AB0243 CONSIDERING THE COMBINATION OF TWO BIOLOGICS IN CASE OF FAILURE OF THE MONOTHERAPY IN JUVENILE ONSET RHEUMATOID ARTHRITIS

Background:The management of rheumatoid arthritis refractory to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) is currently well codified and includes different types of biologics and even targeted sDMARDs. A rotation of biologic therapies is recommended in order to better control the disease.Methods:We report the case of a 20-year-old patient followed in our hospital for the management of a deforming and erosive seropositive rheumatoid arthritis (FR +, ACPA +) with a juvenile onset at the age of 8 years. The diagnosis of an immunopositive polyarticular form of JIA was retained in 2010 (9 years old); the patient was treated with methotrexate (MTX) at a dose of 10 mg per week and methylprednisolone at doses varying between 4 and 10 mg per day. Following the failure of MTX, etanercept was introduced for 6 months without success, followed by tocilizumab in 2012 at a dose of 8mg/kg/month for a year, without good response. In 2014, a course of rituximab (RTX) at a dose of 2 shots of 500mg, 2 weeks apart was prescribed followed 9 months later by etanercept at a dose of 50 mg a week for 3 years then by adalimumab (40mg/ week) because of the multiple treatment failures.In 2018, the repetition of RTX at a dose of 1g, renewed 15 days later, improved the patient for only 3 months. Then, a combination of two biologics, namely RTX (2 x 1g, 15 days apart) and adalimumab 1 month later (40mg / week) was received by the patient with a good response at 3 months. The latter was maintained for 7 months even after stopping the adalimumab following confinement for COVID-19. In September 2020, flares occurred and the adalimumab (ADA) has been delivered but without success during 3 months, stopped later for a benign form of COVID-19 (15 months after RTX). In January 2021, the association RTX + ADA was given again and we hope that it will be as effective as the first prescription.Results:The clinical and biological severity of our patient’s rheumatoid arthritis led us to give a combination of two biological treatments. Indeed, we do not have other therapeutic classes to deliver to her, that encouraged us to rotate between all the available biological therapies in our country. The combination of a CD20 inhibitor (RTX) with a TNF blocker (ADA) was safe and made possible, for the first time, the achievement of clinical and biological remission during 7 months, even after stopping the TNF blocker. Greenwald et al. reported the safety of the combination of RTX + TNF inhibitors in a randomized clinical trial in 51 patients. Its efficacy, a secondary goal of the study, was suggested at 24 weeks by the percentage of ACR 20 and ACR 50 responses that was greater than in the RTX placebo group.Conclusion:The combination of RTX with a TNF blocker can be a real alternative therapy in rheumatoid arthritis with failure to a biological monotherapy.Disclosure of Interests:None declared

Immune response profiling of patients with spondyloarthritis reveals signalling networks mediating TNF-blocker function in vivo

ObjectivesAntitumour necrosis factor (TNF) therapy has revolutionised treatment of several chronic inflammatory diseases, including spondyloarthritis (SpA). However, TNF inhibitors (TNFi) are not effective in all patients and the biological basis for treatment failure remains unknown. We have analysed induced immune responses to define the mechanism of action of TNF blockers in SpA and to identify immunological correlates of responsiveness to TNFi.MethodsImmune responses to microbial and pathway-specific stimuli were analysed in peripheral blood samples from 80 patients with axial SpA before and after TNFi treatment, using highly standardised whole-blood stimulation assays. Cytokines and chemokines were measured in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, and gene expression was monitored using nCounter assays.ResultsAnti-TNF therapy induced profound changes in patients’ innate immune responses. TNFi action was selective, and had only minor effects on Th1/Th17 immunity. Modular transcriptional repertoire analysis identified prostaglandin E2 synthesis and signalling, leucocyte recirculation, macrophage polarisation, dectin and interleukin (IL)-1 signalling, as well as the nuclear factor kappa B (NF-kB) transcription factor family as key pathways targeted by TNF blockers in vivo. Analysis of induced immune responses before treatment initiation revealed that expression of molecules associated with leucocyte adhesion and invasion, chemotaxis and IL-1 signalling are correlated with therapeutic responses to anti-TNF.ConclusionsWe show that TNFi target multiple immune cell pathways that cooperate to resolve inflammation. We propose that immune response profiling provides new insight into the biology of TNF-blocker action in patients and can identify signalling pathways associated with therapeutic responses to biological therapies.

