TNF Inhibitors

What is TNF, what does it have to do with RA, and why might we want to inhibit it?

Tumor Necrosis Factor-alpha is a protein produced by the white blood cells.  It’s job is to fight infection.  It’s a perfectly normal part of the immune system.

Unfortunately, with RA, the immune system works in overdrive.  TNF promotes inflammation, and too much of it is bad (and painful).

There is a whole category of biologic medicines called TNF inhibitors/blockers.  They don’t all work exactly the same way, but in general, they bind onto TNF-α to prevent inflammation.  This is a good thing if you have an overabundance of TNF!

Digging Deeper 

When you look at your lab results, you might notice that sometimes the white blood cell count is broken down so that your doctor can differentiate between various kinds of white cells in the bloodstream.  Add up the numbers (not percents) from the differential and you’ll notice that the sum equals the WBC number in your Complete Blood Count (the percent should total 100%).

These different kinds of white cells have different jobs in our immune system.  The lymphocytes, in particular, are what we’re interested in right now.  There are three types of lymphocytes.

B-cells, T-cells, and natural killer cells are all different kinds of lymphocytes (which means they’re different kinds of white blood cells).  Natural Killer cells are larger; B-cells and T-cells are smaller.

T-cells and Natural Killer cells produce proteins called cytokines.  There are different types of cytokines – including Tumor Necrosis Factor Alpha (and yes, since there’s a TNF-α, you’d be correct in suspecting that there’s also a TNF-β, but the RA literature I’ve read doesn’t seem too concerned with it).

These cytokines (proteins made by certain types of white cells) do amazing things to fight off infection.  Unfortunately, with RA they act on the body even if there’s no infection.  Systemically, TNF acts on the hypothalamus to generate fever and suppress appetite – we’ve all experienced this when fighting illness, but it can happen with RA, too.  Now you know why.   TNF also kicks off a process called an acute phase response (which, interestingly enough, can show up in your bloodwork as elevated CRP), and can also cause insulin resistance and a host of other problems.  Locally, TNF can cause heat, redness, swelling, and pain – as seen in joints affected by RA.

TNF Blockers

Of the nine biologic medicines currently approved by the FDA, five are TNF blockers.  Block the TNF, and you block the cause of the heat, redness, swelling and pain.

A look at the non-proprietary drug names shows that four of them end in -mab.  A -mab ending means that these medicines are monoclonal antibodies.  With monoclonal antibodies, once an effective antibody is developed, all of that medication made is a clone of a single original antibody cell.  Enbrel, on the other hand, is not a monoclonal antibody, but a fusion protein.

Cimzia (one of the monoclonal antibodies) is the only PEGylated TNF inhibitor.  What this means, in practice, is that the drug is supposed to be less toxic and last longer in the system.

It is rare, but possible, for someone to develop antibodies to TNF blockers.  If a TNF blocker stops working, and subsequent TNF blockers never work when they are tried, it is unlikely that the fourth or fifth TNF blocker will work.  In that case, it would be time to switch to a different type of biologic medication.

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Discussion of macrophages will occur in a future post.

Edited 4/3/11 with updated illustration