RESEARCH

Sex differential association of dermatomyositis with Sjögren syndrome

Chia-Chun Tseng MD, Shun-Jen Chang PhD, Wen-Chan Tsai PhD, Tsan-Teng Ou MD, Cheng-Chin Wu MD, Wan-Yu Sung MD, Ming-Chia Hsieh PhD, Jeng-Hsien Yen PhD

n Cite as: CMAJ 2017 February 6;189:E187-93. doi: 10.1503/cmaj.160783

ABSTRACT

BACKGROUND: Although dermatomyo- Dec. 31, 2011. Each patient was matched with dermatomyositis after adjusting for sitis and Sjögren syndrome share sero- to, at most, 5 control patients from the age, sex, rheumatoid arthritis, systemic logic autoantibodies and genetic poly- National Health Insurance Research lupus erythematosus and systemic scle- morphisms, population data about the Database by age, sex and entry date. Cox rosis (HR 2.67, 95% CI 2.01–3.54). The incidence of Sjögren syndrome in pa- regression was used to calculate the haz- association was more pronounced in tients with dermatomyositis is unavail- ard ratio (HR) and 95% confidence inter- the male cohort (HR 2.69, 95% CI able. We performed a nationwide ­cohort val (CI) of Sjögren syndrome after adjust- 1.19–6.09). study to explore the potential relation ing for age, sex, rheumatoid arthritis, between dermatomyositis and Sjögren systemic lupus erythematosus and sys- INTERPRETATION: We found a sex differ- syndrome and, if an association exists, temic sclerosis. ential association of Sjögren syndrome to elucidate whether it varies by sex. among patients with dermatomyositis RESULTS: A total of 1602 patients with independent of age and concomitant METHODS: We identified all patients with dermatomyositis and 7981 control autoimmune disease. Further studies newly diagnosed dermatomyositis from patients were enrolled in the study. are required to determine the clinical the Registry of Catastrophic Illness Data- There was a positive association of hav- importance of this association for both base in Taiwan between Jan. 1, 1998, and ing Sjögren syndrome among patients outcomes and therapeutic options.

ermatomyositis is an autoimmune disease with multiple Both dermatomyositis and Sjögren syndrome share common dermatologic changes, chronic muscle inflammation, autoantibodies (e.g., anti-poly(U)-binding-splicing factor,12 anti­ proximal muscle weakness and extramuscular manifesta- nuclear antibodies,13,14 anti–Sjögren-syndrome-related antigen A Dtions, including interstitial lung disease. Immunologically, there [anti-SSA],13,15 anti–Sjögren­-syndrome-related antigen B [anti- are several autoantibody specificities, each associated with par- SSB]13,16) and genetic polymorphisms (e.g., interferon regulatory ticular clinical features. Incidence of dermatomyositis is 1.0 per factor 5 [IRF5 rs4728142]).17,18 In addition, patients with Sjögren syn- 100 000 person-years in British Columbia.1 Despite the gains in drome have a 4-fold higher mortality,19 with surviving patients incur- knowledge of dermatomyositis, the overall mortality is still up to ring a lifetime of increased medical expenses, among other costs.20,21 sevenfold higher than that of the general population.2 Addition- It is important to gain a more accurate understanding of this ally, those with dermatomyositis have a substantially increased increased risk of Sjögren syndrome in dermatomyositis. Although morbidity when compared with the population at large.3 The research into dermatomyositis showed sex differences in risk fac- increased risk of malignant disease,2 cardiovascular events4 and tors,22 cytokine expression,23 autoantibodies profile24 and certain interstitial lung disease5 in dermatomyositis is well-established. dermatomyositis-related outcomes,2 it is unknown whether the However, the risk of other comorbidities in dermatomyositis has association with Sjögren syndrome differs among men and been overlooked. Although an association with Sjögren syndrome women with dermatomyositis. has been shown in other autoimmune diseases, including rheu- We undertook this study to determine the incidence of Sjögren matoid arthritis,6 systemic lupus erythematosus7 and systemic syndrome in dermatomyositis when compared with control sclerosis,8 data on Sjögren syndrome in patients with dermato- patients in a general population and examined whether the associa- myositis are sparse and mostly limited to case reports.9–11 tion between dermatomyositis and Sjögren syndrome varies by sex.

