eMedicine Specialties > Ophthalmology > Connective Tissue Disorders

Sjogren Syndrome

Author: James V Aquavella, MD, Professor of Ophthalmology, Department of Ophthalmology, University of Rochester School of Medicine, University of Rochester Eye Institute
Coauthor(s): Zoe R Williams, MD, Staff Physician, Department of Ophthalmology, University of Rochester School of Medicine, Strong Memorial Hospital; Shobha Boghani, MD, Assistant Professor, Department of Ophthalmology, Strong Memorial Hospital, University of Rochester
Contributor Information and Disclosures

Updated: Feb 19, 2008

Introduction

Background

Sjögren syndrome (SS) is an autoimmune disorder characterized by salivary and lacrimal gland dysfunction, resulting in keratoconjunctivitis sicca (KCS) and xerostomia (ie, dry mouth) as a result of immune lymphocytes that infiltrate these secretory glands. Nasal and vaginal mucous membranes are also commonly affected. Other systemic manifestations, most commonly rheumatoid arthritis and systemic lupus erythematosus, can be associated. Although several reports of this condition were documented in the late 1800s, Henrik Sjögren, a Swedish ophthalmologist, described the clinical and pathological findings of this syndrome affecting menopausal women in a classic monograph in 1933.

Sjögren syndrome may occur alone (primary) or in conjunction with other autoimmune diseases (secondary). Primary Sjögren syndrome has 2 subsets: patients with systemic immune dysfunction but no defined connective tissue dysfunction, and patients who lack evidence of systemic immune dysfunction or defined connective tissue disease. Secondary Sjögren syndrome occurs in patients who have defined connective tissue disease. The most commonly associated connective tissue diseases are rheumatoid arthritis and systemic lupus erythematosus, but Sjögren syndrome has also been reported in conjunction with progressive systemic sclerosis, Hashimoto thyroiditis, polymyositis, polyarteritis nodosa, and Waldenström macroglobulinemia.

Pathophysiology

The pathogenesis of Sjögren syndrome has not been fully elucidated, but the central role of glandular epithelial cells has been identified as key to understanding the disease. An environmental stimulus (eg, viral infection) is believed to trigger inappropriate apoptosis of glandular epithelial cells, producing autoantigens that trigger lymphocytic infiltration of the secretory glands with subsequent production of autoantibodies and cytokines. Dysfunction of residual glandular epithelial cells may also contribute to deficient tear production. Additionally, it has been demonstrated that there is a reduced rate of apoptosis among immune-stimulated lymphocytes, thus exacerbating the loss of glandular secretory function.

Studies have shown that CD4+ T lymphocytes play a key role in the pathogenesis of Sjögren syndrome. T cells have been demonstrated to induce apoptosis of epithelial cells by 3 mechanisms: Fas-FasL interaction, protease release, and cytokine production. FasL is expressed on activated T lymphocytes. Binding of activated T lymphocytes with ubiquitously expressed Fas antigen leads to apoptosis of susceptible epithelial cells.

Patients with Sjögren syndrome demonstrate an imbalance in cytokine production. In addition, in primary Sjögren syndrome, there is increased expression of IFN in the minor salivary glands. Studies have confirmed that primary Sjögren syndrome has a systemic expression, including extraglandular manifestations in the lungs (interstitial pneumonitis) and the kidneys (interstitial nephritis).

Sjögren syndrome is also characterized by increased B cell activity. An antigen-driven B cell response has been proposed to occur in the salivary glands of patients with Sjögren syndrome. Patients with Sjögren syndrome are at an increased risk of developing B cell non-Hodgkin lymphoma and other lymphoproliferative disorders. In fact, 5% of patients with primary Sjögren syndrome develop B cell non-Hodgkin lymphoma. This increased risk has been attributed to B cell hyperactivity and reduced natural killer cell activity.

Frequency

United States

The incidence has been estimated by the San Diego criteria as 0.5%.

International

The European study group estimates an incidence of 3-5%.

Mortality/Morbidity

Severe dry eyes can cause corneal scarring, ulceration, infection, and even perforation.

Sex

The female-to-male ratio is 9:1.

Age

Although primarily a disease of postmenopausal women, age can range from 22-70 years, with the average age being 43 years. There is often a delay of 5-10 years between disease onset and diagnosis.

Sjögren syndrome has also been reported in children who developed recurrent parotid gland enlargement.

