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Statins as antiinflammatory and immunomodulatory agentsA future in rheumatologic therapy.

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Vol. 54, No. 2, February 2006, pp 393–407
DOI 10.1002/art.21521
© 2006, American College of Rheumatology
Statins as Antiinflammatory and Immunomodulatory Agents
A Future in Rheumatologic Therapy?
Aryeh M. Abeles and Michael H. Pillinger
late. We summarize the known potential antiinflammatory and immunomodulatory effects of statins at the
cellular level. Finally, we review the data on the possible
efficacy of statins in autoimmune/inflammatory diseases
in both animal models and human trials.
Hydroxymethylglutaryl-coenzyme A inhibitors
(HMG-CoA inhibitors, or statins) were initially identified as fungal extracts in 1976 (1). They were subsequently developed as cholesterol-lowering drugs, and
have been shown in numerous clinical trials to reduce
both cardiovascular morbidity and mortality (2–6).
However, studies also revealed that statins yield a larger
mortality benefit than can be readily explained by their
cholesterol-lowering effects alone, since their benefits
occur too quickly to be explained by effects on atherosclerotic plaque (7), and are greater than lipid-lowering
alone would predict (8). Additionally, statins appear to
have beneficial effects on human diseases, such as
multiple sclerosis (MS) (9) and osteoporosis (10), that
have no direct association with cholesterol levels.
These findings, together with growing awareness
that atherosclerosis is itself an inflammatory disease, led
to the suggestion that, in addition to lowering cholesterol, statins modify atherosclerosis via antiinflammatory mechanisms. A broader hypothesis followed naturally: that statins might have general antiinflammatory
and/or immunomodulatory effects. Research over the
last 10 years has elucidated a number of mechanisms by
which statins may exert antiinflammatory effects (7,11).
In this article, we review the mechanisms of the action of
statins, and the specific signaling pathways they modu-
Biochemical effects of statins
Statin-sensitive biosynthetic pathways. Statins
inhibit the rate-limiting step of cholesterol synthesis by
preventing HMG-CoA from being reduced to mevalonate via HMG-CoA reductase (Figure 1). Mevalonate
is the necessary substrate not only for cholesterol biosynthesis, but also for the synthesis of several other
biologically important lipid intermediates by means of
alternative synthetic pathways; statins also have the
potential to inhibit synthesis of these products. Two such
intermediates are the 15-carbon isoprenoid farnesyl
pyrophosphate (FPP) and the 20-carbon isoprenoid
geranylgeranyl pyrophosphate (GGPP); these serve as
lipid attachments (via the activity of farnesyltransferase
and geranylgeranyl transferase [GGT], respectively) required for proper localization and activation of a variety
of proteins, including monomeric GTPases (12,13).
GTPases, so-named for their intrinsic autolytic
GTPase activity, are intracellular switches that play
essential roles in numerous cellular processes, including
gene expression, actin cytoskeleton regulation, membrane trafficking, proliferation, apoptosis, and migration
(14,15). The GTPase Rho, and Rho-like proteins, regulate adhesion complex formation, as well as a number of
inflammatory pathways, such as the JNK and p38 MAP
kinase cascades (16,17). Experimental evidence suggests
that statins may inhibit inflammation predominantly by
inhibiting Rho family protein activity (18). Other GTPases that may be inhibited by statins include Ras family
proteins, which primarily transduce signals from growth
factor receptors and regulate the MAP kinase, ERK.
Dr. Pillinger’s work was supported by a research grant from
the Arthritis Foundation, New York Chapter, and a Clinician Scholar
Educator Award from the American College of Rheumatology.
Aryeh M. Abeles, MD, Michael H. Pillinger, MD: New York
University School of Medicine, the Hospital for Joint Diseases, and the
Manhattan VA Hospital of the New York Harbor Healthcare System,
New York, New York.
Address correspondence and reprint requests to Michael H.
Pillinger, MD, Department of Medicine, Manhattan VA Hospital, 423
East 23rd Street, New York, NY 10010. E-mail: michael.pillinger@
Submitted for publication May 11, 2005; accepted in revised
form September 21, 2005.
Figure 1. Statin-sensitive biosynthetic pathways. HMG-CoA ⫽
hydroxymethylglutaryl-coenzyme A; PP ⫽ pyrophosphate; FTI ⫽
farnesyltransferase inhibitor; GGTI ⫽ geranylgeranyl transferase inhibitor.
Whereas Rho proteins (along with Rab proteins, which
regulate vesicular trafficking) are typically geranylgeranylated, Ras proteins (along with heterotrimeric G
proteins and nuclear lamins) are farnesylated (14).
Experimental manipulation of statin-sensitive
pathways. It is possible to elucidate how statins exert
their antiinflammatory effects by manipulating specific
steps in the cholesterol and isoprenoid synthesis pathways. In vivo, it is important to differentiate effects
caused by decreased isoprenoid levels from those caused
by lowering cholesterol. To this end, a few options are
available. Most directly, cholesterol can be measured in
statin-treated and untreated conditions. If no difference
in cholesterol exists between the conditions, then an
antiinflammatory effect cannot be attributed to cholesterol lowering. Because statins do not lower cholesterol
levels in mice, all of the antiinflammatory effects of
statins in mouse models of disease are, of necessity,
cholesterol independent (19). Differentiating a
cholesterol-lowering effect from an isoprenoid-lowering
effect can also be accomplished (in vivo or in vitro) by
using a specific cholesterol synthesis inhibitor such as
squalestatin, which acts downstream of isoprenoid intermediate synthesis, and therefore affects cholesterol synthesis exclusively (20).
