Population-based study of patients with primary Sjögren's syndrome and lymphoma: lymphoma subtypes, clinical characteristics, and gender differences.

Objective: To examine lymphoma subtypes, clinical characteristics, and gender differences in patients with primary Sjögren's syndrome (pSS) and lymphoma in a population-based setting.Method: Patients with Sjögren's syndrome and lymphoma diagnoses were identified by linkage of the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007. Clinical data were collected from medical records and lymphoma tissues were re-examined. The lymphoma subtype distribution was compared with the Swedish Lymphoma Register.Results: We identified 105 pSS patients with lymphoma. Diffuse large B-cell lymphoma (DLBCL) (32%) and marginal zone lymphoma [MZL including mucosa-associated lymphoid tissue (MALT) lymphoma] (31%) were the most common lymphoma subtypes. The proportion of DLBCL was not increased compared to the general population reference (32%, p = 1), in contrast to MZL (general population 5%, p < 0.0001). Compared to DLBCL, MALT lymphoma was diagnosed at a younger age (55 vs 67 years, p = 0.0001), and earlier after patient-reported sicca onset (7 vs 18 years, p = 0.0001) and pSS diagnosis (2 vs 9 years, p = 0.0005). Sixteen of the pSS-lymphoma cases were men (15%), twice the proportion in general pSS populations. Compared to women, men had a shorter median time from pSS diagnosis to lymphoma diagnosis (1 vs 8 years, p = 0.0003) and more often had lymphoma in the salivary glands (56% vs 29%, p = 0.04).Conclusion: DLBCL and MZL are common in pSS patients, but only MZL/MALT lymphoma occurs at an increased relative frequency in pSS compared to the general population. The study supports increased awareness of signs of lymphoma in men in the first years after pSS diagnosis.

Concomitant Ro/SSA and La/SSB antibodies are biomarkers for the risk of venous thromboembolism and cerebral infarction in primary Sjögren's syndrome.

BACKGROUND: To assess the risk of incident cardiovascular disease in patients with primary Sjögren's syndrome, overall and stratified by Ro/SSA and La/SSB autoantibody status. METHODS: A cohort of patients with primary Sjögren's syndrome in Sweden (n = 960) and matched controls from the general population (n = 9035) were included, and data extracted from the National Patient Register to identify events of myocardial infarction, cerebral infarction and venous thromboembolism. Hazard ratios were estimated using cox proportional hazard regressions. RESULTS: During a median follow-up of 9.5 years, the overall hazard ratio (HR) was 1.6 (95% CI 1.2-2.1) for myocardial infarction, 1.2 (95% CI 0.9-1.7) for cerebral infarction and 2.1 (95% CI 1.6-2.9) for venous thromboembolism. Patients positive for both Ro/SSA and La/SSB autoantibodies had a substantially higher risk of cerebral infarction (HR 1.7, 95% CI 1.0-2.9) and venous thromboembolism (HR 3.1, 95% CI 1.9-4.8) than the general population. These risks were not significantly increased in Ro/SSA- and La/SSB-negative patients. Among autoantibody-positive patients, the highest HR of cerebral infarction was seen after ≥10 years disease duration (HR 2.8, 95% CI 1.4-5.4), while the HR for venous thromboembolism was highest 0-5 years after disease diagnosis (HR 4.7, 95% CI 2.3-9.3) and remained high throughout disease duration. CONCLUSIONS: Primary Sjögren's syndrome is associated with a markedly increased risk of cardiovascular disease and the presence of Ro/SSA and La/SSB autoantibodies identify the subgroup of patients carrying the highest risk. These findings suggest that monitoring and prevention of cardiovascular disease in this patient group should be considered.

Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome.

