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Abstract Introduction We aim to assess the association of patient-reported pain and remission or low disease activity (LDA) at 3 months (M) in patients receiving baricitinib or other treatments in RA-BE-REAL. Methods RA-BE-REAL reports on patients with rheumatoid arthritis (RA) who were prescribed, for the first time, baricitinib (cohort A) or a tumour necrosis factor inhibitor (TNFi) (cohort B-TNFi) or any other mode of action (OMA) (cohort B-OMA). Pain was measured using the visual analogue scale (VAS) (0–100 mm) and clinically meaningful pain improvement thresholds of ≥ 30%, ≥ 50% and ≥ 70% from baseline to 3, 6, 12 and 24 M. Results At 3 M, the mean change from baseline (CFB) pain VAS of patients in remission/LDA was − 32.6 mm (cohort A), − 27.3 mm (cohort B-TNFi) and − 28.0 mm (cohort B-OMA). Almost half the patients who were in remission/LDA receiving baricitinib achieved ≥ 70% pain relief. At 3 M, the proportion of patients in remission/LDA with pain VAS ≤ 20 mm was 62.1% (cohort A), 55.0% (cohort B-TNFi) and 55.6% (cohort B-OMA), while for those not in remission/LDA, it was 8.5% and 8.7% (cohort A and B-TNFi, respectively) and 5.3% (B-OMA). More patients on baricitinib achieved pain improvement in all analyzed thresholds than patients in cohort B-TNFi and B-OMA at 3 M. At 24 M, − 26.2 mm (cohort A), − 20.8 mm (cohort B-TNFi) and − 16.0 mm (cohort B-OMA) mean CFBs in pain measurement were observed. For baricitinib and the other treatments, residual pain decreased with achievement of remission/LDA and was sustained up to 24 M. Conclusions Patients in remission/LDA receiving baricitinib are more likely to achieve pain control than patients receiving TNFi/OMA.

Abstract This commentary explores the potential cardiovascular (CV) benefits of combining methotrexate (MTX) and Janus kinase inhibitors (JAKis) in the treatment of rheumatoid arthritis (RA). While European guidelines recommend MTX as first-line treatment, concerns about the CV risks associated with JAKis have emerged. This article reviews the existing literature to assess the role of concomitant MTX in reducing CV risk when used with JAKis. Clinical trials confirm the efficacy of JAKis in combination with MTX in terms of treatment outcomes in RA. However, the number of major adverse cardiovascular events (MACEs) reported is too low to draw conclusions on adverse CV outcomes. Indirect evidence does, however, suggest potential protective effects of MTX on CV outcomes, as several mechanisms may contribute to MTX’s cardioprotective effects, including reduced inflammation, adenosine monophosphate-activated protein kinase (AMPK) activation, increased cholesterol efflux, and adenosine accumulation. These mechanisms and the available data may support the case for CV benefits of concomitant MTX when JAKis are used in the treatment of patients with RA, although further research is needed. In particular, the lipid paradox associated with RA highlights the complex relationship between RA treatments (MTX, JAKis, tumor necrosis factor (TNF) inhibitors, and interleukin (IL)-6 receptor inhibitors), inflammation, different lipid profiles, and CV risk. In the absence of contraindications and when MTX is tolerated, this commentary suggests the concomitant use of MTX and JAKis as a preferred option for optimizing CV protection in patients with RA.

Abstract Introduction High baseline neutrophil-to-lymphocyte ratio (NLR) in rheumatoid arthritis (RA) has been associated with positive responses to biologic tumor necrosis factor inhibition and negative responses to conventional synthetic disease-modifying antirheumatic drug (csDMARD) triple therapy. Datasets from three randomized clinical trials in patients with RA were used to test the hypothesis that baseline NLR is associated with improved clinical response to filgotinib in methotrexate (MTX)-naïve or MTX-experienced RA populations. Methods Patients from FINCH 1 (inadequate response to MTX, MTX-IR; NCT02889796), FINCH 2 (inadequate response to biologic DMARDs; NCT02873936), and FINCH 3 (MTX-naïve; NCT02886728) were classified as baseline NLR-High or baseline NLR-Low based on a previously published cut point of 2.7. In total, 3365 patients were included across the three studies. Differences in clinical outcomes and patient-reported outcomes (PROs) were determined using linear-regression models. Results Control-arm patients (placebo + MTX/placebo + csDMARD) classified as NLR-High exhibited worse continuous clinical and PRO responses at week 12 across clinical trials compared to NLR-Low patients. In contrast, NLR-High patients who received FIL 200 mg + MTX/csDMARD exhibited consistently better responses after 12 weeks compared to NLR-Low patients across clinical trials, clinical endpoints, and PROs. These trends were most prominent among the MTX-IR population. Conclusion The 2.7 baseline NLR cut point could be used to enrich for patients most likely to benefit from the addition of filgotinib to background MTX/csDMARD. Use of baseline NLR as part of therapeutic decision-making would not require additional diagnostics and could contribute to improved outcomes for patients with RA. Trial Registration Clinicaltrials.gov: NCT02889796; NCT02873936; NCT02886728.

