DAS28-γGT for the prediction of major cardiovascular events in rheumatoid arthritis: results from the ESPOIR cohort.

OBJECTIVE: To validate the predictive value of the DAS28 γ-glutamyl transferase (DAS28-γGT) for the occurrence of major cardiovascular (CV) events (MACE) in the 'Etude et Suivi des Polyarthrites Indifférenciées Récentes' ESPOIR cohort. METHODS: Analysis of 13-year outcome from the ESPOIR cohort. RA patients with missing data for baseline γGT activity and those not followed-up to 1 year were excluded. Baseline DAS28-γGT was calculated using the following formula: 0.56*√TJ-28 + 0.28 * √SJ-28 + 2*ln(γGT) + 0.014 * GH. Our primary outcome was the merit of the DAS28-γGT in predicting the occurrence of MACE. RESULTS: Among the 696 patients [536 women, mean (s.d.) age of 49 (12) years], 34 MACE were recorded, with a mean time to event of 71 (44) months. Receiver operating characteristic curve analysis indicated that a DAS28-γGT >9.4 had the best sensitivity and specificity for the diagnosis of MACE during the observation period. DAS28-γGT >9.4 was predictive of the occurrence of MACE, with a hazard ratio (HR) of 3.11 (95% CI 1.41, 5.43). Multivariate Cox analyses confirmed higher DAS28-γGT (HR 2.44, 95% CI 1.05, 5.64) together with age (HR 1.04, 95% CI 1.01, 1.07) and diabetes mellitus (HR 4.12, 95% CI 1.55, 10.95) as independent predictors of MACE. There was a dose effect of the DAS28-γGT for MACE-risk prediction, which was in line with the application of the Framingham risk score. CONCLUSION: The DAS28-γGT was identified in this large prospective cohort as an independent predictor of MACE in patients with RA. The DAS28-γGT is a simple and useful tool to evaluate CV risk in routine and warn the clinician about the CV risk burden in patients with RA.

A prospective survey on therapeutic inertia in psoriatic arthritis (OPTI'PsA).

OBJECTIVES: Clinical inertia, or therapeutic inertia (TI), is the medical behaviour of not initiating or intensifying treatment when recommended by clinical recommendations. To our knowledge, our survey is the first to assess TI around psoriatic arthritis (PsA). METHODS: Eight hundred and twenty-five French rheumatologists were contacted via email between January and March 2021 and invited to complete an online questionnaire consisting of seven clinical vignettes: five cases ('oligoarthritis', 'enthesitis', 'polyarthritis', 'neoplastic history', 'cardiovascular risk') requiring treatment OPTImization, and two 'control' cases (distal interphalangeal arthritis, atypical axial involvement) not requiring any change of treatment-according to the most recent PsA recommendations. Rheumatologists were also questioned about their routine practice, continuing medical education and perception of PsA. RESULTS: One hundred and one rheumatologists completed this OPTI'PsA survey. Almost half the respondents (47%) demonstrated TI on at least one of the five vignettes that warranted treatment optimization. The complex profiles inducing the most TI were 'oligoarthritis' and 'enthesitis' with 20% and 19% of respondents not modifying treatment, respectively. Conversely, clinical profiles for which there was the least uncertainty ('polyarthritis in relapse', 'neoplastic history' and 'cardiovascular risk') generated less TI with 11%, 8% and 6% of respondents, respectively, choosing not to change the current treatment. CONCLUSION: The rate of TI we observed for PsA is similar to published data for other chronic diseases such as diabetes, hypertension, gout or multiple sclerosis. Our study is the first to show marked clinical inertia in PsA, and further research is warranted to ascertain the reasons behind this inertia.

Two-year treatment persistence with subcutaneous abatacept in rheumatoid arthritis: results from the French cohort of the ASCORE study.

