Glucocorticoids (hereinafter referred to as hormones) are widely used in China, but there are phenomena of unreasonable clinical use. Improper use includes both overuse, i.e., using hormones when they should not be used, and underuse, i.e., not using hormones when they should be used, or using small doses of hormones when large doses should be used. Both overuse and underuse can cause damage to patients’ health.
The prevalence of systemic lupus erythematosus (SLE) in China is high, with a large sample of one-time surveys (over 30,000 people) showing a prevalence of 70/100,000 people and up to 113/100,000 among women.
There are differences in the use of hormones for SLE by different doctors, so there is an urgent need to standardize the application of hormones in SLE and try to develop simple, standardized and reasonable principles of hormone application according to different conditions so that more patients can benefit.
1.Basic principles of hormone therapy for SLE
The basic principles of hormone therapy for SLE include
For the induction of remission and long-term maintenance treatment, the starting dose should be adequate, and then the dose should be slowly reduced for long-term maintenance;
Evaluate the severity and activity of SLE and develop an individualized treatment plan;
Evaluate whether there are relative contraindications to hormone use, and for patients with relative contraindications, strictly assess the need for hormone use according to the condition;
Prednisolone or methylprednisolone is recommended for patients with hepatic impairment;
Observe the efficacy and assess the organ function during treatment;
Monitor possible complications during hormone use and adjust the treatment plan in a timely manner.
2. Hormone usage and dosage
The usage of hormone includes systemic application (intravenous injection and oral administration) and local application (local skin application, joint cavity injection, intraocular injection, etc.). Depending on the needs of the disease, hormones can be given in the morning, every other day or in daily doses. Hormones can be divided into 4 dose ranges.
Small dose: Prednisone ≤7,5mg/d (methylprednisolone ≤6mg/d);
Medium dose: Prednisone 7,5-30mg/d (methylprednisolone 6-24mg/d);
High dose: Prednisone 30-100mg/d (methylprednisolone >24-80mg/d);
Shock therapy: methylprednisolone 500-1000mg/d intravenously for 3 days.
The higher the dose of hormone, the more effective it is, but also the greater the side effects. Hormones are like a double-edged sword, and how to minimize the side effects of hormones while pursuing the efficacy is one of the most important concerns of clinicians.
3. Application of hormones in SLE treatment
(1) Definition of SLE severity and lupus crisis
Mild SLE: refers to SLE with clear diagnosis and no involvement of important target organs (including kidney, blood system, respiratory system, cardiovascular system, digestive system and central nervous system).
Moderate and heavy SLE: refers to the involvement of important organs and affects their functions.
Renal involvement: glomerulonephritis, acute glomerulonephritis, nephrotic syndrome;
Hematologic involvement: hemolytic anemia, granulocytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura;
Neurological involvement: convulsions, impaired consciousness, coma, stroke, transverse myelitis, mononeuritis or polyneuritis, psychiatric symptoms, demyelination syndrome;
Digestive system involvement: intestinal obstruction, mesenteric vasculitis, acute pancreatitis;
Respiratory involvement: alveolar hemorrhage, pulmonary hypertension, pneumonia, pulmonary interstitial fibrosis, etc;
Cardiovascular system involvement: pericardial tamponade, myocarditis, etc;
Other: skin vasculitis, severe skin damage, myositis, etc.
Definition of lupus crisis: life-threatening acute and severe SLE is called lupus crisis, and the main clinical manifestations include
Acute glomerulonephritis ;
Severe central nervous system damage;
Severe hemolytic anemia;
Severe thrombocytopenic purpura;
Severe granulocyte deficiency;
Severe heart damage;
Severe lupus pneumonia or alveolar hemorrhage;
Severe lupus hepatitis;
Severe vasculitis, etc.
(2) Treatment of mild SLE
For the treatment of mild SLE, hormone is not the first choice of treatment drug.
Firstly, non-steroidal anti-inflammatory drugs and antimalarial drugs are applied, and hormones can be considered after the treatment is ineffective.
Short-term topical application of hormones can be used for the treatment of skin mucosal lesions, but the use of strong hormonal topical drugs for the face should be avoided as much as possible, and even if used, it should not exceed 1 week.
