CURRENT APPROACHES TO THE TREATMENT OF SJÖGREN’S DISEASE – A REVIEW OF IMMUNOMODULATORY AND BIOLOGICAL THERAPIES
DOI:
https://doi.org/10.31435/ijitss.2(50).2026.5477Keywords:
Sjögren’s Disease, Interferon Signature, Immunomodulation, Targeted Therapies, Monoclonal Antibodies, JAK InhibitorsAbstract
Introduction and purpose: Sjögren’s disease (SjD) is a systemic autoimmune process in which traditional symptomatic treatment often fails to prevent organ complications. Thanks to intensive research into its pathogenesis, new therapeutic targets are being discovered, which may enable the causal treatment of the disease. This paper provides a review of modern therapeutic strategies, with a particular focus on JAK/BTK/SYK inhibitors, the CD40-CD40L pathway, and anti-CD20 therapy. Based on the latest clinical trial results, the article analyzes the potential of immunomodulation in modifying the course of SjD and preventing its systemic manifestations.
Description of the state of knowledge: Current scientific consensus defines Sjögren's disease as a complex, multifactorial autoimmune condition. The progression of the disease is primarily driven by the overexpression of factors such as BAFF and APRIL, excessive interferon production, and specific lymphocyte populations, including follicular helper T-cells (Tfh) and CD8+ GZMK+ T-cells. Despite a detailed understanding of these molecular mechanisms, effective disease-modifying treatment remains elusive. Currently, researchers' attention is focused on therapies targeting novel signaling pathways.
Conclusions: Modern treatment of Sjögren’s disease is evolving toward disease-modifying therapies that target the molecular mechanisms of epithelial inflammation and the type I interferon signature. Key strategies include targeted B- and T-cell immunomodulation and the inhibition of intracellular signaling pathways, which effectively reduce systemic activity and offer a significant steroid-sparing effect. The future of therapy relies on personalized medicine and the use of regenerative medicine, including exosomes, to restore the function of damaged glands.
References
Manfrè, V., Chatzis, L. G., Cafaro, G., Fonzetti, S., Calvacchi, S., Fulvio, G., Navarro Garcia, I. C., La Rocca, G., Ferro, F., Perricone, C., Bartoloni, E., & Baldini, C. (2022). Sjögren's syndrome: One year in review 2022. Clinical and Experimental Rheumatology, 40(12), 2211–2224. https://doi.org/10.55563/clinexprheumatol/43z8gu
Björk, A., Mofors, J., & Wahren-Herlenius, M. (2020). Environmental factors in the pathogenesis of primary Sjögren's syndrome. Journal of Internal Medicine, 287(5), 475–492. https://doi.org/10.1111/joim.13032
Yao, Y., Ma, J. F., Chang, C., Xu, T., Gao, C. Y., Gershwin, M. E., & Lian, Z. X. (2021). Immunobiology of T cells in Sjögren's syndrome. Clinical Reviews in Allergy & Immunology, 60(1), 111–131. https://doi.org/10.1007/s12016-020-08793-7
Brito-Zerón, P., Retamozo, S., & Ramos-Casals, M. (2023). Sjögren syndrome. Síndrome de Sjögren. Medicina Clínica, 160(4), 163–171. https://doi.org/10.1016/j.medcli.2022.10.007
