5 Questions About Mechanistic Differences in Biologic Agents for Rheumatoid Arthritis

HLA-DRB1 risk alleles that contain the shared epitope (SE) are strongly associated with rheumatoid arthritis (RA)—SEs are present in a large percentage of individuals with RA and those with anti-cyclic citrullinated protein 2 (anti-CCP2) positivity.

Research has shown that abatacept is more effective for the management of RA with SE compared with RA without SE.¹ However, head-to-head comparisons of biologic agents are limited, and mechanistic differences between biologics remain poorly understood.

Results from a single-blinded, head-to-head clinical trial presented at EULAR 2019² indicated that individuals with early, active RA who received treatment with abatacept had higher efficacy responses compared with those who received treatment with adalimumab. Efficacy responses were even higher among those with SE positivity.

Rheumatology Consultant caught up with Vivian Bykerk, BSc, MD, a rheumatologist at Hospital for Special Surgery in New York, New York, and coauthor of the study, about the research.

RHEUM CON: Why is there a need for biomarkers for the management of RA?

Vivian Bykerk: We currently do not have biomarkers available to indicate which disease will be more severe than another or which treatment will work better than another. Thus, the need for prognosis and treatment guidance could be informed by biomarkers. These have yet to be discovered.

Rheumatology Consultant: Are individuals with RA and anti-CCP2 positivity more difficult to treat?

VB: Anti-CCP2 is an autoantibody made in mucosal tissues such as the lung and oral cavity. It has a role in the initiation of RA, and also in damage progression. The literature does not indicate that this antibody will result in RA being more difficult to treat. On the contrary, its presence indicates RA will respond better to certain medications. However, it is a poor prognostic factor and an indication that treatment should be initiated in the presence of inflammatory arthritis.

RHEUM CON: Were you surprised by the study findings?

VB: This was a relatively small study that suggested individuals with early RA who were anti-CCP2 positive and have at least 1 copy of SE had better disease control after treatment with abatacept compared with adalimumab. I am not surprised by this based on what we know about the pathogenesis of RA. However, this has never been observed in a study that compared 2 biological agents.

Underlying genetic mechanisms >>

RHEUM CON: Were there any differences observed in the incidence of serious infections between the 2 cohorts?  

VB: There was statistically no difference in serious infections between the 2 active treatment groups in our study. The rates of serious infections were typical of what one might see among patients with very active RA.

RHEUM CON: Why do you think it is important for a rheumatologist to understand the underlying genetic mechanisms in individuals with RA?

VB: The expression of underlying genes which are translated to molecular pathways that contribute to persistent auto immunity is central to our understanding of RA. There are several genes that significantly contribute to disease pathogenesis. However, there are many variations of genes and other factors like epigenetics that influence how a gene affects a given individual. Major histocompatibility complex (MHC) class II genes that code for the SE likely influence early adaptive immunity with manifestations such as the production of anti-citrullinated peptides. So, there is a rationale to measure the presence of the SE, but whether or not it will perform as it did in our study still needs further investigation. Thus, I do not think we should be widely testing for the SE; its predictive ability for response to differing biologics requires further validation. Of note in our study, patients recruited were all anti-CCP positive, many with very high titers. This is not always the case for patients diagnosed with RA treated in settings of routine care. However, rheumatologists should be optimistic about these kinds of findings. Such findings could ultimately guide treatment choices based on both clinical knowledge and a biomarker. For the future, we will aim to confirm these findings and other cohorts of early RA, as well as conduct larger studies. Furthermore, we need to evaluate whether or not this test is cost-effective, and whether its use might improve long term outcomes if it indeed indicates which biologic mechanism of action to use to make management choices.

References:

1. Oryoji K, Yoshida K, Kashiwado Y, et al. Shared epitope positivity is related to efficacy of abatacept in rheumatoid arthritis. Ann Rheum Dis. 2018;77(8):1234-1236. doi:10.1136/annrheumdis-2017-211430.
2. Rigby W, Buckner J, Bridges L, et al. The effect of HLA-DRB1 risk alleles on the clinical efficacy of abatacept and adalimumab in seropositive biologic-naïve patients with early, moderate-to-severe RA: data from a head-to-head single-blinded trial [LB0008]. Ann Rheum Dis. 2019;78(suppl 2):A263. https://scientific.sparx-ip.net/archiveeular/?c=a&searchfor=LB0008&view=1&item=2019LB0008. Accessed August 7, 2019.

For more RA content, visit the Resource Center.

For more EULAR content, visit the Resource Center.