T.L. Jansen

The effectiveness and medication costs of three anti-TNF agentsα in the treatment of rheumatoid arthritis from prospective clinical practice data

AIMnto evaluate the effects of adalimumab, etanercept and infliximab on disease activity, functional ability and quality of life and the medication costs in a naturalistic design.nnnMETHODSnAll patients from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register starting on tumour necrosis factor (TNF)alpha-blocking agents for the first time were monitored and assessed by trained research nurses every 3 months. The primary outcome was the Disease Activity Score (DAS28) course over the 12 months follow-up, analysed by linear mixed models. Secondary outcomes were the Health Assessment Questionnaire (HAQ), EuroQol five dimensions (EQ-5D) and the Short-Form 36 items (SF36) scores, and medication-related total costs.nnnRESULTSnThe DAS28 and SF-36 physical component scale decreased in all three medication groups over 12 months, but the decrease was larger for adalimumab and etanercept in comparison to infliximab (p<0.001). The analyses of the HAQ and the EQ-5D scores showed the same (non-significant) trend, namely that at 12 months, the functionality and quality of life was better for adalimumab and etanercept patients. With regard to the medication costs, infliximab treatment resulted in significantly higher costs over the follow-up period than treatments with either adalimumab or etanercept. The comparison between adalimumab and etanercept showed a significant difference in the 12-month DAS28 course (p = 0.031). There were no additional indications for differences in effectiveness or costs between adalimumab and etanercept.nnnCONCLUSIONnThe evaluation of the effectiveness and costs showed that adalimumab and etanercept are more or less equal and favourable compared to infliximab in the first year of treatment.

Effectiveness of a third tumor necrosis factor-α-blocking agent compared with rituximab after failure of 2 TNF-blocking agents in rheumatoid arthritis.

Objective. To compare the effectiveness of a third tumor necrosis factor-α (TNF-α)-blocking agent with rituximab after failure of 2 TNF-blocking agents in patients with rheumatoid arthritis (RA) in daily clinical practice. Methods. Patients receiving a third TNF-blocking agent or rituximab after failure of 2 TNF-blocking agents were selected from a Dutch biologic registry. The primary outcome was the results from the Disease Activity Score of 28 joints (DAS28) over the first 12 months after start of the third biologic using mixed-model analyses. Secondary outcomes included the course of the Health Assessment Questionnaire (HAQ) and the separate components of the DAS28 over the first 12 months and the change from baseline in DAS28 and HAQ at 3 and 6 months. Results. The overall course of the DAS28 over the first 12 months was significantly better for rituximab (p = 0.0044), as also observed for the HAQ, although the latter results were not statistically significant (p = 0.0537). The erythrocyte sedimentation rates, C-reactive protein, and swollen joint counts showed a better course for rituximab (p = 0.0008, p = 0.0287, p = 0.0547, respectively), but not the tender joint counts or visual analog scale for general health. DAS28 decreased significantly in both groups at 3 and 6 months (p ≤ 0.024), but the change in HAQ was significant for rituximab only at 3 months (p = 0.009). Conclusion. During the first 12 months of therapy, a larger improvement in disease activity and a trend toward a larger decrease in functional disability was observed in patients receiving rituximab. Switching to a biologic with another mechanism of action might be more effective after failure of 2 TNF-blocking agents in RA.

Effectiveness of Tumor Necrosis Factor Inhibitors in Combination with Various csDMARD in the Treatment of Rheumatoid Arthritis: Data from the DREAM Registry

