Biologic Therapy in the Treatment of Sjögren’s Syndrome: a Clinical Perspective

  • Chadwick R. Johr
  • Frederick B. Vivino
Other CTD: Inflammatory Myopathies and Sjogren's (P Basharat, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Other CTD: Inflammatory Myopathies and Sjögren's


Purpose of review

Sjögren’s syndrome (SS) is an autoimmune disease characterized by sicca symptoms, musculoskeletal pain, and systemic manifestations. Biologic therapies have been successful in the treatment of autoimmune diseases and are being studied and used more extensively in SS. In this review, we discuss the burden of illness, challenges with clinical trials, new clinical practice guidelines, biologic therapies, and novel therapies in the treatment of SS.

Recent findings

Trials have shown that tumor necrosis factor-alpha (TNF-α) inhibitors are not helpful for most SS patients. Rituximab has demonstrated improvement in fatigue, gland function, and disease activity in small studies of SS though larger randomized-controlled-trials have failed to reach their primary endpoints. Non-controlled studies of belimumab and abatacept have reported positive results. New clinical practice guidelines have been published to assist in the management of SS including specific recommendations regarding the use of biologic therapies.


Biologic therapies show a lot of promise in the treatment of SS. Further studies are pending and new results will likely lead to future changes in the standard of care of this complex disease.


Sjögren’s syndrome Treatment Biologic Rituximab Clinical Guidelines 


Compliance with Ethical Standards

Conflict of Interest

Dr. Johr reports consulting honoraria from Kaiser Associates, L.E.K. Consulting, and KeyQuest Health, Inc. outside the submitted work and is a member of the Sjögren’s Syndrome Foundation Board of Directors.