© 2017 Joule Inc. or its licensors CMAJ | FEBRUARY 6, 2017 | VOLUME 189 | ISSUE 5 E187 RESEARCH sources of data for the comparison group The NHIRDandtheRegistryofCatastrophicIllnesswere domly samplingpatientchartsandimposesfinesforfalseclaims. missions specialiststoregularlyreviewmedicalrecordsbyran- within theBureauofNationalHealthInsurance.Thebureaucom- based onthe2002American–EuropeanConsensusGroupCriteria. the RegistryofCatastrophicIllnessforSjögrensyndromeisapproved claimants inthesampleddataandoriginalNHIRD. age, sexormeaninsuredpayroll-relatedamountbetweenthe representative national sample has comparable distribution in 1 000 000 patientsfromallbeneficiariesintheoriginalNHIRD.This registered. TheNHIRDdatasetconsistedofarandomlyselected the originalNHIRDinwhichpatientswithcatastrophicillnessare strophic Illness.TheRegistryofCatastrophicIllnessisasubpart Insurance Research Database (NHIRD) andtheRegistry ofCata- nostic criteria.Thisstudyused2databases:theNationalHealth cation ofDiseases,9thRevision,ClinicalModification(ICD-9)diag- services. DiseasesareclassifiedaccordingtoInternationalClassifi- claims databaseincludesdataonoutpatient,inpatientanddental E188 strophic Illnesswereidentified. of dermatomyositis (ICD-9 code 710.3) in the Registry of Cata From Jan.1,1998,toDec.31,2011,allpatientswithanewdiagnosis Study cohort gram, withacoveragerateofmorethan99.6%. In 1995,TaiwanlaunchedtheNationalHealthInsurance(NHI)pro- Data source Methods the datafilesforresearchpurposes. encrypted allpersonalidentificationnumbersbeforereleasing this approach. tis/Sjögren syndrome, to inadequateduration toassesslong-termexposure status. Patients withfollow-uptimeofless than1yearwereexcludedowing criteria to ensure that the follow-up timewasthe same at baseline. were matchedforage,sexand entry dateundersimilarexclusion services. Thepatientsinthedermatomyositis andcontrolcohorts trol patientswerematcheddates onwhichtheyusedanymedical sponding patientwithdermatomyositis.Theentrydatesforthecon - dermatomyositis were selected from the NHIRD for each corre excluded. Forthecontrolcohort,nomorethan5patientswithout drome beforeorwithin1yearofadermatomyositisdiagnosiswere than 20 the entrydatefordermatomyositiscohort.Patientsyounger of dermatomyositisintheRegistryCatastrophicIllnesswasset as reports andfulfillmentofBohanPetercriteria. tion, laboratorystudies,electromyographyresults,pathologic their casesarereviewedbyspecialists,basedonclinicalpresenta- myositis areregisteredintheRegistryofCatastrophicIllnessafter istration isapproved,copaymentwaived.Patientswithdermato- can applyforregistrationintheRegistryofCatastrophicIllness.Ifreg- strophic diseases, including dermatomyositisand Sjögren syndrome, For diagnosisaccuracy,aroutinepeerreviewisconducted For patient privacy, the National Health Research Institutes Under NHIregulations,insuredbeneficiarieswhohavecata- years ofageorpatientswithadiagnosisSjögrensyn- 28 The date on which the patients received a diagnosis Thedateonwhichthepatientsreceivedadiagnosis 28,29 respectively,inpreviousstudies. 28 Previous studies have validated Previousstudieshavevalidated 28 CMAJ and for dermatomyosi- 25 | FEBRUARY 6, 2017 The NHI medical TheNHImedical 27 Registration in Registrationin 26 30 - - | VOLUME 189 Sjögren syndromeinthedatabasehasbeenvalidated. tients withSjögrensyndrome(ICD-9code710.2).Thecodingfor of CatastrophicIllness,whichevercamefirst. 2011, orthediagnosisdateofSjögrensyndromeinRegistry low-up end point was either the date of last visit before Dec. 31, were performedusingSAS(version9.4,Institute). less than0.05wereconsideredsignificant.Allstatisticalanalyses groups werecomparedusinglog-ranktests.Two-sidedp ences inthefulltime-to-eventdistributionsbetweenstudy groups wereestimatedusingKaplan–Meieranalysis,anddiffer - cumulative incidencesofSjögrensyndromeamongdifferent myositis (i.e.,malestatus×dermatomyositis)wasincluded.The parameter representinginteractionbetweensexanddermato- To assess differences in HR for Sjögren syndrome by sex, a arthritis, systemic lupus erythematosus and systemic sclerosis). age, sexandconcomitantautoimmunediseases(rheumatoid ratio (HR)ofdermatomyositiswith95%CIsafteradjustingfor trol patients,usingtheindirectstandardizationmethod. tomyositis to theexpected cases of Sjögren syndrome among con- observed casesofSjögrensyndromeamongpatientswithderma- populations. Age-adjustedstandardizedIRistheratioof