Objective. To analyze and compare the effectiveness and drug survival in patients with rheumatoid arthritis, as measured by 28-joint Disease Activity Score (DAS28) and Health Assessment Questionnaire–Disability Index (HAQ-DI), of tumor necrosis factor inhibitor (TNFi) monotherapy, TNFi + leflunomide (LEF), TNFi + sulfasalazine (SSZ), TNFi + other conventional synthetic disease-modifying antirheumatic drugs (csDMARD), and TNFi + methotrexate (MTX) therapy, in daily practice. Methods. Data were collected from the DREAM registry. Patients beginning their first TNFi treatment were included in the study: TNFi monotherapy (n = 320), TNFi + SSZ (n = 103), TNFi + LEF (n = 80), TNFi + other csDMARD (n = 99), TNFi + MTX alone (n = 919), TNFi + MTX + other csDMARD (n = 412). Treatment effectiveness was analyzed using DAS28 and HAQ-DI with linear mixed models and the TNFi drug survival was analyzed using Kaplan-Meier curves and Cox regression. All analyses have been corrected for confounders. Results. The patients who received TNFi + MTX had significantly better DAS28 and HAQ-DI values over time (both p < 0.001) and longer TNFi drug survival than TNFi monotherapy (p < 0.001). TNFi + SSZ and TNFi + other csDMARD had significantly better DAS28 values over time (p = 0.001) and longer drug survival (p = 0.001) versus TNFi monotherapy. TNFi + LEF was not significantly better compared to monotherapy. Adding other csDMARD to the TNFi + MTX combination provided no added value. Conclusion. Preferably, TNFi should be prescribed together with MTX. If this is not possible, we advise the use of other csDMARD.

AB0629 A critical appraisal of the competence of crystal identification by rheumatologists.

Background The gold standard for diagnosing crystal arthritis is aspiration of synovial fluid and subsequent polarized microscopy on the punctured fluid. However, various studies have shown a lack of consistency in results of crystal analysis among different observers. We have proposed to certify dedicated colleagues by confirming skill of crystal identification and to increase our insight in general about expertise with the identification of crystals in synovial fluid. By obtaining these data concerning current microscopical performance, we aim to find areas of crystal recognition which are open for further improvement. Objectives The primary objective is to confirm the expertise of physicians with the identification of crystals in synovial fluid/tissue. An online test prepared for the Study of Updated Gout criteria: acr/eulaR (SugaR) emphasizes the recognition of monosodium urate (MSU) crystals, plus the identification of a predefined set as non-MSU crystals; this online test also includes identification of other crystals, such as calcium pyrophosphate dihydrate (CPP), cholesterol, oxalate and apatite. Our secondary objective is to find out whether observer factors are related to microscopical performance. Methods Diagnosticians from different countries, who are working in the rheumatology field and performing microscopic analysis were asked to participate to qualify for entrance to the SugaR Study. The first part of the test included a number of questions concerning personal/professional data. The second part contained 30 slides with images of crystals and other look-a-likes from synovial fluid: crystals shown were 8 MSU, 5 CPP, 4 cholesterol, 2 oxalate and 1 apatite. The test also included slides with potentially confusing look-a-likes. Results Up to January 1st 2013, 56 persons performed the online test; 46% (n=43) of them identified each one of the 20 crystals correctly. With respect to MSU crystals 77% identified 8 MSU crystals, 91% identified at least 7 out of 8 MSU crystals; 68% of all attendees identified 5 CPP crystals and 91% at least 4 out of 5 CPP crystals. See table. Ability to recognize crystals when they are there (%) Conclusions Almost half of the attendees performed well at identifying a diversity of crystals: MSU crystals appeared easier to identify than CPP. The objective performance regarding crystal identification can be improved in all. There seems to be no clear relationship between confidence of expertise and actual expertise. Disclosure of Interest None Declared

Limited value for ultrasonography in predicting flare in rheumatoid arthritis patients with low disease activity stopping TNF inhibitors

ObjectivenUltrasonography (US) can be used for treatment decisions in RA patients. This study investigated the added value of US to clinical variables in predicting flare in RA patients with longstanding low disease activity when stopping TNF inhibitors (TNFi).nnnMethodsnCox models with and without using US added to clinical variables were developed in the Potential Optimization of Expediency of TNFi-UltraSonography study. RA patients (n = 259), using >1 year TNFi and csDMARD with DAS28 < 3.2 for 6 months prior to inclusion, were followed for 52 weeks after stopping TNFi. The added value of US was assessed in two ways: first, by the extent to which individual predictions for flare at 52 weeks with and without US differed; and second, by comparing how US information improved the prediction to classify patients at 52 weeks in the low risk (<33% flare), intermediate risk (33-50%) and high risk (50-100%) groups.nnnResultsnAlthough US was predictive of flare at group level (multivariate hazard ratio = 1.7; 95% CI: 1.1, 2.5), individual predictions for flare at 52 weeks with and without US differed little (median difference 3.7%; interquartile range: -7.8 to 6.5%). With US, 15.9% of patients were designated low risk; without US, 14.6%. In fact, 12.0% of patients were US-classified as low risk with/without knowing US.nnnConclusionnIn RA patients with longstanding low disease activity, at time of stopping TNFi, US is a predictor for flare at group level, but at the patient level, US has limited added value when common clinical parameters are used already, though the predictive value of clinical predictors is modest as well.

