Uncharted waters: mesenchymal stem cell treatment for pediatric refractory rheumatic diseases; a single center case series

The treatment of pediatric rheumatic diseases has advanced greatly over past two decades with the discovery and widespread use of biologics, allowing improved disease control in many cases. However, a significant number of patients, including those with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD) and juvenile idiopathic arthritis (JIA) continue to have significant disease activity despite maximized usage of conventional therapeutic agents. Further investigations are needed for exploring new treatment modalities to improve patient outcomes.

Transplantation of mesenchymal stem cell (MSC), also known as medicinal signaling cells, has been used to treat steroid-refractory graft-versus-host disease (GVHD), while studied for its potential efficacy in many different illnesses ranging from multiple sclerosis to myocardial infarction with promising results [1]. MSC are known to have immunomodulatory properties and theoretically may ameliorate rheumatic diseases by suppressing T cell proliferation, B cell activation, and inflammatory cytokine production [2‐4]. It is equally important to know, however, that while beneficial immunomodulation is most often noted, under certain conditions and in a different milieu, MSC may be pro-inflammatory [5]. With the anti-inflammatory and immunosuppressive properties in mind, researchers have investigated how MSC treatment would affect the course of SLE in certain adult populations with promising results [6‐8]. Furthermore, a recent systematic review of MSC treatment in refractory adult rheumatoid arthritis ultimately only uncovered 4 relevant studies, which ultimately suggested MSC had a short-term benefit in treating rheumatoid arthritis [9]. Since MSC research remains a political, cultural, and religious area of contention, the breadth of research, especially in the pediatric population, is scarce within the United States. In this retrospective case series, we present our experience of MSC treatment in three patients who independently undertook this treatment after second opinion visits to commercial clinics licensed in the US or abroad.

As patients and parents advocate for themselves, physicians must become aware of therapies offered that are unconventional and unregulated. Some of these therapies may prove beneficial when studied under carefully regulated clinical trials, but some may prove harmful. The patients presented in this series had years of poorly controlled disease and failed multiple non-biological and biological DMARDs prior to initiating MSC treatment. In each case, the parents or patient became frustrated with conventional therapies and sought out therapies in this country or others that promised a cure. The clinics they found were quite costly, but all boasted of improved quality of life without or with much less disease and pain. Fortunately, in this series, all the MSC transplants were well tolerated and no patient had serious adverse effects such as infection, emboli, ectopic growth, or malignancy. Although some mild adverse effects were endorsed, all patients felt that MSC treatment was beneficial in achieving disease remission as noted with drastic improvement in patient global assessment. It should be remarked that disease remission may be confounded by conjunctive treatment as seen in case 2 (co-administration of MSC and a short trial of tocilizumab) and case 3 (an intra-articular steroid injection after MSC treatment). In addition to clinical improvement, laboratory changes revealed normalization of ESR, although specific autoantibody titers did not change.

There are many similarities that become apparent when comparing these three patients who received MSCs. Although each patient had unrelated pediatric rheumatic diseases, the perceived benign potential benefit of MSC and how they can modulate the immune response led families to choose this experimental and adjunctive treatment regimen for their children. The decisions to adopt MSC treatment was difficult since stem cell research is lacking in the field of pediatric rheumatology. A recent case series of 6 refractory JIA patients demonstrated MSC was safe, and though improvement was noted in multiple outcome variables, caution in interpreting benefit was mentioned as the study was non-blinded [10]. Macrophage activation syndrome was also seen in one of the patients with systemic-onset JIA. Another recent study also showed MSC led to reduction in inflammatory cytokines, improved immune network effects, adjusted immune tolerance, and alleviated symptoms in 10 children with JIA [11]. These two studies do not provide sufficient evidence for recommendation of MSC therapy in JIA or any rheumatic disease. Hence, none of these patients nor their families were recommended by their care team providers to pursue MSC therapy; the decision was solely made by the family, against medical advice. All families paid for MSC treatment out-of-pocket; current treatment is very expensive and averages in the tens of thousands of dollars per transfusion. One family sold their car, and a second family re-mortgaged their home to pay for the treatment they felt was necessary to alleviate their child’s rheumatic disease. In addition, when the disease became more active in patient 2, conventional therapies were refused with the plan to seek out another MSC treatment when the family can afford it.

MSCs are multipotent progenitor cells that can differentiate into various cell lines, including myocytes, adipocytes, chondrocytes, and osteoblasts under proper in vitro conditions. They were first hypothesized in the late nineteenth century but was formally discovered in the 1970s by Alexander Friedenstein [12, 13]. In 1991, Arnold Caplan, Ph.D., first named these cells MSCs [14]. Historically, MSCs have been isolated from cell cultures, but their native residence in vivo remained unknown for many years. It was not until the revelation of vascular pericytes (cells that enclose small blood vessels like capillaries) and their expressed MSC markers CD73, CD90 and CD105 that MSCs were discovered in vivo [15, 16]. MSCs are harvested from donors (allogeneic) or from the patient (autologous), mostly from bone marrow, adipose tissue, and placental/umbilical cord. Tissue banks and harvesting facilities have specific criteria and procedures for procurement of MSCs for clinical use, but no universal guidelines for the manufacturing process exist leading to heterogenous MSC yields [17].

