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Contains fulltext : 290958.pdf (Publisher’s version ) (Open Access) Hepatotoxicity is a serious adverse drug reaction related to methotrexate (MTX). However, the cause of drug-induced liver injury (DILI) is still unclear and unpredictable. Genetic risk factors may predispose for MTX-DILI. Therefore, we conducted a nested case-control genome-wide association study to explore genetic risk factors associated with MTX-DILI. Seven international groups contributed blood samples and data of patients with rheumatoid arthritis who used MTX. MTX-DILI was defined as an alanine aminotransferase (ALT) level of at least three times the upper limit of normal (ULN), to increase contrast controls ALT levels did not raise above two times the ULN. Per study site, control subjects and patients with MTX-DILI (ratio 3:1) were matched for age, gender, and duration of MTX use. Patients were genotyped using Illumina GSA MD-24v1-0 and data were imputed using the 1000 Genomes reference panel. Single-nucleotide polymorphisms (SNPs) were analyzed using an additive genetic model, corrected for sex, country, and age. A P-value of ≤ 5 × 10(-8) was considered significant, whereas a P-value of ≤ 5 × 10(-6) was considered suggestive. A total of 108 MTX-DILI cases and 311 controls were included for association analysis. None of the SNPs were significantly associated with MTX-DILI. However, we found seven suggestive genetic variants associated with MTX-DILI (P-values 7.43 × 10(-8) to 4.86 × 10(-6) ). Of those, five SNPs were in the intronic protein-coding regions of FTCDNL1, BCOR, FGF14, RBMS3, and PFDN4/DOK5. Investigation of candidates SPATA9 (rs72783407), PLCG2 (rs60427389), RAVER2 (rs72675408), JAK1 (rs72675451), PTPN2 (rs2476601), MTHFR C677T (rs1801133), and into the HLA region did not show significant findings. No genetic variants associated with MTX-DILI were found, whereas suggestive SNPs need further investigation. 01 april 2023

Objectives The use of long-term corticosteroids during pregnancy has been growing over the past decades. Corticosteroids can be given when an auto-inflammatory disease like rheumatoid arthritis (RA) is too active. Several studies have shown that long-term corticosteroids use in pregnancy is associated with maternal and fetal adverse outcomes, like preeclampsia, shorter gestational age, lower birth weight, and rapid catch-up growth. These last two outcomes could influence the insulin resistance later in life. Our objective was to investigate whether prednisone use in pregnant women with RA induces insulin resistance in offspring. Methods One hundred three children were included after their mother had participated in a prospective cohort study on RA and pregnancy. Forty-two children were in utero exposed to prednisone and 61 were non-exposed. To assess insulin resistance, we measured homeostasis model of assessment insulin resistance (HOMA-IR) and serum adiponectin and lipid levels, corrected for body fat distribution. Results An average of 6 mg prednisone on a daily use gave no difference in mean HOMA-IR (SD) between the children who were prednisone-exposed in utero (1.10 (0.84)) and those non-exposed (1.09 (0.49)). No difference was found in mean adiponectin level, body fat distribution, or lipid levels such as total cholesterol, fasting triglyceride, or high-density lipoprotein. Conclusion Children who are prednisone-exposed in utero (low dose) have no increased risk for insulin resistance at the age of approximately 7 years. These findings are reassuring because the prednisone use during pregnancy is increasing worldwide. Further research has to be performed to evaluate if the insulin resistance remains absent in the future. Key Points• What is already known on this topic—long-term corticosteroids use in pregnancy is associated with fetal adverse outcomes, like lower birth weight and rapid catch-up growth which can influence the insulin resistance later in life.• What this study adds—long-term corticosteroids use in pregnant women with rheumatoid arthritis has no increased risk for insulin resistance in the offspring.• How this study might affect research, practice, or policy—findings are reassuring because prednisone use during pregnancy is increasing worldwide. Further research should evaluate if the insulin resistance remains absent in the future.

Objectives Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have never been studied. Our objective was to describe the pregnancy outcomes of partners of men diagnosed with IA. Methods We performed a multicentre cross-sectional retrospective study conducted in the Netherlands. Men with IA who were over 40 years old that reported at least one positive pregnancy test were included. To analyse the impact of IA on pregnancy outcomes, pregnancies were classified into two groups: pregnancies conceived after the diagnosis of IA and before the diagnosis of IA. Results In total, 408 male participants diagnosed with IA reported 897 singleton pregnancies that resulted in 794 live births. Pregnancies conceived after the diagnosis of IA had higher rate of miscarriage (12.27 vs 7.53%, P = Conclusions This is the largest study to describe the pregnancy outcomes of partners of men diagnosed with IA and the first to demonstrate that paternal IA is associated with a higher risk of miscarriage. Notwithstanding, the overall rate of miscarriage reported in our study could be comparable to previously reported population estimates.

Objectives Psoriasis impacts health-related quality of life (HRQoL) in PsA patients. However, this is not adequately measured with a general HRQoL questionnaire. The aim of this study was to quantify the degree of psoriasis evolution in PsA patients over the first year of follow-up and to evaluate whether the impact of psoriasis on HRQoL can be adequately measured with a dermatology-specific HRQoL questionnaire. Methods Data were used from PsA patients in the Dutch south west Early Psoriatic Arthritis cohort. Psoriasis severity was measured with the Psoriasis Area and Severity Index (PASI). Dermatology-specific HRQoL was assessed with the Skindex-17 questionnaire. We used a Sankey diagram to illustrate the evolution of psoriasis severity during the first year of follow-up. To assess the association between psoriasis severity and the symptoms and psychosocial subscale of the Skindex-17, a linear regression analysis with hierarchical variable selection and zero-inflated negative binominal regression analysis were performed, respectively. Results We included 644 patients; 109 (17%) patients had no psoriasis (PASI = 0), 456 (71%) had mild psoriasis (PASI 12). Psoriasis severity did not fluctuate much during the first year. PASI was significantly associated with both subscales of the Skindex-17 at baseline and 12 months. Conclusion Psoriasis severity in PsA patients is mostly mild but impacts HRQoL when measured using a dermatology-specific HRQoL questionnaire. For optimal management of PsA patients, we recommend rheumatologists acquire information on skin burden by using a dermatology-specific HRQoL questionnaire.

ObjectivesIn patients with rheumatoid arthritis (RA), high disease activity impairs fertility outcomes and increases the risk of adverse pregnancy outcomes. The aim of this study was to determine the feasibility of a modern treatment approach, including treat-to-target (T2T) and the prescription of tumour necrosis factor (TNF) inhibitors, in patients with RA with a wish to conceive or who are pregnant.MethodsPatients were derived from the Preconception Counseling in Active RA (PreCARA) cohort. Patients with a wish to conceive or who are pregnant were treated according to a modified T2T approach, in which the obvious restrictions of pregnancy were taken into account. Results of the PreCARA study were compared with results of the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) study, a historic reference cohort on RA during pregnancy. Patients in the PARA cohort were treated according to the standards of that time (2002–2010). Differences in disease activity over time between the two cohorts were tested using a linear mixed model.Results309 patients with RA were included in the PreCARA study, 188 children were born. 47.3% of the patients used a TNF inhibitor at any time during pregnancy. Mean disease activity over time in the PreCARA cohort was lower than in the reference cohort (pConclusionsThis first study on a modern treatment approach in pregnant patients with RA shows that LDA and remission are an attainable goal during pregnancy, with 90.4% of patients achieving this in the third trimester.