Demarchi, J., Papasidero, S., Medina, M. A., Klajn, D., Chaparro Del Moral, R., Rillo, O., Martiré, V., Crespo, G., Secco, A., Catalan Pellet, A., Amitrano, C., Crow, C., Asnal, C., Pucci, P., Caeiro, F., Benzanquen, N., Pirola, J. P., Mayer, M., Zazzetti, F., Velez, S., … Raiti, L. (2017). Primary Sjögren's syndrome: Extraglandular manifestations and hydroxychloroquine therapy. Clinical Rheumatology, 36(11), 2455–2460. https://doi.org/10.1007/s10067-017-3822-3
Brito-Zerón, P., Flores-Chávez, A., Horváth, I. F., Rasmussen, A., Li, X., Olsson, P., Vissink, A., Priori, R., Armagan, B., Hernandez-Molina, G., Praprotnik, S., Quartuccio, L., Inanç, N., Özkızıltaş, B., Bartoloni, E., Sebastian, A., Romão, V. C., Solans, R., Pasoto, S. G., Rischmueller, M., … Sjögren Big Data Consortium. (2023). Mortality risk factors in primary Sjögren syndrome: A real-world, retrospective, cohort study. EClinicalMedicine, 61, 102062. https://doi.org/10.1016/j.eclinm.2023.102062
Behbodikhah, J., Ding, B., Jacob, B., Batool, N., Belilos, E., De Leon, J., Carsons, S. E., & Reiss, A. B. (2025). Sjogren's disease and elevated cardiovascular risk: Mechanisms and treatment. Journal of Cardiovascular Development and Disease, 12(9), 367. https://doi.org/10.3390/jcdd12090367
Qin, B., Wang, J., Yang, Z., Yang, M., Ma, N., Huang, F., & Zhong, R. (2015). Epidemiology of primary Sjögren's syndrome: A systematic review and meta-analysis. Annals of the Rheumatic Diseases, 74(11), 1983–1989. https://doi.org/10.1136/annrheumdis-2014-205375
Ramos-Casals, M., Baer, A. N., Brito-Zerón, M. D. P., Hammitt, K. M., Bouillot, C., Retamozo, S., Mackey, A., Yarowsky, D., Turner, B., Blanck, J., Fisher, B. A., Akpek, E. K., Baldini, C., Bootsma, H., Bowman, S. J., Dörner, T., Laing, L., Lieberman, S. M., Mariette, X., Pflugfelder, S. C., … International Task Force on Nomenclature of Sjögren Disease. (2025). 2023 International Rome consensus for the nomenclature of Sjögren disease. Nature Reviews Rheumatology, 21(7), 426–437. https://doi.org/10.1038/s41584-025-01268-z
Goules, A. V., Chatzis, L., Pezoulas, V. C., Patsouras, M., Mavragani, C., Quartuccio, L., Baldini, C., De Vita, S., Fotiadis, D. I., & Tzioufas, A. G. (2024). Identification and evolution of predictors of Sjögren's disease-associated mucosa-associated lymphoid tissue lymphoma development over time: A case-control study. The Lancet Rheumatology, 6(10), e693–e702. https://doi.org/10.1016/S2665-9913(24)00183-8
Baldini, C., Chatzis, L. G., Fulvio, G., La Rocca, G., Pontarini, E., & Bombardieri, M. (2024). Pathogenesis of Sjögren's disease: One year in review 2024. Clinical and Experimental Rheumatology, 42(12), 2336–2343. https://doi.org/10.55563/clinexprheumatol/i8iszc
Verstappen, G. M., Pringle, S., van der Geest, K. S., Kroese, F. G., & Bootsma, H. (2026). T cells in Sjögren's disease: Update on their role in salivary gland pathogenesis and treatment. Current Opinion in Immunology, 99, 102739. https://doi.org/10.1016/j.coi.2026.102739
Pelkas, C., Franke, K. B., Vincent, F. B., & Rischmueller, M. (2025). Novel therapies in Sjögren's disease: A systematic review of the literature. Best Practice & Research Clinical Rheumatology, 39(4), 102084. https://doi.org/10.1016/j.berh.2025.102084
Baldini, C., Fulvio, G., La Rocca, G., & Ferro, F. (2024). Update on the pathophysiology and treatment of primary Sjögren syndrome. Nature Reviews Rheumatology, 20(8), 473–491. https://doi.org/10.1038/s41584-024-01135-3