intervals (CIs)ofSjögrensyndromeinthetotal,maleandfemale adjusted standardizedincidenceratio(IR)and95%confidence control patientsstratifiedbyageandsex,calculatedtheage- per 1000person-years)amongpatientswithdermatomyositisand 1 yearaftercohortentrytotheendoffollow-up. matomyositis diagnosis. The follow-up periodwascalculatedfrom up time.Follow-uptimewasdefinedasstarting1yearafterader- the firstyearafterentryintocohortwasnotcountedasfollow- within 1yearafteradiagnosisofdermatomyositiswereexcluded, Because patientswithSjögrensyndrome preceding ordiagnosed Statistical analysis 710.1) matosus (ICD-9code710.0)orsystemicsclerosis Rheumatoid arthritis(ICD-9code714.0),systemiclupuserythe- Covariate assessment The RegistryofCatastrophicIllness Outcome measure mean age (± standard deviation) of male patients was 49.45 of CatastrophicIllnessand7981 controlpatientsfromNHIRD.The We selected 1602 patients with dermatomyositis from the Registry Results (KMUHIRB-EXEMPT(I)-20150051). Review BoardofKaohsiungMedicalUniversityHospital This studywasexemptfromethicsapprovalbytheInstitutional Ethics approval studies haveusedasimilarapproach. ICD-9 codefromtheRegistryofCatastrophicIllness.Previous tained dataontherespectiveautoimmunediseasesbased Multivariate Coxregressionwasusedtodeterminethehazard We firstcalculatedtheincidenceofSjögrensyndrome(cases 31 often overlaps with Sjögren syndrome. Thus, we ob- | ISSUE 5 29 29 wasusedtoidentifypa- 29 Thefol- values RESEARCH E189 Control 36 (0.65) n = 5501 310 (5.64) 684 (12.43) 956 (17.38) 708 (12.87) 1522 (27.67) 1285 (23.36) 46.86 ± 14.09 5.21 (2.89–9.42) 5.88 (3.82–9.04) 3.08 (1.33–7.11) 5.90 (4.64–7.50) 5.92 (3.82–9.16) 6.89 (3.76–12.62) 7.33 (4.49–11.97) 7.14 (1.71–29.87) Rate ratio (95% CI) ratio Rate 0.9 Women, no. (%)* Women, no. 9 (0.83) 71 (6.53) n = 1088 6189.53 7949.00 8902.50 1924.17 4508.67 11306.67 40780.58 141 (12.96) 252 (23.16) 298 (27.39) 180 (16.54) 137 (12.59) Follow-up 47.44 ± 14.37 Dermatomyositis ISSUE 5 ISSUE | Control Control n = 7981 3 (1.56) 23 (3.72) 20 (2.52) 40 (3.54) 27 (3.03) 14 (3.11) 127 (3.11) Sex differential incidence rate ratio of Sjögren ratio of rate incidence Sex differential syndrome 12.37 (95% standardized IR was cohort, age-adjusted In the male stan- cohort, age-adjusted (Table 3). In the female CI 2.68–57.02) that (Table 4), lower than was 5.42 (95% CI 3.42–8.57) dardized IR rate trends of a higher incidence cohort. Consistent of the male in the male cohort than in the female ratio of Sjögren syndrome and Table 4) when stratified by age. cohort were noted (Table 3 between dermatomyositis and sex Interactive effects model, dermatomyositis (HR 2.67,In the multivariable regression to rheumatoid arthritis (HR 3.79, 95%95% CI 2.01–3.54) in addition lupus erythematosus (HR 3.97, 95% CI 2.99– CI 2.92–4.92), systemic - (HR 1.53, 95% CI 1.03–2.28) was associ 5.28) and systemic sclerosis for of Sjögren syndrome after adjusting ated with a higher incidence VOLUME 189 VOLUME | No. (incidence) No. Control 32 (1.29) n = 2480 207 (8.35) 355 (14.31) 624 (25.16) 569 (22.94) 345 (13.91) 348 (14.03) 48.45 ± 15.35 0.9 Men, no. (%)* Men, no. 942.00 449.33 1084.00 1269.83 2068.83 1754.50 7568.50 FEBRUARY 6, 2017 FEBRUARY | Follow-up† 8 (1.56) n = 514 CMAJ 47 (9.14) 75 (14.59) 67 (13.04) 64 (12.45) 136 (26.46) 117 (22.76) 49.45 ± 15.32 n = 1602 Dermatomyositis Dermatomyositis 9 (9.55) 5 (11.13) = 0.9) cohorts. 21 (19.37) 22 (17.33) 43 (20.78) 39 (22.23) 139 (18.37) No. (incidence)* No. = 0.9) and female (p = 0.9) and p value ≥ 80 ≥ 70, < 80 ≥ 50, < 60 ≥ 60, < 70 ≥ 40, < 50 ≥ 30, < 40 Age group, yr group, Age ≥ 20, < 30 20–29 30–39 Note: CI = confidence interval. CI = confidence Note: per 1000 person-years). rate (incidence syndrome of newly*Numbers diagnosed Sjögren period (person-years). follow-up †The total Age, yr Age, Table 2: Age-adjusted standardized incidence ratio of Sjögren syndrome in patients with dermatomyositis, stratified by age by stratified with dermatomyositis, in patients syndrome Sjögren of ratio incidence standardized 2: Age-adjusted Table Age, yr, mean ± SD mean yr, Age, deviation. SD = standard Note: *Unless otherwise indicated. Characteristic Table 1: Age distribution of patients with dermatomyositis and control patients at baseline at patients and control with dermatomyositis patients of distribution 1: Age Table 40–49 50–59 60–69 ≥ 70 Total ratio incidence standardized Age-adjusted

