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A novel HPLC MS/MS assay for the biochemical detection of adherence to tofacitinib with evidence of sensitive measurement using real-world patient samples is reported.

Psoriatic arthritis (PsA) is a heterogeneous chronic musculoskeletal disease, affecting up to 30% of people with psoriasis. Research into PsA pathogenesis has led to the development of targeted therapies, including Tumor Necrosis Factor inhibitors (TNF-i). Good response is only achieved by ~60% of patients leading to ‘trial and error’ drug management approaches, adverse reactions and increasing healthcare costs. Robust and well-validated biomarker identification, and subsequent development of sensitive and specific assays, would facilitate the implementation of a stratified approach into clinical care. This review will summarise potential genetic biomarkers for TNF-i (adalimumab, etanercept and infliximab) response that have been reported to date. It will also comment upon the importance of managing clinical confounders when understanding drug response prediction. Variants in multiple gene regions including TNF-A, FCGR2A, TNFAIP3, TNFR1/TNFR1A/TNFRSF1A, TRAIL-R1/TNFRSF10A, FCGR3A have been reported to correlate with TNF-i response at various levels of statistical significance in patients with PsA. However, results were often from heterogenous and underpowered cohorts and none are currently implemented into clinical practice. External validation of genetic biomarkers in large, well-documented cohorts is required, and assessment of the predictive value of combining multiple genetic biomarkers with clinical measures is essential to clinically embed pharmacogenomics into PsA drug management.

Background/Aims MTX non-adherence is associated with reduced response, increased healthcare costs to the NHS and reduced quality of life for the patient. Often the prescriber is unable to determine if a patient is taking their medication as prescribed. There is a need to measure adherence directly to facilitate more precise and objective measurements of adherence to add to the clinicians tools and help to open up honest discussions and supportive interventions with patients. Our group has previously developed a sensitive biochemical assay for the detection of MTX adherence, MIRA is a feasibility trial designed to assess the feasibility of a randomised controlled trial of MTX biochemical adherence biofeedback. Methods MIRA is a prospective multi-centre randomised controlled trial to examine the feasibility of a fully powered randomised controlled trial to examine if a biochemical adherence guided intervention is superior to standard clinical care in RA patients prescribed MTX. RA patients prescribed oral MTX for ≥ two years were randomised 1:1 to receive biochemical adherence biofeedback or control. Clinico-demographics, biochemical MTX adherence and DAS-28 and were measured at baseline and three months. Participants in the intervention cohort were telephoned with their biochemical adherence results and adherence was explored. Ethical approval for MIRA was given by the North West - Haydock Research Ethics Committee (19/NW/0047) and all participants provided written informed consent. Results 57 participants were recruited, withdrawal rate was 14% and reasons given were intercurrent illness, lost contact, withdrawn consent and one patient died during follow-up leaving full outcome data available for 49 participants. Baseline clinico-demographics were similar in control and intervention cohorts (Table 1). Biochemical adherence worsened in the control cohort and improved in the intervention cohort (17 to 30%, 15 to 8% respectively). Change in DAS(CDP)-28 during the trial worsened in the control cohort but improved in the intervention cohort (-0.04 STD 1.26 and 0.38 STD 0.78 respectively). Conclusion The results of the MIRA trial have demonstrated that the use of a biochemical adherence blood test with biofeedback is feasible as part of a clinical trial. The intervention demonstrated early evidence for efficacy justifying the need for a full definitive trial. Disclosure J. Bluett: None. K.L. Hyrich: None. B. Keevil: None. P. Doran: None. A. Barton: None.

Background/Aims Tumour necrosis factor inhibitors (TNFi) are commonly prescribed to treat rheumatoid arthritis (RA), but response to TNFi is not universal and there are no validated pre-treatment biomarkers of treatment response at present. Proteins have many features that make them ideal potential biomarkers, as they carry out diverse biological processes, interact with drugs and can reflect post-translational modifications. This study aimed to identify protein biomarkers associated with response to TNFi in patients with RA. Methods Participants were recruited from a UK-based prospective multi-centre study of patients fulfilling either the 1987 ACR or 2010 ACR/EULAR classification for RA starting biologic treatment for the first time. Quantitative proteomics was performed using Sequential Window Acquisition of all THeoretical fragment ion spectra mass spectrometry (SWATH-MS) in sera from study participants before and after three months of treatment with the TNFi etanercept. Linear regression models were used to study the association between protein levels and the composite 28-joint count Disease Activity Score (DAS28) and its sub-components, adjusting for baseline covariates including age, biological sex disease duration and baseline DAS28. Sub-network analysis was carried out using the DIAMOnD algorithm, followed by functional enrichment analysis. Results Of the total 180 participants recruited, 134 (74.44%) were female, with a median age of 56.90 years and median pre-treatment DAS28 of 5.9. Eight individual proteins were found to be significantly associated with RA clinical outcome measures (see Table). Sub-network analysis identified the ontological theme with the strongest association as being positive regulation of response to endoplasmic reticulum (ER) stress (-log10(P) ∼ 7). Conclusion This longitudinal study of 180 patients with RA commencing etanercept has identified several putative protein biomarkers of treatment response and identified ER stress as an underlying pathway. The ER stress pathway has been previously reported to contribute to RA pathogenesis via synoviocyte proliferation and stimulation of pro-inflammatory cytokine production. Disclosure S.F. Ling: None. C. Yap: None. N. Nair: None. J. Bluett: None. A.W. Morgan: None. J.D. Isaacs: None. A.G. Wilson: None. K.L. Hyrich: None. A. Barton: None. D. Plant: None.

