Smoking, disease characteristics and serum cytokine levels in patients with primary Sjögren’s syndrome

Smoking, disease characteristics and serum cytokine levels in patients with primary Sjögren’s... Smoking affects several disease processes. Epidemiological studies have previously found a negative association between primary Sjögren’s syndrome (pSS) and smoking. The aim of this study was to examine whether markers of disease activ- ity and cytokine expression in pSS patients differ between ever and never smokers. Fifty-one consecutive pSS patients and 33 population controls were included in the study. Clinical and standard laboratory parameters were registered. Serum cytokines (IL-1β, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-18, IL-33, IFN-α, IFN-γ, TNF-α, EGF, BAFF, Fas- ligand, RANTES, TGF-β1) were assessed. A positive lip biopsy was less prevalent among ever smoking patients compared to never smokers (81 vs 100%; p = 0.03). However, except for TNF-α, which was higher in ever smokers, no differences in cytokine levels were found when comparing ever and never smoking pSS patients. Furthermore, no significant differences were found between ever and never smoking patients in the ESSDAI total score, IgG levels, or complement levels. However, IL-6, IL-12, IL-17 and IL-18 were significantly increased in pSS patients compared to controls. In this study, a negative association between ever smoking and positive lip biopsy was found, confirming previous reports. Expected differences in cytokine levels compared to controls were noted, but no major differences were found between ever and never smoking pSS patients. Taking into account the negative association between pSS diagnosis and smoking in epidemiological studies, possible explanations include a local effect of smoking on salivary glands rather than systemic effects by cigarette smoke. Keywords Sjögren’s syndrome · Cytokines · Cigarette smoking · Autoimmune diseases Abbreviations EGF Epidermal growth factor AECG American-European Consensus Group C3 Complement factor 3 BAFF B-cell activating factor C4 Complement factor 4 COPD Chronic obstructive pulmonary disease ESSDAI EULAR Sjögren’s Syndrome Disease Activity Preliminary data was presented at the 14th International Index Symposium on Sjögren’s Syndrome as a poster. ESSPRI EULAR Sjögren’s Syndrome Patient Reported Index Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0029 6-018-4063-8) contains GOLD Global Initiative for Lung Disease supplementary material, which is available to authorized users. * Peter Olsson Department of Rheumatology and Inflammation Research, peterx.olsson@med.lu.se The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden Department of Clinical Sciences, Malmö, Rheumatology, Janssen Cilag, Solna, Sweden Lund University, Malmö, Sweden Department of Autoimmunology and Biomarkers, Statens Department of Rheumatology, Skåne University Hospital, Serum Institut, Copenhagen, Denmark Malmö, Sweden Reumatologmottagningen SUS Malmö, Jan Waldenströms Department of Congenital Disorders, Center for Neonatal gata 1B, 20502 Malmö, Sweden Screening, Statens Serum Institut, Copenhagen, Denmark Department of Rheumatology, Linköping University Hospital, Linköping, Sweden Vol.:(0123456789) 1 3 1504 Rheumatology International (2018) 38:1503–1510 IFN-α2a Interferon-alpha 2a foci formations in biopsies from smoking pSS patients, there IFN-γ Interferon gamma are minor inflammatory infiltrates including CD20+ cells IL Interleukin that are not present in healthy controls, thus suggesting that ILD Interstitial lung disease smoking might inhibit the migration of lymphocytes into IgG Immunoglobulin G the salivary glands [14, 16, 18]. Cytokine aberrations have pSS Primary Sjögren’s syndrome previously been demonstrated in pSS patients compared to RF Rheumatoid factor healthy controls [19], especially in pSS patients in whom RANTES Regulated upon activation, normal T-cell germinal centre formation has been demonstrated in sali- anti-SSA Anti-Sjögren’s syndrome A vary gland biopsies [20]. As reviewed by Arnson et al., ciga- anti-SSB Anti-Sjögren’s syndrome B rette smoke may also affect both immune cells and cytokine TGF-β1 T ransforming growth factor-beta 1 production [12]. To our knowledge, no other studies have Th T-helper cell been performed analysing cytokine expression in relation TNF-α Tumour necrosis factor-α to smoking in pSS patients. Taken together, the relation between pSS and smoking should be further explored. The aims of this study were Introduction (1) to investigate differences in markers of disease activity and serum cytokine levels between ever and never smoking Primary Sjögren’s syndrome (pSS) is an autoimmune dis- pSS patients and (2) to assess differences in cytokine levels ease characterised by inflammation and destruction of the between pSS patients vs population-based controls. exocrine glands, classically causing oral and ocular dry- ness. Extraglandular organs such as lungs, kidneys, skin and nervous system may also be involved in the disease [1, 2]. Materials and methods The underlying pathogenesis is poorly understood, but one hypothesis states that viral triggering in combination with Patients and controls genetic susceptibility may result in an autoimmune attack directed against endogenous proteins and apoptotic material. At the Department of Rheumatology, Skåne University The reaction results in an upregulation of proinflammatory Hospital Malmö, Sweden, consecutive patients with pSS cytokines, such as IFNα, IFNγ, and BAFF, as well as in an have been followed and registered since 1984. The reg- activation of B- and T-cells with a subsequent destruction ister entailed 380 patients at the time of the study. Fifty- of exocrine glands [3]. one consecutive outpatients who had been diagnosed Smoking has well known negative effects, e.g. increased with pSS by a specialist in rheumatology and fulfilled the risk of several malignancies, development of COPD, cardio- American-European Consensus Group (AECG) criteria vascular disease, and rheumatoid arthritis, but on the other [21], seen from May to December in 2012, at our depart- hand ameliorates clinical symptoms in other diseases, e.g. ment were included in the study (females 49/51, median Behcet’s disease, ulcerative colitis and Parkinson’s disease age 61, IQR: 52; 69). Clinical and laboratory parameters [4–11]. An immunosuppressive effect by the cigarette smoke were assessed according to a structured protocol including has been suggested, since not only smoke but also nicotine ESSDAI (EULAR Sjögren’s Syndrome Disease Activity alone has been shown to exert effects on the immune system Index) and ESSPRI (EULAR Sjögren’s Syndrome Patient [12, 13]. Reported Index) [22]. Median ESSDAI-total value was 7, A negative association between pSS diagnosis and smok- (IQR: 1; 10). Forty of the patients had performed a lower ing has previously been reported by our group and others lip biopsy of which 37 were positive. A positive lip biopsy [14–17]. It