In recent years, immunosuppressive therapies have been widely used in clinical practice and have achieved encouraging therapeutic results in some immune hematological diseases. However, immunosuppressive therapy can also destroy the normal immune response, and these agents are mostly cytotoxic, so we must pay attention to the toxic side effects brought about by immunosuppressive therapy.
1, anti-lymphocyte globulin (ALG) / anti-thymocyte globulin (ATG) toxic side effects
Since Mathe et al. first applied ALG/ATG for the treatment of heavy aplastic anemia (SAA). It has been more than 20 years since Mathe et al. Nowadays, ALG/ATG has become the main treatment for SAA patients who are not suitable for allogeneic bone marrow transplantation (Allo-BMT) treatment.
1.1. Allergic-like reactions are more common and occur during the course of treatment. The main appearances are fever and polymorphic rash.
1.2, serum sickness reaction mostly occurs within one to two weeks after treatment, mainly manifesting chills and high fever, skin erythema, urticaria-like rash, joint pain, generally after treatment with adrenocorticosteroids (also known as glucocorticoids), the symptoms disappear. Not life-threatening.
1.3, bleeding tendency aggravated due to platelet depletion resulting in a serious reduction in platelets, with hematuria and intracranial hemorrhage is common, alleviated by hemostatic drugs and platelet transfusion.
1.4, severe hypoalbuminism is prone to fungal, viral and mycobacterial infections, and animal experiments have shown that ALG can activate potential viruses. In recent years, due to the strengthening of isolation measures. Hematopoietic cell growth factor (G-CSF) and broad-spectrum effective antibiotic applications can reduce this adverse reaction.
2, the toxic side effects of cyclosporine A (CsA).
CsA is a more specific immunosuppressant, since Firday et al. (1984) first applied CsA to successfully treat SAA. It is also used in autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), myelodysplastic syndrome (MDS), cyclic neutropenia, acquired hemophilia, and prevention of rejection in organ transplantation (including Allo-BMT), etc. CsA CsA has the advantages of not suppressing bone marrow, generally not easily inducing infection, and being safe for outpatient and primary use.
2.1, nephrotoxicity is more common, with increasing dose, glomerular filtration rate and clearance rate decreased. Blood creatinine, blood urea nitrogen increase, long-term application of CsA. renal function can gradually decline, and even slow I renal failure. To reduce nephrotoxicity. The initial dose should be as small as 3-5 mg/(kg?d), then gradually increased and maintained in small doses, and the CsA blood concentration and blood creatinine value should be monitored during administration. The blood concentration of 200-400ug/mL is preferred, and the blood creatinine should be monitored as the base before the drug is administered, and controlled below 1.5 times the base during the drug administration, otherwise the drug should be reduced or stopped.
2.2, hepatotoxicity Often occurs in the early stage of drug use and is dose-related. Performance cholestasis. Hyperbilirubinemia, elevated transaminases, lactate dehydrogenase, alkaline phosphatase. Hypoproteinemia. Gallstones, pancreatitis and intestinal perforation in some patients. Most patients with hepatotoxicity improve after dose reduction or discontinuation, and are self-limiting. Liver function should be checked regularly during the drug administration.
2, 3, thrombosis CsA can promote ADP-induced platelet aggregation. It increases the release of thromboxane A2 (TXA2) and thrombin production, and increases factor VIII and thrombin activity. Reduces prostaglandin production and induces thrombosis.
2.4, induce infection transplant patients long-term application of CsA. Especially in combination with glucocorticoids cause excessive spasm suppression. It is easy to induce bacterial, fungal, viral, pneumocystis infection and tuberculous pericarditis. The drug should be suspended in case of serious infection.
2.5, other tremors, convulsions, paralysis of hands and feet, gastrointestinal reactions, gingival hyperplasia, hirsutism, skin pigmentation, male breast enlargement, hypertension, hyperglycemia and high triglycerides.
The above CsA side effects are related to the dose and blood concentration, so reduce the dose appropriately. Monitor blood levels regularly so that only immunosuppressive effects are caused without serious adverse effects. The combination with ketoconazole, fluconazole, barbiturate, and youmitidine can increase the blood concentration of CsA; meperidine, erythromycin, and verapamil can aggravate the toxic effects of CsA; chlorotonin and amphotericin B antibiotics can aggravate the nephrotoxicity of CsA.
3, the toxic side effects of cyclophosphamide {CTX).
CTX is one of the strongest drugs in the current application of various immunosuppressive agents, but also the alkylating agent as the most used in immunosuppression. It is currently used directly in ITP, AI} , allergic purulent nephritis and SPA. High-dose CTX (HD-CTX) is often used in the pretreatment of Allo-BMT, and in recent years it has been reported that a few patients have recovered their own hematopoietic function after pretreatment with HD-CTX without receiving AIlo-BMT. It is suggested that HD-CTX alone may be effective in the treatment of SAA; Tisdely et al. (2000) found that HD-CTX alone or HD-CTX in combination with ALG/ATG and CsA had similar efficacy in the treatment of SAA.
