Autonomic nervous symptoms in primary Sjogren's syndrome.

OBJECTIVES: Objective signs of autonomic dysfunction (AD) have been reported in patients with primary SS (pSS) while the presence of associated symptoms has not been systematically studied. Therefore, the aims of this study were (i) to assess the presence and severity of various AD symptoms in pSS patients and (ii) to relate AD symptoms to other clinical features of pSS. METHODS: Thirty-eight pSS patients and 200 population-based controls were studied for presence and severity of AD symptoms using the Autonomic Symptom Profile (ASP), a validated self-completed questionnaire evaluating various AD symptoms. In addition, patients were investigated by three different objective autonomic nervous function tests. RESULTS: pSS patients scored significantly higher in the parasympathetic [secretomotor disorder, urinary disorder, gastroparesis (females only) and pupillomotor disorder] as well as sympathetic (orthostatic intolerance and vasomotor disorder) ASP domains compared with controls. Consequently, the standardized ASP total score was significantly increased in pSS patients [1.77 (0.57, 3.15) vs - 0.21 (-0.82, 0.72); P = 0.00] and 45% of pSS patients had an ASP total score >/=2 s.d. Furthermore, the autonomic nervous function tests showed signs of objective parasympathetic and sympathetic dysfunction as well. However, the ASP domain and total scores showed limited associations with the objective autonomic nervous function test parameters as well as clinical and serological factors of pSS. CONCLUSIONS: pSS patients showed subjective and objective signs of both a parasympathetic and a sympathetic dysfunction. However, AD symptoms showed limited associations with objective autonomic nervous function as well as other clinical features of the disease.

Dysphagia and dysmotility of the pharynx and oesophagus in patients with primary Sjögren's syndrome.

OBJECTIVES: To assess the prevalence of pharyngeal and oesophageal symptoms and dysmotility in patients with primary Sjögren's syndrome (pSS) and relate these to autonomic nervous function. METHODS: Twenty consecutive pSS patients, according to the American-European Consensus Criteria (AECC), and 30 age- and sex-matched controls from the Swedish general population registry were studied. All subjects completed a pharyngeal and oesophageal symptoms questionnaire and were examined by pharyngeal and oesophageal video radiography. In addition, the pSS patients were examined by two different autonomic nervous function tests, the deep breathing test [calculating the expiration/inspiration (E/I) ratio] and the finger skin blood flow test [the vasoconstriction (VAC) index]. RESULTS: pSS patients experienced significantly more dysphagia compared with controls (65% vs. 3%; p<0.001). Pharyngeal (45% vs. 7%; p<0.01), oesophageal (80% vs. 7%; p<0.001) and gastro-oesophageal reflux symptoms (60% vs. 23%; p<0.01) were also more prevalent in pSS patients compared with controls while pharyngeal (15% vs. 17%; p = NS) and oesophageal dysmotility (40% vs. 30%; p = NS) were not. Dysphagia was not associated with dysmotility but was found to be associated with a decreased E/I ratio [-1.05 (-1.51 to -0.40) in patients with dysphagia vs. -0.21 (-0.39 to 0.65) in patients without dysphagia; p<0.01]. CONCLUSION: Subjective swallowing difficulties were more common in pSS patients than in controls while objective signs of pharyngeal and oesophageal dysmotility were not. Dysphagia in pSS patients does not seem to be related to video radiographical signs of dysmotility but may be related to an impaired parasympathetic function.

Progress and regression within primary Sjögren's syndrome.

The purpose of this review is to give a modern view and an update of important areas in primary Sjögren's syndrome (SS), which may be the most common of the autoimmune systemic rheumatic diseases. Interest in aspects of primary SS including clinical manifestations, pathogenesis, aetiology, treatment, prognosis, etc has increased during the past three decades, the volume of scientific papers and the number of theses being the indicators. However, only a fraction of the money that is used for research into rheumatoid arthritis (RA) is used for SS, and the statement that SS is under-diagnosed, under-treated and under-researched will still be valid for several years to come. The topics that are focused on in this review are: (a) clinical areas with subsections on signs and symptoms, terminology, predictors for development of non-Hodgkin malignant lymphoma (NHML) and prognosis, (b) treatment, (c) the Danger model (aetiopathogenesis) and (d) pathology, including immunoglobulin G4 (IgG4)-positive cells.

Lymphoma and other malignancies in primary Sjögren's syndrome: a cohort study on cancer incidence and lymphoma predictors.