The goals of this study were to examine whether machine-learning algorithms outperform multivariable logistic regression in the prediction of insufficient response to methotrexate (MTX), secondly, to examine which features are essential for correct prediction, and finally, to investigate whether the best performing model specifically identifies insufficient responders to MTX (combination) therapy. The prediction of insufficient response (3-month Disease Activity Score 28-Erythrocyte-sedimentation rate (DAS28-ESR) &gt, 3.2) was assessed using logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, and extreme gradient boosting (XGBoost). The baseline features of 355 rheumatoid arthritis (RA) patients from the &ldquo, treatment in the Rotterdam Early Arthritis CoHort&rdquo, (tREACH) and the U-Act-Early trial were combined for analyses. The model performances were compared using area under the curve (AUC) of receiver operating characteristic (ROC) curves, 95% confidence intervals (95% CI), and sensitivity and specificity. Finally, the best performing model following feature selection was tested on 101 RA patients starting tocilizumab (TCZ)-monotherapy. Logistic regression (AUC = 0.77 95% CI: 0.68&ndash, 0.86) performed as well as LASSO (AUC = 0.76, 95% CI: 0.67&ndash, 0.85), random forest (AUC = 0.71, 95% CI: 0.61 = 0.81), and XGBoost (AUC = 0.70, 95% CI: 0.61&ndash, 0.81), yet logistic regression reached the highest sensitivity (81%). The most important features were baseline DAS28 (components). For all algorithms, models with six features performed similarly to those with 16. When applied to the TCZ-monotherapy group, logistic regression&rsquo, s sensitivity significantly dropped from 83% to 69% (p = 0.03). In the current dataset, logistic regression performed equally well compared to machine-learning algorithms in the prediction of insufficient response to MTX. Models could be reduced to six features, which are more conducive for clinical implementation. Interestingly, the prediction model was specific to MTX (combination) therapy response.

ObjectiveThe aim of the current study was to evaluate the 2-year cost-utility ratio between tapering conventional synthetic disease-modifying antirheumatic drugs (csDMARD) first followed by the tumour necrosis factor (TNF)-inhibitor, or vice versa, in patients with rheumatoid arthritis (RA).MethodsTwo-year data of the Tapering strategies in Rheumatoid Arthritis trial were used. Patients with RA, who used both a csDMARD and a TNF-inhibitor and had a well-controlled disease (disease activity score ≤2.4 and swollen joint count≤1) for at least 3 months, were randomised into gradual tapering the csDMARD first followed by the TNF-inhibitor, or vice versa. Quality-adjusted life years (QALYs) were derived from the European Quality of life questionnaire with 5 dimensions. Healthcare and productivity costs were calculated with data from patient records and questionnaires. The incremental cost-effectiveness ratio and the incremental net monetary benefit were used to assess cost effectiveness between both tapering strategies.Results94 patients started tapering their TNF-inhibitor first, while the other 95 tapered their csDMARD first. QALYs (SD) were, respectively, 1.64 (0.22) and 1.65 (0.22). Medication costs were significantly lower in the patients who tapered the TNF-inhibitor first, while indirect cost were higher due to more productivity loss (p=0.10). Therefore, total costs (SD) were €38 833 (€39 616) for tapering csDMARDs first, and €39 442 (€47 271) for tapering the TNF-inhibitor (p=0.88). For willingness-to-pay (WTP) levels €83 800 tapering the TNF-inhibitor first has the highest probability.ConclusionOur economic evaluation shows that costs are similar for both tapering strategies. Regardless of the WTP, tapering either the TNF-inhibitor or the csDMARD first is equally cost effective.Trial registration numberNTR2754.

Objective: Interleukin-17A (IL-17A) and tumor necrosis factor (TNF) contribute to the pathogenesis of psoriatic arthritis (PsA). However, their functional relationship in PsA synovitis has not been fully elucidated. Additionally, although CD8+ T cells in PsA have been recognized via flow cytometry as a source of IL-17A production, it is not clear whether CD8+ T cells secrete IL-17A under more physiologically relevant conditions in the context from PsA synovitis. This study was undertaken to clarify the roles of IL-17A and TNF in the synovial fluid (SF) from patients with PsA and investigate the impact of CD8+ T cells on IL-17A production. Methods: IL-17A+ T cells were identified by flow cytometry in SF samples from 20 patients with active PsA, blood samples from 22 treatment-naive patients with PsA, and blood samples from 22 healthy donors. IL-17A+ T cells were sorted from 12 PsA SF samples and stimulated using anti-CD3/anti-CD28 or phorbol myristate acetate (PMA) and ionomycin ex vivo, alone (n = 3) or together with autologous monocytes (n = 3) or PsA fibroblast-like synoviocytes (FLS) (n = 5–6). To evaluate the differential allogeneic effects of neutralizing IL-17A and TNF, SF CD4+ T cells and PsA FLS cocultures were also used (n = 5–6). Results: Flow cytometry analyses of SF samples from patients with PsA showed IL-17A positivity for CD4+ and CD8+ T cells (IL-17A, median 0.71% [interquartile range 0.35–1.50%] in CD4+ cells; median 0.44% [interquartile range 0.17–1.86%] in CD8+ T cells). However, only CD4+ T cells secreted IL-17A after anti-CD3/anti-CD28 activation, when cultured alone and in cocultures with PsA monocytes or PsA FLS (each P < 0.05). Remarkably, CD8+ T cells only secreted IL-17A after 4- or 72-hour stimulation with PMA/ionomycin. Anti–IL-17A and anti-TNF treatments both inhibited PsA synovitis ex vivo. Neutralizing IL-17A strongly inhibited IL-6 (P < 0.05) and IL-1β (P < 0.01), while anti-TNF treatment was more potent in reducing matrix metalloproteinase 3 (MMP-3) (P < 0.05) and MMP-13. Conclusion: CD8+ T cells, in contrast to CD4+ T cells, in SF specimens obtained from PsA patients did not secrete IL-17A following T cell receptor activation. Overlapping, but distinct, effects at the level of inflammatory cytokines and MMPs were found after neutralizing IL-17A or TNF ex vivo in a human model of PsA synovitis.

Background Information about the possible effect of rheumatic diseases on male sexual function and reproduction (sexual health) is scarce and difficult to summarize. Factors known to impair sexual health, such as inflammation, medication use and hypogonadism can be present in a significant proportion of male patients with rheumatic diseases. Objectives The objective of our study was to systematically review the literature for the influence of paternal rheumatic disease on sexual health, such as sexual function, reproductive hormones, male fertility, pregnancy and offspring outcomes. Data sources English language articles identified through Embase, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Google Scholar and the Clinical trial registries of Europe and the USA published until February 2019. Study appraisal and synthesis methods Literature was synthesized in narrative form and in summary tables. Outcomes were categorized as: sexual function, reproductive hormones, fertility and pregnancy and offspring outcomes. Results are presented per category and per disease. Results 9735 articles were identified with our search strategy. After removal of duplicates, excluding articles by screening titles and abstracts and assessing eligibility by reading 289 fulltext articles, 87 articles fulfilled the eligibility criteria. All included studies enrolled patients diagnosed with a rheumatic disease and had results at least on one of the outcome categories. Sexual function was the most common category, followed by reproductive hormones, fertility and pregnancy and offspring outcomes. Sexual function is impaired in a high proportion of patients with rheumatic diseases. This was statistically significant in most of the studies where a control group was available. Clinically relevant abnormalities in reproductive hormones were mainly identified in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and a positive correlation with disease activity were reported. Semen quality in men with rheumatic diseases can be impaired in patients with SLE, SpA, sarcoidosis, BD and MWS. Sperm count and motility were the most common semen quality parameters affected. No negative effect of paternal RA and vasculitis on pregnancy outcomes were reported in 3 studies. No studies reporting the effect of paternal disease on offspring outcomes were identified. Limitations Most of the studies included in this review suffer from an inconsistent methodological quality, definitions of outcomes varied in several studies, a wide variety of screening questionnaires and/or diagnostic tools were used and results might only apply to the specific populations that were studied. Conclusions This systematic review suggests that sexual health is impaired in men with rheumatic diseases. The degree and extent of sexual health impairment vary per disease. More research is needed to fully understand the link between rheumatic diseases and impaired male sexual health. Meanwhile, rheumatologists should be aware of this association and discuss it with their patients. Implications of key findings Sexual health of men with rheumatic diseases can be impaired by the disease itself. Especially in men trying to conceive, information on sexual function, reproductive hormones and sperm quality are needed to identify these problems. Treatment resulting in lower disease activity can improve overall sexual health in man with rheumatic diseases and facilitate their journey to fatherhood. Systematic review registration number PROSPERO 2018 CRD42018099845.

