For Peer Review Hudaifa Alani¹, Julian R

Scandinavian Journal of Rheumatology

Systematic review and meta-analysis of the epidemiology of polyautoimmunity in Sjögren’s syndrome (secondary Sjögren’s syndrome)For Peer focusing Review on autoimmune rheumatic diseases

Journal: Scandinavian Journal of Rheumatology

Manuscript ID SJR-2016-0514.R2

Manuscript Type: Article

Date Submitted by the Author: 18-Apr-2017

Complete List of Authors: Alani, Hudaifa; Kettering General Hospital NHS Foundation Trust Henty, Julian; University College London Thompson, Nicolyn; University College London Jury, EC; University College London Ciurtin, Coziana; University College London, Department of Rheumatology

secondary Sjogren's syndrome, epidemiology, Meta-analysis, systematic Keywords: review, polyautoimunity

Scandinavian Journal of Rheumatology

United Kingdom United United Kingdom United and Coziana Ciurtin³* Coziana and Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

Systematic review and meta-analysis of the epidemiology of epidemiology of meta-analysis the review Systematic and For Peer Review Hudaifa Alani¹, Julian R. Henty², Nicolyn L Thompson³, Elizabeth Jury³ Jury³ L Elizabeth Nicolyn R. Thompson³, Henty², Hudaifa Julian Alani¹, Sjögren's syndrome Sjögren's : article : Polyautoimmunity in : Polyautoimmunity polyautoimmunity in Sjögren’s syndrome (secondary Sjögren’s syndrome) focusing on autoimmune rheumatic diseases rheumatic diseases autoimmune focusing on Sjögren’s syndrome) (secondary in syndrome Sjögren’s polyautoimmunity uthors: uthors: type Submission title Short A Kingdom United 8UZ, Kettering, NN16 General ¹Kettering Hospital, London, London, College Physics, University of Medical ²Department

³Department of Rheumatology, University College London, London, London, London, College University of Rheumatology, ³Department

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Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review , phone: +44(0)2034479035, fax: +44(0)20344797268 . fax: +44(0)20344797268 , +44(0)2034479035, phone: author: *Corresponding 2PG, email: NW1 Road, London, Euston 250 College London, University of Rheumatology, Department FRCP, Ciurtin, PhD, Dr. Coziana [email protected] associated associated with sSS. The ögren’s syndrome, prevalence, sex ratio, systematic review, meta-analysis. meta-analysis. review, ratio, sex systematic prevalence, syndrome, ögren’s l manifestations, laboratory features and causes of death Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review Prevalence rates of sSS vary widely in different populations. Both meta-analyses conducted in the RA and SLE populations were secondary Sjögren’s syndrome, polyautoimmunity in Sj polyautoimmunity syndrome, Sjögren’s secondary The epidemiology of polyautoimmunity in Sjögren's syndrome (secondary Sjögren's Sjögren's (secondary is in syndrome - of syndrome sSS) and Sjögren's not well-defined not was epidemiology polyautoimmunity The : : A systematic literature search of PubMed and Embase databases (updated to March 2016) was performed to identify all published The literature search identified 1639 citations, out of which 42 fulfilled the inclusion criteria. Only 19 studies had moderate to good revalence rates of pSS were summarised with PRs and 95% CIs. CIs. and 95% PRs with were summarised pSS rates revalence of quality quality and were selected for the meta-analysis. According to a random-effects model, the pooled PR for sSS associated with RA was 19.5% characterised by a high degree of study heterogeneity. The results of this meta-analysis highlighted the need for better quality population studies. studies. population for quality need better the highlighted meta-analysis this results of The heterogeneity. a of study by high degree characterised Keywords Results: (95% (95% CI 11.2 to 27.8) and the pooled PR for sSS associated with SLE was 13.96% (95% CI 8.88 to 19.04). The female/male ratio of sSS in the population. SLE in the to 32.4) CI 1.22 (95% 16.82 to and 256) (95% CI 7.09 14.7 RA was population Conclusion: investigated investigated before using a systematic approach. We conducted a systematic review of the epidemiology ofarthritis (RA), systemic lupus sSS erythematosus (SLE), scleroderma associatedand myositis, assessing the with prevalence rates (PRs) rheumatoid and clinical and serological features of sSS. Methods:

Abstract Abstract Objective: data on prevalence rate, demographic proﬁle, clinica p Page 3 of 71 Page 4 of 71 Previous Previous or or the purpose of Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review ur ur systematic review, we used the acceptedpreviously of terminology sSS, which enabled us to identify all the relevant papers. In addition, the apers focused predominantly on prevalence studies and distinct immunologic differences between different sSS subtypes, rather than term “polyautoimmunity” refers to clusters of autoimmune conditions, which may include or not autoimmune rheumatic diseases (8). o differences in clinical presentations or controversies regarding the patients’ diagnosis. diagnosis. the patients’ regarding or controversies clinical presentations differences in exocrine exocrine glands and epithelium, feature that is considered the histological hallmark of the disease The (1). T cell mediated attack on salivary and lacrimal glands results in chronic inflammation, which is considered in the majority of cases the cause leading to glandular andatrophy deficient glandular function (2). Although, the temporal relationship between the presence changes of associated glandular with ageing inflammatory and/or infiltrate disease and progression atrophic/fibrotic is difficult to appreciate, (3).SS with patients of and prognostication stratification the minor salivary gland biopsy have their role in the SS is characterised clinically by symptoms of dry mouth (xerostomia) and dry eyes (xerophthalmia), known as sicca symptoms. SS can progress to affect many organ systems (lung, kidney, gastro-intestinal tract, skin, musculoskeletal, and peripheral and rarely central nervous system), and as a result, other clinical manifestations ranging from mild to (5). lymphoma risk of with increased associated is SS (4). In addition, and lung disease interstitial failure neuropathy, renal more severe disease may occur, including: arthralgias, vasculitis, peripheral SS can occur either alone as primary SS (pSS) or in erythematosus (SLE), rheumatoid arthritis association (RA), systemic sclerosis (SSc), or dermatomyositis with(DM), in which case it another is known as secondary SS well-defined autoimmune condition, such as systemic lupus (sSS) (6). Although, some researchers prefer to use the term of “polyautoimmunity” associated with SS rather than sSS (7, 8), f Introduction of infiltration ofcases majority isin the with lymphocytic associated which autoimmune disorder, is(SS) chronic a syndrome systemic Sjögren’s p

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review The diagnosis of SS cannot be made on a single test or symptom. The variability in presentation of SS has led to a difficulty over the years in establishing universally accepted classification criteria. Therefore, there has been a variation in prevalence estimates in the few epidemiological studies that have been documented, as they used different classification criteria (1, 9). Although the clinical features of pSS are relatively well- accepted and cited criteria are the American-European consensus group classification criteria (AECG), which were published in 2002 as a researched researched in large epidemiological studies (10, 11), there are very few studies looking at the and epidemiology clinical and serological features of sSS. The authors felt that a systematic review of the epidemiology of sSS was needed in order to establish any significant differences in the Over the last few decades, diagnostic criteria have varied according to different national and international groups. At present, the most widely revision from the original European Study group criteria described in 1996 (2, 12). Interestingly, the presence of anti-Ro/La antibodies has not forcriteria were and SS recently developed validated (14, do 15). notAlthough, they any introducechanges, significant have been they validated SS. in expert diagnosing opinion the role of emphasised and patient cohorts, international in three Methodology We performed a andPUBMED EMBASE search for articles involving humans only, published between 1984 and 2016. The MESH terms used 1). (Figure of treatment studies and case-series, case reports, studies, questionnaire animal studies, editorials, commentaries, were: secondary Sjögren’s, epidemiology of Sjögren's syndrome, secondary Sjögren’s and systemic lupus erythematosus, secondary Sjögren’s and rheumatoid arthritis, secondary Sjögren’s and systemic sclerosis/scleroderma/CREST syndrome, and secondary Sjögren’s and myositis. As criteria for study selection, we considered all the studies on the epidemiology, diagnosis and follow-up of patients with sSS. We excluded presentation of sSS according to the background rheumatic condition of patients that might have impact on their long-term management. management. long-term their on might impact have that patients of condition rheumatic to the background according presentation of sSS been included asaclassification formandatory criteria sincesSS, it was tonot shown be in significant previous analysis (13). New classification Page 5 of 71 Page 6 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review tests of heterogeneity among studies). studies). among tests of heterogeneity 2 We appreciate a risk of reporting bias for the majority of studies as they addressed different populations and used different classification criteria for sSS. The study quality was weighted as poor, moderate and good based on the following criteria: number of patients, the use of established SS classification criteria, data about patient sex, ethnicity and disease duration, inclusion of lip biopsy in the classification criteria (especially as data under the following headings: prevalence and demographics of secondary Sjögren’s syndrome in different autoimmune diseases, clinical and laboratory features of Sjögren’s syndrome in different Sjögren’s autoimmune syndrome. Prevalence rates diseases, were calculated and using 95% CI. morbidity Pooled and prevalence rates mortality and sex associated ratios were calculated with using and the I Q on (based effects model a secondary random Results: The initial research yielded 1639 articles, which were screened for titles and inclusion and exclusion abovementioned criteria (the process of is selectiondetailed 1). in paper Figure an detailed additional Following manual abstracts, of which 37 were selected for review based on the further. analysed criteria were and the inclusion which met abstracts, and full papers 42 identified articles, we relevant of search other the serology is likely to be positive furtherwasnotreached, which consensus by case HA evaluated thein Thewere studiesand consensus. CC. wasan by 82% independently There in lupus patients, irrespective of concomitant SS). assessmentquality included were of study Thedetails three authors.two ofthe made assessmentbasedby the graded on and (EJ) authorthe third The assessment of study quality was reviewed We extracted data on prevalence, demographic proﬁle, clinical manifestations, laboratory features, underlying autoimmune diseases and causes tables. in them and available, organised articles, selected where from the of death Studies were grouped according to the following patient categories: 1). secondary Sjögren’s and systemic lupus erythematosus, 2). secondary Sjögren’s and rheumatoid arthritis, 3). secondary Sjögren’s and scleroderma and 4). secondary Sjögren’s and myositis. We present our results Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review designs included were retrospective, cross-sectional and prospective (Table 2). The number of patients used in each study ranged from 6 to 2694. to 2694. from 6 study each ranged in used patients of 2). The number (Table and cross-sectional prospective were retrospective, included designs used. they criteria classification the not specify Nine did studies (9). criteria other (1), and criteria We found 18 studies which looked at the prevalence of RA-sSS (between 1987-2013) (16-33), 13 for SLE-sSS (1998-2015) (34-46), 6 for SSc- sSS (1983-2013) (47-52) and 3 for myositis-sSS (2011-2014) (53-55). The prevalence ranged from 3.6%-55% for RA-sSS, 5%-22% SLE-sSS, 14%-60% SSc-sSS and 10-23% for myositis-sSS. In the RA-sSS studies three of the highest reported prevalence all came from studies carried in in Table 1. Based on this selection, 9 SLE studies and 11 RA studies assessed as having moderate to good meta-analysis. quality were included in the final diseases autoimmune with different associated of SS demographics Prevalence and Our search identified 40 worldwide studies, which evaluated the prevalence of sSS in patients with RA, SLE, SSc and myositis. The study Criteria sSS, (14), ECC (7), Japanese as AECG patientsclassification classify including having across to Different different were studies criteria the used 23). 20, (31- 39.8%)(18, patients out on Greek in Greece Gender of all studies (17/37) highlighted the ethnicity of the patients included in the study. study. the included in patients the ethnicity of the highlighted of all (17/37) studies Prevalence Prevalence Not Not all studies reported the gender of the patients, however in the 15 that did, females were predominantly affected (82%-100%). Less than half Page 7 of 71 Page 8 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review 36.1, p<0.001; 41.3 vs. 35.8, p=0.003; 50.8 vs. 43.6, p=0.01; 41 vs. 35 andp=0.03, 49.5 vs. 41.4 p<0.001). This was not found to be the case for RA-sSS patients when compared to RA patients as reported by two studies (63.0 vs. 59.2, p=0.33 and 66.36 vs. 62.40, p=NS) (21, 28). There of studiesprevalence cumulative Two rate that rolethe ofsSS.found occurrence any diseaseto in whether RAthe duration reported regard plays diseases: autoimmune with different of associated features sSS laboratory and Clinical We identified 17 studies assessing the clinical and laboratory features of sSS (Tables 3-4). The reported clinical features varied depending on In In five studies (36, 39, 42, 44, 45) SLE-sSS patients were reported to be significantly older when compared to those with SLE only (48.3 vs. was also no significant difference in age between SSc vs. SSc-sSS patients reported in three studies (56 vs. 54, p=NS; 50.2 vs. 55, p=0.18, and (50-52). 48.3 p=NS) vs. 50.5 Disease duration was reported in 26/40 studies and varied across all studies ranging from 4 months -12 years for RA-sSS (16, 20-23, 25, 27-29, (53-55). myositis-sSS for years 67 months to and 20 (47, 50-52), SSc-sSS 7-8 (34-37,44), 42, years 41, 39, SLE-sSS years 32,3-46 33), Only the RA-sSS studies looked into the relationship between disease duration and sSS incidence rate. There were conflicting reports with 28). 25, 22, (21, four studies other by supported was not however, finding This (19, 29). duration RA sSS did with increase at. looked with sSS being was which associated condition Age Age Disease duration Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review compared compared to RA patients (22, 27), while the other half reported no significant (27). involvement and CNS lung, renal thyroiditis, lymphadenopathy, including clinical features difference (21, 28). Only one reported study looked at other Laboratory analysis was mainly focused on RF, anti-CCP, CRP and ESR levels. There was inconsistency concerning the reported RF levels. involvement and central nervous system (CNS) involvement. Renal involvement was found to be across significantly five studies (36, 37, 39, 44, reduced 45), while thyroiditis was found to be higher.significantly in CNS involvement prevalence, although reduced in SLE-sSS patients SLE-sSS patients, was not significant in any of the three studies. Only one study reported no cases of lymphoma in their cohort of 26 SLE-sSS Regarding serological markers, only anti-Ro/SSA and anti-La/SSB antibodies were raisedsignificantly in SLE-sSS compared to SLE patients in five studies (36, 37, 39, 42, 44). Anti-dsDNA was 45). (36, in significant two studies was only this although patients, lower in SLE-sSS higher was Thrombocytopenia in SLE patients and this reached significance in four studies (37, 39, 42, 44). Koskenmies et al. reported that sSS was most commonly observed in patients with subacute cutaneous lupus erythematosus (SCLE) and SLE . p<0.001) (43) 2.3%, vs. (16.4% vs. 22.1% erythematosus lupus than with discoid in patients Five studies addressed clinical features of RA-sSS patients (21, 22, 25, 27, 28). The majority reported data on joint swelling, tender joints and patients RA-sSS in higher were significantly joints tender reported 28 the that score).studies Half joints(DAS 28 score assessing activity disease Three studies (22, 25, 27) reported higher levels of RF in RA-sSS patients, one being significant, while the (21, 28). although studies, not significant opposite was found in two other Of the seven studies (36, 37, 39, 42, 44-46) assessing clinical features of SLE-sSS, the majority reported data on the presence of renal patients (36), although they reported 8 cases of lymphoma in their pSS comparative group (N=86) . (N=86) comparative group pSS their in of lymphoma cases they 8 reported although patients (36), RA-sSS RA-sSS SLE-sSS SLE-sSS Page 9 of 71 Page 10 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review Four studies (47, 50-52) reported data about lung involvement, mainly pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH). PF occurred significantly less frequently in SSc-sSS patients. Only one study reported lower occurrence of PAH in SSc-sSS, which was significant (52). The majority of studies looked at anti-topoisomerase 1 antibodies and anti-centromere (ACA) levels. ACA levels were significantly higher in 1 antibodies. of anti-topoisomerase the prevalence regarding there However,was discrepancy (50-52). three studies all patients across SSc-sSS In one study, all six patients with both diseases presented with a pattern of muscle weakness typical of IBM (53). Five IBM-sSS patients were treated with prednisolone and methotrexate, four of whom had temporary symptomatic improvement to treatment. response a had transient 27% whom in only only group IBM comparison to the (6-24 in response months). This was a far greater Immunogenetic analysis was carried out in two studies. In one study there was no significant difference between the SLE and SLE-sSS patients when looking at the HLA alleles (42). However, in another study, the HLA associations distinguished the SLE group from those with SLE-sSS. SSc-sSS SSc-sSS Myositis-sSS Immunogenetics SLE-sSS Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review Those Those with SLE were found to have increased phenotype and allele (36). that significant was p<0.001) DQB1*0602 (both frequencies for DRB1*1501 (p=0.020 and p=0.015, respectively) and In the study mentioned above (53), all six patients carried the HLA-DRB1*0301 allele or its equivalent HLA-DR3 serological specificity. They also carried either all or some of the major markers of the 8.1 MHC ancestral haplotype. This allele was also among thereported Norwegian patients (25%), included whichin another study afound prevalence of of rheumatic 24%, disorders which is as twice to high be highly prevalent (55). reported previously as sSS with associated mortality Morbidity and In a few RA studies other aspects of the disease including its effect on quality of life and its involvement in haematological malignancies was studied. In three of the five studies measuring health status there was no difference in the DAS-28 mean scores in RA-sSS compared to RA patients (21, 25, 28). In two other studies (22, 27) however, a higher DAS-28 score was found in RA-sSS patients, compared to RA patients (6.44 vs. 5.96, Myositis-sSS Myositis-sSS Health status Health status RA-sSS p=0.02 and 5.08 vs. 4.20, p=<0.001, respectively). respectively). vs. 4.20, p=<0.001, p=0.02 5.08 and Page 11 of 71 Page 12 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review . (45) reported a significantly reduced overall mortality in patients with SLE-sSS compared to SLE patients (4% vs. 13.5%, . looked at the survival of sSS patients in a population-based sample in Minnesota, USA between 1976 and 1992. Of the 74 cases et al et al Furthermore, Furthermore, when studied separately, the mortality was increased in sSS compared to pSS patients (p=<0.005), with the majority of sSS

