Secondary Sjögren's Syndrome Patients Research Articles

Tear Proteomics Approach to Distinguishing Primary from Secondary Sjögren’s Syndrome for Dry Eye Patients with Long-Term Instillation of Eyedrops

The diagnosis and monitoring of Sjögren syndrome (SS) is often difficult, requiring a multidisciplinary approach with invasive procedures. Our aim is to elucidate the tear protein alterations of dry eye disease (DED) with primary SS (pSS) and secondary SS (sSS) with the long-term instillation of eyedrops. We collected clinical demographics and tear fluid (TF) samples from DED patients with no autoimmune diseases (non-SS-DED), pSS-DED, and sSS-DED patients, followed by TF screening with tandem mass tagging-labeling gel-free proteomics assay. Bioinformatic analysis via Ingenuity Pathway Analysis was used to identify functional pathways and interacting networks. Validation of candidate proteins with enzyme-linked immunosorbent assay on the tear samples was done. The top functional pathways of the two comparisons (sSS-DED vs. pSS-DED and sSS-DED vs. non-SS-DED) were both associated with inflammation and stress-related signaling. After constructing an interaction network model with the selected candidate proteins, five proteins were identified. A Disintegrin and Metalloproteinase domain-containing protein 10 (ADAM10) was found to be an important candidate biomarker in all groups, followed by epidermal growth factor (EGF) in TF. This study revealed novel DED markers, ADAM10 and EGF, in differentiating between primary and secondary SS patients from tears by in-depth proteomic analysis.

Ocular Involvement in Sjögren Syndrome: Risk Factors for Severe Visual Impairment and Vision-Threatening Corneal Complications

To assess the risk factors for severe visual impairment (SVI) and corneal complications in primary and secondary Sjögren syndrome (SS). Retrospective case series. Ocular data of all consecutive SS patients presenting to an eye-care network and receiving a diagnosis according to 2012 American College of Rheumatology criteria over the past 8 years were reviewed. risk factors associated with SVI (best-corrected visual acuity <20/200) and vision-threatening corneal complications (ulceration or perforation) at presentation were evaluated using multivariate analysis and odds ratios (OR). Of the 919 patients, 285 (31%) had primary and 634 (69%) had secondary SS. The most common cause of secondary SS was rheumatoid arthritis (98.1%), followed by systemic lupus erythematosus (0.79%), psoriasis (0.79%), and scleroderma (0.6%). Among the 1,838 eyes, SVI was noted in 10%, and 2.5% had corneal complications at presentation. The presence of corneal scarring (P < .00001; OR: 3.00), corneal ulceration (P < .00001; OR: 12.96), low Schirmer values (P= .0084; OR: 0.93), cataract (P= .0036; OR: 2.4), glaucoma (P= .04; OR: 4.09), and age at diagnosis (P= .005; OR: 1.02) were independent risk factors for developing SVI. The risk factors for corneal complications were presence of scleritis (P < .0001; OR: 8.9) and a diagnosis of secondary SS (P= .009; OR: 2.94). In patients with SS, severity of dryness, corneal ulceration and scarring, cataract, and glaucoma are factors associated with poor visual acuity. Eyes with scleritis have a greater risk of developing vision-threatening corneal complications and therefore should be monitored closely.

Autoimmune rheumatic diseases increase dementia risk in middle-aged patients: A nationwide cohort study.