Achieving low disease activity (LDA) is important in patients with psoriatic arthritis. It is of value to know if health-related quality of life (HRQoL) of patients who reached musculoskeletal low disease activity can be further improved by additionally achieving remission of their psoriasis. So, the aim of this study was to assess HRQoL in patients with active psoriasis who reached disease activity in psoriatic arthritis (DAPSA) LDA after one year of follow-up.Data were collected from the Dutch south west Psoriatic Arthritis cohort. Musculoskeletal disease activity was measured using DAPSA. Patients who reached DAPSA-LDA after one year were divided based on reaching psoriasis remission (Psoriasis Area and Severity Index [PASI]1). HRQoL and work productivity were compared between both groups.After one year, 230 (44%) patients with active psoriasis at baseline reached DAPSA-LDA, of which 108 (47%) patients achieved psoriasis remission. The group of patients with active psoriasis (n=122, 53%) contained more men (p=0.023) and scored lower on the 12-item Psoriatic Arthritis Impact of Disease questionnaire (p=0.012). On the Skindex-17 psychosocial subscale, 31% experienced moderate to high impairment and on the symptoms subscale 28% experienced a lot of symptoms. Work productivity did not differ between both groups.The majority of patients with DAPSA-LDA and active psoriasis after one year has a good HRQoL. However, a proportion of these patients still experiences considerable skin burden. We recommend rheumatologists to continue assessing and treating psoriasis to reduce skin burden in PsA patients who achieved musculoskeletal low disease activity.

Background: Considering the importance of getting the right patient at the right location to maintain and optimize quality of life of inflammatory arthritis patients, appropriate referral by general practitioners is essential. This study aims to assess the effect and cost effectiveness of different referral strategies for inflammatory arthritis in primary care patients. Methods: This study follows a cluster randomized controlled trial design. General practitioners from primary care centers in Southwest-The Netherlands are randomly assigned to either one of the two strategic interventions for referring adult patients who are in the opinion of the general practitioner suspected of inflammatory arthritis: 1) Standardized digital referral algorithm based on existing referral models PEST, CaFaSpA and CARE; 2) Triage by a rheumatologist in the local primary care center. These interventions will be compared to a control group, e.g. usual care. The primary outcome is the percentage of patients diagnosed with inflammatory arthritis by the rheumatologist. Secondary outcomes are quality of life as a patient reported outcome, work participation and healthcare costs. These data, including demographic and clinical parameters, are prospectively collected at baseline, three, six, and twelve months. Discussion: If this study can demonstrate improvements in appropriate referrals to the rheumatologist, thereby improving cost-effectiveness, there is sufficient supporting evidence to implement one of the referral strategies as a standard of care. Finally, with these optimization strategies a higher quality of care can be achieved, that might be of value for all patients with arthralgia. Trial Registration: NCT03454438, date of registration: March 5, 2018. Retrospectively registered: https://clinicaltrials.gov/ct2/show/NCT03454438?term=NCT03454438&draw=1&rank=1.

ObjectivesThe impact of inflammatory arthritis (IA) on male fertility remains unexplored. Our objective was to evaluate the impact of IA on several male fertility outcomes; fertility rate (number of biological children per man), family planning, childlessness and fertility problems.MethodsWe performed a multicentre cross-sectional study (iFAME-Fertility). Men with IA 40 years or older who indicated that their family size was complete were invited to participate. Participants completed a questionnaire that included demographic, medical and fertility-related questions. To analyse the impact of IA on fertility rate, patients were divided into groups according to the age at the time of their diagnosis: ≤30 years (before the peak of reproductive age), between 31 and 40 years (during the peak) and ≥41 years (after the peak).ResultsIn total 628 participants diagnosed with IA were included. Men diagnosed ≤30 years had a lower mean number of children (1.32 (SD 1.14)) than men diagnosed between 31 and 40 years (1.60 (SD 1.35)) and men diagnosed ≥41 years (1.88 (SD 1.14)).This was statistically significant (p=0.0004).The percentages of men diagnosed ≤30 and 31–40 years who were involuntary childless (12.03% vs 10.34% vs 3.98%, p=0.001) and who reported having received medical evaluations for fertility problems (20.61%, 20.69% and 11.36%, p=0.027) were statistically significant higher than men diagnosed ≥41 years.ConclusionsThis is the first study that shows that IA can impair male fertility. Men diagnosed with IA before and during the peak of reproductive age had a lower fertility rate, higher childlessness rate and more fertility problems. Increased awareness and more research into the causes behind this association are urgently needed.

AimTo identify differentially methylated positions (DMPs) and regions (DMRs) that predict response to Methotrexate (MTX) in early rheumatoid arthritis (RA) patients.Materials and methodsDNA from baseline peripheral blood mononuclear cells was extracted from 72 RA patients. DNA methylation, quantified using the Infinium MethylationEPIC, was assessed in relation to response to MTX (combination) therapy over the first 3 months.ResultsBaseline DMPs associated with response were identified; including hits previously described in RA. Additionally, 1309 DMR regions were observed. However, none of these findings were genome-wide significant. Likewise, no specific pathways were related to response, nor could we replicate associations with previously identified DMPs.ConclusionNo baseline genome-wide significant differences were identified as biomarker for MTX (combination) therapy response; hence meta-analyses are required.

This study aimed to identify baseline metabolic biomarkers for response to methotrexate (MTX) therapy in rheumatoid arthritis (RA) using an untargeted method. In total, 82 baseline plasma samples (41 insufficient responders and 41 sufficient responders to MTX) were selected from the Treatment in the Rotterdam Early Arthritis Cohort (tREACH, trial number: ISRCTN26791028) based on patients&rsquo, EULAR response at 3 months. Metabolites were assessed using high-performance liquid chromatography-quadrupole time of flight mass spectrometry. Differences in metabolite concentrations between insufficient and sufficient responders were assessed using partial least square regression discriminant analysis (PLS-DA) and Welch&rsquo, s t-test. The predictive performance of the most significant findings was assessed in a receiver operating characteristic plot with area under the curve (AUC), sensitivity and specificity. Finally, overrepresentation analysis was performed to assess if the best discriminating metabolites were enriched in specific metabolic events. Baseline concentrations of homocystine, taurine, adenosine triphosphate, guanosine diphosphate and uric acid were significantly lower in plasma of insufficient responders versus sufficient responders, while glycolytic intermediates 1,3-/2,3-diphosphoglyceric acid, glycerol-3-phosphate and phosphoenolpyruvate were significantly higher in insufficient responders. Homocystine, glycerol-3-phosphate and 1,3-/2,3-diphosphoglyceric acid were independent predictors and together showed a high AUC of 0.81 (95% CI: 0.72&ndash, 0.91) for the prediction of insufficient response, with corresponding sensitivity of 0.78 and specificity of 0.76. The Warburg effect, glycolysis and amino acid metabolism were identified as underlying metabolic events playing a role in clinical response to MTX in early RA. New metabolites and potential underlying metabolic events correlating with MTX response in early RA were identified, which warrant validation in external cohorts.

