Association between Carotid Intima-Media Thickness and the Use of Biological or Small Molecule Therapies in Patients with Rheumatoid Arthritis

Objective: The objective of this study was to assess the association of carotid intima-media thickness (CIMT), and also the presence of atheromatous plaque, with biological and targeted synthetic disease-modifying antirheumatic drugs, in an established cohort of patients with rheumatoid arthritis (RA). Patients and Methods: We conducted a cross-sectional observational study based on a cohort of patients with RA and a registry of healthy controls, in whom the CIMT and presence of atheromatous plaque were assessed by ultrasound. Data were collected on disease activity, lab results and treatments. Descriptive and bivariate analyses were performed and two multivariate linear regression models (with CIMT as the dependent variable) were constructed to identify variables independently associated with CIMT in our sample of patients with RA. Results: A total of 176 individuals (146 patients with RA and 30 controls) were included. A higher percentage of patients than controls had atheromatous plaque (33.8% vs. 12.5%, p = 0.036), but no differences were found in terms of CIMT (0.64 vs. 0.61, p = 0.444). Compared to values in patients on other therapies, the CIMT was smaller among patients on tumour necrosis factor alpha (TNFα) inhibitors (mean [SD]: 0.58 [0.10] vs. 0.65 [0.19]; p = 0.013) and among those on Janus kinase inhibitors (mean [SD]: 0.52 [0.02] vs. 0.64 [0.18]; p < 0.001), while no differences were found as a function of the use of the other therapies considered. The multivariate linear regression analysis to identify factors associated with CIMT in our patients, adjusting for traditional cardiovascular risk factors such as hypertension, high levels of low-density lipoproteins, diabetes mellitus and smoking, showed that male sex, older age and having a greater cumulative erythrocyte sedimentation rate were independently associated with a larger CIMT, while patients on TNFα inhibitors had a CIMT 0.075 mm smaller than those on other treatments. Conclusions: The use of TNFα inhibitors may protect against subclinical atherosclerosis in patients with RA, patients on this biologic having smaller CIMTs than patients on other disease-modifying antirheumatic drugs. Nonetheless, these results should be confirmed in prospective studies with larger sample sizes.

Performance of 4 methods for screening of latent tuberculosis infection in patients with chronic inflammatory arthritis under TNFα inhibitors: a 24-month prospective study

Background The reactivation rate of tuberculosis in patients with chronic inflammatory arthritis (CIA) on TNFα inhibitors (TNFi) and baseline negative screening for latent tuberculosis infection (LTBI) is higher than in the general population. Aim To compare the performance of tuberculin skin test (TST), TST-Booster, ELISPOT (T-SPOT.TB) and QuantiFERON-TB Gold in tube (QFT-IT) to detect LTBI in patients with CIA on TNFi. Patients and methods A total of 102 patients with CIA [rheumatoid arthritis (RA), n = 40; ankylosing spondylitis (AS), n = 35; psoriatic arthritis (PsA), n = 7; and juvenile idiopathic arthritis (JIA), n = 20] were prospectively followed-up for 24 months to identify incident LTBI cases. Epidemiologic data, TST, T-SPOT.TB, QFT-IT and a chest X-ray were performed at baseline and after 6 months of LTBI treatment. Results Thirty six percent (37/102) of patients had positive TST or Interferon Gamma Release Assays (IGRAs) tests. Agreement among TST and IGRAs was moderate (k = 0.475; p = 0.001), but high between T-SPOT.TB and QFT-IT (k = 0.785; p < 0.001). During the 24-Month follow-up, 15 (18.5%) incident cases of LTBI were identified. In comparison to TST, the IGRAs increased the LTBI diagnosis power in 8.5% (95% CI 3.16–17.49). TST-Booster did not add any value in patients with negative TST at baseline. After 6-Month isoniazid therapy, IGRAs results did not change significantly. Conclusions Almost 20% of CIA patients had some evidence of LTBI, suggesting higher conversion rate after exposition to TNFi. TST was effective in identifying new cases of LTBI, but IGRAs added diagnostic power in this scenario. Our findings did not support the repetition of IGRAs after 6-Month isoniazid therapy and this approach was effective to mitigate active TB in 2 years of follow-up.

