PD-1 agonists show promise in treating rheumatoid arthritis by restoring immune balance 

For millions living with rheumatoid arthritis (RA), the path to effective treatment is often a frustrating cycle of trial and error. Typically beginning with disease-modifying antirheumatic drugs (DMARDs) like methotrexate, the goal is low disease activity. Yet RA’s heterogeneity means many patients cycle through various therapies—biologic DMARDs like anti-TNF agents, JAK inhibitors, IL-6 receptor antagonists, T-cell costimulation inhibitors, and B-cell depleting agents—without achieving true remission.

“Right now, the natural thought of a rheumatologist is, ‘I’m going to put them on methotrexate, and then if that doesn’t work, I’m going to put them on an anti-TNF. And if that doesn’t work, I have about seven other drugs out there to treat them with,’” explains Dr. Jonathan Graf, Professor of Medicine at the University of California, San Francisco. This sequential approach, while standard, often fails to address the disease’s root cause.

Despite advances in treatment options, achieving remission in rheumatoid arthritis remains a significant challenge. A substantial proportion of patients do not sustain low disease activity, much less durable remission, regardless of the criteria used. Recent Phase 3 clinical trials have provided important insights into remission rates with newer treatment options. According to the SELECT-COMPARE study, approximately 29% of methotrexate-inadequate responder (MTX-IR) patients achieved DAS28-CRP remission. Similar remission rates were observed in biologic-inadequate responder (biologic-IR) patients, as demonstrated in the SELECT-BEYOND trial. However, when more stringent measures such as the Clinical Disease Activity Index (CDAI) or the Simplified Disease Activity Index (SDAI) are applied, remission rates tend to be lower. Sustained remission over time remains a significant challenge in rheumatoid arthritis management.

These findings are corroborated by the Swedish nationwide study, which also reported low sustained remission rates—22.2% for CDAI, 21.3% for SDAI, and 17.5% for ACR/EULAR criteria—using stringent measures. A 2022 French study following patients over seven years found that about 58% achieved remission by year seven. Finally, adalimumab, considered the “gold standard” TNF therapy, has declining retention rates over time, according to a study in Rheumatology and Therapy. While at one year, 64% of patients remain on the therapy, by year five, only 42% continue treatment. By year eight, that figure falls to 38%.

From symptom suppression to immune reset

Now, a novel approach targeting the PD-1 pathway could offer what Dr. Paul F. Lizzul, Chief Medical Officer at AnaptysBio, describes as “a fundamentally different approach.” One that “resets” the immune system, Graf adds.

Rheumatoid arthritis is a complex and heterogeneous autoimmune disease characterized by chronic inflammation of the joints. The diversity in genetic backgrounds, environmental exposures, and immune system behaviors among patients contributes to this complexity. At the cellular level, research has revealed that up to 80% of T cells in the inflamed joints of any RA patients express PD-1, an important marker of immune activation. This isn’t just a local phenomenon—these PD-1 positive T cells are found to be significantly elevated in the joint tissue and elevated two-fold in circulating blood compared to healthy individuals, as Chen et al. found in Clinical & Translational immunology.

“There’s an abnormal population of PD-1 high expressing cells that shouldn’t be circulating,” Graf explains. “By targeting these cells, we can potentially reset the immune system and provide a more durable response.”

Why traditional approaches often fall short

Traditional RA treatments focus on managing the symptoms of inflammation by targeting specific cytokines or immune cells. From anti-TNF agents blocking key inflammatory proteins to JAK inhibitors interrupting cellular signaling, each advance has brought progress. Yet while beneficial for some, these targeted approaches often fail to provide comprehensive disease control due to the disease’s complexity.

“Traditional approaches to treating inflammation, whether in rheumatoid arthritis or other conditions, have focused on single cytokines and signaling pathways. This is a very different approach,” Lizzul explains. The challenge lies in RA’s complexity—while one inflammatory pathway is blocked, others may continue driving disease activity.

Evidence of this limitation can be seen in the ARCTIC REWIND TNF study, where nearly two-thirds of patients in stable remission experienced disease flares after attempting to taper off their TNF therapy, highlighting the limitations of current treatments.

This inherent limitation of single-target approaches has led researchers to seek solutions that address the disease’s underlying immune dysregulation.

