Primary Sjögren’s syndrome: Extraglandular manifestations and hydroxychloroquine therapy


The use of hydroxychloroquine (HCQ) in Primary Sjögren’s Syndrome (pSS) has been assessed in different studies over the last years, with conflicting results regarding its efficacy in sicca syndrome and extraglandular manifestations (EGM). The goal of this study was to compare the incidence rate of EGM in pSS patients with and without HCQ therapy.

We performed a multicenter retrospective study, including patients with pSS (European classification criteria) with at least 1 year of follow-up. Subjects with concomitant fibromyalgia, autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis were excluded. Demographics and pSS characteristics were recorded. The EGM were defined by EULAR-SS disease activity index (ESSDAI). Patients were divided into two groups according to their use or not of HCQ therapy. We evaluated the use of HCQ and its relationship to EGM. HCQ therapy was defined as the continuous use of the drug for at least 3 months. A descriptive analysis of demographics and pSS characteristics was performed. We compared the incidence of EGM between groups defined by HCQ therapy using chi2 test or Fisher’s exact test. A total of 221 patients were included (97.3% women), mean age, 55.7 years (SD 14). Mean age at diagnosis, 48.8 years (SD 15); median disease duration, 60 months (IQR 35–84). One hundred and seventy patients (77%) received HCQ. About half of the patients had at least one EGM during the course of the disease, 20% of them developed an EGM before the onset of the sicca syndrome and 26% simultaneously with dryness symptom. Overall, EGM were less frequent in those on HCQ therapy (36.5% vs 63.5%, p < 0.001). Considering each EGM individually, the following manifestations were more frequent in the non-treated group: arthritis (p < 0.001), fatigue (p < 0.001), purpura (p = 0.01), Raynaud phenomenon (p = 0.003), and hypergammaglobulinemia (p = 0.006). Immunosuppressive treatment was indicated on 28 patients (12.7%), 13 of which were receiving also HCQ. The first reason for those treatments was the presence of arthritis in 12/28 patients (42.8%), and the drug used in all the cases was methotrexate. Only three patients required immunosuppressive therapy with cyclophosphamide, due to the presence of glomerulonephritis, vasculitis, and interstitial lung disease. None of the patients received biologic therapy. The lower incidence of EGM was observed in patients on HCQ therapy supports its efficacy in pSS. However, further large scale prospective studies are needed to confirm these findings.

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

Fig. 1


  1. 1.

    Ramos-Casals M, Brito-Zeron P, Siso-Almirall A, Bosch X (2012) Primary Sjögren syndrome. BMJ 344.

  2. 2.

    Fox RI (2005) Sjögren’s syndrome. Lancet 366:321–331.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Brito-Zerón P, Sisó-Almirall A, Bové A, Kostov BA, Ramos-Casals M (2013) Primary Sjögren syndrome: an update on current pharmacotherapy options and future directions. Expert Opin Pharmacother 14:279–289.

    Article  PubMed  Google Scholar 

  4. 4.

    Mavragani CP, Moutsopoulos NM, Moutsopoulos HM (2006) The management of Sjögren’s syndrome. Nat Clin Pract Rheumatol 2:252–261.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Ter Borg EJ, Kelder JC (2016) Polyarthritis in primary Sjögren’s syndrome represents a distinct subset with less pronounced B cell proliferation a Dutch cohort with long-term follow-up. Clin Rheumatol 35:649–655.

    Article  PubMed  Google Scholar 

  6. 6.

    Scagliusi P, Minenna G, D’Amore M, Scagliusi A (2005) New therapeutic perspectives in Sjögren syndrome: leflunomide. Recenti Prog Med 96:194

    PubMed  Google Scholar 

  7. 7.

    Kedor C, Zernicke J, Hagemann A, Gamboa LM, Callhoff J, Burmester GR, Feist E (2016) A phase II investigator-initiated pilot study with low-dose cyclosporine A for the treatment of articular involvement in primary Sjögren’s syndrome. Clin Rhreumatol 35:2203–2210.

    Article  Google Scholar 

  8. 8.

    Patel R, Shahane A (2014) The epidemiology of Sjögren’s syndrome. Clin Epidemiol 6:247–255.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, Bosch X, Tzioufas AG (2012) Topical and systemic medications for the treatment of primary Sjögren’s syndrome. Nat Rev Rheumatol 8:399–411.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Gottenberg JE, Ravaud P, Puéchal X, Le Guern V et al (2014) Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA 312:249–258.