ObjectiveDementia is a common neurological disease that substantially affects public health. A previous study revealed that dementia occurs when the body’s immune system attacks the cells of the brain, indicating that dementia may be similar to autoimmune rheumatic diseases (ARDs). In the current retrospective cohort study, we focused on middle-aged ARD patients (45 years or older) to investigate the association between ARDs in middle-aged people and dementia by using a nationwide population-based database in Taiwan.MethodOur study analyzed the medical data of the Taiwanese population from 2001 to 2012, with a follow-up period extending until the end of 2011. We identified middle-aged patients with ARDs by using the Taiwan National Health Insurance Research Database. We selected a comparison cohort from the general population that was randomly frequency-matched by age (in 5-year increments), sex, and index year and further analyzed the dementia risk by using a Cox regression model that considers sex, age, and comorbidities.ResultsThe study enrolled 34,660 middle-aged ARD patients (77% female, mean age = 59.8 years) and 138,640 controls. The risk of developing dementia was 1.18 times higher for middle-aged patients with ARDs compared with patients without ARDs after adjustment for age, sex, and comorbidities. Among the patients with ARDs, the subgroups with rheumatoid arthritis, systemic lupus erythematosus, and Sjögren syndrome (SS) were associated with a significantly higher dementia risk (adjusted hazard ratio [HR] 1.14, 95% confidence index [CI] 1.06–1.32; adjusted HR 1.07, 95% CI 0.86–1.34; adjusted HR 1.46, 95% CI 1.32–1.63, respectively). Furthermore, primary SS and secondary SS patients had the highest risks of dementia among all the ADR subgroups (adjusted HR 1.35, 95% CI 1.18–1.54; adjusted HR 1.67, 95% CI 1.43–1.95 respectively).ConclusionThis nationwide retrospective cohort study demonstrated that dementia risk is significantly higher in middle-aged patients with ARDs compared with the general population.

Usefulness of MR imaging of the parotid glands in patients with secondary Sjögren's syndrome associated with rheumatoid arthritis

Objective. To assess the correlation between MR imaging (MRI) of parotid glands with X-ray sialography, histopathology of the labial salivary glands, and salivary secretion, in patients with secondary Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA).Methods. Non-contrast MRI of the parotid glands was performed in 13 secondary SS patients associated with RA who satisfied the revised Japanese diagnostic criteria for SS (1999), and the ACR/EULAR classification criteria for RA (2010). The MRI findings were classified according to the degree of high-intensity signal on T1-weighted images (T1WI) and short inversion time inversion recovery (STIR) images into five grades (0–4), using the modified Nagasaki University grading method. The results of MRI grading were compared with the Rubin and Holt staging of X-ray sialography (0–4), the Greenspan grading of labial salivary gland histopathology (0–4), and salivary secretion by the gum test (ml/10 min).Results. All 13 patients were females, with a mean age of 50.2 ± 11.3 years. According to the MRI grading, 3 patients were Grade 1, 5 were Grade 2, 5 were Grade 3, and none was Grade 0 or Grade 4. The mean stage by X-ray sialography was 1.7 ± 1.0, the mean grade by histopathology was 2.4 ± 1.2, and the mean volume of salivary secretion was 9.7 ± 3.9 ml. The MRI grading correlated significantly with the Rubin and Holt staging and Greenspan grading (P < 0.01 each, Spearman's rank correlation), and significantly and inversely with the results of the gum test (P < 0.05).Conclusion. The results suggest that MRI of the parotid glands is a useful noninvasive tool for evaluating destruction and inflammation in the salivary glands.

In Vivo Confocal Microscopy of Meibomian Glands in Sjögren's Syndrome

To evaluate morphologic changes in meibomian glands (MGs) and the status of periglandular inflammation in patients with primary and secondary Sjögren's Syndrome (SS) using in vivo confocal laser microscopy (LSCM). Twenty patients with primary SS (SSI), 25 with secondary SS (SSII), 20 with MG dysfunction (MGD), and 25 age- and gender-matched control subjects were enrolled consecutively. Each participant completed an Ocular Surface Disease Index questionnaire and underwent a full eye examination, including tear film break-up time (BUT), fluorescein and lissamine green staining, Schirmer test, and an LSCM examination of the MGs, the last to determine acinar unit density and diameter, glandular orifice diameters, meibum secretion reflectivity, inhomogeneous appearance of glandular interstice, and acinar wall. All parameters indicated statistically significant differences among groups (P < 0.001, Kruskal-Wallis test). LSCM demonstrated no differences between SSI and SSII (Mann-Whitney U test). Compared with control subjects, SS subjects' MGs showed more periglandular inflammation and higher secretion reflectivity (P < 0.001, Mann-Whitney U test). Compared with MGD patients, SS patients' MGs had higher acinar density, smaller diameters, greater density of periglandular inflammatory cells, and lower secretion reflectivity (P < 0.001, Mann-Whitney U test). In SS patients, the two measured confocal signs of inflammation were significantly interrelated and correlated with corneal fluorescein staining (P ≤ 0.01, Spearman correlation coefficient). Acinar density and diameters were strongly correlated among themselves (P < 0.001) and with BUT (P < 0.05). LSCM is capable of effectively revealing morphologic and inflammatory changes in MGs and showed discernible patterns of MG abnormalities in SS and MGD not easily distinguishable by the usual clinical exams.