While statin effects in vitro are, of necessity,
independent of effects on serum cholesterol levels,
statins may still alter cell responses by lowering the
intrinsic cholesterol content of cell membranes. In particular, cholesterol in cell membranes tends to be concentrated in lipid rafts, focal patches of membrane that
are enriched in protein signaling assemblies. A number
of these assemblies have been shown to regulate inflammatory responses. For example, T cell activation of the
I␬B kinase complex, which leads to activation of NF-␬B,
depends on lipid rafts (21). Lowering cholesterol may
disrupt these rafts and alter the inflammation signaling
properties of the cells (22).
Similarly, the membranes of phagocytic vacuoles
are enriched with cholesterol in leukocytes such as
neutrophils (23). Whether statins alter vacuolar membranes, with effects on phagocytosis, inflammation,
and/or antigen processing, remains to be determined.
Changes in cholesterol levels may also directly alter
intracellular signaling molecules via membraneindependent effects. For instance, the activity of
oxysterol-binding protein, a scaffolding protein that regulates ERK-1/2 activity, is directly regulated by interaction with cholesterol (24). Failure of the selective cholesterol synthesis inhibitor squalestatin to reproduce the
effects of statins on any particular inflammatory phenotype suggests that the statin effect under study is not
mediated by alterations in the cholesterol content of the
Specific farnesyltransferase inhibitors (FTIs) prevent the attachment of FPP to Ras and other farnesylated proteins, resulting in nascent unfarnesylated Ras
isoforms (H-Ras, N-Ras, K-Ras) (25). Similarly, inhibition of GGT using specific GGT inhibitors (GGTIs)
prevents Rho protein (RhoA, RhoB, Cdc42, Rac-1, and
others) geranylgeranylation (12). Unprenylated Ras and
Rho proteins mislocalize to the cytosol and are generally
inactive. Thus, FTIs and GGTIs replicate specific, but
not global, effects of statins. By comparing the in vitro
and/or in vivo effect of FTIs or GGTIs with the effect of
statins, one can assess which subset of prenylated proteins (farnesylated or geranylgeranylated) may be responsible for a given statin effect.
Alternatively, one can test whether a specific
statin effect can be overcome by repletion with exogenous FPP or GGPP. If a statin-mediated effect is
duplicated by inhibiting transfer of a particular isoprenoid intermediate, and rescued by exogenous supplementation of that intermediate, it is likely that the statin
effect is caused by decreased levels of that isoprenoid
(and, in turn, lower levels of activated prenylated proteins). A cruder method of substrate rescue often used is
rescue with mevalonate, the cholesterol intermediate
just downstream of HMG-CoA (further elaborated below). Since mevalonate synthesis is localized upstream of
the branch point between cholesterol and isoprenoid
synthesis, when mevalonate rescue successfully reverses
a statin effect, nothing is learned about which mevalonate product may be responsible for that effect.
A more specific determination of which prenylated protein may be the target of a given statin effect is
possible by direct measurement of the activated protein
(infrequently reported in the statin literature) or by
pharmacologic or genetic inhibition or stimulation of a
specific GTPase (7).
Statins as antiinflammatory drugs: effects on cells
and tissues
Numerous studies have confirmed that statins
have a wide range of effects on cells and tissues involved
in inflammation and/or autoimmunity.
Inhibition of leukocyte–endothelial adhesion.
Statins have been reported to inhibit interactions between leukocytes and endothelial cells (ECs) that necessarily precede leukocyte egress from the vasculature
(26–28). Different groups of adhesion molecules sequentially mediate leukocyte rolling, adhesion, and diapedesis, or transmigration through the vascular wall
(29). The first step, leukocyte rolling, occurs by the
interaction of selectins on one cell with sialyl-Lewis
residues on a cognate cell (29). The next step, leukocytetight adhesion, occurs through the interaction of leukocyte integrins (e.g., lymphocyte function–associated
antigen 1 [LFA-1], Mac-1 [CD11b/CD18]) with counterligands on ECs (e.g., intercellular adhesion molecule 1
[ICAM-1]) (29). Finally, transmigration of leukocytes
through the endothelium and the vascular wall is mediated by chemokines, such as monocyte chemotactic
protein 1 (MCP-1) (30).
Initial studies showed that statins down-regulate
expression of adhesion molecules on ECs and leukocytes; these studies have been described in previous
reviews (8,31). However, subsequent in vitro studies
demonstrated that statins actually increase the expression of these molecules in inflammatory settings, suggesting that statin effects may be context dependent
(32–35). Perhaps of greater significance is that a number
of ex vivo human studies showed that statins downregulate the soluble concentration of these molecules.
Shed (soluble) adhesion molecules are well-known
markers for atherosclerotic disease (36–38), and several
studies indicated that statins down-regulate circulating
soluble ICAM-1, vascular cell adhesion molecule 1
(39–41), and E- and P-selectin (42,43). However, not all
studies that examined the effects of statins on the soluble
levels of these molecules have replicated these findings
While the effects of statins on adhesion molecules in vitro may be inconsistent, statins consistently
inhibit endothelial–leukocyte adhesion in complex models. For example, statins decrease leukocyte–endothelial
adhesion in vitro in experiments performed under conditions of physiologic flow. Intravital microscopy, which
allows for real-time in vivo examination of study animals,
confirms that statins inhibit leukocyte–EC interaction in
post-mesenteric venules of rats (27,46,47). Statin inhibition of leukocyte–endothelial adhesion has also been
directly observed using in vivo confocal microscopy (48).
A number of direct and indirect mechanisms may
account for the observed inhibitory effect of statins on
intercellular adhesion. Importantly, statins inhibit the
formation of focal adhesion complexes (FACs) in human ECs. Because FACs represent the tether points and
signaling foci for transmembrane adhesion molecules,
subsequent disruption of adhesion should be unsurprising (18). This effect is likely due to inhibition of several
members of the Rho family that work together to form
these complexes (49). The in vitro inhibition of FACs by
statins is reversed with the addition of mevalonate (18).
