The

long-term

efficacy

and

safety

of

new

biological

therapies

for

psoriasis

Long-term

therapy

is

often

required

for

psoriasis

This

article

reviews

the

most

recent

long-term

clinical

data

for

biological

agents

that

have

been

approved

or

for

which

late-stage

development

data

have

been

released

for

the

treatment

of

patients

with

moderate

to

severe

plaque

psoriasis

Efficacy

data

are

available

for

up

to

five

courses

of

alefacept

-LRB-

approximately

weeks

of

therapy

-RRB-

months

-LRB-

weeks

-RRB-

of

continuous

efalizumab

weeks

of

continuous

etanercept

and

weeks

of

bimonthly

infliximab

Data

sources

include

publications

product

labeling

and

posters

presented

at

recent

international

scientific

meetings

Alefacept

appears

to

continue

to

be

efficacious

over

multiple

treatment

courses

for

some

responsive

patients

The

efficacy

of

efalizumab

achieved

during

the

first

weeks

of

therapy

appears

to

be

maintained

or

improved

through

at

least

weeks

of

continuous

treatment

The

efficacy

of

etanercept

appears

to

be

maintained

through

at

least

weeks

of

continuous

treatment

Infliximab

demonstrates

a

high

response

rate

soon

after

initiation

which

appears

to

be

maintained

through

weeks

but

declines

modestly

with

therapy

out

to

weeks

After

weeks

approximately

of

efalizumab-treated

and

of

etanercept-treated

patients

remaining

on

therapy

achieved

improvement

from

baseline

in

Psoriasis

Area

and

Severity

Index

as

did

of

infliximab

patients

who

did

not

miss

more

than

two

infusions

Safety

data

suggest

that

these

agents

may

be

used

for

long-term

administration

Long-term

data

from

psoriasis

trials

continue

to

accumulate

Recent

data

suggest

that

biological

therapies

have

efficacy

and

safety

profiles

suitable

for

the

long-term

treatment

of

patients

with

moderate

to

severe

psoriasis

Introduction

Psoriasis

is

a

chronic

inflammatory

immune-mediated

disease

characterized

by

periods

of

spontaneous

remission

and

relapse

-LSB-

-RSB-

Conventional

nonbiological

therapies

for

moderate

to

severe

psoriasis

such

as

cyclosporine

methotrexate

and

phototherapy

have

proved

effective

in

suppressing

symptoms

and

many

dermatologists

have

at

least

a

decade

of

experience

using

these

treatment

modalities

-LSB-

-RSB-

Because

of

the

chronic

nature

of

psoriasis

many

patients

require

lifelong

symptom

management

Conventional

nonbiological

systemic

therapies

have

been

successfully

used

as

continuous

therapy

in

some

patients

for

extended

periods

-LRB-

e.g.

methotrexate

-RRB-

however

for

some

patients

the

long-term

use

of

these

agents

may

be

limited

by

known

toxicities

including

nephrotoxicity

-LRB-

cyclosporine

-RRB-

-LSB-

-RSB-

hepatotoxicity

-LRB-

methotrexate

-RRB-

-LSB-

-RSB-

skin

cancer

-LRB-

psoralen-ultraviolet

A

phototherapy

or

PUVA

-RRB-

-LSB-

-RSB-

and

prolonged

teratogenicity

-LRB-

oral

retinoids

-RRB-

-LSB-

-RSB-

Current

treatment

guidelines

recommend

limiting

the

administration

of

cyclosporine

to

short-term

-LRB-

-RRB-

intermittent

therapy

or

to

no

longer

than

years

continuously

-LSB-

-RSB-

reducing

the

dosage

and

minimizing

lifetime

exposure

to

methotrexate

and

ultraviolet

irradiation

-LSB-

-RSB-

and

avoiding

treatment

with

oral

retinoids

and

several

other

conventional

antipsoriatic

therapies

in

women

of

childbearing

potential

-LSB-

-RSB-

Available

data

suggest

that

when

used

according

to

contemporary

guidelines

and

with

appropriate

monitoring

for

toxicity

conventional

nonbiological

treatments

can

be

reasonably

safe

and

tolerable

-LSB-

-RSB-

However

minimizing

toxicity

while

still

providing

continuous

control

of

psoriasis

symptoms

over

a

patient

's

lifetime

represents

a

clinical

challenge

An

improved

understanding

of

the

immunologic

basis

of

psoriasis

led

to

the

development

of

several

targeted

biological

therapies

that

attempt

to

address

the

challenge

of

providing

long-term

continuous

disease

control

The

first

biological

agent

approved

for

the

treatment

of

adult

patients

with

moderate

to

severe

chronic

plaque

psoriasis

alefacept

-LRB-

Amevive

Biogen

Idec

Inc.

-RRB-

is

currently

registered

for

use

in

several

countries

including

the

United

States

but

not

the

European

Union

-LRB-

EU

-RRB-

Two

others

efalizumab

-LRB-

Raptiva

Genentech

Inc.

Serono

International

S.A.

-RRB-

and

etanercept

-LRB-

Enbrel

Amgen

Inc.

Wyeth

Pharmaceuticals

-RRB-

are

also

registered

for

this

indication

in

multiple

countries

including

the

EU

and

the

United

States

Another

biological

infliximab

-LRB-

Remicade

Centocor

Inc.

Schering-Plough

Corp.

-RRB-

has

presented

Phase

III

clinical

trial

data

for

the

treatment

of

psoriasis

and

recently

became

registered

for

use

in

the

EU

The

clinical

trials

programs

for

these

four

agents

have

demonstrated

their

safety

and

efficacy

in

patients

with

psoriasis

over

an

initial

period

of

several

months

longer-term

results

are

now

becoming

available

One

other

biological

agent

adalimumab

-LRB-

Humira

Abbott

Laboratories

-RRB-

is

at

an

earlier

stage

of

development

for

psoriasis

and

has

completed

Phase

II

clinical

trials

for

the

disease

This

article

reviews

the

latest

clinical

data

available

regarding

the

long-term

efficacy

of

these

biological

agents

for

treatment

of

psoriasis

Alefacept

Alefacept

is

a

fusion

protein

between

human

leukocyte

function-associated

-LRB-

-RRB-

and

the

human

antibody

Fc

region

By

binding

to

the

antigen

on

T

cells

alefacept

prevents

T-cell

activation

and

triggers

apoptosis

preferentially

targeting

memory-effector

T

cells

-LSB-

-RSB-

Alefacept

has

been

evaluated

as

a

weekly

intravenous

-LRB-

IV

-RRB-

administration

and

as

a

weekly

intramuscular

-LRB-

IM

-RRB-

injection

-LRB-

Amevive

-LSB-

alefacept

-RSB-

prescribing

information

Cambridge

Mass

Biogen

Inc.

August

-RRB-

however

only

the

IM

dose

is

currently

available

The

efficacy

and

safety

of

a

course

of

weekly

IM

alefacept

mg

were

evaluated

in

a

randomized

placebo-controlled

Phase

III

trial

of

adult

patients

with

chronic

plaque

psoriasis

-LSB-

minimum

of

body

surface

area

-LRB-

BSA

-RRB-

affected

by

psoriasis

-RSB-

-LSB-

-RSB-

Two

weeks

after

the

treatment

phase

was

completed

-LRB-

study

week

-RRB-

the

Psoriasis

Area

and

Severity

Index

-LRB-

PASI

-RRB-

improved

by

at

least

from

baseline

-LRB-

-RRB-

in

of

the

patients

who

received

alefacept

mg

per

week

with

achieving

at

least

a

improvement

from

baseline

-LRB-

-RRB-

-LRB-

Amevive

-LSB-

alefacept

-RSB-

prescribing

information

-RRB-

This

compares

with

rates

of

and

respectively

for

patients

randomized

to

placebo

-LRB-

n

P

for

both

comparisons

-RRB-

Mean

percentage

PASI

improvement

from

baseline

for

a

course

of

alefacept

IM

therapy

is

shown

in

Fig

Fig.

