Increasing incidence in relapsing-remitting MS and high rates among young women in Finland : a thirty-year follow-up

Resea ch A icle Inc easing Incidence in Relapsing-Remi ing MS and High Ra es among Young Women in Finland: A Thi y-Yea Follow-Up Ma ja-Liisa Sumelah i,1,2 Ma kus H. A. Holmbe g,1Annukka Mu onen,1 Heini Huh ala,3and I ina Elo aa a1,2 1School o Medicine, Uni e si y o Tampe e, A o 312, 33014 Tampe e, Finland 2Tampe e Uni e si y Hospi al, P.O. Box 2000, 33521 Tampe e, Finland 3School o Heal h Sciences, Uni e si y o Tampe e, 33014 Tampe e, Finland Co espondence should be add essed o Ma ja-Liisa Sumelah i; [email p o ec ed] Recei ed 28 May 2014; Re ised 23 Sep embe 2014; Accep ed 9 Oc obe 2014; Published 9 No embe 2014 Academic Edi o : Bianca Weins ock-Gu man Copy igh © 2014 Ma ja-Liisa Sumelah i e al. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion License, which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Objec . Gende and disease cou se speci ic incidences we e s udied in high- and medium- isk egions o MS in Finland. Me hods. Age- and gende -speci ic incidences wi h 95% CIs we e calcula ed in 10-yea pe iods om 1981 o 2010. Pose diagnos ic c i e ia we e used and compa ed wi h he McDonald c i e ia om 2001 o 2010. Associa ion be ween age and diagnos ic delay o e ime was assessed by using he K uskal-Wallis es . Resul s. 1419 (89%) RRMS and 198 (11%) PPMS cases we e included. RRMS incidence inc eased wi h he emale o male a io (F/M) om 4,2/105(F/M 1.9) o 9,7 (2.3), while ha o PPMS dec eased om 1,2 (1.6) o 0,7 (1.2). The use o McDonald c i e ia did no change he conclusion. The dec easing diagnos ic delay and age a diagnosis in RRMS we e associa ed wi hin he 10-yea pe iods and con as ed hose in PPMS. Inc easing emale isk in RRMS was obse ed in he high- isk egion. Conclusion. Inc easing RRMS incidence and high emale a ios shown in each age g oup indica e gende -speci ic in luences ac ing al eady om childhood. A mo e p ecise de ini ion o he isk ac o s and hei ac ion in MS is needed o p o ide a be e unde s anding o unde lying pa hological p ocesses and a a ionale o he de elopmen o new p e en i e and ea men s a egies. 1. In oduc ion Inc easing incidence in MS conce ns he ising emale o male (F/M) a io [1] and elapsing- emi ing (RRMS) ype o he disease [2]. I has become appa en ha en i onmen al ac o s play an ac i e ole, bu li le is known abou he ac o s ha ca y he gende - and disease-cou se-speci ic e ec s. The accumula ed e idence indica es ha la i udinal, gene ic, and local en i onmen al ac o s in e ac o cause MS, and a ecen s udy has con i med ha he la i udinal e ec s a e becoming mo e ele an a pola and in e media e la i udes o he RR pheno ype, pa icula ly in women [2]. The clinical and pa hological spec um o mul iple scle- osis is he e ogeneous [3]. Di e en sub ypes a e belie ed o sha e he same gene ic a chi ec u e [4], and se e al lines o e idence sugges ha mul iple scle osis suscep ibili y genes, pa icula ly HLA-DRB1∗15, in luence he pheno ypic exp ession o he disease, al hough some o he e idence on his aspec o he disease is con lic ing [5]. The majo i y o MS cases may be classi ied as elapsing- emi ing MS (RRMS) om onse and, in abou 10–30% o cases, as p ima y p og essi e MS (PPMS). Clinical di e ences indica e a younge age a onse and emale p eponde ance (F/M 2.2) in RRMS e sus low F/M a ios (abou 1.3) and olde age in PPMS [6]. A uni ying concep oday holds ha mul iple scle osis can be conside ed as one disease wi h di e en pheno ypes [7]. The clinical seg ega ion o disease cou ses is highly ele- an , as he cu en disease-modi ying ea men s (DMT) a e e ec i e mainly agains elapsing MS [8]. Recen changes in diagnos ic c i e ia o MS ha e add essed he need o eliable disease ype iden i ica ion in MS. Howe e , se e al issues ega ding PPMS ecogni ion ha e emained [9], al hough he c i e ia p oposed in 2001 [10] and s ic u iliza ion o Hindawi Publishing Co po a ion Mul iple Scle osis In e na ional Volume 2014, A icle ID 186950, 8 pages h p://dx.doi.o g/10.1155/2014/186950 2Mul iple Scle osis In e na ional hela es McDonaldc i e ia om2010[11]p esumably help in a oiding diagnos ic e o s. Recen obse a ions ha e poin ed a s able incidence a es wi h PPMS, whe eas RRMS