Rheumatoid arthritis (RA) is an autoimmune disease characterised by persistent inflammation of the synovial joints as well as other tissues and organs. Left untreated, it can lead to joint damage, disability and even increased mortality. The disease is driven by inflammatory cytokines that contribute to the chronic inflammation seen in RA. Interleukin-6 (IL-6) is a key pathological cytokine and a target for treatments aiming to alleviate local and systemic inflammation. Despite advances in understanding RA and the introduction of new treatments, achieving sustained remission remains challenging. This review explores the role of IL-6 in RA pathogenesis, its potential as a treatment target and the significance of personalised medicine in RA management. IL-6 has a dual signalling mechanism, classical and trans-signalling, which influences various intracellular pathways. While several targeted therapies have emerged, no single mechanism-based therapy is universally effective due to the diversity and complexity of the disease. Different approaches to targeting IL-6 have been tested, including biologic blockade of receptors or ligands, and inhibition of IL-6 signalling. IL-6 receptor inhibitors have been validated as RA therapeutics, either alone or in combination with other treatments. Tocilizumab, the first approved IL-6 inhibitor, blocks both soluble and membrane-bound IL-6 receptors, reducing the inflammatory cascade. Clinical trials confirm the efficacy and safety of tocilizumab and its role as a treatment option for patients unresponsive to conventional therapies. The benefits of IL-6 inhibition extend beyond reduced joint inflammation to the amelioration of comorbidities like anaemia, cardiovascular disease, depression and osteoporosis. Tailoring treatment to patients’ profiles and comorbidities is essential for optimal outcomes. A ‘treat-to-profile’ approach, focusing on a holistic view of the patient, could improve personalised medicine strategies. Biosimilars – lower-cost alternatives to biologics – further enhance the accessibility and cost-effectiveness of treatment. IL-6 inhibitors present a valuable treatment option for RA management, particularly for patients with specific comorbidities.

Abstract Introduction Our aim was to evaluate protein biomarker changes related to the administration of filgotinib, a Janus kinase (JAK) 1 preferential inhibitor, in patients with moderately to severely active rheumatoid arthritis (RA) with inadequate response to methotrexate. Methods Plasma and serum samples were collected from patients enrolled in FINCH 1 (NCT02889796), a Phase 3 trial. Patients with stable backgrounds of methotrexate were randomly assigned once-daily oral filgotinib 200 or 100 mg, subcutaneous adalimumab 40 mg every 2 weeks (W), or placebo. Up to 35 biomarkers were analyzed at baseline, W4, and W12 with enzyme-linked immunosorbent assays and chemiluminescence and electrochemiluminescence assays. Results At baseline, four distinct biomarker clusters were identified. The strongest intragroup correlations were in bone-cartilage resorption/inflammation and JAK/signal transducer and activator of transcription (STAT) signaling activity. At baseline, significant positive correlations were identified for cytokines with patient-reported pain and with patient measures of fatigue. Filgotinib reduced levels of cytokines associated with inflammation and cell migration as early as W4 and through W12. Compared to adalimumab, filgotinib induced significant reductions in bone-related turnover biomarkers, N-telopeptide of type 1 collagen and C-telopeptide 1, as well as biomarkers associated with baseline disease activity. No baseline predictors of therapeutic response to filgotinib were identified. Conclusions Filgotinib reduced peripheral protein biomarkers associated with JAK/STAT signaling, inflammatory signaling, immune cell migration, and bone resorption as soon as W4 in FINCH 1. Effects were dose-dependent and consistent with the clinical efficacy of filgotinib observed in FINCH 1. The changes in peripheral biomarkers associated with filgotinib treatment in methotrexate-experienced patients are consistent with changes observed in both methotrexate-naïve and biologic disease-modifying antirheumatic drug-experienced RA populations. These data demonstrate dose-dependent effects of preferential JAK1 inhibition by filgotinib on peripheral blood protein biomarkers in methotrexate-experienced patients with RA. Trial Registration ClinicalTrials.gov, NCT02889796.