Background/Aims It is not currently possible to accurately predict tumour necrosis factor inhibitor (TNF-i) response in psoriatic arthritis (PsA). In rheumatoid arthritis, suboptimal adherence to TNF-i and reduced drug levels have been associated with decreased response. Suboptimal treatment adherence (16%-81%) has been reported in PsA although little is known about the impact on TNF-i response. Self-reported adherence may be biased, but direct drug measurements offer an objective adherence evaluation. The objective of this study is to assess the relationship between self-reported adherence, drug levels, and drug response to TNF-i in PsA. Methods Blood samples and adherence questionnaires were collected at 3, 6 and 12 months for PsA patients prescribed biologic or targeted synthetic anti-rheumatic drugs in a UK multi-centre observational study (OUTPASS). Self-reported adherence was measured using two previously validated questionnaires (MARS5 and Treatment). Adherence was classified as self-reporting never missing or delaying a dose, unless medically advised. Adalimumab (ADA) and etanercept (ETN) drug levels were measured at 3 and 6 months using commercially available ELISAs. Clinical response was assessed using PsARC and ΔDAS28 between baseline and 3, 6 and 12 months. Univariate regression and general estimating equations were used to assess associations across timepoints. Results In the OUTPASS cohort (46% ADA, 40% ETN), 42% of patients self-reported non-adherence within the first 12 months of treatment. Patients with self-reported non-adherence at 6 months using the MARS5 questionnaire were significantly less likely to achieve a PsARC response at 6 months [odds ratio (OR)=0.40, P = 0.047] in univariate regression. Non-adherence, reported using the Treatment questionnaire, was associated with decreased PsARC response over 12 months [OR = 0.52, P = 0.031]. There was no association (P > 0.05) between whether a patient returned a self-reported adherence questionnaire and response. Drug levels at 3 months (n = 70 (ADA), 73 (ETN)) were associated with drug levels at 6 months (n = 61 (ADA), 67 (ETN)) for both ADA [β = 0.47, P = 0.001] and ETN [β = 0.41, P = 0.018] paired samples. Higher 3-month ADA levels were associated with increased ΔDAS28 response at 3 months [β = 0.11, P = 0.036] and PsARC response at 12 months [OR = 1.39, P = 0.028]. Higher 3-month ETN levels were associated with increased PsARC response at 3 months [OR = 1.50, P = 0.026]. Increased ADA levels were associated with improved ΔDAS28 over 12 months [β = 0.07, P = 0.001] and higher ETN levels associated with enhanced PsARC response [OR = 1.17, P = 0.022] over 12 months. Levels of neither drug were associated (P > 0.05) with any self-reported adherence measures at any time point. Conclusion There was no association between self-reported adherence and TNF-i drug levels in ADA or ETN-treated PsA patients. Objectively measured adherence via drug level measurements were more strongly associated with drug response than self-reported measures, particularly using ΔDAS28 as the measure of response. Disclosure P.D.K. Curry: None. A.P. Morris: None. M. Jani: None. H. Chinoy: Grants/research support; HC received grant support from Eli Lilly and UCB. A. Barton: Grants/research support; AB has received fees/grant awards from Galapagos, Scipher Medicine, Roche-Chugai, Pfizer and BMS. J. Bluett: Grants/research support; JB has received a research grant award from Pfizer. Other; JB has received travel/conference fees from UCB, Pfizer and Eli Lilly.

Background/Aims Dose tapering of biologic therapies is supported by both ACR and EULAR guidelines. Identification of appropriate patients may deliver cost savings whilst minimising the risk of disease flare. To audit dose tapering activity for patients treated with bDMARD for rheumatoid (RA), psoriatic arthritis (PsA) and ankylosing spondylosis (AS) meeting locally agreed criteria over three years. Methods All patients treated with a bDMARD for RA, PsA or AS fulfilling criteria for dose tapering between 1st October 2019 - 1st October 2021 were identified from electronic health records (EHR). Rituximab patients were excluded due to reactive treatment responding to flare. Patients were required to have been on their bDMARD for = > one year, not prescribed oral steroids / treated with parenteral steroids in the past six months, no swollen joints in the past six months, and not failed dose tapering in the previous year. RA patients were ineligible if DAS ≥3.2 in the previous year; PsA if their biologic was prescribed by dermatology /active psoriasis; AS patients if BASDAI score of > 4 in past year. Records were flagged to prompt a shared decision-making discussion between the treating clinician and patient during routine appointments; additional patients were identified through clinical assessment. Failing dose tapering was defined as a post tapering flare requiring dose increase within one year. Patients were tapered by increasing the interval of a bDMARD. Results The number of patients that dose tapered increased from 24 in 2019 to 51 in 2021, making a total estimated NHS list saving of up to £170,000 per annum. (Table 1). Tapering was unsuccessful for 7/116 (6%) due to post tapering flares. Patients flaring after tapering were reassessed urgently and had their bDMARD dose reviewed. More patients were eligible than identified from EHR search due to missing data in coding; 787 (61%) across all years. Conclusion Dose tapering was well tolerated in eligible patients making this a safe and acceptable initiative. Use of EHR data and behavioural prompts for clinicians supported this in practice. Cost savings were reinvested to increase pharmacy support for homecare prescription management. Disclosure H. Light: None. J. Firth: None. J. Bluett: Grants/research support; JB has received a research grant from Pfizer. Other; JB has received travel/conference fees from UCB, Pfizer and Eli Lilly. K. Kinsey: None.