OP0181 Prediction of Flare after Stopping TNF-Inhibitor by Baseline Ultrasonography and Patient Characteristics in Rheumatoid Arthritis Patients with Low Disease Activity: 12-Month Results

Background A significant number of rheumatoid arthritis (RA) patients can reach low disease activity (LDA) by using TNF-inhibitors (TNF-i), but this therapy can cause serious side-effects and is expensive. Therefore it could be expedient to stop in case of LDA, unless a relapse can be predicted. Ultrasonography of joints seems to be a predictor in this respect in smaller studies. The Dutch POET (Potential Optimalisation of Expediency of TNF-i (TNF-inhibitor)) study, is a multicenter randomized prospective cohort study investigating if in patients with RA with LDA on TNF-i and conventional DMARD, the TNF-i can be stopped. Patients were randomized to continue or stop TNF-i. Part of this study is the POET-ultrasonography (US) study. Objectives To investigate whether US, at the time of stopping TNF-i in RA patients with LDA, is an additive predictor for flare besides clinical data. Methods Data were analysed of 251 patients who stopped TNF-i in the POET study. Participating patients had RA according to ACR 1987 criteria, >6 months a DAS28 <3.2 (LDA) and treatment with TNF-i >1 year next to a conventional DMARD, with no dose change 6 months prior to randomisation. Nineteen trained ultrasonographers performed at baseline of the study US (with different US machines) of 20 joints: MCP 1–5 dorsal and volar, wrist and MTP 2–5 dorsal aspect, all bilaterally. The joints were graded on grayscale (GS; 0–3) and power Doppler (PD; 0–3). US signs of arthritis were defined as GS>1 and/or PD>0. Trial visits were performed every 3 months during 12 months and intercurrently when flare was suspected. Flare was defined as DAS28 >3.2 and at least >0.6 increase compared to the baseline DAS28. Univariate and multivariate Cox-regression was performed guided by clinical factors described in the literature and US. Results The Kaplan Meier curve for patients with US signs of arthritis in one or more joints shows greater/higher risk of flare and shorter relapse-free period compared to the curve for patients without US signs of arthritis, p= (figure). At multivariate analysis (table), correcting for potentially clinical predictors, US detected arthritis stayed a statistically significant predictor of flare; HR 1.69; 95% CI 1.11 to 2.53. The predictive value of US seems not that strong that it can be used in individual patients. Regression Coefficient Hazard ratio (95% CI) IgM RF (+) −0.51 0.60 (0.35–1.05) Anti-CCP (+) 0.25 1.29 (0.76–2.17) Erosiveness (+) 0.23 1.26 (0.82–1.95) Disease duration (years) 0.24 1.27 (0.97–1.67) Sex (male) 0.06 1.06 (0.71–1.59) BMI 0.01 1.01 (0.97–1.06) csDMARD (number) −0.04 0.96 (0.72–1.27) TNF-inhibitor (number) −0.01 0.99 (0.89–1.11) US (+)* 0.52 1.69 (1.11–2.53) *P-value <0.05. Conclusions The presence of US arthritis is associated with an earlier flare and a higher flare rate compared to those with negative US taking into account demographic and clinical patient characteristics. Disclosure of Interest F. Lamers-Karnebeek Grant/research support from: Abbvie, J. Luime: None declared, P. van Riel: None declared, J. Jacobs: None declared, T. Jansen: None declared

