Fibrates as therapy for osteoarthritis and rheumatoid arthritis? A systematic review

Ther Adv Musculoskel Dis

(2013) 5(1) 33 –44

DOI: 10.1177/ 1759720X12468659

© The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

Therapeutic Advances in Musculoskeletal Disease Review

http://tab.sagepub.com 33

IntroductionOsteoarthritis (OA) is primarily described as a disease of cartilage damage, although there is growing evidence that synovium (hyperplasia and infiltration of monocytes), subchondral bone (remodeling) and adipose tissue (secretion of chemokines, cytokines and growth factors) are also involved [Aspden, 2008; Hunter, 2009; Clockaerts et al. 2010]. Recently, OA has been linked with atheromatous vascular disease, sys-temic inflammation caused by obesity, and dys-lipidemia [Conaghan et al. 2005; Wang et al. 2008, 2009; Davies-Tuck et al. 2009]. Atheromatous vascular disease in the subchondral bone might

enhance the OA disease process by decreasing cartilage nutrition or through direct ischemic effects on the subchondral bone [Conaghan et al. 2005]. In addition, visceral adipose tissue secretes cytokines and adipokines that are able to stimu-late inflammatory and catabolic processes in the cartilage. Fatty acids have been shown to influ-ence cartilage metabolism [Henrotin et al. 2003]. Based on these studies, OA might partly be con-sidered as a systemic and metabolic disease [Katz et al. 2010].

Rheumatoid arthritis (RA) is a systemic immune disease, in which activated monocytes/macrophages

Fibrates as therapy for osteoarthritis and rheumatoid arthritis? A systematic reviewInge C.M. van Eekeren, Stefan Clockaerts, Yvonne M. Bastiaansen-Jenniskens, Eric Lubberts, Jan A.N. Verhaar, Gerjo J.V.M. van Osch and Sita M. Bierma-Zeinstra

Abstract: Fibrates are used as lipid-lowering drugs to prevent cardiovascular pathology. Fibrates are ligands of peroxisome proliferator-activated receptor α (PPARα). Besides altering lipid metabolism, PPARα ligands exert anti-inflammatory effects on various cell types. In this study, we hypothesized that PPARα agonists exert beneficial effects on osteoarthritis (OA) and rheumatoid arthritis (RA) by their local anti-inflammatory effects, but also by their systemic influences.A systematic literature search of Medline and EMBASE databases was performed up to August 2011. The main search items were osteoarthritis, rheumatoid arthritis, peroxisome proliferator-activated receptor alpha and fibrates. Inclusion criteria were in vivo or in vitro studies regarding humans or animals in which the effects of PPARα ligands were studied.Six in vivo human studies, four in vivo animal studies and seven in vitro studies were included. The in vivo human studies showed all beneficial clinical effects of PPARα ligands, but studies were small and only four were randomized. Ligands for PPARα significantly reduced pain, swelling of the joints and decreased systemic inflammatory markers. In vitro and in vivo animal studies indicate that PPARα agonists inhibit bone resorption, and reduce inflammatory and destructive responses in cartilage and synovium.PPARα agonists such as fibrates should be considered as potential therapeutic strategy for RA. There is no clinical evidence for their use in OA, although in vitro studies indicate that PPARα agonists demonstrate different joint-protective effects locally, and systemic effects on inflammation, serum lipid levels and vascular pathology. Animal studies should be performed and after confirmation of the protective effects of PPARα, large randomized controlled trials could investigate fibrates in OA and RA.

Keywords: fibrates, osteoarthritis, peroxisome proliferator activated receptor α, rheumatoid arthritis

Correspondence to: Stefan Clockaerts, MD Erasmus MC, University Medical Center Rotterdam, Room GK 1053, PO Box 2040, 3000 CA Rotterdam, The Netherlands

Monica Orthopedic Research (MoRe) Foundation and Monica Hospital, Antwerp, Belgium [email protected]

Inge C.M. van Eekeren, MD Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Yvonne M. Bastiaansen-Jenniskens, PhD Jan A.N. Verhaar, MD, PhD Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Eric Lubberts, PhD Departments of Rheumatology and Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Gerjo J.V.M. van Osch, PhD Departments of Orthopaedics and Otorhinolaryngology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

Sita M. Bierma-Zeinstra, PhD Departments of Orthopaedics and General Practice, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

468659 TAB511759720X12468659Therapeutic Advances in Musculoskeletal DiseaseICM van Eekeren, S Clockaerts2013

Therapeutic Advances in Musculoskeletal Disease 5 (1)

34 http://tab.sagepub.com

produce proinflammatory cytokines and che-mokines, and stimulate CD4+ T-cell-mediated immune reactions which induce inflammatory and destructive processes in synovium, cartilage, bone and bone marrow [Jenkins et al. 2002; Pratt et al. 2009; Schett and Firestein, 2010]. The destructive processes in cartilage might be stimu-lated by lipoproteins, such as low-density lipopro-tein (LDL). Lipoproteins are involved in cartilage degradation in patients with RA by enhancing production of matrix metalloproteinase (MMP)-3 and reactive oxygen species (ROS) [Henrotin et al. 2003; Kakinuma et al. 2004]. Similar to OA, RA is associated with cardiovascular disease, type II diabetes mellitus and dyslipidemia, indicating that metabolic diseases are a part of the RA dis-ease process [Shahin et al. 2010].

The search for disease-modifying drugs for OA has mainly focused on cartilage. However, the dis-ease process in both OA and RA is probably influ-enced by systemic and metabolic disturbances and inflammatory processes. In this regard, peroxi-some proliferator-activated receptor α (PPARα) ligands such as fibrates might be of interest. PPARα agonists reduce serum triglycerides, increase serum high-density lipoproteins and have a moderate lowering effect on serum LDLs.

