Background/Aim: The management of difficult-to-treat rheumatoid arthritis (D2T-RA) is frequently complicated by the occurrence of severe adverse events (SAEs) that severely restrict therapeutic options. Emerging evidence suggests that refractory disease in seropositive patients may be driven by resilient immune cell subsets, such as T peripheral helper (Tph) cells and age-associated B cells (ABCs), which escape standard immune suppression. Case Report: We present the case of a 33-year-old female with high-titer seropositive RA Anti-cyclic citrullinated peptide (CCP) >200 U/ml and Sjogren’s syndrome who exhibited sequential resistance to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor (TNF) inhibitors. Subsequent treatment with the janus kinase (JAK) inhibitor upadacitinib was complicated by multi-dermatomal Herpes Zoster infection and a deep vein thrombosis (DVT) event, necessitating permanent drug withdrawal due to safety concerns. Despite a mechanistic switch to B-cell depletion therapy (rituximab), the patient maintained high disease activity (DAS28: 4.98). Longitudinal deep immunophenotyping revealed a distinct pathogenic cellular signature characterizing this refractory state. We observed a sustained expansion of programmed death-1 -positive (PD-1+) effector memory T helper cells (a proxy for Tph cells) and persistent circulating plasmablasts, indicating continuous B-cell differentiation. Furthermore, the B cell compartment showed a progressive accumulation of cluster of differentiation 21 (CD21)-low ABCs. While cluster of differentiation 39 (CD39)+Helios+ regulatory T cells fluctuated, they failed to suppress the inflammatory drive. Conclusion: This case highlights the clinical complexity of managing D2T-RA when JAK inhibitors are contraindicated due to thromboembolic and infectious risks. The immunophenotypic data suggests that a resilient Tph-ABC interaction axis underpins the mechanism of therapeutic resistance, pointing towards the need for combination strategies targeting these specific cellular reservoirs.
Wu et al. (Fri,) studied this question.