Common comorbidities and survival in MS: Risk for stroke, type 1 diabetes and infections

Common como bidi ies and su i al in MS: Risk o s oke, ype 1 diabe es and in ec ions Annukka Mu onen, MD1, Samu Ku ki, PhD2, Ka a iina Hänninen, BM3, Me ja Soilu- Hänninen, MD3, PhD, Ma ja-Liisa Sumelah i, MD, PhD1 1 Uni e si y o Tampe e, 33014- TaY, Finland and Tampe e Uni e si y Hospi al, Depa men o Neu ology, PL 2000,33521 Tampe e, Finland. Mu onen.Annukka.S@s uden .u a. i 2Au ia Biobank, Uni e si y o Tu ku and Tu ku Uni e si y Hospi al, PL 52, 20521 Tu ku, Finland. Samu.Ku ki@ yks. i 3Tu ku Uni e si y Hospi al, Di ision o Clinical Neu osciences and Uni e si y o Tu ku, PL 52, 20521 Tu ku, Finland Ka a iina.Hanninen@u u. i Me ja.Soilu-Hanninen@ yks. i Add ess o co espondence: Ma ja-Liisa Sumelah i e-mail: Ma ja-Liisa.Sumelah i@u a. i. Pos al add ess: A o, 33014 SF-Uni e si y o Tampe e. Tel. +358 40 587 4149 Au ho s ha e no hing o disclose Key wo ds: Mul iple Scle osis; Su i al; Como bidi y; Ci cula o y diseases; Type 1 diabe es; In ec ions This is he pos p in e sion o he a icle, which has been published in Mul iple Scle osis and Rela ed Diso de s. 2018, 19, p. 109-114. h ps://doi.o g/10.1016/j.msa d.2017.10.019 1. In oduc ion Mul iple scle osis (MS) is a p og essi e au oimmune disease causing disabili y and p ema u e mo ali y. Pa hologically MS is cha ac e ized by in lamma ion, demyelina ion and neu odegene a ion in he cen al ne ous sys em (CNS). (1) O he mechanisms in CNS include changes in ascula pe usion, ac i a ion o mic oglia and in ace eb al ascula changes like blood-b ain ba ie leakage. (2,3) Au oimmune diso de s, in ec ions and ci cula o y diseases a e common in MS popula ion. (4,5,6) Se e al diso de s in hese disease g oups a ec b ain and he ne ous sys em in MS, such as ca dio- and ce eb o ascula diseases, hype ension and diabe es. (7) The e is a isk o p ema u e mo ali y in MS (8,9) and he majo cause o dea h a e in ec ions. I is inc easingly ecognized ha he common causes o dea h obse ed in gene al popula ion a e p esen also in MS, such as ca dio ascula causes and s oke (8-11). A he same ime indings ega ding he p e alence o se e al ascula como bidi ies in MS a e con lic ing (12). An almos wo- old inc eased isk o ce eb o ascula como bidi y and a signi ican isk o ca dio ascula como bidi y a e MS onse has been ecen ly epo ed (13). This obse a ion has aised a ques ion o con e ging causal pa hways o he coexis ing diseases and a need o s udy he e ec s in a b oade spec um o como bidi ies in MS. Vascula aspec s in MS a e hus ecognized and he epo ed isk may be explained on basis o he in lamma o y and ascula mechanisms p esen in bo h MS and ci cula o y diseases, in addi ion o suspec ed e ec o sha ed gene ic and li e-s yle isk ac o s. (14, 15) Ou s udy bases on hese obse a ions and hypo heses. We s udied he age- and gende adjus ed isk o ci cula o y diseases in an MS popula ion diagnosed and ollowed-up in a la ge uni e si y hospi al dis ic in Sou hwes Finland. We ocused on ischemic ce eb o- and ca dio ascula diseases and ela ed diso de s, diabe es and acu e and ch onic in ec ions. An es ablished public heal h ca e sys em and popula ion egis e s in Finland o m a eliable basis in ou su ey. By access o adminis a i e and pa ien speci ic da a om he Hospi al Dis ic o Sou hwes Finland we s udied he coinciden isk and su i al e ec o ci cula o y diseases and ela ed como bidi ies in MS, o assess he need o p e en i e ac ions and p ac ical ea men s a egies. 