Characteristics of Patients with Primary Sjögren’s Syndrome and Non-specific Chronic Sialadenitis: A Subtype in Elderly Patients

Primary Sjögren’s syndrome (pSS) is a common chronic, systemic autoimmune disease characterized by progressive lymphocytic infiltration that mainly affects the salivary and lachrymal glands, and leads to dryness of the mouth and eyes. Secondary Sjögren’s syndrome (sSS) refers to the disease when it occurs in association with another systemic autoimmune disease, such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or dermatomyositis. Although pSS primarily affects the exocrine glands, it may also affect extra-glandular systems including musculoskeletal, cutaneous, renal, pulmonary, and neurological systems [1].

Focal lymphocytic sialadenitis (FLS) is vital for the diagnosis and classification of pSS; therefore, labial salivary gland (LSG) biopsy is commonly performed because it is a simple procedure with few risks [2]. Focus score (FS) refers to the mean number of mononuclear cell infiltrates containing at least 50 inflammatory cells per 4 mm² of periductal or perivascular tissue adjacent to normal-appearing acini. Positive biopsies are defined as FS ≥ 1 [3]. The histopathological findings can be classified into FS ≥ 1 per 4 mm² (FS ≥ 1), lymphocytic infiltration without focus or FS < 1 per 4 mm² (0 < FS < 1), within normal limits (FS = 0), non-specific chronic sialadenitis (NSCS, including sclerosing chronic sialadenitis, which is advanced stage of NSCS), insufficient tissue for diagnosis, or other conditions [3‐6]. NSCS is characterized by acinar atrophy, interstitial fibrosis, and duct dilation, and is often accompanied by lymphoid infiltrates [6]. The features of NSCS are relatively common and increase with age in the population, but these features may coexist with pSS, even presenting with aggregation-like FLS that do not have diagnostic value [4, 7]. Previous studies have extensively evaluated the associations of high FS with clinical manifestations in pSS patients [8‐10], but the characteristics of pSS with NSCS were seldom investigated.

In the present study, we evaluated the associated features in pSS patients with NSCS in a large cohort mainly from northwest China who underwent LSG biopsies. In addition, we compared the pSS patients with NSCS to the controls with sicca symptoms and NSCS but no other manifestations (i.e., sicca NSCS controls).

NSCS is a common pathology of LSG [6, 7]. In the current study, we investigated the characteristics of pSS patients with NSCS using LSG pathological reports from 425 patients with suspected SS who underwent LSG biopsy in which 217 confirmed pSS patients were analyzed. We categorized the 217 pSS patients into three groups: FS ≥ 1 (104 [47.9%]), 0 ≤ FS < 1 (76 [35.0%]), and NSCS (37 [17.1%]). We compared these three groups, with special emphasis on the NSCS group.

Our result showed that pSS patients with NSCS were much older than those non-NSCS pSS patients (58.3 ± 11.0 years in NSCS group vs. 48.5 ± 14.9 years in FS ≥ 1 group or 45.3 ± 13.7 years in 0 ≤ FS < 1 group). Chronic sialadenitis is a common finding in elderly populations [16, 17]. Daniels [17] studied 362 LSG specimens from patients with suspected SS and found that 17 had inflammation associated with acinar atrophy and interstitial fibrosis (indicating NSCS). In that study, the mean age was higher in the NSCS group (62.3 ± 9 years) compared to the FS < 1 group (50.3 ± 16 years) and FS ≥ 1 groups (44.6 ± 17 years to 55.8 ± 15 years); however, organ involvement and serological tests were not analyzed. Our result regarding age is consistent with the result of Daniels [17]. Interestingly, only three cases (8.1%) in the NSCS group were aged < 45 years compared to 40 (38.5%) in the FS ≥ 1 group and 37 (48.7%) in the 0 ≤ FS < 1 group in our study. In multivariate logistic regression analysis, we found that age was associated with NSCS, but duration and ESSDAI were not. Therefore, we concluded that NSCS in pSS was solely associated with age and seldom occurred under the age of 45 years.

We found that pSS patients with NSCS had similar clinical features to those of non-NSCS pSS individuals. We assessed the involved organs in pSS patients and calculated the ESSDAI. The manifestations and laboratory variables in the NSCS group were not significantly different between the NSCS group and FS ≥ 1 and 0 ≤ FS < 1 groups. Nearly one-third of the 217 pSS patients had hematological involvement, including leukocytopenia and thrombocytopenia. The frequency of lung, nerve, and kidney involvement was much lower, but their involvement has a significant impact on the prognosis. The prevalence of ESSDAI ≥ 10 in the FS ≥ 1 group (27.9%) was higher than that in the 0 ≤ FS < 1 group (19.7%) and NSCS group (13.5%), which indicated that patients with FS ≥ 1 may have a greater risk of severe conditions, although the differences did not reach statistical significance. Risselada et al. [8] found that cumulative ESSDAI was significantly correlated with LFS, and FS ≥ 3 was associated with lymphoma. In our study, we mainly focused on NSCS in pSS patients so we did not further analyze the patients with FS ≥ 1. Sharma et al. [18] investigated the differences between pSS patients with and without focal infiltration, and found that the two subgroups were not clinically different, except for the higher degree of corneal staining with Lissamine green, serum anti-La antibodies, and elevated IgG in patients with FS ≥ 1. In our study, patients with FS ≥ 1 also had no significant differences compared to the 0 ≤ FS < 1 group (which included 25 patients with FS = 0), except for ANA titer ≥ 1:3200, positive anti-La, and elevated ESR. In addition, the FS ≥ 1 group had an increased prevalence of increased IgG. These results were similar to those of Sharma et al. [18], who compared to FS ≥ 1 and FS = 0, while our study compared FS ≥ 1 and 0 ≤ FS < 1. In another study, Park et al. [19] found that positive histopathologic assessment in salivary glands had little impact on the clinical features of pSS when FS ≥ 1 patients were compared with FS < 1 patients. Therefore, we speculate that FS ≥ 1 may not be associated with clinical manifestations, such as systemic involvement, but a higher FS may be related to a more severe condition.

