Long-Term Outcomes of Abatacept in Individuals at Risk of Rheumatoid Arthritis: Insights from the ALTO Study

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting millions globally, characterized by joint inflammation, pain, and progressive disability. While current treatments focus on managing established disease, preventing or delaying the onset of RA in high-risk individuals has emerged as a crucial research focus. The ALTO study—the long-term follow-up of the APIPPRA trial—provides critical insights into how early intervention with abatacept, a T-cell co-stimulation modulator, impacts disease progression in individuals at risk of RA.

This article delves into the findings of the ALTO study, exploring its implications for early intervention, long-term safety, and risk stratification in preclinical RA.

Understanding Rheumatoid Arthritis Risk and Disease Interception

Rheumatoid arthritis is driven by autoimmune mechanisms that attack joint tissues, leading to pain, stiffness, and, over time, irreversible damage. While RA can occur spontaneously, research has identified a preclinical phase in which individuals display certain biomarkers and symptoms but have not yet developed clinical arthritis.

Two key indicators of RA risk are:

1. Anti-citrullinated protein antibodies (ACPA) – autoantibodies targeting citrullinated proteins.
2. Inflammatory joint pain (arthralgia) – pain without overt joint swelling.

Individuals positive for ACPA and other autoantibodies are considered high-risk for developing RA, making them prime candidates for disease interception trials aimed at delaying or preventing the onset of RA.

The concept of disease interception emphasizes predicting disease before clinical manifestation and intervening early to reduce progression. Abatacept has emerged as a potential therapeutic agent in this context due to its ability to modulate T-cell activation, a critical driver of autoimmunity.

The APIPPRA and ALTO Studies: Design and Methods

The Arthritis Prevention In the Preclinical Phase of Rheumatoid Arthritis with Abatacept (APIPPRA) trial was a phase 2b, randomized, double-blind, placebo-controlled study. It enrolled 213 high-risk individuals across the UK and the Netherlands, who received either:

• Abatacept: 125 mg subcutaneous injections weekly for 52 weeks (n=110)
• Placebo: weekly injections for the same duration (n=103)

The primary endpoint was the time to development of clinical synovitis, RA according to ACR–EULAR 2010 criteria, or initiation of disease-modifying antirheumatic drugs (DMARDs).

The ALTO (APIPPRA Long-Term Outcome) study extended follow-up for 4–8 years, allowing researchers to evaluate:

• Durability of abatacept’s effect
• Long-term safety profile
• Risk stratification based on autoantibody profiles

Importantly, participants and clinical assessors remained masked to treatment assignment throughout the ALTO follow-up, ensuring unbiased data collection.

Key Findings: Abatacept Delays RA Onset

The ALTO study enrolled 143 participants from the original APIPPRA cohort. Median follow-up time from randomization was 55 months, providing a substantial dataset for assessing long-term outcomes.

1. Delayed Progression to RA

Abatacept treatment delayed progression to RA for up to 4 years. Kaplan–Meier survival analysis revealed:

• 4-year restricted mean survival times: 34.0 months in the abatacept group vs. 29.1 months in the placebo group
• Difference: 4.9 months (95% CI 0.1–9.6; p=0.044)

While the initial delay observed at 2 years persisted, the magnitude diminished over time. By 6 years, cumulative progression to RA was similar between groups (73% abatacept vs. 70% placebo), indicating that abatacept delays but does not prevent RA long-term.

2. Autoantibody Profile Predicts Response

ALTO explored how baseline autoantibody profiles influenced disease progression and treatment response:

• High IgG ACPA titers (≥340 IU/mL): these participants were at higher risk of progression but showed a better response to abatacept.
• Extended autoantibody serotype (positive for all five measured autoantibodies: RF, IgG ACPA, IgA ACPA, anti-carbamylated, and anti-acetylated protein antibodies):
  • Placebo group: faster progression to RA
  • Abatacept group: greater separation of arthritis-free survival curves at 2 years
  • Effect sustained up to 6 years

These findings suggest that risk stratification using autoantibody profiles could optimize early intervention strategies.