THU0493 Association of the Toll-Like Receptor 4 (TLR4) Gene with Gout

Background Gout results from innate immune response to monosodium urate (MSU) crystals that form when serum urate is elevated. Identification of genetic risk factors for hyperuricemia and the MSU immune response is therefore important for insight into the etiology of gout. Whilst genome-wide association studies have provided significant insights into the causes of hyperuricemia there are no confirmed loci for non-serum urate pathways in gout. Recently association of the rs2149356 variant in the TLR4 locus with gout was reported in a Chinese sample set (odds ratio TT genotype =1.88, P=8x10–5)1. TLR4 triggers innate immune response to endogenous ligands, including MSU crystals2. Objectives To test rs2149356 for association in European and New Zealand (NZ) Polynesian gout case-control sample sets. Methods All gout cases were clinically ascertained according to the American Rheumatism Association criteria. European cases (n=1606) were recruited from New Zealand (n=599), by the Eurogout consortium within the European Crystal Network (n=784) and by the Arthritis Genomics Recruitment Initiative in Australasia (AGRIA; n=223). European non-gouty controls (n=8066) were recruited from NZ (n=875) and sourced from the Atherosclerosis Risk in Communities (n=4144) and Framingham Heart (n=3047) studies. There were 872 New Zealand Maori and Pacific Island (Polynesian) cases and 1088 controls. Genotyping was done by Taqman and statistical analysis by STATA. Results Using unstratified controls the T allele, but not the TT genotype, was associated with gout in Europeans (ORTallele=1.09, P=0.05; ORTTgenotype=1.15, P=0.13). There was no evidence for association in Polynesians (ORTallele=0.90, P=0.12; ORTTgenotype=0.88, P=0.31). However, comparison of cases to hyperuricemic controls strengthened evidence for association with gout in Europeans (ORTallele=1.18, P=0.004; ORTTgenotype=1.38, P=0.017), but made no difference in Polynesians (ORTallele=, P=0.30; ORTTgenotype=0.87, P=0.47). Conclusions The previous report of association of TLR4 with gout in Chinese was replicated in Europeans but not Polynesians. Strengthening of association using hyperuricemic controls is consistent with a role for this locus in gouty inflammation in the presence of hyperuricemia. Subject to further replication, TLR4 represents the first non-serum urate genetic risk locus identified in gout, and provides support for a role of TLR4 in etiology. References Qing et al. PLoS One 2013;5:e64845. Liu-Bryan et al. Arthritis Rheum 2005;52:2936 Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4781

An Economic Evaluation of Stopping Versus Continuing Tumor Necrosis Factor Inhibitor Treatment in Rheumatoid Arthritis Patients With Disease Remission or Low Disease Activity: Results From a Pragmatic Open-Label Trial

To evaluate, from a societal perspective, the incremental cost‐effectiveness of withdrawing tumor necrosis factor inhibitor (TNFi) treatment compared to continuation of these drugs within a 1‐year, randomized trial among rheumatoid arthritis patients with longstanding, stable disease activity or remission.

AB0263 Predictive value of a single measurement of the multi-biomarker disease activity (MBDA) score for disease flares within 6 and 12 months in rheumatoid arthritis patients using tumor necrosis factor inhibitors and conventional synthetic dmards

Background Rheumatoid Arthritis (RA) patients in the maintenance phase should be treated by escalating antirheumatics up to stable low disease activity and then often are treated with tumor necrosis factor inhibitors (TNFi) and conventional synthetic disease modifyers (csDMARD). Once this phase has been reached the risk of flare is an issue once drugs are to be tapered or discontinued. Objectives To examine the ability of the multi-biomarker disease activity (MBDA) score as predictor for disease flare in rheumatoid arthritis (RA) patients with stable low disease activity using tumor necrosis factor inhibitors (TNFi) and conventional synthetic disease modifyers (csDMARD). Methods Data were used from the continuation control group of the Dutch multicenter, open-label, POET trial, in which patients with stable low disease activity (disease activity score [DAS28] <3.2 for at least 6 months] were randomized to either stop or continue TNFi treatment. Three indicators of disease relapse were assessed: 1) flare based on DAS28 (DAS28 ≥3.2 with ΔDAS28 >0.6), 2) flare based on escalation of any DMARD therapy, and 3) flare based on physician-reported disease activity. Associations between baseline MBDA score and meeting the different criteria for disease flare within 6 or 12 months of follow-up were examined using univariate analysis and multivariate logistic regression adjusting for baseline DAS28 score. Results For this post-hoc analysis, baseline serum samples to measure MBDA scores were available for 225/286 (78.7%) of the patients randomized to the TNFi continuation group (88.9% also used methotrexate, another 8.0% used another csDMARD and 3.1% used no csDMARD): 86.2% with a first TNFi, 11.6% with second TNFi and 2.2% with a third TNFi. Within 12 months, 19.1% of patients had experienced a DAS28 flare, 12.0% had medication escalation and 8.0% had ≥1 physician-reported flare. Median time to DAS28-based flare was 26 weeks (IQR:13–28). Univariately, patients with high baseline MBDA (>44) scores (n=31) were at increased risk of experiencing a DAS28 flare within 6 (OR =4.39, P=0.001) or 12 (OR =2.78, P=0.015) months. MBDA scores were not associated with increased risk of medication escalation or physician-reported flare. After adjustment for baseline DAS28 scores, high MBDA score remained predictive for risk of flare within 6 months (OR =3.15, P=0.017), but not for flare within 12 months (OR =2.05, P=0.107). Conclusions MBDA score may be of additional value in predicting DAS28 flares but not in predicting medication escalations or physician-reported flares in RA patients on TNFi in stable low disease activity. Acknowledgements We wish to acknowledge all POET investigators and all who gave their contributions to the POET project. Disclosure of Interest P. M. Klooster: None declared, M. Ghiti-Moghadam: None declared, F. Lamers-Karnebeek: None declared, H. Vonkeman: None declared, E. Sasso Shareholder of: Myriad Genetics, Employee of: Crescendo Bioscience, P. Riel: None declared, M. Laar: None declared, T. L. Jansen: None declared

