Histopathology in primary Sjögren's syndrome: Diagnosis, clinical trials and new insights

Abstract

Histopathology in primary Sjogren’s syndrome Salivary gland biopsies play an important role in the diagnosis and stratification of patients with primary Sjogren’s syndrome (pSS). Histopathological characteristics of a pSS salivary gland biopsy are a focus score ≥1 and the presence of lymphoepithelial lesions (LELs). In this thesis we show that LELs likely develop from a crosstalk between intra-epithelial B-cells and ductal cells. In addition, germinal centres, which indicate higher disease activity, can be found. In this thesis we show that these germinal centres are best identified with a Bcl-6 stain. About 5-10% of pSS patients will develop a non-Hodgkin’s lymphoma, most commonly of the mucosa-associated lymphoid tissue (MALT)-subtype. This thesis shows that pSS associated MALT lymphomas express FcRL4 on B-cells. These FcRL4+ B-cells can also be found in smaller numbers in the salivary gland tissue of pSS patients without lymphoma, particularly within LELs. The significant higher number of FcRL4+ B-cells in the parotid gland tissue compared to labial gland tissue, can explain why pSS associated MALT lymphomas predominantly occur in the parotid gland. This thesis shows that the presence of Bcl-6+ germinal centres in diagnostic labial gland biopsies of pSS patients is not predictive for parotid MALT lymphoma. This thesis shows that after rituximab treatment, the number of CD20+ (FcRL4+) B-cells declines in the parotid gland tissue of pSS patients. Furthermore, the number of CD20+ B-cells/mm2 indicates which pSS patients will benefit from rituximab treatment. This thesis also shows that abatacept treatment results in a decline of germinal centres due to the inhibition of T-cell dependent B-cell activation and a decline of (activated) Tfh-cells. Standardized analysis of salivary gland tissue in clinical studies can contribute in unraveling the pathophysiology of, and the therapy choices in patients with pSS.