2. Ma e ials and me hods This s udy was egis e ed and app o ed by he Tu ku Clinical Resea ch Cen e , Finland. E hical commi ee app o al was ob ained om he join E hics Commi ee o he Tampe e Uni e si y and Pi kanmaa Hospi al Dis ic , Finland. Fo da a mining, we used he adminis a i e Clinical Da a Reposi o y o he Uni e si y Hospi al o Tu ku con aining elec onic heal h eco ds a he Hospi al Dis ic o Sou hwes Finland. These a e collec ed di ec ly and e ospec i ely mon hly om he ope a ional pa ien da a sys ems om he cen al and uni e si y hospi als o he egion by using ICD-10 codes (In e na ional S a is ical Classi ica ion o Diseases and Rela ed Heal h P oblems 10 h Re ision (ICD-10)-WHO Ve sion o 2016) om 1.1.2004 o 31.12.2012. All esiden cases wi h MS (ICD-10 code G35) we e included. The ca chmen o da a conce ned bo h ali e and deceased MS pa ien s ollowed om 1.1.2004. Case asce ainmen ollowed he ini ial da a mining by sc u iny o each pa ien documen by au ho K.H. o mee he s udy inclusion c i e ia o de ini e MS by McDonald c i e ia (16). Pa ien documen s o he con i med MS cases wi h diagnoses o ca diac (acu e myoca dial in a c I21), ischemic s oke (ce eb al in a c , I62) and o he ascula diseases o he b ain we e nex sc u inized by he au ho s (M-L.S, A.M, M.S-H) o diagnos ic asce ainmen , including in o ma ion on pa aclinical diagnos ics (da e and esul s o b ain CT o MRI scans, ECG and speci ic labo a o y esul s). The ICD codes o causes o dea h among he deceased MS cases we e collec ed om he pa ien eco ds. Como bidi ies diagnosed bo h be o e and a e he da e o diagnosis o de ini e MS we e included in he analysis. Con i med MS cases in his nes ed case con ol s udy we e gende - and age ma ched o con ols d awn om he same popula ion coho . A 10- old gende - and age (based on bi h yea ) - ma ched con ol popula ion was andomly chosen om he CDR pa ien pool and ano he sepa a e age- and gende -ma ched 10- old con ol popula ion was used o e i y he s abili y o he esul s in he dis ic . All ICD-10 codes o each hospi al isi we e a ailable o MS and con ol cases esiding in he ca chmen a ea om 1.1.2004 o 31.12.2012. We collec ed da a o ICD codes I06-I71 in Diseases o Ci cula o y Disease g oup, Chap e IX, I00-I71 and o o he speci ic diagnoses unde he s udy i espec i e o ime o age a each diagnosis. Da es o dea h we e a ailable om CDR. 2.1. S a is ical analyses Kaplan-Meie (KM) su i al analysis was applied o s udy he mean su i al imes. A sepa a e KM analysis was pe o med o s udy he e ec o CD mo bidi y (I00-I71 codes). Signi icance was assessed by log- ank es . The odds a ios, OR’s, we e calcula ed wi h 95% con idence in e als (95% CI) and p- alues we e calcula ed using Pea son’s χ2 es . All s a is ical es s we e wo- ailed and p- alues less han 0.05 we e conside ed s a is ically signi ican . S a is ical analyses we e pe o med using R S a is ics e sion 3.0.2 wi h s anda d packages. 