Introduction
(Article introduction authored by Conquest Editorial Team)
In recent years, significant strides have been made in understanding the genetic, environmental, and immunological factors contributing to rheumatoid arthritis (RA).
Detection of serum autoantibodies to citrullinated protein antigens (ACPA) along with symptoms like inflammatory joint pain has enhanced the ability to identify individuals at high risk of developing RA within a couple of years.
Abatacept, a biological disease-modifying antirheumatic drug, targets T-cell activation by modulating co-stimulatory signals. Studies have shown its efficacy in treating active RA, both alone and in combination with other drugs, particularly in patients with inadequate responses to conventional treatments.
Furthermore, research suggests that abatacept may be effective, especially in early-stage RA patients, indicating the importance of co-stimulatory signals in the early phases of the disease.
Considering its mechanism of action and the role of T cells in early RA development, we sought to investigate the potential of abatacept in individuals at high risk of developing RA.
Methods
The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited.
Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months.
Masking was achieved by providing four kits with pre-filled syringes with coded labels of abatacept or placebo every 3 months.
The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021.
Results
Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were enrolled, and of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo (Fig 1). Of 59 participants who did not meet eligibility criteria, 13 had progression of symptoms, including development of clinical arthritis. Seven participants declined to participate and one could not be contacted. Overall, 42 participants withdrew (21 in each group), 32 before and ten after a primary event. 89 (81%) of 110 participants in the abatacept group and 82 (80%) of 103 participants in the placebo group completed the study.
In the intention-to-treat analysis, a significantly lower proportion of participants in the abatacept group (6%) compared to the placebo group (29%) met the primary endpoint by 12 months. This trend continued at 24 months, with 25% in the abatacept group and 37% in the placebo group
meeting the end point. Kaplan-Meierarthritis-freesurvivalplots favored abatacept at 24 months (p=0.044). The estimated proportion remaining arthritis-free was higher in the abatacept group at both 12 months (92.8% vs. 69.2%) and 24 months (70.4% vs. 58.5%), (Fig 2).
The unadjusted Cox regression model initially favored abatacept over placebo with an HR of 0.61 (95% CI 0.37–0.99), but the proportional hazards assumption was violated (p=0.0025).
However, for the first 12 months, the assumption held, showing a HR of 0.20 (95% CI 0.09–0.45). Consequently, restricted mean survival time was used as a summary statistic, indicating a significant difference favoring abatacept in arthritis-free survival at 24 months (p=0.0016).
Similar results were observed in the per-protocol analysis. Although 80 participants took disease-modifying antirheumatic drugs or corticosteroids during the study, fewer in the abatacept group required these medications compared to placebo at both 12 and 24 months.
Additionally, at 12 months, participants in the placebo group had a higher proportion of swollen joints compared to the abatacept group, with less substantial differences at 24 months. Reductions in pain and disease activity scores favored abatacept at the end of the treatment period but were not sustained at 24 months.
Consistent positive responses favoring abatacept were observed at 12 months across various measures including function, pain, emotional wellbeing, quality of life, anxiety, and certain domains of the IPQ-R questionnaire.
However, these effects were not sustained by 24 months. Symptom improvements were noted in the abatacept group, particularly in joint pain, perception of joint swelling, and sleep problems, as indicated by the SPARRA questionnaire.
Radiographic assessments showed fewer participants with worsening scores in the abatacept group compared to placebo, particularly in synovial hypertrophy and vascularity, although these effects weren’t maintained after treatment cessation.
Adverse events were comparable between groups, though certain events like gastrointestinal, haematological, neurological, and others were higher in the abatacept group.
Serious adverse events were reported in both groups, with no clear association with the study drug. Additionally, pregnancies were reported in both groups, with a slightly higher incidence in the abatacept group.
Discussion
The phase 2B study results demonstrate that abatacept treatment reduces progression to clinically apparent arthritis in adults at high risk of developing rheumatoid arthritis during the treatment phase. Even after treatment cessation, the number of events remained lower in the abatacept group, indicating sustained efficacy.
However, by 24 months, symptom burden, including quality-of-life assessments and pain, as well as ultrasonography of subclinical inflammation, were similar between groups, suggesting that the effects of 12 months of abatacept treatment were not sustained. These findings suggest that T-cell co-stimulation plays a role in the progression from the at-risk state to rheumatoid arthritis, but harmful adaptive immune reactions contribute to the symptom burden associated with the at-risk state. Pathogenic immune responses re-emerge after treatment withdrawal, indicating that they are not modified permanently by a fixed period of co-stimulation modulation.
The study design, including encouraging participants to remain in the study regardless of outcomes, might also influence the observed effects. Other interception trials have shown mixed results, highlighting the challenges in preventing or delaying the onset of rheumatoid arthritis. The APIPPRA trial strengths include its real-life clinical setting, robust primary endpoint, and evaluation of the effects of study drug on subclinical synovitis.
Limitations include the short follow-up period and challenges in assessing clinically meaningful changes in response to the study drug. Non-adherence rates were similar to other interception trials, suggesting a need for better adherence strategies in future trials.
In conclusion, the study demonstrates the feasibility of rheumatoid arthritis interception trials and suggests that sustained efficacy of abatacept treatment beyond 12 months might be required. Criteria to distinguish the at-risk phase from early rheumatoid arthritis are needed to support trial design, and the benefits of biological therapy must be balanced against upfront treatment costs and challenges in predicting individuals at high risk.
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