Abstract Introduction Tofacitinib is an oral Janus kinase inhibitor for treatment of ankylosing spondylitis (AS). Using mediation modelling, we describe interrelationships between fatigue, pain, morning stiffness, C-reactive protein (CRP) and tofacitinib treatment in patients with AS. Methods Data from phase 2 (NCT01786668)/phase 3 (NCT03502616) studies of patients receiving tofacitinib 5 mg twice daily (BID) or placebo were used. Initial models included treatment as the independent binary variable (tofacitinib 5 mg BID versus placebo); fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F; model A] or Bath AS Disease Activity Index [BASDAI] Q1 [model B]) as the dependent variable; and pain (total back pain/nocturnal spinal pain [model A] or pain measured by BASDAI Q2/3 [model B]), morning stiffness (BASDAI Q5/6) and CRP as mediator variables. Results Pooled data from 370/371 patients were included in models A/B. Initial models demonstrated that tofacitinib treatment affects fatigue mainly indirectly via pain and morning stiffness. As a result, initial models were respecified to exclude direct treatment effect and the indirect effect via CRP. For respecified model A, 44.0% of the indirect effect of tofacitinib treatment on fatigue was mediated via back pain/morning stiffness, 40.0% via morning stiffness alone and 16.0% via back pain alone (all P

Abstract Background Rheumatoid arthritis (RA) is a chronic inflammatory disease that is associated with joint pain and stiffness. Biologics represent some of the most effective treatments for RA, but previous guidance from the National Institute for Health and Care Excellence (NICE) has limited their use to patients with severely active disease. This has meant patients with moderately active RA have been treated as if they have an acceptable disease state, despite many cases where the inflammation has a major impact on joint damage, mobility, pain and quality of life. However, recent guideline changes (NICE TA715) have approved the use of three biologics — adalimumab, etanercept and infliximab — for the treatment of moderately active RA. Main body In response to these changes, we have held discussions with medical teams from across the UK to consider the main implications for implementation of these new recommendations, as well as any differences in approach that may exist at a local level. Several key challenges were identified. These included establishing methods of educating both physicians and patients concerning the new availability of the biologic treatments, with suggestions of various organisations that could be approached to circulate informative material. Identifying which patients with moderately active RA stand to benefit was another discussion topic. Relying solely on scoring systems like Disease Activity Score in 28 Joints (DAS28) was acknowledged to have limitations, and alternative complementary approaches such as ultrasound, as well as assessing a patient’s co-morbidities, could also be useful tools in determining those who could benefit from biologics. An additional challenge for the process of patient identification has been the increase in the use of telemedicine consultations in response to the coronavirus disease 2019 (COVID-19) pandemic. More use of patient-reported outcomes was raised as one possible solution, and the importance of maintaining up-to-date databases on patient disease scores and treatment history was also stressed. Conclusion While challenges exist in education and identifying patients who may benefit from the use of biologics, the NICE TA715 recommendations hold great potential in addressing an unmet need for the treatment of moderate RA.

Abstract Introduction The aim of this work is to compare real-world outcomes of patients with rheumatoid arthritis (RA) receiving adalimumab (ADA) bio-originator (non-switchers) to those who had switched from ADA bio-originator to an ADA biosimilar (switchers) on the basis of the hypothesis that these outcomes would differ. Methods Data were drawn from the Adelphi RA Disease Specific Programme™, a point-in-time survey of physicians and their patients in Europe (France, Germany, Italy, Spain, UK) in 2020. Physicians completed a questionnaire for their next ten adult patients with RA, followed by four additional patients who had switched from ADA bio-originator to an ADA biosimilar (switchers). Physician- and patient-reported outcomes (PROs) for switchers and non-switchers were compared by propensity score matching. Results Three hundred and three rheumatologists provided data for 160 non-switchers and 225 switchers, 140 patients provided data; 51 non-switchers, 89 switchers. According to physician-reported disease activity, non-switchers were more likely to improve on their current ADA treatment than switchers (68%, n = 108 vs. 26%, n = 59 p

Plain Language Summary Baricitinib is an oral agent widely approved for the treatment of moderately to severely active rheumatoid arthritis). Although baricitinib (and other agents) have demonstrated efficacy at the population level, treatment responses vary considerably between individual patients. This study assessed four baricitinib phase 3 clinical studies and categorized patient responses into response groups based on the Clinical Disease Activity Index (CDAI) using a growth mixture model. We then evaluated baseline characteristics and corresponding disease measures within the response groups. In patients with no prior treatment with biological disease-modifying anti-rheumatic drugs (bDMARDs), 65–71% of patients had rapid responses to treatment, while smaller groups had gradual (10–17%) or partial (18–22%) responses. In patients with prior bDMARD experience, rapid and partial responders each comprised 42% of patients while 15% had limited response. Gradual responders generally had higher baseline CDAI versus rapid responders, but achieved low disease activity (LDA) by 24, versus 12 weeks for rapid responders. Across response groups, patients who continued treatment generally maintained their response up to 52 weeks, and where joint erosion was assessed (in bDMARD-naïve patients), generally saw maintenance of joints during continued therapy. The identification of a gradual responder group, which demonstrated good response but required more time to achieve LDA, is relatively novel and should be considered when setting treatment expectations, particularly in patients with high baseline disease activity. In addition, in bDMARD-experienced patients, many patients did not achieve LDA but maintained a substantial partial response with continued therapy.

