Sjögren's syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farima Kahe M.D. [2] Ayesha A. Khan, MD[3]

In 1892, Johann von Mikulicz-Radecki was to first to describe a patient with enlargement of the parotid and lacrimal glands associated with a round-cell infiltrate and acinar atrophy. In 1933, Henrik Sjögren was the first to describe 19 females with clinical and pathological manifestations of the Sjögren’s syndrome. American-European Consensus Group(AECG) and American College of Rheumatology (ACR) established the criteria for Sjögren’s syndrome in 2002 and 2012 according to clinical findings. Common causes of Sjögren’s syndrome include viral infection such as Epstein-Barr virus (EBV), Coxsackie virus, Hepatitis C virus, Cytomegalovirus (CMV), Human herpesvirus 6 (HHV-6), Retroviruses, and genetic factors. The incidence of Sjögren’s syndrome is approximately 4 per 100,000 individuals worldwide. The prevalence of Sjögren’s syndrome is approximately 43 per 100,000 individuals worldwide. Female are more commonly affected by Sjögren’s syndrome than male. The majority of Sjögren’s syndrome cases are reported in China, Japan, and California. Common risk factors in the development of Sjögren’s syndrome include family history of autoimmune diseases, serological markers such as low complement levels and cryoglobulinemia and parotid gland enlargement. The symptoms of Sjögren’s syndrome usually develop in the 4th and 5th decade of life, and start with symptoms such as ocular and oral dryness. Common complications of Sjögren’s syndrome include blurred vision and corneal damage, optic neuritis, and lymphoma. Prognosis is generally good and presence of low complement level is associated with a particularly poor prognosis among patients with Sjögren’s syndrome. The most common symptoms of Sjögren’s syndrome include ocular and oral symptoms. Patients with Sjögren’s syndrome may have a positive history of rheumatoid arthritis (RA), systemic lupus erythematous (SLE) and non-Hodgkin B-cell lymphoma. Physical examination of patients with is usually remarkable for dryness of all mucous membranes such as mouth, eyes, lips, anal and rectal. Laboratory findings consistent with the diagnosis of Sjögren’s syndrome include elevated erythrocyte sedimentation rate (ESR), cytopenia, the presence of anti-SSA/Ro, anti-SSB/La. Findings on an ultrasound suggestive of Sjögren’s syndrome are hypoechoic and inhomogeneous salivary glands, parenchymal inhomogeneity in the submandibular glands and focal or diffuse hypoechoic or anechoic foci in glands. Parotid gland CT scan may be helpful in the diagnosis of Sjögren’s syndrome and finding include abnormal diffuse fat tissue deposition and diffuse punctate calcification. The most commonly used tests for dry eyes of Sjögren’s syndrome include Schirmer’s test, ocular surface staining and tear break-up time. Pharmacologic medical therapies for dry eye, dry mouth, and other sicca symptoms of Sjögren’s syndrome are pilocarpine, cevimeline and artificial tears. The mainstay of treatment for Sjögren’s syndrome is medical therapy. Surgery is usually reserved for patients with occlusion of the lacrimal puncta, salivary gland malignancy and recurrent parotitis refractory to medical management.

In 1892, Johann von Mikulicz-Radecki was to first to describe a patient with with enlargement of the parotid and lacrimal glands associated with a round-cell infiltrate and acinar atrophy. In 1933, Henrik Sjögren was the first to describe 19 females with clinical and pathological manifestations of the Sjögren’s syndrome.

American-European Consensus Group(AECG) and American College of Rheumatology (ACR) established the criteria for Sjögren’s syndrome in 2002 and 2012 according to clinical findings.

