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Synonyms: Gougerot's syndrome, sicca complex
There is lymphocytic infiltration of exocrine glands, producing the main symptoms of xerophthalmia (dry eyes), xerostomia (dry mouth) and enlargement of the parotid glands.
The disease is called primary if it develops in isolation and secondary if it occurs with other autoimmune diseases - usually rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or scleroderma. Current thinking has identified a host of factors (eg, immunological, genetic, hormonal and inflammatory) that may be involved in causing the primary syndrome. One theory is that inflammation or dysfunction of the exocrine glands sets up an autoimmune reaction.
Several studies of the epidemiology of Sjögren's syndrome report a prevalence between 0.4 and 0.8%. Prevalence rises with age but age of onset is usually in the 30s or 40s. Rarely, it can occur in childhood. There is a preponderance of women. The female to male ratio is 9:1.
There are as yet no chromosomal regions identified by linkage studies (eg, twin studies) which yield definitive proof of a genetic component but circumstantial evidence is heavily in favour of a genetic aetiology. There is a genetic predisposition for the disease but the HLA association varies among ethnic groups.
Development of complications such as neuropathy and lymphoma may be more likely in patients with vitamin D deficiency.
The most common presenting features are dry eyes and dry mouth. However, these are common complaints and may affect as many as a third of elderly people. Hence, whilst dry eyes and dry mouth are common features of Sjögren's syndrome, most people who present with such symptoms do not have the disease. As well as fibrosis and atrophy of glands predisposing to sicca syndrome in the elderly, they may also be taking drugs with antihistamine or anticholinergic effects. Dry mouth may present with a number of related complaints:
- Difficulty eating dry food, typically cracker biscuits.
- Habit of having a glass of water by the bed at night.
- Altered sense of taste.
- Difficulty with dentures.
- Complaint of the tongue sticking to the roof of the mouth.
- Speaking for long periods of time causes hoarseness.
- Dental and periodontal problems.
- Oral candidiasis and angular cheilitis.
Dry eyes tend to cause a gritty sensation. There is a predisposition to blepharitis and the eyes may be sticky in the morning.
There are a number of other features that can occur with the disease:
- There may be recurrent parotitis, usually bilateral. Glands are usually enlarged but this is not often the presenting feature.
- Dryness of the mucosa of the trachea and bronchi may present as a dry cough.
- Dryness of the pharynx and oesophagus may cause difficulty in swallowing, and lack of saliva and secretions may predispose to gastro-oesophageal reflux.
- There can be dry skin and vaginal dryness causing dyspareunia.
- Disease of the pancreas can lead to malabsorption and even acute pancreatitis or chronic pancreatitis but a more likely cause of elevated serum amylase is parotitis.
- Fatigue is a common feature.
- About 20% have Raynaud's phenomenon.
- Rare features include polyneuropathy that may be a sensory peripheral neuropathy, cranial neuropathy, usually of the facial or trigeminal nerves, or vasculitis which can produce a mononeuritis multiplex.
- Look at the eyes. There may be dilatation of the conjunctival vessels. Look for corneal lesions and gently pull down the lower eyelid to assess the tear pool. There may be blepharitis.
- The mouth may look dry and a wooden tongue depressor may stick to the tongue. There may be evidence of infection including oral candidiasis and dental caries.
- Submandibular glands may be enlarged but more obvious is bilateral enlargement of the parotid glands. A unilateral and hard salivary gland tumour should prompt immediate referral. Other salivary gland disorders may need to be considered.
- There may be features of other autoimmune disorders such as RA, SLE, scleroderma and even primary biliary cirrhosis or chronic hepatitis.
There may be a number of associated autoimmune conditions, such as the variant of scleroderma: calcinosis, Raynaud's phenomenon, (o)esophageal motility disorder, sclerodactyly and telangiectasia (CREST). There may be joint pain, swelling and fatigue or recurrent miscarriage with antiphospholipid syndrome.