Objectives Evaluate relationships between changes in dermatologic assessments and quality of life (QoL) measures; quantify dermatologic symptom severity impacts on QoL in patients with psoriatic arthritis (PsA) treated with tofacitinib.Methods Data were from two phase III studies; patients received tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg every other week, or placebo advancing to tofacitinib 5 or 10 mg BID at Month 3. Repeated measures longitudinal models assessed relationships between dermatologic assessments (predictors) Itch Severity Item (ISI), Physician’s Global Assessment of Psoriasis (PGA-PsO), and Patient’s Global Joint and Skin Assessment-Visual Analog Scale-Psoriasis question (PGJS-VAS-PsO), and QoL measures (outcomes) Dermatology Life Quality Index (DLQI) and Short Form-36 Health Survey Version 2 (SF-36v2). Models included one predictor and one outcome.Results Direct, approximately linear relationships existed between predictors and outcomes. ISI/PGA-PsO/PGJS-VAS-PsO improvements from baseline of ≥3/≥2/≥40-mm VAS corresponded with clinically meaningful DLQI improvements; improvements from baseline of ≥4/≥3/≥40-mm VAS generally corresponded with clinically meaningful improvements across component scores and all SF-36v2 domains.Conclusions Substantial links exist between dermatologic symptoms and QoL in patients with PsA, potentially informing patient-centered care and research. Rheumatologists should be aware of dermatologic manifestations and QoL impacts in patients with PsA.ClinicalTrials.gov NCT01877668; NCT01882439

Objective Pain reduction with baricitinib was assessed in patients with rheumatoid arthritis (RA) who either used opioids or did not use opioids during three randomized, double‐blind phase 3 trials. Methods Analysis populations were as follows: i) baricitinib 4 mg once daily versus placebo groups integrated from RA‐BEAM (NCT01710358) for patients with inadequate response (IR) to methotrexate, RA‐BUILD (NCT01721057) with IR to conventional disease‐modifying antirheumatic drugs, and RA‐BEACON (NCT01721044) with IR to at least one tumor necrosis factor inhibitors; ii) baricitinib 2 mg versus placebo from RA‐BUILD and RA‐BEACON; and iii) adalimumab 40 mg every other week versus placebo from RA‐BEAM. Pain was measured by the Patient Assessment of Pain Visual Analog Scale. Analysis of covariance modeling assessed differences in pain reduction between treatments at each time point through Week 24, with an interaction term to test heterogeneous treatment effects across opioid users and nonusers. Results Baricitinib 4 mg had greater pain reduction versus placebo in opioid users and nonusers (P < 0.05) at all time points starting from Week 1; the pain reduction was similar between opioid users and nonusers. Baricitinib 2 mg had greater pain reduction versus placebo in opioid users and nonusers starting at Week 4. A significant difference in pain reduction was not observed for adalimumab versus placebo in the opioid users but was observed in nonusers at all time points. Conclusion Pain reduction was observed and was similar between opioid users and nonusers with baricitinib 2 mg and 4 mg but not adalimumab in this post hoc analysis.

Background While treat-to-target (T2T) is endorsed for the management of rheumatoid arthritis (RA), data on the degree of implementation in clinical practice are limited. This study investigated the use of T2T for RA in a real-world setting across Europe.Methods The Adelphi RA Disease-Specific Programme was a point-in-time survey of rheumatologists and their consulting patients with RA conducted between January and October 2020 in Belgium, France, Germany, Italy, Spain and the UK. Rheumatologists completed an attitudinal survey, and a record form for their next 10–12 consulting patients, who were invited to voluntarily complete a patient-reported questionnaire. Data collected included clinical characteristics, treatment patterns and attitudes towards T2T.Results Overall, 316 rheumatologists provided data for 3120 patients, of whom 1108 completed the questionnaire. While 86.1% of rheumatologists estimated using T2T principles in clinical practice, only 66.6% of patients were reported by their physician to be managed using a T2T approach. Achieving disease remission was the most commonly reported treatment goal identified by rheumatologists (79.7%), followed by symptom control (47.8%) and reducing impact on quality of life (44.5%). 40.8% of rheumatologists and their patients were in agreement that a treatment goal had been set. When there was agreement on treatment goals, we observed better patient satisfaction, engagement and treatment success.Conclusions Despite recommendations, the T2T approach in RA appears to be suboptimally implemented in clinical practice. This highlights the importance of patient-centricity in the decision-making process to define meaningful targets and select appropriate treatments to improve disease outcomes.

