Are We Putting the “Cart” Before the Horse in Systemic Sclerosis? A Review of the CAR-T Studies in Scleroderma

Objectives Chimeric antigen receptor T-cell (CAR-T) therapy is emerging as a novel approach for systemic sclerosis (SSc). We reviewed the current trial landscape—including study design, therapeutic targets, comparative arms—and integrated these findings with the most recent SSc case series.

Methods On August 20, 2026, we searched ClinicalTrials.gov and ClinicalTrialsRegister.eu using “scleroderma” OR “systemic sclerosis” AND “CAR-T,” and screened references from published studies; identifying 29 actively recruiting trials; extracted prespecified data, including trial identifiers, targets, eligibility criteria, SSc participant details, interstitial lung disease (ILD) rules, product source, immunosuppression protocols, hospitalization requirements, comparators, sponsors, and study designs.

Results Most targeted CD19: 27/29 trials (11 CD19-only; 16 multitarget constructs, ie, CD19 plus BCMA). One study each targeted CD20 or BCMA alone. Products were autologous in 20/29 and allogeneic (“off-the-shelf ”) in 9/29. Only 2 trials were randomized, and just 1 used an active comparator (rituximab). Mostly early diffuse cutaneous SSc (dcSSc) were eligible for inclusion. SSc enrollment was often within broader autoimmune “basket” trials; or SSc-specific studies (n=12). ILD eligibility criteria were inconsistently reported in trial registration: unspecified in 22/29, permitted in 5/29 (with limitations) and required in 1/29. Most protocols mandated immunosuppression washouts and lymphodepletion (Table 1). Three reports demonstrated feasibility and early clinical benefit in SSc. The BREAKFREE-1 update described a multicenter CD19 CAR-T with acceptable safety and encouraging signals in 5 SSc patients.[1] Another reported deep B-cell depletion and clinical responses in 2 patients with dcSSc.[2] Schett et al presented the largest series to date: 6 patients with dcSSc showed improvements in skin and lung disease with manageable safety (low-grade cytokine release, no major neurotoxicity).[3]

Conclusion The SSc CAR-T landscape is promising but fragmented—dominated by early-phase, non-comparative designs with several targets and treatment regimens. Progress could be accelerated by: (1) harmonized eligibility and outcome measures across CD19, CD20, and BCMA programs; (2) fewer and larger multicenter trials; (3) inclusion of comparators or delayed-start designs; and (4) transparent reporting of subsets of SSc and SSc-ILD patients to learn whether it is “too late” for some patients to have optimal benefit. Early clinical signals support further development, but the high cost and risk of inequitable access demand parallel strategies for affordability and global access of CAR-T benefits.

References [1.] Khanna D. Ann Rheum Dis 2025;84:841-2. [2.] Wang X. Cell 2024;187:4890-904.e9. [3.] Auth J. Lancet Rheumatol 2025;7:e83-93.