I. Overview
Systemic lupus erythematosus (SLE) is an autoimmune-mediated diffuse connective tissue disease with immune inflammation as the prominent manifestation. The presence of multiple autoantibodies in the serum, represented by antinuclear antibodies, and multisystem involvement are the two main clinical features of SLE. For the diagnosis and treatment of SLE should include the following.
1. clarifying the diagnosis.
2, assessing the severity and activity of SLE disease, Li Xegang, Department of Nephrology, Dezhou People’s Hospital
3, developing a routine treatment plan for SLE.
4, dealing with difficult to control cases.
5.Rescuing critical cases of SLE.
6.Managing or preventing drug side effects.
7, dealing with special cases faced by SLE patients, such as pregnancy, surgery, etc.
The first three of them are routine, while the last four often require the participation of experienced specialists and multidisciplinary collaboration.
Clinical manifestations
The epidemiology of SLE in the United States is reported in a number of regional surveys, the prevalence of 14.6-122/100,000 people, and a large series of one-time survey in Shanghai textile workers, the prevalence of 70/100,000 people, and up to 115/100,000 women. The clinical manifestations are complex and varied. Most patients have an insidious onset and only one to two systems are involved at the beginning, showing mild arthritis, rash, occult nephritis, thrombocytopenic purpura, etc. Some patients are stable in a subclinical state or light lupus for a long time, some patients can suddenly change from light to severe lupus, and more patients gradually develop multi-system damage from light; some patients have multiple systems involved at the onset, and even show lupus crisis. The natural course of SLE is mostly characterized by alternating exacerbation and remission of the disease.
1. Systemic manifestations: Patients with SLE often have fever, which may be a manifestation of SLE activity, but infectious factors should be excluded, especially when fever occurs during immunosuppressive therapy, which requires more vigilance. Fatigue is a common but easily neglected symptom of SLE, and is often a precursor of lupus activity.
2. skin and mucous membranes: erythema distributed in a butterfly shape on the bridge of the nose and cheeks of both cheekbones are characteristic changes of SLE. skin damage in SLE includes photosensitivity, alopecia, palmar and perineural erythema, discoid erythema, nodular erythema, lipofuscinosis, reticular bruising and Raynaud’s phenomenon. no obvious pruritus in SLE rash, obvious pruritus indicates allergy. pruritic rash after immunosuppressive therapy should be noted for fungal infection. In SLE patients receiving hormonal and immunosuppressive therapy, unexplained localized burning skin pain may be a precursor to herpes zoster. oral ulcers or mucosal erosions are common in SLE. Oral fungal infections should be noted in oral erosions after immunosuppressive and/or antimicrobial therapy.
3. Joints and muscles: Symmetrical multi-joint pain and swelling are often present and usually do not cause bone destruction. Aseptic femoral head necrosis should be noted in patients with SLE on hormone therapy who present with vague discomfort in the hip region. myalgia and muscle weakness may occur in SLE, and a few may have increased muscle enzyme profiles. For patients taking hormones for a long time, hormone-induced myopathy should be excluded.
LN has a significant impact on the prognosis of SLE, and renal failure is one of the major causes of death in SLE. The World Health Organization (WHO) pathological staging of LN is: type I normal, type II thylakoid proliferative, type III focal segmental proliferative, type IV diffuse proliferative, type V membranous, and type VI glomerulosclerotic. Pathological staging has positive implications for estimating prognosis and guiding treatment, usually type I and II have a better prognosis, and type IV and VI have a worse prognosis. However, the pathological types of LN are convertible, with the possibility of conversion to worse types for types I and II and a good prognosis for types IV and V with immunosuppressive therapy. Renal pathology also provides indicators of LN activity, such as proliferative glomerular cell changes, fibrinoid necrosis, nuclear fragmentation, cellular crescent, hyaline emboli, metallic rings, inflammatory cell infiltration, and inflammation of the tubular interstitium are indicative of LN activity; while glomerulosclerosis, fibrous crescent, tubular atrophy, and interstitial fibrosis are indicators of chronic LN. High activity indicators, kidney damage progresses faster, but active treatment can be reversed; chronic indicators suggest irreversible degree of kidney damage, drug treatment can only slow down but not reverse the continued rise of chronic index.