Incidence rate of Sjögren syndrome in dermatomyositis Incidence rate of Sjögren incidental Sjögren syndrome were identifiedA total of 266 cases of group anddermatomyositis the in period, 139 during the follow-up The incidence rate of Sjögren syndrome127 in the control group. 1000 person-years in the dermatomyositis was 18.37 cases per - 3.11 cases per 1000 person-years in the con group, compared with standardized IR was 5.92 (95% CI 3.82– trol group. Age-adjusted similar trends persisted. 9.16) (Table 2). When stratified by age, (± 15.32) 15.35) 48.45 (± group and the dermatomyositis years in deviation) of age (± standard control group. The mean years in the years in the dermatomyositis was 47.44 (± 14.37) female patients (Table 1). Thein the control group 46.86 (± 14.09) years group and the in both was the same the two groups between distribution age male (p RESEARCH E190 stratified by age and sex, similar trends persisted. A history of der- patients withdermatomyositisthanamongthosewithout.When We haveshownahigherincidenceofSjögrensyndromeamong Interpretation in bothmen(p cumulative incidenceofSjögrensyndromethanthecontrolgroup seen. Thedermatomyositisgroupwasassociatedwithahigher 0.001) (datanotshown).Whenstratifiedbysex,asimilarresultwas Sjögren syndromewhencomparedwiththecontrolgroup(p Overall, patientswithdermatomyositishadahigherincidenceof Cumulative incidencesofSjögrensyndrome 2.69, 95%CI1.19–6.09)(Table5). denced byahigherhazardratiowhencomparedwithcontrols(HR Sjögren syndromeandmalesexwithdermatomyositis,asevi- ( arthritis, systemic lupus erythematosus and systemic sclerosis) age, sexandotherconcomitantautoimmunediseases(rheumatoid ). There appeared to be a significant correlation between Table 5).Thereappearedtobeasignificantcorrelationbetween 50–59 40–49 30–39 Age-adjusted standardized incidence ratio ≥ 70 60–69 20–29 Total †The total follow-up period(person-years). diagnosedSjögren*Numbers ofnewly syndrome (incidence rate per1000person-years). Note: CI=confidence interval. Age, yr by age Table 4:Age-adjusted standardized incidence ratio of Sjögren syndrome infemale patients withdermatomyositis, stratified †The total follow-up period(person-years). diagnosedSjögren*Numbers ofnewly syndrome (incidence rate per1000person-years). Note: CI=confidence interval. 20–39 Age, yr Table 3:Age-adjusted standardized incidence ratio of Sjögren syndrome inmalepatients withdermatomyositis, stratified by age Total 40–59 Age-adjusted standardized incidence ratio ≥