SAT0488 ETANERCEPT CONCENTRATION IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Background:Etanercept (ETN) is the most used TNF blocker in children with JIA. There is still limited real-life data of etanercept concentrations in children, especially in association with dosing.Objectives:The aim of the study was to investigate association between ETN dosing and serum trough concentration in children with non-systemic JIA.Methods:We conducted a multicenter retrospective study of 180 Finnish JIA patients (Table 1) receiving ETN either as monotherapy or in combination with one or more DMARDs (Table 2). Prior biologicals were used by 17 % of the patients. Patients were divided into two groups, ETN started before or after one year of diagnosis (Figure 1). ETN concentration samples (collected 2014-2017) were analyzed using validated enzyme-linked immunosorbent assay (ELISA) in Sanquin Diagnostics, Amsterdam, the Netherlands.Results:Demographics at etanercept start and diagnoses are shown in Table 1. Duration of the treatment with ETN, ETN doses, concentrations and concomitant medications at the time of concentration measurement are shown in Table 2.Association between ETN dose and concentration is shown in Figure 1.Those who started medication early (< 1 year from diagnosis) were younger than those who started later (Table 1) and association between ETN dose and concentration was more obvious (Figure 1).Conclusion:There was an association between etanercept dose used and serum trough concentration and it was more evident when medication was started early after diagnosis, when the patients were younger and BSA lower.References:[1]Kneepkens EL et al. Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up. Ann Rheum Dis 2015;74(10):1825-9.[2]Bader-Meunier B et al. Etanercept concentration and immunogenicity do not influence the response to Etanercept in patients with juvenile idiopathic arthritis. Semin Arthritis Rheum 2019;48(6):1014-1018.Disclosure of Interests:None declared

Management – medikamentöse und nicht-medikamentöse Therapie der axialen Spondyloarthritis

ZusammenfassungDer Begriff axiale Spondyloarthritis umfasst sowohl Patienten mit schon vorhandenen Röntgenveränderungen in den Sakroiliakalgelenken oder der Wirbelsäule als auch Patienten in der früheren rein entzündlichen Phase ohne strukturelle Knochenveränderungen. Die Grundlagen der Therapie sind physikalische Therapie und nicht-steroidale Antirheumatika, konventionelle DMARDs spielen im therapeutischen Vorgehen keine Rolle. Die klinische Krankheitsaktivität wird gemessen mit zusammengesetzten Scores, dem BASDAI und dem ASDAS, wobei letzterer außer ‚patient reported outcome‘ – Parametern auch das CRP enthält. Sind Patienten weiterhin aktiv trotz konventioneller Therapie, kommen Biologika zum Einsatz, TNF-Blocker oder IL-17-Inhibitoren. Im Gegensatz zu anderen chronisch-entzündlichen Erkrankungen haben sich andere bisher getestete Biologika als ineffektiv erwiesen, JAK-Inhibitoren könnten eine weitere Therapiemöglichkeit für die Zukunft darstellen. Zur Zeit lässt sich nicht voraussagen, welche axSpA Patienten auf welches Biologikum besser ansprechen.