3. Resul s A o al o 1074 con i med MS cases, 315 men and 759 women, we e iden i ied in a popula ion o 472 139. The dis ibu ion o p e alen cases in 2004 and new inciden cases om 2004 o 2012 by sex and age a en y is shown in Table 1. The da e o en y is he i s hospi al isi due o any cause. Du ing he ollow-up dea h in MS occu ed in 5.9% (n 70, 34 women and 36 men). The main cause o dea h was in ec ions (n 38, 54.3%). O he speci ic causes in he ci cula o y diseases g oup (n 5, 7.1%) we e one case o acu e myoca dial in a c , ou cases o ischemic s oke and one case o suba achnoid haemo hage. Causes in o he disease g oups we e espi a o y insu iciency (n 6, 8.6%), cance (n 3, 4.3%) and in oxica ion (n 2, 2.9%). The es o he dea h causes ep esen ed o he causes o dea h (n 16, 22.9%). The mean su i al ime in MS was 82.4 yea s compa ed o 85.6 yea s in he age and gende ma ched con ol popula ion, di e ence was s a is ically signi ican (KM log ank p <0.001), KM cu e shown in Figu e 1. The MS p e alence in 31.12.2012 was 212.6 / 105 (95% CI 199.5-225.8), 121.4 (114.5-128.4) o men and 258.3 (247.9-268.6) o women (17). The diagnosed concomi an ci cula o y sys em diseases in ICD I06-I71 a any poin o disease ajec o y including dea h du ing he ollow-up in 2004-2012 we e included in he second KM analysis shown in Figu e 2. The isk ela ed o ci cula o y disease diagnoses in MS was s a is ically signi ican , log ank p<0.001: he mean su i al ime among MS cases wi h ci cula o y diseases was 79.5 yea s and wi hou ci cula o y diseases 85.4 yea s. Su i al among con ols was 85.6 yea s. The odds a ios (OR) conce ning MS and con ol cases in speci ic ci cula o y diseases ICD- g oups I06-I71 (n=340) a e shown in he addi ional da a. The numbe o MS, age- and gende ma ched con ol cases and OR’s o speci ic ci cula o y diseases diagnoses a e p esen ed in Table 2. An almos 50% g ea e isk o ischemic ce eb al in a c in MS (n 25), OR 1.49 (95% CI 1.03-2.35), was s a is ically signi ican . A s a is ically signi ican and o e wo- old isk was obse ed also o o he s okes (n 9) including bo h suba achnoid and in ace eb al haemo hages: OR 2.5 (1.24-5.06). Acu e myoca dial in a c (n 18, 1.85%) showed no inc eased isk in MS, OR was 1.49 (0.91-2.43). Diagnoses wi h o he ce eb o ascula diseases by code I67 (n 9) and sequelae o ce eb o ascula disease I69 (n 18) may o e lap he acu e s oke diagnoses why hey we e assessed sepa a ely. Respec i e OR’s we e high, 2.5 (1.24-5.06) and 1.73 (1.06-2.83). Ischemic s oke (ce eb al in a c , I63) was con i med ei he as a como bid diagnosis (n 21) o an immedia e cause o dea h (n 4). Case asce ainmen was based on indings in CT scan o MRI in 92% (23/25 cases), loca ion was mainly pa ie al in middle a e y egion (n 11), pos e io (n 6) and subco ical (n 6). Female o male a io was 0.79 (11/13 cases). Mean age a ce eb al in a c was 69.5 yea s, median 69 yea s (SD 10.58), 71.6/71 yea s (SD 9.93) o women and 67.86/67.5 yea s (SD 11.15) o men (χ2 p=0.23, s a is ically nonsigni ican ). All cases in I67 (suba achnoid and in ace eb al haemo hage) we e adiologically con i med. Diagnosis o acu e myoca dial in a c diagnosis based on ECG and blood es s. The numbe o MS, age- and gende ma ched con ol cases and OR’s o common ci cula o y disease ela ed isk ac o s a e p esen ed in Table 3. Type 1 diabe es showed a wo- old isk, OR 2.1 (1.3-3.36). A s a is ically nonsigni ican isk was obse ed o ype 2 diabe es, ansien ischemic a ack (TIA), a ial ib illa ion, o he ca diac a hy hmia, hype ension, hype lipidaemia and obesi y in MS. The numbe o MS, age- and gende ma ched con ol cases and OR’s o a numbe o acu e and ch onic in ec ions a e p esen ed in Table 4. wi h de ailed esul s. The coinciden isk o he hospi al ea ed in ec ions showed an inc eased isk o u ina y, espi a o y and pe iodon al in ec ions in MS. 4. Discussion The lowe mean su i al ime o 82.4 yea s in MS compa ed o 85.6 yea s in he con ol popula ion was s a is