PPARα ligands exert anti-inflammatory effects on various cell types, including macrophages, smooth muscle cells, endothelial cells, lymphocytes and other cell types. The activation of PPARα inhibits the nuclear translocation of nuclear factor κB (NFκB) by the upregulation of inhibitor κB (IκB) [Chung et al. 2008; Lalloyer and Staels, 2010]. Other inflammatory pathways such as mitogen-activated protein kinase phosphorylation may also be influenced by fibrates [Crisafulli and Cuzzocrea, 2009]. As shown in Figure 1, fibrates may have a pleiotropic effect on OA and RA through their effect on several pathways. By exerting anti-inflammatory effects, they can decrease cartilage and bone destruction and have less synovial and systemic inflammation. In addition, fibrates decrease the influence of the dislipidemiae and vascular pathology [Findlay, 2007; Wang et al. 2008; Alagona, 2010; Clockaerts et al. 2010; Rubenfire et al. 2010; Krysiak et al. 2011].

We performed a systematic search for studies investigating the effects of fibrates or other PPARα ligands in in vitro and in vivo studies on OA and RA. In this study, we hypothesized that PPARα agonists exert beneficial effects on OA and RA by their anti-inflammatory effects, but also by their systemic influences.

Figure 1. Pleiotropic effect of fibrates on osteoarthritis and rheumatoid arthritis.

ICM van Eekeren, S Clockaerts et al.


Methods

Data sources and searchesA systematic literature search of Medline and EMBASE databases was performed for studies in English, Dutch and German up to August 2011. The main search items were osteoarthritis, rheu-matoid arthritis, fibrates and PPARα. The follow-ing keywords were used: (arthritis OR osteoarthrit*) OR (cartilage OR synovium OR chondrocytes OR synoviocytes OR subchondral bone OR osteoclasts OR osteoblasts) AND ((‘peroxisome proliferator activated’ NEAR/2 receptor*) OR PPAR* OR (fibric NEAR/2 acid*) OR clofibr* OR fibrate* OR atromid OR beclobrate OR beclobrinic acid OR bezafibrate OR binifibrate OR ciprofibrate OR clinofibrate OR dulofibrate OR eniclobrate OR etofibrate OR etofylline clofibrate OR fenofibrate OR fenofibric acid OR halofenate OR metagli-dasen OR methylclofenapate OR nicofibrate OR simfibrate OR tazasubrate).

Additionally, reference lists of the selected papers were screened for further publications.

Study selectionArticles were screened by their title and abstract by one observer (ICMvE) and checked by a sec-ond observer (SC). After inclusion, full text arti-cles were read for further screening. Inclusion criteria were in vitro studies using human or ani-mal material, in vivo animal studies, randomized controlled trials (RCTs) or clinical trials in which the effects of PPARα ligands on OA or RA were studied. Case reports, editorials, reviews and let-ters were excluded.

Assessment of quality and data extractionMethodological quality of the clinical studies was assessed by one observer (ICMvE) and checked by a second observer (SC) using the quality scor-ing table of the Cochrane reviews with a maxi-mum score of five points and a minimum score of 0 points representing sequence generation, allo-cation concealment, blinding of participants, per-sonnel and outcome assessors, data outcome and selective outcome reporting. Quality items of in vivo animal studies were analyzed with a list of quality criteria compiled by Sniekers and col-leagues [Sniekers et al. 2008]. For in vitro studies no quality items were scored. The scores of publi-cations were noted and data were pooled inde-pendently of outcome quality.

Data of the in vivo human and animal studies were extracted by one observer (ICMvE) and in vitro data were summarized by another observer (SC). All general features, such as author, journal, year of publication, aim, type of drug used and patient information were extracted. The specific variables for in vivo human studies were level of pain [visual analog score (VAS) of the patient], scores for clinical assessment based on morning stiffness, grip strength and articular index [Ritchie et al. 1969], inflammatory markers [C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)], and blood pressure as a marker for cardiovascular disease.

The variables extracted from the animal studies consisted of joint swelling, assessment of histol-ogy (synovial hyperplasia and infiltration of immune cells) serum parameters (such as CRP, ESR), radiographic changes and bone volume.

Data synthesis and analysisClinical data were standardized by calculating effect sizes [with mean ± standard deviation (SD); difference in outcomes for both groups divided by the SD of the outcome]. If the data were not expressed as mean ± SD, we entered an increase (↑) or reduction (↓) of the symptoms, or no effect (o) depending on the statistical significance of the results (p < 0.05).

The results were summarized separately for clinical effects (clinical severity and occurrence of RA or OA) and mechanistic effects (systemic inflammatory parameters, inflammation and destruction in car-tilage, synovial immune cell infiltration, bone changes, improvement in systemic and local lipid profile and prevention of vascular pathology).

ResultsA total of 19 publications met all the inclusion cri-teria: six in vivo human studies, four in vivo animal studies and nine in vitro studies (Figure 2). The six in vivo studies were scored for methodological quality resulting in a maximum score of 5. As shown in Table 1, all in vivo human studies were of poor methodological quality, resulting in a high risk of bias. The study of Goto scored best with 3 (missing clear allocation concealment and free of other bias) and the noncontrolled trial of Forster and colleagues scored worst with 0 (Table 1) [Forster and McConkey, 1986; Goto, 2010]. The animal studies were screened based on the



Figure 2. Flow chart.

list of quality compiled by Sniekers and colleagues [Sniekers et al. 2008]. The most prevalent short-comings were the mentioning of dropouts, sample size number, age and body weight of the animals.

