WHAT IS ALREADY KNOWN ON THIS TOPIC
Chimeric antigen receptor T-cell (CAR-T) cell therapy has revolutionised the treatment of B-cell malignancies, but evidence for its application in rheumatic autoimmune diseases remains limited to case reports and small series without systematic synthesis.
WHAT THIS STUDY ADDS
This systematic review demonstrates that CAR-T therapy achieves sustained drug-free remissions with high response rates across six rheumatic conditions, with markedly milder toxicity.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These findings support the accelerated development of randomised controlled trials and highlight the need for specialised rheumatology-haematology collaboration centres to deliver this potentially curative therapy for patients with treatment-refractory disease.
Introduction
Autoimmune rheumatic diseases affect approximately 10% of the global population, with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and inflammatory myopathies representing the most prevalent and debilitating manifestations. 1 These heterogeneous disorders are characterised by immune dysregulation, chronic inflammation and progressive multiorgan damage. 2 Despite significant advances in understanding disease pathogenesis and targeted biological therapies, a subset of patients experiences treatment-refractory disease with progressive organ damage and substantial morbidity. 2
Early intervention with effective therapies can improve long-term outcomes. Current treatment strategies have substantially improved patient outcomes, with the majority of patients achieving disease control with conventional and biological disease-modifying agents. 3 Nevertheless, a minority of patients respond inadequately to these therapies, particularly in severe or refractory cases. Current therapeutic paradigms for such patients involve chronic immunosuppression that may not fully address the underlying pathogenic mechanisms, potentially resulting in cumulative toxicity, increased risk of infection and infrequently achieving drug-free remission. For patients with treatment-refractory disease, this therapeutic landscape underscores the potential value of innovative approaches that might fundamentally reset immune dysregulation rather than merely suppress inflammatory pathways. 4
The central role of aberrant B-cell function in autoimmune pathogenesis has been established through two decades of clinical experience with B-cell-targeted therapies, particularly rituximab. 2 B lymphocytes contribute to autoimmune pathogenesis through multiple mechanisms beyond antibody production, including antigen presentation, cytokine secretion and pathogenic T-cell activation. The specific contributions of autoreactive B cells vary across rheumatic conditions: in SLE, B cells produce pathogenic autoantibodies, including anti-double-stranded DNA and anti-Smith antibodies that drive immune complex deposition and organ damage; in systemic sclerosis (SSc), B cells contribute to fibrosis through autoantibody production (anti-topoisomerase I, anti-RNA polymerase III) and profibrotic cytokine secretion; in inflammatory myopathies, myositis-specific autoantibodies (anti-Jo-1, anti-SRP (signal recognition particle), anti-Mi-2) produced by autoreactive B cells correlate with distinct clinical phenotypes and in RA, B cells produce rheumatoid factor (RF) and anticitrullinated protein antibodies that perpetuate joint inflammation. 5 Conventional B-cell-depleting therapies have demonstrated efficacy in RA, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and SLE, validating B cells as therapeutic targets. 6 However, these approaches typically achieve incomplete depletion, particularly within tissue niches and lymphoid organs, potentially explaining their variable and often transient clinical benefits.
Building on this foundation, chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has emerged as a promising therapeutic approach, with multiple clinical trials currently registered for rheumatic diseases. CAR-T therapy has transformed haematological malignancy treatment, demonstrating unprecedented efficacy in refractory conditions. 7 Following regulatory approval of CD19-directed CAR-T products for B-cell malignancies and B-cell maturation antigen (BCMA)-targeted CAR-T cells for multiple myeloma by the US Food and Drug Administration, cumulative clinical experience has established their capacity for profound and sometimes durable responses in previously treatment-resistant diseases. 8 The encouraging results in oncological applications prompted the exploration of potential therapeutic applications in autoimmune conditions, particularly those with established B-cell pathophysiology. 9
The rationale for employing CAR-T cell approaches in autoimmune disorders is supported by both mechanistic and clinical perspectives. CAR-T cells may overcome the limitations of conventional B-cell depletion through more profound and sustained elimination of target populations, potentially disrupting immunological memory and enabling immune system recalibration. 10 Recent case reports and small clinical series have documented encouraging initial results in refractory autoimmune diseases, suggesting substantial potential clinical benefits. 1 However, the transition from proof-of-concept studies to widespread clinical implementation faces significant barriers, including narrow patient eligibility criteria, substantial treatment costs, safety concerns and fundamental differences between autoimmune diseases and haematological malignancies. 11
This systematic review aimed to collate and critically evaluate the current evidence for CAR-T cell therapy in autoimmune rheumatic diseases, focusing on safety profiles, clinical efficacy parameters, durability of therapeutic response and methodological quality across published studies.
Methods
Search strategy and selection criteria
This systematic review of primary research studies examining CAR-T cell therapy for autoimmune rheumatic diseases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 12 13 The methods for this systematic review are described in detail in a published protocol and registered online with PROSPERO (registration number: CRD42025641602).
Studies were eligible if they reported clinical outcomes following the administration of any CAR-T cell construct in at least one patient with a defined autoimmune rheumatic condition. This review included case reports, case series, observational studies and clinical trials. We excluded review articles, editorials, conference abstracts without full-text publications and studies that focused solely on malignancies without autoimmune manifestations. Studies reporting CAR-T therapy exclusively for neurological autoimmune conditions were included only when the condition had established rheumatological overlap or systemic manifestations. There were no restrictions on geographical location or language of publication.
Searches were performed from inception to 15 February 2025, across PubMed, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov and BASE. Key concepts included ‘chimeric antigen receptor’, ‘CAR-T’ and ‘engineered T cells’ combined with autoimmune and rheumatic disease terms (full search terms are provided in the online supplemental information ). The searches were supplemented by a manual review of the reference lists of the included studies and relevant review articles. Searches were performed by one reviewer (AS) and uploaded to systematic review management software. Two reviewers (AS and TCT) screened the titles, abstracts and full texts using standardised forms. Discrepancies were resolved through discussion, with reasons for exclusion recorded and summarised in a PRISMA flow diagram.
