BackgroundRheumatologists are the primary prescribers of methotrexate (MTX) for the treatment of rheumatoid arthritis (RA) in the United Kingdom (UK), however rheumatologists' views on their clinical practices are largely unknown. The authors conducted a qualitative study that highlighted a number of factors that contributed to their ability to discuss and commence MTX, which included how emotionally and cognitively prepared patients were to discuss treatments. The aim of this study was to further explore these themes with an online survey.ObjectivesThe aims of this study were:1)To establish the views of rheumatologists about MTX for the treatment of rheumatoid arthritis (RA), 2)To examine if rheumatologists' views influenced discussing or commencing MTX during the initial consultation.MethodsAn online survey was designed and subsequently refined based on interviews with rheumatologists in the UK. The survey asked rheumatologists about their clinical setting, and their views and practices with respect to treating RA with MTX. Rheumatologists were asked how often specific pieces of MTX information were discussed during a consultation to commence MTX (5=Always to 1=never). They were also asked to identify the barriers to discussing these issues. The questionnaire included a factorial survey ie. two patient vignettes where we manipulated the following factors; male/female, emotionally prepared/unprepared and no/negative prior knowledge. Rheumatologists could select “information overload” as a barrier to communication with the patient. Random mixed effects models tested if these patient factors and information overload associated with 1) commencing and 2) discussing MTX.ResultsNinety-six rheumatologists seeing approximately eight (IQR:5–12) new patients a week with 15±7 years of experience completed the survey. Rheumatologists reported they often/always discussed ten (IQR 8–11) pieces of information during a consultation (Fig 1A), and information overload was identified as a communication barrier (48%); 52% of rheumatologists expected the nurse to discuss MTX therapy (Fig 1B). Sixty rheumatologists completed one, and 56 rheumatologists two vignettes (n=116). The vignette conditions and information overload significantly associated with “Commencing MTX” (X2=53.85, p <.0001, R2=.21) and discussing MTX (X2=30.9, p =.002, R2=.19). Gender* emotional preparedness (β=-4.27, 95% CI:-7.33,-1.21), and information overload*emotional preparedness (β=-3.03, 95% CI:-5.24, -.82) associated with MTX commencement, whilst only gender*emotional preparedness with discussing MTX (β=-3.86, 95% CI:-6.82, -.90).ConclusionsCurrently UK rheumatologists convey a large amount of information to patients during early consultations. Almost half of rheumatologists identified the need to communicate large amounts of information in clinical consultations as a barrier to discussing MTX therapy. These data reflect the challenge clinicians face in trying to execute effective shared decision-making practices. Strategies to address patients' emotional resp...

