Statins in RA: reduction in CV risk, but also in RA disease activity

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Statins in RA: reduction in CV risk, but also in RA disease activity

Rheumawire

June 17, 2004 18:30 Zosia Chustecka

Glasgow, Scotland - The first controlled trial in rheumatoid arthritis

(RA) patients with the statin lipid-lowering agent atorvastatin

(Lipitor®, Pfizer) has shown not only that the drug exerted its expected

effects on cholesterol levels, but also that it reduced RA disease

activity. The results from the Trial of Atorvastatin in Rheumatoid

Arthritis (TARA), a 6-month study in 116 patients, appear in the June

19, 2004 issue of the Lancet [1].

These RA patients were already being treated with disease-modifying

antirheumatic drugs (DMARDs), but the addition of atorvastatin had a

significant effect on suppressing acute-phase variables (C-reactive

protein [CRP] and erythrocyte sedimentation rate [ESR]) and on reducing

the swollen joint count. " A clinically apparent anti-inflammatory effect

is remarkable, given that atorvastatin was developed mainly on the basis

of lipid-lowering properties, " say the researchers.

" However, the size of the improvement was actually very small,

especially compared with what you might expect with a TNF inhibitor, for

example, and so the excitement lies as much in the potential as in the

actual reality of the results, " lead investigator Professor Iain McInnes

(Center for Rheumatic Diseases, Glasgow Royal Infirmary, Scotland) tells

rheumawire in an interview. " It suggests that the statins are targeting

something in RA that is worth targetingif we understood what they did

and how they did it, we may be able to develop better anti-inflammatory

drugs that could be taken orally. "

" The other thing that is very important in this study is that this is

the first time we've really been sure that statins exert their

lipid-lowering and vascular-marker-protective effects even in rheumatoid

arthritis, " he adds. There's always been a concern that the level of

inflammation in RA is so high that somehow the statins wouldn't manage

to exert their lipid-lowering and local effects inside the blood

vessels, he explains, but " now we've shown that they can. In fact, the

effect was as large as would be expected in a patient without RA, so

we've shown that the statin has done its job. "

These data seem almost too good to be truehitting both the inflammation

in RA and 1 of the major traditional risk factors for cardiovascular

disease with one product, which is already on the market, comments an

accompanying editorial [2]. But there are caveats before statins can be

generally recommended for rheumatoid arthritis in general practice, it

continues. The observed clinical efficacy in RA was marginal in relation

to both conventional DMARDs and the biologics, particularly the TNF

inhibitors. Also, the effect of statins on the immune and inflammatory

systems is not well understood, and there are no long-term safety data

for statins in patients with inflammatory disease. But these

restrictions should not reduce the value of this work, and the results

should encourage further study.

The editorialists, Drs Lars Klareskog and Anders Hamsten (Karolinska

Institute, Stockholm, Sweden), also comment that although the study was

of limited size and short term, the findings support the use of

atorvastatin, and presumably of other statins, to prevent cardiovascular

disease in patients with rheumatoid arthritis.

However, McInnes is more circumspect, saying: " What I wouldn't like to

happen is for the world's rheumatologists to suddenly start prescribing

satins for every rheumatoid arthritis patientI think that would be

counterproductive, and it's not what we said or suggested in our paper,

and we would be very uncomfortable and probably very unpopular if the

news came out that way. "

His advice to rheumatologists is: " If a patient has rheumatoid arthritis

and traditional cardiovascular risk factors, consider using a statin,

and use it according to the current guidelines on the use of statins.

What our study has done is provided reassurance that the statin will

work to reduce the traditional risk factors for cardiovascular disease

despite the patient having rheumatoid arthritis. "

However, the situation is different if the patient doesn't have

traditional cardiovascular risk factors. " Although we now know that RA

itself is an independent risk factor for cardiovascular disease, we

can't suggest that you use a statin for RA alone until we have we have

the data showing an effect on clinical end pointsmyocardial infarctions

and strokein this patient population, " he says. " We are planning a

longer-term study to look at this, but so far the data show only an

effect on surrogate end points and so do not justify the use of a statin

in the absence of other cardiovascular risk factors. " He adds, " This is

a subtle point, but an important one. "

Atorvastatin produced significant reductions in total cholesterol, LDL

cholesterol, triglycerides, and VLDL cholesterol concentrations. The

levels of LDL cholesterol and triglycerides were reduced " substantially

. . despite the context of high-grade inflammation, " the researchers

comment. " This fact provides a direct coronary heart disease protective

pathway in rheumatoid arthritis for atorvastatin via traditional

risk-factor modification. "

The drug also produced a significant reduction in RA disease activity

(measured on the Disease Activity Score [DAS] 28), in swollen joint

counts and in the levels of CRP and ESR, which declined by 50% and 29%,

respectively, relative to placebo. The effect on RA disease was

statistically significant but " modest, " the researchers write. But was

it clinically significant? " To be honest, we're not sure, " says McInnes.

" The size of the effect was about the same as you might see with

hydroxychloroquine, so it's a very mild effect . . . it's nothing like

the benefit we would see with TNF inhibitors, not even half of it, " he

explains. This means that a statin wouldn't be worth considering as a

monotherapy, but it may be useful in combination with other agents, he

says, rather like hydroxychloroquine, which shows a synergistic benefit

when used in a triple-therapy combination. Used in a DMARD combination,

the statin could provide not only adjunctive immunomodulatory potential

but also vascular protection.

" Although the magnitude of change is modest, the significant reduction

in DAS28 provides proof of concept that the pathways targeted by statins

offer therapeutic opportunity in inflammatory disease, " the researchers

write. " We believe that our study should provide impetus for the

development of statin analogs on the basis of their anti-inflammatory

profile. "

Sources

McCarey DW, McInnes IB, Madhok R, et al. Trial of

atorvastatin in rheumatoid arthritis (TARA): a double-blind, randomized

placebo-controlled trial. Lancet 2004; 363:2015-2021.

Klareskog L and Hamsten A. Statins in rheumatoid

arthritis--two birds with one stone? Lancet 2004; 363:2011-2012.

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