Follistatin-like protein 1 is elevated in systemic autoimmune diseases and correlated with disease activity in patients with rheumatoid arthritis

IntroductionFollistatin-like protein 1 (FSTL1) is a proinflammation mediator implicated in arthritis in rodent animal models. The present study is aimed at assessing FSTL1 levels in systemic autoimmune diseases and correlating them with disease activity in patients with rheumatoid arthritis (RA).MethodsSerum FSTL1 levels from 487 patients with systemic autoimmune diseases and 69 healthy individuals were measured by enzyme-linked immunosorbent assay (ELISA). FSTL1 expression in synovial fluid (SF) and synovial tissues (STs) was determined by ELISA, immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and western blot analysis in RA patients and trauma controls. FSTL1 levels in fibroblast-like synoviocytes (FLSs) from RA patients were determined by real-time PCR and western blot analysis.ResultsSerum FSTL1 levels were significantly elevated in patients with RA, ulcerative colitis, systemic lupus erythematosus, Sjögren's syndrome (SS), systemic sclerosis and polymyositis/dermatomyositis. Serum FSTL1 levels in the RA and secondary SS patients were substantially higher than those in other patients. Serum FSTL1 levels were increased in early RA, rheumatoid factor (RF)- and anti-cyclic citrullinated peptide antibody (ACPA)-negative patients compared to healthy controls. Moreover, serum FSTL1 concentrations were significantly higher in long-standing RA patients than in early RA patients and in the RF- and ACPA-positive RA patients than in RF- and ACPA-negative RA patients. Elevated FSTL1 levels in the STs and SF of RA patients were also observed. FSTL1 levels in serum were markedly higher than those in SF in RA patients. The strongest FSTL1 staining was detected in the cytoplasm of synovial and capillary endothelial cells from RA synovium. Furthermore, FSTL1 was induced in FLSs by inflammatory mediators. Importantly, serum FSTL1 levels were correlated with several important biologic and clinical markers of disease activity, including erythrocyte sedimentation rate, C-reactive protein, RF, ACPA, swollen joint count, patient global visual analogue scale score and Disease Activity Score 28 in the adult RA patient population. Notably, serum FSTL1 levels were significantly diminished following successful treatment and clinical improvement.ConclusionsElevated FSTL1 levels reflect not only joint diseases but also inflammation and tissue degradation in systemic autoimmune diseases. Serum FSTL1 levels may thus serve as a serological inflammatory marker of disease activity in RA patients.

Decrease of blood dendritic cells and increase of tissue-infiltrating dendritic cells are involved in the induction of Sjögren's syndrome but not in the maintenance

