Skip to main content

Main menu

  • Home
  • Content
    • Current issue
    • Past issues
    • Early releases
    • Collections
    • Sections
    • Blog
    • Infographics & illustrations
    • Podcasts
    • COVID-19 Articles
  • Authors
    • Overview for authors
    • Submission guidelines
    • Submit a manuscript
    • Forms
    • Editorial process
    • Editorial policies
    • Peer review process
    • Publication fees
    • Reprint requests
    • Open access
  • CMA Members
    • Overview for members
    • Earn CPD Credits
    • Print copies of CMAJ
  • Subscribers
    • General information
    • View prices
  • Alerts
    • Email alerts
    • RSS
  • JAMC
    • À propos
    • Numéro en cours
    • Archives
    • Sections
    • Abonnement
    • Alertes
    • Trousse média 2022
  • CMAJ JOURNALS
    • CMAJ Open
    • CJS
    • JAMC
    • JPN

User menu

Search

  • Advanced search
CMAJ
  • CMAJ JOURNALS
    • CMAJ Open
    • CJS
    • JAMC
    • JPN
CMAJ

Advanced Search

  • Home
  • Content
    • Current issue
    • Past issues
    • Early releases
    • Collections
    • Sections
    • Blog
    • Infographics & illustrations
    • Podcasts
    • COVID-19 Articles
  • Authors
    • Overview for authors
    • Submission guidelines
    • Submit a manuscript
    • Forms
    • Editorial process
    • Editorial policies
    • Peer review process
    • Publication fees
    • Reprint requests
    • Open access
  • CMA Members
    • Overview for members
    • Earn CPD Credits
    • Print copies of CMAJ
  • Subscribers
    • General information
    • View prices
  • Alerts
    • Email alerts
    • RSS
  • JAMC
    • À propos
    • Numéro en cours
    • Archives
    • Sections
    • Abonnement
    • Alertes
    • Trousse média 2022
  • Visit CMAJ on Facebook
  • Follow CMAJ on Twitter
  • Follow CMAJ on Pinterest
  • Follow CMAJ on Youtube
  • Follow CMAJ on Instagram
Review

Sjögren syndrome

Clio P. Mavragani and Haralampos M. Moutsopoulos
CMAJ October 21, 2014 186 (15) E579-E586; DOI: https://doi.org/10.1503/cmaj.122037
Clio P. Mavragani
Departments of Physiology (Mavragani) and Pathophysiology (Moutsopoulos), Faculty of Medicine, University of Athens, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Haralampos M. Moutsopoulos
Departments of Physiology (Mavragani) and Pathophysiology (Moutsopoulos), Faculty of Medicine, University of Athens, Athens, Greece
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: hmoutsop@med.uoa.gr
  • Article
  • Figures & Tables
  • Responses
  • Metrics
  • PDF
Loading

Sjögren syndrome is a chronic, systemic disorder of an autoimmune nature. It is characterized by lymphocytic infiltration of the exocrine (mainly salivary and lacrimal) glands and by remarkable B-cell hyperactivity. The latter is manifested by hypergammaglobulinemia and the presence of serum autoantibodies, including antinuclear antibodies, rheumatoid factor, cryoprecipitable immunoglobulins and antibodies against two ribonucleoproteinic complexes named Ro/SSA and La/SSB; these antibodies are considered hallmarks of the disease.1,2 Although their exact role is not known, recent data suggest that antibodies against the Ro52 component of the Ro/SSA antigen (a 52kD protein that inhibits proinflammatory responses) might inhibit its regulatory function.3 The condition is nine times more common among women than among men, with peak onset during menopause.1 A recent review suggests that the prevalence ranges from 0.1% to 4.8%,1 with rates increasing with advanced age.4,5 Heterogeneity in inclusion criteria, ethnic origin, sample size and sex distribution between studies contributed to the observed variability.

Although Sjögren syndrome is classically considered to be localized disease of the exocrine glands, mainly manifested with oral and ocular dryness, it also has a wide range of systemic clinical manifestations that affect essentially any organ system, and a small number of cases are complicated by the development of non-Hodgkin lymphoma.1,6 Secondary Sjögren syndrome is associated with an established connective-tissue disease.

As is the case for many autoimmune diseases, the primary etiopathogenetic events are not known. The current hypothesis is that an interplay between environmental contributors (e.g., viruses, stress, hormones) and the patient’s genetic background can lead to inflammatory responses against epithelial tissues. In this review, we summarize the current evidence, mostly from observational, open-label and randomized clinical trials, for the clinical manifestations, diagnosis and management of Sjögren syndrome (Box 1).

Box 1:

Evidence used in this review

Using the MeSH term “Sjögren syndrome,” we searched MEDLINE for randomized controlled trials, systematic reviews and observational studies involving adult humans. We included studies published in English between Jan. 1, 1975, and Nov. 25, 2012. We also manually searched the reference lists of relevant articles retrieved.

What are the clinical features of Sjögren syndrome?

