Sialometry and sialochemistry: diagnostic tools for Sj?gren's syndrome

BACKGROUND—The common occurrence of xerostomia in Sjögren''s syndrome (SS) as well as the easy accessibility of saliva supports the use of sialometry and sialochemistry in the diagnosis of SS. Collection and analysis of whole saliva (oral fluid) is currently the routine technique for sialometry, despite the fact that it is rather inaccurate and impure.OBJECTIVE—To assess the value of glandular sialometry and sialochemistry as diagnostic instruments in SS.METHODS—In a group of 100 consecutive patients referred for diagnosis of SS, glandular secretory flow rates and a spectrum of salivary components (sodium, potassium, chloride, calcium, phosphate, urea, amylase, total protein) were assessed. The patients were classified as positive or negative for SS according to the revised European classification criteria.RESULTS—Patients with SS differed clearly from those who tested negative for SS, showing lower submandibular/sublingual (SM/SL) flow rates and an appreciably changed salivary composition of parotid and SM/SL saliva. Besides changes in salivary flow rate and composition, distinct sialometric profiles were observed, characteristic of either early or late salivary manifestation of SS, or of the xerogenic side effects of medication.CONCLUSIONS—Glandular sialometry and sialochemistry are not only useful tools for differentiating SS from other salivary gland disease in clinical practice, but they also have great potential as diagnostic criteria for SS, showing distinct sialometric and sialochemical changes as well as profiles. Being simple, safe (non-invasive), and sensitive (early disease detection), they have three major advantages over other oral tests for SS.     

原发性干燥综合征与脂代谢紊乱关系初探

目的 了解原发性干燥综合征(pSS)患者血脂水平情况,探讨脂代谢紊乱与pSS的相关因素及可能的机制.方法 选取114例pSS患者和20名健康者对照,回顾性分析血脂水平变化及与临床和实验室指标之间的关系.结果 pSS患者平均血清高密度脂蛋白胆固醇(HDL-c)与载脂蛋白A1(apoA1)水平低于正常(P<0.05).pSS中39.5%存在血脂异常,血脂异常组较健康对照组平均病程较长,腮腺肿大发生率高,红细胞沉降率(ESR)增快、唾液流率降低明显(P<0.05).Logistic回归分析发现腮腺肿大与pSS患者出现血脂异常相关.经单独或联合调脂治疗,pSS症状可得到改善,而随着疾病活动性减轻,血清脂质也恢复正常.结论 pSS患者存在血脂水平异常,且脂类代谢的紊乱与pSS的病情密切相关.控制血脂升高、改善有害脂质可能对pSS的治疗起到积极的作用.     

Sjögren's syndrome (SS) in patients with human T cell leukemia virus I associated myelopathy: paradoxical features of the major salivary glands compared to classical SS

OBJECTIVE: To characterize imaging features of the major salivary glands in patients with human T cell leukemia virus I (HTLV-I) associated myelopathy (HAM) associated with Sj?gren's syndrome (SS), and to compare these features with those in HAM negative patients with SS. METHODS: The study population included 31 HAM patients (12 had associated SS), 15 HTLV-I seropositive/HAM negative patients with SS, and 41 HTLV-I seronegative patients with SS. Twenty HAM negative patients with sicca syndrome only were also studied. Diagnostic imaging (sialography, magnetic resonance imaging, and sonography) of the salivary glands, labial gland biopsy, Schirmer test, Saxon test, and serological tests were performed on these patients. RESULTS: The parotid and submandibular glands in 11 (92%) of the 12 HAM patients with SS completely lacked the abnormal imaging features characteristic of the disease, while they displayed decreased salivary flow rates at levels similar to those in the HAM negative patients with SS. The labial glands from the HAM patients with SS exhibited significantly lower magnitudes of mononuclear cell aggregation compared with those in the HAM negative patients with SS. In contrast, all HAM negative patients with SS showed abnormal imaging features characteristic of the disease, and the severity in salivary dysfunction correlated well with the imaging findings. CONCLUSION: These results suggest that SS in patients with HAM may occur in part via a mechanism distinctive from classical SS in HAM negative patients.     