TNF-Induced Lupus. A Case-Based Review

: Nowadays, tumor necrosis factor alpha (TNFα) inhibitors have revolutionised the treatment of inflammatory arthritides by demonstrating efficacy with an acceptable toxicity profile. However, autoimmune phenomena and clinical entities have been reported ranging from an isolated presence of autoantibodies to full-blown autoimmune diseases, among them, drug-induced lupus (DIL). Case Presentation: A 62-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate and prednisone, was treated with adalimumab (ADA). 4 months later, she presented acute cutaneous eruptions after sun exposure, positive ANA (1/640 fine speckled pattern), Ro (SSA) and anti-Smith (Sm) antibodies with no other clinical or laboratory abnormalities. The diagnosis of DIL was made, ADA was discontinued and she was treated successfully with prednisone plus local calcineurin inhibitors. Conclusion: Thus, we review the literature for cases of DIL development in patients treated with TNFα inhibitors. Rheumatologists should be aware of the possible adverse events and the requirement of careful clinical evaluation and monitoring.

Differential impacts of TNFα inhibitors on the transcriptome of Th cells

Background Targeting TNFα is beneficial in many autoimmune and inflammatory diseases, including rheumatoid arthritis. However, the response to each of the existing TNFα inhibitors (TNFis) can be patient- and/or disease-dependent. In addition, TNFis can induce the production of type 1 interferons (IFNs), which contribute to their non-infection side effects, such as pustular psoriasis. Thus far, the molecular mechanisms mediating the drug-specific effects of TNFis and their induction of type 1 IFNs are not fully understood. Methods Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors and stimulated in vitro with anti-CD3 and anti-CD28 in the absence or presence of adalimumab, etanercept, or certolizumab. Th cells were isolated from the stimulated PBMCs, and their RNA was subjected to RNA-seq and quantitative polymerase chain reaction. Results Adalimumab and etanercept, which contain Fc, but not certolizumab, which does not contain Fc, inhibited the expression of several effector cytokines by Th cells within anti-CD3/anti-CD28-stimulated PBMCs. Transcriptomic analyses further showed that adalimumab, but not certolizumab, reciprocally induced type 1 IFN signals and the expression of CD96 and SIRPG in Th cells. The unique effects of adalimumab were not due to preferential neutralization of soluble TNFα but instead were mediated by several distinct mechanisms independent or dependent of Fc-facilitated physical interaction between Th cells and CD14+ monocytes. Conclusions TNFis can have drug-specific effects on the transcriptional profile of Th cells.

Treatment of ankylosing spondylitis during pregnancy

Aims of the trial – to study the frequency of drug use in pregnant women with ankylosing spondylitis (AS), to determine the effect of discontinuation of drugs of various groups, as well as the dose of non-steroidal anti-inflammatory drugs (NSAIDs) used, on AS activity during gestation.Material and methods. 50 pregnancies in 49 patients with AS that met the modified New York criteria of 1984. The average age of the patients was 31.7±4.9 years, the duration of the disease was 134.4±85.8 months. The visits were conducted at 10–11, 20–21 and 31–32 weeks of gestation. The BASDAI in the month of conception and in the I, II and III trimesters of pregnancy was: 1.4 [0.6; 3.3], 2.3 [1.2; 4.4], 2.8 [1.4; 4.2] and 2.2 [1.6; 4.0], respectively. The total dose of NSAIDs was determined by the NSAID intake index (Dougados M., 2011).Results and discussion. NSAIDs. After inclusion in the study, the drug of choice was ibuprofen, which was canceled for all women not later than on 32 week of gestation. At the time of conception and in the first, second and third trim. NSAIDs were taken by 23 (46%), 20 (40%), 30 (60%) and 21 (43.8%) women, respectively. NSAIDs intake index in I trimester (5.8 [2.9; 11.8]) was lower than before pregnancy (28.6 [16.7; 50]) and in II (15.5 [4.7; 30.9]) and III trimesters (24.4 [9.5; 50]) (p<0.05). No relationship between the index of ibuprofen intake, as well as the fact of withdrawal of NSAIDs and AS activity throughout gestation was found. Sulfasalazine (SS) in correspondence with arthritis was taken 3 months before conception by 11 (22%) women, during pregnancy – by 6 (12%) women at a dose of 1.25±0.25 g. Withdrawal of SS was not associated with recurrence of arthritis. Glucocorticoids (GC) at a dose of 7.5±2.5 mg 3 months before pregnancy and in the I, II and III trimesters of pregnancy were taken by 1 (2%), 4 (8%), 8 (16%) and 10 (20.8%) women, of whom 1 patient had arthritis and 1 had inflammatory bowel disease. The rest of the patients received GC due to high AS activity due to axial manifestations and the unavailability of TNFα inhibitors. Against the background of taking GC, the AS activity did not decrease: BASDAI in the II and III trimesters was 5.5±0.6 and 5.8±1.3 (p>0.05). TNFα inhibitors: 3 months before pregnancy and in the trim. of pregnancy were taken by 11 (22%), 7 (14%), 6 (12%) and 2 (4.2%) patients. In those who canceled therapy (both independently and on the recommendation of a rheumatologist) on the eve of pregnancy, an increase in AS activity was noted; BASDAI in the month of conception and in I, II, III trimesters was: 2.7 [0.8; 3.5], 5.1 [3.1; 5.9], 5.5 [5; 6] and 6.7 [5.3; 7.3] (p<0.05) compared to the month of conception. Cancellation of TNF-α in the month of conception was a risk factor for high AS activity (BASDAI>4) in the II trimester (OR=30.4; 95% CI: 1.5–612.3; p=0.03) and in the III trimester (OR=32.7; 95% CI: 1.6–662.2; p=0.02).Conclusion. NSAIDs and GC in low doses do not reduce the activity of AS. Withdrawal of TNF-α inhibitors on the eve of pregnancy is a predictor of high AS activity. It is necessary to increase the knowledge of rheumatologists and patients about the therapeutic possibilities during pregnancy to avoid unjustified drug withdrawal.