60 <0.001)andwomen(p No. (incidence)* No. (incidence)* 117 (21.92) 31 (26.60) 38 (24.74) 19 (19.94) 20 (26.19) 3 (11.14) 13 (11.58) 6 (9.24) 5 (10.59) 22 (9.86) 4 (6.28) Dermatomyositis Dermatomyositis <0.001)(Figure1). n =1088 n =514 CMAJ Follow-up† Follow-up† | FEBRUARY 6, 2017 1122.33 2231.67 1165.25 1535.75 5336.83 472.25 637.08 953.08 269.42 763.67 649.67 < No. (incidence) No. (incidence) | VOLUME 189 ated withincreasedT-cellactivation, syndrome combinedwithotherautoimmunediseaseswasassoci- this study, studies to clarify whether Sjögren syndrome associated this study,studiestoclarifywhetherSjögrensyndromeassociated stantial riskofSjögrensyndromeindermatomyositisasshown distinct disease subset of dermatomyositis. Considering the sub Thus, Sjögrensyndromeindermatomyositispotentiallydefinesa more so than with the respective autoimmune diseases alone. thyroid disease, myositis deterioration,malignantdisease, drome. with concurrent anti-SSA antibodies, hallmarks of Sjögren syn- Reportedly, phenotypes(e.g.,myositis)maybealteredinpatients myositis patientsandthephysiciansguidingtheirtreatment. matomyositis andbeingmale. temic sclerosis.Therewasalsoastronginteractionbetweender- tant rheumatoidarthritis,systemiclupus erythematosus andsys- Sjögren syndrome,evenafteradjustingforage,sexandconcomi- matomyositis wassignificantlyassociatedwithsubsequent stolic dysfunction, 118 (4.04) 2 (0.90) 2 (0.52) 5 (0.91) 9 (0.78) 19 (3.11) 26 (4.11) 36 (4.29) 22 (5.25) 13 (4.32) 2 (1.68) Sjögren syndromehasimportantimplicationsfordermato­ 13 Thesealterationsincludeperivascularinflammation, n =2480 Control n =5501 Control | ISSUE 5 37 cardiacelectricalinstability 33 interstitiallungdisease Follow-up 11555.25 2231.25 3839.58 5484.42 Follow-up 29225.33 6110.75 6327.25 8397.50 4188.25 1193.00 3008.58 35 Raynaudphenomenon, Rate ratio (95%CI) 34 11.81 (2.29–60.88) 12.05 (2.21–65.81) 12.37 (2.68–57.02) 12.66 (5.83–27.49) 12.71 (4.53–35.64) 32 Rate ratio (95%CI) anddeath. leftventriculardia- 6.41 (3.39–12.11) 6.47 (3.84–10.90) 6.64 (1.11–39.75) 5.77 (3.66–9.11) 4.99 (2.72–9.14) 5.43 (4.20–7.01) 5.42 (3.42–8.57) 2.14 (0.81–5.62) 38 andlymphoma, 32 Sjögren Sjögren 15 36 39 -

