Evolution of monoclonal gammopathy of undetermined significance in patients treated with JAK inhibitors for rheumatic diseases: data from the MAJIK-SFR registry.

OBJECTIVE: Monoclonal gammopathy of undetermined significance (MGUS) is common, but there are scarce data regarding the effect of DMARDs on this premalignant condition. We aimed to evaluate the impact of JAK inhibitors (JAKis) on MGUS when initiated for an active rheumatic disease. METHODS: Patients with monoclonal abnormality prior to JAKi initiation for an active rheumatic disease were identified through the MAJIK-SFR Registry, a French multicentre prospective study. Clinical and biological data were collected using a standardized case report form. RESULTS: Twenty patients were identified with a mean age of 65 years and a diagnosis of RA (n = 15), PsA (n = 3), and axial SpA (n = 2). The JAKi prescribed was baricitinib (n = 9), tofacitinib (n = 6) or upadacitinib (n = 5), with a mean duration of 15.5 months. Seventeen patients had individualized serum monoclonal protein (IgG kappa n = 9; IgG lambda n = 4; IgM kappa n = 3; IgA lambda n = 1) ranging from 0.16 to 2.3 g/dl, and three patients did not have an initial measurable spike but they had a positive serum immunofixation. With a follow-up of 4-28 months, the serum monoclonal protein level decreased in 8 of 17 patients (47%), remained stable in 8 patients (47%) and increased in 1 patient (6%). The maximal decrease observed was an initial IgG kappa of 2.3 g/dl, decreasing to 0.2 g/dl at month 14. CONCLUSION: This study provides reassuring and promising data on MGUS evolution in patients treated with JAKis for rheumatic diseases, which may guide the choice of treatment in patients with both conditions.

OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response.

Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS(+) blood Tfh cells in SLE. OX40 signals promoted naive and memory CD4(+) T cells to express multiple Tfh cell molecules and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE.

Can efficacy and safety data from clinical trials of rituximab in RA be extrapolated? Insights from 1984 patients from the AIR-PR Registry.

OBJECTIVES: To investigate whether the efficacy and safety data from drug-registration trials can be extrapolated to real-life RA patients receiving RTX. METHODS: The AIR-PR registry is a French multicentre, prospective cohort of RA patients treated with RTX in a real-life setting. We compared treatment responses at 12 months and serious AEs between eligible and non-eligible patients, by retrieving the eligibility criteria of the three rituximab-registration trials. We determined critical eligibility criteria and modelled the benefit-risk ratio according to the number of fulfilled critical eligibility criteria. RESULTS: Among 1984 RA patients, only 9-12% fulfilled all eligibility criteria. Non-eligible patients had less EULAR response at 12 months (40.3% vs 46.9%, p= 0.044). Critical inclusion criteria included SJC ≥ 4, TJC ≥ 4, CRP ≥ 15 mg/l, and RF positivity. Critical exclusion criteria were age >80 years, RA-associated systemic diseases, ACR functional class IV, other DMARD than methotrexate, and prednisone > 10 mg/day. Only 20.8% fulfilled those critical eligibility criteria. During the first year, serious AEs occurred for 182 (9.2%) patients, (70.3% serious infections) and patients with ≥1 critical exclusion criterion were at higher risk (HR 3.03; 95%CI 2.25-4.06; for ≥ 3 criteria vs 0). The incremental risk-benefit ratio decreased with the number of unmet critical inclusion criteria and of fulfilled exclusion criteria. CONCLUSION: Few real-life RA patients were eligible for the drug-registration trials. Non-eligible patients had lower chance of response, and higher risk of serious AEs. Efficacy and safety data obtained from those trials may not be generalizable to RA patients receiving RTX in real-world clinical practice.

Stricter treat-to-target in RA does not result in less radiographic progression: a longitudinal analysis in RA BIODAM.