percentage

psoriasis

area

and

severity

index

-LRB-

PASI

-RRB-

improvement

from

baseline

in

randomized

placebo-controlled

Phase

III

studies

of

biological

agents

for

the

treatment

of

psoriasis

ETANERCEPT

Results

for

etanercept

or

mg

twice

weekly

for

weeks

-LSB-

-RSB-

Sample

size

at

each

PASI

assessment

was

not

reported

EFALIZUMAB

Results

for

the

use

of

efalizumab

mg/kg/week

for

weeks

followed

by

a

open-label

extension

phase

-LSB-

-RSB-

The

efficacy-evaluable

population

for

this

study

included

all

patients

randomized

to

efalizumab

treatment

-LRB-

n

-RRB-

which

differs

from

other

efalizumab

trials

-LRB-

and

those

of

the

other

agents

discussed

-RRB-

that

include

only

patients

who

received

at

least

dose

of

the

study

drug

Following

are

the

sample

sizes

at

each

PASI

assessment

represented

by

the

data

points

For

efalizumab

week

week

week

week

week

week

week

week

For

placebo

week

week

week

week

week

-LSB-

-RSB-

ALEFACEPT

Alefacept

results

for

the

available

intramuscular

-LRB-

IM

-RRB-

dose

-LSB-

-RSB-

Drug

was

administered

weekly

for

weeks

followed

by

observation

for

weeks

In

this

study

patients

were

randomized

to

receive

alefacept

mg

IM

and

patients

to

receive

placebo

Sample

sizes

at

each

PASI

assessment

were

not

provided

Statistical

comparisons

were

not

reported

Note

Data

for

infliximab

were

not

available

Alefacept

has

demonstrated

the

longest

psoriasis

remission

times

among

biological

agents

for

psoriasis

Patients

who

achieved

after

a

course

of

alefacept

mg

per

week

-LRB-

n

-RRB-

maintained

at

least

a

response

for

a

median

period

of

approximately

months

-LSB-

-RSB-

Thus

the

long-term

use

of

alefacept

as

a

remittive

therapy

has

been

explored

through

extension

studies

of

additional

treatment

courses

for

patients

who

were

enrolled

in

alefacept

IV

or

IM

Phase

III

trials

Efficacy

data

have

been

presented

for

up

to

five

courses

of

alefacept

therapy

-LRB-

i.e.

approximately

weeks

of

treatment

-RRB-

although

PASI

responses

are

available

for

only

the

IV

formulation

-LSB-

IM

results

were

provided

using

Physician

's

Global

Assessment

-LRB-

PGA

-RRB-

-RSB-

-LRB-

A.

Menter

et

al.

unpublished

data

presented

at

the

Annual

Meeting

of

the

American

Academy

of

Dermatology

-RRB-

The

analyses

were

performed

on

the

as-treated

patient

population

and

a

patient

was

considered

a

responder

if

he

or

she

achieved

a

response

anytime

during

each

treatment

course

Using

these

criteria

response

rates

for

IV

alefacept

increased

from

during

the

first

course

of

therapy

-LRB-

n

-RRB-

to

during

course

-LRB-

n

-RRB-

PGA

response

rates

for

the

IM

formulation

increased

from

of

patients

classified

as

clear

or

almost

clear

during

course

-LRB-

n

-RRB-

to

during

course

-LRB-

n

-RRB-

but

the

response

rate

decreased

to

less

than

during

course

-LRB-

n

-RRB-

Alefacept

therapy

appears

to

be

well

tolerated

even

with

long-term

use

The

primary

concern

with

alefacept

is

T-lymphocyte

depletion

Alefacept

should

not

be

initiated

in

patients

with

T-lymphocyte

counts

below

normal

and

biweekly

T-cell

monitoring

is

recommended

during

each

treatment

course

-LRB-

Amevive

-LSB-

alefacept

-RSB-

prescribing

information

-RRB-

Alefacept

should

be

withheld

if

T-cell

counts

fall

below

cells/μl

and

discontinued

if

they

remain

low

for

a

month

Patients

treated

with

alefacept

during

Phase

III

trials

demonstrated

a

low

incidence

of

malignancy

serious

infections

requiring

hospitalization

and

hypersensitivity

reactions

-LRB-

Amevive

-LSB-

alefacept

-RSB-

prescribing

information

-RRB-

The

integrated

safety

database

for

alefacept

includes

a

total

of

alefacept-treated

psoriasis

patients

and

includes

patients

who

have

received

up

to

nine

courses

of

alefacept

therapy

-LRB-

n

-RRB-

over

a

period

Despite

the

paucity

of

data

for

multiple

treatment

courses

the

incidence

of

common

adverse

events

-LRB-

e.g.

headache

nasopharyngitis

influenza

upper

respiratory

tract

infection

and

pruritus

-RRB-

serious

adverse

events

infections

malignancies

and

autoantibody

production

appeared

to

fluctuate

little

with

additional

treatment

although

the

safety

of

long-term

alefacept

therapy

will

need

to

continue

to

be

assessed

Efalizumab

Efalizumab

is

a

recombinant

humanized

monoclonal

antibody

against

the

α

subunit

-LRB-

-RRB-

of

which

modulates

several

key

steps

in

the

immunopathogenesis

of

psoriasis

including

initial

T

cell

activation

trafficking

from

the

circulation

into

psoriatic

lesions

and

reactivation

therein

-LSB-

-RSB-

Multiple

Phase

III

clinical

trials

have

demonstrated

the

efficacy

safety

and

health-related

quality-of-life

-LRB-

HRQOL

-RRB-

benefits

of

weeks

of

subcutaneous

-LRB-

SC

-RRB-

efalizumab

therapy

in

patients

with

moderate

to

severe

chronic

plaque

psoriasis

-LSB-

-RSB-

As

will

be

discussed

later

available

clinical

data

support

the

efficacy

of

extending

efalizumab

treatment

beyond

weeks

as

reflected

in

the

European

guidelines

-LRB-

European

Medicines

Agency

Raptiva

-LSB-

efalizumab

-RSB-

summary

of

product

characteristics

-RRB-

The

Phase

III

study

that

served

as

the

basis

for

efalizumab

labeling

evaluated

the

efficacy

and

safety

of

efalizumab

mg/kg

weekly

-LSB-

-RSB-

A

total

of

adult

patients

with

moderate

to

severe

chronic

plaque

psoriasis

-LRB-

baseline

PASI

and

BSA

affected

-RRB-

were

randomized

to

receive

efalizumab

-LRB-

n

-RRB-

or

placebo

-LRB-

n

-RRB-

double-blind

for

weeks

all

patients

were

then

eligible

to

receive

extended

efalizumab

open-label

treatment

for

an

additional

weeks

-LSB-

-RSB-

A

significant

efalizumab

treatment

effect

relative

to

placebo

was

achieved

at

weeks

and

extended

treatment

conferred

additional

clinical

benefit

Using

an

intent-to-treat

-LRB-

ITT

-RRB-

analysis

with

the

last

observation

carried

forward

-LRB-

LOCF

-RRB-

for

patients

with

missing

data

the

percentage

of

efalizumab-treated

patients

who

achieved

increased

from

at

week

-LRB-

vs.

with

placebo

P

-RRB-

to

at

week

Similarly

the

percentage

of

efalizumab-treated

patients

who

achieved

and

increased

from

to

and

from

to

at

weeks

and

respectively

The

mean

percentage

PASI

improvement

relative

to

baseline

increased

from

at

week

to

at

week

-LRB-

Fig.

-RRB-

-LSB-

-RSB-

Mean

percentage

PASI

improvement

appeared

to

increase

throughout

the

duration

without

any

evidence

of

a

plateau

effect

Two

additional

Phase

III

studies

with

similar

placebo-controlled

double-blind

initial

treatment

periods

support

the

efficacy

and

safety

of

efalizumab

therapy

over

weeks

-LSB-

-RSB-

An

open-label

Phase

III

study

evaluated

the

efficacy

safety

and

tolerability

of

up

to

months

of

continuous

efalizumab

treatment

At

the

time

of

this

writing

results

through

weeks

of

the

trial

and

through

months

-LRB-

weeks

-RRB-

of

the

trial

have

been

published

-LSB-

-RSB-

and

data

through

months

-LRB-

weeks

-RRB-

have

been

presented

-LRB-

A.B.

Gottlieb

et

al.

unpublished

results

reported

at

the

annual

meeting

of

the

American

Academy

of

Dermatology

-RRB-

A

total

of

patients

with

moderate

to

severe

plaque

psoriasis

received

weekly

efalizumab

mg/kg

for

weeks

of

the

patients

who

completed

the

initial

treatment

period

patients

-LRB-

-RRB-

achieved

or

a

static

Physician

's

Global

Assessment

-LRB-

sPGA

-RRB-

of

mild

minimal

or

clear

at

week

and

were

allowed

to

receive

maintenance

treatment

with

efalizumab

mg/kg

per

week

for

up

to

additional

months

-LRB-

weeks

-RRB-

-LSB-

-RSB-

At

completion

of

the

first

treatment

period

of

patients

achieved

Preliminary

results

showed

that

by

week

responses

were

observed

in

of

the

ITT

population

-LRB-

n

-RRB-

and

in

of

patients

-LRB-

n

last

observation

carried

forward

-RRB-

who

were

analyzed

by

means

of

a

maintenance

group

analysis

which

included

only

patients

eligible

to

receive

continued

efalizumab

An

as-treated

analysis

indicated

that

of

patients

-LRB-

n

-RRB-

achieved

at

week

-LRB-

results

through

week

are

shown

in

Fig.

