Skip to main content

Advertisement

SpringerLink
Log in

Cutaneous and Mucosal Manifestations of Sjögren’s Syndrome

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Sjögren’s syndrome is currently considered an “autoimmune epithelitis,” as exocrine glands, especially salivary and lacrimal, are progressively destructed by an immune-mediated process associated with specific serum autoantibodies and local lymphocyte infiltrate. Xerostomia remains a key complain in patients with Sjögren’s syndrome but should be evaluated also for other causes such as xerogenic medications, followed by radiation and chemotherapy for head and neck cancers, hormone disorders, infections, or other connective tissue diseases. Further, xerophtalmia (also known as dry eye) frequently associated with keratoconjunctivitis sicca cumulatively affects approximately 10–30% of the general population with increasing incidence with age and is more frequently secondary to non-autoimmune diseases. On the other hand, numerous patients with Sjögren’s syndrome manifest signs of systemic dryness involving the nose, the trachea, the vagina, and the skin, suggesting that other glands are also affected beyond the exocrine epithelia. Skin involvement in Sjögren’s syndrome is relatively common, and various manifestations may be present, in particular xeroderma, eyelid dermatitis, annular erythema, and cutaneous vasculitis. Additional skin non-vasculitic manifestations include livedo reticularis which may occur in the absence of vasculitis, and localized nodular cutaneous amyloidosis possibly representing lymphoproliferative diseases related to Sjögren’s syndrome. The treatment of skin and mucosal manifestations in Sjögren’s syndrome is similar regardless of the cause, starting from patient education to avoid alcohol and tobacco smoking and to pursue dental hygiene. In conclusion, a strict collaboration between the dermatologist and the rheumatologist is essential in the adequate management of Sjögren’s syndrome skin and mucosal manifestations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

SjS:

Sjögren’s syndrome

SLE:

Systemic lupus erythematosous

RA:

Rheumatoid arthritis

SSc:

Systemic sclerosis

PBC:

Primary biliary cholangitis

HLA:

Human leukocyte antigen

IRF5:

Interferon regulatory factor 5

STAT4:

Signal transducer and activator of transcription 4

IL:

Interleukin

IFN:

Interferon

TNF:

Tumor necrosis factor

Th:

T helper

SGEC:

Salivary gland epithelial cells

BEC:

Biliary epithelial cells

APC:

Antigen-presenting cells

TGFbeta:

Transforming growth factor beta

NK:

Natural killer

IgG:

Immunoglobulin G

IgM:

Immunoglobulin M

BAFF:

B cell-activating factor

ANA:

Antinuclear antibodies

PAMPs:

Pathogen-associated molecular patterns

PRRs:

Pattern recognition receptors

TLR:

Toll-like receptors

NOD:

Nucleotide-binding oligomerization domain

RF:

Rheumatoid factor

ACA:

Anti-centromere antibodies

CENP:

Centromeric protein

AMA:

Anti-mitocondrial antibodies

anti-CCP:

Anti-cyclic citrullinated peptide

Fc:

Fragment crystallizable region

TBUT:

Tear breakup time

scLE:

Subacute cutaneous lupus erythematosus

ESSDAI:

European League Against Rheumatism Sjögren’s syndrome disease activity index

AD:

Atopic dermatitis

AE:

Annular erythema

DM:

Dermatomyositis

EULAR:

European League Against Rheumatism

ANCA:

Anti-neutrophil cytoplasmic antibody

HCQ:

Hydroxychloroquine

DMARDs:

Disease-modifying antirheumatic drugs

BLys:

B lymphocyte stimulator

IVIg:

Intravenous immunoglobulins

References

  1. Maciel G, Crowson CS, Matteson EL, Cornec D (2016) Prevalence of primary Sjogren’s syndrome in a population-based cohort in the United States. Arthritis Care Res (Hoboken). doi:10.1002/acr.23173

  2. Civilibal M, Canpolat N, Yurt A, Kurugoglu S, Erdamar S, Bagci O, Sever L, Kasapcopur O, Caliskan S, Arisoy N (2007) A child with primary Sjogren syndrome and a review of the literature. Clin Pediatr (Phila) 46(8):738–742. doi:10.1177/0009922807301945

    Article  Google Scholar 

  3. Efe C, Wahlin S, Ozaslan E, Berlot AH, Purnak T, Muratori L, Quarneti C, Yuksel O, Thiefin G, Muratori P (2012) Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and associated extrahepatic autoimmune diseases. Eur J Gastroenterol Hepatol 24(5):531–534. doi:10.1097/MEG.0b013e328350f95b

    Article  PubMed  Google Scholar 

  4. Ji J, Sundquist J, Sundquist K (2016) Gender-specific incidence of autoimmune diseases from national registers. J Autoimmun 69:102–106. doi:10.1016/j.jaut.2016.03.003

    Article  PubMed  Google Scholar 

  5. Vivino FB (2017) Sjogren’s syndrome: clinical aspects. Clin Immunol. doi:10.1016/j.clim.2017.04.005

  6. Theander E, Jacobsson LT (2008) Relationship of Sjogren’s syndrome to other connective tissue and autoimmune disorders. Rheum Dis Clin N Am 34(4):935–947, viii-ix. doi:10.1016/j.rdc.2008.08.009

    Article  Google Scholar 

  7. Fragoulis GE, Fragkioudaki S, Reilly JH, Kerr SC, McInnes IB, Moutsopoulos HM (2016) Analysis of the cell populations composing the mononuclear cell infiltrates in the labial minor salivary glands from patients with rheumatoid arthritis and sicca syndrome. J Autoimmun 73:85–91. doi:10.1016/j.jaut.2016.06.008

    Article  CAS  PubMed  Google Scholar 

  8. Mavragani CP, Fragoulis GE, Moutsopoulos HM (2012) Endocrine alterations in primary Sjogren’s syndrome: an overview. J Autoimmun 39(4):354–358. doi:10.1016/j.jaut.2012.05.011

