Sjogren’s Syndrome

History

Sjogren’s syndrome is a chronic autoimmune condition caused by lymphocytic infiltration into the exocrine glands and other organs. It is characterized by dry mouth and dry eyes from involvement of the salivary and lacrimal glands as well as a variety of extraglandular manifestations.

Sjogren’s syndrome can be classified as primary disease, which has no association with connective tissue diseases, or secondary disease, which is associated with features of other well-defined connective tissue diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, or scleroderma. Primary Sjögren’s syndrome can be further subclassified into the glandular and the extraglandular types.^1,2

Jan Mikulicz-Radecki is credited with describing Sjögren’s syndrome for the first time in 1892, when he reported the case of a 42-year-old man with bilateral enlargement of the parotid and lacrimal glands associated with a small-round-cell infiltrate. Mikulicz syndrome covered a wide range of conditions, including tuberculosis lymphoma, sarcoidosis, and other infections but is no longer recognized due to a lack of sufficient prognostic or therapeutic information.²

Sjögren’s syndrome is named after the Swedish ophthalmologist Henrik Sjögren, who encountered a patient with dry eyes, dry mouth, and pain in multiple joints in 1929. Henrik Sjögren realized that these symptoms could constitute a separate disorder and he began classifying such patients under the umbrella diagnosis “keratoconjunctivitis sicca.” Clinical and microscopical tests were carried out with great care. By 1933, Dr. Sjögren had seen 19 cases of keratoconjunctivitis sicca and titled his thesis “Zur Kentniss der Keratoconjunctivitis Sicca.”³

Several different standards for the classification of Sjögren’s syndrome have been proposed, using a combination of different laboratory indicators and clinical symptoms along with variations in the test method of the normal and abnormal values of the critical points. However, none of the classifications have been jointly supported by the American College of Rheumatology (ACR) and the European Union of Rheumatism (EULAR; now known as European Alliance of Associations for Rheumatology).⁴

In 2002, the American-European Consensus Group (AECG) proposed a standard classification of Sjögren’s syndrome. Diseases and conditions that must be ruled out before making a diagnosis of primary Sjögren’s syndrome are infection with the hepatitis C virus (HCV), AIDS, preexisting lymphoma, sarcoidosis, previous radiation treatment of the head and neck, graft-vs-host disease, and use of anticholinergic drugs.⁴

In 2012, the ACR-Sjögren’s International Collaborative Clinical Alliance (SICCA) recommended new criteria for the diagnosis of Sjögren’s syndrome. These criteria were based on guidelines from the ACR to the extent possible for a disease whose diagnosis requires the involvement of multiple clinical specialties.⁵

In 2014, a comparison between AECG and ACR criteria found a concordance rate of 0.81 and showed that some items, primary regarding ocular involvement, required further revision. Investigators from both AECG and Sjögren’s International Collaborative Clinical Alliance collaborated to develop the 2016 ACR/EULAR classification criteria for primary Sjögren’s syndrome.⁶

The ACR-EULAR classification criteria for primary Sjögren’s syndrome⁷ applies to any individual who meets the inclusion criteria; who does not have a history of head and neck radiation treatment, active HCV infection, AIDS, sarcoidosis, amyloidosis, graft vs host disease (GVHD), or immunoglobulin G (IgG)4-related disease (IgG4-RD); and who has a score 4 or higher when summing the weights from 5 criteria items.

The criteria items include labial salivary gland with focal lymphocytic sialadenitis and focus score of ≥1 foci/4 mm2 (score: 3), anti-SSA/Ro positive (score: 3), ocular staining score ≥5 (or van Bijsterveld score ≥4) in at least 1 eye (score: 1), Schirmer’s test ≤5 mm/5 minutes in at least 1 eye (score: 1), unstimulated whole saliva flow rate ≤0.1 mL/minute (score: 1).