is not known whether these observations rep- was defined according to the AECG criteria (i.e. ≥ 1 focus resent causality. A negative association between smoking of 50 cells or more per 4 mm ). Anti-SSA positivity was and presence of anti-SSA antibodies and presence of focal found in 40/51 patients. Demographic and clinical data sialadenitis in lower lip biopsies, respectively, have also been on patients and controls are summarised in Table 1. When demonstrated which supports the possibility that smoking investigating the effect of smoking on presence of positive affects the disease itself [14, 16]. For example, one can lip biopsy and presence of SSA/SSB antibodies, smoking argue that smoking could mask the disease by reducing the status at the time of diagnosis was used since the biop- foci formation whereby patients might not fulfil the AECG sies and analysis of SSA/SSB antibodies were performed or ACR/EULAR criteria, or that smoking may inhibit the at the time of diagnosis. The patients were also investi- development of the disease. Previous studies have shown a gated for presence of chronic obstructive pulmonary dis- dose dependent effect of smoking on the presence of focal ease (COPD) and interstitial lung disease (ILD) as part of sialadenitis and have also shown that although there are no another study, as previously reported [23]. Briefly, COPD 1 3 Rheumatology International (2018) 38:1503–1510 1505 Table 1 Demographic Cases (n = 51) Controls (n = 33) characteristics of 51 consecutive patients and 33 controls Age, years 61 (52; 69) 47 (39; 61) Sex, females 49/51 (96) 19/33 (58) Current/not current smokers 4/51 (8) 7/33 (21) Ever/never smokers 24/51 (47) NA Fulfilling the AECG for pSS 51/51 (100) NA Fulfilling the ACR/EULAR criteria for pSS 51/51 (100) NA Disease duration, years 12 (6; 18) NA Anti-SSA antibody seropositives 40/51 (78) NA Anti-SSB antibody seropositives 24/51 (47) NA ANA seropositives 40/51 (78) NA RF seropositives 26/51 (51) NA IgG, g/l 13.0 (10.1; 15.5) NA C3, g/l 1.01 (0.86; 1.20) NA C4, g/l 0.18 (0.13; 0.21) NA Lower lip biopsy, focus score ≥ 1% 37/40 (93) NA ESSPRI total score 6 (5; 7) NA ESSDAI total score 7 (1; 10) NA Nonexocrine symptoms/signs, any of the below % 25/51 (49) NA Lymphadenopathy and/or lymphoma ever % 3/51 (6) NA Arthritis ever % 4/51 (8) NA Cutaneous symptoms ever % 10/51 (20) NA Interstitial lung disease ever % 9/51 (18) NA Chronic obstructive lung disease ever % 21/51 (41) NA Renal involvement ever % 4/51 (8) NA Myositis ever % 0/51 (0) NA Peripheral nervous system involvement ever % 1/51 (2) NA Raynaud phenomenon ever % 4/51 (8) NA Disease characteristics of the 51 consecutive patients with pSS. Values are presented as n/n available (%) or median (IQR) unless otherwise specified pSS primary Sjögren’s syndrome, AECG American-European Consensus Group criteria, ACR Amer ican College of Rheumatology, EULAR European League Against Rheumatism, ANA antinuclear antibody, RF rheumatoid factor, IgG immunoglobulin G, C3 complement factor 3, C4 complement factor 4, ESSPRI EULAR Sjögren Patient Reported Index, ESSDAI EULAR Sjögren Disease Activity Index, EULAR Euro- pean League Against Rheumatism, ILD interstitial lung disease Defined as presence of peripheral traction bronchiectasis, honey combing or ground glass opacities was defined according to the Global Initiative for Lung Cytokine analyses Disease (GOLD) criteria [24] and ILD was defined as presence of ground glass attenuation, traction bronchiec- Serum samples from patients and controls were obtained tasis, or honeycombing in high-resolution CT scans. and stored at − 80 °C until analysis. Since, to our knowl- Population-based controls, living in the city of Malmö edge, no other studies on cytokine expression in relation or its surroundings were randomly selected from the Swed- to smoking and pSS previously have been published, the ish population register and asked via mail if they were selection of cytokines was based on findings in previous willing to participate in the study. If informed consent studies analysing cytokines in pSS patients compared was received, the subject was invited to the Department of to healthy controls (e.g. BAFF, IFNg, IFNa, EGF) and Rheumatology outpatient clinic, where data on age, sex, cytokines stimulating different pathways: T-cell activat- medical history, medication, present pregnancy and cur- ing cytokines (e.g. RANTES, IL-2), B-cell activating rent smoking were registered, and a physical exam was cytokines (e.g. BAFF, IL-4, IL-10, IL-6), the Th-17 path- performed. Thirty-three controls were included (females way (IL-17), and general proinflammatory cytokines (e.g. 19/33, median age 47, IQR 39; 61). IL-1B, TNF-α, IL-6, IFNg). 1 3 1506 Rheumatology International (2018) 38:1503–1510 The serum samples were analysed with four different Results panels, all using the Meso-Scale platform. Panel 4 was pur- chased from Meso-Scale for Interferon-α2a (IFN-α2a Ultra- Amongst the 51 patients, 47% were ever smokers (8% cur- sensitive kit, K151ACC). Panel 1–3 were in-house made rent smokers, 39% former smokers) (Table 1). Amongst assays. Panel 1 included B-cell activating factor (BAFF), ever smokers at the time of diagnosis, significantly fewer Epidermal Growth Factor (EGF), Fas-ligand, Interleu- patients had a focal sialadenitis (81 vs 100%; p = 0.03) kin-3 (IL-3), IL-33, Regulated upon Activation, Normal (Table  2). The ESSDAI total score, the ESSPRI total T-cell Expressed and presumably Secreted (RANTES), and score, IgG, C3, and C4 levels did not significantly differ Transforming growth factor β 1 (TGF-β1). Panel 2 included between ever and never smoking pSS patients (Table 2). IFN-γ, IL-2, -6, -8, -10, -12, -17, -18, -1β, tumour necrosis Levels of IL-6, IL-12, IL-17 and IL-18 were significantly factor-α (TNF-α). Panel 3 was IL-4. Further details on these increased in pSS patients compared to controls whilst no assays are given in the Supplementary text. Concentrations major differences between pSS patients and controls for were calculated with Discovery Workbench software (Meso- the other cytokines were found (Table 3). Scale) from calibration curves using four-parameter logistic When comparing ever and never smoking pSS patients, fit. only TNF-α levels were significantly higher in the former Based on previous reports, the panels were assessed for group (Table 4). Also, when analysing only anti-SSA posi- proneness to interaction with heterophilic antibodies using tives as well as pSS patients with shorter than median dis- pooled IgM/IgA rheumatoid factor (RF) positive sera and ease duration amongst pSS patients, a similar lack of asso- pooled healthy control sera with and without HBR Plus ciation was found. No significant difference was observed (Scantibodies Laboratory, Santee, CA, USA) without any in cytokine levels between patients with or without COPD, significant difference in cytokine levels [25, 26]. Subsequent or ILD, respectively. analyses were performed without any additional blocker. Thirty-three