Systemic lupus erythematosus (SLE) is a common autoimmune disease with multiple organ damage. Before the 1950s, SLE was considered incurable, but since 1948, when adrenocorticosteroids were first used to treat SLE, the survival rate of SLE patients has improved year by year. Subsequently, the widespread use of immunosuppressive agents, represented by cyclophosphamide, has improved the prognosis of SLE patients, and significant progress has been made in the treatment of SLE. Adrenocorticosteroids and immunosuppressive drugs are still the main drugs used in the treatment of SLE today.
However, although traditional immunosuppressive drugs can provide relief, their secondary infections and drug toxicity limit their clinical use. Specific biologic agents targeting a specific part of the pathogenesis of SLE have become a major advance in the treatment of SLE in recent years. The immunosuppressive agents and biologics used in the treatment of SLE are described below.
I. Immunosuppressants
1.Methotrexate (MTX)
MTX is a folic acid analogue, which is an antagonist of folic acid metabolism and can block the synthesis of DNA and RNA, and also has anti-inflammatory and anti-immune effects. SLE patients, especially those with arthritic manifestations.
The main side effects of MTX are gastrointestinal reactions, hepatotoxicity, lung damage, and hematological abnormalities. Folic acid supplementation can reduce or prevent the side effects.
2.Cyclophosphamide (CTX)
CTX is an alkylating agent of nitrogen mustard hydrochloride, which was first used as an anti-tumor drug, and was applied in the treatment of rheumatic diseases after 1950s, and gradually became one of the basic therapeutic drugs. CTX exerts its cytotoxic, immunosuppressive and anti-inflammatory effects by inhibiting the proliferation of T and B lymphocytes, suppressing the response of lymphoblastoid cells to antigenic stimulation and lowering the serum immunoglobulin level.
The main adverse effects of CTX include bone marrow suppression, genitourinary toxicity, gastrointestinal reactions, infections, etc. CTX can also increase the incidence of tumors. The incidence of tumors can be increased.
3. azathioprine (AZA)
AZA is a cell cycle specific antimetabolic drug. AZA is mainly used in lupus nephritis and discoid lupus. In general, AZA is weaker than CTX and cannot be used as the drug of choice for lupus nephritis (LN).
However, its adverse effects are small and it can be treated with AZA in patients with chronic progressive lupus. Its main side effects are gastrointestinal reactions, bone marrow suppression, liver damage, tumors, hypersensitivity reactions, etc.
4.Leflunomide (LEF)
LEF is a new type of immunosuppressant approved by FAD in 1998 for the treatment of rheumatoid arthritis and started to be used in China in 1999. It is a small-molecule isoflutole compound that inhibits the activity of dihydroorotic acid dehydrogenase and tyrosine kinase to reduce the formation of pyrimidines, resulting in impaired DNA synthesis and thus inhibiting the proliferation and activation of lymphocytes and the resulting immune response.
The drug mainly inhibits the proliferation of lymphocytes and has little effect on leukocytes and platelets. At present, the reports on the use of leflunomide in the treatment of SLE at home and abroad are all summaries of pilot studies with small samples, which initially confirmed its effectiveness in reducing SLE activity and lupus nephritis and arthritis, but its exact efficacy and status in the treatment of SLE need to be further confirmed in multicenter large-scale clinical trials. Its major adverse effects include diarrhea, pruritus, transient transaminase elevation and leukocyte reduction, and hair loss. Animal tests have found that it also has teratogenic effects, so it is prohibited in patients who are pregnant or about to become pregnant.
5, cyclosporin A (cyclosporinA, CsA)
CsA is a hydrophobic cyclized peptide composed of 11 amino acids, which has a wide range of immunosuppressive effects. It is mainly used in the induction phase of immune response, i.e. antigen recognition and clonal proliferation phase, and has a high selective inhibitory effect on cellular immunity and humoral immunity to thymus-dependent antigens. In the treatment of SLE, CsA reduces antibody levels and proteinuria in patients and reduces hormone dosage.
