Table e-1. Published studies reporting the association between comorbidities and outcomes in multiple sclerosis

Author

(Year)

Contine

nt

Country Source/

Population/

Sample Size

Study

Design

Diagnostic

Criteria: MS/

Established by

Comorbidity

Studied

Diagnostic

criteria:

Comorbidity/

Established by

Outcomes

Studied

Relevant

Findings

Arnett14

(2005)

North

America

USA

(Pacific

Northwest)

From

neurologists

and support

groups in

Northwestern

US, no history

of alcohol/drug

abuse, no

severe motor or

visual

impairment, no

premorbid

learning

Longitudin

al

Neurologist

confirmed:

Poser

Depression

(Chicago

Multiscale

Depression

Inventory)

Questionnaire

(Chicago

Multiscale

Depression

Inventory)

Cognitive

Functioning

(PASAT,

SDMT, Visual

Elevator, 7/24

Spatial Recall,

reading span,

CVLT, Tower

of London,

Verbal

Selective

Reminding test,

Tower of

All cognitive

indices correlated

with mood.

Negative

evaluative

depressive

symptoms most

consistently

predicted

cognitive

dysfunction.

disability,

53

Hanoi)

Braley15

(2014)

North

America

USA

(Michigan)

University of

Michigan MS

Clinic,

195

Cross-

sectional

Neurologist

diagnosed:

criteria NR

Obstructive

Sleep Apnea

(OSA)

Questionnaire/

STOP-Bang

score ≥3

Fatigue

(Fatigue

Severity Scale)

STOP-Bang

scores associated

with higher FSS

score adjusting

for age, sex,

BMI, sleep

duration,

depression,

disease-

modifying

therapy use,

presence of

restless legs

syndrome (beta =

0.25, SE =0.10,

p=0.01)

Brass16

(2014)

North

America

USA

(California)

Membership

list of the

Northern

California

Chapter of the

National MS

Society, age

≥18

2375

Cross-

sectional

Self-report Sleep

Disorders

(restless leg

syndrome

(RLS),

insomnia,

OSA)

Questionnaire/

STOP-Bang

score ≥3,

Restless Legs

Syndrome

questionnaire

score 4,

Insomnia

Severity Index

≥15

Fatigue

(Fatigue

Severity Scale

≥36)

Fatigue was

associated with

screening

positive for OSA

(OR 1.850;

1.538-2.226),

insomnia

(p<0.001), and

RLS (p<0.001)

Chwasti

ak17

(2005)

North

America

USA

(Washingto

n)

Members of

King County,

WA, MS

Association,

739

Cross-

sectional

Self-report Depression,

Anxiety,

Substance-

Use

Disorders

Mail survey

CES-D ≥

One question

screen for

anxiety

Fatigue

(Modified

Fatigue Impact

Scale ≥15=

disabling)

Depression

associated with

disabling fatigue

accounting for

clinical course

and disability

Patient Health

Questionnaire

Alcohol screen

≥1

Drug misuse

single question

(OR 6.24; 4.16-

9.35).

Dallmeij

er18

(2009)

Europe Netherland

s

(Amsterda

m)

Newly

diagnosed MS,

source NR

146

Longitudin

al

NR Cardiovascul

a,

Respiratory,

Musculoskele

tal, Diabetes,

Other

CIRS (self-

report)

Physical

Functioning

(Functional

Independence

Measure)

Musculoskeletal

comorbidity had

a negative effect

on the course of

physical

functioning.

Patients with

musculoskeletal

comorbidities had

a 5 point decline

in the motor scale

of the Functional

Independence

Measure while

those without

such

comorbidities

experienced only

a 2 point decline

(p=0.005). Other

comorbidities had

no effect.

D’Hoog

he19

(2012)

Europe Belgium Definite MS

registered with

Flemish MS

Society

1372

Cross-

sectional

Self-report Alcohol Self-report Disability (self-

assessment

scale), time to

reach EDSS 6

equivalent

Moderate alcohol

intake (1 drink

weekly to ≥2

drinks daily)

associated with

decreased risk of

EDSS 6 as

compared to no

alcohol intake

(HR 0.61; 0.46-

0.80) in those

with relapsing

onset MS. No

association in

progressive onset

MS.

