Clinical trial landscape analysis of stem cell therapy for autoimmune rheumatic diseases

Abstract

Background:

Autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis and osteoarthritis, are debilitating conditions with limited curative options. Stem cell therapy offers promising regenerative and immunomodulatory benefits.

Methods:

We analyzed global clinical trial data from the Informa Trialtrove database up to 31 March 2025, identifying 449 relevant trials on stem cell therapy for ARDs. Trials were assessed by phase, disease type, stem cell source, and geographic distribution.

Results:

Most trials employed mesenchymal stem cells (75.8%), with osteoarthritis (46.7%) and rheumatoid arthritis (12.6%) being the most targeted conditions. China led trial activity (26.7%), driven by supportive policies and funding. While 58.8% of trials were completed, 13.1% were terminated, often due to recruitment or funding limitations. Innovations such as CAR-MSCs, iPSC-derived therapies, and exosome-based strategies are expanding the therapeutic frontier.

Conclusion:

Stem cell therapy is rapidly advancing in ARDs, supported by growing clinical evidence and technological innovations. However, standardized, multicenter phase III trials are essential to confirm long-term efficacy and safety. This evolving landscape holds potential to transform AIRD management.

Dear Editor,

To ensure full transparency and adherence to best practices in artificial intelligence (AI)-related research reporting, this study complies with the TITAN Guidelines 2025 for transparency in the reporting of AI^[1].

Autoimmune rheumatic diseases (ARDs) are a group of chronic, systemic disorders characterized by system immune dysfunction that leads to inflammation and damage in joints, muscles, connective tissues, and internal organs. Common ARDs include rheumatoid arthritis (RA), osteoarthritis (OA), systemic lupus erythematosus (SLE), dermatomyositis/ polymyositis, psoriasis, scleroderma, ankylosing spondylitis (AS), and Djogren’s syndrome. Current treatment strategies for rheumatic and immune diseases are shifted from conventional treatment towards personalized medicine to offer more effective treatment with less adverse effects (AEs). Conventional treatments are predominantly relied on non-steroidal anti-inflammatory drugs (NSAIDs), small molecule targeted therapies, and biological agents targeting tumor necrosis factor (TNF; e.g., etanercept, infliximab, adalimumab), interleukin-6 (IL-6; e.g., tocilizumab), and B-cells (e.g., an anti-CD20 monoclonal antibody – rituximab)^[2]. The increasing adoption of biological therapies offers new therapeutic hope for patients with ARDs who once faced restricted treatment choices. However, these treatments are not cost-effective and have limited curative effect, which underscore the urgent need for precise and optimizing approaches. To address the shortcomings of these conventional treatment options, alternative strategies have been developed to provide new insights and directions for treating ARDs. These strategies encompass genetic testing and pharmacogenomics^[2], stem cell therapies (SCT)^[3], machine-learning (ML)^[4,5] and artificial intelligence (AI) driven approaches^[5,6], chimeric antigen receptor-modified mesenchymal stem cells (CAR-MSCs)^[7,8], as well as emerging technologies such as exosomes, 3D bioprinting, and CRISPR-based gene editing^[9].

HIGHLIGHTS

• Mesenchymal stem cells (MSCs) dominate the therapeutic field due to their accessibility and multi-lineage differentiation potential.

• Emerging technologies such as gene editing and artificial intelligence, along with combination therapies, possess the transformative potential to further optimize stem cell therapies, thereby accelerating clinical translation.

• Stem cell therapy holds the potential to revolutionize the management of AIRDs, bringing new hope to patients afflicted with these conditions.

China has become a global leader in stem cell therapy research and development over the past decade (Fig. 2C), driven by regulatory reforms, substantial national funding, and inclusion in the 14th Five-Year Plan. The National Key R&D Program, launched in 2016, has invested over ¥3.5 billion (~US$500 million) in stem cell and regenerative medicine projects through 2020. Additional funding comes from provincial governments in innovation hubs like Shanghai Zhangjiang and Beijing Zhongguancun. Regulatory oversight by the National Health Commission (NHC) and National Medical Products Administration (NMPA), guided by the “2015 Administrative Measures on Stem Cell Clinical Research”, ensures ethical and procedural standards (Fig. 2E). Facilitating the clinical translation of research findings. This leadership is further supported by China’s rapid progress in cutting-edge biotechnologies, particularly the integration of CRISPR-based gene editing with stem cell therapies^[7]. The synergy between technological innovation and national policy has strengthened the therapeutic precision and application of stem cell-based interventions, especially for autoimmune and genetic diseases. To contextualize this leadership within the global landscape, we analyzed 449 clinical trials on stem cell therapies for autoimmune rheumatic diseases (ARDs) from the Informa Trialtrove database and ClinicalTrials.gov (as of 31 March 2025) (Fig. 1). MSCs dominate the therapeutic landscape, with osteoarthritis and rheumatoid arthritis being the most studied conditions. Our analysis outlines current trends, geographic patterns, and emerging research hotspots in this evolving field.