Epidemiology

Sjogren’s syndrome is an autoimmune disorder affecting more than 4 million people in the United States.⁸ The incidence and prevalence have been observed to differ depending on the study design and classification criteria used for the study. The reported prevalence ranges between 0.01% and 0.72% and the incidence ranges from 3 to 11 cases per 100,000 individuals.⁹

A systematic review and meta-analysis published in 2014 estimated that the overall pooled incidence rate for primary Sjögren’s syndrome was 6.92 (95% CI, 4.98-8.86) per 100,000 person-years. The prevalence rate of primary Sjögren’s syndrome for all populations included in the literature search was 60.82 (95% CI, 43.69-77.94) instances per 100,000 individuals. This number dropped to 43.03 (95% CI, 25.74-60.31) if only population-based studies were included in the analysis.¹⁰

The epidemiologic profile of Sjögren’s syndrome is quite typical at the onset of the disease which may facilitate early diagnosis. Most studies estimate that Sjögren’s syndrome has a female-to-male ratio of approximately 9:1.¹¹

Furthermore, men and women have different phenotypic expressions of Sjögren’s syndrome; compared with women, men have severe ocular involvement and less prominent systemic and immunologic involvement. Although Sjögren’s syndrome can affect people of all ages, it is most commonly diagnosed in women between the ages of 30 and 50 years. It is uncommon in children, and the female-to-male ratio among children is lower than that among adults.⁹

Etiology and Risk Factors

Genetic Predisposition

Alleles in the major histocompatibility complex (MHC) class II gene region, particularly the human leukocyte antigen (HLA)-DR and HLA-DQ alleles, are linked to Sjögren’s syndrome. These gene correlations differ depending on a patient’s ethnic origin. For example, the haplotype HLA-DRB1*0301-DRB3*0101-DQA1*0501-DQB1*0201 was found to be associated with the development of primary Sjögren’s syndrome in White individuals from California. Similarly, women from Japan and China had a higher prevalence of the haplotype HLA-DRB1*08032/DQA1*0103/DQB1*0601, DRB1*08032, and HLA-DRB1*0405-DRB4*0101-DQA1*0301-DQB1*0401 alleles associated with Sjögren’s syndrome.¹²

Environmental Factors

Infectious agents, particularly viruses, may play a role in Sjogren’s syndrome etiology. Viruses are hypothesized to increase autoantibody formation by molecular mimicry, which results in tissue damage.¹²

Certain viruses such as HCV, HIV, Epstein-Barr virus, cytomegalovirus, human T-lymphotropic virus type 1, human herpesvirus 6, and coxsackievirus are proposed as possible inducers of Sjögren’s syndrome given that they may cause persistent infection of the salivary glands, leading to organ damage.¹³ Smoking has been implicated as another risk factor for Sjögren’s syndrome in some studies.⁹

Hormonal Factors

Reduced estrogen levels have been linked to Sjogren’s syndrome-like symptoms in animal studies. In one animal study showed that mice that were unable to generate estrogen due to inactivated aromatase genes experienced autoimmune symptoms similar to those of Sjogren’s syndrome. Human research, on the other hand, has yielded conflicting outcomes regarding the role of hormone levels in Sjogren’s syndrome.¹²

A case-control study of 2680 women from the Sjogren’s International Collaborative Clinical Alliance registry found that women with primary Sjogren’s syndrome have lower estrogen exposure and cumulative menstrual cycling compared to patients with sicca symptoms. Increasing estrogen exposure was negatively associated with the development of primary Sjogren’s syndrome.¹⁴

Sjogren’s Syndrome Prognosis

The overall prognosis of patients with Sjögren’s syndrome is favorable. The life expectancy of individuals with primary Sjögren’s syndrome is similar to that of the general population, however, the quality of life is impacted by the manifestations of the disease. In patients with secondary Sjögren’s syndrome, life expectancy depends on the underlying primary disease.¹⁵

Risk factors for a poor prognosis in patients with primary Sjögren’s syndrome include presence of extra-glandular manifestations, malignant lymphoma particularly B-cell lymphoma, hematological malignancies, primary biliary cirrhosis, autoimmune hepatitis, pulmonary arterial hypertension, and amyloidosis.¹⁶ An analysis of a multicenter registry of 1580 patients with primary Sjögren’s syndrome found that 13% of patients develop a potentially life-threatening systemic disease such as lymphoma with a mortality rate of 20%.¹⁷

The presence of Sjögren’s syndrome is considered a high-risk category in pregnancy, because the disease can cause complications resulting in premature deliveries and spontaneous abortions. Sjögren’s syndrome is likely to worsen during the postpartum period as women have an increased risk of experiencing pulmonary hypertension. Women with Sjögren’s syndrome who are pregnancy experience more complications during pregnancy compared with women without the disease.¹⁸

Sjogren’s Syndrome Diagnosis & Presentation

Dry eyes, dry mouth, fatigue, and joint pains are common symptoms of Sjögren’s syndrome. Mild anemia, high ESR, high IgG levels with positive antinuclear antibodies (ANA), Ro autoantibodies, and La autoantibodies are all common findings on blood tests. Complement studies show low C4 levels.¹⁹ Arthralgia and a typically nonerosive polyarthritis are the most prevalent extraglandular symptoms of Sjögren syndrome, occurring in approximately half of patients.¹⁵

Physical Examination Findings

Clinical features of primary Sjögren’s syndrome can have glandular, extraglandular epithelial, and extraglandular nonepithelial manifestations.¹³ General and constitutional symptoms include fever, fatigue, and widespread pain.²⁰ Glandular manifestations, known as sicca symptoms, present as dry eye, mouth, skin, vagina, nose, and trachea.