Data analysis
The results were extracted by a single reviewer (AS) and verified by a second reviewer (TCT). The standardised data extraction forms included study characteristics, patient demographics, CAR-T cell treatment details, safety outcomes, efficacy outcomes and follow-up data. Methodological quality was assessed using the Joanna Briggs Institute Critical Appraisal Tools for Case Reports and Case Series, 14 the Risk of Bias in Non-Randomised Studies of Interventions tool for non-randomised clinical studies 14 15 and the National Institutes of Health Quality Assessment tool for Early-Phase Clinical Trials. Quality assessments were conducted independently by two reviewers (AS and TCT), and discrepancies were resolved by consensus. Due to the heterogeneity of the study designs, patient populations and outcome measures, quantitative synthesis was not performed. We conducted a qualitative synthesis to organise the results based on the study design, patient characteristics, treatment protocols and clinical outcomes. The results are presented descriptively, emphasising the safety profiles, clinical efficacy parameters, response durability and methodological quality. Quantitative synthesis was not performed because of substantial heterogeneity. The results are presented through qualitative synthesis with descriptive analysis.
Results
Study selection and characteristics
A systematic search identified 4971 potentially relevant records across five databases ( online supplemental table S1 , figure 1 ): PubMed (n=78), Scopus (n=897), Cochrane CENTRAL (n=9), ClinicalTrials.gov (n=181) and BASE (n=3806). Following deduplication, 78 unique records were identified. 58 records were excluded for epidemiological research without therapeutic intervention (n=15), conventional treatment studies (n=14), diagnostic investigations (n=11), comorbidity studies without CAR-T cell intervention (n=8), surgical approaches (n=6), non-autoimmune focus (n=2) and genetic studies without therapeutic outcomes (n=4) ( online supplemental table S2 ). Seven additional studies were excluded because they focused on neurological autoimmune disorders (n=6) or haematological malignancies without an underlying rheumatic disease (n=1) ( online supplemental table S3 ). All 12 remaining articles met the eligibility criteria for the qualitative synthesis of rheumatic autoimmune diseases. 16 , 27
Patient demographics and clinical characteristics
12 studies encompassed 44 patients with severe treatment-refractory rheumatic autoimmune diseases ( table 1 ); one patient was reported in two publications. 19 27 Studies comprised case reports (n=8, 66.7%), 1618 , 21 23 24 27 case series (n=3, 25.0%) 22 25 26 and clinical trials (n=1, 8.3%). 17
Table 1
Study characteristics and patient demographics
1Anti-Jo-1 antibody-associated myositis with ILD. 2Anti-topoisomerase I antibody-positive diffuse cutaneous disease. 3SRP-IMNM with SSc overlap. 4Mixed cohort: SLE, IIM and SSc. 5Most common childhood inflammatory myopathy with calcinosis risk. 6Secondary DLBCL complicating chronic RA inflammation. 7ISN/RPS classification: classes III–V require aggressive immunosuppression. 8Mixed diffuse proliferative and membranous LN. 9Skin involvement proximal to elbows/knees with organ complications. 10MALT lymphoma transformation in 5% of patients with Sjögren’s syndrome. 11Triple-positive APS, highest thrombotic risk category. * Claus et al 19 and Merkt et al 27 report the same patient with complementary data. aPL, antiphospholipid; APS, antiphospholipid syndrome; CK, creatine kinase; Cy, cyclophosphamide; DAS28, Disease Activity Score 28; dcSSc, diffuse cutaneous systemic sclerosis; DLBCL, diffuse large B-cell lymphoma; DMARD, disease-modifying antirheumatic drug; DVT, deep vein thrombosis; ESSDAI, EULAR Sjögren’s Syndrome Disease Activity Index; EULAR, European Alliance of Associations for Rheumatology; HCQ, hydroxychloroquine; ICE, Ifosfamide, Carboplatin and Etoposide; Ig, immunoglobulin; IIM, idiopathic inflammatory myopathies; ILD, interstitial lung disease; ISN/RPS, International Society of Nephrology/Renal Pathology Society; LN, lupus nephritis; MALT, Mucosa-Associated Lymphoid Tissue; MMF, mycophenolate mofetil; mRSS, modified Rodnan skin score; MSC, mesenchymal stem cell; MTX, methotrexate; NIH AI, National Institutes of Health Activity Index; NR, not reported; NSIP, non-specific interstitial pneumonia; PE, plasma exchange; PGA, Physician Global Assessment; RA, rheumatoid arthritis; R-CHOP, Rituximab, Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), Prednisone; R-CNOP, Rituximab, Cyclophosphamide, Mitoxantrone, Vincristine and Prednisolone; SjD, Sjögren’s disease; SLE, systemic lupus erythematosus; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; SRP-IMNM, signal recognition particle-immune-mediated necrotising myopathy; SSc, systemic sclerosis; VKA, vitamin K antagonist.
| Study | Country | Design | Patients (n) | Primary diagnosis | Disease duration, years median (range) | Previous therapies | Disease severity at baseline |
| Pecher et al 16 | Germany | Case report | 1 | Antisynthetase syndrome with myositis and ILD 1 | ≥1.5 | Corticosteroids, MTX, leflunomide, baricitinib, rituximab | Severe (grade 4 weakness, active myositis, ILD) |
| Claus et al * 19 | Germany | Extended case study | 1 | Scl70+dcSSc 2 | NR | NR | Moderate to severe (lung fibrosis, progressive NSIP) |
| Wang et al 25 | China | Case series | 3 | SRP-IMNM and dcSSc with ILD 3 | 5.5 (1–10) | Multiple DMARDs, biologics, intravenous Ig, PE, MSC transplantation | Severe (CK 2295 U/L, mRSS 26–39) |
| Müller et al 22 | Germany | Case series | 15 | SLE (8); IIM (3); SSc (4) 4 | SLE: 4.0 (1–20); IIM: 2.0 (1–5); SSc: 2.0 (1–11) | Median 5 treatments; corticosteroids, MMF, MTX, HCQ, Cy, rituximab | SLE: moderate to severe (SLEDAI-2K 13, WHO III–V nephritis); IIM: severe (CK 4298 U/L); SSc: severe (mRSS 25.5) |
| Nicolai et al 20 | Italy | Case report | 1 | Refractory juvenile dermatomyositis 5 | 6.0 | Corticosteroids, MTX, ciclosporin, MMF, HCQ, intravenous Ig, Cy, PE, rituximab | Severe (PGA 10/10, calcinosis universalis) |
