Rheumatoid arthritis (RA) is an autoimmune disease characterized by the progressive erosion of the synovial membrane, destruction of cartilage, bone erosion, and, ultimately, the loss of joint functionality. Additionally, RA may exhibit various systemic effects that can cause severe disability. Although the introduction of biological disease-modifying antirheumatic drugs (DMARDs) has revolutionized the standard of care, a substantial proportion of the population do not achieve significant responses or develop resistance. Additionally, patients that do respond to DMARDs can have numerous adverse effects as well as limited ability to regenerate lost tissue. Here, we discuss the immunology of RA, how mesenchymal stem cells (MSCs) block the pathology of RA, and we provide an overview of animal and clinical studies supporting the use of MSCs in the treatment of RA. We also describe preliminary data using our proprietary pluripotent derived MSCs (pMSC) that can be utilized for induction of antigen-specific tolerance.

Keywords: rheumatoid arthritis, autoimmune disease, immunomodulation, regenerative therapy, joint inflammation, clinical studies, stem cell therapy

Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting approximately 0.5-1% of the global population,¹ characterized by immune-mediated synovial inflammation and joint deterioration. Additionally, numerous extra-articular manifestations have been reported, including accelerated atherosclerosis, heart attacks, pericarditis, and pulmonary pathology.²

In general, because of the critical role of inflammation in the pathogenesis of RA, patients are usually started on non-steroidal anti-inflammatory drugs (NSAIDS); however, more recent practice has been the concurrent initiation of disease-modifying antirheumatic drugs (DMARDs). These agents are slow acting but have been demonstrated to inhibit the radiological progression of RA. Such agents typically include: 1) hydroxychloroquine, which acts in part as a Toll-like receptor (TLR) 7/9 antagonist,³ thus decreasing innate immune activation;⁴ 2) leflunomide, an antimetabolite that inhibits pyrimidine synthesis and protein tyrosine kinase activity,⁵ leading to suppression of T cell responses,⁶ inhibition of dendritic cell (DC) activation⁷ and augmentation of T regulatory (Treg) cell activity;^8-10 3) injectable gold compounds such as auranofin, which directly or through metabolites such as dicyanogold have been demonstrated to inhibit T cell and antigen-presenting cell activation,^11,12 as well as cause T helper 2 (Th2) deviation;¹³ 4) sulfasalazine, was used since 1950, and acts primarily through inhibition of cyclooxygenase and lipoxygenase;¹⁴ and 5) methotrexate, an antifolate that inhibits T cell activation and proliferation, that has been one of the golden standards for RA.¹⁵ Typically, combinations of DMARDs with glucocorticoids are used, or alternatively pulse of high-dose glucocorticoids are administered to cause a general inhibition of inflammation.¹⁶

The TNF-α targeting agents, Remicade, Enbrel, and Humira, sometimes referred to as “biological DMARDs” are used primarily after response to conventional DMARDs has failed.¹⁷ Although improvement in quality of life has occurred as a result of biological DMARDs, substantial progress remains to be made. For example, TNF-alpha blockers have been associated with reactivation of infectious diseases, autoantibody formation and the possibility of increased lymphoma risk.^18-20 Thus, to date, one of the major limitations to RA therapy has been the inability to specifically inhibit autoreactive responses while sparing immune responses to other stimuli.

Because RA is driven by immunity against “self” antigens, the possibility exists of specifically inhibiting the pathological response through “reprogramming” of immune effectors in a manner allowing for selective silencing (and/or eliminating) of autoreactive clones. While current treatments for RA are non-cognate when it comes to antigen specificity, the possibility of inducing tolerance would literally be a cure for this disease without the side effects of ongoing immune suppression.

Immunological tolerance is the state of selective ignorance towards self, while maintaining intact ability to kill “non-self”. Tolerance induction, which may occur at the “central” or “peripheral” levels involves mechanisms that suppress or redirect immune responses against self-antigens,²¹ innocuous environmental antigens such as allergens,²² or transplanted tissues.²³

Central tolerance is primarily established in the thymus for T cells and bone marrow for B cells, where autoreactive lymphocytes are eliminated or rendered non-functional.²⁴

For T cells, thymic epithelial cells and dendritic cells present self-antigens in the context of major histocompatibility complex (MHC) molecules. Thymocytes (T cell precursors) with high-affinity TCRs are deleted via negative selection, which is executed by dendritic cells and macrophages present in the thymic medulla or at the cortico-medullary junction. In addition, thymic medullary epithelial cells (MECs) that ectopically express tissue-specific proteins under the control of a transcription factor called Autoimmune regulator (Aire) present such self-peptides to developing T cells with autoreactivity for such antigens. As a result, the latter are eliminated or skewed towards a regulatory phenotype.^25,26

For B cells, central tolerance occurs through clonal deletion or receptor editing in the bone marrow. Autoreactive B cells encountering self-antigens undergo apoptosis or rearrange their B-cell receptor (BCR) genes to reduce self-reactivity.²⁷ These processes ensure that only lymphocytes with low-to-moderate affinity for self-antigens exit to the periphery, minimizing autoimmune risk. Although studies are conflicting, it appears that Treg cells are needed for B regulatory cell generation and that B regulatory cells are not positively selected for in the bone marrow.²⁸

Peripheral tolerance complements central mechanisms by controlling mature lymphocytes that escape central deletion, essentially acting as a “backup” system. Anergy, a state of functional unresponsiveness, is induced when T cells receive TCR stimulation (signal 1) without co-stimulatory signals (signal 2), such as CD28-B7 interactions.²⁹ For example, in the absence of inflammation, dendritic cells presenting self-antigens in steady-state conditions induce T-cell anergy, preventing autoimmunity. Another key mechanism is the induction of Tregs, which maintain immune homeostasis by suppressing helper and cytotoxic T cells,^30-32 B cells,³³ and downregulating the ability of the dendritic cell to initiate immunity.³⁴

Tregs are critical in mucosal tolerance, exemplified by oral tolerance, where ingestion of antigens (e.g., food proteins) induces Treg differentiation in gut-associated lymphoid tissues.^35,36 This process, mediated by transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), not only prevents food allergy but has been used therapeutically in a wide range of autoimmune models ranging from rheumatoid arthritis,³⁷ to type 1 diabetes,³⁸ to multiple sclerosis.³⁹ Similarly, in transplantation, tolerance can be induced by co-stimulatory blockade (e.g., abatacept CTLA-4-Ig or anti-CD40L antibodies), promoting Treg expansion and anergy in alloreactive T cells,⁴⁰ thus eliminating the need for chronic immunosuppressants by “educating” the immune system not to reject the foreign graft.