5. Neurological damage: also known as neuropsychiatric lupus. In mild cases, only migraine, personality changes, memory loss or mild cognitive impairment are observed; in severe cases, cerebrovascular accidents, coma and persistent status epilepticus may be manifested. Central nervous system manifestations include aseptic meningitis, cerebrovascular disease, demyelination syndrome, headache, movement disorders, myelopathy, seizures, acute psychosis, anxiety, cognitive disorders, mood disorders, psychotic disorders; peripheral nervous system manifestations include Green-Barre syndrome, plant nervous system dysfunction, mononeuropathy, myasthenia gravis, cranial neuropathy, plexiform neuropathy, multiple neuropathy, totaling 19 types. The presence of one or more of these manifestations, and the exclusion of secondary factors such as infections and drugs, combined with imaging, cerebrospinal fluid, and electroencephalography, can diagnose neuropsychiatric lupus. Neuropsychiatric lupus with diffuse higher cortical dysfunction is mostly associated with anti-neuronal antibodies and anti-ribosomal P protein (Ribsomal P) antibodies; psychiatric neurological lupus with focal neurolocalization signs can be further divided into two cases, one with positive antiphospholipid antibodies and the other often with systemic vasculitis manifestations and obvious disease activity, which should be focused on in the treatment. Transverse myelitis is uncommon in SLE, and once it occurs, it should be treated actively as early as possible. Otherwise, irreversible damage is caused. It manifests as paralysis or weakness of the lower extremities accompanied by positive pathological signs. Magnetic resonance examination of the spinal cord can clarify the diagnosis.
6. Hematologic manifestations: SLE often presents with anemia and/or leukopenia and/or thrombocytopenia. Anemia may be chronic disease anemia or nephrogenic anemia. SLE itself can be leukopenic, and cytotoxic drugs used to treat SLE often cause leukopenia, which needs to be differentiated. leukopenia in SLE usually occurs before treatment or when the disease relapses, and most are sensitive to hormone therapy; Leukopenia due to cytotoxic drugs occurs in association with drug use and recovery is somewhat regular. Thrombocytopenia is associated with platelet antibodies, antiphospholipid antibodies, and impaired maturation of bone marrow megakaryocytes. Some patients have lymph node enlargement and/or splenomegaly at the beginning of the disease or during active disease.
7. Pulmonary manifestations: SLE often presents with pleurisy, and if combined with pleural effusion, its nature is exudate. In young patients (especially women) with exudative plural effusion, the possibility of SLE should be noted in addition to tuberculosis. radiological features of SLE pulmonary parenchymal infiltrates are more widely distributed and variable shadows. compared with infectious pneumonia with the same degree of X-ray manifestations, SLE pulmonary damage has relatively mild cough symptoms, less sputum, and generally no yellow mucous sputum. if SLE patients present with significant cough, mucous sputum or yellow sputum, suggesting bacterial infection of the respiratory tract. Tuberculosis infection often presents atypically in SLE. Patients with persistent fever should be alerted to the possibility of hematogenous disseminated pulmonary tuberculosis and should undergo weekly chest radiographs and, if necessary, high resolution CT (HRCT) of the lungs, combined with sputum, broncho-alveolar lavage smears and culture, to clarify the diagnosis and provide timely treatment. Fibrosis, manifested as shortness of breath after activity, dry cough, hypoxemia, and pulmonary function tests often show decreased diffusion function. SLE may also present with pulmonary hypertension, pulmonary infarction, and shrinking-lung syndrome. The latter manifests as a reduction in lung volume, diaphragmatic uplift, discoid pulmonary dystrophy, respiratory muscle dysfunction, without involvement of lung parenchyma, pulmonary vasculature, or systemic muscle weakness, myositis, or vasculitis.