controls (median age 47 (range 39–61 years), 19 females) were included, of whom 21% Statistics were current smokers (Table  1). Amongst controls, sex and age correlated poorly to cytokine levels. In patients When analysing differences in cytokine levels between ever with pSS, disease duration was negatively correlated to and never smokers as well as between cases and controls the IL-10 (r = − 0.32, p = 0.02), IL -12 (r = − 0.34, p = 0.02) Mann–Whitney U test was used. Spearman’s rank test was and TNF-α (r = − 0.40, p = 0.004) and positively to TGF- used for correlations. Chi test was used for comparison of β1 (r = 0.29, p = 0.04). There were no significant correla- binary parameters. A p value below 0.05 was considered tions between the ESSDAI total score and serum cytokine significant for all analyses. Separate analyses included cases levels (data not shown). Current smokers entailed only with shorter disease duration (above median) and anti-SSA four patients, therefore statistical analyses were not per- seropositive patients. formed on this group separately. The statistic calculations were performed using SPSS ver- sion 22 for Macintosh. Table 2 Comparison of clinical + Ever smokers (pSS) n = 24 Never smokers (pSS) n = 27 p value parameters, IgG levels and complement levels between Focal sialadenitis 14/17 (82) 23/23 (100) 0.03* never smoking and ever Anti-SSA- and or SSB- 20/24 (83) 20/27 (74) 0.43 smoking pSS patients positive ESSDAI 7.5 (1.5; 10) 7 (1; 11) 0.85 ESSPRI 6 (5; 7) 6 (4; 8) 0.68 IgG (g/l) 12.9 (10.1; 17.2) 13.0 (10.1; 15.2) 0.62 C3 (g/l) 1.02 (0.92; 1.22) 0.99 (0.84; 1.16) 0.60 C4 (g/l) 0.19 (0.13; 0.21) 0.16 (0.13; 0.20) 0.40 Values are presented as median (IQR) or n/n available (%) *p < 0.05 Mann–Whitney U test 1 3 Rheumatology International (2018) 38:1503–1510 1507 Table 3 Comparison of + Cases pg/ml, median (IQR) n = 51 Controls, pg/ml, median (IQR) n = 33 p value cytokine levels between pSS patients and controls IL-1β 0 (0; 0) 0 (0; 0) 0.92 IL-2 0 (0; 25.0) 0 (0; 24.4) 0.86 IL-3 0 (0; 67.8) 0 (0; 88.7) 0.84 IL-4 0 (0; 0) 0 (0; 0) 0.20 IL-6 25.2 (14.0; 30.9) 15.3 (10.6; 22.0) 0.003** IL-8 19.9 (15.9; 22.8) 16.7 (14.1; 20.8) 0.06 IL-10 0 (0; 0) 0 (0; 0) 0.18 IL-12 7.4 (0; 10.8) 0 (0; 8.3) 0.02* IL-17 0 (0; 51.2) 0 (0; 0) 0.002** IL-18 294 (187.7; 500.3) 214.5 (119.0; 297.5) 0.008** IL-33 11.2 (0; 16.1) 12.5 (0; 17.7) 0.62 IFN-α 0 (0; 0) 0 (0; 0) 0.53 IFN- γ 0 (0; 1.3) 0 (0; 1.0) 0.43 TNF-α 12.1 (5.7; 16.9) 8.5 (5.9; 11.5) 0.14 BAFF 265.6 (182.4; 376.2) 276.1 (142.9; 391.6) 0.79 EGF 139.8 (60.0; 227.1) 136.4 (93.2; 177.3) 0.89 Fas ligand 9.5 (7.2; 15.3) 11.4 (6.9; 15.2) 0.48 RANTES 15673.7 (11374.1; 25397.6) 17073.0 (13345.9; 20037.8) 0.56 TGF-β1 22.4 (6.7; 35.6) 12.7 (9.2; 36.6) 0.75 *p < 0.05 **p < 0.01 Mann–Whitney U test Table 4 Comparison of + Ever smokers (pSS) n = 24 Never smokers (pSS) n = 27 p value cytokine levels between never pg/ml, median (IQR) pg/ml, median (IQR) smoking and ever smoking pSS patients IL-1β 0 (0; 0) 0 (0; 0) 0.30 IL-2 0 (0; 28.4) 0 (0; 19.2) 0.85 IL-3 0 (0; 0) 0 (0; 96.9) 0.36 IL-4 0 (0; 0) 0 (0; 0) 1.0 IL-6 25.0 (14.4; 29.4) 25.2 (13.0; 36.7) 0.94 IL-8 21.8 (15.9; 24.1) 18.3 (15.5; 21.4) 0.18 IL-10 0 (0; 0) 0 (0; 39.3) 0.74 IL-12 9.7 (5.6; 12.9) 7.1 (0; 9.8) 0.20 IL-17 0 (0; 75.7) 39.0 (0; 46.6) 0.86 IL-18 364.3 (250.4; 659.3) 234.5 (166.3; 500.3) 0.06 IL-33 11.2 (0; 19.3) 11.2 (0; 15.6) 0.95 IFN-α 0 (0; 0) 0 (0; 0) 0.51 IFN-γ 0.7 (0; 1.3) 0 (0; 1.0) 0.58 TNF-α 13.8 (7.2; 20.8) 7.5 (4.9; 15.9) 0.03* BAFF 256.1 (191.9; 375.2) 265.6 (156.7; 388.3) 0.95 EGF 154.8 (55.4; 252.0) 133.9 (70.8; 202.8) 0.53 FAS ligand 10.3 (7.3; 16.6) 9.2 (6.5; 12.6) 0.50 RANTES 17051.1 (11883.2; 27559.6) 15443.0 (9730.2; 19827.9) 0.46 TGF-β1 21.2 (4.2; 26.9) 22.4 (9.3; 55.0) 0.14 *p < 0.05 Mann–Whitney U test 1 3 1508 Rheumatology International (2018) 38:1503–1510 finding. However, the lack of difference in BAFF levels Discussion between patients and controls was unexpected since BAFF is considered a hallmark of pSS in several studies [41, 42] In this study, a negative association between a history of and considered as a potential biomarker [43]. A possible smoking and focal sialadenitis in patients with pSS was explanation might be that these consecutive patients had a found which is in line with previous reports. The negative lower disease activity than patients in previous studies or association between pSS diagnosis and smoking could be that the in-house made kit was not specific enough. Prob- due to the dryness of the oral cavity and eyes potentially lems with analysing BAFF due to lack of specificity for causing more irritation by the smoke. Cigarette smoking BAFF caused by posttranslational glycosylations or alter- is also reported to cause reduced salivary rates and altera- native spliced forms have previously been reported [44]. tion of the saliva composition [27, 28]. To the best of our The type I interferon system is activated in pSS and is knowledge, there are no studies investigating the effect of thought to play an important role in the disease development smoking on salivary gland biopsies in healthy controls. [45, 46]. Type I interferons consists of at least 17 different The reported effect on salivary flow does not reach the subtypes, of which there are 13 different subtypes of IFNα. levels required for diagnosing pSS but might potentially In this study, IFNα2a was investigated. Despite choosing an decrease the already diminished salivary flow in pSS ultra-sensitive kit, the majority of samples were below the patients, thereby explaining the lower frequency of current measurable range. This is a common problem and a reason smokers amongst pSS patients. Still, it does not explain why mRNA from interferon-sensitive genes, the so-called the lower frequency of focal sialadenitis in ever smoking IFN-signature, is often measured rather than IFNα itself. patients. Since the salivary glands are in close proximity Unfortunately, mRNA was not available in this study. Ana- to the inhaled smoke, a possible explanation for this find- lysing the IFN-signature in salivary gland cells or monocytes ing could be that cigarette smoke interferes with the local from pSS patients with different smoking exposures would immune response either by nicotine binding to nicotine be interesting, since smoking has been shown to suppress receptors on immune cells or by other compounds in the the effect of type I IFNs [47]. inhaled smoke acting anti-inflammatory [12, 13, 29, 30]. Most patients included in the study had a longstanding Apart from the lower frequency of positive lip biopsy, disease (median disease duration 12 years) and disease dura- there were no significant differences in other standard clini- tion correlated negatively to the proinflammatory cytokines cal and laboratory characteristics between ever and never IL-10, IL-12 and TNF-α and positively to the anti-inflam- smokers. Furthermore, there were no major differences in matory cytokine TGF-ß, indicating that the disease develops