ically signi ican . Howe e , li e expec ancy was educed much less han in ea lie s udies showing 6-7 yea s sho e li e expec ancy in MS (8, 9, 18). This suppo s imp o ed su i al in pa ien coho s om he e a o disease modi ying he apies and is in line wi h he ecen s udy om No way showing a nea no mal s anda dised mo ali y a io in he pa ien coho moni o ed om 1997 o 2012 (18). The high mo ali y o ce eb o ascula diseases in he Finnish gene al popula ion (19) was he e shown o conce n also he MS popula ion. Resul suppo s he Danish s udy (5) and co obo a es su i al disad an age epo ed o ce eb o ascula diseases among MS pa ien s. (10-13) Su i al disad an age ela ed o ci cula o y disease como bidi y was signi ican in ou s udy. The mean su i al ime was lowe o MS cases wi h any ci cula o y diseases ela ed diagnosis in ICD-10 I06-I71 g oup, 79.5 yea s, in compa ison wi h he 85.4 yea s in MS pa ien s wi hou i . The speci ic isk o he common isk ac o s o hese diseases, such as hype ension, hype lipidaemia o ca diac diso de s and a hy hmias, we e low also in ou MS popula ion (20) along wi h o he isk ac o s o ischemic s oke, excep o ype 1 diabe es. MS pa ien s we e ollowed up du ing a 9-yea pe iod in 2004-2012. The ca chmen a ea in he Hospi al Dis ic o Sou hwes Finland ep esen s a high- isk egion o MS, whe e p e alence was 212/105in 2012. (17) MS coho o igina ed om an adminis a i e da abase and a e con i ma ion o MS diagnosis 9.6% o cases we e excluded, which amoun is simila o o he epo s using adminis a i e ca chmen . (5, 20) Pa ien eco ds we e examined o con i ma ion o MS, ischemic b ain and myoca dial in a c s and o causes o dea h, why we belie e o ha e eliable da a o he s a is ical assessmen conce ning hese diagnoses. The diagnosis o ype 1 diabe es was conside ed eliable in his popula ion due o egula hospi al con ols. S eng h o ou s udy is he public heal h ca e sys em, whe e heal h ca e is a ailable o all Finnish ci izen and an equal ea men p ac ice is ollowed. The na ional and hospi al egis e s in Finland base on pe sonalized iden i ica ion code and a e ega ded eliable. The adminis a i e heal h egis y co e s almos he en i e popula ion o he s udy egion and p o ides objec i e da a a oiding bias ela ed o pa ien ecall. MS is diagnosed and ea ed by neu ologis in cen al and uni e si y hospi als why we belie e o ha e a ep esen a i e sample o MS pa ien s om a la ge hospi al dis ic . A 10- old sample o he gene al non-MS popula ion ensu e ha s udy obse a ions e lec gene al pa e ns o co-occu ence o heal h p oblems among MS pa ien s, which may no be accu a e in small clinical samples, due o sampling, o e e al biases. We obse ed an inc eased isk o ci cula o y diseases in MS popula ion as compa ed o age- and sex ma ched con ol popula ion du ing he ollow-up. E idence ha au oimmuni y may play an essen ial ole in he pa hogenesis o a he oscle osis (21) is suppo ed by epo s on inc eased isk o ce eb o- and ca dio ascula diso de s in se e al immune-media ed diseases, such as MS (22), heuma oid a h i is (23, 24) and ype 1 diabe es (25). These esul s sugges ha hese in lamma o y diseases may sha e pa hological links wi h ce eb o ascula diseases. Howe e , al hough in lamma ion is shown o con ibu e o s oke isk (26), o he ypical isk ac o s may be absen in MS. (25, 27) This iew was suppo ed by obse a ions in ou da a, as o he common ce eb o ascula isk ac o s, such as TIA, a ial ib illa ion and o he a hy hmias, showed no inc eased