We have demonstrated previously that, in primary Sjögren's syndrome (SS), immature myeloid dendritic cells (DCs) are decreased in blood and mature myeloid DCs are accumulated in salivary glands, suggesting recruitment of the myeloid DCs from blood to salivary glands. To verify whether this finding is universal in patients of not only primary SS but also secondary SS, in this study we analysed the blood DCs of secondary SS patients. We examined 24 secondary SS and 29 primary SS patients. A direct correlation between the decreased number of myeloid DCs and the duration of Sicca syndrome in primary and secondary SS was observed; namely, the reduction of myeloid DCs in blood was restored spontaneously with duration time of Sicca syndrome. We also examined the immunohistochemical staining of salivary glands of SS patients with monoclonal antibodies against fascin, CD11c and human leucocyte antigen DR (HLA-DR). Fascin(+) or CD11c(+)/HLA-DR(+) mononuclear cells were present in the salivary glands of secondary SS patients, as in primary SS. However, fascin(+) mononuclear cells were barely detected in the salivary glands of a chronic phase of SS patients. We also found a negative correlation between the frequency of blood myeloid DCs and salivary gland-infiltrating DCs in secondary SS patients, as well as primary SS. Our results suggest that the reduction of blood myeloid DCs and preferential trafficking of myeloid DCs into salivary glands is a common event in the early stage of SS. Myeloid DCs may play essential roles in the pathogenesis of Sicca syndrome of SS by initiating T helper cell immune responses.

Proteomic study of salivary peptides and proteins in patients with Sjögren's syndrome before and after pilocarpine treatment

To investigate the effect of pilocarpine on the salivary peptide and protein profile in patients with primary Sjögren's syndrome (SS) and to study the differences between patients with primary SS, patients with SS associated with other rheumatic diseases, and healthy control subjects. Saliva specimens were obtained from 9 primary SS patients, 9 secondary SS patients, and 10 healthy controls. Samples were analyzed for levels of 62 different salivary proteins using high-performance liquid chromatography coupled with mass spectrometry using a spectrometer equipped with an electrospray ionization source. In 6 of the primary SS patients, saliva was collected at 30 minutes, 60 minutes, and 24 hours after taking 5 mg of pilocarpine. Before pilocarpine, approximately 60% of salivary proteins in samples from primary SS patients were not identifiable or showed lower levels than those in healthy controls. After 30-60 minutes following pilocarpine treatment, approximately one-third of the less represented proteins was found in a similar percentage of primary SS patients and controls. Almost all of the proteins that were detectable at lower levels in primary SS patients compared with controls reached levels similar to those in controls at 30-60 minutes after pilocarpine. The parotid gland proteins had the best response to pilocarpine. Primary SS patients were characterized by higher alpha-defensin 1 levels and by the presence of beta-defensin 2. Secondary SS patients showed an intermediate protein profile between that of the primary SS patients and the controls. Pilocarpine partially restored the levels and numbers of identifiable proteins in saliva from patients with primary SS. Higher levels of alpha-defensin 1 and the presence of beta-defensin 2 in the saliva of patients with primary SS could be markers of oral inflammation in this patient group.

Salivary dysfunction associated with systemic diseases: systematic review and clinical management recommendations

The objective of this study was to identify systemic diseases associated with hyposalivation and xerostomia and develop evidence-based management recommendations for hyposalivation/xerostomia. Literature searches covered the English language medical literature from 1966 to 2005. An evidence-based review process was applied to management studies published from 2002 to 2005. Several systemic diseases were identified. From studies published 2002 to 2005, 15 were identified as high-quality studies and were used to support management recommendations: pilocarpine and cevimeline are recommended for treating hyposalivation and xerostomia in primary and secondary Sjögren's syndrome (SS). IFN-alpha lozenges may enhance saliva flow in primary SS patients. Anti-TNF-alpha agents, such as infliximab or etanercept, are not recommended to treat hyposalivation in SS. Dehydroepiandrosterone is not recommended to relieve hyposalivation or xerostomia in primary SS. There was not enough evidence to support any recommendations for the use of local stimulants, lubricants, and protectants for hyposalivation/xerostomia. However, professional judgment and patient preferences may support the use of a specific product for an individual patient. These evidence-based management recommendations should guide the clinician's management decisions for patients with salivary dysfunction related to systemic disease. Future treatment strategies may include new formulations of existing drugs, e.g., local application of pilocarpine. Recent discoveries on gene expression and a better understanding of the etiopathogenesis of SS may open new treatment options in the future.

Can low dose diagnostic dental radiation trigger Sjögren’s syndrome?

