Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Topical and systemic medications for the treatment of primary Sjögren's syndrome

Abstract

The treatment of primary Sjögren's syndrome (SS) is based principally on the management of sicca features and systemic manifestations. Sicca manifestations are treated symptomatically through administration of topical therapies, such as saliva substitutes and artificial tears; in patients with residual salivary gland function, stimulation of salivary flow with a sialogogue is the therapy of choice. The management of extraglandular features must be tailored to the specific organ or organs involved; however, limited data have been obtained from controlled trials in SS to guide the treatment of systemic symptoms using therapies including antimalarials, glucocorticoids, immunosuppressive drugs and biologic agents. Nevertheless, randomised controlled trials of biologic agents that target molecules and receptors involved in the aetiopathogenesis of primary SS have initiated a new era in the therapeutic management of the disease, although the potential risks and benefits of these agents must be carefully considered. In this Review, we analyse the evidence regarding the efficacy of the therapeutic agents currently available to treat the manifestations of SS. On the basis of this evidence, we provide guidance on the use of these agents in different clinical scenarios.

Key Points

  • The primary therapeutic approach to sicca manifestations in Sjögren's syndrome (SS) should be symptomatic relief, using artificial tears and saliva substitutes

  • The treatment of choice for patients with moderate or severe oral dryness and residual salivary gland function is an oral muscarinic agonist

  • Patients with severe or refractory keratoconjunctivitis sicca might require the addition of topical cyclosporine A to suppress the underlying inflammation

  • The management of extraglandular features must be tailored to the specific organ involved, mainly using corticosteroids and immunosuppressive agents

  • Controlled trials of biologic agents in patients with SS have demonstrated the lack of efficacy of TNF blockade, whereas more promising results have been obtained with B-cell-targeted therapies, especially rituximab

  • The overall low level of evidence from therapeutic studies in primary SS underscores the need for considerably larger trials

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Proposed therapeutic algorithm for the treatment of sicca features in SS.
Figure 2: Proposed therapeutic algorithm for treatment of the main extraglandular manifestations of SS.

Similar content being viewed by others

References

  1. Fox, R. I. Sjögren's syndrome. Lancet 366, 321–331 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Kassan, S. S. & Moutsopoulos, H. M. Clinical manifestations and early diagnosis of Sjögren syndrome. Arch. Intern. Med. 164, 1275–1284 (2004).

    Article  PubMed  Google Scholar 

  3. Ramos-Casals, M., Tzioufas, A. G., Stone, J. H., Sisó, A. & Bosch, X. Treatment of primary Sjögren syndrome: a systematic review. JAMA 304, 452–460 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Alpöz, E. et al. The efficacy of Xialine in patients with Sjögren's syndrome: a single-blind, cross-over study. Clin. Oral Investig. 12, 165–172 (2008).

    Article  PubMed  Google Scholar 

  5. Alves, M. B., Motta, A. C., Messina, W. C. & Migliari, D. A. Saliva substitute in xerostomic patients with primary Sjögren's syndrome: a single-blind trial. Quintessence Int. 35, 392–396 (2004).

    PubMed  Google Scholar 

  6. Aagaard, A., Godiksen, S., Teglers, P. T., Schiødt, M. & Glenert, U. Comparison between new saliva stimulants in patients with dry mouth: a placebo-controlled double-blind crossover study. J. Oral Pathol. Med. 21, 376–380 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Johansson G. et al. Effects of mouthrinses with linseed extract Salinum without/with chlorhexidine on oral conditions in patients with Sjögren's syndrome. A double-blind crossover investigation. Gerodontology 18, 87–94 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Rhodus, N. L. & Bereuter, J. Clinical evaluation of a commercially available oral moisturizer in relieving signs and symptoms of xerostomia in postirradiation head and neck cancer patients and patients with Sjögren's syndrome. J. Otolaryngol. 29, 28–34 (2000).

    CAS  PubMed  Google Scholar 

  9. van der Reijden, W. A., van der Kwaak, H., Vissink, A., Veerman, E. C. & Amerongen, A. V. Treatment of xerostomia with polymer-based saliva substitutes in patients with Sjögren's syndrome. Arthritis Rheum. 39, 57–63 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Visch, L. L., Gravenmade, E. J., Schaub, R. M., Van Putten, W. L. & Vissink, A. A double-blind crossover trial of CMC- and mucin-containing saliva substitutes. Int. J. Oral Maxillofac. Surg. 15, 395–400 (1986).

