Ju-Yang Jung; Chang-Hee Suh

doi:10.4078/jrd.2015.22.3.146

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Jung and Suh: Update of Sjögren's Syndrome

Review Article

J Rheum Dis 2015;22(3):146-153.

Published online: 31 October 2015

DOI: https://doi.org/10.4078/jrd.2015.22.3.146

Update of Sjögren's Syndrome

Ju-Yang Jung, Chang-Hee Suh

Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea

Corresponding to: Chang-Hee Suh, Department of Rheumatology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 443-749, Korea. E-mail: chsuh@ajou.ac.kr

Received 10 May 2015 Revised 28 May 2015 Accepted 28 May 2015

This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

We reviewed the recent findings in diagnosis, pathogenesis and management of Sjögren's syndrome. New diagnostic classification criteria for Sjögren's syndrome were published by the American College of Rheumatology in 2012, and validation was completed. Salivary gland ultrasonography has been examined as a diagnostic and prognostic marker for Sjögren's syndrome, and the results have revealed that it has high specificity and low sensitivity. Disease activity assessment tools for Sjögren's syndrome have been developed and validated for upcoming clinical trials. Several associated genes were identified by genomewide association studies, with large cohorts in Europe and China. Several single nucleotide polymorphisms of Sjögren's syndrome are related to germinal center formation and lymphoma development. New treatment modalities, including inter-leukin-1 receptor antagonist, anti-CD20, anti-BAFF/Blys, and CTLA4-immunoglobulin were investigated, but the optimal therapeutic compounds have yet to be found.

Keywords: Sjögren's Syndrome, Classification, Ultrasonography, Genes, Therapy

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Table 1.

The revised American-European Consensus Group (AECG) classification criteria and the American College of Rheumatology (ACR) classification criteria for Sjögren's syndrome (SS)

AECG Classification	ACR Classification
Inclusion criteria
I. Ocular symptoms: a positive response to at least one of the following questions:	None
1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?
2. Do you have a recurrent sensation of sand or gravel in the eyes?
3. Do you use tear substitutes more than 3 times a day?
II. Oral symptoms: a positive response to at least one of the following questions:	None
1. Have you had a daily feeling of dry mouth for more than 3 months?
2. Have you had recurrently or persistently swollen salivary glands as an adult?
3. Do you frequently drink liquids to aid in swallowing dry food?
III. Ocular signs – that is, objective evidence of ocular involvement defined as a positive result for at least one of the following two tests: 1. Schirmer' s I test, performed without anesthesia (≤5 mm in 5 minutes)	Keratoconjunctivitis sicca with ocular staining score ≥3 (assuming that individual is not currently using daily eye drops for glaucoma and has not had corneal surgery or cosmetic eyelid surgery in the last 5 years)
2. Rose Bengal score or other ocular dye score (≥4 according to van Bijsterveld' s scoring system)
IV. Histopathology: in minor salivary glands (obtained through normal appearing mucosa) focal lymphocytic sialoadenitis, evaluated by an expert histopathologist, with a focus score ≥ 1, defined as number of lymphocytic foci (which are adjacent to normal-appearing mucous acini and contain more than 50 lymphocytes) per 4 mm² of glandular tissue	Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis with a focus score ≥1 focus/4 mm²
V. Salivary gland involvement: objective evidence of salivary gland involvement defined by a positive result for at least one of the following diagnostic tests:	None
1. Unstimulated whole salivary flow (≤1.5 ml in 15 min)
2. Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary or destructive pattern), without evidence of obstruction in major ducts
3. Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer
VI. Autoantibodies: presence in the serum of the following autoantibodies:	Positive serum anti-SSA/Ro and/or anti-SSB/La or (positive rheumatoid factor and ANA titer ≥1:320)
1. Antibodies to Ro (SSA) or La (SSB) antigens, or both
Classification rules
For Primary SS:	For Sjögren's Syndrome:
In patients without any potentially associated disease, primary SS may be defined as follows:	The classification of SS, which applies to individuals with signs/symptoms that may be suggestive of SS, will be met in patients who have at least 2 of the 3 objective features previously described
a. The presence of any 4 of the 6 items is indicative of primary SS, as long as either item IV (Histopathology) or VI (Serology) is positive
b. The presence of any 3 of the 4 objective criteria items (that is, items III, IV, V, VI)
c. The classification tree procedure represents a valid alternative method for classification, although it should be more properly used in clinical-epidemiological survey
For Secondary SS:
In patients with a potentially associated disease (for instance, another well defined connective tissue disease), the presence of item 1 or item II plus any 2 from among items III, IV and V may be considered as indicative of secondary SS	Eliminated the distinction between primary and secondary forms of SS
Exclusion criteria
1. Past head and neck radiation treatment	Prior diagnosis of any of the following conditions would
2. Hepatitis C infection	exclude participation in SS studies or therapeutic trials
3. Acquired Immunodeficiency Syndrome (AIDS)	because of overlapping clinical features or
4. Pre-existing lymphoma	interference with criteria tests:
5. Sarcoidosis
6. Graft versus host disease	1. History of head and neck radiation treatment
7. Use of anticholinergic drugs (since a time shorter than 4-fold the half life of the drug)	2. Hepatitis C infection
	3. Acquired Immunodeficiency Syndrome
	4. Sarcoidosis
	5. Amyloidosis
	6. Graft versus host disease
	7. IgG4-related disease

AECG: American-European Consensus Group, ACR: American College of Rheumatology. Cited from the article Rasmussen et al.(Ann Rheum Dis 2014;73:31-8) [10].

Table 2.

Clinical trials for the treatment of Sjögren's syndrome

Drug	Type of study	Patient (n)/period	Enrollment date	Study location	Result
Rituximab	RCT	30/48 wk	August 2006 to September 2007	Netherland	Improvement of stimulated whole saliva flow rate
Rituximab	RCT	120/24 wk	March 2008 to January 2011	France	No significant difference
Rituximab	RCT	110/48 wk	August 2011 to December 2013	UK	No result
Belimumab	Open-label	30/52 wk	March 2010 to June 2012	Europe	Improvement in dryness, fatigue, VAS
					Decreased ESSDAI and ESPRI
Abatacept	Open-label	15/48 wk	August 2010 to May 2012	Netherland	Decreased ESSDAI, ESSPRI RF, IgG during treatment
Low dose cyclosporin A	Open-label	30/16 wk	March 2010 to October 2014	Germany	No result
CFZ533	RCT	30/12 wk	October 2014 to July 2016	USA, Europe	Ongoing
SS-1 (Chinese herbal formula)	RCT	60/7 mo	February 2014 to January 2016	Taiwan	Ongoing
VAY736	RCT	30/12 wk	May 2014 to June 2017	USA, Europe	Ongoing
AMG557/ MEDI5872	RCT	42/12 wk	January 2014 to November 2016	USA	Ongoing
Baminercept	RCT	72/24 wk	July 2012 to May 2015	USA	Ongoing
Tocillizumab	RCT	110/24 wk	July 2013 to March 2017	France	Ongoing

ESSDAI: EULAR Sjögren's syndrome disease activity index, ESSPRI: EULAR Sjögren's syndrome patient reported index, IgG: mmunoglobulin G, RCT: randomized controlled trial, RF: rheumatoid factor, VAS: visual analogue scale.

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