-RRB-

-LSB-

-RSB-

Results

in

this

trial

support

the

sustained

efficacy

of

up

to

months

of

continuous

efalizumab

treatment

-LRB-

A.B.

Gottlieb

et

al.

unpublished

results

reported

at

the

annual

meeting

of

the

American

Academy

of

Dermatology

-RRB-

Fig.

of

patients

achieving

improvement

from

baseline

psoriasis

area

and

severity

index

-LRB-

PASI

-RRB-

Solid

lines

indicate

intention-to-treat

analyses

broken

lines

indicate

as-treated

analyses

-LRB-

efalizumab

-RRB-

or

modified

ITT

analysis

-LRB-

infliximab

-RRB-

ETANERCEPT

Results

shown

are

from

an

etanercept

study

in

which

patients

received

etanercept

mg

-LRB-

n

-RRB-

etanercept

mg

-LRB-

n

-RRB-

or

placebo

-LRB-

n

-RRB-

twice

weekly

for

weeks

followed

by

open-label

etanercept

mg

twice

weekly

for

up

to

additional

weeks

-LSB-

-RSB-

Efficacy

was

evaluated

in

the

ITT

population

Published

data

beyond

weeks

are

not

available

however

the

data

presented

at

several

international

medical

congresses

-LSB-

e.g.

European

Academy

of

Dermatology

and

Venereology

-LRB-

EADV

-RRB-

American

Academy

of

Dermatology

-LRB-

AAD

-RRB-

-RSB-

suggest

that

the

additional

efficacy

initially

achieved

with

etanercept

mg

twice

weekly

beyond

that

obtained

with

the

dose

might

not

be

sustained

in

the

long

term

following

dose

reduction

-LRB-

unpublished

data

presented

at

the

EADV

and

summer

AAD

meetings

-RRB-

EFALIZUMAB

Results

are

shown

for

efalizumab

from

an

open-label

Phase

III

study

-LRB-

n

-RRB-

of

efalizumab

mg/kg/week

for

weeks

followed

by

mg/kg/week

for

up

to

additional

months

in

patients

who

achieved

or

a

static

Physician

's

Global

Assessment

-LRB-

sPGA

-RRB-

of

mild

minimal

or

clear

at

week

-LSB-

-RSB-

The

dosage

received

during

the

first

weeks

was

higher

than

that

later

approved

for

clinical

use

-LRB-

mg/kg/week

-RRB-

Efficacy

was

evaluated

in

the

intent-to-treat

-LRB-

ITT

-RRB-

population

throughout

the

study

and

is

presented

through

weeks

as-treated

analysis

is

shown

after

weeks

through

week

Sample

sizes

for

as-treated

analysis

are

as

follows

week

week

week

-LSB-

-RSB-

The

shaded

portion

specifies

a

response

window

framed

by

the

most

conservative

measure

of

efficacy

-LRB-

ITT

-RRB-

and

the

response

of

patients

that

remain

on

therapy

-LRB-

as-treated

-RRB-

ALEFACEPT

Results

are

shown

for

alefacept

mg

administered

intravenously

-LRB-

IV

-RRB-

-LRB-

A.

Menter

et

al.

unpublished

data

presented

at

the

annual

meeting

of

the

American

Academy

of

Dermatology

-RRB-

long-term

response

rates

for

the

alefacept

intramuscular

-LRB-

IM

-RRB-

dosing

regimen

have

not

been

reported

Each

course

represents

weekly

alefacept

infusions

followed

by

a

minimum

of

weeks

of

treatment-free

observation

The

second

course

was

initiated

weeks

after

the

first

course

-LSB-

-RSB-

additional

treatment

courses

were

initiated

when

the

patient

was

deemed

by

the

investigator

to

require

systemic

therapy

or

phototherapy

for

psoriasis

recurrence

Course

represents

patients

who

may

have

received

up

to

total

weeks

of

alefacept

treatment

Sample

sizes

are

as-treated

numbers

INFLIXIMAB

Results

are

shown

for

infliximab

patients

who

were

randomized

to

receive

IV

infliximab

mg/kg

or

placebo

at

initiation

week

week

and

then

every

weeks

through

week

-LSB-

-RSB-

Analyses

through

week

were

performed

using

the

ITT

population

-LRB-

infliximab

n

placebo

n

-RRB-

analyses

through

week

were

based

on

a

modified

ITT

population

-LRB-

n

-RRB-

where

missing

data

were

considered

as

nonresponse

for

patients

who

withdrew

from

the

study

due

to

preselected

reasons

-LRB-

mainly

related

to

lack

of

efficacy

patients

who

withdrew

for

other

reasons

were

omitted

from

the

analysis

-RRB-

Some

limitations

of

the

study

are

noted

At

initiation

of

the

trial

the

label-supported

dosage

of

mg/kg

had

not

been

established

thus

a

dosage

of

mg/kg

was

administered

during

the

initial

period

It

was

subsequently

demonstrated

that

the

safety

and

efficacy

do

not

differ

for

the

and

doses

-LSB-

-RSB-

In

addition

although

relatively

few

patients

were

affected

-LRB-

-RRB-

a

dose

increase

of

up

to

mg/kg

was

allowed

up

through

months

of

the

study

Use

of

the

LOCF

procedure

during

analysis

of

ITT

data

might

introduce

bias

in

the

final

result

depending

on

the

response

of

the

patient

the

bias

could

overestimate

or

underestimate

the

final

result

Clinical

trials

have

shown

that

efalizumab

is

generally

well

tolerated

and

has

a

favorable

safety

profile

over

an

initial

treatment

period

-LSB-

-RSB-

Results

of

the

extended

studies

described

here

support

the

continued

safety

and

tolerability

of

efalizumab

treatment

periods

longer

than

weeks

-LSB-

-RSB-

The

most

common

adverse

events

associated

with

efalizumab

administration

are

acute

flulike

symptoms

-LRB-

headache

chills

fever

myalgia

vomiting

and

nausea

-RRB-

observed

primarily

following

the

first

two

doses

After

the

third

and

subsequent

doses

the

incidence

of

acute

adverse

events

in

efalizumab-treated

patients

is

comparable

to

that

observed

in

placebo

recipients

The

extended

treatment

studies

have

shown

that

with

the

exception

of

an

expected

reduction

in

acute

adverse

events

the

incidence

and

intensity

of

adverse

events

during

the

second

and

subsequent

treatment

periods

are

similar

to

those

observed

during

the

first

weeks

To

date

no

evidence

of

cumulative

or

end-organ

toxicity

has

been

found

with

efalizumab

Thrombocytopenia

has

been

reported

during

efalizumab

clinical

trials

-LRB-

Raptiva

-LSB-

efalizumab

-RSB-

package

insert

South

San

Francisco

Calif

Genentech

Inc.