Sjögren’s syndrome (SS) is a chronic autoimmune disorder that can affect several organ systems. Sjögren’s syndrome is classified into a “primary” form that is a separate entity from other well-defined autoimmune disorders and a “secondary” form that is associated with other well-defined autoimmune conditions, such as SLE, rheumatoid arthritis, progressive systemic sclerosis, and primary biliary cirrhosis. These forms of Sjögren’s syndrome are different in their serologic and histopathologic findings as well as their genetic components. Both genetic and immune factors contribute to the pathogenesis of the disease. In the most common presentation of Sjögren’s syndrome, lymphocytes infiltrate the lacrimal and salivary glands and impair their function, hence causing the main characteristic symptoms such as dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca). CD4+ T-cells are predominant in mild and moderate salivary gland infiltrations, while B cells play the major role in severe lesions. Sjögren’s syndrome may also manifest itself with dryness of skin and other mucosal surfaces or even cause systemic extraglandular disturbances such as arthritis, vasculitis, renal, pulmonary, hematopoietic, and neurologic involvement. In general, a combination of lymphocytic infiltration, B lymphocyte hyperreactivity, production of certain autoantibodies, genes mostly involved in the production of MHC molecules and certain viral infections which are all linked to the pathogenesis of Sjögren’s syndrome.

Common causes of Sjögren’s syndrome include viral infection such as Epstein-Barr virus (EBV), Coxsackie virus, Hepatitis C virus, Cytomegalovirus (CMV), Human herpesvirus 6 (HHV-6), Retroviruses and genetic factors.

The incidence of Sjögren’s syndrome is approximately 4 per 100,000 individuals worldwide. The prevalence of Sjögren’s syndrome is approximately 43 per 100,000 individuals worldwide. The mortality rate of Sjögren’s syndrome is approximately 1.38. Female are more commonly affected by Sjögren’s syndrome than male. The majority of Sjögren’s syndrome cases are reported in China, Japan, and California.

Common risk factors in the development of Sjögren’s syndrome include family history of autoimmune diseases, serological markers such as low complement levels and cryoglobulinemia and parotid gland enlargement.

There is insufficient evidence to recommend routine screening for Sjögren’s syndrome.

The symptoms of Sjögren’s syndrome usually develop in the 4th and 5th decade of life, and start with symptoms such as ocular and oral dryness.

Common complications of Sjögren’s syndrome include blurred vision and corneal damage, optic neuritis and lymphoma.

Prognosis is generally good and presence of low complement level is associated with a particularly poor prognosis among patients with Sjögren’s syndrome.

The most common symptoms of Sjögren’s syndrome include ocular and oral symptoms. Patients with Sjögren’s syndrome may have a positive history of rheumatoid arthritis (RA), systemic lupus erythematous (SLE) and non-Hodgkin B-cell lymphoma.

Physical examination of patients with is usually remarkable for dryness of all mucous membranes such as mouth, eyes, lips, anal, and rectal.

Laboratory findings consistent with the diagnosis of Sjögren’s syndrome include elevated erythrocyte sedimentation rate (ESR), cytopenia, presence of anti-SSA/Ro, and anti-SSB/La.

There are no ECG findings associated with Sjögren’s syndrome.

Findings on an ultrasound suggestive of Sjögren’s syndrome are hypoechoic and inhomogeneous salivary glands, parenchymal inhomogeneity in the submandibular glands and focal or diffuse hypoechoic or anechoic foci in glands. There are no echocardiography findings associated with Sjögren’s syndrome.

Parotid gland CT scan may be helpful in the diagnosis of Sjögren’s syndrome and finding include abnormal diffuse fat tissue deposition and diffuse punctate calcification.

Findings on MRI suggestive of Sjögren’s syndrome include loss of homogeneity kin signal intensity on T1-weighted MR images and fat saturation suppressed focal high-intensity areas on T1-weighted images.

There are no other imaging findings associated with Sjögren’s syndrome.

The most commonly used tests for dry eyes of Sjögren’s syndrome include Schirmer’s test, ocular surface staining and tear break-up time.

Pharmacologic medical therapies for dry eye, dry mouth, and other sicca symptom of Sjögren’s syndrome are pilocarpine, cevimeline and artificial tears.