Diagnostic Workup

A diagnosis of primary Sjögren syndrome requires both clinical and laboratory features after the exclusion of other causes. Sjögren syndrome should be suspected in people with sicca symptoms persisting longer than 3 months, after other potential causes and possible adverse drug reactions have been ruled out. Patients who experience sicca symptoms, particularly dry eyes and dry mouth, for more than 3 months require further function, serological, and histological examinations.¹⁵

Basic evaluation include unstimulated salivary flow rate, Schirmer test, lissamine green or fluorescein test, ANA or Ro/anti- Sjögren-syndrome-related antigen A autoantibodies (SSA) titers, and labial salivary gland biopsy. Extended diagnostic evaluation includes arthrosonography, joint tap, pulmonary function test, high-resolution computed tomography, electroneuromyography, and spinal tap.¹⁵

Objective Tests for Sicca Symptoms

The diagnostic gold standard for sicca symptoms is direct measurement of salivation, but it is time-consuming and not feasible in routine practice. Although the Schirmer and Saxon tests are easy to conduct, their results do not always correlate with patient complaints. Vital stains are applied topically to visualize and grade corneal and conjunctival lesions associated with keratoconjunctivitis sicca.¹⁵

Laboratory Testing

Diagnostic Markers in Serum/Plasma

Anti-SSA antibodies are seen in two-thirds of patients with Sjogren’s syndrome and rheumatoid factor is present in approximately half of patients.²¹

Rheumatoid factor, ANA, and extractable nuclear antigen antibodies are additional clinical and diagnostic indicators often used in evaluation for Sjögren’s syndrome, but their role is minor compared with other Sjögren’s syndrome classification criteria.³ Presence of rheumatoid factor does not distinguish primary Sjögren’s syndrome from SLE. Patients with Sjögren’s syndrome often lack antibodies to double-stranded DNA which are significant to the diagnosis of SLE.²¹

The presence of ANA titers greater than 1:160 and with fine granular patterns suggests the possibility of anti-Ro/SSA and/or anti-La/SSB antibodies.¹⁵

Biopsy

Biopsy of the salivary glands is crucial to the diagnosis of primary Sjögren syndrome. The presence of foci of at least 50 mononuclear cells in a periductal or periacinal distribution is the most characteristic biopsy feature of primary Sjögren syndrome, with an 82.4% sensitivity and 82.6% specificity when compared with other tests.²²

Patients with primary Sjögren’s syndrome are at a 14-fold increased risk of developing lymphomas, particularly B-cell lymphoma, compared with patients without Sjögren’s syndrome. Chronic swelling of the salivary gland may require an open biopsy.²⁰

Imaging Studies

Salivary Gland Ultrasonography
Salivary gland ultrasonography is presently the imaging technique of choice. Ultrasonography is noninvasive, low cost, easy to use, and convenient.²² The characteristic appearance of the parotid salivary gland is irregular black circular areas and white lines instead of the plain gray appearance.²⁰

Salivary gland ultrasonography is superior to other forms of imaging such as sialography, but has less sensitivity compared with MRI to detect parenchymal inhomogeneity, particularly in the early stages of primary Sjögren’s syndrome.²³

Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) findings in a given patient with Sjögren’s syndrome can change over time depending on the disease severity and duration. Early signs include swollen parotid glands due to inflammation-induced glandular edema.²² Use of MRI is the standard reference for parotid tumor assessment, particularly lymphoma.²³

Patients with a longer history of chronic illness can show atrophy of parotid glands and larger areas of cystic change such as lymphoepithelial cysts and/or cystic destruction. In advanced disease, fatty replacement, parenchymal calcifications, and intraparotid masses of lymph node collections can be detected on MRI.²²