OBJECTIVES: To investigate whether meticulously following a treat-to-target (T2T)-strategy in daily clinical practice will lead to less radiographic progression in patients with active RA who start (new) DMARD-therapy. METHODS: Patients with RA from 10 countries starting/changing conventional synthetic or biologic DMARDs because of active RA, and in whom treatment intensification according to the T2T principle was pursued, were assessed for disease activity every 3 months for 2 years (RA-BIODAM cohort). The primary outcome was the change in Sharp-van der Heijde (SvdH) score, assessed every 6 months. Per 3-month interval DAS44-T2T could be followed zero, one or two times (in a total of two visits). The relation between T2T intensity and change in SvdH-score was modelled by generalized estimating equations. RESULTS: In total, 511 patients were included [mean (s.d.) age: 56 (13) years; 76% female]. Mean 2-year SvdH progression was 2.2 (4.1) units (median: 1 unit). A stricter application of T2T in a 3-month interval did not reduce progression in the same 6-month interval [parameter estimates (for yes vs no): +0.15 units (95% CI: -0.04, 0.33) for 2 vs 0 visits; and +0.08 units (-0.06; 0.22) for 1 vs 0 visits] nor did it reduce progression in the subsequent 6-month interval. CONCLUSIONS: In this daily practice cohort, following T2T principles more meticulously did not result in less radiographic progression than a somewhat more lenient attitude towards T2T. One possible interpretation of these results is that the intention to apply T2T already suffices and that a more stringent approach does not further improve outcome.

The response to TNF blockers depending on their comparator in rheumatoid arthritis clinical trials: the lessebo effect, a meta-analysis.

OBJECTIVE: To compare the effect of the biological reference agents (infliximab, etanercept, adalimumab) in RA in pivotal superiority placebo-controlled trials (reference agent vs placebo) vs their effect in equivalence active comparator-controlled trials (reference agent vs biosimilar). METHODS: The PubMed, EMBASE and Cochrane databases were searched for randomized, double-blind, controlled trials up to March 2020 comparing a biological reference agent vs placebo or biosimilar. The study assessed the ACR 20/50/70 responses of the reference agent in these groups (Reference-pbo and Reference-bs, respectively). The effect of the reference agent in both groups was estimated with 95% CI, pooled using random-effects models and then compared using a meta-regression model. RESULTS: We included 31 trials. The main characteristics of the population (disease duration and activity, % seropositivity and methotrexate dose) of the population in both groups were similar. The meta-analysis found a better ACR20 response to the biological originator in the Reference-bs group with a global rate of 70% (95% CI, 66, 74) compared with 59% (95% CI, 55, 62) in the reference-pbo group (P =0.001). A significant difference was also found for ACR 50 [44% (95% CI, 39, 50) vs 35% (95% CI, 31, 39), respectively, P <0.01]. CONCLUSION: The effect of the reference biologic agent was better when compared with an active drug to a placebo. This could be linked to an increased placebo effect in active comparator-controlled studies or a nocebo effect in placebo-controlled studies. This effect can be called the lessebo effect.

Risk of diverticulitis and gastrointestinal perforation in rheumatoid arthritis treated with tocilizumab compared to rituximab or abatacept.

OBJECTIVE: To compare the risk of diverticulitis and gastrointestinal perforation (GIP) in RA treated with tocilizumab (TCZ) compared with rituximab (RTX) and abatacept (ABA). METHODS: We conducted a population-based study using three observational French registries on TCZ, RTX and ABA in RA. Using a propensity score approach, we compared the risk of diverticulitis or GIP in these patients. RESULTS: With inverse probability weighting, there was an increased risk of diverticulitis in TCZ-treated patients compared with RTX- or ABA-treated patients [hazard ratio (HR)=3.1 (95% CI: 1.5, 6.3), P =0.002]. Moreover, patients treated with TCZ had also an increased risk of GIP due to diverticulitis compared with those treated with RTX or ABA [HR=3.8 (1.1-13.6), P =0.04], resulting in an overall increased risk of GIP [HR=2.9 (1.1-7.8), P =0.03], while no significant increased risk of GIP due to any other aetiology was found in TCZ treated patients. Diverticulitis and GIP occurred earlier with TCZ than other drugs after the last perfusion (P =0.01), with atypical clinical presentation (slow transit in 30%, P =0.04) and lower acute-phase reactants at the time of the event (P =0.005). CONCLUSION: TCZ for RA was associated with increased odds of diverticulitis as well as GIP due to diverticulitis as compared with RTX and ABA. Our study confirms the increased odds of GIP in patients receiving TCZ, which might be explained by an increased risk of diverticulitis with misleading clinical presentation.