Dela Cruz, A., Kartha, V., Tilston-Lunel, A., Mi, R., Reynolds, T. L., Mingueneau, M., Monti, S., Jensen, J. L., Skarstein, K., Varelas, X., & Kukuruzinska, M. A. (2021). Gene expression alterations in salivary gland epithelia of Sjögren's syndrome patients are associated with clinical and histopathological manifestations. Scientific Reports, 11(1), 11154. https://doi.org/10.1038/s41598-021-90569-w
Nakamura, H., Tanaka, T., Noguchi, M., Atsumi, T., Warner, B. M., & Chiorini, J. A. (2025). Investigation of lysosome-associated membrane protein 3 highlighting the role of lysosome in pathophysiology and treatment of Sjögren disease. Arthritis & Rheumatology. Advance online publication. https://doi.org/10.1002/art.43347
Bettacchioli, E., Saraux, A., Tison, A., Cornec, D., Dueymes, M., Foulquier, N., Hillion, S., Roguedas-Contios, A. M., Benyoussef, A. A., Alarcon-Riquelme, M. E., Pers, J. O., Devauchelle-Pensec, V., PRECISESADS Clinical Consortium, & PRECISESADS Sjögren Consortium. (2024). Association of combined anti-Ro52/TRIM21 and anti-Ro60/SSA antibodies with increased Sjögren disease severity through interferon pathway activation. Arthritis & Rheumatology, 76(5), 751–762. https://doi.org/10.1002/art.42789
Pranzatelli, T. J. F., Perez, P., Ku, A., Matuck, B., Huynh, K., Sakai, S., Abed, M., Jang, S. I., Yamada, E., Dominick, K., Ahmed, Z., Oliver, A., Wasikowski, R., Easter, Q. T., Baer, A. N., Pelayo, E., Khavandgar, Z., Kleiner, D. E., Magone, M. T., Gupta, S., … Warner, B. M. (2024). GZMK+CD8+ T cells target a specific acinar cell type in Sjögren's disease. Research Square. https://doi.org/10.21203/rs.3.rs-3601404/v2
Matsui, K., & Sano, H. (2017). T helper 17 cells in primary Sjögren's syndrome. Journal of Clinical Medicine, 6(7), 65. https://doi.org/10.3390/jcm6070065
Blinova, V. G., Vasilyev, V. I., Rodionova, E. B., & Zhdanov, D. D. (2023). The role of regulatory T cells in the onset and progression of primary Sjögren's syndrome. Cells, 12(10), 1359. https://doi.org/10.3390/cells12101359
Vivino, F. B., Bunya, V. Y., Massaro-Giordano, G., Johr, C. R., Giattino, S. L., Schorpion, A., Shafer, B., Peck, A., Sivils, K., Rasmussen, A., Chiorini, J. A., He, J., & Ambrus, J. L., Jr. (2019). Sjogren's syndrome: An update on disease pathogenesis, clinical manifestations and treatment. Clinical Immunology, 203, 81–121. https://doi.org/10.1016/j.clim.2019.04.009
Dörner, T., Posch, M. G., Li, Y., Petricoul, O., Cabanski, M., Milojevic, J. M., Kamphausen, E., Valentin, M. A., Simonett, C., Mooney, L., Hüser, A., Gram, H., Wagner, F. D., & Oliver, S. J. (2019). Treatment of primary Sjögren's syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity. Annals of the Rheumatic Diseases, 78(5), 641–647. https://doi.org/10.1136/annrheumdis-2018-214720
Bowman, S. J., Fox, R., Dörner, T., Mariette, X., Papas, A., Grader-Beck, T., Fisher, B. A., Barcelos, F., De Vita, S., Schulze-Koops, H., Moots, R. J., Junge, G., Woznicki, J. N., Sopala, M. A., Luo, W. L., & Hueber, W. (2022). Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: A randomised, double-blind, placebo-controlled, phase 2b dose-finding trial. Lancet, 399(10320), 161–171. https://doi.org/10.1016/S0140-6736(21)02251-0