Dr. Vivino reports personal fees and grant support from Biogen-Idec, Inc., personal fees, grant, and non-financial support from Immco Diagnostics, Inc., and personal fees from Novartis, Inc. outside the submitted work; also, former member of the Sjögren’s Syndrome Foundation Board of Directors, former Chair of SSF Medical & Scientific Advisory Board and, former Chair of the SSF Clinical Practice Guidelines Committee. Author of cited articles in this paper.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by either of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Vivino F. Sjögren’s syndrome: clinical aspects. Clin Immunol. 2017;182:48–54.Google Scholar
  2. 2.
    Voulgarelis M, Dafni U, Isenberg D, et al. Malignant lymphoma in primary Sjögren’s syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjögren’s Syndrome. Arthritis Rheum. 1999;42(8):1765–72.<1765::AID-ANR28>3.0.CO;2-V.CrossRefPubMedGoogle Scholar
  3. 3.
    Baimpa E, Dahabreh I, Voulgarelis M, et al. Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects. Medicine (Baltimore). 2009;88(5):284–93. Scholar
  4. 4.
    Smedby K, Vajdic C, Falster M, et al. Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the Interlymph Consortium. Blood. 2008;111(8):4029–38. Scholar
  5. 5.
    Heaton JM. Sjögren’s syndrome and systemic lupus erythematosus. Br Med J. 1959;1(5120):466–9. Scholar
  6. 6.
    Buchholz P, Steeds C, Stern L, et al. Utility assessment measure the impact of dry eye disease. Ocul Surf. 2006;4(3):155–61. Scholar
  7. 7.
    Fox R. Extraglandular manifestations of Sjögren syndrome (SS): dermatologic, arthritis, endocrine, pulmonary, cardiovascular, gastroenterology, renal, urology, and gynecologic manifestations. In: Fox R, Fox C, editors. Sjögren syndrome: practical guidelines to diagnosis and therapy. New York City: Springer; 2011.Google Scholar
  8. 8.
    Schiffman R, Walt J, Jacobsen G, et al. Utility assessment amongpatients with dry eyes disease. Ophthalmology. 2003;110(7):1412–9. Scholar
  9. 9.
    Christensen L, Petersen P, Thorn J, et al. Dental caries and dental health behavior of patients with primary Sjögren’s syndrome. Acta Odontol Scandinavica. 2001;59(3):116–2.CrossRefGoogle Scholar
  10. 10.
    Fox PC, Bowman SJ, Segal B, Vivino FB, Murukutla N, Choueiri K, et al. Oral involvement in primary Sjögren syndrome. J Am Dent Assoc. 2008;139(12):1592–601. Scholar
  11. 11.
    Sutcliffe N, Stoll T, Pyke S, Isenberg DA. Functional disability and end-organ damage in patients with systemic lupus and Sjögren’s syndrome. J Rheumatol. 1998;25(1):63–8.PubMedGoogle Scholar
  12. 12.
    Valtysdottir ST, Gudbjornsson B, Hallgren R. Psychological well-being in patients with primary Sjögren’s syndrome. Clin Exp Rheumatol. 2000;18:597–600.PubMedGoogle Scholar
  13. 13.
    Strombeck B, Ekdahl C, Manthorpe R, et al. Health related quality of life in primary Sjögren’s syndrome, rheumatoid arthritis and fibromyalgia compared to normal population data using SF-36. Scand J Rheumatol. 2000;29:20–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang Q, Wang X, Chen H, Shen B. Sjögren’s syndrome is associated with negatively variable impacts on domains of health-related quality of life: evidence from Short Form 36 questionnaire and a meta-analysis. Patient Prefer Adherence. 2017;11:905–11. Scholar
  15. 15.
    Segal B, Bowman SJ, Fox PC, et al. Primary Sjögren’s syndrome: health experiences and predictors of health quality among patients in the United States. Health Qual Life Outcomes. 2009;7(46):1–9.Google Scholar
  16. 16.
    Stewart C, Berg K, Cha S, et al. Salivary dysfunction and quality of life in Sjögren syndrome: a critical oral-systemic connection. J Am Dent Assoc. 2008;139(3):291–9. Scholar
  17. 17.
    Callaghan R, Prabu A, Allan R, et al. UK Sjögren’s interest group, direct healthcare costs and predictors of costs in patients with primary Sjögren’s syndrome. Rheumatology. 2007;46(1):105–11. Scholar
  18. 18.
    Vitali C, Tavoni A, Neri R, et al. Fibromyalgia features in patients with primary Sjögren’s syndrome: evidence of a relationship with psychological depression. Scand J Rheumatology. 1989;18(1):21–7.CrossRefGoogle Scholar
