A new hope with CAR T-cell therapy for refractory idiopathic inflammatory myopathies: a systematic review.

Introduction

Idiopathic inflammatory myopathies (IIM) comprise a heterogeneous group of systemic autoimmune disorders characterized primarily by chronic skeletal muscle inflammation, progressive proximal muscle weakness, and frequent extramuscular involvement, including the skin, lungs, and other organs. Based on clinical features and myositis-specific autoantibodies (MSAs), IIM can be classified into several major subtypes, including dermatomyositis (DM), antisynthetase syndrome (ASyS), inclusion body myositis (IBM), and immune-mediated necrotizing myopathy (IMNM). The pathogenesis of IIM reflects a complex interplay between innate and adaptive immune mechanisms, with B cells occupying a central role [ 1 ]. Beyond their function as antibody-producing cells, B cells act as professional antigen-presenting cells, amplifying autoimmune responses through interactions with follicular helper T cells and other immune subsets. Upon differentiation into plasma cells, they generate pathogenic MSAs that are closely linked to distinct clinical phenotypes and disease trajectories [ 2 , 3 ]. Consistent with this paradigm, elevated expression of B-cell-activating factors within the muscle microenvironment, together with the presence of plasma cells and memory B cells in affected muscle tissue, supports the concept that skeletal muscle may function as an ectopic niche for B-cell clonal expansion and terminal differentiation [ 4 , 5 ]. Moreover, circulating autoreactive B cells in IIM often exhibit a predominantly non-class-switched IgM + phenotype, suggesting enhanced migratory capacity, tissue homing, and subsequent local maturation into pathogenic effector cells [ 6 , 7 ].

Despite increasing insights into disease mechanisms, the therapeutic management of IIM remains challenging. First-line treatment with glucocorticoids and conventional immunosuppressive agents is frequently limited by cumulative toxicity and broad immunosuppressive effects. Targeted biologic therapies, most notably the anti-CD20 monoclonal antibody rituximab, have demonstrated clinical benefit in subsets of patients. However, these agents often require repeated or prolonged administration and are constrained by primary non-response, relapse following treatment discontinuation, and treatment-limiting immunogenicity [ 8 ]. In contrast, chimeric antigen receptor (CAR) T-cell therapy represents a fundamentally distinct immunotherapeutic strategy. CAR T cells are genetically engineered to recognize and eliminate target cells in a major histocompatibility complex (MHC)-independent manner, enabling highly specific and potent cytotoxic activity [ 9 ]. Compared with monoclonal antibodies, CAR T-cell therapy offers the potential advantages of enhanced tissue penetration, sustained in vivo persistence, and more profound depletion of pathogenic B-cell populations, which together may facilitate a durable “reset” of aberrant humoral immunity [ 8 ]. These properties make CAR-based approaches particularly attractive for refractory autoimmune diseases driven by long-lived or tissue-resident B cells.

Nevertheless, the application of CAR T-cell therapy in IIM remains at an early exploratory stage, with evidence largely limited to case reports and small case series. A systematic synthesis of the emerging clinical experience, including efficacy signals, safety profiles, and unresolved challenges, is currently lacking. Therefore, this systematic review aims to comprehensively summarize the available literature on CAR T-cell therapy in refractory IIM, critically evaluate reported clinical outcomes and adverse events, and identify key knowledge gaps and priorities for future research and clinical translation.

Methods

Search strategy and selection criteria

This systematic review was conducted in accordance with the PRISMA guidelines. The completed PRISMA checklist is provided in the Supplementary Table S1 . The review protocol was prospectively registered in PROSPERO (registration number: CRD420251123601). The objective was to synthesize the available clinical evidence on the efficacy and safety of CAR T-cell therapy and related CAR-based therapeutic approaches in patients with IIM. A comprehensive literature search was performed in MEDLINE, PubMed, Embase, Web of Science, and the Cochrane Library from database inception to 15 August 2025. The complete search strategies are provided in the Supplementary Table S2 . Eligible studies investigated the use of CAR T-cell therapy in adult and/or pediatric patients with IIM. When multiple publications originated from the same research group or cohort, potential overlap in patient populations was carefully assessed at the individual-patient level. If multiple reports described the same patient, the patient was counted only once in the aggregated dataset. Earlier reports were used to extract baseline characteristics and data from the initial treatment phase, whereas later reports were used to supplement extended follow-up or additional non-redundant treatment-course information, provided that duplicate data points were not entered twice. Studies were excluded if they were preclinical in nature, did not report clinical efficacy outcomes, or were not published in English.

Study selection and data extraction

Two reviewers (X.S. and F.P.) independently conducted study screening and data extraction using a two-stage process, consisting of initial title and abstract screening followed by full-text assessment for eligibility. All retrieved records were screened independently by both reviewers, and each full-text report was assessed independently for eligibility. Disagreements were resolved through discussion and, when necessary, adjudication by a third reviewer (Y.G.). The following data were extracted: bibliographic information (authors, year of publication, and sample size); intervention characteristics (product name, manufacturer or sponsor, CAR target antigen, construct design, and dosing regimen); study design features (study type, single- or multicenter setting, inclusion criteria, and duration of follow-up); baseline participant characteristics (sex, age, creatine kinase [CK] levels, Manual Muscle Testing-8 [MMT-8] scores, and visual analogue scale [VAS] assessments); pharmacokinetic and pharmacodynamic parameters (time to peak CAR T-cell expansion and timing of B-cell depletion and reconstitution); safety outcomes, including CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), infections, haematologic toxicities, and hypogammaglobulinaemia; and efficacy outcomes, including changes in CK levels, MMT-8 scores and related functional measures, total improvement score (TIS), physician global assessment (PGA), immunoglobulin concentrations, and achievement of drug-free remission. Drug-free remission was defined as the complete discontinuation of oral glucocorticoids and all immunosuppressive agents, sustained through the end of the reported follow-up period or longer. Patients requiring ongoing intravenous immunoglobulin (IVIG) replacement were not classified as having achieved strict drug-free remission and were reported separately.