Clinical

History

Ocular signs and symptoms of Sjögren syndrome are similar to those seen in dry eye states.

  • Subjective complaints of ocular irritation may vary and include the following:  
    • Burning
    • Stinging
    • Itching
    • Foreign body sensation
    • Lid irritation and swelling
    • Photophobia
    • Ocular fatigue
    • Mucoid discharge

Physical

Two important clues that the patient may have dry eyes include diurnal fluctuation and exacerbation of symptoms during specific activities or environmental conditions. It is common for symptoms to become worse at night or upon awakening because tear production decreases during sleep. Air conditioning, smoky or windy conditions, and airplane travel may worsen the symptoms by creating excessive drying of the deficient tear film. Activities, such as reading, working at the computer, or watching television, may make the patient more symptomatic, as the blink rate decreases with prolonged visual effort.

  • Sjögren syndrome consists of a triad of dry eyes, dry mouth, and an autoimmune disease. At least 2 of the 3 clinical components need to be present to qualify for diagnosis. For a definitive diagnosis of Sjögren syndrome, all criteria below should be met; however, 3 of the 4 criteria are sufficient for a presumptive diagnosis. The most comprehensive diagnostic criteria include the following:  
    • An abnormally low Schirmer test with clinical evidence of KCS defined by the presence of rose bengal or fluorescein staining
    • Objective evidence of decreased salivary gland flow
    • Evidence of lymphocytic infiltration of the labial salivary glands, proven by a biopsy specimen containing at least 4 glandular lobules with an average of at least 2 foci of 50 or more lymphocytes/4 mm2 of tissue
    • Evidence of a systemic autoimmune process as manifested by the presence of serum autoantibodies, including antinuclear antibody (ANA), rheumatoid factor (RF), or Sjögren syndrome specific antibodies (ie, anti-Ro [SS-A], anti-La [SS-B])
  • Three objective findings are useful in determining the ocular component of Sjögren syndrome, as follows:
    •  Absence of nasal-lacrimal reflex tearing
    • Degree of ocular surface alteration by rose bengal or fluorescein staining
    • Presence of autoantibodies in serum
  • Accelerated tear break-up time may be noted.
  • Nasal stimulation may dramatically increase tearing in patients who do not have Sjögren syndrome.

Causes

  • The etiology of Sjögren syndrome is likely multifactorial. A combination of viral, genetic, neural, and environmental factors is thought to be involved. Viruses, such as Epstein-Barr virus (EBV), hepatitis C virus, enteroviruses, and human T-lymphotropic virus (HTLV), have been implicated as triggers in the development of Sjögren syndrome.
  • Developments in the fields of immunology and molecular biology have contributed significantly to the understanding of the pathogenesis of Sjögren syndrome. One report in 1985 showed human leukocyte antigen DR (HLA-DR) expression in epithelial cells of salivary gland biopsy specimens taken from patients with Sjögren syndrome. The predominant lymphocytic infiltrate consisted of helper T cells. Other studies found that lymphoproliferation in the lacrimal glands consisted predominantly of B and CD4 lymphocytes along with a small percentage of CD8 lymphocytes.
  • The exact etiology for the pathologic changes that occur in Sjögren syndrome has not been determined. EBV may play a role. One study found that parotid saliva samples and salivary gland biopsy specimens from 8 of 20 patients with Sjögren syndrome contained EBV DNA by slot blot hybridization. Another study using polymerase chain reaction (PCR) reported detection of EBV genomic sequences in peripheral blood mononuclear cells, lacrimal glands, and tears of patients with primary Sjögren syndrome.
  • EBV genomes can be detected in 35% of normal lacrimal glands. EBV genotype analysis by PCR revealed that only type I EBV genomes could be detected in 35% of normal lacrimal glands. EBV genotype analysis by PCR revealed that only type II EBV nuclear antigens (EBNA-2-deleted) gene sequences were amplified from normal lacrimal glands. In contrast, type I EBV genomes (but not EBNA-2-deleted EBV sequences) were amplified from lacrimal gland biopsy specimens obtained from patients with Sjögren syndrome. All of this information suggests that persistent EBV infection plays a role in the lacrimal gland pathology of Sjögren syndrome. The genomic search for critical genes is difficult as a result of the multigenic pattern of inheritance and the strong role of undefined environmental factors.
  • Tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory cytokine, has been found to be increased in the glands of patients with Sjögren syndrome. Local inhibition of TNF-alpha has been studied in animal models with promising therapeutic results.
  • Patients with dry eye associated with Sjögren syndrome have been found to have elevated levels of interleukin 6 (IL-6) and TNF-alpha in their tears. The IL-6 level is associated with disease severity and was found to correlate with tear film and ocular surface parameters (eg, tear film break-up time, Schirmer test, tear clearance, goblet cell density, keratoepithelioplasty score) in a study by Yoon et al.1
  • Two types of pathologic changes have been observed in the salivary glands: the benign epithelial lesion occurring primarily in the parotid glands and the focal lymphocytic sialadenitis occurring in other major and minor salivary glands. These benign lymphoepithelial lesions may be associated with or transform into lymphomas.
  • Immunogenetics  
    • In 1977, HLA-DR3 and HLA-Dw3 were reported to be associated with Sjögren syndrome. Another study found that primary Sjögren syndrome had a significantly increased frequency of HLA-B8 and HLA-DR3, whereas patients with secondary Sjögren syndrome had an increased frequency of HLA-DR4.
    • HLA-type is correlated strongly with the production of SS-A (Ro) and SS-B (La) autoantibodies. Both Ro and La positivity is seen most commonly with primary Sjögren syndrome, and these patients usually have HLA-B8 haplotype.
  • Even in patients with Sjögren syndrome with marked sicca, biopsy specimens have revealed that 50% of glandular cells are still present. These results emphasize the importance of immune factors, such as cytokines and autoantibodies, in decreasing neurosecretory circuits and inducing glandular dysfunction. An antibody against muscarinic M3 receptor has been implicated leading to the development of orally administered agonists of the M3 receptor.

