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Arthritis und Rheuma 2024; 44(02): 112-119
DOI: 10.1055/a-2214-5058
Schwerpunkt

Zielgerichtete Immuntherapien beim primären Sjögren-Syndrom

Nadine Zehrfeld
1   Klinik für Rheumatologie & Immunologie, Medizinische Hochschule Hannover
,
Torsten Witte
1   Klinik für Rheumatologie & Immunologie, Medizinische Hochschule Hannover
,
Diana Ernst
1   Klinik für Rheumatologie & Immunologie, Medizinische Hochschule Hannover
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ZUSAMMENFASSUNG

Das primäre Sjögren-Syndrom ist eine komplexe und sehr heterogene Erkrankung, die mit einer chronischen Epitheliitis der exokrinen Drüsen einhergeht und somit zur Sicca-Symptomatik führt. In mehr als der Hälfte der Fälle kommt es jedoch auch zu extraglandulären Verläufen. Aktuelle EULAR-Therapieempfehlungen orientieren sich an klinischen Manifestationen und Wirkstoffen, die auch beim systemischen Lupus erythematodes genutzt werden. Empfehlungen für den Einsatz von Biologika-Therapien gibt es wenige: Rituximab bei schweren neurologischen und/oder vaskulitischen Manifestationen, Abatacept bei therapierefraktärer Arthritis und Belimumab bei therapierefraktärer Parotisschwellung. Doch viele neue Wirkansätze werden aktuell in Studien verfolgt. Insbesondere die Daten zu Ianalumab, Iscalimab und Dazodalibep sind vielversprechend. Weitere ganz neue Wirkprinzipien in der rheumatologischen Therapie, wie der Proteasomen-Inhibitor Bortezomib, niedrig dosiertes I2, Pl3Kδ-Inhibitoren oder der Einsatz von mesenchymalen Stammzellen sind ebenfalls Gegenstand aktueller Studien.

Schlüsselwörter

Sjögren-Syndrom - Biologika-Therapien - CD40-Inhibitoren - BAFF-R-Inhibitoren - Zytokin-Inhibitoren


Publication History

Article published online:
16 April 2024

© 2024. Thieme. All rights reserved.