Given that CAR T-cell therapy in IIM remains an emerging and exploratory therapeutic approach, the number of high-quality published clinical studies is limited. To ensure comprehensive capture of the available clinical evidence, abstracts from major international scientific conferences were included alongside peer-reviewed journal publications. When numerical data were not explicitly reported in the text but were presented graphically, values were approximated by digitizing figures using OriginPro 2024.

Risk of bias assessment

Because the available evidence consisted primarily of case reports and small case series, methodological quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklist for case reports [ 10 ] and the JBI critical appraisal checklist for case series [ 11 ], as appropriate to study design. Two reviewers independently performed the appraisal, and disagreements were resolved through discussion and, when necessary, consultation with a third reviewer.

Statistical analyses

Continuous variables are reported as mean ± standard deviation (SD) or median with interquartile range (IQR), as appropriate based on data availability and distribution. Categorical variables are summarized as counts and proportions. Given the small sample size and heterogeneity of study designs, analyses were primarily exploratory and descriptive in nature. All statistical analyses were performed using SPSS version 25.0 and GraphPad Prism version 9.

Outcomes

Study selection

The database search identified 454 records. After the removal of 146 duplicate entries, 308 records underwent title and abstract screening. Following full-text review, 10 studies met the inclusion criteria and were incorporated into the qualitative and quantitative synthesis, as depicted in the PRISMA flow diagram (Fig. 1 ). One additional study was available only as a conference abstract presented at the EULAR 2025 Congress; no full-text manuscript was accessible at the time of review. Overall, the included studies reported clinical data on 12 patients with IIM.

Study characteristics

All included studies were either single-patient case reports or small case series involving patients with active, refractory IIM who received CAR T-cell therapy after failure of at least two prior immunosuppressive or immunomodulatory treatments (Table 1 ). The studies originated from Germany ( n = 4) [ 12 – 15 ], the United States ( n = 2) [ 16 , 17 ], Italy ( n = 1) [ 18 ], Spain ( n = 1) [ 19 ], and China ( n = 2) [ 20 , 21 ]. In total, 12 patients were included, comprising 10 adults and 2 paediatric cases. Diagnoses included DM ( n = 3) [ 16 , 18 , 19 ], IMNM ( n = 5) [ 16 , 17 , 20 , 21 ], and ASyS ( n = 4) [ 12 – 15 ] (Table 2 ). One patient (patient 10) was reported in both studies [ 13 , 15 ]; these two publications referred to the same individual and were linked during data extraction, and the patient was counted only once in the total of 12 unique patients. All patients exhibited clinically and biologically active disease at baseline, with persistent muscle weakness and/or extramuscular involvement accompanied by elevated muscle enzymes or other laboratory markers of ongoing inflammation prior to CAR T-cell therapy.

The detailed results of the JBI critical appraisal are provided in Supplementary Table S3 . The seven case reports provide detailed documentation across all key domains. However, the three case series showed more variable quality, with some unclear reports on inclusion criteria, completeness, and demographic details, particularly in the conference abstract by Mozaffar et al. [ 16 ]. Despite generally adequate reporting in case reports, the overall evidence remains highly susceptible to selection, reporting, and publication bias due to the uncontrolled and descriptive nature of all included studies.

In addition, data from two prospective cohort studies (CASTLE/LICATS) [ 22 , 23 ] were reviewed to contextualize cohort-level safety profiles and emerging efficacy signals associated with CAR-based therapies in autoimmune disease. To avoid duplicate patient inclusion, these cohort studies were not counted among the 10 included studies, and no individual-level data from these cohorts were pooled with the aggregated patient dataset.

CAR therapeutic products

Among the 10 included studies, one evaluated an allogeneic CAR-based product [ 20 ], whereas the remaining nine employed autologous CAR T-cell therapy. All studies administered lymphodepleting chemotherapy with fludarabine and cyclophosphamide prior to CAR T-cell infusion [ 13 , 21 ]. With respect to antigen specificity, CD19-directed CAR T-cell therapy was reported in nine studies, while two studies utilized B-cell maturation antigen (BCMA)-targeted constructs. Notably, Müller et al. [ 13 ] described an antigen-switch, sequential-targeting strategy in a patient who relapsed after an initial CD19 CAR T-cell infusion, failed to respond to repeat CD19-directed therapy, and subsequently received BCMA-targeted CAR T cells, highlighting the potential relevance of antigen escape and plasma cell-directed targeting in refractory disease. All CAR constructs incorporated a CD3ζ signaling domain. The majority used 4-1BB (CD137) as the co-stimulatory domain, with the exception of the construct reported by Haase et al. [ 12 ], which employed CD28. Regarding the transmembrane domain, CAR products developed by the Erlangen/Miltenyi group utilized TNFRSF19, whereas other constructs employed CD8α. The hinge region was predominantly derived from CD8α across studies [ 13 – 15 , 18 ]. CAR T-cell dosing was largely uniform, with all but one patient receiving 1 × 10 6 CAR-positive cells per kilogram body weight. In the exception reported by Müller et al. [ 13 ], a second CD19-directed infusion at 1.3 × 10 6 CAR-positive cells/kg failed to expand in vivo, prompting subsequent administration of a BCMA-targeted product at a higher dose of 6 × 10 6 CAR-positive cells/kg.

Efficacy outcomes

Of the 12 reported cases, 11 had evaluable efficacy outcomes with a minimum follow-up duration of 1 month. One patient (8.3%) remained in the treatment phase at the time of reporting, and post-infusion efficacy data were not yet available [ 16 ]. Follow-up data were available for 10 (83.3%), 6 (50.0%), and 3 (25.0%) patients at 3, 6, and 12 months, respectively.