Clinical effects

Human studiesFour randomized controlled trials and two non-controlled trials have been reported for the use of fibrates in RA (Table 1). Goto and Bird and col-leagues reported a significant reduction in VAS

score in patients with RA and dislipidemia after treatment with fibrates [Bird et al. 1983, Goto, 2010]. Reynolds and colleagues mentioned a nonsignificant reduction in pain [Reynolds et al. 1981]. McConkey and colleagues demonstrated a significant reduction in clinical score (subjective clinical state score) for RA based on question-naires in patients feeling better or worse after treatment with fibrates than before treatment [McConkey et al. 1980]. Dixon and colleagues and Bird and colleagues reported a significant improvement in the articular index [Ritchie et al. 1969] and early morning stiffness after treatment with 300 mg clobuzarit. This reduction was not seen with 100 mg clobuzarit [Bird et al. 1983; Dixon et al. 1983]. Bird and colleagues also showed a significant improvement in grip strength when 100 mg or 300 mg clobuzarit was given, which was not seen in the study by Dixon and col-leagues [Bird et al. 1983; Dixon et al. 1983]. Reynolds and colleagues found no improvement in all assessments of function after the use of 50 mg clobuzarit [Reynolds et al. 1981]. No clini-cal studies for OA have been performed.

Animal studiesThree publications reported the clinical effect on RA through collagen-induced arthritis (CIA) or adjuvant-induced arthritis (AIA) (Table 2). Bloxham and colleagues investigated swelling of the joints in rats and found that 100 mg/kg clobu-zarit significantly reduced swelling in AIA and 60 mg/kg clobuzarit significantly reduced joint swelling in CIA [Bloxham et al. 1990]. Okamoto and colleagues showed a significant reduction in swelling of joints after treatment with fenofibrate [Okamoto et al. 2005]. This was confirmed by Castillero and colleagues, who found a significant reduction in swelling and erythema in rats treated with 300 mg/kg fenofibrate [Castillero et al. 2011].

MechanismsWe reviewed possible etiological factors of OA and RA, such as systemic inflammation, destruc-tion of cartilage, synovitis, bone changes, vascular pathology and altered lipid profiles, which are potentially altered by fibrates.

Reduction of systemic inflammatory parametersMcConkey and colleagues reported a significant reduction in CRP and ESR serum levels with



Tabl

e 1.

Ove

rvie

w o

f in

vivo

hum

an tr

ials

.

Stu

dy

Type

Scor

eP

atie

nts

(n)

Dru

gFo

llow

up

Out

com

e

Con

trol

Inte

rven

tion

Type

Dos

age

Pai

nmar

ker

BP

DFu

nctio

n

VAS

CR

PES

RSy

sD

ias

Gri

p st

reng

thM

orni

ng

stiff

ness

Art

icul

ar

inde

x

Got

o$ [2

010]

RC

TR

A3

2123

Feno

fibra

te20

0 m

g/da

y6

mon

ths

0.67

*0.

1–0

.03

0.06

–0.0

7-

-–

Bir

d et

al.$

[198

3]R

CT

RA

231

‡25

Clo

buza

rit

100

and

300

mg/

day

24 w

eeks

↓*↓*

↓*/↓

*–

–↑*

/↑*

o/↓*

o/↑*

Dix

on

et a

l.$ [1

983]

RC

TR

A2

60‡

30C

lobu

zari

t10

0 an

d 30

0 m

g/da

y24

wee

ks–

0.10

/0.8

5*–

––

0.60

/0.5

30.

82/0

.86*

0.70

/0.7

5*

Rey

nold

s et

al.$

[198

1]R

CT

RA

120

20C

lobu

zari

t50

mg/

day

6 m

onth

s–

↓↓

––

↑↓

↑

McC

onke

y et

al.$

[198

0]T

RA

1–

34C

lobu

zari

t50

–200

mg/

day§

1 ye

ar–

↓*↓*

––

–-

–

Fors

ter

and

McC

onke

y [1

986]

TR

A0

-3

Clo

buza

rit

200

mg/

day

2 ye

ars

–↓

––

––

––

Out

com

es g

iven

as

effe

ct s

ize

(cal

cula

ted

with

diff

eren

ce in

out

com

es fo

r bo

th g

roup

s di

vide

d by

the

stan

dard

dev

iatio

n of

the

outc

ome)

.*p

< 0

.05;

–, m

issi

ng v

alue

; ↑, i

ncre

ase,

eff

ect s

ize

cann

ot b

e de

term

ined

; ↓, r

educ

tion,

eff

ect s

ize

cann

ot b

e de

term

ined

.$C

ompa

res

with

bas

elin

e on

ly.

‡Fou

r gr

oups

take

n to

geth

er in

to p

atie

nts

give

n cl

ofib

rate

(100

mg

and

300

mg

a da

y) a

nd n

ot g

iven

clo

fibra

te.

§Sta

rted

with

50

mg/

day

and

incr

ease

d in

sta

ges

to 2

00 m

g/da

y.B

PD

, blo

od p

ress

ure;

co,

cro

ssov

er; C

RP

, C-r

eact

ive

prot

ein;

DA

S, d

isea

se a

ctiv

ity s

core

; Dia

s, d

iast

olic

; ESR

, ery

thro

cyte

sed

imen

tatio

n ra

te; R

A, r

heum

atoi

d ar

thri

tis; R

CT,

ran

dom

ized

con

trol

led

tria

l, SJ

C, s

wol

-le

n jo

int c

ount

; Sys

, sys

tolic

; T, t

rial

one

gro

up o

nly;

TJC

, ten

der

join

t cou

nt; V

AS,

vis

ual a

nalo

g sc

ore.



