Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.

BACKGROUND: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. METHODS: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). FINDINGS: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. INTERPRETATION: Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. FUNDING: Bristol Myers Squibb.

How do patient reported outcome measures affect treatment intensification and patient satisfaction in the management of psoriatic arthritis? A cross sectional study of 503 patients.

OBJECTIVES: The ASSIST study investigated prescribing in routine psoriatic arthritis (PsA) care and whether the patient reported outcome: PsA Impact of Disease questionnaire (PsAID-12), impacted treatment. This study also assessed a range of patient and clinician factors and their relationship to PsAID-12 scoring and treatment modification. METHODS: Patients with PsA were selected across the UK and Europe between July 2021-March 2022. Patients completed the PsAID questionnaire, with the results shared with their physician. Patient characteristics, disease activity, current treatment methods, treatment strategies, medication changes and patient satisfaction scores were recorded. RESULTS: 503 patients recruited. 36.2% had changes made to treatment, 88.8% of this had treatment escalation. Overall, the mean PsAID-12 score was higher for patients with treatment escalation; the PsAID-12 score was associated with odds of treatment escalation (OR: 1.58; p< 0.0001). However, most clinicians reported PsAID-12 did not impact their decision to escalate treatment, instead supporting treatment reduction decisions. Physician's assessment of disease activity had the most statistically significant effect on likelihood of treatment escalation, (OR = 2.68, per 1-point score increase). Escalation was more likely in patients not treated with biologic therapies. Additional factors associated with treatment escalation included: patient characteristics, physician characteristics, disease activity and disease impact. CONCLUSION: This study highlights multiple factors impacting treatment decision making for individuals with PsA. PsAID-12 scoring correlates with multiple measures of disease severity and odds of treatment escalation. However, most clinicians reported the PsAID-12 did not influence treatment escalation decisions. PsAID scoring could be used to increase confidence in treatment de-escalation.

Using Polygenic Risk Scores to Aid Diagnosis of Patients With Early Inflammatory Arthritis: Results From the Norfolk Arthritis Register.

OBJECTIVE: There is growing evidence that genetic data are of benefit in the rheumatology outpatient setting by aiding early diagnosis. A genetic probability tool (G-PROB) has been developed to aid diagnosis has not yet been tested in a real-world setting. Our aim was to assess whether G-PROB could aid diagnosis in the rheumatology outpatient setting using data from the Norfolk Arthritis Register (NOAR), a prospective observational cohort of patients presenting with early inflammatory arthritis. METHODS: Genotypes and clinician diagnoses were obtained from patients from NOAR. Six G-probabilities (0%-100%) were created for each patient based on known disease-associated odds ratios of published genetic risk variants, each corresponding to one disease of rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, spondyloarthropathy, gout, or "other diseases." Performance of the G-probabilities compared with clinician diagnosis was assessed. RESULTS: We tested G-PROB on 1,047 patients. Calibration of G-probabilities with clinician diagnosis was high, with regression coefficients of 1.047, where 1.00 is ideal. G-probabilities discriminated clinician diagnosis with pooled areas under the curve (95% confidence interval) of 0.85 (0.84-0.86). G-probabilities <5% corresponded to a negative predictive value of 96.0%, for which it was possible to suggest >2 unlikely diseases for 94% of patients and >3 for 53.7% of patients. G-probabilities >50% corresponded to a positive predictive value of 70.4%. In 55.7% of patients, the disease with the highest G-probability corresponded to clinician diagnosis. CONCLUSION: G-PROB converts complex genetic information into meaningful and interpretable conditional probabilities, which may be especially helpful at eliminating unlikely diagnoses in the rheumatology outpatient setting.

An international multi-centre analysis of current prescribing practices and shared decision-making in psoriatic arthritis.