In autoimmune diseases like type 1 diabetes, antigen-specific immunotherapy aims to restore tolerance to autoantigens (e.g., insulin peptides). Low-dose administration of insulin peptides to at-risk individuals induces antigen-specific Tregs, reducing islet-specific T-cell responses.^41,42 In allergy, allergen-specific immunotherapy (e.g., subcutaneous or sublingual administration of pollen extracts) desensitizes patients by skewing immune responses from Th2-driven IgE production to Treg-mediated IL-10 and IgG4 production, thus alleviating symptoms.^43,44 In transplantation, mixed chimerism protocols, where donor hematopoietic stem cells are infused into recipients under non-myeloablative conditioning, establish long-term tolerance by deleting alloreactive T cells and promoting donor-specific Treg development.⁴⁵

These examples underscore the potential of tolerance induction to rewire immune responses, offering durable solutions without the need for broad immunosuppression.

In conclusion, immunological tolerance induction is an ideal means of selectively “switching off” autoimmune attacks, such as those causing pathology in RA, while leaving other components of the immune system intact so as to not compromise the patient’s ability to fight infections and cancers.

To therapeutically implement antigen-specific tolerance-inducing strategies to RA, it is essential to have knowledge of autoantigens that are present in a majority of the patient population and contribute to disease. There are numerous antigens that have been determined or speculated to act as immunological targets of autoreactive T cells in RA which include citrullinated fibrinogen,^46,47 aggrecan,⁷⁸ vimentin,⁴⁹ α-enolase,⁵⁰ and filaggrin,⁵¹ as well as glucose-6-phosphate isomerase,⁵² hsp60,⁵³ hsp70,⁵⁴ and heterogeneous nuclear ribonucleoprotein A2.⁵⁵ Of the known antigens, collagen II is perhaps the most studied. We will discuss this in detail with the understanding that other autoantigens exist and can similarly be used for induction of tolerance.

Collagen II is an extracellular matrix component found primarily in the synovial tissue that is usually sequestered from immunological attack. Induction of an RA-like disease has been reported in inbred murine strains following immunization of xenogeneic collagen II in the presence of adjuvant.⁵⁶

Supporting a causative immunopathological effect of collagen II specific T cells were experiments in which the RA-like disease could be transferred to naïve recipients by administration of lymph node cells.⁵⁷ Subsequent work cloning T cell lines from synovial membranes of patients with RA demonstrated existence of collagen II-specific T cells that persisted for a period of at least 3 years in vivo.⁵⁸ Subsequent PCR-studies of the T cell receptor beta chains confirmed the oligoclonal expansion of collagen II-reactive cells in patients.⁵⁹ In 1993, Weiner’s group reported a double-blind, placebo-controlled trial of 60 patients with advanced RA treated by oral administration of chicken collagen II for a period of 3 months. Responses in terms of decreased number of swollen joints were observed in the treated population but not in placebo controls. Of the patients treated, four presented with complete remission of disease. No treatment-associated adverse effects were noted.⁶⁰ Unfortunately, Phase III trials using oral tolerance in RA have not met primary efficacy endpoints.⁶¹

Given the general failure of oral tolerance in RA, more specific approaches have involved stimulation of tolerogenic responses using ex vivo manipulated DC. Dendritic cells (DC) under physiological conditions promote tolerance, and when exposed to injury/damage signals mature and induce T cell activation. By ex vivo manipulating antigen-pulsed, donor-specific DCs, we have previously been able to induce antigen-specific suppression of immunity and generation of T regulatory (Treg) cells Tolerogenic modifications of DC performed by our group have included exposure of DCs to small-molecule immune suppressants,^62-64 transfection with tolerogenic genes^65-66 and silencing of immune stimulatory genes.^67-70 In our previous work, we demonstrated the ability to prevent RA induction by pulsing immature DCs with collagen II (CII) and suppressing DC maturation with chemical or genetic means.^71-74 Limitations of these data have been the lack of robust inhibition of inflammatory responses when administration of manipulated DC was performed at various time points subsequent to disease onset. The general failure of antigen-specific approaches, both in oral tolerance, as well as DC-based approaches may be the result of underlying inflammatory reactions. The advantage of utilizing mesenchymal stem cells as “living anti-inflammatory” agents is that the cells produce more anti-inflammatory agents the more inflammation is present. Additionally, the multiple mechanisms employed by MSCs may not only prevent inflammation but also stimulate regenerative processes. This is different than biological DMARDs, which reduce pathology but do not stimulate regeneration.

The possibility of using systemically-administered mesenchymal stem cells (MSCs) as a cellular therapy for RA has several conceptual advantages that address the previously mentioned drawbacks of current approaches. One such advantage is that the MSC may be viewed as a “smart” immune modulator. In contrast with currently available therapies, which globally cause immune suppression, production of anti-inflammatory factors by MSCs appears to be dependent on their environment, with upregulation of factors such as TGF-beta, HLA-G, IL-10, and neuropilin-A ligands galectin-1 and Semaphorin-3A in response to immune/inflammatory stimuli but little in the basal state.^75-79 Additionally, systemically administered MSC possess the ability to selectively home to injured/hypoxic areas by recognition of signals such as HMGB1 or CXCR1, respectively.^80-83

The ability to home to the sites of injury, combined with selective induction of immune modulation only in response to inflammatory/danger signals, suggests the possibility that systemically administered MSC do not cause global immune suppression.^84-85 This is supported by clinical studies using MSCs for other inflammatory conditions, which to date, have not reported global immune suppression associated adverse effects.^86-88 Another important aspect of MSC therapy is the ability of these cells to regenerate injured tissues through direct differentiation into articular tissue,⁸⁹ as well as their ability to secret growth factors capable of augmenting endogenous regenerative processes.⁹⁰