OBJECTIVES: While multiple studies have investigated treatment persistence rates with intravenous abatacept, limited information is available about real-world treatment continuation with the subcutaneous form. The international ASCORE study described the characteristics and treatment persistence of real-world patients with rheumatoid arthritis (RA) receiving subcutaneous abatacept. This article presents the findings of the French cohort. METHODS: This was an observational study in French RA patients who initiated subcutaneous abatacept between August 2014 and January 2017. The primary endpoint was treatment maintenance at 2 years, analysed according to the number of previous biologic therapies. RESULTS: Of 546 evaluable patients, 281 (51.5%) were biologic-naive, 265 (48.5%) had experienced failure with 1 (n=134; 24.5%) or ≥2 (n=131; 24.0%) biologic therapies. At enrolment, patients who had experienced failure with ≥1 biologic therapy had more erosions and a longer duration of RA compared with biologic-naive patients, but had comparable mean disease activity scores. Overall, 43.0% of patients (95% confidence interval 38.6-47.2) were still taking subcutaneous abatacept at 2 years, which was comparable with that in other countries participating in ASCORE. The abatacept persistence rate was higher in biologic-naive patients (48.8%) than in those with 1 (40.9%) or ≥2 (32.8%) biologic therapy failures. The main reason for discontinuing abatacept was lack of efficacy (46.6%). CONCLUSIONS: In current practice in France, the rate of subcutaneous abatacept persistence at 2 years was comparable with that of the intravenous form. Treatment persistence was higher when abatacept was used as first-line versus later-line biologic therapy.

Comparison of SARS-COV-2 humoral response between rheumatoid arthritis, psoriatic arthritis and spondyloarthritis patients and controls in two unvaccinated cohorts.

OBJECTIVES: To compare the humoral response after a SARS-CoV-2 infection in an inflammatory rheumatic disease population with a healthy control population in a case-control study. METHODS: Cases: between March and September 2021, all consecutive unvaccinated patients followed for rheumatoid arthritis (RA), spondyloarthritis (SpA) or psoriatic arthritis (PsA) in 16 hospitals in France were systematically screened with a SARS-CoV-2 serological test. Patients with a positive test were included in the COVID-RIC-2 cohort. CONTROLS: between June and July 2020, healthcare professionals working in the Toulouse University Hospital were screened with a SARS-CoV-2 serological test. Those with a positive test were included in the COVID-BIOTOUL cohort and matched to those from COVID-RIC-2 by age, sex and time-sampling on infection date. ANALYSES: total SARS-CoV-2 antibody titres were centrally measured and compared. RESULTS: 95 patients from COVID-RIC-2 (mean age 49 years, 76% females, median delay of COVID infection: 149 days) including 48 RA, 33 SpA and 14 PsA were compared to 95 matched controls. Globally, there was no significant difference of SARS-CoV-2 antibody titres between both populations: 155 Binding Antibody Units (BAU) (IQR:7-376) in COVID-RIC-2 vs. 120 BAU (IQR:35-320) in COVID-BIOTOUL. There was a trend towards higher antibody titres in patients from COVID-RIC-2 with severe COVID-19 symptoms. In COVID-RIC-2, there was no impact of age, sex, time-sampling or underlying disease on antibody titres and patients taking glucocorticoids, abatacept or rituximab trended toward having lower antibody titres after COVID-19 infection. CONCLUSIONS: This study provides reassuring data on humoral response after COVID-19 infection in patients treated with disease-modifying anti-rheumatic drugs.

Efficacy of subcutaneous vs intravenous infliximab in rheumatoid arthritis: a post-hoc analysis of a randomized phase III trial.

