pragmatic, Randomized, Multicenter Trial.

OBJECTIVE: To determine whether intensive combinations of conventional synthetic disease-modifying antirheumatic drugs (csDMARDS) achieve similar clinical benefits more cheaply than high-cost biologics such as tumor necrosis factor inhibitors (TNFi) in patients with active rheumatoid arthritis (RA) whose illness has failed to respond to methotrexate and another DMARD. METHODS: We used within-trial cost-effectiveness and cost-utility analyses from health and social care and 2 societal perspectives. Participants were recruited into an open-label, 12-month, pragmatic, randomized, multicenter, 2-arm, noninferiority trial in 24 rheumatology clinics in England and Wales. Costs were linked with the Health Assessment Questionnaire (HAQ; primary outcome) and quality-adjusted life years derived from 2 measures (Short-Form 36 health survey and EuroQol 5-domain 3-level instrument). RESULTS: In total, 205 participants were recruited, 104 in the csDMARD arm and 101 in the TNFi arm. Participants in the csDMARD arm with poor response at 6 months were offered TNFi; 46 participants (44%) switched. Relevant cost and outcome data were available for 93% of participants at 6-month follow-up and for 91-92% of participants at 12-month follow-up. The csDMARD arm had significantly lower total costs from all perspectives (6-month health and social care adjusted mean difference -£3,615 [95% confidence interval (95% CI) -4,104, -3,182]; 12-month health and social care adjusted mean difference -£1,930 [95% CI -2,599, -1,301]). The HAQ score showed benefit to the csDMARD arm at 12 months (-0.16 [95% CI -0.32, -0.01]); other outcomes/follow-ups showed no differences. CONCLUSION: Starting treatment with csDMARDs, rather than TNFi, achieves similar outcomes at significantly lower costs. Patients with active RA and who meet the National Institute for Health and Care Excellence criteria for expensive biologics can be treated with combinations of intensive csDMARDs in a cost-effective manner.

A systematic review of guidelines for managing rheumatoid arthritis.

BACKGROUND: We systematically reviewed current guidelines for managing rheumatoid arthritis (RA) to evaluate their range and nature, assess variations in their recommendations and highlight divergence in their perspectives. METHODS: We searched Medline and Embase databases using the terms 'clinical practice guidelines' and 'rheumatoid arthritis' from January 2000 to January 2017 together with publications of national and international bodies. We included guidelines providing recommendations on general RA management spanning a range of treatments and published in English. We undertook narrative assessments due to the heterogeneity of the guidelines. RESULTS: We identified 529 articles; 22 met our inclusion criteria. They were primarily developed by rheumatologists with variable involvement of patient and other experts. Three dealt with early RA, one established RA and 18 all patients. Most guidelines recommend regular assessments based on the Outcome Measures in Rheumatology core dataset; 18 recommended the disease activity score for 28 joints. Twenty recommended targeting remission; 16 suggested low disease activity as alternative. All guidelines recommend treating active RA; 13 made recommendations for moderate disease. The 21 guidelines considering early RA all recommended starting disease modifying drugs (DMARDs) as soon as possible; methotrexate was recommended for most patients. Nineteen recommended combination DMARDs when patients failed to respond fully to monotherapy and biologics were not necessarily indicated. Twenty made recommendations about biologics invariably suggesting their use after failing conventional DMARDs, particularly methotrexate. Most did not make specific recommendations about using one class of biologics preferentially. Eight recommended tapering biologics when patients achieved sustained good responses. CONCLUSIONS: Five general principles transcend most guidelines: DMARDs should be started as soon as possible after the diagnosis; methotrexate is the best initial treatment; disease activity should be regularly monitored; give biologics to patients with persistently active disease who have already received methotrexate; remission or low disease activity are the preferred treatment target.

Kidney disease in Africans with HIV and tuberculosis.

OBJECTIVE: To describe the spectrum of kidney disease in African patients with HIV and tuberculosis (TB). METHODS: We used data from three cohorts: consecutive patients with HIV/TB in South London (UK, 2004-2016; n = 95), consecutive patients with HIV/TB who underwent kidney biopsy in Cape Town (South Africa, 2014-2017; n = 70), and consecutive patients found to have HIV/TB on autopsy in Abidjan (Cote d'Ivoire, 1991; n = 100). Acute kidney injury (AKI) was ascertained using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In the Cape Town cohort, predictors of recovery of kidney function at 6 months were assessed using Cox regression. RESULTS: In the London cohort, the incidence of moderate/severe AKI at 12 months was 15.1 (95% CI 8.6-26.5) per 100 person-years, and the prevalence of chronic and end-stage kidney disease (ESKD) 13.7 and 5.7%, respectively. HIV-associated nephropathy (HIVAN) was diagnosed in 6% of patients in London, and in 6% of autopsy cases in Abidjan. Evidence of renal TB was present in 60% of autopsies in Abidjan and 61% of kidney biopsies in Cape Town. HIVAN and acute tubular necrosis (ATN) were also common biopsy findings in Cape Town. In Cape Town, 40 patients were dialyzed, of whom 28 (70%) were able to successfully discontinue renal replacement therapy. Antiretroviral therapy status, CD4 cell count, estimated glomerular filtration rate (eGFR) at biopsy and renal histology, other than ATN, were not predictive of eGFR recovery. CONCLUSION: Kidney disease was common in Africans with HIV/TB. Monitoring of kidney function, and provision of acute dialysis to those with severe kidney failure, is warranted.