Durmus2

0 (2013)

Europe Turkey

(Istanbul)

Patients

followed in MS

and

Demyelinating

Disorders and

Child

Neurology

Units in

Istanbul

University,

Cross-

sectional

McDonald

2001

Seizures International

League Against

Epilepsy

classification

Clinical course

Annual relapse

rate

EDSS

Occurrence of

seizures was

associated higher

mean EDSS

(p=0.004), higher

relapse rate

(p≤0.001). No

difference in

clinical course.

Istanbul

Medical

Faculty,

136

Egner21

(2003)

North

America

United

States

Secondary

analysis of data

from

educational

telerehabilitatio

n intervention,

Severely

mobility

impaired with

EDSS ≥7

27

Longitudin

al

NR Depression CES-D

≥16

Fatigue

(Fatigue

Severity Scale

≥4)

Depression and

fatigue were

correlated (r =

0.646, p<0.001),

though no

consistent

relationship over

time was found

Espinola North Mexico Demyelinating Cross- McDonald Any DSM SCID-IV and Relapses No correlations

-

Nadurill

e22

(2010)

America diseases clinic

of the National

Institute of

Neurology and

Neurosurgery

of Mexico,

37

sectional 2005 Axis I

disorder

(depression,

anxiety,

dysthymic,

bipolar

disorder)

the

Montgomery-

Asberg

Depression

Rating Scale

HAM-A

≥14

Disability

(EDSS)

between severity

measures of

anxiety and

depression and

number of

relapses, EDSS

scores (no details

reported)

Finlayso

n23

(2013)

North

America

USA

(Illinois)

Community-

dwelling

recruited from

advertisements,

181

Longitudin

al

Self-report Diabetes,

Stroke,

Arthritis,

Heart

Condition,

Respiratory

Problems,

Thyroid

Condition

Self-report Fatigue

(Fatigue Impact

Scale [FIS])

FIS-physical

scores were

worse in those

with heart

conditions as

compared to

those without,

and in those with

respiratory

problems as

compared to

those without.

Foster24

(2012)

North

America

USA

(New

York)

From cohort

study of

genetic and

environmental

risk factors for

progression

272

Cross-

sectional

McDonald

2001

Alcohol

Consumption

Self-report Disability

(EDSS,

MSSS); T1 and

T2 lesion

volumes,

global and

central atrophy

measures

Disability (EDSs)

was lower,

normalized

lateral ventricle

volume was

lower, and

normalized grey

matter volume

was higher in

those who had

consumed

alcohol for a

shorter period of

time (<15 years)

as compared to

those who

consumed it for

>15 years

Ghajarz

adeh25

(2012)

Asia Iran

(Tehran)

Patients

referred to MS

clinic of Sina

hospital

(Affiliated

hospital of

Tehran

University of

Medical

Sciences)

100

Cross-

sectional

McDonald Depression Self-report

(Beck

Depression

Inventory – 10-

18 = mild, 19-

29 moderate,

30-63 = severe)

Fatigue

(Modified

Fatigue Impact

Scale)

Depression was

correlated with

fatigue (r= 0.49,

p=0.01)

Gottberg

26 (2007)

Europe Sweden

(Stockholm

County)

166 Cross-

sectional

Medical

records

Depression Self-report

(Beck

Depression

Cognitive and

Physical

Functioning

Depressed more

likely to have

below normal

Inventory ≥13) (SDMT, free

recall portion

of the Free

Recall and

Recognition of

12 Random

Words Test,

timed walk,

nine hole peg

test, ADL,

Sickness

Impact Profile)

memory (29%)

than non-

depressed (9%,

p=0.005).

Depression not

associated with

other cognitive

measures, timed

walk, nine hole

peg test, ADL.

Depression

associated with

worse SIP scores

for mobility and

ambulation.

Kister27 North

America

USA MS patients

>18 years old

attending

Cross-

sectional

McDonald Migraine Validated

questionnaire

from American

Disability

(PDDS);

Number of

As compared to

those without

migraine,

(2010) (New

York)

clinics visits

204

Depression,

Anxiety

Migraine

Prevalence and

Prevention

Study, PHQ-9,

PHQ for

anxiety

lesions on brain

MRI (T1, T2,

gadolinium-

enhancing; also

T2 lesions in

periventricular

white matter,

subcortical

white matter,

corpus

callosum,

brainstem,

basal ganglia);

Fatigue

(Fatigue

severity scale)

migraineurs had

higher depression

and anxiety

scores, and more

fatigue (all

p<0.001).