RESEARCH

and E191 17 80 and auto- 22 1601 40 syndrome. Furthermore, the IRF5 Furthermore, 46

1201 s In mice, BAFF overexpression BAFF mice, In 100 44 0 l Conversely, BAFF receptor blockade Conversely, which increased risk of Sjögren syn- increased risk of Sjögren which 45 15 08 Dermatomyositi Contro Observation time (mo) Moreover, dermatomyositis is associated with dermatomyositis is associated Moreover, 06 18 - Furthermore, genetic studies of pediatric derma 24 ISSUE 5 ISSUE | 04

Thus, common cytokines (IL-4, BAFF), gene polymorphism Thus, common cytokines 02 B Future studies may help address these possibilities. 47 49 These data indicated distinct immunopathologic mechanisms These data indicated distinct immunopathologic 48

Although the incidence of Sjögren syndrome in this study wasAlthough the incidence 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00

Cumulative incidence of Sjögren syndrom Sjögren of incidence Cumulative

rs4728142) and autoantibodies (anti-SSA) probably underpinIRF5 rs4728142) and autoantibodies e higher overall in women than in men, the incidence rate ratio for the than in men, the incidence rate ratio for higher overall in women - than that of the female cohort. The differen male cohort was higher syndrome between male and female tial association of Sjögren may be explained by the differentpatients with dermatomyositis in the different sexes. Past studiespathogenesis of dermatomyositis sex differences in risk factors of dermatomyositis showed , decreased autoantibodies and sialoadenitis. decreased of dermatomyositis between men and women. Alternatively, it is alsoof dermatomyositis between men and women. thatmen in exists whatever changes dermatomyositis that possible For example, der- protects them from developing Sjögren syndrome. on expression of matomyositis exerted sex differential effects and autoimmune dis- S100A4, a protein implicated in inflammatory eases. the link between dermatomyositis and Sjögren ­ the link between dermatomyositis ( tomyositis showed sexual dimorphism in the gene–gene interac- tomyositis showed sexual dimorphism in tion. a high frequency of anti-SSA, a high Sjögren syndrome. Strengths and limitations the sample size from The population-based nature of the cohort, approach to data gath- actual clinical settings, and the validated ering strengthened the reliability of this study. rs4728142 variant was associated with both dermatomyositis variant was associated rs4728142 aggravated salivary gland inflammation (sialoadenitis) and and (sialoadenitis) salivary gland inflammation aggravated syndrome. increased Sjögren syndrome Disease Damage Index. Damage Disease syndrome antibody profiles. drome. VOLUME 189 VOLUME | In 44 80 0.9 0.02 0.03 < 0.001 < 0.001 < 0.001 < 0.001 p value 1601 40 FEBRUARY 6, 2017 FEBRUARY | 1201 CMAJ 00 (95% CI) Adjusted HR* HR* Adjusted 1.00 (0.99–1.01) 3.92 (1.98–7.75) 2.67 (2.01–3.54) 2.69 (1.19–6.09) 3.79 (2.92–4.92) 3.97 (2.99–5.28) 1.53 (1.03–2.28) and those with Sjögren syn- and those with Sjögren 01 40 Dermatomyositis Control 08 Observation time (mo) and those with Sjögren syndrome. and those with Sjögren 43 06 04