    Article  CAS  PubMed  Google Scholar 

  11. Aragona, P., Di Stefano, G., Ferreri, F., Spinella, R. & Stilo, A. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren's syndrome patients. Br. J. Ophthalmol. 86, 879–884 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Aragona, P., Papa, V., Micali, A., Santocono, M. & Milazzo, G. Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br. J. Ophthalmol. 86, 181–184 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Brignole, F., Pisella, P. J., Dupas, B., Baeyens, V. & Baudouin, C. Efficacy and safety of 0.18% sodium hyaluronate in patients with moderate dry eye syndrome and superficial keratitis. Graefes Arch. Clin. Exp. Ophthalmol. 243, 531–538 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Condon, P. I. et al. Double blind, randomised, placebo controlled, crossover, multicentre study to determine the efficacy of a 0.1% (w/v) sodium hyaluronate solution (Fermavisc) in the treatment of dry eye syndrome. Br. J. Ophthalmol. 83, 1121–1124 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McDonald, C. C., Kaye, S. B., Figueiredo, F. C., Macintosh, G. & Lockett, C. A randomised, crossover, multicentre study to compare the performance of 0.1% (w/v) sodium hyaluronate with 1.4% (w/v) polyvinyl alcohol in the alleviation of symptoms associated with dry eye syndrome. Eye (Lond.) 16, 601–607 (2002).

    Article  CAS  Google Scholar 

  16. Toda, I., Shinozaki, N. & Tsubota, K. Hydroxypropyl methylcellulose for the treatment of severe dry eye associated with Sjögren's syndrome. Cornea 15, 120–128 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Aragona, P., Stilo, A., Ferreri, F. & Mobrici, M. Effects of the topical treatment with NSAIDs on corneal sensitivity and ocular surface of Sjögren's syndrome patients. Eye (Lond.) 19, 535–539 (2005).

    Article  CAS  Google Scholar 

  18. Avisar, R., Robinson, A., Appel, I., Yassur, Y. & Weinberger, D. Diclofenac sodium, 0.1% (Voltaren Ophtha), versus sodium chloride, 5%, in the treatment of filamentary keratitis. Cornea 19, 145–147 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Guidera, A. C., Luchs, J. I. & Udell, I. J. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology 108, 936–944 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Avunduk, A. M., Avunduk, M. C., Varnell, E. D. & Kaufman, H. E. The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye patients: a clinical and immunocytochemical study. Am. J. Ophthalmol. 136, 593–602 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Marsh, P. & Pflugfelder, S. C. Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren syndrome. Ophthalmology 106, 811–816 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Pflugfelder, S. C. et al. A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. Am. J. Ophthalmol. 138, 444–457 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Hong, S., Kim, T., Chung, S. H., Kim, E. K. & Seo, K. Y. Recurrence after topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren's syndrome. J. Ocul. Pharmacol. Ther. 23, 78–82 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Dastjerdi, M. H., Hamrah, P. & Dana, R. High-frequency topical cyclosporine 0.05% in the treatment of severe dry eye refractory to twice-daily regimen. Cornea 28, 1091–1096 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gündüz, K. & Ozdemir, O. Topical cyclosporin treatment of keratoconjunctivitis sicca in secondary Sjögren's syndrome. Acta. Ophthalmol. (Copenh.) 72, 438–442 (1994).

    Article  Google Scholar 

  26. Kunert, K. S., Tisdale, A. S., Stern, M. E., Smith, J. A. & Gipson, I. K. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch. Ophthalmol. 118, 1489–1496 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Roberts, C. W., Carniglia, P. E. & Brazzo, B. G. Comparison of topical cyclosporine, punctal occlusion, and a combination for the treatment of dry eye. Cornea 26, 805–809 (2007).

    Article  PubMed  Google Scholar 

  28. Sall, K. N., Cohen, S. M., Christensen, M. T. & Stein, J. M. An evaluation of the efficacy of a cyclosporine-based dry eye therapy when used with marketed artificial tears as supportive therapy in dry eye. Eye Contact Lens 32, 21–26 (2006).