Hormones (prednisone ≤10mg/d, or methylprednisolone ≤8mg/d) help control the disease and usually have fewer side effects.
(3) Treatment of moderately active SLE
The treatment of moderately active SLE is generally divided into 2 phases, namely induction of remission and maintenance therapy. Hormone combined with immunosuppressive therapy is recommended.
Induction remission therapy: the hormone dosage is usually 0,5-1 mg?kg-1?d-1 of prednisone (0,4-0,8 mg?kg-1 of methylprednisolone).
mg?kg-1?d-1) in the morning, or in divided doses if acute symptoms such as persistent high fever need to be controlled. Concomitant immunosuppressive drugs are usually required.
Maintenance therapy: After 4-8 weeks of induction remission therapy, the hormone is slowly reduced by 10% of the original dose every 1-2 weeks to prednisone 0,5 mg kg-1 d-1 (methylprednisolone 0,4 mg kg-1 d-1), and then the rate of reduction is slowed down according to the condition.
If the condition allows, maintain the treatment dose: prednisone <10mg/d (methylprednisolone <8mg/d).
In the process of drug reduction, if the disease is unstable, the original dose can be maintained temporarily or increased as appropriate or combined with immunosuppressive therapy.
(4) Treatment of severe SLE
Treatment of severe SLE especially emphasizes individualized regimens and requires the combination of other immunosuppressive drugs.
Treatment of severe SLE is also divided into 2 phases, namely induction of remission and maintenance therapy.
Induction of remission: the hormone dosage is usually prednisone 1
mg?kg-1?d-1 standard dose (methylprednisolone 0,8 mg?kg-1?d-1) in the morning at dawn. Type III, IV, V+III/V+IV lupus nephritis can be considered with intravenous methylprednisolone 500-1000 mg for 3-d shock treatment.
Maintenance treatment: 2 weeks after the disease is stabilized or within 8 weeks of treatment, the hormone is slowly reduced at a rate of 10% of the original dose every 1-2 weeks to prednisone 0,5 mg?kg-1?d-1 (methylprednisolone 0,4 mg?kg-1?d-1), and the reduction rate is slowed down according to the disease.
In the process of drug reduction, if the disease is unstable, the original dose may be temporarily maintained, or the dose may be increased or combined with immunosuppressive therapy as appropriate.
Immunosuppressants such as cyclophosphamide, azathioprine, methotrexate, mycophenolate, cyclosporine, tacrolimus, etc. can be used. Cyclophosphamide is one of the first-line drugs in the treatment of severe SLE, especially in patients with severe lupus nephritis and vasculitis.
The most classical regimens for the induction of remission in lupus nephritis are the American College of Rheumatology (ACR) regimen and the European League Against Rheumatism (EULAR) regimen.
ACR regimen: intravenous cyclophosphamide (500-1000 mg/m2 once a month for 6 times, followed by repeating every 3 months for 2 years) combined with methylprednisolone shock therapy (500-1000 mg/d for 3 d), followed by sequential prednisone therapy (0, 5-1, 0 mg?kg-1?d-1, tapering). This regimen evolved from the National Institutes of Health (NIH) regimen.
EULAR regimen: intravenous cyclophosphamide (500 mg once every 2 weeks for 6 times) combined with methylprednisolone shock therapy (0,5-0,75 mg/d for 3 d), followed by prednisone 0,5 mg?kg-1?d-1, tapering after 4 weeks, and reducing to prednisone ≤10 mg/d for maintenance in 4-6 months.
(5) Treatment of lupus crisis
For lupus crisis, high-dose methylprednisolone shock therapy is usually required to help patients overcome the crisis.
High-dose methylprednisolone shock therapy is 500-1000mg of methylprednisolone, added with 100-250ml of 5% glucose, slowly infused intravenously for 1-2h, once a day, and applied continuously for 3 d as a course of treatment. If lupus crisis is still not controlled, shock treatment can be repeated after 5-30 d of shock treatment according to the condition.
After the shock treatment, oral prednisone 0,5-1mg?kg-1?d-1 (methylprednisolone 0,4-0,8mg?kg-1?d-1) should be administered for about 4-8 weeks.