June

-RRB-

and

recently

a

statement

about

the

development

of

hemolytic

anemia

has

been

added

to

the

prescribing

information

-LRB-

Raptiva

-LSB-

efalizumab

-RSB-

package

insert

-RRB-

Worsening

of

psoriasis

and

psoriasis

variants

has

been

observed

in

of

efalizumab

patients

during

therapy

-LRB-

i.e.

generalized

inflammatory

flare

-RRB-

and

in

of

patients

following

abrupt

discontinuation

of

efalizumab

-LRB-

i.e.

rebound

-RRB-

-LSB-

-RSB-

The

likelihood

of

experiencing

rebound

was

inversely

related

to

the

PASI

response

at

week

of

patients

experiencing

rebound

were

nonresponders

and

only

had

achieved

-LSB-

-RSB-

New-onset

or

worsening

arthritis

has

been

infrequently

reported

during

clinical

trials

and

postmarketing

-LRB-

Raptiva

-LSB-

efalizumab

-RSB-

package

insert

-RRB-

Based

on

available

clinical

data

from

up

to

months

of

continuous

treatment

efalizumab

does

not

appear

to

be

associated

with

an

increased

risk

of

malignancy

or

opportunistic

infections

observed

in

immunosuppressed

hosts

-LSB-

-RSB-

Because

the

numbers

of

patients

evaluated

in

the

long-term

studies

have

been

relatively

small

the

incidence

of

malignancy

and

infection

will

be

assessed

postmarketing

-LRB-

Raptiva

-LSB-

efalizumab

-RSB-

package

insert

-RRB-

Etanercept

Etanercept

is

a

recombinant

fusion

protein

comprising

domains

of

the

human

tumor

necrosis

factor

-LRB-

TNF

-RRB-

receptor

and

human

which

inhibits

the

activity

of

TNF-α

a

proinflammatory

cytokine

implicated

in

psoriasis

The

efficacy

safety

and

HRQOL

benefits

of

and

weeks

of

etanercept

therapy

in

patients

with

moderate

to

severe

chronic

plaque

psoriasis

-LRB-

baseline

PASI

and

of

BSA

affected

-RRB-

have

been

demonstrated

in

Phase

III

clinical

trials

-LSB-

-RSB-

There

is

also

clinical

experience

with

etanercept

in

other

indications

such

as

rheumatoid

arthritis

-LRB-

RA

-RRB-

Recommended

dosage

in

the

EU

is

mg

administered

SC

twice

weekly

for

up

to

weeks

Dosing

at

mg

twice

weekly

is

also

possible

for

the

first

weeks

followed

by

a

step-down

to

mg

twice

weekly

Based

on

published

clinical

data

European

guidelines

indicate

that

nonresponders

should

discontinue

etanercept

after

weeks

and

that

reinitiation

of

etanercept

treatment

is

possible

after

discontinuation

-LRB-

European

Medicines

Agency

Enbrel

-LSB-

etanercept

-RSB-

summary

of

product

characteristics

-RRB-

In

the

United

States

a

prefilled

syringe

recently

became

available

and

the

recommended

dosing

of

etanercept

is

mg

twice

weekly

for

the

first

weeks

of

treatment

followed

by

step-down

to

mg

once

weekly

-LRB-

Enbrel

-LSB-

etanercept

-RSB-

package

insert

Thousand

Oaks

Calif

Immunex

Corporation

October

-RRB-

A

placebo-controlled

double-blind

Phase

III

study

demonstrated

the

safety

and

efficacy

of

and

weeks

of

etanercept

treatment

-LSB-

-RSB-

A

total

of

patients

were

randomized

to

receive

placebo

or

etanercept

mg

once

weekly

mg

twice

weekly

or

mg

twice

weekly

via

SC

injection

for

weeks

Etanercept

recipients

who

completed

the

initial

treatment

period

continued

on

their

assigned

dosage

for

an

additional

weeks

Whereas

efficacy

was

originally

reported

only

in

patients

who

received

at

least

dose

of

study

drug

-LRB-

n

-RRB-

-LSB-

-RSB-

some

data

were

subsequently

reanalyzed

for

all

patients

who

were

enrolled

and

randomized

irrespective

of

whether

the

study

drug

was

administered

-LRB-

Enbrel

-LSB-

etanercept

-RSB-

package

insert

-RRB-

These

data

are

discussed

herein

to

allow

for

a

more

accurate

comparison

with

ITT

data

from

efalizumab

clinical

trials

This

reanalysis

showed

that

among

patients

randomized

to

receive

etanercept

or

mg

twice

weekly

-LRB-

the

dosages

most

similar

to

those

now

recommended

in

Europe

and

the

United

States

-RRB-

and

of

patients

respectively

achieved

at

week

increasing

to

and

at

week

-LRB-

Enbrel

-LSB-

etanercept

-RSB-

package

insert

-RRB-

The

mean

percentage

PASI

improvement

reported

in

patients

who

received

at

least

dose

of

etanercept

or

mg

increased

from

to

respectively

at

week

to

and

at

week

However

it

appears

that

the

mean

percentage

PASI

improvement

began

to

plateau

around

week

-LRB-

Fig.

-RRB-

Results

from

the

first

weeks

of

a

continuous

etanercept

therapy

global

Phase

III

psoriasis

study

were

recently

published

In

the

initial

placebo-controlled

double-blind

phase

of

the

study

patients

were

randomized

to

receive

placebo

or

etanercept

or

mg

twice

weekly

all

patients

were

then

eligible

to

receive

open-label

etanercept

mg

twice

weekly

for

up

to

additional

weeks

Results

at

and

weeks

were

reported

for

all

randomized

patients

who

received

at

least

dose

of

study

drug

-LRB-

n

-RRB-

using

the

LOCF

procedure

for

analysis

and

for

all

randomized

patients

regardless

of

whether

they

received

study

drug

-LRB-

n

-RRB-

with

the

assumption

that

patients

with

missing

data

had

not

met

the

criteria

for

response

at

that

end

point

-LSB-

-RSB-

At

weeks

and

of

all

patients

randomized

to

receive

etanercept

or

mg

twice

weekly

respectively

achieved

-LRB-

vs.

for

placebo

P

both

comparisons

-RRB-

The

response

rate

was

slightly

higher

among

patients

who

received

at

least

dose

of

etanercept

or

mg

-LRB-

and

respectively

-RRB-

increasing

to

and

at

week

-LSB-

-RSB-

Data

presented

for

this

study

at

scientific

meetings

-LSB-

meeting

of

the

European

Academy

of

Dermatology

and

Venereology

-LSB-

EADV

-RSB-

and

meeting

of

the

American

Academy

of

Dermatology

-LRB-

AAD

-RRB-

-RSB-

indicated

that

among

patients

continuing

on

etanercept

mg

twice

weekly

the

response

achieved

at

week

was

maintained

through

week

of

continuous

treatment

and

suggested

that

the

greater

response

rate

initially

observed

after

weeks

in

the

group

initially

randomized

to

etanercept

mg

twice

weekly

decreased

slightly

after

per-protocol

dose

reduction

with

response

rates

reaching

a

similar

level

in

both

groups

during

the

open-label

treatment

phase

-LRB-

W.

Sterry

unpublished

data

-RRB-

A

randomized

placebo-controlled

multicenter

Phase

III

study

to

evaluate

the

safety

and

efficacy

of

etanercept

mg

twice

weekly

over

the

course

of

years

is

currently

ongoing

Preliminary

results

after

weeks

of

therapy

were

recently

reported

-LRB-

S.K.

Tyring

et

al.

unpublished

data

presented

at

the

summer

meeting

of

the

American

Academy

of

Dermatology

-RRB-

In

this

trial

patients

were

randomized

to

receive

either

etanercept

mg

-LRB-

n

-RRB-

or

placebo

twice

weekly

for

weeks

-LRB-

n

-RRB-

followed

by

open-label

etanercept

mg

twice

weekly

Etanercept

demonstrated

statistically

significant

improvements

in

PASI

response

rates

compared

with

placebo

by

week

of

therapy

Response

rates

continued

to

increase

through

weeks

of

therapy

after

which

they

appeared

to

plateau

Approximately

of

patients

achieved

a

response

at

week

with

a

similar

proportion

at

week

Clinical

data

support

the

safety

and

tolerability

of

weeks

of

etanercept

treatment

in

patients

with

psoriasis

-LSB-

-RSB-

Published

results

from

psoriasis

clinical

trials

showed

that

etanercept

was

generally

well

tolerated

Adverse

events

observed

during

the

initial

placebo-controlled

period

were

typically

mild

to

moderate

in

intensity

and

occurred

with

similar

frequency

in

etanercept

and

placebo

groups

-LSB-

-RSB-

No

apparent

change

in

the

adverse

events

profile

occurred

during

the

second

period

of

the

trials

-LSB-

-RSB-

Safety

outcomes

of

the

long-term

Phase

III

psoriasis

clinical

trial

particularly

for

patients

who

received

mg

twice

weekly

have

not

yet

been

presented

in

detail

however

a

preliminary

analysis

integrating

data

from

the

Phase

II

and

Phase

III

etanercept

clinical

trials

in

which

many

patients

received

the

dosage

suggested

that

no

new

pattern

of

adverse

events

emerged

during

up

to

weeks

of

treatment

-LRB-

A.B.

Gottlieb

et

al.

unpublished

data

presented

at

the

annual

meeting

of

the

American

Academy

of

Dermatology

-RRB-

Psoriasis

clinical

trials

revealed

no

evidence

of

increased

risk

of

opportunistic

infections

tuberculosis

or

skin

cancers

during

up

to

weeks

of

etanercept

treatment

-LRB-

A.B.

