Sjogren Syndrome 

Updated: Apr 07, 2020
Author: Sriya K Ranatunga, MD, MPH; Chief Editor: Herbert S Diamond, MD 

Overview

Practice Essentials

Sjögren syndrome is a systemic chronic inflammatory disorder characterized by lymphocytic infiltrates in exocrine organs. The disorder most often affects women, and the median age of onset is around 50 to 60 years. Most individuals with Sjögren syndrome present with sicca symptoms, such as xerophthalmia (dry eyes), xerostomia (dry mouth), and parotid gland enlargement, which is seen in the image below.[1] (See Presentation.)

Marked bilateral parotid gland enlargement in a pa Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding.

In addition, numerous extraglandular features may develop, such as the following:

  • Arthralgia
  • Arthritis
  • Myalgia
  • Pulmonary disease
  • Gastrointestinal disease
  • Leukopenia
  • Anemia
  • Lymphadenopathy
  • Neuropathy
  • Vasculitis
  • Renal tubular acidosis
  • Lymphoma

About 50% of patients with Sjögren syndrome have cutaneous findings, such as dry skin (xeroderma), palpable and nonpalpable purpura, and/or urticaria.[1] (See Etiology, Presentation, and Workup.)

Primary Sjögren syndrome occurs in the absence of another underlying rheumatic disorder, whereas secondary Sjögren syndrome is associated with another underlying rheumatic disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or scleroderma. Given the overlap of Sjögren syndrome with many other rheumatic disorders, it is sometimes difficult to determine whether a clinical manifestation is solely a consequence of Sjögren syndrome or is due to one of its overlapping disorders.

Importantly, classic clinical features of Sjögren syndrome may also be seen in infections with certain viruses. These include hepatitis C virus, human immunodeficiency virus (HIV), and human T-cell lymphotrophic virus (HTLV). (See DDx.) 

Most patients with primary Sjogren syndrome have two specific antibodies: against Ro (SS-A) and La (SSB) antigens. (See Workup.)

Treatment for Sjögren syndrome is largely based on symptoms (eg, lotion for dry skin, artificial tears for dry eyes). Rituximab has shown promise in the treatment of severe extraglandular manifestations (eg, vasculitis, cryoglobulinemia, peripheral neuropathy). Patients must be monitored carefully for the potential development of lymphoma, as the risk for this disease is significantly higher than in the general population. (See Treatment and Medication.)

For more information on other aspects of Sjögren syndrome, see Pediatric Sjögren Syndrome and Ophthalmologic Manifestations of Sjögren Syndrome.

Classification criteria

A number of classification criteria for Sjögren syndrome were designed primarily for clinical research studies but are also often used to help guide clinical diagnoses. The American-European Consensus Group’s criteria for the classification of Sjögren syndrome were proposed in 2002 and are the most commonly used criteria for the diagnosis of Sjögren syndrome. A new set of classification criteria was developed by the Sjögren’s International Collaborative Clinical Alliance (SICCA) investigators and accepted as a provisional criteria set by the American College of Rheumatology (ACR) in 2012.

In 2012, investigators from the SICCA team and the EULAR Sjögren’s Task Force formed the International Sjögren’s Syndrome Criteria Working Group. The Task Force's work was published in 2016 as ACR/European League Against Rheumatism (EULAR) classification criteria for primary Sjögren syndrome.[2]

American-European Consensus Group classification

The American-European Consensus Group (AECG) criteria for the classification of Sjögren syndrome are outlined below.[3, 4] These criteria allow a diagnosis of Sjögren syndrome in patients without sicca symptoms or who have not undergone a biopsy.

According to the American-European classification system (as modified by Tzioufas and Voulgarelis[5] ), diagnosis of primary Sjögren syndrome requires at least four of the criteria listed below; in addition, either criterion number 5 or criterion number 6 must be included. Sjögren syndrome can be diagnosed in patients who have no sicca symptoms if three of the four objective criteria are fulfilled. The criteria are as follows:

  1. Ocular symptoms - Dry eyes for more than 3 months, foreign-body sensation, use of tear substitutes more than 3 times daily
  2. Oral symptoms - Feeling of dry mouth, recurrently swollen salivary glands, frequent use of liquids to aid swallowing

  3. Ocular signs - Schirmer test performed without anesthesia (< 5 mm in 5 min), positive vital dye staining results

  4. Oral signs - Abnormal salivary scintigraphy findings, abnormal parotid sialography findings, abnormal sialometry findings (unstimulated salivary flow < 1.5 mL in 15 min)

  5. Positive minor salivary gland biopsy findings

  6. Positive anti–SSA or anti–SSB antibody results

Secondary Sjögren syndrome is diagnosed when, in the presence of a connective-tissue disease, symptoms of oral or ocular dryness exist in addition to criterion 3, 4, or 5, above.

Application of these criteria has yielded a sensitivity of 97.2% and a specificity of 48.6% for the diagnosis of primary Sjögren syndrome. For secondary Sjögren syndrome, the specificity is 97.2% and the sensitivity, 64.7%.[6]

Exclusion criteria include any of the following:

  • Past head-and-neck irradiation
  • Hepatitis C virus infection
  • Acquired immunodeficiency syndrome (AIDS)
  • Prior lymphoma
  • Sarcoidosis
  • Graft versus host disease
  • Use of anticholinergic drugs

ACR/EULAR classification criteria for primary Sjogren syndrome

According to the ACR/EULAR classification criteria, individuals are classified as having primary Sjögren syndrome if they have a total score of 4 or higher, derived from the sum of the weights assigned to the following[2] :

  • Focal lymphocytic sialadenitis and focus score of ≥1 foci/4 mm² in labial salivary gland biopsy samples  –  weight/score 3
  • Anti-SSA/Ro positive  – weight/score 3
  • Ocular Staining Score ≥5 (or van Bijsterveld score ≥4) in at least one eye  –  weight/score 1
  • Schirmer’s test ≤5 mm/5 min in at least one eye – weight/score 1
  • Unstimulated whole saliva flow rate ≤0.1 mL/min – weight/score 1

For inclusion, patients must have at least one symptom of ocular or oral dryness, defined as a positive response to at least one of the following questions:

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

Exclusion criteria include any of the following:

  • History of head-and-neck radiation treatment
  • Active hepatitis C infection (with confirmation by polymerase chain reaction [PCR]) testing
  • AIDS
  • Sarcoidosis
  • Amyloidosis
  • Graft versus host disease
  • IgG4-related disease

Complications

Complications related to Sjögren syndrome include the following (see Prognosis, Treatment, and Medication):

  • Emergence of disorders associated with Sjögren syndrome, such as SLE and RA

  • Infection of the parotid gland, typically staphylococcal, streptococcal, or pneumococcal - clues include unilateral worsening of symptoms, along with tenderness, warmth, and erythema

  • Emergence of parotid tumors - watch for unusually hard or unilateral parotid enlargement

  • Pregnant patients with antiRo/SS-A antidodies are at risk for fetal loss, complete heart block in the fetus ,and neonatal lupus syndrome in the newborn

  • Emergence of pseudolymphomas (pleomorphic cells that do not meet the criteria for malignancy) and non-Hodgkin B-cell lymphomas (see the image below)[5]

    Clinical photograph and photomicrograph of a 48-ye Clinical photograph and photomicrograph of a 48-year-old man with Sjögren syndrome with a large left parotid mass. On biopsy, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type was identified. Microscopic section of parotid biopsy, stained with immunoperoxidase for kappa light chains (brown-stained cells), showed monoclonal population of B cells, confirming the diagnosis.

Patient education

Educate patients with Sjögren syndrome on avoidance strategies and self-care issues for the treatment of dry mouth, eyes, skin, and vagina. Patient education pamphlets regarding the disease are available through the Arthritis Foundation. The Sjögren’s Syndrome Foundation, founded in 1983, is a good resource for patients. The foundation can be contacted at 6707 Democracy Blvd, Ste 325, Bethesda, MD, 20817; (800) 475-6473, (301) 530-4415 (fax).

For patient education information, see the Arthritis Center, as well as Sjögren’s Syndrome.

Etiology

Sjögren syndrome can occur as a primary disease of exocrine gland dysfunction or in association with several other autoimmune diseases (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis, scleroderma, systemic sclerosis, cryoglobulinemia, polyarteritis nodosa). These primary and secondary types occur with similar frequency, but the sicca complex seems to cause more severe symptoms in the primary form.

Virtually all organs may be involved. The disease commonly affects the eyes, mouth, parotid gland, lungs, kidneys, skin, and nervous system.

The etiology of Sjögren syndrome is not well understood. The presence of activated salivary gland epithelial cells expressing major histocompatibility complex (MHC) class II molecules and the identification of inherited susceptibility markers suggest that environmental or endogenous antigens trigger a self-perpetuating inflammatory response in susceptible individuals. In addition, the continuing presence of active interferon pathways in Sjögren syndrome suggests ongoing activation of the innate immune system.[7, 8] Together, these findings suggest an ongoing interaction between the innate and acquired immune systems in Sjögren syndrome.

Association with the human leukocyte antigen

The frequency of HLA-DR52 in patients with primary Sjögren syndrome is estimated to be 87%, but it is also significantly increased in secondary Sjögren syndrome that occurs with rheumatoid arthritis or systemic lupus erythematosus.

The genetic associations in Sjögren syndrome vary among ethnic groups. In white persons, for instance, the condition is linked to human leukocyte antigen (HLA)–DR3, HLA-DQ2, and HLA-B8,[9] whereas the linkage is to HLA-DRB1*15 in Spanish persons[10] and to HLA-DR5 in Greek and Israeli persons.[11]

Some evidence indicates that the true association of Sjögren syndrome may be with HLA-DQA1, which is in linkage disequilibrium with HLA-DR3 and HLA-DR5.[12] These HLA associations appear restricted to individuals with Sjögren syndrome who have antibodies to the antigens SSA and SSB rather than to the disease manifestations themselves.[13]

Possible disease triggers

Viruses are viable candidates as environmental triggers, although proof of causation has remained elusive, and certainly no single virus has been implicated. Epstein-Barr virus (EBV), HTLV-1, human herpesvirus 6 (HHV-6), HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) may have a role. Sjögrenlike syndromes are seen in patients infected with HIV, HTLV-1, and hepatitis C.[14, 15, 16]

Damage and/or cell death due to viral infection or other causes may provide triggering antigens to Toll-like receptors in or on dendritic or epithelial cells, which, by recognizing pathogen-associated patterns, are activated and begin producing cytokines, chemokines, and adhesion molecules. As T and B lymphocytes migrate into the gland, they themselves become activated by dendritic and epithelial cells, thereafter acting as antigen-presenting cells.[17]

Expressed antigens include SSA/Ro, SSB/La, alpha-fodrin and beta-fodrin, and cholinergic muscarinic receptors.[13] Dendritic cell triggering by immune complexes formed from SSA ̶ anti-SSA (or other immune complexes) may propagate the ongoing innate and acquired immune activation.