cytokine levels, except for TNF-α, which was higher in ever towards a less inflammatory state over time. smokers. The latter finding should be interpreted with cau- In line with previous reports [14, 16], we found a lower tion. The TNF-α levels were generally low, and if smok- frequency of positive lip biopsy among ever smokers at the ing was indeed associated with a higher degree of systemic time of diagnosis. However, we did not find evidence that inflammation, one would expect other proinflammatory ever smoking affects cytokine expression, IgG levels, com- cytokines to be significantly increased as well in ever smok - plement levels or disease activity, measured by the ESSDAI- ers. Also, given the numerous statistical analyses, this single score, in pSS patients. It is possible that cytokine concentra- statistical significance should not be over-interpreted. tions and ESSDAI-scores would have differed between ever An increase in several proinflammatory cytokines (IL-6, and never smokers as well if measured at time of diagnosis. IL-12, IL-17, IL-18) was observed in pSS patients com- Another possible explanation could be that smoking might pared to controls. pSS is a disease characterised by an ae ff ct ina fl mmation locally in the salivary glands rather than insidious onset and slow progression of exocrinopathy. the systemic inflammation of the disease. Also, the group of Since the exocrine inflammation is mainly local, most pre - currently smoking patients was small in this study, which vious studies have measured cytokine expression in biop- makes it difficult to draw conclusions about temporary sies [31, 32] and saliva [33] or production by peripheral effects of current smoking on cytokine levels. Since cur - mononuclear cells [34]. However, several other studies rent smokers are underrepresented in epidemiological data, have also shown cytokine aberrations in serum including it would be of interest in future studies to compare a larger the increase in IL-6, IL-17, and IL-18 in the current study group of currently smoking pSS patients with former and [35–39]. Furthermore, regarding the observed increase in never smoking patients concerning cytokine levels. IL-12 in pSS patients, polymorphisms of the IL12A gene The study has some limitations, including the limited have been shown to be associated with pSS in a genome- sample size of the study and the low number of current wide association-study [40]. smokers amongst the pSS patients. Furthermore, the major- The observed difference in cytokine expression between ity of the patients had long-standing disease, and we cannot pSS patients and controls in our study is thus an expected exclude that cytokine patterns, and their relation to smoking 1 3 Rheumatology International (2018) 38:1503–1510 1509 index: analysis of 921 Spanish patients (GEAS-SS Registry). history, may be different in recently diagnosed patients. The Rheumatology 53(2):321–331 cross-sectional study design is also a limitation. Finally, 3. Nocturne G, Mariette X (2013) Advances in understanding the the control group was not exactly matched on sex and age. pathogenesis of primary Sjogren’s syndrome. 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Clin Exp Rheumatol 19(5 Suppl 24):S77–S78 smoking on salivary glands rather than systemic effects of 10. Calkins BM (1989) A meta-analysis of the role of smoking in cigarette smoke may explain the previously observed nega- inflammatory bowel disease. Dig Dis Sci 34(12):1841–1854 tive association between smoking and pSS. 11. van der Mark M, Nijssen PC, Vlaanderen J, Huss A, Mulleners WM, Sas AM et al (2014) A case-control study of the protective effect of alcohol, coffee, and cigarette consumption on Parkinson Acknowledgements We acknowledge Käth Nilsson for assisting in the disease risk: time-since-cessation modifies the effect of tobacco collection and storing of serum samples, Jan-Åke Nilsson for input on smoking. PLoS One 9(4):e95297 the statistical analysis and Karin Skaarup, Karina Liebmann Madsen, 12. Arnson Y, Shoenfeld Y, Amital H (2010) Effects of tobacco smoke and Malene Billsten Zent for the analysis of serum cytokines. on immunity, inflammation and autoimmunity. J Autoimmun 34(3):J258–J265 Funding The study was supported by grants from the Sjögren’s syn- 13. Sopori M (2002) Effects of cigarette smoke on the immune sys- drome foundation, ALF-Skåne, the Kocks Foundation, the Internal tem. Nat Rev Immunol 2(5):372–377 Research Funds of Skåne University Hospital, and the Swedish Rheu- 14. Manthorpe R, Benoni C, Jacobsson L, Kirtava Z, Larsson A, matism Association. Liedholm R et al (2000) Lower frequency of focal lip sialadenitis (focus score) in smoking patients. Can tobacco diminish the sali- Compliance with ethical standards vary gland involvement as judged by histological examination and anti-SSA/Ro and anti-SSB/La antibodies in Sjogren’s syndrome? Ann Rheum Dis 59(1):54–60 Conflict of interest The authors declare no conflicts of interest. 15. Karabulut G, Kitapcioglu G, Inal V, Kalfa M, Yargucu F, Keser G et al (2011) Cigarette smoking in primary Sjogren’s syndrome: Ethical statement The study was approved by the Regional Ethical positive association only with ANA positivity. Mod Rheumatol Review Board for Southern Sweden (Lund, Sweden; LU 2012/98). 21(6):602–607 All patients gave written informed consent according to the Declara- 16. Stone DU, Fife D, Brown M, Earley KE, Radfar L, Kaufman CE tion of Helsinki. et al (2017) Effect of tobacco smoking on the clinical, histopatho- logical, and serological manifestations of Sjogren’s syndrome. Open Access This article is distributed under the terms of the Crea- PLoS One 12(2):e0170249 tive Commons Attribution 4.0 International License (http://creat iveco 17. 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HuangFu WC, Liu J, Harty RN, Fuchs SY (2008) Cigarette smok- (1999) Increased frequency of cells secreting interleukin-6 and ing products suppress anti-viral effects of Type I interferon via interleukin-10 in peripheral blood of patients with primary phosphorylation-dependent downregulation of its receptor. FEBS Sjogren’s syndrome. Scand J Immunol 49(5):533–538 Lett 582(21–22):3206–3210 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology International Springer Journals

Smoking, disease characteristics and serum cytokine levels in patients with primary Sjögren’s syndrome

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Medicine & Public Health; Rheumatology
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Abstract