    Article  PubMed  Google Scholar 

  11. 11.

    Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL et al (2002) Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    The Canadian Hydroxychloroquine Study Group (1991) A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med 324:150–154

    Article  Google Scholar 

  13. 13.

    Wallace D (1994) Antimalarial agents and lupus. Rheum Dis Clin N Am 20:243–263

    CAS  Google Scholar 

  14. 14.

    Saunders SA, Capell HA, Stirling A, Vallance R, Kincaid W, McMahon AD, Porter DR (2008) Triple therapy in early active rheumatoid arthritis: a randomized, single-blind, controlled trial comparing step-up and parallel treatment strategies. Arthritis Rheum 58:1310–1317

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Willis R, Seif AM, McGwin G Jr, Martinez-Martinez LA, González EB, Dang N, Papalardo E, Liu J, Vilá LM, Reveille JD, Alarcón GS, Pierangeli SS (2012) Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort. Lupus 21:830–835.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Kruize AA, Hené RJ, Kallenberg CG, van Bijsterveld OP, van der Heide A, Kater L, Bijlsma JW (1993) Hydroxychloroquine treatment for primary Sjögren’s syndrome: a two year double blind crossover trial. Ann Rheum Dis 52:360–364

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Yoon CH, Lee HJ, Lee EY, Lee EB, Lee WW, Kim MK, Wee WR (2016) Effect of hydroxychloroquine treatment on dry eyes in subjects with primary Sjögren’s syndrome: a double-blind randomized control study. J Korean Med Sci 31:1127–1135.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Fox RI, Chan E, Benton L, Fong S, Friedlaender M, Howell FV (1988) Treatment of primary Sjögren’s syndrome with hydroxychloroquine. Am J Med 85:62–67

    CAS  Article  PubMed  Google Scholar 

  19. 19.

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

    Article  PubMed  Google Scholar 

  20. 20.

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

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

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Wang SQ, Zhang LW, Wei P, Hua H (2017) Is hydroxychloroquine effective in treating primary Sjogren’s syndrome: a systematic review and meta-analysis. BMC Musculoskeletal Disord 18:186.

    Article  Google Scholar 

  23. 23.

    Zazzetti F, Rivero M, Duartes Noe DE, Gallacher A, Schiel A, Khoury MC, Laborde HA, Barreira JC (2010) Frequency of systemic manifestations in patients with primary Sjogren’s syndrome in Argentina. Reumatol Clin 6:299–302.

    Article  PubMed  Google Scholar 

  24. 24.

    Ramos-Casals M, Brito-Zeron P, Solans R, Camps MT, Casanovas A et al (2014) Systemic involvement in primary Sjögren’s syndrome evaluated by the EULAR-SS disease activity index: analysis of 921 Spanish patients. Rheumatology (Oxford) 53:321–331.

    Article  Google Scholar 

  25. 25.

    Ramos-Casals M, Brito-Zeron P, Seror R, Bootsma H, Bowman S et al (2015) Characterization of systemic disease in primary Sjögren’s syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements. Rheumatology (Oxford) 54:2230–2238.

    Google Scholar 

  26. 26.

    Brito-Zerón P, Theander E, Baldini C, Seror R, Retamozo S et al (2016) Early diagnosis of primary Sjögren’s syndrome: EULAR-SS task force clinical recommendations. Expert Rev Clin Immunol 12:137–156.

    Article  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to J. Demarchi.

Ethics declarations

Conflicts of interest

The following authors have declared conflicts of interest:

Rafael Chaparro del Moral is Biotherapeutics Medical Manager at AbbVie.

Federico Zazzetti is Immunology Medical Manager at Janssen.

Sofía Velez is Senior Medical Science Liaison at Janssen.

The other remaining authors declare no conflicts of interest.

Ethical approval

The study was approved by the institutional review board or ethics committee at each participating site and was conducted in accordance with the principles of the Declaration of Helsinki.

Statement of informed consent

All patients provided written informed consent.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Demarchi, J., Papasidero, S., Medina, M.A. et al. Primary Sjögren’s syndrome: Extraglandular manifestations and hydroxychloroquine therapy. Clin Rheumatol 36, 2455–2460 (2017).

Download citation


  • Extraglandular manifestations
  • Hydroxychloroquine
  • Primary Sjögren’s syndrome
  • Treatment