Glandular pathology

The pathology of a typical involved salivary or lacrimal gland in Sjögren syndrome reveals aggregations of lymphocytes—periductal at first, then panlobular. These cells are primarily CD4 T cells (75%) and memory cells, with 10% B cells and immunoglobulin-secreting plasma cells. Although individual lobules can be destroyed, salivary gland biopsy samples from patients with Sjögren syndrome typically retain 40%-50% of their viable glandular structure. Therefore, inflammatory destruction of salivary and lacrimal glands may not fully account for the symptoms of Sjögren syndrome.[18]

Studies suggest that the disease process of Sjögren syndrome has a neuroendocrine component. Proinflammatory cytokines released by epithelial cells and lymphocytes may impair neural release of acetylcholine. In addition, antibodies to acetylcholine (muscarinic) receptors may interfere with the neural stimulation of local glandular secretion,[19] perhaps by interfering with aquaporin.[20] Moreover, a study reports that M3 muscarinic receptor antibodies may cause autonomic dysfunction in patients with Sjögren syndrome.[21, 22]

Current studies have also focused on the role of apoptotic mechanisms in the pathogenesis of primary Sjögren syndrome. A defect in Fas-mediated apoptosis, which is necessary for down-regulation of the immune response, can result in a chronic inflammatory destruction of the salivary gland, resembling Sjögren syndrome.[23]

Owing to these structural and functional changes in the lacrimal and salivary glands, their aqueous output is diminished. In the eye, tear hyperosmolarity results and is itself a proinflammatory stimulus, resulting in an inflammatory cascade on the ocular surface,[24] with evidence of immune activation of the conjunctival epithelium and local cytokine and metalloproteinase production. Damage to the corneal epithelium, already vulnerable due to inadequate tear film protection, ensues, with resultant epithelial erosions and surface irregularity.

Extraglandular involvement

Extraglandular involvement in Sjögren syndrome manifests in part as hypergammaglobulinemia and the production of multiple autoantibodies, especially ANA and RF. This may be due to polyclonal B-cell activation, but the cause of this expanded activation is not known.

Involvement of other organs and tissues may result from effects of these antibodies, immune complexes, or lymphocytic infiltration and occurs in one third of patients with Sjögren syndrome. Prolonged hyperstimulation of B cells may lead to disturbances in their differentiation and maturation and may account for the greatly increased incidence of lymphoma in these patients.[25]

Sex hormones

Sex hormones may influence the immunologic manifestations of primary Sjögren syndrome, because the disease is much more common in women than in men. The prevalence of serologic markers tends to be lower in male patients than in female patients. Although the role of sex hormones (eg, estrogens, androgens) in the pathogenesis of primary Sjögren syndrome remains unknown, adrenal and gonadal steroid hormone deficiency probably affects immune function.

Epidemiology

In the United States, Sjögren syndrome is estimated to be the second most common rheumatologic disorder, behind SLE. Sjögren syndrome affects 0.1-4% of the population. This wide range, in part, reflects the lack of uniform diagnostic criteria.[26] Internationally, comparative studies between different ethnic groups have suggested that Sjögren syndrome is a homogeneous disease that occurs worldwide with similar prevalence and affects 1-2 million people.

The female-to-male ratio of Sjögren syndrome is 9:1. Sjögren syndrome can affect individuals of any age but is most common in elderly people. Onset typically occurs in the fourth to fifth decade of life.

The systemic phenotype of primary Sjögren syndrome is strongly influenced by personal factors (eg, age, gender, ethnicity, place of residence, according to an analysis by the Sjögren Big Data Consortium, a five-continent multicenter registry, of a cohort that included 10,007 patients (9352 female, mean age 53 years) with recorded European League Against Rheumatism's Sjögren syndrome disease activity index (ESSDAI) scores available.[27] Findings (all P < 0.001) were as follows:

  • Males had a higher mean ESSDAI than females (8.1 vs 6.0, respectively).
  • Patients diagnosed at < 35 years had a higher mean ESSDAI than those diagnosed at > 65 years (6.7 vs 5.6).
  • By ethnicity, the highest global ESSDAI scores were reported in blacks/African Americans (6.7), followed by whites (6.5), Asians (5.4), and Hispanics (4.8).
  • Black/African American patients showed the highest frequencies in the lymphadenopathy, articular, peripheral and central nervous system, and biological domains.
  • White patients showed the highest frequencies in the glandular, cutaneous, and muscular domains.
  • Asian patients showed the highest frequencies in the pulmonary, renal, and hematological domains.
  • Hispanic patients showed the highest frequenies in the constitutional domain.
  • Systemic activity and disease activity was higher in patients from southern countries.

Prognosis

Sjögren syndrome carries a generally good prognosis. In patients who develop a disorder associated with Sjögren syndrome, the prognosis is more closely related to the associated disorder (eg, SLE, lymphoma). Interestingly, primary Sjögren syndrome is associated with lower cardiovascular risk factors and lower risk of serious cardiovascular events such as myocardial infarction and stroke, in comparison with SLE.​[28]

Although salivary and lacrimal function generally stabilize, the presence of SSA and/or hypocomplementemia may predict a decline in function.[29]

Morbidity and mortality

Morbidity associated with Sjögren syndrome is mainly associated with the gradually decreased function of exocrine organs, which become infiltrated with lymphocytes. The increased mortality rate associated with the condition is primarily related to disorders commonly associated with Sjögren syndrome, such as SLE, RA, and primary biliary cirrhosis. Patients with primary Sjögren syndrome who do not develop a lymphoproliferative disorder have a normal life expectancy.[30]

Lymphoma

Among patients with Sjögren syndrome, the incidence of non-Hodgkin lymphoma is 4.3% (18.9 times higher than in the general population), with a median age at diagnosis of 58 years. The mean time to the development of non-Hodgkin lymphoma after the onset of Sjögren syndrome is 7.5 years.

The most common histologic subtype of non-Hodgkin lymphoma in Sjögren syndrome is mucosa-associated lymphoid tissue (MALT) lymphoma, which can develop in any nonlymphoid tissue infiltrated by periepithelial lymphoid tissue—most commonly the salivary glands, but also the stomach, nasopharynx, skin, liver, kidneys, and lungs. The progression of these infiltrates to lymphoma occurs slowly and in a stepwise fashion. Lymphoma is present at more than 1 site in 20% of patients at initial diagnosis.

The results of one study suggest that diagnostic labial salivary gland tissue biopsy can be used to detect germinal center ̶ like lesions, which can be a highly predictive and easily obtained marker for non-Hodgkin lymphoma in primary Sjögren syndrome patients.[31]

Risk factors for lymphoma include the following;

  • Salivary gland enlargement
  • Regional or generalized lymphadenopathy
  • Hepatosplenomegaly
  • Palpable purpura
  • Leukopenia
  • Renal insufficiency
  • Loss of a previously positive polyclonal gammopathy
  • Development of a monoclonal gammopathy or a monoclonal cryoglobulinemia
  • RF positivity
  • Anti-SSA/SSB positivity
  • Hypocomplementemia

Pregnancy complications

Women with Sjögren syndrome are at higher risk for experiencing complications during pregnancy. Worsening of pulmonary hypertension and increased rates of spontaneous abortion and preterm deliveries have been reported.[32]

Children born to mothers with antibodies against SSA/Ro are at an increased risk of neonatal lupus and congenital heart block. If one such child develops congenital heart block, the risk for congenital heart block during a subsequent pregnancy is 15%.

Antiphospholipid syndrome

Patients with Sjögren syndrome who have antiphospholipid antibodies can develop the clinical features of antiphospholipid syndrome, which include increased fetal wastage and vascular thromboses.

 

Presentation

History

The clinical presentation of Sjögren syndrome may vary. Most patients are women, and onset is usually at age 40-60 years, but the syndrome also can affect men and children. The onset is insidious. The first symptoms in primary Sjögren syndrome can be easily overlooked or misinterpreted, and diagnosis can be delayed for as long as several years.

Xerophthalmia (dry eyes) and xerostomia (dry mouth) are the main clinical presentations in adults. Bilateral parotid swelling is the most common sign of onset in children.

Extraglandular involvement in Sjögren syndrome falls into two general categories: periepithelial infiltrative processes and extraepithelial extraglandular involvement. Periepithelial infiltrative processes include interstitial nephritis, liver involvement, and bronchiolitis and generally follow a benign course.

Extraepithelial extraglandular involvement in Sjögren syndrome is related to B-cell hyperreactivity, hypergammaglobulinemia, and immune complex formation and includes palpable purpura, glomerulonephritis, and peripheral neuropathy. These latter manifestations occur later in the course of Sjögren syndrome and are associated with a higher risk of transformation to lymphoma.[5]

Symptoms of Sjögren syndrome can decrease the patient's quality of life in terms of its physical, psychological, and social aspects.

Sicca symptoms (dry eyes and dry mouth)

Although dry eyes and dry mouth are the most common symptoms in patients with Sjögren syndrome, most patients who report these symptoms have other underlying causes. The incidence of sicca symptoms increases with age. Indeed, more than one third of elderly persons have sicca symptoms. Whether this is part of the normal aging process (associated with fibrosis and atrophy observed on some lip biopsy studies) or is due to the accumulation of associated illnesses and medications is unclear.[33]

Common medications that can cause sicca symptoms in any age group include antidepressants, anticholinergics, beta blockers, diuretics, and antihistamines. Anxiety can also lead to sicca symptoms. Women who use hormone replacement therapy may be at increased risk of dry eye syndrome.[34]

Patients may describe the effects dry mouth in the following ways:

  • Inability to eat dry food (eg, crackers) because it sticks to the roof the mouth

  • Tongue sticking to the roof of the mouth

  • Putting a glass of water on the bed stand to drink at night (and resulting nocturia)

  • Difficulty speaking for long periods of time or the development of hoarseness

  • Higher incidence of dental caries and periodontal disease

  • Altered sense of taste

  • Difficulty wearing dentures

  • Development of oral candidiasis with angular cheilitis, which can cause mouth pain

Dry eyes may be described as red, itchy, and painful. However, the most common complaint is that of a gritty or sandy sensation in the eyes. Symptoms typically worsen throughout the day, probably due to evaporation of the already scanty aqueous layer. Some patients awaken with matting in their eyes and, when severe, have difficulty opening their eyes in the morning. Blepharitis can also cause similar morning symptoms.

Parotitis

Patients with Sjögren syndrome may have a history of recurrent parotitis, often bilateral. Although in some patients the parotid glands become so large that the patients report this as a problem, more often the examining physician discovers them.

Cutaneous symptoms

Nonvasculitic cutaneous manifestations in Sjögren syndrome include the following[35] :

  • Dryness
  • Eyelid dermatitis
  • Pruritus
  • Erythema annulare

Cutaneous vasculitis, such as palpable purpura, develops in some patients with Sjögren syndrome, especially those with hypergammaglobulinemia or cryoglobulinemia.[35, 36] Raynaud phenomenon is observed in approximately 20% of patients.

