Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by local or systemic inflammatory responses, with insidious onset and high potential morbidity and mortality rates. SLE patients exhibit a diverse range of symptoms and signs, and the production of autoantibodies serves as an important basis for its clinical diagnosis. Currently, the clinical treatment of SLE primarily relies on hormones and immunosuppressants. However, due to their poor specificity, long-term use of these medications can be accompanied by severe, even life-threatening adverse reactions. In recent years, the emergence of novel targeted drugs has provided new options for the clinical treatment of SLE. These targeted drugs are characterized by convenience of administration, minimal adverse reactions, significant efficacy, rapid metabolism, and high specificity.
Anti-inflammatory Treatment for SLE
Glucocorticoids (GCs) are the first-line drugs in the clinical treatment of SLE patients. They effectively inhibit the elevation of connective tissue levels and regulate histamine levels, exerting anti-inflammatory effects and inhibiting capillary dilation, thereby significantly improving the patient's symptomatic manifestations. GCs also stabilize lysosomal membranes, improve shock conditions, and enhance clinical treatment outcomes. However, these medications often cause a series of adverse reactions, such as osteoporosis, digestive system complications, Cushing's syndrome, and cardiovascular diseases like hypertension.
In the treatment of SLE, the dosage, type, and duration of GC administration are adjusted based on factors such as whether the disease is newly onset, the severity of the condition, the presence of infection, the pathological type of kidney involvement, and whether there is renal dysfunction or hematological crises. Hormone therapy can be divided into three stages: induction of remission, maintenance, and relapse treatment. High doses of GCs combined with immunosuppressants are used during the induction of remission phase. During the maintenance phase, the dosage is gradually reduced to the minimum therapeutic dose. If the disease relapses, the dosage is increased to an appropriate level based on the patient's condition and then gradually reduced again once the condition stabilizes. The rational use of GCs has significantly improved the survival rate of SLE patients.
Immunosuppressive Therapy for SLE
Immunosuppressants are a class of commonly used drugs in the treatment of rheumatic diseases. They control cellular and humoral immune responses within the body by inhibiting abnormal immune expression, thereby reducing tissue immune damage and achieving the goal of lowering the patient's immune response. Combination therapy is often employed to enhance the efficacy of these drugs. The mechanisms of action of these immunosuppressants include eliminating sensitized lymphocytes, eliminating lymphocytes involved in abnormal immune responses, clearing non-lymphoid cells in non-specific inflammation, and inhibiting the function of residual lymphoid cells. Commonly used immunosuppressants include cyclophosphamide (CTX), azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), calcineurin inhibitors, hydroxychloroquine (HCQ), and the traditional Chinese medicine tripterygium glycosides.
①Cyclophosphamide (CTX)。CTX is a bifunctional alkylating agent and a non-specific drug for the cell cycle. It can affect the functions of DNA and RNA, with a pronounced effect on the S phase, thereby interfering with DNA synthesis and exerting a cytotoxic effect. CTX exerts its action by inhibiting lymphocyte proliferation, particularly potent against B cells, and also has toxic effects on T cells. Additionally, it inhibits both humoral and cellular immunity. CTX has shown good efficacy in the treatment of SLE, particularly lupus nephritis (LN). However, alkylating agents like CTX are associated with adverse reactions such as bone marrow suppression, infection, gonadal suppression, or increased risk of malignancy. Long-term high-dose CTX treatment is gradually being replaced by the combined or sequential use of GCs and other immunosuppressants.
②Azathioprine (AZA).AZA is a purine analog whose metabolite, mercaptopurine, interferes with purine synthesis and exhibits cytotoxic effects. It inhibits both cell-mediated and antibody-mediated immune responses, suppressing nucleic acid biosynthesis through multiple pathways, thereby preventing the proliferation of cells involved in immune recognition and amplification. Furthermore, the incorporation of thiopurine analogs into DNA chains can lead to DNA damage. Clinically, AZA is most commonly used in patients with mild to moderate SLE to reduce the dosage of GCs. It is also employed as an alternative to CTX in the treatment of lupus nephritis (LN). AZA has demonstrated significant efficacy in clinically relieving LN patients, consolidating therapeutic outcomes, and reducing relapses.
③Mycophenolate Mofetil (MMF).MMF inhibits the de novo synthesis pathway of purines without affecting the salvage pathway, thereby inhibiting lymphocyte activation and the generation of T cells, B cells, and antibodies. It also reduces platelet destruction. MMF's unique immunosuppressive properties make it free from bone marrow and gonadal suppression, contributing to its high safety profile. Additionally, MMF inhibits the conversion of glycoproteins, leading to decreased adhesion between T cells and endothelial cells. It also exhibits effects such as reducing macrophage activity and inhibiting vascular smooth muscle proliferation. Research suggests that MMF can reduce the deposition of immune complexes in the kidney, providing some relief in mitigating kidney damage.