8, cardiac manifestations: SLE patients often appear pericarditis, manifested as pericardial effusion, but pericardial tamponade is rare. sLE may have myocarditis, arrhythmia, in most cases the myocardial damage of SLE is less serious, but in severe SLE, can be accompanied by cardiac insufficiency, as a poor prognostic indication. sLE may appear warty endocarditis (Libman-Sack endocarditis), pathological manifestations are The difference between warty endocarditis and infective endocarditis is that warty endocarditis is most commonly seen on the ventricular side of the posterior mitral leaflet and does not cause a change in the nature of the heart murmur. SLE can have coronary artery involvement, manifesting as angina pectoris and ST-T changes on the ECG, or even acute myocardial infarction. In addition to the participation of coronary arteritis in the pathogenesis, long-term use of glucocorticoids to accelerate atherosclerosis and antiphospholipid antibodies leading to arterial thrombosis may be the other two main causes of coronary artery lesions.
9, digestive system manifestations: SLE can appear nausea, vomiting, abdominal pain, diarrhea or constipation, of which diarrhea is more common, can be accompanied by protein-losing enteritis, and cause hypoproteinemia. In the active stage of SLE, mesenteric vasculitis may appear, and its manifestation resembles acute abdomen, and it may even be misdiagnosed as gastric perforation or intestinal obstruction and surgically explored. The disease should be considered when SLE has significant systemic activity, gastrointestinal symptoms and positive abdominal signs (rebound pain, tenderness), except for infection, electrolyte disorders, drugs, and other acute abdominal conditions. SLE can also be complicated by acute pancreatitis. increased liver enzymes are common in SLE, with only a few cases of severe liver damage and jaundice.
10. Other: The ocular involvement of SLE includes conjunctivitis, uveitis, fundus changes, optic neuropathy and so on. The fundus changes include hemorrhage, optic papillar edema, retinal exudate, etc. Optic neuropathy can lead to sudden blindness. sLE is often accompanied by secondary dry syndrome with exocrine gland involvement, manifested as dry mouth and dry eyes, often with positive serum anti-SSB and anti-SSA antibodies.
11, SLE immune abnormalities: mainly reflected in the anti-nuclear antibody profile (ANAs). Immunofluorescent anti-nuclear antibodies (IFANA) is a screening test for SLE. The diagnostic sensitivity of SLE is 95%, and the specificity is relatively low at 65%. In addition to SLE, ANAs are often present in the serum of other connective tissue diseases, and low titers of ANAs can be seen in some chronic infections.
ANAs include a range of autoantibodies directed against antigenic components of the cell nucleus. Among them, anti-double-stranded DNA (ds-DNA) antibodies have a diagnostic specificity of 95% and a sensitivity of 70% for SLE, and are associated with disease activity and prognosis; anti-Sm antibodies have a diagnostic specificity of 99% for SLE, but a sensitivity of only about 25%, and the presence of these antibodies is not significantly related to disease activity; anti-ribosomal P protein (rRNP) antibodies are associated with psychiatric symptoms of SLE Anti-single-stranded DNA, anti-histone, anti-u1RNP, anti-SSA and anti-SSB antibodies can also be found in the serum of SLE, but their diagnostic specificity is low because they are also seen in other autoimmune diseases. Anti-SSB is associated with secondary dry syndrome.
Other autoantibodies are antiphospholipid antibodies associated with antiphospholipid antibody syndrome (including anticardiolipin antibodies and lupus anticoagulant); anti-erythrocyte antibodies associated with hemolytic anemia; anti-platelet antibodies associated with thrombocytopenia; and anti-neuronal antibodies associated with neuropsychiatric lupus. In addition, patients with SLE often present with positive serum rheumatoid factor, hypergammaglobulinemia and hypocomplementemia.Immunopathological examination of SLE includes the cutaneous lupus band test, which shows deposits of immunoglobulins (IgG, IgM, IgA, etc.) and complement (C3c, C1q, etc.) at the superficial dermal junction of the skin and is specific for SLE.Renal immunofluorescence in LN shows mostly A variety of immunoglobulins and complement components are deposited, which is called “full brightness”.
