Sjögren Syndrome: Clinical Manifestations, Diagnosis, and Management

Sjögren syndrome (SS) is a systemic autoimmune disease characterized mainly by the presence of keratoconjunctivitis sicca and xerostomia. Patients also may experience inflammation of the joints, muscles, nerves, lungs, gastrointestinal tract, thyroid, lymph nodes, or any other organ of the body, as well as fatigue, disturbed sleep, and memory problems.

The etiology and pathophysiology of SS are not well understood, and diagnosis presents a challenge. Although there is no cure, management includes pharmacologic and nonpharmacologic interventions with the goal of improving quality of life by treating the sicca and fatigue symptoms.

SS can occur as a solitary condition (primary or sicca syndrome) in the absence of other autoimmune diseases. In contrast, secondary SS develops alongside or as a consequence of other autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and scleroderma. The etiology and pathophysiology of SS are complex and are not well understood.

Numerous genetic, environmental, and hormonal factors have been postulated to establish the condition. SS is the second most prevalent chronic rheumatic autoimmune disease (after RA). The mean age of onset is in the 4th or 5th decade, with a prevalence of approximately 0.5% in the general population. It is estimated that 0.4 million to 3.1 million individuals are affected in the United States alone, with a female to male ratio of 9 to 1. However, males present with a more severe form of the disease.

SS has distressing physical, emotional, and financial impacts on patients.

In 2017, a survey conducted to measure these effects concluded that more than half of patients (53%) with severe dryness also experienced fatigue. The survey revealed that SS adds significant burdens to patients’ lives, relationships with friends, families, and sexual partners. Moreover, 28% of patients had to stop work, reduce their working hours, or take a lighter job due to their disease.

The exact cause of SS is still obscure, but it involves (as do all autoimmune diseases) several interacting factors rather than a single individual factor. The key features of the pathogenesis  of SS include lymphocytic infiltration of the exocrine glands (predominantly the lacrimal and salivary glands), the release of inflammatory mediators and cytokines, and the production of autoantibodies.

The clinical manifestations of the disease can be divided into glandular and extraglandular features. A retrospective study of 80 patients with primary SS followed for a median of 7.5 years reported that all patients experienced dry eyes and dry mouth, and this was the only manifestation in 31% of the patients. Extraglandular involvement occurred in 25% of the patients included in the study. Moreover, 2.5% developed non-Hodgkin lymphoma (NHL).

Glandular manifestations include dry mouth, dry eyes, salivary and lacrimal gland enlargement (which occurs in approximately 50% of patients during the course of the disease, and vaginal dryness and associated dyspareunia. Patients with keratoconjunctivitis sicca report a sensation of foreign body and burning in the eyes. Xerostomia results in difficulty swallowing and talking. The patient’s oral health is significantly affected; they are 10 times prone to dental caries and recurrent oral Candida albicans infection compared with the general population.

Approximately 5% to 10% of all primary SS patients would eventually develop NHL of B-cell lineage, arising from mucosal associated lymphoid tissue, lymph nodes, and exocrine glands, particularly the parotid gland. Based on 2 series, the transition to lymphoma occurred 6.5 to 7.5 years after the diagnosis of SS. It is essential to rule out malignant NHL when a SS patient presents with a swollen salivary gland. Multiple extraglandular organs may be affected in patients with SS, including the skin, joints, blood vessels, lungs, kidneys, gynecologic system, and nervous system.

Patients with SS also experience fatigue and sleep disorders, which are attributed to the disruption caused by xerostomia stimulating polydipsia with resultant polyuria. Depression is highly prevalent among SS patients, occurring 5 times more often compared with healthy control patients as indicated in a large meta-analysis. A cohort study evaluating the cognitive aspects of SS patients also concluded that 33% to 49% have depression. Fibromyalgia is present in 22% to 33% of patients with primary SS.