Sjögren's syndrome (SS), first described by Swedish ophthalmologist Henrik Sjögren in 1930, is a chronic inflammatory, autoimmune disorder characterized by diminished lacrimal and salivary glands secretion resulting in keratoconjunctivitis sicca and xerostomia. One factor instrumental in severe salivary gland damage and salivary flow decrement is radiation therapy. Apoptosis, implicated in autoimmune diseases, has been shown to be responsible for this damage. However, there are no studies investigating the effect of diagnostic radiation (low dose) on salivary glands. A safe level of radiation has not been established thus far. Diagnostic radiation has been used from 1896, but generally applied only from 1916. Dr. Sjögren identified SS in 1930. It is possible that the introduction of X-rays for diagnostic purposes is associated with SS onset. Available data show drastically reduced use of diagnostic dental radiation in developing countries and a concomitantly drastically reduced or lack of SS in these countries. In countries like India with a population of 1.1 billion (health care level II country), primary SS has been reported to be rare (total of 27 and 23 primary SS and secondary SS patients respectively reported thus far), while a health care level I country like USA, with a population of 300 million, there are about 2-4 million SS patients. Health care level IV countries do not have a single reported case of SS. There is also evidence for ultraviolet radiation inducing subcutaneous lupus erythematosus, an autoimmune disorder. We hypothesize that diagnostic dental radiation could be a factor for the development of SS as a result of either radiation induced apoptosis or through oxidative modification of proteins.

Peripheral nervous system involvement complicated due to vasculitis in cases of primary Sjögren's syndrome: case studies in a single hospital and a literature review

To determine the background features of peripheral nervous system (PNS) involvement in cases of primary Sjögren's syndrome (SS), we studied the nervous system involvement, mainly that of PNS, in patients with primary SS who were admitted to our hospital during a period of 19 years. Nine of 82 admitted patients with primary SS had PNS involvement and 12 had central nervous system (CNS) involvement. Among 182 secondary SS patients, 25 had CNS involvement, and none had PNS involvement. The nine patients with PNS involvement were older and their disease duration was shorter than those with CNS involvement and either primary or secondary SS. Four patients exhibiting active progression of PNS involvement had concomitant vasculopathy clinically that was confirmed by nerve or skin biopsy examination, with an increase in the serum C-reactive protein level. According to the literature, among 17 reported SS patients with PNS involvement, 13 had primary SS, and 13 had vasculitis as confirmed by biopsy examination. Nervous system involvement in cases of SS is not rare. PNS involvement was observed mostly in elderly patients with primary SS, and its active progression was concomitant with vasculopathy.

Role of Salivary IgA in the Pathogenesis of Sjögren Syndrome

Saliva IgA autoantibodies against M 3 muscarinic acetylcholine receptors (mAChRs) could be a new marker for the diagnosis for Sjögren syndrome (SS) dry mouth. Saliva IgA from dry mouth primary SS (pSS) or secondary SS patients tested by ELISA recognized membrane parotid gland acinar cell antigens and the synthetic 25-mer peptide corresponding to the second extracellular loop of human M 3 mAChRs. Moreover, the IgA fraction was able to inhibit the [ 3H]QNB binding to parotid acinar membrane mAChRs. In addition, the IgA prevented carbachol stimulation of protein secretion by the parotid gland. As controls, IgA and saliva from women without dry mouth and from normal control subjects gave negative results on ELISA, binding, and biological assays, thus demonstrating the specificity of the reaction. IgA autoantibodies against mAChR may be considered among the immunoglobulin factors implicated in the pathophysiology of the development of pSS dry mouth and could be a new marker for differentiating SS dry mouth from non-SS dry mouth.

