According to Sohu, CCTV's "approaching Science" once reported that a Ms. Qin, who had suffered from rheumatoid arthritis for 11 years, tried stem cell therapy with the mentality of trying stem cell therapy after failing to use various methods. Unexpectedly, the symptoms were significantly improved, and two years after the end of stem cell therapy, she got rid of the shackles of long-term use of hormone drugs and became a mother.

In China, about 122 million patients suffer from a variety of arthritis, including rheumatoid arthritis, osteoarthritis and so on. Among them, rheumatoid arthritis (rheumatoid arthritis,RA) is not a common joint inflammatory disease, it is a chronic systemic autoimmune disease, the disease mainly affects the synovial joint in the early stage, but will eventually spread to the lungs, blood vessels and other parts of the body.

CCTV reported that arthritis is not only a "senile disease", the incidence is getting younger and younger. 

Until now, more than 80% of patients with rheumatoid arthritis in China have not reached clinical remission. It can be seen that the difficulty of curing rheumatoid arthritis has brought great challenges to the clinic. There is an urgent need for new treatment programs to alleviate the disease progression. As a kind of autoimmune disease, a large number of studies in recent years have confirmed that stem cells are safe and effective in autoimmune diseases such as graft-versus-host disease (GVHD), systemic lupus erythematosus, psoriasis and so on. 

Stem cells have the ability to differentiate into bone and cartilage, can repair damaged tissue, have immunomodulatory effect, inhibit pro-inflammatory factors and reduce inflammatory response, and have shown good results in some studies on rheumatoid arthritis. it is expected to become a new method for the intervention of rheumatoid arthritis.

Rheumatoid arthritis (RA): a difficult problem in clinical medicine

RA is a common chronic and autoimmune disease, which is mainly characterized by synovitis, progressive joint and bone destruction, resulting in joint swelling and pain, morning stiffness, joint bone damage, joint deformity and so on. If there is no timely and effective treatment, there is even a risk of disability in the later stage of the disease, which will have a great impact on the work and life of the patients. 

It often occurs in the fingers and wrists. In addition to pain, long-term rheumatoid arthritis can even lead to loss of joint function and joint deformity if the condition is not controlled in time. It can also invade the skin, eyes, lungs, heart, kidney, salivary glands, nerve tissue, bone marrow blood vessels and other tissues and organs, posing a great threat to health and endangering life.

Deformed joint lesions can be seen under X-ray in patients with rheumatoid arthritis. 

Women between the ages of 40 and 60 are the biggest victims, with a clinical incidence of about 3 times that of men. Although RA is not fatal, long-term suffering from illness seriously affects the health and quality of life of patients. The following are common major hazards:

1、Affect joint function: acute stage patients can appear joint swelling and pain, morning stiffness, affecting daily life.The course of the disease is long, especially the patients who have not received formal treatment, joint destruction, deformity, fixation, resulting in disability, loss of self-care ability, a serious decline in the quality of life.

2、Systemic damage: when RA is complicated with heart, lung, eye, kidney, nervous system and other damage, the corresponding clinical manifestations appear, which complicates the condition and increases medical expenses.

3、Increase the incidence of infection: RA patients often need to use corticosteroids, immunosuppressants, biological agents, etc., after the use of these drugs, patients may have decreased immunity, prone to secondary infections, affecting the quality of life.

4、Increased mortality: studies have shown that the median life expectancy of RA patients is lower than that of the control population. Infection, kidney disease and respiratory failure are the main reasons for the increase of mortality in patients with rheumatoid arthritis.

The occurrence of RA may be related to heredity, sex hormones, environmental factors and immune disorders. The disease is a Th17-driven disease, and the imbalance of Th17/Treg is a key factor in RA. At the same time, the ratio of M1/M2 macrophages in RA is greater than 1, which is related to higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and more osteoclasts, which play a key role in bone resorption and joint destruction. 

Synovitis is the earliest and most important lesion of RA. When the inflammation becomes chronic, small focal necrosis begins to occur in the contact area between articular cartilage and synovium, and the granulation tissue in the synovium forms pannus extending to the cartilage surface. In the late stage, there are granulation tissue and fibrous tissue adhesion on the articular surface, forming fibrous ankylosis, and then ossification develops into ossification ankylosis.

Common abnormal indexes in physical examination of rheumatoid arthritis. 

At present, there is no very good plan for the treatment of RA. Even if conventional drugs are used, they can only relieve symptoms in stages or to a certain extent, prevent further destruction of joints and maintain joint function. These drugs mainly rely on non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids and modified antirheumatic drugs (DMARDs). Long-term use will inevitably lead to varying degrees of adverse reactions. Including infection, myelosuppression, liver and kidney function damage and so on.

Drugs used to treat RA will have varying degrees of side effects. 

In addition to drug treatment, although some biological agents have also achieved good results, about 30% of the patients did not respond satisfactorily to the treatment in the trial, and cartilage and bone injuries continued to progress even if clinical remission was achieved. New alternative therapies are urgently needed to alleviate disease progression.

Research Progress of Stem cells in the treatment of Rheumatoid Arthritis (RA)

For RA, it may be possible to induce inflammatory relief through permanent immune tolerance, so as to prevent the continuous deterioration of joint structure and repair existing injuries. The development of stem cell tissue engineering is bringing new opportunities to this challenging topic.

1、Mesenchymal stem cells (MSCs) in the treatment of RA. 

MSCs can inhibit the proliferation of T cells, increase the proportion of Treg cells, inhibit the function of B cells and reduce the number of B cells, affect the maturation of dendritic cells, induce the production of M2 macrophages, inhibit the activation of M1 macrophages, and then improve the symptoms of rheumatoid arthritis. 