Gottlieb

et

al.

unpublished

data

-RRB-

Whereas

long-term

data

from

clinical

trials

in

many

patients

receiving

etanercept

for

other

indications

such

as

RA

support

the

general

safety

and

tolerability

of

the

dosage

there

have

been

infrequent

cases

of

tuberculosis

and

rare

cases

of

demyelinating

disorders

pancytopenia

and

congestive

heart

failure

-LRB-

Enbrel

-LSB-

etanercept

-RSB-

package

insert

European

Medicines

Agency

Enbrel

-LSB-

etanercept

-RSB-

summary

of

product

characteristics

-RRB-

Infliximab

Infliximab

a

chimeric

monoclonal

antibody

that

binds

membrane-bound

and

soluble

TNF-α

is

still

under

evaluation

for

use

in

patients

with

psoriasis

Infliximab

has

demonstrated

efficacy

in

psoriasis

patients

in

randomized

placebo-controlled

Phase

II

trials

-LSB-

-RSB-

However

the

results

of

an

international

multicenter

randomized

placebo-controlled

Phase

III

trial

of

adult

patients

with

plaque

psoriasis

-LRB-

baseline

PASI

and

of

BSA

affected

-RRB-

were

recently

reported

-LSB-

-RSB-

Patients

were

randomized

to

receive

IV

infliximab

mg/kg

-LRB-

n

-RRB-

or

placebo

-LRB-

n

-RRB-

at

initiation

week

and

week

and

then

every

weeks

through

week

The

placebo

group

crossed

over

to

infliximab

treatment

at

week

but

the

study

remained

blinded

throughout

Patients

who

discontinued

the

study

early

because

of

lack

or

loss

of

response

or

for

whom

insufficient

data

were

available

were

treated

as

not

achieving

the

end

points

for

analysis

of

the

ITT

population

At

week

of

treatment

the

response

rate

was

in

the

infliximab-treated

group

and

in

the

placebo-treated

group

This

level

of

response

was

sustained

through

week

At

week

the

proportion

of

the

ITT

population

that

achieved

dropped

to

However

excluding

patients

who

missed

infusions

the

rate

at

week

was

-LRB-

n

-RRB-

The

reason

for

the

moderate

reduction

in

efficacy

is

unclear

but

may

be

due

to

the

development

of

inhibitory

antibodies

in

a

percentage

of

the

patients

The

safety

profile

for

infliximab

during

this

extended

treatment

Phase

III

trial

appears

to

be

comparable

to

those

observed

during

earlier

studies

-LSB-

-RSB-

The

incidence

of

adverse

events

and

serious

adverse

events

in

infliximab-treated

patients

was

slightly

elevated

relative

to

those

in

placebo

recipients

through

the

first

weeks

of

treatment

and

one

patient

who

received

infliximab

died

of

sepsis

Elevations

in

aminotransferases

were

also

observed

in

some

infliximab-treated

patients

In

this

trial

infection

rates

were

comparable

between

the

treated

and

placebo

groups

however

like

etanercept

postmarketing

data

from

infliximab-treated

patients

with

RA

Crohn

's

disease

or

other

indications

for

which

infliximab

is

approved

suggest

a

potential

increased

risk

for

events

such

as

opportunistic

infections

-LRB-

e.g.

tuberculosis

-RRB-

lymphoma

or

congestive

heart

failure

Adalimumab

Adalimumab

is

a

fully

human

monoclonal

antibody

that

binds

TNF-α

It

is

currently

being

evaluated

in

Phase

III

clinical

studies

for

the

treatment

of

moderate

to

severe

plaque

psoriasis

Results

from

a

Phase

II

randomized

double-blind

placebo-controlled

multicenter

clinical

trial

have

been

presented

-LRB-

K.B.

Gordon

et

al.

unpublished

data

presented

at

the

annual

meeting

of

the

American

Academy

of

Dermatology

-RRB-

Patients

were

randomized

to

receive

placebo

-LRB-

n

-RRB-

or

adalimumab

either

an

first

dose

followed

by

mg

every

other

week

-LRB-

EOW

n

-RRB-

or

an

first

and

second

dose

followed

by

mg

every

week

-LRB-

n

-RRB-

for

weeks

In

the

preliminary

analysis

and

presentation

and

of

the

patients

receiving

adalimumab

EOW

or

every

week

respectively

achieved

a

response

compared

to

of

the

patients

receiving

placebo

-LRB-

n

-RRB-

However

a

careful

reanalysis

of

the

data

suggested

that

the

true

efficacy

was

several

percentage

points

lower

-LRB-

R.G.B.

Langley

et

al.

unpublished

data

presented

at

the

Fall

European

Academy

of

Dermatology

and

Venereology

-RRB-

Adverse

events

were

similar

to

placebo

with

headache

injection

site

pain

nausea

elevated

triglycerides

cough

sinus

congestion

and

fatigue

most

common

Injection

site

pain

was

more

frequent

in

the

adalimumab

group

-LRB-

-RRB-

than

in

the

placebo

group

-LRB-

-RRB-

Comparison

of

biological

agents

In

the

absence

of

head-to-head

clinical

trials

it

is

difficult

to

accurately

compare

the

efficacy

of

the

biological

agents

for

psoriasis

However

most

of

these

agents

use

comparable

evaluations

of

treatment

efficacy

Alefacept

is

an

exception

as

it

is

used

as

remittive

therapy

and

alefacept

data

are

presented

using

the

as-treated

population

and

response

at

any

time

analyses

Thus

although

alefacept

appears

to

maintain

efficacy

in

responsive

patients

over

multiple

courses

of

treatment

-LRB-

Fig.

-RRB-

its

efficacy

can

not

be

readily

compared

with

efalizumab

etanercept

or

infliximab

Available

long-term

data

indicate

that

the

improvements

in

psoriasis

achieved

during

the

first

weeks

of

efalizumab

therapy

are

maintained

or

improved

through

at

least

weeks

of

continuous

treatment

Data

support

the

efficacy

of

efalizumab

through

at

least

months

of

continuous

treatment

The

efficacy

of

etanercept

mg

administered

twice

weekly

appears

to

be

maintained

through

at

least

weeks

of

continuous

treatment

Preliminary

findings

of

the

response

rate

in

patients

who

step

down

from

etanercept

mg

twice

weekly

to

mg

twice

weekly

suggest

that

the

initial

improvements

achieved

with

etanercept

mg

twice

weekly

beyond

what

is

observed

with

the

twice-weekly

dose

are

slightly

reduced

following

the

recommended

dose

reduction

For

infliximab

the

very

high

response

rates

obtained

after

weeks

of

treatment

appear

to

be

sustained

through

weeks

but

show

a

moderate

reduction

through

weeks

with

infusions

every

weeks

Week

response

rates

were

for

efalizumab-treated

patients

and

approximately

for

etanercept-treated

patients

-LRB-

as-treated

populations

Fig.

-RRB-

The

response

rate

at

week

for

infliximab

was

in

patients

who

did

not

miss

more

than

infusion

-LRB-

Fig.

-RRB-

The

longer-term

studies

summarized

here

are

not

directly

comparable

because

of

differences

in

patient

eligibility

for

initial

enrollment

and

maintenance

treatment

and

inclusion

in

efficacy

analyses

For

example

in

contrast

to

the

long-term

etanercept

study

patients

in

the

efalizumab

open-label

trial

were

eligible

for

maintenance

treatment

only

if

they

achieved

a

reasonable

response

during

the

first

weeks

This

included

the

majority

-LRB-

-RRB-

of

patients

completing

the

initial

treatment

phase

For

the

ITT

efficacy

analyses

-LRB-

presented

through

weeks

-RRB-

all

efalizumab-treated

patients

were

included

even

those

who

did

not

achieve

or

sPGA

of

mild

minimal

or

clear

at

week

and

were

required

to

discontinue

the

trial

Direct

data

comparisons

are

further

compromised

by

the

available

analyses

Efalizumab

data

are

presented

as

both

an

ITT

analysis

for

weeks

and

an

as-treated

analysis

for

weeks

through

Etanercept

data

are

presented

as

an

ITT

analysis

through

weeks

Results

from

the

long-term

infliximab

study

are

presented

as

an

ITT

analysis

for

the

first

weeks

of

the

trial

and

thereafter

are

presented

as

a

modified

ITT

population

where

missing

data

were

considered

as

nonresponsive

for

patients

who

withdrew

from

the

study

for

preselected

reasons

Given

that

psoriasis

is

a

chronic

incurable

disease

the

availability

of

long-term

data

is

critical

for

dermatologists

evaluating

treatment

options

There

is

a

paucity

of

long-term

data

derived

from

robust

clinical

trials

for

conventional

nonbiological

psoriasis

therapies

therefore

dermatologists

generally

rely

on

treatment

guidelines

and

personal

experience

in

making

their

decisions

about

long-term

administration

of

therapies

such

as

methotrexate

and

cyclosporine

Because

biologicals

represent

a

new

approach

to

the

management

of

psoriasis

long-term

data

are

of

particular

importance

for

this

therapeutic

class

Alefacept

appears

to

be

an

effective

therapy

for

inducing

extended

remissions

in

a

small

population

of

patients

and

it

has

a

demonstrated

safety

profile

for

remittive

use

The

long-term

data

available

to

date

for

efalizumab

indicate

that

initial

improvements

in

psoriasis

are

sustained

for

up

to

months

Data

from

multiple

clinical

trials

indicate

that

of

patients

achieved

in

the

first

months

of

therapy

-LSB-

-RSB-

in

an

extended

trial

of

patients

receiving

continuous

therapy

up

to

months

of

the

patients

achieved

at

the

end

point

-LRB-

C.L.