Diagnostic points
Lupus should be alerted if there are manifestations of multi-system involvement (with symptoms of more than two systems mentioned above) and evidence of autoimmunity. Due to the complex and diverse clinical manifestations of SLE, early atypical SLE may manifest as follows: recurrent fever of unknown origin, with anti-inflammatory and antipyretic treatment often ineffective; multiple and recurrent arthralgia and arthritis, often lasting for years without producing deformities; persistent or recurrent pleurisy and pericarditis; pneumonia that cannot be cured by antibiotic or anti-TB treatment; rash that cannot be explained by other causes, reticular bruising, the Raynaud’s phenomenon; renal disease or persistent unexplained proteinuria; thrombocytopenic purpura or hemolytic anemia; unexplained hepatitis; recurrent spontaneous abortion or deep vein thrombosis or stroke episodes, etc. All need to be vigilant to avoid the delay of diagnosis and treatment.
2, diagnostic criteria: the current universal use of the American College of Rheumatology in 1997 revised SLE classification criteria. SLE can be diagnosed after excluding infections, tumors and other connective tissue diseases, with a high sensitivity and specificity of 95% and 85% respectively. It is important to emphasize that the patient may not have all 4 of the criteria at the beginning of the disease. Of the 11 criteria, immunologic abnormalities and high titers of antinuclear antibodies are more diagnostic. Once a patient has immunological abnormalities, even if the clinical diagnosis is not sufficient, close follow-up should be done to make early diagnosis and early treatment.
1.Buccal erythema, fixed erythema, flat or elevated, in the prominent part of both cheekbones
2.Disciform erythema, flaky erythema raised above the skin, adhered with keratinous debris and hair follicle plugs; old lesions may occur atrophic scarring
3.Photosensitivity: significant reaction to sunlight, causing a rash, known from the medical history or observed by the doctor
4, oral ulcers, observed by a physician in the oral cavity or nasopharynx, usually painless
5, arthritis, non-erosive arthritis involving 2 or more peripheral joints with pressure, swelling or effusion
6, Plasmacytitis, pleurisy or pericarditis
7, renal lesions: urine protein >0.5g/24 hours or ++++, or tubular pattern (red blood cells, hemoglobin, granules, or mixed tubular pattern)
8, neuropathy: seizures or psychosis, except drugs or known metabolic disorders
9, hematologic disorders: hemolytic anemia, or leukopenia, or lymphocytopenia, or thrombocytopenia
10. Immunologic abnormalities: positive anti-ds-DNA antibodies, or positive anti-Sm antibodies, or positive antiphospholipid antibodies (the latter includes one of three: anti-cardiolipin antibodies, or positive lupus anticoagulant, or false-positive syphilis serologic test lasting at least 6 months)
11. Antinuclear antibodies: abnormal titers of antinuclear antibodies at any time and in the absence of drug-induced “drug lupus”
3. Assessment of SLE disease activity and severity of disease.
(1) SLE activity manifestations
Various clinical symptoms of SLE, especially the newly appeared symptoms, can indicate the activity of the disease. Most laboratory indicators associated with SLE are also related to disease activity. The main manifestations suggesting SLE activity are: central nervous system involvement (which may manifest as d-epilepsy, psychosis, organic encephalopathy, visual abnormalities, cranial neuropathy, lupus headache, cerebrovascular accident, etc., but central nervous system infection needs to be excluded), renal involvement (including tubuluria, hematuria, proteinuria, pusuria), vasculitis, arthritis, myositis, skin and mucosal manifestations (such as new erythema, alopecia, mucosal ulcers), pleuritis, pericarditis, hypocomplementemia, increased DNA antibody titers, unexplained fever, decreased blood trisomy (excluding drug-induced myelosuppression), and increased sedimentation. Several internationally accepted criteria for determining SLE activity include: SLEDAI ( Systemic Lupus Erythematosus Disease Activity Index), SLAM ( Systemic Lupus Activity Measure), OUT (Henk Jan Out score ), etc. Among them, SLEDAI is the most commonly used (see Appendix Table 2), and its theoretical total score is 105, but the actual majority of patients have a score of less than 45, and those with an activity score of 20 or more suggest very obvious activity.