The clinical features of Sjögren syndrome can be largely divided into those related to exocrine dysfunction (glandular) and those that affect organs other than the exocrine glands (extraglandular or systemic). The latter can be further divided into nonspecific features, those characterized by periepithelial infiltrates in parenchymal organs and those that result from immunocomplex deposition as a result of B-cell hyperactivity.7,8 Most patients with Sjögren syndrome (about 90%) have an indolent benign course; however, a small but important number of cases (5%–10%) are complicated by immunocomplex pathology and lymphoid neoplasia, both of which are associated with high mortality (a 3.25-fold increase compared with the general population).6,7,9

The main features of glandular and extraglandular manifestations in Sjögren syndrome are shown in Table 1.6,7,9–40 Besides sicca features, easy fatigability is one of the most frequent symptoms, occurring in 70% of patients with primary Sjögren syndrome; these patients typically report functional disability and an increased need for rest.13,26,41 Patients with primary Sjögren syndrome may show several psychopathologic features depending on premorbid personality traits and in association with antibodies against neuropeptides.42 Increased rates of neuroticism, psychoticism, obsessiveness, hypochondriasis, paranoid ideation, somatization, obsessive–compulsive symptoms, sleep disturbances and defective coping strategies have been reported.7,43–47

View this table:
  • View inline
  • View popup
Table 1:

Clinical manifestations of primary Sjögren syndrome

Non-Hodgkin lymphoma is a well-recognized complication of Sjögren syndrome.6,39 Peripheral neuropathy, glomerulonephritis, lymphopenia, vasculitis or purpuric lesions, low C4 levels, cryoglobulinemia and the presence of germinal centres in salivary gland biopsy samples are well-recognized adverse predictors of lymphoma.7,9,39,40 In a comparative analysis involving patients with mucosa-associated lymphoid tissue lymphoma with or without underlying autoimmune disease, there were no differences in the rate of relapse, time to relapse or survival.48

How should a diagnosis of Sjögren syndrome be made?

The key to prompt diagnosis is clinical evaluation for every patient who presents with symptoms of oral or ocular dryness. This evaluation should include a complete systems review, including specific questions to assess oral and ocular dryness, clinical examination and investigations to assess the degree of exocrine gland dysfunction, the presence of relevant immunologic abnormalities and the extent of organ involvement. Because sicca symptomatology can be attributed to several different clinical entities, the differential diagnosis is extensive (Box 2).26,49–51 In a prospective multicentre trial, the prevalence of Sjögren syndrome in a cohort of patients with clinically important aqueous-deficient dry eye was 11.6%.52 In contrast, in a closed rural community, about 15% of patients (n = 35) with sicca symptoms who underwent full evaluation for Sjögren syndrome fulfilled the classification criteria for the diagnosis.53

Box 2:

Differential diagnosis of Sjögren syndrome26,49–51

  • Medications (e.g., diuretics, antihistamines)

  • Viral infections (e.g., HIV infection, hepatitis C virus infection)

  • Tumours (e.g., parotid gland tumour)

  • Metabolic disorders (diabetes mellitus, lipoproteinemia types II, IV and V)

  • Irradiation

  • Sarcoidosis

  • Chronic graft-versus-host disease

  • Lymphoma

  • Amyloidosis

  • IgG4-related sialadenitis

  • Autoimmune thyroid disease

In clinical practice, patients who present with sicca symptoms should be offered assessment of lacrimal gland function (measuring tear production using Schirmer test [wetting on a paper strip of ≤ 5 mm in 5 min]; sensitivity 76.9%; specificity 4%–72%) and examination of the cornea and conjunctiva using rose bengal or lissamine green stain (reveals punctuate or filamentary keratitis lesions, typical of keratoconjunctivitis sicca; sensitivity 64.3%; specificity 81.7%). Unstimulated saliva secretion should also be measured (in a graded tube; > 1.5 mL in 15 min is considered normal; sensitivity 56.1%; specificity 80.7%). A biopsy of a minor salivary gland should be performed to assess the presence of lymphocytic infiltrates around salivary gland epithelium (hallmark of Sjögren syndrome; sensitivity 82.4%; specificity 86.2%).54 An average focus score of 1 or greater in the salivary gland biopsy sample is considered indicative of Sjögren syndrome. The focus score is calculated as the number of lymphocyte foci per 4-mm2 surface based on a survey of at least four lobules. A focus is a cluster of at least 50 lymphocytes.55

Other investigations include a full blood count, chemistry panel, chest radiography, protein electrophoresis, testing for antinuclear antibodies, antibodies against Ro/SSA and La/SSB autoantigens and rheumatoid factor, and viral testing for hepatitis C virus, HIV and human T-lymphotropic virus 1. Antibodies against thyroid antigens and thyroid function should be evaluated, given the association between autoimmune thyroid disease and sicca complaints.50 Antibodies against Ro/SSA can be detected in 70%–100% of patients with Sjögren syndrome; La/SSB antibodies can be detected in 35%–70%. Antibodies against La/SSB are considered to be a highly specific diagnostic marker for Sjögren syndrome.3,56 According to the classification criteria, the presence of these antibodies along with other features suggestive of Sjögren syndrome is sufficient for establishing the diagnosis, even in the absence of a positive salivary gland biopsy.57

Once the diagnosis is established, additional investigational tests (e.g., cryoglobulins, complement levels, immunofixation) should also be offered, particularly to patients with peripheral purpura, peripheral neuropathy, salivary gland enlargement or in situ demonstration of salivary gland lymphoma. Upper endoscopy, bone marrow biopsy and computed tomography scans of the neck, thorax and abdomen should be performed to detect the potential development and extent of lymphoma.

To aid in the classification of Sjögren syndrome, the international research community proposed the American–European Consensus Criteria for Sjögren’s Syndrome (Box 3), which require the presence of either focal lymphocytic infiltrates in minor salivary glands with a focus score of 1 or more, or the presence of SSA or SSB autoantibodies along with features suggestive of salivary or lacrimal gland involvement.57 A new set of preliminary criteria was recently proposed by the American College of Rheumatology; these criteria are based solely on objective criteria58 (Box 3).

