Young women are more likely to suffer from lupus erythematosus! How to treat the "immortal cancer"?

Recently, systemic lupus erythematosus (SLE) has become a hotly discussed disease, and the entry #Young women are more susceptible to lupus# has even entered the top 5 hot searches. Why are young women more susceptible to the disease? Because women have higher levels of estrogen, especially women of childbearing age, who have increased levels of estrogen and prolactin. Excessive estrogen secretion will stimulate macrophages to secrete too many anti-inflammatory factors, which will further activate B cells, leading to an increase in autoantibodies, making it easy to develop autoimmune diseases. Therefore, the incidence of SLE in women is 10 times higher than that in men.

SLE is a systemic autoimmune disease with the main clinical features of multi-system and multi-organ involvement, repeated relapses and remissions, and the presence of a large number of autoantibodies in the body. If not treated in time, it will cause irreversible damage to the affected organs and eventually lead to the death of the patient. Studies have shown that the 5-year survival rate of SLE patients has increased from 50% to 60% in the 1950s to more than 90% in the 1990s, and has gradually stabilized from 2008 to 2016. SLE has changed from an acute, highly lethal disease to a chronic, controllable disease, which is inseparable from the increased awareness and attention paid to SLE by clinicians and patients.

At present, the main methods for clinical treatment of SLE include drug therapy, plasma exchange or immunoadsorption adjuvant therapy, lifestyle adjustment, etc. This article summarizes the drugs currently recommended for the treatment of SLE for the benefit of readers.

Western medicine treatment

At present, Western medicine for the treatment of SLE mainly includes four categories: hormones, hydroxychloroquine, immunosuppressants, and biological agents. The specific usage methods are as follows.

1. Hormones

Hormones are the basic drugs for controlling SLE. An individualized hormone treatment plan should be formulated according to the disease activity and the type and severity of the affected organs. The dosage and usage should be adjusted according to the disease activity, duration of medication, and adverse reactions of hormones.

•For patients with mildly active SLE, when hydroxychloroquine or nonsteroidal anti-inflammatory drugs are ineffective, low-dose steroids (≤10 mg/d prednisone or equivalent doses of other steroids) may be considered.

• Patients with moderately active SLE can be treated with hormones [0.5~1 mg/(kg·d) or equivalent doses of other hormones] combined with immunosuppressants.

•For patients with severely active SLE, hormones [≥1 mg/(kg·d) prednisone or equivalent doses of other hormones] combined with immunosuppressants can be used for treatment. After the condition stabilizes, the hormone dosage can be adjusted appropriately.

•SLE patients with lupus crisis can be treated with hormone pulse combined with immunosuppressants.

2. Hydroxychloroquine

The new treatment guidelines recommend hydroxychloroquine for all SLE patients except those with contraindications. Hydroxychloroquine treatment of SLE is beneficial for controlling the disease, improving symptoms of lupus nephritis and neurological lupus, reducing relapses and improving survival rates. Long-term use of hydroxychloroquine by SLE patients can reduce disease activity, reduce the risk of organ damage and thrombosis, improve blood lipids and improve survival rates. Hydroxychloroquine is relatively safe and is generally recommended for long-term use by lupus patients if there are no contraindications.

Although some studies have shown that the adverse reactions of hydroxychloroquine are mild when the treatment dose is lower than 5 mg/(kg∙d), most studies believe that the effective dose of hydroxychloroquine for lupus is 6.5 mg/(kg∙d), so the clinical efficacy of lower doses of hydroxychloroquine still needs further verification. In summary, the European League Against Rheumatism's updated recommendations on the treatment of SLE in 2019 suggest that 6.5 mg/(kg∙d) of hydroxychloroquine should be used during the induction remission period of SLE, and the hydroxychloroquine dose can be considered to be reduced during the maintenance treatment period.

However, since hydroxychloroquine is ocular toxic, patients taking hydroxychloroquine are advised to undergo an eye-related risk assessment: high-risk patients are advised to undergo an eye examination once a year, and low-risk patients are advised to undergo an eye examination once a year starting from the fifth year of medication.

3. Immunosuppressants

The use of immunosuppressants can reduce the cumulative use of hormones and prevent disease relapse. For patients with refractory (poor response to conventional therapy) or recurrent SLE, the use of immunosuppressants can reduce the use of hormones, control disease activity, and improve clinical remission rates. For SLE patients with organ involvement, appropriate immunosuppressants should be selected based on a comprehensive consideration of factors such as the patient's clinical manifestations, fertility requirements, drug safety, and cost.