ObjectivesTo evaluate the 2-year clinical effectiveness of two gradual tapering strategies. The first strategy consisted of tapering the conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) first (i.e., methotrexate in ~90%), followed by the tumour necrosis factor inhibitor (TNF-inhibitor), the second strategy consisted of tapering the TNF-inhibitor first, followed by the csDMARD.MethodsThis multicentre single-blinded randomised controlled trial included patients with rheumatoid arthritis (RA) with well-controlled disease for ≥3 consecutive months, defined as a Disease Activity Score (DAS) measured in 44 joints ≤2.4 and a swollen joint count ≤1, which was achieved with a csDMARD and a TNF-inhibitor. Eligible patients were randomised into gradual tapering the csDMARD followed by the TNF-inhibitor, or vice versa. The primary outcome was the number of disease flares. Secondary outcomes were DMARD-free remission (DFR), DAS, functional ability (Health Assessment Questionnaire Disability Index (HAQ-DI)) and radiographic progression.Results189 patients were randomly assigned to tapering their csDMARD (n=94) or TNF-inhibitor (n=95) first. The cumulative flare rate after 24 months was, respectively, 61% (95% CI 50% to 71%) and 62% (95% CI 52% to 72%). The patients who tapered their csDMARD first were more often able to go through the entire tapering protocol and reached DFR more often than the group that tapered the TNF-inhibitor first (32% vs 20% (p=0.12) and 21% vs 10% (p=0.07), respectively). Mean DAS and HAQ-DI over time, and radiographic progression did not differ between groups (p=0.45, p=0.17, p=0.8, respectively).ConclusionThe order of tapering did not affect flare rates, DAS or HAQ-DI. DFR was achievable in 15% of patients with established RA, slightly more frequent in patients that first tapered csDMARDs. Because of similar effects from a clinical viewpoint, financial arguments may influence the decision to taper TNF-inhibitors first.

Aim: To study the performance of a clinical pharmacogenetic model for the prediction of nonresponse in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) in combination with other synthetic or biologic disease-modifying anti-rheumatic drugs . This prediction model includes gender, smoking status, rheumatoid factor positivity and four genetic variants in AMPD1 (rs17602729), ATIC (rs2372536), ITPA (rs1127354) and MTHFD1 (rs17850560). Methods: A total of 314 RA patients from three Dutch studies were retrospectively included. Eligible patients were adults diagnosed with RA and had a treatment duration with MTX and follow-up for at least two study evaluation visits. Prediction model risk scores at the first and second evaluation were calculated and compared with the actual nonresponse (disease activity score >2.4). Regression and receiver operating characteristic curve analyses of the prediction model were performed. Also, the sensitivity, specificity and the positive and negative predictive values (PPV and NPV) were determined. Results: The receiver operating characteristic area under the curve was 75% at first and 70% after second evaluation. At the second evaluation, prediction nonresponse had a sensitivity of 67% (CI: 54–78%), specificity of 69% (CI: 60–77%), PPV of 52% (CI: 45–60%) and NPV of 80% (CI: 73–85%). Conclusions: This study demonstrates that the clinical pharmacogenetic model has an inadequate performance for the prediction of nonresponse to MTX in RA patients treated with combination therapies.

ObjectivesThe main objective of this study was to determine whether the DNA methylation profile of children born to mothers with rheumatoid arthritis (RA) is different from that of children born to mothers from the general population. In addition, we aimed to determine whether any differences in methylation are associated with maternal RA disease activity or medication use during pregnancy.MethodsFor this study, genome-wide DNA methylation was measured at cytosine-phosphate-guanine (CpG) sites, using the Infinium Illumina HumanMethylation 450K BeadChip, in 80 blood samples from children (mean age=6.8 years) born to mothers with RA. As controls, blood samples from 354 children (mean age=6.0 years) from the population-based Generation R Study were used. Linear mixed models were performed to investigate differential methylation between the groups, corrected for relevant confounders.ResultsA total of 147 CpGs were differentially methylated between blood samples of children born to mothers with RA and the control blood samples. The five most significantly associated CpGs were cg06642177, cg08867893, cg06778273, cg07786668 and cg20116574. The differences in methylation were not associated with maternal RA disease activity or medication use during pregnancy.ConclusionsDNA methylation at 147 CpGs differed between children born to mothers with RA and children born to mothers from the general population. It remains unknown whether the identified associations are causal, and if so whether they are caused by the disease or treatment. More research, including replication of these results, is necessary in order to strengthen the relevance of our findings for the later-life health of children born to mothers with RA.

Objectives: We aimed to describe sonographic structural and inflammatory changes in entheses of patients with recently diagnosed psoriatic arthritis (PsA), patients with established PsA, and young healthy volunteers, and to investigate whether the MAdrid Sonographic Enthesitis Index (MASEI) enables us to distinguish these groups in an extreme comparison. Method: New and established PsA patients and healthy volunteers (aged 20–30 years) were recruited. The triceps, quadriceps, patellar, Achilles and elbow extensor tendon insertion, and plantar fascia entheses were investigated sonographically for structural changes, erosions, calcifications, increased thickness, bursitis, and power Doppler (PD) signal according to the MASEI. Results: The study included 25 new and 25 established PsA patients, and 25 healthy volunteers. Increased thickness and PD signal in knee entheses were common for patients and healthy volunteers, while changes at other locations predominantly occurred in patients only. PD was recoded (1, one spot; 1.5, two or three spots; 2, confluent signal; 3, severe confluent signal) and thickness of knee entheses excluded. This resulted in different modified MASEI scores between PsA patients and young healthy controls: median (interquartile range) modified MASEI of 13 (10–22.5) in new PsA, 13.5 (9.5–18) in established PsA, and 3 (1–8.5) in healthy volunteers (p = 0.002). Conclusions: Structural ultrasound changes and PD in entheses are common in both new and established PsA and healthy controls. MASEI score did not differentiate PsA patients from young healthy volunteers. After recoding of PD severity and excluding thickness of knee entheses, marked differences between PsA patients and healthy controls were observed.

Background At present, there are no prognostic parameters unequivocally predicting treatment failure in early rheumatoid arthritis (RA) patients. We investigated whether baseline ultrasonography (US) findings of joints, when added to baseline clinical, laboratory, and radiographical data, could improve prediction of failure to achieve Disease Activity Score assessing 28 joints (DAS28) remission (

Objective.Psoriatic arthritis (PsA) is a multifaceted disease. Affecting joints, skin, entheses, and dactylitis, its effect on health-related quality of life (HRQOL) could be substantial. We aim to assess HRQOL in patients newly diagnosed with PsA and analyze its associations with disease manifestations.Methods.Data collected at time of diagnosis from patients with PsA included in the Dutch south-west Early Psoriatic Arthritis cohort (DEPAR) study were used. HRQOL was assessed using 8 domains of the Medical Outcomes Study Short Form-36 (SF-36) questionnaire. Patients were classified based on primary manifestation in arthritis subtypes (i.e., mono-, oligo-, or polyarthritis) and other subtypes (i.e., enthesitis, dactylitis, and axial disease). In all patients, presence of arthritis, enthesitis, dactylitis, psoriasis, and chronic inflammatory back pain was determined. Multivariable linear regression was used to determine associations of PsA manifestations with HRQOL.Results.Of 405 patients, primary manifestation was peripheral arthritis in 320 (78 monoarthritis, 151 oligoarthritis, and 91 polyarthritis), enthesitis in 37, axial disease in 9, and dactylitis in 39. Mean scores of SF-36 domains were lower than the Dutch reference population and similar across arthritis subtypes. A higher number of enthesitis locations and tender joints, and presence of chronic back pain, were independently associated with worse SF-36 scores. Psoriasis and dactylitis were not associated with worse scores.Conclusion.HRQOL was diminished in PsA at time of diagnosis compared to the Dutch reference population, and tender joints, enthesitis at clinical examination, and back pain as indicators of pain affected HRQOL.

textabstractAIMS: To explore how young people with juvenile-onset rheumatic and musculoskeletal diseases (jRMDs) and their parent(s) experience care during preparation for the upcoming transfer to adult services, and to develop a clinical transition pathway.METHOD: A survey was conducted with 32 young people aged between 14 and 20 years with jRMDs, and their parents ( n =33), treated at the department of paediatric rheumatology in a tertiary care children's hospital in the Netherlands.RESULTS: More than 30% of young people would have liked to discuss topics such as educational and vocational choices in a clinic, but did not get the opportunity. Preparation for transition was poor as was training in self-management skills. One third of parents had feelings of anxiety about the upcoming transfer. Results from the survey and evidence-based principles of transitional care were used to develop the clinical transition pathway. The pathway focuses on starting transition early, developing self-management skills, joint consultations and supporting parents in giving young people control of their clinical care.CONCLUSION: Care does not currently meet the needs of young people in the process of transition to adult rheumatology services. The clinical transition pathway developed as a result of the study is a tool that may improve this process.