A novel way in which statins may regulate
leukocyte–endothelial adhesion is by directly binding to
a novel regulatory site, the L-site (named for lovastatin),
on the integrin LFA-1 found on leukocytes (50). LFA-1,
a ␤2 integrin, is critical in the development of inflammatory arthritis in the K/BxN serum transfer mouse
model of arthritis. Ablating LFA-1, either by using a
CD11a-null mouse or by coadministration of K/BxN
serum with monoclonal antibodies to LFA-1, prevents
induction of (and ameliorates established) disease (51).
When statins (excepting pravastatin, which does not
interact with the L-site) bind to LFA-1, they effect
allosteric changes in the integrin that prevent ICAM-1
binding. This effect is both cholesterol- and isoprenoidindependent, and may interfere not only with
endothelial–leukocyte interaction, but also with T cell
activation, since LFA-1 is a weak T cell costimulator.
Since this novel docking site on LFA-1 was discovered,
statin derivatives with much higher affinity for the L-site
have been developed, such as LFA-878, which was
recently shown to be effective in a rat model of inflammation (52). LFA-878 possesses no activity as an HMGCoA reductase inhibitor.
Statins inhibit the in vitro and in vivo production
of MCP-1, a major chemoattractant for monocytes and
T lymphocytes, and, as noted earlier, a signal for leukocyte diapedesis. Simvastatin inhibits the production of
MCP-1 by human ECs stimulated by C-reactive protein
(CRP), interleukin-1␤ (IL-1␤), or lipopolysaccharide
(LPS) in vitro (53), and both lovastatin and simvastatin
decrease MCP-1 production in human peripheral monocytes (54,55). These effects are reversed with the addition of mevalonate (54). Withdrawal of cerivastatin from
pretreated vascular smooth muscle cells induces MCP-1
production, an effect that is replicated when these cells
are coincubated with cerivastatin plus GGPP, which
suggests that it occurs via geranylgeranylated proteins
(56). Rosuvastatin diminishes MCP-1 production in the
vessel walls of hypercholesterolemic mice (54), and
atorvastatin and pravastatin decrease MCP-1 expression
in vessel walls of hypercholesterolemic swine (57). Fluvastatin, atorvastatin, cerivastatin, and simvastatin significantly decrease circulating MCP-1 levels in patients
with hypercholesterolemia (58–61). Statins also decrease levels of the chemokine IL-8 (59,62), another
important regulator of leukocyte adhesion and chemoattraction. Statin effects on these and other soluble mediators may therefore indirectly alter the conditions for
leukocytes to migrate to sites of inflammation.
Effects on endothelial cell nitric oxide synthase
(eNOS), inducible NOS (iNOS), and oxidative products.
Endothelial cell NOS is expressed by vascular endothelium and generates NO, which exerts protective effects
on ECs and prevents their activation (63,64). Statins
up-regulate eNOS expression in vitro (62,65,66) and in
vivo (67) by prolonging eNOS messenger RNA (mRNA)
survival (68). In vitro, cotreatment of statin-treated ECs
with either mevalonate or GGPP reverses this effect,
suggesting the involvement of one or more Rho proteins
(69,70). Direct measurement of Rho activity in
mevastatin-treated ECs shows that Rho inhibition correlates with statin-induced eNOS up-regulation, and
that Rho inhibition was rescued by GGPP but not by
FPP (69). In support of a role for Rho in downregulating eNOS expression, direct inhibition of Rho
with Clostridium botulinum C3 transferase or by transfection of a dominant-negative (DN) RhoA mutant
increases eNOS expression. Conversely, activation of
Rho by Escherichia coli cytotoxic necrotizing factor 1
decreases eNOS expression. Thus, statins appear to
increase eNOS levels and eNOS activity by downregulating a pathway that involves Rho proteins (69).
In contrast to eNOS-derived NO, iNOS-derived
NO is frequently used by cells as a proinflammatory
signal; statins inhibit the induction of iNOS in several
cell types. Lovastatin and mevastatin were shown to
inhibit LPS-induced iNOS expression and activity in rat
macrophages and microglia (71). That initial study led
investigators to study the central nervous system–
protective effects of statins, because iNOS is known to
mediate neuronal toxicity. Pitavastatin prevents
ischemia-induced brain injury in a rodent model, largely
by preventing iNOS expression while maintaining eNOS
expression (72). Similar results were seen with atorvastatin in a rat spinal injury model (73). Simvastatin
decreases iNOS induction in embryonic cardiac myoblasts stimulated with IL-1␤ or tumor necrosis factor ␣
(TNF␣), an effect that is reversed by GGPP and duplicated with a Rho kinase inhibitor (74). Lovastatin,
atorvastatin, and fluvastatin decrease both LPS- and
interferon-␥ (IFN␥)–stimulated iNOS expression in murine macrophages by reducing iNOS transcription, an
effect that is reversed by mevalonate, GGPP, or FPP
(75). Atorvastatin, cerivastatin, and pravastatin all decrease TNF␣/IFN␥-stimulated iNOS expression in
mouse aortic endothelium (76).
In addition to effects on NO production, statins
inhibit formation of oxygen radicals by ECs (77,78). Two
mechanisms appear responsible for this observed effect.
First, statins prevent activation of the NADPH oxidase
complex, which generates superoxide, apparently due to
their inhibitory effect on the Rho family GTPase Rac-1
(77,79). Second, statins inhibit angiotensin-induced
NADPH oxidase activation by down-regulating the concentration of the angiotensin II type 1 receptor (79).
Inflammatory cytokines and other secreted mediators: regulation of transcription. Statins reduce the
production of a number of inflammatory cytokines.