OBJECTIVE: In the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome (pSS), pre-existing lymphoma is not an exclusion criterion for pSS diagnosis, as in earlier criteria. We aimed to explore whether there are differences between pSS patients with and without pre-existing lymphoma at pSS diagnosis. METHOD: Patients with ICD-7-10 codes for Sjögren's syndrome (SS) and a diagnosis of malignant lymphoma before or after SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n = 224). Clinical data were collected from medical records. Lymphoma diagnoses were evaluated by tissue review. Characteristics of pSS patients with and without pre-existing lymphoma were compared. RESULTS: We identified 107 patients with pSS as the reason for an SS diagnosis code and a verified lymphoma. Of these, 18 (17%) had a pre-existing lymphoma at pSS diagnosis, defined as lymphoma diagnosed before or within 6 months of pSS diagnosis. Male gender (39% vs 10%, p = 0.006), enlarged lymph nodes during the pSS disease (61% vs 27%, p = 0.01), mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs 22%, p = 0.02), and salivary gland lymphoma (61% vs 26%, p = 0.006) were more common in patients with a pre-existing lymphoma at pSS diagnosis. Other pSS characteristics were similar. CONCLUSION: In a substantial proportion of patients, particularly in men, pSS remains undiagnosed until after lymphoma diagnosis. The study highlights the importance of pSS investigation in patients with lymphoma, especially MALT lymphoma, in the salivary glands.

Multiplex cytokine analyses in patients with rheumatoid arthritis require use of agents blocking heterophilic antibody activity.

OBJECTIVES: Heterophilic antibodies, such as rheumatoid factor (RF), are known to interfere with enzyme-linked immunosorbent assays (ELISAs). Treatment of rheumatoid arthritis (RA) with tumour necrosis factor (TNF)-α blockers is well established. The aims of this study were to develop a protocol for blocking the interaction of present heterophilic antibodies and to validate this procedure by evaluating the effect on correlations of cytokine levels to clinical response in RA patients treated with adalimumab. METHOD: Fourteen patients with active RA were evaluated at baseline and 3 months after starting adalimumab treatment. Cytokines were analysed with a commercial 12-plex bead ELISA. To block interference by RF, a commercial blocker (HeteroBlock) was used. To determine the optimal concentration of HeteroBlock, patient sera were analysed with different concentrations of HeteroBlock. Subsequently, baseline and follow-up sera from the 14 patients were analysed and correlated with clinical outcome. RESULTS: Measured cytokine levels were reduced in the majority of samples when adding the blocker. The optimal concentration of HeteroBlock was 1600 µg/mL of serum. Sera with high RF levels were more prone to produce false positive values, although some RF-negative sera also demonstrated evidence of interference. HeteroBlock did not interfere with the analysis. In RA patients treated with adalimumab, changes in interleukin (IL)-6 levels between baseline and follow-up correlated with changes in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in sera with added HeteroBlock. CONCLUSIONS: When analysing sera from patients with RA with multiplex bead ELISA, the assay should be evaluated for interference by heterophilic antibodies, and if present corrected with, for example, HeteroBlock.

The forced oscillation technique is a sensitive method for detecting obstructive airway disease in patients with primary Sjögren's syndrome.

OBJECTIVES: To study signs of obstructive airway disease (OAD) in patients with primary Sjögren's syndrome (pSS) using the forced oscillation technique (FOT). METHOD: Thirty-seven female pSS patients (median age 64, range 38-77 years) without previous physician-diagnosed OAD, participating in a longitudinal follow-up study of pulmonary function, and 74 female population-based controls (median age 64, range 47-77 years), also without physician-diagnosed OAD, and matched with regard to age, height, weight, and tobacco consumption, were included in the study. The pSS patients and controls were studied by the FOT, evaluating resistance and reactance of the respiratory system. RESULTS: pSS patients had significantly increased resistances at 5-25 Hz, decreased reactance at 10-35 Hz, and an increased resonant frequency (Fres) in comparison with controls. Resistance was correlated negatively and reactance positively to the vital capacity (VC), the forced expiratory volume in 1 s (FEV1), and the diffusing capacity for carbon monoxide (DLCO). Compared with controls, pSS patients with (n = 14) and without OAD (n = 21), as determined by spirometry, had significantly increased resistances at 5-25 Hz and decreased reactances at 10-35 Hz. In never-smoking subjects, identical FOT signs were found. CONCLUSIONS: pSS patients showed FOT signs of obstruction affecting both peripheral and central airways. pSS patients without spirometric signs of OAD and never-smoking pSS patients also showed clear FOT signs of obstruction. FOT therefore seems to be a sensitive method for detecting obstruction in pSS patients.