    Article  CAS  PubMed  Google Scholar 

  9. Amador-Patarroyo MJ, Arbelaez JG, Mantilla RD, Rodriguez-Rodriguez A, Cardenas-Roldan J, Pineda-Tamayo R, Guarin MR, Kleine LL, Rojas-Villarraga A, Anaya JM (2012) Sjogren’s syndrome at the crossroad of polyautoimmunity. J Autoimmun 39(3):199–205. doi:10.1016/j.jaut.2012.05.008

    Article  CAS  PubMed  Google Scholar 

  10. Skopouli FN, Moutsopoulos HM (1994) Autoimmune epitheliitis: Sjogren’s syndrome. Clin Exp Rheumatol 12(Suppl 11):S9–11

    PubMed  Google Scholar 

  11. Selmi C, Bowlus CL, Gershwin ME, Coppel RL (2011) Primary biliary cirrhosis. Lancet 377(9777):1600–1609. doi:10.1016/S0140-6736(10)61965-4

    Article  CAS  PubMed  Google Scholar 

  12. Cornec D, Jamin C, Pers JO (2014) Sjogren’s syndrome: where do we stand, and where shall we go? J Autoimmun 51:109–114. doi:10.1016/j.jaut.2014.02.006

    Article  PubMed  Google Scholar 

  13. Goules AV, Tzioufas AG (2016) Primary Sjgren’s syndrome: clinical phenotypes, outcome and the development of biomarkers. Autoimmun Rev 15(7):695–703. doi:10.1016/j.autrev.2016.03.004

    Article  CAS  PubMed  Google Scholar 

  14. Oxholm P, Asmussen K (1996) Primary Sjogren’s syndrome: the challenge for classification of disease manifestations. J Intern Med 239(6):467–474

    Article  CAS  PubMed  Google Scholar 

  15. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, Rasmussen A, Scofield H, Vitali C, Bowman SJ, Mariette X, International Sjogren's Syndrome Criteria Working G (2017) 2016 American College of Rheumatology/European league against rheumatism classification criteria for primary Sjogren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 69(1):35–45. doi:10.1002/art.39859

    Article  PubMed  Google Scholar 

  16. Kabasakal Y, Kitapcioglu G, Karabulut G, Tezcan M, Balkarli A, Aksoy A, Yavuz S, Yilmaz S, Kasifoglu T, Kalyoncu U, Dalkilic E, Tufan A, Mercan R, Yildiz F, Senturk T, Onen F, Bes C, Erken E, Tunc E, Kamali S, Tarhan E, Yazici A, Duzgun N, Bicakcigil M, Yilmaz S, Ozmen M, Ocal L, Alibaz-Oner F, Solmaz D, Cobankara V, Nalbant S, Kasapoglu Gunal E, Kaskari D, Goker B (2017) Criteria sets for primary Sjogren’s syndrome are not adequate for those presenting with extraglandular organ involvements as their dominant clinical features. Rheumatol Int 37(5):675–684. doi:10.1007/s00296-017-3691-8

    Article  PubMed  Google Scholar 

  17. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, Rasmussen A, Scofield H, Vitali C, Bowman SJ, Mariette X, International Sjogren's Syndrome Criteria Working G (2017) 2016 American College of Rheumatology/European league against rheumatism classification criteria for primary Sjogren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis 76(1):9–16. doi:10.1136/annrheumdis-2016-210571

    Article  PubMed  Google Scholar 

  18. Giacomelli R, Afeltra A, Alunno A, Baldini C, Bartoloni-Bocci E, Berardicurti O, Carubbi F, Cauli A, Cervera R, Ciccia F, Cipriani P, Conti F, De Vita S, Di Benedetto P, Doria A, Drosos AA, Favalli EG, Gandolfo S, Gatto M, Grembiale RD, Liakouli V, Lories R, Lubrano E, Lunardi C, Margiotta DPE, Massaro L, Meroni P, Minniti A, Navarini L, Pendolino M, Perosa F, Pers JO, Prete M, Priori R, Puppo F, Quartuccio L, Ruffatti A, Ruscitti P, Russo B, Sarzi-Puttini P, Shoenfeld Y, Somarakis GA, Spinelli FR, Tinazzi E, Triolo G, Ursini F, Valentini G, Valesini G, Vettori S, Vitali C, Tzioufas AG (2017) International consensus: what else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren’s syndrome)?: the unmet needs and the clinical grey zone in autoimmune disease management. Autoimmun Rev. doi:10.1016/j.autrev.2017.07.012

  19. Sun Y, Zhang W, Li B, Zou Z, Selmi C, Gershwin ME (2015) The coexistence of Sjogren’s syndrome and primary biliary cirrhosis: a comprehensive review. Clin Rev Allergy Immunol 48(2–3):301–315. doi:10.1007/s12016-015-8471-1

    Article  CAS  PubMed  Google Scholar 

  20. Selmi C, Meroni PL, Gershwin ME (2012) Primary biliary cirrhosis and Sjogren’s syndrome: autoimmune epithelitis. J Autoimmun 39(1–2):34–42. doi:10.1016/j.jaut.2011.11.005

    Article  CAS  PubMed  Google Scholar 

  21. Chaigne B, Lasfargues G, Marie I, Huttenberger B, Lavigne C, Marchand-Adam S, Maillot F, Diot E (2015) Primary Sjogren’s syndrome and occupational risk factors: a case-control study. J Autoimmun 60:80–85. doi:10.1016/j.jaut.2015.04.004

    Article  PubMed  Google Scholar 

  22. Selmi C, Leung PS, Sherr DH, Diaz M, Nyland JF, Monestier M, Rose NR, Gershwin ME (2012) Mechanisms of environmental influence on human autoimmunity: a National Institute of Environmental Health Sciences expert panel workshop. J Autoimmun 39(4):272–284. doi:10.1016/j.jaut.2012.05.007