    Article  PubMed  Google Scholar 

  29. Stevenson, D., Tauber, J. & Reis, B. L. Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease: a dose-ranging, randomized trial. The Cyclosporin A Phase 2 Study Group. Ophthalmology 107, 967–974 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Toker, E. & Asfuroğlu, E. Corneal and conjunctival sensitivity in patients with dry eye: the effect of topical cyclosporine therapy. Cornea 29, 133–140 (2010).

    Article  PubMed  Google Scholar 

  31. Perry, H. D. et al. Evaluation of topical cyclosporine for the treatment of dry eye disease. Arch. Ophthalmol. 126, 1046–1050 (2008).

    Article  PubMed  Google Scholar 

  32. Sall, K., Stevenson, O. D., Mundorf, T. K. & Reis, B. L. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology 107, 631–639 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Kim, E. C., Choi, J. S. & Joo, C. K. A comparison of vitamin A and cyclosporine A 0.05% eye drops for treatment of dry eye syndrome. Am. J. Ophthalmol. 147, 206–213 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Barber, L. D., Pflugfelder, S. C., Tauber, J. & Foulks, G. N. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology 112, 1790–1794 (2005).

    Article  PubMed  Google Scholar 

  35. Tauber, J. et al. Double-masked, placebo-controlled safety and efficacy trial of diquafosol tetrasodium (INS365) ophthalmic solution for the treatment of dry eye. Cornea 23, 784–792 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Schiødt, M., Oxholm, P. & Jacobsen, A. Treatment of xerostomia in patients with primary Sjögren's syndrome with sulfarlem. Scand. J. Rheumatol. Suppl. 61, 250–252 (1986).

    PubMed  Google Scholar 

  37. Kriegbaum, N. J., von Linstow, M., Oxholm, P. & Prause, J. U. A follow-up study of the progress of keratoconjunctivitis sicca and response to treatment in primary Sjögren's syndrome. Scand. J. Rheumatol. 18, 193–196 (1989).

    Article  CAS  PubMed  Google Scholar 

  38. Walters, M. T., Rubin, C. E., Keightley, S. J., Ward, C. D. & Cawley, M. I. A double-blind, cross-over, study of oral N-acetylcysteine in Sjögren's syndrome. Scand. J. Rheumatol. Suppl. 61, 253–258 (1986).

    CAS  PubMed  Google Scholar 

  39. Aframian, D. J. et al. Pilocarpine treatment in a mixed cohort of xerostomic patients. Oral Dis. 13, 88–92 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Aragona, P., Di Pietro, R., Spinella, R. & Mobrici, M. Conjunctival epithelium improvement after systemic pilocarpine in patients with Sjögren's syndrome. Br. J. Ophthalmol. 90, 166–170 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gibson, J., Halliday, J. A., Ewert, K. & Robertson, S. A controlled release pilocarpine buccal insert in the treatment of Sjögren's syndrome. Br. Dent. J. 202, E17 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Papas, A. S. et al. Successful treatment of dry mouth and dry eye symptoms in Sjögren's syndrome patients with oral pilocarpine: a randomized, placebo-controlled, dose-adjustment study. J. Clin. Rheumatol. 10, 169–177 (2004).

    Article  PubMed  Google Scholar 

  43. Rhodus, N. L., Liljemark, W., Bloomquist, C. & Bereuter, J. Candida albicans levels in patients with Sjögren's syndrome before and after long-term use of pilocarpine hydrochloride: a pilot study. Quintessence Int. 29, 705–710 (1998).

    CAS  PubMed  Google Scholar 

  44. Peluso, G. et al. Proteomic study of salivary peptides and proteins in patients with Sjögren's syndrome before and after pilocarpine treatment. Arthritis Rheum. 56, 2216–2222 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Rhodus, N. L. Oral pilocarpine HCl stimulates labial (minor) salivary gland flow in patients with Sjögren's syndrome. Oral Dis. 3, 93–98 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. Rosas, J. et al. Usefulness of basal and pilocarpine-stimulated salivary flow in primary Sjögren's syndrome. Correlation with clinical, immunological and histological features. Rheumatology (Oxford) 41, 670–675 (2002).