| Szabo et al 23 | Germany/Hungary | Case report | 1 | RA with secondary DLBCL 6 | RA: 12.0; DLBCL: newly diagnosed | Corticosteroids, MTX, HCQ, tocilizumab, R-CNOP | RA: severe (DAS28 6.43); DLBCL: stage IV/B |
| Wang et al 17 | China | Phase 1 multicentre trial | 13 | SLE with LN classes III–V 7 | 7.0 (1–21) | Corticosteroids (85%); HCQ (85%); MMF (62%); Cy (46%); belimumab (54%) | Severe (LN classes III–V) |
| Wang et al 24 | China | Case report | 1 | SLE with LN class IV–V 8 | 5.0 | Corticosteroids, MTX, HCQ, thalidomide, traditional Chinese medicine | Moderate (SLEDAI-2K 14, NIH AI>4) |
| Auth et al 26 | Germany | Prospective case series | 6 | dcSSc 9 | 3.0 (2.1–3.8) | MMF, azathioprine, Cy, nintedanib, MTX, rituximab, tocilizumab (≥2 per patient) | Severe (mRSS 26, ILD 30%, cardiac involvement 50%) |
| Sheng et al 18 | China | Case report | 1 | SjD with concurrent DLBCL 10 | SjD: 10.0; DLBCL: newly diagnosed | R-CHOP×6, lenalidomide, ICE+zanubrutinib×2 | SjD: mild (ESSDAI 5); DLBCL: stage IIIA |
| Friedberg et al 21 | Austria | Case report | 1 | SLE with APS and secondary DLBCL 11 | SLE/APS: 20.0; DLBCL: 2.0 | VKA, HCQ, prednisolone; R-CHOP×6, polatuzumab vedotin+rituximab | Triple aPL+, recurrent DVT, refractory DLBCL |
| Merkt et al * 27 | Germany | Case report | 1 | Scl70+dcSSc 2 | Progressive (months) | Cy, mycophenolate, nintedanib | Severe (progressive NSIP, mRSS elevated) |
The disease categories included SLE/lupus nephritis (LN) (n=3 studies, 15 patients, 34.1%), SSc (n=4 studies, 10 patients, 22.7%), inflammatory myopathies (n=2 studies, 16 patients, 36.4%), RA (n=1 study, 1 patient, 2.3%), Sjögren’s disease (n=1 study, 1 patient, 2.3%) and antisynthetase syndrome (n=1 study, 1 patient, 2.3%). Of note, two studies (Claus et al 19 and Merkt et al 19 27 ) reported the same patient with SSc; that is, the actual count of patients with SSc was nine across four studies.
Disease duration demonstrated remarkable chronicity across all rheumatic conditions, with a mean of 6.8 years. SLE showed a median of 7.0 years (range 1–21) in LN 17 and 20.0 years in SLE with antiphospholipid (aPL) syndrome (APS). 21 SSc demonstrated a median of 3.0 years (range 2.1–3.8), 26 while inflammatory myopathies showed a median of 2.0–6.0 years across studies. 22
Exhaustive treatment exposure occurred in 100% of the studies, with a median of 5 previous treatments (range 2–14) 22 and ≥2 treatment failures per patient documented. 26 Treatments included corticosteroids, conventional disease-modifying antirheumatic drugs (DMARDs) (methotrexate, hydroxychloroquine, cyclophosphamide (Cy) and mycophenolate), rituximab and biologics. Complex treatment histories included multiple DMARDs, biologics, intravenous immunoglobulin (Ig), plasma exchange and mesenchymal stem cell transplantation. 25
Baseline severity confirmed uniformly severe presentations across all categories of rheumatic diseases. LN included classes III–V with median proteinuria of 3.2 g/24 hours, 17 SLE Disease Activity Index 2000 (SLEDAI-2K) scores of 13 with class III–V nephritis 22 and SSc with modified Rodnan scores of 26 (range 24–31). 26 Complex presentations included SRP myopathy with SSc 17 and triple-positive APS with diffuse large B-cell lymphoma (DLBCL). 21 The paediatric case involved refractory juvenile dermatomyositis with Physician Global Assessment 10/10 despite comprehensive treatment failure over 6 years. 20
CAR-T cell treatment characteristics
Table 2 and figure 2 show the manufacturing workflow and dual-targeting strategies. In included studies, product characteristics demonstrated the predominant use of second-generation CAR constructs (n=10 studies, 83.3%) with third-generation architectures (n=2 studies, 16.7%). 19 27 Target antigen selection focused on B-cell lineage depletion, with CD19 most frequently targeted (n=10 studies, 83.3%), followed by dual-target approaches combining CD19 with CD20 23 or BCMA.
Table 2
CAR-T cell product characteristics and treatment protocols
¹Second-generation CAR-T with one co-stimulatory domain (CD28/4-1BB) plus CD3ζ for enhanced activation and persistence. ²CD19, a B-cell lineage glycoprotein for targeted B-cell depletion; BCMA targets plasma cells. ³CD28 provides rapid activation but shorter persistence versus 4-1BB. ⁴Lentiviral vectors provide stable integration; transduction efficiency indicates the percentage of successfully modified cells. ⁵Fresh product administration may offer advantages over cryopreserved alternatives. 64-1BB provides longer persistence and memory T-cell formation. 7Third generation with two co-stimulatory domains (CD28+4-1BB); clinical benefit over second generation unclear. 8Higher Cy doses (1000 mg/m²) are used for severe refractory cases. 9CliniMACS Prodigy enables automated point-of-care manufacturing. 10Academic GMP facilities provide cost-effective alternatives to commercial production. 11Axicabtagene ciloleucel, an FDA-approved commercial product repurposed for autoimmune use. 12Standard lymphodepletion doses: Flu 30 mg/m²×3, Cy 300–500 mg/m²×3. 13Academic facilities have lower costs but limited scalability compared with commercial platforms. 14CD19.28.ζ, a standard second-generation architecture with CD28 co-stimulation. 15MB-CART19.1, a multicentre German academic construct used in clinical trials. 16Dual CD19+CD20 targeting prevents antigen escape mechanisms. 17Zamtocabtagene autoleucel, the first dual-target CAR-T product for autoimmune diseases. 18BCMA+CD19 dual targeting addresses both activated B-cells and plasma cells. 19Differential co-stimulation optimises each CAR component for specific target cell types. 20Cy-only lymphodepletion is based on protocol optimisation to reduce toxicity. 21cCAR with dual antigen targeting capability. 22IL-15 domain enhances CAR-T persistence through survival signals. * denotes data derived from specific extended case studies or related publications for the same patient (eg, Claus et al 19 and Merkt et al 27 ). BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; CAR-T, chimeric antigen receptor T-cell; cCAR, compound CAR; Cy, cyclophosphamide; FDA, Food and Drug Administration; Flu, fludarabine; GMP, good manufacturing practice; IL, interleukin; NR, not reported.