    Article  PubMed  Google Scholar 

  23. Gershwin ME, Terasaki I, Graw R, Chused TM (1975) Increased frequency of HL-A8 in Sjogren’s syndrome. Tissue Antigens 6(5):342–346

    CAS  PubMed  Google Scholar 

  24. Teos LY, Alevizos I (2017) Genetics of Sjogren’s syndrome. Clin Immunol. doi:10.1016/j.clim.2017.04.018

  25. Huang R, Yin J, Chen Y, Deng F, Chen J, Gao X, Liu Z, Yu X, Zheng J (2015) The amino acid variation within the binding pocket 7 and 9 of HLA-DRB1 molecules are associated with primary Sjogren’s syndrome. J Autoimmun 57:53–59. doi:10.1016/j.jaut.2014.11.006

    Article  CAS  PubMed  Google Scholar 

  26. Chen K, Liu J, Cao X (2017) Regulation of type I interferon signaling in immunity and inflammation: a comprehensive review. J Autoimmun. doi:10.1016/j.jaut.2017.03.008

  27. Nezos A, Gravani F, Tassidou A, Kapsogeorgou EK, Voulgarelis M, Koutsilieris M, Crow MK, Mavragani CP (2015) Type I and II interferon signatures in Sjogren’s syndrome pathogenesis: contributions in distinct clinical phenotypes and Sjogren’s related lymphomagenesis. J Autoimmun 63:47–58. doi:10.1016/j.jaut.2015.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Teruel M, Alarcon-Riquelme ME (2016) The genetic basis of systemic lupus erythematosus: what are the risk factors and what have we learned. J Autoimmun 74:161–175. doi:10.1016/j.jaut.2016.08.001

    Article  CAS  PubMed  Google Scholar 

  29. Nielsen PR, Kragstrup TW, Deleuran BW, Benros ME (2016) Infections as risk factor for autoimmune diseases—a nationwide study. J Autoimmun 74:176–181. doi:10.1016/j.jaut.2016.05.013

    Article  PubMed  Google Scholar 

  30. Watad A, Azrielant S, Bragazzi NL, Sharif K, David P, Katz I, Aljadeff G, Quaresma M, Tanay G, Adawi M, Amital H, Shoenfeld Y (2017) Seasonality and autoimmune diseases: the contribution of the four seasons to the mosaic of autoimmunity. J Autoimmun. doi:10.1016/j.jaut.2017.06.001

  31. Kivity S, Arango MT, Ehrenfeld M, Tehori O, Shoenfeld Y, Anaya JM, Agmon-Levin N (2014) Infection and autoimmunity in Sjogren’s syndrome: a clinical study and comprehensive review. J Autoimmun 51:17–22. doi:10.1016/j.jaut.2014.02.008

    Article  CAS  PubMed  Google Scholar 

  32. Konsta OD, Le Dantec C, Charras A, Cornec D, Kapsogeorgou EK, Tzioufas AG, Pers JO, Renaudineau Y (2016) Defective DNA methylation in salivary gland epithelial acini from patients with Sjogren’s syndrome is associated with SSB gene expression, anti-SSB/LA detection, and lymphocyte infiltration. J Autoimmun 68:30–38. doi:10.1016/j.jaut.2015.12.002

    Article  CAS  PubMed  Google Scholar 

  33. Barrera MJ, Bahamondes V, Sepulveda D, Quest AF, Castro I, Cortes J, Aguilera S, Urzua U, Molina C, Perez P, Ewert P, Alliende C, Hermoso MA, Gonzalez S, Leyton C, Gonzalez MJ (2013) Sjogren’s syndrome and the epithelial target: a comprehensive review. J Autoimmun 42:7–18. doi:10.1016/j.jaut.2013.02.001

    Article  CAS  PubMed  Google Scholar 

  34. Tsuneyama K, Van de Water J, Nakanuma Y, Cha S, Ansari A, Coppel R, Gershwin ME (1994) Human combinatorial autoantibodies and mouse monoclonal antibodies to PDC-E2 produce abnormal apical staining of salivary glands in patients with coexistent primary biliary cirrhosis and Sjogren’s syndrome. Hepatology 20(4 Pt 1):893–898

    Article  CAS  PubMed  Google Scholar 

  35. Manganelli P, Quaini F, Andreoli AM, Lagrasta C, Pilato FP, Zuccarelli A, Monteverdi R, D'Aversa C, Olivetti G (1997) Quantitative analysis of apoptosis and bcl-2 in Sjogren’s syndrome. J Rheumatol 24(8):1552–1557

    CAS  PubMed  Google Scholar 

  36. Kong L, Ogawa N, McGuff HS, Nakabayashi T, Sakata KM, Masago R, Vela-Roch N, Talal N, Dang H (1998) Bcl-2 family expression in salivary glands from patients with primary Sjogren’s syndrome: involvement of Bax in salivary gland destruction. Clin Immunol Immunopathol 88(2):133–141

    Article  CAS  PubMed  Google Scholar 

  37. Ohlsson M, Jonsson R, Brokstad KA (2002) Subcellular redistribution and surface exposure of the Ro52, Ro60 and La48 autoantigens during apoptosis in human ductal epithelial cells: a possible mechanism in the pathogenesis of Sjogren’s syndrome. Scand J Immunol 56(5):456–469

    Article  CAS  PubMed  Google Scholar 

  38. Fragoulis GE, Vakrakou AG, Papadopoulou A, Germenis A, Kanavakis E, Moutsopoulos HM, Manoussakis MN (2015) Impaired degradation and aberrant phagocytosis of necrotic cell debris in the peripheral blood of patients with primary Sjogren’s syndrome. J Autoimmun 56:12–22. doi:10.1016/j.jaut.2014.08.004