JAK inhibitors and risk of major cardiovascular events or venous thromboembolism: a self-controlled case series study.

PURPOSE: JAK-inhibitors (JAK-i) might be associated with venous (VTE) and arterial thromboembolic events (ATE). To evaluate the association between JAK-i and the risk of VTE and ATE. METHODS: A self-controlled case series was performed using data from the nationwide French healthcare insurance system database SNDS. We included all patients treated with JAK-i (baricitinib or tofacitinib), and having presented at least one VTE or ATE between November 1, 2017 and June 30, 2019. Associations were estimated using the incident rate ratio (IRR). Two post-exposure periods (until day 30 and until day 60) were individualized. RESULTS: Among 5870 patients with JAK-i dispensing, 92 had an incident VTE or ATE within the study period. Their median age at JAK-i initiation was 65.7 years [IQR: 56.1-75.8] and 65.2% were female (n = 60). Before event incidence, 65.2% (n = 60) received baricitinib, 32.6% (n = 30) tofacitinib and 2.2% (n = 2) had both medications. Moreover, 41.3% (n = 38) presented a VTE and 58.7% (n = 54) an ATE. The median time-to-onset after JAK-i initiation was 4.6 months [IQR: 2.5-9.2] for VTE and 6.1 months [IQR: 3.0-8.5] for ATE. An IRR of 8.27 (95% CI 3.41-20.04) for VTE was detected during JAK-i treatment and remained increased over the 30-day period of post-exposure (6.52 [2.02-21.11]). An IRR of 9.27 (3.68-23.34) was also found for ATE, which remained increased over the 30-day period of post-exposure (10.12 [3.27-31.37]). No increased risk was detected during long-term post-exposure for either VTE or ATE. CONCLUSIONS: This study shows evidence of an increased risk of VTE and ATE associated with the use of baricitinib and tofacitinib.

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Methotrexate and rheumatoid arthritis associated interstitial lung disease.

QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.

TGFß promotes low IL10-producing ILC2 with profibrotic ability involved in skin fibrosis in systemic sclerosis.

OBJECTIVE: Innate lymphoid cells-2 (ILC2) were shown to be involved in the development of lung or hepatic fibrosis. We sought to explore the functional and phenotypic heterogeneity of ILC2 in skin fibrosis within systemic sclerosis (SSc). METHODS: Blood samples and skin biopsies from healthy donor or patients with SSc were analysed by immunostaining techniques. The fibrotic role of sorted ILC2 was studied in vitro on dermal fibroblast and further explored by transcriptomic approach. Finally, the efficacy of a new treatment against fibrosis was assessed with a mouse model of SSc. RESULTS: We found that ILC2 numbers were increased in the skin of patients with SSc and correlated with the extent of skin fibrosis. In SSc skin, KLRG1- ILC2 (natural ILC2) were dominating over KLRG1+ ILC2 (inflammatory ILC2). The cytokine transforming growth factor-ß (TGFß), whose activity is increased in SSc, favoured the expansion of KLRG1- ILC2 simultaneously decreasing their production of interleukin 10 (IL10), which regulates negatively collagen production by dermal fibroblasts. TGFß-stimulated ILC2 also increased myofibroblast differentiation. Thus, human KLRG1- ILC2 had an enhanced profibrotic activity. In a mouse model of SSc, therapeutic intervention-combining pirfenidone with the administration of IL10 was required to reduce the numbers of skin infiltrating ILC2, enhancing their expression of KLRG1 and strongly alleviating skin fibrosis. CONCLUSION: Our results demonstrate a novel role for natural ILC2 and highlight their inter-relationships with TGFß and IL10 in the development of skin fibrosis, thereby opening up new therapeutic approaches in SSc.