The mainstay of treatment for Sjögren’s syndrome is medical therapy. Surgery is usually reserved for patients with occlusion of the lacrimal puncta, salivary gland malignancy, and recurrent parotitis refractory to medical management.

Sjögren’s syndrome is inherited condition, there is no particular way to prevent developing the disease.

Secondary prevention by Smoking cessation. Smoking can irritate and dry out your mouth. Increase your fluid intake. Take sips of fluids, particularly water, throughout the day. Avoid drinking coffee or alcohol since they can worsen dry mouth symptoms. Also avoid acidic beverages such as colas and some sports drinks because the acid can harm the enamel of your teeth. Stimulate saliva flow. Sugarless gum or citrus-flavored hard candies can boost saliva flow. Because Sjogren’s syndrome increases your risk of dental cavities, limit sweets, especially between meals. Try artificial saliva. Saliva replacement products often work better than plain water because they contain a lubricant that helps your mouth stay moist longer. These products come as a spray or lozenge.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

In 1892, Johann von Mikulicz-Radecki was to first to describe a patient with with enlargement of the parotid and lacrimal glands associated with a round-cell infiltrate and acinar atrophy. In 1933, Henrik Sjögren was the first to describe 19 females with clinical and pathological manifestations of the Sjögren’s syndrome.

• In 1892, Johann von Mikulicz-Radecki was to first to describe a patient with enlargement of the parotid and lacrimal glands associated with a round-cell infiltrate and acinar atrophy.^[1]
• In 1933, Henrik Sjögren was the first to describe 19 females with clinical and pathological manifestations of the Sjögren’s syndrome.
• In 1951, Sjögren published a paper describing 80 patients with keratoconjunctivitis sicca associated with Sjögren’s syndrome.
• In 1976, the first symposium on Sjogren’s syndrome was held in Sweden.^[2]
• In 1980, autoantibodies to the centromere proteins (CENP) were found in 40% of patients with Sjögren’s syndrome.^[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

American-European Consensus Group (AECG) and American College of Rheumatology (ACR) established the criteria for Sjögren’s syndrome in 2002 and 2012 according to clinical findings.

• In 2002, American-European Consensus Group (AECG) established the Sjögren’s syndrome criteria based on the clinical observations, which include:^{[1][2][3][4][5]}
  • 1. Ocular symptoms: a positive result to at least one of the following questions:
    • 1.1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?
    • 1.2. Do you have a recurrent sensation of sand or gravel in the eyes?
    • 1.3. Do you use tear substitutes more than 3 times a day?
  • 2. Oral symptoms: a positive result to at least one of the following questions:
    • 2.1. Have you had a daily feeling of dry mouth for more than 3 months?
    • 2.2. Have you had recurrently or persistently swollen salivary glands as an adult?
    • 2.3. Do you frequently drink liquids to aid in swallowing dry food?
  • 3. Ocular signs: positive result for at least one of the following two tests:
    • 3.1. Schirmer’s test, performed without anaesthesia (≤5 mm in 5 minutes)
    • 3.2. Rose bengal score or other ocular dye score (≥4 according to van Bijsterveld’s scoring system)
  • 4. Histopathology: number of lymphocytic foci score ≥1 focus/4 mm2 of glandular tissue
  • 5. Salivary gland involvement: positive result for at least one of the following diagnostic tests:
    • 5.1. Unstimulated whole salivary flow (≤1.5 ml in 15 min)
    • 5.2. Parotid sialography showing the presence of diffuse sialectasis (punctate, cavitary or destructive pattern), without evidence of obstruction in the major ducts
    • 5.3. Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer
  • 6. Autoantibodies: presence in the serum of the following autoantibodies:
    • 6.1. Antibodies to Ro (SSA) or La (SSB) antigens, or both