OBJECTIVES: Shared decision-making (SDM) is advocated to improve patient outcomes in Psoriatic arthritis (PsA). We analysed current prescribing practices and the extent of SDM in PsA across Europe. METHODS: The ASSIST study was a cross-sectional observational study of PsA patients aged ≥18 years attending face-to-face appointments between July 2021-March 2022. Patient demographics, current treatment and treatment decisions were recorded. SDM was measured by the clinician's effort to collaborate (CollaboRATE questionnaire) and patient communication confidence (PEPPI-5 tool). RESULTS: 503 patients were included from 24 centres across the UK, France, Germany, Italy and Spain. Physician- and patient-reported measures of disease activity were highest in the UK. Conventional synthetic DMARDs constituted a higher percentage of current PsA treatment in UK than continental Europe (66.4% vs 44.9%), which differed from biologic DMARDs (36.4% vs 64.4%). Implementing treatment escalation was most common in the UK. CollaboRATE and PEPPI-5 scores were high across centres. Of 31 patients with low CollaboRATE scores (<4.5), no patients with low PsAID-12 scores (<5) had treatment escalation. However, of 465 patients with CollaboRATE scores ≥4.5, 59 patients with low PsAID-12 scores received treatment escalation. CONCLUSIONS: Higher rates of treatment escalation seen in the UK may be explained by higher disease activity and a younger cohort. High levels of collaboration in face-to-face PsA consultations suggests effective implementation of the SDM approach. Our data indicate that, in patients with mild disease activity, only those with higher perceived collaboration underwent treatment escalation. Prospective studies should examine the impact of SDM on PsA patient outcomes. TRIAL REGISTRATION: clinicaltrials.gov, NCT05171270.

GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

Utility of Musculoskeletal Ultrasound in Psoriatic Arthritis.

PURPOSE: Psoriatic arthritis (PsA) is a chronic autoimmune disease that causes a variety of musculoskeletal abnormalities. Musculoskeletal ultrasound in PsA is becoming increasingly popular, both in clinical practice and research. This narrative reviews recent literature on the utility of ultrasound in PsA. METHODS: A search of PubMed was used to identify publications written in English, with titles containing the term psoriatic arthritis and either ultrasound, ultrasonography, or sonographic. A total of 178 publications were identified; those that were not relevant (n = 59), were not original research (n = 45), or that had small (<30) sample sizes (n = 34) were excluded, leaving 40 studies for review of the use of ultrasound in various aspects of PsA. Publications with similar findings were grouped into seven domains: (1) the use of ultrasound findings compared to clinical assessment; (2) the use of ultrasound in the assessment of enthesitis; (3) the use of ultrasound in the assessment of nails; (4) the use of ultrasound as a screening tool in patients with psoriasis at risk for PsA; (5) the use of ultrasound in differentiating PsA from other similar conditions; (6) the use of ultrasound as a measure of disease activity; and (7) the use of ultrasound compared to MRI. FINDINGS: In recent studies, ultrasound measures of inflammation tended to agree with objective clinical findings of disease, such as swollen joint counts, while being less influenced by subjective measures, such as pain. Ultrasound has utility in the assessment of enthesitis and psoriatic nail disease in PsA, and as an overall measure of disease activity. Ultrasound-based outcomes measures have been used in observational studies and in clinical trials involving PsA, and may have utility as a measure of treatment response. The findings from recent studies suggest that ultrasound may have utility in improving the accuracy and precision of screening programs designed to identify subclinical PsA in cohorts of patients with psoriasis; however, cost-efficacy remains to be determined. Beyond screening, ultrasound may have utility in the diagnosis of PsA in patients with suspected inflammatory arthritis, and ultrasound measures of inflammation agree with MRI measures of inflammation, meaning that incorporating ultrasound into clinical practice might help to overcome the barriers associated with MRI. IMPLICATIONS: As ultrasound technology continues to advance, and associated costs decrease, it is likely that ultrasound will become more integrated into the clinical journeys of patients with PsA.

Non-trough adalimumab and certolizumab drug levels associated with a therapeutic EULAR response in adherent patients with rheumatoid arthritis.