(2) Assessment of the severity of SLE disease
Mild SLE is: SLE diagnosis is clear or highly suspected, the clinical condition is stable, the target organs that can be involved in SLE (including kidney, hematological system, lung, heart, digestive system, central nervous system, skin, joints) function normally or stably, it is non-fatal, and there are no obvious toxic side effects of SLE treatment drugs.
Severe SLE includes: ① Heart: coronary vascular involvement? s endocarditis, myocarditis, pericardial tamponade, pernicious hypertension; ② lungs: pulmonary hypertension, pulmonary hemorrhage, pneumonia, pulmonary infarction, pulmonary atrophy, interstitial fibrosis; ③ digestive system: mesenteric vasculitis, acute pancreatitis; ④ hematological system: hemolytic anemia, granulocytopenia (WBC <1,000/mm3 ), thrombocytopenia (<50, 000/mm3 ), thrombotic thrombocytopenic purpura, arteriovenous thrombosis; ⑤ renal: persistent unremitting glomerulonephritis, acute glomerulonephritis, nephrotic syndrome; ⑥ neurological: convulsions, acute impaired consciousness, coma, stroke, transverse myelitis, mononeuritis/polyneuritis, psychogenic seizures, demyelinating syndrome; ⑦ other: including cutaneous vasculitis, diffuse severe skin lesions, ulcers, macules, myositis, non-infectious hyperthermia with signs of failure, etc.
Lupus crisis refers to acute life-threatening severe SLE, including acute lupus nephritis, severe central nervous system damage, severe hemolytic anemia, thrombocytopenic purpura, granulocyte deficiency, severe heart damage, severe lupus pneumonia, severe lupus hepatitis, severe vasculitis, etc.
The assessment of SLE activity and the severity of the disease is a prerequisite for the development of the treatment plan.
IV. Treatment
1.General treatment
(1) Patient education: correctly understand the disease, eliminate fear, understand the significance of regular medication, and emphasize the necessity of long-term follow-up. Avoid excessive exposure to ultraviolet light, use anti-UV products, avoid excessive fatigue, self-awareness of signs of disease activity, cooperation with treatment, compliance with medical advice, and regular follow-up.
(2) Symptomatic treatment and removal of various factors affecting the prognosis of the disease, such as attention to the control of hypertension, prevention and control of various infections.
2.Medication: There is no cure for SLE, but proper treatment can enable most patients to achieve complete remission of the disease. SLE is a highly heterogeneous disease, clinicians should grasp the ratio of risk to benefit of treatment according to the severity of the disease. It is important to be clear about both the toxic side effects of drugs and to understand the vitality that drugs bring to patients.
(1) Treatment of mild SLE.
In mild SLE, although there is lupus activity, the symptoms are mild and only exhibit photosensitivity, rash, arthritis or mild plasma membrane inflammation without obvious visceral damage. Therapeutic drugs include.
① Non-steroidal anti-inflammatory drugs (NSAIDs) can be used to control joint swelling and pain. Adverse effects of peptic ulcer, bleeding, kidney and liver function should be noted when taking them.
②Anti-malarial drugs can control rash and reduce photosensitivity, commonly chloroquine 0.25 qd, or hydroxychloroquine 0.4 mg/d in two doses. The main adverse effect is fundus lesions. Those who have been using the drug for more than 6 months can stop it for one month, and those who have significant vision loss should have their fundus examined to clarify the cause. In addition, those who have a history of heart disease, especially bradycardia or conduction block, are prohibited from taking antimalarials.
③ Short-term local application of hormones for rashes, but the use of strong hormonal topical drugs should be avoided on the face, and once used, should not exceed one week.
④Small doses of hormones, (e.g. prednisone ≤10mg/d) can reduce symptoms.