Simvastatin and fluvastatin decrease IL-6 and IL-1␤
production by stimulated human umbilical vein endothelial cells (HUVECs); this is reversed with the addition of
mevalonate, FPP, or GGPP (80). Atorvastatin and simvastatin markedly decrease IL-1␤ production by peripheral blood mononuclear cells (PBMCs) of patients
with coronary artery disease (81). In separate, randomized prospective studies of patients with hypercholesterolemia and hypertension, treatment with simvastatin
resulted in decreased circulating IL-1␤, and IL-1␤ production by isolated PBMCs, respectively (82,83). Both
atorvastatin and simvastatin significantly decrease levels
of circulating IL-6 and TNF␣, in addition to IL-1␤, in
patients with hypercholesterolemia (39,41,59,84). Carotid plaques resected from patients taking statins contain significantly lower concentrations of IL-6 (P ⫽
0.0005), suggesting that statins do, indeed, alter local
inflammation in atherosclerotic lesions (85).
Matrix metalloproteinases (MMPs) are neutral
proteases that act extracellularly to digest collagen and
other connective tissue molecules. MMP dysregulation
plays a critical role in tissue destruction in rheumatoid
arthritis (RA) (86,87) and in gastric ulceration (88) and
atherogenic vascular damage (89,90). Statins have been
reported to decrease production of MMPs 1, 3, and 9 in
human macrophages and vascular smooth muscle cells
(91), MMPs 1 and 9 in carotid plaques (85), and MMP-3
in IL-1␤–stimulated chondrocytes (92). In our own
studies on rheumatoid synovial fibroblasts, MMP-1 secretion was strongly inhibited by FTI but not GGTI or
squalestatin, suggesting that statin inhibition of MMP
secretion in these cells may be mediated via Ras, rather
than Rho, proteins (Abeles AM, et al: unpublished
Statins likely inhibit the expression of multiple
inflammatory cytokines through one or several common
mechanisms. The ability of statins to inhibit NF-␬B
activation in monocytes or ECs exposed to inflammatory
stimuli suggests that this transcriptional regulator of
⬎40 inflammatory genes may be an important statin
target (93–95). The strength of statin NF-␬B inhibition
varies, however, according to drug, cell type, and stimulus (93–95). In vivo evidence for statin-induced NF-␬B
repression comes from a rabbit model in which administering atorvastatin to atherogenic rabbits reduces
NF-␬B activation in both arterial smooth muscle and
macrophages (96). Down-regulation of Rho-related protein activation is one probable mechanism for this effect,
since NF-␬B is known to be activated via Rho GTPases
(97). In vitro, NF-␬B suppression by statins has been
reversed by mevalonate, FPP, and GGPP (93). Given
the centrality of NF-␬B in inflammatory diseases, the
ability of statins to inhibit NF-␬B may support the
clinical relevance of these agents as antiinflammatory
Statins also activate antiinflammatory transcription factors known as peroxisome proliferator–activated
receptors (PPARs). PPARs are intracellular, ligandactivated transcription factors that interfere with NF-␬B
transcriptional activity (98–100). In vitro, statins induce
the expression of PPAR␣ and PPAR␥ mRNA and
protein in stimulated ECs, macrophages, and hepatocytes (80,101,102). Statin-induced PPAR up-regulation
is reversed by mevalonate and GGPP, but not by
squalene, which implies a Rho target (80,101). Concordantly, GGTI induces PPAR␣ activity, as does transfec-
tion with DN RhoA, but not DN Cdc42 or DN Rac
Other apparent statin targets that have been
implicated in inflammatory and/or rheumatic diseases
include the MAP kinase families of signal transduction
molecules (ERK, JNK, and p38 families) (103–105), as
well as the JAK/STAT signaling pathways (106).
Statins as immunomodulators. Statins decrease
T cell activation. In vitro, statins inhibit IFN␥-inducible
class II major histocompatibility complex (MHC) expression in macrophages and ECs, an effect that is
reversed by mevalonate (107). In contrast, statins have
no effect on class I MHC expression in ECs. Statins’
inhibition of stimulated class II MHC expression is
accompanied by decreased class II MHC mRNA levels
and lower levels of class II MHC transactivator mRNA
(107). Decreased expression of class II MHC proteins
may lead to reduced T cell activation during antigen
presentation: in mixed lymphocyte reactions, atorvastatin decreases T cell activation and proliferation (107). In
addition, simvastatin has been shown to inhibit T cell
ERK activation through a Ras-dependent mechanism,
and to decrease T cell p38 activation by a Rhodependent mechanism; the former effect was reversed
by FPP, and the latter by GGPP (108). That study also
directly confirmed that statin treatment results in decreased Rho, Ras, and Rac association with lipid membranes.
Another mode by which statins inhibit T cell
activation may be through inhibition of costimulatory
molecules necessary during antigen presentation. The
actions of statins on LFA-1, discussed above, may reduce
not only leukocyte adhesion, but also costimulatory
signaling. Statins also down-regulate expression of the
costimulatory molecule CD40 (109,110). The latter finding may be relevant to RA, since overexpression of
CD40 and CD40 ligand (CD40L) in the rheumatoid
synovium (synovial fibroblasts and lymphocytes, respectively) may play a role in RA pathogenesis (111). Indeed,
interruption of CD40–CD40L interaction has been identified as a potential therapeutic target in RA (112,113).
Patients taking statin drugs exhibit decreased T
cell activity. The plasma concentration of the Th1 cytokine IL-2 is lower in patients taking statins (114). Ex
vivo, T cells of patients taking fluvastatin or simvastatin
secrete less IFN␥ and IL-2 than prior to treatment (115).
The in vivo effects of T cell inhibition by statins are
elaborated upon below, in a discussion on animal models
of inflammation.
