Ruediger Mueller

The Effect of Comedication With a Conventional Synthetic Disease-Modifying Antirheumatic Drug on Drug Retention and Clinical Effectiveness of Anti-Tumor Necrosis Factor Therapy in Patients With Axial Spondyloarthritis

To explore the effect of comedication with conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) on drug retention and clinical effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (SpA).

The effect of comedication with a csDMARD on drug retention and clinical effectiveness of anti‐TNF therapy in patients with axial spondyloarthritis

To explore the effect of comedication with conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) on drug retention and clinical effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (SpA).

OP0096 Tobacco smoking is associated with increased disease activity in HLA-B27 positive axial spondyloarthritis patients, but does not alter the course of disease activity

Background Smoking is associated with increased disease activity in patients with ankylosing spondylitis (AS) and early axial spondyloarthritis (SpA) in cross-sectional studies, however causation has not been established. Objectives To investigate the impact of smoking on disease activity in patients with axial SpA. Methods We included all patients from a Swiss population-based axial SpA cohort (SCQM) with available smoking and HLA-B27 status fulfilling the ASAS 2009 criteria for axial SpA. The primary and secondary outcomes for this analysis were the BASDAI and the AS disease activity score (ASDAS-CRP) respectively. The primary exposure of interest was smoking (ever/never) and a secondary analysis examined smoking as current/past/never. We compared clinical and demographic characteristics between smokers and non-smokers cross-sectionally. The course of BASDAI and ASDAS were analysed using random slope multivariate longitudinal regression models, adjusted for the following potential confounders: baseline levels of BASDAI or ASDAS, anti-TNF treatment, age at first symptoms, disease duration, gender, HLA-B27, BMI and education. Results Of the 1129 patients who fulfilled our inclusion criteria, 60% fulfilled the modified New York criteria, 62% were smokers (37% current smokers, 25% past smokers), 84% were HLA-B27 positive, 66% were male, mean age was 39.7 years and mean symptom duration at baseline was 13,5 years. As shown in previous reports, smoking was associated with a higher level of baseline disease activity. Mean BASDAI levels were +0.7 (95% CI: +0.4;+1.0) higher in smokers, with no difference between former and current smokers (wilcoxon test p=0.6). The association of smoking and BASDAI levels varied with regards to HLA-B27 status in the adjusted model (effect modification by HLA-B27, p=0.004). The adjusted mean BASDAI levels were 0.8 (95% CI: +0.3;+1.4) higher in HLA-B27 smokers compared to non-smokers, while no significant differences were observed in HLA-B27 negative smokers (-0.35 [95% CI: -0.9;+0.2]). The adjusted longitudinal evolution of BASDAI was similar between smokers and non-smokers (p=0.7). Similar results were found using ASDAS as the outcome. Conclusions In this large observational cohort of axial SpA, the cross-sectional associations between smoking and BASDAI or ASDAS levels depended on the HLA-B27 status; only HLA-B27 positive patients demonstrated increased disease activity with smoking. However, smoking did not alter the long-term evolution of BASDAI and ASDAS in axial SpA, challenging the notion of a causal effect of this environmental factor on disease activity. Disclosure of Interest None Declared

The prevalence of anticitrullinated protein antibodies increases with age in healthy individuals at risk for rheumatoid arthritis

Transition from genetic risk to the development of systemic autoimmunity associated with rheumatoid arthritis (RA) is considered a key step for the development of RA and often referred to as the immune onset of the disease. The aim of this study is to identify predictors for the presence of anticitrullinated protein antibodies (ACPA) as a marker of systemic autoimmunity associated with RA in a high-risk population, an ongoing cohort of first-degree relatives of patients with RA. We assessed the presence of ACPA in individuals without clinical evidence of RA. We examined characteristics associated with ACPA positivity using general estimation equations to account for multiple observations per individual. A total of 1159 serum samples from 1025 subjects were analyzed, 69 samples (6%) were ACPA-positive, and 227 (20%) positive for rheumatoid factor. Participants had a median age of 45xa0years (interquartile range (IQR): 33–55) at baseline and 76% were women. Overall, ACPA positivity increased with age (pxa0<xa00.001). Among women, ACPA positivity was particularly associated with the age group 45 to 55xa0years (pxa0=xa00.003), but not among men (pxa0=xa00.7). In multivariable adjusted analyses, age older than 45, female sex and tobacco smoking were independently associated with ACPA positivity. In our cohort, the presence of ACPA was associated with older age and peaked in women around age 45 to 55xa0years, the perimenopausal period, suggesting that the development of ACPA may be favored by the decline in ovarian function.

Change from subcutaneous to intravenous abatacept and back in patients with rheumatoid arthritis as simulation of a vacation: a prospective phase IV, open-label trial (A-BREAK).

