Sjögren’s Syndrome

Sjögren syndrome (SS) is an autoimmune, inflammatory condition where glandular tissues, such as the salivary and lacrimal glands, are infiltrated by lymphocytes, resulting in decreased tear and saliva production. The disease mainly affects middle-aged women, and is associated with other autoimmune conditions. Patients may experience symptoms and complications related to dry eyes and mouth. There is a wide range of extraglandular manifestations, including Raynaud’s phenomenon, neuropathy, and cutaneous vasculitis. Patients are also at an increased risk of developing non-Hodgkin’s lymphoma. Diagnosis is based on the presence of symptoms, and is validated by the clinical examination, serologic studies, or salivary gland biopsy. A multidisciplinary approach is needed to manage patients and targets symptomatic relief, with immunosuppressive therapy reserved for severe symptoms.

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Overview

Definition

Sjögren’s syndrome (SS), also known as sicca syndrome, is a chronic autoimmune and inflammatory condition leading to decreased lacrimal and salivary gland function, resulting in dry eyes (xerophthalmia) and mouth (xerostomia).

Epidemiology

  • The 2nd most common rheumatologic disorder
  • Prevalence: 0.1%–4% of the population 
  • Predominantly seen in women (female : male ratio of 9:1)
  • Age of onset: middle age (40–55 years of age)
  • ½ of patients have another autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus).

Etiology

Primary SS:

  • Etiology is unknown.
  • Possible genetic predisposition: 
    • HLA-DR3
    • HLA-DQ2
    • HLA-DR5
  • Possible viral connection: 
    • Epstein-Barr virus (EBV)
    • Chronic hepatitis C
    • Human T cell leukemia virus 1
    • Human herpesvirus 6
    • Human immunodeficiency virus (HIV)

Secondary SS:

Presents in association with another autoimmune disease:

  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Polymyositis
  • Scleroderma

Pathophysiology

The overall mechanism for SS is unclear:

  • Process may be set off by an environmental trigger in a patient with a genetic predisposition.
  • Dendritic cells migrate into salivary and lacrimal glands → release interferons
  • Lymphocytes (usually CD4 T cells) and B cells infiltrate the glands.
  • Interferons stimulate B cell activating factor (BAFF) production → promotes irregular B cell maturation → B cells release autoantibodies
  • T cells and duct epithelial cells produce more cytokines.
  • Cytokines and autoantibodies cause damage and atrophy of the glandular and ductal epithelium → ↓ exocrine production (↓ tear and saliva production).
  • Other exocrine glands throughout the body can be involved, as well.

Lymphocytic infiltration of the parotid gland in a patient with SS

Image: “Anti-salivary gland protein 1 antibodies in two patients with Sjogren’s syndrome: Two case reports” by Vishwanath S, Shen L, Suresh L, Ambrus JL. License: CC BY 2.0.

Clinical Presentation

Glandular manifestations

  • Keratoconjunctivitis sicca:
    • Symptoms:
      • Xerophthalmia
      • Gritty or sandy feeling
      • Redness
      • Blurry vision
      • Entropion/ectropion
    • Findings:
      • ↓ Tear production
      • Injured corneal tissues 
    • Corneal complications:
      • Ulceration
      • Perforation
  • Salivary hypofunction:
    • Symptoms:
      • Xerostomia
      • Dysphagia
      • Food sticking in the mouth
      • Change in taste
      • Difficulty speaking for long periods of time
    • Findings:
      • Dry tongue and lips
      • Glassy appearance of the palate
      • Absent sublingual salivary pooling
      • Enlarged salivary and parotid glands
    • Complications:
      • Dental caries 
      • Oral candidiasis
      • Parotitis
      • Esophagitis
      • Weight loss due to difficulty eating
  • Other glands:
    • Nasal dryness
    • Dry cough
    • Vaginal dryness: 
      • Vulvar infections
      • Dyspareunia

