Review article J Indian Rheumatol Assoc 2003 : 11 : 76 - 78

ROLE OF STATINS IN AUTOIMMUNE DISEASE

Sandeep Grover
Senior Resident, Clinical Immunology,
Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow.

Abstract:
Statins inhibit HMG-CoA reductase reducing cholesterol biosynthesis. It also has diverse effects on
cellular metabolism and remarkably, these agents prolong graft survival in cardiac transplant cases which
is independent of its cholesterol lowering properties. Several mechanisms have been suggested by which
Statins mediate immunosuppression. It has been shown useful in animal models of Rheumatoid arthritis,
and if these observations are confirmed in human disease, it could be an ideal agent to treat RA, where
in, more deaths occur due to atherosclerosis.
Key words: Statins, Autoimmune disease, Rheumatoid arthritis, Systemic Lupus Erythematosus,
Atherosclerosis.

Statins are a class of drugs, which act as 3-
hydroxy-3methylglutamyl-coenzyme A (HMG-CoA)
reductase inhibitors and are used for treatment of hy-
percholesterolemia became of their lipid-lowering ef-
fects resulting in the decrease of intra cellular choles-
terol1,2. A reduction in cholesterol may influence vari-
ous pathogenic processes such as atherosclerosis or
thrombosis, large-scale interventional trials having shown
that statin therapy reduces the risk of cardiovascular
disease3.
HMG-CoA reductase is an enzyme in the cho-
lesterol biosynthetic pathway that catalyses the con-
version of HMG-CoA to mevalonic acid. Downstream
metabolites in this pathway include farnesyl pyrophos-
phate and geramylgeranyl pyrophosphate which are
required for post-translational prenylation of many
molecules in the electron transport chain4, thereby im-
plying possible diverse effects on cells metabolism and
physiology apart from decreasing cholesterol levels.
A lot of interest has been generated in the
mechanisms of interaction of low-grade chromic inflam-
Address for correspondence
Sandeep Grover,
Senior Resident, Clinical Immunology,
Sanjay Gandhi Post Graduate Institute of Medical Sciences,
Lucknow
mation with vascular risk factors, leading to the devel-
opment of atherosclerosis. Patients with rheumatoid
arthritis (RA), who have persistently high levels of in-
flammation, have been shown to have a greater risk of
developing cardiovascular disease. Indeed, in most
mortality studies of RA patients, excessive cardiovas-
cular deaths predominated, with a risk ratio of about
25. Several recent observations show that chronic in-
flammation is associated with early atherosclerosis and
aberrant cellular and humoral immune responses are
important in its pathogenesis6. Therefore, it is logical
that therapeutic intervention in chronic inflammatory and
cardiovascular diseases might be closely linked and
agents prescribed as immunomodulators or lipid modu-
lators might act in either capacity.
Pravastatin was found to decrease the incidence
of hemodynamically significant rejection episodes in
cardiac transplant patients. This effect was not signifi-
cantly correlated to reduction in cholesterol levels in
these patients7. Subsequent studies have revealed many
immunological pathways sensitive to modulation by
statins:
1. Statins inhibit interferon--inducible class II
transactivator (CIITA) to decrease the induction/up-
 S Grover
regulation of MHC class II molecules on professional
& non- professional antigen presenting cells8.
2. Statins bind to 2 integrin and thereby block T-cell
co-stimulation by means of lymphocyte function-asso-
ciated antigen-1 (LFA-1)9.
3. In monocytes and macrophages, statins decrease
chemotaxis, lipopolysaccharide (LPS) mediated re-
lease of tumour necrosis factor- (TNF-), activation
of NO synthase8 and LPS-stimulated secretion of ma-
trix metalloproteinase-910.
These immunological effects indicate the po-
tential role of statins in modifying initiation and amplifi-
cation of immune inflammatory responses.
The argument for the role of statins in autoim-
mune diseases becomes stronger with accumulating
evidence of their influence on bone metabolism.
Lovastatin and Simvastatin were the only 2 compounds
among 30,000 tested, to have the ability to stimulate
the bone morphogenetic protein-2 (BMP-2) promoter
in an osteoblast cell line11. BMPs are the most potent