Physiologically, the role of MSCs in RA is a matter of debate. Nakagawa et al.,⁹³ used radiolabeling of bone marrow cells to demonstrate migration of bone marrow stromal cells into the synovium of rats suffering from collagen-induced arthritis (CIA). While inference was made to contribution of the MSC to synovial proliferation, a causal relationship was not demonstrated.⁹¹ Subsequently, it was reported that MSCs differentiate into nurse-like cells that promote adhesion of lymphocytes to the synovium.⁹² Indeed, in patients with RA, but not healthy controls, bone marrow MSC-generating capacity is markedly reduced.⁹³ Whether this is due to systemic TNF-alpha suppression of bone marrow,⁹⁴ or exhaustion of MSC precursors by heightened demand is not known. However, there are suggestions of the latter based on observations of shorter telomeres in MSC derived from RA patients.⁹³ The concept of MSC contributing to pathology was demonstrated in the CIA model by Djouad et al.,⁹⁵ who reported that administration of MSC resulted in upregulation of Th1 immunity as determined by increased interferon production. and worsening of symptoms.⁹⁵ The investigators attributed this to their observations that TNF-alpha abrogates immune regulatory activities of MSC. This study, however, was contradicted by several more recent studies in which inhibition of arthritogenesis, or even regression of disease was observed. Mao et al.,⁹⁶ demonstrated that administration of rat MSC intravenously into DBA mice with full-blown CIA resulted in regression of disease, which was correlated with decreased production of TNF-alpha and IL-17.⁹⁶ Gonzalez et al.,⁹⁷ administered ex vivo-expanded human adipose-derived MSCs into the animals using the same model. Inhibition of disease progression was observed, which correlated with increased Treg numbers that were specific for CII. This study supports the previous principle discussed that an antigen-nonspecific tolerizing event may contribute to development of antigen-specific suppression.⁹⁷ In addition to immune modulation, it is possible that cartilage tissue generated de novo from MSCs possesses a decreased level of immunogenicity.⁹⁸ The overall anti-inflammatory/immune modulatory effects of MSCs have been demonstrated in a variety of settings, including in the mouse model of multiple sclerosis,^99,100 transplant rejection,¹⁰¹ diabetes,¹⁰² SLE,¹⁰³ and autoimmune enteropathy.¹⁰⁴

Due to the systemic nature of RA, MSC have been primarily administered intravenously to treat this condition. Numerous studies have attested to the safety of single and multiple administration of these cells,¹⁰⁵ with clinical trials demonstrating efficacy signals in a broad range of inflammatory conditions from heart failure,¹⁰⁶ to stroke,¹⁰⁷ to liver failure,¹⁰⁸ and multiple sclerosis.¹⁰⁹ Despite promising trials, currently the only MSC to have received marketing approval in the USA has been Ryoncil (remestemcel-L).¹¹⁰

Umbilical cord MSC (UC-MSC)

The original use of MSC in RA was a 2012 study that involved four patients with treatment-refractory disease. Supporting the efficacy of UC-MSC therapy, three of the patients had reduction in erythrocyte sedimentation rate (ESR) (a sensitive but non-specific measure of inflammation), DAS-28, and pain VAS score at 1 and 6 months after infusion. Two of the three responding patients had a European League against Rheumatism (EULAR) moderate response at 6 months but experienced a relapse at 7 and 23 months, respectively. The treatments did not cause any adverse effects though.¹¹¹ These promising initial results led to expanded studies.

A subsequent study reported in 2013 treated 172 patients with active RA who had inadequate responses to standard of care. The patients were separated into Group 1 who received DMARDs plus culture media or Group 2 (no need to use grouping) who received UC-MSC 4×10⁷ cells per timepoint via intravenous injection. No serious adverse effects were observed during or after infusion. The serum levels of tumor necrosis factor-alpha and interleukin-6 decreased and the percentage of Tregs in peripheral blood was increased after the first treatment. Significant disease remission was reported according to the American College of Rheumatology improvement criteria, the 28-joint disease activity score (DAS28), and the Health Assessment Questionnaire. The therapeutic effects were maintained for 3-6 months without continuous administration, correlating with the increased percentage of regulatory T cells of peripheral blood. No benefits were observed in control cohort that received DMARDS plus medium without UC-MSCs.¹¹²

Wang et al.,¹¹³ in 2016 used UC-MSC to treat juvenile idiopathic arthritis (JIA). Ten patients were treated with UC-MSCs and received a second infusion three months later. Synovial white blood cell count, ESR, TNF-alpha, IL-6 and CRP were significantly decreased while Tregs were increased, with these changes being maintained 6 months after treatment. These results suggest that UC-MSCs can reduce inflammatory cytokines, augment immune tolerance, and effectively alleviate the symptoms and they might provide a safe and novel approach for JIA treatment.¹¹³

In 2018, Park et al.,¹¹⁴ performed the CURE-iv trial, which was a phase I, uncontrolled, open-label trial for RA patients with moderate disease activity despite treatment with methotrexate. The patients received a single intravenous infusion of 2.5×10⁷, 5×10⁷, or 1×10⁸ hUCB-MSCs for 30 minutes, three patients in each cluster, with an increment of cell numbers when there was no dose-limited adverse event. There was no major toxicity in all clusters up to 4 weeks after the infusion. Significant improvements in ESR and DAS28 were observed at 4 weeks, as well as reduction of inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α at 24 hours were observed in the cluster infused with 1×10⁸ MSCs.¹¹⁴

In a study in 2019, four RA patients aged 18-64 years were recruited in the study. During the treatment, patients were treated with 40 mL UC-MSC suspension product (2 ×10⁷ cells/20 mL) via intravenous injection immediately after the infusion of 100 mL saline. One year and 3 years after UC-MSC cells treatment, the routine, liver and kidney function and immunoglobulin examination showed no abnormalities, which were all in the normal range. The ESR, CRP, RF (Rheumatoid Factor) of 1 year and 3 years after treatment and anti-CCP of 3 years after treatment were detected to be lower than that of pretreatment, which showed significant change (p<0.05). Health index and joint function index (DAS28) decreased 1 year and 3 years after treatment.¹¹⁵

