Re: Anti-TNF Therapy of RA: What Can We Learn about Chronic Disease?

[Guest guest]

TNFa is (always? often?) bound for some time to the membrane of the

cell that produces it, before being cut free by enzymes to drift thru

humors and carry a signal to other cells. Therefore, antibodies like

anti-TNF might be able to promote destruction of cells with membrane-

bound TNF. I'm not sure what all cells express TNF, but macrophages

do. Infected macrophages would be quite likely to express TNF.

Therefore TNF antibodies have the theoretical potential to

selectively destroy macrophages infected with bacteria that may

contribute to RA and crohns.

But this idea predicts that the therapeutic effect of anti-TNFa

should be related to bacterial destruction, and should therefore

probably extend well beyond the effective lifetime of anti-TNF

activity in the body. Data I looked at suggest that this extended

benefit does not occur. Therefore theres really nothing to support

the idea that anti-TNF helps patients clear intracellular bacteria,

tho its still possible. More likely, the primary effect is one of

immunosuppression.

>

> Anti- TNF Therapy of Rheumatoid Arthritis: What Can We Learn about

> Chronic Disease?

>

> Chapter Authors: Marc Feldmann, Fionula M. Brennan, Ewa Paleolog,

> Cope, , , Jim Woody, Ravinder N.

> Maini

>

> Series: Novartis Foundation Symposia

>

> Summary

> The importance of tumour necrosis factor (TNF) in rheumatoid

> arthritis (RA) was initially proposed on the basis of analysis of

> cytokine gene regulation at the local site of the disease, the

> synovium. This was then verified in animal models and established

in

> an extensive series of clinical trials, culminating in now 250 000

> treated patients with either of two approved TNF inhibitors,

> antibody or fusion protein. The degree and magnitude of clinical

> benefit has enabled analyses of the mechanism by which anti-TNF

> benefits, and hence insights into important steps in the disease

> process. It was found that essentially all aspects of RA were

> ameliorated, and important mechanisms of benefit involved

diminution

> of multiple pro-inflammatory cytokines, adhesion molecules and

> chemokines, leading to reduced cell trafficking, reduced

> angiogenesis and most importantly halting of joint destruction.

What

> of the problems? Safety is better than prior drugs, but there is a

> small increase in severe infections, smaller than might have been

> anticipated. Cost is the major drawback limiting greater use. In

> view of the central pathological processes down-regulated, and

their

> role in many diseases, the early clinical success of anti-TNF in RA

> led to subsequent successful trials and registration in Crohn's

> disease and juvenile rheumatoid arthritis, and successful trials in

> ankylosing spondylitis, psoriasis and psoriatic arthritis. The era

> of anti-cytokine therapeutics is just dawning.

>

> http://www3.interscience.wiley.com/cgi-bin/summary/109088430/SUMMARY

>