OP0052 FACTORS ASSOCIATED WITH REMISSION AT 5 YEARS OF FOLLOW-UP IN EARLY ONSET AXIAL SPONDYLOARTHRITIS: RESULTS FROM THE DESIR COHORT

Background:The disease course of axial SpA (axSpA) is highly variable and can be characterized by ongoing axial inflammation and radiographic progression associated with restricted mobility of the spine, reduced function and disability leading to impairment in quality of life. Control of disease activity is a primary aim in axSpA management. To assess disease activity the Ankylosing Spondylitis Disease Activity Score-C-reactive protein (ASDAS-CRP) is often considered as a reference tool. The data on remission are spare in axSpA and the identification of long-term remission factors, enabling the patient’s management to be adapted, seems necessary but remains unclear.Objectives:To evaluate the proportion of patients in remission according to ASDAS-CRP at 5 years of follow-up, to describe their characteristics in comparison with patients with active disease at that time, and to identify baseline factors associated with remission at 5 years of follow-up.Methods:We included all patients from the DESIR (Devenir des Spondylarthropathies Indifférenciées Récentes) cohort with available data on ASDAS-CRP at 5-year follow-up and TNFα inhibitors exposure. Patients in remission, defined as an ASDAS-CRP<1.3, and with active disease were compared according to their main demographic, clinical, biological and radiological characteristics. A logistic model stratified on TNFα inhibitors exposure was used in the main analysis. Sensitivity analyses among patients with axSpA diagnosis confirmed by rheumatologist at 5-years were performed.Results:A total of 614 patients were followed in the DESIR cohort at M60. After excluding those with missing data on ASDAS score (n= 163) and TNFα inhibitors exposure (n= 2), analyzed patients were 449 (73%). Excluded patients had similar baseline characteristics to those included in the analysis. Among patients unexposed to TNFα inhibitors (n=247), 77 (31%) were in remission (37,8±8,3 years; 55% men, 58% NSAID users), 170 (69%) weren’t (39,8±8,6 years; 42% men, 81% NSAID users). Among exposed patients (n=202), 34 (17%) were in remission (36,1±8,1 years; 71% men, 29% NSAID users), 168 (83%) weren’t (39,5±9,0 years; 41% men, 63% NSAID users) (Figure 1). Overall, patients in remission were more frequently men, HLA-B27+, with high education and lower BMI at 5-year of follow-up. The baseline factors associated with remission at 5 years of follow-up from the multivariate analysis are presented in Table 1.Table 1.Baseline factors associated with remission at 5-year follow-up (multivariate analysis)TNFα: Tumor Necrosis Factor alpha; ORa: adjusted Odd Ratio; 95%IC: 95% confidence interval; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BMI: Body Mass Index.Conclusion:The overall remission rate at 5 years was 25%, 31% among patients unexposed to TNFα inhibitors and 17% among those exposed. This study reveals the difficulty in achieving 5-year remission in recent axSpA, especially in the most active forms at baseline; socio-educational factors and overweight also appear to be related.Acknowledgements:L Pina Vegas received a Master 2 grant from the French Society of Rheumatology (Bourse Master 2ème Année 2019)Disclosure of Interests:Laura Pina Vegas: None declared, Emilie Sbidian: None declared, Daniel Wendling: None declared, Philippe Goupille: None declared, Salah Ferkal: None declared, Philippe Le Corvoisier: None declared, Bijan Ghaleh: None declared, Alain Luciani: None declared, Pascal Claudepierre Speakers bureau: Abbvie, Janssen, Lilly, MSD, Novartis, Pfizer, Consultant of: Abbvie, Pfizer, Roche-Chugai, Bristol-Myers Squibb, MSD, UCB, Novartis, Janssen, Lilly, Celgene (consulting fees, less than 10,000 $ each)., Employee of: Roche Chugai, Sanofi Aventis, Celgene, Pfizer, MSD, Novartis and BMS (investigator).