Pulmonary symptoms

Patients with Sjögren syndrome can develop dryness of the tracheobronchial mucosa (xerotrachea), which can manifest as a dry cough.[37] Less often, patients develop dyspnea from an interstitial lung disease that is typically mild.[37, 38] Patients may develop recurrent bronchitis or even pneumonitis (infectious or noninfectious).

Gastrointestinal symptoms

Dryness of the pharynx and esophagus frequently leads to difficulty with swallowing (deglutition), in which case patients usually describe food becoming stuck in the upper throat.[37] Lack of saliva may lead to impaired clearance of acid and may result in gastroesophageal reflux and esophagitis.

Abdominal pain and diarrhea can occur. Rarely, patients develop acute or chronic pancreatitis, as well as malabsorption due to pancreatic insufficiency. However, caution is advised when interpreting laboratory results because an elevated amylase level may arise from the parotid gland.

Patients with gastritis should be tested for Helicobacter pylori infection, because of its association with gastric mucosa–associated lymphoid tissue lymphomas.[39]

Patients with Sjögren syndrome are at increased risk for delayed gastric emptying, which can cause early satiety, upper abdominal discomfort, nausea, and vomiting.[40]

Cardiac symptoms

Pericarditis and pulmonary hypertension, with their attendant symptomatology, can occur in Sjögren syndrome.[41] Orthostatic symptoms related to dysfunction of autonomic control of blood pressure and heart rate is associated with increased severity of Sjögren syndrome.[42]

Neurologic symptoms

The occurrence of central nervous system (CNS) and spinal cord involvement in Sjögren syndrome is estimated by various studies to be 8-40%, with manifestations including myelopathy, optic neuropathy, seizures, cognitive dysfunction, and encephalopathy.[25, 43, 44] Attempts must be made to distinguish other causes of these symptoms, including concomitant SLE, multiple sclerosis, cerebrovascular disease, and Alzheimer disease.

Sensory, motor, or sensorimotor peripheral neuropathy, often subclinical, can be detected in up to 55% of unselected patients with Sjögren syndrome.[45] Symptoms of distal paresthesias may be present. Cranial neuropathies can develop, particularly trigeminal neuropathy or facial nerve palsy. Mononeuritis multiplex should prompt a search for a vasculitis.

Progressive weakness and paralysis secondary to hypokalemia due to underlying renal tubular acidosis can occur and is potentially treatable.[46]

Renal symptoms

Renal calculi, renal tubular acidosis, and osteomalacia, nephrogenic diabetes insipidus, and hypokalemia can occur secondary to tubular damage caused by interstitial nephritis, the most common form of renal involvement in Sjögren syndrome.

Interstitial cystitis, with symptoms of dysuria, frequency, urgency, and nocturia, is strongly associated with Sjögren syndrome.[47, 48]

Glomerulonephritis can be caused by Sjögren syndrome but is uncommon and is usually attributable to another disorder, such as SLE or mixed cryoglobulinemia.

Additional symptoms

Nasal dryness can result in discomfort and bleeding. Women may also have a dry vagina, which can lead to dyspareunia, vaginitis, and pruritus.

Patients with Sjögren syndrome may report fatigue, joint pain, and, sometimes, joint swelling. A careful review of systems must be performed to differentiate these from the manifestations of other disorders (see DDx). Fibromyalgia is common in patients with Sjögren syndrome, with a prevalence of about 31%.[49]

Women with Sjögren syndrome may have a history of recurrent miscarriages or stillbirths, and women and men may have a history of venous or arterial thrombosis. These are related to the presence of antiphospholipid antibodies (eg, lupus anticoagulant or anticardiolipin antibodies).

Secondary Sjogren syndrome

Secondary Sjögren syndrome appears late in the course of the primary disease. However, in some patients, primary Sjögren syndrome may precede SLE by many years. Secondary Sjögren syndrome is usually mild, and sicca symptoms are the main feature. Unlike patients with primary Sjögren syndrome, persons with the secondary type have significantly fewer systemic manifestations. These manifestations include the following:

  • Salivary gland swelling
  • Lung involvement
  • Nervous system involvement
  • Renal involvement
  • Raynaud phenomenon
  • Lymphoproliferative disorders

In secondary Sjögren syndrome, symptoms of the primary disease predominate. Secondary Sjögren syndrome does not modify the prognosis or outcome of the basic disease. Polyarteritis nodosa and Sjögren syndrome may also coexist, perhaps best viewed as an overlap syndrome.[50]

Physical Examination

The physical signs of primary Sjögren syndrome can be divided into glandular and extraglandular signs.

Glandular signs

Ocular

While it is important to look for corneal lesions and a decreased tear pool in the lower conjunctiva during physical examination, patients with Sjögren syndrome should be referred to an ophthalmologist for more formal testing of keratoconjunctivitis sicca (KCS). This testing applies grading criteria of inflammatory changes that can direct therapy aimed at preventing corneal damage.[51] In addition, conditions that mimic KCS, such as blepharitis, conjunctivitis, and uveitis can be ruled out or treated.

Patients with Sjögren syndrome may have dilated conjunctival vessels, as well as pericorneal injection and dullness or irregularity of the corneal image. Blepharitis may be present as an alternate or additional problem, particularly if the lower eyelid is inflamed.

Mucinous threads and filamentary keratosis can be detected during a slit-lamp examination. The relative lack of the aqueous layer also leads to rapid tear breakup.

In the Schirmer test, a bent piece of Whatman number 41 filter paper is placed in the lower conjunctiva, and the amount of tearing on the filter paper is recorded. Normal wetting is greater than 15 mm after 5 minutes, whereas a definitive positive result is less than 5 mm after 5 minutes. This test can help to exclude or confirm significant dryness of the eyes, but it is not disease-specific. Furthermore, false-positive results occur. An evaluation of the diagnostic performance of the Schirmer test yielded a sensitivity of 42% and a specificity of 76% for Sjögren syndrome. (See the image below.)[52]

Photograph that demonstrates the Schirmer test, wh Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome. The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis.

Oral

Oral signs include the following:

  • Dryness

  • Tongue - Red, smooth, and dry (see the image below)

  • Dental caries - Severe and progressive

  • Parotid duct narrowing

  • Lips - Red, dry, and scaly

  • Cracks at the corners of the mouth

  • Chronic oral candidiasis

    Dryness of the mouth and tongue due to lack of sal Dryness of the mouth and tongue due to lack of salivary secretion is characteristic of xerostomia associated with Sjögren syndrome. Mouth dryness may produce a deep red tongue, as shown here, and dental caries are common.

Look for a decreased sublingual salivary pool. The tongue may stick to the tongue depressor. Patients with Sjögren syndrome may develop frequent caries, sometimes in unusual locations such as the incisor surface and the gum line.

Patients with Sjögren syndrome are prone to develop oral candidiasis. In addition to white patches, watch for petechial lesions, loss of tongue papilla, erythema and fissuring of the tongue, erythema on other mucosal surfaces, and angular cheilosis. Oral candidiasis can be seen under dentures.

Gingival inflammation has been found to be more evident in the individuals with Sjögren syndrome, particularly those with secondary Sjögren syndrome.[53] Periodontal disease can lead to loss of teeth.

Parotid glands

Sjögren syndrome appears to negatively affect the periodontal condition. Recurrent swelling of the parotid glands (22-66% of patients) occurs; submaxillary and sublingual gland swelling also sometimes takes place.

Bilateral parotid gland enlargement is common in persons with Sjögren syndrome (see the image below). Some waxing and waning of size may occur. Exudates from the parotid gland are largely lymphocytes.

Marked bilateral parotid gland enlargement in a pa Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding.

Rock-hard or unilateral parotid gland enlargement should prompt referral to an otolaryngologist for biopsy to exclude a tumor. Other causes of parotid enlargement include diabetes, sarcoidosis, amyloidosis, diffuse infiltrative lymphocytic syndrome (DILS) of HIV disease, hepatitis C, and alcoholism. Acute, unilateral parotitis may be caused by Sjögren syndrome, infection, or obstruction, although the latter 2 conditions are more often associated with a very tender parotid gland and accompanying fever.

Other mucous membranes

Other mucous membrane signs include the following:

  • Atrophic changes in the mucous membranes of the upper respiratory tract, leading to nasal dryness, recurrent infections, hoarseness, and aphonia

  • Atrophic rhinitis

  • Atrophic changes in the vulva and vagina resulting in pruritus and vaginitis

  • Dryness of the anal and rectal mucous membranes (eg, pruritus, inflammation)

Cutaneous

Dryness of the skin occurs in 50% of patients with Sjögren syndrome; scaling occurs in about 25% of patients. The skin may be irritable, with secondary lichenification. Partial or complete loss of sweating may be present.

Hair may be dry, sparse, and brittle; diffuse alopecia may involve the scalp, limbs, axillae, or pubis. Nail folds may show capillaroscopic abnormalities, which are associated with the presence of antiendothelial cell antibodies.[54] Erythema of the nose and cheeks may be present.

Patients with Sjögren syndrome can develop a nonpalpable or palpable, vasculitic purpura, with lesions that are typically 2-3 mm in diameter and located on the lower extremities. The lesions, which can ulcerate, occur most often in patients with hypergammaglobulinemia or cryoglobulinemia.[36, 35]

Annular erythema with scales, localized especially on the face and neck, is recognized as a cutaneous manifestation of Sjögren syndrome. The patches are recurrent and resolve without hyperpigmentation; no photosensitivity is observed.[55]  Annular erythema is a common cutaneous manifestation in Japanese and other Asian patients; however, it is rarely seen in white patents.[56]

In Japanese patients with Sjögren syndrome, annular erythema is divided into the following 3 types:

  • Sweet disease–like annular erythema with an elevated border
  • Subacute cutaneous lupus erythematosus–like, marginally scaled erythema
  • Papular erythema

Those lesions bear some clinical similarities to the annular lesions of subacute cutaneous lupus erythematosus, but their histopathologic features are distinct from those of subacute cutaneous lupus erythematosus. Significant mucin depositions are observed.

Extraglandular signs

Gastrointestinal

Gastrointestinal tract signs include the following:

  • Esophageal motility abnormalities

  • Pancreatic involvement

  • Splenomegaly

  • Digestive symptoms (due to atrophy of the gastric mucous membrane with achlorhydria)

  • Hepatitis (13%)

Pulmonary

Pulmonary abnormalities occur in 9-29% of cases; they are similar in primary and secondary Sjögren syndrome. Lung signs include the following[57] :

  • Pulmonary fibrosis

  • Pulmonary hypertension

  • Recurrent chest infections

  • Granulomatous infiltration and fibrosing alveolitis

  • Restrictive ventilatory defect

  • Impaired gas transfer

  • Bibasilar rales – Can be heard in patients with interstitial lung disease

Articular

Articular changes (eg, arthritis) occur in 42% of patients with Sjögren syndrome; arthritis can be a component of either the primary or secondary form of the disease. One third of patients with RA have Sjögren syndrome.

Symmetrical, polyarticular, inflammatory arthritis suggests underlying RA or a connective-tissue disease such as SLE or scleroderma. The arthritis in patients with primary Sjögren syndrome is typically nonerosive and mild.