Migraine not

associated with

disability.

Migraine not

associated with

number or

distribution of T2

lesions or

gadolinium-

enhancing

lesions. More T1

lesions in

headache free

group (p<0.05)

Koch29

(2008)

Europe Netherland

s

Patients

attending

outpatient

clinic for

annual

assessments

228

Longitudin

al

Poser Depression Self-report

(CES-D ≥16)

Fatigue

(Fatigue

Severity Scale);

Disability

(EDSS);

Progression

over 10 years;

secondary

progression

Depression

associated with

disability, 10-

year progression

or secondary

progression

Koch28

(2009)

Europe Netherland

s

(Gronigen)

Patients

attending the

Groningen

University

Medical Center

MS Clinic

Cross-

sectional

NR Depression Self-report

(CES-D ≥16)

Fatigue

(Fatigue

Severity Scale)

CES-D scores

inde-

pendently

associated with

severe fatigue

412 (odds ratio per

point increase:

1.09; 1.05–1.13,

p< 0.0001).

Marrie10

(2009)

North

America

United

States

NARCOMS

Registry

population,

8983

Cross-

sectional

Self-report Diabetes,

hypertension,

hyperlipidem

ia, heart

disease,

peripheral

vascular

disease,

depression,

anxiety,

bipolar

disorder,

psychosis,

Self-report

(validated

questionnaire)

Disability

(Patient

Determined

Disease Steps)

Odds of moderate

as compared to

mild disability at

diagnosis were

higher in

participants with

vascular

comorbidity

(odds ratio (OR)

1.51; 95% CI:

1.12-2.05) and in

those with

obesity (OR 1.38;

liver disease,

renal disease,

arthritis,

irritable

bowel

syndrome,

fibromyalgia,

uveitis,

systemic

lupus

erythematosu

s, rheumatoid

arthritis,

migraine,

autoimmune

thyroid

disease,

Sjogren’s

95% CI: 1.02-

1.87). The odds

of severe as

compared to mild

disability were

higher in

participants with

musculoskeletal

(OR 1.81; 95%

CI: 1.25-2.63) or

mental (OR 1.62;

95% CI: 1.23-

2.14)

comorbidity.

syndrome,

inflammatory

bowel

disease,

cataracts,

glaucoma,

breast cancer,

lung cancer,

rectal cancer,

colon cancer

Marrie31

(2010)

North

America

United

States

NARCOMS

Registry

population

(volunteers),

8983

Longitudin

al

Self-report Vascular

comorbidity

(diabetes,

hypertension,

hyperlipidem

ia, heart

disease,

peripheral

Self-report

(validated

questionnaire)

Disability

(Patient

Determined

Disease Steps)

Vascular

comorbidity,

whether present

at symptom

onset, diagnosis,

or later in the

disease course, is

associated with a

vascular

disease)

substantially

increased risk of

disability

progression

Median time

from MS onset to

needing a

unilateral

assistive device

to walk was 18.8

(95% CI: 18.4,

19.3) years in

participants

without

comorbidities,

but was 6.0 years

earlier in

participants with

comorbidities

Marrie30

(2011)

North

America

United

States

NARCOMS

Registry

population

8983

Longitudin

al

Self-report Visual

(cataracts,

glaucoma,

uveitis) and

vascular

comorbidity

(diabetes,

hypertension,

hyperlipidem

ia, heart

disease,

peripheral

vascular

disease)

Self-report

(validated

questionnaire)

Visual

Disability

(Performance

Scales Visual)

Adjusting for

age, sex, race,

education, annual

income, health

insurance, marital

status, region,

year of symptom

onset, age of

symptom onset

and treatment,

risk of mild

visual disability

higher among

participants with

vascular (HR

1.45; 1.39-1.51)

and visual (HR

1.47; 1.37-1.59)

comorbidities.

Findings were

similar for

moderate and

severe visual

disability.