Moreover, there was increased BAFF in both patients Moreover, there was 42 02 A Cumulative incidence rates of Sjögren syndrome among patients in the dermatomyositis and control groups in both (A) men and (B) women Cumulative incidence rates of Sjögren syndrome among patients in the dermatomyositis and and IL-4 knockout mice lack immune-mediated secretory and IL-4 knockout mice rs4728142 and anti-SSA. Serum IL-4 is increased in bothIRF5 rs4728142 and anti-SSA. 41

0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35

Cumulative incidence of Sjögren syndrom Sjögren of incidence Cumulative Although we did not explore the mechanism of association mechanism of association did not explore the Although we e Note: CI = confidence interval. CI = confidence Note: arthritis, rheumatoid dermatomyositis, term, sex, interaction age, for *Adjusted sclerosis. and systemic lupus erythematosus systemic Age Variable Table 5: Hazard ratio for Sjögren syndrome in multivariable in multivariable syndrome Sjögren for ratio 5: Hazard Table analyses Female sex Female Dermatomyositis (male term Interaction dermatomyositis) arthritis Rheumatoid lupus erythematosus Systemic sclerosis Systemic with dermatomyositis drome, patients with Sjögren syndrome, BAFF levels correlated with Sjögrenpatients with Sjögren

Figure 1: (both p < 0.001, estimated by the log-rank test). with dermatomyositis might have independent prognostic impor - prognostic have independent might with dermatomyositis tance are needed. - expla plausible syndrome, Sjögren and dermatomyositis between autoantibody genetic and include shared serological, nations may factor (IL-4), B-cell activating namely interleukin-4 components, (BAFF), patients with dermatomyositis dysfunction. RESEARCH 4. 3. 2. ies anti-transcription intermediaryfactor1γ ease, particularly non-Hodgkin lymphoma, and the possible role of sitis andSjögrensyndromehadincreasedriskofmalignantdis- limited ourabilitytoassesswhetherpatientswithdermatomyo­ E192 1. References shows abetterresponse, myositis. BecausetreatmentintheearlyphasesofSjögrensyndrome ferential association of Sjögren syndrome in patients with dermato- This nationwideretrospectivecohortstudyshedslightonthesexdif- Conclusion should beaddressedbyfuturestudies. characteristics is­ drome indermatomyositisregardtophenotypesorserologic Further investigationtoclarifytheincidenceofSjögrensyn- were thosewhopresentedwithSjögrensyndromewasunknown. whether patientswithdermatomyositispositiveforanti-SSA dermatomyositis wereunavailableinadministrativedatabases, to accountforourfindings. increased riskofnon-Hodgkinlymphoma, eases. between patientswithandwithoutantecedentautoimmunedis- studies showedsimilardelaystodiagnosisofSjögrensyndrome tween dermatomyositisandSjögrensyndrome.However,past tis andcontrolpatientsmightplayaroleintheconnectionbe- ences indelaytodiagnosisbetweenpatientswithdermatomyosi- Sjögren syndrome. overestimation, of the association between dermatomyositis and misclassification wouldbiastowardunderestimation,ratherthan the likelihoodthatchangesinrateswouldbedetected.Therefore, Sjögren syndromewasnotdifferential,andthuswoulddecrease tive databases. However, inclusionof anycasesthat were not Sjögren syndromecouldprovidenewtargetsoftherapy. studies ofsexdifferentialassociationdermatomyositiswith suggest acommonpathophysiologyinthese2diseases.Mechanistic relationship betweendermatomyositisandSjögrensyndromecould to therisksofSjögrensyndromeinthesepatients.Inaddition, the cohort andidentifyingthecontributionsofdifferentautoantibodies Sjögren syndrometoclinicaloutcomeswithinadermatomyositis drome in dermatomyositis by investigating the association of important. FuturestudiesshouldclarifythemeaningofSjögrensyn- 51 Because clinical phenotypes or serologic characteristics of Finally, although patients with Sjögren syndrome had an Retrospective cohort study designsraise concerns that differ- Misclassification cannot betotally excluded in the administra- based study. stroke inadultswithpolymyositisanddermatomyositis: ageneralpopulation- Rai Curr RheumatolRep2012;14:275-85. Marie matol myositis andpolymyositisinTaiwan:anationwide populationstudy. Kuo [abstract]. ArthritisRheum2011;​ autoimmune rheumaticdiseases(SARDs)inBritishColumbia,Canada Avina-Zubieta asaserologicalmarkerformalignantdisease. 31 SK, Accordingly, differences in delay to diagnosis is unlikely Accordingly,differencesindelaytodiagnosisisunlikely CF, 2011; I . Choi See Morbidity andmortalityinadultpolymyositis anddermatomyositis. 165: LC, HK, Rheumatology (Oxford) JA, 1273- Yu warranted. Sayre Sayre KH, 9. et al. EC, EC, 53,54 et al. Bernatsky Incidence, cancerriskandmortalityof dermato- early recognition of the condition is earlyrecognitionoftheconditionis 63(Suppl 10):1846. Risk ofmyocardial infarctionandischaemic 2016; S , 55: et al. 461- CMAJ (anti-155/140)antibod- Adult prevalence ofsystemic 9. 50 administrativedata | FEBRUARY 6, 2017 52