Box 3:

Classification criteria for Sjögren syndrome

American/European classification criteria57

Ocular symptoms (at least one)

  • Persistent, troublesome dry eyes every day for longer than three months

  • Recurrent sensation of sand or gravel in the eyes

  • Use of a tear substitute more than three times per day

Oral symptoms (at least one)

  • Feeling of dry mouth every day for at least three months

  • Recurrent feeling of swollen salivary glands as an adult

  • Need to drink liquids to aid in swallowing dry foods

Objective evidence of dry eyes (at least one)

  • Schirmer test ≤ 5 mm/5min

  • Van Bijsterveld score ≥ 4 (after lissamine test)

Objective evidence of salivary-gland involvement (at least one)

  • Salivary-gland scintigraphy

  • Parotid sialography

  • Unstimulated salivary flow (≤ 1.5 mL/15 min, ≤ 0.1 mL/min)

Histological features

  • Positive biopsy sample of a minor salivary gland (focus score > 1; refers to a cluster of ≥ 50 lymphocytes per lobule when at least four lobules are assessed)

Autoantibodies

  • Presence of antibodies to SSA (Ro/SSA) or to SSB (La/SSB)

Classification

  • Primary Sjögren syndrome requires the presence of four of six criteria, including a positive biopsy sample of a minor salivary gland or antibodies against SSA or SSB, or three of the four objective criteria

  • Secondary Sjögren syndrome requires an established connective-tissue disease and one sicca symptom plus any three of the four objective criteria

  • Exclusions: previous radiotherapy to the head and neck, lymphoma, sarcoidosis, graft-versus-host disease, infection with hepatitis C virus or HIV, or the use of anticholinergic drugs

American College of Rheumatology criteria58

  • Antibodies against SSA (Ro/SSA) or SSB (La/SSB), or positive rheumatoid factor and antinuclear antibody levels of 1:320 or greater

  • Labial salivary gland biopsy showing focal lymphocytic sialadenitis with a focus score ≥ 1 focus/4 mm2

  • Keratoconjunctivitis sicca with ocular staining score ≥ 3 (assumes that the patient is not currently using daily eye drops for glaucoma and has not had corneal surgery or cosmetic eyelid surgery in the last five yr)

  • Classification of Sjögren syndrome, which applies to patients with signs or symptoms suggestive of Sjögren syndrome, requires the presence of at least two of the three aforementioned objective features.

  • Exclusions: history of head and neck radiation treatment, infection with hepatitis C virus, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease or IgG4-related disease

What therapies are effective for mucosal dryness in Sjögren syndrome?

The treatment of mucosal dryness related to Sjögren syndrome is mainly intended to alleviate symptoms and prevent complications such as dental caries, dysphagia and oral candidiasis. As general measures, alcohol, smoking and medications such as diuretics, antidepressants (with the exception of selective serotonin reuptake inhibitors, especially escitalopram and fluoxetine) and antihistamines should be avoided because they exacerbate mucosal dryness; air conditioning should also be avoided. Mouth hygiene, thorough dental follow-up, stimulation of salivary flow (sugar-free gum or citrus juice) and administration of saliva substitutes are generally advised for the management of oral dryness.59 Salivary substitutes have been shown to improve subjective symptoms of oral dryness (e.g., burning mouth, difficulties with mastication and swallowing) without affecting the rate of salivary output.60 Painful enlargement of salivary glands can be alleviated by local application of moist heat and administration of non-steroidal anti-inflammatory drugs after bacterial infection and lymphoma have been ruled out.

Ocular dryness should initially be treated with preservative-free teardrops or eye lubricants containing either sodium hyaluronate or hydroxypropyl methylcellulose, which improve both subjective symptoms and objective signs of ocular dryness (e.g., Schirmer test, rose bengal staining, impression cytology scores).61–64 In cases of moderate to severe dry eye disease, cyclosporine drops (0.05%) for six months were shown to lead to remarkable improvement in Schirmer test and corneal staining scores and subjective ocular symptoms (e.g., reduced blurred vision, use of artificial tears).65

Among patients with residual gland function, the beneficial use of two cholinergic agents was shown in controlled studies. Patients who used pilocarpine (10–30 mg once daily) showed statistically significant improvements in dryness (oral, ocular, nasal, vaginal, skin) and salivary flow rates. Cevimeline use (30 mg three times daily) has been also associated with improved subjective oral and ocular symptoms, increased salivary flow rates and objective ocular signs.66 Although steroid-containing ophthalmic solutions have shown short-term benefits, caution should be taken with prolonged use because serious adverse effects (e.g., raised intraocular pressure, worsening or development of cataracts, impaired corneal wound healing, increased risk of infection risk) may occur.66–69 Women with vaginal dryness and dyspareunia may benefit from vaginal lubricants, as suggested by studies not focused on Sjögren syndrome.70 In patients with earlier disease onset and preserved salivary function, improvements have been shown using both subjective (visual analog scale [VAS] scores for sicca symptoms) and objective measures after treatment with rituximab (monoclonal antibody against CD20).71

What therapies are effective for the management of systemic features in Sjögren syndrome?