- Amyloidosis, immunoglobulin-related
- Chronic pancreatitis
- Graft-versus-host disease
- Rheumatoid arthritis
- Salivary gland tumours
- Non-Sjögren's sicca syndrome
- FBC is usually normal, although anaemia of chronic disease may be a feature. Abnormal white cell count may suggest a lymphoma. ESR may be raised but is nonspecific.
- Rheumatoid factor is more often positive in Sjögren's syndrome than it is in rheumatoid disease.
- Antinuclear antibodies are often positive, even without SLE, and there may be positive antiphospholipid antibodies.
- Antibodies against alpha-fodrin and Ro/La autoantigens (antigens related to cell membranes) may be raised in non-Sjögren's sicca syndrome.
- In the Schirmer test, a bent piece of filter paper is placed into the lower conjunctiva and left there for five minutes. In normal people the paper will be wet to 15 mm or beyond after five minutes, whereas a definitive positive result is less than 5 mm after five minutes. This test can be useful to help exclude or confirm significant dryness of the eyes but it is not specific for the disease.
- Imaging of the salivary glands - one study found that salivary gland ultrasound performed well compared with more invasive diagnostic procedures. For more complex cases, sialography or salivary scintigraphy may assist in diagnosis. Scintigraphy may be helpful in identifying non-Sjögren's sicca syndrome. Dynamic magnetic resonance sialography is a new technique which is proving helpful.
- In cases of uncertainty, biopsy of a salivary gland may be required. Usually one of the minor glands from the inner lip is preferred to a parotid. Histology will reveal gland infiltration.
- Creatinine clearance may reduce in up to 50% of patients.
- CT scan may be contributory if it is suspected that lymphoma is developing. MRI scan of the salivary glands may help to identify changes associated with chronic sialadenitis.
The diagnosis of Sjögren's syndrome is based on the Copenhagen criteria and, more recently, American-European consensus criteria. This is a combination of clinical features and investigations. The condition may be suspected when persistent dry mouth or dry eye syndrome develops. Autoimmune screening tests may then reveal a positive rheumatoid factor and/or antinuclear antibodies and the patient is then appropriately referred to a rheumatologist. When presentation is with glandular swelling (commonly parotid glands), referral to a head and neck specialist for consideration of biopsy is appropriate.
There is no specific treatment for the disease but symptoms can be contained. The Systemic Clinical Activity Index (SCAI) has been developed to assess systemic involvement in primary Sjögren's syndrome. Factors analysed to develop the index included fatigue, musculoskeletal involvement and Raynaud's syndrome.
Anticholinergic drugs should be avoided.
Artificial tears should be applied liberally. There are various types and some of the more viscous ones need less frequent application. Patients may try several and see which ones they prefer. If application at intervals of less than four hours is required then preservative-free preparations are preferred to reduce irritation. Overnight a more viscous preparation such as Lacri-Lube® may be helpful. Oral pilocarpine has been used with some success for ocular as well as oral symptoms. Humidifiers may be helpful. Severe dryness may require special glasses to improve the humidification of the eyes or temporary or permanent blockage of the puncta (thus preventing tear drainage) by electrocautery or other means.
Patients should be encouraged to drink plenty to keep the mouth moist. Artificial saliva is available and pilocarpine tablets are licensed for those who have some residual salivary function left. The dose is 5 mg tablets to be taken four times daily, before each meal and at night. Saliva contains IgA and other anti-infective agents and so attention to dental hygiene is required and periodic use of antiseptic mouthwash may be beneficial. Topical fluoride and avoidance of sugars are recommended. A possible role for immunosuppressant agents (eg, cyclophosphamide) in the relief of ocular and oral symptoms has been identified. Trials involving anti-tumour necrosis factor (TNF) alpha inhibitors have been disappointing but those involving the use of B-cell depleting agents (eg, rituximab) have been more encouraging.
Vaginal lubricants may be required and infections such as vaginal candidiasis are more likely. Dry skin may benefit from emollients. Hydroxychloroquine may be useful in suppressing arthralgia and skin symptoms.
- Associated autoimmune diseases may become manifest and need management.