Dörner, T., Bowman, S. J., Fox, R., Mariette, X., Papas, A., Grader-Beck, T., Fisher, B. A., Barcelos, F., De Vita, S., Schulze-Koops, H., Moots, R. J., Junge, G., Woznicki, J., Sopala, M., Avrameas, A., Luo, W. L., & Hueber, W. (2025). Safety and efficacy of ianalumab in patients with Sjögren's disease: 52-week results from a randomized, placebo-controlled, phase 2b dose-ranging study. Arthritis & Rheumatology, 77(5), 560–570. https://doi.org/10.1002/art.43059
Campinho Ferreira, C., Bandeira, M., Pereira da Costa, R., Matias, S., Duarte, A. C., Marques-Gomes, C., Fernandes Esteves, B., Cunha, A., Santos, M., Silva, L., Oliveira, C., Almeida, I., Augusto, D., Rua, C., Melo, A. T., Romão, V. C., & Leite Silva, J. (2026). Safety and effectiveness of rituximab therapy in Sjögren's disease: A PORTRESS—the Portuguese registry of Sjögren's disease-based study. Clinical Rheumatology, 45(2), 1091–1098. https://doi.org/10.1007/s10067-026-07930-5
Ramos-Casals, M., Brito-Zerón, P., Bombardieri, S., Bootsma, H., De Vita, S., Dörner, T., Fisher, B. A., Gottenberg, J. E., Hernandez-Molina, G., Kocher, A., Kostov, B., Kruize, A. A., Mandl, T., Ng, W. F., Retamozo, S., Seror, R., Shoenfeld, Y., Sisó-Almirall, A., Tzioufas, A. G., Vitali, C., … EULAR-Sjögren Syndrome Task Force Group. (2020). EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies. Annals of the Rheumatic Diseases, 79(1), 3–18. https://doi.org/10.1136/annrheumdis-2019-216114
Fisher, B. A., Mariette, X., Papas, A., Grader-Beck, T., Bootsma, H., Ng, W. F., van Daele, P. L. A., Finzel, S., Noaiseh, G., Elgueta, S., Hermann, J., McCoy, S. S., Akpek, E., Bookman, A., Sopala, M., Montecchi-Palmer, M., Luo, W. L., Scheurer, C., Hueber, W., & TWINSS Study Group. (2024). Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): Week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study. Lancet, 404(10452), 540–553. https://doi.org/10.1016/S0140-6736(24)01211-X
Espié, P., He, Y., Koo, P., Sickert, D., Dupuy, C., Chokoté, E., Schuler, R., Mergentaler, H., Ristov, J., Milojevic, J., Verles, A., Groenewegen, A., Auger, A., Avrameas, A., Rotte, M., Colin, L., Tomek, C. S., Hernandez-Illas, M., Rush, J. S., & Gergely, P. (2020). First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody. American Journal of Transplantation, 20(2), 463–473. https://doi.org/10.1111/ajt.15661
He, J., Chen, J., Miao, M., Zhang, R., Cheng, G., Wang, Y., Feng, R., Huang, B., Luan, H., Jia, Y., Jin, Y., Zhang, X., Shao, M., Wang, Y., Zhang, X., Li, J., Zhao, X., Wang, H., Liu, T., Xiao, X., … Li, Z. (2022). Efficacy and safety of low-dose interleukin 2 for primary Sjögren syndrome: A randomized clinical trial. JAMA Network Open, 5(11), e2241451. https://doi.org/10.1001/jamanetworkopen.2022.41451
Retamozo, S., Acar-Denizli, N., Rasmussen, A., Horváth, I. F., Baldini, C., Priori, R., Sandhya, P., Hernandez-Molina, G., Armagan, B., Praprotnik, S., Kvarnstrom, M., Gerli, R., Sebastian, A., Solans, R., Rischmueller, M., Pasoto, S. G., Valim, V., Nordmark, G., Kruize, A., Nakamura, H., … Sjögren Big Data Consortium. (2019). Systemic manifestations of primary Sjögren's syndrome out of the ESSDAI classification: Prevalence and clinical relevance in a large international, multi-ethnic cohort of patients. Clinical and Experimental Rheumatology, 37(Suppl. 118, 3), 97–106.