Across the evaluable cohort, CK levels demonstrated a marked and sustained decline following CAR T-cell therapy (Fig. 2 ). The median CK decreased from 895.2 U/L (IQR 265.2-2682.9) at baseline to 518.6 U/L (IQR 248.4-787.7; n = 7) at 2 months, 306.1 U/L (IQR 87.9-641.4) at 3 months, 85.9 U/L (IQR 64.5-776.0) at 6 months. Parallel improvements were observed in muscle strength as assessed by MMT-8. The median MMT-8 score increased from 117.4 (IQR 97.9-124.9) at baseline to 137.0 (IQR 117.0-149.8) at 2 months, 147.8 (IQR 136.7-150.0) at 3 months, and 149.8 (IQR 136.0-150.0) at 6 months.

Several case reports assessed treatment response using the PGA (Fig. 2 ), demonstrating a sustained decline following CAR T-cell therapy that paralleled improvements in muscle strength and systemic inflammatory markers [ 12 , 18 , 20 ]. In addition, Nicolai et al. and Wang et al. [ 10 , 18 ] incorporated the patient global assessment (PtGA) to capture patient-reported perceptions of therapeutic benefit, complementing physician-assessed outcomes. The TIS was reported in multiple studies [ 13 – 15 , 20 ]; however, its interpretability was limited by incomplete longitudinal reporting. Specifically, Müller et al. [ 13 ] provided TIS data only for patient 10 during the initial CAR T-cell treatment period, without corresponding measurements following relapse or subsequent retreatment, thereby constraining longitudinal and cross-study comparability. Wang et al. [ 20 ] additionally reported the Health Assessment Questionnaire (HAQ) index as a complementary patient-reported outcome measure, offering further insight into functional status and quality of life.

Muscle imaging

Muscle magnetic resonance imaging (MRI) was performed in three patients and consistently demonstrated marked regression of inflammatory changes following CAR T-cell therapy. In patient 6, baseline MRI revealed patchy muscle edema and myofiber injury involving the thigh musculature. Follow-up imaging at day 90 showed a substantial reduction in edema and improvement in muscle atrophy, with near-complete radiographic resolution by day 120. Similarly, patients 7 and 8 exhibited reductions in focal enhancing lesions, attenuation of diffuse myositis-related signal abnormalities, and improvement in subcutaneous calcifications, collectively consistent with a pronounced local anti-inflammatory effect at the tissue level.

Interstitial lung disease and pulmonary function

Among the five patients explicitly reported to have interstitial lung disease (ILD), longitudinal chest computed tomography (CT) imaging was available for one patient. In this case (patient 1), serial CT scans demonstrated progressive resolution of bilateral pulmonary consolidations and a reduction in cystic changes. These radiographic improvements were accompanied by substantial clinical recovery, enabling discontinuation of supplemental oxygen and decannulation of a tracheostomy tube. In addition, patients 1 and 9 exhibited objective improvements in pulmonary function test parameters. In patient 1, pulmonary and systemic improvement coincided with declining serum ferritin levels and a parallel reduction in Krebs von den Lungen-6 (KL-6), supporting stabilization and partial reversal of ILD activity.

Drug-free remission

Among the 11 patients with IIM who had available follow-up data, 6 (54.5%) achieved drug-free remission following CAR T-cell therapy. Drug-free remission was defined as sustained discontinuation of systemic glucocorticoids and conventional immunosuppressive agents [ 14 , 15 , 17 , 18 , 20 , 21 ]. One additional patient (8.3%) was able to discontinue glucocorticoids and immunosuppressants but required ongoing monthly IVIG replacement to manage CAR T-cell-associated hypogammaglobulinemia [ 19 ]. This patient was therefore not classified as having achieved drug-free remission. Two patients (16.7%) remained on low-dose glucocorticoid therapy at last follow-up [ 12 , 16 ]. One patient (8.3%) was hospitalized for pulmonary embolism on day 38 after CAR T-cell infusion, despite an initial decline in serum CK by day 29. The prolonged recovery and intercurrent complication may have confounded subsequent assessment of therapeutic response in this case [ 16 ]. Notably, patient 10 achieved approximately nine months of clinical remission following the initial CD19-directed CAR T-cell infusion before experiencing disease relapse [ 13 ]. A second infusion of the same CD19-targeted CAR T-cell product failed to induce in vivo CAR T-cell expansion or clinical improvement. After bridging therapy with daratumumab, subsequent treatment with a BCMA-targeted CAR T-cell product successfully re-induced remission, which was sustained in a drug-free state for more than nine months at last follow-up.

Safety outcomes

Of the 12 patients who received CAR T-cell therapy, 11 were evaluable for safety analyses (Table 3 ); one patient (patient 5) was excluded due to insufficient follow-up (< 1 month). Overall, CAR T-cell therapy was associated with a manageable safety profile across the evaluable cohort. CRS was the most frequently observed adverse event, occurring in 6 patients (54.5%). All CRS episodes were mild to moderate in severity (grade 1–2). Specifically, 5 patients (45.5%) experienced grade 1 CRS, and 2 patients (18.2%) developed grade 2 CRS; patient 10 experienced distinct CRS episodes following CD19- and BCMA-targeted CAR T-cell infusions, respectively. All CRS events were effectively managed with standard interventions, including tocilizumab ( n = 5), corticosteroids ( n = 2), and the interleukin-1 receptor antagonist anakinra ( n = 1). One case of ICANS was reported (grade 1), presenting as mild dizziness and resolving promptly following administration of low-dose glucocorticoids. Post-infusion infections were documented in 4 patients (36.4%). Reported infections included pulmonary Pseudomonas aeruginosa infection with concomitant rhinovirus, a mild pulmonary herpes simplex virus infection, cytomegalovirus viremia, and an upper respiratory tract infection (Supplementary Table S4 ). All infectious events resolved with standard antimicrobial or supportive therapy, and no infection-related mortality occurred. Transient hematologic toxicities were observed in 5 patients (45.5%), including neutropenia ( n = 2; grade 3 in one patient and grade 4 in one patient), lymphopenia ( n = 2; grade 2), and anemia ( n = 1; grade 2). One patient also experienced a transient elevation in hepatic transaminases (grade 2). All hematologic and biochemical abnormalities resolved spontaneously or improved with supportive care, and no cases of persistent bone marrow suppression were reported. Hypogammaglobulinemia developed in 4 patients (36.4%). Two patients required ongoing IVIG replacement, whereas the remaining two exhibited reduced immunoglobulin levels that did not necessitate routine supplementation. Non-hematologic adverse events included one pulmonary embolism, which was assessed as unrelated to CAR T-cell therapy, and one episode of nonspecific enteritis. No cases of hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) were observed during the treatment period. Notably, París-Muñoz et al. [ 19 ] reported a pediatric patient with anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (patient 1) who had developed secondary MAS prior to CAR T-cell therapy. Genetic testing excluded primary HLH, and MAS with a predominantly neurologic component was suspected. Following CAR T-cell therapy, MAS manifestations improved, accompanied by normalization of inflammatory biomarkers, suggesting effective control of hyperinflammatory activity.