3. Symptom Relief During Treatment

Abatacept was effective in reducing symptom burden during the treatment period, including joint pain and functional impairment. However, benefits waned after treatment cessation, highlighting that ongoing therapy may be necessary to maintain symptom control in at-risk individuals.

4. Radiographic Outcomes

X-rays of hands and feet showed very low erosion and joint space narrowing scores, indicating minimal structural damage during the follow-up period. No significant differences were observed between groups, reflecting the preclinical nature of the study population.

Safety Profile of Abatacept

Safety data from the ALTO study confirmed that abatacept was well tolerated:

• Serious adverse events: 18 in abatacept group, 13 in placebo group; none drug-related
• Events of special interest: 51 in abatacept group, 44 in placebo group, including infections, cardiovascular events, and pregnancies
• Only one mild fungal nail infection was possibly related to abatacept

These findings underscore the long-term safety of short-term abatacept therapy in high-risk individuals.

Implications for Clinical Practice

The ALTO study provides important insights for clinicians and researchers:

1. Early intervention can delay RA onset: even a 12-month course of abatacept delayed progression by up to 4 years.
2. Autoantibody profiling guides therapy: individuals with high-risk profiles benefit most from targeted intervention.
3. Continuous monitoring may be necessary: symptom relief is temporary, suggesting ongoing immune modulation may be required for sustained benefit.
4. Preclinical RA research should focus on personalized strategies: combining clinical, imaging, and serological markers could refine risk assessment and intervention timing.

Limitations and Considerations

While ALTO provides robust long-term data, several limitations exist:

• Gap between the end of APIPPRA and ALTO recruitment may have affected precise outcome capture
• Not all original participants enrolled in ALTO, although primary events were retrospectively assessed
• Symptom assessments post-treatment showed convergence between groups, suggesting temporary benefit

Despite these limitations, ALTO remains one of the most comprehensive long-term follow-ups of disease interception in RA.

Future Directions in RA Prevention

The ALTO findings highlight the need for continued research into:

• Mechanisms of disease progression: understanding T-cell subsets and autoantibody features
• Optimized treatment duration: defining how long early intervention should continue for maximal benefit
• Refined risk stratification: integrating biomarkers, imaging, and genetic data for personalized prevention strategies
• Novel therapeutic targets: expanding beyond abatacept and current DMARDs to prevent autoimmunity at its source

Conclusion

The ALTO study confirms that short-term abatacept therapy delays the onset of rheumatoid arthritis in high-risk individuals, particularly those with extensive autoantibody profiles. While progression is ultimately not prevented, the delay provides a critical window for monitoring, lifestyle modification, and early therapeutic intervention.

Long-term follow-up is essential to capture both durability of treatment effects and safety outcomes, and risk stratification based on autoantibody profiles can guide personalized disease interception strategies.

For patients, clinicians, and researchers, ALTO underscores a paradigm shift from reactive treatment to proactive prevention in rheumatoid arthritis.

References

1. Cope AP, et al. Long-term outcomes of abatacept in individuals at risk of developing rheumatoid arthritis (ALTO): a randomized, double-blind, placebo-controlled trial. Lancet Rheumatology. 2026.
2. Deane KD, et al. Preclinical rheumatoid arthritis: epidemiology, risk factors, and preventive strategies. Nat Rev Rheumatol. 2020;16:573–586.
3. van Schie KA, et al. Autoantibody profiles in predicting rheumatoid arthritis progression. Arthritis Rheumatol. 2021;73:123–134.
4. Filer A, et al. Disease interception in rheumatoid arthritis: results from APIPPRA and ARIAA trials. Ann Rheum Dis. 2024;83:102–110.
5. Smolen JS, et al. Treating early rheumatoid arthritis: opportunities and challenges. Lancet. 2020;395:998–1010.

Disclaimer

This blog is intended for educational and informational purposes only. It does not constitute medical advice. Patients should consult a qualified healthcare provider before making any treatment decisions related to rheumatoid arthritis or other health conditions.