OBJECTIVES: To assess the risk of lymphoproliferative disease or other malignancy (standardised incidence ratios (SIRs)), in patients with primary Sjögren's syndrome according to the American-European Consensus Criteria (AECC), compared with patients with sicca syndrome (non-AECC) and the background population. To identify predictors of malignancy and describe lymphoma types and survival probabilities. METHODS: A linked register study using information from the Malmö Primary SS Register, Swedish Cancer Register, and Cause-of-Death Register for calculation of SIRs was carried out. Detected lymphomas were reclassified according to the WHO classification. Cox regression analysis was used to study the predictive value of clinical, laboratory, and histological findings at the time of diagnosis. RESULTS: 507 patients with a median follow up of 8 years (range 1 month to 19 years) were included. SIRs (95% confidence interval (CI)) for malignancies in total and for non-Hodgkin's lymphomas (NHL) were 1.42 (0.98 to 2.00) and 15.57 (7.77 to 27.85), respectively, in those fulfilling the AECC (n = 286). In non-AECC sicca patients (n = 221) SIR for malignancy of any kind was 0.77 (0.41 to 1.32); no lymphoproliferative neoplasms were detected. Significant predictors of lymphoproliferative disease were purpura/skin vasculitis (hazard ratio (HR) = 4.64, 95% CI 1.13 to 16.45), low complement factor C3 (HR = 6.18, 95% CI 1.57 to 24.22), low C4 (HR = 9.49, 95% CI 1.94 to 46.54), CD4+ T lymphocytopenia (HR = 8.14, 95% CI 2.10 to 31.53), and a low CD4+/CD8+ T cell ratio < or = 0.8 (HR = 10.92, 95% CI 2.80 to 41.83). 7/12 (58%) NHLs were diffuse large B cell lymphomas. CONCLUSION: A 16-fold increased risk for development of NHL was found. CD4+ T lymphocytopenia is an additional strong risk factor for developing lymphoma.

Immunohistochemistry of the B-cell component in lower lip salivary glands of Sjögren's syndrome and healthy subjects.

Serial sections of lower lip salivary gland (LSG) biopsies were examined by immunohistochemistry, using a battery of B- and partly T-related antibodies (CD5, CD20, CD21, CD27, CD38, CD45RO, CD79a, Bcl-2 and Bcl-6) in different groups of subjects: healthy controls and clinically verified smoking or nonsmoking cases of primary Sjögren's syndrome (SS). The purpose was to characterize the B-cell pattern of the lymphocytic foci and of the tiny perivascular infiltrates preceding the development of foci. Hyperplastic tonsil was used as stain control. In normal LSG, widely dispersed CD38+ and CD79a+ as well as some CD5+ cells are a normal constituent, with lack of staining with the other antibodies. In SS/LSG, the lymphocytic foci showed staining with all the antibodies, with variable degrees of overlapping or nonoverlapping. In SS/LSG of nonsmokers, CD20+ B cells make up a prominent part of the fully developed periductal lymphocytic foci, not overlapping with CD45RO. Also, CD20+ B cells did not overlap in the infiltrates with colocalized CD27+/CD38+ cells. CD20+ B cells and CD45RO+ T cells also occur as minute infiltrates perivascularly in areas of no foci in SS/LSG as well as in SS smokers lacking the typical foci. Smokers lack foci, but tiny infiltrates express CD20 as well CD45R0. Our findings suggest that CD20+ B cells and CD45RO+ T cells are early immigrants in the LSG of SS of smokers as well as nonsmokers and that another subgroup of CD27+/CD38+ B cells gradually mix with the first two to form the characteristic foci in SS/LSG. The simultaneous demonstration of CD20+ and CD27+ B cells in SS/LSG may constitute a significant diagnostic tool. Further, the findings suggest that the early immigrating lymphocytes may have been primed at a site remote from the glands before arriving via the blood to the gland tissue.

Late neonatal lupus erythematosus onset in a child born of a mother with primary Sjögren's syndrome.

BACKGROUND: The neonatal lupus syndrome can be present as congenital heart block (CHB) or as neonatal lupus erythematosus (NLE), both seldom passively acquired autoimmune diseases. CHB starts around week 20 of pregnancy and is a lifelong event, whereas NLE is self limiting and usually starts at the 6th week of the child's age-the maximum recorded up to week 20. CASE REPORT: An asymptomatic mother with primary Sjogren's syndrome and anti-SSA/Ro52, anti-SSA/Ro60, and anti-SSB/La autoantibodies is described who, at gestational week 23 during her first pregnancy, was diagnosed as having a male fetus with CHB due to third degree atrioventricular block. The boy from the second pregnancy developed skin eruptions which clinically and by biopsy were compatible with NLE at week 20+1 post partum. CONCLUSIONS: Our case of NLE, starting at week 20+1 of age, seems to be the latest reported clinical case of NLE. Development of CHB and NLE in two consecutive boy pregnancies is unusual.

