Rheumatoid arthritis - abatacept
Rheumatoid arthritis is an autoimmune disease that affects the synovial lining of the joints, and it disproportionately affects women. Initially, the joints become stiff, swollen and painful, but as the disease progresses bone begins to erode and the ligaments supporting the joints are damaged as a result of enzymes being released from inflammatory cells that digest bone and cartilage. Tendon sheaths can also be affected, leading them to rupture.
Rheumatoid arthritis is an autoimmune disease that affects the synovial lining of the joints, and it disproportionately affects women. Initially, the joints become stiff, swollen and painful, but as the disease progresses bone begins to erode and the ligaments supporting the joints are damaged as a result of enzymes being released from inflammatory cells that digest bone and cartilage. Tendon sheaths can also be affected, leading them to rupture.
The inflammation and joint disruption are mediated by T-cell activation, which results in the production of cytokines and the regulation of downstream immune responses. This activation requires a double activation: the activation of an antigen specific receptor on the T-cell, and a co-stimulatory signal. Blocking this co-stimulatory signal prevents the T-cell from being activated, and hence prevents the immune response. Bristol-Myers Squibb has developed abatacept for just this purpose.1
Numerous clinical trials have been carried out. In one, 339 patients with active RA who had been treated with methotrexate were given 10 or 2 mg/kg abatacept or placebo intravenously on days 1, 15 and 30, and then every 30 days for 12 months, in addition to methotrexate.2 A significantly greater proportion of those given the higher dose had a good response than those given placebo; the lower dose proved much less effective. Those who had completed this study could continue for a one-year open label extension with the higher dose plus methotrexate, and a total of 75 completed the course. Response rates were similar at the end of the second year, and almost half had achieved remission.3
It has also been investigated in combination with the anti-tumour necrosis factor treatment etanercept.4 Again, those given abatacept - in this case at a dose level of 2mg/kg - demonstrated significantly higher response rates.
A Phase III trial has been carried out in patients who responded inadequately to anti-TNF treatment.5 A total of 391 patients, who had discontinued the anti-TNF therapy, were given 10mg/kg abatacept or placebo on days 1, 15 and 29 and then every 28 days for six months, in addition to at least one disease-modifying antirheumatic drug at a stable dose. Half of the abatacept group responded, compared to one-fifth of the placebo group.
It is also being investigated as a potential treatment for systemic lupus erythematosus.