Much of the evidence that statins exert their
antiinflammatory properties through small molecule
Table 1. Effects of statins on animal models of inflammatory and/or autoimmune disease
Animal model
Drugs tested
Carrageenan-induced footpad edema
Air-pouch model of inflammation
Experimental allergic asthma
Simvastatin, lovastatin, pravastatin
Experimental colitis
Experimental autoimmune myocarditis
Experimental autoimmune uveitis
Lovastatin, atorvastatin
Experimental autoimmune encephalomyelitis
Lovastatin, atorvastatin
Experimental sepsis
Antiphospholipid syndrome
Systemic lupus erythematosus (NZB/NZW
Rheumatoid arthritis (collagen-induced
Equivalent to indomethacin
Equivalent to indomethacin
Decreased lung pathology;
cultured lymphocytes
produced less IFN␥, IL-6
Decreased colon inflammation,
permeability, histologic
Decreased functional and
histologic scores; decreased
myocardial NF-␬B
Decreased clinical and
histologic retinal pathology
Decreased disease activity
(number and size of CNS
lesions); decreased class II
MHC expression on CNS
Decreased shock, mortality
Decreased thrombus formation
Decreased disease activity;
delayed glomerular injury
Decreased disease incidence,
activity, and histologic
scores; not replicated in
followup study
Simvastatin, atorvastatin,
* IFN␥ ⫽ interferon-␥; IL-6 ⫽ interleukin-6; CNS ⫽ central nervous system; MHC ⫽ major histocompatibility complex.
GTPases is indirect, but direct evidence supporting the
theory that statins act on inflammation by inhibiting
these molecular switches continues to accumulate.
Treating fibroblasts in vitro with simvastatin significantly
decreased the concentrations of fully modified forms of
RhoA, Cdc42, and Rac-1; a similar effect in vitro and in
vivo was seen in monocytes treated with atorvastatin (116).
Another study demonstrated that simvastatin decreased
membrane translocation of Ras (completely reversed by
coincubation with FPP) and Rho (completely reversed by
coincubation with GGPP) in macrophages (105).
Statins as antiinflammatory agents in animal models
Various animal models have demonstrated that
statins may act as antiinflammatory drugs (Table 1),
from simple models of inflammation, such as
carrageenan-induced footpad edema, to more complex
ones, such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA).
Statins in simple animal models of inflammation. In a comparison of simvastatin and indomethacin
for treatment of carrageenan-induced footpad edema in
mice, the agents had similar efficacy (117). One hour
prior to induction of footpad edema, animals received
placebo, indomethacin, or simvastatin via oral gavage.
The resultant footpad swelling in the treatment groups
was significantly less than in the control group (P ⫽
0.0001), and there was no significant difference in swelling between indomethacin- and simvastatin-treated
Statins are also effective in a mouse air-pouch
model of inflammation (118). A subcutaneous dorsal
pouch is created by injection of air; thereafter, an irritant
(e.g., LPS, carrageenan) is injected into the pouch.
Administration of the study drug is initiated before
administration of the inflammatory stimulus. The air
pouch is later excised and examined for leukocyte concentration and leukocyte products. In this model, lovastatin, pravastatin, and simvastatin significantly decreased leukocyte recruitment into pouches (P ⬍ 0.01,
P ⬍ 0.01, and P ⬍ 0.05, respectively) injected with either
LPS or carrageenan. The statin effects were comparable
with those of indomethacin, and were reversed by coadministration of mevalonate. Moreover, all 3 statins decreased air-pouch levels of IL-6, and lovastatin decreased RANTES and MCP-1 levels (not investigated in
the other 2 statins). Whereas lovastatin did not reduce
serum cholesterol levels in these studies, the squalene
synthase inhibitor squalestatin had no antiinflammatory
effect despite significantly lowering serum cholesterol.
Thus, the effects of statins on IL-6, RANTES, and
MCP-1 expression were cholesterol independent.
Statins in animal models of nonrheumatic autoimmune and inflammatory diseases. Statins are also
effective in more complex animal models of autoimmune disease. For example, simvastatin ameliorates a
murine model of allergic asthma (119). Mice treated
with intraperitoneal (IP) simvastatin had significantly
less lung inflammation as seen on histologic analysis.
Mice treated with either enteral (40 mg/kg per day) or
parenteral simvastatin (40 mg/kg per day) prior to
intranasal ovalbumin challenge had significantly lower
total cell counts and eosinophil counts as determined by
bronchoalveolar lavage; only IP-administrated simvastatin lowered macrophage counts and IL-4 and IL-5 levels.
Lymphocytes cultured from thoracic lymph nodes of
killed mice to which simvastatin 40 mg/kg per day had
been administered by either route produced significantly
less IFN␥ and IL-6 than did those of control groups.
IP pravastatin (1 mg/kg per day) has been shown
to reduce the severity of Dextran sulfate–induced colitis,
an animal model of inflammatory bowel disease (IBD)
(120). Study mice treated with pravastatin, when compared with placebo-treated mice, maintained their body
weight and had significantly lower disease activity indices. Pravastatin decreased colon inflammation and colon
epithelium permeability, prevented shortening of the
colon, and blocked changes in colon histology. Mechanisms by which the drug may have exerted its protective
effects included down-regulation of the mucosal addressin cell adhesion molecule 1, and prevention of
mucosal eNOS degradation. The protective effects of
pravastatin in Dextran sulfate–induced colitis were not
found in eNOS-deficient mice, suggesting that eNOS
regulation was critical to the statin effect.