• Exclusion criteria: if any of the following disorders is present, patients with the classification criteria are excluded.
  • Prior head and/or neck irradiation
  • Infection with hepatitis C virus (HCV)
  • Acquired immunodeficiency syndrome (AIDS)
  • Lymphoma
  • Sarcoidosis
  • Graft-versus-host disease
  • Recent use of medications with anticholinergic properties

• Sjögren’s syndrome may be classified as either primary or secondary:
  • Primary Sjögren’s syndrome
    • Positive salivary gland biopsy or anti-Ro/SSA and/or anti-La/SSB autoantibodies and have a total of four out of the six above items
    • Three out of the four objective items (ocular signs, biopsy, salivary gland involvement, or autoantibodies)
  • Secondary Sjögren’s syndrome
    • If a connective tissue disease is present, and if both of the following criteria are met:
      • Symptoms of ocular or oral dryness
      • Any two of the following three objective items:
        • Ocular signs
        • Positive salivary gland biopsy
        • Abnormal tests of salivary gland function

• American College of Rheumatology (ACR) established the criteria for Sjögren’s syndrome in 2012 for at least two of the three following findings:^[6]
  • Positive serum anti-Ro/SSA and/or anti-La/SSB antibody testing OR a positive rheumatoid factor and an antinuclear antibody (ANA) titer ≥1:320
  • Ocular staining score ≥3 (assuming the individual is not concurrently using daily eye drops)
  • Presence of focal lymphocytic sialadenitis with a focus score ≥1 focus/4 mm2 in labial salivary gland biopsy samples

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farima Kahe M.D. [2], Farbod Zahedi Tajrishi, M.D.

Sjögren’s syndrome (SS) is a chronic autoimmune disorder that can affect several organ systems. Sjögren’s syndrome is classified into a “primary” form that is a separate entity from other well-defined autoimmune disorders and a “secondary” form that is associated with other well-defined autoimmune conditions, such as SLE, rheumatoid arthritis, progressive systemic sclerosis, and primary biliary cirrhosis. These forms of Sjögren’s syndrome are different in their serologic and histopathologic findings as well as their genetic components. Both genetic and immune factors contribute to the pathogenesis of the disease. In the most common presentation of Sjögren’s syndrome, lymphocytes infiltrate the lacrimal and salivary glands and impair their function, hence causing the main characteristic symptoms such as dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca). CD4+ T-cells are predominant in mild and moderate salivary gland infiltrations, while B cells play the major role in severe lesions. Sjögren’s syndrome may also manifest itself with dryness of skin and other mucosal surfaces or even cause systemic extraglandular disturbances such as arthritis, vasculitis, renal, pulmonary, hematopoietic, and neurologic involvement. In general, a combination of lymphocytic infiltration, B lymphocyte hyperreactivity, production of certain autoantibodies, genes mostly involved in the production of MHC molecules and certain viral infections which are all linked to the pathogenesis of Sjögren’s syndrome.

The pathogenesis of Sjögren’s syndrome can be linked to both genetic and nongenetic components. These factors are associated with disease susceptibility, development and progression:^[1]

Multiple genes are involved in the pathogenesis of Sjögren’s syndrome. Genome-wide association and molecular studies of salivary gland biopsies from patients with Sjögren’s syndrome have revealed HLA-DR molecules, homing receptors, and genes encoding components of both innate and adaptive immune systems (particularly MHCs, interferons and interleukins) all play important roles in the disease, although ethnicity seems to affect them.^[2][3][4]

As previously demonstrated for other systemic rheumatic diseases, factors affecting the regulation of gene expression such as genetic recombination, non-coding RNA molecules and histone methylation, may also all contribute to the pathogenesis of Sjögren’s syndrome.^[5] Moreover, evidence suggests that while the Sjögren’s syndrome is more common in identical twins, the concordance rate is only about 20 percent, further highlighting the role of epigenetics.^[6]

