Difficult to treat rheumatoid arthritis: Sequential therapy with different personalized biological targets could be an option

Difficult to treat (D2T) rheumatoid arthritis (RA) is considered a clinical setting that physicians already label as very complicated to address from a therapeutic point of view for various reasons [ [1] Nagy G. Roodenrijs N.M.T. Welsing P.M. et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis. 2021; 80 (Epub 2020 Oct 1. PMID: 33004335; PMCID: PMC7788062): 31-35https://doi.org/10.1136/annrheumdis-2020-217344 Crossref Scopus (192) Google Scholar ]. In particular, the Committee that developed the definition of D2T established that, to label a patient as D2T, >2 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and ≥2 biologic (b) or targeted synthetic (ts) DMARDs with different mode of action should have failed, together with another clinical or radiological item among: -at least moderate disease activity (according to validated composite measures including joint counts, e.g. DAS28-ESR>3.2 or CDAI>10); -signs (including acute phase reactants and imaging) and/or symptoms suggestive of active disease; -inability to taper glucocorticoid treatment (below 7.5 mg/day of prednisone equivalent); -rapid radiographic progression (with or without signs of active disease); -well-controlled disease according to the above standards, but still having RA symptoms that cause a reduction in quality of life. This definition encompasses around 4–20 % of RA patients attending a clinic [ [2] Messelink M.A. Roodenrijs N.M.T. van Es B. et al. Identification and prediction of difficult-to-treat rheumatoid arthritis patients in structured and unstructured routine care data: results from a hackathon. Arthritis Res Ther. 2021; 23 (PMID: 34238346; PMCID: PMC8265126): 184https://doi.org/10.1186/s13075-021-02560-5 Crossref Scopus (12) Google Scholar , [3] David P. Di Matteo A. Dass S. Marzo-Ortega H. Wakefield R.J. Bissel L.A. et al. Poly-refractory Rheumatoid Arthritis: an uncommon subset of difficult to treat disease with distinct inflammatory and non-inflammatory phenotypes. Arthritis Rheumatol. 2023; (accepted 7 December - h t t p s:/ /doi- org. ezproxy.unicatt.it/10.1002/art.42767) Crossref Google Scholar ]. Among the relevant clinical elements that contribute to the D2T state, the patient phenotype appears really important. It has been stated that various factors can contribute to a poor response to a specific bDMARD (i.e., obesity, smoking, concomitant fibromyalgia, pharmacogenetics, etc., which can strongly influence the underlying immunology) and of course each factor determines a personalized phenotype [ [4] de Hair M.J.H. Jacobs J.W.G. Schoneveld J.L.M. et al. Difficult-to-treat rheumatoid arthritis: an area of unmet clinical need. Rheumatology (Oxford). 2018; 57 (PMID: 29029308): 1135-1144https://doi.org/10.1093/rheumatology/kex349 Crossref PubMed Google Scholar ]. It seems clear that the clinical phenotype depends on the factors listed above, however the biology of RA synovial tissue should play the main role, since targeting certain immunological pathways with specific drugs can leave other parts of the inflammation pathogenesis uncontrolled (Fig. 1).