MSC transplantation has remained a very specialized treatment modality with which few rheumatologists feel comfortable utilizing. Regulating authorities globally have investigated its potential for treatment in a whole host of diseases. Canada, New Zealand, and some European Union countries have approved Prochymal (Produced by Megaloblast and is an allogenic culture expanded adult MSC derived from bone marrow), while in Japan, Temcell (a similar product to Prochymal) has been approved for GVHD [18]. In the United States, MSC have been conferred orphan drug designation by the US Food and Drug Administration but has not been fully approved. Furthermore, no standard dosing has been published for pediatric rheumatic disease. There have been a few studies investigating the clinical efficacy and safety of MSC treatment in adult SLE with intravenous doses ranging from 1 × 10⁶ MSCs/kg/dose to 2 × 10⁸ MSCs/kg/dose [19]. In this case series, dosages ranged from 1.2 × 10⁶ MSCs/kg/dose to 6.5 × 10⁶ MSCs/kg/dose. In contrast, recommended dosing for MSC therapy in acute GVHD is 1 × 10⁶ MSCs/kg/dose to 2 × 10⁶ MSCs/kg/dose weekly for a total of 4 doses. Studies have shown that providers do not tightly adhere to recommended dosing of GVHD with an average dose of 1.4 × 10⁶ MSCs/kg and three total doses administered (range is 1–10 doses administered) [20]. With such varying doses in MSCs, adverse events might be expected in the comparatively higher-dosed infusion, but overall, studies have not shown significant adverse events, which is consistent with our observations [19, 20]. Yet, there are concerns that MSCs exhibit both a proinflammatory and an anti-inflammatory effect depending on conditions of culture and the donor’s immune milieu. While MSCs are thought to be primarily anti-inflammatory, there are studies that suggest that there are two subtypes of MSCs, one of which is pro-inflammatory, MSC1 [21]. It is reported that MSC1 induces a proinflammatory MSC phenotype that releases monocyte chemoattractant protein-1 (MCP-1), which increases the M1 proinflammatory phenotype. M1 macrophages secrete many cytokines, including interleukin-1β, tumor necrosis factor-α, and vascular endothelial growth factor, leading to an inflammatory state [21‐26]. In addition, there has been some concern for tumorigenic potential of MSCs, but a recently published systematic review did not find this correlation to be significant; no serious adverse events were reported in this study [27]. Although the conditions required for optimal MSC therapy are not worked out, these factors must be considered in any clinical trial. Further research and controlled clinical trials with mandatory reporting of adverse events are essential and will assist pediatric rheumatologists in weighing the risks and benefits to this new treatment modality. Standardized procurement, preparation, cell viability, and the number of cell cycles and treatment protocols should be established for pediatric rheumatic disease. In addition, the necessity of stopping standard therapies must be studied as patients risk potentially life-threatening disease flares.

This case series demonstrates variability in the utilization of MSCs transplantation in the source of cells, types of cells, and route of administration. Two patients received allogeneic umbilical tissue-derived MSCs, while one patient received autologous adipose tissue-derived MSCs. Recent research has suggested that allogeneic MSC transplantation may be more immunosuppressive than autologous MSCs. MSCs derived from lupus patients have shown dysfunction in both proliferation and immunoregulation and appear to be phenotypically senescent [28]. All patients received systemic treatment via intravenous route, though two patients also received local injection (joint, lymph node, and intranasal). Local administration leads to increased complexity of differentiated engrafted MSCs due to microenvironmental milieu. On the other hand, systemic treatment allows infused MSCs to traffic to injured and inflamed tissues through chemokines and growth factors [29]. Dosing intervals also ranged from monthly to yearly infusions. Since there has been a scarcity of MSC research in pediatric rheumatology, variability is understandable. With an increase of MSC treatment publications in the past few years, more families will continue to seek this emerging therapy for their children with refractory disease, despite the experimental status of MSC transplant. This study aims to bring awareness, and caution, of this novel treatment to the pediatric rheumatology community as families will often seek this therapy without informing the treating team, stopping all medications prior to transplant without physician knowledge. In addition, the transplant physicians in these three cases did not communicate with the primary rheumatology team prior to stopping previous medications and initiating transplant. Although stem cell therapy remains controversial, especially in the United States, ongoing research and close scrutiny of the viability of MSC in ameliorating refractory pediatric rheumatic disease are necessary for the safety of all patients given the above considerations.

This retrospective series highlights the potential of mesenchymal stem cell therapy in refractory pediatric rheumatic diseases. The immunomodulatory effects of MSC treatment on autoimmune inflammatory disease make it a promising adjunctive treatment modality in certain cases. These three families took the chance and overcame multiple barriers (ie. expensive cost, travel out of the country, risk of disease flares, risk of side effects in uncontrolled settings) as a self-decision. We are compelled to share this experience as a possible sign of changing public perception and a silent request for awareness. Based on this, we suggest further evaluation of the safety and efficacy of MSC therapy is warranted for our patients within the premises of our subspecialty.