Comparison of parotid and minor salivary gland biopsy specimens in the diagnosis of Sj?gren's syndrome

We conducted a prospective study comparing minor salivary gland and parotid gland biopsy specimens obtained simultaneously from 24 patients who were undergoing evaluation for primary Sj?gren's syndrome (SS). Adequate tissue for study was obtained with all minor salivary gland biopsies and 19 of 24 parotid gland biopsies. Parotid inflammation was seen in 6 of 11 patients whose minor salivary gland biopsy results indicated SS, but in none of 8 patients who had normal findings on minor salivary gland biopsy. Patients with parotid inflammation were older and had a higher frequency of dry eyes and mouth, abnormal results on Schirmer's test, serious extraglandular involvement, and serologic abnormalities. We conclude that parotid gland biopsy adds very little to the minor salivary gland biopsy in the diagnosis of primary SS, but that parotid inflammatory changes may reflect disease duration and/or severity.     

Sialometry and sialochemistry: a non-invasive approach for diagnosing Sjögren''s syndrome

Background: Analysis of salivary variables has frequently been proposed as a diagnostic tool for Sjögren''s syndrome (SS). Because univocal salivary reference values are lacking, it is currently rather difficult to use sialometry and sialochemistry for diagnosing SS unless major changes have occurred in salivary secretion and composition. Objective: To define reference values of several salivary variables, which offer a possible new and non-invasive means of diagnosing SS. Methods: Cut off points were selected from receiver operating characteristic curves of gland-specific sialometrical and sialochemical variables, which have proved to be potentially relevant for diagnosing SS in a previous study—that is, sodium, chloride, and phosphate concentration in stimulated parotid and submandibular/sublingual (SM/SL) saliva, unstimulated and stimulated SM/SL flow rates, and lag phase of parotid secretion, respectively. By combining the most discriminating variables, two different diagnostic approaches for SS were applied in a group of 100 patients and subsequently evaluated in a second group of 20 patients. The first approach was to combine variables by applying their cut off points into sets of criteria for a positive diagnosis of SS. The second approach was to construct a logistic regression model that predicts the true state of a patient (SS or non-SS). From both approaches, the tests with highest likelihood ratio combined with the smallest number of rejected cases were selected for clinical use. Results: The most accurate test combined the stimulated SM/SL flow rate and parotid sodium and chloride concentration as salivary variables for diagnosing SS; it had a sensitivity of 0.85 and a specificity of 0.96. The selected tests proved equally accurate in the second group of patients. Conclusions: Because the proposed non-invasive diagnostic tools can be easily applied, do not need a laboratory other than for routine blood testing, and are very accurate, gland-specific sialometry and sialochemistry may eventually replace other, more invasive, diagnostic techniques for diagnosing SS.     

Labial salivary gland biopsy in Sj?gren's syndrome. Assessment as a diagnostic criterion in 362 suspected cases

Xerostomia is an unsatisfactory diagnostic criterion for the salivary component of Sj?gren's syndrome (SS). To determine the diagnostic usefulness of the presence of focal sialadenitis in labial salivary gland (LSG) biopsy specimens, 362 patients suspected of having SS prospectively underwent a unique LSG biopsy procedure. The pattern and severity of LSG inflammation were compared with measurements of parotid flow rate, and the presence or absence of symptomatic xerostomia, major salivary gland enlargement, keratoconjunctivitis sicca (KCS), and other connective tissue diseases (CTD). LSG biopsy focus scores of greater than 1 correlated more closely with the diagnoses of KCS alone and with KCS plus a CTD than did either reduced parotid flow rate or symptoms of xerostomia (P less than 0.0005 and P less than 0.05, respectively). Focal sialadenitis in an adequate LSG specimen is an objective criterion and a more disease-specific feature of SS than xerostomia or any other feature of salivary disease. The salivary component of SS should be redefined as the presence of LSG focal sialadenitis.     

Parotid sialography and minor salivary gland biopsy in the diagnosis of Sj?gren's syndrome. A comparative study of 84 patients

Parotid sialography and labial salivary gland biopsy were performed in 84 patients with clinical features of primary or secondary Sj?gren's syndrome (SS). Signs of focal sialoadenitis were found in 73/84 patients (87%), but only 37 (44%) scored 4 which is considered diagnostic for classic SS. In contrast 55/84 patients (66%) showed some sialographic abnormalities. In patients with both primary and secondary SS, hypergammaglobulinemia and anti-SSA antibodies appeared to be the serological variables more closely related to the entity of either sialographic or histologic abnormalities. In primary SS extraglandular manifestations and recurrent parotid swelling were significantly associated with parotid sialography and labial salivary gland biopsy changes, respectively. Our study indicates that currently both radiological and histological examination are necessary for the assessment of salivary gland involvement in SS.     