Although the latter study did not investigate the
effects of pravastatin on Rho protein activation in the
colon, increased activation of RhoA has been found
both in inflamed intestinal mucosa of IBD patients and
in the colons of rats with trinitrobenzenesulfonic acid–
induced colitis (121). Use of Y-27632 to inhibit Rho
kinase significantly reduces colonic inflammation in rats
with experimental colitis by preventing NF-␬B activation. Thus, it may be that pravastatin ameliorates experimental IBD secondary to inhibition of Rho proteins,
and statins may prove efficacious in human IBD for the
same reason. No clinical studies of statin treatment of
IBD have been performed yet, but monocytes from
patients with Crohn’s disease treated in vitro with ator-
vastatin (10 ␮M) produce significantly reduced levels of
TNF␣ (by 45%) and MCP-1 (by 42%) (122).
Experimental autoimmune myocarditis, an animal model in which myocarditis is stimulated by myosin
immunization, is alleviated by oral fluvastatin treatment.
Rats treated with high-dose fluvastatin had improved
functional and histologic scores when compared with
placebo-treated rats. Fluvastatin inhibits myocardial inflammation by decreasing the production of the Th1
cytokines IFN␥ and IL-2, inhibiting expression of NF-␬B
in the myocardium, decreasing IL-4, IL-6, IL-10, IL-1␤,
and TNF␣ transcription in the myocardium, and preventing T helper cells from infiltrating the heart (123).
IP lovastatin (20 mg/kg per day), but not oral
lovastatin or atorvastatin, ameliorates intraocular inflammatory disease in a mouse model (i.e., experimental
autoimmune uveitis). IP lovastatin treatment decreased
retinal vascular leak and clinical and histologic retinal
pathology. This effect was reversed with mevalonate but
not with squalene, suggesting an action on one or more
prenylated proteins. The cell type(s) through which
lovastatin mediated this effect is unclear, but lovastatin
significantly suppressed in vitro transendothelial migration of mouse lymphocytes; lymphocyte transmigration
was restored with the addition of mevalonate (124).
Statins dramatically altered the course of EAE,
the animal model for MS, in a number of independent
studies (125–128). EAE is a T cell–driven disease in
which animals are immunized with myelin proteins and,
upon a second injection of these proteins, CD4⫹ T cells
recognizing myelin antigens are activated, which leads to
relapsing paralysis and central nervous system demyelination (129). Lovastatin and atorvastatin administered
prophylactically both have been reported to prevent
EAE, and to reverse established EAE in affected animals. Atorvastatin dramatically inhibits class II MHC
expression on central nervous system microglia in mice
with EAE, which leads to decreased T cell activation
(127). In addition, atorvastatin completely inhibits in
vitro class II MHC expression in IFN␥-stimulated microglia; coincubation with mevalonate abrogates this
effect. These findings have led to clinical trials of statins
in the treatment of MS, which are addressed below.
Statins may hold therapeutic promise not only for
autoimmune diseases, but also for other inflammatory
conditions, such as sepsis. Emerging data on statins in
animal models of sepsis are encouraging. Simvastatin
provides a dramatic improvement in mortality in a
murine model of sepsis. Mice pretreated with simvastatin prior to cecal ligation and perforation had a mean
survival time ⬃4 times that of untreated mice. The
simvastatin-treated animals also did not experience
drops in blood pressure or cardiac output while septic. In
addition, monocytes obtained from the simvastatintreated mice had significantly reduced adhesion to ECs
under physiologic flow conditions compared with those
from untreated mice (an effect reversed by mevalonate)
(130). A human ex vivo study showed that oxidative
stress, known to increase morbidity and mortality in
sepsis, may be decreased by simvastatin in patients with
sepsis. Simvastatin prevented Rac-2 activation in stimulated monocytes, and decreased superoxide anion production in whole blood by 40% in 14 patients with sepsis
A retrospective study of 388 human patients with
bacteremic infections suggested that statins decreased
mortality from sepsis. Deaths attributable to infection
occurred in only 3% of patients taking statins (upon
presentation to and during their hospital stay) versus
20% of those patients not taking statins. Multivariate
analysis further revealed that only statin use was associated with a decreased mortality rate (132). In a prospective observational cohort study of 361 patients with
bacterial infection, statin use was independently associated with a significantly lower rate of severe sepsis (P ⫽
0.001), in addition to a lower relative risk of death (0.43)
(133). The results of the latter 2 studies are not yet
conclusive; a randomized controlled trial of statin use in
sepsis may be warranted.
Statins in animal models of rheumatic diseases.
A limited number of animal studies have begun to
address whether statins can alter the outcomes of rheumatic diseases. Fluvastatin decreased anti– ␤ 2 glycoprotein I–mediated endothelial activation in vitro
(but not in the presence of mevalonate) (134), and
prevented large thrombi from forming in an animal
model of antiphospholipid antibody syndrome (infusion
of mice with human IgG antibodies from patients with
antiphospholipid syndrome) (135). Statin-treated animals developed thrombi no larger than those formed in
control mice infused with normal human IgG (135). In
separate studies, fluvastatin has been shown to decrease
leukocyte–endothelial adhesion in postcapillary venules
(135). Fluvastatin also significantly decreases expression
of tissue factor by HUVECs exposed to human antiphospholipid antibodies (136).
Atorvastatin decreases disease activity in an animal model of lupus. (NZB ⫻ NZW)F1 (NZB/NZW)
mice develop spontaneous autoimmune disease similar
to lupus. Administering atorvastatin (30 mg/kg per day
IP) to these animals resulted in lower anti–doublestranded DNA antibody levels, reduced proteinuria,
lower serum urea levels, and delayed glomerular injury
relative to untreated NZB/NZW mice. In addition,
atorvastatin decreased class II MHC expression on B
cells and monocytes, B cell and T cell activation, and T
cell proliferation in the treated mice (137).
