A study using single-cell analysis reveals immune dysregulation in rheumatoid arthritis (RA) flare versus drug-free remission. Researchers used immunomodulatory drug withdrawal in RA remission to synchronize flare processes and characterize immune changes. Mass cytometry and single-cell sequencing identified three circulating cellular subsets associated with RA flare: CD4+ and CD8+ T cells, and CD27+ CD86+ CD21- B cells. Distinct lymphocyte subsets, including cytotoxic and exhausted CD4+ memory T cells, memory CD8+ CXCR5+ T cells, and IGHAI1+ plasma cells, were primed for activation in flare patients. Regulatory memory CD4+ T cells (Treg cells) increased at flare onset but showed dysfunctional regulatory marker expression compared to drug-free remission. Significant clonal expansion was observed in T cells, but not B cells, after drug cessation, particularly in memory CD8+ T cell subsets. The study suggests a model of immune dysregulation for RA flare, with potential for future translational research towards novel treatments and prevention strategies. RA was previously viewed as a disease of irreversible joint inflammation, but modern disease-modifying anti-rheumatic drugs (DMARDs) have enabled disease remission. However, managing long-term DMARD therapy after remission remains a challenge. Clinical trials show that about half of RA patients in remission can stop conventional synthetic DMARDs (csDMARDs) and achieve drug-free remission (DFR). However, even patients in sustained drug-induced remission can experience disease flares, which risk joint damage and reduce quality of life. DMARDs have potential toxicity, require expensive monitoring, and can hinder normal lifestyle. Strategies to minimize DMARDs could reduce toxicity and improve quality of life, while also reducing healthcare costs. Reliable biomarkers for remission and flare could help personalize DMARD therapy. However, RA flares are difficult to study due to their unpredictable nature. Clinical trials of controlled DMARD cessation provide an experimental medicine model to synchronize flare processes, allowing detailed study of immunological pathways. The study used high-dimensional mass cytometry and single-cell RNA sequencing data from a clinical trial of csDMARD cessation to provide insights into the cellular features distinguishing flare and DFR in RA patients. The data suggest a conceptual model of RA flare in terms of immune dysregulation with memory CD4+ T cell, memory CD8+ T cell, and B/plasma cell subsets promoting flare processes, and a role for CD4+ Treg cells in maintaining DFR. Mass cytometry revealed an increase in specific memory T and B cell subsets at flare onset. Single-cell sequencing of circulating flare-associated memory T and B cells revealed distinct cellular clusters. Circulating abundance and marker expression profiles differed between flare and DFR, especially within CD4+ T cells. CD4+ regulatory T cells increased at flare onset but showed a gene expression profile distinct from DA study using single-cell analysis reveals immune dysregulation in rheumatoid arthritis (RA) flare versus drug-free remission. Researchers used immunomodulatory drug withdrawal in RA remission to synchronize flare processes and characterize immune changes. Mass cytometry and single-cell sequencing identified three circulating cellular subsets associated with RA flare: CD4+ and CD8+ T cells, and CD27+ CD86+ CD21- B cells. Distinct lymphocyte subsets, including cytotoxic and exhausted CD4+ memory T cells, memory CD8+ CXCR5+ T cells, and IGHAI1+ plasma cells, were primed for activation in flare patients. Regulatory memory CD4+ T cells (Treg cells) increased at flare onset but showed dysfunctional regulatory marker expression compared to drug-free remission. Significant clonal expansion was observed in T cells, but not B cells, after drug cessation, particularly in memory CD8+ T cell subsets. The study suggests a model of immune dysregulation for RA flare, with potential for future translational research towards novel treatments and prevention strategies. RA was previously viewed as a disease of irreversible joint inflammation, but modern disease-modifying anti-rheumatic drugs (DMARDs) have enabled disease remission. However, managing long-term DMARD therapy after remission remains a challenge. Clinical trials show that about half of RA patients in remission can stop conventional synthetic DMARDs (csDMARDs) and achieve drug-free remission (DFR). However, even patients in sustained drug-induced remission can experience disease flares, which risk joint damage and reduce quality of life. DMARDs have potential toxicity, require expensive monitoring, and can hinder normal lifestyle. Strategies to minimize DMARDs could reduce toxicity and improve quality of life, while also reducing healthcare costs. Reliable biomarkers for remission and flare could help personalize DMARD therapy. However, RA flares are difficult to study due to their unpredictable nature. Clinical trials of controlled DMARD cessation provide an experimental medicine model to synchronize flare processes, allowing detailed study of immunological pathways. The study used high-dimensional mass cytometry and single-cell RNA sequencing data from a clinical trial of csDMARD cessation to provide insights into the cellular features distinguishing flare and DFR in RA patients. The data suggest a conceptual model of RA flare in terms of immune dysregulation with memory CD4+ T cell, memory CD8+ T cell, and B/plasma cell subsets promoting flare processes, and a role for CD4+ Treg cells in maintaining DFR. Mass cytometry revealed an increase in specific memory T and B cell subsets at flare onset. Single-cell sequencing of circulating flare-associated memory T and B cells revealed distinct cellular clusters. Circulating abundance and marker expression profiles differed between flare and DFR, especially within CD4+ T cells. CD4+ regulatory T cells increased at flare onset but showed a gene expression profile distinct from D