Several studies have indicated an association between Sjögren’s syndrome and some viral infections. Following transmission, some viruses invade and damage the secretory gland cells. This could later cause a cascade of events leading to autoimmune response and immune-mediated tissue injury. Though the evidence is not definitive yet, both EBV and Coxsackie virus are thought to be having a role in causing primary Sjögren’s syndrome.^[7] There are also certain types of viruses including HIV, HTLV-1 and hepatitis C virus that can cause SS-like syndromes.^[8]

The exact pathogenesis of Sjögren’s syndrome is not fully understood. However, it has been suggested that a combination of genetic predisposing factors, tissue damage (e.g. by viral insult), infiltration of lymphocytes to the excreting glands, and production of certain cytokines and autoantibodies contribute to the development and progression of the disease. The Immune-mediated components of the pathogenesis include:

1. Lymphocytic infiltration and cytokines:

The basic mechanism underlying the symptoms of Sjögren’s syndrome involves infiltration of lymphocytes into the exocrine glands. Lymphocytes within the glandular tissues or other sites trigger a set of immune response reactions resulting in the release of cytokines such as Interferon-gamma, IL-17, B-cell activating factor, and the production of characteristic autoantibodies. Together with the activation of metalloproteinases, these events lead to glandular cell apoptosis, dysfunction of residual glandular cells, disorganization of the secreting gland and tissue injury. While the infiltrating B and T cells both remain somehow resistant to apoptosis themselves, it is mainly the T cell component that induces apoptosis signals to the glandular epithelial cells. TH17 cells and the IL-17 they produce can also boost local inflammation in Sjögren’s syndrome along with a change in cytokine balance between T helper 1 and 2 cells in favor of T helper 1.^[9]

2. Autoantibodies:

Anti-Ro/SSA and Anti-La/SSB (both from IgG subclass) are the most common autoantibodies found in sera of patients with Sjögren’s syndrome. These antibodies may also be produced locally in salivary glands.^[10] Other antibodies such as ANA, RF and those agains acetylcholine receptors are also present in a variety of patients.

• Anti-Ro/SSA

Anti-Ro/SSA is found in more than 70-90 percent^[11] of patients and is produced against an autoantigen consisting of a complex of two polypeptide (52 and 60 kDa) chains along with cytoplasmic RNAs. Anti-52 kD antibodies are more strongly associated with the primary form of Sjögren’s syndrome, while anti-60 kD antibodies are common in Sjögren’s syndrome associated with SLE.^[12]

• Anti-La/SSB

Fifty percent of Sjögren’s syndrome patients have Anti-La/SSB autoantibodies. The gene encoding SSB has two promoter sequence sites, allowing it to encode two different size mRNAs– a feature that increases the likelihood of gene switching under disease conditions.^[13]

It has been well-documented that genetics play an important role in Sjögren’s syndrome. A familial and ethnic tendency to develop the disease in addition to an increased risk of autoimmune disorders in relatives of patients with Sjögren’s syndrome support this concept. Genes in both HLA and non-HLA regions of the genome have been proposed in the pathogenesis of Sjögren’s syndrome:

MHC genes, including those in the HLA-DR region are strongly associated with Sjögren’s syndrome. However, there is significant heterogeneity of associations between different ethnic groups. For instance, there are reported associations for HLA-DR5 in Greek patients^[14], HLA-DRB1*15 in Spanish patients^[15] and a variety of other HLA alleles among Han Chinese^[16] and Japanese^[17] patients. Moreover, Caucasian patients with primary Sjögren’s syndrome are reported to have higher amounts of HLA-DQB1*0201 and HLA-DQA1*0501. HLA-DR alleles are not the only HLA alleles linked with Sjögren’s syndrome. Evidence suggests that the presence of greater numbers of HLA-DQA1 and HLA-DQB1 alleles in a person markedly increases the risk of producing anti-Ro/SSA autoantibodies with a gene dose effect.^[18]