Systemic therapy should be considered for patients showing systemic features and should be tailored to the organs affected and to the severity. Because of a lack of robust data from controlled studies, the management of extraglandular manifestations is mainly based on case-series reports, open-label studies and expert opinion based on biological rationale and experience with other autoimmune diseases. Therapeutic options for the systemic manifestations of Sjögren syndrome are shown in Table 2.59,66,72,73

View this table:
  • View inline
  • View popup
Table 2:

Therapeutic options for systemic features in Sjögren syndrome59,66,72,73

In patients for whom arthralgia or myalgia is the predominant symptom, hydroxychloroquine therapy has been shown to improve arthralgia, myalgia and joint inflammation; methotrexate can be used in cases of inflammatory arthritis.72,74 For cases of persistent arthritis, rituximab has been shown to significantly improve the tender and swollen joint count.75 A pilot open-label study reported that weekly administration of methotrexate to patients with Sjögren syndrome reduced the frequency of parotid gland enlargement, dry cough and purpura.76 In patients with primary Sjögren syndrome, blockade of tumor necrosis factor α (infliximab and etanercept) does not appear to be effective in reducing subjective and objective measures of salivary and lacrimal function or joint inflammation; augmentation of the already activated type I interferon/B-cell activating factor (BAFF) axis has been suggested to account for this failure.77,78

Cytotoxic drugs (e.g., cyclophosphamide) are reserved for severe extraglandular manifestations, including cutaneous vasculitis and glomerulonephritis. Given that B-cell activation is a disease cornerstone, choosing targeted therapies against B cells is a logical approach.6,72 Improvement in fatigue scores in a randomized controlled trial and demonstrated efficacy in extraglandular features (e.g., cryoglobulinemic vasculitis) and peripheral neuropathy with reduction of disease activity indices imply that rituximab is a promising therapeutic strategy for Sjögren syndrome.73,75,79–82

Unanswered questions

Key questions remain with regard to disease pathogenesis, clinical spectrum and therapeutic strategies. Four main questions are the focus of basic and clinical research: the identification of proximal triggers (exogenous or endogenous factors) that account for epithelial activation and immunological injury; the thorough characterization of various clinical phenotypes and association with distinct pathogenetic pathways such as type I interferon/BAFF axis–designation of tailored therapies; determination of the underlying genetic, epigenetic and immunologic mechanisms of lymphomagenesis related to Sjögren syndrome; and the implementation of preventative therapeutic strategies against lymphoma development in high-risk patients with Sjögren syndrome.

Key points
  • Sjögren syndrome is a chronic autoimmune disease that mainly affects middle-aged women.

  • Clinical manifestations are mainly classified as glandular (manifested mainly by dry eyes and mouth) or extraglandular (systemic).

  • About 5%–10% of cases are complicated by the development of lymphoma.

  • Diagnosis is made by observing ocular and oral dryness, by measuring serum autoantibody levels and by observing periductual lymphocyte infiltration in salivary gland biopsy samples.

  • Local measures and cholinergic agents are the main therapeutic methods used to alleviate oral and ocular dryness. B-cell targeted therapies are reserved for the systemic manifestations of the syndrome.

Footnotes

  • Competing interests: None declared.

  • This article has been peer reviewed.

  • Contributors: Clio Mavragani drafted the manuscript and Haralampos Moutsopoulos critically revised it. Both authors contributed to data collection and approved the final version.