Urinary tract

Patients with Sjögren syndrome have significantly more urinary problems than do those without Sjögren syndrome. Patients may have the following:

  • Irritated bladder

  • Suprapubic pain

  • Renal tubular dysfunction - Patients with primary Sjögren syndrome commonly are first seen because of renal impairment, usually from renal tubular dysfunction[58]

  • Renal tubular acidosis - This affects one third of patients with Sjögren syndrome; a correlation apparently exists between hypergammaglobulinemia and distal renal tubular acidosis[58]

  • Interstitial nephritis - This is rare, occurring in 4% of cases; it is often accompanied by cryoglobulinemia, a decreased level of complement, and the presence of circulating immune complexes

  • Impaired renal concentrating ability, generalized aminoaciduria

Neurologic

A combination of lesions and relapses can suggest multiple sclerosis. Myelopathy rarely occurs in the course of primary Sjögren syndrome. It appears as Brown-Séquard syndrome, acute transverse myelitis, or progressive myelopathy. Clinically, cases with nervous system involvement present with paraparesis or paraplegia resulting from lesions at the thoracic or cervicothoracic levels.

Peripheral neuropathy occurs in 10-35% patients with primary Sjögren syndrome. Peripheral nerve dysfunction—such as trigeminal sensory neuropathy, mononeuropathy multiplex, distal sensorimotor polyneuropathy, or pure sensory neuropathy—may occur. This tends to be a small-fiber peripheral neuropathy.[59] Painful, distal paresthesias in the feet may be evident, as may abnormal sweating. Examination may reveal findings that include decreased pinprick sensation.

Isolated cranial nerve involvement rarely occurs in primary Sjögren syndrome. CNS involvement also is less common (10-25% of patients with Sjögren syndrome) than are other types of involvement; CNS pathology ranges from neuropathy, hemiparesis, transverse myelitis, and dystonia to encephalopathy and dementia.

In Sjögren syndrome, focal brain lesions can be present in the cerebral white matter. In addition, dysregulation of hypothalamic-pituitary-adrenal and thyroid axes can cause some neurologic disturbances.

 

DDx

Diagnostic Considerations

Sjögren syndrome is associated with a wide variety of other disorders, which may contribute to underdiagnosis or misdiagnosis. A careful review of systems is needed to detect problems such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, polymyositis, chronic active hepatitis, idiopathic pulmonary fibrosis, primary biliary cirrhosis,[60] and autoimmune thyroid disease.[61]

Xerophthalmia, xerostomia, and enlargement of the parotid glands can result from adverse effects of drugs and other diseases. HIV infection can result in diffuse infiltrative lymphocytosis syndrome (DILS), which is characterized by parotid enlargement; involvement of the renal, lung, and gastrointestinal systems; and a low frequency of autoantibody presence. Chronic graft versus host disease may mimic symptoms associated with idiopathic Sjögren syndrome.[62] SLE might be considered, especially at onset of the disease.

Histologic findings of the following disorders can be consistent with Sjögren syndrome:

  • Sarcoidosis
  • Graft versus host disease
  • HIV infection
  • HTLV-1 infection
  • Hepatitis C virus (HCV) infection
  • Keratoconjunctivitis sicca

Sicca

Differential diagnoses to consider in patients with sicca include the following:

  • Medications (eg, antidepressants, anticholinergics, beta-blockers, diuretics, antihistamines, some antiarrhythmic and antiepileptic drugs)
  • Anxiety and depression
  • Viral infections (eg, mumps)
  • Complications from contact lenses
  • Dehydration
  • Hypervitaminosis A
  • Neurotropic keratitis
  • Mucous membrane pemphigoid
  • Environmental irritants
  • Mouth breathing
  • Chronic blepharitis
  • Chronic conjunctivitis
  • Rosacea
  • Therapeutic radiation or surgery to the head and neck
  • Age
  • Alzheimer disease
  • Parkinson disease
  • Bell palsy
  • Amyloidosis
  • Sarcoidosis
  • Lymphoma

Parotid enlargement

Differential diagnoses to consider in patients with parotid enlargement include the following:

  • Viral infection (eg, mumps, Epstein-Barr virus, cytomegalovirus, coxsackievirus A, influenza)
  • DILS associated with HIV disease
  • Granulomatous diseases (sarcoidosis, tuberculosis, leprosy)
  • Hyperlipoproteinemia
  • Hepatic cirrhosis
  • Hepatitis C
  • Bulimia
  • Recurrent parotiditis of childhood
  • Chronic pancreatitis
  • Acromegaly
  • Amyloidosis
  • Gonadal hypofunction
  • Diabetes mellitus
  • Salivary gland tumor (primarily unilateral)
  • Bacterial infection (primarily unilateral)
  • Chronic sialadenitis (primarily unilateral)
  • Lymphoma

Associated disorders

Importantly, evaluate the patient for disorders associated with Sjögren syndrome, including the following:

  • AIDS
  • Rheumatoid arthritis
  • Systemic lupus erythematosus (SLE)
  • Scleroderma
  • Polymyositis
  • Primary biliary cirrhosis
  • Thyroiditis
  • Chronic active hepatitis
  • Mixed cryoglobulinemia
  • Celiac sprue

Differential Diagnoses

 

Workup

Approach Considerations

Some laboratory tests can be used to assess salivary and lacrimal involvement in Sjögren syndrome. However, no single test is sufficiently sensitive or specific in the diagnosis of Sjögren syndrome. The condition is properly diagnosed only when the results of various tests are simultaneously positive and when subjective symptoms and serologic abnormalities are present.[63]

Laboratory test results may indicate the following:

  • Elevated erythrocyte sedimentation rate (ESR)

  • Anemia

  • Leukopenia

  • Eosinophilia

  • Hypergammaglobulinemia

  • Presence of antinuclear antibodies (ANAs), especially anti-Ro and anti-La

  • Presence of rheumatoid factor (RF)

  • Presence of anti–alpha-fodrin antibody (reliable diagnostic marker of juvenile Sjögren syndrome)

  • Creatinine clearance may be diminished in up to 50% of patients

Multiple autoantibodies are associated with Sjögren syndrome.[64] In a study in which atypical autoantibodies were evaluated in 82 patients with primary Sjögren syndrome, an immunologic overlap (defined by the presence of autoantibodies typical of other systemic autoimmune diseases) was evident in 20% of the patients. The clinical significance of these atypical autoantibodies varied widely.[65]

Patients with primary Sjögren syndrome may have positive test results for lupus anticoagulant and/or anticardiolipin antibodies, and some patients develop clinical events (ie, fetal wastage, arterial and/or venous thrombosis) associated with antiphospholipid syndrome. Anti ̶ salivary duct antibodies are present in most cases of secondary Sjögren syndrome.

Type II cryoglobulins are noted, particularly in patients with palpable and nonpalpable vasculitic purpura. Hepatitis C should be sought in these patients.

In some studies, patients with Sjögren syndrome have an increased frequency of autoimmune thyroid disease with hypothyroidism (10-15%). Lymphocytic i)nfiltration can be observed in the thyroid gland.

Elevations of serum immunoglobulin G4 (IgG4), found in IgG4-related plasmacytic disease (which can mimic the glandular infiltrations of Sjögren syndrome), are not seen in Sjögren syndrome.[66, 67]

Antibodies to carbonic anhydrase 11 can be seen in patients with Sjögren syndrome who have primary billiary cirrhosis.[60]

Schirmer test

The Schirmer test is probably the only test available in the emergency department (ED) that can be used to strongly support or refute suspicion of Sjögren syndrome. A test strip of number 41 Whatman filter paper is placed near the lower conjunctival sac to measure tear formation. Healthy persons wet 15 mm or more of the paper after 5 minutes. A positive test occurs when less than 5 mm of the strip is wet after 5 minutes. A Schirmer test is shown in the image below.

Photograph that demonstrates the Schirmer test, wh Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome. The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis.

Rheumatoid factor

RF is present in 52% of patients with primary Sjögren syndrome and in 98% of patients with the secondary disease, occurring even when rheumatoid arthritis is not present. Consider a diagnosis of  rheumatoid arthritis if the patient has symmetrical polyarticular synovitis.

The presence of RF has been independently associated with elevated risk for lymphoma in patients with primary Sjögren syndrome.[68] However, loss of a previously positive RF finding can be observed in some patients with Sjögren syndrome who develop lymphoma.

Antinuclear antibodies

ANAs are typically present in patients with Sjögren syndrome. Consider the diagnosis of systemic lupus erythematosus (SLE) in patients with ANAs only if symptoms and signs typical of SLE are present.

Serum protein electrophoresis

Patients with Sjögren syndrome often have a polyclonal gammopathy. Loss of a previously detected polyclonal gammopathy can be observed in some patients with Sjögren syndrome who develop lymphoma. Development of a monoclonal gammopathy can also signal the development of a lymphoma.

Staining

Rose bengal is an aniline dye that stains epithelial surfaces with diminished mucin protection or with exposed epithelial cell membranes. Conjunctival staining can be detected with the naked eye. Slit-lamp examination is performed after rose bengal staining to detect abnormal uptake in the cornea.

Lissamine green staining works similarly but is less irritating to the eye. Fluorescein staining can be used to detect corneal damage.

Salivary testing

Sialometry is a good measure of the degree of decreased salivary flow and helps to establish xerostomia, but the findings do not narrow the differential diagnoses.

Saliva from patients with Sjögren syndrome has elevated levels of sodium, chloride, lactoferrin, and IgA, but these findings are not specific.

Sedimentation rate

The ESR is elevated in 80% of patients with Sjögren syndrome, but the finding is nonspecific.

Protein profiling

Protein profiling (tear proteomics) has revealed reproducible patterns in patients with primary Sjögren syndrome and appears to hold promise as a diagnostic test for this disorder.[69]

Additional test considerations

Other test results to consider are as follows:

  • High total protein level or a low albumin level - Should prompt the clinician to perform serum protein electrophoresis

  • High alkaline phosphatase level - Should prompt consideration of primary biliary cirrhosis

  • Elevated transaminase levels - Consider the possibility of chronic active hepatitis, which can be associated with sicca symptoms, or hepatitis C, which can cause mild salivary gland enlargement; however, mild (< 2-fold) increases in transaminase levels have been observed in 22% of patients with Sjögren syndrome[70]

  • Low bicarbonate level - Consider evaluating patients with a low bicarbonate level for type I (distal) renal tubular acidosis; less commonly, patients can also develop proximal renal tubular acidosis with Fanconi syndrome

  • Hypokalemia - This condition, which is occasionally severe enough to lead to periodic paralysis, can be observed in patients with type I renal tubular acidosis; however, it can also be observed in patients who have Sjögren syndrome without renal tubular acidosis[46]

SSA and SSB

Antibodies against SSA/Ro are found in approximately 50% of patients with the disease (75% of patients with primary Sjögren syndrome and 15% of patients with secondary Sjögren syndrome). Thus, the absence of anti-SSA/Ro antibodies does not eliminate the diagnosis of primary or secondary Sjögren syndrome.