| Study | CAR construct generation | Target antigen(s) | Co-stimulatory domain | Lymphodepletion regimen | CAR-T dose (×10⁶ cells/kg) | Manufacturing platform | Product characteristics |
| Pecher et al 16 | Second-generation ¹ | CD19² | NR | Flu 25 mg/m²×3+Cy 1000 mg/m²×1 8 | 1.23 | CliniMACS Prodigy (Miltenyi) 9 | Academic product 10 |
| Claus et al * 19 | Third-generation 7 | CD19² | CD28+4-1BB 3,6 | Flu 30 mg/m²+Cy 500 mg/m² (days −4 to −2) 12 | 5.0 (400×10⁶ total) | Academic GMP facility 13 | Third-generation construct; 18-month persistence 7 |
| Wang et al 25 | Second-generation ¹ | CD19² | CD28³ | Flu+Cy (standard doses) 12 | 2.0 | Academic GMP facility 13 | CD19.28.ζ construct 14 |
| Müller et al 22 | Second-generation ¹ | CD19² | NR | Flu+Cy (standard doses) 12 | NR (>1×10⁹ total)⁶ | CliniMACS Prodigy (Miltenyi) 9 | MB-CART19.1 15 ; 18%–44% transduction⁴ |
| Nicolai et al 20 | Second-generation ¹ | CD19² | 4-1BB 6 | Cy 1000 mg/m²×2+Flu 90 mg/m²×3 8 | 1.0 | CliniMACS Prodigy (Miltenyi) 9 | Fresh product⁵; lentiviral vector⁴ |
| Szabo et al 23 | Second-generation ¹ | CD19+CD20², 16 | 4-1BB 6 | Flu+Cy (standard doses) 12 | NR | CliniMACS Prodigy (Miltenyi) 9 | Zamtocabtagene autoleucel 17 ; fresh product⁵ |
| Wang et al 17 | Second-generation ¹ | BCMA+CD19², 18 | CD28 (BCMA)+4-1BB (CD19) 19 | P1–P2: Flu 30 mg/m²+Cy 300 mg/m²; P3–P13: Cy 300 mg/m² only 18 | 3.0 (P11: 1.5 initial) | iCell Gene Therapeutics | cCAR 21 with IL-15 domain 22 |
| Wang et al 24 | Second-generation ¹ | BCMA+CD19², 18 | NR | Cy 300 mg/m²×3 20 | 3.0 | In-house manufacturing | Dual-target construct 18 |
| Auth et al 26 | Second-generation ¹ | CD19² | NR | Flu 25 mg/m²×3+Cy 1000 mg/m²×1 8 | 1.0 | CliniMACS Prodigy (Miltenyi) 9 | MB-CART19.1 15 ; lentiviral vector⁴ |
| Sheng et al 18 | Second-generation ¹ | CD19² | CD28³ | Flu 30 mg/m²×3+Cy 500 mg/m²×3 12 | 2.0 | Commercial | Axicabtagene ciloleucel 11 |
| Friedberg et al 21 | Second-generation ¹ | CD19² | CD28³ | Flu 90 mg/m² total+Cy 1500 mg/m² total | NR | Commercial (Kite Pharma) | Axicabtagene ciloleucel 11 |
| Merkt et al * 27 | Third-generation 7 | CD19² | CD28+4-1BB³ ,6 | Flu 30 mg/m²+Cy 500 mg/m² (days −4 to −2) 12 | 5.0 (400×10⁶ total) | Academic GMP facility 13 | Retroviral transduction; combination therapy |
Co-stimulatory domain selection revealed preferential CD28 signalling (n=5 studies), providing rapid T-cell activation. The 4-1BB domain was employed in two studies, 20 23 with a unique implementation of differential co-stimulation whereby BCMA targeting used CD28 while CD19 targeting employed 4-1BB within the same dual-target construct. 17
Protocol modifications included higher Cy dosing (1000 mg/m²) in three studies. 16 20 26 Protocol evolution was demonstrated, transitioning from standard fludarabine-Cy to Cy monotherapy (300 mg/m²×3 days) in later patients, suggesting safety-driven optimisation. 17
CAR-T dosing revealed substantial variation, ranging from 1.0×10⁶ cells/kg to 3.0×10⁶ cells/kg, with most studies employing 1.0–3.0×10⁶ cells/kg. Transduction efficiency ranged from 18%–44% 22 to 74%–75%, with fresh product administration noted, 20 23 potentially offering advantages over cryopreserved alternatives.
Safety profile
As early-phase trials, safety evaluation represented the primary objective across all included studies. Cytokine release syndrome (CRS) was the most frequent acute complication, occurring in 100% of studies with available data (10/10), although severity remained predominantly mild-to-moderate, with grade 1–2 presentations comprising 100% of cases. No grade ≥3 CRS was reported in any of the rheumatological studies ( table 3 ).
Table 3
Safety profile and adverse events
¹Profound B-cell depletion (from 19.7% to 0.03%) demonstrates effective CAR-T activity. 2Partial Ig recovery suggests beginning B-cell reconstitution. 3No tocilizumab indicates mild CRS not requiring cytokine blockade. 4Grade 3–4 cytopenias require transfusion/growth factor support. 5Hypogammaglobulinaemia (67%) requires monitoring for infections. 6Grade 4 ICANS, life-threatening neurotoxicity with cerebral oedema/seizures. 7URIs; mild complications without opportunistic infections. 8Uncommon hypogammaglobulinaemia suggests better humoral immunity preservation. 9Symptomatic management without tocilizumab indicates self-limiting CRS. 10Bacterial superinfection post-viral illness represents the most serious infectious complication. 11IgG >600 mg/dL, threshold for adequate humoral immunity. 12Persistent B-cell aplasia at day +180 indicates durable CAR-T activity. 13High COVID-19 incidence (62%) with hospitalisation (23%) reflects viral infection vulnerability. 14Cy-related leukopenia distinguishes lymphodepletion from CAR-T toxicity. 15Leucogen, filgrastim for neutropenia management. * indicates primary safety data endpoints verified in phase I trials. CAR-T, chimeric antigen receptor T-cell; CRS, cytokine release syndrome; Cy, cyclophosphamide; G-CSF, granulocyte colony-stimulating factor; ICANS, immune effector cell-associated neurotoxicity syndrome; Ig, immunoglobulin; MMF, mycophenolate mofetil; NR, not reported; URI, upper respiratory infection; UTI, urinary tract infection.
