Are the side effects of cyclophosphamide preventable and reversible?

How to make good use of the sharp weapon - CTX in the treatment of rheumatism? Cyclophosphamide (CTX) is a broad-spectrum anti-tumor drug of alkylating agents.
It is the strongest known immunosuppressive agent of alkylating agents.
, after being absorbed by the body, it is metabolized in the liver to produce active metabolites and play a role
.

CTX kills immune cells by damaging DNA, and has immunosuppressive, immunomodulatory, and anti-inflammatory effects.
Because of its definite curative effect, low cost, and low cost, CTX is also widely used as an immunosuppressant in the treatment of non-tumor rheumatic immune diseases
.

This article aims to clarify the canonical use of CTX
.

01Which rheumatic immune diseases can be treated with CTX? CTX can be used in almost all rheumatic immune diseases caused by autoimmune disorders, but it is more used for relatively serious diseases with autoimmune nervous system damage, lung damage, kidney damage and other visceral system damage
.

Systemic lupus erythematosus (SLE) with poor response to glucocorticoids or lupus crisis, rapidly progressive nephritis, rapidly developing renal insufficiency, massive pericardial effusion, diffuse hemorrhagic alveolitis and acute severe interstitial pulmonary disease, severe Thrombocytopenic purpura, severe myocardial damage, and SLE encephalopathy, especially grand mal seizures, subarachnoid hemorrhage, and coma
.

ANCA-related vasculitis (mainly including granulomatosis with polyangiitis, microscopic polyangiitis, and allergic granulomatosis with vasculitis), due to the rapid progression of the disease and many organs involved, hormones and CTX should be combined as soon as possible
.

Polyarteritis nodosa, Takayasu arteritis, Behcet's disease and other organs involving the nervous system, large blood vessels, digestive system, eyes, lungs, kidneys, epididymis and other organs also often need to be combined with CTX
.

Other connective tissue diseases such as rheumatoid arthritis leading to interstitial pneumonia, polymyositis, dermatomyositis leading to pleurisy due to lung disease, pleural effusion, pulmonary hypertension, pulmonary fibrosis and advanced restrictive lung disease; or Polymyositis has been treated with high-dose hormones for 2 months, and the clinical symptoms, serum CK and 24h urinary creatine excretion have not improved; scleroderma involving the respiratory system causes extensive pulmonary interstitial fibrosis, abnormal lung function, or Involving the kidneys; Sjögren's syndrome combined with nervous system, kidney damage, interstitial pneumonia, thyroid, lymph node, liver damage, low blood cells (especially those with low platelets), myositis and rapid disease progression, etc.
CTX is also effective.
Especially in more severe cases of systemic vasculitis
.

What is the usage and dosage of 02CTX? At present, the treatment of rheumatic immune diseases with CTX can be roughly classified into the following three treatment plans: high-dose pulse therapy: the usage is 0.
5-1g/m2 body surface area, or each dose is 10-16mg/kg, add 0.
9% sodium chloride solution to 250ml , intravenous infusion slowly, the time should be more than 1h
.

Keep leukocytes at 1x109～3x109/L, except for critical condition once every 2 weeks, usually pulse once every 4 weeks, after 6 times of pulse therapy, change to once every 3 months, and stop after 1 year after the condition is stable Shock, the cumulative amount of 6 ~ 8g after the withdrawal
.

Pulse therapy is more effective than oral therapy
.

The oral dose of CTX is 2 mg/kg per day, taken orally in two divided doses
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After the condition is stable and remission, the drug should be continued for more than one year, and the dose should be gradually reduced until the treatment is terminated
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Re-treatment is still effective if the drug is discontinued and relapses
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Low-dose pulse therapy: CTX 400mg, intravenous injection, once every 2 weeks for 3 months, then changed to once every 4 weeks for 6 months, this method and the above high-dose pulse therapy index scores have improved significantly , there was no significant difference in efficacy, but the low-dose shock group had better safety, and the incidence of adverse reactions was significantly lower than the high-dose shock group
.

Continuous medium-dose administration: 400-600 mg per week, divided into 2-3 intravenous injections, or 100-200 mg orally every day, the total effective amount is 4-6 g, and if it reaches 12 g, the effective rate is about 60%
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A second approach is recommended, CTX 400 mg intravenously every 2 weeks for 3 months, then every 4 weeks for 6 months
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It usually takes 3 to 6 months of continuous treatment to evaluate the efficacy.
After induction of remission, the dosage of treatment can be reduced or the treatment interval can be extended.
The course of treatment generally takes 2 to 3 years, or it can be replaced with other alternative drugs to maintain and consolidate.
Adjust the treatment plan in time
.

03CTX9 toxic side effects, how to prevent? Our treatment for rheumatic immune diseases is to use the effect of CTX, which can cause damage to the immune system at large doses, but it will not be "disturbed" by CTX.
Relatively speaking, the dose selected by our rheumatology department for the treatment of immune diseases is far Much smaller than the therapeutic dose of oncology and hematology departments, let's take a look at the possible side effects of CTX: digestive system CTX common digestive system side effects include gastrointestinal toxicity such as nausea, vomiting and diarrhea, and intestinal motility disorders can also occur And pseudomembranous colitis, the incidence is about 60% to 90%, but the symptoms are mostly not serious, and disappear 2-3 days after stopping the drug
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If the patient is more sensitive, preventive drugs such as metoclopramide and ondansetron can be used
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CTX can also cause liver damage, hepatocyte necrosis, hyperemia in the center of hepatic lobules, accompanied by elevated aminotransferase.
The liver damage is generally mild and can be recovered after stopping the drug.
If the liver damage is serious, the treatment plan should be adjusted in time and CTX should be discontinued
.