Kaegi, C., Wuest, B., Schreiner, J., Steiner, U. C., Vultaggio, A., Matucci, A., Crowley, C., & Boyman, O. (2019). Systematic review of safety and efficacy of rituximab in treating immune-mediated disorders. Frontiers in Immunology, 10, 1990. https://doi.org/10.3389/fimmu.2019.01990
Tieu, J., Smith, R. M., Gopaluni, S., Kumararatne, D. S., McClure, M., Manson, A., Houghton, S., & Jayne, D. R. W. (2021). Rituximab associated hypogammaglobulinemia in autoimmune disease. Frontiers in Immunology, 12, 671503. https://doi.org/10.3389/fimmu.2021.671503
Zeng, L., Yang, K., Wu, Y., Yu, G., Yan, Y., Hao, M., Song, T., Li, Y., Chen, J., & Sun, L. (2024). Telitacicept: A novel horizon in targeting autoimmunity and rheumatic diseases. Journal of Autoimmunity, 148, 103291. https://doi.org/10.1016/j.jaut.2024.103291
Shi, F., Xue, R., Zhou, X., Shen, P., Wang, S., & Yang, Y. (2021). Telitacicept as a BLyS/APRIL dual inhibitor for autoimmune disease. Immunopharmacology and Immunotoxicology, 43(6), 666–673. https://doi.org/10.1080/08923973.2021.1973493
Lim, Z. F. S., Hoi, A. Y., Vincent, F. B., Ooi, J. D., Morand, E. F., Rischmueller, M., & Ting, Y. T. (2025). Regulatory T cell therapy for Sjögren's disease: From pathogenesis to targeted treatment. Journal of Translational Autoimmunity, 11, 100311. https://doi.org/10.1016/j.jtauto.2025.100311
Xu, D., Fang, J., Zhang, S., Huang, C., Huang, C., Qin, L., Li, X., Chen, M., Liu, X., Liu, Y., Li, Z., Hu, J., Bao, C., Wei, W., Tian, J., Duan, X., & Zeng, X. (2024). Efficacy and safety of telitacicept in primary Sjögren's syndrome: A randomized, double-blind, placebo-controlled, phase 2 trial. Rheumatology, 63(3), 698–705. https://doi.org/10.1093/rheumatology/kead265
Chen, X., Sun, M., Wang, L., Yang, Y., & Dai, H. (2025). Response to telitacicept in optic neuritis associated with Sjogren's syndrome: A case report and literature review. Journal of Neurology, 272(7), 462. https://doi.org/10.1007/s00415-025-13099-9
Wu, J., Song, Y., Wang, W., Yuan, X., & Du, R. (2025). Case series: Effectiveness and safety of telitacicept in Chinese patients with primary Sjögren's disease. International Journal of Rheumatic Diseases, 28, Article e70174. https://doi.org/10.1111/1756-185X.70174
Jiang, W., Zhang, L., Zhao, Y., He, X., Hu, C., & Liu, Y. (2020). The efficacy and mechanism for action of iguratimod in primary Sjögren's syndrome patients. International Ophthalmology, 40(11), 3059–3065. https://doi.org/10.1007/s10792-020-01490-6
Shao, Q., Wang, S., Jiang, H., & Liu, L. (2021). Efficacy and safety of iguratimod on patients with primary Sjögren's syndrome: A randomized, placebo-controlled clinical trial. Scandinavian Journal of Rheumatology, 50(2), 143–152. https://doi.org/10.1080/03009742.2020.1809701
St Clair, E. W., Baer, A. N., Ng, W. F., Noaiseh, G., Baldini, C., Tarrant, T. K., Papas, A., Devauchelle-Pensec, V., Wang, L., Xu, W., Pham, T. H., Sikora, K., Rees, W. A., & Alevizos, I. (2024). CD40 ligand antagonist dazodalibep in Sjögren's disease: A randomized, double-blinded, placebo-controlled, phase 2 trial. Nature Medicine, 30(6), 1583–1592. https://doi.org/10.1038/s41591-024-03009-3
Blagov, A. V., Kashtalap, V. V., Lapshina, K. O., Karimova, A. E., Asoyan, A. Z., & Orekhov, A. (2025). New strategies for treating Sjogren's syndrome. Cellular and Molecular Biology, 71(4), 111–119. https://doi.org/10.14715/cmb/2025.71.4.14