incidence a es a e ising [12,13]. Finland is a coun y in no he n Eu ope be ween he la i udes 60 and 70∘andbelongs o hehigh- iska easo MS, oge he wi h No dic a eas [2]. MS incidence has inc eased signi ican ly om 1981 o 2010 also in Finland, especially in he high- isk egions [14]. The high- isk a eas in Finland a e loca ed in wes e n Finland, especially in Sein¨ ajoki and Vaasa, whe e espec i e o al incidences we e 12.5 pe 105 pe son-yea s and 8.3/105in 2010. The MS isk was wo old in Sein¨ ajoki (SIR1.9) and signi ican ly highe in Vaasa (1.2) compa ed wi h neighbo ing Pi kanmaa (compa a o , 1.0). The incidence in Pi kanmaa was 6.7/105, which is ega ded as a medium- isk a e in Finland. In his s udy we aim o s udy he disease-cou se- and gende -speci ic incidence ends in he high- isk dis ic s o Sein¨ ajoki and Vaasa and he medium- isk dis ic o Pi kanmaa, while also conside ing he e ec o changing diagnos ic me hods and c i e ia. In e ms o he ecen global ends in MS, we assume ha he inc ease in RRMS is also seen in ou s udy coho . Gi en ha he s udy popula ions a e gene ically and socioeconomically s able, we hypo hesize ha he en i onmen al e ec s a e e lec ed analogically in incidences in he dis ic s, which would e lec he ac ion o he unde lying pa homechanism and common epigene ic ac o s in isk g oups. 2. Ma e ial and Me hods The Na ional Ins i u e o Heal h and Wel a e and local e hical s anda ds commi ee app o ed e ospec i e sc u i- nizing o iden i ied pa ien eco ds in he hospi als unde he s udy. Residence o cases was upda ed by pe sonalized iden i ica ion numbe and by yea o diagnosis a S a is ics Finland (h p://www.s a . i/). A de ailed desc ip ion o s udy popula ion, case collec- ion, and case asce ainmen is p esen ed elsewhe e [14]. Hos- pi al dis ic s unde he s udy belong o Tampe e Uni e si y Hospi al egion in wes e n Finland, shown in Figu e 1.The high- isk a ea comp ises he Sein¨ ajoki and Vaasa Cen al Hospi al dis ic s and medium- isk a ea he Pi kanmaa dis ic . The o al popula ion in he dis ic s was 850,630 in 2010. Neu ological se ices o diagnosis and ea men a e e enly dis ibu ed among he hospi als. Magne ic esonance imaging (MRI) has been a ailable om 1990 in Pi kanmaa and om 1993 in o he hospi als. Cases we e included in he analysis when hey ul illed he c i e ia o clinically de ini e (CD) o labo a o y-suppo ed de ini e (LSD) MS by Pose e al. [15] be ween 1 Janua y 1981 and 31 Decembe 2010 and esided in he s udy dis ic s in he yea o diagnosis. Cases om 1 Janua y 1981 o 31 Decembe 2010 wi h diagnoses o mo bus demyelinans and op ic neu i is (340, 341 in ICD 8-9, G35, G37.4, and H46 in ICD 10) we e i s iden i ied om he egis ies in he hospi als, whe e diagnosis was made by a neu ologis . Pa ien documen s we e hen sc u inized by he au ho s (MH, AM, and MLS). Case assessmen included pa aclinical es s and 70∘ 60∘ Vassa Sein  ajoki Pi kanmaa Helsinki Figu e 1: Map o Finland. Finland lies in Scandina ia, No h Eu ope, be ween la i udes 60 and 70∘N. Gul o Bo hnia in no he n pa o Bal ic Sea limi s he wes coas . The o al popula ion was 5.4 million in 2010. Loca ions o Cen al Hospi als in Sein¨ ajoki (do s) and Vaasa (da k g ey) and Uni e si y Hospi al o Tampe e a Pi kanmaa dis ic (oblique lines) a e poin ed in he map. hei ime poin , le el, and esul s; o MRI, e oked po en ials (EP) including isual, b ains em audi o y, and senso y EPs; and ce eb ospinal luid (CSF). The yea o onse and yea o de ini e diagnosis we e eco ded, and in o ma ion on speci ic onse symp oms was collec ed. The classi ica ion o disease cou se was ee alua ed o asce ain whe he he c i e ia o RRMS o PPMS we e me [16]. To sc u inize he e ec o changing diagnos ic me hods and c i e ia in he coho , we ee alua ed he coho diagnosed om 2001 o 2010 by he McDonald c i e ia p esen ed in 2001 [10]. The dis ibu ion o onse symp oms was calcula ed by diseasecou sein hewholecoho .Ini ialMSsymp oms we e ca ego ized in he ollowing g oups: mo o (including py amidalsymp omssuchasmo o hemipa esiso pa esis in he uppe limbs and medulla y symp oms, mainly mo o pa apa esis), b ains em (diplopia, igeminal senso y symp- oms, o acial dys unc ion), isual (dis u bances seen in op ic o e obulba neu i is), senso y, and o he symp oms (ce ebella dys unc