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Background Methotrexate (MTX) remains the disease-modifying anti-rheumatic drug of first choice in rheumatoid arthritis (RA) but response varies. Predicting non-response to MTX could enable earlier access to alternative or additional medications and control of disease progression. We aimed to identify baseline predictors of non-response to MTX and combine these into a prediction algorithm. Methods This study included patients recruited to the Rheumatoid Arthritis Medication Study (RAMS), a UK multi-centre prospective observational study of patients with RA or undifferentiated polyarthritis, commencing MTX for the first time. Non-response to MTX at 6 months was defined as “no response” using the European League Against Rheumatism (EULAR) response criteria, discontinuation of MTX due to inefficacy or starting biologic therapy. The association of baseline demographic, clinical and psychosocial predictors with non-response was assessed using logistic regression. Predictive performance was assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots. Results Of 1050 patients, 449 (43%) were classified as non-responders. Independent multivariable predictors of MTX non-response (OR (95% CI)) were rheumatoid factor (RF) negativity (0.62 (0.45, 0.86) for RF positivity versus negativity), higher Health Assessment Questionnaire score (1.64 (1.25, 2.15)), higher tender joint count (1.06 (1.02, 1.10)), lower Disease Activity score in 28 joints (0.29 (0.23, 0.39)) and higher Hospital Anxiety and Depression Scale anxiety score (1.07 (1.03, 1.12)). The optimism-corrected AUC was 0.74. Conclusions This is the first model for MTX non-response to be developed in a large contemporary study of patients commencing MTX in which demographic, clinical and psychosocial predictors were considered. Patient anxiety was a predictor of non-response and could be addressed at treatment commencement.

Background Oral methotrexate (MTX) is the first-line therapy for patients with rheumatoid arthritis (RA). However, approximately one quarter of patients discontinue MTX within 12 months. MTX failure, defined as MTX cessation or the addition of another anti-rheumatic drug, is usually due adverse event(s) and/or inefficacy. The aims of this study were to evaluate the rate and predictors of oral MTX failure. Methods Subjects were recruited from the Norfolk Arthritis Register (NOAR), a primary care-based inception cohort of patients with early inflammatory polyarthritis (IP). Subjects were eligible if they commenced MTX as their first DMARD and were recruited between 2000 and 2008. Patient-reported reasons for MTX failure were recorded and categorised as adverse event, inefficacy or other. The addition of a second DMARD during the study period was categorised as failure due to inefficacy. Cox proportional hazards regression models were used to assess potential predictors of MTX failure, accounting for competing risks. Results A total of 431 patients were eligible. The probability of patients remaining on MTX at 2 years was 82%. Competing risk analysis revealed that earlier MTX failure due to inefficacy was associated with rheumatoid factor (RF) positivity, younger age at symptom onset and higher baseline disease activity (DAS-28). MTX cessation due to an adverse event was less likely in the RF-positive cohort. Conclusions RF-positive inflammatory polyarthritis patients who are younger with higher baseline disease activity have an increased risk of MTX failure due to inefficacy. Such patients may require combination therapy as a first-line treatment.

Previous research has shown that statin adherence for the primary prevention of CVD is lower compared to secondary prevention populations. Therefore the aim of this systematic review was to review predictors of statin adherence for the primary prevention of CVD. A systematic search of papers published between Jan 1984 and May 2017 was conducted in PubMed, PsycINFO, EMbase and CINAHL databases. A study was eligible for inclusion if; 1) it was a study of the general population or of patients with familial hypercholesterolemia, hypertension, diabetes or arthritis; 2) statins were prescribed; 3) adherence was defined and measured as the extent to which patients followed their statin regimen during the period of prescription, and 4) it was an original trial or observational study (excluding case reports). A study was subsequently excluded if 1) results were not presented separately for primary prevention; 2) it was a trial of an intervention (for example patient education). Papers were reviewed by two researchers and consensus agreed with a third. A quality assessment (QA) tool was used to formally assess each included article. To evaluate the effect of predictors, data were quantitatively and qualitatively synthesised. In total 19 studies met the inclusion criteria and nine were evaluated as high quality using the QA tool. The proportion of patients classed as \"adherent\" ranged from 17.8% to 79.2%. Potential predictors of statin adherence included traditional risk factors for CVD such as age, being male, diabetes and hypertension. Income associated with adherence more strongly in men than women, and highly educated men were more likely and highly educated women less likely to be adherent. Alcohol misuse and high BMI associated with non-adherence. There was no association between polypharmacy and statin adherence. The evidence base for the effect of other lifestyle factors and health beliefs on statin adherence was limited. Current evidence suggests that patients with more traditional risk factors for CVD are more likely to be adherent to statins. The implications for future research are discussed.