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  • Literatur

  • 1 Mihai A, Caruntu C, Jurcut C. et al The spectrum of extraglandular manifestations in primary sjögren’s syndrome. J Pers Med 2023; 13 (06) 961 DOI: 10.3390/jpm13060961.
    CrossrefPubMedGoogle Scholar
  • 2 Ramos-Casals M, Font J, Garcia-Carrasco M. et al Primary sjögren syndrome: Hematologic patterns of disease expression. Medicine (Baltimore) 2002; 81 (04) 281-292 DOI: 10.1097/00005792-200207000-00004.
    CrossrefPubMedGoogle Scholar
  • 3 Ramos-Casals M, Brito-Zerón P, Bombardieri S. et al EULAR recommendations for the management of sjögren’s syndrome with topical and systemic therapies. Ann Rheum Dis 2020; 79 (01) 3-18 DOI: 10.1136/annrheumdis-2019-216114.
    CrossrefPubMedGoogle Scholar
  • 4 Litinskiy MB, Nardelli B, Hilbert DM. et al DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 2002; 03 (09) 822-829 DOI: 10.1038/ni829.
    CrossrefPubMedGoogle Scholar
  • 5 Daridon C, Devauchelle V, Hutin P. et al Aberrant expression of BAFF by B lymphocytes infiltrating the salivary glands of patients with primary sjögren’s syndrome. Arthritis Rheum 2007; 56 (04) 1134-1144 DOI: 10.1002/art.22458.
    CrossrefPubMedGoogle Scholar
  • 6 Kroese FGM, Abdulahad WH, Haacke E. et al B-cell hyperactivity in primary sjögren’s syndrome. Expert Rev Clin Immunol 2014; 10 (04) 483-499 DOI: 10.1586/1744666X.2014.891439.
    CrossrefPubMedGoogle Scholar
  • 7 Posada J, Valadkhan S, Burge D. et al Improvement of severe fatigue following nuclease therapy in patients with primary sjögren’s syndrome: A randomized clinical trial. Arthritis Rheumatol 2021; 73 (01) 143-150 DOI: 10.1002/art.41489.
    CrossrefPubMedGoogle Scholar
  • 8 Jakez-Ocampo J, Atisha-Fregoso Y, Llorente L. Refractory primary sjögren syndrome successfully treated with bortezomib. J Clin Rheumatol 2015; 21 (01) 31-32 DOI: 10.1097/RHU.0000000000000210.
    CrossrefPubMedGoogle Scholar
  • 9 Sun R, Gu W, Ma Y. et al Relapsed/refractory acquired thrombotic thrombocytopenic purpura in a patient with sjögren syndrome: Case report and review of the literature. Medicine (Baltimore) 2018; 97 (43) e12989 DOI: 10.1097/MD.0000000000012989.
    CrossrefPubMedGoogle Scholar
  • 10 Chen H, Qi X, Li Y. et al Iguratimod treatment reduces disease activity in early primary sjögren’s syndrome: An open-label pilot study. Mod Rheumatol 2021; 31 (02) 394-398 DOI: 10.1080/14397595.2020.1789335.
    CrossrefPubMedGoogle Scholar
  • 11 Meiners PM, Vissink A, Kallenberg CGM. et al Treatment of primary sjögren’s syndrome with anti-CD20 therapy (rituximab). A feasible approach or just a starting point?. Expert Opin Biol Ther 2011; 11 (10) 1381-1394 DOI: 10.1517/14712598.2011.605352.
    CrossrefPubMedGoogle Scholar
  • 12 Pijpe J, van Imhoff GW, Spijkervet FKL. et al Rituximab treatment in patients with primary sjögren’s syndrome: An open-label phase II study. Arthritis Rheum 2005; 52 (09) 2740-2750 DOI: 10.1002/art.21260.
    CrossrefPubMedGoogle Scholar
  • 13 Meijer JM, Meiners PM, Vissink A. et al Effectiveness of rituximab treatment in primary sjögren’s syndrome: A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010; 62 (04) 960-968 DOI: 10.1002/art.27314.
    CrossrefPubMedGoogle Scholar
  • 14 Dass S, Bowman SJ, Vital EM. et al Reduction of fatigue in sjögren syndrome with rituximab: Results of a randomised, double-blind, placebo-controlled pilot study. Ann Rheum Dis 2008; 67 (11) 1541-1544 DOI: 10.1136/ard.2007.083865.
    CrossrefPubMedGoogle Scholar