isk, no was he e any isk o seconda y hype ension, hype lipidaemia o obesi y. Resul di e s om obse a ions in heuma oid a h i is and ype 1 diabe es popula ions, whe e se e al common isk ac o s exis , bu co obo a es obse a ions in o he MS popula ions whe e p e alence o diabe es, hype ension, and hype lipidaemia ha e been simila o a es in gene al popula ion. (20) Gi en he obse a ion o inc eased isk o s oke, which is diagnosed in hospi al, and he low como bidi y o some o he mos common ascula disease isk ac o s, ou esul s a e disco dan bu in acco dance wi h o he s udies. (20) Limi a ion in ou s udy popula ion howe e conce ns he ca chmen o hese isk diagnoses om he e ia y ca e hospi al da a, as mos o hese condi ions a e ecognized and ea ed mainly in he p ima y ca e. I also emains unknown o wha con en he obse ed ci cula o y disease isk is ela ed o me abolic synd ome in MS, a ques ion which has emained open also in o he s udies add essing his ela ion and he inc eased isk o obesi y o changes in body composi ion, hype ension, dyslipidaemia o ype II diabe es in MS (27). Al hough adminis a i e da a a e conside ed a alid means o acking diabe es, hype ension, and hype lipidaemia in MS (27) he so a inconclusi e esul s om hospi al da a ega ding common ci cula o y disease isk ac o s in MS as shown he e could be elabo a ed by linkage o o he da abases and p ima y ca e da a. Respi a o y in ec ions we e he majo cause o dea h and he high a es o acu e and ch onic espi a o y, u ina y and pe iodon al in ec ions we e p esen also in ou MS coho . (8, 11, 28) Acu e and ch onic in ec ious diseases a e ela ed o isk o s oke (29) and in ec ions may be a speci ic isk ac o in MS popula ion. The e is a connec ion be ween he immunological and ascula ac o s (30), which suppo s he sugges ed hypo hesis on he sha ed in lamma o y mechanisms in MS and ischemic s oke (31). The con ol o in lamma ion and in ec ions appea as impo an modi iable ac o s in MS ela ed ci cula o y disease isk. E idence om obse a ional s udies shows ha accina ion agains in luenza is associa ed wi h a educed isk o s oke, myoca dial in a c ion and all-cause mo ali y. (32) The p e en i e seasonal and H1N1 accines a e sa e and e icacious also among MS pa ien s, no is he e any educed esponse o accina ion agains in luenza associa ed o majo i y o immunomodula o y d ugs used in MS. (33) The independen coinciden ela i e isk o ype 1 diabe es in ou MS popula ion was high and co obo a es esul s in o he s udies (34). In Finland, he incidence o bo h ype 1 diabe es and MS a e high (35). The au oimmune pa hogenesis o MS and ype 1 diabe es (6) as well as socioeconomic, en i onmen al and la i ude co ela ed ac o s may con ibu e o he p edisposi ion o hese immune-media ed diseases. The global and s eep inc ease in bo h ype 1 and 2 diabe es (36) and MS incidences eco ded in he las hal o he 1990’s may be a se ious signal o unheal hy changes in he en i onmen and li e s yle. These may a ec he pene ance o disease suscep ibili y genes in au oimmune diseases and may also be in ol ed in he high ci cula o y disease isk obse ed in MS and ype 1 diabe es in Finland. The modi iable isk ac o s in ype 1 diabe es, MS and ci cula o y diseases include childhood obesi y and smoking. (37) MS pa ien s oday expec a longe su i al. The long disease ajec o y combines an inc eased isk o como bidi ies common in he gene al popula ion, as shown he e o ischemic s oke isk along wi h o he s udies. Consis