Early Arthritis Clinic Cohort Research Articles

Cost-Effectiveness of the Early Arthritis Clinic Organizational Model.

Early diagnosis and tight control improve outcomes of rheumatoid arthritis (RA). However, whether establishing an early arthritis clinic (EAC) is sustainable for national health systems is not known. This analysis aimed to compare effectiveness and costs of an EAC compared to patients followed by the current standard of care. A retrospective study on administrative health databases of patients with a new diagnosis of RA was conducted: 430 patients followed in an EAC were enrolled, and 4 non-EAC controls were randomly matched for each. During 2 years of follow-up, the mean health care costs (outpatient, inpatient, pharmaceutical, and global) and 3 effectiveness measures (number and length of hospitalization and quality of care) of the EAC and non-EAC were estimated. The incremental cost-effectiveness ratio was calculated as well as the cost-effectiveness acceptability curve. The cohorts included patients with a mean age of 55.4 years, and 1,506 patients (70%) were female. The mean pharmaceutical (2,602 versus 1,945 euros) and outpatient (2,447 versus 1,778 euros) costs were higher in the EAC cohort. Conversely, a higher rate of non-EAC patients had a low adherence to quality-of-care indicators. The expected number of hospitalizations and the length of stay were statistically significantly higher in the non-EAC versus EAC. Despite an expected increase in outpatient costs (visits and diagnostic tests) and pharmaceutical costs, the reduction in terms of number and length of hospitalizations and the higher adherence to international quality-of-care guidelines support the effectiveness of the EAC model.

O08 Developing a DNA methylation signature for predicting rheumatoid arthritis using a machine learning pipeline

Abstract Background/Aims Early diagnosis and intervention improves outcomes of immune mediated rheumatic and musculoskeletal diseases (RMDs) but may be hampered by diagnostic uncertainty. The extent to which rationally selected molecular parameters add value to clinical characteristics for diagnostic prediction in undifferentiated disease states warrants investigation. B lymphocytes play an increasingly recognised role in rheumatoid arthritis (RA) pathogenesis, and cell-specific methylation patterns link environmental exposures to genetic risk. We derived and tested the practical utility of a B lymphocyte-derived DNA methylation signature for predicting RA in an early arthritis clinic cohort. Methods CD19+ B cell and peripheral blood mononuclear cell (PBMC) whole genome DNA methylation array data were available, respectively, from 109 inflammatory arthritis patients naïve to immunomodulatory drugs (Newcastle, UK; 38% confirmed to have a diagnosis of RA within 1 year) and 50 untreated undifferentiated arthritis (UA) patients (Leiden, The Netherlands; 68% classifiable RA within 1 year by 1987 ACR criteria versus alternate diagnoses). A bespoke machine learning pipeline employed a sequential model-based optimisation (SMBO) procedure for selecting, tuning and applying methods amongst ten feature-selection, six data-sampling and two classification algorithms in the Newcastle “training cohort.” The predictive performance of the resultant optimised molecular classifier was assessed in the independent Leiden “test cohort” alongside a previously described clinical prediction rule, using comparative area under receiver operating characteristic (AUROC) curves. A modification to the clinical prediction rule that incorporated a single parameter to reflect molecular classification was also assessed. The pipeline was implemented using the R machine learning package mlr. Results Using the SMBO approach, 27 CpGs maximally discriminatory for RA were selected from B lymphocyte DNA methylome training data, and a molecular classifier was derived using the random forest algorithm. Applied to the independent PBMC methylome in UA patients, the classifier and the validated Leiden prediction rule performed similarly in predicting RA (AUROC [95% CI] = 0.8 [0.66-0.94] versus 0.78 [0.64-0.92]). Interestingly, incorporating a molecular risk score based on the 27-CpG signature into the validated Leiden clinical prediction rule significantly improved its performance (AUROC [95% CI] = 0.89 [0.79-0.98] versus 0.78 [0.64-0.92]; p = 0.048). When applied to the sub-cohort of 25 patients in the Leiden cohort who were negative for anti-citrullinated peptide autoantibodies (ACPA), enhanced performance of the modified over the un-modified clinical prediction rule was maintained (AUROC [95% CI] = 0.82 [0.65-1] versus 0.70 [0.45-0.95], respectively), although the difference did not reach statistical significance in this smaller cohort. Conclusion We provide a proof of principle for the application of a B lymphocyte-derived epigenetic signature to enhance prediction of RA in UA patients using stored PBMCs. Further refinement of our pipeline represents a plausible means to expedite the diagnosis in undifferentiated RMDs and could offer pathophysiological insight. Disclosure N. Naamane: None. E. Niemantsverdriet: None. N. Thalayasingam: None. N. Nair: None. A.D. Clark: None. K. Murray: None. B. Hargreaves: None. L.N. Reynard: None. S. Eyre: None. A. Barton: None. A.H.M. van der Helm-van Mil: None. A.G. Pratt: None.