Pharmacokinetics and pharmacodynamics

Patient 5 was not evaluable for pharmacokinetic or pharmacodynamic analyses due to insufficient follow-up. With the exception of patient 10, who failed to demonstrate CAR T-cell expansion following the second CD19-directed infusion, all other evaluable patients exhibited measurable in vivo CAR T-cell expansion after infusion. Peak expansion generally occurred within 1–3 weeks (range, 7–22 days), a pattern that was consistent across reports. In most cases, CAR T cells remained detectable in peripheral blood for approximately 22–65 days. Notably, the allogeneic CAR-based product demonstrated more sustained persistence, with detectable expansion lasting up to six months.

B-cell depletion and reconstitution

Effective peripheral B-cell depletion was achieved in all evaluable patients except patient 10. In the majority of cases, circulating B cells became undetectable within approximately two weeks following lymphodepletion and CAR T-cell infusion, with depletion sustained for several weeks to at least two months. Patient 10 achieved complete peripheral B-cell depletion after the initial CD19-directed CAR T-cell infusion; however, no B-cell depletion was observed following a second infusion of the same CD19-targeted product, consistent with the absence of CAR T-cell expansion. After subsequent treatment with BCMA-directed CAR T cells, peripheral CD19 + B cells remained undetectable for 41 days. Lymph node histology obtained three months after BCMA CAR T-cell infusion revealed complete elimination of CD138 + plasma cells, while CD20 + B cells persisted, indicating differential targeting of plasma cell and mature B-cell compartments.

B-cell reconstitution typically began approximately two months after infusion. Several studies reported that early B-cell repopulation was skewed toward transitional (CD24 + CD38 + CD27 − ) and naïve (CD27 − ) subsets, accompanied by sustained depletion of memory (CD27 + ) B cells and plasmablasts. This pattern suggests a partial reconstitution of the B-cell compartment with delayed recovery of antigen-experienced populations [ 17 , 18 ].

Discussion

The therapeutic management of IIM has long been constrained by a limited armamentarium, with clinical decision-making frequently reliant on expert consensus rather than robust, high-level evidence [ 29 ]. Current treatment strategies are largely nonspecific and are often undermined by incomplete efficacy, cumulative toxicity, and restricted accessibility [ 30 ]. Against this backdrop of substantial unmet clinical need, CAR T-cell therapy has emerged as a potentially transformative immunotherapeutic approach. However, until now, the clinical experience with CAR T-cell therapy in IIM has remained fragmented and unsystematically appraised. In this systematic review, we synthesized the available clinical evidence to provide an objective assessment of the efficacy, safety, and biological plausibility of CAR T-cell therapy in refractory IIM.

Across 10 clinical reports encompassing 12 adult and pediatric patients, all individuals exhibited active, treatment-refractory disease despite failure of at least two prior conventional and/or biologic immunosuppressive therapies. Within this highly selected population, published reports suggested clinical improvement across multiple disease domains after CAR T-cell therapy. Muscle involvement improved substantially, with consistent gains in objective strength measures such as MMT-8 scores and marked reductions in serum CK levels from elevated baseline values toward the normal range, reflecting meaningful attenuation of muscle injury and functional recovery. Systemic disease activity also declined sharply, as captured by physician- and patient-reported outcome measures. Importantly, CAR T-cell therapy enabled substantial treatment de-escalation. Approximately half of the patients achieved sustained drug-free remission, while others required only low-dose glucocorticoids or supportive immunoglobulin replacement to manage therapy-associated hypogammaglobulinemia. Beyond skeletal muscle, therapeutic effects extended to key organ manifestations. Muscle magnetic resonance imaging demonstrated pronounced resolution of inflammatory lesions, and patients with interstitial lung disease ILD exhibited clinical stabilization or radiographic improvement. Collectively, these findings suggest that CAR T-cell therapy may exert broad immunomodulatory effects across multiple disease compartments in IIM.

Notably, these responses were observed in a cohort characterized by profound treatment refractoriness. Ten of the 12 patients (83.3%) had previously received rituximab, an anti-CD20 monoclonal antibody that depletes circulating B cells, yet failed to achieve durable clinical benefit. Although rituximab effectively eliminates CD20 + B cells from the peripheral blood, its capacity to eradicate pathogenic B-lineage populations in tissue niches is limited [ 31 , 32 ]. CD20 is not expressed on long-lived plasma cells or most plasmablasts, which are major sources of myositis-specific autoantibodies, nor on certain memory B-cell subsets residing in secondary lymphoid organs. Hence, these compartments remain intrinsically resistant to anti-CD20-mediated depletion [ 33 , 34 ]. This biological limitation is consistent with clinical trial data indicating that B-cell depletion alone is insufficient for disease control in a subset of patients with IIM [ 35 ]. In contrast, CAR T-cell therapy offers the potential for more comprehensive targeting of the B-cell lineage, including tissue-resident and antibody-secreting populations, thereby enabling a more profound and durable reconfiguration of pathogenic humoral immunity.