One study (22) looked at other health status measures including pain visual analogue scale Assessment (VAS) Questionnaire scale, (M-HAQ), fatigue and VAS found and that Modified the Health RA-sSS patients scored significantly higher in all three tests in comparison to RA 24 24 (33%) had sSS and 50 (67) had pSS. It found that when compared with the general population, SS patients had increased mortality (p=0.04). (36, (36, 45). Martens patients (43.1 vs. 32.9, p =<0.01; 49.8 vs. 39.7, p=0.03, and 1.75 vs. 1.55, p=0.04, respectively). Another study (28) looked at both M-HAQ and patients having associated RA (p= 0.86) (56). associated 0.86) (p= RA patients having RA-sSS Haematological malignancy and mortality and mortality malignancy Haematological SLE-sSS Nossent p=0.01). In two studies in which patients where followed up for three years and 8 years respectively, none of the patients developed lymphoma pain VAS tests and reported similar findings in both groups of patients (0.84 vs. 0.81, p=0.7, and 35.9 vs. 42.4, p=0.3, respectively). respectively). 42.4, p=0.3, and vs. 35.9 0.81, p=0.7, (0.84 vs. patients of groups both findings in similar reported and pain VAS tests = 99.98 for 2 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

. compared the incidence of NHL in 9,469 RA patients and 709 sSS patients. This study found the For Peer Review et al described a new clinical phenotype of “ACA-positive limited scleroderma/SS overlap syndrome”, which in their retrospective et al. the SLE studies and 99.92 for the RA studies; therefore, we used a random effect statistical model for calculating the pooled prevalence). The 3. 2 and Figures are in presented the meta-analysis results of We also analysed the sex ratio of sSS patients in the SLE and RA populations, which revealed a clear predominance of female patients (four RA studies that reported all patientstheir sSS/RA females). were The female: male ratios were CI 16.82 (95% 1.22 to 32.4)for the patients SLE-sSS population. for RA-sSS the to CI 256) 7.09 and (95% 14.7 Discussions incidence of NHL to be almost two-fold in patients with RA-sSS (8.7, CI=4.3-1.6) compared to RA patients (4.5, CI=1.5-11) (56). (56). CI=1.5-11) RA(4.5, patients compared to CI=4.3-1.6) (8.7, RA-sSS in patients with totwo-fold almost NHL of be incidence With regard to haematological malignancies, studies have reported increased incidence of lymphoma non-Hodgkin’s (NHL) in RA-sSS patients. A Finnish study carried out by Kauppi Baldini (57). lymphoma of non-Hodgkin's risk a at high course but clinical a benign by SSc study characterised was SLE RA and with sSS associated ratios sex of and rates of analysis Meta- prevalence The results of the meta-analysis revealed a pooled prevalence of 13.96% (95% CI 8.88 to 19.04) in the populationSLE and 19.5% (95% CI 11.2 to 27.8) in the RA population. The statistical analysis of the selected studies revealed a high degree of heterogeneity as expected (I SSc-sSS SSc-sSS Page 13 of 71 Page 14 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review Secondary SS is characterised by a heterogeneity of clinical manifestations, serological markers and symptoms, which are influenced by rheumatic rheumatic diseases are lacking. Previous studies were interested in comparing the clinical and laboratory features alone or (as associated thewith sSS majority of the included studies systematicin this review), or aimed to compare the of epidemiology pSS vs. of an autoimmune disease antibody positivity (59), or had significantly higher levels of IL-2 and IL-6 in their saliva (60). An old study also suggested that extraglandular (61). compared to sSS in common pSS more features are Our study could not address any controversies regarding the accuracy of patients’ diagnosis (e.g. many clinicians’ might decide based on their expert opinion to diagnose a patient as having RA associated with SS rather than symmetrical polyarthritis in the addition, context our systematic of review primary does SS). not In imply that patients with sSS associated with different ARDs have similar features (e.g. SLE and SS moderate-good quality studies were included in the meta-analysis, the studies with poor quality were also detailed in the paper. In addition, our sSS sSS (this was beyond the scope of our systematic analysis). Other papers explored the communality clinical of picture serological in abnormalities distinct and autoimmuneshared rheumatic diseases, such as RA and pSS (58), or autoimmune diseases, is advocated better described as that “polyautoimmunity” (7), as discussed the in introduction. However, this association terminology is not of particularly SS with multiple exact in relation to the presence of clinical and serological features of SS in the (8). diseases autoimmune other of associations with SS refers it to also review), as context of rheumatic conditions (which is the focus of this There is evidence of a great degree of heterogeneity within all these populations; although previous research established that pSS is associated with a different disease phenotype compared to sSS: e.g. pSS patients had a higher frequency of parotid gland enlargement and Ro and La patients’ patients’ underlying pathology. Unfortunately, large prospective studies comparing patients with sSS associated with different autoimmune patients might have similar clinical presentation, which is not the case with patients with SS associated with SD or myositis). Even if only The The confidence intervals of sex Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review espite the effort to define the sSS patient population better, clinicians are still unable to answer practical questions regarding the difference in atios in the SLE and RA patients with associated sSS reflected again the high heterogeneity of the studies and the inclusion of studies, which reported the presence of sSS exclusively in the female population. female population. in the exclusively sSS of the reported presence to patients defined as having overlapping syndromes rather than sSS (57) or which contained no data about sSS prevalence (62). about prevalence sSS no data contained or which (57) than rather sSS syndromes overlapping as having to defined patients Our analysis revealed that sSS is more common in women, irrespective of the underlying autoimmune disease. r D systematic review systematicalso for even reported review the if approach, systematicarticle relevant on theme, papers as such not selected by referring our papers the long term outcome of sSS associated with an autoimmune disease compared to having only an autoimmune disease, or regarding the best way way to stratify these enablepatients of the to choice suitable the Ittherapeutic most options. is that sSS is recognized characterised significant by amount of variability in clinical presentation, which is influenced by the concomitant autoimmune disease; however, different studies reported various various epidemiological features in the context of similar background autoimmune disease. This variation can be in part explained by classification criteria applied, as well theas patient selection criteria, their or ethnicity genetic SS and background, possible reporting bias (45, 63). Our results show that Raynaud’s phenomenon, thyroiditis and Ro, La antibody positivity seemed to be more frequent in SLE-sSS patients compared to SLE group, while renal involvement and presence of dsDNA, and anti Sm antibodies were more common in the latter group. A less clearly defined trend was in identified the case ofand thrombocytopaenia lung involvement, while the CNS involvement was reported in only one study as more frequent in the SLE-sSS group. group. SLE-sSS in the frequent as more The number of tender and swollen joints was more commonly reported in the RA compared to RA-sSS group, however, the RA-sSS group had more CNS involvement, Raynaud’s phenomenon, thrombocytopaenia and hypergammaglobulinaemia. and hypergammaglobulinaemia. thrombocytopaenia Raynaud’s phenomenon, CNS more involvement, Page 15 of 71 Page 16 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review conditions, and the quality of the studies was poor, no assumptions can be made about the difference made in for patients’ clinical the phenotype, apart from additional clinical symptoms of dryness, presentation and a possible of subset of patients SSc-sSS with overlap syndrome with (57). milder presentation disease Importantly, studies of both SLE and SSc populations hinted at the possibility that these patients have the highest risk of lymphoma of all the 57). (44, disease autoimmune groups Our systematic review included mainly prevalence studies (as the large population studies were lacking) and reported prevalence incidence figures (as sSS is reported rather in patient groups rather than general population, and the than appreciation of the newly diagnosed cases per year necessitates long prospective studies not available in the literature). The quality of the studies included in the analysis was poor to moderate were excluded from the final analysis); variable number of patients included (from 6 having to SS based on 2694); salivary gland different biopsy (14 studies proportion included the of biopsy as a patients classification criteria for classified all the as sSS patients, and 5 studies for a variable proportion of patients); limited geographic areas (only one study evaluated patients from extrapolate data two to different other populations countries), (there and were no difficulty studies to from South America, Africa or Oceania). There was also evidence statistical of significant heterogeneity in our meta-analysis of sSS prevalence in SLE and RA patients, studies. differences between probably due to both, clinical and methodological sSS in the context criteriaunderlying for ofdifferent the regarding diagnostic/classification unmet a an The authors foridentified consensus need autoimmune diseases, especially in the group of SLE/sSS, which is characterised gland biopsy. salivary a absence positive of in the diagnosis difficult by shared clinical and serological features that make the In In the and themyositis scleroderma groups, main differences seenwere in theof antibodiespositivity (the more characteristic being disease ones prevalent in their corresponding group). However, as there was no significant overlap between the clinical features of these autoimmune criteria of classification becausecriteria reasons: and did not of use patient studies (12 inclusion following heterogeneity significant validated the