Ultrasonographic changes of major salivary glands in primary Sjogren's syndrome. Diagnostic value of a novel scoring system

OBJECTIVES: To reveal typical ultrasonographic (US) changes in major salivary glands associated with Sjogren's syndrome (SS) and to determine the diagnostic value of a novel US scoring system. METHODS: In 218 consecutive patients with suspected SS, US of both parotid and submandibular salivary glands was performed besides the regular diagnostic procedure following the American-European Consensus Group criteria of 2002. Five US parameters were assessed: echogenicity, inhomogeneity, number of hypoechogenic areas, the hyperechogenic reflections and clearness of the borders of the salivary gland. The grades of these five parameters for all four salivary glands were summed. The final US score ranged from 0 to 48. RESULTS: SS was established in 68 patients. The remaining 150 subjects, in whom SS was not confirmed, constituted our control group. All five US parameters were significantly associated with SS. The patients with SS had significantly higher US scores than those not diagnosed with SS (P<0.01). Setting the cut-off US score at 17 resulted in the best ratio of specificity (98.7%) to sensitivity (58.8%). CONCLUSIONS: Well-defined US changes in the major salivary glands summarized in our novel scoring system were typical of SS patients. Advanced structural changes found on US imaging almost invariably represent SS salivary gland involvement.     

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

OBJECTIVE: To investigate the effect of pilocarpine on the salivary peptide and protein profile in patients with primary Sj?gren'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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Oral and sialochemical findings in patients with autoimmune rheumatic disease

Forty-two patients with autoimmune rheumatic diseases were evaluated for oral-dental findings and a biopsy of labial minor salivary glands was obtained. Stimulated parotid salivary gland function was assessed and levels of total protein, chloride and albumin in these secretions measured. The patients were stratified into three groups according to the severity of labial gland histopathology (normal histology, 1+ and 2+). Individuals with chronic inflammatory disease of the minor salivary glands had no decrease in stimulated parotid salivary flow but were found to have a greater incidence of oral soft tissue changes commonly associated with salivary dysfunction. However, there were no statistically significant differences in total protein or chloride levels between the groups and no albumin was detected in any samples. These data suggest that stimulated parotid function may be a poor indicator of the extent of salivary involvement in individuals with autoimmune-mediated salivary gland disease.     

Salivary gland involvement in chronic pancreatitis of various etiologies

OBJECTIVE: Both the pancreas and salivary glands show many histological and functional similarities. Recently, autoimmune pathogenesis has been postulated in some chronic pancreatitis cases. To examine whether a cell-mediated phenomenon involving the pancreas has a secondary effect on the salivary glands, we assessed the frequency of salivary gland dysfunction in patients with chronic pancreatitis of various etiologies. METHODS: Function of the salivary glands was examined by sialochemistry and salivary gland scintigraphy in patients with chronic pancreatitis (n = 33), Sjogren's syndrome (n = 45), and controls (n = 28). Etiologies of chronic pancreatitis were alcoholic (19 cases), idiopathic (seven cases), and autoimmune (seven cases). RESULTS: Concentrations of Na+, amylase, and beta2-microglobulin in saliva were investigated. In submandibular and parotid gland scintigraphy, time-activity curves were generated, and the ratios of peak count density and washout were calculated.Concentrations of Na+ in saliva of patients with idiopathic chronic pancreatitis and of beta2-microglobulin in saliva of patients with idiopathic and autoimmune chronic pancreatitis were significantly elevated than those of the control group. In submandibular and parotid gland scintigraphy, the peak count density ratio of patients with all chronic pancreatitis and washout ratio of patients with alcoholic and idiopathic chronic pancreatitis were significantly lower than those of the control group. CONCLUSIONS: Salivary gland function was frequently impaired in the course of chronic pancreatitis of various etiologies. Salivary gland dysfunction might be the result of a common pathophysiological effect of alcohol in patients with alcoholic chronic pancreatitis and the aggressive immune mechanism against the pancreatic and the salivary ducts in patients with autoimmune and idiopathic chronic pancreatitis.     

A study to standardize quantitative evaluation of parotid gland scintigraphy in patients with Sjögren's syndrome

OBJECTIVE: To standardize quantitative parotid gland scintigraphy for diagnosing Sj?gren's syndrome (SS). METHODS: Forty-five patients with SS and 23 controls were studied. Dynamic images were obtained up to 50 min after the injection of 185 MBq 99mTc-pertechnetate and salivary excretion was stimulated with lemon juice orally at 40 min after the injection. Peak count and uptake speed in the uptake phase, and excretion speed and excretion fraction in the excretion phase were calculated. RESULTS: The levels of peak count, uptake speed, and excretion speed in the patients with SS were significantly lower than the levels in the controls, whereas there was no significant difference of excretion fraction level between the patients with SS and the controls. The calculations of peak count and excretion speed levels, which were closely related with the focus scores of minor salivary glands and the amount of stimulated whole saliva, showed higher reproducibility, sensitivity, and specificity than those of uptake speed and excretion fraction levels. CONCLUSION: The calculations of peak count and excretion speed were eligible to standardize quantitative parotid gland scintigraphy for diagnosing SS.     