Tabl

e 2.

Ove

rvie

w o

f ani

mal

stu

dies

.

Stud

yA

nim

al (s

trai

n)Tr

eatm

ent

Adm

inis

trat

ion

Dos

age

Freq

uenc

yA

geN

umbe

rFo

llow

up

Out

com

e

Sw

olle

n jo

ints

Infil

trat

ion

imm

une

cells

Bon

eEf

fect

Oka

mot

o et

al.

[200

5]

Rat

s (L

ewis

)A

IAFe

nofib

rate

Ora

l10

mg/

kg10

0 m

g/kg

Dai

ly7

wee

ks–

18 d

ays

↓*↓*

––

Cas

tille

ro

et a

l. [2

011]

Rat

s (W

ista

r)A

IAFe

nofib

rate

Ora

l30

0 m

g/kg

Dai

lyN

= 1

6/16

/16

15 d

ays

↓*–

–

Blo

xham

et

al.

[199

0]

Rat

s (A

HH

/R)

Rat

s(A

P1/

R2)

AIA

CIA

Clo

buza

rit

Ora

l10

mg/

kg30

mg/

kg10

0 m

g/kg

60 m

g/kg

Dai

lyN

= 5

/5/5

/5/5

/5/5

N =

8/8

/8/8

/8/8

/85

days

15 d

ays

↓ ↓ ↓* ↓*

–R

adio

grap

hic

asse

ssm

ent

0.97

*

Still

et a

l. [2

008]

Rat

s(W

ista

r)-

Bez

afib

rate

Subc

utan

eous

in

ject

ion

10 m

g/kg

Dai

ly3

mon

ths

N =

15/

15/1

512

wee

ks–

–Tr

abec

ular

bo

neC

ortic

al b

one

Bon

e m

ass

0.55

*0.

96*

0.13

Out

com

es g

iven

as

effe

ct s

ize

(cal

cula

ted

with

diff

eren

ce in

out

com

es fo

r bo

th g

roup

s di

vide

d by

the

stan

dard

dev

iatio

n of

the

outc

ome)

.*p

< 0

.05;

↓, r

educ

tion,

eff

ect s

ize

cann

ot b

e de

term

ined

.A

IA, a

djuv

ant-

indu

ced

arth

ritis

; CIA

, col

lage

n-in

duce

d ar

thri

tis.



fibrate treatment in patients with RA, while in the study by Goto, fibrates had no effect [McConkey et al. 1980; Goto, 2010]. Bird and colleagues demonstrated a significant reduction in CRP and ESR after treating patients with RA with 300 mg clofibrate, which was also shown by Dixon and colleagues for CRP [Bird et al. 1983; Dixon et al. 1983]. Reynolds and colleagues reported a non-significant reduction in CRP and ESR levels [Reynolds et al. 1981].

Reduction of inflammation and destruction in cartilageNone of the human trials investigated the effects of fibrates on cartilage. In addition, cartilage was never evaluated in the studies examining the effects of fibrates using animal models for OA or RA. However, seven in vitro studies investigated the effect of fibrates or other PPARα ligands on cartilage.

In in vitro studies, PPARα agonists were able to counteract the interleukin (IL)-1β-induced increase in MMP1, -3 and -13 production in cartilage [Francois et al. 2006; Clockaerts et al. 2011]. Similar effects were also observed for production of nitric oxide, prostaglandin E2 and release of glycosaminoglycans, although this was contradicted by Bordji and colleagues and Fahmi and colleagues, who reported that the addition of PPARα ligands did not counteract the effects of IL1β on the production of nitric oxide proteo-glycan synthesis and MMP-13 by rat and human chondrocytes [Bordji et al. 2000; Fahmi et al. 2001; Clockaerts et al. 2011]. PPARα ligands inhibited the transforming growth factor (TGF)-β stimulated production of proteogly-cans and collagen in chondrocytes [Poleni et al. 2007, 2010]. PPARα ligands also inhibited the stimulatory effect of TGF-β1 on tissue inhibitor of matrix metalloproteinase 1 gene expression and protein synthesis [Poleni et al. 2010].

Reduction in synovial immune cell infiltrationNo human clinical studies have examined the effect of fibrates on synovium.

Okamoto and colleagues significantly suppressed the progression of arthritis by adding fenofibrate in an adjuvant-induced arthritis model in female Lewis rats. Histological assessment demonstrated a reduction in infiltration of immune cells in

synovial tissue and less pannus formation [Okamoto et al. 2005].

In vitro data demonstrate that production of IL-6, IL-8 and granulocyte monocyte colony-stimulating factor were inhibited by PPARα ligands in IL-1β-stimulated synovial fibroblasts from patients with RA [Okamoto et al. 2005]. However, Cheng and colleagues showed no effect of Wy14643 (PPARα ligand) on IL-1-induced prostaglandin E2 pro-duction in synovial fibroblasts [Cheng et al. 2004].

Inhibition of bone changes in arthritic jointsNo clinical studies have been published on the effect of fibrates on subchondral bone.

Using rats with collagen-induced arthritis, Bloxham and colleagues showed a significant reduction of erosive bone changes and new peri-osteal bone formation in rats treated with fibrates versus nontreated rats [Bloxham et al. 1990]. Still and colleagues demonstrated an elevated serum concentration of osteocalcin that is indicative for an increase in bone formation in rats and a signifi-cantly higher metaphyseal bone mineral density in animals treated with fibrates, while there was no significant difference between their body weights [Still et al. 2008]. Still and colleagues also showed a significantly greater trabecular bone volume and trabecular number, and total cross-sectional areas at the tibia–fibula junction were higher due to increases in cortical bone area [Still et al. 2008].