[This corrects the article DOI: 10.1371/journal.pone.0215999.].

Objective To evaluate the effect of different concomitant disease modifying antirheumatic drugs (DMARDs) on the persistence with antitumour necrosis factor (anti-TNF) therapies in patients with rheumatoid arthritis (RA). Method This analysis included 10 396 patients with RA registered with the British Society for Rheumatology Biologics Register, a prospective observational cohort study, who were starting their first anti-TNF therapy and were receiving one of the following DMARD treatments at baseline: no DMARD (n=3339), methotrexate (MTX) (n=4418), leflunomide (LEF) (n=610), sulfasalazine (SSZ) (n=308), MTX+SSZ (n=902), MTX+ hydroxychloroquine (HCQ) (n=401) or MTX+SSZ+HCQ (n=418). Kaplan–Meier survival analysis was used to study the persistence with anti-TNF therapy in each DMARD subgroup up to 5 years. Multivariate Cox proportional hazard models, stratified by anti-TNF used and start year and adjusted for a number of potential confounders, were used to compare treatment persistence overall and according to the reason for discontinuation between each of the DMARD subgroups, using MTX as reference. Results One-year drug survival (95% CI) for the first anti-TNF therapy was 71% (71% to 72%) but this dropped to 42% (41% to 43%) at 5 years. Compared with MTX, patients receiving no DMARD, LEF or SSZ were more likely to discontinue their first anti-TNF therapy while patients receiving MTX in combination with other DMARDs showed better treatment persistence. Conclusions These results support the continued use of background DMARD combinations which include MTX. Consideration should be given to the discontinuation of LEF and SSZ monotherapy at the time anti-TNF therapies are started, with the possible exception of the SSZ+ETN combination.

Karin Lundberg and colleagues explore gene-gene and gene-environment interactions in susceptibility to rheumatoid arthritis, reporting an association of HLA-DRB1, PTPN22 and smoking stratified by the autoantigen CEP-1. Gene-environment associations are important in rheumatoid arthritis (RA) susceptibility, with an association existing between smoking, HLA- DRB1 'shared epitope' alleles, PTPN22 and antibodies to cyclic citrullinated peptides(CCP) 1 , 2 . Here, we test the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated α-enolase 3 , 4 , accounts for an important portion of these associations. In 1,497 individuals from three RA cohorts, antibodies to the immunodominant citrullinated α-enolase CEP-1 epitope 4 were detected in 43–63% of the anti-CCP–positive individuals, and this subset was preferentially linked to HLA-DRB1*04 . In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22 and smoking showed the strongest association with the anti-CEP-1–positive subset (odds ratio (OR) of 37, compared to an OR of 2 for the corresponding anti-CEP-1–negative, anti-CCP–positive subset). We conclude that citrullinated α-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of RA.

ObjectivesPatients with rheumatoid arthritis (RA) are at increased risk of lymphoma compared with the general population. There are concerns that tumour necrosis factor inhibitors (TNFi) may exacerbate this risk. However, since the excess risk of lymphoma in RA is related to the cumulative burden of inflammation, TNFi may conversely reduce the risk of lymphoma by decreasing the burden of inflammation. The aim of this study was to compare the risk of lymphoma in subjects with RA treated with TNFi with those treated with non-biological therapy.MethodsSubjects diagnosed by a rheumatologist with RA enrolled in the British Society for Rheumatology Rheumatoid Arthritis Register (BSRBR-RA), a prospective cohort study, were followed until first lymphoma, death or until 30 November 2013. Rates of lymphoma in the TNFi and non-biological-treated cohorts were compared using Cox regression.Results11 931 TNFi-treated patients were compared with 3367 biological-naive patients. 84 lymphomas (88 (95% CI 70 to 109) per 100 000 person-years) were reported in the TNFi cohort and 30 lymphomas (154 (95% CI 104 to 220)) in the biological-naive cohort. After adjusting for differences in baseline characteristics, there was no difference in the risk of lymphoma for the TNFi versus the biological-naive group: HR 1.00 (95% CI 0.56 to 1.80). No risk differences were observed for individual TNFi.ConclusionsIn medium-term follow-up, there is no evidence that tumour necrosis factor inhibition influences the risk of lymphoma over the background risk in subjects with RA.