OBJECTIVES: Interventions aimed at increasing TNF-α inhibitor serum drug levels (SDLs) may improve treatment response; however, previous studies suggesting SDL cut-offs have not accounted for treatment adherence. The aim of this study was to establish the relationship between adalimumab/certolizumab SDLs and EULAR good vs non-/moderate response and to define SDL cut-offs associated with good response in fully adherent patients. METHODS: In a prospective observational study, 475 patients with RA were treated with certolizumab (n = 192) or adalimumab (n = 283). At baseline and 3, 6 and 12 months, patients had 28-joint DAS, self-reported treatment adherence and SDLs measured. Fully adherent patients were analysed as a subgroup. Follow-up data at 3, 6 and 12 months were analysed separately. Median SDLs were compared in good vs non-/moderate response patients and receiver operating characteristics (ROC) curves were used to establish cut-off SDLs. RESULTS: Fully adherent good responders had significantly higher median adalimumab/certolizumab SDLs compared with non-/moderate responders (P = 0.04 and P = 0.0005, respectively). ROC analysis reported 3 month non-trough adalimumab SDLs discriminated good vs non-/moderate response with an area under the curve (AUC) of 0.63 (95% CI 0.52, 0.75), with a cut-off of 7.5 mg/l being 39.1% specific and 80.9% sensitive. Similarly, 3 month non-trough certolizumab SDLs discriminated good vs non-/moderate response with an AUC of 0.65 (95% CI 0.51, 0.78), with a cut-off of 26.0 mg/l being 43.9% specific and 77.8% sensitive. CONCLUSION: In fully adherent patients, higher SDLs are detected in good responders, suggesting that interventions to improve SDLs, such as encouraging adherence, could improve treatment response. The 3 month non-trough SDL cut-offs of 7.5 mg/l for adalimumab and 26.0 mg/l for certolizumab may be useful in clinical practice.

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials.

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis.

Renal sarcoidosis associated with certolizumab pegol treatment for psoriatic arthritis.

We present a case of certolizumab-associated renal sarcoidosis, the first reported case in a patient with psoriatic arthritis (PsA) that was effectively treated with corticosteroids. A 55-year-old Caucasian man with PsA diagnosed at age 47 and plaque psoriasis since his early twenties was on certolizumab pegol (CZP) for 7 months before presenting to the emergency department with seizures and renal failure. A renal biopsy confirmed renal sarcoidosis. His CZP therapy was stopped, and after several months taking prednisolone at a reducing regime, his renal function improved, and his PsA remained under control. When considering further treatment options for his PsA keeping in mind that other drugs, especially tumour necrosis factor-alpha inhibitors, have been reported to be associated with sarcoidosis, tofacitinib was considered to be a future treatment option acceptable to the patient, given current National Institute for Health and Care Excellence guidelines approving its use in PsA and the lack of reports of tofacitinib-associated sarcoidosis in the literature.

SARS-CoV-2 vaccination and new-onset myasthenia gravis: A report of 7 cases and review of the literature.

Myasthenia gravis (MG) is an antibody-mediated immune disorder of the neuromuscular junction. SARS-CoV-2 is now recognised as a trigger factor for autoimmune diseases and to cause immune-mediated dysregulation, likely due to molecular mimicry induced by viral antigens. SARS-CoV-2 vaccination, similarly, results in exposure to viral antigen. Here we report 7 cases of new-onset myasthenia gravis in timely association with SARS-CoV-2 vaccination, including the first paediatric case identified to date. We also reviewed the literature for other new-onset MG cases reported within 4 weeks of SARS-CoV-2 vaccination and discuss our findings in the context of altered (auto)immunity following SARS-CoV-2 vaccination and/or infection.

Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling.