Enhanced DNA-dependent protein kinase activity in Sjögren's syndrome B cells.

OBJECTIVE: To examine the stress response, including the role of DNA-dependent protein kinase (DNA-PK), in B cells from Sjögren's syndrome (SS) patients. METHODS: B-cell lines were exposed to gamma radiation and then postincubated to allow inducible stress functions to develop. The magnitude of the DNA damage response was monitored with respect to DNA-PK phosphorylation of a p53 peptide, defence protein levels (Ku, DNA-PK catalytic subunit, ATM, p21 and p53) and flow cytometric determination of cell cycle phases and apoptosis. RESULTS: B cells from SS patients, compared with healthy controls, displayed enhancement of two stress functions in undamaged cells: DNA-PK kinase activity and apoptosis. In addition, SS showed enhanced cell cycle arrest in gamma-irradiated cells. CONCLUSIONS: Strong kinase activity of DNA-PK, functioning not only in a DNA damage response but also in immunoglobulin gene rearrangement, may be an important component of the heightened stress response displayed by SS cells. In combination with recent reports, our data indicate that constitutional hyper-reactivity to danger signals is a basic pathogenetic factor in SS.

Fibrosis regression induced by intravenous gammaglobulin treatment.

OBJECTIVES: To review case histories of patients in whom fibrosis played a significant role in the pathogenesis of their disease, and to determine whether intravenous gammaglobulin (IVIg) contributed to the regression of their fibrotic condition. METHODS: Eight patients with excess fibrotic reaction in the course of diverse diseases were analysed; a tendency that reverted with different IVIg treatment options. Myelofibrosis was predominant in three patients (a patient with a myeloproliferative syndrome, one with systemic lupus erythematosus, and one with Sjögren's syndrome). Three patients had scleroderma as their main feature, one patient had hepatitis C cirrhosis, and one had idiopathic thrombocytopenic purpura. RESULTS: Fibrotic excess was reduced in all the patients by IVIg treatment. In five patients the disease as a whole benefited from the infusion of immunoglobulins. CONCLUSION: IVIg may enhance resorption of fibrosis and promote healing in patients with fibrotic associated disorders.

Enhanced DNA damage-induced p53 peptide phosphorylation and cell-cycle arrest in Sjögren's syndrome cells.

BACKGROUND: Cells from primary Sjögren's syndrome (SS) patients have been reported to show alterations in DNA repair and p53 expression. The DNA-dependent protein kinase (DNA-PK) autoantigen may be involved in both of these alterations in relation to cellular DNA damage responses. We conducted this study of cell-cycle kinetics and p53 to find additional evidence for an abnormal stress response role in the pathogenesis of SS. DESIGN: DNA-dependent protein kinase activity, p53 peptide phosphorylation and p53 protein levels were determined in gamma-irradiated long-term T lymphocyte cultures. Cell-cycle progression of peripheral blood mononuclear cells was analysed with flow cytometry. RESULTS: No significant differences in the DNA-PK activities or p53 protein levels appeared between the SS patients and the healthy individuals. However, patients with the SS hallmark Ro/SS-A and La/SS-B autoantibodies showed enhancement of both p53 peptide phosphorylation (P = 0.036) and G1 cell-cycle arrest (P = 0.015) in response to gamma radiation. CONCLUSIONS: Sjögren's syndrome cells express an enhanced G1 checkpoint function which may be mediated partly by p53 phosphorylation, suggesting that an abnormal stress response in SS is of relevance for the development of this autoimmune disease.

Ku protein and DNA strand breaks in lip glands of normal and primary Sjögren's syndrome subjects: lack of correlation with apoptosis.