    Article  CAS  Google Scholar 

  47. Tsifetaki, N. et al. Oral pilocarpine for the treatment of ocular symptoms in patients with Sjögren's syndrome: a randomised 12 week controlled study. Ann. Rheum. Dis. 62, 1204–1207 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vivino, F. B. et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92–01 Study Group. Arch. Intern. Med. 159, 174–181 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Wu, C. H. et al. Pilocarpine hydrochloride for the treatment of xerostomia in patients with Sjögren's syndrome in Taiwan—a double-blind, placebo-controlled trial. J. Formos. Med. Assoc. 105, 796–803 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Fife, R. S. et al. Cevimeline for the treatment of xerostomia in patients with Sjögren syndrome: a randomized trial. Arch. Intern. Med. 162, 1293–1300 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Komai, K. et al. Sjögren's syndrome patients presenting with hypergammaglobulinemia are relatively unresponsive to cevimeline treatment. Mod. Rheumatol. 19, 416–419 (2009).

    Article  PubMed  Google Scholar 

  52. Leung, K. C. et al. The efficacy of cevimeline hydrochloride in the treatment of xerostomia in Sjögren's syndrome in southern Chinese patients: a randomised double-blind, placebo-controlled crossover study. Clin. Rheumatol. 27, 429–436 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Ono, M. et al. Therapeutic effect of cevimeline on dry eye in patients with Sjögren's syndrome: a randomized, double-blind clinical study. Am. J. Ophthalmol. 138, 6–17 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Petrone, D. et al. A double-blind, randomized, placebo-controlled study of cevimeline in Sjögren's syndrome patients with xerostomia and keratoconjunctivitis sicca. Arthritis Rheum. 46, 748–754 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Suzuki, K. et al. Effect of cevimeline on salivary components in patients with Sjögren syndrome. Pharmacology 74, 100–105 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Takagi, Y., Katayama, I., Tashiro, S. & Nakamura, T. Parotid irrigation and cevimeline gargle for treatment of xerostomia in Sjögren's syndrome. J. Rheumatol. 35, 2289–2291 (2008).

    Article  PubMed  Google Scholar 

  57. Yamada, H. et al. Efficacy prediction of cevimeline in patients with Sjögren's syndrome. Clin. Rheumatol. 26, 1320–1327 (2007).

    Article  PubMed  Google Scholar 

  58. Izumi, M. et al. Corticosteroid irrigation of parotid gland for treatment of xerostomia in patients with Sjögren's syndrome. Ann. Rheum. Dis. 57, 464–469 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Miyawaki, S., Nishiyama, S. & Matoba, K. Efficacy of low-dose prednisolone maintenance for saliva production and serological abnormalities in patients with primary Sjögren's syndrome. Intern. Med. 38, 938–943 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Fox, P. C. et al. Prednisone and piroxicam for treatment of primary Sjögren's syndrome. Clin. Exp. Rheumatol. 11, 149–156 (1993).

    CAS  PubMed  Google Scholar 

  61. Pijpe, J. et al. Progression of salivary gland dysfunction in patients with Sjogren's syndrome. Ann. Rheum. Dis. 66, 107–112 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Ramos-Casals, M. et al. High prevalence of serum metabolic alterations in primary Sjögren's syndrome: influence on clinical and immunological expression. J. Rheumatol. 34, 754–761 (2007).

    CAS  PubMed  Google Scholar 

  63. Kruize, A. A. et al. Hydroxychloroquine treatment for primary Sjögren's syndrome: a two year double blind crossover trial. Ann. Rheum. Dis. 52, 360–364 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tishler, M., Yaron, I., Shirazi, I. & Yaron, M. Hydroxychloroquine treatment for primary Sjögren's syndrome: its effect on salivary and serum inflammatory markers. Ann. Rheum. Dis. 58, 253–256 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rihl, M., Ulbricht, K., Schmidt, R. E. & Witte, T. Treatment of sicca symptoms with hydroxychloroquine in patients with Sjögren's syndrome. Rheumatology (Oxford) 48, 796–799 (2009).

    Article  CAS  Google Scholar 

  66. Fox, R. I. et al. Treatment of primary Sjögren's syndrome with hydroxychloroquine. Am. J. Med. 85, 62–67 (1988).

    Article  CAS  PubMed  Google Scholar 

  67. Fox, R. I., Dixon, R., Guarrasi, V. & Krubel, S. Treatment of primary Sjögren's syndrome with hydroxychloroquine: a retrospective, open-label study. Lupus 5 (Suppl. 1), S31–S36 (1996).