Extraglandular manifestations

  • Cutaneous:
    • Xerosis (dry skin)
    • Raynaud’s phenomenon
    • Cutaneous vasculitis: 
      • Palpable purpura
      • Urticarial lesions
      • Ulcerations
    • Erythema nodosum
    • Livedo reticularis
    • Vitiligo
    • Lichen planus
  • Musculoskeletal:
    • Fatigue
    • Proximal muscle weakness (inflammatory myopathy)
    • Fibromyalgia
    • Arthralgia
    • Arthritis
  • Neurologic: 
    • Cognitive dysfunction
    • Peripheral polyneuropathy
    • Mononeuritis multiplex
    • Demyelinating disorders
  • Psychiatric: depression
  • Respiratory: 
    • Interstitial lung disease
    • Cystic lung disease
  • Cardiac (rare):
    • Pericarditis
    • Myocarditis
    • Heart block
  • Gastrointestinal: gastritis
  • Hematologic:
    • Anemia
    • Monoclonal gammopathy
    • Waldenstrom’s macroglobulinemia
    • Non-Hodgkin’s lymphoma
  • Endocrine:
    • Pancreatitis
    • Autoimmune thyroid disease
  • Renal:
    • Interstitial nephritis
    • Glomerulonephritis
    • Renal tubular acidosis

Diagnosis

Laboratory evaluation

  • Anti-SSA/Ro and anti-SSB/La antibodies (present in 60%–70% of patients)
  • Antinuclear antibodies
  • Rheumatoid factor (present in 40%–60% of patients)
  • Complete blood count:
    • Anemia
    • Leukopenia
    • Thrombocytopenia
  • Basic metabolic panel:
    • Creatinine → evaluate for renal involvement
    • ↓ Potassium and bicarbonate → renal tubular acidosis
  • ↑ Erythrocyte sedimentation rate (ESR) 
  • Urinalysis → evaluate for renal involvement:
    • Proteinuria
    • Hematuria

Ophthalmologic evaluation

  • Schirmer’s test: 
    • Measures tear production
    • Filter paper is placed in the lower eyelid.
    • Wetness is measured after 5 minutes.
    • < 5 mm wetness is considered a positive test.
  • Fluorescein slit-lamp examination and red bengal staining: 
    • Evaluates the cornea and conjunctiva for damage
    • Stain highlights areas of devitalized tissue.

Salivary gland evaluation

  • Sialometry:
    • Measures the rate of saliva production
    • Unstimulated saliva is collected and measured over 15 minutes.
    • Can also be done with stimulation of saliva (with citric acid or pilocarpine)
  • Scintigraphy:
    • Measures salivary gland function through radionuclide uptake
    • Very low uptake is highly specific for SS.
  • Imaging:
    • Ultrasound:
      • Multiple hypoechoic areas with convex borders
      • Hyperdense linear bands, cysts, and calcifications
    • Magnetic resonance imaging (MRI): nodular “honeycomb” appearance of the parotid gland
  • Biopsy: 
    • Performed on a lower lip salivary gland 
    • Histologic findings:
      • Periductal collections of tightly aggregated lymphocytes (focal lymphocytic sialadenitis)
      • Parenchymal atrophy
      • Fibrosis
      • Scattered lymphoid cells

Diagnostic criteria

Several criteria have been proposed to aid in the diagnosis of SS. The following is from the American-European Consensus Group (requires 4 of 6 criteria, including a positive biopsy or autoantibodies):

  • Ocular symptoms (at least 1):
    • Dry eyes for ≥ 3 months
    • Foreign body sensation in the eyes
    • Use of artificial tears ≥ 3 times per day
  • Oral symptoms (at least 1):
    • Dry mouth for ≥ 3 months
    • Recurrent or persistently swollen salivary glands
    • Need for liquids to swallow dry foods
  • Ocular signs (at least 1):
    • Positive Schirmer’s test
    • Positive dye staining on the surface of the eye
  • Oral signs (at least 1):
    • Positive sialography
    • Positive scintigraphy
  • Positive biopsy
  • Positive anti-Ro or anti-La (or both)

Management and Complications

Management

  • Multidisciplinary approach (rheumatologist, dentist, and ophthalmologist)
  • Primary SS with disease limited to ocular and oral symptoms:
    • Oral hygiene
    • Smoking cessation
    • Use of a humidifier 
    • Eye protection
    • Artificial tears and saliva substitute
    • Muscarinic agonists: 
      • Pilocarpine
      • Cevimeline
  • Extraglandular involvement:
    • Glucocorticoids
    • Hydroxychloroquine
    • Disease-modifying antirheumatic drugs (DMARDs):
      • Methotrexate
      • Leflunomide
      • Azathioprine
      • Sulfasalazine
    • Rituximab for severe disease that does not respond to the above therapies
  • Secondary SS can be improved by managing the primary autoimmune disease.