In the current pSS group, 37 (17.1%) had NSCS, of whom 31 (83.7%) had anti-SSA and 15 (40.5%) had anti-SSB antibodies. The diagnosis mainly depended on the clinical presentations and autoantibodies. Daniels et al. [6] investigated a large cohort from the database of the Sjögren’s International Collaborative Clinical Alliance and found that among 1726 participants with sialadenitis, 668 (38.7%) patients had NSCS/SCS, of whom 91 (14%) had positive serum anti-SSA/SSB. Therefore, the pathology of NSCS with anti-SSA/SSB is frequently encountered in clinical practice. Few studies have investigated the differences between pSS with NSCS and the general population with NSCS. To investigate this, we selected 37 individuals with NSCS, who only had sicca symptoms and were otherwise healthy, named sicca NSCS controls. As expected, there were no differences in mean ages in all individuals and subgroups between pSS patients with NSCS and sicca NSCS controls. Only one sicca NSCS control was aged 20–44 years compared to three NSCS pSS, which was in agreement with the fact that NSCS seldom occurs before 45 years of age, regardless of whether the patient has pSS. In these two groups, the most frequent age group was 45–65 years, followed by > 65 years, which may be because some individuals aged over 65 years have sicca symptoms but may not seek medical attention for it. Syrjänen et al. [20] studied 78 healthy individuals aged 19–87 years who underwent LSG biopsy and found that acinar atrophy was not present in individuals aged under 50 years; however, the prevalence of acinar atrophy progressively increased with age. In addition, the degree of fibrosis, ductal dilatation, and fatty infiltration increased with advancing age. Our findings are consistent with this report, suggesting that NSCS may increase with age.

Because sicca NSCS controls did not have organ involvement, most disease manifestations are not listed in Table 3, except for dry mouth, dry eyes, and rampant caries, which were similar between the groups. The aforementioned age-associated changes can result in reduced acinar capacity and may lead to decreased saliva production. However, immunological features comprising high ANA titer, positive anti-SSA, and anti-SSB, and high IgG were predominantly found in pSS patients with NSCS. Based on a combination of these features and clinical manifestations, the diagnosis of pSS was confirmed. In addition, we analyzed the levels of lymphocytic infiltration in LSG tissues of these two groups and found that the prevalence of a high level of infiltration was significantly greater in pSS with NSCS than sicca NSCS controls (48.6 vs. 10.8%, respectively). In addition, lymphocytic infiltrates in some pSS patients with NSCS may mimic foci, but are not located adjacent to normal-appearing acini. Therefore, we speculate that there is greater lymphocytic infiltration in pSS with NSCS compared to sicca NSCS controls. When pSS occurs in individuals with NSCS, a typical focus may be not present because a focus is defined as infiltration adjacent to normal-appearing acini [20]. When such patients with NSCS are considered to have pSS, the extent of lymphocytic infiltration should be determined. NSCS may be a pathological subtype of pSS in elderly patients, even though it is common in the general elderly population.

The presence of anti-SSA or a positive salivary gland biopsy is mandatory for the diagnosis of pSS, but the classification criteria are more suitable for use in clinical trials and epidemiologic studies to allow standardization and comparability of findings across studies [11, 21, 22]. The clinical manifestations of pSS are heterogeneous and the diagnosis must be based on the clinical assessment of all data, including clinical findings, laboratory tests, and pathological examination. The clinical diagnosis based on expert opinion is also important [22]. In this study, a small number of biopsy-negative patients (nine with 0 ≤ FS < 1 and six with NSCS) without anti-SSA were clinically diagnosed with pSS after evaluation by the experienced rheumatologist in our team based on the typical manifestations, high titer of ANA, and positive anti-Ro52. Some of these biopsy-negative tissues exhibited significant lymphocytic infiltration or had a focus, but did not achieve FS ≥ 1. Moreover, LSG biopsy had some limitations. Examination of multiple tissue sections in the same specimen may identify focal infiltration in some biopsy-negative patients because mild FLS foci are unevenly distributed [23]. Another possibility is that the biopsy may not obtain the damaged LSG, thereby not accurately reflecting the condition of the salivary glands [22].

There were some limitations in this study. This study included a relatively small number of pSS patients with NSCS and sicca NSCS controls; however, these patients were identified from among 425 LSG biopsy participants, which was a relatively large cohort. In future studies, a large cohort should be included to verify these results. Another limitation was that the pathological reports regarding the degree of lymphocytic infiltration in NSCS were subjective, but the evaluation was performed by the same experienced pathologist. In addition, we did not examine lymphoepithelial lesions and germinal centers of LSG tissues in pathological reports, which needs to be addressed in future studies.

In our study, pSS patients with NSCS had similar clinical features to those of non-NSCS pSS individuals. Furthermore, NSCS was associated with age, but not other variables of pSS. We found that NSCS seldom occurred before the age of 45 both in pSS and sicca NSCS controls who were otherwise healthy. The features of NSCS were acinar atrophy, interstitial fibrosis, and ductal dilation, which were often accompanied by some lymphocytic infiltration. These findings were relatively common and increased with age in both the general population and pSS patients. NSCS may be a subtype of pSS in elderly patients.