The in vitro differentiation of peripheral blood monocytes to osteoclasts is inhibited by PPARα ligands as well as the resorptive activity of mature osteoclasts [Okamoto et al. 2005; Chan et al. 2007; Still et al. 2008]. PPARα ligands are also able to increase the number of osteoblastic colo-nies and induce osteoblastic maturation [Jackson and Demer, 2000; Still et al. 2008].

Improvement of systemic and local lipid profile, prevention of vascular pathologyNo reports have been published concerning the indirect effect of lipid lowering and prevention of vascular pathology on the OA or RA disease process. No studies have investigated the effect of fibrate therapy on synovial fluid lipid concentrations.



DiscussionThis study indicates that fibrates or other PPARα agonists might lead to clinical improvement in RA. For OA, we found no clinical studies con-cerning these products. This overview of in vitro, animal studies and human clinical studies shows that PPARα ligands target many tissues, includ-ing tissues of the joint and its environment. This multiple targeting results in diminished systemic parameters of inflammation in patients with RA, but may also reduce pain, as indicated by decreased VAS scores, improved clinical scores and reduced swelling of the joints. PPARα ligands might also inhibit bone resorption. An effective dose of fibrates which could benefit patients with RA cannot be determined and no dose–response relationship was presented in any study.

OA has primarily been described as a ‘wear and tear’ disease with loss of cartilage structure. However, inflammation is considered an impor-tant aspect of the OA pathogenesis and therefore some etiopathogenic mechanisms might be simi-lar for OA and RA. Levels of cytokines in the synovial fluid of patients with OA are in some cases as high as in patients with RA, and inflam-matory and destructive responses have been described in OA and RA cartilage [Bondeson et al. 2010; Simopoulou et al. 2010; Sverdrup et al. 2010]. Furthermore, OA and RA are both characterized by infiltration of immune cells in the synovium. Subchondral bone alterations occur in both diseases and both diseases are not limited to the joint, but may have systemic conse-quences or systemic causes. Low-grade systemic inflammation has been described in both OA and RA [Hulejova et al. 2007]. In general, OA and RA have a multifactorial etiopathogenesis. Therefore, it might be possible to expect some of the observed effects of fibrates in patients with RA, and in patients with OA.

In the available studies we found no evidence for metabolic mechanisms of actions of PPARα ago-nists in OA and RA, although there is growing evi-dence that reinforces the hypothesis that PPARα agonists can prevent OA and RA by their systemic effects. First, cytokines and adipokines secreted by intra-articular adipose tissue may enhance inflam-matory and destructive processes in cartilage [Clockaerts et al. 2010]. We found no studies reporting the effects of PPARα agonists on adi-pose tissue, but studies show that PPARα agonists lower CRP serum levels and inhibit monocyte release of IL-6, IL-1β, monocyte chemoattractant

protein-1 and tumor necrosis factor α [Krysiak et al. 2011]. A recent meta-analysis concluded that short-term treatment of fenofibrate decreases CRP levels in a heterogeneous group. Although not all PPARα ligands have exactly the same phar-macokinetics, the main mechanisms of action are thought to be comparable [Miller and Spence, 1998; Ye et al. 2011]. In people with obesity, it is known that inflammation is partly caused by vis-ceral and subcutaneous adipose tissue, and even more specific, by adipose tissue-related mac-rophages [Clockaerts et al. 2010]. Second, studies have reported an association between serum lipid levels and the development of OA and RA [Nurmohamed, 2007; Wang et al. 2008, 2009; Davies-Tuck et al. 2009; Nurmohamed and Dijkmans, 2009]. The concentration of choles-terol and fatty acids in serum might be correlated with synovial fluid concentrations, and these lipids might be capable of altering cartilage metabolism [Findlay, 2007; Wang et al. 2008]. Therefore, it is likely that PPARα agonists may have a preventive effect on the development of RA and OA through their lipid-lowering modalities. Finally, the link between vascular pathology and OA is becoming more and more established, and vascular pathol-ogy is also an important consequence of RA. A recent study by Hoeven and colleagues showed an association between the intima media thickness (or carotic plaque) and the prevalence of OA in the knee, distal interphalangeal and metacar-pophalangeal OA in women [Hoeven et al. 2012].

Since PPARα agonists such as fibrates are known to prevent atherosclerosis by altering lipid com-position and by their anti-inflammatory effects, they have the potential to prevent OA by counter-acting this underlying risk factor [Alagona, 2010; Ji et al. 2010; Rubenfire et al. 2010].

Other lipid-lowering drugs, such as statins, are also shown to exert pleiotropic effects [Ridker et al. 2009]. Several studies already described that statins have potential beneficial effects on RA and OA [Paraskevas, 2008; Lazzerini et al. 2010; Baker et al. 2011] and this was also observed by Clockaerts and colleagues in the Rotterdam Study, a large open population study, where there was a 50% decrease in incidence and progression of knee OA in statin users [Clockaerts et al. 2012]. Statins and fibrates might exhibit similar poten-tial beneficial effects on the joint and on systemic metabolic dysregulations. However, fibrates are drugs with a higher bioavailability compared with statins. For example, fenofibrate is rapidly



converted into its active metabolite, fenofibric acid, which is protein bound (primarily to albu-min) for 99%. Plasma levels of fenofibric acid peak after 6–8 h after oral administration and it has a half life of 20 h and may therefore reach the joint in higher concentrations and over a longer period [Tziomalos and Athyros, 2006]. Statins, however, are largely taken up by the liver and undergo first-pass metabolism [Lazzerini et al. 2010]. The overall tolerability of fibrates com-pared with statins or the combination shows no difference, and there is no difference in adverse advents [Farnier et al. 2012].