  • 15 Seror R, Sordet C, Guillevin L. et al Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary sjögren’s syndrome. Ann Rheum Dis 2007; 66 (03) 351-357 DOI: 10.1136/ard.2006.057919.
    CrossrefPubMedGoogle Scholar
  • 16 Carsons SE, Vivino FB, Parke A. et al Treatment guidelines for rheumatologic manifestations of sjögren’s syndrome: Use of biologic agents, management of fatigue, and inflammatory musculoskeletal pain. Arthritis Care Res (Hoboken) 2017; 69 (04) 517-527 DOI: 10.1002/acr.22968.
    CrossrefPubMedGoogle Scholar
  • 17 Bowman SJ, Everett CC, O’Dwyer JL. et al Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary sjögren’s syndrome. Arthritis Rheumatol 2017; 69 (07) 1440-1450 DOI: 10.1002/art.40093.
    CrossrefPubMedGoogle Scholar
  • 18 Batten M, Groom J, Cachero TG. et al BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med 2000; 192 (10) 1453-1466 DOI: 10.1084/jem.192.10.1453.
    CrossrefPubMedGoogle Scholar
  • 19 Mariette X, Roux S, Zhang J. et al The level of BLyS (BAFF) correlates with the titre of autoantibodies in human sjögren’s syndrome. Ann Rheum Dis 2003; 62 (02) 168-171 DOI: 10.1136/ard.62.2.168.
    CrossrefPubMedGoogle Scholar
  • 20 James K, Chipeta C, Parker A. et al B-cell activity markers are associated with different disease activity domains in primary sjögren’s syndrome. Rheumatology (Oxford) 2018; 57 (07) 1222-1227 DOI: 10.1093/rheumatology/key063.
    CrossrefPubMedGoogle Scholar
  • 21 De Vita S, Quartuccio L, Seror R. et al Efficacy and safety of belimumab given for 12 months in primary sjögren’s syndrome: The BELISS open-label phase II study. Rheumatology (Oxford) 2015; 54 (12) 2249-2256 DOI: 10.1093/rheumatology/kev257.
    CrossrefPubMedGoogle Scholar
  • 22 Mariette X, Seror R, Quartuccio L. et al Efficacy and safety of belimumab in primary sjögren’s syndrome: Results of the BELISS open-label phase II study. Ann Rheum Dis 2015; 74 (03) 526-531 DOI: 10.1136/annrheumdis-2013-203991.
    CrossrefPubMedGoogle Scholar
  • 23 Marinho A, Delgado Alves J, Fortuna J. et al Biological therapy in systemic lupus erythematosus, antiphospholipid syndrome, and sjögren’s syndrome: Evidence- and practice-based guidance. Front Immunol 2023; 14: 1117699 DOI: 10.3389/fimmu.2023.1117699.
    CrossrefPubMedGoogle Scholar
  • 24 Pollard RPE, Abdulahad WH, Vissink A. et al Serum levels of BAFF, but not APRIL, are increased after rituximab treatment in patients with primary sjogren’s syndrome: Data from a placebo-controlled clinical trial. Ann Rheum Dis 2013; 72 (01) 146-148 DOI: 10.1136/annrheumdis-2012-202071.
    CrossrefPubMedGoogle Scholar
  • 25 Mariette X, Barone F, Baldini C. et al A randomized, phase II study of sequential belimumab and rituximab in primary sjögren’s syndrome. JCI Insight 2022; 07 (23) e163030 DOI: 10.1172/jci.insight.163030. 10.1172/jci.insight.163030
    CrossrefPubMedGoogle Scholar
  • 26 Bowman SJ, Fox R, Dörner T. et al 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 2022; 399 10320 161-171 DOI: 10.1016/S0140-6736(21)02251-0.
    CrossrefPubMedGoogle Scholar
  • 27 Sato S, Miller AS, Inaoki M. et al CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction: Altered signaling in CD22-deficient mice. Immunity 1996; 05 (06) 551-562 DOI: 10.1016/s1074-7613(00)80270-8.
    CrossrefPubMedGoogle Scholar
  • 28 Wallace DJ, Hobbs K, Clowse MEB. et al Long-term safety and efficacy of epratuzumab in the treatment of moderate-to- severe systemic lupus erythematosus: Results from an open-label extension study. Arthritis Care Res (Hoboken) 2016; 68 (04) 534-543 DOI: 10.1002/acr.22694.
