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 Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis, systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus).

Etiology

Primary SS:

• Etiology is unknown.
• Possible genetic predisposition: 
  • HLA-DR3
  • HLA-DQ2
  • HLA-DR5
• Possible viral connection: 
  • Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus (EBV)
  • Chronic hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus
  • 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 Polymyositis Polymyositis (PM) is an autoimmune inflammatory myopathy caused by T cell-mediated muscle injury. The etiology of PM is unclear, but there are several genetic and environmental associations. Polymyositis is most common in middle-aged women and rarely affects children. Polymyositis
• Scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. 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 Interferons Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons
• Lymphocytes (usually CD4 T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells) and B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells infiltrate the glands.
• Interferons stimulate B cell activating factor (BAFF) production → promotes irregular B cell maturation → B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells release autoantibodies
• T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells and duct epithelial cells produce more cytokines.
• Cytokines and autoantibodies cause damage and atrophy of the glandular and ductal epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium → ↓ exocrine production (↓ tear and saliva production).
• Other exocrine glands throughout the body can be involved, as well.

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 Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
  • Hydroxychloroquine
  • Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. 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 Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care 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 Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs agents, antidepressants, antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. 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 Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. Conjunctivitis: inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. 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 Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines, antibiotics, or corticosteroids.
• Mumps Mumps Mumps is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. Mumps is typically a disease of childhood, which manifests initially with fever, muscle pain, headache, poor appetite, and a general feeling of malaise, and is classically followed by parotitis. Mumps Virus/Mumps: an acute, contagious, viral disease that presents with painful, bilateral parotid swelling. The parotid swelling in SS is not painful. Complications include orchitis Orchitis Epididymitis and orchitis are characterized by acute inflammation of the epididymis and the testicle, respectively, due to viral or bacterial infections. Patients typically present with gradually worsening testicular pain and scrotal swelling along with systemic symptoms such as fever, depending on severity. Epididymitis and Orchitis, meningoencephalitis, and pancreatitis. The diagnosis is clinical, and management is supportive. Mumps Mumps Mumps is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. Mumps is typically a disease of childhood, which manifests initially with fever, muscle pain, headache, poor appetite, and a general feeling of malaise, and is classically followed by parotitis. Mumps Virus/Mumps can be prevented with a vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination.
• 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 Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. 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.