More on Sjogren Syndrome

Overview: Sjogren Syndrome
Differential Diagnoses & Workup: Sjogren Syndrome
Treatment & Medication: Sjogren Syndrome
Follow-up: Sjogren Syndrome
References
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References

  1. Yoon KC, Jeong IY, Park YG, Yang SY. Interleukin-6 and tumor necrosis factor-alpha levels in tears of patients with dry eye syndrome. Cornea. May 2007;26(4):431-7. [Medline].

  2. Koufakis DI, Karabatsas CH, Sakkas LI, Alvanou A, Manthos AK, Chatzoulis DZ. Conjunctival surface changes in patients with Sjogren's syndrome: a transmission electron microscopy study. Invest Ophthalmol Vis Sci. Feb 2006;47(2):541-4. [Medline].

  3. Villani E, Galimberti D, Viola F, Mapelli C, Ratiglia R. The cornea in Sjogren's syndrome: an in vivo confocal study. Invest Ophthalmol Vis Sci. May 2007;48(5):2017-22. [Medline].

  4. Spiteri A, Mitra M, Menon G, Casini A, Adams D, Ricketts C, et al. Tear lipid layer thickness and ocular comfort with a novel device in dry eye patients with and without Sjögren's syndrome. J Fr Ophtalmol. Apr 2007;30(4):357-64. [Medline].

  5. Aguilar AJ, Fonseca L, Croxatto JO. Sjogren's syndrome: a comparative study of impression cytology of the conjunctiva and buccal mucosa, and salivary gland biopsy. Cornea. May 1991;10(3):203-6. [Medline].

  6. 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. Dec 2005;46(12):4474-9. [Medline].

  7. Aragona P, Di Pietro R. Is it safe to use topical NSAIDs for corneal sensitivity in Sjögren's syndrome patients?. Expert Opin Drug Saf. Jan 2007;6(1):33-43. [Medline].

  8. Aragona P, Di Pietro R, Spinella R, Mobrici M. Conjunctival epithelium improvement after systemic pilocarpine in patients with Sjogren's syndrome. Br J Ophthalmol. Feb 2006;90(2):166-70. [Medline].

  9. Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ. Sjögren's syndrome. A clinical, pathological, and serological study of sixty-two cases. 1965. Medicine (Baltimore). Nov 1992;71(6):386-401; discussion 401-3. [Medline].

  10. Chused TM, Kassan SS, Opelz G, Moutsopoulos HM, Terasaki PI. Sjögren's syndrome association with HLA-Dw3. N Engl J Med. Apr 21 1977;296(16):895-7. [Medline].