  19. 19.
    Valtysdottir S, Gudbjornsson B, Lindqvist U, et al. Anxiety and depression in patients with primary Sjögren’s syndrome. J Rheumatol. 2000;27(1):165–9.PubMedGoogle Scholar
  20. 20.
    Choi B, Oh H, Lee Y, et al. Prevalence in clinical impact of fibromyalgia in patients with primary Sjögren’s syndrome. Clin Exp Rheumatol. 2016;34(2 Suppl 96):S9–13.PubMedGoogle Scholar
  21. 21.
    Ostuni P, Botsios C, Sfriso P, Punzi L, Chieco-Bianchi F, Semerano L, et al. Fibromyalgia in Italian patients with primary Sjögren’s. Joint Bone Spine. 2002;69(1):51–7. Scholar
  22. 22.
    Fox RI, Fox CM. Sjögren syndrome: why do clinical trials fail? Rheum Dis Clin N Am. 2016;42(3):519–30. Scholar
  23. 23.
    Jonsson R, Theander E, Sjöström B, Brokstad K, Henriksson G. Autoantibodies present before symptom onset in primary Sjögren syndrome. JAMA. 2013 Nov 6;310(17):1854–5. Scholar
  24. 24.
    Trocchio E. The time is now for Sjögren’s. Moisture Seekers. 2016;34(1):12.Google Scholar
  25. 25.
    Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E, et al. EULAR Sjögren’s Task Force, EULAR Sjögren’s Syndrome Disease Activity Index: development of a consensus systemic disease activity index for primary Sjögren’s syndrome. Ann Rheum Dis. 2010;69(6):1103–9. Scholar
  26. 26.
    Seror R, Theander E, Brun JG, Ramos-Casals M, Valim V, Dörner T, et al. EULAR Sjögren’s Task Force. Validation of EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann Rheum Dis. 2015;74(5):859–66. Scholar
  27. 27.
    Cornec D, Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, et al. Development of the Sjögren’s Syndrome Responder Index, a data-driven composite endpoint for assessing treatment efficacy. Rheumatology (Oxford). 2015;54(9):1699–708. Scholar
  28. 28.
    Taylor S, Trocchio E. SSF's national patient survey reveals significant physical and emotional burdens of Sjögren's. The Moisture Seekers. 2017;35(4):1–2, 4–7.Google Scholar
  29. 29.
    Sullivan B, Crews L, Messmer E, et al. Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications. Acta Ophthalmol. 2014;92:161–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Shiboski S, Shiboski C, Criswell L, et al. Sjögren’s International Collaborative Clinical Alliance (SICCA) Research. American College of Rheumatology Classification Criteria for Sjögren’s Syndrome: a data driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance Cohort. Arthritis Care Res. 2012;64(4):475–87.CrossRefGoogle Scholar
  31. 31.
    Mishra R, Vivino F. Diagnosis and management of fatigue in Sjögren’s syndrome. In: Wallace D, Alexander E, Carsons S, Hammitt K, Vivino F, editors. The Sjögren’s book. 4th ed. New York: Oxford University Press; 2012.Google Scholar
  32. 32.
    Usmani Z, Hlavac M, Rischmueller M, et al. Sleep disordered breathing in patients with primary Sjögren’s syndrome: a group controlled study. Sleep Med. 2012;13(8):1066–70. Scholar
  33. 33.
    Gudbjornsson B, Broman JE, Hetta J, et al. Sleep disturbances in patients with primary Sjögren’s syndrome. Br J Rheumatol. 1993;32(12):1072–6. Scholar
  34. 34.
    Garcia-Carrasco M, Jiménez-Herrera E, Gálvez-Romero J, et al. Vitamin D and Sjögren syndrome. Autoimmun Rev. 2017;16(6):587–93. Scholar
  35. 35.
    •• Vivino FB, Carsons SE, Foulks G, et al. New treatment guidelines for Sjögren’s disease. Rheum Dis Clin Am. 2016;42:531–51. Review of new guidelines for Sjögren’s syndrome including treatment of dry-mouth, dry-eye, musculoskeletal pain, fatigue and use of biologics.CrossRefGoogle Scholar
  36. 36.
    Foulks G, Forstot S, Donshik P, et al. Clinical guidelines for management of dry eye associated with Sjögren disease. The ocular surface. 2015;13(2):118–32.CrossRefPubMedGoogle Scholar
  37. 37.
    Zero D, Brennan M, Daniels T, et al. Clinical practice guidelines for oral management of Sjögren’s disease: dental caries prevention. J Am Dent Assoc. 2016;147(4):295–305.CrossRefPubMedGoogle Scholar
  38. 38.