Smoking affects several disease processes. Epidemiological studies have previously found a negative association between primary Sjögren’s syndrome (pSS) and smoking. The aim of this study was to examine whether markers of disease activ- ity and cytokine expression in pSS patients differ between ever and never smokers. Fifty-one consecutive pSS patients and 33 population controls were included in the study. Clinical and standard laboratory parameters were registered. Serum cytokines (IL-1β, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-18, IL-33, IFN-α, IFN-γ, TNF-α, EGF, BAFF, Fas- ligand, RANTES, TGF-β1) were assessed. A positive lip biopsy was less prevalent among ever smoking patients compared to never smokers (81 vs 100%; p = 0.03). However, except for TNF-α, which was higher in ever smokers, no differences in cytokine levels were found when comparing ever and never smoking pSS patients. Furthermore, no significant differences were found between ever and never smoking patients in the ESSDAI total score, IgG levels, or complement levels. However, IL-6, IL-12, IL-17 and IL-18 were significantly increased in pSS patients compared to controls. In this study, a negative association between ever smoking and positive lip biopsy was found, confirming previous reports. Expected differences in cytokine levels compared to controls were noted, but no major differences were found between ever and never smoking pSS patients. Taking into account the negative association between pSS diagnosis and smoking in epidemiological studies, possible explanations include a local effect of smoking on salivary glands rather than systemic effects by cigarette smoke. Keywords Sjögren’s syndrome · Cytokines · Cigarette smoking · Autoimmune diseases Abbreviations EGF Epidermal growth factor AECG American-European Consensus Group C3 Complement factor 3 BAFF B-cell activating factor C4 Complement factor 4 COPD Chronic obstructive pulmonary disease ESSDAI EULAR Sjögren’s Syndrome Disease Activity Preliminary data was presented at the 14th International Index Symposium on Sjögren’s Syndrome as a poster. ESSPRI EULAR Sjögren’s Syndrome Patient Reported Index Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0029 6-018-4063-8) contains GOLD Global Initiative for Lung Disease supplementary material, which is available to authorized users. * Peter Olsson Department of Rheumatology and Inflammation Research, peterx.olsson@med.lu.se The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden Department of Clinical Sciences, Malmö, Rheumatology, Janssen Cilag, Solna, Sweden Lund University, Malmö, Sweden Department of Autoimmunology and Biomarkers, Statens Department of Rheumatology, Skåne University Hospital, Serum Institut, Copenhagen, Denmark Malmö, Sweden Reumatologmottagningen SUS Malmö, Jan Waldenströms Department of Congenital Disorders, Center for Neonatal gata 1B, 20502 Malmö, Sweden Screening, Statens Serum Institut, Copenhagen, Denmark Department of Rheumatology, Linköping University Hospital, Linköping, Sweden Vol.:(0123456789) 1 3 1504 Rheumatology International (2018) 38:1503–1510 IFN-α2a Interferon-alpha 2a foci formations in biopsies from smoking pSS patients, there IFN-γ Interferon gamma are minor inflammatory infiltrates including CD20+ cells IL Interleukin that are not present in healthy controls, thus suggesting that ILD Interstitial lung disease smoking might inhibit the migration of lymphocytes into IgG Immunoglobulin G the salivary glands [14, 16, 18]. Cytokine aberrations have pSS Primary Sjögren’s syndrome previously been demonstrated in pSS patients compared to RF Rheumatoid factor healthy controls [19], especially in pSS patients in whom RANTES Regulated upon activation, normal T-cell germinal centre formation has been demonstrated in sali- anti-SSA Anti-Sjögren’s syndrome A vary gland biopsies [20]. As reviewed by Arnson et al., ciga- anti-SSB Anti-Sjögren’s syndrome B rette smoke may also affect both immune cells and cytokine TGF-β1 T ransforming growth factor-beta 1 production [12]. To our knowledge, no other studies have Th T-helper cell been performed analysing cytokine expression in relation TNF-α Tumour necrosis factor-α to smoking in pSS patients. Taken together, the relation between pSS and smoking should be further explored. The aims of this study were Introduction (1) to investigate differences in markers of disease activity and serum cytokine levels between ever and never smoking Primary Sjögren’s syndrome (pSS) is an autoimmune dis- pSS patients and (2) to assess differences in cytokine levels ease characterised by inflammation and destruction of the between pSS patients vs population-based controls. exocrine glands, classically causing oral and ocular dry- ness. Extraglandular organs such as lungs, kidneys, skin and nervous system may also be involved in the disease [1, 2]. Materials and methods The underlying pathogenesis is poorly understood, but one hypothesis states that viral triggering in combination with Patients and controls genetic susceptibility may result in an autoimmune attack directed against endogenous proteins and apoptotic material. At the Department of Rheumatology, Skåne University The reaction results in an upregulation of proinflammatory Hospital Malmö, Sweden, consecutive patients with pSS cytokines, such as IFNα, IFNγ, and BAFF, as well as in an have been followed and registered since 1984. The reg- activation of B- and T-cells with a subsequent destruction ister entailed 380 patients at the time of the study. Fifty- of exocrine glands [3]. one consecutive outpatients who had been diagnosed Smoking has well known negative effects, e.g. increased with pSS by a specialist in rheumatology and fulfilled the risk of several malignancies, development of COPD, cardio- American-European Consensus Group (AECG) criteria vascular disease, and rheumatoid arthritis, but on the other [21], seen from May to December in 2012, at our depart- hand ameliorates clinical symptoms in other diseases, e.g. ment were included in the study (females 49/51, median Behcet’s disease, ulcerative colitis and Parkinson’s disease age 61, IQR: 52; 69). Clinical and laboratory parameters [4–11]. An immunosuppressive effect by the cigarette smoke were assessed according to a structured protocol including has been suggested, since not only smoke but also nicotine ESSDAI (EULAR Sjögren’s Syndrome Disease Activity alone has been shown to exert effects on the immune system Index) and ESSPRI (EULAR Sjögren’s Syndrome Patient [12, 13]. Reported Index) [22]. Median ESSDAI-total value was 7, A negative association between pSS diagnosis and smok- (IQR: 1; 10). Forty of the patients had performed a lower ing has previously been reported by our group and others lip biopsy of which 37 were positive. A positive lip biopsy [14–17]. It is not known whether these observations rep- was defined according to the AECG criteria (i.e. ≥ 1 focus resent causality. A negative association between smoking of 50 cells or more per 4 mm ). Anti-SSA positivity was and presence of anti-SSA antibodies and presence of focal found in 40/51 patients. Demographic and clinical data sialadenitis in lower lip biopsies, respectively, have also been on patients and controls are summarised in Table 1. When demonstrated which supports the possibility that smoking investigating the effect of smoking on presence of positive affects the disease itself [14, 16]. For example, one can lip biopsy and presence of SSA/SSB