No association of primary Sjögren's syndrome with Fcγ receptor gene variants.

The genetic background of primary Sjögren's syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcγ receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fcγ receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N=527) and controls (N=528) were genotyped for the Fcγ receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fcγ receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS.

Epstein-Barr virus early antigen diffuse (EBV-EA/D)-directed immunoglobulin A antibodies in systemic lupus erythematosus patients.

OBJECTIVE: We sought to determine whether the serological response towards lytic cycle antigens of Epstein-Barr virus (EBV) is altered in systemic lupus erythematosus (SLE) patients. METHOD: We used enzyme-linked immunosorbent assay (ELISA) to investigate the prevalence of EBV early antigen diffuse (EBV-EA/D) antibodies in sera from 60 patients with SLE, 40 with scleroderma (SSc), 20 with primary Sjögren's syndrome (pSS), 20 with rheumatoid arthritis (RA), 20 healthy controls, and also subjects with various circulating autoantibodies. Samples from patients were obtained from clinics specialized within the diseases in Denmark and Sweden and samples from healthy controls were obtained from volunteers. RESULTS: A significant elevated titre of immunoglobulin (Ig)A, IgG, and IgM EBV-EA/D antibodies was found in SLE patients compared to healthy controls, a finding not explained by immunosuppressive treatment or disease activity. The largest difference was observed for IgA EBV-EA/D antibodies (p = 0.0013) with a seropositive rate of 58% in SLE patients and 0% in healthy controls. RA and SSc patients and individuals seropositive for anti-Scl-70 were additionally found to have elevated titres of IgA EBV-EA/D antibodies (40%, p = 0.014; 60%, p = 0.015; and 38.5%, p = 0.045, respectively). However, the titres were generally lower than in SLE patients. CONCLUSION: Our findings support an association between EBV and SLE. The elevated titre of EBV-EA/D-directed IgA antibodies found in SLE patients could suggest reactivation of EBV in epithelial cells or reinfection of epithelial cells after reactivation in B cells, indicating lack of control of the latent infection.

A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome.

We performed a candidate gene association study in 540 patients with primary Sjögren's Syndrome (SS) from Sweden (n=344) and Norway (n=196) and 532 controls (n=319 Swedish, n=213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P=9.9 × 10(-5), OR 1.68, the family with sequence similarity 167 member A-B-lymphoid tyrosine kinase (FAM167A-BLK) locus, P=4.7 × 10(-4), OR 1.37 and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene, P=7.4 × 10(-4), OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS.

Complement inhibitor C4b-binding protein in primary Sjögren's syndrome and its association with other disease markers.

A subgroup of patients suffering from primary Sjögren's syndrome (pSS) display unexplained low levels of complement components C3 and/or C4 which is associated with increased risk of non-Hodgkin's lymphoma. C4b-binding protein (C4BP) is a major fluid-phase complement inhibitor which can influence C4 and C3 levels. Therefore we analysed C4BP levels in the sera of patients with pSS to better understand the disturbances in complement in pSS. Associations with other disease markers were also investigated to define a possible role of C4BP as marker of high-risk disease course. Plasma levels of C4BP were analysed in pSS patients (n=86) and in controls (n=68) by ELISA. C4BP levels from 49 patients were correlated to disease activity markers and autoantibody profiles. We found that total C4BP plasma levels were significantly higher in pSS patients compared with controls. C4BP levels correlated to the acute phase response, to levels of C4 and C3 as well as to the CD4+/CD8+ T-cell ratio. C4BP levels were inversely related to IgG levels, extent of autoantibody production and global disease activity. C3dg levels, a marker of complement activation, displayed a negative correlation to C4 levels but interestingly not to C4BP levels. In conclusion, C4BP levels are increased in patients suffering from pSS proportional to their acute phase response. However, in the most active cases, with the most widespread autoantibody production, C4BP levels were decreased in parallel with levels of C3 and C4 and CD4+ T cells, suggesting that disturbed complement regulation may contribute to pathogenicity in pSS.

Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome.

Primary Sjögren's syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) >1.4 and P-values <0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P=2.5 x 10(-9). The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.

Pathogenesis of autoimmune diseases: antibodies against transglutaminase, peptidylarginine deiminase and protein-bound citrulline in primary Sjögren's syndrome, multiple sclerosis and Alzheimer's disease.

Coeliac disease (CD) is becoming a model for understanding the pathogenesis of autoimmune disorders. In CD, antibodies against transglutaminase 2 (TG2) and specific residues of gliadins have been identified. A similar situation is seen in rheumatoid arthritis (RA) with both anti-citrullinated protein antibodies (ACPA) and auto-antibodies against the citrullinating enzyme, peptidylarginine deiminase (PAD). Previously, we have suggested that a complex between an enzyme and its modified substrate constitutes the neoantigen in autoimmune diseases. Our hypothesis is challenged by findings in patients of primary Sjögren's syndrome (pSS) who do not express ACPA, but who have been reported to carry anti-PAD. The aims of our investigation were to reproduce the study claiming the presence of anti-PAD in pSS and screen for ACPA and antibodies against TG2 and PAD in pSS (n = 78), multiple sclerosis (MS) (n = 85) and Alzheimer's disease (AD) (n = 79) using ELISA. With blood donors (n = 100) as controls, no increased occurrence of autoantibodies was found among the patient groups tested. Contrary to what has been published previously, patients with pSS do not express anti-PAD. The hypothesis of a complex between an enzyme and its modified substrate constituting the neoantigen in autoimmune diseases is still valid. The prevalence of anti-PAD, anti-TG2 and ACPA is comparatively restricted. PAD and TG2 do not seem to be involved directly in autoimmune mechanisms in pSS, MS or AD.

Effects of exercise on aerobic capacity and fatigue in women with primary Sjogren's syndrome.

OBJECTIVE: To investigate the effect of a moderate to high intensive exercise program on two primary outcomes (aerobic capacity, fatigue), and three secondary outcomes [anxiety, depression and health-related quality of life (HRQoL)] in women with primary Sjögren's syndrome (primary SS). METHODS: Twenty-one women with primary SS were ranked according to degree of fatigue and allocated to an exercise group (TG; n = 11) or a control group (CG; n = 10). The exercise method was Nordic walking for 45 min three times a week for 12 weeks. Outcome measures assessed at baseline and after 12 weeks were aerobic capacity, fatigue, ratings of perceived exertion (RPE), anxiety, depression and HRQoL. RESULTS: Nine women in the TG and 10 women in the CG completed the study. Analysis showed significant differences between the groups regarding aerobic capacity (P = 0.03), fatigue (P = 0.03), RPE (P = 0.03), and depression (P = 0.02) with the better values for the TG. There were no differences in anxiety or HRQoL. CONCLUSION: Our findings support the use of appropriate aerobic exercise in the treatment of primary SS.

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.

Assessment of fatigue in primary Sjögren's syndrome: the Swedish version of the Profile of Fatigue.

OBJECTIVE: To translate the disease-specific Profile of Fatigue (ProF) into Swedish and to evaluate the reliability and validity of the Swedish version. METHODS: Forward and back translations were performed. Seventy patients with primary Sjögren's syndrome (PSS), 48 control persons, and two rheumatologists participated. Test-retest reliability, internal consistency, content, construct and discriminant validity were investigated. RESULTS: The translation was accepted without modifications. The test-retest reliability varied between moderate and good (weighted Kappa = 0.51-0.63). Internal consistency was high (Cronbach's alpha = 0.97). Construct validity was proved by significant correlations of the questionnaire items with the Visual Analogue Scale (VAS) for fatigue (r(s) = 0.55-0.70), and the Physical Function (PF) (r(s) = -0.20 to -0.41) and Vitality (VT) scales (r(s) = -0.60 to -0.77) of the MOS 36-Item Short-Form Health Survey (SF-36). Content validity was mainly judged as good. A significant difference between the scorings of the patients and the scorings of the control group was seen (mean difference 1.6, p<0.005). CONCLUSION: The Swedish version of the ProF is a relatively reliable and valid instrument for the measurement of fatigue in patients with PSS.

