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.
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