④Methotrexate (MTX).As a dihydrofolate reductase inhibitor, MTX disrupts the normal synthesis of purines, thereby affecting the synthesis of thymidine. It acts on the S phase of cell division, inhibiting DNA biosynthesis, and exerts a certain anti-inflammatory effect. However, clinical studies have revealed that MTX is also associated with immune-mediated drug hypersensitivity reactions and other adverse effects, mainly manifested as skin redness and itching, gastrointestinal reactions, and damage to liver and kidney function. In severe cases, bone marrow suppression can occur, leading to complications such as infections or even death, indicating a relatively poor safety profile for patients using this medication.
⑤Calcineurin Inhibitors (CNI).CNI encompasses cyclosporine and tacrolimus. CNI primarily inhibit the calcineurin of T lymphocytes, thereby preventing the binding of activated T-cell nuclear factor to DNA and suppressing the expression of interleukin IL-2. IL-2 plays a crucial role in the survival and differentiation of T cells, and CNI inhibits T-cell function by reducing IL-2 expression. Due to their selective action on lymphocytes, CNI do not exhibit bone marrow or gonadal suppression. Tacrolimus has been shown to be non-inferior to MMF in the treatment of lupus nephritis (LN), and when combined with low-dose steroids and MMF, it demonstrates superior efficacy compared to cyclophosphamide pulse therapy. The European guidelines for SLE treatment recommend the addition of low-dose CNI for severe nephrotic syndrome or LN with suboptimal response to treatment.
⑥Hydroxychloroquine (HCQ).HCQ is a commonly used antimalarial drug in clinical practice, often administered in combination with immunosuppressive agents. Its pharmacological mechanisms encompass both anti-inflammatory and immunomodulatory effects. A study by the Toronto SLE research team revealed that using antimalarial drugs for over 60% of the time during the first five years of the disease can reduce the frequency of SLE episodes and limit the cumulative extent of damage as well as the cumulative dosage of glucocorticoids (GCs). The alkalinization induced by HCQ leads to lysosomal swelling and vacuolation, subsequently inhibiting lysosomal functions such as enzyme release, receptor recycling, plasma membrane repair, cellular signaling, and energy metabolism. The immunomodulatory effects of this drug are mediated through mechanisms of immunosuppression, anti-inflammation, anticoagulation, and photoprotection, contributing to maintaining metabolic balance, protecting organs, improving SLE activity, and reducing mortality, infections, and other complications. The 2020 Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus recommend combining immunosuppressive agents for patients who do not respond adequately to GC and HCQ therapy or who are unable to reduce the GC dosage to a relatively safe level.
⑦Tripterygium Glycosides.Tripterygium Glycosides are traditional Chinese medicine extracts with anti-inflammatory and immunomodulatory properties. They can block the production of 5-hydroxytryptamine, histamine, and prostaglandin E2, thereby inhibiting inflammatory responses and disrupting the cascade reaction of inflammatory mediators. Additionally, they inhibit the production of IL-2 and its receptor effects, inducing apoptosis in activated lymphocytes. Tripterygium Glycosides exhibit a significant inhibitory effect on the early stages of SLE-induced inflammatory responses, such as increased vascular permeability, exudation, and edema. In terms of immunomodulation, Tripterygium Glycosides directly suppress hyperactive B-cell function, providing adjuvant therapy for SLE and notably improving patients' immune function.
Targeted Drugs
In recent years, with the rapid advancements in pharmaceutical research, various targeted drugs have emerged, primarily categorized into two major types: biological agents and small-molecule targeted drugs. Their primary mechanisms involve inhibiting the activation of B and T lymphocytes, blocking interactions between immune cells, and suppressing the production of cytokines. Targeted drugs can act specifically on diseased sites, increasing the local concentration of the drug at the target site to reduce toxicity to normal tissues and cells, thereby enhancing the specificity of treatment.
① Targeting B Lymphocytes
Belimumab received formal approval from the FDA and the European Medicines Agency (EMA) in 2011, becoming the first targeted drug approved for the treatment of SLE. B-lymphocyte stimulator (BAFF) is a tumor necrosis factor (TNF)-like cytokine that supports the survival and differentiation of B cells at various stages of development. Belimumab targets BAFF with high affinity, and the binding of the drug affects the receptor on the B-cell surface where BAFF acts, inhibiting B-cell proliferation, differentiation, and autoantibody production in the serum. Studies have shown that belimumab can significantly slow down SLE disease activity and reduce the dosage of prednisone and glucocorticoids (GCs), but long-term use of this drug may increase the risk of depression.