Leonardi

et

al.

manuscript

in

preparation

-RRB-

Studies

evaluating

the

long-term

use

of

etanercept

are

under

way

but

only

limited

data

are

currently

available

as

suggested

by

the

current

limit

for

etanercept

therapy

in

Europe

At

weeks

of

patients

who

received

etanercept

mg

twice

weekly

achieved

-LSB-

-RSB-

Available

data

suggest

that

improvements

are

maintained

for

weeks

as

of

patients

receiving

mg

twice

weekly

achieved

-LRB-

S.K.

Tyring

et

al.

unpublished

data

presented

at

the

summer

meeting

of

the

American

Academy

of

Dermatology

-RRB-

Importantly

the

safety

data

reported

to

date

indicate

that

the

safety

profiles

of

efalizumab

and

etanercept

allow

for

continuous

long-term

administration

Infliximab

has

demonstrated

excellent

response

rates

with

induction

and

extended

therapy

with

an

infusion

schedule

optimal

The

approval

of

biological

therapies

that

is

the

T-cell-modulators

alefacept

and

efalizumab

and

the

TNFα

antagonist

etanercept

along

with

the

development

of

other

TNFα

antagonists

such

as

infliximab

and

adalimumab

represent

significant

advances

for

the

management

of

psoriasis

Their

efficacy

and

safety

profiles

suggest

that

they

may

be

suitable

for

remittive

or

continuous

long-term

administration

providing

dermatologists

with

new

options

for

the

long-term

management

of

their

patients

with

psoriasis

The

safety

and

efficacy

data

from

ongoing

clinical

trials

and

the

experience

of

dermatologists

are

important

to

define

further

how

these

agents

can

best

be

integrated

into

the

psoriasis

armamentarium

O O O O O O O B O O B O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O B O B O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O B O O O B O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O B O B O O O O O B O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O B O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O B O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O B O O O O B O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O

biological alefacept efalizumab etanercept infliximab psoriasis


Energy

metabolism

altered

proteins

sirtuins

and

ageing

converging

mechanisms

The

predominant

molecular

symptom

of

ageing

is

the

accumulation

of

altered

gene

products

Nutritional

studies

show

that

ageing

in

animals

can

be

significantly

influenced

by

dietary

restriction

Genetics

has

revealed

that

ageing

may

be

controlled

by

changes

in

intracellular

NAD/NADH

ratio

regulating

sirtuin

activity

Physiological

and

other

approaches

indicate

that

mitochondria

may

also

regulate

ageing

A

mechanism

is

proposed

which

links

diet

exercise

and

mitochondria-dependent

changes

in

NAD/NADH

ratio

to

intracellular

generation

of

altered

proteins

It

is

suggested

that

ad

libitum

feeding

conditions

decrease

NAD

availability

which

also

decreases

metabolism

of

the

triose

phosphate

glycolytic

intermediates

and

dihydroxyacetone-phosphate

which

can

spontaneously

decompose

into

methylglyoxal

-LRB-

MG

-RRB-

MG

is

a

highly

toxic

glycating

agent

and

a

major

source

of

protein

advanced-glycosylation

end-products

-LRB-

AGEs

-RRB-

MG

and

AGEs

can

induce

mitochondrial

dysfunction

and

formation

of

reactive

oxygen

species

-LRB-

ROS

-RRB-

as

well

as

affect

gene

expression

and

intracellular

signalling

In

dietary

restriction

induced

fasting

NADH

would

be

oxidised

and

NAD

regenerated

via

mitochondrial

action

This

would

not

only

activate

sirtuins

and

extend

lifespan

but

also

suppress

MG

formation

This

proposal

can

also

explain

the

apparent

paradox

whereby

increased

aerobic

activity

suppresses

formation

of

glycoxidized

proteins

and

extends

lifespan

Variation

in

mitochondrial

DNA

composition

and

consequent

mutation

rate

arising

from

dietary-controlled

differences

in

DNA

precursor

ratios

could

also

contribute

to

tissue

differences

in

age-related

mitochondrial

dysfunction

NAD

and

life-span

Genetic

studies

using

a

range

of

organisms

have

indicated

that

enzymes

called

sirtuins

are

linked

to

the

control

of

ageing

and

life-span

-LRB-

Longo

and

Kennedy

Leibiger

and

Berggren

Lin

and

Guarente

-RRB-

Sirtuins

catalyse

NAD-dependent

deacetylation

of

histones

-LRB-

and

other

proteins

-RRB-

with

the

concomitant

release

of

nicotimanide

and

O-acetyl-ADP-ribose

-LRB-

Howitz

et

al.

-RRB-

Other

studies

have

suggested

that

metabolism

of

the

redox

couple

NAD/NADH

provides

a

link

between

sirtuin

activity

and

the

control

of

cell

senescence

and

organism

life-span

-LRB-

Denu

Belenky

et

al.

Bordone

and

Guarente

-RRB-

NAD-dependent

protein

deacetylation

helps

maintain

the

juvenile

phenotype

whereas

inhibition

of

deacetylation

activity

by

NADH

or

nicotinamide

or

by

NAD

unavailability

promote

the

onset

of

cellular

aging

and

decrease

organism

lifespan

Ageing

dietary

restriction

and

NAD

Ageing

can

be

delayed

in

various

organisms

by

dietary

restriction

-LRB-

DR

-RRB-

induced

by

a

permanent

decrease

in

calorie

intake

-LRB-

called

caloric

restriction

CR

-RRB-

Recent

observations

have

shown

that

an

intermittent

feeding

-LRB-

IF

-RRB-

protocol

which

need

not

involve

any

overall

reduction

in

calorie

intake

can

also

delay

ageing

-LRB-

Martin

et

al.

Masternak

et

al.

Mattson

and

Wan

-RRB-

The

mechanisms

by

which

DR

delays

ageing

and

increases

life-span

are

far

from

completely

understood

-LRB-

Sinclair

-RRB-

It

is

likely

however

that

both

CR

and

IF

promote

similar

effects

on

the

frequency

of

glycolysis

and

subsequent

fasting

periods

-LRB-

Hipkiss

and

-RRB-

i.e.

glycolysis

would

be

discontinuous

only

operating

post-prandialy

In

contrast

glycolysis

would

be

almost

continuous

under

ad

libitum

-LRB-

AL

-RRB-

feeding

conditions

It

is

suggested

that

during

the

periods

of

fasting

-LRB-

induced

by

either

CR

or

IF

-RRB-

the

NAD/NADH

ratio

would

differ

from

that

prevailing

in

the

AL

case

where

fasting

would

be

unlikely

or

negligible

In

the

AL

condition

continuous

glycolytic

throughput

would

tend

to

provoke

an

accumulation

of

NADH

and

lower

NAD

availability

whereas

the

CR

and

IF-induced

fasting

would

decrease

glycolytic

NAD

demand

and

increase

NADH

oxidation

and

NAD

regeneration

Ageing

and

accumulation

of

altered

proteins

At

the

biochemical

level

ageing

is

characterized

by

the

accumulation

of

altered

protein

molecules

The

changes

in

protein

structure

result

from

intrinsic

polypeptide

instability

as

well

as

the

actions

of

deleterious

endogenous

and

exogenous

agents

-LRB-

see

Hipkiss

Schoneich

and

refs

therein

-RRB-

As

yet

it

is

unclear

how

changes

in

NAD

metabolism

might

induce

generation

of

altered

proteins

which

characterise

the

aged

phenotype

Protein

glycation

and

ageing

Formation

of

protein

advanced

glycation

end-products

-LRB-

AGEs

-RRB-

is

an

important

consequence

of

ageing

and

is

increased

particularly

under

conditions

of

uncontrolled

glucose

metabolism

-LRB-

e.g.

hyperglycaemia

-RRB-

-LRB-

see

Ahmed

and

Thornally

Thornalley

and

refs

therein

for

recent

reviews

-RRB-

Protein

AGEs

can

themselves

induce

inflammatory

conditions

and

provoke

production

of

reactive

oxygen

species

-LRB-

ROS

-RRB-

which

can

further

compromise

cell

function

Indeed

recent

studies

have

shown

that

decreasing

dietary

AGE

intake

preserves

defence

functions

against

oxidative

stress

and

decreases

tissue

damage

in

humans

and

extends

lifespan

in

mice

while

increasing

dietary

AGE

intake

is

correspondingly

deleterious

and

accelerates

ageing

and

decreases

life-span

-LRB-

Cai

et

al.

