Sjogren's Syndrome

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Written by: Dr Jeremy Steinberg – created: 16 December 2022; last modified: 12 March 2023

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Sjogren's Syndrome
Synonym Sjogren's disease
Epidemiology Prevalence 0.04%. Onset middle age particularly in women.
Causes Autoimmune disease
Pathophysiology Cyclical innate and adaptive immune system activation with lymphocytic infiltration of affected tissue
Clinical Features Glandular and extraglandular disease
Diagnosis Objective findings of dry mouth or dry eyes plus serologic or histologic findings.
Tests ANA, Anti-Ro, Anti-La, RF, biopsy, MRI or USS
Prognosis Normal life expectancy

Sjögren's syndrome (SS) is a chronic autoimmune disease that is characterised by lymphocytic infiltration of the salivary, lacrimal, and other exocrine glands leading to dry eyes and dry mouth along with autoantibodies. It can also result in skin disease, arthritis, nephritis, cytopaenia, pneumonitis, vasculitis, peripheral neuropathy, myelopathy, and cognitive dysfunction. The clinical features are divided into exocrine glandular features and extraglandular features.

Definitions

  • Sjogren's disease - synonym for SS
  • Sicca syndrome - synonym for SS
  • Sicca complex - dryness of the eyes and mouth. Doesn't specify autoimmunity
  • Keratoconjunctivitis sicca (KCS) - ocular findings of SS
  • Dry eye syndrome (DES) - can be due to conditions such as SS and meibomian gland dysfunction. Only 10% of patients have SS.
  • Mikulicz syndrome - parotid and lacrimal gland enlargement from any cause. Including SS or other conditions such as IgG4 related disease.

Epidemiology

SS is most common in women, the female to male ratio often exceeds 10:1. It usually is diagnosed between 40-60 but it can occur in younger and older individuals as well.[1] The overall prevalence is estimated at 43 per 100,000 people (0.043%).[2] Dry eye and mouth occurs in up to 30% of older adults. This can be due to medication side effects and age-related atrophy of gland tissue.

Pathogenesis

The pathogenesis is one of targeted inflammation of the lacrimal and salivary glands with B-lymphocyte hyperactivity.[1]

Both genetic and non-genetic factors are thought to be involved. It is thought that SS occurs following an environmental trigger, likely viral (but no single virus has been implicated), in a genetically susceptible individual. The immune response involves both innate and adaptive immunity leading to autoimmunity and chronic inflammation. There is a cycle of mutual stimulation of the innate and acquired immune systems resulting in glandular injury.

The pathologic lesion is a lymphocytic infiltration of affected organs. The most frequently affected tissues are the lacrimal and salivary glands whereby there is focal aggregation of lymphocytes that start around the ducts and spread to the entire lobule. Infiltrates can also occur in extraglandular sites. Other mechanisms contribute to glandular dysfunction including antibodies to the muscarinic receptors that impair neural innervation of the gland as well as deleterious effects of cytokines on neurotransmitter release.

Specific autoantibodies are found in SS, particularly anti-Ro/SSA and anti-La/SSB in 60-80% of individuals. ANA antibodies are positive in around 90% of patients. High RF factor is also common. Autoantibodies can be found many years before the onset of SS. Autoantibodies alone are not sufficient for disease induction.

Clinical Presentation

SS occurs on a spectrum with a range of presentations. Symptoms can include fatigue, arthralgia, polyarthritis, renal, neurologic, cutaneous, endocrine, hepatic, vasculitis, pulmonary, and haematologic manifestations.

On the mild to moderate side, patients have dry eyes and mouth along with fatigue, cognitive dysfunction, and myalgia. The diagnosis is confirmed by positive antibodies and/or gland biopsy. Without laboratory or histological studies the presentation may be identical to fibromyalgia or even patients with depression who have anticholinergic side effects from medication.

On the severe end patients may have frank salivary gland swelling and adenopathy. There may be cryoglobulinaemia, low complement, Hodgkin lymphoma, and extraglandular disease. Antibodies may again be positive.

In a minority of patients there is primary extraglandular involvement with limited eye or mouth symptoms. The diagnosis may be made, e.g. with positive antibodies, during workup of neuropathies, nephropathies, interstitial pneumonitis, or haematologic abnormalities.

Diagnosis

There is no single test. The diagnosis is made with having both objective clinical and laboratory features, following exclusion of other causes. The diagnosis can't be made with the presence of autoantibodies and no compatible symptoms.

Objective clinical findings of mouth or eye dryness: this includes one of abnormal Schirmer test of either eye, abnormal sialometry or Saxon test for the glands, or radiological evidence such as on MRI, CT, or US.

