Paul Emery

Objective The tapering of biologic disease‐modifying antirheumatic drug (b‐DMARD) therapy for patients with rheumatoid arthritis (RA) in stable remission is frequently undertaken, but specific guidance on how to successfully taper is lacking. The objective of this study is to identify predictors of flare in patients in stable b‐DMARD–induced clinical remission, who did or did not follow structured b‐DMARD tapering. Methods Patients with RA receiving b‐DMARD treatment who had achieved sustained remission according to a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) <2.6 for ≥6 months were offered tapering. Clinical, ultrasound (US) (total power Doppler [PD]/grayscale abnormalities), CD4+ T cell subsets, and patient‐reported outcomes (PROs) were collected at inclusion. The primary endpoint was the occurrence of flare (loss of DAS28‐CRP remission) over 12 months …

BackgroundIndividuals 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.MethodsThe 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 …

ObjectivesTo assess cigarette smoking’s effects on efficacy of the preferential Janus kinase (JAK) 1 inhibitor filgotinib and drug persistence in patients with rheumatoid arthritis (RA).MethodsEfficacy in non-smokers, former smokers, and current smokers from phase 3 filgotinib trials was analyzed, including patients with inadequate response (IR) to methotrexate (MTX) or biologic disease-modifying antirheumatic drugs (bDMARDs) or who were MTX-naïve. Proportions achieving Disease Activity Score in 28 joints with C-reactive protein (DAS28[CRP]) ≤ 3.2 were compared using logistic regression. Retrospective claims-based switching data were reviewed.ResultsWeek 12 (W12) DAS28(CRP) ≤ 3.2 was achieved by 50, 61, and 62% of MTX-IR non-smokers, former smokers, and current smokers taking filgotinib 200 mg (FIL200) + MTX vs. 23, 16, and 32% taking placebo + MTX (p < 0.001, < 0.001, and 0 …

Background Upadacitinib (UPA), an oral JAK inhibitor, was shown to be safe and effective in improving the signs and symptoms of moderate-to-severe RA through 84 weeks (wks) when administered as monotherapy in patients (pts) with a prior inadequate response to MTX in the phase 3 SELECT-MONOTHERAPY trial (NCT02706951).[1]Objectives To evaluate the efficacy and safety of UPA monotherapy up to wk 260 from the long-term extension (LTE) of SELECT-MONOTHERAPY.Methods Pts with active RA on stable MTX were randomly assigned to either continue MTX (cMTX) or switch to UPA monotherapy at 15 mg (UPA15) or 30 mg (UPA30) once daily (QD) during the 14-wk randomized, double-blind treatment period. From wk 14, the start of the LTE, pts receiving cMTX were switched to UPA15 or 30 per pre-specified assignment at baseline; pts randomly assigned to UPA15 or 30 continued their initial …

Biomarkers for the classification of rheumatoid arthritis (RA), and particularly for anti-citrullinated peptide antibody (ACPA)-negative patients, remain an important hurdle for the early initiation of treatment. Taking advantage of DNA-methylation patterns specific to early RA, quantitative methylation-specific qPCR (qMSP) offers a robust technology for the development of biomarkers. We developed assays and established their value as RA classification biomarkers. Methods DNA-methylation data were screened to select candidate CpGs to design qMSP assays. Eight assays were developed and tested on two early inflammatory arthritis cohorts. Logistic regression and bootstrapping were used to demonstrate the added value of the qMSP assays. Result Differentially methylated CpG data were screened for candidate CpG, thereby meeting the qMSP assay requirements. The top CpG candidate was in the TNF gene, for which we successfully developed a qMSP assay. Significantly lower DNA-methylation levels were observed in RA (p < 4 × 10−9), with a high predictive value (OR < 0.54/AUC < 0.198) in both cohorts (n = 127/n = 157). Regression using both datasets showed improved accuracy = 87.7% and AUC = 0.944 over the model using only clinical variables (accuracy = 85.2%, AUC = 0.917). Similar data were obtained in ACPA-negative patients (n = 167, accuracy = 82.6%, AUC = 0.930) compared to the clinical variable model (accuracy = 79.5%, AUC = 0.892). Bootstrapping using 2000 datasets confirmed that the AUCs for the clinical+TNF-qMSP model had significant added value in both analyses. Conclusion The qMSP technology is robust …