Psychiatric dysfunction in connective tissue diseases: association with Sjögren's syndrome

We studied 217 patients with connective tissue disease (CTD), comprising 55 patients with primary Sjögren's syndrome (SS), 34 with secondary SS, and 128 without SS. Psychiatric manifestations were investigated using three questionnaires: the Arthritis Impact Measurement Scale 2 (AIMS2), the Cornell Medical Index (CMI), and the Beck Depression Inventory (BDI). Stratified analysis revealed that the frequency of a neurotic state (levels III + IV in CMI) in both primary SS patients (53%; 29% + 24%) and secondary SS patients (67%; 41% + 26%) was significantly greater than in CTD patients without SS (34%; 20% + 14%) (P < 0.05 and P < 0.001, respectively). The median and Q1–Q3 BDI scores in secondary SS patients (7.5 and 4.0–20.0) were significantly higher than those in CTD patients without SS (5.0 and 1.0–10.0) (P < 0.05). Neither the frequency of a neurotic state nor the BDI score differed significantly between patients with primary SS and those with secondary SS. Regression analysis showed significant correlations between the AIMS2 level-of-tension scale and CMI classifications (rs = 0.676, P < 0.001), and between the AIMS2 mood scale and BDI score (rs = 0.679, P < 0.001). SS should always be borne in mind when patients with sicca syndrome and multifarious psychiatric complaints are examined.

A comparison of intraoral Candida carriage in Sjögren's syndrome patients with healthy xerostomic controls

Objective. Determination of the incidence of Candida carriage in patients with Sjögren's syndrome (SS) and xerostomic controls to assess the influence of immunologic disturbances in SS on carriage. Study design. A total of 16 primary SS patients, 12 secondary SS patients, and 14 xerostomic controls were included in the study. Sampling was performed using an oral rinse method. Aliquots (100 μl) were spread onto CHROMagar∗ and incubated for 48 hours. Species identification was confirmed by the germ tube test and API ID32C.† Total colony-forming units per milliliter (CFU/ml) were counted and statistical analyses performed by the Kruskal-Wallis test. Results. Candida carriage in primary SS, secondary SS, and xerostomic patients was 81.25%, 66.7%, and 71.4%, respectively. There were no statistically significant differences in total CFU/ml. A wide range of species was isolated in each group. Conclusion. The immunologic disturbances seen in SS do not significantly influence the intraoral Candida carriage in patients with a dry mouth.

An association between salivary gland disease and serological abnormalities in Sjögren's syndrome

In the labial salivary glands (LSGs) of 16 primary and 18 secondary Sjögren's syndrome (SS) patients, infiltrating lymphocytes were histologically and immunohistochemically examined; also, the serum levels of rheumatoid factor, antinuclear antibodies, anti-DNA antibodies, anti-SS-A and anti-SS-B antibodies, and immunoglobulins (including IgG, IgM and IgA) were all assayed. An immunohistochemical analysis of the lymphocyte subsets in LSGs revealed that severe lymphocytic infiltration was frequently accompanied by marked B cell accumulation both in primary and secondary SS patients. Furthermore, local B cell accumulation was also closely associated with elevated levels of anti-SS-A and anti-SS-B antibodies and IgG, and this association was statistically significant in the group with primary SS but not in the group with secondary SS. Thus, local lymphocytic infiltration, especially B cell accumulation, in the salivary glands is suggested to be involved in serological abnormalities in primary SS, while complicated autoimmune diseases other than SS may also be involved in serological abnormalities in secondary SS.

An immunohistological study of secondary Sjögren's syndrome.

The labial biopsies from 13 patients with secondary Sjögren's syndrome (SS) and four disease controls were examined with a panel of monoclonal antibodies to human leucocyte antigens. Large numbers of T cells were found in most of the biopsies. In seven SS patients the T helper/inducer subset was found to be predominant. Antibody to HLA class I antigens consistently stained leucocytes, but other cell types stained more variably. Although the staining with antibody to HLA class II antigen was often weak, approximately as many cells stained with this antibody as with an antileucocyte antibody, implying that the T cells were activated. Anti-IgD revealed membrane staining of a corona of IgD-positive cells in structures resembling germinal centres. Isolated cells throughout the sections also showed strong cytoplasmic staining with anti-IgD. These results suggest a role for T-cell-dependent local antibody synthesis in the pathogenesis of the disease.