OBJECTIVES: The primary endpoint of the pivotal phase III study of infliximab (IFX) s.c. demonstrated non-inferiority of s.c. to i.v. IFX, based on 28-joint DAS-CRP (DAS28-CRP) improvement at week (W) 22 (NCT03147248). This post-hoc analysis investigated whether numerical differences in efficacy outcomes at W30/54 were statistically significant, using conservative imputation methods. METHODS: Patients with active RA and inadequate response to MTX received IFX i.v. 3 mg/kg at W0 and W2 (induction) and were randomized (1:1) to IFX s.c. 120 mg every 2 weeks or i.v. 3 mg/kg every 8 weeks thereafter (maintenance). Patients randomized to IFX i.v. switched to IFX s.c. from W30-54. This post-hoc analysis compared efficacy outcomes for s.c. and i.v. groups pre-switch (W30) and post-switch (W54) using last observation carried forward (LOCF) and non-responder imputation (NRI) methods. RESULTS: Of 343 randomized patients, 165 (IFX s.c.) and 174 (IFX i.v.) were analysed. At W30, significantly improved outcomes were identified with s.c. vs i.v. IFX for DAS28-CRP/DAS28-ESR/Clinical Disease Activity Index (CDAI)/Simplified Disease Activity Index (SDAI) scores (LOCF); ACR/good EULAR responses, DAS28-CRP/Boolean remission, and DAS28-CRP/DAS28-ESR/CDAI/SDAI low disease activity and remission (LOCF and/or NRI); and minimal clinically important difference in HAQ score (LOCF and NRI). After switching to IFX s.c. from IFX i.v., fewer significant between-group differences were identified at W54. CONCLUSION: IFX s.c. showed improved efficacy at W30 compared with IFX i.v., and the reduced between-group difference in efficacy outcomes at W54 after switching supports the results suggesting benefits of IFX s.c. compared with IFX i.v. at W30. TRIAL REGISTRATION: ClincialTrials.gov, http://clinicaltrials.gov, NCT03147248, https://clinicaltrials.gov/ct2/show/NCT03147248.

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.

Clinical significance of a self-reported familial occurrence of rheumatoid arthritis among patients with recent-onset arthritis: data from the ESPOIR cohort.

OBJECTIVES: To assess, in patients with recent-onset arthritis, whether a self-reported familial occurrence of rheumatoid arthritis (RA) is associated with a clinical presentation of the disease, final diagnosis, long-term outcome and treatment decisions. METHODS: The study was conducted from data of patients included between 2002 and 2005 in the early arthritis ESPOIR cohort. Patients were recruited on the basis of having at least two swollen joints for >6 weeks and <6 months, no other diagnosis than RA and no previous exposure to glucocorticoids or disease-modifying antirheumatic drugs (DMARDs). Patients were stratified into two groups according to the presence of a self-reported familial occurrence of RA at baseline. Data concerning final diagnosis (2-year visit), long-term outcome (5-year visit) and therapeutic decisions were compared between the 2 groups of patients, using logistic and Cox regression models. RESULTS: At baseline, 115 patients (14.1%) reported a familial occurrence of RA and showed, as compared with the remaining participants, higher prevalence of extra articular manifestations (EAMs) (51.8% vs. 39.6%, p=0.01) and severe EAMs (7.9% vs. 3.1%, p 0.01). Both unadjusted (hazard ratio, 1.57; 95% CI, 1.1-2.21; p = 0.01) and adjusted analysis (hazard ratio, 1.51; 95% CI, 1.06-2.15; p=0.02) identified a higher probability for the initiation of a targeted DMARD over time among patients with a self-reported familial occurrence of RA. CONCLUSIONS: In the specific context of early arthritis, a self-reported familial occurrence of RA is associated with the future decision to initiate a targeted DMARD.

Sjögren's syndrome associated with erosive rheumatoid arthritis alters its prognosis and long-term therapeutic response: a case-control study.

10% of rheumatoid arthritis (RA) cases are associated to so-called secondary Sjögren's syndrome (SS). These RA cases have higher DAS, fewer remissions. Is this linked to a poor response to DMARDs (disease-modifying anti-rheumatic drugs)? No study has addressed this question to date. Does the association between secondary Sjögren's syndrome (SS) and rheumatoid arthritis (RA) affect the therapeutic response to DMARDs and long-term prognosis? We conducted a retrospective case-control study: 39 RA associated with SS was (anti-SSA antibodies and/or Chisolm stage III or IV) were compared to 39 isolated cases of erosive RA matched by age, duration of progression and gender. The DAS CRP was higher in the RA + SS group in patients with disease progression of 16 years: 2.6 (1.5-4.5) compared to the RA group: 1.6 (1.3-2.8) (p = 0.0001) while fewer patients were in remission: 61 vs. 92% (p = 0.002). A higher number of B DMARDs have been prescribed: RA + SS = 3.04 (1-7); RA = 1.7 (1-5) (p = 0.004). Anti-TNFs are less effective when RA is associated with SS: 30 vs. 70%. Conversely, Rituximab is more effective when RA is associated with SS: 80 vs. 30%. Erosive RA-related SS exacerbates the clinical course of the condition: higher DAS, fewer remissions. This is linked to reduced treatment efficacy: higher number of DMARDs prescribed, reduced efficacy of anti-TNF drugs. RA-related SS could modify sensitivity to biotherapies: lower percentage of remissions and resistance to anti-TNF drugs.