Objective The British Society for Rheumatology Biologics Register (BSRBR) has collected data on adverse events including pregnancies in patients with rheumatoid arthritis treated with anti-tumour necrosis factor (anti-TNF) therapy. The purpose of this report is to summarise the pregnancy outcomes in women treated with anti-TNF in the BSRBR. Methods Patients were categorised according to anti-TNF exposure as follows: (1) exposure to anti-TNF and to methotrexate (MTX) and/or leflunomide (LEF) at conception (n=21 pregnancies); (2) exposure to anti-TNF at conception (n=50); (3) exposure to anti-TNF prior to conception (n=59); (4) no exposure to anti-TNF (control group; n=10). Results Eighty-eight live births in a total of 130 pregnancies were reported in patients who received anti-TNF before or during pregnancy. The rate of spontaneous abortion was highest among patients exposed to anti-TNF at the time of conception (with MTX/LEF 33% and without MTX/LEF 24%). This compared with 17% spontaneous abortions in those with prior exposure to anti-TNF and 10% spontaneous abortions in the control group. Ten terminations were performed. Conclusion Although the results to date have been promising, no firm conclusions can be drawn about the safety of anti-TNF during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception cannot yet be changed.

Background The contribution of smoking to rheumatoid arthritis (RA) is hypothesized to be mediated through formation of anti-citrullinated protein antibodies (ACPA). In RA, however, autoantibodies such as ACPA, rheumatoid factor (RF), and anti-carbamylated protein antibodies (anti-CarP) often occur together, and it is thus unclear whether smoking is specifically associated with some autoantibodies rather than others. We therefore investigated whether smoking is only associated with ACPA or with the presence of multiple RA-related autoantibodies. Methods A population-based Japanese cohort ( n  = 9575) was used to investigate the association of smoking with RF and anti-cyclic citrullinated peptide antibodies (anti-CCP2) in individuals without RA. Furthermore, RA patients fulfilling the 1987 criteria from three early arthritis cohorts from the Netherlands ( n  = 678), the United Kingdom ( n  = 761), and Sweden ( n  = 795) were used. Data on smoking, RF, anti-CCP2, and anti-CarP were available. A total score of autoantibodies was calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by logistic regression. Results In the population-based non-RA cohort, no association was found between smoking and one autoantibody (RF or anti-CCP2), but smoking was associated with double-autoantibody positivity (OR 2.95, 95% CI 1.32–6.58). In RA patients, there was no association between smoking and the presence of one autoantibody (OR 0.99, 95% CI 0.78–1.26), but smoking was associated with double-autoantibody positivity (OR 1.32, 95% CI 1.04–1.68) and triple-autoantibody positivity (OR 2.05, 95% CI 1.53–2.73). Conclusions Smoking is associated with the concurrent presence of multiple RA-associated autoantibodies rather than just ACPA. This indicates that smoking is a risk factor for breaking tolerance to multiple autoantigens in RA.

United Kingdom guidelines for the use of biologic disease modifying anti-rheumatic drugs (bDMARDS) for rheumatoid arthritis (RA) require patients to have active disease (Disease Activity Score [DAS28] >5.1) and have failed ≥2 previous conventional synthetic DMARDs (csDMARD). Patients with moderate disease activity (MDA) do not meet these criteria, yet often have poor outcomes. This study aimed to identify trajectory groups of disability scores over three years in RA patients with MDA. The study included biologic-naïve patients receiving csDMARDs only with MDA (3.2

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