Adipose tissue MSC

In a 2016 clinical trial, allogeneic adipose derived MSC were administered to patients with active refractory RA (failure to at least two biologicals) were randomized to receive three intravenous infusions of allogeneic adipose MSC product called “Cx611”. Fifty-three patients received either a placebo or a treatment at doses of 1 million/kg, 2 million/kg, or 4 million/kg on days 1, 8, and 15, and were monitored for 24 weeks. Of those, 20 patients got 1 million/kg and had a 45% improvement rate at 1 month and 25% at 3 months; 20 patients got 2 million/kg and showed a 20% improvement rate at 1 month and 15% at 3 months; 6 patients received 4 million/kg and had a 33% improvement rate at 1 month and 17% at 3 months; and 7 patients received a placebo, with a 29% improvement rate at 1 month and 0% at 3 months.¹¹⁶

A 2022 trial reported the use of single, intravenous infusion of autologous, adipose-derived MSC in 15 RA patients. ACR66/68 scores for both S/TJC showed significant improvements with large effect sizes (ES) at week 52 vs baseline (p <0.01, ES = 0.83 and p <0.001, ES = 0.93 respectively). A difference in CRP levels with a small effect size was observed at week 4 (p =0.229, ES = 0.33) with further improvement at week 52 (p =0.183, ES = 0.37).¹¹⁷

Bone marrow MSC

In 2018, an Iranian study was to evaluate the effects of intravenous administration of autologous bone marrow-derived MSCs in nine refractory RA patients who received a single intravenous dose of 1×10⁶ autologous bone marrow-derived MSCs/kg. A significant decreasing trend in Th17 percentage and geometric mean fluorescence intensity for IL-17A following injection of MSCs at 12 months compared to time point zero was observed. Furthermore, a significant increase in regulatory T cell percentage was seen at the end of the first month after the intervention. DAS28-ESR decreased significantly at 1 and 12 months after MSC therapy. VAS score showed a significant decreasing trend during the follow-up periods.¹¹⁸

In another juvenile arthritis study, six patients who failed biologicals received 2 million/kg intravenous infusions of allogeneic bone-marrow derived MSC. No acute infusion reactions were observed and a lower post-treatment than pre-treatment incidence in AEs was found. Statistically significant decreases were found 8 weeks after one MSC infusion in VAS well-being (75-56), the JADAS-71 (24.5-11.0) and the cJADAS10 (18.0-10.6).¹¹⁹

In 2020, a clinical trial used a single dose of 1×10⁶ per kg autologous bone marrow MSCs in 13 patients suffering from refractory RA. The results showed that the gene expression of forkhead box P3 (FOXP3) in peripheral blood mononuclear cells (PBMCs) considerably increased at month 12. Additionally, they found a substantial increasing trend in the culture supernatant levels of IL-10 and transforming growth factor-beta 1 (TGF-β1) in PBMCs from the beginning of the intervention up to the end. These data reflect the sufficient immunoregulatory effect of autologous BM-MSCs on regulatory T cells in patients suffering from refractory RA.¹²⁰

A 2024 study investigated the efficacy of 3 monthly intravenous infusions of allogeneic bone marrow-derived clonal mesenchymal stromal cells (BM-cMSCs) in six refractory RA patients. BM-cMSC infusions were well tolerated, with no SAEs reported. VAS scores improved in three patients, with two achieving sustained pain relief and quality-of-life enhancement. Four patients met ACR20 at week 16, while SDAI and CDAI scores indicated disease activity reduction in three patients. IL-10 increased in five patients, while pro-inflammatory markers TNF-α and IL-17 decreased in the same individuals.¹²¹

The above-mentioned clinical trials demonstrate the overall safety of administration of mesenchymal stem cells; however, efficacy is a matter of debate. One way to increase efficacy is the utilization of more immature types of stem cells, or “tailor-made” stem cells. Unfortunately, in many situations, the issue of donor-to-donor variability remains substantial. One way of overcoming this is the generation of MSC from pluripotent sources, especially if these pluripotent sources are personalized.

Immorta Bio Inc. has previously reported the ability of generating self-renewing, immortal pluripotent stem cells (Personalized Regenerative Cells (PRC)) from peripheral blood by application of proprietary dedifferentiation technology. Due to their ability for self-renewal, PRC can be genetically modified to express one or more autoantigens. Preliminary data shows successful differentiation of PRC into mesenchymal stem cells, which we term “pMSC”. By varying culture conditions, pMSC corresponding to various biological ages have been produced. Preliminary data shows superior reduction of RA score in the CIA model as compared to standard MSC types. Given the tolerogenic potential of these cells, work is being performed to generate autoantigen expressing autologous MSC, which we believe will be true facilitators of immunological tolerance induction.

DBA/1 LacJ female mice (ten per group), seven-ten weeks of age, were intradermally immunized (Day 0) at the base of the tail with 200 μg of bovine type II collagen (CII) (Sigma-Aldrich, St. Louis, MO, USA) with complete Freund's adjuvant (CFA) (Sigma). On Day 21 after priming, the mice received an intraperitoneal booster injection with 200 μg. Mice were examined visually three times a week for the appearance of arthritis in the peripheral joints, and an arthritis score index for disease severity was given as follows: 0 - no evidence of erythema and swelling; 1 -erythema and mild swelling confined to the mid-foot (tarsals) or ankle joint; 2 -erythema and mild swelling extending from the ankle to the mid-foot; 3 - erythema and moderate swelling extending from the ankle to the metatarsal joints; 4 -erythema and severe swelling encompassing the ankle, foot, and digits. The maximum possible score per mouse was 16. The severity of arthritis was also determined by the quantification of the paw swelling measured with a dial gauge caliper. Scoring was done by two independent observers, without knowledge of the experimental and control groups. Mesenchymal stem cells were administered two times a week for two weeks after the last booster shot. Mesenchymal stem cells were administered intravenously at a concentration of 500,000 cells per mouse. Control consisted of dermal fibroblasts, bone marrow MSC and umbilical cord MSC, which were obtained from ATCC. pMSC were produced from expanded PRC (Figure 1).

Figure 1 Efficacy of proprietary pluripotent-derived mesenchymal stem cells (pMSCs) in collagen-induced arthritis (CIA) model.

DBA/1 LacJ mice with collagen-induced arthritis (CIA) received intravenous infusions of different MSC preparations twice weekly for two weeks following disease onset. Disease severity was assessed by clinical arthritis scoring (0–4 per paw; maximum score 16 per mouse) and paw thickness measurements. Treatment with Immorta Bio’s proprietary pMSCs resulted in significantly greater reduction in arthritis scores and paw swelling compared to bone marrow-derived MSCs, umbilical cord MSCs, and dermal fibroblast controls.