Early recognition of joint inflammation will increase treatment efficacy in rheumatoid arthritis (RA). Yet, conventional power Doppler (PD) ultrasound might not be sufficiently sensitive to detect minor inflammation. We investigated the sensitivity of high-frame rate Doppler, combined with singular value decomposition technique, to suppress tissue signals, for microvascular flow in a flow phantom setup and in a proof-of-principle study in healthy controls and in RA patients with different disease activities. In the flow phantom, minimal detectable flow velocity was a factor 3 lower with high-frame-rate PD than with conventional PD ultrasound. In the proof-of-principle study we detected a positive PD signal in all volunteers, diseased or healthy, with high-frame-rate PD ultrasound. We saw a gradual increase in PD signal in RA patients depending on disease activity. In conclusion, high-frame rate Doppler is more sensitive in detecting vascularisation than conventional PD ultrasound.

Objective To identify a combination of clinical factors associated with low disease activity and remission in the third trimester during pregnancy in women with rheumatoid arthritis (RA). Methods This study is embedded in the Pregnancy-Induced Amelioration of Rheumatoid Arthritis study, a prospective cohort study. There were data available on 190 pregnancies from first trimester until delivery. Multivariate regression analyses were performed on the disease activity (Disease Activity Score in 28 joints [DAS28] using the C-reactive protein [CRP] level) in the third trimester. Independent covariates were the DAS28-CRP-3 in first trimester, prednisone and sulfasalazine use in the first trimester, parity, methotrexate use in the past, autoantibody status, the presence of erosions, and RA disease duration. Results In multivariate regression models, the DAS28-CRP-3, use of prednisone in the first trimester, and the presence of autoantibodies were negatively associated with low disease activity (DAS28-CRP-3

Glucocorticoids are given during pregnancy when rheumatoid arthritis (RA) is too active. It could lead to increased risk of cardiovascular diseases (CVD) and type 2 diabetes mellitus (T2DM) in the offspring. Elevated RA disease activity during pregnancy is associated with low birth weight and rapid post-natal growth. Both can negatively influence the body composition later in life. This study shows that prednisone use or RA disease activity in pregnant women with RA had no influence on the body composition of prepubertal offspring. Furthermore, no components of the metabolic syndrome (MetS) were present in the children, which minimalize the change on CVD or T2DM later in life. This reassuring conclusion might lead to a different therapeutic view when glucocorticoid treatment during pregnancy is inevitable.

Objective Subfertility is frequently encountered among female rheumatoid arthritis (RA) patients and has been associated with disease activity and antirheumatic drugs. However, little is known about the results of the fertility assessments in these women. Our aim was to study the outcome of fertility assessments in subfertile women with RA. Methods A cross-sectional study was performed in a nationwide cohort of female RA patients who were pregnant or trying to conceive between 2002 and 2010 (Pregnancy-Induced Amelioration of Rheumatoid Arthritis Study). Patients who had given consent for future contact (n = 260) received a questionnaire on reproductive history, fertility examinations, and fertility treatments. Medical files were obtained from attending gynecologists. Results A completed questionnaire was returned by 178 women (68%), of whom 96% had ended their efforts to conceive. Eighty-two subjects (46%) had at least 1 subfertile episode, and for 61 women a diagnosis for subfertility was available. Unexplained subfertility (48%) and anovulation (28%) were the most common gynecologic diagnoses, and both occurred more often in RA patients than reported in the general population. Women with unexplained subfertility more often used nonsteroidal antiinflammatory drugs (NSAIDs) during the periconceptional period. Seventeen percent of all pregnancies were conceived after fertility treatments. Fertility treatments had equal or higher pregnancy rates in RA compared to other subfertile populations. Conclusion Unexplained subfertility is more often diagnosed in subfertile female RA patients than in the general population, and is related to periconceptional NSAID use. Despite the higher incidence of subfertility in women with RA, the outcome of fertility treatments in these women appears favorable.

OBJECTIVE: . To compare the screening performance of the Psoriasis Epidemiology Screening Tool (PEST), Psoriatic Arthritis Screening and Evaluation (PASE) and Early Arthritis for Psoriatic Patients (EARP) questionnaires for detecting PsA among psoriasis patients in a primary care setting.METHODS: In a cross-sectional study, 473 primary care psoriasis patients at risk for PsA completed the PEST, PASE and EARP questionnaires and were clinically evaluated by a trained research nurse. A PsA case was defined by a rheumatologist according to the CASPAR criteria. Sensitivity and specificity were determined for the PEST and EARP cut-offs (⩾3) and the PASE cut-offs (⩾44 and ⩾47).RESULTS: PsA was diagnosed in 53 patients. The PEST had a sensitivity of 0.68 and a specificity of 0.71. The PASE was validated for two different cut-offs. The cut-off of 47 led to a sensitivity of 0.59 and a specificity of 0.66, whereas the lower cut-off of 44 led to a sensitivity of 0.66 and a specificity of 0.57. For the EARP we found a sensitivity of 0.87 with a specificity of 0.34.CONCLUSION: The PEST questionnaire has the most favourable trade-off between sensitivity and specificity to screen for PsA. However, as the prevalence of psoriasis and PsA is fairly low in primary care, screening only psoriasis patients with musculoskeletal complaints may be a better allocation of resources.

BACKGROUND: A substantial number of patients with chronic low back pain (CLBP) have axial spondyloarthritis (axSpA), but early recognition of these patients is difficult for general practitioners (GPs). The Case Finding Axial Spondyloarthritis (CaFaSpA) referral strategy has shown to be able to identify patients with CLBP at risk for axSpA, but its impact on clinical daily practice is yet unknown.OBJECTIVE: To assess the effect of the CaFaSpA referral strategy on pain caused by disability in primary care patients with CLBP.METHODS: Within this clustered randomized controlled trial 93 general practices were randomized to either the CaFaSpA referral model (intervention) or usual primary care (control). In each group primary care patients between 18 and 45 years with CLBP were included. The primary outcome was disability caused by CLBP, measured with the Roland Morris Disability Questionnaire (RMDQ) at baseline and four months. Secondary outcome was the frequency of new axSpA diagnosis. Descriptive analyses were performed, and a linear mixed-effects model was used.RESULTS: In total 679 CLBP patients were included of which 333 patients were allocated to the intervention group and 346 to the control group. Sixty-four percent were female and mean age was 36.2 years. The mean RMDQ score at baseline was 8.39 in the intervention group and 8.61 in the control group. At four months mean RMDQ score was 7.65 in the intervention group and 8.15 in the control group. This difference was not statistically significant (p = 0.50). Six (8%) out of the 75 finally referred patients, were diagnosed with axSpA by their rheumatologist.CONCLUSIONS: The CaFaSpA referral strategy for axSpA did not have an effect on disability after four months caused by CLBP. However, the strategy is able to detect the axSpA patient within the large CLBP population sufficiently. Trial registration number: NCT01944163, Clinicaltrials.gov.