In one study, simvastatin proved effective in
ameliorating CIA, an animal model of RA (138). This
study had a prophylactic and a therapeutic arm (statin
treatment before and after induction of disease). Mice in
the prophylactic group were randomized to 4 dosage
schedules: placebo, or simvastatin at 10 mg/kg, 20 mg/kg,
or 40 mg/kg per day. Mice in the therapeutic arm
received either control treatment or simvastatin at 40
mg/kg per day. In both arms of the study, mice receiving
simvastatin at 40 mg/kg per day had significant improvement versus controls, with a decreased disease incidence
and articular index in the prophylactic group, and a
decreased articular index and fewer arthritic paws developing in the therapeutic group. In the therapeutic
arm, histologic scores of joints dramatically improved
with simvastatin (P ⬍ 0.01). Lymphocyte cultures from
lymph nodes of statin-treated mice with CIA produced
less TNF␣ and IFN␥ than did lymphocyte cultures from
control mice. T cell proliferation was also significantly
suppressed in lymphocyte cultures from simvastatintreated animals. However, a more recent study did not
replicate these findings using atorvastatin, rosuvastatin,
or simvastatin (139).
While these results are intriguing, it must be
noted that the statin doses used in animal models of
inflammatory disease have typically been higher than
those used in human therapy. Whereas statins are
typically prescribed in a range of 0.1–1.0 mg/kg per day,
the doses used in animal experiments have been as high
as 40 mg/kg per day.
Statin trials in human inflammatory and autoimmune
Animal models of human disease may yield insight into disease pathogenesis and treatment, but cannot substitute for actual human data; statin efficacy in
animal models has therefore led to clinical trials in
inflammatory and/or autoimmune diseases.
Statins in human trials of nonrheumatic autoimmune diseases. Two small initial randomized controlled trials (RCTs) investigating statins for prevention
of allograft kidney rejection showed significantly lower
rejection rates in statin-treated patients (140,141). However, 3 subsequent RCTs demonstrated no significant
differences between short-term rejection rates between
Table 2. Effects of statins in rheumatic disease clinical trials*
Disease, ref.
Kanda et al, 2004 (150)
Drugs tested
ACR50 in 39%
Abud-Mendoza et al, 2003 (151)
McCarey et al, 2004 (155)
ACR50 in 90% at 4 weeks;
ACR70 in 70% at 8 weeks
DAS28 improvement (⫺0.5);
no improvement in subjective
Open-label, single-arm, 24 patients,
12 weeks
Open-label, single-arm, 10 patients
Double-blind, placebo-controlled,
116 patients, 6 months; more
patients taking methotrexate in
treatment group
Beattie et al, 2005 (158)
Increased incidence of hip OA
in 1 of 5 radiologic parameters (OR 1.9);
statin use did not worsen
preexisting OA
Prospective observational cohort,
5,674 women in osteoporosis
study; patients taking statins
were more obese at baseline
SLE (nephritis)
Abud-Mendoza et al, 2003 (151)
Decrease in proteinuria (from a
mean of 4.9 gm/day to
2.0 gm/day) in all patients
Case series, open-label, 3 patients
taking 80 mg/day simvastatin
Garcia-Martinez et al, 2004 (157)
No steroid-sparing effect
Retrospective, unblinded; 54
patients; 17 taking statins, most
at low doses
* RA ⫽ rheumatoid arthritis; ACR50 ⫽ American College of Rheumatology 50% criteria for improvement; DAS28 ⫽ 28-joint Disease Activity
Score; OA ⫽ osteoarthritis; OR ⫽ odds ratio; SLE ⫽ systemic lupus erythematosus; GCA ⫽ giant cell arteritis.
patients in the intervention and control arms (142–144).
It is unclear whether these studies failed to replicate the
earlier findings because of drug inefficacy or because of
drug choice and dosage. One study, for example, used
only 10 mg of simvastatin per day in the treatment arm,
which was 12.5% of the daily maximum recommended
dose (142).
In more recent trials, statins have begun to look
promising. In 2004, a single-arm, open-label trial involving 30 individuals taking 80 mg of simvastatin per day for
relapsing–remitting MS was reported (9). After 6
months of treatment, the number of gadoliniumenhancing brain lesions decreased by 44% (P ⬍ 0.0001)
and the volume of the lesions decreased by 41% (P ⫽
0.0018) when compared with the lesions noted on pretreatment magnetic resonance imaging. A randomized,
double-blind, placebo-controlled study investigating
atorvastatin for the treatment of MS is now under way.
Statins may also play a role in preventing cancer,
including (but not limited to) colorectal cancer (145),
and they may hold promise for treating established
cancer (146). Although the role of inflammation in
cancer is increasingly recognized (146–149), it is not yet
known whether statins can modulate malignancy directly
via their antiinflammatory effects.
Statins in human trials of rheumatic diseases.
Despite a great deal of excitement about the antiinflam-
matory potential of statins in rheumatic diseases, only a
small number of studies have actually been carried out
to evaluate the efficacy of statins in these settings
(Table 2).
Two small preliminary studies, 1 carried out
in Japan and 1 conducted in Mexico, revealed dramatic
RA disease improvement in statin-treated patients
(150,151). In the Japanese study, a 12-week, open-label,
single-arm study of 24 patients receiving 10 mg of
simvastatin daily, 39% of the treatment group met the
American College of Rheumatology (ACR) 50% improvement criteria (achieved an ACR50 response)
(152). The group in Mexico conducted an 8-week,
open-label study of simvastatin at a dosage of 40 mg
daily; after 4 weeks, 9 of 10 patients achieved an ACR50
response; by the end of the study, 7 of 10 patients
achieved an ACR70 response. These exceptional response rates should be interpreted with caution, however. These studies were very small, their design allowed
for observer bias, and their reported ACR response
rates were equal to or better than those found with
currently approved biologic agents. A recent crosssectional study of patients in the National Databank for
Rheumatic Diseases (153) revealed that statin use was
independently associated with modestly reduced Health
Assessment Questionnaire (HAQ) scores (154).