Anti-tumour necrosis factors (anti-TNFs) are established as first-line biological therapy for rheumatoid arthritis (RA) with over two decades of accumulated clinical experience. Anti-TNFs have well established efficacy/safety profiles along with additional benefits on various comorbidities. However, up to 40% of patients may respond inadequately to an initial anti-TNF treatment because of primary non-response, loss of response, or intolerance. Following inadequate response (IR) to anti-TNF treatment, clinicians can consider switching to an alternative anti-TNF (cycling) or to another class of targeted drug with a different mechanism of action, such as Janus kinase inhibitors, interleukin-6 receptor blockers, B-cell depletion agents, and co-stimulation inhibitors (swapping). While European League Against Rheumatism recommendations for pharmacotherapeutic management of RA, published in 2020, are widely regarded as helpful guides to clinical practice, they do not provide any clear recommendations on therapeutic choices following an IR to first-line anti-TNF. This suggests that both cycling and swapping treatment strategies are of equal value, but that the treating physician must take the patient’s individual characteristics into account. This article considers which patient characteristics influence clinical decision-making processes, including the reason for treatment failure, previous therapies, comorbidities, extra-articular manifestations, pregnancy, patient preference and cost-effectiveness, and what evidence is available to support decisions made by the physician.

Abstract Background Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA). Methods Patients with moderate to severe RA who had received ≥12 weeks’ stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85. Results A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints–C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms. Conclusions These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA. Trial registration ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016.

Abstract Introduction The Janus kinase (JAK) inhibitor therapeutic class has shown significant clinical benefit in the treatment of rheumatoid arthritis (RA). We sought to gain insight into the mode of action and immunological effects of filgotinib, a JAK1 selective inhibitor, in active RA by analyzing secreted and cell-based biomarkers key to RA pathophysiology in two phase 2b trials of filgotinib in active RA. Methods Immune cell subsets and 34 serum biomarkers were analyzed longitudinally over 12 weeks using blood samples collected from patients with active RA receiving filgotinib (100 or 200 mg once daily) or placebo (PBO) in the two phase 2b trials (DARWIN 1, on a background of methotrexate, and DARWIN 2, as monotherapy). Results Consistently across both studies, filgotinib treatment decreased multiple immune response biomarkers that have key roles in RA for immune response, and decreased markers that promote matrix degradation, angiogenesis, leukocyte adhesion, and recruitment. Filgotinib did not significantly modulate T and natural killer (NK) lymphoid subsets, but slightly increased B cell numbers after 12 weeks. Multiple correlations were observed for changes in biomarkers with disease activity score 28-CRP. MIP1β showed modest predictivity at baseline for ACR50 response at 12 weeks in the 100 mg filgotinib dose across both studies (AUROC, 0.65 and 0.67, p

Abstract Background The in vitro pharmacology of baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level. Methods Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC50) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24 h obtained from JAKi-treated subjects. Time above IC50 and average daily percent inhibition of pSTAT formation were calculated for each JAKi, cytokine, and cell type. Results Distinct JAKis displayed different in vitro pharmacologic profiles. For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower IC50 values and increased time above IC50 translating to a greater overall inhibition of STAT signaling during the dosing interval. All JAKis tested inhibited JAK1/2-dependent cytokines (e.g., IL-6 and interferon [IFN]-γ), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-α, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), but often to significantly differing degrees. Conclusions Different JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. Notably, baricitinib inhibited JAK1/3 signaling to a lesser extent than upadacitinib and tofacitinib, while upadacitinib, baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF.

Abstract Trial design We present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class co-stimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis. Methods The study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants who were at least 18 years old, who reported inflammatory sounding joint pain (clinically suspicious arthralgia) and who were found to be positive for serum autoantibodies associated with rheumatoid arthritis (RA) were eligible for enrolment. All study subjects were randomly assigned to receive weekly injections of investigational medicinal product, either abatacept or placebo treatment over the course of a 52-week period. Participants were followed up for a further 52 weeks. The primary endpoint was defined as the time to development of at least three swollen joints or to the fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA using swollen but not tender joints, whichever endpoint was met first. In either case, swollen joints were confirmed by ultrasonography. Participants, care givers, and those assessing the outcomes were all blinded to group assignment. Clinical assessors and ultrasonographers were also blinded to each other’s assessments for the duration of the study. Conclusions There is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. We discuss the rationale behind choice and duration of treatment and the challenges associated with defining the “at risk” state and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA. Trial registration Current Controlled Trials, ID: ISRCTN46017566. Registered on 4 July 2014.