    CrossrefPubMedGoogle Scholar
  • 29 Steinfeld SD, Tant L, Burmester GR. et al Epratuzumab (humanised anti-CD22 antibody) in primary sjögren’s syndrome: An open-label phase I/II study. Arthritis Res Ther 2006; 08 (04) R129 DOI: 10.1186/ar2018.
    CrossrefPubMedGoogle Scholar
  • 30 Machado AC, Dos Santos LC, Fidelix T. et al Effectiveness and safety of abatacept for the treatment of patients with primary sjögren’s syndrome. Clin Rheumatol 2020; 39 (01) 243-248 DOI: 10.1007/s10067-019-04724-w.
    CrossrefPubMedGoogle Scholar
  • 31 van Nimwegen JF, Mossel E, van Zuiden GS. et al Abatacept treatment for patients with early active primary sjögren’s syndrome: A single-centre, randomised, double-blind, placebo-controlled, phase 3 trial (ASAP-III study). The Lancet Rheumatology 2020; 02 (03) e153-e163 https://doi.org/10.1016/S2665-9913(19)30160-2 DOI: 10.1016/S2665-9913(19)30160-2.
    CrossrefPubMedGoogle Scholar
  • 32 Pontarini E, Verstappen GM, Grigoriadou S. et al Blocking T cell co-stimulation in primary sjögren’s syndrome: Rationale, clinical efficacy and modulation of peripheral and salivary gland biomarkers. Clin Exp Rheumatol 2020; 38 (Suppl. 126) S222-S227
    Google Scholar
  • 33 Belkhir R, Gestermann N, Koutero M. et al Upregulation of membrane-bound CD40L on CD4 + T cells in women with primary sjögren’s syndrome. Scand J Immunol 2014; 79 (01) 37-42 DOI: 10.1111/sji.12121.
    CrossrefPubMedGoogle Scholar
  • 34 Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM. Characteristics of the minor salivary gland infiltrates in sjögren’s syndrome. J Autoimmun 2010; 34 (04) 400-407 DOI: 10.1016/j.jaut.2009.10.004.
    CrossrefPubMedGoogle Scholar
  • 35 Benjamin A Fisher, Xavier Mariette, Athena S Papas. et al Iscalimab (CFZ533) in patients with sjögren’s disease: Week 24 efficacy and safety results of a randomized, placebo-controlled, phase 2b dose-ranging study. Arthritis Rheumatol 2023; 75 (suppl 9)
    Google Scholar
  • 36 St Clair E, Wang L, Alevios I. et al Dazodalibep, a CD40L antagonist, in a phase 2, randomized, double-blind, placebo-controlled, crossover trial of subjects with sjögren’s disease having unacceptable symptomatic burden but limited extraglandular organ involvement. Arthritis Rheumatol 2023; 75 (suppl. 9)
    Google Scholar
  • 37 Norheim KB, Harboe E, Gøransson LG, Omdal R. Interleukin-1 inhibition and fatigue in primary sjögren’s syndrome – a double blind, randomised clinical trial. PLoS One 2012; 07 (01) e30123 DOI: 10.1371/journal.pone.0030123.
    CrossrefPubMedGoogle Scholar
  • 38 Felten R, Devauchelle-Pensec V, Seror R. et al Interleukin 6 receptor inhibition in primary sjögren syndrome: A multicentre double-blind randomised placebo-controlled trial. Ann Rheum Dis 2021; 80 (03) 329-338 DOI: 10.1136/annrheumdis-2020-218467.
    CrossrefPubMedGoogle Scholar
  • 39 van Baarsen LG, Wijbrandts CA, Rustenburg F. et al Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment. Arthritis Res Ther 2010; 12 (01) R11 DOI: 10.1186/ar2912.
    CrossrefPubMedGoogle Scholar
  • 40 Zandbelt MM, de Wilde P, van Damme P. et al Etanercept in the treatment of patients with primary sjögren’s syndrome: A pilot study. J Rheumatol 2004; 31 (01) 96-101
    Google Scholar
  • 41 Chimenti MS, Talamonti M, Novelli L. et al Long-term ustekinumab therapy of psoriasis in patients with coexisting rheumatoid arthritis and sjögren syndrome. report of two cases and review of literature. J Dermatol Case Rep 2015; 09 (03) 71-75 DOI: 10.3315/jdcr.2015.1207.