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 (h2SNP) 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 (h2SNP = 0.63), which was similar to the heritability of PsC (h2SNP = 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.

Background Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Methods We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. Findings Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314–26 796) in the suspend methotrexate group and 10 798 U/mL (8970–12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57–3·04; p Interpretation A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups. Funding National Institute for Health and Care Research.

Aim: TNF inhibitor drugs are a treatment option for rheumatoid arthritis, but response is not universal. Response is typically measured using the composite 4-component (4C) disease activity score 28 (DAS28) which contains more subjective measures. This study used a validated 2-component (2C) DAS28 score to determine whether SNPs associated with response were replicated in the UK population. Materials & methods: A literature review identified TNF inhibitor response SNPs. Linear regression was conducted to replicate associations with 4C or 2C-DAS28 response. Results: Eighteen independent SNPs were analyzed in 1828 patients. One and four associations with 4C and 2C-DAS28 response respectively were identified (p ≤ 0.05). Conclusion: Further genetic associations were replicated using the 2C-DAS28 which may reflect the objective nature of 2C-AS28.

Psoriatic arthritis (PsA) is a heterogeneous chronic musculoskeletal disease, affecting up to 30% of people with psoriasis. Research into PsA pathogenesis has led to the development of targeted therapies, including Tumor Necrosis Factor inhibitors (TNF-i). Good response is only achieved by ~60% of patients leading to 'trial and error' drug management approaches, adverse reactions and increasing healthcare costs. Robust and well-validated biomarker identification, and subsequent development of sensitive and specific assays, would facilitate the implementation of a stratified approach into clinical care. This review will summarise potential genetic biomarkers for TNF-i (adalimumab, etanercept and infliximab) response that have been reported to date. It will also comment upon the importance of managing clinical confounders when understanding drug response prediction. Variants in multiple gene regions including TNF-A, FCGR2A, TNFAIP3, TNFR1/TNFR1A/TNFRSF1A, TRAIL-R1/TNFRSF10A, FCGR3A have been reported to correlate with TNF-i response at various levels of statistical significance in patients with PsA. However, results were often from heterogenous and underpowered cohorts and none are currently implemented into clinical practice. External validation of genetic biomarkers in large, well-documented cohorts is required, and assessment of the predictive value of combining multiple genetic biomarkers with clinical measures is essential to clinically embed pharmacogenomics into PsA drug management.

Background/Aims In 2017 an audit and survey of giant-cell arteritis (GCA) services were conducted across northwest England (reported previously). This re-survey in 2020, following publication of revised BSR guidance, sought to identify what changes were made in the intervening period, and provided the opportunity to assess the impact of COVID-19. Methods Rheumatologists from 16 hospitals in northwest England were invited to complete a survey in July 2020. Questions focused on service provision for GCA, including pathways, diagnostics and steroid prescription. Results Responses were received from 14/16 sites in 2017, and 15/16 in 2020. 9/15 (60%) sites reported that the 2017 audit and survey prompted changes to GCA services, with two (13%) stating that it clarified the need for implementation of existing plans. Two sites had a GCA pathway in 2017. Four of the seven sites who committed to introducing one have now done so, bringing the total in 2020 to six. Eight of the nine remaining sites plan to implement one, six with a specific date within six months. Six (40%) have completed additional local audit/QI since 2017. Temporal artery (TA) ultrasound (US) is now available in an additional four sites, bringing the total to 6/15 (40%) in 2020. Two sites reported improvement in both time between first rheumatology consultation and TA biopsy, and time to receive results (now Conclusion The original audit and survey of current GCA practice in 2017 highlighted areas for improvement for each site, and regionally. Sites contributing to this re-survey report that the exercise stimulated them to improve their current care. The 2017 exercise showed a strong correlation between reported practice (survey) and actual practice (audit), leading us to have confidence that responses provided a true picture of care. This work demonstrates the power of audit to drive improvement, at a regional level. Disclosure C.A. Sharp: None. J. Little: None. A. Shahbaz: None. E.F. Wood: None. S. Wig: None. P. Watson: None. S. Varughese: None. L. Teh: None. P. Shah: None. C. Saleh: None. L. Ottewell: None. L. Newton: None. S.R. Moore: None. E. McCarthy: Consultancies; E.M. has received consultancy fees from Chugai. E. MacPhie: None. K. Lazarewicz: None. J. Brockbank: None. J. Bluett: None. L. Mercer: None.

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.