ion, a igue o psychia ic p oblems, and epilep ic seizu es). Age-adjus ed gende - and disease-cou se-speci ic inci- dence a es pe 105pe son-yea s we e calcula ed wi h a 95% con idence in e al (CI) om 1 Janua y 1981 o 31 Decembe 2010, and his pe iod was di ided in o h ee subpe iods: Mul iple Scle osis In e na ional 3 Table 1: Age-adjus ed incidence o RRMS and PPMS pe 105pe son-yea s wi h 95% CIs and F/M a ios om 1981 o 2010 in en-yea pe iods. Disease cou se RRMS PPMS Pe iod Pe son-yea s Numbe o new cases Incidence F/M Numbe o new cases Incidence F/M I 95% CI I 95% CI 1981–1990 6208067 280 4.2 3.7–4.6 1.9 80 1.2 0.9–1.4 1.6 1991–2000 6142661 526 8.5 7.8–9.2 2.0 72 1.2 0.9–1.4 1.9 2001–2010 6326284 613 9.7 8.9–10.5 2.3 46 0.7 0.5–0.7 1.2 1981–1990, 1991–2000, and 2001–2010. The incidence o he 5-yea pe iods did no change ou o e all conclusions (da a no shown). Fu he mo e, o a oid chance a ia ion, we used 10-yea pe iods in ou calcula ions. S a is ical analyses we e pe o med using SPSS 9.0 o Windows. Co ela ion o diagnos ic age (age a diagnosis) and delay ( ime om onse o diagnosis) ac oss h ee ime pe iods was conduc ed using K uskal-Wallis es s [17] wi h Bon e oni adjus men o mul iple compa isons. Wi h he K uskal-Wallis es , a chi- squa es a is icisused oe alua e hedi e encesinmean anks o assess he null hypo hesis ha he medians a e equal ac oss he g oups. A 𝑃 alue o <0.05 wi h Bon e oni co ec ion was conside ed s a is ically signi ican . 3. Resul s F om 1 Janua y 1981 o 31 Decembe 2010, a o al o 1617 MS cases me he inclusion c i e ia in s udy dis ic s (933 cases in Sein¨ ajoki and Vaasa and 684 cases in Pi kanmaa). A o al o 1105 (68%) women and 512 (32%) men we e included. RRMS was obse ed in 1419 cases (89%) and PPMS in 198 cases (11%). F/M a ios in RRMS we e 2.1 (965 women, 454 men) andinPPMS1.2(109/89). Changes in age-adjus ed incidences pe 105pe son-yea s wi h 95% CIs o he h ee s udy pe iods 1981–1990, 1991– 2000, and 2001–2010 a e p esen ed in Table 1.A wo old inc ease in RRMS ( om 4.2 (3.7–4.6) o 9.7 (8.9–10.5)/105) and a dec ease in PPMS ( om 1.2 (0.9–1.4) o 0.7 (0.5–0.7)) we eobse ed.A hesame ime he emale/male(F/M) a ios in RRMS inc eased om 1.9 o 2.3 and dec eased in PPMS om 1.6 o 1.2. In RRMS g oup he mean age a diagnosis was 36.3 and in PPMS 45.3 yea s. We s udied he age and gende e ec by diseasecou sebycalcula ing heF/M a iosineach en-yea age g oup, p esen ed in Figu e 2 showing an excep ionally high F/M a io o 5 : 1 (𝑛=34/7 cases) in RRMS age g oup <20 yea s. A e his he dis ibu ion showed an app oxima ely wo old a io om 20 o 59 yea s in RRMS, while ha in PPMS was 1 : 1. In addi ion o age and gende di e ence, he dis ibu ion o onse symp oms showed a signi ican di e ence by disease cou se (𝑃 = 0.000), shown in Figu e 3. In RRMS, b ains em (26%), isual (25%), and senso y symp oms (24%) we e equally dis ibu ed and showed a emale p eponde ance: F/M a ios we e 2.0, 2.1, and 2.7. In PPMS, mo o symp oms ( o al 53%) showed an F/M a io o 0.8. (The dis ibu ion o onse symp oms showed no egional di e ence, no shown.) Incidences in bo h he medium- isk Pi kanmaa and wes - e n high- isk egion showed inc easing RRMS, dec easing 6 5 4 3 2 1 0Age a diagnosis (y) RRMS F/M a io PPMS <20 20–29 30–39 40–49 50–59 60–69 Figu e 2: F/M a ios in en-yea age g oups. F/M a io in RRMS emained abou wo old o highe om 20 o 59 yea s and in PPMS a io was abou 1 : 1, excep o a sligh ly highe a io in he 40–49 age g oup. The F/M a io in RRMS is signi ican in age g oup younge han 20 yea s, whe e he a io o women o men was 5 : 1 (𝑁=34/7 cases), and no PPMS cases we e obse ed. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% RRMS PPMS B ains em Visual ack Senso y ack Medulla y and py amidal ack Mul iple onse symp oms O he symp oms Figu e 3: Dis ibu ion o onse symp oms in RRMS and PPMS g oups diagnosed om 1981 o 2010. PPMS, and pa allel ends o men and women om 1981 o 2010 (Figu es 4(a) and 4(b)). The inc eased incidence o RRMS showed egional di e ences: F/M a ios inc eased om 1.5, 1.9 o 2.3 in high- isk egion, while a ios we e s able (2.8, 2.3, and 2.3) in Pi kanmaa. This was ue also in PPMS wi h he opposi e downwa d incidence: F/M a ios declined (1.6, 0.7 o 0.8) in he high- isk dis ic and inc eased (1.6, 1.4, and 2.6) a medium- isk dis ic . 