Despite the availability of RCTs investigating the effect of fibrates on RA, we could not perform a meta-analysis due to the differences in outcome parameters used. We found no clinical studies investigating the effect of PPARα ligands on OA. Other limitations of our study include the use of data of different kinds of species. The effects of PPARα ligands are species dependent, which can influence the results. This is however a well-known problem in in vitro research.

Well-designed RCTs are needed to reinforce the potential inhibitory effect of fibrates on OA and RA development and progression, but only after examination of potential underlying mechanisms, such as the role of systemic inflammation caused by obesity, vascular pathology and dyslipidemia. Spontaneous OA and RA animal models with metabolic alterations such as vascular pathology and disturbed lipid metabolism should be per-formed to investigate the effect of fibrates on OA and RA development and progression. These studies will help to determine the inclusion crite-ria for a well-designed human randomized clini-cal trial to investigate the effect of fibrates on OA and RA development.

ConclusionOA and RA have a complex and multifactorial etiology. PPARα agonists such as fibrates may prevent disease progression by their ability to modify cartilage, synovium and bone responses in both diseases. For RA, fibrates seem to improve pain and function. For OA, however, there is no clinical evidence.

The effect of PPARα agonists on OA or RA devel-opment through the lowering of serum or intra-articular lipid levels, the prevention of vascular pathology or the inhibition of cytokine or

adipokine production remains to be elucidated. Animal models for OA and RA, with metabolic alterations, should be performed. After confirma-tion of a protective effect on joints, well-designed RCTs, using well-defined inclusion criteria, can be started to investigate the symptom improve-ment and disease-modifying properties of fibrates in OA and RA.

Key messages(1) PPARα agonists should be considered as a

potential therapeutic strategy for OA and RA.

(2) PPARα agonists seem to demonstrate dif-ferent joint-protective effects locally and systematically.

(3) Animal models for OA and RA with meta-bolic alterations should be performed.

FundingThis study/work was performed (partly) within the framework of the Dutch Top Institute Pharma project # T1-213. Stefan Clockaerts received a scholarship of the University of Antwerp and the Anna Foundation.

Conflict of interest statementNone of the authors have any financial or per-sonal relationships with other people or organiza-tions that could inappropriately influence this work to disclose.

ReferencesAlagona, P., Jr (2010) Fenofibric acid: a new fibrate approved for use in combination with statin for the treatment of mixed dyslipidemia. Vasc Health Risk Manag 6: 351–362.

Aspden, R. (2008) Osteoarthritis: a problem of growth not decay? Rheumatology (Oxford) 47: 1452–1460.

Baker, J., Walsh, P. and Mulhall, K. (2011) Statins: a potential role in the management of osteoarthritis? Joint Bone Spine 78: 31–34.

Bird, H., Dixon, J., Finney, P., Leatham, P., Lowe, J., Pickup, M. et al. (1983) A Clinical and biochemical evaluation of clozic, a novel disease modifying drug in rheumatoid arthritis. Clin Exp Rheumatol 1: 93–99.

Bloxham, D., Bradshaw, D., Cashin, C., Dodge, B., Lewis, E., Westmacott, D. et al. (1990) Biologic properties of romazarit (Ro 31-3948), a potential disease-modifying antirheumatic drug. J Pharmacol Exp Ther 252: 1331–1340.



Bondeson, J., Blom, A., Wainwright, S., Hughes, C., Caterson, B. and Van Den Berg, W. (2010) The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum 62: 647–657.

Bordji, K., Grillasca, J., Gouze, J., Magdalou, J., Schohn, H., Keller, J. et al. (2000) Evidence for the presence of peroxisome proliferator-activated receptor (PPAR) alpha and gamma and retinoid Z receptor in cartilage. PPARgamma activation modulates the effects of interleukin-1beta on rat chondrocytes. J Biol Chem 275: 12243–12250.

Castillero, E., Nieto-Bona, M., Fernandez-Galaz, C., Martin, A., Lopez-Menduina, M., Granado, M. et al. (2011) Fenofibrate, a PPAR{alpha} agonist, decreases atrogenes and myostatin expression and improves arthritis-induced skeletal muscle atrophy. Am J Physiol Endocrinol Metab 300: E790–E799.

Chan, B., Gartland, A., Wilson, P., Buckley, K., Dillon, J., Fraser, W. et al. (2007) PPAR agonists modulate human osteoclast formation and activity in vitro. Bone 40: 149–159.

Cheng, S., Afif, H., Martel-Pelletier, J., Pelletier, J., Li, X., Farrajota, K. et al. (2004) Activation of peroxisome proliferator-activated receptor gamma inhibits interleukin-1beta-induced membrane-associated prostaglandin E2 synthase-1 expression in human synovial fibroblasts by interfering with EGR-1. J Biol Chem 279: 22057–22065.

Chung, J., Seo, A., Chung, S., Kim, M., Leeuwenburgh, C., Yu, B. et al. (2008) Molecular mechanism of PPAR in the regulation of age-related inflammation. Ageing Res Rev 7: 126–136.

Clockaerts, S., Bastiaansen-Jenniskens, Y., Feijt, C., Verhaar, J., Somville, J., De Clerck, L. et al. (2011) Peroxisome proliferator activated receptor alpha activation decreases inflammatory and destructive responses in osteoarthritic cartilage. Osteoarthritis Cartilage 19: 895–902.

