Rituximab Prevents the Progression of B-cell Driven Inflammatory Infiltrate in the Minor Salivary Glands of Primary Sjogren’s Syndrome by Downregulating Immunological Pathways Key in Ectopic Germinal Centre Organization: Results from the TRACTISS Trial

Elena Pontarini¹, Farzana Chowdhury¹, Elisabetta Sciacca¹, Sofia Grigoriadou¹, Felice Rivellese¹, Davide Lucchesi¹, Katriona Goldmann¹, Liliane Fossati-Jimack¹, Paul Emery², Wan-Fai NG³, Nurhan Sutcliffe⁴, Colin C Everett⁵, Catherine Fernandez⁵, Anwar Tappuni⁶, Myles Lewis¹, Costantino Pitzalis⁷, Simon J Bowman⁸ and Michele Bombardieri¹, ¹Queen Mary University of London, William Harvey Research Institute, London, United Kingdom, ²Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and Leeds NIHR Biomedical Research Centre, Leeds, United Kingdom, ³Translational and Clinical Research Institute, Newcastle University,, Newcastle, United Kingdom, ⁴Royal London Hospital, Bart’s Health NHS Trust, London, United Kingdom, ⁵Leeds Institute for Clinical Trials Research, University of Leeds, Leeds, United Kingdom, ⁶Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Queen Mary University of London, London, United Kingdom, ⁷Queen Mary University of London, London, United Kingdom, ⁸Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom

Meeting: ACR Convergence 2021

Keywords: B cells, RNA sequencing, salivary gland biopsies, Sjögren's syndrome, TRACTISS

Session Information

Date: Sunday, November 7, 2021

Session Title: Abstracts: Sjögren's Syndrome – Basic & Clinical Science (0984–0987)

Session Type: Abstract Session

Session Time: 4:15PM-4:30PM

Background/Purpose: The pathogenic role of B-cells in primary Sjögren’s Syndrome (pSS) is well established and B cell abnormalities are hallmarks of the disease. Because of the substantial role of B-cells, rituximab (RTX), has been considered a potential biologic disease modifying drug in pSS. To date, the TRial for Anti-B-Cell Therapy In patients with pSS (TRACTISS) is the largest multi-centre, placebo-controlled trial with RTX. Despite the unmet primary endpoints (30% reduction in fatigue or oral dryness, measured by visual analogue scale), RTX treated patients showed an improvement in unstimulated whole salivary flow. The study provides the first longitudinal transcriptomic and histological analysis at 3 time points over 48 weeks of labial salivary glands (SGs) of pSS patients treated with RTX, in comparison to placebo, from the TRACTISS cohort.

Methods: 26 pSS patients randomised to RTX or placebo arm consented for labial SG biopsies at baseline, weeks 16 and 48. Patients received two 1000mg cycles of RTX or placebo at baseline and week 24. The histological analysis was performed by digital imaging (QuPath software), RNA was extracted from matched labial SG lobules and sequenced with Illumina platform.

Results: Placebo-treated labial SGs showed a worsening of inflammation with an increment of B-cell density, development of new follicular-dendritic cell (FDC) networks, and a higher ectopic germinal centre (GC) prevalence at week 48, compared to RTX-treated patients. RTX downregulated genes involved in immune cell recruitment and inflammatory aggregate organisation (e.g. CCR7, CCL19, CD52, and PDCD1) and gene signature-based analysis of 64 immune cell types highlighted how RTX preferentially blocked class-switched- and memory-B-cells infiltration in SGs at week 48. Pathway analyses confirmed the downregulation of leukocyte migration, MHC class II antigen presentation, and T-cell co-stimulation immunological pathways, such as the CD40 receptor complex pathway. The analysis of placebo SGs transcriptomic at week 48 showed a higher expression of genes linked to ectopic GC organisation in female compared to male subjects. Gender was confirmed as a key co-variate responsible for most of the variation in the PrincipalComponentAnalysis, together with the SG focus score and the foci area fraction.

Conclusion: Treatment with RTX showed beneficial effects on labial SG inflammatory infiltration in pSS, by downregulating genes involved in immune cell recruitment, activation and organisation in ectopic GCs. Although a clear association with the clinical improvement in unstimulated salivary flow observed at week 48 in RTX-treated patients could not be established given the low number of patients consenting to 3 longitudinal biopsies it is conceivable that RTX is responsible for preserving exocrine function through the above-described mechanisms.

Disclosures: E. Pontarini, None; F. Chowdhury, None; E. Sciacca, None; S. Grigoriadou, None; F. Rivellese, None; D. Lucchesi, None; K. Goldmann, None; L. Fossati-Jimack, None; P. Emery, Abbvie, 2, 5, 6, Sanofi, 2, 6, BMS, 2, 5, 6, Novartis, 2, 6, Gilead, 2, 6, Samsung, 2, 5, 6, Celltrion, 2, 6, Eli Lilly, 2, 5, 6, MSD, 2, 6, Pfizer, 2, 6, Roche, 2, 6, Amgen Inc., 2, 6, Sandoz, 2, UCB, 1, 5, 6, Boehringer Ingelheim, 1, 5, 6, Merck, 1, 5, 6; W. NG, None; N. Sutcliffe, None; C. Everett, None; C. Fernandez, None; A. Tappuni, None; M. Lewis, None; C. Pitzalis, None; S. Bowman, Novartis, 1, 2, Astrazeneca, 2, Biogen, 2, BMS, 2, Celgene, 2, Medimmune, 2, MTPharma, 2, Ono, 2, UCB, 2, xtlbio, 2; M. Bombardieri, Amgen/Medimmune, 2, 5, Janssen, 2, 5, GSK, 2, UCB, 2.

To cite this abstract in AMA style:

Pontarini E, Chowdhury F, Sciacca E, Grigoriadou S, Rivellese F, Lucchesi D, Goldmann K, Fossati-Jimack L, Emery P, NG W, Sutcliffe N, Everett C, Fernandez C, Tappuni A, Lewis M, Pitzalis C, Bowman S, Bombardieri M. Rituximab Prevents the Progression of B-cell Driven Inflammatory Infiltrate in the Minor Salivary Glands of Primary Sjogren’s Syndrome by Downregulating Immunological Pathways Key in Ectopic Germinal Centre Organization: Results from the TRACTISS Trial [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/rituximab-prevents-the-progression-of-b-cell-driven-inflammatory-infiltrate-in-the-minor-salivary-glands-of-primary-sjogrens-syndrome-by-downregulating-immunological-pathways-key-in-ectopic-g/. Accessed January 28, 2023.

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