The “surgical precision” of PD-1 targeting

Recognizing these limitations, researchers are exploring ways to modulate the immune system to broadly impact immunological outcomes and restore balance. Targeting the Programmed Death-1 (PD-1) pathway, a critical regulator of immune responses, is central to this innovation. “By targeting PD-1 directly, we’re taking advantage of an endogenous pathway and cell type that’s present in all of us. Normally, it functions properly, but in diseases like RA, the system is out of balance. Our PD-1 agonist aims to restore homeostasis,” Lizzul elaborates.

Graf uses a climate control analogy to illustrate this paradigm shift: “Think about the environment in which one lives. In Phoenix, you have to keep the air conditioning running all summer to keep the house cool. If the air conditioning stops working, you’re in trouble. Move to San Diego—the climate outside controls the climate inside. Electricity bills will be much less because you won’t need air conditioning.” Similarly, by resetting the immune system—changing the body’s internal “climate”—therapies like rosnilimab aim to reduce the need for constant intervention.

The approach works in three key ways: by specifically targeting the depletion of amplifiedPD-1high T cells, including depleting T follicular and peripheral helper cells, and reducing the inflammatory state of activated PD-1intermediate T cells that drive the autoimmune response, while still preserving normal immune function for protection against infections and other diseases, and reducing potential side effects by minimizing broad immunosuppression.

A unique Phase 2b RA trial design

AnaptysBio’s Phase 2b trial for rosnilimab, enrolling over 400 participants, roughly split between both DMARD naïve and DMARD refractory patients, demonstrates the company’s commitment to this novel approach. This represents a significant increase compared to typical Phase 2 trials.

“While most Phase 2 trials study 100–150 patients, this is a 400-plus patient trial,” highlights Graf. “They’ve deliberately structured enrollment to include both biologically naïve patients and those with biological experience. It’s a bold approach…shows confidence in the pathway.”

Toward new horizons in RA treatment

Graf reflects on the potential impact of immune reset: “What if we could get to patients sooner and reset their immune system? Instead of suppressing it for decades, we might change the disease course entirely.”

Returning to the example of the 32-year-old patient, this approach offers hope for a future where long-term reliance on medications is reduced or eliminated. “Telling a 32-year-old woman who’s going to have RA for the rest of her life that we’ll cycle through medicines, hoping one will control the disease well enough—a lot of people would say, ‘I would like my disease to be changed. Maybe I don’t have to be on drugs 40 years from now,'” notes Graf.

This vision of potentially modifying the disease course, rather than just managing symptoms, represents a fundamental shift in how we think about treating RA. Instead of accepting lifelong medication cycling as inevitable, this approach aims to restore normal immune function by specifically targeting and removing pathogenic cells while preserving healthy immune responses.

The success of PD-1 agonists like rosnilimab could herald a paradigm shift in autoimmune disease treatment. “We’re very excited about this target and what it means for patients, not only in rheumatology but across the board,” says Dr. Lizzul. “A PD-1 agonist approach allows us to broadly impact different dysregulated pathways that may be contributing to the overall disease manifestation.”

The Phase 2b trial “deliberately has enrolled patients so there’s a sizable number who are biologic-naïve and a sizable number who are biologic-experienced,” explains Graf. This design allows researchers to investigate whether targeting the immune reset can benefit patients across the spectrum of disease progression.

The implications extend far beyond the current trial. By getting rid of problematic immune cells while allowing the rest to resume their normal role, PD-1 agonists offer the potential for durable remission without constant medication adjustments. This approach may improve upon earlier attempts at immune modulation, offering what Graf describes as “the ability to not only globally agonize the PD-1 system to downregulate pathways but potentially remove the cells that shouldn’t be there.”

For the millions living with RA, particularly younger patients facing decades of treatment, this represents more than just another therapy option. “Right now, in RA, we often think about holding back the disease. But the real thing should be, ‘If we get patients early enough in their RA, can we reset their immune system so they don’t have to be on drugs for the next 50 years?'” Graf asks.

This vision of transforming RA treatment from disease management to potential cure marks a pivotal moment in rheumatology. By shifting from symptom suppression to immune reset, adopting a targeted approach with surgical precision, and raising expectations beyond cycling medications, rosnilimab and similar therapies offer new hope. The potential to fundamentally alter the disease course, rather than simply manage symptoms, could reshape how we think about treating not just RA, but potentially a broad range of autoimmune conditions. For patients, physicians, and drug developers alike, this represents a promising new horizon in autoimmune disease treatment.

 

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Filed Under: Immunology, Rheumatology
Tagged With: autoimmune therapy, biologics, clinical trials, immune reset, PD-1, rheumatoid arthritis, rosnilimab
 

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