Munteis3

2 (2007)

Europe Spain

(Cataluna)

Neurology

clinic at

Hospital

Universitario

del Mar/

Untreated MS

patients at

baseline

measurement,

93

Longitudin

al

Neurologist

diagnosed:

McDonald

2001

Autoimmune

Thyroid

Disorders

Clinical

symptoms of

thyroid

dysfunction/

Billevicz and

Crooks scales.

Clinical

hypothyroidism

, TSH level ≥5

Disability

(EDSS)

Relapses

Patients with

positive anti-

thyroid

antibodies (ATA)

had higher

frequency of low

EDSS score

(81%) than those

with negative

antibodies

(73.2%, p ns).

U/l and free T4

<0.72 ng/dl.

Subclinical

hypothyroidism

:

TSH level ≥5

U/l and free T4

0.72–1.52

ng/dl.

Overt

hyperthyroidis

m

TSH <0.1 lU/l

and free T4

Positive ATA not

associated with

number of

relapses (p=0.4)

>1.52 ng/dl

Subclinical

hyperthyroidis

m

TSH <0.1 lU/l

and T4 0.72–

1.52 ng/dl.

Oliviera3

3 (2014)

South

America

Brazil

(Londrina,

Parana)

Neurology

Outpatient

Department of

State

University of

Londrina,

relapsing

remitting and

secondary

Cross-

sectional

McDonald

2010

Insulin

Resistance

(homeostasis

model

assessment)

Total

cholesterol,

HDL-C,

Peripheral

blood samples,

measured

height and

weight, blood

pressure

Disability

(EDSS)

Insulin resistance

associated with

greater disability

(EDSS), p=0.030

BMI associated

with disability

(p=0.0033)

progressive

110

LDL-C,

triglyceride

levels

Blood

pressure

Body mass

index

Total cholesterol,

LDL-C, HDL-C

and trigylcerides

not associated

with disability

(data not shown)

Patten34

(2012)

North

America

Canada Post-census

study

(Participation

and Activity

Limitations

Survey)

245

Cross-

sectional

Mental

Disorders

Self-report

(specific

disorder not

recorded)

Functional

Impairment

(Health

Utilities Index-

III)

Mental disorders

are associated

with a higher

level of disability

in MS but, with

the exception of

com

munication, there

was no evidence

of synergistic

interaction

between mental

disorders and MS

in contributing to

health-related

impairments

Poder35

(2009)

North

America

Canada

(Nova

Scotia)

Dalhousie MS

Research Unit

251

Cross-

sectional

Neurologist

diagnosed:

McDonald

2005

Social

Anxiety

General

anxiety

Depression

Social Anxiety

SPIN ≥19

General

Anxiety

HADS ≥11

Disability

(EDSS)

Social anxiety

not correlated

with disability (r

= 0.07).

Generalized

anxiety not

correlated with

disability (r=

0.02). Depression

associated with

greater disability

(r = 0.36, p<0.01)

Shugaiv3

6 (2015)

Europe Turkey Case records

(source NR)

141

Cross-

sectional

McDonald

criteria 2010

Uveitis Uveitis clinics/

International

Uveitis Study

Group criteria

Disability

(EDSS);

Progression

Index

Median disability

(EDSS) scores

were lower in

those with uveitis

(2.0; range 0-4.5)

than those

without uveitis

(3.0; range 1.0-

9.5, p=0.004).

Median

progression index

scores were

lower in those

with uveitis (0.2;

range 0.0-1.8)

than those

without uveitis

(0.4; range 0.1-

2.7, p<0.001)

Siepman

37 (2008)

Europe Netherland

s

(Rotterdam

and

Amsterdam

)

Departments of

Neurology

Erasmus

Medical

Center, VU

Medical

Center, 3

additional

hospitals in

Rotterdam,

recently

diagnosed

101

Cross-

sectional

Neurologist

diagnosed:

Poser

Depression;

Anxiety

Self-report

(HADS ≥8)

Cognitive

Functioning

(Rao’s Brief

Repeatable

Battery),

Disability

(EDSS)

Higher HADS

depression scores

associated with

higher EDSS

(r=0.35, p<0.01),

and lower scores

on SDMT and

WLG. HADS

depression ≥8

had lower scores

on SDMT

(p=0.06),

PASAT3

(p=0.03) adjusted

for age, sex,

education, but not

after adjustment

for EDSS, time

since symptom

onset. HADS

anxiety

associated with

SDMT but not

after adjustment.

