Advances in current research on the immunopathogenesis of Sjögren’s syndrome and targeted therapeutic strategies

doi:10.16150/j.1671-2870.2024.03.005

Abstract

Abstract:

Sjögren's syndrome (SS) is a prevalent systemic autoimmune disease, primarily affecting exocrine glands, characterized by lymphocyte and plasma cell infiltration. Patients typically exhibit dry mouth and eyes, with potential involvement of the digestive tract, lungs, and kidneys. In China, SS prevalence ranges from 0.29% to 0.77%, rising to 3.00%-4.00% among the elderly. In Europe, the prevalence is approximately 0.23%. The pathogenesis of SS involves interactions of multiple cells and cytokines, including salivary gland epithelial cells, T-cells, B-cells, dendritic cells, interferon (IFN), interleukin (IL), tumour necrosis factor (TNF) and inflammasomes. Currently, glandular therapy for SS is primarily localised, while treatment for systemic involvement is mainly borrowed from other autoimmune diseases, with no approved targeted drugs yet. Among the targeted therapeutic agents for SS, rituximab, a B-cell targeted therapy, is the most studied and has shown improved salivary efficacy in SS patients with cryoglobulin vasculitis. BAFF inhibitors, CD40 targeting agents, and mesenchymal stem cells have also demonstrated cartain therapeutic effects. For most systemic involvement, glucocorticoids (GCs) are the first-line treatment, while immunosuppressants and biologics serve as second-line options for GCs-tolerant or resistant patients. Although many potential therapeutic targets have been identified, few drugs have been clinically translated. Currently, there is a need to develop relatively safe and effective treatment regimens with minimal adverse effects through comprehensive patient assessment and multidisciplinary collaboration. Future SS drug research will focus on targeted therapies, adverse effects reduction, and multi-drug combinations.

Key words: Dry syndrome, Immune mechanism, Targeted drugs

CLC Number:

YUAN Xiang, LI Xiaomei. Advances in current research on the immunopathogenesis of Sjögren’s syndrome and targeted therapeutic strategies[J]. Journal of Diagnostics Concepts & Practice, 2024, 23(03): 278-284.