Tumor Necrosis Factor (TNF) Blocking Agents are Associated with Lower Risk for Alzheimer’s Disease in Patients with Rheumatoid Arthritis and Psoriasis

This large, retrospective case-control study of electronic health records from 56 million unique adult patients examined whether or not treatment with a Tumor Necrosis Factor (TNF) blocking agent is associated with lower risk for Alzheimer’s disease (AD) in patients with rheumatoid arthritis (RA), psoriasis, and other inflammatory diseases which are mediated in part by TNF and for which a TNF blocker is an approved treatment. The analysis compared the diagnosis of AD as an outcome measure in patients receiving at least one prescription for a TNF blocking agent (etanercept, adalimumab, and infliximab) or for methotrexate. Adjusted odds ratios (AORs) were estimated using the Cochran-Mantel-Haenszel (CMH) method and presented with 95% confidence intervals (CIs) and p-values. RA was associated with a higher risk for AD (Adjusted Odds Ratio (AOR) = 2.06, 95% Confidence Interval: (2.02-2.10), P-value <0.0001) as did psoriasis (AOR = 1.37 (1.31-1.42), P <0.0001), ankylosing spondylitis (AOR = 1.57 (1.39-1.77), P <0.0001), inflammatory bowel disease (AOR = 2.46 (2.33-2.59), P < 0.0001), ulcerative colitis (AOR = 1.82 (1.74-1.91), P <0.0001), and Crohn’s disease (AOR = 2.33 (2.22-2.43), P <0.0001). The risk for AD in patients with RA was lower among patients treated with etanercept (AOR = 0.34 (0.25-0.47), P <0.0001), adalimumab (AOR = 0.28 (0.19-0.39), P < 0.0001), or infliximab (AOR = 0.52 (0.39-0.69), P <0.0001). Methotrexate was also associated with a lower risk for AD (AOR = 0.64 (0.61-0.68), P <0.0001), while lower risk was found in patients with a prescription history for both a TNF blocker and methotrexate. Etanercept and adalimumab also were associated with lower risk for AD in patients with psoriasis: AOR = 0.47 (0.30-0.73 and 0.41 (0.20-0.76), respectively. There was no effect of gender or race, while younger patients showed greater benefit from a TNF blocker than did older patients. This study identifies a subset of patients in whom systemic inflammation contributes to risk for AD through a pathological mechanism involving TNF and who therefore may benefit from treatment with a TNF blocking agent.

Facettenreiche Symptomatik mit Gelenkschmerzen, Exanthem und Augenbeteiligung

Zusammenfassung Anamnese und klinischer Befund In dieser Fallserie stellen wir 4 Patienten vor, die mit unterschiedlichen Symptomen in unserer rheumatologischen Spezialklinik vorgestellt wurden und die letztlich dieselbe Erkrankung hatten. Zu dem breiten Spektrum der vorliegenden Symptome gehörten neben Arthralgien und Myalgien auch ein makulopapulöses Exanthem und eine Sehstörung. Ein Patient wurde wegen aktiver ankylosierender Spondylitis und rezidivierender Uveitis mit einem TNF-Blocker behandelt. In der klinischen Untersuchung wurden Gelenkschwellungen und Hautveränderungen festgestellt. Untersuchungen Serologisch wurden bei allen Patienten ein erhöhter TTPA- sowie ein positiver RPR-Test festgestellt. Diagnose Bei den Patienten wurde Syphilis diagnostiziert. Therapie und Verlauf Die ersten 3 Patienten erhielten eine einmalige intramuskuläre Injektion mit 2,4 Mil. Benzathinpenicillin G. Der 4. Patient wurde mit Penicillin 6 Mio 4/d i. v. über 14 Tage aufgrund seiner bestehenden Immunsuppression behandelt. Folgerung Bei Vorliegen unspezifischer und zum Teil diffuser Symptome, mit welchen sich Patienten in der Rheumatologie häufig stellen, kann ätiopathogenetisch auch eine nicht primär rheumatologische, z. B. infektiöse Genese vorliegen. Die in den letzten Jahren in Deutschland wieder zunehmende Inzidenz der Syphilis ist auch in der rheumatologischen Versorgung zu beachten.