Clockaerts, S., Bastiaansen-Jenniskens, Y., Runhaar, J., Van Osch, G., Van Offel, J., Verhaar, J. et al. (2010) The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review. Osteoarthritis Cartilage 18: 876–882.

Clockaerts, S., Osch, G., Bastiaansen-Jenniskens, Y., Verhaar, J., Glabbeek, F., Meurs, J. et al. (2012) Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam Study. Ann Rheum Dis 71: 642–647.

Conaghan, P., Vanharanta, H. and Dieppe, P. (2005) Is progressive osteoarthritis an atheromatous vascular disease? Ann Rheum Dis 64: 1539–1541.

Crisafulli, C. and Cuzzocrea, S. (2009) The role of endogenous and exogenous ligands for the peroxisome proliferator-activated receptor alpha (PPAR-alpha) in the regulation of inflammation in macrophages. Shock 32: 62–73.

Davies-Tuck, M., Hanna, F., Davis, S., Bell, R., Davison, S., Wluka, A. et al. (2009) Total cholesterol and triglycerides are associated with the development of new bone marrow lesions in asymptomatic middle-aged women – a prospective cohort study. Arthritis Res Ther 11: R181.

Dixon, J., Sitton, N., Surrall, K., Martin, M., Pickup, M. and Bird, H. (1983) The effect of drugs on serum histidine levels in rheumatoid arthritis. Rheumatol Int 3: 145–149.

Fahmi, H., Di Battista, J., Pelletier, J., Mineau, F., Ranger, P. and Martel-Pelletier, J. (2001) Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-1beta-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes. Arthritis Rheum 44: 595–607.

Farnier, M., Marcereuil, D., De Niet, S., Ducobu, J., Steinmetz, A., Retterstol, K. et al. (2012) Safety of a fixed-dose combination of fenofibrate/pravastatin 160 mg/40 mg in patients with mixed hyperlipidaemia: a pooled analysis from a database of clinical trials. Clin Drug Investig 32: 281–291.

Findlay, D. (2007) Vascular pathology and osteoarthritis. Rheumatology (Oxford) 46: 1763–1768.

Forster, P. and McConkey, B. (1986) The effect of antirheumatic drugs on circulating immune complexes in rheumatoid arthritis. Q J Med 58: 29–42.

Francois, M., Richette, P., Tsagris, L., Fitting, C., Lemay, C., Benallaoua, M. et al. (2006) Activation of the peroxisome proliferator-activated receptor alpha pathway potentiates interleukin-1 receptor antagonist production in cytokine-treated chondrocytes. Arthritis Rheum 54: 1233–1245.

Goto, M. (2010) A comparative study of anti-inflammatory and antidyslipidemic effects of fenofibrate and statins on rheumatoid arthritis. Mod Rheumatol 20: 238–243.

Henrotin, Y., Bruckner, P. and Pujol, J. (2003) The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthritis Cartilage 11: 747–755.

Hoeven, T., Kavousi, M., Clockaerts, S., Kerkhof, H., Van Meurs, J., Franco, O. et al. (2012) Association of atherosclerosis with presence and progression of osteoarthritis: the Rotterdam Study. Ann Rheum Dis 6 May (Epub ahead of print).

Hulejova, H., Baresova, V., Klezl, Z., Polanska, M., Adam, M. and Senolt, L. (2007) Increased level



of cytokines and matrix metalloproteinases in osteoarthritic subchondral bone. Cytokine 38: 151–156.

Hunter, D. (2009) Osteoarthritis. Med Clin North Am 93: xv–xviii.

Jackson, S. and Demer, L. (2000) Peroxisome proliferator-activated receptor activators modulate the osteoblastic maturation of MC3T3-E1 preosteoblasts. FEBS Lett 471: 119–124.

Jenkins, J., Hardy, K. and McMurray, R. (2002) The pathogenesis of rheumatoid arthritis: a guide to therapy. Am J Med Sci 323: 171–180.

Ji, Y., Wang, Z., Li, Z. and Liu, J. (2010) Modulation of LPS-mediated inflammation by fenofibrate via the TRIF-dependent TLR4 signaling pathway in vascular smooth muscle cells. Cell Physiol Biochem 25: 631–640.

Kakinuma, T., Yasuda, T., Nakagawa, T., Hiramitsu, T., Akiyoshi, M., Akagi, M. et al. (2004) Lectin-like oxidized low-density lipoprotein receptor 1 mediates matrix metalloproteinase 3 synthesis enhanced by oxidized low-density lipoprotein in rheumatoid arthritis cartilage. Arthritis Rheum 50: 3495–3503.

Katz, J., Agrawal, S. and Velasquez, M. (2010) Getting to the heart of the matter: osteoarthritis takes its place as part of the metabolic syndrome. Curr Opin Rheumatol 22: 512–519.

Krysiak, R., Gdula-Dymek, A. and Okopien, B. (2011) Monocyte-Suppressing Effect of Bezafibrate but Not Omega-3 Fatty Acids in Patients with Isolated Hypertriglyceridaemia. Basic Clin Pharmacol Toxicol 109: 23–29.

Lalloyer, F. and Staels, B. (2010) Fibrates, glitazones, and peroxisome proliferator-activated receptors. Arterioscler Thromb Vasc Biol 30: 894–899.

Lazzerini, P., Capecchi, P., Selvi, E., Lorenzini, S., Bisogno, S., Baldari, C. et al. (2010) Statins and the joint: multiple targets for a global protection? Semin Arthritis Rheum 40: 430–446.