    Article  PubMed  Google Scholar 

  39. Monks J, Rosner D, Geske FJ, Lehman L, Hanson L, Neville MC, Fadok VA (2005) Epithelial cells as phagocytes: apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release. Cell Death Differ 12(2):107–114. doi:10.1038/sj.cdd.4401517

    Article  CAS  PubMed  Google Scholar 

  40. Singh N, Cohen PL (2012) The T cell in Sjogren’s syndrome: force majeure, not spectateur. J Autoimmun 39(3):229–233. doi:10.1016/j.jaut.2012.05.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Spengler U, Moller A, Jung MC, Messer G, Zachoval R, Hoffmann RM, Eisenburg J, Paumgartner G, Riethmuller G, Weiss EH et al (1992) T lymphocytes from patients with primary biliary cirrhosis produce reduced amounts of lymphotoxin, tumor necrosis factor and interferon-gamma upon mitogen stimulation. J Hepatol 15(1–2):129–135

    Article  CAS  PubMed  Google Scholar 

  42. Li S, Yang D, Peng T, Wu Y, Tian Z, Ni B (2017) Innate lymphoid cell-derived cytokines in autoimmune diseases. J Autoimmun. doi:10.1016/j.jaut.2017.05.001

  43. Lin X, Rui K, Deng J, Tian J, Wang X, Wang S, Ko KH, Jiao Z, Chan VS, Lau CS, Cao X, Lu L (2015) Th17 cells play a critical role in the development of experimental Sjogren’s syndrome. Ann Rheum Dis 74(6):1302–1310. doi:10.1136/annrheumdis-2013-204584

    Article  CAS  PubMed  Google Scholar 

  44. Matsui K, Sano H (2017) T helper 17 cells in primary Sjogren’s syndrome. J Clin Med 6(7). doi:10.3390/jcm6070065

  45. Gan Y, Zhao X, He J, Liu X, Li Y, Sun X, Li Z (2017) Increased interleukin-17F is associated with elevated autoantibody levels and more clinically relevant than interleukin-17A in primary Sjogren’s syndrome. J Immunol Res 2017:4768408. doi:10.1155/2017/4768408

    Article  PubMed  PubMed Central  Google Scholar 

  46. Cornec D, Devauchelle-Pensec V, Tobon GJ, Pers JO, Jousse-Joulin S, Saraux A (2012) B cells in Sjogren’s syndrome: from pathophysiology to diagnosis and treatment. J Autoimmun 39(3):161–167. doi:10.1016/j.jaut.2012.05.014

    Article  CAS  PubMed  Google Scholar 

  47. Varin MM, Le Pottier L, Youinou P, Saulep D, Mackay F, Pers JO (2010) B-cell tolerance breakdown in Sjogren’s syndrome: focus on BAFF. Autoimmun Rev 9(9):604–608. doi:10.1016/j.autrev.2010.05.006

    Article  CAS  PubMed  Google Scholar 

  48. Carubbi F, Alunno A, Cipriani P, Bartoloni E, Ciccia F, Triolo G, Gerli R, Giacomelli R (2014) Rituximab in primary Sjogren’s syndrome: a ten-year journey. Lupus 23(13):1337–1349. doi:10.1177/0961203314546023

    Article  CAS  PubMed  Google Scholar 

  49. Meijer JM, Meiners PM, Vissink A, Spijkervet FK, Abdulahad W, Kamminga N, Brouwer E, Kallenberg CG, Bootsma H (2010) Effectiveness of rituximab treatment in primary Sjogren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 62(4):960–968. doi:10.1002/art.27314

    Article  CAS  PubMed  Google Scholar 

  50. Haacke EA, Bootsma H, Spijkervet FKL, Visser A, Vissink A, Kluin PM, Kroese FGM (2017) FcRL4+ B-cells in salivary glands of primary Sjogren’s syndrome patients. J Autoimmun 81:90–98. doi:10.1016/j.jaut.2017.03.012

    Article  CAS  PubMed  Google Scholar 

  51. Jonsson MV, Szodoray P, Jellestad S, Jonsson R, Skarstein K (2005) Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjogren’s syndrome. J Clin Immunol 25(3):189–201. doi:10.1007/s10875-005-4091-5

    Article  CAS  PubMed  Google Scholar 

  52. Quartuccio L, Isola M, Baldini C, Priori R, Bartoloni Bocci E, Carubbi F, Maset M, Gregoraci G, Della Mea V, Salvin S, De Marchi G, Luciano N, Colafrancesco S, Alunno A, Giacomelli R, Gerli R, Valesini G, Bombardieri S, De Vita S (2014) Biomarkers of lymphoma in Sjogren’s syndrome and evaluation of the lymphoma risk in prelymphomatous conditions: results of a multicenter study. J Autoimmun 51:75–80. doi:10.1016/j.jaut.2013.10.002

    Article  PubMed  Google Scholar 

  53. Globinska A, Pawelczyk M, Piechota-Polanczyk A, Olszewska-Ziaber A, Moskwa S, Mikolajczyk A, Jablonska A, Zakrzewski PK, Brauncajs M, Jarzebska M, Taka S, Papadopoulos NG, Kowalski ML (2017) Impaired virus replication and decreased innate immune responses to viral infections in nasal epithelial cells from patients with allergic rhinitis. Clin Exp Immunol 187(1):100–112. doi:10.1111/cei.12869

    Article  CAS  PubMed  Google Scholar 

  54. Zhang C, Tian Z (2017) NK cell subsets in autoimmune diseases. J Autoimmun. doi:10.1016/j.jaut.2017.02.005

  55. Bernacchi E, Bianchi B, Amato L, Giorgini S, Fabbri P, Tavoni A, Bombardieri S (2005) Xerosis in primary Sjogren syndrome: immunohistochemical and functional investigations. J Dermatol Sci 39(1):53–55. doi:10.1016/j.jdermsci.2005.01.017