Among non-HLA genes, TNIP1, IRF5, BLK, STAT4, IL12A, and CXCR5 are all reported to have a significant genome-wide association.^[19] TNIP1 and IRF5 are involved in innate immune system and the others play a role in acquired immunity. TNIP1 works alongside with TNFAIP3 (A20) to suppress NF-kB, which is associated with inflammatory response and the production of lymphocytes in Sjögren’s syndrome.^[20]

Other non-HLA genes have also been identified, but haven’t reached a significant association level in genome-wide association studies; these include:^[21]

• Those involved in innate immunity:
  • MBL2
  • FCGR2B
  • LTA
  • TNF
  • NCR3
  • NFKBIA
• Those involved in acquired immunity:
  • TAP2
  • EBF1
  • PTPN22
  • TNFRSF4
  • IL10

The most important conditions associated with Sjögren’s syndrome include:

• Lymphomas:
  • MALT lymphomas
  • Diffuse B cell lymphoma
  • T cell lymphoma

Lymphomas, particularly low-grade non-Hodgkin lymphomas with MALT pathology, occur more frequently in patients with Sjögren’s syndrome. T-cell lymphomas and higher-grade diffuse B-cell lymphomas are other possible complications of Sjögren’s syndrome, but are much less common.^[22] The most frequent sites of involvement in MALT lymphomas are mucosal locations where Sjögren’s syndrome affects, such as salivary glands or the gastrointestinal tract (MALT); or in the lung, where bronchial-associated lymphoid tumor (BALT) lymphomas can occur.^[23] Additionally, MALT and diffuse large cell lymphomas of marginal zone origin^[24] frequently affect cervical lymph nodes and the submandibular and parotid glands. A comparison between biopsies from Sjögren’s syndrome patients who later presented with a NHL and those without NHL has linked the presence of germinal center-like structures with an elevated risk for developing lymphoma.^[25] Moreover, mutations and downregulation of A20 (TNFAIP3), a regulator of NF-kB, is associated with increased germinal center formation and MALT lymphomas in Sjögren’s syndrome.^[26] Polymorphisms of CXCR5, a gene involved in organizing these structures, are also linked with both SS and NHL.^[27]

• Other rheumatologic disorders such as:
  • SLE
  • Rheumatoid arthritis
  • Systemic sclerosis
  • Primary biliary cirrhosis

• Sjögren’s syndrome has no characteristic gross pathology. The findings are mainly non-specific, including enlargement of the salivary glands because of the lymphocytic infiltration resulting in hyperplasia of salivary ductal epithelium. The infiltrates include focal aggregates (50 or more lymphocytes) starting around the ducts and progressing to involve the entire lobule. The process results in the destruction of some lobules. However, the overall architecture and the appearance of the gland remains intact.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

Common causes of Sjögren’s syndrome include viral infection such as Epstein-Barr virus (EBV), Coxsackie virus, hepatitis C virus, Cytomegalovirus (CMV), Human herpesvirus 6 (HHV-6), Retroviruses and genetic factors.

• HIV is a life-threatening cause of Sjögren’s syndrome.

Sjögren’s syndrome may be caused by:^{[1][2][3][4][5][6]}

• Viral infection
  • Epstein-Barr virus (EBV)
  • Coxsackie virus
  • Hepatitis C virus
  • Cytomegalovirus (CMV)
  • Human herpesvirus 6 (HHV-6)
  • Retroviruses
    • HTLV-I
    • Human endogenous retrovirus and LTRs
    • HIV
• Genetic factors
  • HLA genes
    • HLA-DQB1*0201 and HLA-DQA1*0501 in Caucasian patients
    • DRB1*0803-DQA1*0103-DQB1*0601 in Han Chinese
    • HLA-DR5 in Greek patients
    • DRB1*0405-DRB4*0101-DQA1*0301-DQB1*0401 in Japanese patients
    • DRB1*15 in Spanish patients
  • Non-HLA genes
    • MBL2
    • FCGR2B
    • LTA
    • TNF
    • NCR3
    • NFKBIA
    • TAP2
    • EBF1
    • PTPN22
    • TNFRSF4
    • IL10

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	No underlying causes
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	Epstein-Barr virus (EBV), Coxsackie virus, hepatitis C virus, Cytomegalovirus (CMV) , Human herpesvirus 6 (HHV-6), Retroviruses, HTLV-I , Human endogenous retrovirus and LTRs, HIV
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

List the causes of the disease in alphabetical order.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2]

Sjögren’s syndrome must be differentiated from other diseases that cause arthritis and rash.