A diffuse infiltrative CD8 lymphocytosis syndrome in human immunodeficiency virus (HIV) infection: a host immune response associated with HLA-DR5

STUDY OBJECTIVE: To describe the clinical, immunologic, and immunogenetic features of a diffuse infiltrative lymphocytic disorder resembling Sj?gren syndrome in persons infected with human immunodeficiency virus (HIV). DESIGN: Clinical case study. SETTING: University-affiliated hospitals and outpatient clinics. PATIENTS: Consecutive sample of 17 patients. MEASUREMENTS AND MAIN RESULTS: All of the 17 patients had bilateral parotid gland enlargement; 14 had xerostomia and 6 had xerophthalmia. Of the 17 patients, 14 had generalized lymphadenopathy, 10 had histologically proved lymphocytic interstitial pneumonitis, 4 had neurologic involvement, and 3 had lymphocytic infiltration of the gastrointestinal tract. Gallium scanning in all of 11 tested patients showed abnormal salivary gland uptake. Minor salivary gland biopsies showed more than 2 lymphocytic foci per 4 mm2 tissue in all of 11 tested patients, the infiltrate consisting predominantly of CD8 cells. Fifteen patients had circulating CD8 lymphocytosis; the principal phenotype of these cells was CD8+ CD29+. Rheumatoid factor and antinuclear antibodies were infrequent, and none of the patients had anti-Ro/SS-A or anti-La/SS-B antibodies. HLA-DR5 was significantly more frequent in the black patients (10 of 12) compared with controls (13 of 45). Only one patient developed an opportunistic infection during 544 patient-months of study, and none has died of AIDS. CONCLUSIONS: A distinct syndrome primarily characterized by parotid gland enlargement, sicca symptoms, and pulmonary involvement occurs in HIV infection. This disorder is associated with CD8 lymphocytosis and the presence of HLA-DR5, and appears to be a genetically determined host immune response to HIV.     

Sjogren's syndrome in Israel: Primary versus secondary disease

Summary Sixty Israeli patients, 30 with primary Sjögren's syndrome (SS) and 30 with rheumatoid arthritis (RA) and secondary SS, were evaluated. The Schirmer-1 test and a positive labial salivary gland biopsy were found to be the most helpful tools in assessing the diagnosis of SS. Extraglandular features such as Raynaud's phenomenon, lymphadenopathy and CNS involvement as well as parotid gland enlargement (p<0.05) were more common in primary SS. Antinuclear antibodies, especially anti-Ro (SSA) and anti-La (SSB) were also more common in primary SS (p<0.05). Our results are in accord with those of many European centers, despite the different genetic background.     

Clinical manifestations and early diagnosis of Sjögren syndrome

Sj?gren syndrome (SS) is a common autoimmune disease evidenced by broad organ-specific and systemic manifestations, the most prevalent being diminished lacrimal and salivary gland function, xerostomia, keratoconjunctivitis sicca, and parotid gland enlargement. Primary SS presents alone, and secondary SS occurs in connection with autoimmune rheumatic diseases. In addition, symptoms do not always present concurrently. This diversity of symptomatic expression adds to the difficulty in initial diagnosis. Armed with the recently refined criteria for diagnosis, specialists, such as rheumatologists, primary care physicians, ophthalmologists, and dentists, who would otherwise focus only on those symptoms that encompass their areas of expertise, can get a comprehensive image of the presenting patient, leading to earlier identification and treatment of SS.     