Serological or histological findings: Anti-Ro/SSA +/- Anti-La antibodies or positive labial salivary gland biopsy showing focal lymphocytic sialednitis. In the presence of isolated anti-La antibodies, biopsy is required to confirm the diagnosis. A diagnosis of secondary SS can be made without antibodies or biopsy in the presence of a well-established systemic rheumatological disease such as SLE or RA. Also acceptable are positive anticentromere antibodies without systemic sclerosis or findings of ANA greater or equal to 1:320 along with positive RF.

In individuals with isolated extraglandular disease, the diagnosis can be made with positive biopsy and anti-Ro antibodies.

2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren Syndrome[3]
The classification of primary Sjögren syndrome applies to any individual who meets the inclusion criteria,* does not have any of the conditions listed as exclusion criteria, and has a score of ≥4 when the weights from the five

criteria items below are summed.

Item Weight or Score
Labial salivary gland with focal lymphocytic sialadenitis and

focus score of ≥1 foci/4 mm

3
Anti-SSA/Ro positive 3
Ocular staining score ≥5 (or van Bijsterveld score ≥4) in at

least one eye §∥

1
Schirmer test ≤5 mm/5 minutes in at least one eye § 1
Unstimulated whole saliva flow rate ≤0.1 mL/min §§¶ 1
*These inclusion criteria are applicable to any patient with at least one symptom of ocular or oral

dryness, defined as a positive response to at least one of the following questions:

  1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?
  2. Do you have a recurrent sensation of sand or gravel in the eyes?
  3. Do you use tear substitutes more than three times a day?
  4. Have you had a daily feeling of dry mouth for more than 3 months?
  5. Do you frequently drink liquids to aid in swallowing dry food?

or in whom there is suspicion of Sjögren syndrome (SS) from the European League Against Rheumatism
SS Disease Activity Index questionnaire (at least one domain with a positive item).
†Exclusion criteria include prior diagnosis of any of the following conditions, which would exclude diagnosis of SS and participation in SS studies or therapeutic trials because of overlapping clinical features or interference with criteria tests: (1) history of head and neck radiation treatment, (2) active hepatitis C infection (with confirmation by PCR), (3) AIDS, (4) sarcoidosis, (5) amyloidosis, (6) graft-versus-host disease, or (7) IgG4-related disease.
‡The histopathologic examination should be performed by a pathologist with expertise in the diagnosis of focal lymphocytic sialadenitis and focus score count using the protocol described by Daniels et al.[4]
§Patients who are normally taking anticholinergic drugs should be evaluated for objective signs of salivary hypofunction and ocular dryness after a sufficient interval without these medications for these components to be a valid measure of oral and ocular dryness.
∥Ocular Staining Score described by Whitcher et al[5]; van Bijsterveld score described by van Bijsterveld.[6]
§¶Unstimulated whole saliva flow rate measurement described by Navazesh and Kumar.[7]

Differential Diagnosis

Differential Diagnosis of SS
  • Age-related Sicca Syndrome
  • IgG4-related disease
  • Eosinophilic sialodochitis
  • Benign lymphoepithelial sialadenitis and dacryoadenitis
  • Lymphona and other haematologic malignancy
  • Sarcoidosis
  • Hepatitis C
  • HIV
  • Graft-versus-host disease
  • Sicca induced by immune checkpoint inhibitors
  • Systemic vasculitis
Differential Diagnosis of Dry Eye

Primarily evaporative

  • Eyelid and ocular surface disease
  • Meibomian gland dysfunction
  • Poor eyelid congruity
  • Facial nerve paralysis
  • Low blink rate (e.g., Parkinson disease, video terminal use)
  • Extrinsic causes that enhance evaporation
    • Trachoma (vitamin A deficiency)
    • Use of topical anesthetic drops
    • Excessive use of preservative-containing drops
    • Contact lens wear
    • Allergic conjunctivitis