BackgroundVacation can present a major problem to patients with rheumatoid arthritis (RA) treated with weekly subcutaneous biologics, including subcutaneous (SC) abatacept. Therefore, the replacement of four SC doses of abatacept by a single dose of intravenous (IV) abatacept may present an acceptable alternative to cover a 4-week interval needed for vacations. In the study presented, we analyzed the efficacy and safety of this intervention followed by a switch back to SC abatacept after 4xa0weeks.MethodThis open-label, prospective, single-arm, 24-week trial recruited patients with established RA in low disease activity (LDA) or in remission on treatment with SC abatacept for at least 3xa0months to receive a single dose of IV abatacept (baseline) followed by a break of 4xa0weeks and then continuation of weekly SC abatacept from day 28 on. Disease-modifying anti-rheumatic drug (DMARD)-inadequate or biologic-inadequate responders (or both) were included.ResultsThe baseline characteristics of the 49 patients (per protocol) were typical for a cohort of RA patients with established disease (mean disease duration of 8.31xa0years) in LDA under treatment with synthetic DMARDs and a biologic. Two patients (one flare and one patient decision) dropped out of the study. The proportions of patients with disease activity score in 28 joints (DAS-28) of not more than 3.2 at day 28 were 93.9xa0% (95xa0% confidence interval (CI) 83.5–97.9) and 93.6xa0% (95xa0% CI 82.8–97.8) at the end of the study (day 168). The average DAS-28 values were 1.74 (standard deviation (SD)u2009±u20090.72) at baseline, 2.03 (SDu2009±u20091.03) at day 28, and 1.96 (SDu2009±u20090.92) at the end of the study (day 168). Pre-exposure to IV abatacept and having failed methotrexate or anti-tumor necrosis factor (anti-TNF) did not influence the average DAS-28 or the proportion of patients maintaining LDA over time. The average health assessment questionnaire disability index (HAQ-DI) was stable throughout the study. Adverse events (AEs) occurred in 75xa0% of subjects. Four serious AEs were described during the study. None of them was related to the investigational product, and all serious AEs could be resolved during hospitalization.ConclusionThis prospective, open-label study of abatacept shows for the first time that switching from weekly SC to IV abatacept and back after 4xa0weeks is an effective and safe way to bridge vacations in RA patients in LDA or remission. (NCT1846975, registered April 19, 2013.)

Clinical and radiographic course of early undifferentiated arthritis under treatment is not dependent on the number of joints with erosions at diagnosis: results from the Swiss prospective observational cohort

Objective To analyse whether early arthritis patients who do not fulfil the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 classification criteria for rheumatoid arthritis (RA) have a different course of the disease dependent on whether they can or cannot be classified as RA because of radiographic disease (EULAR task force) at diagnosis. Methods For this observational study within the Swiss RA cohort SCQM, we included patients with early undifferentiated arthritis (disease duration ≤1 year), who had not received any previous disease-modifying antirheumatic drugs (DMARDs). 2010 ACR/EULAR criteria negative patients were separated into two groups (radiographic vs non-radiographic arthritis) depending on whether or not they had radiographic changes defined as erosive disease by a EULAR task force (≥3 joints with erosions). The primary outcome measure was the radiographic progression detected employing the Ratingen erosion score. Health Assessment Questionnaire (HAQ) and DAS-28 were used as secondary outcome measures. The average observation period was 4 years. Results A total of 592 patients were analysed. 240 were not classifiable as RA by application of the 2010 ACR/EULAR criteria at baseline. In 57 patients, radiographs at the first visit were not available. 133 patients had radiographic arthritis and 50 non-radiographic arthritis. Treatment was initiated in all patients with DMARDs, mostly methotrexate. No differences in DAS-28 and HAQ scores were found during follow-up. The average erosion scores were higher among patients with initially radiographic arthritis throughout the study. The progression of erosion scores over time, however, was higher in patients with initially non-radiographic arthritis with less subsequent radiological progression (3.3 erosions/year vs 0.4, respectively, p<0.0001). Conclusions The clinical and radiographic course of early undifferentiated arthritis under treatment was not dependent on the presence of erosions in three or more joints (ie, the definition of radiographic disease by the EULAR task force) at diagnosis in our cohort.