antibodies, smoking argue that smoking could mask the disease by reducing the status at the time of diagnosis was used since the biop- foci formation whereby patients might not fulfil the AECG sies and analysis of SSA/SSB antibodies were performed or ACR/EULAR criteria, or that smoking may inhibit the at the time of diagnosis. The patients were also investi- development of the disease. Previous studies have shown a gated for presence of chronic obstructive pulmonary dis- dose dependent effect of smoking on the presence of focal ease (COPD) and interstitial lung disease (ILD) as part of sialadenitis and have also shown that although there are no another study, as previously reported [23]. Briefly, COPD 1 3 Rheumatology International (2018) 38:1503–1510 1505 Table 1 Demographic Cases (n = 51) Controls (n = 33) characteristics of 51 consecutive patients and 33 controls Age, years 61 (52; 69) 47 (39; 61) Sex, females 49/51 (96) 19/33 (58) Current/not current smokers 4/51 (8) 7/33 (21) Ever/never smokers 24/51 (47) NA Fulfilling the AECG for pSS 51/51 (100) NA Fulfilling the ACR/EULAR criteria for pSS 51/51 (100) NA Disease duration, years 12 (6; 18) NA Anti-SSA antibody seropositives 40/51 (78) NA Anti-SSB antibody seropositives 24/51 (47) NA ANA seropositives 40/51 (78) NA RF seropositives 26/51 (51) NA IgG, g/l 13.0 (10.1; 15.5) NA C3, g/l 1.01 (0.86; 1.20) NA C4, g/l 0.18 (0.13; 0.21) NA Lower lip biopsy, focus score ≥ 1% 37/40 (93) NA ESSPRI total score 6 (5; 7) NA ESSDAI total score 7 (1; 10) NA Nonexocrine symptoms/signs, any of the below % 25/51 (49) NA Lymphadenopathy and/or lymphoma ever % 3/51 (6) NA Arthritis ever % 4/51 (8) NA Cutaneous symptoms ever % 10/51 (20) NA Interstitial lung disease ever % 9/51 (18) NA Chronic obstructive lung disease ever % 21/51 (41) NA Renal involvement ever % 4/51 (8) NA Myositis ever % 0/51 (0) NA Peripheral nervous system involvement ever % 1/51 (2) NA Raynaud phenomenon ever % 4/51 (8) NA Disease characteristics of the 51 consecutive patients with pSS. Values are presented as n/n available (%) or median (IQR) unless otherwise specified pSS primary Sjögren’s syndrome, AECG American-European Consensus Group criteria, ACR Amer ican College of Rheumatology, EULAR European League Against Rheumatism, ANA antinuclear antibody, RF rheumatoid factor, IgG immunoglobulin G, C3 complement factor 3, C4 complement factor 4, ESSPRI EULAR Sjögren Patient Reported Index, ESSDAI EULAR Sjögren Disease Activity Index, EULAR Euro- pean League Against Rheumatism, ILD interstitial lung disease Defined as presence of peripheral traction bronchiectasis, honey combing or ground glass opacities was defined according to the Global Initiative for Lung Cytokine analyses Disease (GOLD) criteria [24] and ILD was defined as presence of ground glass attenuation, traction bronchiec- Serum samples from patients and controls were obtained tasis, or honeycombing in high-resolution CT scans. and stored at − 80 °C until analysis. Since, to our knowl- Population-based controls, living in the city of Malmö edge, no other studies on cytokine expression in relation or its surroundings were randomly selected from the Swed- to smoking and pSS previously have been published, the ish population register and asked via mail if they were selection of cytokines was based on findings in previous willing to participate in the study. If informed consent studies analysing cytokines in pSS patients compared was received, the subject was invited to the Department of to healthy controls (e.g. BAFF, IFNg, IFNa, EGF) and Rheumatology outpatient clinic, where data on age, sex, cytokines stimulating different pathways: T-cell activat- medical history, medication, present pregnancy and cur- ing cytokines (e.g. RANTES, IL-2), B-cell activating rent smoking were registered, and a physical exam was cytokines (e.g. BAFF, IL-4, IL-10, IL-6), the Th-17 path- performed. Thirty-three controls were included (females way (IL-17), and general proinflammatory cytokines (e.g. 19/33, median age 47, IQR 39; 61). IL-1B, TNF-α, IL-6, IFNg). 1 3 1506 Rheumatology International (2018) 38:1503–1510 The serum samples were analysed with four different Results panels, all using the Meso-Scale platform. Panel 4 was pur- chased from Meso-Scale for Interferon-α2a (IFN-α2a Ultra- Amongst the 51 patients, 47% were ever smokers (8% cur- sensitive kit, K151ACC). Panel 1–3 were in-house made rent smokers, 39% former smokers) (Table 1). Amongst assays. Panel 1 included B-cell activating factor (BAFF), ever smokers at the time of diagnosis, significantly fewer Epidermal Growth Factor (EGF), Fas-ligand, Interleu- patients had a focal sialadenitis (81 vs 100%; p = 0.03) kin-3 (IL-3), IL-33, Regulated upon Activation, Normal (Table  2). The ESSDAI total score, the ESSPRI total T-cell Expressed and presumably Secreted (RANTES), and score, IgG, C3, and C4 levels did not significantly differ Transforming growth factor β 1 (TGF-β1). Panel 2 included between ever and never smoking pSS patients (Table 2). IFN-γ, IL-2, -6, -8, -10, -12, -17, -18, -1β, tumour necrosis Levels of IL-6, IL-12, IL-17 and IL-18 were significantly factor-α (TNF-α). Panel 3 was IL-4. Further details on these increased in pSS patients compared to controls whilst no assays are given in the Supplementary text. Concentrations major differences between pSS patients and controls for were calculated with Discovery Workbench software (Meso- the other cytokines were found (Table 3). Scale) from calibration curves using four-parameter logistic When comparing ever and never smoking pSS patients, fit. only TNF-α levels were significantly higher in the former Based on previous reports, the panels were assessed for group (Table 4). Also, when analysing only anti-SSA posi- proneness to interaction with heterophilic antibodies using tives as well as pSS patients with shorter than median dis- pooled IgM/IgA rheumatoid factor (RF) positive sera and ease duration amongst pSS patients, a similar lack of asso- pooled healthy control sera with and without HBR Plus ciation was found. No significant difference was observed (Scantibodies Laboratory, Santee, CA, USA) without any in cytokine levels between patients with or without COPD, significant difference in cytokine levels [25, 26]. Subsequent or ILD, respectively. analyses were performed without any additional blocker. Thirty-three controls (median age 47 (range 39–61 years), 19 females) were included, of whom 21% Statistics were current smokers (Table  1). Amongst controls, sex and age correlated poorly to cytokine levels. In patients When analysing differences in cytokine levels between ever with pSS, disease duration was negatively correlated to and never smokers as well as between cases and controls the IL-10 (r = − 0.32, p = 0.02), IL -12 (r = − 0.34, p = 0.02) Mann–Whitney U test was used. Spearman’s rank test was and TNF-α (r = − 0.40, p = 0.004) and positively to TGF- used for correlations. Chi test was used for comparison of β1 (r = 0.29, p = 0.04). There were no significant