4Mul iple Scle osis In e na ional 0 5 10 15 20 25 Pi kanmaa RRMS, women RRMS, men PPMS, women PPMS, men Incidence/105 1981–1990 1991–2000 2001–2010 (a) 0 5 10 15 20 25 RRMS, women RRMS, men PPMS, women PPMS, men Incidence/105 1981–1990 1991–2000 2001–2010 Sein  ajoki and Vaasa, pooled (b) Figu e 4: RRMS and PPMS incidence ends in medium- isk dis ic Pi kanmaa (a) and high- isk dis ic s Sein¨ ajoki and Vaasa (b) om 1981 o 2010. Table 2: Use o MRI scans in he diagnos ics o MS by disease cou ses (RRMS and PPMS) in he s udy coho diagnosed om 1981 o 2010. Pe iod 1981–1990 1991–2000 2001–2010 To al 1981–2010 𝑁%𝑁%𝑁%𝑁% RRMS cases 280 526 613 1419 All scans/RRMS 113 40 446 85 599 97 1158 82 B ain 102 36 388 74 467 76 957 67 Spinal 5 2 13 2 20 3 38 3 B ain + spinal 6 2 45 9 112 18 163 12 PPMS cases 80 72 46 198 All scans/PPMS 16 20 56 78 43 93 115 58 B ain 9 11 33 46 30 65 72 36 Spinal 1 1 7 10 2 4 10 5 B ain + spinal 6 8 16 22 11 24 33 17 3.1. Case Asce ainmen and Diagnos ic C i e ia. Du ing he hi y yea s o ollow-up bo h diagnos ic c i e ia and case asce ainmen ha e changed. Use o pa aclinical es s in case asce ainmen showed an inc easing use o MRI scans: om 40% up o 97% in RRMS and om 20% o 93% in PPMS (Table 2). Scans including bo h b ain and spinal co d emained low and pu e spinal scans we e a ely pe o med. The numbe o no mal indings in he i s diagnos ic MRI scanswassimila in he wog oups(6.3%inRRMSand8.6% in PPMS, no shown). The e was no di e ence in MRI use be ween men and women (no shown). Diagnos ic ce eb ospinal luid (CSF) analysis has been used cons an ly, pe o med in 92% (𝑛 = 1299) o RRMS cases and 90% (𝑛 = 178) o cases wi h PPMS; no empo al change was seen (𝑃 = 0.4in PPMS and 0.2 in RRMS). Posi i e indings (inc eased IgG index >0.6 and oligoclonal bands in immunoelec opho esis) we e seen in 89% in RRMS and 91% in PPMS g oups. The numbe o no mal CSF indings inc eased in he RRMS g oup om 5.4% o 12%. E oked po en ials, including isual, b ains em audi o y, and senso y po en ials,we euseddec easingly.InRRMS(𝑛 = 337, 24%), a posi i e esul (p olonged la ency) was seen in 76% (𝑛 = 256) o all s udied EPs. In PPMS (𝑛=61, 31%), EP was posi i e in 97% (𝑛=49). We ha e obse ed a dec easing diagnos ic delay om onse symp oms o diagnosis in his coho . The median diag- nos ic delay has dec eased om 4.0 yea s o 2.0 yea s (chi- squa e es , 𝑃 < 0.001) du ing he s udy pe iods [14]. This was mainly explained by imp o ed diagnos ics in MS. Dec easing delay was shown o conce n especially RRMS cou se and male PPMS in his s udy (Table 3). The K uskal-Wallis es s we e used o compa e he empo al ela ionship be ween hemeanagesa diagnosisanddiagnos icdelayswi hin he h ee en-yea pe iods om 1981 o 2010. Dec easing ages Mul iple Scle osis In e na ional 5 Table 3: Mean age a diagnosis and diagnos ic delay (yea s) p esen ed by disease cou se and gende du ing he s udy pe iods 1981–1990, 1991–2000, and 2001–2010. Disease cou se Pe iod RRMS PPMS Female Male Female Male Mean delay (y) Mean age (y) Mean delay (y) Mean age (y) Mean delay (y) Mean age (y) Mean delay (y) Mean age (y) 1981–1990 4 36 3 37 2 44 4 43 1991–2000 2 37 2 36 3 44 3.5 43 2001–2010 2 35 1 35 3 53 2.5 50 Table 4: RRMS and PPMS incidences (I) and o al incidence pe 105pe son-yea s wi h 95% con idence in e als (CIs) by Pose and McDonald c i e ia in he whole s udy coho om 2001 o 2010. C i e ia Pose McDonald 𝑁% Incidence 95% CI 𝑁% Incidence 95% CI Disease cou se RRMS 613 93 9.7 8.9–10.5 556 94 8.8 8.1–9.5 PPMS 46 7 0.7 0.5–0.9 35 6 0.6 0.4–0.8 To al 659 100 10.4 9.6–11.2 591 100 9.3 8.5–10.1 in RRMS we e associa ed wi h dec easing diagnos ic delays among bo h men (𝑃 = 0.035) and women (𝑃 = 0.036)o e ime. In PPMS g oup inc easing ages o women associa ed wi h inc easing delays (𝑃 < 0.0001), while inc easing ages o men we e obse ed in he p esence o dec easing delays, esul being nonsigni ican . To s udy he e ec o changes in diagnos ic c i e ia, we ee alua ed cases diagnosed be ween 2001 and 2010 using he McDonald c i e ia published in 2001 [10]andcalcula ed incidences o compa ison wi h he g oup diagnosed wi h Pose c i e ia. Resul s a e shown in Table 4.InMcDonald g oup loss o 11 cases (24%) in PPMS and 57 cases (9%) in