Abbreviations: ANA: Antinuclear antibody, RF: Rheumatoid factor, Anti-CCp: Anti-cyclic citrullinated protein antibody, Anti U1RNP: Anti-U1 ribonucleoprotein antibodies , Anti Sm : Anti-Sm antibodies, Anti Ro: Anti Ro antibody also called anti-Sjögren’s-syndrome-related antigen A antibody, Anti-dsDNA: Anti-double stranded DNA.

Disease		Arthritis					Auto-antibodies							Raynaud phenomenon	Rash pattern	Distinguishing/specific features
		Polyarthritis	Tenderness	Edema	Deformity /Erosion	Pattern	ANA	RF	Anti-CCp	Anti U1RNP	Anti Sm	Anti Ro	Anti-dsDNA
Sjögren’s syndrome[1]		+/-	+/-	–	–	Lower extremity, axiallary creases	↑	–	–	–	↑	↑	–	–	Xerosis, scaly skin, annular erythema	Keratoconjunctivitis sicca
Systemic lupus erythematosus[2]		+	+	+	–	Small joints	↑	–	–	–	↑	↑	–	+	Malar rash and photosensitivity
Rheumatoid arthritis (RA)[3]		+	+	+	+	Small and large joints	–	↑↑	↑↑	–	–	–	–	+	Subcutaneous nodules	Erosive arthropathy
Rhupus[4]		+	+	+	+	Small and large joints	↑	↑	↑	↑	↑	–	↑	+	Malar rash and photosensitivity	Erosive arthropathy
Mixed connective tissue disease (MCTD)[5]		–	–	–	+	Small and large joints	–	↑↑	↑	–	–	–	–	+	Cutaneous eruptions, gottron’s papules, photodistributed erythema, poikiloderma, and calcinosis cutis	Overlapping features of SLE, systemic sclerosis (SSc), and polymyositis (PM) that lead to more than one diagnosis
Undifferentiated connective tissue disease (UCTD)[6]		+	–	–	–	Lower extremity	↑	↑	–	–	↑	–	–	+	Erythematous macules, patches, or papules with delicate scale	Multiple connective tissue diseases with no enough criteria for a single diagnosis
Systemic sclerosis (SSc)[7]		+/-	+	+	+/-	Lower extremity	↑↑	–	–	–	↑	–	↑	+	Hyperkeratosis, edema, and erythema	Sclerodactyly, Telangiectasias, Calcinosis, Malignant hypertension, acute renal failure
Vasculitis	Giant cell[8]	–	+	+	–	Distal extremity	–	–	–	–	–	–	–	–	Rare	Involvement of cranial branches of arteries, visual loss
	Takayasu[9]	–	+/-	+/-	–	Transient extremity	–	–	–	–	–	–	–		Erythema nodosum, pyoderma gangrenosum	Absent or weak peripheral pulse
	Poly-arteritis nodosa[10]	–	+/-	–	–	General and mild	–	–	–	–	–	–	–		Tender erythematous nodules, purpura, livedo reticularis, bullous or vesicular eruption	Testicular pain or tenderness and neuropathies
Behçet’s syndrome[11]		+/-	+/-	+/-	–	medium and large joints	–	–	–	–	–	–	–	–	Recurrent and usually painful mucocutaneous ulcers, acneiform lesions, papulo-vesiculo-pustular eruptions, superficial thrombophlebitis	Male dominancy
Kikuchi’s disease[12]		–	+/-	–	–	medium and large joints	↑/↓	–	–	–	–	–	–	–	Transient skin rashes, malar rash, erythematous macules, patches, papules, or plaques	May be associated with SLE
Serum sickness[13]		+	+	+/-	–	General	–	–	–	–	–	–	–	–	Pruritic rash, urticaria and/or serpiginous macular rash	Self-limited
Psoriatic arthritis[14]		–	–	–	–	Small and large joints	–	–	–	–	–	–	–	–	Psoriasis and onychodystrophy	Dactylitis (sausage digits)
Human parvovirus B19 infection[15]		+	+	–	–	Small joints	–	–	–	–	–	–	–	–	Erythematous rashes	Rare in adults, fifth’s disease in children