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review CC was funded by a British Research (BRC-III/003). grant Research Council British CCa by funded was 2. 2011;141:1-9. Lett Immunol pathogenesis. Jonsson 3. R, Vogelsang P, Volchenkov R, Espinosa A, Wahren-Herlenius M, Appel as its focus potential a on with syndrome Sjogren's primary in S. histopathology gland salivary F.review of A Barone SJ, Bowman RM, Brown BA, Fisher The complexity of Sjogren's syndrome: novel aspects on 2012;39:199-205. Autoimmun J polyautoimmunity. of crossroad 9. 2006;45:187-91. (Oxford) Rheumatology 1982-2003. Alamanos Y, Tsifetaki N, Voulgari PV, Venetsanopoulou AI, Siozos C, 10. Drosos AA. of Epidemiology primary Sjogren's syndrome in north-west Greece, 2014;66:454-63. Res Care Arthritis area. Maldini C, Seror R, Fain O, Dhote R, Amoura Z, De Bandt M, et al. Epidemiology of primary Sjogren's syndrome in a French multiracial/multiethnic References: ofofcharacteristics sSS, evaluatethis which aimed the ofto meta-analysis epidemiology thisIn conclusion,and the isfirst the review systematic heterogeneous population. Because of the lack of prospective longitudinal data in large population studies, there are still unanswered questions diseases. autoimmune common features less in laboratory and clinical their or patients of these malignancy related risk to the Acknowledgement: 1. 2012;39:9-14. Autoimmun J review. critical a syndrome: Sjogren's for criteria Classification S. Bombardieri AG, Tzioufas R, Talarico C, Baldini 2015;74:1645-50. Dis Rheum Ann biomarker. trials clinical a 4. 5. 2014;6:247-55. Epidemiol Clin syndrome. Sjogren's of epidemiology The A. Shahane R, Patel 2013;65:816-21. Res Care Arthritis study. population-based a syndrome: Johnsen 6. SJ, Brun JG, Goransson LG, Smastuen MC, viii-ix. 2008;34:935-47, Johannesen TB, Haldorsen K, et al. Theander Risk E, 7. Jacobsson of LT. Relationship non-Hodgkin's of Sjogren's lymphoma syndrome to in other connective primary tissue and Sjogren's autoimmune disorders. Rheum 2016;42:457-72. Am Dis Clin North Am. Anaya JM, Rojas-Villarraga 8. A, Mantilla RD, Arcos-Burgos M, Sarmiento-Monroy JC. Polyautoimmunity in Sjogren Syndrome. Rheum Dis Clin North Amador-Patarroyo MJ, Arbelaez JG, Mantilla RD, Rodriguez-Rodriguez A, Cardenas-Roldan J, Pineda-Tamayo R, et al. Sjogren's syndrome at the Page 17 of 71 Page 18 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-8. 2002;61:554-8. Dis Rheum Ann Group. Consensus American-European the by proposed criteria European the of version 13. 1993;36:340-7. Rheum Arthritis Community. European theby supported action concerted prospective a of Results syndrome. Vitali C, Bombardieri S, Moutsopoulos HM, Balestrieri 14. G, Bencivelli W, Bernstein RM, et al. Preliminary criteria for the classification of Sjogren's Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of League Rheumatology/European Against 11. 11. 2015;74:1983-9. Dis Rheum Qin B, Wang J, Yang Z, Yang M, 12. Ma N, Huang F, et al. Epidemiology of primary Sjogren's syndrome: a systematic review and meta-analysis. Ann Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjogren's syndrome: a revised classification criteria Rheumatism for primary Sjogren's A syndrome: consensus and methodology involving data-driven three international patient cohorts. 2017;76:9-16. Dis Rheum Ann 15. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of League Rheumatology/European Against 2003;62:897-900. Dis Ann Rheum severity. disease of estimates and manifestations 20. 2002;31:361-70. Rheum Arthritis Semin populations. European ofMediterranean meta-analysis and Greece in associations Ioannidis JP, Tarassi K, Papadopoulos IA, Voulgari PV, 2012;15:284-8. Dis Rheum J Int profile. treatment and activity disease to itsassociation and arthritis, rheumatoid Boki KA, Papasteriades CA, et 22. al. Shared epitopes and rheumatoid 1999;58:415-22. Dis arthritis: Rheum disease Ann arthritis. rheumatoid with patients 636 in variables disease and tear production, and saliva symptoms, T. Axell Sicca JL, Jensen TK, Kvien T, Uhlig 23. 1987;14:1098-103. Andonopoulos AP, Drosos AA, Skopouli FN, Acritidis NC, 24. Moutsopoulos HM. Secondary Sjogren's syndrome in rheumatoid arthritis. J Rheumatol 2000;27:2611-6. Rheumatol J arthritis. rheumatoid with inpatients syndrome Sjogren's Mattey DL, Gonzalez-Gay MA, Hajeer 25. AH, Dababneh A, Thomson W, Garcia-Porrua C, et al. 2011;57:319-22. Bras Association between HLA-DRB1*15 and Antero DC, secondary Parra AG, Miyazaki FH, Gehlen M, Skare TL. Secondary Sjogren's syndrome and disease activity of rheumatoid arthritis. Rev Assoc Med Rheumatism Rheumatism Classification Criteria for Primary Sjogren's Syndrome: 2017;69:35-45. Rheum Arthritis Cohorts. A Consensus and Data-Driven Methodology Involving 16. Three International Patient 2003;62:722-7. Dis Rheum Ann years. 46 over factors risk C, WM, O'Fallon Turesson CS, SE, Crowson trends and arthritis: Mattesonincidence Gabriel in Extra-articular disease EL. rheumatoid manifestations 17. 2006;24:305-8. ExpRheumatol Clin in Turkey. 526 patients of hospital Calguneri M, Ureten K, Akif Ozturk M, Onat AM, Ertenli I, Kiraz S, et al. manifestations of Extra-articular rheumatoid arthritis: results of a university 18. 1992;35:745-8. Rheum Arthritis study. serologic Drosos AA, Lanchbury JS, Panayi GS, Moutsopoulos HM. Rheumatoid arthritis in Greek and British 19. patients. A comparative clinical, radiologic, and Carmona L, Gonzalez-Alvaro I, Balsa A, Angel Belmonte M, Tena X, Sanmarti R. Rheumatoid arthritis 21. in Spain: occurrence of extra-articular Haga HJ, Naderi Y, Moreno AM, Peen E. A study of the prevalence of sicca symptoms and secondary Sjogren's syndrome in patients with Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review 26. 26. 4:S61-9. Suppl Thai2012;95 Assoc MedJ arthritis. rheumatoid with Kosrirukvongs P, Ngowyutagon P, Pusuwan P, Koolvisoot A, Nilganuwong 27. S. Prevalence of dry eye syndrome and Sjogren's syndrome in patients He J, Ding Y, Feng M, Guo J, Sun X, Zhao J, et al. Characteristics of Sjogren's syndrome in rheumatoid arthritis. Rheumatology (Oxford) 2013;52:1084-9. 2013;52:1084-9. 28. 2016;5:1287-93. Res JMed MedBr Arthritis. Rheumatoid Abdelghani KB, Mahmoud I, Chatelus E, Sordet 29. C, Gottenberg JE, Sibilia J. Clinical and Serological Features of SjogrenSyndrome in Patients with 2007;21(5):907-27. Rheumatol. Res Clin Pract Best arthritis. ofrheumatoid and complications manifestations Extra-articular G. Koduri A, Young 30. 30. 2005;140:808-13. Fujita M, Igarashi T, Kurai T, Sakane M, Yoshino S, 31. Takahashi H. Correlation between dry eye and rheumatoid arthritis activity. Am J Ophthalmol. 1990;94:655-9. (Barc) Clin Med arthritis]. rheumatoid of time the course to reference Special syndrome. Martinez Castro E, Olive Marques 32. A, Bonet Llorach M, Carbonell Abello J, Cobo Valeri E, Aliko A, Ciancaglini Junca R, Alushi A, Tafaj A. Valdor Sicca symptoms, and lacrimal and salivary flow S.in Albanian patients with rheumatoid arthritis. J Oral [Rheumatoid Pathol arthritis and Sjogren's 2000;59:230-2. Dis Rheum 36. 2004;50:882-91. Rheum Arthritis syndrome. Sjogren's primary with comparison and profiles laboratory and clinical erythematosus: lupus Manoussakis MN, Georgopoulou C, Zintzaras E, Spyropoulou M, Stavropoulou A, Skopouli FN, et al. Sjogren's syndrome associated with systemic Med 2010;39:651-6. 2010;39:651-6. Med 33. Int2000;19:213-7. Rheumatol arthritis. rheumatoid Cimmino MA, Salvarani C, Macchioni P, Montecucco C, 34. Fossaluzza V, Mascia MT, et al. Extra-articular manifestations in 587 Italian patients with patients with systemic lupus erythematosus and of sicca probability the symptoms determine to status fulfilling antibody anti-Ro/La criteria and age Usepatient of for et S, al. A, Heaton Bawendi T, secondary Plant Sjogren's C, Gordon T, Marshall A, syndrome. Prabu Rheumatology (Oxford) 2003;42:189- 91. 35. McDonagh JE, Isenberg DA. Development of additional autoimmune diseases in a population of patients with systemic lupus erythematosus. Ann 37. Gilboe IM, Kvien TK, Uhlig T, Husby G. Sicca symptoms and secondary Sjogren's syndrome in systemic lupus erythematosus: comparison with rheumatoid arthritis and correlation with disease variables. Ann Rheum Dis 2001;60:1103-9. 2001;60:1103-9. Dis Rheum Ann variables. disease with correlation and arthritis rheumatoid 38. Int2014;34:11-24. Rheumatol Spain. from Northwest erythematosus lupus Alonso MD, Martinez-Vazquez F, L, Riancho-Zarrabeitia Diaz de Teran T, Miranda-Filloy JA, Blanco R, et al. Sex differences in patients with systemic 39. 2008;27:339-43. Rheumatol Clin patients. of542 study aChina: in syndrome Pan HF, Ye DQ, Wang Q, 40. Li WX, Zhang N, Li XP, et al. Clinical and laboratory profiles 2015;e000084. SciMed Lupus of disease. 'pure' with those from differ disease systemic autoimmune overlap with Patients Erkan D. AB, Levine MD, lupus Lockshin erythematosus associated with Sjogren 41. 41. 2015;2015:298506. Dis Autoimm Families. Lupus R, Aggarwal Anaya JM, KA, Koelsch Kurien BT, Scofield RH. between Association Secondary and Primary Sjogren's Syndrome in a Large Collection of 42. 2006;67:924-30. Immunol Hum erythematosus. lupus systemic and Szanto A, Szodoray P, Kiss E, Kapitany A, Szegedi G, Zeher M. serologic, Clinical, and genetic profiles of patients with syndrome Sjogren's associated Page 19 of 71 Page 20 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review systemic lupus. Ann Rheum Dis 2007;66:410-3. 2007;66:410-3. Dis Rheum Ann lupus. systemic 47. Osial TA, Jr., Whiteside TL, Buckingham RB, Singh G, Barnes EL, Pierce JM, et al. Clinical and serologic study of Sjogren's syndrome in patients with 43. 43. 2008;17:337-47. Lupus manifestations. cutaneous with patients S, Koskenmies TM, Jarvinen P, Onkamo Panelius J, Tuovinen U, Hasan T, et al. and Clinical laboratory of characteristics Finnish lupus erythematosus 44. 2010;37:1143-9. Rheumatol J subset. Baer AN, Maynard JW, Shaikh F, Magder 45. LS, Petri M. Secondary Sjogren's syndrome in systemic lupus erythematosus defines 46. a distinct disease 1998;7(4):231-4. Lupus. syndrome. Sjogren's secondary of impact and frequency VII: erythematosus lupus Systemic AJ. Swaak JC, Nossent familial in syndrome Sjogren's of secondary diagnosis with a associated is disease thyroid B. Autoimmune Namjou Harley JB, Bruner GR, RH, Scofield 1983;26:500-8. Rheum Arthritis sclerosis. systemic progressive 48. 1988;15:965-8. Rheum J sclerosis. Drosos AA, Andonopoulos AP, Costopoulos JS, Stavropoulos ED, Papadimitriou CS, Moutsopoulos HM. Sjogren's syndrome in 49. progressive systemic 1991;18:1685-8. Rheumatol J scleroderma. systemic Drosos AA, Pennec YL, Elisaf M, Lamour A,50. Acritidis NC, Jouquan JR, et al. Sjogren's syndrome in patients with the CREST variant of progressive to and relationship syndrome Sjogren's Sibilia MC, J, Vacher-Lavenu J, M, et sclerosis-associated Ardizonne Sordet Avouac C, al. Depinay Systemic C, 55. 2015;22:672-e41. J Eur Neurol. study. epidemiology clinical a population-based in Norway; myositis inclusion body of et al. Stjarne High prevalence J, T, Bitter H, L, Sveberg Garen EA, Antal GC, Dobloug 56. 1997;8:201-4. Control Causes Cancer (Finland). arthritis rheumatoid Kauppi M, Pukkala E, Isomaki H. Elevated incidence of hematologic malignancies in patients with Sjogren's syndrome compared with patients with 57. 2013;31:272-80. Rheum Exp Clin lymphoma. risk of high at but involvement organ mild with entity clinical distinct Baldini C, Mosca M, Della Rossa A, Pepe P, Notarstefano C, Ferro F, et al. Overlap of ACA-positive systemic sclerosis and Sjogren's syndrome: a the limited cutaneous subtype: results of a prospective study of sicca syndrome in 133 consecutive patients. Arthritis Rheum 2006;54:2243-9. 2006;54:2243-9. Rheum Arthritis patients. consecutive in133 syndrome sicca of study aprospective of results subtype: cutaneous limited the 51. 2007;46:321-6. Rheum sclerosis. Salliot C, Mouthon L, Ardizzone M, Sibilia J, Guillevin L, Gottenberg JE, et 52. al. Sjogren's syndrome is associated with and not secondary to systemic 2013;16:88-92. Kobak S, Oksel F, Aksu K, Y. Kabasakal The of frequency sicca symptoms and Sjogren's syndrome in patients with sclerosis. systemic Int J Rheum Dis 53. 2011;113:559-63. Neurosurg Neurol Clin haplotype. ancestral theMHC 8.1 and HLA-DR3 of in carriers syndrome Rojana-udomsart A, Needham M, Luo YB, Fabian 54. V, Walters S, Zilko PJ, et al. 2010;77:125-30. Spine The Bone Joint patients. 169 study of retrospective association classification: for clinical Relevance dermatopolymyositis: of primary to comparison sporadic inclusion body myositis and Vancsa Sjogren's A, Gergely L, Ponyi A, Lakos G, Nemeth J, Szodoray P, et al. Myositis-specific and myositis-associated antibodies in overlap myositis in 58. 2015;53:61-8. Reumatologia patients. syndrome Sjogren's Koszarny A, Majdan M, Dryglewska M, Tabarkiewicz 59. J. Prevalence of selected organ-specific autoantibodies in rheumatoid arthritis and 2010;37:800-8. Rheumatol J primary syndrome. Sjogren's secondary and primary between G, Avila-Casado C, Hernandez-Molina C, Cardenas-Velazquez F, Calderillo ML, Hernandez-Hernandez Marroquin V, et al. Similarities and differences prevalence of sSS and RA sSS and prevalence of Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review Disease duration Disease duration Relation between : Studies reporting the disease duration and relationship with the sSS prevalence in RA patients. in RA prevalence sSS with the and duration the relationship disease reporting : Studies syndrome, syndrome, secondary Sjogren's syndrome, and patients with primary Sjogren's syndrome receiving varying doses of interferon for symptomatic treatment 60. 60. Streckfus C, Bigler 2001;5:133-5. OralInvest Clin study. preliminary a the condition: of L, Navazesh M, Al-Hashimi I. Cytokine 61. concentrations in stimulated whole saliva 1994;13:438-41. among patients Rheum Clin disease. secondary versus in Israel: primary syndrome et S, al. Sjogren's Bendet I, E, Bombardieri M, Ehrenfeld A, Aharon Avni M, Tishler with primary Sjogren's 62. SSwith secondary association and with of characteristics RA NA, patients Clinical KP. Liao Shadick ME, Weinblatt CK, LE, FritsML, Iannaccone Brown 63. 1990;17:201-4. Andonopoulos AP, Skopouli FN, Dimou GS, Drosos AA, Moutsopoulos HM. Sjogren's syndrome in systemic lupus erythematosus. J Rheumatol. legends: Figure selection. of study Figure 1: Flowchart patients. in SLE sSS prevalence of the of Figure 2: Meta-analysis in RA patients. sSS prevalence of the of Figure 3: Meta-analysis Table 1 Study joint damage. Rheumatology (Oxford) 2015;54:816-20. 2015;54:816-20. (Oxford) Rheumatology damage. joint Page 21 of 71 Page 22 of 71 Prevalence at 1 year at4%, and 1 Prevalence year None None disease duration duration disease Prevalence at 10 years 17%, after years and 30 25% years 10 after 12% None None Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review 10.63 years 10.63 years 10 years 10 years 12.2 years 12.2 years 15.6 years -