Mesenchymal stem cells (MSCs) have emerged as promising candidates for the treatment of rheumatoid arthritis (RA) by addressing both inflammatory and degenerative aspects of the disease. Preclinical and clinical data demonstrate that MSCs can reduce inflammation, promote regulatory immune responses, and potentially contribute to tissue regeneration. However, variability in donor-derived MSC performance remains a key limitation. Our preliminary findings using proprietary pluripotent-derived MSCs (pMSCs) suggest enhanced therapeutic potential, particularly in inducing antigen-specific tolerance. Given the tolerogenic potential of these cells, work is being performed to generate autoantigen expressing autologous MSC which we believe will be true facilitators of immunological tolerance induction.

These results support further development of pMSC-based therapies as a next-generation, targeted, and personalized treatment strategy for RA.

None.

The authors declare that there are no conflicts of interest.

1. Firestein GS, Harris ED, Genovese MC, et al. Kelley’s textbook of rheumatology. Philadelphia, USA. Elsevier Saunders. 2007;7:996–1042.
2. Shekh MR, Ahmed N, Kumar V. A review of the occurrence of rheumatoid arthritis and potential treatments through medicinal plants from an Indian perspective. Curr Rheumatol Rev. 2024;20(3):241–269.
3. Han J, Li X, Luo X, et al. The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling. Biomed Pharmacother. 2020;132:110848.
4. Sun S, Rao NL, Venable J, et al. TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflamm Allergy Drug Targets. 2007;6(4):223–235.
5. Chong AS, Huang W, Liu W, et al. In vivo activity of leflunomide: pharmacokinetic analyses and mechanism of immunosuppression. Transplantation. 1999;68(1):100–109.
6. Dimitrova P, Skapenko A, Herrmann ML, et al. Restriction of de novo pyrimidine biosynthesis inhibits Th1 cell activation and promotes Th2 cell differentiation. J Immunol. 2002;169(6):3392–3399.
7. Kirsch BM, Zeyda M, Stuhlmeier K, et al. The active metabolite of leflunomide, A77 1726, interferes with dendritic cell function. Arthritis Res Ther. 2005;7(3):R694–R703.
8. Qiao G, Yang L, Li Z, et al. A77 1726, the active metabolite of leflunomide, attenuates lupus nephritis by promoting the development of regulatory T cells and inhibiting IL-17-producing double negative T cells. Clin Immunol. 2015;157(2):166–174.
9. Zhu M, Xu Q, Li X-L, et al. Modulating effects of leflunomide on the balance of Th17/Treg cells in collageninduced arthritis DBA/1 mice. Cent Eur J Immunol. 2014;39(2):152–158.
10. Wang TY, Li J, Li C-Y, et al. Leflunomide induces immunosuppression in collagen-induced arthritis rats by upregulating CD4+CD25+ regulatory T cells. Can J Physiol Pharmacol. 2010;88(1)45–53.
11. Tepperman K, Roy PW, Moloney BF, et al. Dicyanogold effects on lymphokine production. Met Based Drugs. 1999;6(4–5):301–309.
12. Han S, Kim K, Song Y, et al. Auranofin, an immunosuppressive drug, inhibits MHC class I and MHC class II pathways of antigen presentation in dendritic cells. Arch Pharm Res. 2008;31(3):370–376.
13. Kim TS, Kang BY, Lee MH, et al. Inhibition of interleukin-12 production by auranofin, an anti-rheumatic gold compound, deviates CD4(+) T cells from the Th1 to the Th2 pathway. Br J Pharmacol. 2001;134(3):571–578.
14. Taggart AJ. Sulphasalazine in arthritis--an old drug rediscovered. Clin Rheumatol. 1987;6(3):378–383.
15. Bansard C, Lequerré T, Daveau M, et al. Can rheumatoid arthritis responsiveness to methotrexate and biologics be predicted? Rheumatology (Oxford). 2009;48(9):1021–1028.
16. Bijlsma JW, Hoes JN, Everdingen AVA, et al. Are glucocorticoids DMARDs? Ann NY Acad Sci. 2006;1069:268–274.
17. Nanda S, Bathon JM. Etanercept: a clinical review of current and emerging indications. Expert Opin Pharmacother. 2004;5(5):1175–1186.
18. Shakoor N, Michalska M, Harris CA, et al. Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet. 2002;359(9306):579–580.
19. Dinarello CA. Anti-cytokine therapeutics and infections. 2003;21(Suppl 2):S24–S34.
20. Davis JS, Ferreira D, Paige E, et al. Infectious complications of biological and small molecule targeted immunomodulatory therapies. Clin Microbiol Rev. 2020;33(3):e00035-19.
21. Ge J, Yin X, Chen L. Regulatory T cells: masterminds of immune equilibrium and future therapeutic innovations. Front Immunol. 2024;15:1457189.
22. Stoumpos A, Heine G, Saggau C, et al. The role of allergen-specific regulatory T cells in the control of allergic disease. Curr Opin Immunol. 2025;92:102509.
23. Jeyamogan S, Leventhal JR, Mathew JM, et al. CD4(+)CD25(+)FOXP3(+) regulatory T cells: a potential "armor" to shield "transplanted allografts" in the war against ischemia reperfusion injury. Front Immunol. 2023;14:1270300.
24. Zhang P, Lu Q. Genetic and epigenetic influences on the loss of tolerance in autoimmunity. Cell Mol Immunol. 2018;15(6):575–585.
25. Sohn SJ, Thompson J, Winoto A. Apoptosis during negative selection of autoreactive thymocytes. Curr Opin Immunol. 2007;19(5):510–515.
26. Jordan MS, Boesteanu A, Reed AJ, et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol. 2001;2(4):301–306.
27. Nemazee D. Mechanisms of central tolerance for B cells. Nat Rev Immunol. 2017;17(5):281–294.
28. Kinnunen T, Chamberlain N, Morbach H, et al. Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood. 2013;121(9):1595–1603.
29. Harding FA, McArthur JG, Gross JA, et al. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992;356(6370):607–609.