    Article  PubMed  Google Scholar 

  68. Cankaya, H. et al. Effects of hydroxychloroquine on salivary flow rates and oral complaints of Sjögren patients: a prospective sample study. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 110, 62–67 (2010).

    Article  PubMed  Google Scholar 

  69. Yavuz, S., Asfuroğlu, E., Bicakcigil, M. & Toker, E. Hydroxychloroquine improves dry eye symptoms of patients with primary Sjögren's syndrome. Rheumatol. Int. 31, 1045–1049 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Drosos, A. A., Skopouli, F. N., Galanopoulou, V. K., Kitridou, R. C. & Moutsopoulos, H. M. Cyclosporin A therapy in patients with primary Sjögren's syndrome: results at one year. Scand. J. Rheumatol Suppl. 61, 246–249 (1986).

    CAS  PubMed  Google Scholar 

  71. Skopouli, F. N., Jagiello, P., Tsifetaki, N. & Moutsopoulos, H. M. Methotrexate in primary Sjögren's syndrome. Clin. Exp. Rheumatol. 14, 555–558 (1996).

    CAS  PubMed  Google Scholar 

  72. van Woerkom, J. M. et al. Safety and efficacy of leflunomide in primary Sjögren's syndrome: a phase II pilot study. Ann. Rheum. Dis. 66, 1026–1032 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Willeke, P. et al. Mycophenolate sodium treatment in patients with primary Sjögren syndrome: a pilot trial. Arthritis Res. Ther. 9, R115 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Price, E. J., Rigby, S. P., Clancy, U. & Venables, P. J. A double blind placebo controlled trial of azathioprine in the treatment of primary Sjögren's syndrome. J. Rheumatol. 25, 896–899 (1998).

    CAS  PubMed  Google Scholar 

  75. ter Borg, E. J. et al. Treatment of primary Sjögren's syndrome with D-penicillamine: a pilot study. Neth. J. Med. 60, 402–406 (2002).

    CAS  PubMed  Google Scholar 

  76. Pillemer, S. R. et al. Prominent adverse effects of thalidomide in primary Sjögren's syndrome. Arthritis Rheum. 51, 505–506 (2004).

    Article  PubMed  Google Scholar 

  77. Nakayamada, S. et al. Efficacy and safety of mizoribine for the treatment of Sjögren's syndrome: a multicenter open-label clinical trial. Mod. Rheumatol. 17, 464–469 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Nakayamada, S. et al. Usefulness of initial histological features for stratifying Sjögren's syndrome responders to mizoribine therapy. Rheumatology (Oxford) 48, 1279–1282 (2009).

    Article  Google Scholar 

  79. Sugai, S. et al. Efficacy and safety of rebamipide for the treatment of dry mouth symptoms in patients with Sjögren's syndrome: a double-blind placebo-controlled multicenter trial. Mod. Rheumatol. 19, 114–124 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Seitsalo, H. et al. Effectiveness of low-dose doxycycline (LDD) on clinical symptoms of Sjögren's syndrome: a randomized, double-blind, placebo controlled cross-over study. J. Negat. Results Biomed. 6, 11 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Steinfeld, S. D., Demols, P., Van Vooren, J. P., Cogan, E. & Appelboom, T. Zidovudine in primary Sjögren's syndrome. Rheumatology (Oxford) 38, 814–817 (1999).

    Article  CAS  Google Scholar 

  82. Pillemer, S. R. et al. Pilot clinical trial of dehydroepiandrosterone (DHEA) versus placebo for Sjögren's syndrome. Arthritis Rheum. 51, 601–604 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Hartkamp, A. et al. Effect of dehydroepiandrosterone administration on fatigue, well-being, and functioning in women with primary Sjögren syndrome: a randomised controlled trial. Ann. Rheum. Dis. 67, 91–97 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Forsbladd'Elia, H., Carlsten, H., Labrie, F., Konttinen, Y. T. & Ohlsson, C. Low serum levels of sex steroids are associated with disease characteristics in primary Sjogren's syndrome; supplementation with dehydroepiandrosterone restores the concentrations. J. Clin. Endocrinol. Metab. 94, 2044–2051 (2009).

    Article  CAS  Google Scholar 

  85. Aragona, P., Bucolo, C., Spinella, R., Giuffrida, S. & Ferreri, G. Systemic omega-6 essential fatty acid treatment and PGE1 tear content in Sjögren's syndrome patients. Invest. Ophthalmol. Vis. Sci. 46, 4474–4479 (2005).