- 40% to 50% of patients develop extraglandular disease, which may be manifested either by epithelial lymphocytic invasion of the lung, liver, or kidney (resulting in interstitial nephritis) or by skin vasculitis, peripheral neuropathy, glomerulonephritis and low C4 levels - conditions which represent an immune complex-mediated disease.
- Infections of the eyes and mouth are more likely. The parotid gland may be infected with Staphylococcus spp., Streptococcus spp. or pneumococcus.
- Watch out for parotid tumours in a hard, unilateral gland.
- Some, but not all, studies have found an increase in the risk of developing non-Hodgkin's lymphoma, usually around seven or eight years after diagnosis.
Prognosis is generally good unless the condition is part of an associated disorder. There is, however, considerable morbidity. Patients with a low C4 count have a high risk for development of non-Hodgkin's lymphoma and have a worse prognosis with higher mortality rates.
Henrik Samuel Conrad Sjögren (1899-1976) was a Swedish ophthalmologist. He graduated in medicine from the Karolinska Institutet in 1922. He married the daughter of a prominent ophthalmologist from Stockholm and became interested in the subject. He described his syndrome in 1933 in his doctoral thesis 'Zur Kenntnis der Keratoconjunctivitis sicca' but it was not of a sufficient standard for him to be awarded the title of 'docent' and this denied him a career in academic ophthalmology. The paper was translated into English in 1943 and the eponym became part of the English language. In France the term Gougerot's syndrome was used, as in 1925 he had described three cases of atrophy of the salivary glands with dry eyes, dry mouth and dry vagina. Sjögren's work was later but much more thorough and this has earned him the eponym.
Further reading & references
- Nikolov NP, Illei GG; Pathogenesis of Sjogren's syndrome. Curr Opin Rheumatol. 2009 Sep;21(5):465-70.
- Westhoff G, Zink A; [Epidemiology of primary Sjorgren's syndrome]. Z Rheumatol. 2010 Feb;69(1):41-9. doi: 10.1007/s00393-009-0518-3.
- Anaya JM, Delgado-Vega AM, Castiblanco J; Genetic basis of Sjogren's syndrome. How strong is the evidence? Clin Dev Immunol. 2006 Jun-Dec;13(2-4):209-22.
- Agmon-Levin N, Kivity S, Tzioufas AG, et al; Low levels of vitamin-D are associated with neuropathy and lymphoma among patients with Sjogren's syndrome. J Autoimmun. 2012 Sep;39(3):234-9. doi: 10.1016/j.jaut.2012.05.018. Epub 2012 Jul 24.
- Ramos-Casals M, Brito-Zeron P, Siso-Almirall A, et al; Primary Sjogren syndrome. BMJ. 2012 Jun 14;344:e3821. doi: 10.1136/bmj.e3821.
- Hatron PY, Tillie-Leblond I, Launay D, et al; Pulmonary manifestations of Sjogren's syndrome. Presse Med. 2011 Jan;40(1 Pt 2):e49-64. doi: 10.1016/j.lpm.2010.11.002. Epub 2010 Dec 30.
- Ebert EC; Gastrointestinal and hepatic manifestations of Sjogren syndrome. J Clin Gastroenterol. 2012 Jan;46(1):25-30. doi: 10.1097/MCG.0b013e3182329d9c.
- Soy M, Piskin S; Cutaneous findings in patients with primary Sjogren's syndrome. Clin Rheumatol. 2007 Aug;26(8):1350-2. Epub 2006 Aug 17.
- Segal B, Thomas W, Rogers T, et al; Prevalence, severity, and predictors of fatigue in subjects with primary Arthritis Rheum. 2008 Dec 15;59(12):1780-7.
- Mori K, Iijima M, Koike H, et al; The wide spectrum of clinical manifestations in Sjogren's syndrome-associated neuropathy. Brain. 2005 Nov;128(Pt 11):2518-34. Epub 2005 Jul 27.
- Chen KS, Jiang MC, Li CJ, et al; Discrimination between Sjogren's and non-Sjogren's sicca syndrome by J Int Med Res. 2009 Jul-Aug;37(4):1088-96.