Young et al.,2000 Young Uhlig al.,1999 et Uhlig al., 2011 et Antero Abdelghani, 2014 10.2 7 +/- years al.,2003 Carmona et Haga et al.,2012 et Haga al.,2012

Moderate Moderate Moderate Moderate Good Good Poor Study quality

12 patients tested All NA NA tested All tested All NA Salivary Salivary gland biopsy tested

8 years 8 years 18 years 8 years 10.9 years 3.5 years 8.1 NA Disease Disease duration (years/months)

A 22/5 N 9/0 18/0 26/0 52/4 NA Female/male Female/male (n)

A N Caucasian Caucasian Caucasian Caucasian NA Ethnicity NA Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology Systemic lupus erythematosus lupus Systemic N=27 N=28 N=9 N=18 N=26 N=56 N=169 Number Number of sSS (%)cases (19.6%) (13%) (11%) (19%) (9%) (15%) (15%) Studies included in the systematic review systematic included in the Studies : :

Table Table 2 ECC ECC ECC AECG AECG AECG NA Criteria Criteria used For Peer Review

138 215 81 96 283 362 1138 Number Number of patients

Norway/ Norway/ UK Norway UK Greece Hungary USA Country Netherlands (London) (Oslo) (Birmingham) (Athens) (Debrecen) (Oklahoma)

P R R R R R Study design CS

Page 23 of 71 Nossent al,et 1998 McDonagh al,et 2000 Gilboe al, et 2001 Bowman al,et 2003 Manoussakis et 2004al, 2006 2007 Szanto et al, al, Szanto et al,Scofield et Page 24 of 71

Good Poor Good Poor Poor Good Good Poor

All tested All NA tested All NA NA NA tested All tested All

9.1 years 9.1

A A 3.7 years 3.7 NA years 19.5 N N years 20 3.3 NA

A 32/3 NA 253/6 27/0 N 504/44 NA NA

A A Asian Chinese Asian NA N N Mixed (White, Greek Spanish White= 70.7White= African American= 25.5 1.9Hispanic= Asian= 1.2 Black, Hispanic, Asian native) and heumatoid arthritis heumatoid

R Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology N=35 N=17 N=259 N=27 N=28 N=548 N=34 N=24 (6%) (6%) (22%) (14.5%) (18%) (5%) (20%) (31%) (55%)

A A

AECG NA AECG For PeerN Other ReviewAECG Other N

542 77 1790 150 600 2694 111 45

China Finland USA Spain USA USA Greece Spain (Helsinki) (Helsinki) (Marylands) (Lugo)

R R CS CS/R R L P CS

Pan et al, 2008Panal, et Koskenmies et 2008al, Baer al,et 2010 al,et Maria 2013 al,et Lockshin 2015 2015 1987al, Martinez Castro 1990al, et Aggarwal et al,Aggarwal et Andonopoulos et

Moderate Moderate Poor Poor Poor Moderate Poor Moderate Poor Poor Good

All tested All NA NA NA NA NA NA NA NA NA tested All

years

11 months 11

- NA years 12.2 years 10 NA 4 years 10.5 years 46 NA NA NA 10.2

A NA NA NA NA 46/9 NA N NA 7/0 NA 18/2

A Greek/British NA Italian NA N Greek NA Spanish Japanese NA NA Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology GK GK N=43 N=46 N=103 N=22 N=54 N=57 N=58 N=134 N=7 N=28 N=20 (39.8%) (39.8%) BS N=17 (15.9%) (7%) (17.5%) (12.3%) (7%) (32.7%) (9.5%) (17%) (10%) (5.3%) (24.3%)

G N

A A

Other ECC Other ForOther PeerN ECC ReviewOther ECC Japanese N AEC

G=108 636 587 179 732 174 609 788 72 526 82 B= 107 107 B=

Greece/British Norway Italy Spain UK Greece USA Spain Japan Turkey Brazil Ioannina/London Ioannina/London (Oslo) (Northern) (Lugo) (Ioannina/ Athens) (Minnesota) (Tokyo) (Ankara) (Curitiba)

CS CS CS CS P CS R CS P R CS

Page 25 of 71 Drosos et al, Drosos et 1992 al, Uhlig 1999et Cimmino al, et 2000 Mattey al, et 2000 Young al, et 2000 al, Ioannidis et 2002 etTuresson al, 2003 Carmona al, et 2003 2005 Fujita al, et etCalgüneri al, 2006 2011 Antero et al,et Antero Page 26 of 71

Poor Moderate Moderate Good Moderate Good Good Poor Poor Good

NA NA NA 16 patients tested patients 9 NA tested All tested All tested All 91 patients tested tested tested

years

5 years 5 years NA 10.6 9. months 15.10 years 15.6 years 16.9 7.3 NA NA 7

A NA NA NA 64/10 N 76/9 16/1 NA NA 16/3

sis o

NA NA Albanian Chinese French 89.4 White= NA NA NA NA Systemic scle Systemic

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology N=14 N=11 N=13 N=74 N=11 N=85 N=17 N=9 N=14 N=19 (22.2%) (22.2%) (3.6%) (14.8%) (14.5%) (14%) (10.3%) (29%) (20.5%) (60%) (14%)

Other AECG ECC AECG ForAECG PeerAECG ReviewOther Other N AECG

61 307 88 509 76 829 58 44 23 133

Thailand Denmark Albania China France USA USA Greece Greece France (Siriraj) (Siriraj) (Esbjerg) (Tirana) (Beijing) (Strasbourg) (Boston) (Pennsylvania) (Paris)

CS CS CS R CS CS CS P CS P

Kosrirukvongs et Kosrirukvongset 2012al, al, 2012 Haga et J2013 al, He et 2014 2015 al,et Osial 1983 1988al, al, Drosos et 1991 2006 Aliko al,et Aliko 2010 Abdelghani, Brown et al., Andonopoulos et Avouac al, et

Good Good Moderate Poor Poor Poor

All tested All 74 patients NA NA NA NA tested tested

years

7.3 years 8.2 NA years 20 years 6 years 5.5

24/3 38/2 NA 5/1 NA NA

tis

A NA NA NA N NA NA Myosi

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology N=27 N=40 N=41 N=6 N=9 N=10 (22%) (22%) (33.9%) (12%) (23%) (10%)

AECG AECG Roy Le AECG NA NA For AECG Peer Review -

121 118 209 6 169 100 systemic sclerosis 402 pSS

France Turkey (Pisa) Italy Australia Hungar Norway (Paris) (Paris) (Izmir)

R CS R CS CS/R CS Legend: cross-sectional CS – study; – informationNA not Pprospective – study;available; retrospectiveR – study. Page 27 of 71 Kobak et al, 2013 Kobak et Baldini al.,et 2013 Rojana- Udomsart al,et 2011 Vancsa al, et 2010 Dobloug al, et 2014 Salliot et al, 2006 al, Salliot et Page 28 of 71

0% 0% Lymphoma (% patients)

vs. vs. 25

36 vs. 9.5 2.9 Nervous Nervous system involvement (% patients) 18 vs. 19 (p=NS) 19.7 11.5 vs. (p=0.55) (p=0.21) (p=0.35) Psychosis 6.63 vs. (p=0.005) Seizures vs. 9.3 11.6 (p=0.25) NPSLE

38 vs. 19 vs. 19 38 vs. 57.1 66 66.7 48.6 vs. Renal Renal involvement (% patients) (p=0.04) vs. 0 19 (p<0.05) 55.3 11.5 vs. (p=0.005) (p=0.312) (p=0.03) Proteinuria 43.1 29.0 vs. (p<0.001) Haematuria 30.9 22.8 vs. (p=0.008) syndrome vs. 8.9 20 (p<0.001) Nephrotic Nephrotic 24 vs. 28.5 Lung Lung involvement (% patients) 11.811.5 vs. (p=0.891) (p=0.59)

6 21.4 vs. 12.729.6 vs. Thyroiditis (% patients) (p=0.023) (p<0.000)

Lymph adenopathy (%patients) 46.119.2 vs. (p=0.004)

14.2 vs. Photo Photo sensitivity (% patients) 8.6 (p=0.45) 52.9 vs. 68.3 (p=0.001)

SLE vs. SLE-sSS vs. SLE patients

Clinical features of patients with with sSS patients features of Clinical Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology 28 vs. 35.7 Raynaud’ s (% patients) 43.4 vs. 80.8 <0.001)(p (p=0.396) 49.5 66 vs. (p<0.001) Table 3 : Table : 3 For Peer Review

DAS DAS 28 score 60.9 vs. Tender Tender (% patients) 77.1 (p=0.056) joints

Swollen (% patients) joints

88 vs. 88 92 Arthritis (% patients) (p=NS) 51.3 vs. 76.9 (p=0.27) 73.2 vs. 81.3 (p=0.006)

Szanto Szanto et al, Scofield et al, Disease/Ref 1998 Gilboe et 2001 al, 2004 al, 2006 2007 2010 Nossent et al,Nossent et 2008Pan al, Manoussakis Manoussakis et et al,Baer

0.23 2.7 vs. (p=0.010)

4.81 14.9 vs. (p=0.002) 12 9 vs. 14.9 3.7 vs. (p=0.21)

11.744.6 vs. Lung (p<0.001) Unspecified disease 64 vs. 65 fibrosis 45 vs. 11 (p=0.02) PAH 19 vs. 11 (NS) Lung fibrosis 29 vs. 11.1 (p=0.05) PAH 15.1 vs. 7.4 (p=0.60) pulmonary 27.121.6 vs. (p=0.320) 7.5910.8 vs. (p=0.346)

RA vs. RA-sSSRA patientsvs. SSc vs. SSc SSc-sSS patients

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

vs. 1.5 27.2 (p=0.01) 94.7 vs. 92.6 (p= 0.98)

For Peer Review 3.35 vs. 5.9 6.4 vs. 4.3 3.2 vs. 4.20 vs. 5.08 (p<0.001) 2.81 (p=0.1) 3.1 2.7 vs. (p=NS) (p=0.009) 4.13 vs. 4.05 (p=0.8) (p=0.01)

12.1 vs. 6.1 vs. 9.6 vs. 6.1 (p=<0.01) 2.2 vs. 1.1 (p=NS) 14.5 (p=0.019) 5.6 vs. 6.2 (p=0.4) 12.9 vs. 7.0 7.0 vs. 8.5 (p=0.17) 0.28 vs. 0.73 (p=NS) 15.8 (p<0.05) 3.7 vs. 3.2 (p=0.4)

100 100 100 100 100 100 100

Uhlig Uhlig et 1999 al, 2011 2012 2014 al, 2015 Osial et al, 1983 2006 Salliot et 2006 al, Antero Antero et al, He etal, 2013 J Avouac et al, Haga Haga et al, Abdelghani et Brown et al., Page 29 of 71 Page 30 of 71

Lung fibrosis fibrosis 58.930 vs. (p=0.001) PAH 52.6 vs. 30 (p=0.001)

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review

PAH - arterialpulmonary NShypertension; NPSLE-- significant; not neuropsychiatric lupus.

Legend:

2013 Kobak Kobak et al,

9 9 vs. 26 26.37.7 vs. Thrombo Cytopaenia (% patients) (p<0.05) (p=0.03) 36 vs. 25 (p=0.218)

Hyper gamma globulinaemia (% patients)

ESR/CRP (mm/h; mg/l) ESR 26.8 18.6 vs. (p<0.01) CRP 11.9 13.8 vs. (p=0.33)

antibodies

Anticardiolipin Anticardiolipin Other antibodies/ Other antibodies/ markers (% patients) 41 (p=NS)vs. 33 Anti-Sm (p=NS) vs. 15 21 nRNP Anti-U1 (p=NS) vs. 25 26 (p=0.639)52.9 45.8 vs. nRNP Anti-U1 antibodies (p=0.999)12.7 11.5 vs. Anti-Sm (p=0.999)11.3 7.7 vs. Cryoglobulins (p=0.999)14.7 15.8 vs. nRNP Anti-U1 (p=0.603)41.6 37.1 vs. Anti-Sm (p=0.06) 38.7 22.9 vs.