New-onset inflammatory bowel diseases among IL-17 inhibitor-treated patients: results from the case-control MISSIL study.

OBJECTIVES: To describe new-onset IBD (new IBD) in patients treated with IL-17 inhibitors (IL-17i), to assess their incidence and to identify their risk factors in real life. METHODS: A French national registry (MISSIL) aimed to report all cases of new IBD in patients treated with IL-17i from January 2016 to December 2019. Using the estimated number of patients treated by IL-17 in France during the study period, the annual incidence rates of new IBD was reported in IL-17i-treated patients. A case-control study was performed with two controls per new IBD case matched by gender, age and underlying inflammatory disease. RESULTS: Thirty-one cases of new IBD under IL-17i were collected: 27 patients treated for spondyloarthritis and four patients for psoriasis. All were observed with secukinumab (SEK). The median time to onset of new IBD symptoms was 4.0 (1.5-7.5) months. SEK was discontinued in all patients. The evolution was favourable with complete resolution (17/31), improvement (7/31) or stabilization (5/31). Two patients died: one due to a massive myocardial infarction and one due to post-colectomy complications. The incidence of new IBD decreased from 0.69/100 patient-years [PY] (7/1010) in 2016 to 0.08/100 PY (6/7951) in 2019. No previous treatment with etanercept (odds ratio [OR] = 0.33, 95% CI: 0.14-0.80, P = 0.014) and low number of previous biologic therapies (OR = 0.67, 95% CI: 0.47, 0.94, P = 0.021) were significantly associated with new IBD. CONCLUSION: The incidence of new IBD was low and decreased from 2016 to 2019. The outcome was favourable in 24 out of 31 patients, but two patients died.

Impact of disease activity and treatments on ovarian reserve in patients with rheumatoid arthritis in the ESPOIR cohort.

OBJECTIVES: Patients with RA have a higher prevalence of infertility than the general population. This study sought to examine the impact of RA disease activity and treatments on ovarian reserve measured by serum anti-Müllerian hormone (AMH) levels in the ESPOIR cohort. We sought to better define the indications for fertility preservation. METHODS: Patients and serum analysis data were derived from the French national cohort ESPOIR. Enrolled patients (n = 102; 18-37-year-olds) fulfilled ACR/EULAR 2010 criteria for RA. Serum AMH levels were measured at T0, T6, T12, T24 and T36 months post-diagnosis. The impacts of RA activity (DAS28 and CRP level) and treatments (MTX only or with other medications) were evaluated at each study visit. RESULTS: A gradual decrease in patients' serum AMH levels was observed over time, in line with the descending curve described for healthy women. Serum AMH levels of RA patients in comparison with the values considered normal for age did not reveal any significant differences (P > 0.05). We did not observe any impact of RA treatments. We demonstrated an inverse correlation between AMH variation and disease activity (DAS28: r = -0.27, P = 0.003; CRP: r = -0.16, P = 0.06). CONCLUSION: This is the first study to determine serum AMH levels of a large cohort of RA patients over 36 months. Rapid disease activity control appears to be required to limit changes in the ovarian reserve. Fertility preservation is not likely to be necessary if inflammation is promptly controlled. CLINICALTRIALS.GOV IDENTIFIER: NCT03666091.

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.

Biological DMARD efficacy in psoriatic arthritis: a systematic literature review and meta-analysis on articular, enthesitis, dactylitis, skin and functional outcomes.

