Rheumatoid Arthritis: Theander E

Theander E, Jacobsson LT. · Department of Rheumatology, Malmö University Hospital, Lund University, 20502 Malmö, Sweden. · Rheum Dis Clin North Am. · Pubmed #18984413 No free full text.

Abstract: Sjögren's syndrome is a systemic autoimmune disease that frequently presents concomitantly with other systemic connective tissue or organ-specific autoimmune diseases. This association is well described for systemic lupus erythematosus and rheumatoid arthritis. The presence of Sjögren's syndrome influences the expression of the other autoimmune disease to some degree, for instance by increasing fatigue and lymphoma risk. The etiopathogenic mechanism for the simultaneous or sequential development of multiple autoimmune diseases in one individual is not well understood. Common genetic backgrounds and additional immunogenetic, environmental, or hormonal factors may be responsible for the formation of subsets of autoimmune disease clustering. While the most currently accepted classification criteria (American European Consensus Criteria) designate these cases as secondary Sjögrens syndrome, the terms overlapping or associated Sjögren's syndrome are frequently used in the literature to describe these cases.

Theander E, Horrobin DF, Jacobsson LT, Manthorpe R. · Sjögren's Syndrome Research Centre, Department of Rheumatology, Malmö University Hospital, Sweden. · Scand J Rheumatol. · Pubmed #12109650 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy of the essential omega-6 fatty acid Gammalinolenic acid (GLA) on fatigue associated with primary Sjögren's syndrome. METHODS: Ninety patients with primary Sjögren's syndrome (with or without signs of autoimmunity) entered a 6-month double blind placebo-controlled randomised trial with high dose GLA (extracted from Evening Primrose Oil) or corn oil. The primary outcome parameter was fatigue; secondary endpoints were eye dryness, mouth dryness, muscle and joint pain. RESULTS: No statistically significant improvement was found in fatigue assessed by Visual Analogue Scale (VAS) or in the time needed for sleeping/resting during a 24-hour period. No differences were found between the treatment and placebo group. The same applies to the secondary endpoints: no differences in VAS for eye and mouth dryness or pain, no significant changes in Schirmer-1-test, van Bijsterveld score, unstimulated whole sialometry (UWS), or use of artificial tears or analgesics. Only mild side effects were observed. CONCLUSION: According to our study results GLA (Evening Primrose oil) treatment for fatigue in primary Sjögren's syndrome is ineffective.

Zadura AF, Theander E, Blom AM, Trouw LA. · Department of Laboratory Medicine, Lund University, Lund, Sweden. · Scand J Immunol. · Pubmed #19284503 No free full text.

Abstract: 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.

Nordmark G, Kristjansdottir G, Theander E, Eriksson P, Brun JG, Wang C, Padyukov L, Truedsson L, Alm G, Eloranta ML, Jonsson R, Rönnblom L, Syvänen AC. · Section of Rheumatology, Uppsala University, Uppsala, Sweden. · Genes Immun. · Pubmed #19092842 No free full text.

Abstract: 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.

Bodil Roth E, Theander E, Londos E, Sandberg-Wollheim M, Larsson A, Sjöberg K, Stenberg P. · Hospital Pharmacy, Malmö University Hospital, Malmö, Sweden. · Scand J Immunol. · Pubmed #18476880 No free full text.

Abstract: 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.

Lindqvist UR, Alenius GM, Husmark T, Theander E, Holmström G, Larsson PT, Anonymous00344. · Department of Medical Sciences, Rheumatology, University Hospital, Uppsala, Sweden. · J Rheumatol. · Pubmed #18278834 No free full text.