Primarily aqueous deficient

  • Sjögren syndrome
  • Other forms of lacrimal gland disease
  • Aging
  • Inflammatory diseases (e.g., acquired immunodeficiency syndrome, sarcoidosis, lymphoma, graft-versus-host disease)
  • Lacrimal gland duct obstruction from various forms of cicatrizing conjunctivitis
  • Ocular sensory loss leading to reflex hyposecretion and a diminished blink rate
  • Corneal surgery
  • Diabetes mellitus
  • Neurotrophic keratitis
  • Chronic contact lens wear
  • Loss of lacrimal secretory motor function
  • Drugs (e.g., antihistamines, beta blockers, antispasmodics, diuretics)
  • Central seventh nerve damage
Differential Diagnosis of Xerostomia
  • Drug side effect (e.g., single or multiple prescription of drugs with anticholinergic, diuretic, antihypertensive, anxiolytic, or antihistamine effects)
  • Salivary gland diseases, including Sjögren syndrome
  • Poorly controlled diabetes mellitus
  • Dehydration
  • Mouth breathing, nasal obstruction
  • Head and neck irradiation (including high doses of radioactive iodine for thyroid cancer)
  • Psychological factors
Differential Diagnosis of Salivary Gland Enlargmenet

Infectious

  • Viral infections (mumps, Epstein-Barr virus, hepatitis C, human immunodeficiency)
  • Bacterial
  • Acute suppurative parotitis
  • Tuberculosis
  • Fungal

Autoimmune

  • Sjögren syndrome
  • Granulomatous polyangiitis

Inflammatory

  • IgG4-related disease (including Küttner tumor)
  • Allergic parotitis (sialodochitis fibrinosa)
  • Chronic recurrent parotitis
  • Kimura disease

Metabolic (causing sialadenosis, which is characterized by painless, bilaterally symmetric parotid enlargement that is soft and nontender on palpation)

  • Uncontrolled diabetes mellitus
  • Bulimia
  • Alcoholism with liver disease
  • Hyperlipoproteinemia

Neoplastic

  • Lymphoma
  • Leukemia
  • Warthin tumor (papillary cystadenoma lymphomatosum)
  • Diffuse hyperplastic oncocytic hyperplasia

Granulomatous

  • Sarcoidosis

Iatrogenic or self-induced

  • Radioactive iodine
  • Pneumoparotitis (wind instrument players, glass blowers)

Management

Management is similar for primary and secondary SS

General Measures

For mild SS without extraglandular disease systemic therapy is not usually required. Secretagogues plus local therapy for ocular and oral symptoms can be used such as artificial tears.

Smoking increases the risk of dental decay and other oral complications as well as reduces the efficacy of medications such as hydroxychloroquine. It also aggravates small airway disease. Medications that exacerbate drying side effects should be avoided.

Pregnancy counseling should be provided. The most serious adverse fetal outcome in SS is congenital heart block. Other complications are more common such as fetal loss, IUGR, and premature deliver.

Patietns are at increased risk of complications from surgery requiring general anaesthesia. Anticholinergic drugs and the low-humidity environment of the operating theatre predisposes to ocular surface, mucosal, and dental damage. There is increased risk of atelectasis.

Pharmacologic

Pilocarpine and cevimeline are examples of muscarinic agonists used as secretagogues.

For moderate to severe disease systemic therapy is usually used. The approach is similar to SLE and RA. Systemic therapy options include glucocorticoids, hydroxychloroquine, methotrexate, leflunomide, azathioprine, sulfasalazine, mycophenolate, cyclosporine, cyclophosphamide, and rituximab.

References

  1. 1.0 1.1 Hochberg. Sjogren syndrome (chapter 147) In: Rheumatology. 2019
  2. Qin, Baodong; Wang, Jiaqi; Yang, Zaixing; Yang, Min; Ma, Ning; Huang, Fenglou; Zhong, Renqian (2015-11). "Epidemiology of primary Sjögren's syndrome: a systematic review and meta-analysis". Annals of the Rheumatic Diseases. 74 (11): 1983–1989. doi:10.1136/annrheumdis-2014-205375. ISSN 1468-2060. PMID 24938285. Check date values in: |date= (help)
  3. Shiboski CH, Shiboski SC, Seror R, et al; International Sjögren’s Syndrome Criteria Working Group. 2016 American College of Rheumatology/European League Against Rheumatism Classification criteria for primary Sjögren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheum. 2017;69(1):35-45.
  4. Daniels TE, Cox D, Shiboski CH, et al. Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjogren’s syndrome among 1,726 registry participants. Arthritis Rheum. 2011;63:2021-2130.
  5. Whitcher JP, Shiboski CH, Shiboski SC, et al. A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjogren’s Syndrome International Registry. Am J Ophthalmol. 2010;149:405-415
  6. Van Bijsterveld OP. Diagnostic tests in the Sicca syndrome. Arch Ophthalmol. 1969;82:10-14.
  7. avazesh M, Kumar SK, University of Southern California School of Dentistry. Measuring salivary flow: challenges and opportunities. J Am Dent Assoc. 2008;139(suppl):35S-40S.

Literature Review