Although CAR T-cell therapy shows substantial promise for the treatment of IIM, the clinical course of a patient with anti-Jo-1-positive ASyS in this dataset illustrates important challenges that may arise in real-world application. This patient achieved a durable, drug-free remission lasting approximately nine months following an initial CD19-directed CAR T-cell infusion, but subsequently experienced disease relapse. Re-infusion with the same CD19-targeted CAR T-cell product failed to re-establish disease control, potentially reflecting immune-mediated rejection or functional inactivation of the CAR T cells upon repeated exposure to an identical construct [ 13 ]. From a mechanistic perspective, this outcome is biologically plausible. While CD19-directed CAR T-cell therapy effectively depletes circulating and tissue-resident B cells [ 36 ], the production of anti-Jo-1 autoantibodies is largely maintained by CD19-negative long-lived plasma cells. These cells are intrinsically resistant to CD19-targeted depletion, allowing continued autoantibody production and eventual clinical relapse. In contrast, targeting BCMA encompasses a broader spectrum of antibody-secreting cells, including short-lived plasmablasts and tissue-resident long-lived plasma cells [ 37 ]. In this patient, switching to BCMA-targeted CAR T-cell therapy resulted in effective plasma cell ablation, a marked reduction in autoantibody levels, and re-induction of a stable, drug-free remission. This sequential targeting strategy highlights the importance of precisely matching CAR specificity to the dominant pathogenic immune compartment to achieve a deeper and more durable immunologic reset [ 38 ]. At present, no head-to-head studies have directly compared BCMA- versus CD19-directed CAR T-cell therapies in autoimmune diseases. However, experience from multiple myeloma demonstrates that dual-target CAR T-cell approaches simultaneously targeting BCMA and CD19 can enhance depth and durability of response, resulting in prolonged progression-free survival. Emerging data from systemic lupus erythematosus further suggest that combined targeting of CD19 + B cells and BCMA + plasma cells may yield additive or synergistic therapeutic effects in autoimmunity [ 39 , 40 ]. Whether similar dual-antigen strategies confer superior efficacy over single-antigen approaches in IIM remains unknown, as such strategies have not yet been systematically evaluated in this disease. Carefully designed comparative studies will be required to define the optimal antigen targets, sequencing strategies, and risk-benefit profiles for CAR T-cell therapy in IIM.

Across the majority of cases included in this review, circulating CD19 + B cells were eliminated within days of CAR T-cell infusion. B-cell reconstitution typically commenced approximately two months post-treatment and was predominantly characterized by transitional and naïve B-cell subsets. Importantly, this pattern of repopulation was not associated with early disease relapse, supporting the concept of a functional “B-cell reset.” Sustained clinical benefit despite B-cell reconstitution may reflect ongoing CAR T-cell persistence within tissue compartments, where pathogenic B-lineage cells preferentially reside. Moreover, the repopulating B-cell pool appears largely naïve and non-autoreactive, potentially limiting re-engagement of pathogenic immune circuits and facilitating prolonged drug-free remission [ 41 , 42 ]. All patients described in this review were treated with second-generation CAR T-cell constructs. Notably, third-generation CAR T-cell platforms incorporating additional co-stimulatory domains have demonstrated enhanced persistence and more sustained B-cell depletion in preclinical studies and early clinical trials [ 43 ]. Whether such prolonged immunologic effects translate into superior long-term disease control or increase the risk of complications related to extended B-cell aplasia remains an open question. Addressing these issues will require systematic, longitudinal studies with comprehensive immunophenotyping and long-term safety surveillance.

Although these early findings are encouraging, they must be interpreted with caution due to the preliminary nature of the available evidence. To date, CD19- or BCMA-targeted CAR T-cell therapy has been reported in only 12 patients with IIM, primarily through isolated case reports or small case series with limited follow-up. Consequently, any conclusions regarding efficacy are inherently constrained. Moreover, all patients received fludarabine and cyclophosphamide as lymphodepleting chemotherapy prior to CAR T-cell infusion. Although this regimen facilitates CAR T-cell expansion and persistence, it may independently deplete autoreactive lymphocyte populations, making it challenging to disentangle the specific contribution of CAR T cells from that of lymphodepletion [ 44 ]. Second, the included reports lacked contemporaneous control groups receiving optimized standard-of-care therapy, limiting the ability to make comparative efficacy assessments. Publication bias is another important consideration, as cases with dramatic clinical responses are more likely to be reported than those with suboptimal outcomes or severe toxicities. Although we contacted investigators for clarification or additional unpublished information, no additional patient-level data were obtained. As a result, reported response rates may be overestimated, while complication frequencies could be underestimated. Third, the long-term effectiveness and safety of CAR T-cell therapy in IIM remain unestablished. Most patients have been followed for months rather than years, precluding reliable assessment of the durability of drug-free remission, risk of late relapse, or potential cumulative toxicities. Future studies should prioritize larger, prospective, controlled trials comparing CAR T-cell therapy with optimized standard-of-care regimens. Pulmonary involvement represents a major driver of morbidity and mortality in IIM [ 45 ]. Although several patients in this cohort had clinically significant ILD, longitudinal pulmonary assessments were sparse and heterogeneous, often limited to descriptive imaging or sporadic pulmonary function tests. This precludes meaningful conclusions regarding the effects of CAR-based therapy on ILD and highlights the need for standardized, prospective pulmonary endpoints in future trials.

