Sarah Twigg

MTHFR functional genetic variation and methotrexate treatment response in rheumatoid arthritis: a meta-analysis

AIM To date, functional MTHFR SNPs have been tested for their impact on low-dose methotrexate (MTX) response in small rheumatoid arthritis (RA) cohorts. We sought to test their effect in the single largest cohort studied to date, and undertook a meta-analysis utilizing stringent study inclusion criteria. MATERIALS & METHODS RA patients treated with MTX monotherapy from the Yorkshire Early Arthritis Register (YEAR) were genotyped using RFLP assays, and tested for association with treatment efficacy. Studies for meta-analysis were screened by a set of stringent inclusion criteria. RESULTS & CONCLUSION rs1801131 and rs1801133 were not associated with response to MTX in the YEAR cohort, nor did they affect the probability of achieving a low disease activity state. A meta-analysis of comparable studies found no association with these SNPs. MTHFR SNPs rs1801131 and rs1801133 are unlikely to have a clinically meaningful effect on the first 6 months of MTX treatment in early RA.

Relationship between area-level socio-economic deprivation and autoantibody status in patients with rheumatoid arthritis: multicentre cross-sectional study

Objectives The aims of this study were to assess the association between area-level socio-economic deprivation and the phenotype of rheumatoid arthritis (RA), defined by rheumatoid factor (RF) and anticitrullinated peptide antibody (AC PA) status, and to determine whether any observed association can be explained by smoking. Methods The authors performed logistic regression analysis of 6298 patients with RA, defined by American College of Rheumatology classification criteria modified for genetic studies. Analysis was stratified by cohort/recruitment centre. Socio-economic deprivation was measured using the Townsend Index. Results Deprivation predicted RF but not ACPA positivity, independent of smoking. The ORs for trend across tertiles, adjusted for smoking, gender, period of birth and cohort/recruitment centre, were 1.14 (95% CI 1.01 to 1.29) for RF and 1.01 (95% CI 0.87 to 1.16) for ACPA. Even after adjusting for deprivation, smoking was strongly associated with ACPA positivity (OR 1.38, 95% CI 1.22 to 1.55). There was no evidence of any effect modification by the RA risk alleles (HLA-DRB1 shared epitope and PTPN22 rs2476601) that have previously been shown to modify the effect of smoking on ACPA and RF positivity. Conclusions Among patients with RA, deprivation predicted RF positivity but not ACPA positivity. The effect of deprivation did not appear to be explained by smoking. Deprivation may be a marker for previously unrecognised, potentially modifiable environmental influences on the immunological phenotype of RA. Furthermore, given the known associations of RF positivity with prognosis and response to treatment in RA, these findings have potential implications for resource allocation and healthcare delivery.

Metaanalysis of the association of smoking and PTPN22 R620W genotype on autoantibody status and radiological erosions in rheumatoid arthritis.

Objective. To investigate the interrelationships among smoking, protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W (rs2476601) genotype, and anticitrullinated peptide antibody (ACPA) status; and among smoking, PTPN22 R620W genotype, and presence of bone erosions overall and separately by ACPA status in patients with rheumatoid arthritis (RA). Methods. Six studies totaling 2680 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating ACPA status and up to 8 studies totaling 3172 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating presence of erosive damage. Results. Evidence was found for an increase in the odds of ACPA positivity for ever smoking (OR 1.56, 95% CI 1.28–1.90, p = 8.5 × 10−6), carriage of at least 1 of the PTPN22 risk alleles (OR 1.50, 95% CI 1.13–2.00, p = 5.5 × 10−3) and both ever smoking and carriage of at least 1 of the PTPN22 risk alleles (OR 2.22, 95% CI 1.69–2.91, p = 8.3 × 10−9). There was no evidence of an association between presence of erosive damage and smoking status or carriage of PTPN22 risk alleles when analyzed overall or separately by ACPA status. Conclusion. This metaanalysis indicates that both smoking and the PTPN22 risk allele are associated with the risk of ACPA positivity. There was insufficient evidence to establish a relationship in either direction between PTPN22 and smoking with erosive damage, despite evidence that ACPA positivity is associated with erosive damage.