Rituximab (RTX).Rituximab is a human-mouse chimeric monoclonal antibody that selectively targets the B-cell-specific surface molecule CD20. CD20 is a cell surface protein confined to the B-cell lineage, expressed initially in early pre-B cell stages in the bone marrow and persisting throughout B-cell development until the final differentiation into plasma cells. RTX treats SLE by inducing apoptosis through antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, leading to the continuous depletion of B cells and subsequent reduction of autoimmune damage to the body. Since CD20 is absent from hematopoietic stem cells, normal plasma cells, and other normal tissues, RTX can effectively avoid widespread immunosuppression, enhancing the safety of medication. Despite the lack of trial evidence, numerous observational studies have demonstrated RTX's efficacy in treating refractory lupus nephritis (LN) and severe non-renal SLE.
Anifrolumab is an investigational human monoclonal antibody targeting the type I interferon (IFN) receptor subunit 1. In SLE patients, there is a significant elevation of type I IFN gene signatures, and type I IFN is a cytokine involved in inflammatory responses. Therefore, Anifrolumab can be used in the treatment of SLE by blocking the activity of all type I IFNs. Currently, this monoclonal antibody drug is undergoing a pivotal Phase III clinical trial for the treatment of SLE. The results show that the adverse events in the Anifrolumab group, including respiratory infections, nasopharyngitis, and infusion-related reactions, have a lower incidence rate compared to the placebo group. Additionally, the Anifrolumab group demonstrated better outcomes in terms of glucocorticoid (GC) dose reduction and severity of skin manifestations compared to those receiving the placebo.
② Targeting T Lymphocytes
Abatacept is a drug used to treat autoimmune diseases such as rheumatoid arthritis. It is a fusion protein composed of a leukocyte differentiation antigen CTLA-4 fused with the Fc region of an immunoglobulin IgG1. Abatacept regulates T-cell costimulatory molecules by interrupting the interaction between CD80/CD86 and CD28. By blocking the signaling pathway, abatacept prevents T-cell activation. Although clinical trials of abatacept for SLE have not yielded positive results, and anti-CD40L monoclonal antibodies have also shown ineffectiveness in Phase II clinical trials for SLE, considering the safety profile of abatacept in SLE patients, it could be considered as a backup option in refractory cases.
③ Targeting Cytokines
Sifalimumab is a humanized anti-IFN-α antibody. A recent Phase IIb clinical trial demonstrated that Sifalimumab has the ability to inhibit IFN gene expression in patients with moderate to severe active SLE, leading to a reduction in disease activity and joint damage. In addition to interferon-α, other cytokines also play crucial roles in the pathogenesis of SLE. Recent research has found that IL-12 promotes the differentiation of T cells into helper T cell-1 (Th1), while IL-23 promotes the differentiation of Th17. Ustekinumab, a monoclonal antibody targeting IL-12/IL-23, has shown positive results in Phase II clinical studies for SLE. Furthermore, studies have also suggested that instead of blocking cytokines, directly administering certain cytokines can be used in SLE treatment. For instance, recent reports indicate that low-dose IL-2 can increase the proportion of regulatory T cells, thereby treating SLE.
④ Targeting Intracellular Signaling Pathways
Type I interferons play a significant role in the pathogenesis of SLE, and the JAK/STAT signaling pathway is the primary signaling route for Type I interferons. Blocking the JAK/STAT pathway can therefore hinder the effects of Type I interferons. Recent research has revealed that the JAK/STAT pathway is also crucial in maintaining the function of renal-resident T cells in lupus nephritis (LN). JAK inhibitors, such as tofacitinib, can inhibit the function of these T cells, resulting in reduced proteinuria and renal damage. Currently, several JAK inhibitors are clinically used to treat autoimmune diseases like rheumatoid arthritis, but evidence for their efficacy in SLE is still limited. Baricitinib has shown promising results in Phase II clinical studies for SLE, and Phase III trials are ongoing. Small-scale observational studies have found that tofacitinib can be effective in treating skin rashes and arthritis in SLE patients. Additionally, spleen tyrosine kinase inhibitors have been shown to significantly reduce skin and kidney lesions in lupus mice.
References
[1] Guo, J., Li, X., & Zhang, L. (2021). Advances in Drug Therapy for Systemic Lupus Erythematosus. Chinese Journal of Dermatology and Venereology (Integrated Traditional and Western Medicine), 20(05), 525-528.
[2] Chai, F., & Wang, C.F. (2022). Research Progress on Drug Therapy Related to Systemic Lupus Erythematosus. Laboratory Medicine and Clinic, 19(10), 1423-1427.
[3] Yang, N.S. (2020). Trends in Drug Therapy for Systemic Lupus Erythematosus. Peking Union Medical College Hospital Journal, 11(03), 247-251.
About the Author
Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.
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