stimulators of bone formation known and therefore,
statins can have a strong positive effect on bone for-
mation.
Oral Atorvastatin was recently shown to pre-
vent or reverse chronic or relapsing paralysis due to
demyelination in a murine model. This was associated
with a shift from T-helper 1 (Th-1) type immune re-
sponse towards Th-2 type responses in vivo12. These
results suggest a possible role of statins in inflammatory
phase of multiple sclerosis and other Th-1 mediated
autoimmune diseases including diabetes and rheuma-
toid arthritis.
Recently, the role of statins has been examined
in an animal model of arthritis similar to human rheuma-
toid arthritis13. This model is of collagen induced
arthritis, in which arthritis-susceptible mouse strain
(DBA/1j) develop arthritis 25-35 days after immuni-
zation with bovine type II collagen. Simvastatin was
administered daily at 10, 20 and 40 mg/kg through in-
traperitoneal route in prophylactic and therapeutic
regimens. The prophylactic regimen entailed admin-
istration of Simvastatin from day 21 i.e. several days
before the onset of arthritis, while the therapeutic regi-
men started on the day after the onset of arthritis, for
the next 14 days. The dose of Simvastatin in mice was
much higher than that used in humans because of the
relatively rapid induction of rodent HMG-Co reduc-
tase14. Interestingly, even this dose was not associated
with a significant decrease in plasma cholesterol con-
centration in mice. Results of this study showed a sig-
nificant decrease in the severity of arthritis in both the
prophylactic as well as therapeutic group. These re-
sults were achieved with a dose of 40 mg/kg, lower
doses showing no significant beneficial effects. This dose
also decreased the incidence of arthritis by about 50%
in the prophylactic group.
In the same experiment, Simvastatin decreased
serum interleukin-6 (IL-6) levels as well as synovial
cellular infiltration and joint destruction. There was also
evidence for a decrease in Th-1 type response although
there was no increase in Th-2 type activity. The effect
of incubation of human cells with Simvastatin in vitro
was studied with peripheral blood mononuclear cells
from patients with rheumatoid arthritis and normal con-
trols, and with synovial fluid mononuclear cells from
patients with rheumatoid arthritis. Simvastatin decreased
proliferation and IFN- production with no apparent
decrease in T cell viability in each of study groups. Co-
culture experiments indicated that statins decreased the
T-cell stimulated secretion of TNF- by macrophages.
Results of therapy with statins in patients with
refractory rheumatic diseases were examined in a pre-
liminary study from Mexico15. Simvastatin at 80 mg/
day for eight days induced a rapid and significant re-
77
 Role of Statins in Autoimmune Disease
duction in proteinuria in SLE patients refrac-
tory to conventional treatment. At a dose of 20 mg/
day for 8 days, five patients with refractory RA showed
reduction in C-reactive protein levels and an ACR-20
clinical improvement response. They also conducted a
pilot short-term comparative (Simvastatin versus Chlo-
roquine) open clinical trial in 15 RA patients with inad-
equate response to single agent DMARD therapy i.e.
methotrexate. 90 percent of the patients receiving
Simvastatin at 40 mg/day showed an ACR 50 or bet-
ter response after 8 weeks, whereas such a response
was not observed in any patient with chloroquine.
Patients with chronic inflammatory and autoim-
mune diseases need to be treated aggressively to de-
crease cardiovascular risk and to control disease ac-
tivity. Many of these patients also have predisposition
to osteoporosis. The potential benefits of statins on
lipid profiles, immunological pathways and bone me-
tabolism project them therapeutically as single agents
with the ability to contribute to these three therapeutic
objectives. Although concerns remain about the known
and unknown adverse effects of statins like myositis16,
it is hoped that with further research, specifically de-
signed statins with enhanced immunomodulatory effects
will emerge as important components of the therapeu-
tic armamentarium for chronic inflammatory and au-
toimmune diseases like rheumatoid arthritis and SLE.
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