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.

BACKGROUND: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management. METHODS: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed. RESULTS: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies. CONCLUSION: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

Role of stress in the development of rheumatoid arthritis: a case-control study.

OBJECTIVES: The primary objective of this study was to assess the stressful life events preceding the onset of symptoms in RA. The secondary objectives were to assess how early RA patients perceive stress and cope with stressors. METHODS: A case-control study was performed, comparing patients recently diagnosed with RA to age- and gender-matched control subjects recently hospitalized for an unplanned surgical procedure not known to be influenced by stress. The Social Readjustment Rating Scale assessed the cumulative stress induced by stressful life events in the year preceding the onset of symptoms. Coping strategies, stress and anxiety symptoms were evaluated using validated psychological scales. RESULTS: Seventy-six subjects were included in each group. The mean Social Readjustment Rating Scale score was twice as high in cases compared with controls [respectively, 167.0 (172.5) vs 83.3 (124.4), P < 0.001]. The association between cumulative stress and RA was statistically significant only in women, with a dose-dependent association between stress and RA. While female patients with RA attributed more often the onset of symptoms to a life event than female controls (70.2 vs 24.5%, P < 0.001), no significant difference was found when comparing male RA patients with male controls (26.9 vs 18.5%, respectively, P = 0.46). Increased perceived stress score (P = 0.04) and coping based on emotions (P = 0.001) were found in cases compared with controls. CONCLUSION: Patients with early RA reported more life events in the year preceding the onset of symptoms than controls. Gender specificities were found with a significant association between cumulative stress and RA only in women.

Cut-off value to identify a flare using the Flare Assessment in Rheumatoid Arthritis (FLARE-RA) questionnaire: analysis of the TOSCA study.

OBJECTIVE: The Flare Assessment in RA (FLARE-RA) self-administered questionnaire aims to identify patients who had flare in the interval between two consultations. This study aimed to establish a threshold for FLARE-RA score to identify RA flare. METHODS: The Tocilizumab SubCutAneous study evaluated the efficacy and safety of s.c. tocilizumab (TCZ) to patients with active RA. Disease activity was assessed with the DAS28ESR at baseline and at week 2 (W2), W4, W12 and W24. The FLARE-RA questionnaire was administered at W12 and W24. Patient satisfaction, assessed at baseline and W24 with the Patient Acceptable Symptom State (PASS), was used as a surrogate marker of no flare. A correlation was sought between the FLARE-RA score at W12 and W24 and the area under the receiver operating characteristic (ROC) curve (AUC) for monthly DAS28ESR. The optimal FLARE-RA cut-off below which patient satisfaction reached the PASS was explored with an ROC curve. RESULTS: A total of 139 patients were included (mean age 57.3 ± 13.8 years, 74.1% women, mean RA duration 10.8 ± 9.2 years, mean DAS28ESR 5.8 ± 1.1). The correlation between the FLARE-RA score and DAS28ESR AUC was moderate at all times: ρ = 0.41 at W12 (P < 0.0001) and 0.51 at W24 (P < 0.0001). The optimal cut-off for the FLARE-RA score to identify absence of flare (i.e. an acceptable situation based on the PASS) was 2.3 with an AUC of 0.81. CONCLUSION: FLARE-RA and DAS28ESR assessment differ; we propose a FLARE-RA cut-off of 2.3, below which the situation (i.e. without flare) is acceptable for patients.

Current favourable 10-year outcome of patients with early rheumatoid arthritis: data from the ESPOIR cohort.