References

  1. ↵
    1. Mavragani CP,
    2. Moutsopoulos HM
    . The geoepidemiology of Sjögren’s syndrome. Autoimmun Rev 2010;9:A305-10.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Routsias JG,
    2. Tzioufas AG
    . Autoimmune response and target autoantigens in Sjögren’s syndrome. Eur J Clin Invest 2010;40: 1026–36.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Yoshimi R,
    2. Ueda A,
    3. Ozato K,
    4. et al
    . Clinical and pathological roles of Ro/SSA autoantibody system. Clin Dev Immunol. 2012; 2012:606195.
    OpenUrlPubMed
  4. ↵
    1. Drosos AA,
    2. Andonopoulos AP,
    3. Costopoulos JS,
    4. et al
    . Prevalence of primary Sjögren’s syndrome in an elderly population. Br J Rheumatol 1988;27:123–7.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Haugen AJ,
    2. Peen E,
    3. Hulten B,
    4. et al
    . Estimation of the prevalence of primary Sjögren’s syndrome in two age-different community-based populations using two sets of classification criteria: the Hordaland Health Study. Scand J Rheumatol 2008;37:30–4.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Voulgarelis M,
    2. Ziakas PD,
    3. Papageorgiou A,
    4. et al
    . Prognosis and outcome of non-Hodgkin lymphoma in primary Sjögren syndrome. Medicine (Baltimore) 2012;91:1–9.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Skopouli FN,
    2. Dafni U,
    3. Ioannidis JP,
    4. et al
    . Clinical evolution, and morbidity and mortality of primary Sjögren’s syndrome. Semin Arthritis Rheum 2000;29:296–304.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Malladi AS,
    2. Sack KE,
    3. Shiboski S,
    4. et al
    . Primary Sjögren’s syndrome as a systemic disease: a study of participants enrolled in an international Sjögren’s syndrome registry. Arthritis Care Res (Hoboken). 2012; 64:911–8.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Ioannidis JP,
    2. Vassiliou VA,
    3. Moutsopoulos HM
    . Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren’s syndrome. Arthritis Rheum 2002; 46:741–7.
    OpenUrlCrossRefPubMed
    1. Sumida T,
    2. Tsuboi H,
    3. Iizuka M,
    4. et al
    . Anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sjögren’s syndrome. Mod Rheumatol 2013;23:841–5.
    OpenUrlCrossRefPubMed
    1. Skopouli FN,
    2. Papanikolaou S,
    3. Malamou-Mitsi V,
    4. et al
    . Obstetric and gynaecological profile in patients with primary Sjögren’s syndrome. Ann Rheum Dis 1994;53:569–73.
    OpenUrlAbstract/FREE Full Text
    1. Skopouli FN,
    2. Talal A,
    3. Galanopoulou V,
    4. et al
    . Raynaud’s phenomenon in primary Sjögren’s syndrome. J Rheumatol 1990;17:618–20.
    OpenUrlPubMed
  10. ↵
    1. Ng WF,
    2. Bowman SJ
    . Primary Sjögren’s syndrome: too dry and too tired. Rheumatology (Oxford) 2010;49:844–53.
    OpenUrlCrossRefPubMed
    1. Skopouli FN,
    2. Barbatis C,
    3. Moutsopoulos HM
    . Liver involvement in primary Sjögren’s syndrome. Br J Rheumatol 1994;33:745–8.
    OpenUrlCrossRefPubMed
    1. Goules A,
    2. Masouridi S,
    3. Tzioufas AG,
    4. et al
    . Clinically significant and biopsy-documented renal involvement in primary Sjögren syndrome. Medicine (Baltimore) 2000;79:241–9.
    OpenUrlCrossRefPubMed
    1. Mavragani CP,
    2. Fragoulis GE,
    3. Moutsopoulos HM
    . Endocrine alterations in primary Sjögren’s syndrome: an overview. J Autoimmun 2012;39:354–8.
    OpenUrlCrossRefPubMed
    1. Mavragani CP,
    2. Schini M,
    3. Gravani F,
    4. et al
    . Brief report: adrenal autoimmunity in primary Sjögren’s syndrome. Arthritis Rheum 2012;64:4066–71.
    OpenUrlCrossRefPubMed
    1. Euthymiopoulou K,
    2. Aletras AJ,
    3. Ravazoula P,
    4. et al
    . Antiovarian antibodies in primary Sjögren’s syndrome. Rheumatol Int 2007; 27:1149–55.
    OpenUrlCrossRefPubMed
    1. Tsokos M,
    2. Lazarou SA,
    3. Moutsopoulos HM
    . Vasculitis in primary Sjögren’s syndrome. Histologic classification and clinical presentation. Am J Clin Pathol 1987;88:26–31.
    OpenUrlPubMed
    1. Ramos-Casals M,
    2. Anaya JM,
    3. Garcia-Carrasco M,
    4. et al
    . Cutaneous vasculitis in primary Sjögren syndrome: classification and clinical significance of 52 patients. Medicine (Baltimore) 2004;83:96–106.
    OpenUrlCrossRefPubMed
    1. Brito-Zerón P,
    2. Akasbi M,
    3. Bosch X,
    4. et al
    . Classification and characterisation of peripheral neuropathies in 102 patients with primary Sjögren’s syndrome. Clin Exp Rheumatol 2013;31:103–10.
    OpenUrl
    1. Pavlakis PP,
    2. Alexopoulos H,
    3. Kosmidis ML,
    4. et al
    . Peripheral neuropathies in Sjögren syndrome: a new reappraisal. J Neurol Neurosurg Psychiatry 2011;82:798–802.
    OpenUrlAbstract/FREE Full Text
    1. Alexander EL,
    2. Arnett FC,
    3. Provost TT,
    4. et al
    . Sjögren’s syndrome: association of anti-Ro(SS-A) antibodies with vasculitis, hematologic abnormalities, and serologic hyperreactivity. Ann Intern Med 1983;98:155–9.
    OpenUrlCrossRefPubMed
    1. Soliotis FC,
    2. Mavragani CP,
    3. Moutsopoulos HM
    . Central nervous system involvement in Sjögren’s syndrome. Ann Rheum Dis 2004; 63:616–20.
    OpenUrlFREE Full Text
    1. Tsampoulas CG,
    2. Skopouli FN,
    3. Sartoris DJ,
    4. et al
    . Hand radiographic changes in patients with primary and secondary Sjögren’s syndrome. Scand J Rheumatol 1986;15:333–9.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Kassan SS,
    2. Moutsopoulos HM
    . Clinical manifestations and early diagnosis of Sjögren syndrome. Arch Intern Med 2004; 164:1275–84.
    OpenUrlCrossRefPubMed
    1. Youinou P,
    2. Pennec YL,
    3. Katsikis P,
    4. et al
    . Raynaud’s phenomenon in primary Sjögren’s syndrome. Br J Rheumatol 1990;29:205–7.
    OpenUrlCrossRefPubMed
    1. García-Carrasco M,
    2. Siso A,
    3. Ramos-Casals M,
    4. et al
    . Raynaud’s phenomenon in primary Sjögren’s syndrome. Prevalence and clinical characteristics in a series of 320 patients. J Rheumatol 2002; 29:726–30.
    OpenUrlAbstract/FREE Full Text
    1. Papiris SA,
    2. Maniati M,
    3. Constantopoulos SH,
    4. et al