Figure 2.

Overview of clinical trials on stem cell therapy for autoimmune rheumatic diseases. (A) Annual distribution of registered clinical trials by phase from 1997 to 2025. (B) The main reasons for outcomes of terminated trials. (C) The number of clinical trials at different phases. (D) The number of registered clinical trials in the top 15 Countries. (E) Types of clinical trial sponsors. (E) Common rheumatic and immune system diseases treated with different types of stem cells.

Figure 1.

Flowchart of the screening process.

All clinical trials were from 40 countries (China: 133, 26.7%; United States: 72, 14.4%; South Korea: 43, 9.8%) (Fig. 2D) and OA accounted for the largest proportion of the SCTs (233, 46.7%), followed by lupus (80, 16.0%), RA (63, 12.6%), and SS (59, 11.8%), reflecting both high disease burden and unmet therapeutic needs. The majority of trials utilized MSCs (378, 75.8%), with sources including bone marrow, adipose tissue, umbilical cord, dental pulp, and synovium; favored for their accessibility, immunomodulatory functions, and potential for tissue regeneration. While 264 trials (58.8%) have reached completion and 110 (24.5%) are ongoing (Fig. 2A), however, a notable 75 trials (16.7%) were prematurely terminated or closed. These failures often resulted from poor recruitment, lack of therapeutic efficacy, regulatory hurdles, or financial limitations (Fig. 2B). For instance, several terminated trials did not meet interim efficacy endpoints or failed to demonstrate consistent immunological biomarkers of response, underscoring a need for robust mechanistic endpoints and patient stratification at trial onset. Moreover, inconsistency in manufacturing protocols and limited harmonization across trial sites have impeded reproducibility – particularly in multicenter MSC trials.

Mechanistically, most trials focus on empirical symptom relief instead of validated molecular targets. Promising advances include a 2025 Chinese study identifying thiamine monophosphate (TMP) as a predictive biomarker for MSC response in SLE, enhancing remission rates by 78%^[10]. The Mayo Clinic’s CAR-MSCs demonstrated enhanced T-cell modulation in autoimmune models^[7], indicating future directions integrating cell therapy with genetic engineering. Trials should prioritize precise patient selection, omics-based biomarkers, and real-time immune monitoring.

Moreover, SCT related technological innovations used in China including CRISPR-enhanced MSCs, iPSC-derived products (e.g., NCR100) (Fig. 2F) and engineered exosomes are in early-phase (e.g., phase II) evaluation (NCT06741098, NCT06049342). However, challenges remain in regulatory timelines, GMP production costs, and lack of long-term safety data. AI-derived trial optimization may improve efficiency and predictive accuracy.

In conclusion, an increasing number of clinical trials and some encouraging preliminary results have demonstrated the great potential of stem cell therapy for AIRDs. However, challenges still exist in optimizing treatment regimens, ensuring long-term safety, and standardizing outcome assessments. Future research should focus on large-scale, multicenter, phase III trials with standardized designs to clearly determine the efficacy and safety of stem cell therapy. Continuous preclinical exploration of novel cell sources, delivery strategies, and combination therapies will further expand the treatment arsenal. Stem cell therapy holds the potential to revolutionize the management of AIRDs, bringing new hope to patients afflicted with these conditions.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

This work was supported by Science and Technology Plan Project of Jiangxi Provincial Administration of Traditional Chinese Medicine (2023A0020) and Science and Technology Plan Fund of Jiangxi Provincial Health Commission (202410072).

Author contributions

J.X.: writing – original draft; H.W., J.C., and Q.W.: methodology; X.C.: writing – review & editing. All the authors read and approved the final manuscript.

Conflicts of interest disclosure

The authors declared that no conflict of interest, and the declaration is valid.

Research registration unique identifying number (UIN)

None.

Guarantor

Jia Xu and Xiaoyong Chen.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

The dataset generated and analyzed during the current study is available from the corresponding author upon reasonable request.