CsA is usually administered in small doses and long courses. The prominent advantages are less myelosuppressive effects and adverse effects such as renal damage, gastrointestinal reactions, hypertension, liver damage and rubella. Small doses can be used to significantly reduce adverse reactions.
6.Morphomycin (mycophenolatemofetil, MMF)
MMF is a new generation of immunosuppressant, mainly through the inhibition of purine metabolic pathway of hypoxanthine nucleotide dehydrogenase (IMPDH) and selective inhibition of T and B lymphocyte proliferation, which in turn inhibits humoral and cellular immune responses, inhibits the synthesis of cell surface adhesion molecules, inhibits monocyte and lymphocyte infiltration, and limits inflammatory responses. Therefore, MMF has a strong regulatory effect on both humoral and cellular immunity.
MMF can control SLE disease activity, inhibit autoantibody production, reverse elevated blood creatinine, reduce urine protein and red blood cells, improve renal pathology, and reduce the dose of glucocorticoids. Adverse effects are relatively few compared to other immunosuppressive drugs, mainly gastrointestinal reactions, bone marrow suppression and infections. And this drug is more expensive, some people can not apply the drug due to economic problems.
7, tacrolimus (tacrolimus)
FK506 is a macrolide metabolite, its chemical structure is similar to macrolide antibiotics. fK506 mainly acts on lymphocytes, is an inhibitor of T-cell activation, it can inhibit the gene transcription of T-cell activation factors such as IL-2, IL-3, IL-4, granulocyte macrophage colony-stimulating factor, tumor necrosis factor and gamma-interferon, and can inhibit basophils in the skin or lung Granulocytes and mast cells release histamine.
Currently, FK506 is mainly used in the treatment of persistent rash in SLE. Some scholars have applied FK506 to treat SLE patients who have failed to respond to conventional drug therapy, and after 6 months, the vasculitis of the patients was significantly reduced and the SLE activity index decreased. The main adverse effects of FK506 include cardiovascular damage, neurological symptoms, renal and hematologic damage, electrolyte abnormalities, pulmonary interstitial fibrosis, and allergy, but the incidence of adverse effects is low and mostly reversible, and can be improved by reducing the dosage.
8.Chinese medicine extract preparation
It mainly includes Radix Rehmanniae and Paeoniae Generalis. The immunomodulatory effects of Radix et Rhizoma are mainly achieved by enhancing the function of macrophages and natural killer cells, inhibiting thymus, and suppressing the function of T lymphocytes and B cells. At present, its treatment of SLE is mostly adjuvant, and its main adverse effects include suppression of reproductive system, gastrointestinal reactions, bone marrow suppression and circulatory system damage. Because of the more serious effects of Leigongjiang, it should be applied with caution.
Bai Shao is a traditional Chinese medicine that has been used for thousands of years, but the extraction of its active ingredients to treat diseases alone, especially when rheumatic, has only been discovered in recent years. At present, there is only one domestic pharmaceutical company that produces Paeonia lactiflora total glucoside, with a concentration-dependent bidirectional regulatory mechanism on the proliferation of T cells and B cells.
At present, pafolin is mainly used in rheumatoid arthritis, and its application in SLE is at the stage of clinical trial. There is no clinical experience of treating SLE with pafolin alone, and it can only be regarded as an adjuvant drug for treating SLE. The main adverse reactions are gastrointestinal reactions, and there are no reports of bone marrow suppression, liver and kidney damage, etc.
Biological agents
The biological agents for the treatment of SLE can be categorized as follows: 1) activation and regulation of cytokines 2) inhibition of T-cell activation and induction of T-cell tolerance, blocking T-B cell interaction 3) inhibition of B-cell activation, thus inhibiting the production and deposition of pathogenic autoantibodies 4) inhibition of complement activation and deposition
1. Activation and regulation of cytokines
Anti-TNF-α agents
In SLE patients, the high level of TNF-α leads to the overproduction of IL-1, IL-6 and IL-8. Therefore, anti-TNF-α therapy may inhibit this process and thus control and improve the condition of SLE. However, anti-TNF-α agents are mainly used for the treatment of rheumatoid arthritis, and also have certain efficacy in ankylosing spondylitis and psoriasis, and there is a lack of relevant clinical data for the treatment of SLE.