Fatigue, older age, higher body mass index and female gender predict worse disability in early rheumatoid arthritis despite treatment to target: A comparison of two observational cohort studies from the United Kingdom

To compare disease activity and disability over 2 years in early rheumatoid arthritis (RA) before and after implementation of treat‐to‐target therapy and identify predictors of adverse outcome.© 2017, American College of Rheumatology. This is the peer reviewed version of the following article: Twigg, S. , Hensor, E. M., Freeston, J. , Tan, A. L., Emery, P. , Tennant, A. , Morgan, A. W., on behalf of the YEAR and IACON Consortia (2018), Effect of Fatigue, Older Age, Higher Body Mass Index, and Female Sex on Disability in Early Rheumatoid Arthritis in the Treatment to Target Era. Arthritis Care Res, 70: 361-368. ‐ ‐ doi:10.1002/acr.23281, which has been published in final form at https://doi.org/10.1002/acr.23281. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Uploaded in accordance with the publishers self-archiving policy.

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10−7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Patient-reported Outcomes as Predictors of Change in Disease Activity and Disability in Early Rheumatoid Arthritis: Results from the Yorkshire Early Arthritis Register

Objective. To assess patient-reported variables as predictors of change in disease activity and disability in early rheumatoid arthritis (RA). Methods. Cases were recruited to the Yorkshire Early Arthritis Register (YEAR) between 1997 and 2009 (n = 1415). Predictors of the 28-joint Disease Activity Score (DAS28) and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline and change over 12 months were identified using multilevel models. Baseline predictors were sex, age, symptom duration, autoantibody status, pain and fatigue visual analog scales (VAS), duration of early morning stiffness (EMS), DAS28, and HAQ-DI. Results. Rates of change were slower in women than men: DAS28 fell by 0.19 and 0.17 units/month, and HAQ-DI by 0.028 and 0.023 units/month in men and women, respectively. Baseline pain and EMS had small effects on rates of change, whereas fatigue VAS was only associated with DAS28 and HAQ-DI at baseline. In patients recruited up to 2002, DAS28 reduced more quickly in those with greater pain at baseline (by 0.01 units/mo of DAS28 per cm pain VAS, p = 0.024); in patients recruited after 2002, the effect for pain was stronger (by 0.01 units/mo, p = 0.087). DAS28 reduction was greater with longer EMS. In both cohorts, fall in HAQ-DI (p = 0.006) was greater in patients with longer EMS duration, but pain and fatigue were not significant predictors of change in HAQ-DI. Conclusion. Patient-reported fatigue, pain, and stiffness at baseline are of limited value for the prediction of RA change in disease activity (DAS28) and activity limitation (HAQ-DI).

Comorbidities in Anti-Cyclic Citrullinated Peptide Positive At-Risk Individuals Do Not Differ from Those Patients with Early Inflammatory Arthritis

Objectives To compare comorbidities in a cohort of cyclic citrullinated peptide (CCP) antibody positive patients without or prior to onset of inflammatory arthritis (IA) to those in patients with early IA. Methods Baseline data from two established cohorts were used. The first recruited people at risk of IA: CCP antibody positive cases without IA (CCP Cohort, n = 296). The second cohort [the Inflammatory Arthritis CONtinuum study (IACON)] recruited patients with early IA (n = 725). Proportions of patients with given comorbidities were compared between cohorts and then logistic regression was used to determine odds ratios (OR) for the CCP cohort having specific comorbidities, compared to IACON patients. Analyses adjusted for gender, age, smoking status, and body mass index. Results Patients from the CCP cohort were younger (mean age 50, compared to 53 years). The proportion of patients with at least one comorbidity was higher in the IACON than the CCP cohort: (40% compared to 24%, respectively). Results of logistic regression analyses suggested the odds of hypertension, taking a lipid-lowering agent, ischemic heart disease, cerebrovascular disease, lung disease, and diabetes were not increased in either cohort. However, patients in the CCP cohort were more likely to be taking an antidepressant (OR = 1.62, 95% CI 1.03, 2.56, p = 0.037). Conclusion There was no significant difference in comorbidities among people with CCP antibodies but without IA, compared to those of patients with established IA.