OBJECTIVES: There is no hierarchy in the use of biotherapies (bDMARDs) in psoriatic arthritis (PsA) and no published head-to-head comparative studies. Our purpose is to evaluate the respective efficacy of TNF inhibitors, IL12/23 inhibitors (ustekinumab), IL17 inhibitors (secukinumab, ixekizumab) and CTLA4Ig (abatacept) on articular, enthesitis, dactylitis, skin and functional outcomes in PsA. METHODS: Randomised controlled trials assessing bDMARDs in PsA were selected through the MedLine, Cochrane and Embase databases. ACR20/50/70 and PASI75/90 response rates, enthesitis and dactylitis reduction rates and HAQ-DI mean reductions were collected. Pooled meta-analyses were performed to assess relative risks (RR) with their 95% confidence interval (95%CI) for each class of bDMARDs in comparison with placebo. RESULTS: 17 RCTs were analysed. Compared to placebo, all bDMARDs showed higher ACR20 response rates, with RRs ranging from 1.77 (1.31, 2.39) to 3.21 (2.52, 4.08), and a greater HAQ-DI mean reduction. TNF inhibitors, secukinumab and IL17 inhibitors showed higher ACR50/70 and PASI75/90 response rates. TNF inhibitors, secukinumab and IL17 inhibitors showed higher enthesitis resolution rates and only TNF inhibitors and IL17 inhibitors showed higher dactylitis resolution rates, with RRs ranging from 1.41 (1.02, 1.95) to 2.31 (1.60, 3.34) and from 2.07 (1.38, 3.12) to 2.65 (1.79, 3.94), respectively. CONCLUSIONS: All bDMARDs showed higher ACR20 response rates and better HAQ-DI mean reduction compared to placebo. This meta-analysis highlights the variability of bDMARD efficacy on ACR50/70, PASI75/90 and enthesitis or dactylitis response rates. Head-to-head studies are needed to draw definitive conclusions on potential efficacy-related differences between bDMARDs in PsA.

A single nucleotide polymorphism of IL6-receptor is associated with response to tocilizumab in rheumatoid arthritis patients.

Biological disease-modifying anti-rheumatic drugs (bDMARDs) have changed care of patients with rheumatoid arthritis (RA). However, bDMARDs are costly, can lead to serious infections, and induce a sustained remission in only 30% of RA patients. In this study, we sought to determine if the clinical response to treatment with Tocilizumab (TCZ), an IL-6 inhibitor, varied with genetic background. The efficacy of TCZ was assessed using the European League Against Rheumatism (EULAR) response criteria, measured after 3 months of treatment in two samples of French RA patients (TOCI and ROC studies). Single nucleotide polymorphisms (SNPs) in 21 candidate genes were genotyped using KasPar method (LGC-genomics, UK) and then analyzed to determine their contribution to variation in the response to treatment. One hundred twenty-three patients in the TOCI group (79.8%) and 48 patients in the ROC group (80%) experienced good or moderate EULAR response. The clinical response to treatment was associated with SNP genotype in the gene IL6R, with patients with the homozygous AA-genotype for rs12083537 (IL6R) showing a significantly better response than homozygous or heterozygous patients with the G allele [TOCI: 87.5% of responders for AA genotype vs. 72.2% for AG or GG genotype (p = 0.018); ROC patients: 89.2% of responders for AA genotype vs. 65.2% for AG or GG genotype, p = 0.044]. A meta-analysis combining data from the two cohorts confirmed the lower response rate in patients carrying a copy of the G allele (OR (95% CI) = 0.35 (0.16-0.61), p = 0.001). No association was found with any of the other SNPs tested.

Prevalence of inflammatory posterior arch abnormalities on lumbar spine MRI in spondyloarthritis patients compared with low back pain patients.