OBJECTIVES: Psoriatic arthritis (PsA) has a strong genetic component, and the identification of genetic risk factors could help identify the ~30% of psoriasis patients at high risk of developing PsA. Our objectives were to identify genetic risk factors and pathways that differentiate PsA from cutaneous-only psoriasis (PsC) and to evaluate the performance of PsA risk prediction models. METHODS: Genome-wide meta-analyses were conducted separately for 5,065 patients with PsA and 21,286 healthy controls and separately for 4,340 patients with PsA and 6,431 patients with PsC. The heritability of PsA was calculated as a single-nucleotide polymorphism (SNP)-based heritability estimate (h2 SNP ) and biologic pathways that differentiate PsA from PsC were identified using Priority Index software. The generalizability of previously published PsA risk prediction pipelines was explored, and a risk prediction model was developed with external validation. RESULTS: We identified a novel genome-wide significant susceptibility locus for the development of PsA on chromosome 22q11 (rs5754467; P = 1.61 × 10-9 ), and key pathways that differentiate PsA from PsC, including NF-κB signaling (adjusted P = 1.4 × 10-45 ) and Wnt signaling (adjusted P = 9.5 × 10-58 ). The heritability of PsA in this cohort was found to be moderate (h2 SNP = 0.63), which was similar to the heritability of PsC (h2 SNP = 0.61). We observed modest performance of published classification pipelines (maximum area under the curve 0.61), with similar performance of a risk model derived using the current data. CONCLUSION: Key biologic pathways associated with the development of PsA were identified, but the investigation of risk classification revealed modest utility in the available data sets, possibly because many of the PsC patients included in the present study were receiving treatments that are also effective in PsA. Future predictive models of PsA should be tested in PsC patients recruited from primary care.

Pregnancy outcomes of a joint obstetric and rheumatology clinic in a tertiary centre: a 2-year retrospective study of 98 pregnancies.

Objectives: The purpose of this study was to describe the maternal and fetal outcomes in patients with inflammatory rheumatic diseases attending a joint rheumatology and obstetric clinic in the UK. Methods: Electronic records of 98 patients attending the joint rheumatology and obstetric clinic between January 2018 and January 2020 were analysed. Data on patient demographics, characteristics (including age, ethnicity, diagnosis, and medications taken during pregnancy), pregnancy outcomes (miscarriage, stillbirth or live birth), maternal complications [infection, post-partum haemorrhage (PPH) or pre-eclampsia] and fetal complications (sepsis, congenital heart block, prematurity and low birth weight) were tabulated. Subgroups of patients based on maternal diagnosis, medications and Ro/La antibody status were described in a similar manner. Results: The cohort was found to be predominantly Caucasian women >30 years of age, diagnosed with a CTD. Of 98 pregnancies, 97% (n = 95) resulted in a live birth, with only 2% resulting in miscarriage (n = 2) and 1% in stillbirth (n = 1). The median duration of gestation was 38 (interquartile range 37-39) weeks, and the majority of patients had a normal vaginal delivery (35%, n = 34), whereas 30% had emergency Caesarean sections (n = 29). The median birth weight was 3120 (interquartile range 2690-3410) g. The most common maternal complications were PPH (56%, n = 54) and infection (22%, n = 21). The most common fetal complications were prematurity (23%, n = 22) and low birth weight (17%, n = 16). Conclusion: We report favourable outcomes from this service model, including a high live birth rate, a low miscarriage rate and a high median birth weight. With limited reported data of pregnancy outcomes from joint obstetric/rheumatology clinics, this service model might be beneficial in other centres.

Septic arthritis caused by Mycoplasma hominis in a patient with systemic lupus erythematosus.

Mycoplasma hominis is one of the most common commensal organisms of the genitourinary tract. Immunocompromised patients are susceptible to developing severe infections secondary to M. hominis, and rarely, septic arthritis. This case report describes the occurrence of septic arthritis secondary to M. hominis in a 27-year-old woman with systemic lupus erythematosus (SLE), who presented with a 2-week history of left elbow swelling and tenderness, elevated inflammatory markers and joint aspiration findings consistent with infection. Serial blood cultures were negative. She was treated with flucloxacillin; however, failed to respond and so doxycycline was added to cover for atypical organisms. Subsequently, PCR analysis from the joint aspirate found M. hominis on day 16. Fortunately, doxycycline was an effective treatment for this atypical organism. This case outlines the importance of considering atypical organisms such as M. hominis as a cause of septic arthritis in immunosuppressed patients especially those with SLE.