CAR T-cell therapy demonstrated a generally favorable safety profile in this cohort. CRS was the most common adverse event, occurring in 54.5% of patients, and all events were mild to moderate (grade 1–2). Both the frequency and severity of CRS were lower than those observed in hematologic malignancies, where any-grade CRS occurs in approximately 67% of patients, with grade ≥ 3 events in ~ 13% [ 46 ]. The design of the CAR construct, particularly the co-stimulatory domain, influences T-cell expansion kinetics and cytokine release. Clinical data indicate higher CRS rates with CD28-based co-stimulatory domains compared to 4-1BB-based domains [ 47 ]. Consistent with this pattern, the sole patient (patient 9) who received a CD28-costimulated CAR product experienced recurrent grade 1–2 CRS, managed with tocilizumab, dexamethasone, and anakinra [ 46 ]. ICANS was rare, with only one mild case reported, markedly lower than rates observed in oncology cohorts [ 44 , 48 ]. Hematologic toxicities were reported in five patients, occurred early in the treatment course, and were likely attributable to preceding lymphodepleting chemotherapy [ 49 ]. Infections were documented in four patients (36.4%) but were manageable with standard interventions, highlighting the need for careful monitoring of immune-related complications. Notably, no cases of HLH or MAS were observed, a complication associated with high mortality in other CAR T-cell settings [ 50 ]. In one patient with pre-existing secondary MAS, CAR T-cell therapy was associated with symptomatic improvement. Overall, the adverse event profile in this IIM cohort appears milder than that reported in oncology settings, likely reflecting a lower burden of target antigen-expressing cells in autoimmune disease compared with B-cell malignancies.

This work has several important limitations. First, all included studies were case reports, small case series, or conference abstracts, and therefore the current evidence base is inherently vulnerable to selection bias, reporting bias, and publication bias. Given the descriptive and uncontrolled nature of the available evidence, a formal grading of recommendations assessment, development and evaluation (GRADE) assessment was not performed. Many of the included reports represent preliminary data from ongoing studies, and follow-up durations for several participants remain insufficient to evaluate long-term outcomes and safety. Hence, the apparent absence of certain adverse events or the perception of limited therapeutic responses may reflect short observation windows rather than the true long-term profile. In addition, substantial heterogeneity existed in outcome reporting. Efficacy endpoints were not standardized, and only a minority of studies systematically assessed ILD, limiting conclusions regarding pulmonary effects. Continuous variables were reported inconsistently and often without individual-level data, reducing the potential for robust quantitative synthesis. Furthermore, long-term safety remains uncertain due to limited data on late-onset events, including secondary malignancies and potential impacts on fertility and overall immunocompetence. Finally, the small sample size and inclusion of multiple IIM subtypes precluded meaningful analyses of differential efficacy or toxicity across disease phenotypes.

Looking forward, next-generation CAR-based modalities, such as CAR-engineered regulatory T cells (CAR-Tregs) and CAR natural killer cells (CAR-NK), may further expand the therapeutic potential of cell-based immunotherapy in autoimmune diseases. CAR-NK cells offer potential advantages, including MHC-unrestricted target recognition and a possibly lower risk of severe CRS and graft-versus-host disease [ 51 ]. Early clinical signals have been reported in systemic lupus erythematosus and systemic sclerosis [ 52 , 53 ]. CAR-Tregs are designed to suppress the function of antigen-presenting cells and attenuate pathogenic immune responses [ 51 , 54 ]. Preclinical studies indicate that CAR-Tregs can mediate localized immunomodulation in autoimmune disease models [ 55 , 56 ]. However, neither approach has yet been evaluated in IIM, and their relevance to muscle-predominant disease remain unknown. A major challenge relates to accessibility and cost, although allogeneic platforms may improve scalability in the future [ 20 ].

Conclusion

In this review, approximately half of the patients were able to discontinue glucocorticoids and other immunosuppressive agents, suggesting that CAR T-cell therapy may induce a deep immunologic reset. These findings indicate that CAR T-cell therapy represents a promising therapeutic strategy for achieving remission in refractory IIM. Nevertheless, larger prospective studies are needed to establish the durability, safety, and generalizability of remission following CAR T-cell therapy in IIM.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

The authors would like to express their gratitude to EditSprings ( https://www.editsprings.com ) for the expert linguistic services provided.

Author contributions

Xueyan Shan: conceptualisation, investigation, data curation, search strategy and selection criteria, formal analysis, and writing of the original draft. Fengtao Pang: investigation, data curation, Guochun Wang, Yongpeng Ge and Xin Lu: review and editing of the manuscript. All authors had final responsibility for the decision to submit for publication.

Funding

This work was supported by The Elite Medical Professional Project of China-Japan Friendship Hospital (ZRJY2023-GG02).

Data availability

This study is a systematic review. No new primary data were generated. Quantitative values not explicitly reported in the included publications were extracted from published figures using OriginPro for secondary analysis. The curated dataset is available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Yongpeng Ge, Email: gyp2016@163.com.

Xin Lu, Email: luxin_n@163.com.

References

1. Liu T, Chen B, Yin G, Xie Q. Targeting B Cells for the Treatment of Idiopathic Inflammatory Myopathy. Clin Rev Allergy Immunol. 2025;68(1):40. 10.1007/s12016-025-09047-0.

2. Rayavarapu S, Coley W, Kinder TB, Nagaraju K. Idiopathic inflammatory myopathies: pathogenic mechanisms of muscle weakness. Skelet Muscle. 2013;3(1):13. 10.1186/2044-5040-3-13.

3. Pinal-Fernandez I, Muñoz-Braceras S, Casal-Dominguez M, et al. Pathological autoantibody internalisation in myositis. Ann Rheum Dis. 2024;83(11):1549–60. 10.1136/ard-2024-225773.

4. Preuße C, Paesler B, Nelke C, et al. Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis. Acta Neuropathol. 2022;144(2):353–72. 10.1007/s00401-022-02438-z.

5. Anang DC, Walter HAW, Lim J, et al. B-cell receptor profiling before and after IVIG monotherapy in newly diagnosed idiopathic inflammatory myopathies. Rheumatology (Oxford). 2023;62(7):2585–93. 10.1093/rheumatology/keac602.

6. Young-Glazer J, Cisneros A, Wilfong EM, Smith SA, Crofford LJ, Bonami RH. Jo-1 autoantigen-specific B cells are skewed towards distinct functional B cell subsets in anti-synthetase syndrome patients. Arthritis Res Ther. 2021;23(1):33. 10.1186/s13075-020-02412-8.