Background Anti-CCP+ at-risk individuals with musculoskeletal (MSK) symptoms and subclinical synovitis on ultrasound (US) are at high risk of developing inflammatory arthritis (IA). The accepted standard practice is to initiate treatment at progression rather than in the pre-rheumatoid arthritis (RA) phase when they do not have clinical synovitis [1].Objectives We aimed to determine whether imaging characteristics change when individuals with pre-RA progress to IA in order to inform the optimal window of opportunity for therapeutic interventions.Methods Anti-CCP+ at-risk individuals with MSK symptoms but no clinical synovitis from the Leeds CCP cohort were selected for having US subclinical synovitis [Grey scale (GS) ≥1 and Power Doppler (PD) ≥1] prior to IA development and a further US scan performed at clinical synovitis onset (i.e. progression). The US protocol included the metacarpophalangeal joints …

Background/Aims When the COVID-19 pandemic began, steps were taken to minimise risk to those vulnerable to severe outcomes. For immunosuppressed patients with rheumatoid arthritis (RA), consideration was given to reducing risk whilst mindful of compromising control of their underlying condition. At Leeds Teaching Hospitals NHS Trust, patients receiving rituximab (RTX) were considered for a reduced dose regimen. A retrospective study, using real-world data, was undertaken to assess the impact of lower doses of RTX on response to treatment. Methods The clinical records of all patients with RA who had received RTX between March 2020 and March 2021 were reviewed. Demographics and previous RTX exposure were recorded. The dose of RTX given during the specified period was noted. Response to treatment was recorded pragmatically by physicians as good, partial or none, based on patient reported VAS for disease activity and swollen and tender joint counts, given the limitations placed on face-to-face patient review due to the pandemic. The time to subsequent RTX treatment and the need for steroid treatment for flares was also studied. Results The number of patients treated with RTX was 282, of whom 89 patients received full dose (1g x 2 infusions), 192 patients received half dose (500mg x 2 infusions). The mean age was 61 years. 77% were female. 9% were RTX-naive, 80% had previously had full dose. Follow-up data were available for 185/192 of the group receiving 1g and 88/89 of the group receiving 2g. Clinical outcomes were as follows for the two groups (1g RTX vs 2g RTX) no response 10.3% vs 9.1%; partial …

Background Refractory rheumatoid arthritis (refRA) persists in the targeted therapy era with up to 20% of patients failing multiple classes of biologic (b) and/or targeted synthetic (ts) DMARDs.[1,2] Currently, there is limited understanding of the immune composition of refRA.Objectives To characterise the peripheral immune landscape of patients with refRA as compared to early RA.Methods In the Leeds observational cohort study, peripheral blood mononuclear cells were collected from 30 treatment naïve early rheumatoid arthritis (ERA) and 23 refractory rheumatoid arthritis (refRA) patients. ERA patients have <12 months symptoms duration and refRA patients had active (at least moderate disease) RA despite ≥2 classes of b and/or ts DMARDs. Using a panel of 36 antibodies, we conducted mass cytometry by time of flight (CyTOF) analysis to identify alterations in peripheral immune cell subsets and functional …

Background/Aims Anti-CCP positive individuals with musculoskeletal (MSK) symptoms and subclinical synovitis on ultrasound (US) are at high risk of developing inflammatory arthritis (IA). Treatment initiation in these individuals is not accepted practice as they do not have clinical synovitis. We aimed to determine whether imaging characteristics change when individuals with pre-RA progress to IA in order to inform the optimal window of opportunity for therapeutic interventions. Methods Anti-CCP+ at-risk individuals with MSK symptoms from the Leeds CCP cohort were selected for having US subclinical synovitis [Grey scale (GS)≥1 and Power Doppler (PD)≥1] prior to IA development and an US scan performed at clinical synovitis onset. The US protocol included the metacarpophalangeal joints (MCPJs), proximal interphalangeal joints (PIPJs), wrists, elbows, knees, second …