Uribarri

et

al.

b

-RRB-

Hence

it

is

at

least

conceivable

that

decreasing

metabolically-generated

protein

AGEs

could

help

decrease

the

overall

AGE

load

and

could

have

beneficial

effects

by

suppressing

ageing

and

extending

lifespan

NAD

and

accumulation

of

methylglyoxal

an

endogenous

glycating

agent

NAD

is

essential

for

the

metabolism

of

the

glycolytic

intermediate

-LRB-

-RRB-

via

the

action

of

dehydrogenase

-LRB-

GAPDH

-RRB-

generating

-LRB-

DPG

-RRB-

and

NADH

as

products

It

is

argued

above

that

in

the

AL

condition

glycolysis

would

be

continuous

which

would

tend

to

lower

NAD

levels

and

raise

NADH

levels

This

would

occur

especially

should

mitochondrial-mediated

NADH

re-oxidation

to

NAD

be

correspondingly

lowered

to

compensate

for

the

extra

ATP

synthesised

via

glycolysis

assuming

cellular

ATP

demand

remains

unchanged

Limitation

of

NAD

availability

would

lower

GAPDH

activity

and

promote

an

accumulation

of

The

immediate

precursor

of

is

dihydroxyacetone

phosphate

-LRB-

DHAP

-RRB-

both

of

these

trioses

can

glycate

proteins

More

importantly

however

is

the

fact

that

both

and

DHAP

can

spontaneously

decompose

into

methylglyoxal

-LRB-

MG

-RRB-

a

highly

toxic

and

very

reactive

glycating

agent

It

is

likely

therefore

that

changes

in

NAD

availability

could

strongly

influence

MG

production

It

has

previously

been

proposed

that

differences

in

glycolytic

frequency

could

help

explain

why

dietary

restriction

delays

cellular

and

organism

aging

possibly

due

to

decreased

MG

generation

during

DR

conditions

-LRB-

Hipkiss

-RRB-

MG

is

a

highly

active

glycating

agent

which

is

thought

to

be

responsible

for

the

increased

protein/lipid

glycation

detected

during

hyperglycaemic

conditions

and

for

much

of

the

protein/lipid

glycation

associated

with

diabetic

complications

-LRB-

Ahmed

and

Thornalley

Thornalley

-RRB-

Although

MG

is

a

normal

cellular

constituent

its

excessive

production

is

deleterious

-LRB-

plasma

MG

levels

are

raised

to

around

nmol/l

in

young

diabetics

compared

to

about

nmol/l

in

young

non-diabetic

subjects

-LRB-

Han

et

al.

-RRB-

-RRB-

Importantly

MG

can

induce

many

of

the

deleterious

physiological

and

biochemical

changes

characteristic

of

the

aged

phenotype

including

increased

ROS

generation

mitochondrial

dysfunction

apoptosis

and

inhibition

of

cell

division

-LRB-

see

Hipkiss

and

refs

therein

-RRB-

A

number

of

studies

some

very

recent

reinforce

the

notion

that

changes

in

cellular

MG

content

are

important

determinants

of

the

formation

of

altered

protein

that

characterise

senescence

-LRB-

Gomes

et

al.

-RRB-

Even

at

non-toxic

concentrations

MG

can

influence

cell

proliferation

by

forming

adducts

with

growth

factor

receptors

-LRB-

Cantero

et

al.

-RRB-

MG

can

also

inhibit

the

activity

of

GAPDH

-LRB-

Lee

et

al.

-RRB-

causing

triose

phosphate

accumulation

and

thereby

increasing

MG

generation

and

so

inducing

a

highly

deleterious

cycle

MG

can

induce

apoptosis

-LRB-

Nicolay

et

al.

-RRB-

and

also

affect

gene

expression

and

signal

transduction

at

least

in

cultured

cells

-LRB-

Du

et

al.

Yao

et

al.

Ramasamy

et

al.

-RRB-

Two

studies

in

Drosophila

have

shown

that

mutation

in

triosephosphate

isomerase

-LRB-

the

enzyme

which

converts

DHAP

into

preceding

GAPDH

in

the

glycolytic

pathway

and

which

is

known

to

undergo

age-related

post-synthetic

modification

in

vivo

-LRB-

Gracy

et

al.

-RRB-

-RRB-

is

highly

deleterious

causing

paralysis

neurodegeneration

and

decreases

life-span

-LRB-

Gnerer

et

al.

Celotto

et

al.

-RRB-

possibly

because

of

MG

accumulation

Human

studies

have

shown

that

a

deficiency

in

triosephosphate

isomerase

activity

causes

increases

in

the

levels

of

both

DHAP

-LRB-

up

to

-LRB-

Schneider

-RRB-

-RRB-

and

MG

-LRB-

Ahmed

et

al.

-RRB-

and

induces

neuromuscular

degeneration

and

early

death

-LRB-

Schneider

et

al.

Valentine

-RRB-

Other

studies

have

shown

that

MG

induces

apoptosis

in

neutrophils

-LRB-

Gawlowski

et

al.

-RRB-

inhibits

extracellular

matrix

remodelling

-LRB-

Chong

et

al.

-RRB-

and

can

interfere

with

the

stress

response

-LRB-

Oya-Ito

et

al.

-RRB-

by

suppressing

NF-kappaB-responsive

gene

activation

-LRB-

Laga

et

al.

-RRB-

Hence

it

is

reasonable

to

suggest

that

any

increased

MG

generated

in

AL

fed

animals

compared

to

animals

subjected

to

CR

or

IF

could

make

a

significant

contribution

to

cellular

dysfunction

During

the

fasting

periods

in

DR

animals

NADH

generated

during

glycolysis

would

be

oxidized

mitochondrially

for

ATP

production

and

NAD

would

be

regenerated

thereby

allowing

continued

metabolism

and

preventing

triose

phosphate

accumulation

and

consequently

suppressing

MG

generation

This

condition

would

decrease

MG-induced

macromolecular

glycoxidation

mitochondrial

damage

dysfunctional

signalling

and

gene

expression

as

described

above

Such

a

scenario

is

consistent

with

the

findings

that

raising

NAD

levels

or

lowering

NADH

levels

by

increasing

its

oxidation

also

promote

sirtuin

activation

with

concomitant

beneficial

effects

on

cell

survival

etc.

Table

illustrates

the

interrelationship

and

overlap

between

sirtuin

regulation

generation

of

altered

proteins

and

mitochondrial

activity

exerted

by

metabolic

effects

on

NAD

and

NADH

levels

Table

effects

of

aerobic

exercise

and

fasting

induced

by

caloric

restriction

or

intermittent

feeding

on

NAD

and

NADH

levels

methylglyoxal

-LRB-

MG

-RRB-

levels

mitochondrial

-LRB-

mito

-RRB-

activity

and

sirtuin

activityConditionsNADNADH

MGMito

activitySirtuin

activityAd

libitum

fedLowHighHigh

LoweredLoweredFastingHighLowLowIncreasedIncreasedAerobic

exercise

HighLowLowIncreasedIncreasedIncreased

MG

levels

are

partly

responsible

for

the

increased

generation

of

altered

proteins

that

accompanies

ageing

Any

situation

such

as

fasting

which

maintains

NAD

levels

either

via

regeneration

from

NADH

or

by

synthesis

de

novo

or

via

a

scavenging

pathway

would

facilitate

metabolism

of

the

MG

precursors

and

DHAP

and

so

decrease

the

incidence

of

MG-induced

macromolecular

damage

The

increase

in

free-radical-mediated

damage

which

occurs

during

AL

feeding

compared

to

the

CR

and

IF

conditions

might

occur

as

a

result

of

not

only

MG-induced

generation

of

ROS

following

its

reaction

with

proteins

etc.