UNLABELLED: The aim was to examine tissue expression of Ku protein in lower lip salivary gland (LSG) biopsies from cases of primary Sjögren's syndrome (SS) and from normal subjects. METHODS: immunohistochemistry was used with antibodies to Ku70/86 and also Ki67, PCNA and p53. In addition, the Klenow method was applied in order to detect evidence of apoptosis. Sections of hyperplastic tonsil served as additional controls. RESULTS: in normal controls, LSG acinar cells stained negatively whereas LSG excretory duct cell nuclei stained positively with Ku and Klenow and occasionally with PCNA but negatively with Ki67 and p53. In LSG focal sialadenitis of SS cases, some lymphocytic cells showed staining with Ku, Ki67, PCNA, Klenow and p53. In addition to duct cell Ku and Klenow as well as PCNA staining which was not much different from normals, a few ductal epithelial and also mononuclear cells stained with p53. In focal sialadenitis, some acinar cells showed staining with PCNA as well as with Klenow. CONCLUSIONS: our findings in LSG biopsies of SS cases added little to an increased understanding about the pathogenetic mechanisms in the development of focal sialadenitis in SS. However, in normal LSG, ductal epithelial but not acinar cells seem to express a constitutively specific Ku protein and Klenow profile, suggestive of DNA strand breaks but not clearly associated with ongoing apoptotic events. It may reflect an enhanced stress response, which may be pathogenetically important in the early events of focal sialadenitis development in primary Sjögren's syndrome.

New criteria for diagnosing Sjögren's syndrome: a step forward?--or...

Primary Sjögren's syndrome seems to be the most common of the chronic systemic inflammatory connective tissue diseases, according to epidemiological investigations. Basic and clinical research, including treatment within this group, is increasing while simultaneously there is increasing confusion and uncertainty about the classification criteria for Sjögren's syndrome. Within the last three decades nine different classification criteria sets have been introduced including the recent US-European classification criteria set. The diagnostic criteria used in daily practice seem to differ even more and many forget that the function of both the lachrymal glands and the salivary glands should be diminished. Consequently many rheumatologists prefer to diagnose patients according to classification criteria. The advantages and disadvantages of the various classification criteria for primary Sjögren's syndrome are dealt with but it is stressed that the majority of these will exclude former/present smokers (from the diagnoses)--more than half of the population!

Sympathetic dysfunction in patients with primary Sjögren's syndrome.

OBJECTIVE: To investigate autonomic nervous system function in patients with primary Sjögren's syndrome (SS) and relate the findings to clinical variables. METHODS: Autonomic nervous system function was determined in 30 patients with primary SS using the finger skin blood flow test [vasoconstrictory (VAC) index], deep-breathing test [expiration/inspiration (E/I) ratio], and the tilt table (orthostatic) test [acceleration index (AI), brake index (BI), and orthostatic blood pressure]. The results were compared with age matched control materials (finger skin blood flow test, n = 80, and deep-breathing and tilt table tests, n = 56). RESULTS: The VAC index was found to be significantly increased and the E/I ratio significantly decreased in patients compared to controls, indicating both a sympathetic and a parasympathetic dysfunction. Further, the patients, especially the anti-SSA and anti-SSB antibody seropositives, were found to have an abnormal blood pressure reaction to tilt compared to controls. No correlations were found between autonomic nerve function variables measured and the clinical ophthalmologic or the oral tests, performed at the time of diagnosis. CONCLUSION: Patients with primary SS show signs of both sympathetic and parasympathetic dysfunction. Further, immunological mechanisms seem to influence blood pressure in patients with primary SS.

Primary Sjögren's syndrome--treatment of fetal incomplete atrioventricular block with dexamethasone.

Pregnancies in women with autoantibodies against Ro/SSA and/or La/SSB may be associated with permanent and treatment resistant fetal atrioventricular (AV) block. We describe a patient with primary S ogren's syndrome and anti-Ro (60 kDa and 52 kDa) and anti-La autoantibodies, in whom fetal bradycardia with second-degree AV block was detected at 19 + 0 weeks of gestation. Maternal treatment with dexamethasone (4 mg/day po) was started 2 days later. The baby's heart rate improved gradually, returning to normal after about 6 weeks of treatment. Our case illustrates the importance of close monitoring of the fetal heart rate in risk-pregnancies from about week 16 of gestation and initiation of dexamethasone treatment without delay when a block is detected.

Seroprevalence of Helicobacter pylori in primary Sjögren's syndrome.