correla- binary parameters. A p value below 0.05 was considered tions between the ESSDAI total score and serum cytokine significant for all analyses. Separate analyses included cases levels (data not shown). Current smokers entailed only with shorter disease duration (above median) and anti-SSA four patients, therefore statistical analyses were not per- seropositive patients. formed on this group separately. The statistic calculations were performed using SPSS ver- sion 22 for Macintosh. Table 2 Comparison of clinical + Ever smokers (pSS) n = 24 Never smokers (pSS) n = 27 p value parameters, IgG levels and complement levels between Focal sialadenitis 14/17 (82) 23/23 (100) 0.03* never smoking and ever Anti-SSA- and or SSB- 20/24 (83) 20/27 (74) 0.43 smoking pSS patients positive ESSDAI 7.5 (1.5; 10) 7 (1; 11) 0.85 ESSPRI 6 (5; 7) 6 (4; 8) 0.68 IgG (g/l) 12.9 (10.1; 17.2) 13.0 (10.1; 15.2) 0.62 C3 (g/l) 1.02 (0.92; 1.22) 0.99 (0.84; 1.16) 0.60 C4 (g/l) 0.19 (0.13; 0.21) 0.16 (0.13; 0.20) 0.40 Values are presented as median (IQR) or n/n available (%) *p < 0.05 Mann–Whitney U test 1 3 Rheumatology International (2018) 38:1503–1510 1507 Table 3 Comparison of + Cases pg/ml, median (IQR) n = 51 Controls, pg/ml, median (IQR) n = 33 p value cytokine levels between pSS patients and controls IL-1β 0 (0; 0) 0 (0; 0) 0.92 IL-2 0 (0; 25.0) 0 (0; 24.4) 0.86 IL-3 0 (0; 67.8) 0 (0; 88.7) 0.84 IL-4 0 (0; 0) 0 (0; 0) 0.20 IL-6 25.2 (14.0; 30.9) 15.3 (10.6; 22.0) 0.003** IL-8 19.9 (15.9; 22.8) 16.7 (14.1; 20.8) 0.06 IL-10 0 (0; 0) 0 (0; 0) 0.18 IL-12 7.4 (0; 10.8) 0 (0; 8.3) 0.02* IL-17 0 (0; 51.2) 0 (0; 0) 0.002** IL-18 294 (187.7; 500.3) 214.5 (119.0; 297.5) 0.008** IL-33 11.2 (0; 16.1) 12.5 (0; 17.7) 0.62 IFN-α 0 (0; 0) 0 (0; 0) 0.53 IFN- γ 0 (0; 1.3) 0 (0; 1.0) 0.43 TNF-α 12.1 (5.7; 16.9) 8.5 (5.9; 11.5) 0.14 BAFF 265.6 (182.4; 376.2) 276.1 (142.9; 391.6) 0.79 EGF 139.8 (60.0; 227.1) 136.4 (93.2; 177.3) 0.89 Fas ligand 9.5 (7.2; 15.3) 11.4 (6.9; 15.2) 0.48 RANTES 15673.7 (11374.1; 25397.6) 17073.0 (13345.9; 20037.8) 0.56 TGF-β1 22.4 (6.7; 35.6) 12.7 (9.2; 36.6) 0.75 *p < 0.05 **p < 0.01 Mann–Whitney U test Table 4 Comparison of + Ever smokers (pSS) n = 24 Never smokers (pSS) n = 27 p value cytokine levels between never pg/ml, median (IQR) pg/ml, median (IQR) smoking and ever smoking pSS patients IL-1β 0 (0; 0) 0 (0; 0) 0.30 IL-2 0 (0; 28.4) 0 (0; 19.2) 0.85 IL-3 0 (0; 0) 0 (0; 96.9) 0.36 IL-4 0 (0; 0) 0 (0; 0) 1.0 IL-6 25.0 (14.4; 29.4) 25.2 (13.0; 36.7) 0.94 IL-8 21.8 (15.9; 24.1) 18.3 (15.5; 21.4) 0.18 IL-10 0 (0; 0) 0 (0; 39.3) 0.74 IL-12 9.7 (5.6; 12.9) 7.1 (0; 9.8) 0.20 IL-17 0 (0; 75.7) 39.0 (0; 46.6) 0.86 IL-18 364.3 (250.4; 659.3) 234.5 (166.3; 500.3) 0.06 IL-33 11.2 (0; 19.3) 11.2 (0; 15.6) 0.95 IFN-α 0 (0; 0) 0 (0; 0) 0.51 IFN-γ 0.7 (0; 1.3) 0 (0; 1.0) 0.58 TNF-α 13.8 (7.2; 20.8) 7.5 (4.9; 15.9) 0.03* BAFF 256.1 (191.9; 375.2) 265.6 (156.7; 388.3) 0.95 EGF 154.8 (55.4; 252.0) 133.9 (70.8; 202.8) 0.53 FAS ligand 10.3 (7.3; 16.6) 9.2 (6.5; 12.6) 0.50 RANTES 17051.1 (11883.2; 27559.6) 15443.0 (9730.2; 19827.9) 0.46 TGF-β1 21.2 (4.2; 26.9) 22.4 (9.3; 55.0) 0.14 *p < 0.05 Mann–Whitney U test 1 3 1508 Rheumatology International (2018) 38:1503–1510 finding. However, the lack of difference in BAFF levels Discussion between patients and controls was unexpected since BAFF is considered a hallmark of pSS in several studies [41, 42] In this study, a negative association between a history of and considered as a potential biomarker [43]. A possible smoking and focal sialadenitis in patients with pSS was explanation might be that these consecutive patients had a found which is in line with previous reports. The negative lower disease activity than patients in previous studies or association between pSS diagnosis and smoking could be that the in-house made kit was not specific enough. Prob- due to the dryness of the oral cavity and eyes potentially lems with analysing BAFF due to lack of specificity for causing more irritation by the smoke. Cigarette smoking BAFF caused by posttranslational glycosylations or alter- is also reported to cause reduced salivary rates and altera- native spliced forms have previously been reported [44]. tion of the saliva composition [27, 28]. To the best of our The type I interferon system is activated in pSS and is knowledge, there are no studies investigating the effect of thought to play an important role in the disease development smoking on salivary gland biopsies in healthy controls. [45, 46]. Type I interferons consists of at least 17 different The reported effect on salivary flow does not reach the subtypes, of which there are 13 different subtypes of IFNα. levels required for diagnosing pSS but might potentially In this study, IFNα2a was investigated. Despite choosing an decrease the already diminished salivary flow in pSS ultra-sensitive kit, the majority of samples were below the patients, thereby explaining the lower frequency of current measurable range. This is a common problem and a reason smokers amongst pSS patients. Still, it does not explain why mRNA from interferon-sensitive genes, the so-called the lower frequency of focal sialadenitis in ever smoking IFN-signature, is often measured rather than IFNα itself. patients. Since the salivary glands are in close proximity Unfortunately, mRNA was not available in this study. Ana- to the inhaled smoke, a possible explanation for this find- lysing the IFN-signature in salivary gland cells or monocytes ing could be that cigarette smoke interferes with the local from pSS patients with different smoking exposures would immune response either by nicotine binding to nicotine be interesting, since smoking has been shown to suppress receptors on immune cells or by other compounds in the the effect of type I IFNs [47]. inhaled smoke acting anti-inflammatory [12, 13, 29, 30]. Most patients included in the study had a longstanding Apart from the lower frequency of positive lip biopsy, disease (median disease duration 12 years) and disease dura- there were no significant differences in other standard clini- tion correlated negatively to the proinflammatory cytokines cal and laboratory characteristics between ever and never IL-10, IL-12 and TNF-α and positively to the anti-inflam- smokers. Furthermore, there were no major differences in matory cytokine TGF-ß, indicating that the disease develops cytokine levels, except for TNF-α, which was higher in ever towards a less inflammatory state over time. smokers. The latter finding should be interpreted with cau- In line with previous reports [14, 16], we found a lower tion. The TNF-α levels were generally low, and if smok- frequency of positive lip biopsy among ever smokers at the ing was indeed associated with a higher degree of systemic time of diagnosis. However, we did not find evidence that inflammation, one would expect other proinflammatory ever smoking affects cytokine expression, IgG levels, com- cytokines to be significantly increased as well in ever smok - plement levels or disease activity, measured by