Background/Purpose: Granulomatosis with polyangiitis (GPA) and systemic lupus erythematosus (SLE) are autoimmune rheumatic diseases which develop due to failure of immune self-tolerance. T follicular helper cells have been linked with autoimmunity, where they are thought to reduce B cell survival threshold. In contrast, T regulatory cells can suppress autoimmune responses.

Hypothesis:GPA and SLE patients have low T regulatory (T_REG) cell frequencies and high circulating T follicular helper (cT_FH) cell frequencies during severe, active disease.  B cell depletion therapy may correct disease-associated changes of cT_FH and T_REG frequencies in treatment responsive patients.

Methods: A longitudinal study of GPA and SLE patients treated with rituximab, an anti-CD20 monoclonal antibody.

Fluorochrome labelled antibody cell staining (FACS) flow cytometry of peripheral blood mononuclear cells was analysed for CD4⁺CD25^highCD127^low T_REG cells, CD3⁺CD4⁺CXCR5^highPD1^high  cT_FH cells and B lymphocyte subsets pre-rituximab and at 1 month, 3 months and 6-months post-rituximab.

The Birmingham Vasculitis Activity Score (BVAS) and SELENA-SLEDAI score were used to measure disease activity in GPA and SLE patients.

Statistical analysis was done using GraphPad Prism 5. 

Results: Mean age of GPA patients 47 years (25-67), SLE patients 38years (18-64) and healthy controls (HC) 44 years (23-65).

cT_FH%CD4⁺ lymphocytes in HC mean=0.24%, GPA pre-rituximab=0.68% [p=0.02] and SLE pre-rituximab=0.69% [p=0.0001]. GPA 3-months post-rituximab mean cT_FH=0.24% [p=0.02], GPA 6-months post-rituximab mean=0.42% [p=0.01] compared to GPA pre-rituximab. SLE 3-months post-rituximab mean cT_FH=0.34% [p=0.006], SLE 6-months post-rituximab mean cT_FH=0.39% [p=0.09] compared to SLE pre-rituximab.

T_REG%CD4⁺ lymphocytes in HC mean=8.42%, GPA pre-rituximab=5.06% [p=0.001] and SLE pre-rituximab=8.25% [p=0.95].GPA 3-months post-rituximab mean T_REG=7.96% [p=0.04], GPA 6-months post-rituximab mean=6.74% [p=0.1] compared to GPA pre-rituximab. SLE 3-months post-rituximab mean T_REG=12.15% [p=0.03], SLE 6-months post-rituximab mean T_REG=9.68% [p=0.04] compared to SLE pre-rituximab.

GPA pre-rituximab mean BVAS=16, 3-months post-rituximab=3 [p < 0.0001] and 6-months post-rituximab=7 [p=0.06]. BVAS shows a positive correlation with cT_FH cell frequencies r=0.51 [p=0.004] and negative correlation with T_REGcell frequencies r=-0.45 [p=0.01].

Mean SELENA-SLEDAI score pre-rituximab=14, 3-months post-rituximab=4 [p<0.0001] and 6-months post-rituximab=3 [p=0.0003].

SELENA-SLEDAI scores show a positive correlation with cT_FH cell frequencies r=0.50 [p=0.005] and negative correlation with T_REGcell frequencies r=-0.51 [p=0.004].

Conclusion: The frequencies of cT_FH are higher in severe, active GPA and SLE compared to health, whilst the frequencies of T_REG are only lower in GPA compared to health. cT_FH  and T_REGfrequencies were similar to those in healthy controls following successful treatment with rituximab.

 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/alterations-in-circulating-t-follicular-helper-cells-and-t-regulatory-cells-in-autoimmune-rheumatic-diseases-treated-with-b-cell-depletion-therapy-rituximab/