⑤ Weigh the pros and cons of immunosuppressive drugs such as azathioprine, methotrexate or cyclophosphamide if necessary. It should be noted that mild SLE can be aggravated by allergy, infection, pregnancy and childbirth, environmental changes and other factors, and even enter lupus crisis.
(2) Treatment of heavy SLE: Treatment is mainly divided into two stages, namely induction of remission and consolidation therapy. The aim of induced remission is to rapidly control the disease, stop or reverse visceral damage, and strive for complete remission of the disease (including serology, symptoms and functional recovery of damaged organs), but attention should be paid to complications induced by excessive immunosuppression, especially infection and gonadal suppression. Currently, most patients need more than six months to one year to achieve remission for the induction of remission, and should not be rushed.
①Glucocorticoids: With powerful anti-inflammatory effects and immunosuppressive effects, they are the basic drugs for the treatment of SLE. Glucocorticoids inhibit many functions of immune cells and many aspects of immune response, especially the inhibition of cellular immunity, and at high doses, they can significantly inhibit humoral immunity and reduce antibody production, and at large doses, they can have a direct lymphocytic effect. The physiological dose of the hormone is about 7.5 mg/d of prednisone, which mainly inhibits the production of prostaglandins. Since the pharmacological effects of different hormone doses are focused, and there are differences in the sensitivity of hormones between patients and the disease, clinical use should be individualized. In general, the standard dose of prednisone for heavy SLE is 1 mg/kg once daily, and after 2 weeks of stabilization or within 8 weeks of treatment, the dose will be slowly reduced at a rate of 10% every 1~2 weeks to 0.5 mg/kg of prednisone daily, and then the rate of reduction can be slowed down according to the condition; if the condition allows, the hormone dose for maintenance treatment should be less than 10 mg/d of prednisone. If the disease is unstable, the original dose can be temporarily maintained or increased as appropriate or combined with immunosuppressant therapy. One of the immunosuppressants such as cyclophosphamide, azathioprine, methotrexate, etc. can be used in combination to induce faster remission and consolidate the efficacy, and to avoid serious side effects caused by long-term use of larger doses of hormones. In the case of SLE with important organ involvement or even lupus crisis, a larger dose (≥2mg/kg/d) or even Methylprednisolone (MP) shock therapy can be used. The course of treatment and the length of the interval depend on the specific condition and are used for the rescue of critically ill patients in special cases. Methylprednisolone shock therapy often has an immediate effect on lupus crisis, and the duration of treatment and interval depends on the patient’s condition. MP shock therapy can only solve the symptoms in the acute stage, and the effect cannot last, and must be used in conjunction with cyclophosphamide shock therapy, otherwise the condition is prone to recurrence.
The course of hormone therapy for SLE patients is long, so care should be taken to protect the hypothalamic-pituitary-adrenal axis and avoid the use of long-acting and super-long-acting hormones such as dexamethasone and Coninectone (trade name), which have a large impact on this axis. The side effects of hormones include hypertension, hyperglycemia, hyperlipidemia, hypokalemia, osteoporosis, aseptic osteonecrosis, cataract, weight gain, and sodium retention, in addition to infection. Blood pressure, glucose, potassium, lipids, bone density, and chest radiographs should be recorded as a baseline assessment and followed up regularly. It should be noted that side effects of hormones such as aseptic necrosis of the femoral head are not an absolute contraindication to the use of high-dose hormones in cases of severe SLE, especially in life-threatening situations. Common side effects of high-dose MP shock therapy include: flushing, insomnia, headache, fatigue, increased blood pressure, transient blood glucose elevation; serious side effects include: infection, upper gastrointestinal bleeding, sodium retention, induced hypertensive crisis, induced grand mal seizure, psychiatric symptoms, cardiac arrhythmia, and sudden death due to too fast injection rate has been reported, so methylprednisolone shock therapy should emphasize slow Intravenous drip for more than 60 minutes; water-electrolyte and acid-base balance need to be paid attention to before drug administration.