OBJECTIVE: To report the 10-year outcome of an inception cohort of patients with early rheumatoid arthritis (RA), the ESPOIR cohort, and predictors of outcome. METHODS: From 2003 to 2005, 813 patients were included if they had early arthritis (<6 months) with a high probability of RA and had never been prescribed DMARDs. Multivariate analysis was used to evaluate predictors of outcome. RESULTS: In total, 521 (64.1%) RA patients were followed up for 10 years; 35 (4.3%) died, which appears to be similar to the French general population. Overall, 480 (92.1%) patients received a DMARD; 174 (33.4%) received at least one biologic DMARD, 13.6% within 2 years. At year 10, 273 (52.4%) patients were in DAS28 remission, 40.1% in sustained remission, 14.1% in drug-free remission, 39.7% in CDAI remission. Half of the patients achieved a health assessment questionnaire-disability index (HAQ-DI) < 0.5. SF-36 physical component and pain were well controlled. Structural progression was weak, with a mean change from baseline in modified Sharp score of 11.0 (17.9). Only 34 (6.5%) patients required major joint surgery. A substantial number of patients showed new comorbidities over 10 years. Positivity for anti-citrullinated peptides antibodies (ACPA) was confirmed as a robust predictor of long-term outcome. CONCLUSIONS: We report a very mild 10-year outcome of a large cohort of patients with early RA diagnosed in the early 2000s, which was much better than results for a previous cohort of patients who were recruited in 1993. This current favourable outcome may be related to more intensive care for real-life patients.

Evaluation of the impact of a nurse-led program of patient self-assessment and self-management in axial spondyloarthritis: results of a prospective, multicentre, randomized, controlled trial (COMEDSPA).

OBJECTIVE: To evaluate the impact of a nurse-led program of self-management and self-assessment of disease activity in axial spondyloarthritis. METHODS: Prospective, randomized, controlled, open, 12-month trial (NCT02374749). Participants were consecutive axial spondyloarthritis patients (according to the rheumatologist) and nurses having participated in a 1-day training meeting. The program included self-management: educational video and specific video of graduated, home-based exercises for patients; and self-assessment: video presenting the rationale of tight monitoring of disease activity with composite scores (Ankylosing Spondylitis Disease activity Score, ASDAS/Bath Ankyslosing Spondylitis Disease Activity Index, BASDAI). The nurse trained patients to collect, calculate and report (monthly) ASDAS/BASDAI. Treatment allocation was by random allocation to this program or a comorbidities assessment (not presented here and considered here as the control group). RESULTS: A total of 502 patients (250 and 252 in the active and control groups, respectively) were enrolled (age: 46.7 (12.2) years, male gender: 62.7%, disease duration: 13.7 (11.0) years). After the one-year follow-up period, the adherence to the self-assessment program was considered good (i.e. 79% reported scores >6 times). Despite a lack of statistical significance in the primary outcome (e.g. coping) there was a statistically significant difference in favor of this program for the following variables: change in BASDAI, number and duration of the home exercises in the active group, and physical activity (international physical activity score, IPAQ). CONCLUSION: This study suggests a short-term benefit of a nurse-led program on self-management and self-assessment for disease activity in a young axial spondyloarthritis population in terms of disease activity, exercises and physical activity.

Automatic phenotyping of electronical health record: PheVis algorithm.

Electronic Health Records (EHRs) often lack reliable annotation of patient medical conditions. Phenorm, an automated unsupervised algorithm to identify patient medical conditions from EHR data, has been developed. PheVis extends PheNorm at the visit resolution. PheVis combines diagnosis codes together with medical concepts extracted from medical notes, incorporating past history in a machine learning approach to provide an interpretable parametric predictor of the occurrence probability for a given medical condition at each visit. PheVis is applied to two real-world use-cases using the datawarehouse of the University Hospital of Bordeaux: i) rheumatoid arthritis, a chronic condition; ii) tuberculosis, an acute condition. Cross-validated AUROC were respectively 0.943 [0.940; 0.945] and 0.987 [0.983; 0.990]. Cross-validated AUPRC were respectively 0.754 [0.744; 0.763] and 0.299 [0.198; 0.403]. PheVis performs well for chronic conditions, though absence of exclusion of past medical history by natural language processing tools limits its performance in French for acute conditions. It achieves significantly better performance than state-of-the-art unsupervised methods especially for chronic diseases.