    CrossrefPubMedGoogle Scholar
  • 42 Lee J, Lee J, Kwok S. et al JAK-1 inhibition suppresses interferon-induced BAFF production in human salivary gland: Potential therapeutic strategy for primary sjögren’s syndrome. Arthritis Rheumatol 2018; 70 (12) 2057-2066 DOI: 10.1002/art.40589.
    CrossrefPubMedGoogle Scholar
  • 43 Gao R, Pu J, Wang Y. et al Tofacitinib in the treatment of primary sjögren’s syndrome-associated interstitial lung disease: Study protocol for a prospective, randomized, controlled and open-label trial. BMC Pulm Med 2023; 23 (01) 473 0 DOI: 10.1186/s12890-023-02774-0.
    CrossrefPubMedGoogle Scholar
  • 44 Zhang H, Liu Z, Huang L. et al The short-term efficacy of bortezomib combined with glucocorticoids for the treatment of refractory lupus nephritis. Lupus 2017; 26 (09) 952-958 DOI: 10.1177/0961203316686703.
    CrossrefPubMedGoogle Scholar
  • 45 Pu J, Wang X, Riaz F. et al Effectiveness and safety of iguratimod in treating primary sjögren’s syndrome: A systematic review and meta-analysis. Front Pharmacol 2021; 12: 621208 DOI: 10.3389/fphar.2021.621208.
    CrossrefPubMedGoogle Scholar
  • 46 Lyu T, Jiang H, Zeng L. et al Iguratimod suppresses tfh cell differentiation in primary sjögren’s syndrome patients through inhibiting akt/mTOR/STAT3 signaling. Arthritis Res Ther 2023; 25 (01) 152-154 DOI: 10.1186/s13075-023-03109-4.
    CrossrefPubMedGoogle Scholar
  • 47 Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells. Annu Rev Immunol 2013; 31: 675-704 DOI: 10.1146/annurev-immunol-032712-095946.
    CrossrefPubMedGoogle Scholar
  • 48 Puri KD, Gold MR. Selective inhibitors of phosphoinositide 3-kinase delta: Modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies. Front Immunol 2012; 03: 256 DOI: 10.3389/fimmu.2012.00256.
    CrossrefPubMedGoogle Scholar
  • 49 Juarez M, Diaz N, Johnston GI. et al A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary sjögren’s syndrome. Rheumatology (Oxford) 2021; 60 (03) 1364-1375 DOI: 10.1093/rheumatology/keaa410.
    CrossrefPubMedGoogle Scholar
  • 50 He J, Chen J, Miao M. et al Efficacy and safety of low-dose interleukin 2 for primary sjögren syndrome: A randomized clinical trial. JAMA Netw Open 2022; 05 (11) e2241451 DOI: 10.1001/jamanetworkopen.2022.41451.
    CrossrefPubMedGoogle Scholar
  • 51 Liu Y, Li C, Wang S. et al Human umbilical cord mesenchymal stem cells confer potent immunosuppressive effects in sjögren’s syndrome by inducing regulatory T cells. Mod Rheumatol 2021; 31 (01) 186-196 DOI: 10.1080/14397595.2019.1707996.
    CrossrefPubMedGoogle Scholar
  • 52 Seror R, Baron G, Camus M. et al Development and preliminary validation of the sjögren’s tool for assessing response (STAR): A consensual composite score for assessing treatment effect in primary sjögren’s syndrome. Ann Rheum Dis 2022; 81 (07) 979-989 DOI: 10.1136/annrheumdis-2021-222054.
    CrossrefPubMedGoogle Scholar
  • 53 McCoy SS, Woodham M, Bartels CM. et al Symptom-based cluster analysis categorizes sjögren’s disease subtypes: An international cohort study highlighting disease severity and treatment discordance. Arthritis Rheumatol 2022; 74 (09) 1569-1579 DOI: 10.1002/art.42238.
    CrossrefPubMedGoogle Scholar
  • 54 Zippel CL, Beider S, Kramer E. et al Premature stroke and cardiovascular risk in primary sjögren’s syndrome. Front Cardiovasc Med 2022; 09: 1048684 DOI: 10.3389/fcvm.2022.1048684.
    CrossrefPubMedGoogle Scholar