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Primary Sjögren's syndrome

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Abstract

Primary Sjögren's syndrome (pSS) is a relatively common autoimmune systemic rheumatic disease. In addition to sicca syndrome and swollen salivary glands, systemic features manifest in the majority of patients, and are severe in 15%, particularly affecting the joints, skin, lungs, and peripheral nervous system. A recent meta-analysis estimated a pooled relative risk of 13.76 for the development of non-Hodgkin lymphoma, particularly in pSS patients who have parotid enlargement, vasculitis, cryoglobulinemia, and antibodies to Ro and La. pSS is the underlying diagnosis in one-third of mothers of neonates affected by congenital heart block. The diagnosis of pSS is complex and requires a stepwise approach to evaluate symptoms of ocular and oral dryness, objective measures of lacrimal and salivary gland dysfunction, and evidence of autoimmunity with Ro/La autoantibodies and labial salivary gland biopsy. It is essential to eliminate other autoimmune diseases, as well as non-autoimmune causes of sicca syndrome, such as menopause, endocrine diseases, anticholinergic effects of drugs, and fibromyalgia, to delineate pSS patients who are at risk of systemic complications. Recent major advances in the diagnosis of pSS have been the development of classification criteria, which serve as a template for clinical diagnosis, and outcome measures for use in clinical trials and prospective patient cohorts. Clinical data and biological samples from longitudinal cohorts, embedded into clinical practice, will be essential to further improve the diagnosis and management of pSS, increase knowledge about the natural history of the disease, gain insights into its pathogenesis, and stratify patients according to their risk of systemic disease and NHL. At present, there is a gap in evidence regarding the role of structured protocols in the management of pSS. Recent recommendations for the management of sicca symptoms and clinical trials of disease-modifying therapy are discussed.

Section snippets

Sjögren's syndrome

Sjögren's syndrome (SS) is a relatively common systemic autoimmune rheumatic disease, in which lymphocytic infiltration of salivary and lacrimal glands leads to immune-mediated secretory dysfunction. The resulting dryness of the mouth and eyes is termed “sicca syndrome.” SS is referred to as “primary” in patients who do not have an additional systemic rheumatic disease, and “secondary” when immune-mediated sicca syndrome coexists in patients with systemic lupus erythematosus (SLE), scleroderma,

Clinical features of pSS

The clinical and laboratory abnormalities in pSS are listed in Table 3.

Prevalence and incidence

A recent meta-analysis addressed the incidence rate (IR), prevalence rate (PR), gender IR, and age at diagnosis of pSS [48]. The pooled IR of pSS was 6.92 (95% CI 4.98–8.86) per 100,000 person-years at risk. The IRs for females and males were estimated at 12.30 (95% CI 9.07–15.53) and 1.47 (95% CI 0.81–2.12), respectively, resulting in a pooled female-to-male IR ratio of 9.29 (95% CI 6.61–13.04). The overall age of pSS patients at diagnosis was 56 years (95% CI 53–60). Three studies reported

Anti-Ro and anti-La

Antinuclear antibodies (ANAs), rheumatoid factor, and Ro/SSA and La/SSB autoantibodies are key serological findings in pSS, and form part of various criteria for the research classification of disease [57], [58]. ANA are present in the sera of up to 85% [59], and anti-Ro and anti-La autoantibodies are found in 33–74% and 23–52% of patients with pSS, respectively [60]. It is likely that the prevalence of these autoantibodies may be biased upward in some studies, because autoantibody positivity

Histopathology

The principal pathological lesion in pSS is an FLS, predominantly consisting of CD4+ T cells and CD20 + B cells, in the salivary glands, and an analogous lesion may occur in the lacrimal glands. In the absence of pSS-associated serum autoantibodies, a positive labial salivary gland biopsy is a mandatory criterion for classification of pSS [57], ∗[82]. In the majority of pSS patients, the salivary gland inflammatory lesions are fully developed at the time of diagnosis, and remain largely

Pathogenesis

Clinical and laboratory observations have highlighted the central role of the salivary gland epithelial cell (SGEC), and currently it has been suggested that the etiological name of the disease should be “autoimmune epithelitis.” [83] It was initially observed that the characteristic lymphocytic infiltrates were proximal to SGEC, which were subsequently showed to express numerous immunomodulatory molecules, such as cytokines, chemokines, adhesion molecules, MHC molecules, B7 and CD40