Complications

  • Non-Hodgkin’s lymphoma:
    • Occurs in 5%–10% of patients
    • Usually presents around 7 years after onset
  • Pregnancy complications:
    • Premature delivery, intrauterine growth retardation, and fetal loss
    • Neonatal lupus and congenital heart block 
  • Blindness due to corneal scarring
  • Renal failure from progressive renal involvement
  • Pulmonary infections
  • Reduced quality of life

Differential Diagnosis

The differential diagnosis of SS include differentials based on the presenting symptoms as well as other autoimmune disorders:

  • Medication-induced xerophthalmia: Medications such as anticholinergic agents, antidepressants, antihistamines, and beta blockers may cause eye dryness by inhibiting lacrimal gland function. Xerostomia may also be present. Patients with medication-induced xerophthalmia will not have the associated systemic symptoms, and a history of medication initiation will provide a clue to the diagnosis. Laboratory abnormalities will not be present. Management includes symptomatic relief or withdrawal of the offending medication.
  • Conjunctivitis: inflammation of the conjunctiva, causing redness, itching, and decreased visual acuity. Etiologies include viral or bacterial infections, and allergies. Watery or purulent discharge is usually present, and will differentiate conjunctivitis from SS. The diagnosis is clinical, and objective tests for SS will be negative. Management depends on the etiology, but can include topical antihistamines, antibiotics, or corticosteroids.
  • Mumps: an acute, contagious, viral disease that presents with painful, bilateral parotid swelling. The parotid swelling in SS is not painful. Complications include orchitis, meningoencephalitis, and pancreatitis. The diagnosis is clinical, and management is supportive. Mumps can be prevented with a vaccine.
  • Salivary gland tumors: benign or malignant tumors of the parotid or submandibular glands. Patients present with a non-tender mass, which is usually unilateral. Xerostomia and xerophthalmia are not typically present. The diagnosis is made with a biopsy. Malignant tumors are managed with excision and radiation.
  • Sarcoidosis: an inflammatory disorder causing non-caseating granulomas in organs and tissues. The etiology is unclear. The parotid and lacrimal glands can be affected, causing painless enlargement. Associated xerostomia, xerophthalmia, arthritis, and interstitial nephritis can also be seen. The diagnosis is made with biopsy, and corticosteroids are used in the management.

References

  1. Baer, A.N. (2020). Diagnosis and classification of Sjögren’s syndrome. UpToDate. Retrieved January 13, 2021, from https://www.uptodate.com/contents/diagnosis-and-classification-of-sjogrens-syndrome
  2. Baer, A.N. (2020). Overview of the management and prognosis of Sjögren’s syndrome. UpToDate. Retrieved January 13, 2021, from https://www.uptodate.com/contents/overview-of-the-management-and-prognosis-of-sjogrens-syndrome
  3. Baer, A.N. (2020). Clinical manifestations of Sjogren’s syndrome: Exocrine gland disease. In Romain, P.L. (Ed.), Uptodate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-sjogrens-syndrome-exocrine-gland-disease
  4. Baer, A.N. (2020). Clinical manifestations of Sjögren’s syndrome: Extraglandular disease. UpToDate. Retrieved January 13, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-sjogrens-syndrome-extraglandular-disease
  5. Ranatunga, S.K. (2020). Sjogren syndrome. In Diamond, H.S. (Ed.), Medscape. Retrieved January 16, 2021, from https://emedicine.medscape.com/article/332125-overview
  6. Nevares, A.M. (2020). Sjogren syndrome. [online] MSD Manual Professional Version. Retrieved January 16, 2021, from https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/autoimmune-rheumatic-disorders/sj%C3%B6gren-syndrome
  7. Nair, J.J., & Singh, T.P. (2017). Sjogren’s syndrome: Review of the aetiology, pathophysiology & potential therapeutic interventions. Journal of clinical and experimental dentistry, 9(4): e584‒e589. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410683/
  8. Carsons, S.E., & Patel, B.C. (2020). Sjogren syndrome. [online] StatPearls. Retrieved January 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK431049/

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