  11. Cordero-Coma M, Anzaar F, Sobrin L, Foster CS. Systemic immunomodulatory therapy in severe dry eye secondary to inflammation. Ocul Immunol Inflamm. Mar-Apr 2007;15(2):99-104. [Medline].

  12. Daniels TE. Benign lymphoepithelial lesion and Sjogren's syndrome. In: Ellis GL, AuClair PL, eds. Surgical Pathology of the Salivary Glands. WB Saunders; 1991.

  13. Drosos AA, Skopouli FN, Costopoulos JS, Papadimitriou CS, Moutsopoulos HM. Cyclosporin A (CyA) in primary Sjögren's syndrome: a double blind study. Ann Rheum Dis. Sep 1986;45(9):732-5. [Medline].

  14. Fox RI. Sjögren's syndrome: current therapies remain inadequate for a common disease. Expert Opin Investig Drugs. Sep 2000;9(9):2007-16. [Medline].

  15. Fox RI, Konttinen Y, Fisher A. Use of muscarinic agonists in the treatment of Sjögren's syndrome. Clin Immunol. Dec 2001;101(3):249-63. [Medline].

  16. Fox RI, Pearson G, Vaughan JH. Detection of Epstein-Barr virus-associated antigens and DNA in salivary gland biopsies from patients with Sjogren's syndrome. J Immunol. Nov 15 1986;137(10):3162-8. [Medline].

  17. Fox RI, Robinson CA, Curd JG, Kozin F, Howell FV. Sjögren's syndrome. Proposed criteria for classification. Arthritis Rheum. May 1986;29(5):577-85. [Medline].

  18. Gottenberg JE, Cagnard N, Lucchesi C, Letourneur F, Mistou S, Lazure T, et al. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren's syndrome. Proc Natl Acad Sci U S A. Feb 21 2006;103(8):2770-5. [Medline].

  19. Jonsson R, Moen K, Vestrheim D, Szodoray P. Current issues in Sjögren's syndrome. Oral Dis. May 2002;8(3):130-40. [Medline].

  20. Lindahl G, Hedfors E, Klareskog L, Forsum U. Epithelial HLA-DR expression and T lymphocyte subsets in salivary glands in Sjögren's syndrome. Clin Exp Immunol. Sep 1985;61(3):475-82. [Medline].

  21. Lodde BM, Baum BJ, Tak PP, Illei G. Experience with experimental biological treatment and local gene therapy in Sjogren's syndrome: implications for exocrine pathogenesis and treatment. Ann Rheum Dis. Nov 2006;65(11):1406-13. [Medline].

  22. Manthrope R, Frost-Larsen K. Sjogren's syndrome: a review with emphasis on immunological features. Allergy. 1981;36:139-153.

  23. Mavragani CP, Moutsopoulos NM, Moutsopoulos HM. The management of Sjögren's syndrome. Nat Clin Pract Rheumatol. May 2006;2(5):252-61. [Medline].

  24. Miyasaka N, Seaman W, Bakshi A, Sauvezie B, Strand V, Pope R, et al. Natural killing activity in Sjögren's syndrome. An analysis of defective mechanisms. Arthritis Rheum. Aug 1983;26(8):954-60. [Medline].

  25. Mizuno Y, Hara T, Hatae K, Hirano T, Ueda K, Nakamura N, et al. Recurrent parotid gland enlargement as an initial manifestation of Sjögren syndrome in children. Eur J Pediatr. Feb 1989;148(5):414-6. [Medline].

  26. Moutsopoulos HM, Chused TM, Mann DL, Klippel JH, Fauci AS, Frank MM, et al. Sjögren's syndrome (Sicca syndrome): current issues. Ann Intern Med. Feb 1980;92(2 Pt 1):212-26. [Medline].

  27. Murillo-Lopez F, Pflugfelder SC. Disorders of tear production and the lacrimal system. In: Krachmer JH, ed. Cornea. Mosby Year Book; 1997:663-686.

  28. Pepose JS, Akata RF, Pflugfelder SC, Voigt W. Mononuclear cell phenotypes and immunoglobulin gene rearrangements in lacrimal gland biopsies from patients with Sjögren's syndrome. Ophthalmology. Dec 1990;97(12):1599-605. [Medline].

  29. Pflugfelder SC. Lacrimal gland epithelial and immunopathology of Sjogren's syndrome. In: Homma M, ed. Proceedings of the IV International Sjogren's Syndrome Symposium, Kugler. Am Steleveen; 1994.