en wi h o he epo s, limi a ion o in o ma ion ega ding ci cula o y disease mo ali y ela ed li e-s yle ac o s he e conce ns he lack o socioeconomic and li es yle in o ma ion in MS coho s. A he momen , we ha e no in o ma ion on he changes in occupa ional s a us, medica ion, weigh , se um lipid s a us o on indi idual li es yle ac o s such as smoking, die a y habi s, physical ac i i y o heal h beha iou in gene al, bu e idence on accumula ing como bidi y isk in MS suppo s he impo ance o dealing wi h hese ac o s. Li e s yle in e en ions a e jus i iable as he key indings in como bidi y s udies in MS ha e been associa ion o li e-s yle ela ed ype 2 diabe es, hype ension, dyslipidaemia o pe iphe al ascula disease a any poin in he disease cou se wi h a g ea e p og ession in disabili y. (20) These ac o s may add o complex isk o ci cula o y diseases in MS and ha e implica ions o p e en ion and ea men in he ecognized isk g oups. Disad an ages in adminis a i e da abases such as ou s include he lack o s uc u ed da a on li e s yle ac o s. We expec o expand he in o ma ion in ou da abases in he u u e wi h he applica ion o ex mining ools o pa ien epo s and linkage o o he go e nmen al heal h egis ies such as he medica ion eimbu semen egis y o social insu ance ins i u ion o Finland. Table 1. Numbe , mean age and s anda d de ia ion (yea s) a en ollmen om 1.1.2004 o 31.12.2012 among he 1074 MS cases (ICD-10 G35) by gende in he Hospi al Dis ic o Sou hwes Finland. Table 2. The numbe , pe cen age and coinciden odds a io (OR) wi h 95% con idence in e al (CI) o he diagnosed and con i med cases in acu e myoca dial in a c , ce eb al in a c and o he ascula disease o he b ain o MS cases compa ed o age- and gende ma ched con ol cases om 1.1.2004 o 31.12.2012 in he Hospi al Dis ic o Sou hwes Finland. ICD - 10 code Disease MS (n) % Con ols (n) % OR 95% CI I21 Acu e myoca dial in a c 18 1.7 121 1.1 1.49 0.91 – 2.43 I63 Ce eb al in a c 25 2.3 161 1.5 1.55 1.03 – 2.35 I67 O he ascula disease o he b ain 9 0.8 36 0.3 2.50 1.24 – 5.06 Yea o en y Mean age S d de Numbe o cases Yea o en y Mean age S d de Numbe o cases 2004 44.6 12.0 212 2004 47.7 13.8 111 2005 46.8 13.2 159 2005 50.3 14.1 53 2006 44.4 12.7 79 2006 48.2 14.4 34 2007 42.6 14.3 50 2007 49.2 14.5 26 2008 45.4 15.7 61 2008 42.7 13.1 33 2009 44.9 17.6 52 2009 45.1 13.9 18 2010 48.7 14.2 49 2010 49.1 15.1 14 2011 41.9 14.5 52 2011 45.9 15.1 16 2012 45.9 18.5 45 2012 49.6 18.6 10 To al 44.9 13.8 759 To al 47.5 14.1 315 Female Male Table 3. The numbe , pe cen age and coinciden odds a io (OR) wi h 95% con idence in e al (CI) o he common ci cula o y diseases diagnosed in hospi als o MS cases compa ed o age- and gende ma ched con ol cases om 1.1.2004 o 31.12.2012 in he Hospi al Dis ic o Sou hwes Finland. ICD-10 code Disease MS % Con ols % OR 95% CI G45 TIA 12 1.1 136 1.3 0.88 0.49-1.59 I48 A ial o ib illa ion o lu e 18 1.7 350 3.3 0.51 0.33-0.81 I49 O he ca diac a y hmia 18 1.7 189 1.8 0.95 0.59-1.54 I10 Essen ial hype ension 93 8.7 1034 9.6 0.90 0.74-1.10 I70 A he oscle osis 12 1.1 102 1.0 1.18 0.65-2.13 E10 Type I diabe es melli us 20 1.9 95 0.9 2.11 1.32-3.36 E11 Type II diabe es melli us 39 3.6 391 3.6 1.00 0.72-1.38 E78 Hype lipidemia 17 1.2 336 3.1 0.51 0.32-0.81 E66 Obesi y 21 2.0 328 3.1 0.64 0.42-0.99 Table 4. The numbe , pe cen age and coinciden odds a io (OR) wi h 95% con idence in e al (CI) o common acu e and ch onic in ec ions diagnosed in hospi al o MS cases