BackgroundAVERT-2 (a phase IIIb, two-stage study) evaluated abatacept + methotrexate versus methotrexate alone, in methotrexate-naive, anti-citrullinated protein antibody-positive patients with early (≤ 6 months), active RA. This subanalysis investigated whether individual patients who achieved the week 24 Simplified Disease Activity Index (SDAI) remission primary endpoint could sustain remission to 1 year and then maintain it following changes in therapy.MethodsDuring the 56-week induction period (IP), patients were randomized to weekly subcutaneous abatacept 125 mg + methotrexate or abatacept placebo + methotrexate. Patients completing the IP who achieved SDAI remission (≤ 3.3) at weeks 40 and 52 entered a 48-week de-escalation (DE) period. Patients treated with abatacept + methotrexate were re-randomized to continue weekly abatacept + methotrexate, or de-escalate and then …

IntroductionOne target of rheumatoid arthritis (RA) treatment is to achieve early sustained remission; over the long term, patients in sustained remission have less structural joint damage and physical disability. We evaluated Simplified Disease Activity Index (SDAI) remission with abatacept + methotrexate versus abatacept placebo + methotrexate and impact of de-escalation (DE) in anti-citrullinated protein antibody (ACPA)-positive patients with early RA.MethodsThe phase IIIb, randomized, AVERT-2 two-stage study (NCT02504268) evaluated weekly abatacept + methotrexate versus abatacept placebo + methotrexate. Primary endpoint: SDAI remission (≤ 3.3) at week 24. Pre-planned exploratory endpoint: maintenance of remission in patients with sustained remission (weeks 40 and 52) who, from week 56 for 48 weeks (DE period), (1) continued combination abatacept + methotrexate, (2) tapered …

Objectives Inflammatory arthritis (IA) is considered the last stage of a disease continuum, where features of systemic autoimmunity can appear years before clinical synovitis. Time to progression to IA varies considerably between at-risk individuals, therefore the identification of biomarkers predictive of progression is of major importance. We previously reported on the value of three CD4+T cell subsets as biomarkers of progression. Here, we aim to establish the value of 18 lymphocyte subsets (LS) for predicting progression to IA. Methods Participants were recruited based on a new musculoskeletal complaint and being positive for anti-citrullinated-peptide antibody. Progression (over 10 years) was defined as the development of clinical synovitis. LS analysis was performed for lymphocyte lineages, naive/memory subsets, inflammation-related cells (IRC) and regulatory cells (Treg …

Background DARWIN 3 (NCT02065700) is a long-term extension (LTE) study assessing the safety and efficacy of filgotinib (FIL) in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).[1] In the DARWIN 1 (NCT01888874) and DARWIN 2 (NCT01894516) parent studies, patients received FIL in combination with MTX or FIL monotherapy, respectively.Objectives To provide an update on the safety and efficacy of FIL 200 mg (FIL200) in patients with RA, with or without MTX, with a maximum of 8.2 years of exposure.Methods Patients completing the DARWIN 1 (FIL + MTX) and DARWIN 2 (FIL monotherapy) phase 2 studies could enter DARWIN 3, receiving FIL200. The proportion of patients experiencing treatment-emergent adverse events (TEAEs) were reported using the safety analysis set, comprising data from both the parent and LTE studies. Efficacy was assessed from LTE …

ObjectivesThis study aimed to demonstrate how to estimate the value of health gain after patients with a multisystem disease achieve a condition-specific composite response endpoint.MethodsData from patients treated in routine practice with an exemplar multisystem disease (systemic lupus erythematosus) were extracted from a national register (British Isles Lupus Assessment Group Biologics Register). Two bespoke composite response endpoints (Major Clinical Response and Improvement) were developed in advance of this study. Difference-in-differences regression compared health utility values (3-level version of EQ-5D; UK tariff) over 6 months for responders and nonresponders. Bootstrapped regression estimated the incremental quality-adjusted life-years (QALYs), probability of QALY gain after achieving the response criteria, and population monetary benefit of response.ResultsWithin the sample (n = 171 …