Diagnosing SS is somewhat complicated, since patients manifest a wide range of symptoms that are similar to those of many other diseases. Patients are often seen by different specialists for their symptoms, and this makes the diagnosis challenging. There is no single diagnostic test for SS. The diagnosis is made in the presence of compatible clinical and laboratory findings after the exclusion of all the other possible diagnoses. Available SS diagnostic criteria such as those issued by the American-European Consensus Group and of the American College of Rheumatology were not designed to be used in routine clinical practice; instead, they are mainly for scientific communication and research purposes. Nevertheless, these criteria can be helpful in making the clinical diagnosis if they are used appropriately.

The diagnostic evaluation starts with a thorough history and physical examination of patients with suspected cases, including those with persistent dry eyes and/or dry mouth on a daily basis for 3 or more months,¹¹ parotid gland enlargement, and recurrent dental caries. The history and physical examination should be focused on the features of SS and other rheumatic and connective tissue diseases. In addition, basic initially laboratory tests should be obtained, including a complete blood cell count with differential, which might reveal anemia, leukopenia, and thrombocytopenia; an erythrocyte sedimentation rate; a comprehensive metabolic panel; assessment of globulin level, looking for hyperglobulinemia; and urinalysis to check for hematuria and proteinuria.¹⁸ All patients should be evaluated for systemic autoimmunity.

Many patients do not require further tests beyond basic blood investigations and an ocular examination. If ophthalmic examination does not reveal sufficient information to make the diagnosis of SS, or if the salivary gland symptoms predominate, the patient should undergo evaluation of salivary gland function, including sialometry and imaging studies for structural abnormalities. The most commonly used imaging modalities are magnetic resonance imaging and ultrasonography (US).

Five large studies done between 2013 and 2015 showed that US has a sensitivity from 55% to 66% and a specificity from 93% to 98%, which make it a promising tool for evaluating glandular parenchymal abnormalities. All patients should be evaluated for systemic autoimmunity. Results of tests for anti-SSA/Ro antibodies, anti-SSB/La antibodies, antinuclear antibodies, and rheumatoid factor all support the diagnosis of SS. Approximately 60% to 80% of persons with SS have anti-SSA/Ro antibodies, anti-SSB/La antibodies, or both.

Anti-SSB/La antibody is by far more specific, and it is found in persons with SS and SLE. Weak positive results should be interpreted with caution, since 10% and 12.5% of the general population will test positive for anti-SSA/Ro and anti-SSB/La antibodies, respectively. Anticentromere antibodies can be positive in up to 5% of SS patients, particularly in those with features of systemic sclerosis such as Raynaud phenomenon. Anticyclic citrullinated peptide antibodies, which are very specific for RA, can also be found in persons with SS, especially those with predominantly articular involvement. However, more specific tests are guided by the signs and symptoms of other rheumatic diseases.

Clinicians should keep in mind that many causes contribute to sicca symptoms in elderly individuals, such as age-related sicca syndrome, sarcoidosis, hepatitis C, HIV infection, systemic vasculitis, and malignancy. These conditions should be assessed for in the diagnostic workup in patients presenting with classic dry eyes and dry mouth.

Minor salivary gland biopsy is conducted only when no evidence exists of concomitant autoimmune disease or relevant antibodies, weakly positive anti-SSA/Ro and anti-SSB/La antibodies, or when only anti-SSB/La antibody is positive in the absence of anti-SSA/Ro antibody. Labial biopsy also reveals structural abnormalities seen in other conditions. Moreover, it provides information regarding disease prognosis, since a higher grade of lymphoid infiltration and the presence of germinal centers predicts a greater risk of development of NHL.

Patients with SS respond best to treatment provided by a multidisciplinary team, including family physicians, dentists, rheumatologists, ophthalmologists, otorhinolaryngologists, psychiatrists, and other specialists depending on patients’ symptoms. Treatment should be individualized based on disease activity, extraglandular organ involvement, and the presence of underlying or associated autoimmune diseases.

Managing this chronic condition requires using evidence-based pharmacologic and nonpharmacologic interventions, often in combination. Although there is no cure for primary SS, the primary goal of treatment is to improve patients’ quality of life by treating the sicca and fatigue symptoms. Patients must be educated about their disease and the importance of adherence to their treatment regimen and behavioral modifications.

Due to the promising advances in the management of SS, the overall survival of patients does not differ from that of the general population. Symptomatic treatment is usually sufficient and appropriate for sicca symptoms, whereas systemic medications, including disease-modifying therapies, are reserved for systemic extraglandular disease.

