Today’s interesting journal article comes from Bartelds et al., (2011) in JAMA and looks at “Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up.”

It caught my eye as a result of editorial commentary from Lin (2011) in Science and Translational Medicine.  You can check out both of the papers in the references below for more details.

17130 Development of anti drug antibodies with Humira in rheumatoid arthritis

Source: NIH Medline

Rheumatoid arthritis is a progressive, painful autoimmune disease that affects the joints.  As someone with friends and family who have suffered from the condition, I’m interested in how new developments in our understanding of the biology of the disease can help patients.

Essentially, this research was about the clinical relevance of antidrug antibodies and their impact on long-term outcomes, specifically in relation to adalimumab (Humira), which was the third anti-tumor necrosis factor-α (TNF-α) inhibitor to be approved in the United States after infliximab (Remicade) and etanercept (Enbrel).  TNF-α inhibitors have changed the treatment of autoimmune diseases such as rheumatoid arthritis and have become very much part of the treatment paradigm.

One of the challenges of these biologics though, was summed up succinctly by Lin (2011):

“An eventual loss of therapeutic activity has been reported for these biologics, and it is believed that patients develop antidrug antibodies, resulting in diminished treatment response.”

The key question are how often does this occur and why does it happen?

In order to answer this, Bartelds et al., (2011) followed a group of patients with rheumatoid arthritis (n=272) and looked for a correlation in outcomes with the development of antibodies to adalimumab.

What did they find?

  1. Approximately 28% of the RA patients developed antibodies
  2. The presence of the antibodies was linked with treatment failure and increased RA score
  3. Only 4% with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 (34%) antiadalimumab antibody–negative ones

It is not surprise to find that:

“Not only did patients with antiadalimumab antibodies discontinue treatment more often and earlier than patients without antiadalimumab antibodies, they also had a higher disease activity during treatment and only rarely came into remission.”

Interestingly, use of other anti-rheumatic therapies may explain some, but not all, of the results seen with adalimumab therapy:

“Another point of interest is why some patients develop an antidrug antibody response while others do not.

The use of concomitant immunosuppressants has shown to be associated with a lower frequency of antidrug antibodies. This is supported by the baseline differences for patients with and without anti-adalimumab antibodies in this study; patients who later developed antiadalimumab antibodies less often had concomitant methotrexate in a lower dose and more often had no concomitant DMARD at all.”

The authors also suggested that other factors that may impact the antibody development, such as individual genetic differences and changes in RA disease state.

Looking at the baseline characteristics, Barteld et al., (2011) also noticed that:

“Differences in baseline characteristics between antiadalimumab antibody–positive and negative patients in the present study show that patients with antiadalimumab antibodies had higher baseline disease activity and C-reactive protein levels, longer disease duration, and more often erosive disease.”

It is unclear, however, why and how these characteristics of more advanced disease are associated with the development of the antibodies.

What do these results mean?

Lin (2011) summarised this study nicely:

“The discovery of antidrug antibodies is important, especially for anti–TNF-α biologic therapy, because early detection of these antibodies will allow switching RA patients to another drug with a differing mechanism of action, such as methotrexate or TNF-α receptor decoys.”

In other words, we may be able to better optimise therapy for this debilitating disease and spare patients some of the nasty long term consequences:

“In the near future, rheumatologists might be able to use our body’s own biological response to biologics to predict disease responsiveness earlier and to avoid irreversible damages to tissues, including joints, lungs, and kidneys.”

References:

rb2 large gray Development of anti drug antibodies with Humira in rheumatoid arthritisLin, R. (2011). The Biological Response to Biologics Science Translational Medicine, 3 (80), 80-80 DOI: 10.1126/scitranslmed.3002541

Bartelds, G., Krieckaert, C., Nurmohamed, M., van Schouwenburg, P., Lems, W., Twisk, J., Dijkmans, B., Aarden, L., & Wolbink, G. (2011). Development of Antidrug Antibodies Against Adalimumab and Association With Disease Activity and Treatment Failure During Long-term Follow-up JAMA: The Journal of the American Medical Association, 305 (14), 1460-1468 DOI: 10.1001/jama.2011.406