Cyclophosphamide is the basic drug for the treatment of SLE. The effectiveness of CTX in the treatment of SLE has been proven in many clinical trials, but CTX is associated with a number of side effects, including infection, gonadal suppression and malignancy. However, CTX has many side effects, including infection, gonadal suppression and malignancy. This makes it difficult to achieve the optimal balance of efficacy and side effects in clinical applications. This has led to a variety of different treatment options and new drugs that may replace CTX.
1. Traditional CTX treatment regimens
Controlled studies for the treatment of SLE began in the 1960s. Initially, small sample sizes demonstrated that although oral CTX had a lower long-term relapse rate than oral prednisone, its efficacy was not significantly better than the latter.
The National Institutes of Health conducted a series of controlled clinical trials of CTX for SLE and concluded that intermittent cyclophosphamide shock therapy was significantly better than prednisone alone in controlling the progression of renal disease, inducing remission, and protecting renal function, thus establishing CTX as an important drug for the treatment of SLE.
Austin et al. found that there was no significant difference in the efficacy of IV-CTX compared with oral CTX, but the incidence of side effects such as hemorrhagic cystitis and tumor was significantly lower. Therefore, the standard treatment regimen is the NIH regimen, which is divided into a 6-month induction period and a 2-year maintenance period. The induction phase consists of 6 to 7 months of IV-CTX once/month, alone or in combination with intravenous methylprednisolone (oral glucocorticoids are often used as an alternative to 6 months of intravenous methylprednisolone). Maintenance treatment is IV-CTX once every 3 months for 2 years, or for 1 year after remission of the disease.
This regimen is not effective in all patients. Creatinine doubling was seen in 25% of patients in the NIH study. In addition, African-Americans respond less well to CTX than Caucasians.
2. Side effects of CTX treatment
Side effects immediately following IV-CTX treatment include nausea, vomiting, fatigue, and hair loss (usually thinning rather than baldness). Nausea and vomiting can be treated prophylactically with antiemetics, including ondansetron, dolasetron, and palonosetron. 5-HT3 antagonists combined with dexamethasone are more effective than treatment alone, and for severe nausea and vomiting the second-generation 5-HT3 antagonist palonosetron combined with dexamethasone is more effective than the first-generation 5-HT3 antagonists ondansetron and dolasetron combined with dexamethasone.
Prevention of severe delayed nausea and vomiting can be achieved with chlorpromazine, a 5-HT3 antagonist, and dexamethasone, all three of which have comparable efficacy. Weakness is the most common complaint in CTX-treated patients and is usually not directly related to anemia or dehydration. Other more serious side effects that do not occur immediately include myelosuppression, gonadal suppression, hemorrhagic bladder, and malignancy.
Bone marrow suppression due to CTX is often dose related? Granulocyte colony-stimulating factor is not recommended at this time, as it may lead to lupus activity. The dose of CTX should be reduced promptly in the presence of myelosuppression or renal damage, and if cytopenia (neutrophil count 2,000/μL or platelet count 100,000/μL occurs before the next IV-CTX) then the next treatment should wait until the blood cells return to normal. If the next IV-CTX is due but hematocrit reoccurs, the CTX dose should be reduced by 25% (except in cases where ancillary tests such as bone marrow aspiration prove that the hematocrit is due to SLE). If renal damage occurs, CTX dose should be reduced by 25% for blood creatinine of 250-500 μmol/L and by 50% for blood creatinine greater than 500 μmol/L.
SLE patients are susceptible to infections themselves. The use of CTX was previously thought to be more likely to induce and exacerbate infections. A recent study showed that the incidence of infection in SLE patients was 29%, and that pulmonary disease, glucocorticoid dose and antimalarial drug use were independently associated with SLE infection, but the use of immunosuppressive drugs? including CTX, azathioprine, cyclosporine, methotrexate, or mycophenolate, did not increase the risk of major infections such as Escherichia coli, Staphylococcus aureus, Mycobacterium tuberculosis, and Streptococcus pneumoniae, and this study concluded that patients who had been treated with antimalarials were less likely to develop infections.
Gonadal suppression is a very serious side effect of CTX. A multiple linear regression analysis in female patients showed that CTX toxicity to the gonads was linearly related to age, race, duration of disease, and SDI, with age being the determining factor and non-Caucasians more likely to have gonadal damage, and the younger the patient, the shorter the duration of disease, and the lower the basal SDI, the less toxic the damage was. In male patients? the vast majority of patients have unaffected spermatogenesis? Myotestosterone has a protective effect on fertility.
Hemorrhagic cystitis in SLE patients may be due both to the SLE disease itself and to the adverse effects of the immunosuppressive agents used, such as CTX, whose toxic effects on the urinary tract epithelium are mainly caused by its metabolite acrolein. Sodium mesylate can bind to acrolein, so the application of CTX along with sodium mesylate and heavy hydration may reduce the toxic effects of CTX on the bladder.