THU0498 Gender Differences in The Phenotype of Gout and Its Effect on Classification Using The ACR-EULAR Criteria

Background Gout is a quite prevalent disorder in affluent countries, with the prevalence in males being 3–4 times higher than in females [1]. In practice, gout may be perceived as a “males” disorder and it has been suggested that the phenotype of gout differs between males and females, due to selection bias or by nature of the disease. Objectives To analyse whether there are differences between males and females in the phenotype of gout and in the performance of the ACR-EULAR classification criteria. Methods We used the multi-country SUGAR data set in which the ACR-EULAR classification criteria were constructed and validated [2]. In SUGAR, patients with at least one swollen joint or subcutaneous tophus conceivably being due to gout were consecutively included. Presence of MSU crystals in synovial fluid or tophus aspirate was the gold standard for gout, as assessed at inclusion, using microscopy by certified examiners in all included patients. Gout manifestations were standardly assessed without knowing the results of the microscopy. Gout manifestations included in the ACR-EULAR classification criteria were compared between male and female MSU positives. Sensitivity and specificity of the ACR-EULAR criteria, calculated without MSU results, were compared between males and females. To preserve power, the development and validation data sets of SUGAR were combined. Results There were 983 subjects included (71% male), of whom 52% (509/983) were MSU crystal-positive. Sixty-three percent (440/702) of the males and 25% (69/281) of the females were MSU crystal-positive, respectively (p<0.0001). There were no large (>10%) or significant (p<0.05) differences between male and female MSU positives regarding: previous or current involvement of MTP1, mono/oligo/poly-arthritis, joint erythema, painfulness for touch, tophus, largest pain increase within 24 hours, highest level of Serum Uric Acid (SUA) level without treatment, current level of SUA, occurrence of erosions on X-ray, or double contour sign on ultrasound. Male MSU positives more frequently reported: disablement (98% versus 87%; p<0.0001), symptom resolution within 14 days (84% versus 65%; p=0.0002), complete resolution (86% versus 70%; p=0.0004). In the complete sample of 983 subjects, the classification system lead to a median (P25-P75) score of 5 (2–8) in females and 9 (6–14) in males (p<0.0001). Sensitivity and specificity of the classification system to detect MSU crystal positivity were 86% and 79% in the complete sample, and 87% and 89% for females and 85% and 70% for males. Conclusions Male and female gout patients are similar on most important aspects of the gout phenotype. The ACR-EULAR classification criteria perform well in both males and females; sensitivity is the same in males and females, while specificity was better in females. References Kuo CF, Grainge M, Zhang W, Doherty M. Nature Rev Rheum. 2015;11:649–662. Neogi T, Jansen T, Dalbeth N, Fransen J, Schumacher HR et al. Ann Rheum Dis 2015;74:1789–1798. Acknowledgement We are grateful for the contributions of all investigators who submitted subjects in the SUGAR study. Disclosure of Interest None declared