Multiple hit model in RA (1)

Multiple hit model in rheumatoid arthritis

The etiology of rheumatoid arthritis is unknown. A tentative model for the development of RA is so-called ‘multiple hit model’ in which the genetic and environmental factors have to come together within one individual for induction and progression of disease.

In this model, immunity against citrullinated antigens is thought to play a pivotal role in the disease for several reasons: citrullinated antigens are found expressed in the inflamed joints. anti-citrullinated protein antibodies (ACPA) are present (in serum) before the disease becomes manifest and has been found in healthy individuals years before they develop RA. ACPAs are highly specific for RA and are hardly found in persons with other diseases. In genetically predisposed individuals, as a consequence of tissue damage inflicted by for example environmental factors such as smoking more citrullinated proteins are formed. Citrullination has been described as a physiological process during apoptosis. See the graphic for the following steps:

1. Citrullinated proteins (c) are ingested

by antigen presenting cells (APC).

2. The APC presents the citrullinated antigen to T cells.

3. T cells provide help to B cells that start to produce ACPAs in susceptible individuals.

4. ACPAs can be found in sera of these individuals who are than not ill yet.

See the graphic below for the next steps:

5. In case of minor trauma or minor inflammation of the joint, monocytes and granulocytes migrate into the synovium, exert their function and die.

6. The release of the cell contents activates enzymes and evokes a calcium influx that results in citrullination of synovial proteins.

7. The present ACPAs form complexes with the citrullinated proteins.

8. This event leads to the formation of complement and attracts new granulocytes, monocytes and mast cells and process perpetuates. These cells produce locally cytokines such as TNF-α which in turn mediate development of signs and symptoms of joint inflammation (pain, edema, functional deterioration of the affected joints and cartilage and bone destruction).


In patients newly diagnosed with RA in general practice, the first class of drugs usually to be initiated are the... 


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