A tangentially (interesting) related article attached...

Hi Venkatesham,

T cell activation can be targeted e.g. by blocking CD80/86-mediated costimulation with Abatacept. 

Also the CD20-monoclonal antibody Rituximab that targets B cells is effective.

So I think direct targeting of immune  cells is a very interesting option and the challenge will be to target the disease-perpetuating ones while sparing the physiologically important immune cells.

One potential set of targets are the degradative enzymes themselves (MMP's, ADAMS, cathepsins, etc) that mediate the bone/cartilage breakdown in MSK diseases. Though, I don't believe proteinase inhibitors have been successful clinically so far. 

The potential target does not much matter from a clinical standpoint, The therapeutic goal is to induce remission. Also, RA is not one disease but a number of different subsets, each with different pathogenic mechanisms, some through TNF alpha, and others through activation of other cytokines, e.g., IL-1, IL-6, B cells, T cells, etc. Since we do not yet have genetic profiles to treat individual patients, the current approach is empirical hit and miss, until we hit it right, inducing remission in the first, second, or subsequent trials, using different agents with different targets,

The goal of RA treatment is to obtain remission within three months through a treat-to-target approach.

Effectively, DMARDs used for this treatment to date target cytokines , chemokines but also B cells (rituximab), and inhibit T cell activation (Abatacept).

I think the great challenge for the future is to precise the pathophysiology of RA and then develop molecules that target specific cells, specific cytokines and chemokines as well as genes  involved in this pathophysiology given that the ones recommended to date (mainly traditional DMARDs and TNFi) are also used in other similar chronic inflammatory conditions. 

For more details, read the attached paper.

Indeed, I think María is right. And I think the mistake must be made by a B cell because of the epidemiology - increasing incidence with age and stochastic sporadic pattern. T cell diseases should have an incidence skewed to the age of T cell repertoire development - as the seronegative spondarthropathies do. B cells go on making random changes throughout life. RA is very neatly explained by accumulation of B cell clones that can self perpetuate through bystander T cell help and recruit further clones with time.

Inducing remission in 3 months is all very well but the real target is removal of the disease memory cells, as Jakob says. There is a very nice recent paper from the Radbruch group looking at a mechanism for deleting specific B cells using complex ligands. It may be tough to do that for diseases where auto reactive B cells recognise ubiquitous proteins like IgG Fc but somebody should be able to think up a trick for knocking them out specifically. Targeting mediators I think is unlikely to give long term remission. Metalloproteinase inhibition works in animal models of cartilage resorption but has no effect on RA. I thin that is because cartilage is resorbed in RA only when it has already been killed by intra-articular hypoglycaemia induced by TNF. I doubt metalloproteinases damage living cartilage in man.