Tettey38

(2014)

Australia

/NZ

Australia

(southern

Tasmania)

Clinically

definite MS

141

Longitudin

al

McDonald

2001

Adverse

Lipid Profile

Serum samples

(total

cholesterol,

LDL, HDL,

triglycerides,

apolipoprotein

A-I,

apolipoprotein

E,

apolipoprotein

Time to relapse None of the lipid-

related measures

associated with

relapse after

adjustment for

age, baseline

BMI, 25(OH)D,

physical activity,

smoking, statin

use, season,

B) immunomodulato

ry therapy use

Tettey39

(2014)

Australia

/NZ

Australia Clinically

definite MS

178

Longitudin

al

McDonald

2001

Adverse

Lipid Profile

Serum samples

(total

cholesterol,

LDL, HDL,

triglycerides,

apolipoprotein

A-I,

apolipoprotein

E,

apolipoprotein

B)

Disability

(EDSS,

MSSS);

Progression of

Disability

(Change in

EDSs)

Adverse lipid

profile was

associated with

higher levels of

MS disability.

TC/HDL ratio

was associated

with change in

EDSS.

Tinghög

40 (2014)

Europe Sweden National

Patient

Register,

Longitudin

al

ICD-10 G35

≥1

hospitalization

or ≥1 outpatient

Musculoskele

tal, Mental

and

Cardiovascul

ICD-10: M00-

M99, ATC:

M01-M09

Disability

pension

Co-morbidities,

especially

significantly

contribute to MS

4519 specialist visit ar Disorders I00-I99, C01-

C10; F00-F99,

N05-N06

patients’ risk of

disability

pension.

Musculoskeletal

disorders HR

1.49; 1.33-1.67,

mental disorders

HR 2.44; 1.18-

2.74,

cardiovascular

disorders HR

1.02; 0.90-1.16

Tortorell

a41

(2006)

Europe Italy 37 MS patients

with migraine

without aura,

42 MS without

migraine

Cross-

sectional

NR Migraine International

Headache

Society criteria

Structural

Brain

Abnormalities

(MRI)

Migraine

associated with

more frequent

involvement of

the substania

nigra, red nucleus

Excluded

individuals

with

hypertension,

hypercholester

olemia,

diabetes,

vascular/heart

disease, other

major system

and

neurological

conditions

and

periaqueductal

grey matter

(p=0.006) but no

difference in

number of

supratentorial

lesions (p=0.18)

Uribe

San

Martin42

(2014)

South

America

Chile Patients seen at

Pontificia

Universidad

Catolica of

Chile’s MS

Cross-

sectional

McDonald

2010

Epilepsy International

League Against

Epilepsy

Incidence of

cortical lesions

on MRI

Brain volume

No difference in

clinical course or

EDSS. Patients

with poor

epilepsy control

Center, CIS or

MS

310

Cognition (D-

KEFS,

BTACT, Digit

span)

(frequent seizures

or development

of status

epilepticus) had

lower brain

volumes (average

28% less volume,

p=0.01) and

worse cognitive

performance

(average 32%

worse scores,

p=0.03)

Weinsto

ck-

Guttman

43 (2011)

North

America

USA

(Buffalo,

New York)

consecutive

patients,

followed at the

Baird MS

Center, State

Longitudin

al

McDonald

2001

Lipid status HDL, LDL,

triglycerides,

TC, cholesterol

to HDL ratio

Disability

(EDSS,

MSSS); MRI

(contrast-

enhancing

EDSS worsening

associated with

higher baseline

LDL (p = 0.006)

and TC (p =

University of

New York with

clinically

definite MS

patients

178

lesion volume

(CE-LV), CE

lesion number

(CEL number),

T2-LV, T1-LV

and brain

parenchymal

fraction (BPF))

0.001, 0.008)

levels. Similar

patter observed

for MSSS

worsening.

