Unexpected Findings for Adalimumab in RA, pSpA

August 12, 2014

Adalimumab (Humira) may alter production of tumor necrosis factor-alpha in rheumatoid arthritis patients, returning TNFα levels almost to normal. A study looking at antibodies against the drug in psoriatic arthritis found no clear evidence of an effect.

Zamora-Atenza C, Diaz-Torne C, Geli C, et al, Adalimumab regulates intracellular TNFalpha production in patients with rheumatoid arthritis. Arthritis Research & Therapy (2014) 16(4):R153. doi:10.1186/ar4615. Open Access.

Paramarta JE, Baeten DL. Adalimumab serum levels and antidrug antibodies towards adalimumab in peripheral spondyloarthritis: no association with clinical response to treatment or with disease relapse upon treatment discontinuation.Arthritis Research & Therapy (2014) 16:R160  doi:10.1186/ar4675 [Published: 29 July 2014]. Open Access.

Adalimumab (Humira) may alter production of tumor necrosis factor-alpha (TNFα) in rheumatoid arthritis patients, returning TNFα levels almost to normal, according to a small study from Spain.

In vitro levels of intracellular TNFα in monocytes from 12 RA patients after treatment were comparable to those from 5 healthy donors without RA, researchers found.

The patients, most of them women in their mid-50’s who’d had RA for an average of 13 years, had not been treated previously with other biologicals.

Adalimumab (ADA) is a fully human monoclonal antibody that blocks the interaction of TNFα with its receptors, binding to soluble and transmembrane TNFα.

The researchers used flow cytometry to measure levels of membrane and intracellular TNFα in monocytes taken from the RA patients before and after ADA treatment.

After 2, 6 and 12 ADA injections, the team found significant blocking of membrane and soluble TNFα and a progressive increase in the target monocytes in 10 patients who had good/moderate EULAR clinical responses. After 12 injections, levels of iTNFalpha+/CD14+ cells were comparable to those from healthy individuals.

Confronted with this unexpected finding, the researchers cultured healthy donor cells with added TNFα. There was a subsequent decrease in intracellular TNFα monocytes. This suggests that “TNFα signals induce a negative feedback on intracellular TNFα production or an increased traffic of iTNFα to the membrane,” they wrote.

They also studied cells in the two RA patients who did not show EULAR clinical responses. One patient developed anti-ADA antibodies, and did not show TNFα cell upregulation. The second patient discontinued ADA due to adverse events, and iTNFalpha+/CD14+ cells decreased to pre-treatment levels.

RA Patients with good/moderate EULAR response showed therapeutic levels (over 1 μg/ml) of ADA after 12 injections, with no detectable serum anti-ADA  antibodies.

Whether or not anti-ADA antibodies are able to mute the actions of the TNF inhibitor was the focus of another study, this one involving patients with psoriatic arthritis (PsA). The researchers also assessed the baffling question of whether the drug itself can mask the presence of the antibodies, further confusing the question.

Their 26 pSpA patients, part of a larger randomized trial,  had been randomized to ADA or placebo for 12 weeks, with an additional 12 weeks of open-label ADA for the entire cohort, after which the active drug was stopped.

Researchers found no clear association between ADA serum levels or anti-adalimumab antibodies and clinical treatment response. There was also no association with relapse after treatment discontinuation.

Having used the same assays as previous trials which showed a connection between antibodies and treatment failure, these authors assert that the question of an antibody effect remains unresolved.