    •• Carsons S, Vivino F, Parke A, et al. Treatment guidelines for rheumatologic manifestations of Sjögren’s: use of biologics, management of fatigue, and inflammatory musculoskeletal pain. Arthritis Care Res. 2017;69(4):517–27. Review of new guidelines for Sjögren’s syndrome including treatment of musculoskeletal pain, fatigue, and use of biologics.CrossRefGoogle Scholar
  39. 39.
    AGREE Collaboration. Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Qual Saf Health Care. 2003;12(1):18–23.CrossRefGoogle Scholar
  40. 40.
    AGREE Research trust. Appraisal of Guidelines for Research and Evaluation II 2013. Available at Manual-and-23-item-Instrument_2009_UPDATE_2013.pdf.
  41. 41.
    Guyatt G, Oxman A, Visit G, et al. For the GRADE Working Group. Rating quality of evidence and strength of recommendations GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–66. Scholar
  42. 42.
    Zandbelt MM, de Wilde PCM, van Damme PA, et al. Etanercept in the treatment of patients with primary Sjögren’s syndrome: a pilot study. J Rheumatol. 2004;31(1):96–101.PubMedGoogle Scholar
  43. 43.
    Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E, et al. Inefficacy of infliximab in primary Sjögren’s syndrome. Arthritis Rheum. 2004;50(4):1270–6. Scholar
  44. 44.
    Sankar V, Brennan MT, Kok MR, et al. Etanercept in Sjögren's syndrome: a twelve-week randomized, double-blind, placebocontrolled pilot clinical trial. Arthritis Rheum. 2004;50(7):2240–45.Google Scholar
  45. 45.
    Türkoğlu EB, Tuna S, Alan S, et al. Effect of systemic infliximab therapy in patients with Sjögren’s syndrome. Turkish J Ophthal. 2015;45(4):138–40.Google Scholar
  46. 46.
    Moutsopoulos NM, Katsifis GE, Angelov N, Leakan RA, Sankar V, Pillemer S, et al. Lack of efficacy of etanercept in Sjögren syndrome correlates with failed suppression of tumour necrosis factor alpha and systemic immune activation. Ann Rheum Dis. 2008;67(10):1437–43. Scholar
  47. 47.
    Mavragani CP, Niewold TB, Moutsopoulos NM, Pillemer SR, Wahl SM, Crow MK. Augmented interferon-alpha pathway activation in patients with Sjögren’s syndrome treated with etanercept. Arthritis Rheum. 2007;56(12):3995–04. Scholar
  48. 48.
    Kroese FG, Adbulahad WH, Haacke E, et al. B-cell hyperactivity in primary Sjögren’s syndrome. Expert Rev Clin Immunol. 2014;10(4):483–99. Scholar
  49. 49.
    Pontarini E, Fabris M, Quartuccio L, Cappeletti M, Calcaterra F, Roberto A, et al. Treatment with belimumab restores B cell subsets and their expression of B cell activating factor receptor in patients with primary Sjögren’s syndrome. Rheumatology. 2015;54(8):1429–34. Scholar
  50. 50.
    Brown S, Coy NN, Pitzalis C, et al. The TRACTISS protocol: a randomized double blind placebo controlled TRial of Anti-B Cell Therapy In patients with primary Sjögren's Syndrome. BMC Musculoskelet Disord. 2014:15–21.
  51. 51.
    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(7):1440–50. Scholar
  52. 52.
    Devauchelle-Pensec V, Mariette X, Jousee-Joulin S, et al. Treatment of primary Sjögren syndrome with rituximab: a randomized trial. Ann Intern Med. 2014;160(4):233–42. Scholar
  53. 53.
    Meijer JM, Meiners PM, Vissink A, Spijkervet FKL, Abdulahad W, Kamminga N, et al. Effectiveness of rituximab treatment in primary Sjögren’s syndrome. Arthritis Rheum. 2010;62(4):960–8. Scholar
  54. 54.
    Dass S, Bowman SJ, Vital EM, Ikeda K, Pease CT, Hamburger J, 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):1541–4. Scholar
  55. 55.
    Gottenberg J, Ciquetti G, Larroche C, et al. Efficacy of rituximab in systemic manifestations of primary Sjögren’s syndrome: results in 78 patients of the AutoImmune and Rituximab registry. Ann Rheum Dis. 2013;72(6):1026–31. Scholar
  56. 56.
    Mekinian A, Pavaud P, Hatron PY, et al. Efficacy of rituximab in primary Sjögren’s syndrome with peripheral nervous systemic involvement: results from the AIR registry. Ann Rheum Dis. 2012;71:84–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Bootsma H, Kroese FGM, Vissink A. Editorial: rituximab in the treatment of Sjögren's syndrome: is it the right or wrong drug? Arthritis rheumatol. 2017;69(7):1346–49.Google Scholar
  58. 58.