Abstract: OBJECTIVE :Patients with symptoms and signs compatible with psoriatic arthritis (PsA), with or without psoriasis, have been documented in the Swedish Early Psoriatic Arthritis (SwePsA) register. Our aim was to find markers for disease progression and to evaluate treatments for PsA using these data. METHODS: Patients referred to rheumatology outpatient clinics within 2 years of onset were assessed on inclusion and at followup 2 years later. Data collection was performed according to the program for SwePsA, and classification was as described by Moll and Wright and the ClASsification Criteria for Psoriatic ARthritis (CASPAR). Remission was recorded if the patient had no tender or swollen joints and if erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were within the reference range. Patients with early rheumatoid arthritis (RA) recruited from the Swedish Early Rheumatoid Arthritis Register (Ramona) provided comparison data. RESULTS: One hundred thirty-five patients with PsA according to CASPAR were assessed; 44% were classified as having mono/oligoarthritis and 47% as polyarthritis. Two patients (1%) were in remission initially, and 23 (17%) at followup. Patients with polyarticular disease had the highest inflammatory activity, measured by swollen and tender joint counts, ESR, Health Assessment Questionnaire, and self-assessment by visual analog scale of pain and global disease activity. Dactylitis was associated with radiological findings. Compared with RA patients, they had significantly lower CRP, ESR, and number of swollen joints (p = 0.0003, p = 0.0026, p = 0.0380, respectively) at inclusion, but equal numbers of tender joints and self-assessment of pain and disease activity. CONCLUSION: About half the patients had polyarthritis and the other half had mono/oligoarthritis at followup after 2 years. Patients with polyarthritis had the highest inflammatory activity. Apart from ESR, CRP, and swollen joint count, there were no significant differences in activity between RA and polyarticular PsA.

Strömbeck BE, Theander E, Jacobsson LT. · Department of Rheumatology, Malmö University Hospital, SE-205 02 Malmö, Sweden. · Rheumatology (Oxford). · Pubmed #17308315 links to  free full text

Abstract: 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.

Strömbeck B, Theander E, Jacobsson LT. · Department of Rheumatology, Malmö University Hospital, Malmö, Sweden. · Scand J Rheumatol. · Pubmed #16393768 No free full text.

Abstract: 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.

Theander E, Henriksson G, Ljungberg O, Mandl T, Manthorpe R, Jacobsson LT. · Department of Rheumatology, Malmö University Hospital, S-20502 Malmö, Sweden. · Ann Rheum Dis. · Pubmed #16284097 links to  free full text

Abstract: 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.

Theander E, Andersson SI, Manthorpe R, Jacobsson LT. · Department of Rheumatology, Malmö University Hospital, Sweden. · J Rheumatol. · Pubmed #16078325 No free full text.

Abstract: OBJECTIVE: To clarify the spontaneous course of important disease manifestations (a core set of outcome measures) over a period of 5 years in patients with primary Sjögren's syndrome (SS), and to analyze predictors of unfavorable outcome. To test the usefulness of the recently proposed core set of outcome measures. METHODS: A cohort of patients with primary SS according to the American-European consensus criteria (AECC) (n = 58) was followed over a period of 5 years. Measures for subjective and objective disease characteristics, IgG concentrations and health related quality of life were analyzed on 2 occasions and compared. RESULTS: During followup, symptoms of dry eyes, dry mouth, fatigue, and health related quality of life were stable. Regarding objective signs, there was a modest but statistically significant worsening of the van Bijsterveld score. Seropositivity for anti-SSA and low complement levels predicted further decline in the van Bijsterveld score. Floor/ceiling effects in the outcome measures in the core set complicate documentation of further decline, but may allow monitoring of improvement in established primary SS. CONCLUSION: Primary SS, if classified according to the strict AECC criteria, is a bothersome and slowly progressive disease, with fatigue and discomfort developing early. The proposed outcome measures may be suitable for assessing improvement in randomized controlled trials.

Mostafavi B, Akyuz S, Jacobsson ME, Nilsen LV, Theander E, Jacobsson LH. · Department of Rheumatology, Malmö University Hospital, Malmö, Sweden. · J Rheumatol. · Pubmed #15801022 No free full text.

Abstract: OBJECTIVE: To study perinatal characteristics as risk factors for developing primary Sjogren's syndrome (SS). METHODS: This was a case control study with extraction of information from birth records comprising 32 cases with SS (fulfilling the unified American-European classification criteria) and 159 controls. Cases were selected from a patient register of SS cases in Malmö, Sweden. For each case, 5 controls (living in the same catchment area, matched by date of birth, sex, and delivery unit) from the general population were identified. The relative risks of developing SS were assessed as odds ratios (OR). The primary predictor searched for was birth weight. Secondary predictors were breastfeeding during postpartum hospital stay, paternal occupation, placenta weight, gestational length, diseases during pregnancy, maternal age, parity, and history of miscarriage. RESULTS: Significantly increased OR were observed for high birth weight (>/= 4000 vs 3000-3999 g, OR = 3.8 95% confidence interval, CI: 1.3-11.7) and low maternal age (p < 0.05). Low paternal socioeconomic status (OR = 3.2, 95% CI: 1.0-10.5) and being first-born (OR = 2.5 95% CI: 1.0-5.0) tended to be associated with SS. CONCLUSIONS: Our findings suggest that characteristics of the perinatal period may be of etiologic importance in the pathogenesis of SS. Possible mechanisms include modulation of the immune system early in life. It is conceivable that birth weight may be a marker for qualitative and/or quantitative differences in the immune system.