    Article  PubMed  Google Scholar 

  86. Theander, E., Horrobin, D. F., Jacobsson, L. T. & Manthorpe, R. Gammalinolenic acid treatment of fatigue associated with primary Sjögren's syndrome. Scand. J. Rheumatol. 31, 72–79 (2002).

    Article  PubMed  Google Scholar 

  87. Oxholm, P., Manthorpe, R., Prause, J. U. & Horrobin, D. Patients with primary Sjögren's syndrome treated for two months with evening primrose oil. Scand. J. Rheumatol. 15, 103–108 (1986).

    Article  CAS  PubMed  Google Scholar 

  88. Kasama, T. et al. Effect of the H2 receptor antagonist nizatidine on xerostomia in patients with primary Sjögren's syndrome. Mod. Rheumatol. 18, 455–459 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Cummins, M. J., Papas, A., Kammer, G. M. & Fox, P. C. Treatment of primary Sjögren's syndrome with low-dose human interferon α administered by the oromucosal route: combined phase III results. Arthritis Rheum. 49, 585–593 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Shiozawa, S., Tanaka, Y. & Shiozawa, K. Single-blinded controlled trial of low-dose oral IFN-α for the treatment of xerostomia in patients with Sjögren's syndrome. J. Interferon Cytokine Res. 18, 255–262 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Khurshudian, A. V. A pilot study to test the efficacy of oral administration of interferon-α lozenges to patients with Sjögren's syndrome. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 95, 38–44 (2003).

    Article  PubMed  Google Scholar 

  92. Ferraccioli, G. F. et al. Interferon α2 (IFN α2) increases lacrimal and salivary function in Sjögren's syndrome patients. Preliminary results of an open pilot trial versus OH-chloroquine. Clin. Exp. Rheumatol. 14, 367–371 (1996).

    CAS  PubMed  Google Scholar 

  93. Steinfeld, S. D., Demols, P., Salmon, I., Kiss, R. & Appelboom, T. Infliximab in patients with primary Sjögren's syndrome: a pilot study. Arthritis Rheum. 44, 2371–2375 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Mariette, X. et al. Inefficacy of infliximab in primary Sjögren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren's Syndrome (TRIPSS). Arthritis Rheum. 50, 1270–1276 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Zandbelt, M. M. et al. Etanercept in the treatment of patients with primary Sjögren's syndrome: a pilot study. J. Rheumatol. 31, 96–101 (2004).

    CAS  PubMed  Google Scholar 

  96. Sankar, V. et al. Etanercept in Sjögren's syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum. 50, 2240–2245 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Meijer, J. et al. Effective rituximab treatment in primary Sjögren's syndrome: a randomised, double-blind, placebo-controlled trial. Arthritis Rheum. 62, 960–968 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Dass, S. et al. Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann. Rheum. Dis. 67, 1541–1544 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Devauchelle-Pensec, V. et al. Improvement of Sjögren's syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum. 57, 310–317 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Pijpe, J. et al. Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II study. Arthritis Rheum. 52, 2740–2750 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Seror, R. 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. 66, 351–357 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Gottenberg, J. E. et al. Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann. Rheum. Dis. 64, 913–920 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Voulgarelis, M., Giannouli, S., Tzioufas, A. G. & Moutsopoulos, H. M. Long term remission of Sjögren's syndrome associated aggressive B cell non-Hodgkin's lymphomas following combined B cell depletion therapy and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Ann. Rheum. Dis. 65, 1033–1037 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Mekinian, A. et al. Efficacy of rituximab in primary Sjögren's syndrome with peripheral nervous system involvement: results from the AIR registry. Ann. Rheum. Dis. 71, 84–87 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Ramos-Casals, M. et al. Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases. Clin. Exp. Rheumatol. 28, 468–476 (2010).

    CAS  PubMed  Google Scholar 

  106. Steinfeld, S. D. et al. Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren's syndrome: an open-label phase I/II study. Arthritis Res. Ther. 8, R129 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Vissink, A., Kallenberg, C. G. & Bootsma, H. Treatment approaches in primary Sjogren syndrome. JAMA 304, 2015–2016 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Yoon, K. C. et al. Comparison of autologous serum and umbilical cord serum eye drops for dry eye syndrome. Am. J. Ophthalmol. 144, 86–92 (2007).