Anticitrullinated protein antibodies and rheumatoid factor are associated with increased mortality but with different causes of death in patients with rheumatoid arthritis: a longitudinal study in three European cohorts

ObjectivePatients with rheumatoid arthritis (RA)-related autoantibodies have an increased mortality rate. Different autoantibodies are frequently co-occurring and it is unclear which autoantibodies associate with increased mortality. In addition, association with...

SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis

ObjectiveWe recently reported an association of the SPP1 rs9138 and rs11439060 functional variants with the risk of rheumatoid arthritis (RA), the association being greater in anti-citrullinated protein autoantibody (ACPA)-negative patients....

Allele‐Dose Association of the C5orf30 rs26232 Variant With Joint Damage in Rheumatoid Arthritis

There is increasing evidence to indicate that genetic factors contribute significantly to radiologic joint damage in rheumatoid arthritis (RA). The aim of the present study was to determine whether genotypes of 10 recently identified RA susceptibility loci are associated with radiologic severity. A 2-stage study was performed using 3 Northern European RA populations: a British cross-sectional population (discovery cohort; n=885) and the Leiden Early Arthritis Clinic (EAC) cohort (n=581) and Yorkshire Early Arthritis Register (YEAR) cohort (n=418) (validation cohorts). Radiologic damage was assessed using a modified Larsen method for scoring radiographs (in the discovery cohort) or modified Sharp/van der Heijde score (in the 2 validation cohorts). A meta-analysis was performed to bring together the evidence from the 3 studies, using data on radiologic severity of joint damage from a single time point. An allele-dose association of rs26232 was present in the discovery population (P=4×10(-4)); the median modified Larsen scores of radiologic joint damage per genotype were 31 (for those with CC), 27 (for those with CT), and 16 (for those with TT). The allele-dose association of rs26232 was replicated in both the Leiden EAC cohort during the initial 7 years of RA (P=0.04) and the YEAR cohort (P=0.039). In a fixed-effects meta-analysis of all 3 studies, the per T allele effect on the ratio of radiologic severity scores was 0.90 (95% confidence interval 0.84, 0.96; P=0.004). The variant rs26232, in the first intron of the C5orf30 locus, is associated with the severity of radiologic damage in RA and is independent of established prognostic biomarkers. The biologic activities of C5orf30 are unknown, but our genetic data suggest that it is involved in mediating joint damage in RA.

FRI0098 Biomarker-based estimates of risk of radiographic progression in the leiden early arthritis cohort

BackgroundStudies conducted prior to the widespread usage of biologic therapy in patients with rheumatoid arthritis (RA) can provide valuable information regarding the natural course of the disease and the potential...

Performance of classification criteria for peripheral spondyloarthritis and psoriatic arthritis in the Leiden early arthritis cohort

ObjectivesThe performance of spondyloarthritis (SpA) classification criteria is not well-established in general early arthritis cohorts. Therefore, the authors tested their performance in the Leiden Early Arthritis Clinic (EAC) cohort and...

Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis.

The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of high-affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies). High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method. Carriership of the individual alleles HLA-DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti-CCP antibodies. Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4, respectively). An increased rate of joint destruction was observed in SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-, anti-CCP- patients (1.6 points per year) (P < 0.001). HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.

Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCP) affects severity of rheumatoid arthritis

Objective. The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of highaffinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies). Methods. High-resolution HLA–DR and DQ typing and anti–CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method. Results. Carriership of the individual alleles HLA–DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of antiCCP antibodies. Carriers of DQ–DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA–DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8–6.0 and OR 13.3, 95% CI 4.6–40.4, respectively). An increased rate of joint destruction was observed in SE, anti-CCP patients (mean Sharp score 7.6 points per year) compared with that in SE, anti-CCP patients (2.4 points per year) (P 0.04), SE, anti-CCP patients (1.6 points per year) (P < 0.001), and SE, anti-CCP patients (1.6 points per year) (P < 0.001). Conclusion. HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.