Objective.Many factors influence a patient’s preference in engaging in shared decision making (SDM). Several training programs have been developed for teaching SDM to physicians, but none of them focused on the patients’ preferences. We developed an SDM training program for rheumatologists with a specific focus on patients’ preferences and assessed its effects.Methods.A training program was developed, pilot tested, and given to 30 rheumatologists. Immediately after the training and 10 weeks later, rheumatologists were asked to complete a questionnaire to evaluate the training. Patients were asked before and after the training to complete a questionnaire on patient satisfaction.Results.Ten weeks after the training, 57% of the rheumatologists felt they were capable of estimating the need of patients to engage in SDM, 62% felt their communication skills had improved, and 33% reported they engaged more in SDM. Up to 268 patients were included. Overall, patient satisfaction was high, but there were no statistically significant differences in patient satisfaction before and after the training.Conclusion.The training was received well by the participating rheumatologists. Even in a population of rheumatologists that communicates well, 62% reported improvement. The training program increased awareness about the principles of SDM in patients and physicians, and improved physicians’ communicative skills, but did not lead to further improvement in patients’ satisfaction, which was already high.

ObjectiveRheumatoid arthritis (RA) often affects women in their fertile age, and is known to compromise female fertility. Serum anti-Müllerian hormone (AMH) levels are a proxy for the total number of primordial follicles, and a reliable predictor of the age at menopause. Our objective was to study the longitudinal intra-individual decline of serum AMH levels in female RA patients.MethodsFemale RA patients from a nationwide prospective cohort (2002–2008) were re-assessed in 2015–2016. Serum AMH levels were measured using the picoAMH assay and compared with healthy controls. A linear mixed model (LMM) was built to assess the effect of RA-related clinical factors on the decline of AMH levels.ResultsA group of 128 women were re-assessed at an age of 42.6±4.4 years, with a median disease duration of 15.8 (IQR 12.7–21.5) years. The time between first and last AMH assessments was 10.7±1.8 (range 6.4–13.7) years. Participants represented a more fertile selection of the original cohort. At follow-up, 39% of patients had AMH levels below the 10th percentile of controls (95% CI 31% to 48%), compared with 16% (95% CI 9.3% to 22%) at baseline. The LMM showed a significant decline of AMH with increasing age, but no significant effect of RA-related factors on AMH.ConclusionAMH levels in RA patients showed a more pronounced decline over time than expected, supporting the idea that in chronic inflammatory conditions, reproductive function is compromised, resulting in a faster decline of ovarian function over time and probably an earlier age at menopause.

ObjectivesMethotrexate (MTX) is currently the recommended first-line therapy for treating psoriatic arthritis (PsA), despite lacking clear evidence. No estimates of efficacy of MTX in usual care and no clear MTX responsive clinical or laboratory variables are currently available. This study describes the response to MTX monotherapy in newly diagnosed patients with PsA in usual care. Second, we compared clinical variables and cytokine profiles in patients responding and not responding to MTX monotherapy.MethodsWe used data collected in the Dutch southwest Early Psoriatic Arthritis cohoRt study to select patients with PsA with oligoarthritis or polyarthritis, and at least 1 year follow-up. We analysed disease activity at 6 months of patients who started MTX monotherapy and still used MTX monotherapy 1 year after diagnosis. Cytokine profiles were determined at baseline and after 3 and 6 months with a bead-based multi-immunoassay.ResultsWe identified 219 patients of which 183 (84%) patients started MTX monotherapy within 6 months after diagnosis. 90 patients used MTX monotherapy throughout the first year of which 44 patients (24%) reached minimal disease activity(MDA) at 6 months, decreasing to 33 patients (18%) after 1 year. Non-responders had significantly higher concentrations of interleukin (IL) 23 and IL-10 before and during MTX therapy.ConclusionsOur results showed that only 18% of patients with PsA are in sustained MDA after 1 year of MTX monotherapy and non-responders more often had IL-23-driven disease. Our results indicate the need for more treat-to-target and personalised therapy strategies in PsA.

Background The effects of biologicals on reproduction are unknown. Therefore pregnancy during biologicals use is discouraged. However biologicals are frequently prescribed in patients of childbearing potential and many patients become pregnant while using these drugs. Objectives In 2015 EULAR published a broad review article on this matter. Our aim was to update the data based on newly published articles. Methods A search was conducted at 18/10/2017 and then 21/11/2018 in Embase, Medline Ovid, Web Of Science, Cochrane CENTRAL and Google Scholar with specific search terms for each database. Articles were excluded based on title/abstract (double blind, two researchers, NG and HJMJC) and then full text (one researcher, NG). A chart was made based on outcomes of interest(see Table1). The references of included articles were reviewed to include and minimize the missing articles. Results Totally 137 articles were included (79 articles at first round, 51 articles at second round and 7 found after screening the references of the included articles). A descriptive analysis was performed to sum up the data on each separate biological and all the biologicals together. The results are shown in Table1. It should be notified that due to heterogeneity of the data the calculated percentages are up to individual interpretations and cannot be compared to each other. Conclusion From 2015 onwards, there have been many articles published regarding use of biologicals during pregnancy. Despite limitations of our study, such as heterogeneity in being prospective or retrospective and quality of the included articles, no alarm is raised concerning safety issues. Disclosure of Interests Nafise Ghalandari: None declared, Radboud Dolhain Grant/research support from: UCB Pharma B.V, Johanna Hazes: None declared, Eugene van Puijenbroek: None declared, Manavi Kapur: None declared, Hubertina Johanna Maria Josephina Crijns: None declared

Background A substantial amount of patients with chronic low back pain (CLBP) have axial spondyloarthritis (axSpA), but early recognition of these patients is difficult for general practitioners (GPs).1 As a result, several referral strategies have been developed to help physicians identify patients at risk for axSpA within the large group of CLBP patients.2 Most referral strategies were developed in secondary care patients. The only referral strategy that was developed and validated in primary low back patients is the CaFaSpA strategy.3 An essential step before implementing referral strategies in daily clinical practice is the execution of an impact analysis.4 Objectives The purpose of this study is to assess the impact of using a referral strategy on patient outcomes in young primary care patients with CLBP at risk for axSPA. Methods A clustered randomized controlled trial was performed in a primary care setting (ClinicalTrials.gov Identifier: NCT01944163). Each cluster contained the general practices from a single primary care practice and their included patients. Clusters were randomized to either the intervention (use of CaFaSpA referral strategy) or the control group (usual care). Primary outcome was disability caused by CLBP, measured with the Roland Morris Disability Questionnaire (RMDQ) at baseline and 4 months. Secondary outcome was axSpA diagnosis made by a rheumatologist. A linear mixed-effects model was used to analyze mean change in RMDQ score. Results In total 679 patients were included within 93 GP clusters. Sixty-four percent of our study population were female and mean age was 36 years. Median RMDQ score at baseline was 8 (IQR 4-12) in both groups. Compared to baseline, mean RMDQ score decreased by 0.74 points at 4 months (intervention) and by 0.46 points (control) (Fig. 1). This decrease did not significantly differ between groups (p=0.50). Eight percent of the finally referred patients in the intervention group, received an axSPA diagnosis (8%) from the rheumatologist. The median RMDQ among patients who visited the rheumatologist decreased from 8 to 5 after 4 month. This was not statistically significant (p-value=0.17). Conclusion Although the CaFaSpA referral strategy did not have an early impact on disability caused by CLBP, it can be used as a screening strategy for GPs to identify axSpA patients. References [1] Jois RN, Macgregor AJ, Gaffney K. Recognition of inflammatory back pain and ankylosing spondylitis in PC. Rheumatology (Oxford) 2008;47:1364-1366. [2] Abawi O, van den Berg R, van der Heijde D, van Gaalen FA. Evaluation of multiple referral strategies for axial spondyloarthritis in the SPondyloArthritis Caught Early (SPACE) cohort. RMD Open 2017 Apr 7;3(1):e000389-2016-000389. eCollection 2017. [3] van Hoeven L, Vergouwe Y, de Buck PD, Luime JJ, Hazes JM, Weel AE. External Validation of a Referral Rule for Axial Spondyloarthritis in Primary Care Patients with Chronic Low Back Pain. PLoS One 2015 Jul 22;10(7):e0131963. [4] Moons KG. Kengne AP, Grobbee DE, Risk prediction models: II. External validation, model updating, and impact assessment. Heart. 2012;98(9):691-8. Bars indicate 95% confidence intervals for the mean estimates. Disclosure of Interests Maha Jamal Abdelkadir: None declared, Amber Korver: None declared, Martijn Kuijper: None declared, Deirisa Lopes Barreto: None declared, Cathelijne Appels: None declared, Anneke Spoorenberg Grant/research support from: Received unrestricted grants from Pfizer, Novartis and Abbvie pharmaceuticals. They had no influence in design and conduct of the study., Consultant for: Abbvie, Pfizer, MSD, UCB, and Novartis, Bart Koes: None declared, Johanna Hazes: None declared, Lonneke van Hoeven: None declared, Angelique Weel: None declared