7. Dzangué-Tchoupou G, Allenbach Y, Preuße C, Stenzel W, Benveniste O. Mass cytometry reveals an impairment of B cell homeostasis in anti-synthetase syndrome. J Neuroimmunol. 2019;332:212–5. 10.1016/j.jneuroim.2019.04.014.

8. Su M, Zhao C, Luo S. Therapeutic potential of chimeric antigen receptor based therapies in autoimmune diseases. Autoimmun Rev. 2022;21(1):102931. 10.1016/j.autrev.2021.102931.

9. Brudno JN, Maus MV, Hinrichs CS. CAR T Cells and T-Cell Therapies for Cancer: A Translational Science Review. JAMA. 2024;332(22):1924–35. 10.1001/jama.2024.19462.

10. Gagnier JJ, Kienle G, Altman DG, et al. The CARE Guidelines: Consensus-Based Clinical Case Reporting Guideline Development. Headache: J Head Face Pain. 2013;53(10):1541–7.

11. Munn Z, Barker TH, Moola S, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synthesis. 2020;18(10):2127–33.

12. Haase I, Richter J, Holzer MT, et al. A novel approach to refractory idiopathic inflammatory myopathy: CD19 CAR T-cell therapy—case report and literature review. Rheumatology. 2025;64(9):5101–7. 10.1093/rheumatology/keaf190.

13. Müller F, Wirsching A, Hagen M, et al. BCMA CAR T cells in a patient with relapsing idiopathic inflammatory myositis after initial and repeat therapy with CD19 CAR T cells. Nat Med. 2025;31(6):1793–7. 10.1038/s41591-025-03718-3.

14. Taubmann J, Knitza J, Müller F, et al. Comment on: Rescue therapy of anti-synthetase syndrome with CD19-targeted CART cells after failure of several B cell-depleting antibodies: reply. Rheumatology (Oxford). 2024;63(11):e312–4. 10.1093/rheumatology/kead669.

15. Müller F, Taubmann J, Bucci L, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up. N Engl J Med. 2024;390(8):687–700. 10.1056/NEJMoa2308917.

16. Mozaffar T, Naddaf E, Chahin N, et al. OP0316 Reset-myositis TM : clinical trial evaluating rese-cel (resecabtagene autoleucel), a fully human, autologous 4-1BB anti-CD19 CAR T cell therapy in idiopathic inflammatory myopathies. Ann Rheum Dis. 2025;84:254–5. 10.1016/j.ard.2025.05.318.

17. Volkov J, Nunez D, Mozaffar T, et al. Case study of CD19 CAR T therapy in a subject with immune-mediate necrotizing myopathy treated in the RESET-Myositis phase I/II trial. Mol Ther. 2024;32(11):3821–8. 10.1016/j.ymthe.2024.09.009.

18. Nicolai R, Merli P, Moran Alvarez P, et al. Autologous CD19-Targeting CAR T Cells in a Patient With Refractory Juvenile Dermatomyositis. Arthritis Rheumatol. 2024;76(10):1560–5. 10.1002/art.42933.

19. París-Muñoz A, Alcobendas-Rueda RM, Verdú-Sánchez C, et al. CD19 CAR-T cell therapy in a pediatric patient with MDA5 + dermatomyositis and rapidly progressive interstitial lung disease. Med. 2025;6(8):100676. 10.1016/j.medj.2025.100676.

20. Wang X, Wu X, Tan B, et al. Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis. Cell. 2024;187(18):4890–e49049. 10.1016/j.cell.2024.06.027.

21. Qin C, Dong MH, Zhou LQ, et al. Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR-T cell therapy. Proc Natl Acad Sci U S A. 2024;121(6):e2315990121. 10.1073/pnas.2315990121.

22. Hagen M, Müller F, Wirsching A, et al. Local immune effector cell-associated toxicity syndrome in CAR T-cell treated patients with autoimmune disease: an observational study. Lancet Rheumat. 2025;7(6):e424–33. 10.1016/S2665-9913(25)00091-8.

23. Hagen M, Wirsching A, Müller F, et al. OP0316 Reset-myositis TM: clinical trial evaluating rese-cel (resecabtagene autoleucel), a fully human, autologous 4-1BB anti-CD19 CAR T cell therapy in idiopathic inflammatory myopathies. Ann Rheum Dis. 2025;84:369–70. 10.1016/j.ard.2025.05.459.

24. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95). 10.1126/scitranslmed.3002842.

25. Wang D, Wang J, Hu G, et al. A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. Blood. 2021;137(21):2890–901. 10.1182/blood.2020008936.

26. Del Bufalo F, Becilli M, Rosignoli C, et al. Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL. Blood. 2023;142(2):146–57. 10.1182/blood.2023020023.

27. Maschan M, Caimi PF, Reese-Koc J, et al. Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients. Nat Commun. 2021;12:7200. 10.1038/s41467-021-27312-6.

28. Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022;28(10):2124–32. 10.1038/s41591-022-02017-5.

29. Connolly CM, Gupta L, Fujimoto M, Machado PM, Paik JJ. Idiopathic inflammatory myopathies: current insights and future frontiers. Lancet Rheumatol. 2024;6(2):e115–27. 10.1016/S2665-9913(23)00322-3.

30. Connolly CM, Plomp L, Paik JJ, Allenbach Y. Possible future avenues for myositis therapeutics: DM, IMNM and IBM. Best Pract Res Clin Rheumatol. 2022;36(2):101762. 10.1016/j.berh.2022.101762.

31. Uzzan M, Ko HM, Rosenstein AK, Pourmand K, Colombel JF, Mehandru S. Efficient long-term depletion of CD20 + B cells by rituximab does not affect gut-resident plasma cells. Ann N Y Acad Sci. 2018;1415(1):5–10. 10.1111/nyas.13577.