30. Schulze B, Piehler D, Eschke M, et al. CD4(+) FoxP3(+) regulatory T cells suppress fatal T helper 2 cell immunity during pulmonary fungal infection. Eur J Immunol. 2014;44(12):3596–3604.
31. Surls J, Nazarov-Stoica C, Kehl M, et al. Differential effect of CD4+Foxp3+ T-regulatory cells on the B and T helper cell responses to influenza virus vaccination. Vaccine. 2010;28(45):7319–7330.
32. Hartwig T, Zwicky P, Schreiner B, et al. Regulatory T cells restrain pathogenic T helper cells during skin inflammation. Cell Rep. 2018;25(13):3564–3572.e4.
33. Lim HW, Hillsamer P, Banham AH, et al. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol. 2005;175(7):4180–4183.
34. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8(2):191–197.
35. Zhang Y, Li L, Genest G, et al. Successful milk oral immunotherapy promotes generation of casein-specific CD137(+) FOXP3(+) regulatory T cells detectable in peripheral blood. Front Immunol. 2021;12:705615.
36. Bertolini TB, Biswas M, Terhorst C, et al. Role of orally induced regulatory T cells in immunotherapy and tolerance. Cell Immunol. 2021;359:104251.
37. Postlethwaite AE, Jiao Y, Yang C, et al. Optimizing oral immune tolerance to Type II collagen in patients with rheumatoid arthritis: The importance of dose, interfering medication and genetics. Am J Med Sci. 2024;368(4):300–310.
38. Mao R, Yang M, Yang R, et al. Oral delivery of the intracellular domain of the insulinoma-associated protein 2 (IA-2ic) by bacterium-like particles (BLPs) prevents type 1 diabetes mellitus in NOD mice. Drug Deliv. 2022;29(1):925–936.
39. Buerth C, Mausberg AK, Heininger MK, et al. Oral Tolerance induction in experimental autoimmune encephalomyelitis with Candida utilis expressing the immunogenic MOG35-55 peptide. PLoS One. 2016;11(5):e0155082.
40. Kuppan P, Wong J, Kelly S, et al. Long-term survival and induction of operational tolerance to murine islet allografts by co-transplanting cyclosporine a microparticles and CTLA4-Ig. 2023;15(9):2201.
41. Liu M, Feng D, Liang X, et al. Old dog new tricks: PLGA microparticles as an adjuvant for insulin peptide fragment-induced immune tolerance against type 1 diabetes. Mol Pharm. 2020;17(9):3513–3525.
42. Gibson VB, Nikolic T, Pearce VQ, et al. Proinsulin multi-peptide immunotherapy induces antigen-specific regulatory T cells and limits autoimmunity in a humanized model. Clin Exp Immunol. 2015;182(3):251–260.
43. Dantzer JA, Lewis SA, Psoter KJ, et al. Clinical and immunological outcomes after randomized trial of baked milk oral immunotherapy for milk allergy. JCI Insight. 2025;10(1):e184301.
44. Kirmaz C, Kirgiz OO, Bayrak P, et al. Effects of allergen-specific immunotherapy on functions of helper and regulatory T cells in patients with seasonal allergic rhinitis. Eur Cytokine Netw. 2011;22(1):15–23.
45. Tonsho M, Jane MO, Ahrens K, et al. Cardiac allograft tolerance can be achieved in nonhuman primates by donor bone marrow and kidney cotransplantation. Sci Transl Med. 2025;17(782):eads0255.
46. Saraiva AL, Peres RS, Veras FP, et al. Citrullinated human fibrinogen triggers arthritis through an inflammatory response mediated by IL-23/IL-17 immune axis. Int Immunopharmacol. 2021;101(Pt B):108363.
47. Sun Y, Deng W, Yao G, et al. Citrullinated fibrinogen impairs immunomodulatory function of bone marrow mesenchymal stem cells by triggering toll-like receptor. Clin Immunol. 2018;193:38–45.
48. Rims C, Uchtenhagen H, Kaplan MJ, et al. Citrullinated aggrecan epitopes as targets of autoreactive CD4+ T cells in patients with rheumatoid arthritis. Arthritis Rheumatol. 2019;71(4):518–528.
49. Biswas S, Sharma S, Saroha A, et al. Identification of novel autoantigen in the synovial fluid of rheumatoid arthritis patients using an immunoproteomics approach. PLoS One. 2013;8(2):e56246.
50. Yeh FC, Cherng J-H, Chang S-J, et al. Anti-citrullinated alpha-enolase peptide as a highly sensitive autoantigen in patients with rheumatoid arthritis. Heliyon. 2023;9(12):e22745.
51. Simon M, Girbal E, Sebbag M, et al. The cytokeratin filament-aggregating protein filaggrin is the target of the so-called "antikeratin antibodies," autoantibodies specific for rheumatoid arthritis. J Clin Invest. 1993;92(3):1387–1393.
52. Iwanami K, Matsumoto I, Yoshiga Y, et al. Altered peptide ligands inhibit arthritis induced by glucose-6-phosphate isomerase peptide. Arthritis Res Ther. 2009;11(6):R167.
53. Simon D, Kacsándi D, Pusztai A, et al. Natural autoantibodies in biologic–treated rheumatoid arthritis and ankylosing spondylitis patients: associations with vascular pathophysiology. Int J Mol Sci. 2024;25(6):3429.
54. Spiering R, Jansen MAA, Wood MJ, et al. Targeting of tolerogenic dendritic cells to heat–shock proteins in inflammatory arthritis. J Transl Med. 2019;17(1):375.
55. Steiner G, Skriner K, Smolen JS. Autoantibodies to the A/B proteins of the heterogeneous nuclear ribonucleoprotein complex: novel tools for the diagnosis of rheumatic diseases. Int Arch Allergy Immunol. 1996;111(4):314–319.
56. Trentham DE, Townes AS, Kang AH. Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med. 1977;146(3):857–868.
57. Trentham DE, Dynesius RA, David JR. Passive transfer by cells of type II collagen–induced arthritis in rats. J Clin Invest. 1978;62(2):359–366.
58. Londei M, Savill CM, Verhoef A, et al. Persistence of collagen type II–specific T–cell clones in the synovial membrane of a patient with rheumatoid arthritis. Proc Natl Acad Sci USA. 1989;86(2):636–640.
59. Sekine T, Kato T, Hongo KM, et al. Type II collagen is a target antigen of clonally expanded T cells in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis. 1999;58(7):446–450.