    Article  CAS  PubMed  Google Scholar 

  56. Katayama I, Yokozeki H, Nishioka K (1995) Impaired sweating as an exocrine manifestation in Sjogren’s syndrome. Br J Dermatol 133(5):716–720

    Article  CAS  PubMed  Google Scholar 

  57. Katayama I (2016) Abberant sudomotor functions in Sjogren’s syndrome: comparable study with atopic dermatitis on dry skin manifestation. Curr Probl Dermatol 51:62–74. doi:10.1159/000446780

    Article  PubMed  Google Scholar 

  58. Provost TT, Watson R (1992) Cutaneous manifestations of Sjogren’s syndrome. Rheum Dis Clin N Am 18(3):609–616

    CAS  Google Scholar 

  59. Wolf R, Orion E, Tuzun Y (2014) Periorbital (eyelid) dermatides. Clin Dermatol 32(1):131–140. doi:10.1016/j.clindermatol.2013.05.035

    Article  PubMed  Google Scholar 

  60. Chisholm SA, Couch SM, Custer PL (2016) Etiology and management of allergic eyelid dermatitis. Ophthal Plast Reconstr Surg. doi:10.1097/IOP.0000000000000723

  61. Bernacchi E, Amato L, Parodi A, Cottoni F, Rubegni P, De Pita O, Papini M, Rebora A, Bombardieri S, Fabbri P (2004) Sjogren’s syndrome: a retrospective review of the cutaneous features of 93 patients by the Italian group of immunodermatology. Clin Exp Rheumatol 22(1):55–62

    CAS  PubMed  Google Scholar 

  62. Katayama I, Koyano T, Nishioka K (1994) Prevalence of eyelid dermatitis in primary Sjogren’s syndrome. Int J Dermatol 33(6):421–424

    Article  CAS  PubMed  Google Scholar 

  63. Takeo N, Sakai T, Saito-Shono T, Ishikawa K, Hatano Y, Katagiri K, Takahashi Y, Kawano K, Kimoto K, Kubota T, Eshima N, Kojima H, Fujiwara S (2016) Three cases of pigmented cosmetic dermatitis-like eruptions associated with primary Sjogren’s syndrome or anti-SSA antibody. J Dermatol 43(8):947–950. doi:10.1111/1346-8138.13300

    Article  PubMed  Google Scholar 

  64. Ramos-Casals M, Brito-Zeron P, Seror R, Bootsma H, Bowman SJ, Dorner T, Gottenberg JE, Mariette X, Theander E, Bombardieri S, De Vita S, Mandl T, Ng WF, Kruize A, Tzioufas A, Vitali C, Force ESST (2015) Characterization of systemic disease in primary Sjogren’s syndrome: EULAR-SS task force recommendations for articular, cutaneous, pulmonary and renal involvements. Rheumatology (Oxford) 54(12):2230–2238. doi:10.1093/rheumatology/kev200

    Google Scholar 

  65. Ramos-Casals M, Brito-Zeron P, Font J (2007) The overlap of Sjogren’s syndrome with other systemic autoimmune diseases. Semin Arthritis Rheum 36(4):246–255. doi:10.1016/j.semarthrit.2006.08.007

    Article  PubMed  Google Scholar 

  66. Seror R, Ravaud P, Mariette X, Bootsma H, Theander E, Hansen A, Ramos-Casals M, Dorner T, Bombardieri S, Hachulla E, Brun JG, Kruize AA, Praprotnik S, Tomsic M, Gottenberg JE, Devauchelle V, Devita S, Vollenweider C, Mandl T, Tzioufas A, Carsons S, Saraux A, Sutcliffe N, Vitali C, Bowman SJ, EULAR Sjögren’s Task Force (2011) EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjogren’s syndrome. Ann Rheum Dis 70(6):968–972. doi:10.1136/ard.2010.143743

    Article  PubMed  Google Scholar 

  67. Seror R, Theander E, Bootsma H, Bowman SJ, Tzioufas A, Gottenberg JE, Ramos-Casals M, Dorner T, Ravaud P, Mariette X, Vitali C (2014) Outcome measures for primary Sjogren’s syndrome: a comprehensive review. J Autoimmun 51:51–56. doi:10.1016/j.jaut.2013.12.010

    Article  PubMed  Google Scholar 

  68. Hsu S, Le EH, Khoshevis MR (2001) Differential diagnosis of annular lesions. Am Fam Physician 64(2):289–296

    CAS  PubMed  Google Scholar 

  69. Kittridge A, Routhouska SB, Korman NJ (2011) Dermatologic manifestations of Sjogren syndrome. J Cutan Med Surg 15(1):8–14. doi:10.2310/7750.2010.09033

    Article  PubMed  Google Scholar 

  70. Ramos-Casals M, Anaya JM, Garcia-Carrasco M, Rosas J, Bove A, Claver G, Diaz LA, Herrero C, Font J (2004) Cutaneous vasculitis in primary Sjogren syndrome: classification and clinical significance of 52 patients. Medicine (Baltimore) 83(2):96–106

    Article  Google Scholar 

  71. Lawley TJ, Moutsopoulos HM, Katz SI, Theofilopoulos AN, Chused TM, Frank MM (1979) Demonstration of circulating immune complexes in Sjogren’s syndrome. J Immunol 123(3):1382–1387

    CAS  PubMed  Google Scholar 

  72. Alexander EL, Provost TT (1983) Cutaneous manifestations of primary Sjogren’s syndrome: a reflection of vasculitis and association with anti-Ro(SSA) antibodies. J Invest Dermatol 80(5):386–391

    Article  CAS  PubMed  Google Scholar 

  73. Damoiseaux J (2014) The diagnosis and classification of the cryoglobulinemic syndrome. Autoimmun Rev 13(4–5):359–362. doi:10.1016/j.autrev.2014.01.027