OBJECTIVES: This study was conducted in order to compare the prevalence of inflammatory posterior arch abnormalities on lumbar spine MRI between axial spondyloarthritis (axSpA) patients and low back pain (LBP) patients. METHODS: Patients-axSpA patients meeting the 2009 ASAS criteria and chronic LBP patients who had a lumbar spine MRI were selected. MRI-STIR and T1 sagittal images up to T8-T9 were reviewed by two experienced rheumatologists blinded to the diagnosis and clinical data to identify inflammatory posterior arch abnormalities. Analyses-The prevalence of inflammatory posterior arch abnormalities between axSpA and LBP patients was compared. Clinical data were compared in the axSpA group depending on whether or not inflammatory posterior arch abnormalities were present. RESULTS: Ninety-five patients were enrolled in each group. The prevalence of all inflammatory posterior arch abnormalities was the same in the axSpA and LBP groups (58% in the SpA group versus 70% in the LBP group, p = 0.1). However, differences in terms of the prevalence of costotransverse joint arthritis, pedicle oedema above L3 and transverse and spinous process oedema were observed between the two groups (axSpA 27% versus LBP 6%, p = 0.0004). Patients with inflammatory posterior arch abnormalities in the axSpA group had a longer disease duration (11 versus 8 years, p = 0.02), higher CRP levels (median 11 versus 3 mg/l, p = 0.0002) and higher prevalence of radiographic sacroiliitis (84 versus 47%, p = 0.001) compared to patients without inflammatory posterior arch abnormalities. CONCLUSIONS: Costotransverse arthritis, pedicle oedema and transverse process oedema are more frequent in axSpA patients than LBP patients, on lumbar spine MRI depicting TH9-S1. KEY POINTS: • MRI pedicle oedema above L3, transverse process oedema, spinous process oedema or costotransverse arthritis is more frequently observed in axial spondyloarthritis (SpA). • SpA patients with at least one MRI inflammatory lesion on the posterior arch had higher clinical activity scores and biological inflammation. • Facet joint arthritis was more common in patients with chronic low back pain.

Risk of losing remission, low disease activity or radiographic progression in case of bDMARD discontinuation or tapering in rheumatoid arthritis: systematic analysis of the literature and meta-analysis.

OBJECTIVES: To assess the risk of losing remission, low disease activity (LDA) or radiographic progression in the case of (1) discontinuing or (2) tapering doses of biological disease-modifying antirheumatic drugs (bDMARDs) compared with continuation of the initial treatment regimen in rheumatoid arthritis (RA) patients with remission or LDA. MATERIALS AND METHODS: A systematic literature analysis was carried out through May 2017 on the PubMed, Embase, Cochrane and international congress databases, selecting controlled trials comparing bDMARDs discontinuation/tapering versus continuation in RA patients with remission or LDA. The meta-analysis assessed the risk ratio (RR) and 95% CI of losing remission or LDA and the risk of radiographic progression after (1) discontinuing and (2) tapering doses of bDMARDs versus continuing the initial treatment. RESULTS: The meta-analysis comparing bDMARDs discontinuation versus continuation performed on nine trials showed an increased risk of losing remission (RR (95% CI)=1.97(1.43 to 2.73), P<0.0001) or LDA (RR (95% CI)=2.24(1.52 to 3.30), P<0.0001) and an increased risk of radiographic progression (RR (95% CI)=1.09(1.02 to 1.17), P=0.01) in case of bDMARD discontinuation. The meta-analysis comparing bDMARDs tapering versus continuation performed on 11 trials showed an increased risk of losing remission (RR (95% CI)=1.23(1.06 to 1.42), P=0.006) but no increased risk of losing LDA (RR (95% CI)=1.02 (0.85 to 1.23), P=0.81) nor any increased risk of radiographic progression (RR (95% CI)=1.09(0.94 to 1.26), P=0.26) in case of bDMARD tapering. CONCLUSION: Discontinuation of bDMARDs leads to an increased risk of losing remission or LDA and radiographic progression, while tapering doses of bDMARDs does not increase the risk of relapse (LDA) or radiographic progression, even though there is an increased risk of losing remission.

Effectiveness of Exercise Programs in Ankylosing Spondylitis: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To assess the effectiveness of exercise programs on disease activity and function in ankylosing spondylitis (AS) by a systematic review and meta-analysis of randomized controlled trials (RCTs). DATA SOURCES: Medline via PubMed and Cochrane Library. STUDY SELECTION: Reports of RCTs examining the effectiveness of exercise programs for AS published up to May 2017. DATA EXTRACTION: Outcomes were evolution of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) after the completion of exercise programs. Modalities of exercise were compared and the use of biologic therapy was reported. DATA SYNTHESIS: After screening 190 abstracts, we selected 26 reports for detailed evaluation and finally investigated 8 trials that assessed a home-based exercise program (2/8), swimming (1/8), Pilates training (1/8), or supervised exercises (4/8), for a total of 331 patients with AS. Four trials included patients receiving antitumor necrosis factor therapy. All trials except one showed a decrease in BASDAI and BASFI with exercise. The weighted mean difference was -0.90 (95% confidence interval, -1.52 to -0.27; I2=69%; P=.005) for the BASDAI and -0.72 (95% confidence interval, -1.03 to -0.40; I2=0%; P<.00001) for the BASFI in favor of exercise programs. CONCLUSIONS: Despite the small number of patients and the heterogeneity of exercise programs in the RCTs included in this meta-analysis, its results support the potential of exercise programs to improve disease activity and body function in AS.