Anti-Ro is a polyclonal antibody directed against nuclear and nucleolar RNA binding protein of 60KD or cytoplasmic protein of 52KD (E3 ubiquitin ligase) . Patients can have a negative ANA and a positive Ro antibody test if they only have anti-Ro against cytoplasmic protein of 52KD.

Anti-La is an oligoclonal antibody that is predominantly directed against nuclear 47KD RNA binding protein.  

Antibodies against SSA/Ro are present in 50% of patients with SLE and are sometimes found in healthy individuals. Thus, the presence of antibody against SSA/Ro cannot by itself be used to establish a diagnosis of Sjögren syndrome.

Antibodies against SSB/La are present in 40-50% of patients with primary Sjögren syndrome and in 15% of patients with SLE. Finding antibodies against SSB/La in patients without antibodies against SSA/Ro is unusual, but this combination has occurred in patients with primary biliary cirrhosis and autoimmune hepatitis.

Titers of anti-SSA/Ro and anti-SSB/La antibodies do not reflect disease activity. Current enzyme-linked immunosorbent assay (ELISA) tests for these antibodies are more sensitive than previous tests. Thus, the specificity is lower.

Antibodies against SSA/Ro are also associated with the annular erythematous lesions of subacute cutaneous lupus. They are also found in the mothers of newborns with neonatal lupus syndromes and congenital heart block, and some of these mothers have or will develop Sjögren syndrome.

CBC

In patients with Sjögren syndrome, the complete blood count (CBC) is most often within the reference range, but anemia of chronic disease may be present. Pernicious anemia may be associated with the atrophic gastritis.

An abnormal white blood cell (WBC) count, especially with an abnormal differential count, should prompt concerns for a lymphoreticular malignancy. In addition, although a low platelet or WBC count can occur in persons with primary Sjögren syndrome, the finding should also prompt consideration for coexisting SLE.

A mild, normochromic, normocytic anemia is present in 50% of patients. Leukopenia occurs in up to 42% of patients.

Sialography and Scintigraphy

In sialography, radiopaque material is injected into the salivary glands. Sialography is useful to exclude the presence of obstructions or strictures, but the diffuse sialectasis of Sjögren syndrome is seen in various other diseases and is therefore not specific.

Oil-based contrast medium may not be adequately cleared in patients with Sjögren syndrome and, consequently, may damage adjacent tissues and lead to a chronic granulomatous reaction. Performing this procedure with oil-based contrast should be avoided, especially during episodes of acute swelling.

With salivary scintigraphy, the uptake and secretion of sodium pertechnetate technetium-99m (99m Tc) is a gauge of the salivary flow rates and can provide an objective measurement of salivary gland dysfunction. However, the finding of low flow rates is not specific to Sjögren syndrome.

Positive findings on either sialography or scintigraphy fulfill a criterion for objective evidence of Sjögren syndrome by the American-European Consensus Group.[3]

Biopsy

Minor salivary gland biopsy[71] currently is the best single test to establish a diagnosis of Sjögren syndrome. In this procedure, an incision is made on the inner lip, and some minor salivary glands are removed for examination. In patients with a possible diagnosis of this disease but with severe extraglandular symptoms, a lip biopsy is often performed to firmly establish the diagnosis of Sjögren syndrome. Obtaining the biopsy sample from below normal-appearing mucosa is important in order to avoid false-positive results. At least 4 salivary gland lobules should be obtained for analysis.

While this is the most definitive test, performing it is not absolutely necessary from a clinical standpoint. Patients with Sjögren syndrome are essentially treated symptomatically and are observed for the development of other rheumatic disorders or lymphoma. This can be initiated without performing a biopsy. If, however, the diagnosis is in doubt or if a definitive diagnosis is needed, then this is the best test.

Salivary gland biopsy can also help to detect pseudolymphoma or lymphoma, as well as the noncaseating granulomas of sarcoidosis.

One study showed that not all patients undergoing lip biopsy derived diagnostic benefit from this procedure and that clinical symptoms and serology did not predict a positive lip biopsy.[72]

In another study, however, a significant correlation was found between positive findings in minor salivary gland biopsy and the Schirmer test, the rose bengal test, xerostomia, and parotid swelling. The investigators utilized biopsy specimens from the lower lip of 360 patients.[73]

Histologic Findings

Although pathologists use different classification systems, the characteristic findings of minor salivary gland biopsy in a person with Sjögren syndrome include the following (see the image below)[74] :

  • The biopsy shows focal aggregates of at least 50 lymphocytes, and, to a lesser extent, plasma cells and macrophages

  • More than 1 focal aggregate is seen per 4 mm2

  • T cells, predominantly CD4+ cells, are present, unlike the predominance of CD8+ T cells seen in the salivary gland biopsy samples from patients with DILS associated with HIV disease

  • Normal acini are replaced by lymphocytes

  • Focal aggregates are seen in almost all glands

  • Ten percent of the lymphocytes are CD5+ B cells that produce IgM and IgG antibodies, often with a monoclonal or oligoclonal pattern

  • Large foci are present, possibly showing germinal centers

  • Epimyoepithelial islands are uncommon in the minor salivary gland but can be seen in the major salivary glands

    Photomicrograph of a lip biopsy specimen showing t Photomicrograph of a lip biopsy specimen showing two lymphocytic foci adjacent to normal-appearing mucinous acini typical of minor salivary gland abnormalities in Sjögren syndrome.

A score of greater than 1 focus per 4 mm2 has a specificity of 83.5-95% and a sensitivity of 63-81.8% in the diagnosis of Sjögren syndrome. The focus score may be associated with keratoconjunctivitis sicca, the presence of autoantibodies, and, less commonly, xerostomia.

Lymphocytic infiltrates are also seen in other organs. Findings from a gastric mucosal biopsy may show lymphocytic infiltrates with atrophic gastritis. A kidney biopsy may show interstitial lymphocytic infiltration. Lung biopsy can reveal infiltrating CD4+ T cells of a lymphocytic interstitial pneumonitis. Salivary gland biopsy can help to detect pseudolymphoma or lymphoma, as well as the noncaseating granulomas of sarcoidosis.

 

Treatment

Approach Considerations

No curative agents for Sjögren syndrome exist. The treatment of the disorder is essentially symptomatic.[75]

Skin and vaginal dryness

Patients should use skin creams, such as Eucerin, or skin lotions, such as Lubriderm, to help with dry skin. Vaginal lubricants, such as Replens, can be used for vaginal dryness. Vaginal estrogen creams can be considered in postmenopausal women. Watch for and treat vaginal yeast infections.

Arthralgias and arthritis

Acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) can be taken for arthralgias. Consider hydroxychloroquine if NSAIDs are not sufficient for the synovitis occasionally associated with primary Sjögren syndrome. However, hydroxychloroquine does not relieve sicca symptoms. Patients with RA associated with Sjögren syndrome likely require other disease-modifying agents.

Additional treatment considerations

In patients with major organ involvement, such as lymphocytic interstitial lung disease, consider therapy with steroids and immunosuppressive agents, such as cyclophosphamide.

While cyclophosphamide and similar agents may be helpful for treating serious manifestations of Sjögren syndrome or disorders associated with Sjögren syndrome, clinicians should understand that these agents are also associated with the development of lymphomas.

Long-term anticoagulation may be needed in patients with vascular thrombosis related to antiphospholipid antibody syndrome.

In a small group of patients with primary Sjögren syndrome, mycophenolate sodium reduced subjective, but not objective, ocular dryness and significantly reduced hypergammaglobulinemia and RF.[76]

Among the biologic therapies, the greatest experience in primary Sjögren syndrome is with rituximab, an anti-CD20 (which is expressed on B-cell precursors) monoclonal antibody. Anti-B–cell strategies, particularly rituximab, have a promising effect in the treatment of patients with severe extraglandular manifestations of Sjögren syndrome.

Reports on the use of rituximab in patients with primary Sjögren syndrome have emerged in the literature.[77, 78, 79] In a double-blind, randomized, placebo-controlled trial, Meijer et al found that rituximab significantly improved saliva flow rate, lacrimal gland function, and other variables in patients with primary Sjögren syndrome.[80]

In an open-label clinical trial, modest improvements were noted in patient-reported symptoms of fatigue and oral dryness. However, no significant improvement in the objective measures of lacrimal and salivary gland function was noted, despite effective depletion of blood B cells.[81] In a randomized, placebo-controlled, parallel-group study of 120 patients with primary Sjögren syndrome, treatment with rituximab did not alleviate disease activity or symptoms at week 24, although it did alleviate some symptoms at weeks 6 and 16.[82]

Rituximab appears promising in the treatment of vasculitis and intravenous immunoglobulin (IVIG)–dependent ataxic neuropathy.[83, 84] Results from the AIR registry (French) indicated that rituximab appears to be effective in cryoglobulinemia or vasculitis-related peripheral nervous system involvement in primary Sjögren syndrome.[85]

In a prospective study of 78 patients with primary Sjögren syndrome treated with rituximab, significant improvement in extraglandular manifestations was reported, as measured by EULAR [European League Against Rheumatism] Sjögren Syndrome Disease Activity Index (ESSDAI) (disease activity score) and overall good tolerance reported.[86] Several smaller studies of rituximab revealed improvement of arthralgias, regression of parotid gland swelling,[87] and improvement of immune-related thrombocytopenia.[88]

Of the TNF inhibitors, both etanercept and infliximab have failed to demonstrate significant benefit in Sjögren syndrome.

Combination therapy with leflunomide and hydroxychloroquine resulted in a significant decrease in ESSDAI scores and caused no serious adverse events, in a small phase 2a randomized clinical trial from the Netherlands. At 24 weeks, the mean difference in ESSDAI score in the leflunomide-hydroxychloroquine group (n=21), compared with the placebo group (n=7), was –4.35 points after adjustment for baseline values.

Fewer data are available with regard to the role of anti-CD22, anti-BAFF, anti-IL-1, type 1 interferon, and anti-T–cell agents in treatment of primary Sjögren syndrome, with further investigations ongoing. The overall paucity of evidence in therapeutic studies in primary Sjögren syndrome suggests that much larger trials of the most promising therapies are necessary. The investigators concluded that further evaluation of leflunomide–hydroxychloroquine combination therapy in larger clinical trials is warranted.[89, 90]

Emergency department care

The diagnosis of Sjögren syndrome can be made from the ED if the index of suspicion is high. Patients may present with mild symptoms (eg, eye grittiness, eye dryness or discomfort, dry mouth, recurrent caries). Bilateral parotid gland swelling is also a common presentation.

Patients with known Sjögren syndrome should not be taken lightly for their complaint of dry eyes or dry mouth, as these chronic problems can be very distressing and obtrusive.

Inpatient care

Give attention to artificial lubricants and humidified oxygen for intubated and/or sedated patients with Sjögren syndrome.

Outpatient care

Encourage patients with Sjögren syndrome to be active. In addition, patients should be encouraged to avoid exacerbation of dryness symptoms (eg, through smoking or exposure to low-humidity environments). All patients with Sjögren syndrome should be monitored by an ophthalmologist and dentist, in addition to their rheumatologist. Certain patients may be candidates for punctal occlusion, which is usually performed by an ophthalmologist.