3.1 , myelosuppression appeared with 9-14 d of the drug. It causes leukocyte, erythrocyte and platelet reduction, often related to the dose and duration of treatment, and can be restored after discontinuation of the drug.
3.2, gastrointestinal reactions nausea, vomiting, anorexia and diarrhea, etc., HD-CTX intravenous infusion 3-4 h can appear, occasionally can cause ulceration and bleeding of the gastrointestinal mucosa.
3.3, urological toxicity of medium and high doses of CTX treatment, due to the active metabolite of CTX acrolein on the bladder mucosa toxicity leads to hemorrhagic cystitis, urinary frequency, pain and blood in the urine, the severity of the dose-related, can drink a lot of water or intravenous infusion of large amounts of fluid (4 000 ~ 5 000 ml / 24 h) to dilute the concentration of active metabolites in the bladder and reduce the symptoms. It can also be used in combination with sodium lurex sulfonate (mesna) to counteract urinary toxicity. Occasionally, it can cause delayed cystic fibrosis.
3.4, reproductive system toxicity long-term application of CTX can inhibit gonadal function, women appear menstrual irregularities, amenorrhea, ovarian fibrosis, infertility; men appear testicular atrophy, sperm reduction, etc.
4.Toxic side effects of methotrexate (MTX).
MTX is an anti-metabolic drug. It has a strong immunosuppressive effect. In recent years, MTX has been used in combination with CsA to treat SAA, and the combination of the two drugs can effectively reduce the acute and chronic graft-versus-host disease (GVHD) of Allo-BMT in SAA. It can also be used in other immune hematologic diseases.
4.1 , gastrointestinal mucosal damage such as ulcers and pain in the lips, gums, and oral mucosa. Often occur within a few days to a month after the use of the drug, if you continue to use the drug can occur extensive ulceration of the gastrointestinal tract, causing vomiting, abdominal pain, diarrhea. In severe cases, the gastrointestinal tract bleeds. Even death.
4.2, myelosuppression Leukocytes and platelets are reduced, and the degree of myelosuppression is related to the dose and duration of the drug can also cause red lineage megaloblastic changes.
4.3, liver vomiting toxicity mainly manifested in transaminases, alkaline phosphatase and other elevated. Often occur within 3 months of drug use. Occasionally, liver fibrosis is seen. Therefore, patients with chronic liver disease should use caution or reduce the dosage, and closely monitor liver function.
4.4.Other drugs may occasionally cause alopecia, dermatitis, sun allergy, hyperpigmentation, homogeneous pneumonia; it may cause malformation and stillbirth in the first 3 months of pregnancy; MTX also has toxic effects on the kidney, but it is generally mild.
4.5, rain sulphuric acid, salicylic acid, and botrytisine can reduce the renal tubular excretion of MTX, and the toxicity of MTX can be increased if used in combination with the above drugs. Large doses of MTX (HD-MTX) need to be rescued by infusion of formyltetrahydrofolate. To overcome the toxic effects caused by MTX-induced blockade of folic acid metabolism.
5, adrenocorticotropic hormone f also known as glucocorticoids) toxic side effects.
Glucocorticoids have strong immunosuppressive effects and are commonly used in immune hematological diseases such as SLE, ITP, Even’s syndrome and SAA.
5.1, toxic side effects and complications of long-term application of corticosteroids (1) He Xing syndrome: centripetal obesity, full-moon face, acne, hirsutism, hypokalemia, edema, hypertension, hyperlipidemia, hyperglycemia; (2) induced and aggravated infections: fungal, bacterial, viral infections and nodule proliferation, related to dose and course of treatment; (3) mental abnormalities: rare, easily occurring in very large doses; (4) myopathy: easily occurring in (5) bone and joint complications: reduced bone density, osteoporosis, aseptic osteonecrosis, etc. Oral prednisolone 15 mg / d ≥ 6 months. The risk of vertebral fracture increases 3 times; (6) gastrointestinal reactions: epigastric pain, fishy swelling. Gastric and duodenal ulcers, bleeding or perforation. Pancreatitis, etc.: (7) early pregnancy women are prone to fetal malformations, Kamischke et al. (1998) found that long-term oral prednisone in men suffering from cyanosis. Free testosterone levels are reduced.
5.2, the toxic side effects and complications of short-course large-volume glucocorticoid shock therapy large-volume hydrocortisone pick-up, dexamethasone bolus, methylprednisolone (MP) intravenous shock therapy, prone to facial flushing, dizziness, headache, optic papilledema, induced infection, hypertension, hyperlipidemia, gastrointestinal bleeding, cardiac arrhythmia, joint pain, ischemic osteonecrosis, mental abnormalities, occasional anaphylactic shock and other high-dose MP ( HI3MP) applications, the domestic literature to severe infections are common. Foreign literature reports more for ischemic osteonecrosis.