compa ed o age- and gende ma ched con ol cases om 1.1.2004 o 31.12.2012 in he Hospi al Dis ic o Sou hwes Finland. ICD -10 code Disease MS (n) % Con ols (n) % OR 95% CI N10 Acu e pyeloneph i is 88 8.2 116 1.1 7.59 6.01 - 9.57 J22 Unspeci ied acu e lowe espi a o y in ec ion 7 0.7 10 0.1 7.0 3.06 - 16.03 N30 Cys i is 81 7.5 116 1.1 6.98 5.48 - 8.89 J41 Simple and mucopu ulen ch onic b onchi is 4 0.4 7 0.1 5.71 1.93 - 16.92 A41 O he sepsis 29 2.7 62 0.6 4.68 3.14 - 6.97 J18 Pneumonia, unspeci ied o ganism 100 9.3 297 2.8 3.37 2.73 - 4.15 K02 Den al ca ies 25 2.3 90 0.8 2.78 1.82 - 4.24 J20 Acu e b onchi is 25 2.3 102 0.95 2.45 1.61 - 3.73 K05 Gingi i is and pe iodon al diseases 23 2.1 101 0.94 2.28 1.47 - 3.53 A04 O he bac e ial in es inal in ec ions 14 1.3 62 0.6 2.26 1.29 - 3.96 K08 O he diso de s o ee h and suppo ing s uc u es 18 1.7 86 0.8 2.09 1.28 - 3.43 L02 Cu aneous abscess, u uncle and ca buncle 15 1.4 77 0.7 1.95 1.13 - 3.35 A09 In ec ious gas oen e i is and coli is, unspeci ied 29 2.7 164 1.5 1.77 1.20 - 2.60 J06 Acu e uppe espi a o y in ec ions o mul iple and unspeci ied si es 41 3.8 237 2.2 1.73 1.25 - 2.39 Addi ional able. The numbe , pe cen age and coinciden odds a io (OR) wi h 95% con idence in e al (CI) o he ICD-10 ci cula o y disease diagnoses I06-I71 o he MS and age- and gende ma ched con ol cases om 1.1.2004 o o 31.12.2012 in he Hospi al Dis ic o Sou hwes Finland. ICD code Disease MS % Con ols % OR 95% CI I06 Rheuma ic ao ic al e diseases 1 0.09 6 0.06 1.67 0.21 - 13.52 I10 Essen ial (p ima y) hype ension 93 8.66 1034 9.63 0.90 0.74 - 1.10 I11 Hype ensi e hea disease 2 0.19 35 0.33 0.57 0.14 - 2.33 I12 Hype ensi e ch onic kidney disease 1 0.09 3 0.03 3.33 0.40 - 28.10 I15 Seconda y hype ension 7 0.65 23 0.21 3.04 1.36 - 6.79 I20 Angina pec o is 12 1.12 141 1.31 0.85 0.47 - 1.53 I21 Acu e myoca dial in a c ion 18 1.68 121 1.13 1.49 0.91 - 2.43 I22 Subsequen myoca dial in a c ion 2 0.19 2 0.02 10.00 2.05 - 48.82 I23 Ce ain cu en complica ions ollowing myoca dial in a c ion 10.09 2 0.02 5.00 0.58 - 43.34 I25 Ch onic ischemic hea disease 25 2.33 259 2.41 0.97 0.64 - 1.45 I26 Pulmona y embolism 11 1.02 52 0.48 2.12 1.12 - 3.99 I33 Acu e and subacu e endoca di is 1 0.09 4 0.04 2.50 0.30 - 20.75 I34 Non heuma ic mi al al e diso de s 5 0.47 63 0.59 0.79 0.32 - 1.96 I35 Non heuma ic ao ic al e diso de s 4 0.37 65 0.61 0.62 0.23 - 1.67 I36 Non heuma ic icuspid al e diso de s 1 0.09 4 0.04 2.50 0.30 - 20.75 I40 Acu e myoca di is 1 0.09 6 0.06 1.67 0.21 - 13.52 I42 Dila ed ca diomyopa hy 2 0.19 26 0.24 0.77 0.18 - 3.22 I44 A io en icula and le bundle-b anch block 60.56 42 0.39 1.43 0.61 - 3.34 I45 O he conduc ion diso de s 6 0.56 41 0.38 1.46 0.63 - 3.42 I46 Ca diac a es 1 0.09 4 0.04 2.50 0.30 - 20.75 I47 Pa oxysmal achyca dia 9 0.84 84 0.78 1.07 0.54 - 2.12 I48 A ial ib illa ion and lu e 18 1.68 350 3.26 0.51 0.33 - 0.81 I49 O he ca diac a hy hmias 18 1.68 189 1.76 0.95 0.59 - 1.54 I50 Hea ailu e 19 1.77 124 1.15 1.53 0.95 - 2.47 I60 Non auma ic suba achnoid hemo hage 5 0.47 24 0.22 2.08 0.81 - 5.34 I61 Non auma ic in ace eb al hemo hage 4 0.37 26 0.24 1.54 0.54 - 4.37 I63 Ce eb al in a c ion 25 2.33 161 1.50 1.55 1.03 - 2.35 I67 O he ce eb o ascula diseases 9 0.84 36 0.34 2.50 1.24 - 5.06 I69 Sequelae o ce eb o ascula disease 18 1.68 104 0.97 1.73 1.06 - 2.83 I70 A he oscle osis 12 1.12 102 0.95 1.18 0.65 - 2.13 I71 Ao ic aneu ysm and dissec ion 3 0.28 26 0.24 1.15 0.35 - 3.80