60. Trentham DE, Trentham RAD, Orav EJ, et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science. 1993;261(5129):1727–1730.
61. AutoImmune Inc. Biopharmaceutical pioneer for autoimmune disorders.
62. Min WP, Zhou D, Ichim TE, et al. Synergistic tolerance induced by LF15–0195 and anti–CD45RB monoclonal antibody through suppressive dendritic cells. Transplantation. 2003;75(8):1160–1165.
63. Min WP, Zhou D, Ichim TE, et al. Inhibitory feedback loop between tolerogenic dendritic cells and regularoty T cells in transplant tolerance. J Immunol. 2003;170(3):1304–1312.
64. Yang J, Bernier SM, Ichim TE, et al. LF15–0195 generates tolerogenic dendritic cells by suppression of NF–kappaB signaling through inhibition of IKK activity. J Leukoc Biol. 2003;74(3):438–447.
65. Min WP, Gorczynski R, Huang XY, et al. Dendritic cells genetically engineered to express fas ligand induce donor–specific hyporesponsiveness and prolong allograft survival. J Immunol. 2000;164(1):161–167.
66. Gainer AL, Pinzon WLS, Min WP, et al. Improved survival of biolistically transfected mouse islet allografts expressing CTLA4–Ig or soluble Fas ligand. Transplantation. 1998;66(2):194–199.
67. Ichim TE, Li M, Qian H, et al. RNA interference: a potent tool for gene–specific therapeutics. Am J Transplant. 2004;4(8):1227–1236.
68. Ichim TE, Zhong R, Min WP. Prevention of allograft rejection by in vitro generated tolerogenic dendritic cells. Transpl Immunol. 2003;11(3–4):295–306.
69. Hill JA, Ichim TE, Kusznieruk KP, et al. Immune modulation by silencing IL–12 production in dendritic cells using small interfering RNA. J Immunol. 2003;171(2):691–696.
70. Li M, Qian H, Ichim TE, et al. Induction of RNA interference in dendritic cells. Immunol Res. 2004;30(2):215–230.
71. Zheng X, Suzuki M, Zhang X, et al. RNAi–mediated CD40–CD154 interruption promotes tolerance in autoimmune arthritis. Arthritis Res Ther. 2010;12(1):R13.
72. Zheng X, Suzuki M, Ichim TE, et al. Treatment of autoimmune arthritis using RNA interference–modulated dendritic cells. J Immunol. 2010;184(11):6457–6464.
73. Popov I, Li M, Zheng X, et al. Preventing autoimmune arthritis using antigen–specific immature dendritic cells: a novel tolerogenic vaccine. Arthritis Res Ther. 2006;8(5):R141.
74. Ichim TE, Zheng X, Suzuki M, et al. Antigen–specific therapy of rheumatoid arthritis. Expert Opin Biol Ther. 2008;8(2):191–199.
75. Nasef A, Zhang YZ, Mazurier C, et al. Selected Stro–1–enriched bone marrow stromal cells display a major suppressive effect on lymphocyte proliferation. Int J Lab Hematol. 2009;31(1):9–19.
76. Nasef A, Mazurier C, Bouchet S, et al. Leukemia inhibitory factor: role in human mesenchymal stem cells mediated immunosuppression. Cell Immunol. 2008;253(1–2):16–22.
77. Lepelletier Y, Lecourt S, Renand A, et al. Galectin–1 and Semaphorin–3A are two soluble factors conferring T cell immunosuppression to bone marrow mesenchymal stem cell. Stem Cells Dev. 2009;19(7):1075–1079.
78. Renner P, Eggenhofer E, Rosenauer A, et al. Mesenchymal stem cells require a sufficient, ongoing immune response to exert their immunosuppressive function. Transplant Proc. 2009;41(6):2607–2611.
79. Ryan JM, Barry F, Murphy JM, et al. Interferon–gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol. 2007;149(2):353–363.
80. Lisheng W, Meng E, Guo Z. High mobility group box 1 protein inhibits the proliferation of human mesenchymal stem cells and promotes their migration and differentiation along osteoblastic pathway. Stem Cells Dev. 2008;17(4):805–813.
81. Kitaori T, Ito H, Schwarz EM, et al. Stromal cell–derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum. 2009;60(3):813–823.
82. Wang Y, Deng Y, Zhou GQ. SDF–1alpha/CXCR4–mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. Brain Res. 2008;1195:104–112.
83. Shi M, Li J, Liao L, et al. Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: role in homing efficiency in NOD/SCID mice. 2007;92(7):897–904.
84. Wu Y, Zhao RC. The role of chemokines in mesenchymal stem cell homing to myocardium. Stem Cell Rev Rep. 2012;8(1):243–250.
85. Hannoush EJ, Sifri ZC, Elhassan IO, et al. Impact of enhanced mobilization of bone marrow derived cells to site of injury. J Trauma. 2011;71(2):283–289; discussion 289–291.
86. Gunzberg WH, Salmons B. Stem cell therapies: on track but suffer setback. Curr Opin Mol Ther. 2009;11(4):360–363.
87. Kebriaei P, Isola L, Bahceci E, et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft–versus–host disease. Biol Blood Marrow Transplant. 2009;15(7):804–811.
88. Dryden GW. Overview of stem cell therapy for Crohn's disease. Expert Opin Biol Ther. 2009;9(7):841–847.
89. Richardson SM, Hoyland JA, Mobasheri R, et al. Mesenchymal stem cells in regenerative medicine: opportunities and challenges for articular cartilage and intervertebral disc tissue engineering. J Cell Physiol. 2010;222(1):23–32.
90. Bouffi C, Djouad F, Mathieu M, et al. Multipotent mesenchymal stromal cells and rheumatoid arthritis: risk or benefit? Rheumatology (Oxford). 2009;48(10):1185–1189.
91. Nakagawa S, Toritsuka Y, Wakitani S, et al. Bone marrow stromal cells contribute to synovial cell proliferation in rats with collagen induced arthritis. J Rheumatol. 1996;23(12):2098–2103.
92. Ochi T, Yoshikawa H, Maeda TT, et al. Mesenchymal stromal cells. Nurse–like cells reside in the synovial tissue and bone marrow in rheumatoid arthritis. Arthritis Res Ther. 2007;9(1):201.