Theander E, Manthorpe R, Jacobsson LT. · Department of Rheumatology, Malmö University Hospital, Lund University, Lund, Sweden. · Arthritis Rheum. · Pubmed #15077310 links to  free full text

Abstract: OBJECTIVE: This study was undertaken to analyze standardized mortality ratios (SMRs) and causes and predictors of death in primary Sjögren's syndrome (SS) diagnosed according to 3 different classification criteria sets (the Copenhagen criteria, the European criteria, and the American-European consensus criteria (AECC). METHODS: A linked registry study using information from the Malmö Primary SS Registry combined with the Swedish Cause-of-Death Registry was performed, and SMRs were calculated. Kaplan-Meier survival curves and log rank tests were used to compare survival probability between subgroups of patients with primary SS. Cox regression analysis was used to study the predictive value of various laboratory findings at the time of diagnosis. RESULTS: Four hundred eighty-four patients with a median followup of 7 years (range 1 month to 17 years 11 months) were included. The SMR for those fulfilling the AECC (n = 265) was 1.17 (95% confidence interval [95% CI] 0.81-1.63). Thirty-four deaths occurred in this group of patients. Excess mortality was found only for lymphoproliferative malignancy (cause-specific SMR 7.89 [95% CI 2.89-17.18]), corresponding to 2.53 excess deaths per 1,000 person-years at risk. In those not fulfilling the AECC (n = 219), 14 deaths occurred, the SMR was 0.71 (95% CI 0.39-1.20), and no excess mortality due to any specific cause was found. Hypocomplementemia, defined as C3 and/or C4 values in the lowest quartile of the SS patients' values at the time of diagnosis, was a significant predictor of death, mainly due to lymphoproliferative malignancy. CONCLUSION: No increased all-cause mortality could be detected for patients with primary SS compared with the general population. When subgroups of primary SS were compared, excess mortality due to lymphoproliferative malignancy was found in patients fulfilling the AECC, the strongest predictor for unfavorable outcome being low C3 and/or C4 levels at the time of diagnosis.

Theander E, Nilsson I, Manthorpe R, Jacobsson LT, Wadström T. · Sjögren's Syndrome Research Centre, Department of Rheumatology, Malmö University Hospital, Sweden. · Clin Exp Rheumatol. · Pubmed #11791633 No free full text.

Abstract: 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.

Theander E, Brucato A, Gudmundsson S, Salomonsson S, Wahren-Herlenius M, Manthorpe R. · Sjögren's Syndrome Research Centre, Department of Rheumatology, University Hospital of Malmö, Lund University, Stockholm, Sweden. · J Rheumatol. · Pubmed #11246681 No free full text.

Abstract: 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.

Theander E, Hansen O, Jacobsson L, Manthorpe R. · Department of Rheumatology University Hospital Malmö, Sweden. · Scand J Rheumatol. · Pubmed #10665745 No free full text.

Abstract: 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.

Manthorpe R, Benoni C, Jacobsson L, Kirtava Z, Larsson A, Liedholm R, Nyhagen C, Tabery H, Theander E. · Sjögren's Syndrome Research Centre, Division of Rheumatology, Department of Internal Medicine, Malmö University Hospital, S-205 02 Malmö, Sweden. · Ann Rheum Dis. · Pubmed #10627428 links to  free full text

Abstract: 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) or abnormal (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 </= 1) was decreased in all three age groups (10-45: odds ratio 0.27, 95%CI 0.11 to 0.71; 46-60: odds ratio 0.22, 95%CI 0. 08 to 0.59; and >/= 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