Nonpharmacologic interventions include patient education; environmental modification such as air humidification; elimination of the use of anticholinergic drugs; increased water intake; tobacco cessation; and the use of fluoride-containing toothpaste to prevent dental caries. Studies have shown that avoiding factors that provoke fatigue, establishing sleep hygiene, and aerobic endurance training are effective in fighting fatigue. A systematic review of 9 studies that evaluated nonpharmacologic techniques to alleviate dry mouth symptoms included 366 patients with dry mouth of various causes including SS.

Nonpharmacologic interventions included acupuncture, electrostimulation devices, and power toothbrushes. The studies were of poor quality, and all failed to find a statistically significant benefit of improvement in dry mouth symptoms.

Maryam Jadeed, MD, is a family practice resident at Salmaniya Medical Complex in Manama, Bahrain. Samer Nuhaily, MD, is a consultant rheumatologist and medical director at American Medical Center in Manama, Bahrain.  

REFERENCES:
1. Maryam Jadeed, MD, and Samer Nuhaily, MD Citation: Jadeed M, Nuhaily S. Sjögren syndrome: clinical manifestations, diagnosis, and management. Consultant. 2018;58(9):229-241.  

2. Vivino FB. Sjogren’s syndrome: clinical aspects. Clin Immunol. 2017;182:48-54. Fox RI, Michelson PE, Frosio D. Sjögren’s syndrome: a guide for the patient. https://www.dry.org/fox20020816/guide.htm. Revised August 16, 2002. Accessed August 29, 2018. Living with Sjogren’s: summary of major findings. Sjogren’s Syndrome Foundation. 2017. https://www.sjogrens.org/files/articles/SSFLivingwithSjogrens.pdf. Accessed August 29, 2018.

3. Nair JJ, Singh TP. Sjogren’s syndrome: review of the aetiology, pathophysiology & potential therapeutic interventions. J Clin Exp Dent. 2017;9(4):e584-​e589. Bolstad AI, Skarstein K. Epidemiology of Sjögren’s syndrome—from an oral perspective. Curr Oral Health Rep. 2016;3(4):328-336.

4. Nezos A, Mavragani CP. Contribution of genetic factors to Sjögren’s syndrome and Sjögren’s syndrome related lymphomagenesis. J Immunol Res. 2015;2015:754825.

5. Weller ML, Gardener MR, Bogus ZC, et al. Hepatitis delta virus detected in salivary glands of Sjögren’s syndrome patients and recapitulates a Sjögren’s syndrome-like phenotype in vivo. Pathog Immun. 2016;1(1):12-40.

6. Gomes PdS, Juodzbalys G, Fernandes MH, Guobis Z. Advances in the aetiophatogenesis of Sjögren’s syndrome: a literature review. J Oral Maxillofac Res. 2012;3(1):e2. Ramírez Sepúlveda JI, Kvarnström M, Brauner S, Baldini C, Wahren-Herlenius M. Difference in clinical presentation between women and men in incident primary Sjögren’s syndrome. Biol Sex Differ. 2017;8:16. Baer AN. Clinical manifestations of Sjögren’s syndrome: exocrine gland disease. UpToDate. https://www.uptodate.com/contents/clinical-manifestations-of-sjogrens-syndrome-exocrine-gland-disease. Updated November 13, 2017. Accessed August 29, 2018.

7. Stefanski A-L, Tomiak C, Pleyer U, Dietrich T, Burmester GR, Dörner T. The diagnosis and treatment of Sjögren’s syndrome. Dtsch Arztebl Int. 2017;​114(20):354-361. Nocturne G, Mariette X. Sjögren syndrome-associated lymphomas: an update on pathogenesis and management. Br J Haematol. 2015;168(3):317-327.

8. Voulgarelis M, Dafni UG, Isenberg DA, Moutsopoulos HM. Malignant lymphoma in primary Sjögren’s syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjögren’s Syndrome. Arthritis Rheum. 1999;42(8):1765-1772.