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

The incidence of Sjögren’s syndrome is approximately 4 per 100,000 individuals worldwide. The prevalence of Sjögren’s syndrome is approximately 43 per 100,000 individuals worldwide. The mortality rate of Sjögren’s syndrome is approximately 1.38. Female are more commonly affected by Sjögren’s syndrome than male. The majority of Sjögren’s syndrome cases are reported in China, Japan, and California.

• The incidence of Sjögren’s syndrome is approximately 4 per 100,000 individuals worldwide.^[1][2]

• The prevalence of Sjögren’s syndrome is approximately 43 per 100,000 individuals worldwide.^[3][4]

• The mortality rate of Sjögren’s syndrome is approximately 1.38.^[5]

• It can occur at any age, but the mean age is usually in the 4th to 5th decade.^[6]

• There is no racial predilection to Sjögren’s syndrome.

• Female are more commonly affected by Sjögren’s syndrome than male. The female to male ratio is approximately 9 to 1.

• The majority of Sjögren’s syndrome cases are reported in China, Japan, and California.^[7]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

Common risk factors in the development of Sjögren’s syndrome include family history of autoimmune diseases, serological markers such as low complement levels and cryoglobulinaemia and parotid gland enlargement.

• Common risk factors in the development of Sjögren’s syndrome include family history of autoimmune diseases, serological markers such as low complement levels and cryoglobulinaemia and parotid gland enlargement.

• Common risk factors in the development of Sjögren’s syndrome include:^[1][2][3]
  • Family history of autoimmune diseases
  • Male sex
  • Serological markers such as low complement levels and cryoglobulinaemia
  • Parotid gland enlargement
  • Advancing age

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

There is insufficient evidence to recommend routine screening for Sjögren’s syndrome.

There is insufficient evidence to recommend routine screening for Sjögren’s syndrome.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

The symptoms of Sjögren’s syndrome usually develop in the 4th and 5th decade of life, and start with symptoms such as ocular and oral dryness. Common complications of Sjögren’s syndrome include blurred vision and corneal damage, optic neuritis and lymphoma. Prognosis is generally good and presence of low complement level is associated with a particularly poor prognosis among patients with Sjögren’s syndrome.

• The symptoms of Sjögren’s syndrome usually develop in the 4th and 5th decade of life, and start with symptoms such as ocular and oral dryness.^[1]
• If left untreated, 4.3% of patients with Sjögren’s syndrome may progress to develop non-Hodgkin lymphoma.

• Common complications of Sjögren’s syndrome include:^[2][3][4]
  • Dental cavities
  • Yeast infections
  • Blurred vision and corneal damage
  • Pneumonia
  • Bronchitis
  • Lymphoma
  • Peripheral neuropathy
  • Myelitis
  • Optic neuritis

• Prognosis is generally good and presence of low complement level is associated with a particularly poor prognosis among patients with Sjögren’s syndrome.^[5]
• Primary Sjögren syndrome is associated with lower cardiovascular risk factors and lower risk of cardiovascular complications such as myocardial infarction and stroke, in comparison with SLE.^[6]