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Tertiary lymphoid structures (TLSs) in chronic inflammation, including rheumatoid arthritis (RA) synovial tissue (ST), often contain high endothelial venules and follicular dendritic cells (FDCs). Endothelial cell (EC)-specific lymphotoxin β (LTβ) receptor signaling is critical for the formation of lymph nodes and high endothelial venules. FDCs arise from perivascular platelet-derived growth factor receptor β(+) precursor cells (preFDCs) that require specific group 3 innate lymphoid cells (ILC3s) and LTβ for their expansion. Previously, we showed that RA ST contains ECs that express NF-κB-inducing kinase (NIK), which is pivotal in LTβ-induced noncanonical NF-κB signaling. We studied the relation between NIK(+) ECs, (pre)FDCs, and ILC3s with respect to TLSs in RA ST. TLS(+) tissues exhibited a significantly increased expression of genes involved in noncanonical NF-κB signaling, including NIK, and immunohistochemical analysis revealed that NIK was almost exclusively expressed by ECs. ILC3s were present in human RA ST in very low numbers, but not differentially in TLS(+) tissues. In contrast, TLS(+) tissues contained significantly more NIK(+) ECs and perivascular platelet-derived growth factor receptor β(+) preFDCs, which correlated significantly with the quantity of FDCs. We established a strong link between NIK(+) ECs, (pre)FDCs, and the presence of TLSs, indicating that NIK(+) ECs may not only be important orchestrators of lymph node development but also contribute to the formation of TLSs in chronic inflammation.

To analyze the relationship between the type I interferon (IFN) signature and clinical response to rituximab in rheumatoid arthritis (RA) patients.Twenty RA patients were treated with rituximab (cohort 1). Clinical response was defined as a decrease in the Disease Activity Score evaluated in 28 joints (DAS28) and as a response according to the European League Against Rheumatism (EULAR) criteria at week 12 and week 24. The presence of an IFN signature was analyzed in peripheral blood mononuclear cells by measuring the expression levels of 3 IFN response genes by quantitative polymerase chain reaction analysis. After comparison with the findings in healthy controls, patients were classified as having an IFN high or an IFN low signature. The data were confirmed in a second independent cohort (n = 31). Serum IFNα bioactivity was analyzed using a reporter assay.In cohort 1, there was a better clinical response to rituximab in the IFN low signature group. Consistent with these findings, patients with an IFN low signature had a significantly greater reduction in the DAS28 and more often achieved a EULAR response at weeks 12 and 24 as compared with the patients with an IFN high signature in cohort 2 versus cohort 1. The pooled data showed a significantly stronger decrease in the DAS28 in IFN low signature patients at weeks 12 and 24 as compared with the IFN high signature group and a more frequent EULAR response at week 12. Accordingly, serum IFNα bioactivity at baseline was inversely associated with the clinical response, although this result did not reach statistical significance.The type I IFN signature negatively predicts the clinical response to rituximab treatment in patients with RA. This finding supports the notion that IFN signaling plays a role in the immunopathology of RA.

Background and Objectives Rituximab aims to deplete CD20 positive B cells and exerts a significant and often long-lasting clinical effect in a subset of patients with rheumatoid arthritis (RA). The extent of B cell depletion in the inflammatory tissues after rituximab varies between patients and persistence of plasma cells and plasma cell products is associated with clinical non-response. This suggests rituximab may fail to deplete pathogenic B cells. We investigated whether this might be explained by differential expression of B cell survival factors in the inflamed synovial tissue of RA patients. Material and Methods Twenty-four RA patients underwent an arthroscopic synovial biopsy before, 1 month after and 4 months after treatment with rituximab. Treatment was given via two infusions (1,000 mg on day 1 and 15), both without methylprednisolon premedication to be able to study specific biological effects of rituximab. Clinical response was defined as a response according to the European League Against Rheumatism (EULAR) criteria at week 24. Peripheral blood and synovial tissue were analysed for expression and levels of B cell survival factors; BLyS, APRIL, IL-1β, IL6, BLyS, VCAM, ICAM, IFNα, CXCL12 and BLIMP1. Correlation between baseline expression and changes in B cell survival factors and clinical response were calculated using logistic regression analysis. Results We found no significant correlation between baseline expression level of synovial B cell survival factors and clinical response to treatment. After treatment, the expression levels of BLyS, APRIL, IL-1β, IL6, ICAM and BLIMP1 were unaltered. The expression of IFNα and VCAM decreased after treatment, of which VCAM within one month ( P = 0.035, P = 0.022 and P = 0.039, respectively). In contrast, expression of CXCL-12 increased after treatment ( P = 0.046). In clinical responders VCAM expression decreased further between 1 and 4 months after treatment, although a statistical significant difference with non-responders could not be detected. Conclusions Clinical non-response to rituximab is not associated with a higher baseline expression of B cell survival factors in the inflamed synovial tissue of RA patients. However, the persistent expression of survival factors independent of the extent of B cell depletion may promote the persistence of pathogenic B cell subsets in clinical non-responders to treatment.