Sjögren Syndrome and Immunoglobulin-G4 Disease

SjÖgren Syndrome

The syndrome of chronic inflammation of the exocrine glands, principally the salivary and lacrimal glands, was first described by Henrik Sjögren, a Swedish ophthalmologist, who published in 1930 the first complete description of a disorder he named keratoconjunctivitis sicca. He reported that the disorder occurred most often in menopausal women and that arthritis was a prominent feature of the disease, as was a raised erythrocyte sedimentation rate (ESR), anemia, and fever. Since this early description, Sjögren syndrome has been identified as a heterogeneous chronic multisystem autoimmune rheumatic condition, with manifestations ranging from localized glandular disease to more complex systemic and organ system involvement. This disease has been considered to be rare in children and adolescents; however, it has almost certainly been underdiagnosed and is more common than previously realized. It is now recognized that this disorder can affect children and adolescents, and that the presentation may be different from that in adults with this condition, which is one factor contributing to the low recognition of the disorder.

Definition and Epidemiology

Sjögren syndrome (SS) is defined as a chronic autoimmune disease characterized by inflammation of the exocrine glands. The principal inflammatory targets are the salivary and lacrimal glands, resulting in dryness of the mucosal surfaces of the mouth and eyes. However, there can be more extensive exocrinopathy involving the skin, respiratory tract, and urogenital tracts. Extraglandular or systemic features are frequently present as well. Table 29.1 outlines the principal clinical manifestations of SS.

The reported incidence and prevalence of primary SS (pSS) in the adult population varies depending on the population studied, and the study design. A systematic review of 21 studies published between 1995 and 2013 reported an overall incidence of 6.92 (95% confidence interval [CI], 4.98 to 8.86) per 100,000 person-years, and a prevalence rate in population-based studies of 43 cases (95% CI, 25.74 to 60.31) per 100,000 people. Maciel et al. examined the point prevalence of pSS in Olmstead County, Minnesota, finding overall prevalence of 10.3 cases per 100,000 inhabitants; however, only 2.2 cases per 100,000 fulfilled any of the current classification criteria for pSS. These variable results point out that it is likely that clinicians make a diagnosis of pSS based on clinical expertise, and published classification criteria strictly define a smaller population of patients. In addition, the population study from Minnesota may provide more accurate prevalence figures based on rigorous case finding methodology; the systematic review included data from studies that identified cases through sample surveys, a less accurate technique.

To date, there have been no large population studies reporting accurate incidence or prevalence of pSS in childhood. Similar to adult pSS, there is a female predominance reported in pediatric-onset pSS, with female-to-male ratio 5:1 to 7:1. Mean age at initial symptoms were reported to be 10 years, with diagnosis at mean of 12 years by Hammenfors et al.

Classification

SS is described as primary Sjögren syndrome (pSS) when there is no association with other autoimmune disease and as secondary Sjögren syndrome (sSS) when there is another autoimmune disease present, most commonly systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). Other disorders that can be associated with sSS include mixed connective tissue disease, primary biliary cirrhosis, and autoimmune thyroiditis.

Accurately diagnosing pSS is challenging, as many of the cardinal symptoms are common, and there is currently no gold standard diagnostic test. This poses difficulty in performing clinical research in pSS, as a definition of homogeneous patient populations is required. Classification criteria allow the definition of patient groups for clinical research, and a series of such criteria for pSS have been published since the mid-1960s. Since 2002, three classification criteria sets have been developed: the American-European Consensus Group (AECG) criteria in 2002 ( Box 29.1 ), the American College of Rheumatology-Sjögren International Collaborative Clinical Alliance criteria (ACR-SICCA) in 2012 ( Box 29.2 ), and the ACR-European League Against Rheumatism (EULAR) classification criteria in 2016 ( Box 29.3 ). Development of these classification criteria utilized standard methodology, included large numbers of expert clinicians, with extensive performance testing to ascertain reliability and validation. The AECG criteria included a requirement for glandular imaging with scintography or sialography, which is not included in either subsequent criteria sets. The 2012 ACR-SICCA criteria are based on objective tests only, including minor gland biopsy, ocular staining, and antibody testing. The more recent ACR-EULAR criteria set includes elements of both previous criteria sets. It is important to note that these classification criteria are not intended to be applied as diagnostic criteria; in addition they have never been tested in children with pSS.

Bartunkova et al. proposed a set of criteria for the diagnosis of pSS in children, but these have not been validated ( Box 29.4 ). These criteria include parotid enlargement or recurrent parotitis, and additional laboratory tests not included in the adult classification criteria sets (elevated amylase, evidence of renal tubular acidosis [RTA], leukopenia, elevated ESR, antinuclear antibodies (ANAs), rheumatoid factor (RF), and hypergammaglobulinemia). The clinical and laboratory findings included in these proposed diagnostic criteria include findings seen with increased frequency in pediatric SS compared with adult-onset disease. Houghton et al. compared the usefulness of the AECG adult classification criteria and the proposed pediatric diagnostic criteria in a group of six patients in British Columbia, and 128 cases found on literature review. The adult criteria were fulfilled by 14% of the local cases and 39% of reported pediatric cases, whereas the proposed pediatric criteria were fulfilled by 71% of the local cases and 76% of the reported pediatric cases. Although the new proposed pediatric criteria improved the diagnostic accuracy considerably, the conclusion of this study was that neither set of criteria was sensitive compared with the gold standard of clinical diagnosis by a pediatric rheumatologist.

Validation studies of the proposed Bartunkova diagnostic criteria, and of the ACR-EULAR classification criteria should be considered in the pediatric pSS population

Clinical Manifestations