9. Gudbjörnsson B, Broman JE, Hetta J, Hällgren R. Sleep disturbances in patients with primary Sjögren’s syndrome. Br J Rheumatol. 1993;32(12):1072-1076. Cui Y, Li L, Yin R, et al. Depression in primary Sjögren’s syndrome: a systematic review and meta-analysis. Psychol Health Med. 2018;23(2):198-209.

10. Segal BM, Pogatchnik B, Holker E, et al. Primary Sjogren’s syndrome: cognitive symptoms, mood and cognitive performance. Acta Neurol Scand. 2012;​125(4):272-278. Cornec D, Saraux A, Jousse-Joulin S, et al. The differential diagnosis of dry eyes, dry mouth, and parotidomegaly: a comprehensive review. Clin Rev Allergy Immunol. 2015;49(3):278-287. Baer AN. Diagnosis and classification of Sjögren’s syndrome. UpToDate. https://www.uptodate.com/contents/diagnosis-and-classification-of-​sjogrens-syndrome. Updated May 24, 2018. Accessed August 29, 2018.

11. Baldini C, Luciano N, Tarantini G, et al. Salivary gland ultrasonography: a highly specific tool for the early diagnosis of primary Sjögren’s syndrome. Arthritis Res Ther. 2015;17:146.

12. Cornec D, Jousse-Joulin S, Pers JO, et al. Contribution of salivary gland ultrasonography to the diagnosis of Sjögren’s syndrome: toward new diagnostic criteria? Arthritis Rheum. 2013;65(1):216-225.

13. Harley JB, Sestak AL, Willis LG, Fu SM, Hansen JA, Reichlin M. A model for disease heterogeneity in systemic lupus erythematosus: relationships between histocompatibility antigens, autoantibodies, and lymphopenia or renal disease. Arthritis Rheum. 1989;32(7):826-836.

14. Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, Bosch X, Tzioufas AG. Topical and systemic medications for the treatment of primary Sjögren’s syndrome. Nat Rev Rheumatol. 2012;8(7):399-411.

15. Maciel G, Crowson CS, Matteson EL, Cornec D. Incidence and mortality of physician-diagnosed primary Sjögren syndrome: time trends over a 40-year period in a population-based US cohort. Mayo Clin Proc. 2017;92(5):734-743.

16. Aragona P, Di Stefano G, Ferreri R, 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. 2002;86(8):879-884.

17. Condon PI, McEwen CG, Wright M, Mackintosh G, Prescott RJ, McDonald C. 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. 1999;83(10):1121-1124.

18. Robert P-Y, Cochener B, Amrane M, et al. Efficacy and safety of a cationic emulsion in the treatment of moderate to severe dry eye disease: a randomized controlled study. Eur J Ophthalmol. 2016;26(6):145-173.

19. Baudouin C, Figueiredo FC, Messmer EM, et al. A randomized study of the efficacy and safety of 0.1% cyclosporine A cationic emulsion in treatment of moderate to severe dry eye. Eur J Ophthalmol. 2017;27(5):520-530.

20. Sall K, Stevenson OD, Mundorf TK, Reis BL; CsA Phase 3 Study Group. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology. 2000;107(4):631-639.

21. Alpöz E, Güneri P, Önder G, Çankaya H, Kabasakal Y, Köse T. The efficacy of Xialine® in patients with Sjögren’s syndrome: a single-blind, cross-over study. Clin Oral Investig. 2008;12(2):165-172.

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

23. Albrecht K, Callhoff J, Westhoff G, Dietrich T, Dörner D, Zink A. The prevalence of dental implants and related factors in patients with Sjögren syndrome: results from a cohort study. J Rheumatol. 2016;43(7):1380-1385.

24. Vivino FB, Al-Hashimi I, Khan Z, et al; P92-01 Study Group. 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. Arch Intern Med. 1999;159(2):174-181.

25. Wang S-Q, Zhang L-W, Wei P, Hua H. Is hydroxychloroquine effective in treating primary Sjogren’s syndrome: a systematic review and meta-analysis. BMC Musculoskelet Disord. 2017;18(1):186.

26. Forsblad-d’Elia H, Carlsten H, Labrie F, Konttinen YT, 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. 2009;94(6):2044-2051.