    . Lung involvement in primary Sjögren’s syndrome is mainly related to the small airway disease. Ann Rheum Dis 1999;58:61–4.
    OpenUrlAbstract/FREE Full Text
    1. Papiris SA,
    2. Tsonis IA,
    3. Moutsopoulos HM
    . Sjögren’s syndrome. Semin Respir Crit Care Med 2007;28:459–71.
    OpenUrlCrossRefPubMed
    1. Hatzis GS,
    2. Fragoulis GE,
    3. Karatzaferis A,
    4. et al
    . Prevalence and longterm course of primary biliary cirrhosis in primary Sjögren’s syndrome. J Rheumatol 2008;35:2012–6.
    OpenUrlAbstract/FREE Full Text
    1. Maripuri S,
    2. Grande JP,
    3. Osborn TG,
    4. et al
    . Renal involvement in primary Sjögren’s syndrome: a clinicopathologic study. Clin J Am Soc Nephrol 2009;4:1423–31.
    OpenUrlAbstract/FREE Full Text
    1. Moutsopoulos HM,
    2. Cledes J,
    3. Skopouli FN,
    4. et al
    . Nephrocalcinosis in Sjögren’s syndrome: a late sequela of renal tubular acidosis. J Intern Med 1991;230:187–91.
    OpenUrlCrossRefPubMed
    1. Goules AV,
    2. Tatouli IP,
    3. Moutsopoulos HM,
    4. et al
    . Clinically significant renal involvement in primary Sjögren’s syndrome: clinical presentation and outcome. Arthritis Rheum 2013;65:2945–53.
    OpenUrlCrossRefPubMed
    1. Caramaschi P,
    2. Biasi D,
    3. Caimmi C,
    4. et al
    . The co-occurrence of Hashimoto thyroiditis in primary Sjögren’s syndrome defines a subset of patients with milder clinical phenotype. Rheumatol Int 2013;33:1271–5.
    OpenUrlCrossRefPubMed
    1. Moutsopoulos HM,
    2. Balow JE,
    3. Lawley TJ,
    4. et al
    . Immune complex glomerulonephritis in sicca syndrome. Am J Med 1978;64:955–60.
    OpenUrlCrossRefPubMed
    1. Alexander EL
    . Neurologic disease in Sjögren’s syndrome: mononuclear inflammatory vasculopathy affecting central/peripheral nervous system and muscle. A clinical review and update of immunopathogenesis. Rheum Dis Clin North Am 1993;19:869–908.
    OpenUrlPubMed
    1. Wandinger KP,
    2. Stangel M,
    3. Witte T,
    4. et al
    . Autoantibodies against aquaporin-4 in patients with neuropsychiatric systemic lupus erythematosus and primary Sjögren’s syndrome. Arthritis Rheum 2010;62:1198–200.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Baimpa E,
    2. Dahabreh IJ,
    3. Voulgarelis M,
    4. et al
    . Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects. Medicine (Baltimore) 2009;88:284–93.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Theander E,
    2. Vasaitis L,
    3. Baecklund E,
    4. et al
    . Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren’s syndrome. Ann Rheum Dis 2011;70:1363–8.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Hackett KL,
    2. Newton JL,
    3. Frith J,
    4. et al
    . Impaired functional status in primary Sjögren’s syndrome. Arthritis Care Res (Hoboken) 2012; 64:1760–4.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Karaiskos D,
    2. Mavragani CP,
    3. Sinno MH,
    4. et al
    . Psychopathological and personality features in primary Sjögren’s syndrome–associations with autoantibodies to neuropeptides. Rheumatology (Oxford) 2010;49:1762–9.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Drosos AA,
    2. Angelopoulos NV,
    3. Liakos A,
    4. et al
    . Personality structure disturbances and psychiatric manifestations in primary Sjögren’s syndrome. J Autoimmun 1989;2:489–93.
    OpenUrlCrossRefPubMed
    1. Strömbeck B,
    2. Theander E,
    3. Jacobsson LT
    . Assessment of fatigue in primary Sjögren’s syndrome: the Swedish version of the Profile of Fatigue. Scand J Rheumatol 2005;34:455–9.
    OpenUrlCrossRefPubMed
    1. Theander L,
    2. Strömbeck B,
    3. Mandl T,
    4. et al
    . Sleepiness or fatigue? Can we detect treatable causes of tiredness in primary Sjögren’s syndrome? Rheumatology (Oxford) 2010;49:1177–83.
    OpenUrlCrossRefPubMed
    1. Gudbjörnsson B,
    2. Broman JE,
    3. Hetta J,
    4. et al
    . Sleep disturbances in patients with primary Sjögren’s syndrome. Br J Rheumatol 1993;32:1072–6.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Karaiskos D,
    2. Mavragani CP,
    3. Makaroni S,
    4. et al
    . Stress, coping strategies and social support in patients with primary Sjögren’s syndrome prior to disease onset: a retrospective case-control study. Ann Rheum Dis 2009;68:40–6.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Wöhrer S,
    2. Troch M,
    3. Streubel B,
    4. et al
    . MALT lymphoma in patients with autoimmune diseases: a comparative analysis of characteristics and clinical course. Leukemia 2007;21:1812–8.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Nocturne G,
    2. Pavy S,
    3. Lazure T,
    4. et al
    . IgG4 multiorgan lymphoproliferative syndrome as a differential diagnosis of primary Sjögren’s syndrome in men? Ann Rheum Dis 2011;70:2234–5.
    OpenUrlFREE Full Text
  20. ↵
    1. Mavragani CP,
    2. Skopouli FN,
    3. Moutsopoulos HM
    . Increased prevalence of antibodies to thyroid peroxidase in dry eyes and mouth syndrome or sicca asthenia polyalgia syndrome. J Rheumatol 2009;36:1626–30.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Mavragani CP,
    2. Fragoulis GE,
    3. Rontogianni D,
    4. et al
    . Elevated IgG serum levels among primary Sjögren’s syndrome patients: Do they unmask underlying IgG4-Related disease? Arthritis Care Res. 2013 doi:10.1002/acr.22216.
    OpenUrlCrossRef
  22. ↵
    1. Liew MS,
    2. Zhang M,
    3. Kim E,
    4. et al
    . Prevalence and predictors of Sjögren’s syndrome in a prospective cohort of patients with aqueous-deficient dry eye. Br J Ophthalmol 2012;96:1498–503.
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Dafni UG,
    2. Tzioufas AG,
    3. Staikos P,
    4. et al
    . Prevalence of Sjögren’s syndrome in a closed rural community. Ann Rheum Dis 1997;56: 521–5.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Vitali C,
    2. Moutsopoulos HM,
    3. Bombardieri S
    . The European Community Study Group on diagnostic criteria for Sjögren’s syndrome. Sensitivity and specificity of tests for ocular and oral involvement in Sjögren’s syndrome. Ann Rheum Dis 1994;53:637–47.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Stewart CM,
    2. Bhattacharyya I,
    3. Berg K,