    Steinfeld SD, Tant L, Burmester GR, Teoh NKW, Wegener WA, Goldenberg DM, et al. Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren’s syndrome: an open-label phase I/II study. Arthritis Res Ther. 2006;8(4):R129. Scholar
  59. 59.
    Mariette X, Seror R, Quartuccio L, Baron G, Salvin S, Fabris M, 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(3):526–31. Scholar
  60. 60.
    De Vita S, Quartuccio L, Seror R, Salvin S, Ravaud P, Fabris M, et al. Efficacy and safety of belimumab given for 12 months in primary Sjögren’s syndrome: the BELISS open-label phase II study. Rheumatology. 2015;54(12):2249–56. Scholar
  61. 61.
    Adler S, Körner M, Förger F, Huscher D, Caversaccio MD, Villiger PM. Evaluation of histologic, serologic, and clinical changes in response to abatacept treatment of primary Sjögren’s syndrome: a pilot study. Arthritis Care Res. 2013;65(11):1862–8. Scholar
  62. 62.
    Meiners PM, Vissink A, Kroese FGM, Spijkervet FKL, Smitt-Kamminga NS, Abdulahad WH, et al. Abatacept treatment reduces disease activity in early primary Sjögren’s syndrome (open-label proof of concept ASAP study). Ann Rheum Dis. 2014;73(7):1393–6. Scholar
  63. 63.
    Tsuboi H, Matsumoto I, Hagiwara S, Hirota T, Takahashi H, Ebe H, et al. Effectiveness of abatacept for patients with Sjögren’s syndrome associated with rheumatoid arthritis. An open label, multicenter, one-year, prospective study: ROSE (Rheumatoid Arthritis with Orencia Trial toward Sjögren’s syndrome Endocrinopathy) trial. Mod Rheumatol. 2016;26(6):891–9. Scholar
  64. 64.
    Harboe E, Tjensvoll AB, Vefring HK, Gøransson LG, Kvaløy JT, Omdal R. Fatigue in primary Sjögren’s syndrome—a link to sickness behaviour in animals? Brain Behav Immun. 2009;23(8):1104–8. Scholar
  65. 65.
    Norheim KB, Harboe E, Gøransson LG, et al. Interleukin-1 inhibition and fatigue in primary Sjögren’s syndrome—a double blind, randomised clinical trial. PLos ONE. 7(1):e30123.
  66. 66.
    Halse A, Tengner P, Wahren-Herlenius M, et al. Increased frequency of cells secreting interleukin-6 and interleukin-10 in peripheral blood of patients with primary Sjögren’s syndrome. Scand J Immunol. 1999;49(5):533–8. Scholar
  67. 67.
    Tishler M, Yaron I, Geyer O, et al. Elevated tear interleukin-6 levels in patients with Sjögren syndrome. Ophthalmology. 1998;105(12):2327–9.36CrossRefPubMedGoogle Scholar
  68. 68.
    Tishler M, Yaron I, Shirazi I, Yossipov Y, Yaron M. Increased salivary interleukin-6 levels in patients with primary Sjögren’s syndrome. RheumatolInt. 1999;18(4):125–7. Scholar
  69. 69.
    Justet A, Ottavianai S, Dieude P, et al. Tocilizumab for refractory organising pneumonia associated with Sjögren’s disease. BMJ Case Rep. 2015;2015(may14 1):bcr2014209076. Scholar
  70. 70.
    Komai T, Shoda H, Yamaguchi K, Sakurai K, Shibuya M, Kubo K, et al. Neuromyelitis optica spectrum disorder complicated with Sjögren syndrome successfully treated with tocilizumab: a case report. Mod Rheumatol. 2016;26(2):294–6. Scholar
  71. 71.
    Nilolay N, Illei G. Pathogenesis of Sjögren’s syndrome. Curr Opin Rheumatol. 2009;21(5):465–4470.CrossRefGoogle Scholar
  72. 72.
    Voulgarelis M, Tzioufas A. Pathogenetic mechanisms in the initiation and perpetuation of Sjögren’s syndrome. Nat Rev Rheumatol. 2010;6(9):529–37. Scholar
  73. 73.
    Mariette M, Gottenberg J-E. Pathogenesis of Sjögren’s syndrome and therapeutic consequences. Curr Opin Rheumatol. 2010;22(5):471–7.CrossRefPubMedGoogle Scholar
  74. 74.
    Maravragani C, Nezos A, Moutsopoulos H. New advances in the classification, pathogenesis and treatment of Sjögren’s syndrome. Curr Opin Rheumatol. 2013;25:623–9.CrossRefGoogle Scholar
  75. 75.
    Fox R Pathogenesis of Sjögren’s syndrome. UptoDate (P. Shur, P.Romain Eds.), Wolters Kluwer, January 2017.
  76. 76.
    Faustman D, Alevizos I. Investigation of repeat BCG vaccinations in autoimmunity: rationale and phase I trial in Sjögren’s syndrome: S13.3. Scand J Immunol. 2015;81(5):428–9.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Chadwick R. Johr
    • 1
  • Frederick B. Vivino
    • 1
  1. 1.PhiladelphiaUSA

Personalised recommendations