OBJECTIVE: To study the seroprevalence of Helicobacter pylori (H. pylori) infection in patients with primary Sjögren's syndrome (SS), fulfilling the 1993 European classification criteria compared with three different control groups. METHODS: Serological tests investigating the presence of antibodies against H. pylori were performed by Enzyme Immuno Assay (EIA) and confirmed by immunoblot (IB). The samples were tested for antibodies against cytotoxin-associated-protein A (CagA). The three control groups included were: one simultaneously collected age-matched group of orthopaedic outpatients without rheumatological disease, a random primary care patient sample from the same geographic region and a group of age-matched blood donors. RESULTS: 45% of the SS patients (n = 164) were EIA-positive for H. pylori and 30% were positive in the confirming IB assay. 23% had antibodies to the CagA protein. We found a clear and statistically significant increase in seroprevalence with increasing age. These estimates were lower compared to the control group of orthopaedic patients but similar to those in the other two control groups, thus showing the importance of multiple control groups in case control studies. In the group of SS patients there were no significant associations between a positive EIA, IB or CagA for H. pylori and the presence of abnormal serum levels of autoantibodies (ANA, anti-SSA, anti-SSB, rheumatoid factor (RF)) or an abnormal lip biopsy. CONCLUSION: Swedish patients with primary SS do not have higher H. pylori seroprevalence rates than controls. Neither was H. pylori seropositivity associated with the presence of immunological markers of SS such as circulating autoantibodies or a lip biopsy with abnormal focus score.

Effects of mouthrinses with linseed extract Salinum without/with chlorhexidine on oral conditions in patients with Sjögren's syndrome. A double-blind crossover investigation.

OBJECTIVES: To study the effect of mouthrinses with salivary replacement substances on oral conditions in patients with primary Sjögren's syndrome. DESIGN: Cross-over, double-blind study. SETTING: Facilities at the Centre for Oral Health Sciences, Malmö University and at Malmö University Hospital, Malmö, Sweden. SUBJECTS: Twenty-two patients with Sjogren's syndrome. INTERVENTION: Linseed extract Salinum alone (Sal) or with addition of chlorhexidine (Sal/Chx) was used for mouthrinsing during 3-week periods of rinsings separated by a 3-week "wash-out" period. MEASUREMENTS: Recordings of percentages of sites with dental plaque and bleeding on probing, mirror friction test and microbiological analyses. Questionnaire on oral symptoms due to reduced salivation. RESULTS: Dental plaque and bleeding on probing were reduced after Sal and after Sal/Chx. Friction was reduced after both treatments. No significant differences for counts of studied microbial groups were seen after Sal but the total anaerobically cultured microorganisms and of mutans streptococci fell after Sal/Chx (p<0.05 and p<0.001). Symptoms of oral dryness improved following Sal and Sal/Chx (p<0.05 and p<0.001 respectively). Speaking problems and burning mouth symptoms improved after use of Sal (p<0.05). CONCLUSIONS: Positive effects on symptoms in patients with Sjögren's syndrome were seen after use of Salinum without or with chlorhexidine.

Mast cell derangement in salivary glands in patients with Sjögren's syndrome.

Mast cells (MCs) have been implicated in many immune-inflammatory disorders. Deranged mast cell distribution and function may contribute to the local pathomechanisms in the labial salivary glands (LSG) in Sjogren's syndrome (SS). Evidence for MC presence, localization, frequency, subtype, and degree of activation was sought by using reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC)/image analysis, transmission electron microscopy, Western blotting, spectrophotometric activity assay, and radioimmunoassay. The overall expression (densitometric units) of MC tryptase mRNA (1483 +/- 228 vs 1044 +/- 308) did not differ between SS and control LSGs. However, IHC disclosed an uneven distribution of MCs in SS with an absence in lymphocyte foci and increased numbers (cells/mm2 77 +/- 7 vs 38 +/- 4, P < 0.01) elsewhere. Absence of MCs in the lymphocyte foci was not a fixation artefact and was not explained by the presence of "phantom" MCs in these areas. In both SS and controls, 80% of all MCs were chymase containing, but the typical lattices/gratings characteristic for connective tissue MCs (CTMCs) were not found. Instead, MC granules had mostly a homogeneous, finely granular substructure characteristic of "new" granules subjected to a continuous, low-grade release. 32 kDa MC tryptase was found in saliva and its activity/concentration was comparable to that found in controls. However, tryptase output was low in SS (1.30 +/- 0.30 microg/min vs 3.49 +/- 0.66 microg/min, P < 0.001). Normal LSGs contain mostly CTMCs, in close contact with various resident and immigrant cells, characterized by a low-grade release of MC mediators. In SS this normal pattern is disturbed so that MCs are absent in lymphocyte foci (but increased elsewhere in the glands). The net salivary output of MC mediators is low in SS. This derangement of MCs may contribute to the pathogenesis of SS via multiple mechanisms.