Risk factors of serious infections in patients with rheumatoid arthritis treated with tocilizumab in the French Registry REGATE.

Objectives: Observational studies have already reported the risk of serious infections in RA treated with tocilizumab, but in limited samples. The aim of this study was to investigate the predictive risk factors for serious infections in the largest European registry of patients treated with tocilizumab for RA. Methods: A total of 1491 RA patients included in the French REGistry-RoAcTEmra were analysed to calculate the incidence rate of first serious infections rate after initiation of tocilizumab. To identify independent factors associated with serious infections, a Cox model was performed. Results: Among the 1491 patients, average age 56.6 (13.6) years, 125 serious infections occurred in 122 patients (incidence rate of serious infection: 4.7/100 patient-years). Univariate analysis identified initial ACPA positivity as the only factor associated with a lower risk of serious infection [hazard ratio (HR) = 0.56, 95% CI: 0.36, 0.88]. Other factors significantly associated with a higher risk of serious infections were DAS28, concomitant Leflunomide (LEF) treatment, and absolute neutrophil count (ANC) at baseline. Initial ANC above 5.0 × 109/l (HR = 1.94, 95% CI: 1.32, 2.85; P < 0.001), negative ACPA (HR = 1.79, 95% CI: 1.15, 2.78; P = 0.012) at baseline and concomitant LEF treatment (LEF alone vs no treatment, HR = 2.18, 95% CI: 1.22, 3.88; P = 0.009) remained significantly associated with first serious infections in multivariate analysis after imputation for missing data. Conclusion: The rate of first serious infections in current practice is similar to that reported in clinical trials. High ANC (above 5.0 × 109 at baseline), negative ACPA and concomitant therapy with LEF are predictive factors of serious infection, requiring in this case a tighter surveillance.

Autoantibodies to human citrullinated fibrinogen and their subfamilies to the α36-50Cit and ß60-74Cit fibrin peptides similarly predict radiographic damages: a prospective study in the French ESPOIR cohort of very early arthritides.

OBJECTIVE: To investigate whether subfamilies of the RA-specific autoantibodies to human citrullinated fibrinogen (AhFibA) differentially associate with the RA risk factors, HLA-DRB1 shared epitope containing alleles (SE alleles) and cigarette smoking, and thus help to predict the disease outcome. METHODS: AhFibA and their anti-α36-50Cit and anti-ß60-74Cit subfamilies were assayed by ELISA, at baseline, in the French ESPOIR (Etude et Suivi des Polyarthrites Indifférenciées Récentes) cohort composed of undifferentiated arthritides and RA patients of < 6 months' duration. Cigarette smoking, SE alleles' presence, DAS28, HAQ and modified Sharp-van der Heijde Score data were obtained at baseline, and after follow-up. RESULTS: After 3 years, 701 patients were classified as having RA according to the ACR/EULAR 2010 criteria. Among them, 349 (50%), 203 (29%) and 257 (37%) were AhFibA-, anti-α36-50Cit- and anti-ß60-74Cit-positive, respectively. The presence and titres of AhFibA and their subfamilies similarly associated with SE alleles, irrespective of their fine specificity, without significant effect of smoking. Neither their presence nor their titre was associated with DAS28 or HAQ. The presence of at least one subfamily was associated with a faster Sharp/van der Heijde score progression, albeit without correlation with the titre. CONCLUSION: AhFibA and their main subfamilies are similarly associated with SE alleles without additional effect of smoking. Whatever their fine specificity was, their presence (but not their titre) similarly constituted a marker of faster joint destruction.

Non-TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial.

IMPORTANCE: One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists. OBJECTIVE: To compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor. DESIGN, SETTING, AND PARTICIPANTS: A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013. INTERVENTIONS: Patients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections. RESULTS: Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003). CONCLUSIONS AND RELEVANCE: Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000441.