Does a reset strategy offer curative potential?
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Current therapies for rheumatoid arthritis rely on sustained immunosuppression rather than restoration of immune tolerance, with off-drug remission remaining rare. Recent anecdotal reports suggest that CD19-directed chimeric antigen receptor T (CAR-T) cell therapy may be an effective approach.^1-3 The 2026 Congress of EULAR – The European Alliance of Associations for Rheumatology – was the ideal setting for new data in this exciting field.

In an oral abstract presentation on Wednesday 3^rd June, Fredrik Albach presented results for mivocabtagene autoleucel – an autologous, fully human CD19-directed CAR-T cell therapy – from Phase 1 of the prospective, open-label COMPARE trial in six patients with anti-citrullinated protein antibody (ACPA)-positive, treatment-refractory active rheumatoid arthritis. In general, the treatment was well tolerated, with cytokine release syndrome (CRS) limited to mild-to-moderate events, and no immune effector cell-associated neurotoxicity syndrome (ICANS) or unexpected toxicities reported. CAR-T cells expanded rapidly and peaked within 3 weeks, followed by a gradual decline. B cells were effectively depleted in blood and tissues. There was a marked decrease in autoantibodies, with a median reduction greater than 90% and sustained seroconversion to normal ACPA achieved in four patients, and in five for RF-IgM. All participants also had a decrease in disease activity – with a median 49% DAS28-CRP reduction and ACR20/50/70 responses in 5/6, 4/6, and 2/6 patients respectively – and half achieved sustained remission in the absence of oingoing immunosuppressive therapy. B cell repopulation did not result in reappearance of ACPA+ memory B cells, rise in autoantibodies, or increased disease activity. With the exception of one patient who needed to revert to glucocorticoid due to a moderate flare on withdrawal, all remained-off immunosuppressive therapy at the time of data cut-off, with follow-up of 24–36 weeks.

Another group reported on the first multicentre experience of dual-target CAR-T (CD19/BCMA) in 11 patients with refractory systemic sclerosis. All patients achieved rapid B-cell aplasia, and skin thickness scores improved significantly from baseline, with 73% reaching low disease activity. Functional disability (as measured by HAQ-DI) decreased from 1.0 to 0.2, and both physician and patient global assessments fell. As well as skin fibrosis, lung progression was also targeted – with evidence of stabilisation or improvement in lung volume and oxygen transfer, and high-resolution computed tomography scans confirmed regression of interstitial changes in 80% of patients with baseline interstitial lung disease. No flares occurred during follow-up. One patient with overlap syndrome required retreatment, but achieved remission after their second infusion.

Presenting the work, Yajing Zhang from Beijing GoBroad Boren Hospital, China, said “Dual-target CD19/BCMA CAR-T cell therapy induces profound and sustained clinical remission in refractory systemic sclerosis. By effectively targeting both skin fibrosis and lung progression, this immunological 'reset' strategy offers true curative potential, paving the way for Phase 2 trials to redefine the future management of this severe disease”.

Given that CD19 CAR-T cell therapy profoundly reshapes adaptive immunity – and may alter serum IgA – an abstract from Yuichi Maeda and colleagues sought to investigate effects on the gut microbiome and faecal IgA in patients with severe systemic lupus erythematosus, systemic sclerosis, or idiopathic inflammatory myopathy who received zorpocabtagene autoleucel. Compared to healthy controls, α-diversity was markedly reduced in patients before therapy and remained low 6 months after treatment; β-diversity analyses also showed significantly different microbiota composition in patients compared to controls, and there was enrichment of Streptococcus species, consistent with prior reports.⁴ Intriguingly, this overgrowth decreased to levels comparable to those of healthy controls after the treatment. Mucosal immune activity was significantly decreased as evidenced by reduced faecal IgA levels. It was noted that a subset had delayed CD19⁺ B-cell reconstitution, and these patients were found to have significantly lower baseline faecal IgA, whereas baseline serum IgA, IgG, and gut microbial diversity were not associated with this outcome – suggesting that reduced mucosal IgA at baseline may predispose to impaired immune reconstitution following CAR-T cell therapy. Finally, both anti-commensal IgA and IgG levels were significantly reduced 6 months after therapy, indicating sustained attenuation of humoral immune responses against intestinal bacteria. The authors concluded that these immunomicrobial shifts may support long-term disease remission – and highlight that mucosal immune status could be a potential regulator of immune recovery after CAR-T cell therapy.