93. Kastrinaki MC, Sidiropoulos P, Roche S, et al. Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis. Ann Rheum Dis. 2008;67(6):741–749.
94. Papadaki HA, Kritikos HD, Gemetzi C, et al. Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha–mediated effect. Blood. 2002;99(5):1610–1619.
95. Djouad F, Fritz V, Apparailly F, et al. Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen–induced arthritis. Arthritis Rheum. 2005;52(5):1595–603.
96. Mao F, Xu WR, Qian H, et al. Immunosuppressive effects of mesenchymal stem cells in collagen–induced mouse arthritis. Inflamm Res. 2009;59(3):219–225.
97. Gonzalez MA, Rey EG, Rico L, et al. Treatment of experimental arthritis by inducing immune tolerance with human adipose–derived mesenchymal stem cells. Arthritis Rheum. 2009;60(4):1006–1019.
98. Zheng ZH, Li XY, Ding J, et al. Allogeneic mesenchymal stem cell and mesenchymal stem cell–differentiated chondrocyte suppress the responses of type II collagen–reactive T cells in rheumatoid arthritis. Rheumatology (Oxford). 2008;47(1):22–30.
99. Karussis D, Kassis I. The potential use of stem cells in multiple sclerosis: an overview of the preclinical experience. Clin Neurol Neurosurg. 2008;110(9):889–896.
100. Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T–cell anergy. 2005;106(5):1755–1761.
101. Casiraghi F, Azzollini N, Cassis P, et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol. 2008;181(6):3933–3946.
102. Boumaza I, Srinivasan S, Witt WT, et al. Autologous bone marrow–derived rat mesenchymal stem cells promote PDX–1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia. J Autoimmun. 2008;32(1):33–42.
103. Zhou K, Zhang H, Jin O, et al. Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL/lpr mice. Cell Mol Immunol. 2008;5(6):417–424.
104. Parekkadan B, Tilles AW, Yarmush ML. Bone marrow–derived mesenchymal stem cells ameliorate autoimmune enteropathy independently of regulatory T cells. Stem Cells. 2008;26(7):1913–1919.
105. Terai S, Ezoe S, Mano K, et al. Recommendations for the safe implementation of intravenous administration of mesenchymal stromal cells. Regen Ther. 2025;29:171–176.
106. Bartolucci J, Verdugo FJ, González PL, et al. Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1/2 randomized controlled trial (RIMECARD trial [randomized clinical trial of intravenous infusion umbilical cord mesenchymal stem cells on cardiopathy]). Circ Res. 2017;121(10):1192–1204.
107. Lee J, Chang WH, Chung JW, et al. Efficacy of intravenous mesenchymal stem cells for motor recovery after ischemic stroke: a neuroimaging study. Stroke. 2022;53(1):20–28.
108. Liu Y, Dong Y, Wu X, et al. The assessment of mesenchymal stem cells therapy in acute on chronic liver failure and chronic liver disease: a systematic review and meta–analysis of randomized controlled clinical trials. Stem Cell Res Ther. 2022;13(1):204.
109. Petrou, P, Kassis I, Ginzberg A, et al. Long–term clinical and immunological effects of repeated mesenchymal stem cell injections in patients with progressive forms of multiple sclerosis. Front Neurol. 2021;12:639315.
110. Blanc KL, Dazzi F, English K, et al. ISCT MSC committee statement on the US FDA approval of allogenic bone–marrow mesenchymal stromal cells. 2025;27(4):413–416.
111. Liang J, Li X, Zhang H, et al. Allogeneic mesenchymal stem cells transplantation in patients with refractory RA. Clin Rheumatol. 2012;31(1):157–161.
112. Wang L, Wang L, Cong X, et al. Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: safety and efficacy. Stem Cells Dev. 2013;22(24):3192–202.
113. Wang L, Zhang Y, Li H, et al. Clinical observation of employment of umbilical cord derived mesenchymal stem cell for juvenile idiopathic arthritis therapy. Stem Cells Int. 2016;2016:9165267.
114. Park EH, Lim HS, Lee S, et al. Intravenous infusion of umbilical cord blood–derived mesenchymal stem cells in rheumatoid arthritis: a phase Ia clinical trial. Stem Cells Transl Med. 2018;7(9):636–642.
115. Wang L, Huang S, Li S, et al. Efficacy and safety of umbilical cord mesenchymal stem cell therapy for rheumatoid arthritis patients: a prospective phase I/II study. Drug Des Devel Ther. 2019;13:4331–4340.
116. Gracia JMA, Jover JA, Vicuña RG, et al. Intravenous administration of expanded allogeneic adipose–derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single–blind, placebo–controlled phase Ib/IIa clinical trial. Ann Rheum Dis. 2017;76(1):196–202.
117. Vij R, Stebbings KA, Kim H, et al. Safety and efficacy of autologous, adipose–derived mesenchymal stem cells in patients with rheumatoid arthritis: a phase I/IIa, open–label, non–randomized pilot trial. Stem Cell Res Ther. 2022;13(1):88.
118. Ghoryani M, Sarabi JS, Afshari JT, et al. Amelioration of clinical symptoms of patients with refractory rheumatoid arthritis following treatment with autologous bone marrow–derived mesenchymal stem cells: A successful clinical trial in Iran. Biomed Pharmacother. 2019;109:1834–1840.
119. Swart JF, Roock S, Nievelstein RAJ, et al. Bone–marrow derived mesenchymal stromal cells infusion in therapy refractory juvenile idiopathic arthritis patients. Rheumatology (Oxford). 2019;58(10):1812–1817.
120. Ghoryani M, Sarabi ZS, Afshari JT, et al. The sufficient immunoregulatory effect of autologous bone marrow–derived mesenchymal stem cell transplantation on regulatory T cells in patients with refractory rheumatoid arthritis. J Immunol Res. 2020;2020:3562753.
121. Jamshidi A, Maal AB, Alikhani M, et al. Allogeneic bone marrow derived clonal mesenchymal stromal cells in refractory rheumatoid arthritis: a pilot study. Regen Med. 2024;19(12):599–609.