6, primaquine MMF, also known as the poisonous side effects of mescaline
MMF is an anti-metabolic new oral immunosuppressant. It replaces azathioprine. Combined with CsA and glucocorticoids. It is used for the treatment and prevention of acute and chronic rejection of organ transplantation (including AI1 o-BMT).
6.1, Gastrointestinal reactions Diarrhea (at high doses). Nausea, vomiting and gastroenteritis, peptic ulcer, bleeding and perforation in a few patients.
6.2, hematological toxicity is mainly leukopenia and MMF dose related. However, neutrophil deficiency (absolute neutrophil count <0.5×109/L), about 2%.
6.3 , opportunistic infections are prone to viral infections, especially cytomegalovirus (MCV) and herpes zoster virus infections are common, treponema thrive and pneumocystis infections are rare, lethal infections or sepsis less than 2%.
7, immunosuppressive therapy several common toxicities and complications.
7.1, cytotoxic side effects of most immunosuppressants are cytotoxic substances. Such as azathioprine, 6-Lucine, CTX, the degree of cytotoxicity is dose-related, and its target tissue varies with different agents. However, cells that grow and proliferate rapidly are most affected. Such as bone marrow, gastrointestinal tract, skin, etc.. Next is the liver and kidney toxicity. Therefore, the original liver and kidney disease should be used with caution or reduce the dose.
7.2, induced infection immunosuppressive therapy not only inhibits abnormal immune response, but also weakens the normal immune function of the body, so that it can not destroy pathogens in a timely manner and cause infection, such as the occurrence of viral infections.
7.3, impaired reproductive function and induced fetal malformation spermatocytes are fast proliferating cells, vulnerable to cytotoxic damage. Long-term application of alkylating agents such as vincristine damages the germinal epithelium. Therefore, pregnant women, especially in the first three months of pregnancy, should avoid treatment with immunosuppressive agents, and paternal immunosuppressive treatment can also cause fetal malformations. Azathioprine and 6-mercaptopurine have a low probability of causing fetal malformations. If immunosuppressive therapy is necessary during pregnancy, these drugs may be used.
7.4, long-term complications of immunosuppressive drugs are likely to induce malignant tumors or hematologic clonal diseases: the pathogenesis may be: (1) immunosuppressive drugs damage the body’s immune system, which is unable to recognize cells mutated by biological (viral), chemical and physical factors, so that they develop into tumors; (2) immunosuppressive drugs. Especially alkylating agents, which act on nucleic acids. It changes the nucleic acid and produces malignant cell lines: the incidence of malignant tumor is significantly higher than normal population within 1 to 3 years of drug use, and the longer the drug use, the greater the risk of tumor; (3) animal experiments have proved that ALG can activate potential viruses, and those treated with ALG can cause oncogenic viruses to proliferate and induce carcinomas.
ALG/ATG treatment for SAA has a high incidence of distant clonal disease, and in a comprehensive analysis (1995), 451 patients with SAA were treated with ALG/ATG. The incidence of clonal disease was 15 5% [including paroxysmal sleep hemoglobinuria (PNH) 8 9%, MDS 4.9% acute myeloid leukemia (AML) 1.6%, T-cell lymphoma 0.2%]. In a recent report (1998), 209 cases of SAA were treated with ALG/ATG with a median follow-up of 5 a. Clonal disease occurred in 31 cases (19 cases of PNH, 11 cases of MDS, and 11 cases of MDS). Five cases progressed to AML and one case was directly converted to AML). The median time to PNH and MDS was 3 a and 4 a, respectively, and the time to AML was longer. However, the incidence of clonal disease in domestic ALG/ATG for SAA is not high. Kaposi’s sarcoma accounts for 42%-46% of skin tumors. The risk of clonal disease (PNH, MDS, AML) is not increased in aplastic anemia (including SAA patients) treated with CsA alone.Ohara et al. (1997) conducted a retrospective analysis of 167 pediatric SAA cases. showed that the risk of developing clonal disease (MDs/AML) was highly correlated with concomitant use of sA with recombinant G-CSF (rhuG-CSF): l1/50 patients with SAA treated with CsA in combination with G-CSF developed MDS/AML , whereas treatment with CsA or rhu G-CSF alone (total None of the patients treated with CsA or rhu G-CSF alone (6l patients) or with Al1O-BMT (48 patients) developed MDS/AML. CTX is a potential carcinogenic agent, especially in bladder cancer, skin cancer, AML, and non-Hodgkin’s lymphoma (NHL), and is often associated with dose and duration of treatment. The incidence of malignant tumors is low with MMF, and the chance of lymphoproliferative disease or lymphoma is about 1%.
In summary, all types of immunosuppressive agents have varying degrees of toxicity and side effects, and some have significant toxic effects. In the selection of immunosuppressive therapy must weigh the advantages and disadvantages of careful selection of indications, and adjust the dose and duration of treatment at any time. In order to minimize the occurrence of drug side effects and complications.