Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction, significantly impacting patients’ quality of life. Despite therapeutic advances, a subset of patients remains refractory to conventional treatment, including immunosuppressants, biologics, and targeted therapies. These patients are classified as having polyrefractory rheumatoid arthritis, an extremely challenging condition from both therapeutic and clinical perspectives.
In recent years, chimeric antigen receptor (CAR)-T cell therapy has emerged as an innovative approach for oncological diseases and, more recently, for severe autoimmune disorders. Anti-CD19 CAR-T cells have shown great potential in eliminating autoreactive B cells, opening new perspectives for the treatment of polyrefractory RA.
This article reviews the immunological basis of this approach, its mechanisms of action, the latest clinical results, and the challenges that must be overcome for broader implementation.
The role of B cells in rheumatoid arthritis
B cells play multiple roles in the pathophysiology of RA, being responsible for:
1. Autoantibody production:
Rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA) are RA biomarkers and contribute to complement system activation, amplifying joint inflammation.
2. Antigen presentation:
B cells act as antigen-presenting cells to autoreactive T lymphocytes, perpetuating the aberrant immune response.
3. Pro-inflammatory cytokine production:
B cells secrete cytokines such as TNF-α, IL-6, and IL-10, contributing to chronic inflammation and joint degradation.
Anti-CD20 therapy (e.g., rituximab) has shown therapeutic benefits by depleting circulating mature B cells. However, many patients fail to respond adequately, possibly due to the persistence of B cells in the synovium. This reservoir of synovial B cells represents a challenging therapeutic target and may be one of the reasons for the treatment resistance observed in some patients.
CD19 CAR-T cell therapy
CAR-T cell technology was initially developed for the treatment of hematologic malignancies and has shown impressive results in refractory leukemias and lymphomas. Recently, its use has expanded to autoimmune diseases, including systemic lupus erythematosus (SLE), myasthenia gravis, and multiple sclerosis.
Anti-CD19 CAR-T cells are designed to recognize and eliminate B cells, including both those circulating in the peripheral blood and those residing in the synovium, which evade the action of conventional therapies.
The therapeutic process involves the following steps:
1. T cell collection via leukapheresis.
2. Ex vivo genetic modification: T cells are genetically modified to express a CAR specific for CD19.
3. Cell expansion in the laboratory: CAR-T cells are expanded to reach the required therapeutic dose.
4. Patient lymphodepletion with agents such as fludarabine and cyclophosphamide to reduce innate immune response and allow CAR-T expansion.
5. CAR-T infusion, promoting sustained elimination of pathogenic B cells.
The main advantage of this approach is the ability of CAR-T cells to target and eliminate B cells directly within the synovium, a feat that conventional therapies cannot effectively accomplish.
Clinical evidence: 2025 case study
A study published in Annals of the Rheumatic Diseases (2025) reported the first documented case of a patient with polyrefractory RA treated with CD19 CAR-T cells.
Clinical case description
– Patient: 39-year-old woman with seropositive erosive RA for 20 years.
– Therapy failure: Unresponsive to multiple synthetic and biological DMARDs.
– Clinical status before CAR-T therapy:
– DAS-28-CRP: 7.46 (very high disease activity)
– CRP levels: 104 mg/L (normal <5 mg/L)
– RF: 339 U/mL (normal <14 U/mL)
– ACPA: 489.68 U/mL (normal <2.99 U/mL)
– HAQ-DI: 2.88 (severe functional limitation)
The patient had peripheral B cell depletion but a high presence of CD19+ B cells in the synovium (>70%), suggesting a mechanism of resistance to conventional therapies.
Applied CAR-T therapy
– Target molecule: CD19
– CAR-T type: FMC63-28z
– Lymphodepletion:
– Fludarabine (75 mg/m²)
– Cyclophosphamide (900 mg/m²)
– CAR-T cell dose: 1 × 10⁶ cells/kg
Adverse events and clinical response
– Cytokine release syndrome (CRS): Grade 3 on day 2
– Neurotoxicity (ICANS): Grade 4 on day 5
– Supportive treatment: Tocilizumab, anakinra, and corticosteroids
After 100 days, the patient achieved drug-free remission, with normalization of CRP, RF, and ACPA levels (>80% reduction).
This case demonstrates the positive impact of CAR-T cells in targeting B cells within the synovium, one of the main challenges of conventional therapies.
Challenges of CD19 CAR-T therapy in RA
Despite its therapeutic potential, this approach presents several challenges:
1. Severe adverse events: CRS and ICANS can be life-threatening and require strict monitoring.
2. Duration of response: The longevity of remission post-CAR-T therapy is still unknown.
3. Cost and complexity: Personalized therapy requires advanced infrastructure and high production costs.
4. Lack of robust clinical trials: Although promising, more randomized studies are needed to validate safety and efficacy.
Future perspectives
Research is focused on optimizing the safety and effectiveness of CAR-T therapy, including:
1. CAR modification to reduce toxicity (e.g., CARs with 4-1BB co-stimulation).
2. Use of allogeneic CAR-T cells (off-the-shelf products eliminating the need for individualized manufacturing).
3. Development of bispecific CARs to target multiple immune markers for more sustained effects.
Possibility of sustained remission
CD19 CAR-T cell immunotherapy represents a significant advance for patients with polyrefractory RA, offering the possibility of sustained remission. However, challenges such as safety, cost, and production scalability still need to be addressed for wider clinical use.
Celluris, a pioneer in immunotherapy in Latin America, continues to follow advances in CAR-T therapy for autoimmune diseases, reaffirming its commitment to innovation and accessibility in the treatment of cancer and other immune-mediated conditions.
For more information, visit our news page.