Computed Tomography
Computed tomography (CT) imaging is often less expensive, faster, and easier to access than MRI. Risks associated with exposure to ionizing radiation should be considered. In patients with primary Sjogren’s syndrome, CT scans show salivary glands enlarged by inflammation, similar to results seen with MRI.²² 18-Fluorodeoxyglucose (FDG) is commonly used as a radiotracer and mainly distributed in the salivary glands, lymph nodes, and lungs. The uptake of FDG is commonly seen in patients with primary Sjogren’s syndrome. Use of CT may be valuable for staging and assessing disease activity but is limited in its use for the diagnosis of primary Sjogren’s syndrome.²³

Sialography
The anatomy of the ductal system is examined via conventional sialography, a radiographic study requiring cannulation of the Stenson and Wharton ducts and injection of water-soluble iodinated contrast media. Alternating ductal stenosis and dilatation are common abnormalities associated with persistent inflammation caused by the disease.²² Sialography is an invasive examination and its use was not recommended in the ACR/EULAR recommendations published in 2012 or 2016.²³

Sjogren’s Syndrome Differential Diagnosis

Sicca symptoms can be caused by a variety of external factors that cause mucosal dryness, such as allergies, local infections, dehydration, irradiation, or chronic infections with viruses such as HCV, HIV, or human T-lymphotropic virus type 1.⁹ Medication-induced xerostomia through use of antihypertensives, antihistamines, and antidepressants are the most common cause of sicca symptoms. Patients who undergo external beam radiation for the treatment of head and neck tumors or radioactive iodine for the treatment of Graves’ disease and thyroid cancer may also develop sicca symptoms.²²

Symptoms of Sjogren’s syndrome can be mimicked by tuberculosis, sarcoidosis, amyloidosis, and hematologic malignancies.⁹ Other differential diagnoses to consider are sialolithiasis, sialodenosis, and chronic sialadenitis.²²

IgG4­RD was recognized to cause infiltration of the exocrine glands by immune cells and characterized by raised serum and/or tissue IgG4 levels.²⁰ Notably, 7% of patients with Sjögren’s syndrome have been found to have elevated IgG4 levels and these patients should be evaluated for IgG4­RD through histologic and immunohistochemical examination of the salivary glands and other organs.⁹

Sjogren’s Syndrome Management

Nonpharmacologic

Oral symptoms

The lack of sufficient saliva promotes development of dental caries in Sjögren’s syndrome, making it critical for patients to maintain appropriate oral hygiene. To promote residual salivary flow, sugar-free sweets and chewing gums can be used. Sprays and gels containing artificial saliva are also available.¹⁹

Ocular symptoms

Preservative-free artificial tear drops and ointments can alleviate ocular symptoms. Sjögren’s syndrome can be complicated by blepharitis, which is treated with eyelid hygiene. Punctal occlusion is a mechanical procedure to prevent tears from draining and retain natural moisture on the ocular surface.¹⁹

Vaginal symptoms

Vaginal symptoms can be treated with nonhormonal moisturizers. Postmenopausal women may benefit from local hormone replacement therapy.¹⁹

Psychological symptoms

Psychological symptoms can be effectively treated with exercise and self-care measures.¹⁹

Pharmacologic

Systemic Treatments

Nonbiologic Therapies

• Pilocarpine or Cevimeline
• Hydroxychloroquine
• NSAIDs
• Steroids: Oral and intramuscular
• Immunosuppressants
  • Azathioprine
  • Cyclophosphamide
  • Mycophenolate
  • Methotrexate

Biologic Therapies

• Infliximab
• Rituximab
• Belimumab
• Abatacept
• Tocilizumab

Pilocarpine and cevimeline can relieve symptoms of oral and ocular dryness. Ocular inflammation can also be treated with topical corticosteroids or cyclosporine.¹⁹

The first-line treatment for musculoskeletal discomfort and mild inflammatory arthritis associated with Sjögren’s syndrome is hydroxychloroquine. There is some weak evidence that it reduces fatigue.¹⁹ If hydroxychloroquine fails to work, methotrexate given either alone or in combination with hydroxychloroquine should be used.²⁴ Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat general Sjogren’s syndrome symptoms, including muscular pain and joint discomfort.⁴

Prednisone is used to treat Sjögren’s syndrome because of its success in treating other autoimmune illnesses. Low-dose prednisone is used to treat arthritis in Sjögren’s syndrome as well as cutaneous symptoms of the disease. In uncontrolled studies, high doses of prednisone were found to be effective for treatment of renal, lung, and central nervous system symptoms associated with Sjögren’s syndrome.⁹