Anti CCP (% patients)

vs. vs. SLE vs. SLE-sSS vs. SLE patients 71 71 vs. 53 77.3 dsDNA (% patients) (p=NS) 60 vs. 44 (p=0.05) 69.2 (p=0.436) 223.35 vs. 132.51 (p<0.01) Serological features of patients with sSS patients of features Serological Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology Table 4: Table 4: 88 88 vs. 87 100% both ANA (% patients) (p=NS) groups

For Peer) Review 28.6 64 vs. RF RF (% patients/ U/mL) U/mL 48.2 62.2 vs. U/mL (p=0.08) ( p<0.001 31.65U/m vs. L 120.39 u/mL (p=0.126)

38 38 vs. 33 7.0 vs. La/ La/ SSB antibodies (% patients) (p=NS) 11 vs. 56 (p=0.05) 38.5 ( p=<0.001 ) 44 vs. 73.21 (p<0.01) (p<0.01) 44 44 vs. 48 23.9 vs. Ro/ SSA Ro/ antibodies (% patients) (p=NS) 36 vs. 89 (p=0.05) 38.5 (p=0.008) 74 vs. 94.64 et et

Disease/Ref al, 1998 et Uhlig al, 1999 etal, Gilboe 2001 et al, 2004 et Szanto al, 2006 Nossent Manoussakis Page 31 of 71

Page 32 of 71 42 42 vs. 40 0.5 9.5 vs. (p=0.816) 21.917.8 vs. (p=0.14) (p=0.001)

IgA 33.648.5 vs. (p=0.106) IgG 35.654.3 vs. (p=0.010) IgM 10.611.8 vs. (p=0.951)

ESR ESR 20.53 vs. (p=NS)14.90 CRP 1.52 1.20 vs. (p=NS) 20.9 24.8 vs. (p=0.4) CRP vs. 12.614 N/A N/A

(p=0.03) (p=0.004) (p<0.001) m serum m meanlevel - B2 Anticardiolipin 49.1 41.7 vs. nRNP Anti-U1 vs. 13.3 28 Anti-Sm 17.3 9.7 vs. mg/l 1.9 2.4 vs. mg/l(p=0.02) 71.9 vs. 64 vs. 90 70.3 vs. 75 (p=1.0) 136.89 U/mL vs. 125.17 U/mL (p=NS) 77.8 (p=0.5) (p=0.1)

RA vs. RA-sSS vs. RA patients 38.360 vs. (p=0.011) 59.1 vs. 45.4 (p<0.001)

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology 74.4 vs. 51.7 vs. 53.8 vs. 85.7 (p=0.13) 30.630 vs. (p=0.95) 79.8 (p=0.001) (p=0.1)63.6 For Peer Review 75.6 vs. 81.8 vs. vs. 58 70 (p=0.24) 156.46 vs. 54.90 (p=NS) 95.7 (p=0.001) 67.1 (p=0.5)

17.4 17.4 vs. 1.39 vs. 51.4 51.4 (p<0.001) 10 vs. 22.1 (p<0.001) 14.9 (p=0.001)

27.6 27.6 vs. 4.69 vs. 1.5 0 vs. 71.4 71.4 (p<0.001) 26.8 vs. 45.3 (p<0.001) 39.2 (p=0.001) (p=1)

2008 2010 2011 2012 2013 et al, 2014 Pan et Pan al, He etJ al, Abdelghani Baer etal,Baer etal, Antero et Haga al,

(p=0.7) ESR vs. 14 18 (p=NS) CRP 4 vs. 7.5 (p=NS)

(p=0.032) (p=<0.0001) RNP (p=0.04) - U1 - Anti Anti-Scl70 vs. 5 33 ACA vs. 63 12 70Anti-Scl (p=0.66)21.9 15.4 vs. ACA 40.4 61.5 vs. (p=0.09) Cryoglobulins 20vs. 5.3 (p=0.09) Anti-Scl70 55.1 92.5 vs. ACA 26.9 80 vs. (p=0.001) 0vs. 2.3 Jo-1Anti 18.5 0 vs.

73.8 vs. 61.0 (p=0.008)

SSc vs. SSc SSc-sSS patients 10 10 vs. 0

Myositis Myositis vs. patientsmyositis/sSS

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology 25.444 vs. 32 vs. 65 74 vs. 90 (p=NS) 28.290 vs. (p<0.01)

For Peer Review

76.8 76.8 vs. 61.8 (p=0.008) vs. 14 50 vs. 24 53 (p=0.05) 19.2 vs. 72.5 (p=0.001)

5.4 5.4 11 vs. 41 0 vs. 5.1 15 vs. (p=0.576)

8.5 8.5 11 vs. 29 5 vs. 26 0 vs. (p=0.003) 10.3 vs. 32.5 (p=0.048) ACA- ACA- anti-centromere anti-CCP- antibodies; anti-cyclic citrullinated peptideantibody;anti-dsDNA - anti-double DNA; stranded ANA-antinuclear antibody; anti-

Vancsa et Vancsa al, 2015 Osial et al, 1983 2006 Salliot et al, 2006 2013 2010 Legend: Scl70 -anti-topoisomerase Scl70 antibody; anti-Sm - anti-smith antibody;anti-U1-RNP - anti-nuclearribonucleoprotein antibody; - beta B2-m 2 RF-Rheumatoid microglobulin; factor. Brown Brown et al., Avouac et al, Kobak et al, Page 33 of 71 Page 34 of 71

United Kingdom United United Kingdom United and Coziana Ciurtin³* Coziana and Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

³Department of Rheumatology, University College London, London, London, London, College University of Rheumatology, ³Department

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review , phone: +44(0)2034479035, fax: +44(0)20344797268 . fax: +44(0)20344797268 , +44(0)2034479035, phone: author: *Corresponding 2PG, email: NW1 Road, London, Euston 250 College London, University of Rheumatology, Department FRCP, Ciurtin, PhD, Dr. Coziana [email protected] Page 35 of 71 Page 36 of 71 matic review, review, matic - sSS) is not well- associated associated with sSS. The in Sjögren’s syndrome, prevalence, sex ratio, syste sex prevalence, syndrome, in Sjögren’s in Sjögren's syndrome (secondary Sjögren's syndrome l manifestations, laboratory features and causes of death Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review polyimmunitypolyautoimmunity polyimmunitypolyautoimmunity Prevalence rates of sSS vary widely in different populations. Both meta-analyses conducted in the RA and SLE populations were secondary Sjögren’s syndrome, syndrome, Sjögren’s secondary The epidemiology of : : A systematic literature search of PubMed and Embase databases (updated to March 2016) was performed to identify all published The literature search identified 1639 citations, out of which 42 fulfilled the inclusion criteria. Only 19 studies had moderate to good revalence rates of pSS were summarised with PRs and 95% CIs. CIs. and 95% PRs with were summarised pSS rates revalence of quality quality and were selected for the meta-analysis. According to a random-effects model, the pooled PR for sSS associated with RA was 19.5% characterised by a high degree of study heterogeneity. The results of this meta-analysis highlighted the need for better quality population studies. studies. population for quality need better the highlighted meta-analysis this results of The heterogeneity. a of study by high degree characterised Keywords Results: (95% (95% CI 11.2 to 27.8) and the pooled PR for sSS associated with SLE was 13.96% (95% CI 8.88 to 19.04). The female/male ratio of sSS in the population. SLE in the to 32.4) CI 1.22 (95% 16.82 to and 256) (95% CI 7.09 14.7 RA was population Conclusion: Abstract Abstract Objective: defined and was not investigated before using a systematic approach. We conducted a systematic review of the epidemiology of sSS associated with rheumatoid arthritis (RA), systemic lupus erythematosus scleroderma(SLE), and the assessing myositis, prevalence (PRs)rates and clinical features of sSS. and serological Methods: data on prevalence rate, demographic proﬁle, clinica meta-analysis. p Previous Previous . (8) In In addition, the or the purpose of or f glandular atrophy and cause toto leading leading ence ence of glandular inflammatory infiltrate and immunity” associated with SS thanrather(7,SS associated sSS with 8), immunity” auto- . (3) Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology which which is considered in the majority of cases the For Peer Review Although, Although, the temporal relationship between the pres function (2). glandular glandular ntroduction ntroduction exocrine exocrine glands and epithelium, feature that is considered the histological hallmark of the disease The (1). T cell mediated attack on salivary and lacrimal glands results in chronic inflammation, I of infiltration ofcases majority isin the with lymphocytic associated which autoimmune disorder, is(SS) chronic a syndrome systemic Sjögren’s deficient atrophic/fibrotic changes associated with ageing and/or disease progression is difficult to appreciate, the minor salivary gland biopsy have their SS patients of with and prognostication stratification role in the SS is characterised clinically by symptoms of dry mouth (xerostomia) and dry eyes (xerophthalmia), known as sicca symptoms. SS can progress to affect many organ systems (lung, kidney, gastro-intestinal tract, skin, musculoskeletal, and peripheral and rarely central nervous system), and as a result, other clinical manifestations ranging from mild to (5). lymphoma risk of with increased associated is SS (4). In addition, and lung disease interstitial failure more neuropathy, renal severe disease may occur, including: arthralgias, vasculitis, peripheral SS can occur either alone as primary SS (pSS) or in erythematosus (SLE), rheumatoid associationarthritis (RA), systemic sclerosis (SSc), or dermatomyositis with (DM), in which case it another is known as secondary SS well-defined autoimmune condition, such as systemic lupus to useprefer(6).Although, some (sSS) the researchers of “poly term our systematic review, we used the acceptedpreviously of terminology sSS, which enabled us to identify all the relevant papers. term “polyautoimmunity” refers to clusters of autoimmune conditions, which may include or not autoimmune rheumatic diseases papers focused predominantly on prevalence studies and distinct immunologic differences between different sSS subtypes, rather than Page 37 of 71 Page 38 of 71

