TRAPS everywhere!

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!

What is TRAPS?

TRAPS was a syndrome characterised mainly by:

• Recurrent fever, typically lasting longer than a week;
• Abdominal and/or pleuritic pain (with associated nausea,...);
• Associated skin lesions, and/or conjunctivitis;
• Myalgias;
• A wide variety of other symptoms including arthritis.

Pathogenesis of TRAPS

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:

1. Receptors bound to the cell surface continue to be stimulated;
2. Soluble TNF receptor is lowered --- soluble TNF receptor may be an important normal mechanism for mopping up circulating TNF.

What does TNF-alpha normally do?

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:

1. Production of NF-kappa B;
2. Apoptosis (the source of the name "Tumour Necrosis Factor")!

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.

Fine print

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.

How is TRAPS diagnosed?

There are two important components to the diagnosis of TRAPS:

1. The characteristic clinical syndrome;
2. Gene studies confirming a relevant mutation in the TNF-R1 [etc] receptor.

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.

Differential diagnosis

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:

• Familial Mediterranean Fever (FMF) due to an abnormality in the marenostrin (aka pyrin) gene, which codes for a nuclear transcription protein that probably damps down the inflammatory response of neutrophils, eosinophils and monocytes. Features are recurrent fever, polyserositis and arthritis, and Henoch-Schönlein purpura is common. 10% have polyarteritis nodosa, and one quarter get amyloidosis. Colchicine works here (but not in TRAPS). Pyrin appears to mediate IL-1 processing and secretion (and also NF-kappa B activation).
• HIDS - the hyperimmunoglobulinaemia IgD syndrome is similar, but lymphadenopathy and skin vasculitis are common. Oral aphthous ulcers are frequent. The disease is due to deficiency of mevalonate kinase, which can be tested for. Serum IgD levels are very high (over 100 IU/ml, polyclonal). Treatment is tricky, but NSAIDs may help. Inheritance is autosomal recessive, often in Dutch kindreds. IL-1 beta secretion may be increased in this disorder. HIDS is probably the only one of these disorders not associated with amyloidosis. Do statins work in this disorder? See also hids.net!
• Chronic infantile neurological and articular syndrome (CINCA) is another autosomal dominant syndrome, starting in the neonatal period with persistent migratory rash, lymphadenopathy, fever and hepatosplenomegaly. Other peculiar features are deafness, and aseptic meningitis, uveitis and optic papillitis. There are dysmorphic features, notably prominent patellae and enlarged epiphyses, and later on a saddle nose with frontal bossing. Otherwise known as NOMID (Neonatal onset multisystem inflammatory disease).
• Familial cold autoinflammatory syndrome (FCAS) starts in infancy, and is seen mainly after cold exposure. There is fever with urticarial rash, and may be a variety of other symptoms such as conjunctivitis, arthralgias, profuse sweating and drowsiness. There is at present no effective therapy. Synonyms (more or less) are "Familial Cold Urticaria Syndrome, FCU". Autosomal dominant.
• Muckle-Wells syndrome (MWS) is again similar, usually starting in adolescence with fever, urticarial rash and arthralgias. Progressive deafness is characteristic, and amyloidosis (AA) also occurs. Autosomal dominant. FCAS and MWS may be due to mutations in the same gene, the "CIAS" gene on 1q44. Even CINCA may be due to different mutations of this vital gene.
• And what about the PAPA syndrome? --- Pyogenic arthritis with pyoderma gangrenosum and acne!

Treatment and Prognosis

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:

1. corticosteroids;
2. Etanercept (recombinant chimeric TNF alpha receptors).

Clearly, both of the above treatments have the potential for significant harm. Glucocorticoids may be expected to cause:

• Osteoporosis, especially in the long term;
• Hypertension;
• Diabetes or impaired glucose tolerance in susceptible individuals;
• Immune suppression;
• Other corticosteroid effects such as CNS effects, muscle weakness, hypokalaemia and skin atrophy.

Etanercept may result in immune suppression A recent report links exacerbation of enteric tuberculosis to etanercept therapy (Wagner et al).

Symptomatic treatment

Pain may be a substantial problem. Apart from the above, "more specific" therapies, one should provide good analgesia in the form of:

• Non-steroidal anti-inflammatories;
• Opiates or opioids such as tramadol, as required;
• Paracetamol.

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.

Bibliography

1. Wajant H, Pfizenmaier K, Scheurich P Nature: Cell Death and Differentiation 2003 10(1), 45-65 Tumor necrosis factor signaling

2. Wagner TE, Huseby ES and Huseby JS Exacerbation of Mycobacterium tuberculosis enteritis masquerading as Crohn's disease after treatment with a tumor necrosis factor-alpha inhibitor Am. J. Med. 2002 112: 67-69

3. Check out: Drenth JP, Van der Meer JW: Hereditary periodic fever N Engl J Med 2001; 345(24):1748-57.

4. http://fmf.igh.cnrs.fr/infevers/ -- the INFEVERS website contains a list of all known gene mutations.
   See also the NCBI.