After the disease is controlled, the hormone should be gradually reduced until the minimum dose for disease control is reached, in order to avoid the serious adverse reactions caused by the long-term use of large amounts of hormones.
In severe neuropsychiatric lupus, including transverse myelitis, intrathecal dexamethasone 10 mg/methotrexate 10 mg can be administered once a week for 3-5 times, if central infection is excluded.
Methylprednisolone shock therapy can only resolve the symptoms in the acute phase, and subsequent treatment must continue with hormone application and in conjunction with other immunosuppressive agents. The side effects of hormone should be closely observed before, during and after high-dose hormone shock therapy, including the occurrence of complications such as infection, gastrointestinal bleeding, diabetes mellitus and femoral head necrosis.
(6) Treatment of pregnant and lactating patients
Contraindications to pregnancy in patients with SLE.
Severe relapse of SLE within the past 6 months, such as active lupus nephritis, etc;
Severe pre-eclampsia or HELLP syndrome despite treatment;
Severe pulmonary hypertension (expected pulmonary artery systolic pressure > 50 mmHg or symptomatic);
Severe restrictive lung disease (exertional spirometry <1l);< p="">
Chronic renal failure (blood creatinine >247, 8umol/L).
Application of hormones in patients before and during pregnancy;
No significant organ damage before pregnancy, stable condition for 1 year or more, cytotoxic immunosuppressants discontinued for 6 months, hormones do not affect pregnancy when maintained with prednisone ≤10mg/d only.
Hormones should be used with caution during pregnancy and the lowest effective dose should be applied, preferably prednisone <20mg/d.
In the event of active disease, severe life-threatening conditions require immediate termination of pregnancy.
If pregnancy can continue after evaluation of the condition, increase the hormone dose as appropriate (prednisone ≤ 30 mg/d). Prednisone, prednisolone, and methylprednisolone are recommended, and dexamethasone and betamethasone are not recommended.
The use of hormones during the third trimester of pregnancy may increase the risk of fetal cleft lip and palate; therefore, the use of medium to high doses of hormones during the third trimester of pregnancy is not recommended.
Patients who have been treated with hormones for a long time should be treated with stress doses at the time of delivery.
Intravenous methylprednisolone shock therapy may be considered in case of disease recurrence.
In late pregnancy, dexamethasone may be used to promote fetal lung maturation.
During lactation, prednisone is relatively safe at 20-30 mg/d. It is recommended to take hormones for more than 4 h before lactation. Calcium and vitamin D supplementation until the end of the lactation period.
Management of congenital heart block in fetal lupus syndrome: The most common cardiac manifestation of fetal lupus syndrome is congenital heart block, which has a high morbidity and mortality rate. Trans-placental administration of fluorinated hormones (dexamethasone and betamethasone) improves the survival of fetuses with congenital heart block, but these drugs also carry a higher risk of intrauterine growth retardation and preterm delivery.
Prevention of antiphospholipid antibody-induced morbid pregnancy: Antiphospholipid antibodies are present in about 1/4-1/2 of SLE patients, and the main problem facing pregnancies in SLE patients exposed to antiphospholipid antibodies is the increased risk of morbid pregnancy. Anticoagulation therapy is the primary means of prevention, and the combination of hormones and aspirin may reduce the risk of morbid pregnancy, but the occurrence of maternal complications should be considered.
(7) Adverse effects of hormones
Hormone therapy for SLE has a long duration and care should be taken to protect the hypothalamic-pituitary-adrenal axis. It is recommended to avoid long-acting and ultra-long-acting hormones such as dexamethasone, which have a large effect on the hypothalamic-pituitary-adrenal axis.
Long-term or high-dose or irregular use of hormones can induce and aggravate infections, lead to osteoporosis and aseptic necrosis of the femoral head, peptic ulcers, neuropsychiatric disorders, hypertension, diabetes mellitus, hyperlipidemia, sodium retention, hypokalemia, glaucoma, Cushing’s syndrome and a series of other adverse reactions, and in severe cases even lead to death of patients.
The adverse effects of hormone application are related to its dose and duration of treatment, and need to be regularly observed and evaluated to ensure the efficacy and safety, and to improve the survival rate and prognosis of SLE treatment.