Abstract Background Namilumab (AMG203), an immunoglobulin G1 monoclonal antibody that binds with high affinity to granulocyte-macrophage colony-stimulating factor (GM-CSF), was evaluated in a phase II randomized, double-blind, placebo-controlled study to investigate the efficacy and safety in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX-IR) or anti-tumour necrosis factor therapy (TNF-IR). Methods Subcutaneous namilumab (20, 80, or 150 mg) or placebo was administered at baseline and weeks 2, 6, and 10 in patients on stable background methotrexate therapy who were with MTX-IR or TNF-IR. Primary endpoint was mean change from baseline in the 28-joint Disease Activity Score, C-reactive protein version (DAS28-CRP) at week 12 comparing each of the three doses of namilumab to placebo. Safety and tolerability were assessed by adverse events (AEs) and pulmonary parameters. Results were analysed using the per-protocol population. Results One hundred eight patients from Europe and Japan (48.4 ± 12.02 years old; 77.8% female; mean DAS28-CRP 5.60–5.79; rheumatoid factor/anti-citrullinated protein antibodies + 75%) were randomized to placebo or namilumab 20, 80, or 150 mg (n = 27, 28, 25, and 28, respectively). Ninety-two were MTX-IR; 16 were TNF-IR. At week 12, a statistically significant difference in DAS28-CRP (p = 0.005) was seen for namilumab 150 mg versus placebo and separation was seen as early as week 2 for namilumab 150 mg (p

Introduction Inflammatory arthritis (IA) conditions, including rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis, are characterised by inflammatory infiltration of the joints. Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), respectively, reduce the effects of proinflammatory cytokines and immune cells to ameliorate disease. However, immunosuppression can be associated with high rates of serious adverse events (SAEs), including serious infections, and maybe an increased risk of malignancies and cardiovascular events. Currently, there is no empirical evidence on the extent to which contextual factors and risk of bias (RoB) domains may modify these harm signals in randomised trials.Methods and analysis We will search MEDLINE (via PubMed) for systematic reviews published since April 2015 and all Cochrane reviews. From these reviews, randomised trials will be eligible if they include patients with an IA condition with at least one group randomly allocated to bDMARD and/or tsDMARD treatments. A predefined form will be used for extracting data on population characteristics (eg, baseline characteristics or eligibility criteria, such as medication background) and specific harm outcome measures, such as number of withdrawals, numbers of patients discontinuing due to adverse events and number of patients having SAEs. RoB in individual trials will be assessed using a modified Cochrane RoB tool. We will estimate the potentially causal harm effects related to the experimental intervention compared with control comparator as risk ratios, and heterogeneity across randomised comparisons will be assessed statistically and evaluated as inconsistency using the I2 Index. Our metaregression analyses will designate population and trial characteristics and each RoB domain as independent variables, whereas the three harm domains will serve as dependent variables.Ethics and dissemination Ethics approval is not required for this study. Results will be disseminated through publication in international peer-reviewed journals.PROSPERO registration number CRD42020171124.

Abstract Background Rheumatoid arthritis (RA) is associated with significantly diminished health-related quality of life. Patient-reported outcomes (PROs) are considered important in RA; however, some symptoms such as morning joint stiffness (MJS) and fatigue that are considered important by patients are not captured by the American College of Rheumatology “core set” measures for RA trials. The US Food and Drug Administration has endorsed electronic capture of clinical trial data including PROs, and electronic PRO (ePRO) systems may lead to more accurate and complete data capture, improved compliance, and patient acceptance compared with paper-based methods. Our objective was to assess the implementation of ePRO measures of Duration and Severity of MJS, Severity of Worst Tiredness, and Severity of Worst Joint Pain in baricitinib RA-BEAM and RA-BUILD phase 3 randomized clinical trials (RCTs). Methods A daily electronic diary (handheld device; Invivodata®, Inc.) was utilized to capture PRO data in the RCTs. Three “reporting window” options were incorporated to accommodate differences in patients’ routine daily schedules, and alarms were programmed for each reporting window. Duration of MJS was recorded in “hours and minutes,” and Severity of MJS, Worst Tiredness, and Worst Joint Pain were captured on a 0 to 10 rating scale, with a higher score indicating more severe symptoms. The patients and site staff were trained to use the daily electronic diary. Results Patients with moderately to severely active RA used the daily electronic diary in the RA-BEAM study (N = 1305) and RA-BUILD study (N = 684). The average compliance, calculated as total days completed by patients compared with total days expected to complete the diary, through Week 12 was high (RA-BEAM 94% patients; RA-BUILD 93% patients), potentially attributable to appropriate training, clarity of instructions, simple user interface, and electronic device design. Identified process challenges included non-timely issuance of the device, low battery, inadequate training of patients before data collection, inappropriate diary set-up, and first response entry 1 day after the baseline visit. Conclusions High compliance rates support the use of the daily electronic PRO diary in large RCTs. Despite the anticipated issues, the daily electronic diary is expected to reduce recall bias and improve the quality of PRO data collection. Trial registration RA-BEAM (NCT01710358) and RA-BUILD (NCT01721057).