but

also

via

plasma

membrane-mediated

NAD

-LRB-

P

-RRB-

H-oxidase

activity

Furthermore

because

less

ATP

is

required

from

mitochondrial

function

due

to

continuous

ATP

synthesis

via

glycolysis

in

the

AL-fed

state

the

decreased

supply

of

electrons

-LRB-

as

acetyl-CoA

or

from

NADH

-RRB-

to

the

electron

transport

chain

would

tend

to

produce

more

incompletely

reduced

oxygen

moieties

i.e.

oxygen

free-radicals

Any

increased

intra-mitochondrial

ROS

production

could

also

increase

the

probability

of

mitochondrial

dysfunction

Protection

against

MG

is

afforded

by

the

glyoxalase

system

which

consists

of

two

enzymes

glyoxalase

I

-LRB-

GLX

I

-RRB-

which

uses

glutathione

to

convert

MG

to

a

D-lactoyl-glutathione

and

glyoxalase

II

-LRB-

GLX

II

-RRB-

which

completes

the

detoxification

by

generating

D-lactate

and

reduced

glutathione

Over-expression

of

GLX

I

can

inhibit

formation

of

hyperglycaemia-induced

AGEs

-LRB-

Shinohara

et

al.

-RRB-

while

a

deficiency

in

GLX

I

in

humans

is

associated

with

increased

protein

glycation

-LRB-

Miyata

et

al.

-RRB-

GLX

II

activity

may

be

rate-limiting

in

MG

detoxification

GLX

II

over-expression

is

protective

against

MG-induced

cell

death

whilst

its

deficiency

promotes

MG-induced

cell

death

-LRB-

Xu

and

Chen

-RRB-

It

is

also

interesting

that

tumour

necrosis

factor

can

induce

phosphorylation

of

GLX

I

which

also

results

in

substantial

increase

in

cellular

MG

-LRB-

van

Herreweghe

et

al.

-RRB-

Tissue

differences

in

ageing

susceptibility

Tissues

appear

to

age

at

different

rates

as

shown

by

the

varied

incidence

of

dysfunctional

mitochondria

between

tissues

in

the

same

organism

Variation

in

tissue

susceptibility

to

MG

may

reside

partly

in

differing

levels

of

the

glyoxalase

system

together

with

those

molecules

-LRB-

glutathione

polyamines

carnosine

creatine

pyridoxamine

-RRB-

which

normally

exert

protective

carbonyl

scavenging

activity

towards

glycating

agents

such

as

MG

-LRB-

Hipkiss

de

Arriba

et

al.

-RRB-

Dietary-induced

effects

on

metabolism

could

conceivably

also

affect

mitochondrial

DNA

composition

and

hence

mitochondrial

protein

structure

and

function

It

has

been

found

that

mitochondrial

DNA

mutation

rate

may

vary

up

to

three-fold

according

to

the

relative

concentrations

of

the

four

deoxyribonucleoside

triphosphates

in

the

nucleotide

pool

-LRB-

Song

et

al.

Mathews

and

Song

-RRB-

It

is

possible

that

dietary

changes

could

affect

the

composition

of

the

nucleotide

pool

and

thereby

affect

mitochondrial

DNA

composition

during

its

synthesis

Pool

composition

could

vary

between

tissues

and

any

consequent

differences

in

mitochondrial

DNA

mutation

rate

would

contribute

to

tissue-specific

age-related

mitochondrial

change

Thus

mitochondrial

dysfunction

could

be

either

a

cause

or

a

consequence

of

ageing

-LRB-

Hipkiss

-RRB-

depending

on

the

prevailing

circumstances

The

beneficial

effects

of

functional

mitochondria

on

NAD

regeneration

The

recent

observations

-LRB-

i

-RRB-

by

Belenky

et

al.

-LRB-

-RRB-

showing

that

life-span

extension

in

yeast

is

dependent

upon

NAD

synthesis

-LRB-

ii

-RRB-

that

efficient

mitochondrial

function

was

necessary

for

maximal

longevity

in

yeast

-LRB-

Piper

et

al.

-RRB-

and

-LRB-

iii

-RRB-

that

mitochondrial

uncoupling

which

increases

NADH

oxidation

decreases

telomere

damage

and

delays

senescence

in

cultured

human

fibroblasts

-LRB-

Passos

et

al.

-RRB-

are

observations

entirely

consistent

with

the

above

proposal

The

proposed

beneficial

effects

of

NADH

oxidation

to

regenerate

NAD

via

mitochondrial

function

would

also

help

explain

how

aerobic

exercise

may

delay

development

of

the

aged

phenotype

including

production

of

altered

proteins

as

well

as

resolve

the

apparent

paradox

that

increased

oxygen

utilization

suppresses

age-related

change

The

efficient

regeneration

of

NAD

via

effective

mitochondrial

function

is

also

consistent

with

mitochondrial

ageing

theories

which

postulate

that

mitochondrial

dysfunction

is

key

to

the

onset

of

ageing

Also

consistent

with

the

present

proposal

are

the

very

recent

findings

of

Smith

et

al.

-LRB-

-RRB-

who

concluded

that

in

the

yeast

Saccharomyces

cerevisiae

at

least

elevated

respiration

is

an

important

determinant

of

chronological

longevity

They

observed

that

growth

on

non-fermentable

carbon

sources

which

forced

the

cells

to

employ

respiration

exclusively

extended

lifespan

but

which

caloric

restriction

did

not

further

enhance

This

again

illustrates

simplistically

perhaps

the

potential

anti-ageing

functions

of

aerobic

respiration

and

the

deleterious

effects

of

glycolysis

both

possibly

mediated

via

changes

NAD

and

NADH

levels

which

in

turn

regulate

MG

generation

Controversially

however

these

authors

also

found

that

caloric

restriction-mediated

lifespan

extension

occurred

independently

of

sirtuin

activity

in

Saccharomyces

cerevisiae

Other

functions

induced

by

DR

Ageing

is

a

complex

phenomenon

It

is

likely

that

the

rate-limiting

event

which

increases

cellular

and

hence

organism

vulnerability

to

death

may

vary

according

to

circumstances

For

example

anti-oxidant

functions

may

not

be

limiting

in

conditions

where

oxidative

stress

is

not

involved

There

are

an

increasing

number

of

findings

suggesting

that

proteolytic

dysfunction

involving

either

proteasomes

or

autophagy

cause

altered

protein

to

accumulate

and

compromise

cell

survival

and

which

can

be

affected

by

dietary

restriction

-LRB-

Bergamini

et

al.

-RRB-

Conversely

activation

of

autophagy

by

inhibiting

the

target

of

rapamycin

-LRB-

TOR

-RRB-

signalling

pathway

can

increase

lifespan

at

least

in

yeast

-LRB-

Bonawitz

et

al.

-RRB-

and

a

nematode

worm

-LRB-

Henderson

et

al.

-RRB-

The

recent

observation

that

the

sirtuin-like

activity

histone

deacetylase

-LRB-

-RRB-

may

provide

a

mechanistic

link

between

the

autophagic

and

ubiquitin-proteasome

proteolytic

systems

in

Drosophila

-LRB-

Pandey

et

al.

-RRB-

and

the

observation

that

up-regulation

of

neuronal

activity

elevates

the

activity

of

the

α-protease

and

prevents

accumulation

of

the

amyloid

peptide

-LRB-

Qin

et

al.

-RRB-

support

the

idea

that

both

formation

and

degradation

of

aberrant

proteins

are

important

for

control

of

ageing

and

related

disorders

Conclusion

It

is

proposed

that

dietary-induced

changes

in

NAD

and

NADH

levels

as

revealed

by

their

regulation

of

sirtuin

activity

may

also

control

the

concentration

of

deleterious

glycolytic

intermediates

and

DHAP

and

thereby

also

control

formation

of

MG

and

generation

of

protein

AGEs

The

accumulation

of

MG

and

protein

AGEs

may

compromise

tissue

function

including

mitochondrial

activity

and

thereby

contribute

to

organism

ageing

Conversely

conditions

that

stimulate

mitochondrial

function

will

help

regenerate

NAD

maintain

sirtuin

activity

and

decrease

formation

of

protein

AGEs

intra

and

extra-mitochondrial

ROS

can

thereby

delay

ageing

onset

O O O B I O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O B I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O B O B I O B B O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O B O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O

nad
nadh
glycolysis
methylglyoxal
dietary restriction
altered proteins
ageing