POS0085 EVALUATION OF DURATION OF CLINICAL REMISSION IN CHILDREN WITH NON-SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS AFTER WITHDRAWAL OF ANTI – TUMOR NECROSIS FACTOR - ALPHA THERAPY

Background:Juvenile idiopathic arthritis (JIA) is the most common and prevalent rheumatic disease in childhood which is based on a chronic autoimmune inflammation. Inactive disease and remission are now the primary treatment goal in JIA and biologics have been playing an important role to reach this objective.The biologics of the first choice for the treatment of non-systemic JIA are the Tumor Necrosis Factor - alpha (TNFα) inhibitors; on this therapy patients can achieve clinically inactive disease and long-term remission.Currently, little is known about when or how to stop TNFα inhibitors, when a good clinical response is achieved, and therefore no guidelines are available.Objectives:To estimate the length of clinical remission after discontinuation of treatment with TNFα inhibitors in patients with non-systemic juvenile idiopathic arthritis.Methods:A total of 393 patients with JIA who were treated with TNFα inhibitors at the Rheumatology Department of the National Medical Research Center of Children’s Health (Moscow, Russia) were screened for inclusion in this retrospective study.Patients were treated with etanercept 1 times a week, 0.8 mg per kg of body weight per dose, with adalimumab 24 mg/m2 body surface area administered every other week until the end of therapy.Treatment was terminated abruptly. Inactive disease was defined according to the preliminary criteria of Wallace et al.[1]Results:77 patients (27—male, 50—female) with a mean age at diagnosis of 4 years (range 1–18 years) were included in the analysis. Of those, 69 of them discontinued TNFα inhibitors due to a long-term remission on treatment, 8 patients as a result of side effects, and there were excluded from our study.:allergic reaction (n = 5), development of uveitis (n = 1), alopecia (n = 1), recurrent infection (n=11).The clinical subtypes of JIA were RF-negative polyarticular JIA -28 (40,58%) oligoarthritis—38 (55,07%), enthesitis-related arthritis—3 (4,35%).TNFα inhibitors were started after a mean 46,43 (range 1–144) months of disease. The mean duration of therapy with TNFα inhibitors were 46,63 (range 10-113) months, with a mean duration of remission on medication 40,63 (range 6-107) months before withdrawal of TNFα inhibitors.40/69 (57,97 %) patients did not develop a disease exacerbation and remained in long-term remission off medication—more than 24 months.Early flares, that is less than 6 months after termination of TNFα inhibitors, were observed in 4/69 (5,8%) patients.29 (42,03%) patients restarted TNFα inhibitors after exacerbation, due to lack of improvement after no biological DMARDs. All patients in whom TNFα inhibitors were reinitiated responded satisfactorily.Conclusion:Among patients with JIA in whom TNFα inhibitors were discontinued after inactive disease was achieved, 57,97 % had disease in clinical remission more than 24 months after stopping anti-TNFα therapy. No association was observed between the duration of inactive disease prior to TNFα inhibitors cessation and the time to disease relapse. In addition, we also ob- served no correlation between the risk of flare and the length of anti-TNF α therapy after inactive disease was achieved. In our population, TNFα antagonists were withdrawn a median of 38 (4-107) months after inactive disease was achieved. Data from our experience with anti-TNF α agents in the treatment of JIA suggest that 57,97 % of patients can be successfully withdrawn from TNF α antagonists for at least 24 months.References:[1]Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N, for the Childhood Arthritis and Rheumatology Research Alliance (CARRA), the Pediatric Rheumatology Collaborative Study Group (PRCSG), and the Paediatric Rheumatology Interna- tional Trials Organisation (PRINTO). American College of Rheumatology provisional criteria for defining clinical in- active disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011;63:929–36.Disclosure of Interests:None declared.