    4. et al
    . Labial salivary gland biopsies in Sjögren’s syndrome: still the gold standard? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:392–402.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Venables PJ,
    2. Shattles W,
    3. Pease CT,
    4. et al
    . Anti-La (SS-B): A diagnostic criterion for Sjögren’s syndrome? Clin Exp Rheumatol 1989;7:181–4.
    OpenUrlPubMed
  27. ↵
    1. Vitali C,
    2. Bombardieri S,
    3. Jonsson R,
    4. et al
    . Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554–8.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Shiboski SC,
    2. Shiboski CH,
    3. Criswell L,
    4. et al
    . American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64:475–87.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Mavragani CP,
    2. Moutsopoulos HM
    . Conventional therapy of Sjögren’s syndrome. Clin Rev Allergy Immunol 2007;32:284–91.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Alves MB,
    2. Motta AC,
    3. Messina WC,
    4. et al
    . Saliva substitute in xerostomic patients with primary Sjögren’s syndrome: a single-blind trial. Quintessence Int 2004;35:392–6.
    OpenUrlPubMed
  31. ↵
    1. Aragona P,
    2. Papa V,
    3. Micali A,
    4. et al
    . Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br J Ophthalmol 2002;86:181–4.
    OpenUrlAbstract/FREE Full Text
    1. Condon PI,
    2. McEwen CG,
    3. Wright M,
    4. et al
    . Double blind, randomised, placebo controlled, crossover, multicentre study to determine the efficacy of a 0.1% (w/v) sodium hyaluronate solution (Fermavisc) in the treatment of dry eye syndrome. Br J Ophthalmol 1999;83:1121–4.
    OpenUrlAbstract/FREE Full Text
    1. McDonald CC,
    2. Kaye SB,
    3. Figueiredo FC,
    4. et al
    . A randomised, crossover, multicentre study to compare the performance of 0.1% (w/v) sodium hyaluronate with 1.4% (w/v) polyvinyl alcohol in the alleviation of symptoms associated with dry eye syndrome. Eye (Lond) 2002;16:601–7.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Toda I,
    2. Shinozaki N,
    3. Tsubota K
    . Hydroxypropyl methylcellulose for the treatment of severe dry eye associated with Sjögren’s syndrome. Cornea 1996;15:120–8.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Sall K,
    2. Stevenson OD,
    3. Mundorf TK,
    4. et al
    . Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology 2000;107:631–9.
    OpenUrlCrossRefPubMed
  34. ↵
    1. Ramos-Casals M,
    2. Tzioufas AG,
    3. Stone JH,
    4. et al
    . Treatment of primary Sjögren syndrome: a systematic review. JAMA 2010; 304:452–60.
    OpenUrlCrossRefPubMed
    1. Marsh P,
    2. Pflugfelder SC
    . Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren syndrome. Ophthalmology 1999;106:811–6.
    OpenUrlCrossRefPubMed
    1. Hersh PS,
    2. Rice BA,
    3. Baer JC,
    4. et al
    . Topical nonsteroidal agents and corneal wound healing. Arch Ophthalmol 1990;108:577–83.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Vivino FB,
    2. Minerva P,
    3. Huang CH,
    4. et al
    . Corneal melt as the initial presentation of primary Sjögren’s syndrome. J Rheumatol 2001;28:379–82.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Cardozo L,
    2. Bachmann G,
    3. McClish D,
    4. et al
    . Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol 1998;92:722–7.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Meijer JM,
    2. Meiners PM,
    3. Vissink A,
    4. et al
    . Effectiveness of rituximab treatment in primary Sjögren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:960–8.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Mavragani CP,
    2. Moutsopoulos NM,
    3. Moutsopoulos HM
    . The management of Sjögren’s syndrome. Nat Clin Pract Rheumatol 2006;2:252–61.
    OpenUrlCrossRefPubMed
  39. ↵
    1. Ramos-Casals M,
    2. Brito-Zeron P,
    3. Siso-Almirall A,
    4. et al
    . Topical and systemic medications for the treatment of primary Sjögren’s syndrome. Nat Rev Rheumatol 2012;8:399–411.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Fox RI,
    2. Dixon R,
    3. Guarrasi V,
    4. et al
    . Treatment of primary Sjögren’s syndrome with hydroxychloroquine: a retrospective, open-label study. Lupus 1996;5(Suppl 1):S31–6.
    OpenUrlCrossRefPubMed
  41. ↵
    1. Gottenberg JE,
    2. Cinquetti G,
    3. Larroche C,
    4. et al
    . Efficacy of rituximab in systemic manifestations of primary Sjögren’s syndrome: results in 78 patients of the Auto Immune and Rituximab registry. Ann Rheum Dis 2013;72:1026–31.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    1. Skopouli FN,
    2. Jagiello P,
    3. Tsifetaki N,
    4. et al
    . Methotrexate in primary Sjögren’s syndrome. Clin Exp Rheumatol 1996;14:555–8.
    OpenUrlPubMed
  43. ↵
    1. Mariette X,
    2. Ravaud P,
    3. Steinfeld S,
    4. et al
    . Inefficacy of infliximab in primary Sjögren’s syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren’s Syndrome (TRIPSS). Arthritis Rheum 2004;50:1270–6.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Mavragani CP,
    2. Niewold TB,
    3. Moutsopoulos NM,
    4. et al
    . Augmented interferon-alpha pathway activation in patients with Sjögren’s syndrome treated with etanercept. Arthritis Rheum 2007;56:3995–4004.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Dass S,
    2. Bowman SJ,
    3. Vital EM,
    4. et al
    . Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann Rheum Dis 2008;67:1541–4.
    OpenUrlAbstract/FREE Full Text
    1. Mekinian A,
    2. Ravaud P,
    3. Hatron PY,
    4. et al
    . Efficacy of rituximab in primary Sjögren’s syndrome with peripheral nervous system involvement: results from the AIR registry. Ann Rheum Dis 2012; 71:84–7.
    OpenUrlAbstract/FREE Full Text
    1. Mariette X,
    2. Gottenberg JE
    . Pathogenesis of Sjögren’s syndrome and therapeutic consequences. Curr Opin Rheumatol 2010;22: 471–7.
    OpenUrlCrossRefPubMed
  46. ↵
    1. Seror R,
    2. Sordet C,
    3. Guillevin L,
    4. et al
    . Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjögren’s syndrome. Ann Rheum Dis 2007;66:351–7.
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top