RRMS was seen, mainly due o no mal o lacking MRI scans a he ime poin o i s diagnosis (by Pose ). Howe e , he esul ing 10-yea incidence a es we e simila using bo h se s o diagnos ic c i e ia. 4. Discussion Epidemiological obse a ions in no he n Eu ope [2]ha e poin ed o a ising emale and RRMS incidence, which was shown also he e. Du ing he hi y yea s o ollow-up we also obse ed opposi e incidence ends in RRMS and PPMS, cha ac e ized by di e ences in ages a diagnosis and dis i- bu ion o gende and ini ial symp oms. The obse a ion on dec easing age a diagnosis and diagnos ic delay conce ned bo h gende s only in RRMS. In case o PPMS, he e was an inc ease in age a diagnosis and a longe delay o diagnosis. Delay was highe among women wi h PPMS, which may be due oobse edonse symp oms,whichwe emo e ague and unspeci ic compa ed o mo o symp oms obse ed mo e o en among men. Howe e , oge he wi h he inc easing use o MRI, up o 93% in PPMS and 97% in RRMS, and ou ine use o CSF in diagnos ics, esul s indica e a mo e p ecise ecogni ion o MS and e lec imp o ed di e en ial diagnos ics, which a e c ucial in planning sui able ea men s a egies o MS pa ien s. Explana ions o he inc easing MS incidence include inc easedawa enessandimp o emen sincaseasce ain- men and diagnos ic accu acy [13]. In his coho we we e able os udy hechangesincaseasce ainmen du ing hi y yea s and compa e incidence a es using bo h he Pose and McDonald c i e ia du ing he las decade 2001–2010 [10,15]. A somewha unexpec ed loss o 68 cases (4.2%) was seen using he McDonald c i e ia—57 in RRMS and 11 in PPMS— mainly due o no mal o lacking MRI scans a he ime poin o diagnosis by he Pose c i e ia. Howe e , e en ual incidence a es we e simila wi h he wo se s o c i e ia. We hus belie e ha he clinical use o McDonald c i e ia, which unde line he need o MRI use in MS diagnos ics, con- ounded nei he he empo al no he egional compa isons and conclusions in his s udy. Resul s du ing he las s udy decades 1991–2010 e lec he acili a ion o access o MRI. The s anda diza ion o he pe o mance and in e p e a ion o MRI in he 2001 McDon- ald c i e ia ha e p omo ed an ea lie diagnosis o RRMS in many cases o clinically isola ed synd ome [18]. Ne e heless, c i e ia we e c i icized o ejec ing his o ical accoun s o symp oms and ecommended he need o posi i e CSF o he diagnosis o PPMS. This may esul in unde diagnosing o some cases and especially PPMS cases. The e ision o c i e ia in 2005 has had a mino e ec in ou esul s. Howe e , he gene ally inc easing in eg a ion o MRI in o diagnos ic wo k-ups seems o enhance he diagnosis among cases showing clinical elapses a onse . The need o ea ly ea men [8] among hese cases necessi a es a eliable diagnosis, which appea s in his s udy. Ou obse a ion ha a low PPMS incidence was ela ed o a somewha less equen use o MRI aises he ques ion o a possible unde es ima ion o PPMScasesdu ing he ollow-up.Thisisunlikely,as he numbe o PPMS cases was al eady e y low in he beginning 6Mul iple Scle osis In e na ional o he ollow-up. Fu he mo e, he high a e o ini ial mo o symp omsinPPMS,aswasobse edhe e,isassocia edwi h a ela i ely apid disabili y p og ession leading o diagnosis [19–21]. The leng hy diagnos ic delay and somewha less equen use o MRI, howe e , indica e ha diagnosis is delayed in PPMS and i is diagnosed mainly on clinical g ounds. Based on hese da a, we sugges ea ly and epea ed MRI in pa ien s ha p esen wi h symp oms consis en wi h MS in o de o each a disease-cou se-speci ic diagnosis and e alua e sui able he apy op ions. The limi a ion in ou s udy conce ns he common classi- ica ion p oblems in de ining he clinical sub ypes. He e, he diseasecou sewasca ego izedasei he elapsing- emi ing o p ima y p og essi e [16]. Recogni ion and diagnosis o PPMS using diagnos ic c i e ia ha a e p edisposed o inac- cu acy, like he Pose c i e ia, ha e been c i icized as leading o an unde es ima ion o cases, whe eas use o he McDonald c i e ia has been ques ioned due o alidi y and sensi i i y issues [22,23].Ingene al, hemainissueinPPMSis he ecall bias o ini ial symp oms, which can emain uniden i ied and lead o inco ec classi ica ion, ega dless o he c i e ia used. Ano he ca ea is he misclassi ica ion o seconda y p og essi e cases as p ima y p og essi