Monitoring

Most patients with Sjögren syndrome can be monitored at follow-up visits every 3 months and, if the patient is stable, up to every 6 months. Patients with active problems or in whom an emerging associated illness is a concern can be seen as often as monthly.

Surgical Therapy

Occlusion of the lacrimal puncta can be corrected surgically. Electrocautery and other techniques can be used for permanent punctal occlusion.

During surgery, the anesthesiologist should administer as little anticholinergic medication as possible and use humidified oxygen to help avoid inspissation of pulmonary secretions. Good postoperative respiratory therapy should also be provided. Patients are at higher risk for corneal abrasions, so ocular lubricants should be considered.

Biopsies that may be performed in association with Sjögren syndrome include the following:

  • Minor salivary gland biopsy - For diagnostic purposes
  • Parotid gland biopsy - If malignancy is suggested
  • Biopsy of an enlarged lymph node - To help rule out pseudolymphoma or lymphoma

Consultations

Sjögren syndrome and its associated disorders necessitate a total patient perspective that is often best provided by an internist. A rheumatologist with specific training and experience in Sjögren syndrome and its associated disorders is also essential to the management of the condition. In addition, good oral prophylaxis and therapy are necessary.

Involve ophthalmologists early in the care of patients, for rose bengal and fluorescein staining to help to establish the diagnosis and for assessment of the degree of eye damage.

Consultation with an otolaryngologist may be needed early to perform a minor or major salivary gland biopsy if this is deemed necessary to establish a diagnosis. The specialist may also need to perform a parotid biopsy if malignant transformation is suggested.

Depending on the problems, patients with Sjögren syndrome may need to be seen by other specialists, including the following:

  • Nephrologist - To help manage renal tubular acidosis
  • Pulmonologist - To help manage interstitial lung disease
  • Hematologist/oncologist - If pseudolymphoma or lymphoma develops

Dry Eyes

The treatment of dry eyes depends on the severity of the dryness, which is best determined by an ophthalmologist and is graded according to the following[91, 92, 93, 94, 95, 96] :

  • Degree of symptoms
  • Conjunctival injection and staining
  • Corneal damage
  • Tear quality
  • Lid involvement

New therapeutic strategies designed to facilitate AQP5 trafficking to the apical plasma membrane may prove useful in the management of dry eyes in Sjögren syndrome. In addition, data on novel secretagogues and androgen therapies for dry eyes are promising.[83]

A consensus clinical guideline for the management of dry eyes associated with Sjögren syndrome recommends the following[97] :

  • Patient evaluation should include symptoms of both discomfort and visual disturbance along with evaluation of the relative contribution of aqueous production deficiency and evaporative loss of tear volume
  • Objective parameters of tear film stability, tear osmolarity, degree of lid margin disease, and ocular surface damage should be used to stage disease severity and assist in guiding treatment
  • Successful management requires patient education on the nature of the problem, aggravating factors, and treatment goals

Treatment options are used according to the severity and character of dry eye disease and include the following[97] :

  • Tear supplementation and stabilization
  • Control of inflammation of the lacrimal glands and ocular surface
  • Possible stimulation of tear production

Level 1 - Mild symptoms, no corneal signs

Artificial tears should be applied liberally. Patients may need to apply artificial tears more often if they enter a low-humidity environment (ie, air conditioning, airplanes). Artificial tears with hydroxymethylcellulose or dextran are more viscous and can last longer before reapplication is needed. Encourage patients to try various preparations to determine what works best for them.

If artificial tears burn when they are instilled, the preservative in the artificial tears is likely irritating the eye. If artificial tears are used more often than every 4 hours, patients should use a preservative-free preparation to avoid eye irritation from the preservatives.

The use of humidifiers may help. If the patient is living in an area with hard water, he or she should use distilled water. Patients should avoid medications with anticholinergic and antihistamine effects.

Level 2 - Moderate or severe symptoms with tear film signs or visual signs, or mild corneal/conjunctival staining

Patients should use unpreserved tears or gels or nighttime ointments. Patients who wake up in the morning with severe matting in the eyes should use a more viscous preparation (eg, Lacri-Lube) at night. While the more viscous preparations can be applied less often, they can make patients' vision filmy. Therefore, they are best used at night. The more viscous preparations occasionally lead to blepharitis, which can exacerbate sicca symptoms.

The following agents may also be indicated:

  • Topical steroids

  • Secretagogues

  • Cyclosporine A[98]

  • Nutritional supplements

Level 3 - Severe symptoms with marked corneal changes or filamentary keratitis

The following treatments may be indicated:

  • Tetracyclines

  • Autologous serum tears

  • Temporary plugging of the lacrimal puncta to increase the amount of tears that remain in the eyes

Level 4 - Extremely severe symptoms with altered lifestyle, or severe corneal staining, erosions, or conjunctival scarring

The following therapies may be indicated:

  • Systemic anti-inflammatory therapy, including acetylcysteine

  • Topical vitamin A

  • Electrocautery and other techniques for permanent punctal occlusion

  • Glasses fitted with moisture shields to decrease evaporation

Dry Mouth

Patients with dry mouth can liberally drink sips of water and take bottled water with them on trips. They can also place a glass of water at their bedside for nighttime use, as needed.[99] Sugar-free lemon drops can also be used as needed to stimulate salivary secretion. Artificial saliva can be used as needed, although patient tolerance varies. Preparations include Salivart, Saliment, Saliva Substitute, MouthKote, and Xero-Lube. Patients should avoid medications with anticholinergic and antihistamine effects.

The use of humidifiers may help. Distilled water is best in patients living in an area with hard water.

Patients should be seen regularly by a dentist, who may advise fluoride treatments. Toothpaste without detergents can reduce mouth irritation in patients with Sjögren syndrome. Brands include Biotene toothpaste, Biotene mouth rinse, Dental Care toothpaste, and Oral Balance gel.

Watch for oral candidiasis and angular cheilitis and treat them with topical antifungal agents, such as nystatin troches. Oral fluconazole may occasionally be needed. Patients also need to be sure to disinfect their dentures.

Sinusitis and sinus blockade should be treated because these problems may contribute to mouth breathing. Emphasize the use of isotonic sodium chloride solution nasal sprays to avoid antihistamine use.

Pilocarpine or cevimeline tablets are options. Some small studies suggest that interferon alfa may be a useful therapy in the future.

 

Guidelines

Guidelines Summary

In 2016, the Sjögren’s Syndrome Foundation (SFF) published clinical practice guidelines for Sjögren syndrome patients in the United States.[100] The guidelines note that treatment goals remain as follows:

  1. Symptom palliation
  2. Prevention of complications
  3. For rheumatologists, proper selection of patients for immunosuppressive therapy

Dry mouth

Recommendations (and their strength) for Sjögren syndrome patients with dry mouth include the following:

  • Topical fluoride should be used in for caries prophylaxis (strong)
  • Saliva can be increased through gustatory, masticatory stimulation, sugar-free lozenges and/or chewing gum, xylitol, mannitol, and the prescription medications pilocarpine and cevimeline (weak)
  • Chlorhexidine administered by varnish, gel, or rinse may be considered in patients with a high root caries rate (weak)
  • Nonfluoride remineralizing agents may be considered as an adjunct therapy in patients with a high root caries rate (moderate)

Dry eye

For dry eye disease, recommendations vary according to whether meibomian gland disease is present and by the severity of eye involvement, which is determined mainly by the presence or absence of ocular surface staining and the staining pattern.

Aqueous deficiency without meibomian gland disease

For severity 1 disease, recommendations are as follows:

  • Education and modification of the environment or diet
  • Elimination of offending systemic medication
  • Artificial tears, gels, ointments

For severity 2 disease, recommendations are as follows:

  • Omega 3 essential fatty acid supplement
  • Anti-inflammatory therapy with cyclosporine
  • Anti-inflammatory therapy with pulse steroids
  • Punctal plugs
  • Secretagogues
  • Moisture chamber spectacles

For severity 3 disease, recommendations are as follows:

  • Topical autologous serum
  • Contact lenses
  • Permanent punctal occlusion

For severity 4 disease, recommendations are as follows:

  • Systemic anti-inflammatory medication
  • Eyelid surgery

Aqueous deficiency with meibomian gland disease

For severity 1 disease, recommendations are as follows:

  • Education and modification of the environment or diet
  • Elimination of offending systemic medication
  • Artificial tears with lipid component
  • Eyelid therapy: warm compress, massage

For severity 2 disease, recommendations are as follows:

  • Omega 3 essential fatty acid supplement
  • Anti-inflammatory therapy with cyclosporine
  • Anti-inflammatory therapy with topical steroids
  • Topical azithromycin
  • Liposomal spray
  • Possible oral doxycycline
  • Expression of Meibomian glands
  • Punctal plugs
  • Secretagogues
  • Moisture chamber spectacles

For severity 3 disease, recommendations are as follows:

  • Topical autologous serum
  • Contact lenses
  • Permanent punctal occlusion
  • LipiFlow pulsed thermal compression
  • Probing of meibomian gland

For severity 4 disease, recommendations are as follows

  • Systemic anti-inflammatory medication
  • Eyelid surgery

Inflammatory musculoskeletal pain

The SFF guidelines advise that physicians consider the individual patient’s circumstances when weighing risks and benefits of each therapy. Insufficient evidence exists on the effectiveness of disease-modifying antirheumatic drugs (DMARDs) in the treatment of inflammatory musculoskeletal pain in primary Sjögren syndrome, so recommendations were formulated on the basis of expert opinion as guided by the consensus group process.

