Early Rheumatoid Arthritis (ERA) Has Lower Levels of Plasmablasts and Memory B Cells Compared to Long-Standing Rheumatoid Arthritis (LSRA) and Responds to Conventional Therapy with a Normalization of B Cell Subsets Abnormalities.

Background/Purpose: B cells have been shown to be important players in RA chronicity and B cell depletion has been shown to be effective in RF seropositive patients. The aim of the study was to evaluate B cells subpopulations distribution in ERA and LSRA patients and their possible association with clinical or immunological data at baseline or with response to conventional therapy (ERA). Methods: 53 ERA (88.7% females; mean age 53.2_15.1 years; 62% anti-CCP positive) and 49 LSRA, along with 30 healthy controls were studied. Baseline clinical and immunological characteristics and inflammatory status were assessed. Peripheral blood samples were analyzed by flow cytometry for the distribution of circulating B cell subsets by staining with surface markers CD19, CD45, CD38, CD27 and IgD and intracellular marker ZAP70. Plasma levels of IL-6 and BAFF were also determined with ELISAs. 22 ERA patients were followed for 6 months: they were treated with MTX (n=14) and MTX + TNF blockers (n=8). Results: ERA patients showed an higher percentage of Bm2/Bm2’ cells (48.8±20.9%) compared to LSRA patients (33.8±17.8%, p<0.001) and a lower percentage of eBm5 (10.0_7.3%) compared to LSRA (14.1±8.6%, p=0.004) and controls (16.0±7.1%, p<0.001). The percentage of CD19+/IgD-CD27- cells (7.5±4.8%) and CD19+/CD38+CD27+ cells (3.0±4.4%) was lower in ERA compared to LRSA (13.7±7.8%, p<0.001; 8.2±5.2%, p<0.001, respectively) and controls (16.2±9.1%, p<0.001; 8.0±3.5%, p<0.001, respectively). The percentage of CD19+/ZAP70+ cells (6.0±7.1%) was higher in ERA patients compared with controls (2.2±1.4%, p=0.01), while no difference was seen between ERA and LSRA. There were no differences in the distribution of B cell subpopulations between patients RF and anti-CCP positive and negative. ERA patients with baseline high DAS (>3.7) showed an higher percentage of CD19+/CD27+CD38+ cells compared to subjects with moderate DAS (p=0.01). The percentage of CD19+/ ZAP70+ cells was higher in ERA patients with baseline plasma levels of BAFF>780 pg/ml (mean±2 SD of controls) (8.0±8.5%) compared to patients with levels of BAFF <780 pg/ml (3.0±2.3%, p=0.08). Plasma levels of BAFF correlated positively with percentage of CD19+/ZAP70+ cells (r=0.41, p=0.002) and of CD19+/IgD-CD27- cells (r=0.26, p=0.05). In ERA patients followed for 6 months, we observed DAS falling from 3.4 to 1.6 (p<0.001), an increased percentage of Bm1 cells (T0:21.4±17.8% vs T6:32.5±19.2%, p=0.005) and a fall in the percentage of eBm5 (T0:9.9±3.8% vs T6:6.5±4.7%, p=0.01) and of CD19+/ZAP70+ cells (T0:6.7±5.6% vs T6:3.8±3.1%, p=0.02), irrespectively of the type of therapy administered. Conclusion: ERA differs from LSRA for higher levels of naive preswitch B cells, lower levels of memory B cells and plasmablasts. After six months of conventional treatment, a fall of memory B cells and ZAP70+ B cells and an increase of naıve B cells were observed. These results suggest that changing the inflammatory milieu in the early phases of the disease, leads to substantial changes in B cell subsets. Further studies are needed to define the molecular events linked to these effects. Early RA represents the best opportunity to normalize the immunological setting.