Background Tocilizumab is an IL-6 receptor humanised monoclonal antibody treatment option in rheumatoid arthritis (RA) who have not responded or are intolerant of disease modifying anti-rheumatic drugs (DMARDs) or other biologics. Tocilizumab was available initially as an intravenous preparation, dosed according to weight, and more recently as a subcutaneous (SC) preparation given at 162mg/weekly irrespective of body weight. Obesity is highly prevalent in RA and there has been concern that starting or switching patients to SC tocilizumab could reduce its effectiveness in those patients with a higher body weight. The objective of the current study is to investigate the relationship between body weight and DAS28 response at 6 months in tocilizumab naïve RA patients starting SC tocilizumab. Methods The study population comprised RA subjects recruited to the BSRBR-RA up to 30/11/2018 commencing SC tocilizumab for the first time. Patients had to be tocilizumab naïve and have at least one six monthly study follow-ups recorded after starting tocilizumab. Baseline characteristics at point of starting tocilizumab are described. Linear regression, fully adjusted for relevant confounders, was used to investigate the relationship between change in DAS28 score from baseline to six months and body weight per ten kilograms (kg), and in a separate analysis, as BMI category. Multiple imputation was used to handle missing data. Results Three hundred and fifteen patients starting SC tocilizumab were eligible for analysis. The median age was 60 years, majority were female, and had median disease duration of 11 years at baseline. Seventy percent had prior biologic exposure. Median weight was 76kg, and the majority of patients were categorised as normal weight (37%) or pre-obesity (31%) according to BMI. Median DAS28 score was 5.5 at start of treatment with median improvement after 6-months of 2.0 units. The fully adjusted linear regression model showed no association between body weight or BMI and change in DAS28 score at six months (Table 1). Conclusion Data from this study show that body weight does not appear to affect initial response to SC tocilizumab. This is reassuring given that patients are likely to be given subcutaneous tocilizumab due to ease of administration and reduced hospital costs. Disclosures R. Davies None. A. Vivekanantham None. M. Lunt None. K. Watson None. K.L. Hyrich None. J. Bluett None.

Methotrexate (MTX) is the first-line disease-modifying drug of choice in controlling active inflammation of the synovium that characterises rheumatoid arthritis, a chronic autoimmune inflammatory condition. However, many patients do not respond to treatment with MTX or cannot tolerate the medication. Pre-treatment characteristics that predict response to MTX are, therefore, of particular interest and potential clinical utility. Areas covered: This narrative review seeks to cover various genotypic and phenotypic characteristics that have been investigated as predictors of treatment response to MTX in RA. Ovid Medline searches (1946 to January 2018) were carried out for 'methotrexate' and 'rheumatoid arthritis', in combination with relevant terms. All papers identified were English language, with abstracts. Relevant references were also reviewed. Expert commentary: Despite the introduction of biologic medication and targeted therapies, MTX is likely to remain the mainstay of RA treatment, largely due to its much cheaper cost. Development of a multifactorial predictive algorithm for response to MTX may be of clinical utility, as well as routine MTX drug level testing to improve medication adherence and persistence.

Objective In order to develop interventions to optimize MTX use for the treatment of RA we evaluated the rate of, reasons for and predictors of MTX non-adherence during the first 6 months of therapy. Methods The Rheumatoid Arthritis Medication Study (RAMS) is a prospective multicentre cohort study of incident MTX users in the UK. Prior to MTX commencement demographic, clinical and psychological data were collected. A weekly patient-completed diary recorded MTX dose, possible side effects and adherence over 26 weeks. The number of non-adherent weeks was calculated. Potential baseline predictors of ever non-adherence (⩾1 week non-adherent) during the first 6 months of MTX therapy were identified using logistic regression analyses. Results 606 patients with RA were included; 69% female, mean (s.d.) age 60 (13) years and DAS28 score 4.2 (1.2). Over the first 6 months following MTX initiation, 158 (26%) patients were ever non-adherent (71% intentional, 19% non-intentional, 10% unexplained) and mean (s.d.) number of non-adherent weeks was 2.5 (2.1). Multivariable predictors of ever non-adherence included DAS28 [odds ratios (OR) 1.1, 95% CI 1.0, 1.4], fatigue (OR 1.1, 95% CI 1.0, 1.2 per cm), ⩾2 comorbidities vs no comorbidities (OR 1.9, 95% CI 1.1, 3.5) and high medication concerns despite perceived need (OR 1.1, 95% CI 1.0, 1.1 per unit decrease in need/concern differential). Conclusion This is the largest study evaluating early intentional and non-intentional non-adherence to MTX, which has identified that patient beliefs and multi-morbidity strongly link with non-adherence. These findings can direct the design of and provide potential targets for interventions to improve patient adherence.

BackgroundThe first-line therapy for rheumatoid arthritis (RA) is weekly oral methotrexate (MTX) at low dosages (7.5–25 mg/week). However, ~40% of patients are non-adherent which may explain why some do not respond and need to start more expensive biological therapies. To monitor adherence more accurately and develop strategies to improve it, a validated objective MTX adherence test is required.ObjectiveTo develop and validate the diagnostic accuracy of a novel MTX adherence assay using high-performance liquid chromatography–selected reaction monitoring– mass spectrometry (HPLC-SRM-MS) based biochemical analysis of drug levels.Methods20 patients with RA underwent MTX pharmacokinetic assessment using HPLC-SRM-MS MTX plasma concentration analysis over a 6-day period. Directly observed therapy was the reference standard. Pharmacokinetic model validation was performed using independent plasma samples from real-world patients (n=50) with self-reported times of drug administration. Following assay optimisation, the sensitivity of the assay to detect adherence was established using samples from an observational cohort study (n=138).ResultsA two-compartment pharmacokinetic model was developed and validated. Simulations described the sensitivity required for MTX detection over 7 days; subsequent assay optimisation and retesting of samples confirmed that all patients were correctly identified as MTX adherers. Using real-world samples, the assays sensitivity was 95%.ConclusionNon-adherence to MTX is common and can have a significant effect on disease activity. HPLC-SRM-MS plasma analysis accurately detects MTX adherence. The validated objective test could easily be used in clinic to identify patients requiring adherence support.