References 39

[1]	BRITO-ZERÓN P, BALDINI C, BOOTSMA H, et al. Sjogren syndrome[J]. Nat Rev Dis Primers, 2016, 2:16047.
[2]	OZAKI Y, ITO T, SON Y, et al. Decrease of blood dendritic cells and increase of tissue-infiltrating dendritic cells are involved in the induction of Sjögren's syndrome but not in the maintenance[J]. Clin Exp Immunol, 2010, 159(3):315-326. doi: 10.1111/j.1365-2249.2009.04071.x pmid: 20015272
[3]	VAN BLOKLAND S C, VAN HELDEN-MEEUWSEN C G, WIERENGA-WOLF A F, et al. Two different types of sialoadenitis in the NOD- and MRL/lpr mouse models for Sjogren's syndrome: a differential role for dendritic cells in the initiation of sialoadenitis?[J]. Lab Invest, 2000, 80(4):575-585.
[4]	SAEGUSA K, ISHIMARU N, YANAGI K, et al. Treatment with anti-CD86 costimulatory molecule prevents the autoimmune lesions in murine Sjogren's syndrome (SS) through up-regulated Th2 response[J]. Clin Exp Immunol, 2000, 119(2):354-360.
[5]	KAPSOGEORGOU E K, TZIOUFAS A G. Interaction of human salivary gland epithelial cells with B lymphocytes: implications in the pathogenesis of sjögren's syndrome[J]. Mediterr J Rheumatol, 2020, 31(4):424-426. doi: 10.31138/mjr.31.4.424 pmid: 33521577
[6]	VERSTAPPEN G M, KROESE F G M, BOOTSMA H. T cells in primary Sjögren's syndrome: targets for early intervention[J]. Rheumatology (Oxford), 2021, 60(7):3088-3098.
[7]	PONTARINI E, MURRAY-BROWN W J, CROIA C, et al. Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjogren's syndrome with ectopic germinal centres and MALT lymphoma[J]. Ann Rheum Dis, 2020, 79(12):1588-1599.
[8]	IVANCHENKO M, AQRAWI L A, BJÖRK A, et al. FoxP3(+) CXCR5(+) CD4(+) T cell frequencies are increased in peripheral blood of patients with primary Sjogren's syndrome[J]. Clin Exp Immunol, 2019, 195(3):305-309.
[9]	LI P, YANG Y, JIN Y, et al. B7-H3 participates in human salivary gland epithelial cells apoptosis through NF-kappaB pathway in primary Sjogren's syndrome[J]. J Transl Med, 2019, 17(1):268.
[10]	SOYFOO M S, NICAISE C. Pathophysiologic role of Interleukin-33/ST2 in Sjogren's syndrome[J]. Autoimmun Rev, 2021, 20(3):102756.
[11]	MIAO M, HAO Z, GUO Y, et al. Short-term and low-dose IL-2 therapy restores the Th17/Treg balance in the peripheral blood of patients with primary Sjogren's syndrome[J]. Ann Rheum Dis, 2018, 77(12):1838-1840.
[12]	PETERS A, PITCHER L A, SULLIVAN J M, et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation[J]. Immunity, 2011, 35(6):986-996. doi: 10.1016/j.immuni.2011.10.015 pmid: 22177922
[13]	IIZUKA M, TSUBOI H, MATSUO N, et al. A crucial role of RORgammat in the development of spontaneous Sialadenitis-like Sjogren's syndrome[J]. J Immunol, 2015, 194(1):56-67.
[14]	LIU D, CAO T, WANG N, et al. IL-25 attenuates rheumatoid arthritis through suppression of Th17 immune responses in an IL-13-dependent manner[J]. Sci Rep, 2016, 6:36002. doi: 10.1038/srep36002 pmid: 27812008
[15]	CICCIA F, GUGGINO G, RIZZO A, et al. Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjogren's syndrome[J]. Ann Rheum Dis, 2012, 71(2):295-301. doi: 10.1136/ard.2011.154013 pmid: 21979002
[16]	SHEN L, ZHANG C, WANG T, et al. Development of autoimmunity in IL-14alpha-transgenic mice[J]. J Immunol, 2006, 177(8):5676-5686. pmid: 17015757
[17]	ZANDBELT M M, DE WILDE P, VAN DAMME P, et al. Etanercept in the treatment of patients with primary Sjogren's syndrome: a pilot study[J]. J Rheumatol, 2004, 31(1):96-101.
[18]	SANKAR V, BRENNAN M T, KOK M R, et al. Etanercept in Sjogren's syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial[J]. Arthritis Rheum, 2004, 50(7):2240-2245.
[19]	GROOM J, KALLED S L, CUTLER A H, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren's syndrome[J]. J Clin Invest, 2002, 109(1):59-68.
[20]	VAKALOGLOU K M, MAVRAGANI C P. Activation of the type I interferon pathway in primary Sjogren's syndrome: an update[J]. Curr Opin Rheumatol, 2011, 23(5):459-464.
[21]	LEE J, LEE J, KWOK S K, et al. JAK-1 inhibition suppresses interferon-induced BAFF production in human salivary gland: potential therapeutic strategy for primary Sjogren's syndrome[J]. Arthritis Rheumatol, 2018, 70(12):2057-2066.
[22]	AOTA K, YAMANOI T, KANI K, et al. Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells[J]. Inflammation, 2021, 44(1):206-216.
[23]	CUMMINS M J, PAPAS A, KAMMER G M, et al. Treatment of primary Sjogren's syndrome with low-dose human interferon alfa administered by the oromucosal route: combined phase Ⅲ results[J]. Arthritis Rheum, 2003, 49(4):585-593.
[24]	MANOUSSAKIS M N, BOIU S, KORKOLOPOULOU P, et al. Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjogren's syndrome: correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development[J]. Arthritis Rheum, 2007, 56(12):3977-3988.
[25]	BALDINI C, ROSSI C, FERRO F, et al. The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response in primary Sjogren's syndrome[J]. J Intern Med, 2013, 274(5):480-489.
[26]	HUSAIN-KRAUTTER S, KRAMER J M, LI W, et al. The osteopontin transgenic mouse is a new model for Sjogren's syndrome[J]. Clin Immunol, 2015, 157(1):30-42.
[27]	RAMOS-CASALS M, BRITO-ZERÓN P, BOMBARDIERI S, et al. EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies[J]. Ann Rheum Dis, 2020, 79(1):3-18.
[28]	CHU L L, CUI K, POPE J E. Meta-Analysis of Treatment for Primary Sjögren's Syndrome[J]. Arthritis Care Res (Hoboken), 2020, 72(7):1011-1021. doi: 10.1002/acr.23917 pmid: 31058469
[29]	BOWMAN S J, EVERETT C C, O'DWYER J L, et al. Randomized Controlled Trial of Rituximab and Cost-Effectiveness Analysis in Treating Fatigue and Oral Dryness in Primary Sjogren's Syndrome[J]. Arthritis Rheumatol, 2017, 69(7):1440-1450.
[30]	MARIETTE X, SEROR R, QUARTUCCIO L, et al. Efficacy and safety of belimumab in primary Sjogren's syndrome: results of the BELISS open-label phase II study[J]. Ann Rheum Dis, 2015, 74(3):526-531.
[31]	MARIETTE X, BARONE F, BALDINI C, et al. A randomized, phase Ⅱ study of sequential belimumab and rituximab in primary Sjogren's syndrome[J]. JCI Insight, 2022, 7(23):e163030.
[32]	BOWMAN S J, FOX R, DÖRNER T, et al. Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjogren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial[J]. Lancet, 2022, 399(10320):161-171.
[33]	XU D, FANG J, ZHANG S, et al. Efficacy and safety of telitacicept in primary Sjogren's syndrome: a randomi-zed, double-blind, placebo-controlled, phase 2 trial[J]. Rheumatology (Oxford), 2024, 63(3):698-705.
[34]	FISHER B A, SZANTO A, NG W F, et al. Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjogren's syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study[J]. Lancet Rheumatol, 2020, 2(3):e142-e152.
[35]	XU J, WANG D, LIU D, et al. Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjogren syndrome[J]. Blood, 2012, 120(15):3142-3151.
[36]	ALURI H S, SAMIZADEH M, EDMAN M C, et al. Delivery of bone marrow-derived mesenchymal stem cells improves tear production in a mouse model of Sjogren's syndrome[J]. Stem Cells Int, 2017, 2017:3134543.
[37]	LI B, XING Y, GAN Y, et al. Labial gland-derived mesenchymal stem cells and their exosomes ameliorate murine Sjogren's syndrome by modulating the balance of Treg and Th17 cells[J]. Stem Cell Res Ther, 2021, 12(1):478.
[38]	ZHANG X, MIAO M, ZHANG R, et al. Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis: a randomized, double-blind, placebo-controlled phase 2 trial[J]. Signal Transduct Target Ther, 2022, 7(1):67.
[39]	XU J, LIU O, WANG D, et al. In vivo generation of SSA/Ro antigen-specific regulatory T cells improves experimental Sjogren's syndrome in mice[J]. Arthritis Rheumatol, 2022, 74(10):1699-1705.