Conventional second-generation CAR that rely on CD28 or 4-1BBζ often induce supraphysiological signaling, leading to significant toxicities such as CRS or ICANS. A novel construct called E-CAR has been developed to address this – incorporating the CD3ε cytoplasmic domain to optimise signal transduction by recruiting physiological negative regulators and reducing tonic signaling. A poster presented by Xiaobing Wang and colleagues at the 2026 EULAR congress in London shared results from a pilot study of the first in-human use in four patients with systemic lupus erythematosus or systemic sclerosis. The results showed demonstrated deep, tissue-level remission with a superior safety profile compared to conventional designs. The differentiation of E-CAR-T cells into a tissue-resident memory phenotype could represent a novel mechanism for sustained disease control despite peripheral clearance.

Taken together, these findings support the concept of an immunological reset in a significant proportion of patients across different RMD.

Source
Albach FN, et al. CD19 CAR T-Cell Therapy in ACPA-Positive, Treatment-Refractory, Active Rheumatoid Arthritis - Data from the Phase 1 of the Prospective, Interventional COMPARE Trial. Presented at EULAR 2026; OP008. Ann Rheum Dis 2026; DOI: 10.1136/annrheumdis-2026-eular.B.2103.

Cheng F, et al. Clinical Efficacy Angle – Sustained Remission in Refractory Systemic Sclerosis with Dual-Target CAR-T Therapy. Presented at EULAR 2026; OP0311. Ann Rheum Dis 2026; DOI: 10.1136/annrheumdis-2026-eular.B.4629.

Maeda Y, et al. Immune Reset and Microbial Shifts: Gut Microbiota Dynamics After CD19 CAR T-Cell Therapy in Autoimmune Disease. Presented at EULAR 2026; OP0152. Ann Rheum Dis 2026; DOI: 10.1136/annrheumdis-2026-eular.A.343.

Wang X, et al. First-in-Human Autologous Anti-CD19 E-CAR-T Therapy with a Novel CD3ε Domain Induces Deep Tissue Remission and Resident Memory Differentiation in Refractory Autoimmune Diseases. Presented at EULAR 2026; POS0374. Ann Rheum Dis 2026; DOI: 10.1136/annrheumdis-2026-eular.B.1728.

References
1. Haghikia A, et al. Clinical efficacy and autoantibody seroconversion with CD19-CAR T cell therapy in a patient with rheumatoid arthritis and coexisting myasthenia gravis. Ann Rheum Dis 2024;83(11):1597–8. DOI: 10.1136/ard-2024-226017.
2. Albach FN, et al. Targeting autoimmunity with CD19-CAR T-cell therapy: efficacy and seroconversion in diffuse systemic sclerosis and rheumatoid arthritis. Rheumatology (Oxford) 2025;64(6):4075–7. DOI: 10.1093/rheumatology/keaf077.
3. Lidar M, et al. CD-19 CAR-T cells for polyrefractory rheumatoid arthritis. Ann Rheum Dis 2025;84(2):370–2. DOI: 10.1136/ard-2024-226437.
4. Tomofuji Y, et al. Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lupus erythematosus in Japanese. Ann Rheum Dis 2021;80:1575–83. DOI: 10.1136/annrheumdis-2021-220687.

About EULAR
EULAR is the European umbrella organisation representing scientific societies, health professional associations and organisations for people with rheumatic and musculoskeletal diseases (RMDs). EULAR aims to reduce the impact of RMDs on individuals and society, as well as improve RMD treatments, prevention, and rehabilitation. To this end, EULAR fosters excellence in rheumatology education and research, promotes the translation of research advances into daily care, and advocates for the recognition of the needs of those living with RMDs by EU institutions.

Contact
EULAR Communications, communications@eular.org