SS diagnosis and classification

Classification criteria are used to describe cohorts of patients in the research setting. It is also useful to use these criteria as an aide memoire, guide the diagnosis of pSS in the clinical setting, and differentiate patients from those with other autoimmune diseases or nonautoimmune sicca syndrome. Using the American–European Consensus Group (AECG) classification criteria [82], as described below, although time consuming is a relatively straightforward, one off process, which enables

Anti-Ro/SSA and anti-La/SSB

Anti-Ro/La antibodies are the key immunological markers of pSS; however, their prevalence may vary widely according to the method of detection (ELISA, double immunodiffusion, and Western blot analysis). Anti-Ro60 antibodies are more easily detected using a native antigen (95% vs. 54% using recombinant antigens) [100], and Ro60-transfected cells have improved sensitivity for detection of this low-abundance autoantigen by screening ANA, which may be missed in 5% of cases using the standard

Outcome measures

A challenge in defining the natural history and effective strategies in pSS has been in developing good outcome measures and standardized assessment of disease activity, particularly in those patients with systemic manifestations. Traditional outcome measures included quantitation of sicca symptoms or histopathological changes in biopsied specimens. It was widely recognized, however, that these measures do not strongly correlate to patient-reported outcomes (PROs). More recently, pSS-specific

Dry eyes

Dry eye disease is one of the features that impair quality of life and limit activity most in pSS [119]. A consensus clinical guideline for its management was published in 2015 [119]. Evaluation should include symptoms of both discomfort and visual disturbance, as well as determination of the relative contribution of aqueous production deficiency and evaporative loss of tear volume due to meibomian gland dysfunction, both of which may contribute to dry eyes in SS (both primary and secondary).

Cohort studies: embedding research into clinical practice

There is increasing awareness of the importance of patient cohort studies in medical research. They have a number of applications including determination of the incidence, prevalence, and natural history of disease, causes and risks of disease, and disease complications. Standardized collection of clinical data, disease activity, PRO, and biological samples, including DNA, RNA, and sera, is highly recommended to determine new biological prognostic factors and identify disease activity markers.

Summary

Important advances have been made in the development of classification criteria and disease outcome measures in pSS. Increasingly, we are gaining a better understanding of the pathogenesis of disease and biomarkers that could contribute. In order to better define the natural history, pathogenesis, prognosis, and therapeutic strategies for patients with this multisystem condition, both observational studies and controlled trials are required, using these important tools. With a deeper insight

Disclaimers/sources of funding

Nil.

References (141)

  • L. Shen et al.

    Novel autoantibodies in Sjogren's syndrome

    Clin Immunol

    (2012)
  • I. Bastian et al.

    A novel cell-based assay for inhibitory anti-muscarinic type 3 receptor antibodies in primary Sjogren's syndrome

    J Immunol Methods

    (2015)
  • V.K. Bournia et al.

    Subgroups of Sjogren syndrome patients according to serological profiles

    J Autoimmun

    (2012)
  • N.C. Kyriakidis et al.

    A comprehensive review of autoantibodies in primary Sjogren's syndrome: clinical phenotypes and regulatory mechanisms

    J Autoimmun

    (2014)
  • P. Cruz-Tapias et al.

    HLA and Sjogren's syndrome susceptibility. A meta-analysis of worldwide studies

    Autoimmun Rev

    (2012)
  • E.J. ter Borg et al.

    Relation of systemic autoantibodies to the number of extraglandular manifestations in primary Sjogren's Syndrome: a retrospective analysis of 65 patients in the Netherlands

    Semin Arthritis Rheum

    (2011)
  • D. Cornec et al.

    Sjogren's syndrome: where do we stand, and where shall we go?

    J Autoimmun

    (2014)
  • J.P. Whitcher et al.

    A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjogren's Syndrome International Registry

    Am J Ophthalmol

    (2010)
  • P. Brito-Zeron et al.

    Early diagnosis of primary Sjogren's syndrome: EULAR-SS task force clinical recommendations

    Expert Rev Clin Immunol

    (2015)
  • J.F. van Nimwegen et al.

    The impact of primary Sjogren's syndrome on female sexual function

    Rheumatol Oxf

    (2015)
  • M. Ramos-Casals et al.

    Systemic involvement in primary Sjogren's syndrome evaluated by the EULAR-SS disease activity index: analysis of 921 Spanish patients (GEAS-SS Registry)

    Rheumatol Oxf

    (2014)
  • K. Kulkarni

    Unusual presentation of Sjogren syndrome

    South Med J

    (2005)
  • K. Baszis et al.

    Recurrent parotitis as a presentation of primary pediatric Sjogren syndrome

    Pediatrics

    (2012)
  • M. Civilibal et al.

