Joint-Specific Memory and Sustained Risk for New Joint Accumulation in Autoimmune Arthritis.

OBJECTIVE: Inflammatory arthritides exhibit hallmark patterns of affected and spared joints, but in each individual, arthritis affects only a subset of all possible sites. The purpose of this study was to identify patient-specific patterns of joint flare to distinguish local from systemic drivers of disease chronicity. METHODS: Patients with juvenile idiopathic arthritis followed without interruption from disease onset into adulthood were identified across 2 large academic centers. Joints inflamed at each visit were established by medical record review. Flare was defined as physician-confirmed joint inflammation following documented inactive disease. RESULTS: Among 222 adults with JIA, 95 had complete serial joint examinations dating from disease onset in childhood. Mean follow-up was 12.5 years (interquartile range 7.9-16.7 years). Ninety (95%) of 95 patients achieved inactive disease, after which 81% (73 patients) experienced at least 1 flare. Among 940 joints affected in 253 flares, 74% had been involved previously. In flares affecting easily observed large joint pairs where only 1 side had been involved before (n = 53), the original joint was affected in 83% and the contralateral joint in 17% (P < 0.0001 versus random laterality). However, disease extended to at least 1 new joint in ~40% of flares, a risk that remained stable even decades after disease onset, and was greatest in flares that occurred while patients were not receiving medication (54% versus 36% of flares occurring with therapy; odds ratio 2.09, P = 0.015). CONCLUSION: Arthritis flares preferentially affect previously inflamed joints but carry an ongoing risk of disease extension. These findings confirm joint-specific memory and suggest that prevention of new joint accumulation should be an important target for arthritis therapy.

PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell-B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here, we evaluated the phenotypes of CD4+ T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1hiCXCR5-CD4+ T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1hiCXCR5-CD4+ T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5- T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not T follicular helper (Tfh) cells, correlated with both clinical disease activity and the frequency of CD11c+ B cells in SLE patients. PD-1hiCD4+ T cells were found within lupus nephritis kidneys and correlated with B cell numbers in the kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells as a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.