e, which is unlikely in his s udy coho , conside ing he gene ally low numbe o PPMS cases and gene ally ca e ul sc u iny o disease e olu ion in clinical p ac ice. Explana ions o he esul s in ou o me s udy [24] showing a andem inc ease o he wo p og ession ypes e lec he nowadays imp o ed case ecogni ion o PPMS, and, a he end o he day, his esul con adic ed nei he he assump ions no he conclusions in his s udy. The s eng h o his s udy lies in a ca e ul sc u iny o equen medical assessmen s du ing he 30-yea ollow-up, which is belie ed o imp o e he eliabili y o he disease- cou se ecogni ion. MS is diagnosed and ea ed by neu- ologis s in public heal hca e in Finland which is why we ha e a ull co e age o MS pa ien s in his popula ion-based s udy. Fu he mo e, he neu ological se ices and acili ies a e homogenously dis ibu ed h oughou Finland, and he diagnos ic wo k-up is con e gen and based on In e na ional and Na ional Cu en Ca e Guidelines [25]. I has been sugges ed ha he di e en ial gende dis ibu- ion in MS e lec s epigene ic ac o s and gene-en i onmen in e ac ions [26], including sex di e ences on he exp ession o candida e genes on he X o Y ch omosome [27]. Gi en ha he con ibu ing gene ic changes in popula ions a e slow ones, he inc easing emale incidence in MS, heuma oid a h i is in 1995–2007 [28], and o he au oimmune diseases [29] indica es a c ucial ole o globally ac ing changes ha a ec au oimmune disease isk in he ep oduc i e yea s o li e. En i onmen al ac o s a ec ing women, such as con acep ion, die , obesi y, smoking, sunligh exposu e, and i amin D de iciency [27],a eamong he ele an li es yle changes, as well as a highe age a i s childbi h [30] and ewe p egnancies o e a li e ime [31,32]. These e ec s causing inc eased disease isk may be p esen al eady du ing he e al pe iod and in he childhood, suppo ed by he i e old F/M a io among RRMS cases younge han 20 yea s as was seen in his s udy. This esul co obo a es obse a ions o a highe elapse a e among emales and hee ec o ageanddiseasedu a ionondiseaseac i i y [33]. I is, howe e , unclea how en i onmen al ac o s a e sha ed be ween he wo disease cou ses. To complica e in e ence, i is hough ha he di e en pheno ypes in MS a e pa o a disease spec um modula ed by indi idual gene ic p edisposi ion and en i onmen al in luences. In he case o RRMS, en i onmen al ac o s ha a e able o cause unc ionally ele an changes in gene exp ession [34,35] may be p ima ily associa ed wi h ac o s esponsible o in lamma o y eac ions o a pu a i e au oimmune na u e in he cen al ne ous sys em [36]. A be e unde s anding o he ac o s ha unde lie he di e en ial gende and disease-cou se dis ibu ion should shed mo e ligh on MS suscep ibili y ac o s o e all. Regional MS isk in Finland shows eas -wes g adien , and he high- isk egion is loca ed on he wes coas . In his s udy we ha e shown ha inc easing incidence conce ns exclusi ely RRMS cases in high- isk egion Sein¨ ajoki and Vaasa. Recen genome-wide scanning (GWAS) in MS has es ablished he ole o he HLA locus bu also iden i ied common a ian s associa ed wi h MS wi h low odds a ios [37]. To expose a e, high-impac alleles, a GWAS s udy was conduc ed in he high- isk in e nal isola e Sein¨ ajoki dis ic in Finland, whe e se e al la ge amilies wi h MS ha e been obse ed. Resul s showed a STAT3 gene associa ion in MS [38], which implies a isk o ano he au oimmune diseasein hiscoho andhasalso aised hehypo hesis ha some gene ic a ian s may be ei he mo e easily iden i ied o e iologically mo e ele an in ce ain isola ed popula- ions. Also, amily s udies o MS ha e shown an inc eased isk o ype 1 diabe es melli us (DM), which also implies ha ce ain gene ic a ian s may inc ease suscep ibili y o au oimmune disease in gene al [39]. Childhood ype 1 DM incidence ollows MS incidence empo ally [40]andmay signal an inc eased pene ance o disease suscep ibili y genes in au oimmune diseases ha may be mo e easily iden i ied in gene ic isola es o in amilies in high- isk egions o MS. Inc easing a es o elapsing MS in bo h medium- and high- isk dis ic s indica e ha a mo e p ecise de ini ion o he gene ic and en i onmen al isk ac o s and hei ac ion in MS is needed o p o ide a be e unde s anding o he unde lying pa hological p ocesses and e en ually o aid