| Study | CRS grade (%) | ICANS grade (%) | Haematological toxicity | Infectious complications | Ig impact | Management interventions |
| Pecher et al 16 | Grade 1 (100) | None (0) | Grade 2–3 cytopenias (recovered) | None (0) | Recovery: IgG 87%; IgA 67%; IgM 58% 2 | No tocilizumab 3 ; MMF added day 35 |
| Claus et al * 19 | Grade 1 (100) | None (0) | Lymphopenia, B-cell depletion (from 19.7% to 0.03%)¹ | None (0) | B-cell recovery at 18 months | Symptomatic management only |
| Wang et al 25 | Grade 1–2 (67) | Grade 1 (33) | Grade 3–4 neutropenia (100) | None (0) | Hypogammaglobulinaemia (67) 5 | Tocilizumab (33%), intravenous Ig replacement |
| Müller et al 22 | Grade 1–2 (73) | Grade 1 (7) | Grade 4 neutropenia (7) | Pneumonia (7%); mild URIs 7 | Hypogammaglobulinaemia uncommon 8 | Tocilizumab (40%), G-CSF (7%) |
| Nicolai et al 20 | Grade 1 (100) | None (0) | Grade 2–4 cytopenias | None (0) | IgA decreased (recovered week 24) | Symptomatic management only 9 |
| Szabo et al 23 | Grade 1 (100) | None (0) | Recurrent neutropenia, B-cell aplasia (day+180) 12 | None (0) | IgG maintained>4.8 g/L | Antipyretics, intermittent filgrastim |
| Wang et al 17 | Grade 1 (100) | None (0) | Neutropenia (resolved<45 days) | UTI (8%); COVID-19 (62%, hospitalised 23%) 13 | IgA/IgG/IgM reduced; IgA recovered 8 months | Supportive care, intravenous Ig, as needed |
| Wang et al 24 | Grade 1 (100) | None (0) | Leucopenia (Cy-related) 14 | None (0) | IgA/IgG/IgM reduced; recovered 6 months | Symptomatic management, leucogen 15 |
| Auth et al 26 | Grade 1–2 (83) | None (0) | NR | Influenza with bacterial superinfection (17%)10 | IgG maintained>600 mg/dL 11 | Standard supportive care |
| Sheng et al 18 | Grade 2 (100) | Grade 1 (100) | Grade 3–4 cytopenias 4 | None (0) | Decreased post-treatment | Tocilizumab×3, methylprednisolone, intravenous Ig, G-CSF |
| Friedberg et al 21 | Grade 1 (100) | Grade 4 (100) 6 | NR | None (0) | NR | Tocilizumab, corticosteroids |
| Merkt et al * 27 | Grade 1 (100) | None (0) | Transient cytopenias | Empirical antibiotics (day −3) | Not specifically reported | No tocilizumab required |
Immune effector cell-associated neurotoxicity syndrome (ICANS) demonstrated a remarkably low incidence, with only 25% of studies (3/12) reporting neurological complications. Most ICANS presentations were grade 1, with only one case of grade 4 ICANS in a patient with concurrent DLBCL. 21 Neither SSc publication reported ICANS. 19 27
Haematological toxicity demonstrated variable patterns depending on the CAR-T cell construct and lymphodepletion intensity. Neutropenia represented the most common complication, with severe presentations (grade 3–4) often requiring granulocyte colony-stimulating factor support. Infectious complications of variable severity occurred in 18% of the studies (2/11). No opportunistic infections were reported in any of the rheumatological studies.
The impact of Ig showed significant variability across CAR-T targets. CD19-targeted approaches showed mixed effects, with hypogammaglobulinaemia occurring in 67% of one study requiring intravenous Ig replacement, 25 while other studies maintained protective levels. Recovery patterns showed IgG, IgA and IgM recoveries of 87%, 67% and 58%, respectively, on follow-up assessment. 16
Efficacy outcomes
Clinical efficacy demonstrated remarkably high response rates, with 100% of studies (12/12) achieving primary endpoints and response rates of 92%–100% across all rheumatic disease categories ( table 4 ). Third-generation CAR-T therapy in SSc has demonstrated exceptional outcomes with dramatic clinical improvements, including CT regression and functional restoration, accompanied by profound immunological changes, such as natural killer (NK) cell recovery and immune complex normalisation. 19 This case represents the first report of third-generation CAR-T cell use in autoimmune disease and provides unique insights into both clinical efficacy and mechanistic recovery patterns.
Table 4
Clinical efficacy and biomarker response
1Anti-Jo-1 reduction correlates with antisynthetase syndrome improvement. 2DLBCL CR+SjD improvement demonstrates dual malignant/autoimmune efficacy. 3CK normalisation+mRSS reduction >25% is considered a clinically meaningful improvement. 4SRP antibody reduction (−80% in 67%) suggests variable CAR-T penetration. 5Complete aPL/ANA clearance correlates with no thrombotic recurrence. 6DORIS and ACR-EULAR are response criteria for myopathies. 7Activity index reduction of 4.2 points is considered a substantial SSc improvement. 8Type I IFN score normalisation reflects IFN signature resolution. 9Anti-RNA pol III/anti-topo I reductions (−90%) target disease-specific responses. 10RF reduction (from 1200 IU/mL to 13 IU/mL, −99%) correlates with sustained remission. 11Variable follow-up reflects dose-escalation design. 12SLEDAI-2K ≤4 indicates a low disease activity state. 13MFR denotes major clinical response; DORIS CR. 14Universal autoantibody negativity indicates comprehensive B-cell depletion. 15Successful pregnancy demonstrates restored immune/fertility function. 16Dual endpoint: immune reconstitution+therapeutic efficacy. 17CD16 bioactivity normalisation indicates NK cell function restoration. 18ACR-CRISS denotes the Combined Response Index in Systemic Sclerosis. * signifies statistically significant clinical improvement or a primary efficacy endpoint met. ACR-EULAR, American College of Rheumatology-European Alliance of Associations for Rheumatology; ANA, antinuclear antibodies; anti-Sm, anti-RNA pol III, anti-topo I, disease-specific autoantibodies; aPL, antiphospholipid; CAR-T, chimeric antigen receptor T-cell; CD16, NK cell functional biomarker; CK, creatine kinase; CMAS, Childhood Myositis Assessment Scale; CR, complete remission; CRISS, Combined Response Index in Systemic Sclerosis; DLBCL, diffuse large B-cell lymphoma; DORIS, definition of remission in SLE; dsDNA, double-stranded DNA; eGFR, estimated glomerular filtration rate; FVC, forced vital capacity; IFN, interferon; IIM, idiopathic inflammatory myopathies; mRSS, modified Rodnan skin score; NK, natural killer; PGA, Physician Global Assessment; P1-P13, patient identifiers; QoL, quality of life; RA, rheumatoid arthritis; RF, rheumatoid factor; SjD, Sjögren’s disease; SLE, systemic lupus erythematosus; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; SRP, signal recognition particle; SSc, systemic sclerosis.