Improvement of primary biliary cholangitis (PBC) under treatment with sulfasalazine and abatacept

A 51-year-old female patient was diagnosed with primary biliary cholangitis (PBC) in 2012 and rheumafactor-positive, Anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis (RA) in 2013. The diagnosis of a PBC was confirmed by liver biopsy showing portal inflammatory infiltrates with non-suppurative inflammatory lesions of the biliary duct (figure 1). PBC has been treated with ursodeoxycholic acid since 2012.nnnnFigure 1 nDense lymphocytic infiltrates in portal tracts affecting small portal bile ducts, moderate lobular infiltrates.nnnnAfter diagnosis of RA (initial Disease Activity Score 28 (DAS 28)=6.43), therapy was initiated with leflunomide 20u2009mg/day and low-dose oral glucocorticoids, tapered from 20u2009mg/day to zero over 12 weeks. Remission was reached within 4u2009months (DAS 28=1.84). However, elevated …

FRI0088 Comparison of Rheumatoid Factor, Anti-Citrullinated Protein Antibodies, Anti-Carbamylated Protein Antibody, Anti-Peptidyl Arginine Deiminase Type-3 Antibodies and Calprotectin in Patients with Rheumatoid Arthritis and Spondyloarthritis

Background A significant proportion of patients with Rheumatoid Arthritis (RA) are negative for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). There is a unmet need for new biomarkers to better define the severity and prognosis of RA. Objectives To study the sensitivity and specificity of numerous auto-antibodies and calprotectin in RA patients compared with patients with spondyloarthritis (SpA) and to investigate the relationship between these biomarkes and measures of disease activity and severity. Methods Data was obtained from the “Swiss Clinical Quality Management” (SCQM) registry which recruits adults with RA, psoriatic arthritis (PsA) and axial spondylarthritis (axSpA). All patients with a Biobank sample were tested for RF (IgM and IgA, QUANTA Flash (QF), Inova), ACPA (anti-CCP2 (Eurodiagnostica) and anti-CCP3 (IgG QF and QUANTA Lite (QL) and IgA QF, Inova), anti-carbamylated proteins (anti-CarP, carbamylated fetal calf serum, prototype ELISA, Inova), anti-peptidyl arginine deiminase type-3 antibodies (anti-PAD3-E.Coli QF and anti-PAD3-insect QF, Inova) and serum calprotectin (QL prototype ELISA, Inova). The control group consisted of patients with PsA (CASPAR criteria positive) and axSpA (ASAS criteria positive). In univariable analyses we tested for associations between the biomarkers and the 28-joint disease activity score (DAS28) and the presence of erosive disease at inclusion. Multivariable analyses were corrected for age, sex, disease duration and anti-CCP2 positivity. Results A total of 1471 patients were included, 969 with RA and 502 in the SpA control group (317 with axSpA and 185 with PsA). Statistical measures of the biomarkers for the diagnosis of RA are shown in Table 1. In univariable analyses, RA patients positive for anti-PAD3-E.Coli, anti-PAD3-insect or calprotectin were significantly more likely to have a moderate to high DAS28 (DAS28>3.2) than patients with negative values (68.2% vs. 54.8%, p=0.001, 67.7% vs. 56.0%, p=0.027 and 70.4% vs. 56.2%, p=0.020 respectively). RA patients positive for anti-CarP, anti-PAD3-E.Coli or anti-PAD3-insect were significantly more likely to demonstrate joint erosions compared with patients with negative values (66.3% vs. 57.7%, p=0.037, 68.5% vs. 57.7%, p=0.015 and 71.6% vs. 58.3%, p=0.020 respectively). In multivariable analyses, the odd ratios (and 95% confidence intervals) for the association of anti-PAD3-E.Coli, anti-PAD3-insect or calprotectin with a moderate to high DAS28 were 1.65 (1.15, 2.39), 1.64 (1.02, 2.64) and 1.90 (1.08, 3.35) respectively, and for the association of anti-CarP, anti-PAD3-E.Coli or anti-PAD3-insect with joint erosions were 1.32 (0.90, 1.93), 1.43 (0.95, 2.15) and 1.82 (1.05, 3.15) respectively. Conclusions Although anti-PAD3 and calprotectin are only present in a minority of RA patients, they are significantly associated with more active disease and anti-PAD3-insect is significantly associated with the presence of joint erosions, independently of ACPA (anti-CCP2). Disclosure of Interest None declared

AB0251 Female Reproductive Factors and the Development of Anti-Citrullinated Protein Antibodies in Women at Risk of Rheumatoid Arthritis