Urinary system hemorrhagic cystitis may be an irritant reaction caused by acrolein, a metabolite of CTX.
Patients should be encouraged to drink more water during application, and the infusion volume can be increased.
When the dose is applied, it should be hydration and diuretic, and the uroprotectant mesna should be given at the same time
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Mesna reduces the concentration of acrolein and other toxic metabolites in the bladder, and patients with neurocystitis can undergo catheterization or bladder lavage during CTX therapy
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CTX can also cause renal hemorrhage, bladder fibrosis, hemorrhagic cystitis, hydronephrosis, vesicourethral reflux, and even secondary renal cancer, but CTX has relatively low nephrotoxicity compared with other alkylating anticancer drugs
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The acute effect of CTX on hematopoietic stem cells in the hematopoietic system is relatively small.
Generally speaking, the lymphocyte count reaches the minimum 7 to 10 days after treatment, and the granulocyte count reaches the lowest point after 10 to 14 days, but it can quickly return to normal after 21 to 28 days.

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If the recovery of bone marrow hematopoietic function is delayed in patients after CTX treatment, the medication interval needs to be extended
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Immune-related cytopenias can be relieved with appropriate doses of CTX, but symptoms can be exacerbated by concomitant administration of azathioprine
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Repeated CTX shocks need to extend the interval time appropriately, otherwise it will lead to cell reduction
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Thrombocytopenia is rare, and if thrombocytopenia occurs, myelodysplastic syndrome should be alerted
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During the course of treatment, the blood picture should be checked regularly, and the treatment dose and interval time should be adjusted in time
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Immune system CTX is the strongest known alkylating agent immunosuppressant, with strong and long-lasting effects on both T cells and B cells
.

In the process of using CTX, the infection rate of opportunistic infections such as shingles and pneumocystis carinii is increased, especially when combined with other immune preparations such as hormones, serious infections may occur.
Therefore, patients should do Take good personal protection, inject relevant vaccines in advance if necessary, and make timely diagnosis and treatment in the early stage of infection
.

Reproductive system CTX has obvious toxicity to the reproductive system.
For men, it can cause sperm deficiency in men and reduce the function of Leydig cells, which is usually irreversible, and its inhibition of male hormone levels is relatively rare
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CTX is toxic to the granulosa cell layer of female follicles, reduces blood estradiol and progesterone levels, inhibits oocyte maturation, reduces the number of follicles, and ultimately leads to ovarian failure
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Especially women over the age of 40
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The older the patients who received CTX, the more toxic it was to the ovaries
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Gonadotropin-releasing hormone agonists have been studied to protect the ovary against the destruction of CTX, and have a significant inhibitory effect on premature ovarian failure in young women with lupus
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Although gonadotropin-releasing hormone agonist therapy has side effects (eg, bone loss and menopause), it is beneficial for estrogen control and should be considered clinically
.

The teratogenic system CTX has obvious teratogenic and mutagenic effects on both human and animals, especially in the cleavage phase of the pregnancy embryo and the development of organs, resulting in embryo absorption, developmental delay, and deformities such as extremity abnormalities, cleft palate, etc.
, but the toxicity to pregnancy may not be life-long, and it has also been reported that pregnant women with critically ill SLE can produce normal babies after receiving CTX treatment, but the number of such case reports is small
.

Cardiopulmonary toxicity Conventional doses of CTX do not produce cardiotoxicity, but at high doses can produce myocardial necrosis and occasionally pulmonary toxicity, resulting in interstitial pneumonia and/or fibrosis of type II pneumocytes, interstitial infiltration and Interstitial fibrosis
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Induced malignant tumors in patients with rheumatism, especially in patients with rheumatoid arthritis and Wegener's granulomatosis, may develop secondary malignant tumors after receiving CTX therapy.
Reduce the incidence of tumors, while strengthening tumor surveillance for timely detection
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Skin and mucous membrane CTX affects the division of hair follicle cells, and has obvious toxicity to hair and hair follicles, causing hair loss.
The degree of hair loss is related to the dose of CTX, and new hair can gradually grow after stopping the drug
.

CTX inhibits the rapid proliferation of oral mucosa, causing stomatitis and oral ulcers, but it is usually mild and can be relieved on its own
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In the treatment of rheumatic immune diseases, CTX has the advantages of high quality and low price, accurate curative effect, and convenient use
.

In general, as long as the patient's condition is comprehensively assessed, immunodeficiency diseases are excluded, and other infectious diseases are screened, the drug is relatively safe to use in principle
.

Reference [1] Ntali S , Bertsias G , Boumpas DT .
Cyclophosphamide and Lupus Nephritis: When, How, For How Long?[J].
clinical reviews in allergy & immunology, 2011, 40(3):181-191.
[ 2] Zuo Zhengcai, Wang Guihong, Wu Di, et al.
Evaluation of the efficacy and side effects of cyclophosphamide in the treatment of lupus nephritis[J].
Anhui Medicine, 2011(07):887-889.
[3]Paul A.
Monach, Lindsay M .
Arnold, Peter A.
Merkel.
Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: A data-driven review[J].
Arthritis & Rheumatism, 2010.
[4] Zhang Yongwen, Zhang Xiaoli, Shen Siyu, et al.
Discussion on the standardization of cyclophosphamide pulse therapy for rheumatic immune diseases[J].
Anhui Medicine, 2014, 000(007):1205-1208.