he de elopmen o p e en i e and ea men s a egies. We con- clude ha ini ia i es o imp o e he use o popula ion-based egis e s wi h linkages o independen na ional da abases a e needed o gene a e la ge in e na ional coho s wi h sha ed demog aphic and clinical in o ma ion [41]. Con lic o In e es s The au ho s decla e ha he e is no con lic o in e es s ega ding he publica ion o his pape . Acknowledgmen s This wo k was suppo ed by a g an om The Finnish MS Socie y. The au ho s wish o hank he pe sonnel a he Mul iple Scle osis In e na ional 7 Uni e si y Hospi al o Tampe e and Cen al Hospi als in Vaasa and Sein¨ ajoki, Finland. Re e ences [1] A.AlonsoandM.A.He n´ an, “Tempo al ends in he incidence o mul iple scle osis: a sys ema ic e iew,” Neu ology, ol.71,no. 2, pp. 129–135, 2008. [2]M.T ojano,G.Lucchese,G.G azianoe al.,“Geog aphical a ia ions in sex a io ends o e ime in mul iple scle osis,” PLoS ONE, ol.7,no.10,A icleIDe48078,2012. [3] H. Lassmann, W. B ¨ uck, and C. F. Lucchine i, “The immuno- pa hology o mul iple scle osis: an o e iew,” B ain Pa hology, ol. 17, no. 2, pp. 210–218, 2007. [4] P.-A. Gou aud, “When is he absence o e idence, e idence o absence? Use o equi alence-based analyses in gene ic epi- demiology and a conclusion o he KIF1B s10492972∗Callelic associa ion in mul iple scle osis,” Gene ic Epidemiology, ol.35, no. 6, pp. 568–571, 2011. [5]G.C.Deluca,R.Al e man,J.L.Ma ine al.,“Cas ingligh on mul iple scle osis he e ogenei y: he ole o HLA-DRB1 on spinal co d pa hology,” B ain, ol.136,no.4,pp.1025–1034,2013. [6]D.H.Mille andS.M.Lea y,“P ima y-p og essi emul iple scle osis,” The Lance Neu ology, ol.6,no.10,pp.903–912,2007. [7] C. Con a eux and S. Vukusic, “Na u al his o y o mul iple scle osis: a uni ying concep ,” B ain, ol.129,no.3,pp.606–616, 2006. [8] O. H. Kan a ci, I. Pi ko, and M. Rod iguez, “No el immunomo- dula o y app oaches o he managemen o mul iple scle osis,” Clinical Pha macology and The apeu ics, ol.95,no.1,pp.32– 44, 2014. [9] N. Koch-Hen iksen, “The Danish mul iple scle osis egis y: a 50-yea ollow-up,” Mul iple Scle osis, ol.5,no.4,pp.293–296, 1999. [10] W. I. McDonald, A. Comps on, G. Edan e al., “Recommended diagnos ic c i e ia o mul iple scle osis: guidelines om he In e na ional Panel on he Diagnosis o Mul iple Scle osis,” Annals o Neu ology, ol.50,no.1,pp.121–127,2001. [11] C. H. Polman, S. C. Reingold, B. Banwell e al., “Diagnos ic c i e ia o mul iple scle osis: 2010 e isions o he McDonald c i e ia,” Annals o Neu ology, ol.69,no.2,pp.292–302,2011. [12] S.-M. O on, B. M. He e a, I. M. Yee e al., “Sex a io o mul iple scle osis in Canada: a longi udinal s udy,” The Lance Neu ology, ol. 5, no. 11, pp. 932–936, 2006. [13] N. Koch-Hen iksen and P. S. So ensen, “Why does he no h- sou h g adien o incidence o mul iple scle osis seem o ha e disappea ed on he No he n hemisphe e?” Jou nal o he Neu ological Sciences, ol. 311, no. 1-2, pp. 58–63, 2011. [14] M. Holmbe g, A. Mu onen, I. Elo aa a, and M.-L. Sumelah i, “Inc eased emale MS incidence and di e ences in gende - speci ic isk in medium- and high- isk egions in Finland om 1981–2010,” Mul iple Scle osis In e na ional, ol.2013,A icleID 182516, 6 pages, 2013. [15]C.M.Pose ,D.W.Pa y,andL.Scheinbe g,“Newdiagnos ic c i e ia o mul iple scle osis: guidelines o esea ch p o ocols,” Annals o Neu ology, ol.13,no.3,pp.227–231,1983. [16] F. D. Lublin and S. C. Reingold, “De ining he clinical cou se o mul iple scle osis: esul s o an in e na ional su ey,” Neu ology, ol.46,no.4,pp.907–911,1996. [17] W. K uskal and W. A. Wallis, “Use o anks in one-c i e ion a i- ance analysis,” Jou nal o he Ame ican S a is ical Associa ion, ol.47,no.260,pp.583–621,1952. [18] C. M. Dal on, P. A. B ex, K. A. Miszkiel e al., “Applica ion o he new Mcdonald c i e ia o pa ien s wi h clinically isola ed syn- d omes sugges i e o mul iple scle osis,” Annals o Neu ology, ol. 52, no. 1, pp. 47–53, 2002. [19] A. Comps on and A. Coles, “Mul iple scle osis,” The Lance , ol. 359, no. 9313, pp. 1221–1231, 2002. [20] H. T emle , D. Pa y, and V. De onshi e, “The na u al his o y o p ima y p og essi e MS in B i ish Columbia, Canada,” Neu ology, ol.65,no.12,pp.1919–1923,2005. [21] B. Runma ke and O. Ande sen, “P ognos ic ac o s in a mul iple scle osis incidence coho wi h wen y- i e yea s o ollow-up,” B ain, ol.116,no.1,pp.117–134,1993. [22] G. V. McDonnell and S. A. Hawkins, “Clinical s udy o p ima y p og essi e mul iple scle osis in No he n I eland, UK,” Jou nal o Neu ology, Neu osu ge y & Psychia y, ol.64,no.4,pp.451– 454, 1998. [23] S. B. Kelly, K. Kinsella, M. Duggan, N. Tub idy, C. McGuigan, and M. Hu chinson, “A p oposed modi ica ion o he McDonald 2010 c i e ia o he diagnosis o p ima y p og essi e mul iple scle osis,” Mul iple Scle osis, ol.19,no.8,pp.1095–1100,2013. [24]M.