    Article  CAS  PubMed  Google Scholar 

  74. Demirkesen C (2017) Approach to cutaneous vasculitides with special emphasis on small vessel vasculitis: histopathology and direct immunofluorescence. Curr Opin Rheumatol 29(1):39–44. doi:10.1097/BOR.0000000000000346

    Article  CAS  PubMed  Google Scholar 

  75. Quartuccio L, Baldini C, Priori R, Bartoloni E, Carubbi F, Alunno A, Gandolfo S, Colafrancesco S, Giacomelli R, Gerli R, Valesini G, Bombardieri S, De Vita S, the GG (2017) Cryoglobulinemia in Sjogren syndrome: a disease subset that links higher systemic disease activity, autoimmunity, and local B cell proliferation in mucosa-associated lymphoid tissue. J Rheumatol. doi:10.3899/jrheum.161465

  76. Retamozo S, Gheitasi H, Quartuccio L, Kostov B, Corazza L, Bove A, Siso-Almirall A, Gandia M, Ramos-Casals M, De Vita S, Brito-Zeron P (2016) Cryoglobulinaemic vasculitis at diagnosis predicts mortality in primary Sjogren syndrome: analysis of 515 patients. Rheumatology (Oxford) 55(8):1443–1451. doi:10.1093/rheumatology/kew194

    Article  Google Scholar 

  77. Guellec D, Cornec-Le Gall E, Groh M, Hachulla E, Karras A, Charles P, Dunogue B, Abad S, Alvarez F, Gerard F, Devauchelle-Pensec V, Pers JO, Puechal X, Guillevin L, Saraux A, Cornec D, Cri, the French Vasculitis Study G (2015) ANCA-associated vasculitis in patients with primary Sjogren’s syndrome: detailed analysis of 7 new cases and systematic literature review. Autoimmun Rev 14(8):742–750. doi:10.1016/j.autrev.2015.04.009

    Article  CAS  PubMed  Google Scholar 

  78. Meijer JM, Schonland SO, Palladini G, Merlini G, Hegenbart U, Ciocca O, Perfetti V, Leijsma MK, Bootsma H, Hazenberg BP (2008) Sjogren’s syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity? Arthritis Rheum 58(7):1992–1999. doi:10.1002/art.23617

    Article  PubMed  Google Scholar 

  79. Yamamoto T, Ohi M, Nishioka K (2002) Lymphomatoid papulosis associated with Sjogren’s syndrome. J Dermatol 29(3):174–177

    Article  PubMed  Google Scholar 

  80. Zhang Q, Wang X, Chen H, Shen B (2017) Sjogren’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 11:905–911. doi:10.2147/PPA.S132751

    Article  PubMed  PubMed Central  Google Scholar 

  81. Pertovaara M, Korpela M, Uusitalo H, Pukander J, Miettinen A, Helin H, Pasternack A (1999) Clinical follow up study of 87 patients with sicca symptoms (dryness of eyes or mouth, or both). Ann Rheum Dis 58(7):423–427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bolstad AI, Skarstein K (2016) Epidemiology of Sjogren’s syndrome-from an oral perspective. Curr Oral Health Rep 3(4):328–336. doi:10.1007/s40496-016-0112-0

    Article  PubMed  PubMed Central  Google Scholar 

  83. Castro I, Sepulveda D, Cortes J, Quest AF, Barrera MJ, Bahamondes V, Aguilera S, Urzua U, Alliende C, Molina C, Gonzalez S, Hermoso MA, Leyton C, Gonzalez MJ (2013) Oral dryness in Sjogren’s syndrome patients. Not just a question of water. Autoimmun Rev 12(5):567–574. doi:10.1016/j.autrev.2012.10.018

    Article  CAS  PubMed  Google Scholar 

  84. Blochowiak K, Olewicz-Gawlik A, Polanska A, Nowak-Gabryel M, Kociecki J, Witmanowski H, Sokalski J (2016) Oral mucosal manifestations in primary and secondary Sjogren syndrome and dry mouth syndrome. Postepy Dermatol Alergol 33(1):23–27. doi:10.5114/pdia.2016.57764

    Article  PubMed  PubMed Central  Google Scholar 

  85. Cornec D, Saraux A, Jousse-Joulin S, Pers JO, Boisrame-Gastrin S, Renaudineau Y, Gauvin Y, Roguedas-Contios AM, Genestet S, Chastaing M, Cochener B, Devauchelle-Pensec V (2015) The differential diagnosis of dry eyes, dry mouth, and parotidomegaly: a comprehensive review. Clin Rev Allergy Immunol 49(3):278–287. doi:10.1007/s12016-014-8431-1

    Article  PubMed  Google Scholar 

  86. Sharma A, Hindman HB (2014) Aging: a predisposition to dry eyes. J Ophthalmol 2014:781683. doi:10.1155/2014/781683

    Article  PubMed  PubMed Central  Google Scholar 

  87. Yagci A, Gurdal C (2014) The role and treatment of inflammation in dry eye disease. Int Ophthalmol 34(6):1291–1301. doi:10.1007/s10792-014-9969-x

    Article  PubMed  Google Scholar 

  88. Hessen M, Akpek EK (2014) Dry eye: an inflammatory ocular disease. J Ophthalmic Vis Res 9(2):240–250

    PubMed  PubMed Central  Google Scholar 

  89. Generali E, Cantarini L, Selmi C (2015) Ocular involvement in systemic autoimmune diseases. Clin Rev Allergy Immunol 49(3):263–270. doi:10.1007/s12016-015-8518-3

    Article  CAS  PubMed  Google Scholar 

  90. Kyriakidis NC, Kapsogeorgou EK, Tzioufas AG (2014) A comprehensive review of autoantibodies in primary Sjogren’s syndrome: clinical phenotypes and regulatory mechanisms. J Autoimmun 51:67–74. doi:10.1016/j.jaut.2013.11.001