the ESSDAI- ers. Also, given the numerous statistical analyses, this single score, in pSS patients. It is possible that cytokine concentra- statistical significance should not be over-interpreted. tions and ESSDAI-scores would have differed between ever An increase in several proinflammatory cytokines (IL-6, and never smokers as well if measured at time of diagnosis. IL-12, IL-17, IL-18) was observed in pSS patients com- Another possible explanation could be that smoking might pared to controls. pSS is a disease characterised by an ae ff ct ina fl mmation locally in the salivary glands rather than insidious onset and slow progression of exocrinopathy. the systemic inflammation of the disease. Also, the group of Since the exocrine inflammation is mainly local, most pre - currently smoking patients was small in this study, which vious studies have measured cytokine expression in biop- makes it difficult to draw conclusions about temporary sies [31, 32] and saliva [33] or production by peripheral effects of current smoking on cytokine levels. Since cur - mononuclear cells [34]. However, several other studies rent smokers are underrepresented in epidemiological data, have also shown cytokine aberrations in serum including it would be of interest in future studies to compare a larger the increase in IL-6, IL-17, and IL-18 in the current study group of currently smoking pSS patients with former and [35–39]. Furthermore, regarding the observed increase in never smoking patients concerning cytokine levels. IL-12 in pSS patients, polymorphisms of the IL12A gene The study has some limitations, including the limited have been shown to be associated with pSS in a genome- sample size of the study and the low number of current wide association-study [40]. smokers amongst the pSS patients. Furthermore, the major- The observed difference in cytokine expression between ity of the patients had long-standing disease, and we cannot pSS patients and controls in our study is thus an expected exclude that cytokine patterns, and their relation to smoking 1 3 Rheumatology International (2018) 38:1503–1510 1509 index: analysis of 921 Spanish patients (GEAS-SS Registry). history, may be different in recently diagnosed patients. The Rheumatology 53(2):321–331 cross-sectional study design is also a limitation. Finally, 3. Nocturne G, Mariette X (2013) Advances in understanding the the control group was not exactly matched on sex and age. pathogenesis of primary Sjogren’s syndrome. Nat Rev Rheumatol Strengths of the study include the use of consecutive patients 9(9):544–556 4. Doll R, Hill AB (1956) Lung cancer and other causes of death in in standard follow-up, likely representative of the general relation to smoking; a second report on the mortality of British pSS population and the validation of the assays concerning doctors. Br Med J 2(5001):1071–1081 possible interference by rheumatoid factor. 5. Morgan RW, Jain MG (1974) Bladder cancer: smoking, beverages In conclusion, there was a lower prevalence of positive lip and artificial sweeteners. Can Med Assoc J 111(10):1067–1070 6. Fletcher C, Peto R (1977) The natural history of chronic airflow biopsy among pSS patients with a history of ever smoking obstruction. Br Med J 1(6077):1645–1648 which is in accordance with previous studies. No differences 7. Prasad DS, Kabir Z, Dash AK, Das BC (2009) Smoking and cardi- in serum cytokine levels between ever and never smoking ovascular health: a review of the epidemiology, pathogenesis, pre- pSS patients was found. Furthermore, we found increased vention and control of tobacco. Indian J Med Sci 63(11):520–533 8. Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, levels of proinflammatory cytokines (IL-6, IL-12, IL-17, Morinobu A et al (2010) Impact of smoking as a risk factor for IL-18) in pSS patients compared to controls as well as a developing rheumatoid arthritis: a meta-analysis of observational negative correlation between disease duration and proinflam - studies. Ann Rheum Dis 69(1):70–81 matory cytokines indicating that the disease develops to a 9. Rizvi SW, McGrath H Jr. (2001) The therapeutic effect of ciga- rette smoking on oral/genital aphthosis and other manifestations less inflammatory state over time. In pSS, a local effect of of Behcet’s disease. Clin Exp Rheumatol 19(5 Suppl 24):S77–S78 smoking on salivary glands rather than systemic effects of 10. Calkins BM (1989) A meta-analysis of the role of smoking in cigarette smoke may explain the previously observed nega- inflammatory bowel disease. Dig Dis Sci 34(12):1841–1854 tive association between smoking and pSS. 11. van der Mark M, Nijssen PC, Vlaanderen J, Huss A, Mulleners WM, Sas AM et al (2014) A case-control study of the protective effect of alcohol, coffee, and cigarette consumption on Parkinson Acknowledgements We acknowledge Käth Nilsson for assisting in the disease risk: time-since-cessation modifies the effect of tobacco collection and storing of serum samples, Jan-Åke Nilsson for input on smoking. PLoS One 9(4):e95297 the statistical analysis and Karin Skaarup, Karina Liebmann Madsen, 12. Arnson Y, Shoenfeld Y, Amital H (2010) Effects of tobacco smoke and Malene Billsten Zent for the analysis of serum cytokines. on immunity, inflammation and autoimmunity. J Autoimmun 34(3):J258–J265 Funding The study was supported by grants from the Sjögren’s syn- 13. Sopori M (2002) Effects of cigarette smoke on the immune sys- drome foundation, ALF-Skåne, the Kocks Foundation, the Internal tem. Nat Rev Immunol 2(5):372–377 Research Funds of Skåne University Hospital, and the Swedish Rheu- 14. Manthorpe R, Benoni C, Jacobsson L, Kirtava Z, Larsson A, matism Association. Liedholm R et al (2000) Lower frequency of focal lip sialadenitis (focus score) in smoking patients. Can tobacco diminish the sali- Compliance with ethical standards vary gland involvement as judged by histological examination and anti-SSA/Ro and anti-SSB/La antibodies in Sjogren’s syndrome? Ann Rheum Dis 59(1):54–60 Conflict of interest The authors declare no conflicts of interest. 15. Karabulut G, Kitapcioglu G, Inal V, Kalfa M, Yargucu F, Keser G et al (2011) Cigarette smoking in primary Sjogren’s syndrome: Ethical statement The study was approved by the Regional Ethical positive association only with ANA positivity. Mod Rheumatol Review Board for Southern Sweden (Lund, Sweden; LU 2012/98). 21(6):602–607 All patients gave written informed consent according to the Declara- 16. Stone DU, Fife D, Brown M, Earley KE, Radfar L, Kaufman CE tion of Helsinki. et al (2017) Effect of tobacco smoking on the clinical, histopatho- logical, and serological manifestations of Sjogren’s syndrome. Open Access This article is distributed under the terms of the Crea- PLoS One 12(2):e0170249 tive Commons Attribution 4.0 International License (http://creat iveco 17. 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Rheumatology InternationalSpringer Journals

Published: May 30, 2018

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