In the published manuscript [...]

Background: Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. Methods: Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). Findings: We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p

This paper reports on the procedures of mix design preparation, production, placement, and performance evaluation of the first electrically conductive concrete (ECON) heated-pavement system (HPS) implemented at a U.S. airport. While ECON has drawn considerable attention as a paving material for multi-functional pavements, including HPS, the majority of ECON HPS applications and studies have been limited to laboratory scale or include materials/methods that do not conform to regulations enforced by airfield construction practices. Carbon fiber-reinforced ECON provides a promising prospective for application in airfield pavements. In this study, ECON mixtures were prepared in the laboratory using varying cementitious materials, aggregate systems, water-to-cementitious ratios, carbon fiber dosages, and admixtures. The results of tests on laboratory-prepared mixes were utilized to find the most suitable ECON mix design for application in an HPS test section at the Des Moines International Airport. The properties of the ECON produced at the concrete plant were measured and compared with equivalent laboratory-prepared samples. The final mix design exhibited electrical resistivity of 115 Ω-cm in the laboratory and 992 Ω-cm in the field, while completely meeting strength and workability requirements. Despite the higher ECON resistivity obtained in large-scale production, the fabricated HPS exhibited desirable performance with respect to deicing and anti-icing operations. The test section was able to generate a 300–350 W/m2 power density and to effectively melt ice/snow with this level of energy. Keywords: Electrically conductive concrete (ECON), Carbon fiber, Mix design, Des Moines International Airport, Heated Pavement, Snow Melting, Deicing

Ischemic heart disease is the main cause of death globally. Cardioprotection is the process whereby mechanisms that reduce myocardial damage, and activate protective factors, contribute to the preservation of the heart. Targeting these processes could be a new strategy in the treatment of post-ischemic heart failure (HF). Triiodothyronine (T3) and thyroxine (T4), which have multiple effects on the heart, prevent myocardial damage. This study describes the formulation, and characterization, of chemically modified polymeric nanoparticles incorporating T3, to target the thyroid hormone receptors. Modified T3 was conjugated to polylactide-co-glycolide (PLGA) to facilitate T3 delivery and restrict its nuclear translocation. Modified T3 and PLGA-T3 was characterized with 1H-NMR. The protective role of synthesized phosphocreatine (PCr) encapsulated PLGA-T3 nanoparticles (PLGA-T3/PCr NPs) and PLGA-T3 nanoparticles (PLGA-T3 NPs) in hypoxia-mediated cardiac cell insults was investigated. The results showed that PLGA-T3/PCr NPs represent a potentially new therapeutic agent for the control of tissue damage in cardiac ischemia and resuscitation.

Electrically-heated pavements have attracted attention as alternatives to the traditional ice/snow removal practices. Electrically conductive polymer-carbon composite coatings provide promising properties for this application. Based on the concept of joule heating, the conductive composite can be utilized as a resistor that generates heat by electric current and increases the surface temperature to melt the ice and snow on the pavement surface. This research investigates the feasibility of applying an electrically conductive composite coating made with a Polyurethane (PU) binder and micrometer-scale carbon fiber (CMF) filler as the electrical heating materials on the surface of Portland cement concrete (PCC) pavements. PU-CMF composite coatings were prepared using different volume fractions of CMF, applied on the PCC surfaces, and evaluated in terms of volume conductivity, resistive heating ability, durability, and surface friction properties at the proof-of-concept level. A conceptual cost analysis was performed to compare this method with other heated pavement systems with respect to economic viability. Percolative behavior of CMF in PU matrix was captured and most desirable CMF dosage rates in terms of each performance parameter were investigated. Two percolation transition zones were identified for CMF in PU matrix at dosage rate ranges of 0.25–1% and 4–10%. The composites exhibited their most desirable performance and properties at CMF dosage rates greater than 10% and smaller than 15%.