    Article  CAS  PubMed  Google Scholar 

  91. Shen L, Suresh L (2017) Autoantibodies, detection methods and panels for diagnosis of Sjogren’s syndrome. Clin Immunol. doi:10.1016/j.clim.2017.03.017

  92. Rischmueller M, Tieu J, Lester S (2016) Primary Sjogren’s syndrome. Best Pract Res Clin Rheumatol 30(1):189–220. doi:10.1016/j.berh.2016.04.003

    Article  PubMed  Google Scholar 

  93. Risselada AP, Kruize AA, Goldschmeding R, Lafeber FP, Bijlsma JW, van Roon JA (2014) The prognostic value of routinely performed minor salivary gland assessments in primary Sjogren’s syndrome. Ann Rheum Dis 73(8):1537–1540. doi:10.1136/annrheumdis-2013-204634

    Article  PubMed  Google Scholar 

  94. Theander E, Vasaitis L, Baecklund E, Nordmark G, Warfvinge G, Liedholm R, Brokstad K, Jonsson R, Jonsson MV (2011) Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjogren’s syndrome. Ann Rheum Dis 70(8):1363–1368. doi:10.1136/ard.2010.144782

    Article  PubMed  PubMed Central  Google Scholar 

  95. Both T, Dalm VA, van Hagen PM, van Daele PL (2017) Reviewing primary Sjogren’s syndrome: beyond the dryness—from pathophysiology to diagnosis and treatment. Int J Med Sci 14(3):191–200. doi:10.7150/ijms.17718

    Article  PubMed  PubMed Central  Google Scholar 

  96. Wu JJ, Carsons SE (2014) Management of extraglandular manifestations of primary Sjogren’s syndrome. Oral Maxillofac Surg Clin North Am 26(1):101–109. doi:10.1016/j.coms.2013.09.009

    Article  PubMed  Google Scholar 

  97. Valim V, Trevisani VF, de Sousa JM, Vilela VS, Belfort R Jr (2015) Current approach to dry eye disease. Clin Rev Allergy Immunol 49(3):288–297. doi:10.1007/s12016-014-8438-7

    Article  CAS  PubMed  Google Scholar 

  98. Schultz C (2014) Safety and efficacy of cyclosporine in the treatment of chronic dry eye. Ophthalmol Eye Dis 6:37–42. doi:10.4137/OED.S16067

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Wan KH, Chen LJ, Young AL (2015) Efficacy and safety of topical 0.05% cyclosporine eye drops in the treatment of dry eye syndrome: a systematic review and meta-analysis. Ocul Surf 13(3):213–225. doi:10.1016/j.jtos.2014.12.006

    Article  PubMed  Google Scholar 

  100. Liu A, Ji J (2014) Omega-3 essential fatty acids therapy for dry eye syndrome: a meta-analysis of randomized controlled studies. Med Sci Monit 20:1583–1589. doi:10.12659/MSM.891364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Alio JL, Rodriguez AE, WrobelDudzinska D (2015) Eye platelet-rich plasma in the treatment of ocular surface disorders. Curr Opin Ophthalmol 26(4):325–332. doi:10.1097/ICU.0000000000000169

    Article  PubMed  Google Scholar 

  102. Bavinger JC, DeLoss K, Mian SI (2015) Scleral lens use in dry eye syndrome. Curr Opin Ophthalmol 26(4):319–324. doi:10.1097/ICU.0000000000000171

    Article  PubMed  Google Scholar 

  103. Romero-Rangel T, Stavrou P, Cotter J, Rosenthal P, Baltatzis S, Foster CS (2000) Gas-permeable scleral contact lens therapy in ocular surface disease. Am J Ophthalmol 130(1):25–32

    Article  CAS  PubMed  Google Scholar 

  104. Furness S, Worthington HV, Bryan G, Birchenough S, McMillan R (2011) Interventions for the management of dry mouth: topical therapies. Cochrane Database Syst Rev 12:CD008934. doi:10.1002/14651858.CD008934.pub2

    Google Scholar 

  105. Ramos-Casals M, Tzioufas AG, Stone JH, Siso A, Bosch X (2010) Treatment of primary Sjogren syndrome: a systematic review. JAMA 304(4):452–460. doi:10.1001/jama.2010.1014

    Article  CAS  PubMed  Google Scholar 

  106. Vivino FB, Al-Hashimi I, Khan Z, LeVeque FG, Salisbury PL 3rd, Tran-Johnson TK, Muscoplat CC, Trivedi M, Goldlust B, Gallagher SC (1999) Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjogren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92-01 Study Group. Arch Intern Med 159(2):174–181

    Article  CAS  PubMed  Google Scholar 

  107. Gottenberg JE, Ravaud P, Puechal X, Le Guern V, Sibilia J, Goeb V, Larroche C, Dubost JJ, Rist S, Saraux A, Devauchelle-Pensec V, Morel J, Hayem G, Hatron P, Perdriger A, Sene D, Zarnitsky C, Batouche D, Furlan V, Benessiano J, Perrodeau E, Seror R, Mariette X (2014) Effects of hydroxychloroquine on symptomatic improvement in primary Sjogren syndrome: the JOQUER randomized clinical trial. JAMA 312(3):249–258. doi:10.1001/jama.2014.7682

    Article  PubMed  CAS  Google Scholar 

  108. 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 Musculoskelet Disord 18(1):186. doi:10.1186/s12891-017-1543-z

    Article  PubMed  PubMed Central  Google Scholar 

  109. Skopouli FN, Jagiello P, Tsifetaki N, Moutsopoulos HM (1996) Methotrexate in primary Sjogren’s syndrome. Clin Exp Rheumatol 14(5):555–558