Hereditary haemochromatosis presenting to rheumatology clinic as inflammatory arthritis.

Hereditary haemochromatosis (HH) is the most commonly identified genetic disorder in Caucasians. HH has a wide variety of clinical manifestations. As such, the presenting complaint in new diagnoses of HH can be non-specific such as fatigue; however, joint symptoms such as arthralgia are also common. These joint symptoms closely mimic the features of other musculoskeletal diseases such as rheumatoid arthritis (RA). Early diagnosis of HH is key to prevent long-term irreversible complications such as liver damage, diabetes and degenerative joint disease. We present a case of HH which was initially suspected to be early RA, with ultrasound findings of active synovitis. High clinical suspicion, a raised serum ferritin followed by genetic testing for C282Y mutation confirmed the diagnosis of HH. The synovitis responded to corticosteroids and was suspected to be due to pseudogout a known complication of HH. Early diagnosis and treatment resulted in a favourable outcome.

Application of information theoretic feature selection and machine learning methods for the development of genetic risk prediction models.

In view of the growth of clinical risk prediction models using genetic data, there is an increasing need for studies that use appropriate methods to select the optimum number of features from a large number of genetic variants with a high degree of redundancy between features due to linkage disequilibrium (LD). Filter feature selection methods based on information theoretic criteria, are well suited to this challenge and will identify a subset of the original variables that should result in more accurate prediction. However, data collected from cohort studies are often high-dimensional genetic data with potential confounders presenting challenges to feature selection and risk prediction machine learning models. Patients with psoriasis are at high risk of developing a chronic arthritis known as psoriatic arthritis (PsA). The prevalence of PsA in this patient group can be up to 30% and the identification of high risk patients represents an important clinical research which would allow early intervention and a reduction of disability. This also provides us with an ideal scenario for the development of clinical risk prediction models and an opportunity to explore the application of information theoretic criteria methods. In this study, we developed the feature selection and psoriatic arthritis (PsA) risk prediction models that were applied to a cross-sectional genetic dataset of 1462 PsA cases and 1132 cutaneous-only psoriasis (PsC) cases using 2-digit HLA alleles imputed using the SNP2HLA algorithm. We also developed stratification method to mitigate the impact of potential confounder features and illustrate that confounding features impact the feature selection. The mitigated dataset was used in training of seven supervised algorithms. 80% of data was randomly used for training of seven supervised machine learning methods using stratified nested cross validation and 20% was selected randomly as a holdout set for internal validation. The risk prediction models were then further validated in UK Biobank dataset containing data on 1187 participants and a set of features overlapping with the training dataset.Performance of these methods has been evaluated using the area under the curve (AUC), accuracy, precision, recall, F1 score and decision curve analysis(net benefit). The best model is selected based on three criteria: the 'lowest number of feature subset' with the 'maximal average AUC over the nested cross validation' and good generalisability to the UK Biobank dataset. In the original dataset, with over 100 different bootstraps and seven feature selection (FS) methods, HLA_C_*06 was selected as the most informative genetic variant. When the dataset is mitigated the single most important genetic features based on rank was identified as HLA_B_*27 by the seven different feature selection methods, consistent with previous analyses of this data using regression based methods. However, the predictive accuracy of these single features in post mitigation was found to be moderate (AUC= 0.54 (internal cross validation), AUC=0.53 (internal hold out set), AUC=0.55(external data set)). Sequentially adding additional HLA features based on rank improved the performance of the Random Forest classification model where 20 2-digit features selected by Interaction Capping (ICAP) demonstrated (AUC= 0.61 (internal cross validation), AUC=0.57 (internal hold out set), AUC=0.58 (external dataset)). The stratification method for mitigation of confounding features and filter information theoretic feature selection can be applied to a high dimensional dataset with the potential confounders.

Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial.

BACKGROUND: Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status. METHODS: This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28. FINDINGS: Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI -11 to 33], p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups. INTERPRETATION: The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice. FUNDING: Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research.

Translating research into clinical practice: quality improvement to halve non-adherence to methotrexate.

OBJECTIVE: MTX remains the cornerstone for therapy for RA, yet research shows that non-adherence is significant and correlates with response to therapy. This study aimed to halve self-reported non-adherence to MTX at the Kellgren Centre for Rheumatology. METHODS: An anonymous self-report adherence questionnaire was developed and data collected for 3 months prior to the introduction of interventions, and then regularly for the subsequent 2.5 years. A series of interventions were implemented, including motivational interviewing training, consistent information about MTX and development of a summary bookmark. Information on clinic times was collected for consultations with and without motivational interviewing. Surveys were conducted to ascertain consistency of messages about MTX. A biochemical assay was used to test MTX serum levels in patients at two time points: before and 2.8 years following introduction of the changes. Remission rates at 6 and 12 months post-MTX initiation were retrieved from patient notes and cost savings estimated by comparing actual numbers of new biologic starters compared with expected numbers based on the numbers of consultants employed at the two time points. RESULTS: Between June and August 2016, self-reported non-adherence to MTX was 24.7%. Following introduction of the interventions, self-reported non-adherence rates reduced to an average of 7.4% between April 2018 and August 2019. Clinic times were not significantly increased when motivational interviewing was employed. Consistency of messages by staff across three key areas (benefits of MTX, alcohol guidance and importance of adherence) improved from 64% in September 2016 to 94% in January 2018. Biochemical non-adherence reduced from 56% (September 2016) to 17% (June 2019), whilst remission rates 6 months post-initiation of MTX improved from 13% in 2014/15 to 37% in 2017/18, resulting is estimated cost savings of £30 000 per year. CONCLUSION: Non-adherence to MTX can be improved using simple measures including focussing on the adherence and the benefits of treatment, and providing consistent information across departments.

Identification of a novel autoantigen eukaryotic initiation factor 3 associated with polymyositis.

OBJECTIVES: To describe the prevalence and clinical associations of autoantibodies to a novel autoantigen, eukaryotic initiation factor 3 (eIF3), detected in idiopathic inflammatory myositis. METHODS: Sera or plasma from 678 PM patients were analysed for autoantigen specificity by radio-labelled protein immunoprecipitation (IPP). Samples immunoprecipitating the same novel autoantigens were further analysed by indirect immunofluorescence and IPP using pre-depleted cell extracts. The autoantigen was identified through a combination of IPP and MALDI-TOF mass spectrometry, and confirmed using commercial antibodies and IPP-western blots. Additional samples from patients with DM (668), DM-overlap (80), PM-overlap (191), systemic sclerosis (150), systemic lupus erythematosus (200), Sjogren's syndrome (40), rheumatoid arthritis (50) and healthy controls (150) were serotyped by IPP as disease or healthy controls. RESULTS: IPP revealed a novel pattern in three PM patients (0.44%) that was not found in disease-specific or healthy control sera. Indirect immunofluorescence demonstrated a fine cytoplasmic speckled pattern for all positive patients. Mass spectrometry analysis of the protein complex identified the target autoantigen as eIF3, a cytoplasmic complex with a role in the initiation of translation. Findings were confirmed by IPP-Western blotting. The three anti-eIF3-positive patients had no history of malignancy or interstitial lung disease, and had a favourable response to treatment. CONCLUSION: We report a novel autoantibody in 0.44% of PM patients directed against a cytoplasmic complex of proteins identified as eIF3. Although our findings need further confirmation, anti-eIF3 appears to correlate with a good prognosis and a favourable response to treatment.