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BackgroundDespite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have ‘difficult-to-treat RA’. However, uniform terminology and an appropriate definition are lacking.ObjectiveThe Task Force in charge of the “Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis” aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to-treat RA, as the first step.MethodsThe Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting).ResultsThe following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: (1) Treatment according to European League Against Rheumatism (EULAR) recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated); (2) presence of at least one of the following: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; and (3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient.ConclusionsThe proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research.

Background: The majority of patients with rheumatoid arthritis (RA) produce autoantibodies against proteins that have undergone post-translational modfication, e.g. citrullination or carbamylation. There is growing evidence of their relevance and their potential utility to improve diagnosis, patient stratification, and prognosis for precision medicine. Investigating new autoantibody patterns may allow further stratification of patients and identifying subsets of patients that benefit from different treatment modalities. Following the discovery of high autoantibody reactivity against multiple modified proteins the interest in native targets decreased. Even though antibodies reacting with native proteins may also have a role in RA pathogenesis, their reactivity patterns are much less studied.Objectives: To identify novel native autoantigens in RA patients and elucidate patterns within autoantibody reactivity against native autoantigens.Methods: We investigated the reactivity of autoantibodies in plasma pools from 15 anti-CCP positive and 10 anti-CCP negative RA patients and 10 healthy donors against more than 1600 human proteins in native configuration using the Immunome high-density protein microarray.Results: We identified 86 native proteins that were recognized by IgG antibodies from anti-CCP positive RA patients and 76 native proteins recognized by IgG antibodies from anti-CCP negative RA patients, but not by antibodies from healthy donors. Examples of proteins recognized by both patient subgroups are calcium/calmodulin-dependent protein kinase type II subunits, histone deacetylases, keratin, and vimentin. Reactivity against the ribonucleic protein SSB was observed in anti-CCP negative RA patients only.Conclusion: Several human proteins in their native conformation are recognized by autoantibodies from anti-CCP positive as well as anti-CCP negative RA patients. In general, anti-CCP positive patients had higher autoantibody activity than anti-CCP negative patients and healthy donors.References: [1] Konig, M.F., Giles, J.T., Nigrovic, P.A., Andrade, F., 2016. Antibodies to native and citrullinated RA33 (hnRNP A2/B1) challenge citrullination as the inciting principle underlying loss of tolerance in rheumatoid arthritis. Ann. Rheum. Dis. 75, 2022textendash2028.[2] Zheng, Z., Mergaert, A.M., Fahmy, L.M., Bawadekar, M., Holmes, C.L., Ong, I.M., Bridges, A.J., Newton, M.A., Shelef, M.A., 2019. Disordered Antigens and Epitope Overlap Between Anti-Citrullinated Protein Antibodies and Rheumatoid Factor in Rheumatoid Arthritis. Arthritis Rheumatol. art.41074.[3] Sirotti, S., Generali, E., Ceribelli, A., Isailovic, N., De Santis, M., Selmi, C., 2017. Personalized medicine in rheumatology: the paradigm of serum autoantibodies. Autoimmun. Highlights 8.Acknowledgments : The Department of Clinical Immunology at Rigshospitalet Copenhagen is acknowledged for providing the healthy donor blood. The study is part of the PROCIT study financed by the Danish Council for Independent Research (grant no. DFF - 7016-00233). Moreover, the Obelske Family Foundation, the Svend Andersen Foundation, the Spar Nord Foundation and the Danish National Mass Spectrometry Platform for Functional Proteomics (PRO-MS; grant no. 5072-00007B) are acknowledged for grants to the analytical platform are acknowledged for the funding to enabling parts of this study.Disclosure of Interests: Thomas B.G. Poulsen: None declared, Dres Damgaard: None declared, Malene Møller Jørgensen: None declared, Ladislav Senolt: None declared, Jonathan Blackburn Shareholder of: Sengenics Corporation, Consultant of: Director of Sengenics Corporation, Employee of: Director of Sengenics Corporation, Claus Henrik Nielsen: None declared, Allan Stensballe: None declared

ObjectivesPatients with difficult-to-treat rheumatoid arthritis (RA) remain symptomatic despite treatment according to current European League Against Rheumatism (EULAR) management recommendations. These focus on early phases of the disease and pharmacological management. We aimed to identify characteristics of difficult-to-treat RA and issues to be addressed in its workup and management that are not covered by current management recommendations.MethodsAn international survey was conducted among rheumatologists with multiple-choice questions on disease characteristics of difficult-to-treat RA. Using open questions, additional items to be addressed and items missing in current management recommendations were identified.Results410 respondents completed the survey: 50% selected disease activity score assessing 28 joints >3.2 OR presence of signs suggestive of active disease as characteristics of difficult-to-treat RA; 42% selected fatigue; 48% selected failure to ≥2 conventional synthetic disease-modifying antirheumatic drugs (DMARDs) AND ≥2 biological/targeted synthetic DMARDs; 89% selected inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily. Interfering comorbidities, extra-articular manifestations and polypharmacy were identified as important issues missing in current management recommendations.ConclusionsThere is wide variation in concepts of difficult-to-treat RA. Several important issues regarding these patients are not addressed by current EULAR recommendations.