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For Peer Review differences in clinical presentations or controversies regarding the patients’ diagnosis. diagnosis. the patients’ regarding or controversies clinical presentations differences in The diagnosis of SS cannot be made on a single test or symptom. The variability in presentation of SS has led to a difficulty over the years in establishing universally accepted classification criteria. Therefore, there has been a variation in prevalence estimates in the few epidemiological studies that have been documented, as they used different classification criteria (1, 9). Although the clinical features of pSS are relatively well- accepted and cited criteria are the American-European consensus group classification criteria (AECG), which were published in 2002 as a researched researched in large epidemiological studies (10, 11), there are very few studies looking at the and epidemiology clinical and serological features of sSS. The authors felt that a systematic review of the epidemiology of sSS was needed in order to establish any significant differences in the Over the last few decades, diagnostic criteria have varied according to different national and international groups. At present, the most widely revision from the original European Study group criteria described in 1996 (2, 12). Interestingly, the presence of anti-Ro/La antibodies has not forcriteria were and SS recently developed validated (14, do 15). notAlthough, they any introducechanges, significant have been they validated SS. in expert diagnosing opinion the role of emphasised and patient cohorts, international in three Methodology We performed a andPUBMED EMBASE search for articles involving humans only, published between 1984 and 2016. The MESH terms used were: secondary Sjögren’s, epidemiology of Sjögren's syndrome, secondary Sjögren’s and systemic lupus erythematosus, secondary Sjögren’s and rheumatoid arthritis, secondary Sjögren’s and systemic sclerosis/scleroderma/CREST syndrome, and secondary Sjögren’s and myositis. As presentation of sSS according to the background rheumatic condition of patients that might have impact on their long-term management. management. long-term their on might impact have that patients of condition rheumatic to the background according presentation of sSS been included asaclassification formandatory criteria sincesSS, it was tonot shown be in significant previous analysis (13). New classification Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review tests of heterogeneity among studies). studies). among tests of heterogeneity 2 and laboratory features of Sjögren’s syndrome in different Sjögren’s autoimmune syndrome. Prevalence rates diseases, were calculated and using 95% morbidity CI. and Pooled prevalence rates mortality and sex associated ratios were calculated with using and the I Q on (based effects model a secondary random We appreciate a risk of reporting bias for the majority of studies as they addressed different populations and used different classification criteria for sSS. The study quality was weighted as poor, moderate and good based on the following criteria: number of patients, the use of established SS classification criteria, data about patient sex, ethnicity and disease duration, inclusion of lip biopsy in the classification criteria (especially as editorials, commentaries, animal studies, questionnaire studies, case reports, case-series, and studies of treatment (Figure 1). (Figure of treatment studies and case-series, case reports, studies, questionnaire animal studies, editorials, commentaries, data under the following headings: prevalence and demographics of secondary Sjögren’s syndrome in different autoimmune diseases, clinical Results: The initial research yielded 1639 articles, which were screened for titles and inclusion and exclusion abovementioned criteria (the process of is selectiondetailed 1). in paper Figure an detailed additional Following manual abstracts, of which 37 were selected for review based on the further. analysed criteria were and the inclusion which met abstracts, and full papers 42 identified articles, we relevant of search other the serology is likely to be positive furtherwasnotreached, which consensus by case HA evaluated thein Thewere studiesand consensus. CC. wasan by 82% independently There in lupus patients, irrespective of concomitant SS). The assessment of study quality was reviewed criteria for study selection, we considered all the studies on the epidemiology, diagnosis and follow-up of patients with sSS. We excluded We extracted data on prevalence, demographic proﬁle, clinical manifestations, laboratory features, underlying autoimmune diseases and causes tables. in them and available, organised articles, selected where from the of death Studies were grouped according to the following patient categories: 1). secondary Sjögren’s and systemic lupus erythematosus, 2). secondary Sjögren’s and rheumatoid arthritis, 3). secondary Sjögren’s and scleroderma and 4). secondary Sjögren’s and myositis. We present our results Page 39 of 71 Page 40 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review designs included were retrospective, cross-sectional and prospective (Table 2). The number of patients used in each study ranged from 6 to 2694. to 2694. from 6 study each ranged in used patients of 2). The number (Table and cross-sectional prospective were retrospective, included designs used. they criteria classification the not specify Nine did studies (9). criteria other (1), and criteria We found 18 studies which looked at the prevalence of RA-sSS (between 1987-2013) (16-33), 13 for SLE-sSS (1998-2015) (34-46), 6 for SSc- sSS (1983-2013) (47-52) and 3 for myositis-sSS (2011-2014) (53-55). The prevalence ranged from 3.6%-55% for RA-sSS, 5%-22% SLE-sSS, 14%-60% SSc-sSS and 10-23% for myositis-sSS. In the RA-sSS studies three of the highest reported prevalence all came from studies carried the third author (EJ) and graded based on the assessment made by two of the three authors. The details of study quality assessment were assessmentquality included were of study Thedetails three authors.two ofthe made assessmentbasedby the graded on and (EJ) authorthe third in Table 1. Based on this selection, 9 SLE studies and 11 RA studies assessed as having moderate to good meta-analysis. quality were included in the final diseases autoimmune with different associated of SS demographics Prevalence and Our search identified 40 worldwide studies, which evaluated the prevalence of sSS in patients with RA, SLE, SSc and myositis. The study Criteria sSS, (14), ECC (7), Japanese as AECG patientsclassification classify including having across to Different different were studies criteria the used 23). 20, (31- 39.8%)(18, patients out on Greek in Greece Gender Not all studies reported the gender of the patients, however in the 15 that did, females were predominantly affected (82%-100%). Less than half study. the included in patients the ethnicity of the highlighted of all (17/37) studies Prevalence Prevalence Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review 36.1, p<0.001; 41.3 vs. 35.8, p=0.003; 50.8 vs. 43.6, p=0.01; 41 vs. 35 andp=0.03, 49.5 vs. 41.4 p<0.001). This was not found to be the case for RA-sSS patients when compared to RA patients as reported by two studies (63.0 vs. 59.2, p=0.33 and 66.36 vs. 62.40, p=NS) (21, 28). There of studiesprevalence cumulative Two rate that rolethe ofsSS.found occurrence any diseaseto in whether RAthe duration reported regard plays diseases: autoimmune with different of associated features sSS laboratory and Clinical We identified 17 studies assessing the clinical and laboratory features of sSS (Tables 3-4). The reported clinical features varied depending on In five studies (36, 39, 42, 44, 45) SLE-sSS patients were reported to be significantly older when compared to those with SLE only (48.3 vs. was also no significant difference in age between SSc vs. SSc-sSS patients reported in three studies (56 vs. 54, p=NS; 50.2 vs. 55, p=0.18, and (50-52). 48.3 p=NS) vs. 50.5 Disease duration was reported in 26/40 studies and varied across all studies ranging from 4 months -12 years for RA-sSS (16, 20-23, 25, 27-29, (53-55). myositis-sSS for years 67 months to and 20 (47, 50-52), SSc-sSS 7-8 (34-37,44), 42, years 41, 39, SLE-sSS years 32,3-46 33), Only the RA-sSS studies looked into the relationship between disease duration and sSS incidence rate. There were conflicting reports with 28). 25, 22, (21, four studies other by supported was not however, finding This (19, 29). duration RA sSS did with increase at. looked with sSS being was which associated condition Age Age Disease duration Page 41 of 71 Page 42 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review involvement and central nervous system (CNS) involvement. Renal involvement was found to be across significantly five studies (36, 37, 39, 44, reduced 45), while thyroiditis was found to be higher.significantly in CNS involvement prevalence, although reduced in SLE-sSS patients SLE-sSS patients, was not significant in any of the three studies. Only one study reported no cases of lymphoma in their cohort of 26 SLE-sSS Regarding serological markers, only anti-Ro/SSA and anti-La/SSB antibodies were raisedsignificantly in SLE-sSS compared to SLE patients in five studies (36, 37, 39, 42, 44). Anti-dsDNA was 45). (36, in significant two studies was only this although patients, lower in SLE-sSS was Thrombocytopenia higher in SLE patients and this reached significance in four studies (37, 39, 42, 44). Koskenmies et al. reported that sSS was most commonly observed in patients with subacute cutaneous lupus erythematosus (SCLE) and SLE compared to RA patients (22, 27), while the other half reported no significant (27). involvement and CNS lung, renal thyroiditis, lymphadenopathy, including clinical features difference (21, 28). Only one reported study looked at other Of the seven studies (36, 37, 39, 42, 44-46) assessing clinical features of SLE-sSS, the majority reported data on the presence of renal . p<0.001) (43) 2.3%, vs. (16.4% vs. 22.1% erythematosus lupus than with discoid in patients Five studies addressed clinical features of RA-sSS patients (21, 22, 25, 27, 28). The majority reported data on joint swelling, tender joints and patients RA-sSS in higher were significantly joints tender reported 28 the that score).studies Half joints(DAS 28 score assessing activity disease patients (36), although they reported 8 cases of lymphoma in their pSS comparative group (N=86) . (N=86) comparative group pSS their in of lymphoma cases they 8 reported although patients (36), SLE-sSS SLE-sSS RA-sSS Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review Laboratory Laboratory analysis was mainly focused on RF, anti-CCP, CRP and ESR levels. There was inconsistency concerning the reported RF levels. Three studies (22, 25, 27) reported higher levels of RF in RA-sSS patients, one being significant, while the (21, 28). although studies, not significant opposite was found in two other Four studies (47, 50-52) reported data about lung involvement, mainly pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH). PF occurred significantly less frequently in SSc-sSS patients. Only one study reported lower occurrence of PAH in SSc-sSS, which was significant (52). The majority of studies looked at anti-topoisomerase 1 antibodies and anti-centromere (ACA) levels. ACA levels were significantly higher in 1 antibodies. of anti-topoisomerase the prevalence regarding there However,was discrepancy (50-52). three studies all patients across SSc-sSS In one study, all six patients with both diseases presented with a pattern of muscle weakness typical of IBM (53). Five IBM-sSS patients were treated with prednisolone and methotrexate, four of whom had temporary symptomatic improvement to treatment. response a had transient 27% whom in only only group (6-24 IBM comparison to the in response months). This was a far greater SSc-sSS SSc-sSS Myositis-sSS Immunogenetics SLE-sSS Page 43 of 71 Page 44 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review Immunogenetic Immunogenetic analysis was carried out in two studies. In one study there was no significant difference between the SLE and SLE-sSS patients Those with SLE were found to have increased phenotype and allele (36). that significant was p<0.001) DQB1*0602 (both frequencies for DRB1*1501 (p=0.020 and p=0.015, respectively) and In the study mentioned above (53), all six patients carried the HLA-DRB1*0301 allele or its equivalent HLA-DR3 serological specificity. They when looking at the HLA alleles (42). However, in another study, the HLA associations distinguished the SLE group from those with SLE-sSS. also carried either all or some of the major markers of the 8.1 MHC ancestral haplotype. This allele was also among thereported Norwegian patients (25%), included whichin another study afound prevalence of of rheumatic 24%, disorders which is as twice to high be highly prevalent (55). reported previously as sSS with associated mortality Morbidity and In a few RA studies other aspects of the disease including its effect on quality of life and its involvement in haematological malignancies was studied. In three of the five studies measuring health status there was no difference in the DAS-28 mean scores in RA-sSS compared to RA patients (21, 25, 28). In two other studies (22, 27) however, a higher DAS-28 score was found in RA-sSS patients, compared to RA patients (6.44 vs. 5.96, Myositis-sSS Myositis-sSS Health status Health status RA-sSS p=0.02 and 5.08 vs. 4.20, p=<0.001, respectively). respectively). vs. 4.20, p=<0.001, p=0.02 5.08 and Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

One study (22) looked at other health status measures including pain visual analogue scale Assessment (VAS) Questionnaire scale, (M-HAQ), fatigue and VAS found and that Modified the Health RA-sSS patients scored significantly higher in all three tests in comparison to RA 24 24 (33%) had sSS and 50 (67) had pSS. It found that when compared with the general population, SS patients had increased mortality (p=0.04). (36, (36, 45). Martens patients (43.1 vs. 32.9, p =<0.01; 49.8 vs. 39.7, p=0.03, and 1.75 vs. 1.55, p=0.04, respectively). Another study (28) looked at both M-HAQ and patients having associated RA (p= 0.86) (56). associated 0.86) (p= RA patients having RA-sSS Haematological malignancy and mortality and mortality malignancy Haematological SLE-sSS Nossent p=0.01). In two studies in which patients where followed up for three years and 8 years respectively, none of the patients developed lymphoma pain VAS tests and reported similar findings in both groups of patients (0.84 vs. 0.81, p=0.7, and 35.9 vs. 42.4, p=0.3, respectively). respectively). 42.4, p=0.3, and vs. 35.9 0.81, p=0.7, (0.84 vs. patients of groups both findings in similar reported and pain VAS tests Page 45 of 71 Page 46 of 71 = 99.98 for 2 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

. (8) ” (7), as discussed in introduction. Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