| Study | Follow-up (months) | Primary efficacy endpoint | Response rate (%) | Autoantibody reduction | Functional improvement | Time to response |
| Pecher et al 16 | 8.0 | Clinical improvement | 100 | Anti-Jo-1 decreased 1 | Normalised muscle enzymes, improved function | Days to weeks |
| Claus et al * 19 | 18.0 | NK cell recovery+autoantibody clearance 16 | 100 | Scl70: ~40 U/mL→<5 U/mL (−87%); CD16 bioactivity normalised 17 | NK cells increased fivefold; lung fibrosis resolved | 12 weeks (NK), 60 weeks (antibodies) |
| Wang et al 25 | 12.0 | CK normalisation+mRSS reduction 3 | 100 (CK), 67 (mRSS>25%) | SRP antibodies −80% (67% patients) 4 | Functional improvement 100% | 8 weeks |
| Müller et al 22 | 15.0 (4–29) | Disease-specific remission criteria 6 | SLE: 100% DORIS; IIM: 100% ACR-EULAR major response; SSc: activity index −4.2 7 | SLE: dsDNA, anti-Sm disappeared; IIM/SSc: disease-specific antibodies reduced | All discontinued immunosuppression; organ function normalised | SLE: 24 weeks; IIM: 12 weeks |
| Nicolai et al 20 | 8.0 | PGA improvement+CMAS normalisation | 100 | Type I IFN score normalised (24 weeks) 8 | Drug-free remission; skin/muscle normalised | 4 weeks (initial), sustained 8 months |
| Szabo et al 23 | 12.0 | Drug-free remission (RA+DLBCL CR) | 100 | RF: 1200 IU/mL→13 IU/mL (−99%) 10 | Sustained RA remission; improved QoL | 3 weeks (RA), 48 weeks (DLBCL) |
| Wang et al 17 | P1–P2: 25–46; P3–P13: <12 11 | SLEDAI-2K≤4 12 | 92 (SLEDAI-2K≤4); 69 (MFR); 69 (DORIS CR) 13 | All autoantibodies negative at 12 weeks 14 | eGFR improved; proteinuria from −74% to −98% | ≤12 weeks |
| Wang et al 24 | >6.0 | SLEDAI-2K=0 | 100 | Anti-dsDNA negative; complement normalised | Successful pregnancy and delivery 15 | 12 weeks |
| Auth et al 26 | 16.2 (11–19) | ACR-CRISS improvement 18 | 100 | ANA −90%; anti-RNA pol III undetectable; anti-topo I −90% 9 | FVC+195 mL; mRSS −31%; hand function+26% | 12–16 weeks |
| Sheng et al 18 | 6.0 | DLBCL CR+SjD improvement 2 | 100 | ANA negative; anti-Ro-52 negative (first time in 10 years) | Dry mouth improved; pulmonary improvement | 4 weeks (DLBCL), 12 weeks (SjD) |
| Friedberg et al 21 | 12.0 | CR (lymphoma+SLE) | 100 | All aPL antibodies undetectable; ANA negative 5 | No thrombotic recurrence | 4 weeks |
| Merkt et al 27 | 11.0 | Pulmonary function improvement | 100 | Scl70: significant reduction; immune complexes normalised | Dramatic CT improvement; can climb 2–3 floors | 6 months |
SLE demonstrated exceptional outcomes, with 92%–100% response rates. Clinical outcomes included 92% of patients achieving SLEDAI-2K≤4, 69% achieving major clinical response and universal autoantibody negativity at 12 weeks, with proteinuria reductions of 74%–98%. 17 Complete definitions of remission in SLE (DORIS), remission in SLE and 100% American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) major response in inflammatory myopathies were achieved, with all patients discontinuing immunosuppressive therapy. 22
Autoantibody reduction patterns demonstrated consistent, profound effects across all approaches, with elimination depth correlating with clinical response magnitude. CD19-targeted approaches achieved comprehensive elimination, with complete aPL antibody clearance 21 and 90% antinuclear antibody (ANA) reductions with complete anti-RNA polymerase III elimination. 26
Functional improvements consistently exceeded conventional therapeutic expectations, with patients achieving drug-free remission and restoration of daily activities. Renal function restoration was achieved in LN, with estimated glomerular filtration rate improvement and proteinuria reductions of 74%–98%. 17 Remarkable functional recovery included successful pregnancy and delivery following treatment, 24 demonstrating restoration of reproductive health in severe SLE.
Quality assessment
Case reports represented the largest study category (66.7%, 8/12 studies) and demonstrated uniformly high methodological quality, achieving perfect scores of 8/8 across all eight studies. 1618 , 21 23 24 27 Case series studies (25.0%, 3/12 studies) demonstrated moderate methodological quality with consistent scores of 6/8. 22 25 26 The single clinical trial (8.3%, 1/12 studies) showed moderate quality assessment ( online supplemental table S4 ). 17 Both publications reporting the same patient with SSc achieved high-quality scores with comprehensive data reporting. 19 27 The primary limitation affecting clinical trial quality was performance bias, rated as high due to the inherent inability to blind participants to CAR-T cell therapy administration.
Discussion
This systematic review provides the first comprehensive evidence for CAR-T cell therapy, specifically in rheumatic autoimmune diseases, revealing the transformative potential that challenges conventional immunosuppressive paradigms through precision cellular immunotherapy. The remarkable consistency of clinical responses across heterogeneous rheumatic conditions, coupled with a distinctly favourable safety profile compared with oncological applications, positions CAR-T therapy as a paradigm-shifting intervention for treatment-refractory rheumatological diseases.