- Garcia-Carrasco M, Mendoza-Pinto C, Jimenez-Hernandez C, et al; Serologic features of primary Sjogren's syndrome: clinical and prognostic correlation. Int J Clin Rheumtol. 2012 Dec;7(6):651-659.
- Milic VD, Petrovic RR, Boricic IV, et al; Diagnostic value of salivary gland ultrasonographic scoring system in primary J Rheumatol. 2009 Jul;36(7):1495-500. Epub 2009 Jun 1.
- Morimoto Y, Habu M, Tomoyose T, et al; Dynamic magnetic resonance sialography as a new diagnostic technique for patients with Sjogren's syndrome. Oral Dis. 2006 Jul;12(4):408-14.
- Locht H, Pelck R, Manthorpe R; Clinical manifestations correlated to the prevalence of autoantibodies in a large (n=321) cohort of patients with primary Sjogren's syndrome: a comparison of patients initially diagnosed according to the Copenhagen classification criteria with the American-European consensus criteria. Autoimmun Rev. 2005 Jun;4(5):276-81. Epub 2005 Jan 6.
- Manthorpe R; Sjogren's syndrome criteria. Ann Rheum Dis. 2002 Jun;61(6):482-4.
- Brito-Zeron P, Siso-Almirall A, Bove A, et al; Primary Sjogren syndrome: an update on current pharmacotherapy options and future directions. Expert Opin Pharmacother. 2013 Feb;14(3):279-89. doi: 10.1517/14656566.2013.767333. Epub 2013 Jan 25.
- Ramos-Casals M, Tzioufas AG, Stone JH, et al; Treatment of primary Sjogren syndrome: a systematic review. JAMA. 2010 Jul 28;304(4):452-60. doi: 10.1001/jama.2010.1014.
- Bowman SJ, Sutcliffe N, Isenberg DA, et al; Sjogren's Systemic Clinical Activity Index (SCAI)--a systemic disease activity measure for use in clinical trials in primary Sjogren's syndrome. Rheumatology (Oxford). 2007 Dec;46(12):1845-51.
- Aragona P, Di Pietro R, Spinella R, et al; Conjunctival epithelium improvement after systemic pilocarpine in patients with Sjogren's syndrome. Br J Ophthalmol. 2006 Feb;90(2):166-70.
- Egrilmez S, Aslan F, Karabulut G, et al; Clinical efficacy of the SmartPlug in the treatment of primary Sjogren's syndrome with keratoconjunctivitis sicca: one-year follow-up study. Rheumatol Int. 2011 Dec;31(12):1567-70. doi: 10.1007/s00296-010-1527-x. Epub 2010 May 21.
- Papas AS, Sherrer YS, Charney M, et al; Successful Treatment of Dry Mouth and Dry Eye Symptoms in Sjogren's Syndrome Patients With Oral Pilocarpine: A Randomized, Placebo-Controlled, Dose-Adjustment Study. J Clin Rheumatol. 2004 Aug;10(4):169-177.
- Thanou-Stavraki A, James JA; Primary Sjogren's syndrome: current and prospective therapies. Semin Arthritis Rheum. 2008 Apr;37(5):273-92. Epub 2007 Aug 21.
- Meijer J, Meiners P, Vissink A, et al; Effective rituximab treatment in primary Sjogren's syndrome: A randomised, Arthritis Rheum. 2010 Jan 13.
- Voulgarelis M, Tzioufas AG, Moutsopoulos HM; Mortality in Sjogren's syndrome. Clin Exp Rheumatol. 2008 Sep-Oct;26(5 Suppl 51):S66-71.
- Zintzaras E, Voulgarelis M, Moutsopoulos HM; The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med. 2005 Nov 14;165(20):2337-44.
- Henrik Samuel Conrad Sjögren; whonamedit.com
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|Original Author: Dr Laurence Knott||Current Version: Dr Jan Sambrook||Peer Reviewer: Dr Hayley Willacy|
|Last Checked: 15/10/2013||Document ID: 2784 Version: 24||© EMIS|