Common immunosuppressants include: mycophenolate mofetil, cyclophosphamide, leflunomide, azathioprine, tacrolimus, cyclosporine, and methotrexate.

(1) Mycophenolate mofetil: Mainly suitable for patients with moderate to severe SLE.

Advantages: For patients with moderate to severe lupus nephritis, mycophenolate mofetil provides effective treatment during the induction and maintenance phases and reduces the relapse rate.

Common and important adverse reactions: The most common adverse reaction is gastrointestinal discomfort. Some patients may develop infection, bone marrow suppression and liver damage. Due to its teratogenicity, patients who take this drug and wish to become pregnant should not try to become pregnant until at least 6 weeks after stopping the drug.

(2) Cyclophosphamide: It is mainly suitable for patients with moderate to severe lupus nephritis, neuropsychiatric lupus and SLE with immune thrombocytopenia.

Advantages: It is effective for both the induction and maintenance phases of treatment of patients with moderate to severe lupus nephritis, and is an effective immunosuppressant for the treatment of SLE involving the nervous system and blood systems.

Common and important adverse reactions: Common adverse reactions are gastrointestinal discomfort, such as nausea, vomiting, etc. Liver damage and bone marrow suppression are the main adverse reactions. Long-term and high-dose use will increase the risk of tumors. It has clear reproductive toxicity and teratogenicity. It is recommended to stop using it 1 to 3 months before pregnancy.

(3) Leflunomide: Mainly suitable for patients with proliferative lupus nephritis.

Advantages: Effective for proliferative lupus nephritis and well tolerated.

Common and important adverse reactions: Leflunomide can cause liver damage, hypertension, leukopenia, infection and some complications. Since it has teratogenic effects in animal studies, it is recommended to completely wash out the drug before pregnancy before attempting pregnancy.

(4) Methotrexate: Mainly suitable for patients with mild to moderate SLE without renal involvement.

Advantages: It has good efficacy in improving skin, joint inflammation and overall condition of SLE patients.

Common and important adverse reactions: The most important adverse reaction is gastrointestinal discomfort, such as nausea and vomiting. Blood system abnormalities such as anemia, leukopenia and liver damage are more common. Due to its teratogenic effect, it is recommended to discontinue use 1 to 3 months before pregnancy.

(5) Tacrolimus: Mainly suitable for patients with proliferative lupus nephritis, refractory lupus nephritis and SLE with immune thrombocytopenia.

Advantages: It is effective in the induction and maintenance phases of lupus nephritis and can reduce the relapse rate. It can be used to treat refractory lupus nephritis, especially those with prominent proteinuria. Compared with other immunosuppressants or glucocorticoids, tacrolimus has a lower risk of causing serious infection.

Common and important adverse reactions: Common adverse reactions are gastrointestinal discomfort. Some patients may experience kidney and liver damage. Those with impaired liver function need to reduce the dosage of tacrolimus. Renal toxicity, blood sugar and blood pressure should be monitored during medication.

(6) Cyclosporine: Mainly suitable for patients with lupus nephritis and SLE with immune thrombocytopenia.

Advantages: Cyclosporine combined with other immunosuppressants can be used for lupus nephritis that is ineffective with standard treatment and can alleviate blood system damage.

Common and important adverse reactions: The main adverse reactions are renal impairment, increased blood pressure and infection.

(7) Azathioprine: Mainly suitable for patients with moderate SLE.

Advantages: Used for maintenance treatment of SLE. It is relatively safe during pregnancy and has a low incidence of serious infection.

Common and important adverse reactions: The main adverse reactions are bone marrow suppression and liver damage, and the activity of thiopurine methyltransferase needs to be detected.

4. Biological agents

For patients with SLE who have not responded well to conventional treatment or who have relapsed, the use of biologics can significantly increase the complete and partial remission rates of patients, reduce disease activity, disease relapse rates, and reduce the use of hormones. When using biologics, appropriate biologics should be selected based on factors such as drug safety and cost.

(1) Belimumab

Advantages: It can improve the patient's serological indicators, reduce the risk of severe relapse and reduce the amount of hormones used. It can be considered for patients who are not well controlled by conventional treatment.