Forpolyimmunitypolyautoimmunity Peer Review antibody antibody positivity (59), or had significantly higher levels of IL-2 and IL-6 in their saliva (60). An old study also suggested that extraglandular (61). compared to sSS in common pSS more features are Our study could not address any controversies regarding the accuracy of patients’ diagnosis (e.g. many clinicians’ might decide based on their expert opinion to diagnose a patient as having RA associated with SS rather than symmetrical polyarthritis in the addition, context our systematic of review primary does SS). not In imply that patients with sSS associated with different ARDs have similar features (e.g. SLE and SS moderate-good quality studies were included in the meta-analysis, the studies with poor quality were also detailed in the paper. In addition, our Secondary SS is characterised by a heterogeneity of clinical manifestations, serological markers and symptoms, which are influenced by not particularly exact in relation to the presence of clinical and serological features of SS in the context of rheumatic conditions (which is the autoimmune diseases with other of SS to also associations refers as it review), focus of this There is evidence of a great degree of heterogeneity within all these populations; although previous research established that pSS is associated with a different disease phenotype compared to sSS: e.g. pSS patients had a higher frequency of parotid gland enlargement and Ro and La rheumatic rheumatic diseases are lacking. Previous studies were interested in comparing the clinical and laboratory features alone or (as associated thewith sSS majority of the included studies systematicin this review), or aimed to compare the of epidemiology pSS vs. of an autoimmune disease sSS sSS (this was beyond the scope of our systematic analysis). Other papers explored the communality clinical of picture serological in abnormalities distinct and autoimmuneshared rheumatic diseases, such as RA and pSS (58), or autoimmune advocated diseases, is that better the described as association “ of SS with multiple patients might have similar clinical presentation, which is not the case with patients with SS associated with SD or myositis). Even if only patients’ patients’ underlying pathology. Unfortunately, large prospective studies comparing patients with sSS associated with different autoimmune Page 47 of 71 Page 48 of 71 The The confidence intervals of sex Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review espite the effort to define the sSS patient population better, clinicians are still unable to answer practical questions regarding the difference in atios in the SLE and RA patients with associated sSS reflected again the high heterogeneity of the studies and the inclusion of studies, which reported the presence of sSS exclusively in the female population. female population. in the exclusively sSS of the reported presence to patients defined as having overlapping syndromes rather than sSS (57) or which contained no data about sSS prevalence (62). about prevalence sSS no data contained or which (57) than rather sSS syndromes overlapping as having to defined patients Our analysis revealed that sSS is more common in women, irrespective of the underlying autoimmune disease. r D systematic review systematicalso for even reported review the if approach, systematicarticle relevant on theme, papers as such not selected by referring our papers the long term outcome of sSS associated with an autoimmune disease compared to having only an autoimmune disease, or regarding the best way way to stratify these enablepatients of the to choice suitable the Ittherapeutic most options. is that sSS is recognized characterised significant by amount of variability in clinical presentation, which is influenced by the concomitant autoimmune disease; however, different studies reported various various epidemiological features in the context of similar background autoimmune disease. This variation can be in part explained by classification criteria applied, as well theas patient selection criteria, their or ethnicity genetic SS and background, possible reporting bias (45, 63). Our results show that Raynaud’s phenomenon, thyroiditis and Ro, La antibody positivity seemed to be more frequent in SLE-sSS patients compared to SLE group, while renal involvement and presence of dsDNA, and anti Sm antibodies were more common in the latter group. A less clearly defined trend was in identified the case ofand thrombocytopaenia lung involvement, while the CNS involvement was reported in only one study as more frequent in the SLE-sSS group. group. SLE-sSS in the frequent as more The number of tender and swollen joints was more commonly reported in the RA compared to RA-sSS group, however, the RA-sSS group had more CNS involvement, Raynaud’s phenomenon, thrombocytopaenia and hypergammaglobulinaemia. and hypergammaglobulinaemia. thrombocytopaenia Raynaud’s phenomenon, CNS more involvement, Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review CC was funded by a British Research (BRC-III/003). grant Research Council British CCa by funded was References: ofofcharacteristics sSS, evaluatethis which aimed the ofto meta-analysis epidemiology thisIn conclusion,and the isfirst the review systematic heterogeneous population. Because of the lack of prospective longitudinal data in large population studies, there are still unanswered questions diseases. autoimmune common features less in laboratory and clinical their or patients of these malignancy related risk to the Acknowledgement: 1. 2012;39(1-2):9-14. Baldini 2. C, Talarico R, Tzioufas AG, 2011;141(1):1-9. Lett. Immunol pathogenesis. Bombardieri S. Classification criteria for Jonsson 3. R, Sjogren's Vogelsang syndrome: P, a Volchenkov critical R, review. Espinosa Journal A, of Wahren-Herlenius M, autoimmunity. Appel as its focus potential a on with syndrome Sjogren's primary in histopathology S. gland salivary F.review of A Barone SJ, Bowman RM, Brown BA, Fisher The complexity of Sjogren's syndrome: novel aspects on a clinical trials biomarker. Ann Rheum Dis. 2015;74(9):1645-50. 2015;74(9):1645-50. Dis. Rheum Ann biomarker. trials clinical a 4. 2014;6:247-55. epidemiology. Clinical syndrome. Sjogren's of epidemiology The A. Shahane R, Patel Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61(6):554-8. 2002;61(6):554-8. Dis. Rheum Ann Group. Consensus American-European the by proposed criteria European the of version 13. 1993;36(3):340-7. Rheum. Arthritis Community. European theby supported action concerted prospective a of Results syndrome. Vitali C, Bombardieri S, Moutsopoulos HM, Balestrieri 14. G, Bencivelli W, Bernstein RM, et al. Preliminary criteria for the classification of Sjogren's Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of League Rheumatology/European Against crossroad of polyautoimmunity. J Autoimmun. 2012;39(3):199-205. 2012;39(3):199-205. Autoimmun. J polyautoimmunity. of crossroad 9. 2006;45(2):187-91. Rheumatology. 1982-2003. Alamanos Y, Tsifetaki N, Voulgari PV, Venetsanopoulou AI, Siozos C, 10. Drosos AA. of Epidemiology primary Sjogren's syndrome in north-west Greece, 2014;66(3):454-63. &research. care Arthritis area. Maldini C, Seror R, Fain O, Dhote R, Amoura Z, De Bandt M, et al. 11. Epidemiology of primary Sjogren's syndrome in a French multiracial/multiethnic 2015;74(11):1983-9. diseases. rheumatic the of Annals meta-analysis. review and a systematic syndrome: Sjogren's of Qin primary Yang Wang Z, Yang B, J, M, F, N, Ma Epidemiology Huang et al. 12. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjogren's syndrome: a revised classification criteria Rheumatism for primary Sjogren's A syndrome: consensus and methodology involving data-driven three international patient cohorts. 2017;76(1):9-16. Dis. Rheum Ann 15. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of League Rheumatology/European Against 2003;62(9):897-900. Dis. Ann Rheum severity. disease of estimates and manifestations 5. 2013;65(5):816-21. research. & care Arthritis study. population-based a syndrome: Johnsen 6. SJ, Brun JG, Goransson LG, Smastuen MC, viii-ix. 2008;34(4):935-47, Johannesen TB, Haldorsen K, et al. Theander Risk E, 7. Jacobsson of LT. Relationship non-Hodgkin's of Sjogren's lymphoma syndrome to in other connective primary tissue and Sjogren's autoimmune disorders. Rheum 2016;42(3):457-72. Am. Dis Clin North Am. Anaya JM, Rojas-Villarraga 8. A, Mantilla RD, Arcos-Burgos M, Sarmiento-Monroy JC. Polyautoimmunity in Sjogren Syndrome. Rheum Dis Clin North Amador-Patarroyo MJ, Arbelaez JG, Mantilla RD, Rodriguez-Rodriguez A, Cardenas-Roldan J, Pineda-Tamayo R, et al. Sjogren's syndrome at the Rheumatism Classification Criteria for Primary Sjogren's 2017;69(1):35-45. Syndrome: Rheumatol. Arthritis Cohorts. A Consensus and Data-Driven Methodology Involving 16. Three International Patient 2003;62(8):722-7. Dis. Rheum Ann years. 46 over factors risk C, WM, O'Fallon Turesson CS, SE, Crowson trends and arthritis: Mattesonincidence Gabriel Extra-articular disease EL. in rheumatoid manifestations 17. 2006;24(3):305-8. ExpRheumatol. Clin in Turkey. 526 patients of hospital Calguneri M, Ureten K, Akif Ozturk M, Onat AM, Ertenli I, Kiraz S, et al. manifestations of Extra-articular rheumatoid arthritis: results of a university 18. 1992;35(7):745-8. Rheum. Arthritis study. serologic Drosos AA, Lanchbury JS, Panayi GS, Moutsopoulos HM. Rheumatoid arthritis in Greek and British 19. patients. A comparative clinical, radiologic, and Carmona L, Gonzalez-Alvaro I, Balsa A, Angel Belmonte M, Tena X, Sanmarti R. Rheumatoid arthritis in Spain: occurrence of extra-articular Page 51 of 71 Page 52 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review 20. 20. 2002;31(6):361-70. Rheum. Arthritis Semin populations. European ofMediterranean meta-analysis and Greece in associations Ioannidis JP, Tarassi K, Papadopoulos IA, Voulgari PV, 2012;15(3):284-8. Dis. Rheum J Int profile. treatment and activity disease to itsassociation and arthritis, rheumatoid Boki KA, Papasteriades CA, et 22. al. Shared epitopes and rheumatoid 1999;58(7):415-22. Dis. arthritis: Rheum disease Ann arthritis. rheumatoid with patients 636 in variables disease and tear production, and saliva symptoms, T. Axell Sicca JL, Jensen TK, Kvien T, Uhlig 23. 1987;14(6):1098-103. Andonopoulos AP, Drosos AA, Skopouli FN, Acritidis NC, Moutsopoulos 24. HM. Secondary Sjogren's syndrome in rheumatoid arthritis. J Rheumatol. 2000;27(11):2611-6. Rheumatol. J arthritis. rheumatoid with inpatients syndrome Sjogren's Mattey DL, Gonzalez-Gay MA, Hajeer 25. AH, Dababneh A, Thomson W, Garcia-Porrua C, et al. 2011;57(3):319-22. Bras. Association between HLA-DRB1*15 and Antero DC, secondary Parra AG, Miyazaki FH, Gehlen M, Skare TL. Secondary Sjogren's syndrome and disease activity of rheumatoid arthritis. Rev 26. Assoc Med 4:S61-9. 2012;95Suppl Thai. Assoc MedJ arthritis. rheumatoid with Kosrirukvongs P, Ngowyutagon P, Pusuwan P, Koolvisoot A, Nilganuwong 27. S. Prevalence of dry eye syndrome and Sjogren's syndrome in patients 2013;52(6):1084-9. He J, Ding 28. Y, Feng M, Guo 2016;5(10):1287-93. Research. Medical & Medicine of J, Journal British Arthritis. Rheumatoid Sun X, Abdelghani KB, Zhao Mahmoud I, Chatelus J, E, Sordet et 29. C, Gottenberg JE, al. Sibilia J. Characteristics Clinical and of Serological Features of Sjogren's SjogrenSyndrome in syndrome Patients with in 2007;21(5):907-27. Rheumatol. Res Clin Pract Best arthritis. ofrheumatoid and complications manifestations Extra-articular G. rheumatoid Koduri A, Young arthritis. Rheumatology (Oxford). 21. 21. Haga HJ, Naderi Y, Moreno AM, Peen E. A study of the prevalence of sicca symptoms and secondary Sjogren's syndrome in patients with 30. 2005;140(5):808-13. Fujita M, Igarashi T, Kurai T, Sakane M, Yoshino S, 31. Takahashi H. Correlation between dry eye and rheumatoid arthritis activity. Am J Ophthalmol. 1990;94(17):655-9. (Barc). Clin Med arthritis]. rheumatoid of time the course to reference Special syndrome. Martinez Castro E, Olive Marques A, Bonet Llorach M, Carbonell Abello J, Cobo Valeri E, Junca Valdor S. [Rheumatoid arthritis and Sjogren's 32. 32. Aliko A, Ciancaglini R, Alushi A, Tafaj A. Sicca symptoms, and lacrimal and salivary flow in Albanian patients with rheumatoid arthritis. J Oral Pathol 2000;59(3):230-2. Dis. Rheum 36. 2004;50(3):882-91. Rheum. Arthritis syndrome. Sjogren's primary with comparison and profiles laboratory and clinical erythematosus: lupus Manoussakis MN, Georgopoulou C, Zintzaras E, Spyropoulou M, Stavropoulou A, Skopouli FN, et al. Sjogren's syndrome associated with systemic Med. 2010;39(8):651-6. 2010;39(8):651-6. Med. 33. Int.2000;19(6):213-7. Rheumatol arthritis. rheumatoid Cimmino MA, Salvarani C, Macchioni P, Montecucco C, Fossaluzza 34. V, Mascia MT, et al. Extra-articular manifestations in 587 Italian patients 2003;42(1):189-91. Rheumatology. with syndrome. Sjogren's secondary for criteria fulfilling sicca symptoms and erythematosus lupus systemic with patients of probability the determine to status antibody anti-Ro/La and age Usepatient of et S, al. A, Heaton Bawendi T, Plant C, Gordon T, Marshall A, Prabu 35. McDonagh JE, Isenberg DA. Development of additional autoimmune diseases in a population of patients with systemic lupus erythematosus. Ann Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review 37. 37. Gilboe IM, Kvien TK, Uhlig T, Husby G. Sicca symptoms and secondary Sjogren's syndrome in systemic lupus erythematosus: comparison with 2007;66(3):410-3. diseases. rheumatic the of Annals lupus. systemic 47. Osial TA, Jr., Whiteside TL, Buckingham RB, Singh G, Barnes EL, Pierce JM, et al. Clinical and serologic study of Sjogren's syndrome in patients with rheumatoid arthritis and correlation with disease variables. Annals of the rheumatic diseases. 2001;60(12):1103-9. 2001;60(12):1103-9. diseases. therheumatic of Annals variables. disease with correlation and arthritis rheumatoid 38. 2014;34(1):11-24. Int. Rheumatol Spain. from Northwest erythematosus lupus Alonso MD, Martinez-Vazquez F, L, Riancho-Zarrabeitia Diaz de Teran T, Miranda-Filloy JA, Blanco R, et al. Sex differences in patients with systemic 39. 2008;27(3):339-43. Rheumatol. Clin patients. of542 study aChina: in syndrome Pan HF, Ye DQ, Wang Q, 40. Li WX, Zhang N, Li XP, et al. Clinical and 2015;2(1):e000084. laboratory profiles of systemic lupus Lockshin erythematosus associated with MD, Sjogren 41. Levine AB, Erkan 2015;2015:298506. diseases. Autoimmune Families. Lupus D. Patients R, Aggarwal Anaya JM, KA, Koelsch Kurien BT, Scofield RH. between Association Secondary and Primary Sjogren's Syndrome in a Large with Collection of overlap 42. autoimmune disease 2006;67(11):924-30. Immunol. differ Hum erythematosus. lupus systemic and from Szanto A, Szodoray P, Kiss E, Kapitany A, Szegedi those G, Zeher M. serologic, Clinical, and genetic profiles of patients with syndrome Sjogren's associated with 43. 'pure' disease. Lupus 2008;17(4):337-47. Lupus. manifestations. cutaneous with patients Sci Med. S, Koskenmies TM, Jarvinen P, Onkamo Panelius J, Tuovinen U, Hasan T, et al. and Clinical laboratory of characteristics Finnish lupus erythematosus 44. 2010;37(6):1143-9. Rheumatol. J subset. Baer AN, Maynard JW, Shaikh F, Magder 45. LS, Petri M. Secondary Sjogren's syndrome in systemic lupus erythematosus defines 46. a distinct 1998;7(4):231-4. disease Lupus. syndrome. Sjogren's secondary of impact and frequency VII: erythematosus lupus Systemic AJ. Swaak JC, Nossent familial in syndrome Sjogren's of secondary diagnosis with a associated is disease thyroid B. Autoimmune Namjou Harley JB, Bruner GR, RH, Scofield 1983;26(4):500-8. rheumatism. and Arthritis sclerosis. systemic progressive 48. 1988;15(6):965-8. rheumatology. of Journal The sclerosis. Drosos AA, Andonopoulos AP, Costopoulos JS, Stavropoulos ED, Papadimitriou CS, Moutsopoulos HM. Sjogren's syndrome in 49. progressive systemic 1991;18(11):1685-8. Rheumatol. J scleroderma. systemic Drosos AA, Pennec YL, Elisaf M, Lamour 50. A, Acritidis NC, Jouquan JR, et al. Sjogren's syndrome in patients with the CREST variant of progressive to and relationship syndrome Sjogren's Sibilia MC, J, Vacher-Lavenu J, M, et sclerosis-associated Ardizonne Sordet Avouac C, al. Depinay Systemic C, 53. 53. 2011;113(7):559-63. Neurosurg. Neurol Clin haplotype. ancestral theMHC 8.1 and HLA-DR3 of in carriers syndrome Rojana-udomsart A, Needham M, Luo YB, Fabian V, Walters S, Zilko PJ, et al. The association of sporadic inclusion body myositis and Sjogren's the limited cutaneous subtype: results of a prospective study of sicca syndrome in 133 consecutive patients. Arthritis and rheumatism. 2006;54(7):2243-9. 2006;54(7):2243-9. rheumatism. and Arthritis patients. consecutive in133 syndrome sicca of study prospective a of results subtype: cutaneous limited the 51. 2007;46(2):321-6. Rheumatology. sclerosis. Salliot C, Mouthon L, Ardizzone M, Sibilia J, Guillevin L, Gottenberg JE, et 52. al. Sjogren's syndrome is associated with and not secondary to systemic Kobak S, Oksel F, Aksu K, Kabasakal Y. The frequency of sicca symptoms and Sjogren's syndrome in patients with systemic sclerosis. International journal of rheumatic diseases. 2013;16(1):88-92. 2013;16(1):88-92. diseases. rheumatic of journal Page 53 of 71 Page 54 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review 54. 54. 2010;77(2):125-30. Spine. Bone Joint patients. 169 study of retrospective classification: for clinical Relevance dermatopolymyositis: primary to comparison Vancsa A, Gergely L, Ponyi 55. A, Lakos G, Nemeth J, Szodoray P, et al. 2015;22(4):672-e41. J Eur Neurol. study. epidemiology Myositis-specific and myositis-associated clinical a antibodies population-based in Norway; myositis inclusion body of et al. Stjarne High prevalence J, T, Bitter H, L, Sveberg Garen EA, Antal GC, Dobloug in overlap myositis in 56. 1997;8(2):201-4. Control. Causes Cancer (Finland). arthritis rheumatoid Kauppi M, Pukkala E, Isomaki H. Elevated incidence of hematologic malignancies in patients with Sjogren's syndrome compared with patients with 57. 2013;31(2):272-80. rheumatology. experimental and Clinical lymphoma. risk of high at but involvement organ mild with entity clinical distinct Baldini C, Mosca M, Della Rossa A, Pepe P, Notarstefano C, Ferro F, et al. Overlap of ACA-positive systemic sclerosis and Sjogren's syndrome: a syndrome, secondary Sjogren's syndrome, and patients with primary Sjogren's syndrome receiving varying doses of interferon for symptomatic treatment legends: Figure selection. of study Figure 1: Flowchart patients. in SLE sSS prevalence of the of Figure 2: Meta-analysis in RA patients. sSS prevalence of the of Figure 3: Meta-analysis 63. 63. 1990;17(2):201-4. Andonopoulos AP, Skopouli FN, Dimou GS, Drosos AA, Moutsopoulos HM. Sjogren's syndrome in systemic lupus erythematosus. J Rheumatol. 58. 58. 2015;53(2):61-8. Reumatologia. patients. syndrome Sjogren's Koszarny A, Majdan M, Dryglewska M, Tabarkiewicz 59. J. Prevalence of selected organ-specific autoantibodies in rheumatoid arthritis and 2010;37(4):800-8. rheumatology. of Journal The primary syndrome. Sjogren's secondary and primary between G, Avila-Casado C, Hernandez-Molina C, Cardenas-Velazquez F, Calderillo ML, Hernandez-Hernandez Marroquin V, et al. Similarities and differences 60. Streckfus C, Bigler 2001;5(2):133-5. investigations. oral Clinical study. preliminary a the condition: of L, Navazesh M, Al-Hashimi I. Cytokine 61. concentrations in stimulated whole saliva 1994;13(3):438-41. rheumatology. among patients Tishler with M, Aharon A, primary Ehrenfeld M, Avni Sjogren's I, Bendet 62. E, Bombardieri S, et al. Sjogren's syndrome in Israel: primary versus secondary disease. Clinical SSwith secondary association and with of characteristics RA NA, patients Clinical KP. Liao Shadick ME, Weinblatt CK, LE, FritsML, Iannaccone Brown joint damage. Rheumatology. 2015;54(5):816-20. 2015;54(5):816-20. Rheumatology. damage. joint Prevalence at 1 year at4%, and 1 Prevalence year None None Prevalence Prevalence at 10 years 17%, after years and 30 25% years 10 after 12% prevalence of sSS and RA sSS and prevalence of duration disease None None Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review 10.63 years 10.63 years 10 years 10 years 12.2 years 12.2 years 15.6 years - Disease duration Disease duration Relation between