The following recommendations are listed in order of preference for use in the treatment of inflammatory musculoskeletal pain in primary Sjögren syndrome; if a therapy is insufficiently effective, the physician is advised to try the next recommendation in sequence, and so on:

  1. Hydroxychloroquine; first-line treatment
  2. Methotrexate
  3. Hydroxychloroquine plus methotrexate
  4. Short-term (1 month or less) corticosteroids (15 mg or less a day); long-term corticosteroids (≤15 mg/d for more than 1 month) may be useful, but efforts should be made to find a steroid-sparing agent as soon as possible
  5. Leflunomide
  6. Sulfasalazine
  7. Azathioprine (may be a better choice than leflunomide or sulfasalazine in patients with major organ involvement)
  8. Cyclosporine

 Fatigue

The only strongly recommended treatment of fatigue in Sjögren syndrome was exercise.  Hydroxychloroquine may be considered in selected situations

The guidelines include strong recommendations against the use of the following for fatigue:

  • Dehydroepiandrosterone (DHEA)
  • Etanercept
  • Infliximab

Insufficient evidence to issue a recommendation was found for the following therapeutic options for fatigue:

  • Interleukin-1 inhibition (anakinra)
  • Azathioprine
  • Mycophenolate
  • Zidovudine
  • Doxycycline
  • Lamivudine
  • Leflunomide
  • Abatacept
  • Belimumab
  • Epratuzumab

Biological Therapies

The guidelines advise against use of tumor necrosis factor–alpha (TNF-α) inhibitors to treat sicca symptoms in patients with primary Sjögren syndrome. If TNF-α inhibition therapy is used for rheumatoid arthritis or other related overlap conditions in patients with Sjögren syndrome, health care providers should consider and monitor for the following:

  • Lymphoma and other malignancies (risk for non-Hodgkin is elevated)
  • Serious infections, including tuberculosis
  • Invasive fungal infections
  • Hepatitis B reactivation
  • Hepatotoxicity
  • Heart failure
  • Cytopenias
  • Hypersensitivity
  • Serious infusion reactions
  • Demyelinating disease

Rituximab

Rituximab may be considered as a therapeutic option for the following indications in patients with primary Sjögren syndrome:

  • Keratoconjunctivitis sicca (KCS), in patients for whom conventional therapies (eg, topical moisturizers, secretagogues, anti-inflammatory drugs, immunomodulators, punctual occlusion) have proven insufficient
  • Xerostomia, in patients with primary Sjögren syndrome with some evidence of residual salivary production and clinician-determined significant evidence of oral damage, in whom conventional therapies, including topical moisturizers and secretagogues, have proved insufficient

Rituximab may be considered as a therapeutic option for adults with primary Sjögren syndrome and any or all of the following systemic manifestations:

  • Cryoglobulinemia associated with vasculitis
  • Vasculitis
  • Severe parotid swelling
  •  Inflammatory arthritis
  • Pulmonary disease
  • Peripheral neuropathy, especially mononeuritis

Patients and health care providers should be aware that, although uncommon, significant harms may be associated with the use of rituximab and should exercise caution and observe for the following when using rituximab in patients with Sjögren syndrome:

  • Infusion reactions
  • Tumor lysis syndrome in patients with non-Hodgkin lymphoma
  • Progressive multifocal leukoencephalopathy
  • Hepatitis B reactivation with possible fulminant hepatitis
  • Severe mucocutaneous reactions
  • Infections
  • Bowel obstruction and perforation
  • Cardiac arrhythmias and angina
  • Cytopenias
  • Serious bacterial, viral, or fungal infections

Other recommendations regarding rituximab included the following:

  • Particularly careful consideration of risk versus benefit is necessary in pregnant and nursing patients
  • Live vaccines should be avoided in patients taking rituximab

European League Against Rheumatism guidelines

In 2019, the European League Against Rheumatism (EULAR) published guidelines on the management of Sjögren syndrome with topical and systemic therapies.[101]  EULAR recommends that patients with Sjögren syndrome be managed at, or in close collaboration with, centers of expertise following a multidisciplinary approach. Specific recomendations are listed below.

Dry mouth

Baseline evaluation of salivary gland function, including measurement of whole salivary flows, and exclusion of unrelated conditions, is recommended before starting treatment for oral dryness.        

The preferred first therapeutic approach for oral dryness according to salivary gland function may be as follows:

  • Mild dysfunction - Nonpharmacological stimulation (eg, sugar-free acidic candies, lozenges, xylitol, sugar-free chewing gum)
  • Moderate dysfunction - Pharmacological stimulation (eg, pilocarpine, cevimeline; anetholtrithione, bromhexine, N-acetylcysteine in cases of intolerance or non-response)       
  • Severe dysfunction - Saliva substitution  

The guidelines recommend against using any of the following for oral dryness:

  • Hydroxychloroquine
  • Oral glucocorticoids
  • Immunosuppressive agents 
  • Rituximab                            

Dry eyes

The first-line therapeutic approach to ocular dryness includes the use of artificial tears and ocular gels/ointments. Refractory/severe ocular dryness may be managed in stepwise fashion, as follows:

  1. Topical ocular non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids may be prescribed by ophthalmologists as a short-term therapeutic approach (maximum 2–4 weeks); if no response or intolerance, then
  2. Topical cyclosporine; if no response or intolerance, then
  3. Serum eye drops; if no response or intolerance, then 
  4. Rescue therapies - Oral muscarinic agonists or plug insertion

Fatigue and/or pain:

  • Concomitant diseases should be evaluated in patients presenting with fatigue/pain, whose severity should be scored using specific tools (eg, EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI], Profile of Fatigue, Brief Pain Inventory).
  • Consider analgesics or other pain-modifying agents for musculoskeletal pain, considering the balance between potential benefits and side-effects.      

Systemic disease:

  • Treatment of systemic disease should be tailored to organ-specific severity using the EULAR Sjögren's syndrome disease activity index (ESSDAI) definitions.
  • Glucocorticoids should be used at the minimum dose and length of time necessary to control active systemic disease (eg, pulses of methylprednisolone followed by doses of 0.5 mg/kg/d or lower as induction therapy in severe presentations, and doses< 0.5 mg/kg/d in moderate/less-severe presentations, with a final target of withdrawing glucocorticoids in patients with inactive disease as soon as possible or at least trying to target a maintenance dose of 5 mg/daily or less with the aid of glucocorticoid-sparing immunosuppressive agents).
  • Immunosuppressive agents (eg, leflunomide, methotrexate, azathioprine, mycophenolate, cyclophosphamide) should be mainly used as glucocorticoid-sparing agents, with no evidence supporting the choice of one agent over another.            
  • B-cell–targeted therapies (eg, rituximab, epratuzumab, belimumab) may be considered in patients with severe, refractory systemic disease.
  • The systemic organ-specific therapeutic approach may follow, as a general rule, the sequential (or combined) use of glucocorticoids, immunosuppressive agents, and biologics.
  • Treatment of B-cell lymphoma should be individualized according to the specific histological subtype and disease stage.
 

Medication

Medication Summary

Most patients with Sjögren syndrome can be cared for adequately with topical therapy and with avoidance of medications that exacerbate their symptoms. Pilocarpine or cevimeline can be used in cases of xerostomia for which systemic therapy is needed or local therapy is not successful.

Rituximab has shown promise in the treatment of patients with severe extraglandular manifestations of Sjögren syndrome, such as vasculitis, cryoglobulinemia, and peripheral neuropathy.[85, 86] Although some data support its efficacy for glandular involvement, it is not currently used for treatment of sicca symptoms alone.

Gastrointestinal Agents, Other

Class Summary

These agents bind to cholinergic (muscarinic) receptors, increasing the secretion of exocrine glands, including salivary glands.

Pilocarpine (Salagen)

Pilocarpine is a cholinergic parasympathomimetic agent that can be used to enhance secretion by exocrine glands when systemic therapy is needed or local therapy fails.

Artificial saliva

These preparations typically contain methylcellulose, sorbitol, and salts to moisten and lubricate the mouth.

Cevimeline (Evoxac)

Cevimeline is indicated for xerostomia in Sjögren syndrome.

Ophthalmic Lubricants

Class Summary

Various over-the-counter (OTC) preparations of natural tears that provide topical therapy for dry eyes are available. Encourage patients to try different preparations to determine which works best for them.

Artificial tears (Nu-Tears, Murine Tears, Refresh, Tears Naturale)

These preparations contain the equivalent of 0.9% sodium chloride and are used to maintain ocular tonicity. They replace the aqueous layer of tears that is lost in patients with Sjögren syndrome. Preparations that have hydroxymethylcellulose or dextran are more viscous and therefore can last longer before reapplication is needed.

Antimalarials

Class Summary

These agents are used to treat Sjögren syndrome ̶ associated arthritis that is unresponsive to NSAIDs.

Hydroxychloroquine (Plaquenil)

Hydroxychloroquine is an antimalarial agent. Its mechanism of action in inflammatory arthritis is unknown.

Antineoplastics, Alkylating

Class Summary

Consider these agents in patients with Sjögren syndrome who develop a major organ manifestation such as interstitial lung disease.

Cyclophosphamide (Cytoxan)

Cyclophosphamide is an alkylating agent with potent immunosuppressant properties. Dosage adjustments should be based on monitoring clinical response and the CBC or nadir CBC.

Immunomodulators

Class Summary

These agents may regulate key immune factors responsible for inflammation.

Cyclosporine ophthalmic (Restasis)

Cyclosporine ophthalmic is used to relieve dry eyes caused by suppressed tear production secondary to ocular inflammation. It is thought to act as a partial immunomodulator, but the exact mechanism of action is not known.

Corticosteroids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone

Prednisone is an immunosuppressant used in the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear cell activity. Prednisone stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production and activity.

Methylprednisolone (A-Methapred, Solu-Medrol, Depo-Medrol)

Methylprednisolone is available in intravenous (IV)/intramuscular (IM) or oral (PO) form. Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity.

Prednisolone (Pediapred, Prelone, Orapred)

Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is a commonly used oral agent.

Antineoplastics, Monoclonal Antibody

Class Summary

Rituximab has a promising effect in the treatment of patients with severe extraglandular manifestations of Sjögren syndrome. Although some data support its efficacy for glandular involvement, it is not currently used for the treatment of sicca symptoms alone. Rituximab has an off-label indication for Sjögren syndrome.

Rituximab (Rituxan)

Rituximab is a monoclonal antibody directed against the CD20 antigen on maturing B-lymphocytes, leading to the depletion of mature circulating B-cells, which are believed to play an important role in the pathophysiology of primary Sjögren syndrome.

 

Questions & Answers

Overview

What is Sjögren syndrome?

What are the extraglandular features of Sjögren syndrome?

What are the dermatologic features of Sjögren syndrome?

How are primary and secondary Sjögren syndrome differentiated?

Which conditions should be included in the differential diagnoses of Sjögren syndrome?

What are the possible complications of Sjögren syndrome?

Which antibodies are most commonly associated with Sjögren syndrome?

What are the treatment options for Sjögren syndrome?

What are systems used to classify Sjögren syndrome?

When are the American-European Consensus Group (AECG) criteria used in the diagnosis of Sjögren syndrome?

What are the AECG diagnostic criteria for primary Sjögren syndrome?

What are the AECG diagnostic criteria for secondary Sjögren syndrome?

How accurate are the AECG diagnostic criteria for Sjögren syndrome?

What are the AECG criteria for exclusion of a diagnosis of Sjögren syndrome?

What is the American College of Rheumatology/European European League Against Rheumatism (ACR/EULAR) classification criteria used in the diagnosis of Sjögren syndrome?

What should be included in patient education information on Sjögren syndrome?

What are the subtypes of Sjögren syndrome?

What parts of the body are affected by Sjögren syndrome?

What is the pathogenesis of Sjögren syndrome?

What is the frequency of HLA-DR52 in patients with primary Sjögren syndrome?

What is the role of genetics in the etiology of Sjögren syndrome?

What is the role of viral infection in the pathogenesis of Sjögren syndrome?

What is the glandular pathology of Sjögren syndrome?

What is the role of neuroendocrine mechanism in the pathogenesis of Sjögren syndrome?

What is the role of apoptotic mechanisms in the pathogenesis of Sjögren syndrome?

What causes extraglandular involvement in the pathogenesis of Sjögren syndrome?