A larger randomized placebo-controlled study
investigating atorvastatin as a disease-modifying antirheumatic drug (DMARD) in RA (Trial of Atorvastatin
in Rheumatoid Arthritis) also showed modest effects
(155). In this 116-patient study, patients received either
40 mg of atorvastatin per day or placebo in addition to
current DMARD therapy; DMARDs were not allowed
to be changed during the 6-month study. At the end of 6
months, the group receiving atorvastatin showed statistically significant improvements in the 28-joint Disease
Activity Score (DAS28) (156).
Before adding statins to the DMARD arsenal,
however, further studies need to be conducted, because
there were limitations to that study. In particular, a
potentially confounding difference existed between the
control and study groups: 50% of patients in the atorvastatin group were taking methotrexate versus 26% of
patients in the placebo group. Whether the response
rates between the groups was actually due to more
methotrexate use rather than statin use is an important
question. Putting aside these randomization issues, the
increased response in the statin group was actually
modest. The improvement in DAS28 may have reached
the level of statistical significance, but the patients
demonstrated no subjective improvement. That is, the
study group showed improvements in CRP, erythrocyte
sedimentation rate, and the number of swollen joints by
physician examination, but had no improvement in
early-morning stiffness, tender joint count, visual analog
score for pain, patient global assessment, or HAQ score.
Statins have also been investigated in other rheumatic conditions. Statins did not exert a steroid-sparing
effect in giant cell arteritis in one retrospective study,
although more than half of these patients received only
low-dose statin therapy, which rendered the data inconclusive (157). In an in vitro study, statins inhibited
neutrophil activation in response to antineutrophil cytoplasmic antibodies (ANCAs) (103); whether this observation suggests potential utility of statins in ANCAassociated vasculitides remains to be determined. On the
other hand, the authors of a very small study reported
that 3 of 3 patients who had been treated unsuccessfully
with cyclophosphamide and prednisone for lupus glomerulonephritis responded dramatically to 8-day treatment with high-dose simvastatin (80 mg per day) (151).
As mentioned above, statins have been associated
with decreased rates of osteoporosis (of the hip) (10). In
contrast, a recent prospective observational cohort study
indicated that statin use may be associated with the
development of hip osteoarthritis (OA) in elderly
women, possibly related to increased bone density.
However, several caveats regarding this latter study must
be noted: 1) patients taking statins were significantly
more obese than those not taking statins at baseline; 2)
of 5 criteria used to diagnose radiographic hip OA, only
1 showed an increase in the statin group; and 3) statin
use did not worsen existing hip OA during the duration
of the study (158). A trial of statin prophylaxis for
steroid-induced avascular necrosis in lupus patients is
ongoing, with results pending (Belmont HM: personal
In selecting a cholesterol-lowering agent for a
patient with rheumatic disease, rheumatologists may
wish to consider the antiinflammatory effects of statins.
In doing so, the practicing clinician should bear in mind
that individual statins may differ in their antiinflammatory potential. In one study, statins varied by as much as
10-fold in the degree to which they inhibited NF-␬B
activation in stimulated monocytes (cerivastatin ⬎ atorvastatin ⬎ simvastatin ⬎ pravastatin ⬎ lovastatin ⬎
fluvastatin). Given the current limitations of the data,
however, it would be premature to make specific formal
recommendations about the use of any particular statin
as an antiinflammatory agent (94).
Statins as cardioprotective agents in rheumatic
disease. Systemic inflammatory diseases such as RA and
systemic lupus erythematosus (SLE) are associated with
accelerated atherosclerosis, and both RA and SLE patients have a significantly increased risk of myocardial
infarction and death (159–161). Since this increased risk
is not accounted for by traditional risk factors (162), it
has been postulated that systemic inflammation itself
may participate in accelerated atherosclerosis. Moreover, controlling systemic inflammation in patients
with atherosclerotic heart disease may independently
improve cardiovascular risk (163). Statins may therefore be indicated for cardiovascular prophylaxis in
some rheumatic diseases, even in the absence of hypercholesterolemia.
Elevated CRP levels correlate with accelerated
atherosclerosis in RA patients (164). Statins reduce
CRP production in response to stimuli such as IL-6 in
vitro (165) and reduce CRP levels in vivo, correlating
with low-density lipoprotein–independent improvement
in cardiovascular outcome (163,166,167). Whether CRP
is itself pathogenic in atherosclerosis, or whether elevated CRP levels merely reflect the presence of inflammatory mediators such as IL-6, remains to be
determined (168,169). Statins may also ameliorate accelerated atherosclerosis in rheumatic disease via effects
on endothelium. Even young RA patients with low
disease activity have significant endothelial dysfunction
(170,171), and statins improve endothelial function in
patients with RA. Studies to test the effect of statins on
cardiac outcomes in lupus and RA are ongoing.
Over the last decade, it has become increasingly
clear that statins have antiinflammatory properties, independent of their lipid-lowering effects. What is less
clear is whether this class of drugs will prove to be useful
as antiinflammatory agents for “high-grade” inflammatory diseases such as RA, Crohn’s disease, and lupus.
Preliminary data from open-label studies of statin treatment in inflammatory diseases have been impressive, but
must be interpreted with caution, because data emerging
from double-blind placebo-controlled trials have so far
been less definitive. Even if statins prove only mildly
effective in reducing inflammation and/or autoimmunity
in rheumatic diseases, their relative safety, together with
their potential for reducing the inflammatory and lipidmediated processes of accelerated atherosclerosis, suggest that statins may at least prove to be useful adjunctive therapy in patients with rheumatic disease.
The authors wish to thank Steven B. Abramson for
helpful suggestions, and Nada Marjanovic for performing
statin experiments described in this report.
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