Background Sexual function and reproduction are important aspects of quality of life for the majority of men (1,2). In the last decade inflammation has been associated with male factor infertility and sexual dysfunction (3,4). Because many patients with rheumatic diseases have a chronic state of inflammation, it is reasonable to believe that this can result in impaired sexual function and reproduction. Previous research on this topic in Rheumatology mainly focused on the effect of drugs on fertility parameters. Objectives Our objective is to summarize the information on the influence of rheumatic diseases on male sexual function and reproduction. Methods A systematic search of Embase, Medline, Web of science and Cochrane Central was carried out in May 2018 to find relevant papers. The search strategy was extensive and included a complete list of immune mediated diseases from Rheumatology, Dermatology and Gastroenterology and several keywords for our outcomes (sexual function, fertility and pregnancy outcome). This review was registered in PROSPERO(5). The search yielded 6568 articles. Titles and abstracts were screened independently by LP and JC, resulting in 177 papers selected for full text review. Methodological quality of the studies was assessed with the Newcastle Ottawa Scale (6). Results Regarding rheumatic diseases a total of 104 papers were included in the final analysis. 4 diseases (Spondyloarthropathies (SpA), Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis (SSc)) represented 60% of the articles. The overall quality of the studies was low to moderate. Sexual dysfunction (SD) is a common problem for patients with rheumatic diseases and it is usually undiagnosed. It was reported in approximately half of men with RA, SLE and SpA and in almost all the men diagnosed with SSc. It should be noted that, although in several studies increasing age was correlated with a higher prevalence and severity of SD, young patients with SpA or SLE can also be affected. Regarding fertility and reproduction, different results per disease were found. Hypogonadism might be a common problem in men with RA and SLE. Many men with SLE and RA have endocrine axis abnormalities. Interestingly, these disturbances were not detected in SpA patients (See Table 1). Semen quality abnormalities are frequent in SLE patients and this was found to be associated not only with medication toxicities but also with disease activity. The number of children of male patients diagnosed with SLE and SSc was lower than healthy controls. A brief summary of our findings per disease are presented in Figure 1. Conclusion Our findings suggest that not only medication can have detrimental effects on sexual function and reproduction of men with rheumatic diseases but also the disease itself. Therefore, clinicians should be aware of a high prevalence of sexual and reproduction problems in this population and take this into account when counseling them. More research focusing on this association is needed. References [1] Flynn KE, et al. The journal of sexual medicine. 2016;13(11):1642-50. [2] Ilacqua A, et al. Reprod Biol Endocrinol. 2018;16(1):115. [3] Haervig KK, et al.Hum Fertil (Camb). 2018;21(2):146-54. [4] Fijak M, et al. Hum Reprod Update. 2018 Jul 1;24(4):416-441 [5] Perez LF, et al. Retrived from: www.crd.york.ac.uk/prospero/display_record.php?RecordID=99845) [6] Wells GA, et al. Retrieved from: www.ohri.ca/programs/clinical_epidemiology/oxford.asp Disclosure of Interests Luis Fernando Perez: None declared, Bernke te Winkel: None declared, Juan Pablo Carrizales-Luna: None declared, Wichor Bramer: None declared, Saskia Vorstenbosch: None declared, Eugene van Puijenbroek: None declared, Johanna Hazes: None declared, Radboud Dolhain Grant/research support from: UCB Pharma B.V

Background: Methotrexate (MTX) is the preferred drug of most rheumatologists for treating psoriatic arthritis (PsA). Despite its widespread use in clinical practice, scientific evidence of methotrexate on the different manifestations of psoriatic disease is limited. Specifically, data of MTX use in usual care and in early PsA patients are lacking. Objectives: To describe the response to MTX for patients with PsA and an oligoarthritis or polyarthritis phenotype in usual care in the first year after diagnosis, and its impact on different aspects of the disease, including patients not achieving minimal disease activity (MDA) despite continuous exposure to MTX Methods: Data collected in the Dutch southwest Early Psoriatic Arthritis cohort (DEPAR) study were used. Patients with a new diagnosis of PsA who have not started disease-modifying antirheumatic drugs (DMARDs) for PsA were eligible to participate. In this analysis, only patients with a phenotype at time of diagnosis of oligoarthritis or polyarthritis (resp. 2-4 joints involved or 5 or more joints, as defined by the rheumatologist), and at least one year follow up were included. Research nurses collected clinical data and data on medication use every three months in the first year after diagnosis. The following outcomes were used to evaluate disease activity: MDA, EULAR active disease (at least one tender and swollen joint), disease activity index for PsA low disease activity (DAPSA-LDA: DAPSA≤14), and disease activity score 28 low disease activity (DAS28-LDA: DAS28≤3.2). Disease activity at six months of patients who started MTX within six months after diagnosis and have continued using MTX until one year after diagnosis was analyzed. Results: In April 2018, 219 patients had a phenotype of oligoarthritis (n=134, 61%) or polyarthritis (n=85, 39%) at time of diagnosis, and at least one year follow up. In 183 (84%) patients, MTX monotherapy was started within six months after diagnosis. Within the first year, 23 of these used MTX intermittently, 25 switched to a different DMARD, and 45 started a different DMARD while remaining on MTX therapy. The remaining 90 patients used MTX monotherapy throughout the first year and of these we assessed disease activity at 6 months after diagnosis. At 6 months, 38 patients out of these 90 were not in MDA despite continuous MTX treatment, while 44 achieved MDA. Major differences amongst the two groups included tender joint count, physical function, evaluation of pain and global disease activity and impact on health-related quality of life scores (Table 1). Conversely, 18% of all patients started MTX monotherapy were in sustained MDA at one year while continuing MTX monotherapy. Conclusion: The majority of patients with a new diagnosis of PsA with a phenotype of oligoarthritis or polyarthritis started MTX within a year after diagnosis. MTX is maintained as monotherapy in half of these patients, with 18% of them achieving sustained MDA using MTX monotherapy at one year. Interestingly, approximately half of the patients who had continued methotrexate monotherapy were not achieving MDA after six months and they report higher impact of disease on clinical and patient reported outcomes, suggesting need to consider improvement of therapy for these patients. Disclosure of Interests: Kim Wervers: None declared, Hannah den Braanker: None declared, Jolanda Luime: None declared, Ilja Tchetverikov: None declared, Andreas Gerards: None declared, Cathelijne Appels: None declared, Wiebo van der Graaff: None declared, Hans van Groenendael: None declared, Lindy-Anne Korswagen: None declared, Josien Veris-van Dieren: None declared, Johanna Hazes: None declared, Marc Kok: None declared, Marijn Vis Grant/research support from: Novartis