    CAS  PubMed  Google Scholar 

  110. Gottenberg JE, Cinquetti G, Larroche C, Combe B, Hachulla E, Meyer O, Pertuiset E, Kaplanski G, Chiche L, Berthelot JM, Gombert B, Goupille P, Marcelli C, Feuillet S, Leone J, Sibilia J, Zarnitsky C, Carli P, Rist S, Gaudin P, Salliot C, Piperno M, Deplas A, Breban M, Lequerre T, Richette P, Ghiringhelli C, Hamidou M, Ravaud P, Mariette X, Club Rhumatismes et I, the French Society of R (2013) Efficacy of rituximab in systemic manifestations of primary Sjogren’s syndrome: results in 78 patients of the AutoImmune and Rituximab registry. Ann Rheum Dis 72(6):1026–1031. doi:10.1136/annrheumdis-2012-202293

    Article  CAS  PubMed  Google Scholar 

  111. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, Puechal X, Le Guern V, Sibilia J, Gottenberg JE, Chiche L, Hachulla E, Hatron PY, Goeb V, Hayem G, Morel J, Zarnitsky C, Dubost JJ, Pers JO, Nowak E, Saraux A (2014) Treatment of primary Sjogren syndrome with rituximab: a randomized trial. Ann Intern Med 160(4):233–242. doi:10.7326/M13-1085

    Article  PubMed  Google Scholar 

  112. Bowman SJ, Everett CC, O’Dwyer JL, Emery P, Pitzalis C, Ng WF, Pease CT, Price EJ, Sutcliffe N, St Gendi N, Hall FC, Ruddock SP, Fernandez C, Reynolds C, Hulme CT, Davies KA, Edwards CJ, Lanyon PC, Moots RJ, Roussou E, Giles IP, Sharples LD, Bombardieri M (2017) Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjogren’s syndrome. Arthritis Rheumatol. doi:10.1002/art.40093

  113. De Vita S, Quartuccio L, Seror R, Salvin S, Ravaud P, Fabris M, Nocturne G, Gandolfo S, Isola M, Mariette X (2015) Efficacy and safety of belimumab given for 12 months in primary Sjogren’s syndrome: the BELISS open-label phase II study. Rheumatology (Oxford) 54(12):2249–2256. doi:10.1093/rheumatology/kev257

    Google Scholar 

  114. Tsuboi H, Matsumoto I, Hagiwara S, Hirota T, Takahashi H, Ebe H, Yokosawa M, Yagishita M, Takahashi H, Kurata I, Ohyama A, Honda F, Asashima H, Miki H, Umeda N, Kondo Y, Hirata S, Saito K, Tanaka Y, Horai Y, Nakamura H, Kawakami A, Sumida T (2016) Effectiveness of abatacept for patients with Sjogren’s syndrome associated with rheumatoid arthritis. An open label, multicenter, one-year, prospective study: ROSE (Rheumatoid Arthritis with Orencia Trial toward Sjogren’s syndrome Endocrinopathy) trial. Mod Rheumatol 26(6):891–899. doi:10.3109/14397595.2016.1158773

    Article  CAS  PubMed  Google Scholar 

  115. Meiners PM, Vissink A, Kroese FG, Spijkervet FK, Smitt-Kamminga NS, Abdulahad WH, Bulthuis-Kuiper J, Brouwer E, Arends S, Bootsma H (2014) Abatacept treatment reduces disease activity in early primary Sjogren’s syndrome (open-label proof of concept ASAP study). Ann Rheum Dis 73(7):1393–1396. doi:10.1136/annrheumdis-2013-204653

    Article  CAS  PubMed  Google Scholar 

  116. Schreiber K, Nocturne G, Cornec D, Daien CI (2017) Lymphocytes as biomarkers of therapeutic response in rheumatic autoimmune diseases, is it a realistic goal? Clin Rev Allergy Immunol. doi:10.1007/s12016-017-8614-7

  117. Cornec D, Costa S, Devauchelle-Pensec V, Jousse-Joulin S, Marcorelles P, Berthelot JM, Chiche L, Hachulla E, Hatron PY, Goeb V, Vittecoq O, Saraux A, Pers JO (2016) Blood and salivary-gland BAFF-driven B-cell hyperactivity is associated to rituximab inefficacy in primary Sjogren’s syndrome. J Autoimmun 67:102–110. doi:10.1016/j.jaut.2015.11.002

    Article  CAS  PubMed  Google Scholar 

  118. Vitali C, Palombi G, Cataleta P (2010) Treating Sjogren’s syndrome: insights for the clinician. Ther Adv Musculoskelet Dis 2(3):155–166. doi:10.1177/1759720X10363246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Durez P, Tourne L, Feremans W, Mascart-Lemone F, Heenen M, Appelboom T (1998) Dramatic response to intravenous high dose gamma-globulin in refractory vasculitis of the skin associated with Sjogren’s syndrome. J Rheumatol 25(5):1032–1033

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Via A. Manzoni 56, 20089 Rozzano, Milan, Italy

    Elena Generali & Carlo Selmi

  2. Division of Dermatology, Humanitas Research Hospital, Rozzano, Milan, Italy

    Antonio Costanzo

  3. Humanitas University, Rozzano, Milan, Italy

    Antonio Costanzo

  4. Dermatologia Ente Ospedaliero Cantonale, Ospedale Regionale Bellinzona, Bellinzona, Switzerland

    Carlo Mainetti

  5. BIOMETRA Department, University of Milan, Milan, Italy

    Carlo Selmi

Authors
  1. Elena Generali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Costanzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlo Mainetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlo Selmi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlo Selmi.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Funding

None.

Ethical Approval and Informed Consent

No ethics issues are raised relevant to this review article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Generali, E., Costanzo, A., Mainetti, C. et al. Cutaneous and Mucosal Manifestations of Sjögren’s Syndrome. Clinic Rev Allerg Immunol 53, 357–370 (2017). https://doi.org/10.1007/s12016-017-8639-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-017-8639-y

Keywords

Search

Navigation