Excess Mortality Due to Respiratory Causes in Patients With Rheumatoid Arthritis Should be Interpreted in the Context of "Never" or "Ever" Smoking and May be Due to Interstitial Lung Disease: Comment on the Article by Sparks et al.

In the article published recently in Arthritis Care & Research, Sparks et al suggest that there is a “. . .nearly three-fold increased risk of respiratory mortality in women with seropositive RA, compared to women without RA. . .” following their analysis of causes of death in patients with rheumatoid arthritis (RA) enrolled into the Nurses’ Health Study (NHS) (Sparks JA, Chang SC, Liao KP, Lu B, Fine AR, Solomon DH, et al. Rheumatoid arthritis and mortality among women during 36 years of prospective followup: results from the Nurses’ Health Study. Arthritis Care Res [Hoboken] 2016;68:753–62). The authors reported that of 307 women with RA who died during followup, 44 died due to respiratory disease; of these 44 cases, 25 were attributed to chronic obstructive pulmonary disease (COPD). Cigarette smoking is a common risk factor for COPD and seropositive RA (Kallberg H, Ding B, Padyukov L, Bengtsson C, Ronnelid J, Klareskog L, et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis 2011;70:508–11) and would likely explain the observed relationship between RA and death due to COPD. Although the authors claim that the risk of respiratory mortality in women with seropositive RA remained significant despite adjustment for confounders, including smoking, their analyses did not compare “never smokers” to “ever smokers.” They grouped cases according to smoking history in pack-years, with 0–10 packyears as the group with the least amount smoked. Therefore, patients who had never smoked were included in the same category as patients who had smoked 20 cigarettes per day for 10 years. Furthermore, some deaths were attributed to RA itself (presumably this was where complications of RA were causes of death), and of these, 6 cases were due to interstitial lung disease (ILD). These 6 ILD cases (where deaths were attributed to RA) appear to have been excluded from the “death due to respiratory causes” group. This situation is unfortunate, as ILD is a likely explanation for the observed excess mortality due to respiratory disease in RA, and although this scenario was discussed by the authors, it was not investigated further. In summary, although there was an increased risk of death due to respiratory disease among RA cases in this cohort, smoking is a significant confounder that was not completely controlled for in this report. Additionally, ILD may explain the observed excess respiratory mortality in RA, but was incompletely investigated by this study.

FRI0094 Disability in Early Rheumatoid Arthritis May Persist despite Improvement in Disease Activity: Evidence from Yorkshire Early Arthritis Register