: Studies reporting the disease duration and relationship with the sSS prevalence in RA patients. in RA prevalence sSS with the and duration the relationship disease reporting : Studies Young et al.,2000 Young Table 1 al.,1999 et Uhlig al., 2011 et Antero Abdelghani, 2014 10.2 7 +/- years al.,2003 Carmona et Haga et al.,2012 et Haga al.,2012 Study Page 55 of 71 Page 56 of 71

Moderate Moderate Moderate Moderate Good Good Poor Study quality

12 patients tested All NA NA tested All tested All NA Salivary Salivary gland biopsy tested

8 years 8 years 18 years 8 years 10.9 years 3.5 years 8.1 NA Disease Disease duration (years/months)

A 22/5 N 9/0 18/0 26/0 52/4 NA Female/male Female/male (n)

Table Table 2 ECC ECC ECC AECG AECG AECG NA Criteria Criteria used For Peer Review

138 215 81 96 283 362 1138 Number Number of patients

Norway/ Norway/ UK Norway UK Greece Hungary USA Country Netherlands (London) (Oslo) (Birmingham) (Athens) (Debrecen) (Oklahoma)

P R R R R R Study design CS

Nossent al,et 1998 McDonagh al,et 2000 Gilboe al, et 2001 Bowman al,et 2003 Manoussakis et 2004al, 2006 2007 Szanto et al, al, Szanto et al,Scofield et

Good Poor Good Poor Poor Good Good Poor

All tested All NA tested All NA NA NA tested All tested All

9.1 years 9.1

A A 3.7 years 3.7 NA years 19.5 N N years 20 3.3 NA

A 32/3 NA 253/6 27/0 N 504/44 NA NA

A A Asian Chinese Asian NA N N Mixed (White, Greek Spanish White= 70.7White= African American= 25.5 1.9Hispanic= Asian= 1.2 Black, Hispanic, Asian native) and heumatoid arthritis heumatoid

R Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology N=35 N=17 N=259 N=27 N=28 N=548 N=34 N=24 (6%) (6%) (22%) (14.5%) (18%) (5%) (20%) (31%) (55%)

A A

AECG NA AECG For PeerN Other ReviewAECG Other N

542 77 1790 150 600 2694 111 45

China Finland USA Spain USA USA Greece Spain (Helsinki) (Helsinki) (Marylands) (Lugo)

R R CS CS/R R L P CS

Page 57 of 71 Pan et al, 2008Panal, et Koskenmies et 2008al, Baer al,et 2010 al,et Maria 2013 al,et Lockshin 2015 2015 1987al, Martinez Castro 1990al, et Aggarwal et al,Aggarwal et Andonopoulos et Page 58 of 71

Moderate Moderate Poor Poor Poor Moderate Poor Moderate Poor Poor Good

All tested All NA NA NA NA NA NA NA NA NA tested All

years

11 months 11

- NA years 12.2 years 10 NA 4 years 10.5 years 46 NA NA NA 10.2

A NA NA NA NA 46/9 NA N NA 7/0 NA 18/2

G N

A A

Other ECC Other ForOther PeerN ECC ReviewOther ECC Japanese N AEC

G=108 636 587 179 732 174 609 788 72 526 82 B= 107 107 B=

Greece/British Norway Italy Spain UK Greece USA Spain Japan Turkey Brazil Ioannina/London Ioannina/London (Oslo) (Northern) (Lugo) (Ioannina/ Athens) (Minnesota) (Tokyo) (Ankara) (Curitiba)

CS CS CS CS P CS R CS P R CS

Drosos et al, Drosos et 1992 al, Uhlig 1999et Cimmino al, et 2000 Mattey al, et 2000 Young al, et 2000 al, Ioannidis et 2002 etTuresson al, 2003 Carmona al, et 2003 2005 Fujita al, et etCalgüneri al, 2006 2011 Antero et al,et Antero

Poor Moderate Moderate Good Moderate Good Good Poor Poor Good

NA NA NA 16 patients tested patients 9 NA tested All tested All tested All 91 patients tested tested tested

years

5 years 5 years NA 10.6 9. months 15.10 years 15.6 years 16.9 7.3 NA NA 7

A NA NA NA 64/10 N 76/9 16/1 NA NA 16/3

sis o

NA NA Albanian Chinese French 89.4 White= NA NA NA NA Systemic scle Systemic

Other AECG ECC AECG ForAECG PeerAECG ReviewOther Other N AECG

61 307 88 509 76 829 58 44 23 133

Thailand Denmark Albania China France USA USA Greece Greece France (Siriraj) (Siriraj) (Esbjerg) (Tirana) (Beijing) (Strasbourg) (Boston) (Pennsylvania) (Paris)

CS CS CS R CS CS CS P CS P

Page 59 of 71 Kosrirukvongs et Kosrirukvongset 2012al, al, 2012 Haga et J2013 al, He et 2014 2015 al,et Osial 1983 1988al, al, Drosos et 1991 2006 Aliko al,et Aliko 2010 Abdelghani, Brown et al., Andonopoulos et Avouac al, et Page 60 of 71

Good Good Moderate Poor Poor Poor

All tested All 74 patients NA NA NA NA tested tested

years

7.3 years 8.2 NA years 20 years 6 years 5.5

24/3 38/2 NA 5/1 NA NA

tis

A NA NA NA N NA NA Myosi

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology N=27 N=40 N=41 N=6 N=9 N=10 (22%) (22%) (33.9%) (12%) (23%) (10%)

AECG AECG Roy Le AECG NA NA For AECG Peer Review -

121 118 209 6 169 100 systemic sclerosis 402 pSS

France Turkey (Pisa) Italy Australia Hungar Norway (Paris) (Paris) (Izmir)

R CS R CS CS/R CS Legend: cross-sectional CS – study; – informationNA not Pprospective – study;available; retrospectiveR – study. Kobak et al, 2013 Kobak et Baldini al.,et 2013 Rojana- Udomsart al,et 2011 Vancsa al, et 2010 Dobloug al, et 2014 Salliot et al, 2006 al, Salliot et

0% 0% Lymphoma (% patients)

vs. vs. 25

36 vs. 9.5 2.9 Nervous Nervous system involvement (% patients) 18 vs. 19 (p=NS) 19.7 11.5 vs. (p=0.55) (p=0.21) (p=0.35) Psychosis 6.63 vs. (p=0.005) Seizures vs. 9.3 11.6 (p=0.25) NPSLE

6 21.4 vs. 12.729.6 vs. Thyroiditis (% patients) (p=0.023) (p<0.000)

Lymph adenopathy (%patients) 46.119.2 vs. (p=0.004)

14.2 vs. Photo Photo sensitivity (% patients) 8.6 (p=0.45) 52.9 vs. 68.3 (p=0.001)

SLE vs. SLE-sSS vs. SLE patients

DAS DAS 28 score 60.9 vs. Tender Tender (% patients) 77.1 (p=0.056) joints

Swollen (% patients) joints

88 vs. 88 92 Arthritis (% patients) (p=NS) 51.3 vs. 76.9 (p=0.27) 73.2 vs. 81.3 (p=0.006)

Szanto Szanto et al, Scofield et al, Disease/Ref 1998 Gilboe et 2001 al, 2004 al, 2006 2007 2010 Nossent et al,Nossent et 2008Pan al, Manoussakis Manoussakis et et al,Baer Page 61 of 71 Page 62 of 71

0.23 2.7 vs. (p=0.010)

4.81 14.9 vs. (p=0.002) 12 9 vs. 14.9 3.7 vs. (p=0.21)

RA vs. RA-sSSRA patientsvs. SSc vs. SSc SSc-sSS patients

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

vs. 1.5 27.2 (p=0.01) 94.7 vs. 92.6 (p= 0.98)

For Peer Review 3.35 vs. 5.9 6.4 vs. 4.3 3.2 vs. 4.20 vs. 5.08 (p<0.001) 2.81 (p=0.1) 3.1 2.7 vs. (p=NS) (p=0.009) 4.13 vs. 4.05 (p=0.8) (p=0.01)

12.1 vs. 6.1 vs. 9.6 vs. 6.1 (p=<0.01) 2.2 vs. 1.1 (p=NS) 14.5 (p=0.019) 5.6 vs. 6.2 (p=0.4) 12.9 vs. 7.0 7.0 vs. 8.5 (p=0.17) 0.28 vs. 0.73 (p=NS) 15.8 (p<0.05) 3.7 vs. 3.2 (p=0.4)

100 100 100 100 100 100 100

Uhlig Uhlig et 1999 al, 2011 2012 2014 al, 2015 Osial et al, 1983 2006 Salliot et 2006 al, Antero Antero et al, He etal, 2013 J Avouac et al, Haga Haga et al, Abdelghani et Brown et al.,

Lung fibrosis fibrosis 58.930 vs. (p=0.001) PAH 52.6 vs. 30 (p=0.001)

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review

PAH - arterialpulmonary NShypertension; NPSLE-- significant; not neuropsychiatric lupus.

Legend:

2013 Kobak Kobak et al, Page 63 of 71

Page 64 of 71 9 9 vs. 26 26.37.7 vs. Thrombo Cytopaenia (% patients) (p<0.05) (p=0.03) 36 vs. 25 (p=0.218)

Hyper gamma globulinaemia (% patients)

ESR/CRP (mm/h; mg/l) ESR 26.8 18.6 vs. (p<0.01) CRP 11.9 13.8 vs. (p=0.33)

antibodies

Anti CCP (% patients)

For Peer) Review 28.6 64 vs. RF RF (% patients/ U/mL) U/mL 48.2 62.2 vs. U/mL (p=0.08) ( p<0.001 31.65U/m vs. L 120.39 u/mL (p=0.126)

Disease/Ref al, 1998 et Uhlig al, 1999 etal, Gilboe 2001 et al, 2004 et Szanto al, 2006 Nossent Manoussakis

42 42 vs. 40 0.5 9.5 vs. (p=0.816) 21.917.8 vs. (p=0.14) (p=0.001)

IgA 33.648.5 vs. (p=0.106) IgG 35.654.3 vs. (p=0.010) IgM 10.611.8 vs. (p=0.951)

ESR ESR 20.53 vs. (p=NS)14.90 CRP 1.52 1.20 vs. (p=NS) 20.9 24.8 vs. (p=0.4) CRP vs. 12.614 N/A N/A

RA vs. RA-sSS vs. RA patients 38.360 vs. (p=0.011) 59.1 vs. 45.4 (p<0.001)

17.4 17.4 vs. 1.39 vs. 51.4 51.4 (p<0.001) 10 vs. 22.1 (p<0.001) 14.9 (p=0.001)

27.6 27.6 vs. 4.69 vs. 1.5 0 vs. 71.4 71.4 (p<0.001) 26.8 vs. 45.3 (p<0.001) 39.2 (p=0.001) (p=1)

2008 2010 2011 2012 2013 et al, 2014 Pan et Pan al, He etJ al, Abdelghani Baer etal,Baer etal, Antero et Haga al, Page 65 of 71 Page 66 of 71

(p=0.7) ESR vs. 14 18 (p=NS) CRP 4 vs. 7.5 (p=NS)

73.8 vs. 61.0 (p=0.008)

SSc vs. SSc SSc-sSS patients 10 10 vs. 0

Myositis Myositis vs. patientsmyositis/sSS

Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology 25.444 vs. 32 vs. 65 74 vs. 90 (p=NS) 28.290 vs. (p<0.01)

For Peer Review

76.8 76.8 vs. 61.8 (p=0.008) vs. 14 50 vs. 24 53 (p=0.05) 19.2 vs. 72.5 (p=0.001)

5.4 5.4 11 vs. 41 0 vs. 5.1 15 vs. (p=0.576)

Figure 1: Flowchart of study selection

EMBASE (n=498) PUBMED (n=1141) Total n= 1639

Did not meet criteria based on title Pubmed (n=1071) Embase (n=418)

Embase n=80 Pubmed n=70 Total n=150 For Peer Review

Did not meet criteria based on abstract: (n=113) N= 37

Manually added after search n=5

Articles included in systematic review

N=42

Scandinavian Journal of Rheumatology

Page 68 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Pan et 2008 Pan al., et Szanto et al., et 2006 Szantoal., Baer al., Baer et 2000 Gilboe et al., 2001 Gilboe al., et Nossent et al., Nossent al., et 1998 Bowman et al.,2003 Bowman Pooledprevalence McDonagh 2000 McDonagh al., et Aggarwal. al., et 2005 Aggarwal. Manoussakis et al., Manoussakis al., et 2004 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review patients. SLE in ofsSS prevalence ofthe 2: Meta-analysis Figure Page 69 of 71

Page 70 of 71 Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review 1987 (Greece) Drosos et al., 1992 (UK) 1992 etal., Drosos Drosos et al.,1992 et Drosos al., 2011 et Antero etal.,2013 He 2014 Abdelghani., 2010 etal., Aliko Carmona et al., 2003 al., et Carmona 2002 et al., Ioannidis 2012 etal., Haga 1999 etal., Uhlig et al., Andonopoulos Pooled prevalence Pooled -15 -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 inRA patients. of of sSS prevalence the 3: Meta-analysis Figure Scandinavian Journal of Rheumatology Scandinavian Journal of Rheumatology

For Peer Review

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