For severe forms of visceral damage such as pulmonary, cutaneous, renal, neurological and musculoskeletal seen in Sjögren’s syndrome, glucocorticoids or immunosuppressive therapy may be used. Patients with primary Sjögren’s syndrome and significant liver or renal impairment should not use methotrexate.²⁴

Increased use of biologic therapies in Sjögren’s syndrome is based on an improved understanding of the mechanism of Sjögren’s syndrome and the establishment of therapeutic targets for these agents in patients with other autoimmune disorders. In addition, resistance to therapy in primary Sjögren’s syndrome with documented organ damage is an indication for initiation of biologic therapy.⁴

Rituximab is a chimeric anti-CD20 monoclonal antibody that depletes B cells by causing a direct toxic effect on these cells over a period of 4 to 12 months. Rituximab treatment has been found to be effective for patients with primary Sjogren’s syndrome.⁴

The monoclonal anti-BAFF antibody belimumab was shown to be effective in the treatment of Sjögren’s syndrome in a prospective 1-year open-label bicentric study involving 30 patients.⁴

Abatacept, a T-cell-targeted therapy, has been demonstrated in several studies to increase saliva production and decrease systemic symptoms of the condition as well as glandular inflammation.⁴

Infliximab is a TNF-α antagonist that is used to treat certain types of arthritis, bowel disease, and skin disease. Further research is needed to evaluate the efficacy of topical infliximab in patients with Sjögren’s syndrome.⁴

Tocilizumab is an IL-6 receptor antagonist and has been linked to multiple autoimmune disorders. IL-6 levels are higher in the tears, saliva, and blood of patients with Sjögren’s syndrome. Clinical trials of tocilizumab in this setting are ongoing.⁴

Treatment Recommendations for Specific Systemic Manifestations¹⁵

Parotid swelling: NSAIDS and short term oral corticosteroids with dosages less than 20 mg/day for a maximum of 1 month. Antibiotics can be utilized as needed.
Arthritis: hydroxychloroquine with annual ophthalmological follow-ups NSAIDs and short-term oral or intra-articular corticosteroids. Second-line DMARDs such as methotrexate can also be considered.
Interstitial pneumopathy: oral or intravenous corticosteroids, cyclophosphamide in active alveolitis, pirfenidone, or nintedanib.
Tubulointerstitial nephritis: potassium and bicarbonate replacement.
Peripheral neuropathy: antidepressants, gabapentin, oral or intravenous corticosteroids, or intravenous IG.
Cryoglobulinemic vasculitis with organ involvement: methylprednisolone, plasmapheresis, or rituximab.

Monitoring Sjogren’s Syndrome Side Effects

To minimize significant side effects such as elevated blood pressure, weight gain, hyperglycemia, and bone loss, systemic corticosteroids should only be administered for a limited period of time. Patients with primary Sjogren’s syndrome undergoing treatment with methotrexate should receive folic acid supplementation to reduce gastrointestinal side effects.²⁴

Comorbidities

Sjogren’s syndrome is associated with several systemic autoimmune diseases. Concomitant Sjogren’s syndrome has been reported in 14% to 18% of patients with SLE, 7% to 17% of patients with RA, and 12% of patients with systemic sclerosis. The overall management of patients with associated Sjogren’s syndrome is similar to the management of primary Sjogren’s syndrome.⁹

Sjogren’s Syndrome Complications

Malignant lymphoma is a significant complication of Sjogren’s syndrome that can have an impact on prognosis.¹ Other hematologic malignancies (eg, multiple myeloma), liver disorders (eg, primary biliary cirrhosis, autoimmune hepatitis), and cardiovascular disorders (eg, pulmonary arterial hypertension) are all known to be associated with primary Sjogren’s syndrome and have been linked to a poor prognosis.¹

Mortality from Sjogren’s syndrome is usually noted in patients with B-cell lymphoma, severe organ-specific features (including renal failure, interstitial lung disease, and severe cryoglobulinemic vasculitis), cardiovascular disease, and infections.⁹

Patient Education

The types and severity of symptoms in Sjögren’s syndrome vary, but many people are able to lead regular lives. Treatment is focused on alleviating dry eye and mouth symptoms as well as avoiding and treating long-term problems such as infection and dental disease.

With proper management, the majority of patients maintain good health overall, although certain unusual side effects have been reported, including an increased risk of lymphoma. As a result, all patients require ongoing medical attention and follow-up. Several organizations provide support and information to people with Sjogren’s syndrome. These include The American College of Rheumatology, the Arthritis Foundation, and The Sjogren’s Syndrome Foundation, in Sweden.

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