The mechanistic foundation underlying CAR-T efficacy in autoimmune diseases, as illustrated in figure 3 , demonstrates how engineered T cells achieve comprehensive B-cell lineage elimination through targeted immunological synapse formation. The sequential therapeutic cascade from B-cell depletion through autoantibody reduction to sustained clinical remission provides a mechanistic framework that explains the consistent efficacy observed across diverse rheumatic conditions in this systematic review. The evolution from first-generation to advanced CAR constructs has enabled enhanced persistence, reduced toxicity and improved therapeutic outcomes, with third-generation constructs showing particularly promising results in SSc cases. 19 27
CAR-T therapy addresses a fundamental limitation that has constrained rheumatological practice for decades: the inability to selectively eliminate pathogenic immune populations while preserving protective immunity. Unlike conventional DMARDs and biologics, which impose broad immunosuppression with associated infection risks and limited durability, CAR-T approaches enable precision in targeting the autoreactive B-cell lineages responsible for pathogenic autoantibody production. 1 2 This mechanistic specificity represents a conceptual quantum leap beyond current therapeutic paradigms, exemplified by the achievement of 100% DORIS remission in SLE with complete immunosuppression withdrawal across 15 patients in the largest rheumatological case series. 22
The evolution from monovalent CD19 targeting to dual-antigen strategies reflects a growing understanding of B-cell compartment heterogeneity in autoimmune pathogenesis. 3 4 The superior outcomes achieved with combined CD19-BCMA targeting in severe LN, demonstrating 92% achievement of SLEDAI-2K≤4, 17 illuminate how diseases characterised by diverse pathogenic antibody repertoires require comprehensive B-cell lineage elimination. These mechanistic insights fundamentally reframe therapeutic strategies in rheumatology, suggesting that plasma cell-driven diseases, such as SSc with anti-RNA polymerase III antibodies or ANCA-associated vasculitis, may require BCMA-targeted rather than conventional CD19 approaches for optimal efficacy.
The level of autoantibody elimination, ranging from 80% to 99% across studies, provides both mechanistic validation and practical biomarkers for therapeutic monitoring. Disease-specific autoantibody clearance patterns demonstrate remarkable precision: complete aPL antibody elimination in APS, 21 99% RF reduction in RA 23 and comprehensive ANA elimination with undetectable anti-RNA polymerase III levels in SSc. 26 This biomarker responsiveness offers rheumatologists objective measures of therapeutic efficacy unparalleled in autoimmune disease management.
The safety profile observed in rheumatic diseases fundamentally diverges from the oncological CAR-T experience. The universal occurrence of CRS (100% of studies with available data) remained exclusively grade 1–2, with no cases of grade ≥3 severity, in stark contrast to the severe presentations observed in haematological malignancies. 6 11 This fundamental difference suggests that people with autoimmune diseases may be candidates for outpatient CAR-T delivery, transforming accessibility compared with intensive care requirements typical in oncological applications. Although CAR-T therapy achieves therapeutic benefit through targeted B-cell depletion, the mechanism of CRS warrants consideration. CRS is primarily mediated by activated macrophages rather than the CAR-T cells themselves, with monocyte-derived interleukin-6 (IL-6), interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-α) driving the inflammatory cascade following CAR-T cell engagement with target cells. 5 This macrophage-mediated amplification of inflammation represents a double-edged sword: the same proinflammatory signals that contribute to CRS may paradoxically enhance CAR-T efficacy through bystander immune activation. The consistently mild CRS observed in autoimmune applications likely reflects the lower target cell burden compared with haematological malignancies, resulting in reduced macrophage activation and cytokine amplification. Understanding this mechanistic pathway has informed the successful use of tocilizumab (IL-6 receptor blockade) for CRS management without compromising CAR-T efficacy, as demonstrated in 33%–40% of patients across the reviewed studies.
The mechanistic basis for this improved tolerability likely stems from the lower baseline inflammatory burden in autoimmune diseases compared with high-tumour-burden haematological malignancies, along with the reduced CAR-T expansion requirements for B-cell depletion versus tumour elimination. 7 8 The remarkably low incidence of severe immune effector cell-associated neurotoxicity (8% of studies, exclusively in concurrent malignancy cases) further supports the potential for streamlined delivery protocols in rheumatological settings.
However, infectious complications warrant careful consideration during clinical implementation. The absence of opportunistic infections across all rheumatological studies contrasts favourably with conventional immunosuppressive regimens, yet highlights the need for autoimmune-specific monitoring protocols distinct from oncological guidelines. 9 10 The variable impact on Ig levels, ranging from maintained protective levels to transient hypogammaglobulinaemia requiring replacement, emphasises the importance of individualised immune monitoring strategies.
Supporting evidence from neurological autoimmune diseases provides compelling validation of CAR-T efficacy across a broad spectrum of autoimmune diseases. Several studies on neurological disorders have demonstrated similarly impressive outcomes, including complete responses in myasthenia gravis (MG), 28 29 stiff-person syndrome 30 and neuromyelitis optica. 31 These achievements included profound functional restoration, that is, quantitative MG score reduction from 21 to 5, with autoantibody reductions of 53%–100% for acetylcholine receptor antibodies and 93%–96% for voltage-gated calcium channel antibodies, culminating in remarkable functional recovery enabling 3–8 km walking capacity. 29 Advanced targeting strategies have expanded therapeutic possibilities beyond conventional B-cell antigens. RNA-based BCMA targeting in MG achieved 43% response rates with transient CAR expression, 32 whereas BCMA targeting in neuromyelitis optica demonstrated progressive aquaporin-4-IgG negativity, increasing from 70% at 12 weeks to 83% at 6 months. 31 Novel natural killer group 2 member D (NKG2D)-targeted approaches in haematological malignancies have revealed alternative targeting strategies with distinct safety profiles, 33 potentially expanding the therapeutic armamentarium for specific autoimmune subsets.