-L.Sumelah i,P.J.Tiena i,M.Hakama,andJ.Wiks ¨ om, “Mul iple scle osis in Finland: incidence ends and di e ences in elapsing emi ing and p ima y p og essi e disease cou ses,” Jou nal o Neu ology Neu osu ge y and Psychia y, ol.74,no.1, pp.25–28,2003. [25] Wo king G oup Appoin ed by he Finnish Medical Socie y Duodecim and he Finnish Neu ological Socie y, “Cu en ca e guideline: mul iple scle osis,” The Finnish Medical Socie y Duodecim and he Finnish Neu ological Socie y, 2009 and 2012. [26]M.J.Chao,S.V.Ramagopalan,B.M.He e ae al.,“MHC ansmission: insigh s in o gende bias in MS suscep ibili y,” Neu ology, ol.76,no.3,pp.242–246,2011. [27] R. R. Voskuhl and S. M. Gold, “Sex- ela ed ac o s in mul iple scle osis suscep ibili y and p og ession,” Na u e Re iews Neu- ology, ol.8,no.5,pp.255–263,2012. [28] E.Myasoedo a,C.S.C owson,H.M.K eme s,T.M.The neau, and S. E. Gab iel, “Is he incidence o heuma oid a h i is ising?: esul s om Olms ed Coun y, Minneso a, 1955–2007,” A h i is and Rheuma ism, ol.62,no.6,pp.1576–1582,2010. [29] R. Voskuhl, “Sex di e ences in au oimmune diseases,” Biology o Sex Di e ences, ol. 2, no. 1, a icle 1, 2011. [30] J. Sellne , J. K aus, A. Awad, R. Milo, B. Hemme , and O. S ¨ u e, “The inc easing incidence and p e alence o emale mul iple scle osis—a c i ical analysis o po en ial en i onmen al ac o s,” Au oimmuni y Re iews, ol.10,no.8,pp.495–502,2011. [31] P. Holmq is , M. Hamma , A.-M. Land blom, and J. B ynhild- sen, “Age a onse o mul iple scle osis is co ela ed o use o combined o al con acep i es and childbi h be o e diagnosis,” Fe ili y and S e ili y, ol.94,no.7,pp.2835–2837,2010. [32] M. Magya i, N. Koch-Hen iksen, C. C. P lege , and P. S. Sø ensen, “Rep oduc ion and he isk o mul iple scle osis,” Mul iple Scle osis, ol.19,no.12,pp.1604–1609,2013. [33] T.Kalincik,V.Vi ek,V.Jokubai ise al.,“Sexasade e minan o elapse incidence and p og essi e cou se o mul iple scle osis,” B ain, ol.136,no.12,pp.3609–3617,2013. [34] J. A. Lincoln and S. D. Cook, “An o e iew o gene-epigene ic- en i onmen al con ibu ions o MS causa ion,” Jou nal o he Neu ological Sciences, ol.286,no.1-2,pp.54–57,2009. [35] Y. Zhou, S. Simpson J ., A. F. Holloway, J. Cha leswo h, I. an de Mei, and B. V. Taylo , “The po en ial ole o epigene ic modi ica ions in he he i abili y o mul iple scle osis,” Mul iple Scle osis, ol.20,no.2,pp.135–140,2014. 8Mul iple Scle osis In e na ional [36] R. Hohl eld and H. Weke le, “Au oimmune concep s o mul iple scle osis as a basis o selec i e immuno he apy: om pipe d eams o ( he apeu ic) pipelines,” P oceedings o he Na ional Academy o Sciences o he Uni ed S a es o Ame ica, ol.101,no. 2, pp. 14599–14606, 2004. [37] D. A. Ha le , A. Comps on, S. Sawce e al., “Risk alleles o mul iple scle osis iden i ied by a genomewide s udy,” The New England Jou nal o Medicine, ol.357,no.9,pp.851–862,2007. [38] E. Jakkula, V. Lepp¨ a, A.-M. Sulonen e al., “Genome-wide associa ion s udy in a high- isk isola e o mul iple scle osis e eals associa ed a ian s in STAT3 gene,” Ame ican Jou nal o Human Gene ics, ol.86,no.2,pp.285–291,2010. [39] In e na ional Mul iple Scle osis Gene ics Conso ium (IMSGC), “The expanding gene ic o e lap be ween mul iple scle osis and ype 1 diabe es,” Genes & Immuni y, ol.10,pp. 11–14, 2009. [40] C. C. Pa e son, E. Gy¨ u ¨ us, J. Rosenbaue e al., “T ends in childhood ype 1 diabe es incidence in Eu ope du ing 1989– 2008: e idence o non-uni o mi y o e ime in a es o inc ease,” Diabe ologia, ol.55,no.8,pp.2142–2147,2012. [41] K.M.Myh ,N.G y en,Ø.To kildsene al.,“Aneed o na ional egis ies and in e na ional collabo a i e esea ch in mul iple scle osis,” Ac a Neu ologica Scandina ica, ol.195,pp.1–3,2012. 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