We read with interest the article by Furukawa et al 1 suggesting an association between HLA-A 31:01 and methotrexate (MTX)-induced interstitial lung disease (ILD) in Japanese patients with rheumatoid arthritis (RA). MTX-ILD or MTX-pneumonitis (MTX-P) is an idiosyncratic hypersensitivity reaction to MTX that usually occurs within the first year of MTX therapy, inducing inflammation, cytokine release and the activation of CD4+ T-lymphocytes within the lung parenchyma,2–4 with a reported prevalence of 1% of the Caucasian RA population prescribed MTX.5 To investigate this association further, we conducted a genome-wide association study. Rheumatologists working within the National Health Service in the UK identified Caucasian patients …

The application of Raman spectroscopy as a detection method coupled with liquid chromatography (LC) has recently attracted considerable interest, although this has currently been limited to isocratic elution. The combination of LC with rapidly advancing Raman techniques, such as surface-enhanced Raman scattering (SERS), allows for rapid separation, identification and quantification, leading to quantitative discrimination of closely eluting analytes. This study has demonstrated the utility of SERS in conjunction with reversed-phase liquid chromatography (RP-LC), for the detection and quantification of the therapeutically relevant drug molecule methotrexate (MTX) and its metabolites 7-hydroxy methotrexate (7-OH MTX) and 2,4-diamino-N(10)-methylpteroic acid (DAMPA) in pure solutions and mixtures, including spikes into human urine from a healthy individual and patients under medication. While the RP-LC analysis developed employed gradient elution, where the chemical constituents of the mobile phase were modified stepwise during analysis, this did not overtly interfere with the SERS signals. In addition, the practicability and clinical utility of this approach has also been demonstrated using authentic patients' urine samples. Here, the identification of MTX, 7-OH MTX and DAMPA are based on their unique SERS spectra, providing limits of detection of 2.36, 1.84, and 3.26 μM respectively. Although these analytes are amenable to LC and LC-MS detection an additional major benefit of the SERS approach is its applicability toward the detection of analytes that do not show UV absorption or are not ionised for mass spectrometry (MS)-based detection. The results of this study clearly demonstrate the potential application of online LC-SERS analysis for real-time high-throughput detection of drugs and their related metabolites in human biofluids.

Lung disease is one of the most common causes of extra-articular morbidity and mortality in patients with rheumatoid arthritis (RA). Development of pulmonary manifestations may be due to the systemic disease itself; to serious respiratory adverse events such as pneumonitis and infections secondary to therapy; or to lifestyle habits such as smoking. Rheumatologists often need to make important treatment decisions and plan future care in RA patients with respiratory comorbidities, despite the absence of clear evidence or consensus. In this review we evaluate the clinical assessment and management of RA-associated interstitial lung disease, bronchiectasis, serious (including opportunistic) infection, and smoking-related diseases. We summarize the international recommendations for the management of such conditions where available, refer to published best practice on the basis of scientific literature, and propose practical management suggestions to aid informed decision-making.

Eligibility for anti-tumour necrosis factor (TNF) therapy in most European countries is restricted to severe, active rheumatoid arthritis (RA). The DAS28 score is a marker of disease severity and incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein. We aimed to determine the relation between genetic variants known to affect ESR and levels of ESR in patients with active RA. DNA samples were genotyped for four single-nucleotide polymorphisms (SNPs) rs7527798 (CR1L), rs6691117 (CR1), rs10903129 (TMEM57) and rs1043879 (C1orf63). The association between SNPs and baseline ESR, baseline DAS28-ESR, and change in DAS28-ESR was evaluated. Baseline ESR was significantly associated with CR1 rs6691117 genotype (P=0.01). No correlation was identified between baseline DAS28-ESR or change in DAS28-ESR. In conclusion, genetic variation in the gene encoding CR1 may alter ESR levels but not DAS28-ESR, indicating no adjustment for CR1 genotype is required in the assessment of patients with severe active RA.

Treatment response to methotrexate (MTX) for rheumatoid arthritis (RA) is not universal and non-adherence may partially explain this. The aims of this systematic review were to: (1) summarise existing rates of adherence to MTX, (2) identify predictors of adherence to MTX, and (3) assess the association between non-adherence and patient outcomes. The authors conducted a systematic search of papers published from January 1980 to February 2015 in PubMed, PsycINFO, EMBASE and CINAHL databases. Studies were eligible for inclusion if: (1) MTX was used as monotherapy or in combination with other therapies, (2) MTX was used in an RA or inflammatory polyarthritis population, (3) adherence was defined and measured as the extent to which patients followed their MTX regimen during the period of prescription, and (4) it was an original piece of research. In total, 10 studies met the inclusion criteria and 8 were evaluated as high quality. Rates of adherence ranged from 59% to 107%, and exposed differences in definitions of adherence, study methodologies and sample heterogeneity. A number of potential predictors of MTX adherence were identified; the strongest being related to beliefs in the necessity and efficacy of MTX, absence of low mood, mild disease and MTX monotherapy. Furthermore, 3 studies tested the association of adherence with disease activity as an outcome measure; all 3 found non-adherence associated with poor treatment response. This systematic review shows the importance of adherence to MTX treatment and summarises the associated modifiable factors.