Background Disability adversely affects the wellbeing of individuals with rheumatoid arthritis (RA) and contributes to direct and indirect health care costs (1). However, owing to substantial advances in drug treatment for RA, management often focuses on suppression of inflammation. In the United Kingdom, treatment with biological agents is guided by disease activity score from counts of 28 joints (DAS28) (2) and EULAR guidance recommends treatment goals of low disease activity or remission (3). Although these targets are of undoubted importance, the relationship between the treatment target (inflammation or disease activity) and disability is not well described. Objectives 1. Describe the relationship between disease activity and disability over 2 years in early RA 2. Identify predictors of adverse outcome. Methods Cases with rheumatologist-confirmed early RA were recruited to Yorkshire Early Arthritis Register (YEAR). Data from 1415 patients were applied to separate latent growth curve models of change in DAS28 and disability index of Health Assessment Questionnaire (HAQ-DI) over 2 years. A parallel process growth curve model described how HAQ-DI varied with DAS28. Dual trajectory analysis (4) was used to describe distinct dual trajectories of change in both variables. Predictors of likely dual trajectory group membership were identified using multinomial logistic regression. Results Two trajectories of DAS28 (high decreasing DAS28 and low decreasing DAS28) and HAQ-DI (high stable HAQ-DI and low decreasing HAQ-DI) were identified, shown in Figure 1. Four distinct dual trajectory groups were: group 1, high decreasing DAS28 and high stable HAQ-DI (23% of cohort); group 2, high decreasing DAS28 and low decreasing HAQ-DI (1%); group 3, low decreasing DAS28 and high stable HAQ-DI (26%); group 4, low decreasing DAS28 and low decreasing HAQ-DI (50%). Predictors of group 1 membership (compared to group 4) were similar to known predictors of poor outcome in RA: female gender, social deprivation and greater baseline fatigue. Predictors of group 3 membership were the same as group 1, but also included older age and greater overall contribution of tender joint count and visual analogue score to baseline DAS28. Conclusions Persistence of disability despite improvement in disease activity was more likely in older patients and those with greater subjective components of baseline DAS28. This suggests that current therapies, which target inflammation, may not be sufficient to reduce disability in early RA. Future work should examine the impact of comorbidity and pain on function in early RA. References Hallert E, Husberg M, Jonsson D, Skogh T. Rheumatoid arthritis is already expensive during the first year of the disease (the Swedish TIRA project). Rheumatology. 2004;43:1374–82. National Institute for Health and Care Excellence. Rheumatoid arthritis: The management of rheumatoid arthritis in adults. 2009. Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492–509. Nagin DS, Tremblay RE. Analyzing developmental trajectories of distinct but related behaviors: a group-based method. Psychol Methods. 2001;6:18–34. Disclosure of Interest None declared

THU0016 Investigation of RA genetic susceptibility loci contribution to response outcomes following conventional DMARD treatment in early RA

Background The first-line treatment of rheumatoid arthritis (RA) involves the introduction of one or more disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) or more historically sulphasalazine (SSA). Many patients only achieve a partial response to these therapies, ultimately requiring biological therapy. There are currently no predictive biomarkers that are sufficiently robust to inform treatment decisions in routine clinical practice. Objectives To investigate RA genetic susceptibility variants in the context of treatment outcomes in the initial 6 months of conventional DMARD therapy in RA. Methods Clinical data from early RA patients recruited into a multi-centre observational cohort were used, consisting of matched clinical and genotyping data on 608 patients with 6 month follow-up. A multivariate analysis of each of 41 single nucleotide polymorphisms (SNPs) across 34 genomic loci previously associated with susceptibility to RA were investigated for association with primary and secondary treatment outcomes; the primary outcome of improvement in DAS28 (ΔDAS28; baseline DAS28 minus 6month DAS28) after adjustment for baseline DAS28 and baseline HAQ, and the secondary outcome of achieving a low-disease activity state at 6 months (DAS28≤3.2) adjusted for baseline HAQ only. A threshold for nominal association was set at p<0.05, with a Bonferroni adjusted p<1.47×10-3 for 34 tests based on the number of loci tested for association. Results The 608 patients with 6 month follow-up data included in this analysis had a mean age at baseline of 59.4 years (SD 12.9), mean symptom duration of 8.59 months (SD 9.6), (70.7%) were female, 70.8% were seropositive for RF and/or ACPA (RF 70.5%, ACPA 61.4%) and 38.7% achieved a low disease activity state (DAS28≤3.2 at 6months). No differences were observed in treatment outcomes between patients on MTX or SSA (ΔDAS28 p=0.858, DAS28≤3.2 p=0.728). SNPs mapping to the FCGR2A, TRAF1/C5 and UBASH3A loci (rs12746613, rs10760130 and rs3788013 respectively) showed nominal association with ΔDAS28 at 6months follow up (p=0.028, p=0.035, p=0.034, respectively). Two SNPs were found to show nominal association with DAS28≤3.2 at 6months at the STAT4 (rs10181656) and UBASH3A (rs3788013) loci (p=0.004 and p=0.045, respectively). No SNPs were found to be associated with treatment outcomes at the Bonferroni adjusted threshold. Conclusions Genetic variants associated with modulating susceptibility to RA may also have a role in determining treatment outcomes in early RA patients following conventional DMARD treatment. Replication studies in comparable populations are needed in order to interpret these findings robustly. Disclosure of Interest None Declared