Autoinflammatory diseases

Question 1

Compare and contrast the two main autoinflammatory disorders.

Comment on inheritence, age of onset, race, length of fever, symptoms

Answer 1

TRAPS: AD inheritence, age <20, all race, fever 3d - weeks, myalgia and angioedema

FMF: AR, age varied, Turks, Jews, Arabs, Armenians, 0.5d-3d fever, symptoms are serositis and rash

Question 2

What produces TNF?

Answer 2

It is produced by activated macrophages

Question 3

How does TNF metabolism happen?

Answer 3

It is produced by macrophages, it is then sent to the cell surface, where it is membrane bound.

Then it is proteolytically sheared off and is then soluble TNF where it then spreads and can activate other thing (endothelial cells and neutrophils for eg)

Question 4

Describe the structure and function of the TNF-R1 please

Answer 4

This is a large molecule. It has 4 extra cellular components and a large transmembrane/intracellular part.

The typical action of TNFR1 is to set off a signalling cascade, via the “caspase” group of proteins, leading to apoptosis. Typically the cell with the TNFR1 is a neutrophil, so turning this cell off, via apoptosis is a safe way for the body to turn off inflammation.

TNFR2 tends to lead to cell (predom PMN) survival, BUT both TNFR1 and TNFR2 can lead to cell survival and inflammation via the NF-kappa-Beta

Question 5

The following slide is a picture of the MoA of TNFalpha

When looking at the picture describe the role of the free-TNF-R

Describe how, normally, inflammation is regulated in this setting.

Answer 5

see picture

There are specific proteolases that cleave the TNF-R from the transmembrane proteins, this means the response just sort of burns out

Also, the free TNFR then mop up any soluble TNFalpha, also downregulating the response

If we have “mutant” TNFR, then we see that the TNFr can not be cleaved, and then excess soluble TNFalpha is NOT mopped up, leading to ongoing inflammation

An alternative pathology for mutant TNFr is when the TNFR is so deformed that it doesn’t even make it to the cell surface, and in fact, is activated inside the cell! (see section 5)

Question 6

So, what actually can we see in TRAPS? (TNF Receptor Associated Periodic Syndrome)

Answer 6

This is a TNFR abnormality whereby there is inability to cleave the transmembrane part of TNFR,

OR it is constitutionally activated and doesn’t even make it to the cell surface

OR the TRAPS mutation can lead to reduced internalisation, which leads to less apoptosis (the T50M mutation)

The downstream MEASURABLE finding is decrease soluble TNF-R

Question 7

In TRAPS, which amino acid mutation is most important to predict phenotypic abnormality?

(that is to say, losing which of the amino acids due to a mutation would lead to the greatest symptoms?)

Answer 7

Cysteine seems to be one of the most important, because its loss leads to a loss of disulphide bond formation. This must then lead to an abnormal tertiary structure

Of course hydrogen bonds are also important.

Question 8

So what is the treatment for TRAPS, and are there any specific things you need to test for prior to initiation of the treatment?

Answer 8

Steroids are the first choice usually, but there are lots of side effects of this long term (which is often required)

Well, the most useful has been the biologicals. Particularly the anti-TNF agents. The other option is the anti-IL-1-MAb. (IL1 drives the inflammation)

There are at least 5 mutations that respond very badly to infliximab.

T50M

R92Q

C33Y

C30S

C43S

These mutations interact with infliximab and can cause a life threatening exacerbation of the TRAPS

Question 9

What is the difference between the different anti-TNF agents?

Answer 9

Infliximab is chimeric - therefore risk of neutralising antibodies. It is an antibody AGAINST TNF-alpha

Adalimumab is recombinant human.

Both inflix and adalimu can bind to membrane-bound TNF and lead to complement dependent cell lysis or apoptosis.

Etanercept is an Fc region bound to TNF-receptor. Therefore it mops up TNFalpha. This is a slightly less strong mechanism of inhibiting TNFalpha.

Question 10

what is familial Mediterranean Fever?

Answer 10

This is an autosomal recessive condition with really high carrier rates.

consider it as neutrophilic peritonitis/pleurisy/synovitis

Often get operations for concerns about abdomen.

There is persistent inflammation - HIGH risk of AA amyloid

Colchicine is effective

Question 11

What is the particular defect/gene in FMF?

Answer 11

The gene is called “pyrin” and it is associated with regulation of inflammation

It is located in the neutrophil cytosol

Question 12

What is Behcet’s disease?

Answer 12

Overall, it is abnormal T cell response to microbial antigen or a superantigen.

Causes vasculitis, capillaries to aortic root can be affected.

Diagnosis is clinical.

Question 13

What is Still’s disease?

Answer 13

This is a rare, auto-inflammatory condition that is likely polygenic.

We don’t really know how it’s caused, but it appears to be related to dysregulation of the IL1 pathway.

It is currently considered a diagnosis of exclusion.

The classic triad is fevers, joint pain and a distinctive salmon-coloured maculopapular rash

Question 14

Differentials for pyrexia unknown origin

Answer 14

1. Infection
2. Malignancy
3. Drug hypersensitivity
4. Autoimmune disease
5. Sarcoidosis / Amyloidosis
6. Autoinflammatory disorders

Question 15

What are the clinical features of TRAPS?

Answer 15

TNF Receptor Associated Periodic Syndrome:

Febrile Episodes

Skin Inflammation - erythema (erysipiloid rash)

Abdominal pain (sometimes present as ‘surgical’ abdomen)

Orbital oedema

Conjunctivitis

Focal myalgia

Arthritis

Orchitis

AA amyloid (14%)

Monocytic fasciitis

Osteoporosis

Low serum TNFR1

Question 16

Explain the differences between the TNF inhibitors Infliximab, Adalimumab and Etanercept

Answer 16

Infliximab: IgG - Human Fc region, mouse variable region Ab. High affinity for TNFR. As a complete Ab can have effect (eg. apoptotic) on cells –> probably contributes to therapeutic effect.

Adalimumab: recombinant human Ab to TNFR. High affinity for TFNR. As a complete Ab can have effect (eg. apoptotic) on cells –> probably contributes to therapeutic effect.

Etanercept: Human Ig Fc portion fused to two TNF receptors (“mops up TNF”). Lower affinity TNFRII fusion proteins. Serum TNF transiently surges at commencement. No effect on cells - probably reason it is not effective in Crohn’s or Psoriasis (cf. Inlfiximab and Adalimumab). It is effective in RA.