There is convincing evidence to suggest a strong genetic component to psoriatic arthritis (PsA), with studies reporting a 40-fold risk to first-degree relatives of patients with disease. However, compared with rheumatoid arthritis, our understanding of the genetic etiology of PsA is less well-developed. Only three modestly sized genome-wide association studies of PsA have been undertaken to date, but they have identified the HLA-C region, IL12B, TRAF3IP2, and FBXL19 genes as being associated with PsA susceptibility. Results of genome-wide association studies of psoriasis and rheumatoid arthritis have been used to identify candidate genes for subsequent testing in PsA and have led to the identification of additional susceptibility factors for PsA. Most show overlap with psoriasis, whereas the overlap with rheumatoid arthritis is less pronounced. However, two loci show strong evidence for association with PsA but not psoriasis: HLA-B27 and the IL-13 gene locus.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case-control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8(+) memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.

Rheumatoid arthritis (RA) is a common autoimmune disease that causes significant disability and reduced life expectancy. The folate antagonist methotrexate (MTX) is first-line therapy for RA when used weekly at low doses (5-25 mg). However, the true rate of adherence to MTX is uncertain. This is in part due to the different methods of measurement of adherence employed with no biochemical test currently available to determine adherence to low dose MTX. Common methods of MTX measurement include immunoassays in patients with high dose therapy, but these assays cross-react with MTX metabolites and lack the sensitivity required to measure adherence to low dose MTX. HPLC-SRM-MS (selected reaction monitoring-mass spectrometry) has several theoretical advantages over immunoassays with improved specificity, minimal cross-reaction and higher sensitivity. The aim of this study was to develop an assay to measure MTX and its major metabolite 7-OH-MTX in urine as a tool to monitor adherence to low dose MTX in clinic. As a proof of concept, urine samples from 4 participants with RA were measured after directly observed therapy. The assay showed improved sensitivity compared to that reported by immunoassays, with low carryover and high within-run precision. In participant samples, MTX was measurable in the urine for up to 105 hours after administration and 7-OH-MTX was detectable up to 98 hours after administration, suggesting that this assay is suitable for the measurement of adherence to therapy. The assay requires minimal sample preparation and can be adopted by other laboratories with minimal study set up.

Objective. Non-adherence to DMARDs is common, but little is known about adherence to biologic therapies and its relationship to treatment response. The purpose of this study was to investigate the association between self-reported non-adherence to s.c. anti-TNF therapy and response in individuals with RA. Methods. Participants about to start s.c. anti-TNF therapy were recruited to a large UK multicentre prospective observational cohort study. Demographic information and disease characteristics were assessed at baseline. Self-reported non-adherence, defined as whether the previous due dose of biologic therapy was reported as not taken on the day agreed with the health care professional, was recorded at 3 and 6 months following the start of therapy. The 28-joint DAS (DAS28) was recorded at baseline and following 3 and 6 months of therapy. Multivariate linear regression was used to examine these relationships. Results. Three hundred and ninety-two patients with a median disease duration of 7 years [interquartile range (IQR) 3–15] were recruited. Adherence data were available in 286 patients. Of these, 27% reported non-adherence to biologic therapy according to the defined criteria at least once within the first 6-month period. In multivariate linear regression analysis, older age, lower baseline DAS28 and ever non-adherence at either 3 or 6 months from baseline were significantly associated with a poorer DAS28 response at 6 months to anti-TNF therapy. Conclusion. Patients with RA who reported not taking their biologic on the day agreed with their health care professional showed poorer clinical outcomes than their counterparts, emphasizing the need to investigate causes of non-adherence to biologics.

Subcutaneous calcinosis is a well-recognized manifestation of systemic sclerosis (SSc), and is clinically apparent in about 25% of patients. It occurs in both limited and diffuse cutaneous disease, but is more common in patients with limited cutaneous SSc, particularly those with anti-centromere antibody1. The exact mechanism of calcinosis in SSc is unknown and currently there is no approved effective therapy. Although calcinosis usually occurs at …

Background Whilst methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA), it is associated with a rare but potentially life-threatening lung disease, MTX-pneumonitis (MTX-P). Epidemiological studies have provided evidence that MTX-P may be a genetically susceptible disease, supported by the fact that the incidence is much higher in the Japanese population than Europeans. Clinical risk factors are associated with the development of MTX-P; they are however, poorly predictive, there is therefore a need for improved markers of disease susceptibility. To date, only one locus has been associated with MTX-P in the Japanese population (HLA-A 31:01). Objectives To undertake a genome-wide association study (GWAS) for MTX-P in RA to identify genetic predictors of this rare adverse event. Methods Cases of MTX-P were recruited from a UK-wide multi-centre study. Cases were physician diagnosed MTX-P. Controls were recruited from the Rheumatoid Arthritis Medications Study (RAMS), a multi-centre observational study in the UK. Controls were participants with RA taking MTX for at least 1 year without the development of MTX-P and were age:sex matched 3:1 to cases. Results 65 cases and 195 controls were recruited. The study has an 80% power to detect an allele with frequency 0.30 and allelic odds ratio of 3.0. Samples were genotyped on the Illumina HumanCoreExome chip. Following quality control, 62 cases and 172 controls remained with coverage of 236308 SNPs. 48 cases (77%) retrospectively fulfilled either the Carson et al. or Searles et al. unvalidated criteria for MTX-P. 3 SNPs were associated with MTX-P at P 10 -5 , rs6593803 ( p =1.85 X 10 -7 , OR =3.13) maps near GJA5 , rs9299346 ( p =1.76 X 10 -6 , OR =2.76) in GRIN3A and rs1624005 ( p =6.54 X 10 -6 , OR =2.59) maps near LRFN5 . No SNPs reached genome-wide significance. Conclusions 3 SNPs were associated with MTX-P at borderline significance levels. These findings need further corroboration in replication studies. References Ann Rheum Dis 2013;72(1):153-5. Disclosure of Interest None declared