    A child with primary Sjogren syndrome and a review of the literature

    Clin Pediatr (Phila)

    (2007)
  • E. Abrol et al.

    A retrospective study of long-term outcomes in 152 patients with primary Sjogren's syndrome: 25-year experience

    Clin Med

    (2014)
  • R. Seror et al.

    EULAR Sjogren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren's syndrome

    Ann Rheum Dis

    (2010)
  • C. Baldini et al.

    Primary Sjogren's syndrome as a multi-organ disease: impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients

    Rheumatol Oxf

    (2014)
  • N. Luciano et al.

    One year in review 2015: Sjogren's syndrome

    Clin Exp Rheumatol

    (2015)
  • M. Ramos-Casals et al.

    Primary Sjogren syndrome

    BMJ

    (2012)
  • B.M. Segal et al.

    Primary Sjogren's syndrome: cognitive symptoms, mood, and cognitive performance

    Acta Neurol Scand

    (2012)
  • L. Theander et al.

    Sleepiness or fatigue? Can we detect treatable causes of tiredness in primary Sjogren's syndrome?

    Rheumatol Oxf

    (2010)
  • G. Westhoff et al.

    Fatigue and depression predict physician visits and work disability in women with primary Sjogren's syndrome: results from a cohort study

    Rheumatol Oxf

    (2012)
  • F.Z. Cai et al.

    Mild autonomic dysfunction in primary Sjogren's syndrome: a controlled study

    Arthritis Res Ther

    (2008)
  • J.L. Newton et al.

    Autonomic symptoms are common and are associated with overall symptom burden and disease activity in primary Sjogren's syndrome

    Ann Rheum Dis

    (2012)
  • R. Seror et al.

    EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjogren's syndrome

    Ann Rheum Dis

    (2011)
  • C.J. Hilditch et al.

    Upper airway surface tension but not upper airway collapsibility is elevated in primary Sjogren's syndrome

    Sleep

    (2008)
  • B.M. Segal et al.

    Pain severity and neuropathic pain symptoms in primary Sjogren's syndrome: a comparison study of seropositive and seronegative Sjogren's syndrome patients

    Arthritis Care Res Hob

    (2013)
  • E.J. ter Borg et al.

    Lower prevalence of extra-glandular manifestations and anti-SSB antibodies in patients with primary Sjogren's syndrome and widespread pain: evidence for a relatively benign subset

    Clin Exp Rheumatol

    (2014)
  • M. Ramos-Casals et al.

    Characterization of systemic disease in primary Sjogren's syndrome: EULAR-SS task force recommendations for articular, cutaneous, pulmonary and renal involvements

    Rheumatol Oxf

    (2015)
  • M. Ramos-Casals et al.

    Cutaneous vasculitis in primary Sjogren syndrome: classification and clinical significance of 52 patients

    Medicine

    (2004)
  • G. Stojan et al.

    Pulmonary manifestations of Sjogren's syndrome

    Curr Allergy Asthma Rep

    (2013)
  • D. Sene et al.

    Sjogren syndrome-associated small fiber neuropathy: characterization from a prospective series of 40 cases

    Medicine

    (2013)
  • M. Akasbi et al.

    White matter abnormalities in primary Sjogren syndrome

    QJM

    (2012)
  • R. Evans et al.

    Renal involvement in primary Sjogren's syndrome

    Rheumatol Oxf

    (2015)
  • J. Walker et al.

    Increased severity of lower urinary tract symptoms and daytime somnolence in primary Sjogren's syndrome

    J Rheumatol

    (2003)
  • M. Ramos-Casals et al.

    Sjögren’s syndrome

  • A. Schattner et al.

    Thrombotic thrombocytopenic purpura as an initial presentation of primary Sjogren's syndrome

    Clin Rheumatol

    (2002)
  • P. Brito-Zeron et al.

    The clinical spectrum of autoimmune congenital heart block

    Nat Rev Rheumatol

    (2015)
  • T.L. Rivera et al.

    Disease progression in mothers of children enrolled in the research registry for neonatal lupus

    Ann Rheum Dis

    (2009)
  • K. Levesque et al.

    French cohort study of 141 cases of autoimmune congenital heart block

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      Citation Excerpt :

      SS occurs in a primary form not associated with other diseases and secondary syndrome with other autoimmune disorders. Primary SS (PSS) is characterized by lymphocyte infiltration and destruction of salivary and lacrimal glands, and extra glandular manifestation in lungs, kidney, nervous system, skin and musculoskeletal [3]. Assessment of the disease activity in most of the patients is difficult, since dominant symptoms are relatively stable.

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