McConkey, B., Amos, R., Billingham, M., Constable, T., Crockson, R., Crockson, A. et al. (1980) Rheumatoid arthritis: effects of a new agent (ICI 55 897) on serum acute phase proteins and the erythrocyte sedimentation rate. Ann Rheum Dis 39: 18–21.

Miller, D. and Spence, J. (1998) Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet 34: 155–162.

Nurmohamed, M. (2007) Atherogenic lipid profiles and its management in patients with rheumatoid arthritis. Vasc Health Risk Manag 3: 845–852.

Nurmohamed, M. and Dijkmans, B. (2009) Dyslipidaemia, statins and rheumatoid arthritis. Ann Rheum Dis 68: 453–455.

Okamoto, H., Iwamoto, T., Kotake, S., Momohara, S., Yamanaka, H. and Kamatani, N. (2005) Inhibition of NF-kappab signaling by fenofibrate, a peroxisome proliferator-activated receptor-alpha ligand, presents a therapeutic strategy for rheumatoid arthritis. Clin Exp Rheumatol 23: 323–330.

Paraskevas, K. (2008) Statin treatment for rheumatoid arthritis: a promising novel indication. Clin Rheumatol 27: 281–287.

Poleni, P., Bianchi, A., Etienne, S., Koufany, M., Sebillaud, S., Netter, P. et al. (2007) Agonists of peroxisome proliferators-activated receptors (PPAR) alpha, beta/delta or gamma reduce transforming growth factor (TGF)-beta-induced proteoglycans’ production in chondrocytes. Osteoarthritis Cartilage 15: 493–505.

Poleni, P., Etienne, S., Velot, E., Netter, P. and Bianchi, A. (2010) Activation of PPARs α, β/δ, and γ impairs TGF-β1-induced collagens’ production and modulates the TIMP-1/MMPS balance in three-dimensional cultured chondrocytes. PPAR Res 2010: 635912.

Pratt, A., Isaacs, J. and Mattey, D. (2009) Current concepts in the pathogenesis of early rheumatoid arthritis. Best Pract Res Clin Rheumatol 23: 37–48.

Reynolds, P., McLeod, M. and Dick, W. (1981) Clozic (ICI 55,897) in rheumatoid arthritis – a controlled comparison with gold. Br J Clin Pract 35: 306–308.

Ridker, P., Danielson, E., Fonseca, F., Genest, J., Gotto, A., Jr,, Kastelein, J. et al. (2009) Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the Jupiter trial. Lancet 373: 1175–1182.

Ritchie, D., Boyle, J., McInnes, J., Jasani, M., Dalakos, T., Grieveson, P. et al. (1969) Evaluation of a simple articular index for joint tenderness in rheumatoid arthritis. Ann Rheum Dis 28: 196.

Rubenfire, M., Brook, R. and Rosenson, R. (2010) Treating mixed hyperlipidemia and the atherogenic lipid phenotype for prevention of cardiovascular events. Am J Med 123: 892–898.

Schett, G. and Firestein, G. (2010) Mr Outside and Mr Inside: classic and alternative views on the pathogenesis of rheumatoid arthritis. Ann Rheum Dis 69: 787–789.

Shahin, D., Eltoraby, E., Mesbah, A. and Houssen, M. (2010) Insulin resistance in early untreated rheumatoid arthritis patients. Clin Biochem 43: 661–665.



Simopoulou, T., Malizos, K., Poultsides, L. and Tsezou, A. (2010) Protective effect of atorvastatin in cultured osteoarthritic chondrocytes. J Orthop Res 28: 110–115.

Sniekers, Y., Weinans, H., Bierma-Zeinstra, S., Van Leeuwen, J. and Van Osch, G. (2008) Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment - a systematic approach. Osteoarthritis Cartilage 16: 533–541.

Still, K., Grabowski, P., Mackie, I., Perry, M. and Bishop, N. (2008) The peroxisome proliferator activator receptor alpha/delta agonists linoleic acid and bezafibrate upregulate osteoblast differentiation and induce periosteal bone formation in vivo. Calcif Tissue Int 83: 285–292.

Sverdrup, F., Yates, M., Vickery, L., Klover, J., Song, L., Anglin, C. et al. (2010) Protein geranylgeranylation controls collagenase expression in osteoarthritic cartilage. Osteoarthritis Cartilage 18: 948–955.

Tziomalos, K. and Athyros, V. (2006) Fenofibrate: a novel formulation (triglide) in the treatment of lipid disorders: a review. Int J Nanomedicine 1: 129–147.

Wang, Y., Davies-Tuck, M., Wluka, A., Forbes, A., English, D., Giles, G. et al. (2009) Dietary fatty acid intake affects the risk of developing bone marrow lesions in healthy middle-aged adults without clinical knee osteoarthritis: a prospective cohort study. Arthritis Res Ther 11: R63.

Wang, Y., Wluka, A., Hodge, A., English, D., Giles, G., O’Sullivan, R. et al. (2008) Effect of fatty acids on bone marrow lesions and knee cartilage in healthy, middle-aged subjects without clinical knee osteoarthritis. Osteoarthritis Cartilage 16: 579–583.

Ye, J., Kiage, J., Arnett, D., Bartolucci, A. and Kabagambe, E. (2011) Short-term effect of fenofibrate on c-reactive protein: a meta-analysis of randomized controlled trials. Diabetol Metab Syndr 3: 24.

Visit SAGE journals online http://tab.sagepub.com

SAGE journals

Fibrates as therapy for osteoarthritis and rheumatoid arthritis? A systematic review

Documents

Transcript of Fibrates as therapy for osteoarthritis and rheumatoid arthritis? A systematic review