Abatacept response in seropositive RA may be linked to HLA gene

MADRID – Stratification of seropositive RA patients based on the presence of the shared epitope in human leukocyte antigen DRB1 gene alleles might help clinicians to predict which patients are most likely to respond to abatacept, according to results from the “exploratory” Early AMPLE study.

^{Sara Freeman/MDedge News}

Dr. Vivian Bykerk

Clinical responses seen in the study were higher in the abatacept (Orencia) versus adalimumab group, study investigator Vivian P. Bykerk, MD, reported at the European Congress of Rheumatology. Indeed, a 20% improvement in American College of Rheumatology response criteria (ACR20), as well as ACR50 and ACR70 responses, were achieved by 83%, 70%, and 48% of abatacept-treated patients and by 63%, 45%, and 30% of adalimumab-treated patients.

Numerically higher percentages of patients who were treated with abatacept and had the shared epitope in the human leukocyte antigen (HLA) DRB1 (HLA-DRB1) allele achieved ACR20-level improvement when compared against treatment with adalimumab, and the same was seen for ACR50 and ACR70 response rates.

“The results we saw were clearly driven by the presence of the shared epitope, and there may be a differential benefit by treating the shared epitope in early RA patients with abatacept, compared with adalimumab,” said Dr. Bykerk, who is director of the Inflammatory Arthritis Center of Excellence at the Hospital for Special Surgery in New York.

The investigators also observed numerically higher responses on the Simplified Disease Activity Index and Clinical Disease Activity Index as well as the 28-joint Disease Activity Score using C-reactive protein.

The shared epitope is a major histocompatibility complex (MHC) class II protein receptor encoded by some alleles of the HLA-DRB1 gene. It’s found in the majority (70%–80%) of RA patients who are seropositive for anti-citrullinated protein antibodies (ACPAs), and it’s linked to joint destruction.

Prior work has suggested that abatacept may be more effective in RA patients who have the shared epitope than in those who do not, Dr. Bykerk explained.

Early AMPLE (Abatacept versus adalimumab comparison in biologic naive RA subjects with background methotrexate) was a prospective, randomized, single-blind, controlled study that ran for 24 weeks. It’s aim was to look at changes in immune cells and proteins in response to treatment with abatacept and adalimumab, which were both given in combination with methotrexate, and in relation to the presence or absence of the shared epitope.

Since abatacept works directly on T-cell activation, the investigators hypothesized that it should have a greater effect than other agents that work further downstream, such as the tumor necrosis factor (TNF) inhibitor adalimumab.

A total of 80 patients who had RA for less than 1 year and had not previously been treated with a biologic were recruited; all were positive for ACPA, specifically anti–cyclic citrullinated protein 2 (anti-CCP2) antibodies, and 76% had the shared epitope.

“Of note, we observed higher ACPA levels in the shared epitope group, and this requires further observation and understanding,” Dr. Bykerk said. The mean level of anti-CCP2 antibodies in patients with and without the shared epitope were a respective 1,216 U/mL and 368 U/mL.

Patients had been randomized 1:1 to receive either abatacept (125 mg given subcutaneously every week) or adalimumab (40 mg given subcutaneously every 2 weeks) on top of continuing weekly treatment with oral methotrexate.

“For a long time, we’ve wanted to try to match a therapy’s mechanism of action to what’s going on with the patient,” Dr. Bykerk commented in an interview. “Clinical phenotyping is usually not good enough, and we are always guessing,” she added. Plus, she noted, RA treatments tend to be used in the order in which they were approved rather than there being a rationale for using one over another based on their suitability in a particular situation.

The Early AMPLE data “are a first step towards the rational choice of therapy that might be more likely to be sustainable in a patient for a longer period of time and actually continue to modify the disease,” Dr. Bykerk suggested.

TNF inhibitors “work across the board in early disease,” she observed. “The problem is that after a year or two that only 44% of people are left on their first TNF, and why is that?” Reasons for the loss of effect are not known. Using a drug that works in a different way might prove to be the answer, such as seen here with abatacept in seropositive patients with the shared episode, but further studies will be needed to validate the Early AMPLE findings.

Bristol-Myers Squibb sponsored the study. Dr. Bykerk disclosed receiving grant or research support paid to her institution from BMS, as well as Amgen and UCB. She also disclosed acting as a consultant to BMS and multiple other pharmaceutical companies. Several coauthors were employees and shareholders in BMS, or had acted as consultants to BMS.

SOURCE: Rigby W et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):263-4. Abstract LB0008 , doi: 10.1136/annrheumdis-2019-eular.8668.