Background While genetic and epidemiological factors have been used traditionally to evaluate the risk of developing rheumatoid arthritis (RA), the definition of higher risk states has been refined in more recent years through inclusion of serum autoantibodies and symptom complexes, such as inflammatory joint pain. Data from at risk cohorts have reported rates of progression to RA in excess of 50% over 24 months. These combined features have provided a framework for the design of interception studies, aimed at delaying or preventing RA.Objectives We evaluated the feasibility, efficacy and acceptability of T-cell co-stimulation modulation with abatacept in individuals at risk of developing RA in the Arthritis Prevention In the Pre-clinical Phase of RA with Abatacept (APIPPRA) study.Methods APIPPRA is a Phase IIB randomised, double blind, placebo-controlled trial recruiting ACPA+RF+ or ACPAhi (≥3 x ULN) RF …

Interstitial lung disease (ILD) is a leading cause of mortality in patients with rheumatic diseases, including rheumatoid arthritis. 1 The 5-year mortality rate is twice as high in patients with rheumatoid arthritis-associated ILD than in patients with rheumatoid arthritis without ILD. 2 Moreover, a report showed that mortality rates in patients with disease codes for rheumatoid arthritis-associated ILD remained unchanged from 2005–18, even though the overall rheumatoid arthritis mortality rate declined during this time period. 3 Despite the evidence that ILD contributes to premature death in rheumatoid arthritis, screening for ILD in patients with rheumatoid arthritis is not routinely performed in clinical practice and numerous questions remain regarding the management of rheumatoid arthritis-associated ILD. 4 Interstitial lung abnormalities are sometimes incidentally observed in patients with rheumatoid arthritis who undergo …

Background/Aims In rheumatoid arthritis (RA) disease assessment, SDAI and Boolean remission criteria are known to be more stringent in comparison to DAS28-ESR. Comparing remission rates across multiple assessment indices provides a more comprehensive evaluation of disease control. In an early RA trial cohort, we aimed to investigate stringent and multi-criteria remission (MCR) rates and evaluate their proportional change in response to treatment. Methods The ‘VEDERA’ trial randomised 120 treatment-naïve, new-onset RA patients to first-line etanercept+methotrexate (ETN+MTX) or methotrexate treat-to-target (MTX-TT) with escalation to ETN+MTX if not in DAS28-ESR remission at week24. Clinical assessments were completed at baseline, weeks12/24/48 (protocolised phase) up to week96 (standard-of-care). Remission cut-points included: DAS28-ESR ≤2.6, SDAI …

BackgroundWe aimed to identify factors associated with a significant reduction in SLE disease activity over 12 months assessed by the BILAG Index.MethodsIn an international SLE cohort, we studied patients from their ‘inception enrolment’visit. We also defined an ‘active disease’cohort of patients who had active disease similar to that needed for enrolment into clinical trials. Outcomes at 12 months were; Major Clinical Response (MCR: reduction to classic BILAG C in all domains, steroid dose of≤ 7.5 mg and SLEDAI≤ 4) and ‘Improvement’(reduction to<= 1B score in previously active organs; no new BILAG A/B; stable or reduced steroid dose; no increase in SLEDAI). Univariate and multivariate logistic regression with Least Absolute Shrinkage and Selection Operator (LASSO) and cross-validation in randomly split samples were used to build prediction models.Results‘Inception enrolment’(n= 1492) and ‘active …

BackgroundTargeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway.MethodsA systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document.ResultsThe consensus process covered relevant aspects of dosing and populations for different indications of IL …

Background Palindromic rheumatism (PR) is a recognised precursor of rheumatoid arthritis (RA) and is characterised by episodic flares of pain and swelling in and around joints [1]. Up to 50% of PR patients will progress to persistent arthritis (PA) [1]. However, PR is challenging to identify and study longitudinally and risk factors for progression remain unclear [1]. This is the first large UK prospective PR cohort study describing risk factors in patients with PR, the majority of whom were treatment naïve at baseline.Objectives To investigate baseline risk factors associated with progression to PA in PR patients.Methods Patients with suspected PR were recruited to the Leeds PR cohort from regional primary care and secondary care referrals. In the absence of an accepted classification criteria, PR was defined as ‘a confirmed history or physical examination consistent with episodes of joint pain and swelling that returned to …