What is the role of sex hormones in the pathogenesis of Sjögren syndrome?

What is the prevalence and other epidemiologic features of Sjögren syndrome?

What is the prognosis of Sjögren syndrome?

What are the signs of antiphospholipid syndrome in Sjögren syndrome?

What morbidity is associated with Sjögren syndrome?

How much is the risk for non-Hodgkin lymphoma increased in patients with Sjögren syndrome?

What is the most common subtype of non-Hodgkin lymphoma in patients with Sjögren syndrome?

What is a biomarker for non-Hodgkin lymphoma in primary Sjögren syndrome?

What are the risk factors for lymphoma in Sjögren syndrome?

What are the possible complications of Sjögren syndrome in pregnant women?

Presentation

What are the types of extraglandular involvement in Sjögren syndrome?

How does Sjögren syndrome affect quality of life?

What is the significance of a finding of parotitis in the evaluation of Sjögren syndrome?

What are the pulmonary symptoms of Sjögren syndrome?

What are the clinical presentations of secondary Sjögren syndrome?

What is the clinical presentation of Sjögren syndrome?

What are the signs and symptoms of Sjögren syndrome?

Which alternative causes of sicca symptoms should be considered in the evaluation of Sjögren syndrome?

Which medications should be considered alternative causes of sicca symptoms in the evaluation of Sjögren syndrome?

How is dry mouth characterized in Sjögren syndrome?

How are dry eyes characterized in Sjögren syndrome?

What are cutaneous symptoms of Sjögren syndrome?

What are the cutaneous vasculitis symptoms in Sjögren syndrome?

What are the GI symptoms of Sjögren syndrome?

What are the cardiac symptoms of Sjögren syndrome?

What are the neurologic symptoms of Sjögren syndrome?

What are the renal symptoms of Sjögren syndrome?

Which symptoms of Sjögren syndrome are related to the presence of antiphospholipid antibodies?

How do the symptoms of primary Sjögren syndrome compare with those of secondary Sjögren syndrome?

What physical exam findings of the parotid glands suggest Sjögren syndrome?

Which cutaneous findings suggest Sjögren syndrome?

Which urinary conditions are associated with Sjögren syndrome?

What are the two groups of physical signs of primary Sjögren syndrome?

What should be included in the ophthalmologic exam for suspected Sjögren syndrome?

What is the role of the Schirmer test in the evaluation of Sjögren syndrome?

What are the oral signs of Sjögren syndrome?

What are mucous membrane findings suggestive of Sjögren syndrome?

What are physical skin findings suggestive of Sjögren syndrome?

Which findings of hair and nail exam suggest Sjögren syndrome?

What are GI findings suggestive of Sjögren syndrome?

What are respiratory findings suggestive of Sjögren syndrome?

What is the significance of a finding of arthritis in the evaluation of Sjögren syndrome?

Which neurologic findings suggest Sjögren syndrome?

How is peripheral neuropathy manifested in Sjögren syndrome?

Which CNS findings suggest Sjögren syndrome?

DDX

What factors contribute to the underdiagnosis or misdiagnosis of Sjögren syndrome?

How is Sjögren syndrome differentiated from other causes of parotid gland enlargement?

The histologic findings of which disorders are consistent with Sjögren syndrome?

What conditions should be included in the differential diagnoses of Sjögren syndrome in patients with sicca symptoms?

What conditions should be included in the differential diagnoses of Sjögren syndrome in patients with parotid enlargement?

Which disorders associated with Sjögren syndrome should be part of the evaluation?

What are the differential diagnoses for Sjogren Syndrome?

Workup

Which autoimmune findings suggest Sjögren syndrome?

What is the role of serum protein electrophoresis in the diagnosis of Sjögren syndrome?

What is the role of lab tests in the diagnosis of Sjögren syndrome?

Which lab test results suggest Sjögren syndrome?

How frequently are autoantibodies found in the evaluation of Sjögren syndrome?

What is the role of the Schirmer test in the diagnosis of Sjögren syndrome?

How frequently is rheumatoid factor present in Sjögren syndrome?

What is the importance of antinuclear antibodies in the diagnosis of Sjögren syndrome?

What is the role of staining in the evaluation of Sjögren syndrome?

What is the role of salivary testing in the diagnosis of Sjögren syndrome?

What is the role of the erythrocyte sedimentation rate (ESR) in the diagnosis of Sjögren syndrome?

What is the role of protein profiling in the diagnosis of Sjögren syndrome?

Which tests may be considered in the diagnosis of Sjögren syndrome?

What is the role of SSA and SSB antibody testing in the diagnosis of Sjögren syndrome?

What is the role of CBC count in the diagnosis of Sjögren syndrome?

How is sialography used in the diagnosis of Sjögren syndrome?

How is scintigraphy used in the diagnosis of Sjögren syndrome?

What is the significance of positive findings on sialography or scintigraphy in the evaluation of Sjögren syndrome?

What is the best test to establish a diagnosis of Sjögren syndrome?

How is a salivary gland biopsy used in the evaluation of Sjögren syndrome?

What are the characteristic findings of minor salivary gland biopsy in Sjögren syndrome?

How are focal scores interpreted in the diagnosis of Sjögren syndrome?

What is the significance of a finding of lymphocytic infiltrates in the evaluation of Sjögren syndrome?

Treatment

What are the treatment options for Sjögren syndrome?

What are treatment options for skin and vaginal dryness in Sjögren syndrome?

What are the treatment options for arthralgia and arthritis in Sjögren syndrome?

What are the treatment options for major organ involvement in Sjögren syndrome?

How are serious manifestations of Sjögren syndrome managed?

When is long-term anticoagulation indicated in the treatment of Sjögren syndrome?

What is the role of mycophenolate sodium in the treatment of Sjögren syndrome?

What is the role of rituximab in the treatment of Sjögren syndrome?

What is the efficacy of rituximab in the treatment of fatigue and oral dryness caused by Sjögren syndrome?

What is the efficacy of rituximab in the treatment of extraglandular symptoms of Sjögren syndrome?

What is the role of TNF inhibitors in the treatment of Sjögren syndrome?

What is the role of immune mediators in the treatment of Sjögren syndrome?

What is included in emergency department (ED) treatment of Sjögren syndrome?

What is the focus of inpatient care of Sjögren syndrome?

What is included in the outpatient care of Sjögren syndrome?

What is included in the monitoring of Sjögren syndrome?

What is the role of surgery in the treatment of Sjögren syndrome?

When are biopsies indicated in the management of Sjögren syndrome?

What is the purpose of a rheumatology consultation for Sjögren syndrome?

What is the purpose of an ophthalmology consultation for Sjögren syndrome?

What is the purpose of an otolaryngology consultation for Sjögren syndrome?

Which specialist consultations may be necessary in the treatment of Sjögren syndrome?

How are dry eyes graded in Sjögren syndrome?

What new therapeutic strategies are under investigation for the treatment of Sjögren syndrome?

What are the treatment guidelines for dry eye in Sjögren syndrome?

What are the treatment options for dry eyes in Sjögren syndrome?

What are treatments for level 1 dry eye symptoms in Sjögren syndrome?

What are treatments for level 2 dry eye symptoms in Sjögren syndrome?

Which drugs are used in the treatment of level 2 dry eye disease in Sjögren syndrome?

What are the treatments for level 3 dry eye disease in Sjögren syndrome?

What are the treatments for level 4 dry eye disease in Sjögren syndrome?

How is dry mouth due to Sjögren syndrome treated?

What is the role of toothpaste in the treatment of dry mouth in Sjögren syndrome?

How is oral candidiasis treated in Sjögren syndrome?

How is sinusitis and sinus blockade treated in Sjögren syndrome?

Guidelines

According to the Sjögren’s Syndrome Foundation (SSF) guidelines, what are the treatment goals for Sjögren syndrome?

What are the Sjögren’s Syndrome Foundation (SSF) treatment guidelines for dry mouth in Sjögren syndrome?

What is the basis for the SSF recommendations for the treatment of dry eye in Sjögren syndrome?

What are the SSF treatment recommendations for severity 1 dry eye without meibomian gland disease in Sjögren syndrome?

What are the SSF treatment recommendations for severity 1 dry eye with meibomian gland disease in Sjögren syndrome?

What are the SSF treatment recommendations for severity 2 dry eye without meibomian gland disease in Sjögren syndrome?

What are the SSF treatment recommendations for severity 2 dry eye with meibomian gland disease in Sjögren syndrome?

What are the SSF treatment recommendations for severity 3 dry eye without meibomian gland disease in Sjögren syndrome?

What are the SSF treatment recommendations for severity 3 dry eye with meibomian gland disease in Sjögren syndrome?

What are the SSF treatment recommendations for severity 4 dry eye without meibomian gland disease in Sjögren syndrome?

What are the SSF treatment recommendations for severity 4 dry eye with meibomian gland disease in Sjögren syndrome?

How were the Sjögren’s Syndrome Foundation (SSF) guidelines formulated for the treatment of inflammatory musculoskeletal pain in Sjögren syndrome?

What are the Sjögren’s Syndrome Foundation (SSF) treatment guidelines for inflammatory musculoskeletal pain in Sjögren syndrome?

What is the SSF recommended treatment for fatigue in Sjögren syndrome?

Which treatments for fatigue in patients with Sjögren syndrome are not recommended by SSF?

According to SSF guidelines, which treatments have insufficient evidence for their use in treating fatigue in Sjögren syndrome?

What are the SSF guidelines for the use of tumor necrosis factor–alpha (TNF-?) inhibitors in the treatment of Sjögren syndrome?

What are the SSF guidelines indications for the use of rituximab in the treatment of Sjögren syndrome?

For which systemic manifestations of Sjögren syndrome should treatment with rituximab be considered?

What are possible adverse effects of rituximab in the treatment of Sjögren syndrome?

What should be considered when using rituximab to treat Sjögren syndrome?

According to the EULAR guidelines, how should patients with Sjögren syndrome be managed?

What are the EULAR treatment guidelines for dry mouth in Sjögren syndrome?

What are the EULAR Guidelines for the management of Sjogren syndrome?

What are the EULAR treatment guidelines for dry eyes in Sjögren syndrome?

What are the EULAR treatment guidelines for fatigue and/or pain in Sjögren syndrome?

What are the EULAR treatment guidelines for systemic disease in Sjögren syndrome?

Medications

Which medications are used in the treatment of Sjögren syndrome?

Which medications in the drug class Antineoplastics, Monoclonal Antibody are used in the treatment of Sjogren Syndrome?

Which medications in the drug class Corticosteroids are used in the treatment of Sjogren Syndrome?

Which medications in the drug class Immunomodulators are used in the treatment of Sjogren Syndrome?

Which medications in the drug class Antineoplastics, Alkylating are used in the treatment of Sjogren Syndrome?

Which medications in the drug class Antimalarials are used in the treatment of Sjogren Syndrome?

Which medications in the drug class Ophthalmic Lubricants are used in the treatment of Sjogren Syndrome?

Which medications in the drug class Gastrointestinal Agents, Other are used in the treatment of Sjogren Syndrome?