However, some hemorrhagic cystitis is associated with BK virus and cidofovir antiviral therapy is effective. There are case reports that hyperbaric oxygen is also effective in refractory hemorrhagic cystitis. However, is the development of tumors in SLE patients the result of CTX, SLE itself or a combination of both? Further in-depth research is needed.
3.Low dose, short treatment course
The low-dose regimen of CTX for SLE was IV-CTX 500 mg once every two weeks for 6 times, and oral azathioprine was given during the maintenance period. 90 patients with SLE were randomly divided into two groups by Houssiau et al. During the maintenance period, all patients were given AZA orally in combination with glucocorticoids. The renal remission rates were 71% and 54% in the low-dose and conventional regimens, respectively, with no statistically significant difference. After 73 months of follow-up, there was no significant increase in the incidence of end-stage renal disease or 1-fold increase in blood creatinine in the low-dose group compared with the conventional group, and the efficacy of the two regimens was comparable, with a better prognosis for patients who experienced a significant decrease in blood creatinine and urine protein within 6 months of treatment.
There was no difference in mortality, persistent blood creatinine doubling, or incidence of end-stage renal disease in the low-dose group compared after 10 years of follow-up. This may be related to the fact that the SLE patients in this trial were predominantly Caucasian. Most patients were still on oral glucocorticoid, immunosuppressant, and antihypertensive therapy at this time.
4.High-dose CTX
The regimen of high-dose CTX for SLE is IV-CTX 50 mg/kg for 4 d. The regimen of high-dose CTX for SLE is derived from the treatment of aplastic anemia.
Bone marrow examination of several AA patients who survived long-term after allogeneic bone marrow transplantation revealed that their bone marrow cells were of their own origin and not of graft origin, suggesting that it was not bone marrow transplantation that cured these AA patients, but pretreatment with high-dose CTX upfront. So the next clinical trial of high-dose CTX for AA patients was conducted and the results were successful.
High-dose CTX has since been used in the treatment of several autoimmune diseases, including SLE, by the mechanism that normal hematopoietic stem cells express high levels of aldehyde dehydrogenase? The mechanism is that normal hematopoietic stem cells express high levels of aldehyde dehydrogenase and survive against the effects of high-dose CTX, while those lymphocytes that are abnormally activated to produce an autoimmune response are completely removed by CTX.
As a result, the patient’s immune system is rebuilt and normal immune tolerance is regained. normal immune tolerance is regained. High-dose regimens may be considered for patients with refractory SLE who have failed to respond to conventional regimens.
The safety of high-dose IV-CTX therapy has been demonstrated in previous studies by Petri et al. The general side effects include temporary alopecia, nausea, short-term dysplasia and neutropenia with fever, which are still generally tolerated by patients (platelets below 10 × 109/L for those with bleeding tendency, platelet transfusion, and red blood cell suspension for those with erythrocyte pressure volume less than or equal to 25%.
Immunosuppressants, including cyclophosphamide, azathioprine, azathioprine benzoate (CB1348), methotrexate and cyclosporine, are effective in the treatment of SLE, with CTX being more effective. The long-term efficacy of CTX was observed by the National Institutes of Health, which found that.
(1) The efficacy of CTX shock was better than that of prednisone alone, AZP group and oral CTX group, etc. CTX shock + conventional dose prednisone therapy had significant changes on SLE renal function and survival rate.
(2) CTX shock had fewer side effects (including leukocyte drop, infection, hemorrhagic cystitis, gonadal suppression and concurrent tumors) than long-term oral CTX.
(3) Younger patients have better efficacy with CTX than those aged >30 years.
Currently, CTX shock + hormone is considered the best regimen for the treatment of active lupus erythematosus (LE) nephritis, and the main drug for the treatment of heavy lupus nephritis (LN) is CTX rather than for hormone, and treatment with hormone shock without cytotoxic analogs is a new concept of ineffective treatment for type IV LN. It can be seen that the importance of immunosuppressive drugs, especially CTX for the treatment of heavy SLE, but at present, the domestic hormones pay more attention to the immunosuppressive drugs, but the use of weak, because of the fear of side effects, in fact, such as CTX, the tolerance of the country is much higher than that of Westerners, Westerners with the incidence of hemorrhagic cystitis up to 10%-15%, while only 1% of the country, and for example, for those with reduced whole blood, because the patient’s bone marrow hematopoietic function is generally normal. As long as the patient’s bone marrow hematopoiesis is generally normal, it can still be used under close observation. Cyclosporine is effective for some hormone-dependent or drug-resistant SLE. It can provide early relief of symptoms and proteinuria for 3-4 months, and the dose can be gradually reduced (initial dose 2.5mg/kg/d), and CTX shock can be given half a month before stopping the drug to reduce relapse after stopping. However, because of its high toxicity and high price, it is generally not used as the first choice for SLE treatment, but it is more suitable for those who cannot be treated with CTX or cannot tolerate it.