  30. Pflugfelder SC, Crouse C, Pereira I, Atherton S. Amplification of Epstein-Barr virus genomic sequences in blood cells, lacrimal glands, and tears from primary Sjögren's syndrome patients. Ophthalmology. Aug 1990;97(8):976-84. [Medline].

  31. Pflugfelder SC, Crouse CA, Monroy D, Yen M, Rowe M, Atherton SS. Epstein-Barr virus and the lacrimal gland pathology of Sjögren's syndrome. Am J Pathol. Jul 1993;143(1):49-64. [Medline].

  32. Pflugfelder SC, Huang AJ, Feuer W, Chuchovski PT, Pereira IC, Tseng SC. Conjunctival cytologic features of primary Sjögren's syndrome. Ophthalmology. Aug 1990;97(8):985-91. [Medline].

  33. Pflugfelder SC, Whitcher JP, Daniels T. Sjogren's syndrome. In: Pepose J, Holland G, Wilhelmin K. Ocular Infection and Immunity. Mosby: St. Louis.

  34. Prause JU, Frost-Larsen K, Hoj L, Isager H, Manthorpe R. Lacrimal and salivary secretion in Sjögren's syndrome: the effect of systemic treatment with bromhexine. Acta Ophthalmol (Copenh). Jun 1984;62(3):489-97. [Medline].

  35. Ramos-Casals M, Tzioufas AG, Font J. Primary Sjogren's syndrome: new clinical and therapeutic concepts. Ann Rheum Dis. Mar 2005;64(3):347-54. [Medline].

  36. Shearn MA. Sjogren's Syndrome. Major Problems in Internal Medicine. Vol 2. WB Saunders; 1971.

  37. Sjogren HS. Zur kenntnis der keratoconjunctivitis sicca (kratitis folliforms bei hypojunktion der tramemdrusen). Acta Ophthalmol (Copen). 1933;11:1-151.

  38. Tabbara KF. Clinical diseases of tear film. In: Smolin G, Thoft R, eds. Cornea: Scientific Foundations and Clinical Practice. 2nd ed. Little Brown and Co: 1987:477-483.

  39. Tabbara KF, Ostler HB, Daniels TE, Sylvester RA, Greenspan JS, Talal N. sjögren's syndrome: a correlation between ocular findings and labial salivary gland histology. Trans Am Acad Ophthalmol Otolaryngol. May-Jun 1974;78(3):OP467-78. [Medline].

  40. Tsubota K. The importance of the Schirmer test with nasal stimulation. Am J Ophthalmol. Jan 15 1991;111(1):106-8. [Medline].

  41. Zoukhri D. Effect of inflammation on lacrimal gland function. Exp Eye Res. May 2006;82(5):885-98. [Medline].

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Further Reading

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Keywords

SS, keratoconjunctivitis sicca, KCS, xerostomia, dry mouth, dry eyes, autoimmune disorder, rheumatoid arthritis, systemic lupus erythematosus

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Contributor Information and Disclosures

Author

James V Aquavella, MD, Professor of Ophthalmology, Department of Ophthalmology, University of Rochester School of Medicine, University of Rochester Eye Institute
James V Aquavella, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, American Medical Association, Contact Lens Association of Ophthalmologists, and International College of Surgeons
Disclosure: Nothing to disclose.

Coauthor(s)

Zoe R Williams, MD, Staff Physician, Department of Ophthalmology, University of Rochester School of Medicine, Strong Memorial Hospital
Zoe R Williams, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Ophthalmology
Disclosure: Nothing to disclose.

Shobha Boghani, MD, Assistant Professor, Department of Ophthalmology, Strong Memorial Hospital, University of Rochester
Shobha Boghani, MD is a member of the following medical societies: American Academy of Ophthalmology and Contact Lens Association of Ophthalmologists
Disclosure: Nothing to disclose.

Medical Editor

Fernando H Murillo-Lopez, MD, Senior Surgeon, Unidad Privada de Oftalmologia CEMES
Fernando H Murillo-Lopez, MD is a member of the following medical societies: American Academy of Ophthalmology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Jefferson Medical College; Co-Chairman of the Cornea Service, Co-Chairman of Refractive Surgery Department, Wills Eye Hospital
Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, Eye Bank Association of America, Pennsylvania Medical Society, and Philadelphia County Medical Society
Disclosure: Nothing to disclose.

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

 
 
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