ObjectivesThe aim of this study is to evaluate the effectiveness of two tapering strategies after achieving controlled disease in patients with rheumatoid arthritis (RA), during 1 year of follow-up.MethodsIn this multicentre single-blinded (research nurses) randomised controlled trial, patients with RA were included who achieved controlled disease, defined as a Disease Activity Score (DAS) ≤ 2.4 and a Swollen Joint Count (SJC) ≤ 1, treated with both a conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and a TNF inhibitor. Eligible patients were randomised into gradual tapering csDMARDs or TNF inhibitors. Medication was tapered if the RA was still under control, by cutting the dosage into half, a quarter and thereafter it was stopped. Primary outcome was proportion of patients with a disease flare, defined as DAS > 2.4 and/or SJC > 1. Secondary outcomes were DAS, European Quality of Life-5 Dimensions (EQ5D) and functional ability (Health Assessment Questionnaire Disability Index [HAQ-DI]) after 1 year and over time.ResultsA total of 189 patients were randomly assigned to tapering csDMARDs (n = 94) or tapering anti-TNF (n = 95). The cumulative flare rates in the csDMARD and anti-TNF tapering group were, respectively, 33 % (95% CI,24% to 43 %) and 43 % (95% CI, 33% to 53 % (p = 0.17). Mean DAS, HAQ-DI and EQ-5D did not differ between tapering groups after 1 year and over time.ConclusionUp to 9 months, flare rates of tapering csDMARDs or TNF inhibitors were similar. After 1 year, a non-significant difference was found of 10 % favouring csDMARD tapering. Tapering TNF inhibitors was, therefore, not superior to tapering csDMARDs. From a societal perspective, it would be sensible to taper the TNF inhibitor first, because of possible cost reductions and less long-term side effects.Trial registration numberNTR2754

Background: Previous studies have shown that it is possible to taper DMARDs in RA patients with an inactive disease, but this is accompanied with a higher chance of disease flares. Current recommendations advise to taper DMARDs from a clinical viewpoint. However, data on the feasibility of tapering DMARDs from a patient’s perspective are sparse. Objectives: To determine the impact of flare after DMARD-tapering on patients quantifying the changes in patient relevant domains e.g. functional ability, fatigue, quality of life, and worker productivity, and to explore the duration of the effect. Methods: Data were used from all 113 patients that flared after tapering DMARDs in the TARA study, a multicenter randomised controlled trial in which patients in sustained remission (DAS Results: In total, 113 patients experienced a flare. Patients who had a flare had a less stable course of the outcomes over time, compared with patients without flare (Figure 1A-G). When comparing all time points to baseline, statistical significant differences were found for DAS44 (p Conclusion: Having a flare does affect patient reported outcomes. It affects DAS44, VAS general health, morning stiffness, functional ability, quality of life, and fatigue. This effect lasted for more than 6 months. Although we only found minor differences with baseline on group level, on the individual patient level this can still be of great importance. Disclosure of Interests: Elise van Mulligen: None declared, Angelique Weel: None declared, Martijn Kuijper: None declared, Johanna Hazes: None declared, Annette van der Helm - van Mil Grant/research support from: The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting grant, agreement No 714312) and from the Dutch Arthritis Foundation. The funding source had no role in the design and conduct of the study., Pascal de Jong: None declared

Objectives To induce disease remission, early arthritis patients should adhere to their disease-modifying antirheumatic drugs (DMARD) in the first months after diagnosis. It remains unknown why some patients are non-adherent. We aimed to identify patients at risk for non-adherence in the first 3 months of treatment . Methods Adult DMARD-naive early arthritis patients starting synthetic DMARDs filled out items on potential adherence predictors at baseline. Adherence was measured continuously. Non-adherence was defined as not opening the electronically monitored pill bottle when it should have been. Items were reduced and clustered using principal component analysis. The most discriminating items were identified with latent trait models. We used a multivariable logistic regression model to find non-adherence predictors. Results 301 patients agreed to participate. Adherence was high and declined over time. Principal component analysis led to 7 dimensions, while subsequent latent trait models analyses led to 15 dimensions. Two dimensions were associated with adherence, one dimension was associated with non-adherence. Conclusions Information seeking behavior and positive expectations about the course of the disease are associated with adherence. Patients who become passive because of pain are at risk for non-adherence. Practice implications Rheumatologists have cues to identify non-adherence, and may intervene on non-adherence through implementing shared decision making techniques.

__Objective:__ New opportunities have emerged for early diagnosis with the arrival of new technologies that assess the impact of genomics, proteomics, metabolomics, and cytomics on rheumatoid arthritis (RA) risk. This early health technology assessment study assesses the short-term cost effectiveness of 4 add-on diagnostic tests in early inflammatory arthritis patients at risk of RA. __Methods:__ We modeled 4 diagnostic add-on tests to the American College of Rheumatology/European League Against Rheumatism 2010 RA classification criteria, covering the first year after diagnosis, using Rotterdam Early Arthritis Cohort data. Sensitivity, specificity, and costs were assigned to the magnetic resonance imaging of hands and feet (sensitivity 0.90, specificity 0.60, cost €756), interleukin-6 (IL-6) serum level test (sensitivity 0.70, specificity 0.53, cost €50), B cell–related gene expression (sensitivity 0.60, specificity 0.90, cost €150), and gene assay for RA (sensitivity 0.40, specificity 0.85, cost €750), based on literature and expert opinion. Outcomes were evaluated using the unweighted diagnostic net benefit (UDNB) and the incremental cost-effectiveness ratio (ICER) in all patients (n = 552), intermediate-risk patients (n = 263), and seronegative patients (n = 329). __Results:__ The highest UDNB was found when using the B cell assay in intermediate-risk patients (43%, ICER €5,314), while the IL-6 test in seronegative patients resulted in the lowest UDNB (−11.4%, ICER €7,650). If a threshold of €20,000 is applied, the B cell assay would be preferred over the other alternatives, with a 78% probability of being cost effective for intermediate-risk patients, 57% for all patients, and 73% for seronegative patients. __Conclusion:__ Diagnostic add-on tests favoring specificity over sensitivity with a headroom less than €370 per test are cost effective, with the largest diagnostic benefit occurring in intermediate-risk patients.

In this issue of The Journal , Stevenson, et al present an economic model on the cost-effectiveness of biological disease-modifying antirheumatic drugs (bDMARD) for rheumatoid arthritis (RA) in patients who can tolerate methotrexate (MTX)1. Their work formed part of the evidence used by the UK National Institute for Health and Care Excellence (NICE) to update the technology appraisal guidance on the application of bDMARD in RA. In England, because prescription of bDMARD is restricted to patients with RA who have failed at least 2 conventional DMARD and have high disease activity [28-joint Disease Activity Score (DAS28) > 5.1], there was specific interest in the question of whether prescriptions should also be extended to those with moderate disease. The model presented is based on the healthcare setting in England and compares the continuous administration of nonbiological therapy to treatment with sequences of bDMARD in patients with moderate and moderate-to-severe RA. The authors report that the cost per quality-adjusted life-year (QALY) gained by bDMARD strategies over nonbiological DMARD treatment only was £41,600 (US $51,628) for patients with severe RA and £51,100 for patients with moderate to severe RA, a cost well beyond the generally accepted NICE threshold of £20,000–£30,000. In subanalyses, restricting biologicals to patients with the worst prognosis with non-biological therapy only, more favorable cost-effectiveness ratios were found: £25,300 per QALY for severe and £28,500 per QALY for moderate to severe RA. Hence the authors conclude that the cost-effectiveness of the administration of bDMARD in RA in England is questionable and meets currently accepted levels only in subsets of patients with the worst … Address correspondence to Dr. T.M. Kuijper, Maasstad Hospital, Department of Rheumatology, Postbus 9100, 3007 AC Rotterdam, The Netherlands; E-mail: kuijpert{at}maasstadziekenhuis.nl