Background The etiopathogenesis of rheumatoid arthritis (RA) is viewed as a multi-step process whereby environmental factors induce pathologic activation of the immune system that eventually leads to clinical onset of RA in genetically susceptible individuals. Systemic autoimmunity associated with RA is one of the phases preceding the development of the disease. The role of female hormonal factors is controversial and their relation in the transition to systemic autoimmunity has not been studied. Recently, observational studies have suggested differences in the role of female reproductive factors between anti-citrullinated protein antibodies (ACPA) negative and positive RA. Objectives To analyze the association between female reproductive factors and the development of systemic autoimmunity associated with RA. Methods This is a prospective cohort study of first degree relatives (FDRs) of patients with established RA. Only individuals without clinical evidence of RA are enrolled and followed-up yearly. We included in this analysis only female participants with available ACPA status (anti-CCP 2.0 or 3.1) and full information on reproductive factors. The outcome of interest was the presence of ACPA. The predictor of interest was the cumulative lifetime estrogen (CLE) exposure as previously described (1). This composite score integrates a history of menarche ≤10 years, 3 or more pregnancies, hysterectomy, hormonal contraceptive or replacement therapy and age at menopause ≥53 years. Based on the CLE score, women were categorized as being low, moderate or high estrogen exposed. We used logistic regression to analyze univariate and multivariate associations between ACPA positive status, CLE exposure and other specific reproductive factors. Results A total of 583 women FDRs were analyzed, of which 93 (16%) were ACPA-positive. Characteristics were balanced between ACPA positive and negative FDRs with a mean age of 48.3 and 44.9 years and heavy tobacco smoking (>10 pack-years) in 45 and 46% respectively. Positive shared epitope (SE) in 8 and 10% and positive rheumatoid factor in 17% of subjects in both groups. In a multivariate adjusted analysis, low CLE exposure was associated with ACPA positivity (OR 1.88, p=0.03). High CLE exposure was also numerically associated with an increased risk of ACPA (OR 1.57, p=0.36), even though not significantly. We found no significant association between ACPA positivity and SE, ever smoking, obesity, breastfeeding or postmenopausal status. Conclusions In women at increased risk of RA, the development of ACPAs was found to be associated with low lifetime exposure to estrogens, however high lifetime estrogen exposure also tended to increase the risk of ACPAs positivity, suggesting a non-linear association between estrogenic exposure and the development of ACPAs. We plan to replicate these findings in a separate cohort. If this non-linear association was confirmed it could explain some discordant findings in the literature. References Gatto NM et al. Parkinsonism Relat Disord 2014; 20(11):1149-56. Disclosure of Interest None declared

OP0166 Antibodies Against Periodontal Pathogens are not Associated with Joint Swelling or Autoimmunity Associated with RA in a Cohort of Healthy Individuals at Increased Risk of Rheumatoid Arthritis

Background Evidence suggests an association between periodontitis and rheumatoid arthritis (RA). If the association between the two diseases is causal, an immune response against common pathogenic bacteria involved in periodontitis should precede the development of the disease. It is unknown whether periodontitis is associated with early symptoms of the disease in healthy individuals at increased risk of developing RA. Objectives To examine if serum antibodies against pathogenic bacteria involved in periodontitis are associated with early symptoms of the disease in healthy individuals at increased risk of developing RA. Methods This is a nested case-control study of a prospective cohort of first degree relatives of patients with RA (FDRs). FDRs had no established rheumatologic condition at inclusion. All FDRs provide serum at inclusion and are followed prospectively until development of RA. We selected 4 groups of patients, corresponding to different phases of RA disease development (1): Group 1 - FDRs at risk of RA without signs and symptoms of arthritis and no systemic autoimmunity (control group); Group 2 – FDRs with systemic autoimmunity associated with RA (anti-CCP+ or rheumatoid factor+); Group 3 - FDRs with inflammatory arthralgias without clinical arthritis; Group 4 - FDRs who have presented at least one swollen joint (“Unclassified arthritis”). The four groups were matched for tobacco smoking, age, sex and shared epitope status using propensity scores. The primary outcome was the levels of serum immunoglobulin (Ig) G against five selected periodontal pathogens Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Aggregatibacter actinomycetemcomitans and Prevotella intermedia and one commensal oral species (Streptococcus oralis) assessed using validated enzyme-linked immunosorbent assays. We also normalized the absolute levels of IgG against the pathogens using the IgG level against the commensal S.oralis (ratio). Non linear ANCOVA models were fit to test the association between levels of IgGs against pathogenic oral bacteria and specific phases of RA development. Results The four groups each included 51 FDRs balanced for potential confounding factors of periodontitis. Median age was 51 years (IQR: 39 – 60), 70% were women, 27% smokers. Although quantitative differences existed between the four groups of probands, none of the IgG against the periodontal pathogens differed significantly between the groups. Furthermore, IgG levels against P. gingivalis were not associated with seropositivity (ACPA or RF) (p=0.90), age (P=0.15), shared epitope status (p=0.63) or sex (P=0.26). Conclusions Longitudinal studies are still needed to establish the causal involvement of periodontitis, or its associated bacteria, on RA development. However, the results from this case-control study do not suggest that circulating antibody levels against common periodontal pathogens are associated with specific phases of RA development and useful as a prognostic tool. References Ann Rheum Dis 2012;71:638-641 Disclosure of Interest None declared