32. Tur C, Eckstein M, Velden J, et al. CD19-CAR T-cell therapy induces deep tissue depletion of B cells. Ann Rheum Dis. 2025;84(1):106–14. 10.1136/ard-2024-226142.

33. Mei HE, Wirries I, Frölich D, et al. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood. 2015;125(11):1739–48. 10.1182/blood-2014-02-555169.

34. Merino-Vico A, Frazzei G, van Hamburg JP, Tas SW. Targeting B cells and plasma cells in autoimmune diseases: From established treatments to novel therapeutic approaches. Eur J Immunol. 2023;53(1):2149675. 10.1002/eji.202149675.

35. Zhen C, Hou Y, Zhao B, Ma X, Dai T, Yan C. Efficacy and safety of rituximab treatment in patients with idiopathic inflammatory myopathies: A systematic review and meta-analysis. Front Immunol. 2022;13:1051609. 10.3389/fimmu.2022.1051609.

36. Taubmann J, Müller F, Yalcin Mutlu M, et al. CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus. Arthritis Rheumatol. 2024;76(4):497–504. 10.1002/art.42784.

37. Chen W, Hong SH, Jenks SA, et al. Distinct transcriptomes and autocrine cytokines underpin maturation and survival of antibody-secreting cells in systemic lupus erythematosus. Nat Commun. 2024;15(1):1899. 10.1038/s41467-024-46053-w.

38. Wang Y, Cao J, Gu W, et al. Long-Term Follow-Up of Combination of B-Cell Maturation Antigen and CD19 Chimeric Antigen Receptor T Cells in Multiple Myeloma. J Clin Oncol. 2022;40(20):2246–56. 10.1200/JCO.21.01676.

39. Feng J, Huo D, Hong R, et al. Co-infusion of CD19-targeting and BCMA-targeting CAR-T cells for treatment-refractory systemic lupus erythematosus: a phase 1 trial. Nat Med. 2025;31(11):3725–36. 10.1038/s41591-025-03937-8.

40. Wang W, He S, Zhang W, et al. BCMA-CD19 compound CAR T cells for systemic lupus erythematosus: a phase 1 open-label clinical trial. Ann Rheum Dis. 2024;83(10):1304–14. 10.1136/ard-2024-225785.

41. Taubmann J, Müller F, Yalcin Mutlu M, et al. CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus. Arthritis Rheumatol. 2024;76(4):497–504. 10.1002/art.42784.

42. Wilhelm A, Chambers D, Müller F, et al. Selective CAR T cell-mediated B cell depletion suppresses IFN signature in SLE. JCI Insight. 2024;9(12):e179433. 10.1172/jci.insight.179433.

43. Scherlinger M, Nocturne G, Radic M, et al. CAR T-cell therapy in autoimmune diseases: where are we and where are we going? Lancet Rheumatol. 2025;7(6):e434–47. 10.1016/S2665-9913(24)00377-1.

44. Freeley M. CAR T Cell Therapy for Rheumatoid Arthritis. Clin Rev Allergy Immunol. 2025;68(1):100. 10.1007/s12016-025-09113-7.

45. Lundberg IE, Fujimoto M, Vencovsky J, et al. Idiopathic inflammatory myopathies. Nat Rev Dis Primers. 2021;7(1):86. 10.1038/s41572-021-00321-x.

46. Cordas Dos Santos DM, Tix T, Shouval R, et al. A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy. Nat Med. 2024;30(9):2667–78. 10.1038/s41591-024-03084-6.

47. Davey AS, Call ME, Call MJ. The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities. Cancers (Basel). 2020;13(1):38. 10.3390/cancers13010038.

48. Nordmann-Gomes A, Khalili L, Tang W, et al. CAR T-cell therapy in SLE: A systematic review. Semin Arthritis Rheum. 2025;74:152786. 10.1016/j.semarthrit.2025.152786.

49. Fried S, Avigdor A, Bielorai B, et al. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transpl. 2019;54(10):1643–50. 10.1038/s41409-019-0487-3.

50. Sandler RD, Tattersall RS, Schoemans H, et al. Diagnosis and Management of Secondary HLH/MAS Following HSCT and CAR-T Cell Therapy in Adults; A Review of the Literature and a Survey of Practice Within EBMT Centres on Behalf of the Autoimmune Diseases Working Party (ADWP) and Transplant Complications Working Party (TCWP). Front Immunol. 2020;11:524. 10.3389/fimmu.2020.00524.

51. Kong Y, Li J, Zhao X, Wu Y, Chen L. CAR-T cell therapy: developments, challenges and expanded applications from cancer to autoimmunity. Front Immunol. 2025;15:1519671. 10.3389/fimmu.2024.1519671.

52. Gao J, Li M, Sun M et al. Efficacy and safety of allogeneic CD19 CAR NK-cell therapy in systemic lupus erythematosus: a case series in China. Lancet. 2025:S0140-6736(25)01671-X. 10.1016/S0140-6736(25)01671-X.

53. Wang X, Zhang Y, Jin Y, et al. An iPSC-derived CD19/BCMA CAR-NK therapy in a patient with systemic sclerosis. Cell. 2025;188(16):4225–e423812. 10.1016/j.cell.2025.05.038.

54. Arjomandnejad M, Kopec AL, Keeler AM. CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications. Biomedicines. 2022;10(2):287. 10.3390/biomedicines10020287.

55. Boardman DA, Wong MQ, Rees WD, et al. Flagellin-specific human CAR Tregs for immune regulation in IBD. J Autoimmun. 2023;134:102961. 10.1016/j.jaut.2022.102961.

56. Doglio M, Ugolini A, Bercher-Brayer C, et al. Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus. Nat Commun. 2024;15(1):2542. 10.1038/s41467-024-46448-9.

Associated Data

Supplementary Materials

Supplementary Material 1

Data Availability Statement

This study is a systematic review. No new primary data were generated. Quantitative values not explicitly reported in the included publications were extracted from published figures using OriginPro for secondary analysis. The curated dataset is available from the corresponding author upon reasonable request.