Is treat-to-target really working in rheumatoid arthritis? a longitudinal analysis of a cohort of patients treated in daily practice (RA BIODAM).

OBJECTIVES: To investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target. METHODS: RA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 <1.6) as the target. Sustained T2T was defined as T2T followed in ≥2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models. RESULTS: In total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52). CONCLUSION: In daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission.

Role of good oral hygiene on clinical evolution of rheumatoid arthritis: a randomized study nested in the ESPOIR cohort.

OBJECTIVE: There is a relationship between RA and periodontal disease. We aimed to investigate if a good oral hygiene could improve activity of RA. METHODS: The patients with RA according to ACR/EULAR 2010 criteria and included in the French early arthritis ESPOIR cohort were included in a randomized nested study into: (i) intervention group: general recommendations of good oral hygiene including teeth brushing, daily antiseptic mouthwash and twice a year scaling; and (ii) control group: no intervention. The primary end point was the delta DAS28-ESR. RESULTS: Four hundred and seventy-two patients were randomized (238 in intervention and 234 in control). 92/238 from the intervention group accepted the procedure and 81 had a first visit to the dentist. 56% of patients had periodontal disease at baseline. Duration of RA was 9.0±0.7 years. Baseline DAS28-ESR was 2.7±1.3. After a median duration of 24 months, delta DAS28-ESR was -0.17±1.29 and -0.09±1.28 in intervention and control groups, respectively (mean difference (complier average causal effect): -0.37 (95% CI -1.12, 0.37), P = 0.33). In the intervention group, there was a significant decrease of the bacteria involved in the red complex: Porphyromonas gingivalis (P = 0.002), Tannerella forsythia (P = 0.002) and Treponema denticola (P = 0.019). The patients with baseline periodontal disease and those who became negative for one red complex bacterium had a slightly more important decrease of DAS28-ESR. CONCLUSION: Oral hygiene instruction together with regular scaling and polishing of the teeth significantly decreased the load of periodontal pathogens but did not decrease RA activity. This intervention should be tested in patients with earlier RA and more active disease. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01831648.

A simplified radiographic score effectively predicts radiographic progression of early arthritis in a large nationwide French cohort.

OBJECTIVE: Evaluating radiographic progression is a key component of the follow-up of patients with RA. Existing scores are ill-suited to everyday clinical practice. The objective here was to validate a new simplified radiographic score (SRS) for evaluating radiographic progression in patients with early arthritis. METHODS: Patients with arthritis of <6 months' duration were included in the large, prospective, nationwide, French ESPOIR cohort. Radiographs of the hands and feet were obtained at inclusion then 1 and 5 years later. The modified Sharp scores and SRS were determined by blinded readers. Interobserver reliability and intraobserver repeatability of each score, as well as agreement between the two scores, were assessed by computing the intraclass correlation coefficients. The rates of progression over the first year and the next 4 years were determined. RESULTS: The 506 patients with complete data for the first 5 years were included. At inclusion, the intraclass correlation coefficient between the two scores was good for erosions (0.715, P < 0.001), joint space narrowing (0.892, P < 0.001) and the total score (0.896, P < 0.001). Agreement between the two scores was also good for radiographic progression after 1 year (0.781, P < 0.001). The SRS had good positive and negative predictive values for slow and for rapid progression. SRS determination was less time consuming. CONCLUSION: The SRS is effective for monitoring radiographic progression in early arthritis and is easier to use and less time-consuming than the Sharp score. The usefulness of the SRS in clinical practice deserves further evaluation.