BackgroundWork participation among people with rheumatic and musculoskeletal diseases (RMDs) remains reduced when compared to the general population. A EULAR taskforce was established to agree on Points to Consider (PtC) to support people with RMD in healthy and sustainable work participation. Non-pharmacological interventions (NPI) could have an important role in improving work participation in RMDs. However, a comprehensive evidence synthesis of the effectiveness of NPIs in people with RMDs is lacking.ObjectivesTo summarise the literature on effectiveness of NPIs on work participation in people with RMDs.MethodsA search in four databases (MEDLINE, EMBASE, CENTRAL and CINAHL) was performed. Randomised Controlled Trials (RCTs) and Longitudinal Observational Studies (LOS) assessing non-pharmacological/non-surgical interventions until August 2020 were screened. Studies including people with any RMD (except low back pain or work-related RMDs) and assessing a work participation outcome domain (sick leave, work status, presenteeism) were considered eligible. For qualitative evidence synthesis, RCTs and LOS were considered. For quantitative evidence synthesis, only RCTs were considered. For each randomized comparison, standardised mean differences (SMDs) were calculated for the three outcome domains and used as effect size in the meta-analyses; i.e. a negative SMD favouring the NPI over control. Next, Mixed Effects Meta-Regression Analyses were performed, with random effects for randomised comparisons, and a fixed effect factor for the stratified subgroups of clinical interest. Subgroups within diseases (musculoskeletal pain disorders vs. other types of RMDs), risk status for sick leave at baseline (on sick leave or at risk for sick leave; not at risk for sick leave; a combination; or not specified) and single vs. multiple component NPIs were pre-defined. Risk of Bias (RoB) of RCTs was assessed using the Cochrain tool.ResultsOut of 8,864 records, 64 studies (71 treatment comparisons) were included. Studies usually included a mixed population of several RMDs (42%). Most NPIs were conducted in a clinical setting (n=44, 62%) and NPIs usually had multiple components (n=57, 80%), such as vocational support combined with physical training (n=18, 25%). Sick leave was the most frequently reported outcome domain (n=56, 88%). In the qualitative syntheses, 30%/50%/29% of interventions were considered plausible in improving sick leave, work status and presenteeism, respectively.In the quantitative synthesis, NPIs (37 RCTs, 42 comparisons with mostly moderate to high RoB) showed small to moderate effect sizes, favouring NPIs over comparators for sick leave (SMD=-0.23, 95%CI -0.33 to -0.13), work status (SMD=-0.38, 95%CI -0.63 to -0.12) and presenteeism (SMD=-0.25, 95%CI -0.39 to -0.12). The forest plot for sick leave is shown (Figure 1).Subgroup analyses for sick leave revealed that, compared to control, NPIs were not effective in musculoskeletal pain disorders, in contrast to the other types of RMDs. For both other subgroup analyses (baseline risk for sick leave; single vs. multicomponent NPI), NPIs improved sick leave similarly in subgroups compared to the control. Subgroup analyses for work status and presenteeism had generally similar effects in subgroups, but the interpretation requires caution in view of the small number of comparisons. Of note, clinical and methodological heterogeneity between studies was substantial, with some concerns about methodological quality related blinding and completeness of follow up.ConclusionOverall, NPIs seem to have significant, but on the average population level only small to moderate effects on sick leave, work status and presenteeism in RMDs. However, effects on sick leave varied substantially between subgroups. This synthesis suggests that tailoring NPIs to individuals’ needs and context could be clinically valuable.Disclosure of InterestsNone declared.

The thesis contains 9 chapters of which 7 chapters are research articles.

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 wa...

BackgroundMethotrexate (MTX) is the first-line disease modifying anti-rheumatic drug for the treatment of rheumatoid arthritis (RA). However, many patients do not respond adequately or experience adverse effects1,2; therefore, identifying blood-based biomarkers that predict treatment response is a research priority. DNA methylation is an epigenetic marker that modifies but does not alter DNA sequence, and it is thought that MTX may act, at least in part, by inhibiting intracellular methyl donor transfer leading to DNA hypomethylation2.ObjectivesWe aimed to identify differential DNA methylation signatures in whole blood, which may act as biomarkers predictive of response to MTX in patients with RA.MethodsDNA methylation was measured using the HumanMethylation450 BeadChip in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study (RAMS), a one year observational study in the UK including patients with RA starting MTX for the first time. In RAMS, demographic and clinical data are collected prior MTX start (baseline) and at 6 months after commencing MTX. DNA was extracted from whole blood samples collected baseline and at 4 weeks from patients who, at 6 months, had a EULAR good response (n=36) or EULAR poor response (n=36) to MTX. Differentially methylated positions (DMPs) between the baseline and 4 weeks, and between good and poor response were identified using linear regression, adjusting for gender, age, cell composition, baseline disease activity score (DAS28), and smoking status. Analyses also compared methylation with changes in DAS28 and the individual DAS28 components over 6 months. DMPs that showed significant differences in the test cohort were selected for replication by pyrosequencing in an independent group of 100 patients with both baseline and 4 week samples.ResultsBased on percentage change in methylation between pre-treatment and following 4 weeks of therapy, two DMPs were significantly associated with response status in samples taken at 4 weeks (p-value <10-5). Three additional DMPs were associated with change in tender joint count, whilst three other DMPs were associated with change in swollen joint count, and a further four DMPs associated with change in C-reactive protein. Of the four DMPs tested to date, hypermethylation at cg23700278 at baseline suggests replicated association with improvement in swollen joint count by 6 months. The nearest gene to the cg23700278 locus is adrenoceptor alpha 2C (ADRA2C), involved in neurotransmission.ConclusionsThese preliminary results suggest DNA methylation may provide a biomarker of MTX response but requires replication in other data sets.References Verstappen SMM et al. (2012) Int. J. Clin. Rheu. 7(5):559–567.Kim Y, et al. (1996) J. Lab.Clin.Med. 128:165–172. Disclosure of InterestNone declared