Background Persistence with methotrexate (MTX) therapy is longer compared to other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA). The majority of patients with RA stop MTX due to inefficacy or adverse events. There is currently no robust evidence on the clinical and demographic factors that may predict MTX failure in patients with inflammatory polyarthritis (IP) and its subset RA. Objectives To: i) examine patient-reported reasons for stopping MTX in patients with IP and ii) investigate which factors are associated with MTX failure. Methods Subjects in this study were participants in the Norfolk Arthritis Register (NOAR), a Primary care based inception cohort of patients with early IP. All patients recruited to NOAR between 1 January 2000 and 31 December 2008 commencing MTX as their first DMARD within 3 months of their baseline visit with at least 1 follow-up visit were eligible for inclusion. Patients were followed from their time of recruitment to their last follow-up visit up to 18 March 2013. Baseline and annual follow-up assessments are conducted by a research nurse and include age at symptom onset, gender, smoking status, 28-swollen and tender joint count, visual analogue score (VAS) well-being. Blood is taken at baseline for measurement of CRP, shared epitope status, rheumatoid factor (RF), and anti citrullinated protein antibodies (ACPA), DAS28-CRP based on the three-component was calculated. Medication details including start and stop date of any DMARD are recorded at each follow-up visit. Patient-reported reasons for stopping DMARDs are categorised into i) adverse events, ii) remission, iii) inefficacy, or iv) other. Adding a second DMARD within 6 months after MTX commencement was labeled as MTX failure due to inefficacy. Time to MTX failure was assessed by Kaplan-Meier analysis for the total failure group and for those who stopped MTX due to adverse events or inefficacy. Univariable Cox proportional hazards regression models were used to assess potential predictors of MTX failure. Results 431 patients were eligible, and followed for 2035 patient-years. The majority were female (63%) with a median age at symptom onset of 58 (IQR: 48-68) years. Median disease activity at baseline was DAS-28 3.8 (IQR 3.0 – 4.8). At baseline 297 (69%) of the cohort fulfilled the 2010 ACR/EULAR criteria for RA. Over the total study period there were 146 (34%) MTX failures, the probability of patients remaining on MTX at 2 years was 0.79 (95% CI: 0.75 – 0.83). 19% failed due to an adverse event, 9% due to inefficacy, 3% for other reasons and 3% stopped MTX due to disease remission. Smoking at baseline was not associated with early MTX failure (data not shown). RF or ACPA negativity was associated with early MTX failure for all reasons combined (HR: 1.88, 95% CI: 1.33 – 2.66; HR: 2.11, 95% CI: 1.42 – 3.13, respectively). RF or ACPA negativity was associated with early MTX failure due to adverse events but not inefficacy. Shared epitope homozygosity was associated with earlier MTX failure due to inefficacy but not adverse events (HR: 4.21, 95% CI: 1.29 – 13.66; HR: 0.48, 95% CI: 0.20 - 1.17, Table 1). Conclusions Female gender, HAQ, CRP, VAS well-being, shared epitope homozygosity, RF and ACPA negativity were the only clinical/demographic features found to influence MTX persistence. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1866

Background Anti-tumour necrosis factor (TNF) therapy has revolutionised patient prognosis in rheumatoid arthritis. In the UK, continuing anti-TNF therapy requires a sustained response as determined by the disease activity score in 28 joints (DAS28). Adherence to disease modifying anti-rheumatic drugs (DMARDs) is low but little is known about adherence to biological therapies and its association to treatment response. We investigated the association of adherence to subcutaneous anti-TNF therapy and DAS28 in people with rheumatoid arthritis.

Background Anti-tumour necrosis factor (TNF) therapy has revolutionised patient prognosis in rheumatoid arthritis. In the UK, continuing anti-TNF therapy requires a sustained response as determined by the disease activity score in 28 joints (DAS28). Adherence to disease modifying anti-rheumatic drugs (DMARDs) is low but little is known about adherence to biological therapies and its association to treatment response. We investigated the association of adherence to subcutaneous anti-TNF therapy and DAS28 in people with rheumatoid arthritis. Methods Participants were recruited to the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), a large UK multicentre, prospective, observational, cohort study. Demographic information for patients receiving subcutaneous anti-TNF therapy and disease characteristics were assessed at baseline. Self-reported adherence was defined as whether the biological agent was taken on the day agreed with the health-care professional and recorded at 3 and 6 months. DAS28 was recorded at baseline and after 3 and 6 months of therapy. Descriptive statistics, multivariate logistic regression, and linear regression statistics were used to analyse the data. Findings Data were collected for 392 patients with median disease duration of 7 years (IQR 3–15). Adherence data were collected in 286 patients, of whom 57 (20%) reported non-adherence with biological therapy. Older age, reported adherence at 6 months, and being ever non-adherent during the study period were significantly associated with a poorer DAS28 response to anti-TNF therapy after adjustment for disease duration, age at baseline, sex, concurrent DMARDs, non-steroidal anti-inflammatory drug (NSAID) use, and marital status (p=0·017, p=0·047, and p=0·014, respectively). Logistic regression analysis showed that neither demographic (age, sex, and marital status) nor clinical data (disease duration, NSAID and DMARD use, and baseline DAS28) predicted non-adherence. Interpretation Patients with rheumatoid arthritis who reported not taking their biological drug on the day agreed with their health-care professional had poorer clinical outcomes than did those who did take their drug, emphasising the need for strict adherence to biological therapy in patients with this condition. Funding NIHR Manchester Musculoskeletal Biomedical Research Unit.