Higher HDL

levels (p < 0.001)

associated with

lower

gadolinium-

enhancing lesion

volume. Higher

TC associated

with lower brain

parenchymal

fraction (p =

0.033)

Weinsto Europe Czech CIS treated Longitudin Poser Lipid profile Serum HDL-C, Number of No association of

ck-

Guttman

4 (2013)

Republic with

intramuscular

interferon-beta-

1a, 18-55

years, EDSS

≤3.5, ≥2

hyperintense

lesions on

MRI, positive

oligoclonal

bands

135

al LDL-C,

triglycerides,

total

cholesterol

relapses, time

to clinically

definite MS,

Number of T2

and contrast

enhancing

lesions, lesion

volume,

percent change

in whole brain

volume, grey

matter volume,

white matter

volume

time to first

relapse or

number of

relapses with

HDL-C, LDL-C

or total

cholesterol

levels. Higher

LDL-C

associated with

higher

cumulative

number of new

T2 lesions

(p=0.006) and

higher

cumulative

number of

new/enlarging T2

lesions

(p=0.047).

Higher TC levels

associated with

greatere number

of T2 lesions

over two years

(p=0.001).

Cumulative

number of

contrasting

enhancing lesions

was not

associated with

TC (p=0.075) or

DLD-C (p=0.11).

Lower baseline

normalized white

matter brain

volume

associated with

TC (p=0.02) and

with increased

LDL-C

(p=0.047).

Greater precent

decrease in grey

matter volume

over 2 years

associated with

higher LDL-C

(p=0.047) and

TC (p=0.05).

Weisbro

t44

North United CIS or MS

evaluated at a

Cross- International Psychiatric Schedule for

Affective

Cognitive

Impairment

Cognitive

impairment was

(2014) America States

(New

York)

US Pediatric

MS Center,

45

sectional Pediatric

MS Study

Group criteria

Diagnoses Disorders and

Schizophrenia

for School-Age

Children (K-

SADS-PL)

(standardized

neuropsycholo

gical battery)

classified in

20/25 (80%) of

patients meeting

criteria for a

psychiatric

disorder versus

11/20 (55%) of

those without

psychiatric

disorder

(p=0.08).

Anxiety and

mood disorder

had the highest

degree of

cognitive

impairment

Wood45 Australia Australia Prospective Longitudin Neurologist Anxiety; Self-report Fatigue Anxiety

(2013) /NZ

(Southern

Tasmania)

cohort

assembled to

assess

prognostic

impact of

vitamin D and

sunlight in

clinically

definite MS

198

al diagnosed:

McDonald

2001

Depression (HADS)

HADS-A,

HADS-D

Mild

anxiety/depress

ion:

8-10

Severe

anxiety/depress

ion:

11-21

(Fatigue

Severity Scale)

correlated with

fatigue (r = 0.25).

Depression

correlated with

fatigue (r = 0.44.)

Fatigue,

depression and

anxiety cluster

together.

Zephir46

(2014)

Europe France MS and IBD

databases

66

Cross-

sectional

McDonald

2010/ medical

records

IBD Medical

records/

standardized

forms

Disability

(EDSS)

Proportion of

RRMS

converting to

Disability less

severe than in

those with MS-

IBD than those

with MS alone.

SPMS Median EDSS

2.5 (1.5-4.5) for

MS-IBD and 3

(2-6) for MS

alone (OR 0.77;

0.64-0.92).

Proportion

switching to

SPMS lower in

MS-IBD patients

(22%) than MS

only patients

(34%, OR 0.44;

0.20-0.98)

NR = not reported, CIRS = cumulative illness rating scale, SPIN = Social Phobia Inventory, HADS = Hospital Anxiety and Depression Scale,

HAM = Hamilton Anxiety Rating Scale, EDSS = Expanded Disability Status Scale, HDL-C = high density lipoprotein cholesterol, LDL-C = low

density lipoprotein cholesterol, PASAT = Paced Auditory Serial Addition Test, SDMT = Symbol Digit Modalities Test, CVLT = California

Verbal Learning Test, MSSS = Multiple Sclerosis Severity Score, PDDS = Patient Determined Disease Steps, WLG = word list generation,

PRVEP = pattern reversal evoked potentials, RNFL = retinal nerve fibre layer