In this issue

Canadian Medical Association Journal: 186 (15)
CMAJ
Vol. 186, Issue 15
21 Oct 2014
  • Table of Contents
  • Index by author

Article tools

Respond to this article
Print
Download PDF
Article Alerts
To sign up for email alerts or to access your current email alerts, enter your email address below:
Email Article

Thank you for your interest in spreading the word on CMAJ.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Sjögren syndrome
(Your Name) has sent you a message from CMAJ
(Your Name) thought you would like to see the CMAJ web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Sjögren syndrome
Clio P. Mavragani, Haralampos M. Moutsopoulos
CMAJ Oct 2014, 186 (15) E579-E586; DOI: 10.1503/cmaj.122037

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
‍ Request Permissions
Share
Sjögren syndrome
Clio P. Mavragani, Haralampos M. Moutsopoulos
CMAJ Oct 2014, 186 (15) E579-E586; DOI: 10.1503/cmaj.122037
Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • What are the clinical features of Sjögren syndrome?
    • How should a diagnosis of Sjögren syndrome be made?
    • What therapies are effective for mucosal dryness in Sjögren syndrome?
    • What therapies are effective for the management of systemic features in Sjögren syndrome?
    • Unanswered questions
    • Footnotes
    • References
  • Figures & Tables
  • Responses
  • Metrics
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • Generation of anti-idiotypic antibodies to detect anti-spacer antibody idiotopes in acute thrombotic thrombocytopenic purpura patients
  • Tongue Atrophy in Sjogren Syndrome Patients with Mucosa-associated Lymphoid Tissue Lymphoma: Autoimmune Epithelitis beyond the Epithelial Cells of Salivary Glands?
  • Sex differential association of dermatomyositis with Sjogren syndrome
  • Google Scholar

More in this TOC Section

  • Diagnosis and management of postural orthostatic tachycardia syndrome
  • A practical approach to prescribing antiplatelet therapy in patients with acute coronary syndromes
  • Prevention and management of hyperkalemia in patients treated with renin–angiotensin–aldosterone system inhibitors
Show more Review

Similar Articles

Collections

  • Topics
    • Autoimmune disease
    • Immunology

 

View Latest Classified Ads

Content

  • Current issue
  • Past issues
  • Collections
  • Sections
  • Blog
  • Podcasts
  • Alerts
  • RSS
  • Early releases

Information for

  • Advertisers
  • Authors
  • Reviewers
  • CMA Members
  • CPD credits
  • Media
  • Reprint requests
  • Subscribers

About

  • General Information
  • Journal staff
  • Editorial Board
  • Advisory Panels
  • Governance Council
  • Journal Oversight
  • Careers
  • Contact
  • Copyright and Permissions
  • Accessibiity
  • CMA Civility Standards
CMAJ Group

Copyright 2022, CMA Impact Inc. or its licensors. All rights reserved. ISSN 1488-2329 (e) 0820-3946 (p)

All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association or its subsidiaries.

To receive any of these resources in an accessible format, please contact us at CMAJ Group, 500-1410 Blair Towers Place, Ottawa ON, K1J 9B9; p: 1-888-855-2555; e: cmajgroup@cmaj.ca

Powered by HighWire