Summary: There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website (https://peac.hpc.qmul.ac.uk/) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage. : Lewis et al. use histology and RNA-seq of synovial biopsies from a cohort of early rheumatoid arthritis individuals to identify three histological pathotypes and reveal gene modules associated with disease severity and clinical response. Keywords: rheumatoid arthritis, RNA sequencing, personalized medicine, synovial biopsy, ectopic lymphoid structures, lymphoid neogenesis, transcriptomics, Pathobiology of Early Arthritis Cohort study, PEAC

Biological therapies are an effective treatment for a range of immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis, psoriasis, and inflammatory bowel diseases. However, due to their high costs, considerable differences in their utilization exist across the world, even among the various European countries, with many countries restricting access despite professional society guideline recommendations. Adoption of biologics by healthcare providers has been particularly poor in many Central and Eastern European countries. Differences in utilization have also been observed across medical specialties, healthcare providers, and at a regional and national level. The objective of this paper is to provide an overview of the different market access policies for biologics in Europe and to investigate reasons for such differences. One of the potential solutions for providing broader access to IMID patients, where cost is the major barrier, is to encourage the use of biosimilars in place of their reference products. Biosimilars are generally less expensive alternatives to already licensed biological therapies and are approved on the basis that they are similar to the reference product in terms of quality, safety, and efficacy. Budget impact models predict considerable cost savings following the introduction of biosimilars in the next few years. These savings could be used to increase access to biologics and other innovative therapies.

This review describes the IL-20 family of cytokines in rheumatoid arthritis (RA) and spondyloartrhitits (SpA) including psoriatic arthritis. The IL-20 receptor (R) cytokines IL-19, IL-20, and IL-24 are produced in both the peripheral blood and the synovial joint and are induced by Toll-like receptor ligands and autoantibody-associated immune complexes in monocytes. IL-19 seems to have anti-inflammatory functions in arthritis. In contrast, IL-20 and IL-24 increase the production of proinflammatory molecules such as monocyte chemoattractant protein 1 and are associated with bone degradation and radiographic progression. IL-22 is also associated with progression of bone erosions. This suggests that the IL-22RA1 subunit shared by IL-20, IL-22, and IL-24 is important for bone homeostasis. In line with this, the IL-22RA1 has been found on preosteoclasts in early RA. IL-26 is produced in high amounts by myofibroblasts and IL-26 stimulation of monocytes is an important inducer of Th17 cells in RA. This indicates a role for IL-26 as an important factor in the interactions between resident synovial cells and infiltrating leukocytes. Clinical trials that investigate inhibitors of IL-20 (fletikumab) and IL-22 (fezakinumab) in psoriasis and RA have been terminated. Instead, it seems that the strategy for modulating the IL-20 cytokine family should take the overlap in cellular sources and effector mechanisms into account. The redundancy encourages inhibition of more than one cytokine or one of the shared receptors. All IL-20 family members utilize the Janus kinase signaling pathway and are therefore potentially inhibited by drugs targeting these enzymes. Effects and adverse effects in ongoing clinical trials with inhibitors of IL-22 and the IL-22RA1 subunit and recombinant IL-22 fusion proteins will possibly provide important information about the IL-20 subfamily of cytokines in the future.

After publication of the original article [1], the authors have notified us of an error in language used in the text:

Chikungunya fever (CHIKF) is an emerging viral infection that has spread widely, along with its Aedes vectors, throughout the tropics and beyond, causing explosive epidemics of acute illness and persistent disabling arthritis. The rheumatic symptoms associated with chikungunya virus (CHIKV) infection include polyarthralgia, polyarthritis, morning stiffness, joint edema, and erythema. Chronic CHIK arthritis (CCA) often causes severe pain and associated disability. The pathogenesis of CCA is not well understood. Proposed hypotheses include the persistence of a low level of replicating virus in the joints, the persistence of viral RNA in the synovium, and the induction of autoimmunity. In this review, we describe the main hypotheses of CCA pathogenesis, some of which support methotrexate (MTX) treatment which has been shown to be effective in preliminary studies in CCA.

The development of novel “smart” structures by embedding sensing capabilities directly into the construction material during the manufacturing and deployment process has attracted significant attention in autonomous structural health monitoring (SHM). Micro-electromechanical systems (MEMS) provide vast improvements over existing sensing methods in the context of SHM of highway infrastructure systems, including improved system reliability, improved longevity and enhanced system performance, improved safety against natural hazards and vibrations, and a reduction in life cycle cost in both operating and maintaining the infrastructure. Advancements in MEMS technology and wireless sensor networks provide opportunities for long-term, continuous, real-time structural health monitoring of pavements and bridges at low cost within the context of sustainable infrastructure systems. Based on a comprehensive review of literature and vendor survey, the latest information available on off-the-shelf MEMS devices, as well as research prototypes, for bridge, pavement, and traffic applications are synthesized in this paper. In addition, the paper discusses the results of a laboratory study as well as a small-scale field study on the use of a wireless concrete monitoring system based on radio-frequency identification (RFID) technology and off-the-shelf MEMS-based temperature and humidity sensors.