The achievement of primary efficacy endpoints in 100% of rheumatological studies represents ideal success rates for severe autoimmune diseases, substantially exceeding the benchmarks established by conventional DMARDs, biologics or targeted synthetic DMARDs in comparable patient populations. The rapid therapeutic onset within 2–16 weeks offers immediate advantages over conventional approaches requiring months for therapeutic benefit, while the sustained responses documented over extended follow-up periods without ongoing immunosuppression represent a fundamental departure from lifelong therapy paradigms that have defined rheumatological practice. This therapeutic durability suggests disease modification rather than symptomatic palliation, challenging the established concepts of autoimmune disease chronicity and opening possibilities for finite treatment courses in historically incurable conditions. The capacity to restore normal physiology, exemplified by successful pregnancy and delivery following severe LN treatment, demonstrates therapeutic potential extending beyond disease control to the functional restoration of life capabilities. 24
Notably, the integration of CAR-T therapy into rheumatological practice necessitates the fundamental restructuring of treatment algorithms, referral pathways and monitoring protocols. Therapy requires specialised centres combining expertise in autoimmune diseases and cellular therapy, demanding unprecedented collaboration between rheumatologists, haematologists, oncologists and CAR-T specialists. This collaborative model serves a dual purpose: ensuring appropriate delivery of CAR-T therapy when indicated while also providing expert assessment that may identify opportunities for optimised conventional management, potentially avoiding the need for cellular therapy in some patients. The establishment of specialised referral networks should therefore emphasise comprehensive evaluation of treatment history and optimisation opportunities alongside CAR-T candidacy assessment. 16 25 The superior efficacy compared with conventional therapies raises complex questions regarding optimal treatment sequencing. Current evidence suggests maximal benefit when autoreactive B-cells remain accessible before irreversible organ damage occurs. However, several important considerations must temper enthusiasm for early CAR-T intervention. First, optimal utilisation of existing evidence-based therapies remains essential to avoid ‘false’ treatment-refractory situations; many patients labelled as refractory may respond to optimised conventional treatment algorithms, particularly when guideline-concordant care is implemented early in the disease course. This is especially pertinent in RA, where truly refractory disease has become increasingly rare with optimal treat-to-target strategies using conventional DMARDs and biologics—not surprisingly, only one patient with RA was identified in this systematic review. The best predictor of refractory disease remains the response to initial therapy, emphasising the continued importance of optimising cost-effective first-line treatments before considering advanced cellular therapies. Second, reliable prediction of which individual patients will develop treatment-refractory disease remains challenging, limiting our ability to identify appropriate candidates for early CAR-T intervention. Until validated biomarkers or clinical algorithms can prospectively identify patients destined for refractory courses, CAR-T therapy should be reserved for patients with genuine treatment failure despite optimal conventional management, rather than as a first-line approach. 18 19 Cost-effectiveness considerations remain largely unexplored but may prove favourable given the potential for finite treatment courses eliminating lifelong therapy costs, hospitalisations and disease complications. 20 21 The development of allogeneic CAR-T products could address current scalability limitations and manufacturing costs. Furthermore, in vivo CAR engineering has emerged as a promising next-generation approach that may overcome the complex ex vivo manufacturing requirements of current CAR-T therapies. In vivo approaches use nanoparticle-based or viral delivery systems to generate CAR-expressing cells directly within the patient, offering advantages, including streamlined production, elimination of patient-specific manufacturing, reduced costs and simplified logistics. 34 Recent clinical evidence has demonstrated the feasibility of this approach in autoimmune disease, with in vivo CD19 CAR T-cell therapy achieving clinical responses in patients with refractory SLE. 35 , 38 These advances suggest that in vivo CAR engineering may democratise access to cellular immunotherapy for autoimmune diseases by reducing the specialised infrastructure requirements that currently limit widespread implementation.
The limitations of the included studies underscore critical research priorities for advancing CAR-T therapy in rheumatology. The predominance of case reports and small case series among the 12 rheumatological studies (44 patients) reflects the nascent state of this field and highlights the urgent need for large-scale investigations. 22 23 Methodological heterogeneity in CAR constructs, manufacturing processes and dosing regimens necessitates standardisation efforts to optimise therapeutic protocols and enable meaningful cross-study comparisons. Randomised controlled trials with disease-specific endpoints represent the gold standard for definitive efficacy validation; however, they face substantial methodological and ethical challenges. Beyond the ethical considerations of randomising severely ill patients given the dramatic responses observed in case series, the inherent inability to blind participants to CAR-T therapy (requiring lymphodepletion, infusion and characteristic toxicity profiles) introduces unavoidable performance bias. Future trial designs must acknowledge these constraints while maintaining scientific rigour. Potential approaches include randomised delayed-start designs comparing immediate versus deferred CAR-T therapy, registry-based comparisons with propensity-matched controls receiving the best available conventional therapy and composite endpoints incorporating objective biomarkers (autoantibody levels, B-cell counts) alongside clinical assessments to minimise outcome ascertainment bias. Adaptive platform trials allowing multiple CAR constructs to be evaluated against a common control arm may also enhance efficiency while addressing the rapidly evolving therapeutic landscape. 17 24 Alternative study designs, including registry studies, matched cohort analyses and systematic outcome monitoring, may provide viable pathways for evidence generation while maintaining ethical integrity. Long-term safety surveillance also assumes paramount importance given the permanence of genetic modification and the potential for delayed effects. Comprehensive monitoring protocols must address infectious susceptibility patterns, immune reconstitution kinetics, secondary malignancy risks and reproductive health impacts, which are particularly relevant given the young age of many patients with autoimmune diseases. 26 27 The establishment of international registry networks could facilitate systematic outcome tracking and safety signal detection across diverse patient populations and healthcare systems.
For practising rheumatologists, familiarity with CAR-T therapy principles, patient selection criteria and referral pathways will become increasingly essential as this technology transitions from experimental to clinical reality. 28 29 The potential for CAR-T therapy to redefine treatment expectations in rheumatology extends beyond individual patient outcomes to broader healthcare implications, including patient counselling frameworks, shared decision-making processes and quality-of-life considerations for patients transitioning from chronic disease management to potential cure scenarios. 30 31
Conclusions
This systematic review establishes CAR-T cell therapy as a groundbreaking advancement in rheumatological therapeutics, demonstrating unprecedented efficacy across diverse autoimmune conditions, with safety profiles enabling practical clinical implementation. The capacity to achieve sustained remission, enabling immunosuppression withdrawal, challenges core assumptions about autoimmune disease management and opens possibilities for curative rather than palliative therapeutic approaches. While current evidence is primarily derived from small-scale studies reflecting the field’s infancy, the consistency and magnitude of therapeutic responses suggest a transformative potential that warrants accelerated research investment and clinical development efforts. The transition from proof-of-concept to widespread clinical application requires coordinated efforts to address manufacturing standardisation, healthcare system integration, provider education and patient access considerations.
Supplementary material
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: Not applicable.
Data availability free text: This is a systematic review based on published literature; all data are extracted from the included studies cited in the manuscript.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Associated Data
Supplementary Materials
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.