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, N, J 64: 59- 310- 2740- activating factor (BAFF) in subsets of patients with idiopathic inflammatory with idiopathic inflammatory (BAFF) in subsets of patients activating factor 2009;68:836 myopathies. Ann Rheum Dis S100A4 levels associate with disease activity rather than cancer development S100A4 levels associate with inflammatory myopathies. in patients with idiopathic 2014;16:468. Engels Conditions Associated with Risk of Non-Hodgkin Lymphoma using Medicare using Medicare Conditions Associated with Risk of Non-Hodgkin Lymphoma 2016;25:1105-13. Claims (“MedWAS”). Cancer Epidemiol Biomarkers Prev Fujimoto Krystufková Vadacca Niewold revealed by serum interferon alpha phenotype in kine gene polymorphisms J Pediatr 2010;157:653-7. juvenile dermatomyositis. Pleštilová autoantibodies and clinical characteristics in Japanese patients. autoantibodies and clinical characteristics in Japanese 2012; Ikeda bodies target transcription intermediary factor 1 family proteins. bodies target transcription intermediary factor 1 family relationship with chronic inflamma- relationship with lupus erythematosus: drome and systemic activity. tion and disease Groom tom onset in primary Sjögren syndrome. tom onset in primary Sjögren 2011;38:973-9. Pijpe Jonsson and altered B cell differentiation with Sjögren’s syndrome. cell differentiation with and altered B 109: concomitant targeting of CXCL13 and the gates murine Sjögren’s syndrome: hypofunction. BAFF receptor prevents salivary Sharma primary Sjögren’s syndrome: an open-label phase II study. 52: syndrome after two infusions of rituximab (anti-CD20). Devauchelle-Pensec 57: 50. 51. 43. Chia-Chun Tseng, Shun-Jen Chang, and Jeng-Hsien YenContributors: Chia-Chun Tseng, Shun-Jen Chang, and Jeng-Hsien study. Shun-Jen Changcontributed to the conception and design of the of data. Wen-Chanand Ming-Chia Hsieh were involved in the acquisition Sung were involved inTsai, Tsan-Teng Ou, Cheng-Chin Wu, and Wan-Yu Tseng, Shun-Jenthe analysis and interpretation of the data. Chia-Chun All of the authorsChang, and Jeng-Hsien Yen drafted the manuscript. approvedcontent and critically for intellectual manuscript reviewed the the final version to be published. inAcknowledgement: The authors thank all of the patients enrolled Taiwan’s National Health Insurance Research Database and Registry of Catastrophic Illness database. Accepted: Sept. 29, 2016 Correspondence to: Jeng-Hsien Yen, jehsye@kmu​ 44. 48. 49. 52. 45. 53. 47. 46. 54. VOLUME 189 VOLUME |

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