Its main adverse reactions include local injection site irritation, infection, malignancy, and hematologic and neurocirculatory system damage. However, the common adverse reactions are mild, well tolerated and mostly self-limiting. Currently marketed TNF-α antagonist drugs include Infliximab (Remicade), Etanercept (Enbrel), Adalimumab (Humim) and Anakinra (Rineret).
Anti-IL-10 monoclonal antibodies
The immune complex stimulates the synthesis of IL-10 by peripheral blood mononuclear cells, which accelerates T-cell regulation and causes a defect in antibody synthesis by B cells regulated by T cells. Serum IL-10 levels are elevated in patients with active disease and are associated with disease activity.
In an open pre-study, six patients with active SLE were treated with intravenous infusion of murine IgG anti-IL-10 monoclonal antibody for 3 weeks, and at 6-month follow-up, patients had improved skin and joint symptoms, lower SLEDAI scores, and reduced prednisone doses. Therefore, anti-IL-10 antibody is expected to be used in refractory SLE. the antibody is still in clinical trials and no related drug is available yet.
Lymphostat-B
Lymphostat-B is a fully humanized monoclonal antibody against B lymphocyte-stimulating factor (Blys), which belongs to the tumor necrosis factor superfamily and plays an important role in the proliferation, differentiation, survival and antibody production of peripheral blood B lymphocytes, and its high level expression can induce various autoimmune diseases. Lymphostat-B has a high affinity for B cells and can bind to B cell surface stimulating factors to prevent B cells from developing and maturing after stimulation, thus inactivating B cells against natural immune stimulating agents and causing normal apoptosis of autoantibody-producing B lymphocytes.
2.Inhibit T-cell activation and induce T-cell tolerance and block T-B cell interaction
Anti-CD40 ligand monoclonal antibody (anti-CD40L monoclonal antibody)
CD40 is distributed on the surface of B cells, antigen-presenting cells (APCs) and endothelial/epithelial cells, and binds to CD40 ligand (CD40L) on the surface of activated T cells to cause B cell proliferation and differentiation. Anti-CD40L monoclonal antibody slows disease progression by reducing B-cell activation markers and inhibiting autoantibody production and deposition of renal immune complexes. Animal studies have shown that anti-CD40L treatment reduces the severity and prolongs the survival of lupus murine nephritis, significantly reduces anti-ds-DNA antibody levels, and improves renal function.
Toxic T-lymphocyte antigen fusion protein (CTLA-4Ig)
CTLA-4Ig is an antigen expressed on the surface of activated T cells and plays a second signaling role in T cell activation, blocking T cell activation, inhibiting cytokine production, as well as immune response to antigens and autoimmune response. Animal experiments have shown that CTLA-4Ig reduces the secretion and synthesis of IL-2, IL-4, and IL-10, and blocks the production of autoantibodies.
Anti-B7 monoclonal antibodies
The currently identified B7 molecules include B7-1 (CD80) and B7-2 (CD86), which are expressed on APC cells, provide stimulatory signals for T lymphocyte activation, inhibit B7-1 and B7-2 antigen binding, and can down-regulate T-B cell binding in a dose-dependent relationship from the surface.
Experiments showed that simultaneous application of B7-1 and B7-2 to lupus treated mice reduced the level of ds-DNA antibodies, inhibited the development of nephritis and prolonged survival time while application of either antibody alone had no effect, and anti-B7-2 antibody alone only inhibited the production of autoantibodies. The therapeutic effect of anti-B7 monoclonal antibodies is dose-dependent, with only larger doses inhibiting the T-cell costimulatory response. Currently, anti-B7 monoclonal antibodies are not under clinical observation.