Price, E., Bombardieri, M., Kivitz, A., Matzkies, F., Gurtovaya, O., Pechonkina, A., Jiang, W., Downie, B., Mathur, A., Mozaffarian, A., Mozaffarian, N., & Gottenberg, J. E. (2022). Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sjögren's syndrome: A randomized, phase 2, double-blind, placebo-controlled study. Rheumatology, 61(12), 4797–4808. https://doi.org/10.1093/rheumatology/keac167
Bai, W., Liu, H., Dou, L., Yang, Y., Leng, X., Li, M., Zhang, W., Zhao, Y., & Zeng, X. (2022). Pilot study of baricitinib for active Sjogren's syndrome. Annals of the Rheumatic Diseases, 81(7), 1050–1052. https://doi.org/10.1136/annrheumdis-2021-222053
Dhillon, S. (2020). Tirabrutinib: First approval. Drugs, 80(8), 835–840. https://doi.org/10.1007/s40265-020-01318-8
Dörner, T., Kaul, M., Szántó, A., Tseng, J. C., Papas, A. S., Pylvaenaeinen, I., Hanser, M., Abdallah, N., Grioni, A., Santos Da Costa, A., Ferrero, E., Gergely, P., Hillenbrand, R., Avrameas, A., Cenni, B., & Siegel, R. M. (2024). Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjögren's syndrome: Results from a randomised, double-blind, placebo-controlled phase 2 trial. Annals of the Rheumatic Diseases, 83(3), 360–371. https://doi.org/10.1136/ard-2023-224691
Noaiseh, G., Sivils, K. L., Campbell, K., Idokogi, J., Lo, K. H., Liva, S. G., Leu, J. H., Dhatt, H., Ma, K., Leonardo, S., Li, H., Hubbard, J. J., Gottenberg, J. E., & DAHLIAS Study Investigators. (2026). Nipocalimab for the treatment of moderate-to-severe Sjögren's disease: A plain language summary of the DAHLIAS study. Expert Review of Clinical Immunology, 22(1), 5–18. https://doi.org/10.1080/1744666X.2026.2623948
Endo, Y., Hosogaya, N., Fukushige, Y., Narita, S., Jacobs, J., Reiss, W., Imai, Y., Shimizu, T., Koga, T., Yamamoto, H., Sakai, T., Takagi, Y., Sumi, M., & Kawakami, A. (2026). Efficacy and safety of efgartigimod PH20 SC for Sjögren's disease-associated dryness: Study protocol for an investigator-initiated, multicenter, phase 2, randomized, double-blind, placebo-controlled trial (OASIS study). Frontiers in Medicine, 12, 1719757. https://doi.org/10.3389/fmed.2025.1719757
Posada, J., Valadkhan, S., Burge, D., Davies, K., Tarn, J., Casement, J., Jobling, K., Gallagher, P., Wilson, D., Barone, F., Fisher, B. A., & Ng, W. F. (2021). Improvement of severe fatigue following nuclease therapy in patients with primary Sjögren's syndrome: A randomized clinical trial. Arthritis & Rheumatology, 73(1), 143–150. https://doi.org/10.1002/art.41489
Hong, Y., Chen, S., Jiang, X., Zhang, J., Liang, X., Yao, J., Gao, S., & Hua, C. (2025). Exosomes as immunomodulators in autoimmune inflammation: Implications for primary Sjögren's disease. Inflammation Research, 74(1), 91. https://doi.org/10.1007/s00011-025-02053-0
Miglianico, L., Cornec, D., Devauchelle-Pensec, V., Berrouiguet, S., Walter, M., Nabbé, P., Bettacchioli, E., & Stéphan, F. (2022). Identifying clinical, biological, and quality of life variables associated with depression, anxiety, and fatigue in pSS and sicca syndrome patients: A prospective single-centre cohort study. Joint Bone Spine, 89(6), 105413. https://doi.org/10.1016/j.jbspin.2022.105413
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Copyright (c) 2026 Aleksandra Płecka, Maksymilian Szklarski, Karol Józef Szkarłat, Szymon Targosz , Jędrzej Sztajura, Ewa Maraszewska, Michał Stachel, Weronika Szymacha, Karol Zimnicki, Alicja Stępień

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