A prospective study comparing incisional labial to incisional parotid biopsies in the detection and confirmation of sarcoidosis, Sj?gren's disease, sialosis and lymphoma

Simultaneous incisional biopsies of labial minor salivary glands and the superficial lobe of the parotid were accomplished in patients suspicious for sarcoidosis, Sj?gren's disease, sialosis and lymphomatous changes in Sj?gren's disease. Labial minor salivary gland biopsies identified sarcoidosis in 11 of 31 (36%) patients, compared to 29 of 31 (93%) patients using the parotid biopsy (p = 0.005). Similarly, the labial minor salivary gland biopsy confirmed 21 of 36 (58%) patients to have Sj?gren's disease, compared to 36 of 36 (100%) (p = 0.005) patients confirmed using the parotid biopsy. Five patients with normal labial salivary gland biopsies were shown to have idiopathic hypertrophic sialosis with enlarged parotids identified by the parotid biopsy. Five additional patients were diagnosed with lymphoma occurring within the parotid glands of patients with Sj?gren's disease, via the parotid biopsies, that were not identifiable with the labial minor salivary gland biopsy. The parotid biopsy consistently identified each disease entity in an earlier stage, and with more evident histopathology. Neither technique showed appreciable morbidity. Three of 77 patients showed a sensory loss related to labial salivary gland biopsy. No sensory or motor nerve loss was associated with the parotid biopsy.     

Correlations between histopathologic and scintigraphic parameters of salivary glands in patients with Sj?gren’s syndrome

The aim of this study is to evaluate the diagnostic value of quantifying salivary gland scintigraphy in correlation to the labial biopsy findings of Sj?gren’s syndrome (SS). Thirty patients suspected of having SS referred to our clinic for salivary gland scintigraphy were included to this study. All patients underwent salivary gland biopsy as well. The severity of histopathologic changes was graded according to the Chisholm and Mason scoring system. Dynamic scintigraphy was performed and region of interests (ROI) were drawn. Time activity curves for salivary glands were generated. Count rates of maximum, minimum activity after lemon juice stimuli, and last minute activities of parotid and submandibular glands were obtained. On the basis of this ROI counts, excretion fraction (EF%) was calculated for all salivary glands. The mean EF% for normal parotid gland and pathologic parotid gland was 54.5?±?13.9 and 45.8?±?18.42, respectively, while it was 46.7?±?11.7 for the normal submandibular gland and 29.3?±?18.8 for the pathologic submandibular gland. With progression in histopathologic grades from 0 to 4, the EF decreased in all salivary glands. Decreased EF in the salivary glands is correlated with the SS, and salivary gland scintigraphy is a sensitive and valid method for evaluation of the function of the salivary glands.     

Human immunodeficiency virus (HIV) and HIV infected cells in saliva and salivary glands of a patient with systemic lupus erythematosus.

A young woman with systemic lupus erythematosus (SLE) was infected with human immunodeficiency virus 1 (HIV-1) and about 6 years later developed persistent bilateral parotid gland enlargement. It was unclear whether this represented salivary gland involvement as a component of her SLE (secondary Sj?gren's syndrome) or the initial clinical manifestation of her HIV-1 infection. HIV proviral DNA was found in individual salivary glandular secretions and in whole saliva. Additionally, cells positive for HIV RNA were isolated from whole saliva. A parotid gland biopsy revealed infiltrating lymphocytes containing large amounts of HIV RNA.     

Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients

We conducted the current study to characterize the clinical presentation of primary Sj?gren syndrome (SS) in a large cohort of Spanish patients and to determine whether epidemiologic, clinical, and analytical features modulate disease expression. Patients were from the GEMESS Study group, which was formed in 2005 and included 12 Spanish reference centers. By March 2007, the database included 1010 consecutive patients, recruited since 1994, both incident and prevalent cases. The cohort included 937 women and 73 men (ratio, 13:1), with a mean age of 53 years at diagnosis and 59 years at inclusion in the registry. Multivariate analysis showed that male patients had a lower frequency of thyroiditis, Raynaud phenomenon, and antinuclear antibodies. Young-onset patients had a low degree of sicca involvement (xerostomia and parotid enlargement) and a high frequency of immunologic markers (anti-Ro/SS-A and low C4 levels). Patients with disease duration of more than 10 years had a higher prevalence of xerophthalmia, parotid enlargement, lung involvement, and peripheral neuropathy in comparison with incident cases. The subset of patients with anti-Ro/La antibodies had the highest prevalence of most systemic, hematologic, and immunologic alterations (higher frequency of Raynaud phenomenon, altered parotid scintigraphy, positive salivary gland biopsy, peripheral neuropathy, thrombocytopenia, and rheumatoid factor). Hypocomplementemia was associated with a higher frequency of vasculitis and lymphoma, and cryoglobulins with a higher frequency of parotid enlargement, vasculitis, and leukopenia.Epidemiologic, clinical, and analytical features have a significant impact on the clinical presentation of primary SS, influencing the results of the main diagnostic tests, the prevalence and diversity of extraglandular involvement, and the frequency of the main immunologic markers. Primary SS should be considered as a systemic autoimmune disease that can express in many guises beyond sicca involvement.