Common adverse reactions: infection, headache and nausea.

(2) Rituximab (this drug has not been approved by my country Food and Drug Administration)

Advantages: For patients with refractory lupus nephritis and blood system involvement, it can control the disease and reduce the dosage of hormones.

Common adverse reactions: including infection, infusion reaction, etc.

Chinese medicine treatment method

In addition to prescriptions, tripterygium wilfordii glycosides, total glycosides of white peony, dihydroartemisinin, arsenic trioxide, etc. have also been used to treat SLE. Tripterygium wilfordii is a unique anti-rheumatic drug in my country. Tripterygium wilfordii extract has anti-inflammatory, analgesic and immunosuppressive effects and has been used to treat rheumatic diseases in my country for hundreds of years. Tripterygium wilfordii glycosides are a mixed component of Tripterygium wilfordii extract and are currently the most effective drug for the treatment of SLE.

Tripterygium wilfordii glycosides are commonly used to treat skin, mucosal and joint lesions of SLE, with a common dose of 10 to 20 mg twice or three times a day. Because of its good anti-inflammatory and immunosuppressive effects, it can also be used to treat SLE patients with kidney and other organ damage. Tripterygium wilfordii glycosides can be used alone or in combination with other immunosuppressants, depending on the organ involvement and the severity of the disease.

However, tripterygium wilfordii preparations may cause gastrointestinal discomfort, abdominal pain, and liver damage; they may also cause bone marrow suppression and leukopenia; their most important adverse reaction is gonadal toxicity, which inhibits male/female gonadal function. Therefore, clinicians need to fully evaluate when using such drugs.

Total glucosides of paeony can be used for SLE patients with joint lesions. The effect of artemisinin is similar to hydroxychloroquine, so it can also be used to treat some SLE patients.

Innovative drug treatment

With the clinical application of glucocorticoids and new immunosuppressants, the prognosis of SLE patients has improved significantly, but some patients still do not respond well. Such patients are defined as refractory SLE, that is, after induction therapy with high-dose glucocorticoids and multiple cytotoxic drugs, their condition continues to not improve or even worsens in terms of clinical and laboratory indicators.

In recent years, in the process of exploring new methods for the treatment of SLE, researchers have found that mesenchymal stem cells (MSCs) have great potential for the treatment of SLE. Their powerful characteristics of tissue regeneration, inflammation inhibition, and immune regulation can accurately target multiple pathogenesis mechanisms of SLE, and have shown great potential in the treatment of SLE (especially refractory SLE). They can effectively slow down the progression of the disease and improve the quality of life of patients.

Because stem cells have "unlimited" proliferation, multidirectional differentiation potential, hematopoietic support, immune regulation and self-replication, they can be used as ideal "seed" cells for repairing tissue and organ damage caused by lesions. Experts say that MSCs can regulate the release of inflammatory factors, induce immune tolerance, and inhibit autoimmune reactions through various pathways to exert therapeutic effects. MSCs transplantation for the treatment of SLE has the following advantages:

① Allogeneic transplantation does not cause rejection reaction, and the transplantation success rate is high and safe;

② No myeloablation is required before transplantation, and there are no complications such as infection and death;

③The therapeutic effect is good and MSC can play a long-term role after transplantation.

In January 2022, the "Expert Consensus on Allogeneic Mesenchymal Stem Cells for the Treatment of Systemic Lupus Erythematosus" was published in the 26th issue of the Chinese Journal of Rheumatology, which provides a basis for the application of mesenchymal stem cells in SLE. Consensus summary: Currently, more than 1,500 SLE patients worldwide have received mesenchymal stem cell treatment. No serious adverse events have been observed in the process of mesenchymal stem cell treatment of SLE, and patients tolerate it well; mesenchymal stem cell treatment has greatly improved the efficacy and prognosis of SLE patients.

In recent years, mesenchymal stem cells have been used in the treatment of SLE due to their powerful immunomodulatory properties, and many successful cases have been produced. Stem cell transplantation can effectively alleviate the clinical symptoms of SLE, control and reduce the patient's autoimmune response, improve the patient's quality of life and survival rate, and bring new options to patients.

References: "Expert Consensus on Allogeneic Mesenchymal Stem Cells for the Treatment of Systemic Lupus Erythematosus (2022 Edition)" and "Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus in China"