This has also been effectively confirmed in a large number of clinical studies, stem cells can regulate immune function, promote body repair, effectively inhibit the development of the disease, thus bringing new hope for the intervention of RA.

Schematic diagram of the action mechanism of MSCs

1) Clinical study cases: 

a. Kichul Shin researchers at Seoul National University Boramae Medical Center in Seoul, South Korea, used cord blood-derived MSCs to treat RA patients. No severe adverse events or dose-limited toxicity were reported within four weeks after a single infusion of cord blood and MSCs transfusion. 

According to the first phase one-year clinical study for patients with RA, the safety and tolerance of single intravenous infusion of umbilical cord blood MSCs were evaluated, reflecting the effectiveness of umbilical cord blood MSCs in the treatment of RA. Intravenous infusion of umbilical cord blood MSCs may be a treatment option for RA patients.

Clinical trial of intravenous infusion of umbilical cord blood-derived MSCs in the treatment of phase RA Ia

b. Four inpatients with refractory RA were treated with antirheumatic drugs (DMARDs) in Southwest Hospital of Army military Medical University / third military Medical University. Umbilical cord mesenchymal stem cells were infused intravenously once, and the number of cells was 1 × 10 cells / kg. The number of joint swelling and tenderness, ESR and DAS28 (4) were significantly improved in 3 patients after infusion treatment. Allergy, rejection and other serious adverse reactions were not found in all patients, and there were no abnormal changes in blood routine liver and kidney function. 

Note: DAS is an evaluation standard proposed by the European Alliance against Rheumatism (EULAR). It was originally DAS44, that is, 44 designated joints were examined. DAS44 included four core indicators: joint index (RAI), joint swelling number (SJC), acute reactant level (ESR or CRP), and 100mm pain visual simulation scale (VAS100mm). Then, in the process of using the DAS44 evaluation standard, it was found that the joint examination time was longer, and it was found that calculating the swelling number and tenderness number of 28 joints was as effective and reliable as DAS44, so a simplified DAS28 score method was proposed. The following is the DAS28 calculation formula and scoring criteria:

Conclusion: umbilical cord mesenchymal stem cell infusion is safe in the treatment of RA and can improve the condition of some refractory RA patients to some extent. 

c. Professor Wang Liming of PLA 323 Hospital published an article on stem cell treatment of RA in "Drug Design, Development and Therapy". The study recruited 18-year-old patients with rheumatoid arthritis. 

During the treatment, patients received intravenous injection of 40mL UC-MSC (umbilical cord mesenchymal stem cells) suspension product (2 × 10 cells / 20mL) immediately after infusion of 100mL normal saline. All patients maintained individual long-term use of low-dose DMARDs (disease-improving antirheumatic drugs).

Efficacy and safety of umbilical cord mesenchymal stem cells in the treatment of RA patients: a prospective phase I/II study

Results after 1 year and 3 years of UC-MSC cell treatment, there were no abnormalities in blood routine, liver and kidney function and immunoglobulin, all in the normal range.

A 68-year-old male was diagnosed with RA in 1998. In 2010, he was hospitalized for the first time. (a) showed that his hand could not be kept straight. (B) three years after treatment, the use of antirheumatic drugs had been stopped for five years, the hands were stretched freely, and the rheumatic nodules around the joints gradually softened and subsided.

The results of this study show that UC-MSC cells combined with DMARDs is a safe, effective and feasible method for the treatment of RA.

2、Induced pluripotent stem cells (iPSCs) for treatment of RA. 

iPSCs are pluripotent stem cells that can be obtained by reprogramming adult cells, avoiding the ethical problems of using embryonic stem cells. In the treatment research of RA, iPSCs has attracted much attention because of its unique properties. Here are some key points about iPSCs's treatment of RA:

1) Pluripotency and self-renewal: iPSCs has the ability to differentiate into a variety of cell types, including chondrocytes and immune cells, which provides the possibility for tissue repair and immune regulation in RA.

2) Immune regulation: i-MSCs induced by iPSC has immunomodulatory ability and can regulate immune response by secreting anti-inflammatory cytokines and growth factors, which may help to alleviate inflammation in RA.

3) Tissue engineering and regeneration: iPSCs can differentiate into chondrocytes in vitro, which can be used to repair damaged articular cartilage in patients with RA.

4) Disease model construction: iPSCs technology can be used to construct the disease model of RA, which is of great significance for studying the pathogenesis of the disease and testing new drugs.

5) Application of genetic engineering: the latest research progress includes mRNA nanopharmaceuticals synthesized by genetically engineered cell membrane biomimetic technology. This material has the effect of anti-TNF- α and expression of PTEN protein, which provides a new strategy for combined therapy of RA.

Although iPSCs shows great potential in the treatment of RA, there is still no direct mention of the case of iPSCs in the treatment of RA, and further research is needed to fully realize the potential of its clinical application.

3、Research Progress of Enterprises: 

On April 10, 2020, the new drug of human umbilical cord mesenchymal stem cell injection from Beijing Beilai Biotechnology Co., Ltd. was officially approved for the treatment of rheumatoid arthritis (RA). This is the first mesenchymal stem cell product in China for the treatment of rheumatoid arthritis.

小结

To sum up, stem cells have shown good safety and effectiveness in the treatment of rheumatoid arthritis, which can effectively relieve the pain of the disease and improve the deterioration of bone and joint inflammation. I believe that with the in-depth study of stem cell technology, stem cells will eventually break through various difficulties, overcome rheumatoid arthritis and other rheumatoid orthopedic diseases, bring new treatment options for more patients, and reduce the suffering of patients.