    Article  PubMed  Google Scholar 

  109. Noble, B. A. et al. Comparison of autologous serum eye drops with conventional therapy in a randomised controlled crossover trial for ocular surface disease. Br. J. Ophthalmol. 88, 647–652 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Belenguer, R. et al. Influence of clinical and immunological parameters on the health-related quality of life of patients with primary Sjögren's syndrome. Clin. Exp. Rheumatol. 23, 351–356 (2005).

    CAS  PubMed  Google Scholar 

  111. Ostuni, P. et al. Fibromyalgia in Italian patients with primary Sjögren's syndrome. Joint Bone Spine. 69, 51–57 (2002).

    Article  PubMed  Google Scholar 

  112. Engel, P., Gómez-Puerta, J. A., Ramos-Casals, M., Lozano, F. & Bosch, X. Therapeutic targeting of B cells for rheumatic autoimmune diseases. Pharmacol. Rev. 63, 127–156 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Mavragani, C. P. & Kassan, S. S. in Sjögren's Syndrome. Diagnosis and Therapeutics (eds Ramos-Casals, M., Stone, J. & Moutsopoulos, H. M.) 565–570 (Springer-Verlag, Berlin, 2012).

    Google Scholar 

  114. Brito-Zerón, P. & Ramos-Casals, M. Prognosis of patients with primary Sjögren's syndrome [Spanish]. Med. Clin. (Barc.) 130, 109–115 (2008).

    Article  Google Scholar 

  115. Ramos-Casals, M., Brito-Zerón, P., Bové, A. & Sisó, A. in Autoimmune Diseases. Acute and Complex Situations (eds Khamashta, M. A. & Ramos-Casals, M.) 45–66 (Springer-Verlag, London, 2011).

    Google Scholar 

  116. Pollard, R. P. et al. Treatment of mucosa-associated lymphoid tissue lymphoma in Sjögren's syndrome: a retrospective clinical study. J. Rheumatol. 38, 2198–2208 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Pijpe, J. et al. Clinical and histologic evidence of salivary gland restoration supports the efficacy of rituximab treatment in Sjögren's syndrome. Arthritis Rheum. 60, 3251–3256 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Jousse-Joulin, S. et al. Ultrasound assessment of salivary glands in patients with primary Sjögren's syndrome treated with rituximab: quantitative and Doppler waveform analysis. Biologics 1, 311–319 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Lavie, F. et al. Increase of B cell-activating factor of the TNF family (BAFF) after rituximab treatment: insights into a new regulating system of BAFF production. Ann. Rheum. Dis. 66, 700–703 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Strietzel, F. P. et al. Efficacy and safety of an intraoral electrostimulation device for xerostomia relief: a multicenter, randomized trial. Arthritis Rheum. 63, 180–190 (2011).

    Article  PubMed  Google Scholar 

  121. Seror, R. et al. EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index in primary Sjögren's syndrome. Ann. Rheum. Dis. 69, 1103–1109 (2010).

    Article  PubMed  Google Scholar 

  122. Seror, R. et al. EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjögren's syndrome. Ann. Rheum. Dis. 70, 968–972 (2011).

    Article  PubMed  Google Scholar 

  123. Harbour, R. & Miller, J. A new system for grading recommendations in evidence based guidelines. BMJ 323, 334–336 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

M. Ramos-Casals, P. Brito-Zerón and A. Sisó-Almirall are supported by funding from Grants La Marató de TV3 (071810) and Fondo de Investigaciones Sanitarias (080103). The authors wish to thank David Buss for his editorial assistance.

Author information

Authors and Affiliations

Authors

Contributions

M. Ramos-Casals, P. Brito-Zerón and A. Sisó-Almirall contributed equally to researching the data for the article. M. Ramos-Casals, P. Brito-Zerón and X. Bosch contributed equally to the writing of the article. All authors provided substantial contributions to discussion of the content and reviewing and/or editing the manuscript before submission.

Corresponding author

Correspondence to Manuel Ramos-Casals.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ramos-Casals, M., Brito-Zerón, P., Sisó-Almirall, A. et al. Topical and systemic medications for the treatment of primary Sjögren's syndrome. Nat Rev Rheumatol 8, 399–411 (2012). https://doi.org/10.1038/nrrheum.2012.53

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2012.53

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing