Don't you just hate it the way people, especially doctors, are always coining new (and longer) names for disease states? "Familial Hibernian Fever" was bad enough, albeit somewhat euphonious, but how about "Tumour Necrosis Factor alpha Receptor Associated Periodic Syndrome"? Accurate, but it doesn't roll of the tongue, and the acronym TRAPS is rather unimaginative, and thus far from being a great Internet search term!
TRAPS was a syndrome characterised mainly by:
Nobody is certain, but the mechanism by which a point mutation in TNF-R1 causes such widespread inflammation is probably related to inability of the body to split off the TNF receptor into soluble TNF receptor. This has two implications:
TNF is a cell-surface type II, homotrimeric transmembrane protein which is chopped off and released into the extracellular fluid by a metalloprotease called "TACE."
TNF is often painted as a "bad guy", as it mediates severe inflammation. Death in septic shock seems to be strongly related to overwhelming effects of TNF alpha release and actions. Unfortunately, this is only half the picture, as antagonising the effects of TNF in sepsis results in higher death rates. TNF is an important protein that mediates immune defence mechanisms. Turning it off may result in increased susceptibility to a variety of infections.
A lot of the complex cellular actions of TNF have now been elucidated. Simplistically, stimulation of TNF receptors seems to result in two things:
Strangely, the production of NF-kappa B appears to antagonise the tendence of TNF to cause apoptosis. NF-kappa B is probably the most important mediator of inflammatory responses in practically all cells. It is a small intracellular messenger that, when expressed, results in a vast cascade of intracellular processes, that in turn mediate the inflammatory response. It interacts with several other nuclear factors, regulating gene expression. One of the most important of these other factors is called I kappa B.
Steroids inhibit the production of NF-kappa B, and this may explain their anti-inflammatory effects, and why they appear to ameliorate the inflammation seen in TRAPS.
The other agent advocated for treatment of TRAPS, etanercept, appears to act to "mop up" circulating TNF, thus antagonising its effects.
TNF comes mainly from macrophages, especially when they are exposed to bacteria or their products, such as lipopolysaccharide.
TNF-R1 is otherwise known as CD120a, or even p55/60; there's another TNF receptor called TNF-R2 (CD120b, p75/80). Most cells express TNF-R1; we still don't understand how TNF-R1 is cleaved from the cell and released as soluble TNF-R1.
Stimulation of TNF-R1 results, as already mentioned, in apoptosis (via the so-called `death domain'), and gene expression (via something called TRAF, or the family of TNF-associated factors). There's a complex balance between the opposing effects of apoptosis (cell destruction) and gene expression with cell proliferation and an inflammatory response. Generally, NF kappa B results in production of anti-apoptotic factors that antagonise the apoptotic effects of TNF, but this depends on timing and concentration of TNF stimulation. Interactions are fantastically complex --- for a confusing overview, see Wajant et al.
TNF deficient animals are predisposed to infection with mycobacteria, Listeria monocytogenes, Leishmania, and Toxoplasma.
There are two important components to the diagnosis of TRAPS:
TRAPS is probably a lot more common than we think, and underdiagnosed. Several of the original kindreds were Irish, hence the name "Familial Hibernian Fever", but TRAPS has been reported from many countries around the world. It's nevertheless rather rare. The disorder appears to be autosomal dominant, and penetrance is often fairly high, but seems to depend on the specific mutation.
Consider other causes of abdominal pain, etc. Never forget that patients with TRAPS may suffer from any other cause of abdominal pain such as acute appendicitis.
Other similar, rare disorders are:
Although TRAPS used to be considered fairly benign, it's now been realised that amyloidosis occurs in about 25%, depending (again) on the exact gene mutation. We don't know of anything at present that will prevent the amyloidosis. Therapy is thus largely symptomatic although two treatments have been considered promising:
Clearly, both of the above treatments have the potential for significant harm. Glucocorticoids may be expected to cause:
Etanercept may result in immune suppression A recent report links exacerbation of enteric tuberculosis to etanercept therapy (Wagner et al).
Pain may be a substantial problem. Apart from the above, "more specific" therapies, one should provide good analgesia in the form of:
If nausea or vomiting are a problem, these should be managed with anti-emetics.
Attacks may be triggered by, e.g. minor trauma or surgery, and thus may be be anticipated/avoided.
|Date of First Publication: 2006||Date of Last Update: 2006/10/24||Web page author: Click here|