Real world long-term impact of intensive treatment on disease activity, disability and health-related quality of life in rheumatoid arthritis.

BACKGROUND: The emphasis on treating rheumatoid arthritis (RA) intensively reduces disease activity but its impact in routine care is uncertain. We evaluated temporal changes in disease activities and outcomes in a 10-year prospective observational cohort study of patients in routine care at one unit. METHODS: The Guy's and St Thomas' RA cohort was established in 2005. It involved most RA patients managed in this hospital. Clinical diagnoses of RA were made by rheumatologists. Patients were seen regularly in routine care. Each visit included measurement of disease activity scores for 28 joints (DAS28), health assessment questionnaire scores (HAQ) and EuroQol scores. Patients received intensive treatments targeting DAS28 remission. RESULTS: In 1693 RA patients mean DAS28 scores fell from 2005 to 15 by 11% from 4.08 (95% CI: 3.91, 4.25) in 2005 to 3.64 (3.34, 3.78); these falls were highly significant (p < 0.001). DAS28 components: swollen joint counts fell by 32% and ESR by 24%; in contrast tender joint counts and patient global assessments showed minimal or no reductions. The reduction in DAS28 scores was predominantly between 2005 and 2010, with no falls from 2011 onwards. Associated with falls in mean DAS28s, patients achieving remission increased (18% in 2005; 27% in 2015) and the number with active disease (DAS28 > 5.1) decreased (25% in 2005; 16% in 2015). In 752 patients seen at least annually for 3 years, persisting remission (68 patients) and intermittent remission (376 patients) were associated with less disability and better health related quality of life. Over time biologic use increased, but they were used infrequently in patients in persistent remission. CONCLUSIONS: Over 10 years an intensive management strategy in a routine practice setting increased combination DMARD and biologic use: disease activity levels declined; this association is in keeping with a causal relationship. Patients who achieved remission, even transiently, had better functional outcomes than patients never achieving remission.

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.

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.

Mental health, fatigue and function are associated with increased risk of disease flare following TNF inhibitor tapering in patients with rheumatoid arthritis: an exploratory analysis of data from the Optimizing TNF Tapering in RA (OPTTIRA) trial.

BACKGROUND: Tapering of anti-tumour necrosis factor (TNF) therapy appears feasible, safe and effective in selected patients with rheumatoid arthritis (RA). Depression is highly prevalent in RA and may impact on flare incidence through various mechanisms. This study aims to investigate if psychological states predict flare in patients' dose tapering their anti-TNF therapy. METHODS: This study is a post-hoc analysis of the Optimizing TNF Tapering in RA trial, a multicentre, randomised, open-label study investigating anti-TNF tapering in RA patients with sustained low disease activity. Patient-reported outcomes (Health Assessment Questionnaire, EuroQol 5-dimension scale, Functional Assessment of Chronic Illness Therapy fatigue scale (FACIT-F), 36-Item Short Form Survey (SF-36)) were collected at baseline. The primary outcome was flare, defined as an increase in 28-joint count Disease Activity Score (DAS28) ≥0.6 and ≥1 swollen joint. Discrete-time survival models were used to identify patient-reported outcomes that predict flare. RESULTS: Ninety-seven patients were randomised to taper their anti-TNF dose by either 33% or 66%. Forty-one patients flared. Higher baseline DAS28 score was associated with flare (adjusted HR 1.96 (95% CI 1.18 to 3.24), p=0.01). Disability (SF-36 physical component score), fatigue (FACIT-F) and mental health (SF-36 mental health subscale (MH)) predicted flare in unadjusted models. In multivariate analyses, only SF-36 MH remained a statistically significant predictor of flare (adjusted HR per 10 units 0.74 (95% CI 0.60 to 0.93), p=0.01). CONCLUSIONS: Baseline DAS28 and mental health status are independently associated with flare in patients who taper their anti-TNF therapy. Fatigue and function also associate with flare but the effect disappears when adjusting for confounders. Given these findings, mental health and functional status should be considered in anti-TNF tapering decisions in order to optimise the likelihood of success. TRIAL REGISTRATION NUMBERS: EudraCT Number: 2010-020738-24; ISRCTN: 28955701; Post-results.

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.

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.