RESEARCH - Testing anti-TNF agents in lupus

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Rheumawire

November 16 2004

Breaking the ice: testing anti-TNF agents in lupus

Vienna, Austria - A small open-label study of the TNF

inhibitor infliximab (Remicade, Centocor) in patients with systemic

lupus erythematosus (SLE) has shown promising results, and further study

of this class of drugs is warranted in lupus, say the researchers.

However, the scientists, led by Dr Aringer

(Medical University of Vienna, Austria), admit that " TNF blockade as

therapy for SLE is a highly controversial issue. " They report their

findings in the October 2004 issue of Arthritis & Rheumatism [1].

In an accompanying editorial, Dr C Jr

(University of California, San Francisco) says the conclusion of Aringer

et al's study " must be tentative, given the small number of patients and

short follow-up period, " but it is nevertheless " encouraging " [2].

Noteworthy reduction of proteinuria by 60% or more

Aringer and colleagues explain that the concept of

using TNF blockers as a treatment for lupus is contentious because the

use of this class of drugs in rheumatoid arthritis (RA) and Crohn's

disease has led to the formation of autoantibodies to double-stranded

DNA (dsDNA) and a transient lupuslike syndrome in some patients.

But in animal models of lupus, TNF blockers have been

shown to have some benefits, they note. Hence, they decided to conduct a

small open-label study.

Six patients with moderately active lupus (4 with

nephritis and 3 with arthritis refractory to other therapies) were given

4 x 300-mg doses of infliximab (Remicade) in addition to

immunosuppression with azathioprine or methotrexate.

Levels of antibodies to dsDNA and cardiolipin

increased in 4 patients each, but this was not associated with a

decrease in serum complement levels, with vascular events, or with

flares. In contrast, disease activity declined during therapy. And all 3

patients with joint involvement experienced remission of arthritis,

which relapsed 8 to 11 weeks after the last infliximab infusion.

Also, in the 4 patients with lupus nephritis,

proteinuria decreased significantly within 1 week after starting therapy

and was diminished by 60% or more within 8 weeks, remaining at low

levels until the end of the observation period (at least several

months).

" The observed clinical findings under TNF blockade

suggest that infliximab may have a therapeutic effect in patients with

SLE, " say Aringer et al. " In particular, the reduction of proteinuria by

60% or more within a few weeks . . . is noteworthy. "

However, they warn, " These findings must be

interpreted with great caution, given the open nature of this study. "

" To sufficiently address the potential value of

TNF-blocking therapy in SLE, larger and controlled clinical trials are

necessary, " say the Austrian doctors. " The data presented here justify

such trials. "

In his editorial, says clinicians have been

" cautious, indeed almost fearful, in the use of TNF inhibitors to treat

SLE " because of the concerns outlined by Aringer et al. But the Austrian

doctors found something interesting, he says - despite the fact that

anti-dsDNA titers increased, clinical disease activity improved. This

suggests that an increase in autoantibody production is not the same as

an increase in lupus disease activity and should not be viewed as

necessarily a contraindication or impediment to therapy, says.

" Overall, Aringer's study represents an important step

forward in exploring a new approach to the treatment of SLE. As 1 of the

first studies on TNF blockade in SLE, this study is breaking the ice. It

is, at best, preliminary and is far too small to be decisive.

Fortunately, controlled studies with anti-TNF therapy in SLE are planned

and will proceed cautiously, with safety as the main objective, " he

notes.

told rheumawire that he and others are planning

a National Institutes of Health-sponsored multicenter, randomized,

placebo-controlled study of anti-TNF agents in lupus nephritis.

In the meantime, however, " the widespread clinical use

of anti-TNF therapy in patients with SLE is not warranted until further

data become available, " he cautions. However, the studies by Aringer et

al " suggest that there may be subsets of patients or circumstances in

which use of this form of therapy is beneficial, " he adds. " Determining

the risk/benefit ratio in patients with SLE is crucial to this approach

and to what the future holds now that the ice has been broken. "

Nainggolan

Sources

Aringer M, Graninger WB, Steiner G

et al. Safety and efficacy of tumor necrosis factor alpha blockade in

systemic lupus erythematosus. An open-label study. Arthritis Rheum 2004;

50: 3161-3169.

JC Jr, Breaking the ice:

testing tumor necrosis factor alpha blockade in lupus. Arthritis Rheum

2004; 50: 3061-3063.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org