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.

Lower frequency of focal lip sialadenitis (focus score) in smoking patients. Can tobacco diminish the salivary gland involvement as judged by histological examination and anti-SSA/Ro and anti-SSB/La antibodies in Sjögren's syndrome?

OBJECTIVES: Prospectively collected computer database information was previously assessed on a cohort of 300 patients who fulfilled the Copenhagen classification criteria for primary Sjögren's syndrome. Analysis of the clinical data showed that patients who smoked had a decreased lower lip salivary gland focus score (p<0.05). The aim of this original report is to describe the tobacco habits in patients with primary Sjögren's syndrome or stomatitis sicca only and to determine if there is a correlation between smoking habits and focus score in lower lip biopsies as well as ciculating autoantibodies and IgG. METHODS: All living patients with primary Sjögren's syndrome or stomatitis sicca only, who were still in contact with the Sjögren's Syndrome Research Centre were asked to fill in a detailed questionnaire concerning present and past smoking habits, which was compared with smoking habits in a sex and age matched control group (n=3700) from the general population. In addition, the patients previous lower lip biopsies were blindly re-evaluated and divided by the presence of focus score (focus score = number of lymphocyte foci per 4 mm(2) glandular tissue) into those being normal (focus score 1). Furthermore the cohort was divided into three groups; 10-45, 46-60 and >/= 61 years of age. Finally the focus score was related to the smoking habits. Seroimmunological (ANA; anti-SSA/Ro antibodies; anti-SSB/La antibodies; IgM-RF and IgG) samples were analysed routinely. RESULTS: The questionnaire was answered by 98% (n=355) of the cohort and the percentage of current smokers, former smokers and historical non-smokers at the time of lower lip biopsy was not statistically different from that of the control group. Cigarette smoking at the time of lower lip biopsy is associated with lower risk of abnormal focus score (p<0.001; odds ratio 0.29, 95%CI 0.16 to 0.50). The odds ratio for having focal sialadenitis (focus score > 1) compared with having a non-focal sialadenitis or normal biopsy (focus score /= 61: odds ratio 0.36, 95%CI 0.10 to 1.43) although there was only statistical significance in the two younger age groups. Moreover, among current smokers at the time of the lower lip biopsy there was a decreasing odds ratio for an abnormal lip focus score with increasing number of cigarettes smoked per week (p trend 0.00). In the group of former smokers, which included patients that had stopped smoking up to 30 years ago, the results were in between those of the smokers and the historical non-smokers (odds ratio 0.57, 95%CI 0.34 to 0.97, compared with never smokers). Present or past smoking did not correlate with the function of the salivary glands as judged by unstimulated whole sialometry, stimulated whole sialometry or salivary gland scintigraphy. Among former smokers, the median time lapse between the first symptom of primary Sjögren's syndrome and the performance of the lower lip biopsy was approximately half as long as the median time lapse between smoking cessation and biopsy (8 versus 15 years). Hence, symptoms of Sjögren's syndrome are unlikely to have had a significant influence on smoking habits at the time of the biopsy. Among the seroimmunological results only anti-SSA/Ro and anti-SSB/La antibodies reached statistical significance in a manner similar to the way smoking influenced the focus score in lower lip biopsies. On the other hand the level of significance was consistently more pronounced for the influence of smoking on the focus score than for the influence on anti-SSA/Ro and anti-SSB/La autoantibodies. CONCLUSION: This is believed to be the first report showing that cigarette smoking is negatively associated with focal sialadenitis-focus score >1-in lower lip biopsy in patients with primary Sjögren's syndrome. Furthermore, tobacco seems to decrea

AV-block III in a patient with sarcoidosis mimicking Sjögren's syndrome.

A 55-year old woman with a diagnosis of primary Sjögren's Syndrome suddenly developed AV-block III. A diagnostic procedure finally revealed sarcoidosis with multiorgan involvement.