Background Psoriatic Arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis which manifests as a heterogeneous disease with a wide spectrum of disease severity. PsA is a complex disease whereby environmental factors trigger disease in genetically susceptible individuals and multiple genetic factors contribute towards disease susceptibility. The overlap of PsA with psoriasis has resulted in confounding results for genome wide association studies (GWAS) producing difficulty in separating out the 2 diseases. There is however evidence from subgroup analysis of a GWAS to suggest that a locus on chromosome 5q31 is specifically associated with PsA (1). This result has been replicated in two independent studies involving UK and Canadian subjects (2, 3). There is substantial linkage disequilibrium within this locus necessitating the need for fine mapping within the region. Objectives To fine-map the chromosome 5q31 region using a dense set of single nucleotide polymorphisms (SNPs) to refine the association signal to a specific gene or regulatory element. Methods Genotype data for a total of 1518 SNPs spanning the 5q31 region (131.4-132.2Mb) was available for 929 PsA UK cases and 4537 UK healthy controls (www.wtccc.org.uk). Genotyping was performed as part of a wider study targeting confirmed autoimmune susceptibility loci using the Immunochip Illumina iSelect array. A strict quality control (QC) process was applied to the dataset followed by single point analysis using the Armitage test for trend. Results Following stringent QC, the analysis of 1440 high quality SNPs in 862 cases and 4306 controls identified an association to rs715285 (p=8.92×10 -5 ). This localises the association to an intergenic region flanked by the genes: colony stimulating factor 2 ( CSF ) and prolyl 4-hydroxylase, alpha polpeptide II ( P4HA2 ). Conclusions This preliminary analysis localises the association signal for susceptibility to PsA to an intergenic region approximately 500Kb away from the previously identified IL13 SNP (rs20541), demonstrating the importance of fine-mapping. The study highlights two genes for consideration in disease aetiology: the cytokine CSF2 and P4HA2 which encodes a subunit of the proly 4-hydroxylase; a key enzyme involved in collagen synthesis. References Duffin KC, Freeny IC, Schrodi SJ, Wong B, Feng B-J, Soltani-Arabshahi R, et al. Association between IL13 polymorphisms and psoriatic arthritis is modified by smoking. Journal of Investigative Dermatology. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. 2009 Dec;129(12):2777-83. Bowes J, Eyre S, Flynn E, Ho P, Salah S, Warren RB, et al. Evidence to support IL-13 as a risk locus for psoriatic arthritis but not psoriasis vulgaris. Annals of the Rheumatic Diseases. 2011 June 1, 2011;70(6):1016-9. Eder L, Chandran V, Pellett F, Pollock R, Shanmugarajah S, Rosen CF, et al. IL13 gene polymorphism is a marker for psoriatic arthritis among psoriasis patients. Annals of the Rheumatic Diseases. [Multicenter Study Research Support, Non-U.S. Gov’t]. 2011 Sep;70(9):1594-8. Disclosure of Interest None Declared

Background Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. Results from family studies have shown a strong genetic component to risk for developing PsA with heritability estimates of 80–100%. There is evidence from subgroup analysis of a genome-wide association study (GWAS) that a locus on chromosome 5q31 is specifically associated with PsA and not psoriasis. This result has been replicated in two independent studies involving UK and Canadian individuals. A recent GWAS done in a UK population (unpublished data) has refined and strengthened this association to a region approximately 500 kb upstream of the original GWAS. However, substantial linkage disequilibrium within this region means that functional data are needed to determine the causal variant. Methods Genotype data for a total of 179 602 single-nucleotide polymorphisms (SNPs) including the 5q31 region were available for 929 individuals with PsA and 4537 controls (www.wtccc.org.uk). Genotyping was performed with Illumina Immunochip, a custom genotype chip designed for fine mapping of established GWAS loci in autoimmune diseases. The lead SNP from the 5q31 region was selected, and SNPs highly correlated ( r 2 >0·8) to the lead SNP were identified by interrogating 1000 genomes project (May, 2011, release). Data from ENCODE (Encyclopedia of DNA elements) and eQTL (expression quantitative trait loci) were searched with the Regulome database and other publicly available databases to explore evidence for transcription factor binding, DNase hypersensitivity sites, and eQTL. Findings The lead SNP rs715285 (p=8·92 × 10 −5 , odds ratio 1·22) lies within an intergenic region and does not overlie a known transcription factor binding site or DNAse1 hypersensitivity site but was associated with a significant change in gene expression of SLC22A5 (p=8·58 × 10 −51 ) in monocytes. rs27437 is highly correlated with the lead SNP ( r 2 =0·88) and lies within a region that has been identified as a transcription factor binding site, DNase peak and is associated with a significant change in gene expression of SLC22A5 (p=8·58 × 10 −44 ) in monocytes. Interpretation In conclusion, there is a wealth of experimental evidence demonstrating the functional impact of genetic variation in this region associated with PsA. Funding University of Manchester.