Cyclophosphamide (CYC): It is a cell cycle-specific alkylating agent that acts mainly in the S-phase and exerts cytotoxic effects by affecting DNA synthesis. It has a strong inhibitory effect on humoral immunity, inhibits B-cell proliferation and antibody production, and has a long-lasting inhibitory effect. It is one of the effective drugs for the treatment of severe SLE, especially in patients with lupus nephritis and vasculitis, where cyclophosphamide combined with hormone therapy can effectively induce disease remission, stop and reverse the development of lesions, and improve long-term prognosis. The standard cyclophosphamide shock therapy commonly used today is 0.75-1.0 g/m2 body surface area in 200 ml of saline administered intravenously once every 3-4 weeks. Most patients can be in remission for 6 to 12 months and enter the consolidation phase of therapy, and often need to continue cyclophosphamide shock therapy, gradually extending the interval between doses to about once every three months for several years. In the past, it was thought that the cumulative dose of cyclophosphamide should not exceed more than 9-12 g. Recent studies suggest that cumulative doses of cyclophosphamide up to 30 g can lead to a more consolidated long-term efficacy of LN with no reduction in safety. However, since there are individual differences in sensitivity to cyclophosphamide, age, disease, disease duration, and body composition make differences in tolerance to the drug, treatment should be based on the patient’s specific situation, and the dose, shock interval, and duration of treatment should be mastered to achieve efficacy while avoiding adverse effects. The white blood cell count is important for guiding treatment, and care should be taken to avoid low white blood cells, which are generally required to be not less than 3.0×109/L. The impact of cyclophosphamide shock therapy on white blood cells has a certain pattern, with a large dose of cyclophosphamide entering the body, the white blood cells start to fall around the third day, and reach a low point in 7-14 days, after which the white blood cells gradually rise and return to normal in about 21 days. After that, the white blood cells gradually increase and return to normal in about 21 days. For those with an interval of less than 3 weeks, close attention should be paid to monitoring the blood picture. Routine blood tests must be performed before high-dose shock. In addition to leukopenia and induction of infection, side effects of cyclophosphamide shock therapy include gonadal suppression (especially ovarian failure in women), gastrointestinal reactions, alopecia, hepatic impairment, and, rarely, long-term carcinogenic effects (mainly hematologic tumors such as lymphoma), hemorrhagic cystitis, cystic fibrosis, and bladder cancer are common in patients on long-term oral cyclophosphamide therapy, while intermittent cyclophosphamide shock therapy is rare.
Azathioprine: A purine analogue that exerts cytotoxic effects on lymphocytes by inhibiting DNA synthesis. It is less effective than cyclophosphamide shock therapy, especially in controlling renal and neurological lesions, but is better for pluritis, hematologic system, and rash. Dosage 1 to 2.5mg/kg daily, commonly used dose 50 to 100mg/d, i.e. 50mg orally once or twice daily. Side effects include: bone marrow suppression, gastrointestinal reactions, hepatic impairment, etc. A few people who are extremely sensitive to azathioprine may develop severe alopecia and hematopoietic crisis within a short period of time, causing severe granulocyte and platelet deficiency. It should not be used again in the future.
Methotrexate: a dihydrofolate reductase antagonist that exerts cytotoxic effects by inhibiting the synthesis of nucleic acids. It is less effective than cyclophosphamide shock therapy, but is better tolerated for long-term use. Dose 10~15mg once a week. The main side effects include gastrointestinal reactions, oral mucosal erosion, liver function impairment, bone marrow suppression, and occasionally methotrexate leading to pneumonia and pulmonary fibrosis.
⑤ Cyclosporine: It can specifically inhibit the production of IL-2 in T lymphocytes and exert selective cellular immunosuppressive effects, and is a non-cytotoxic immunosuppressive agent. In the treatment of SLE, it is effective for lupus nephritis (especially V-type LN), and can be used at a daily dose of 3-5 mg/kg of cyclosporine, divided into two oral doses. Pay attention to liver and kidney function and hypertension, hyperuricemia, hyperkalemia, etc. during the medication period. Blood concentration should be measured and dose adjusted if available. 30% increase in blood creatinine compared with that before medication is required to reduce or stop the medication. The overall efficacy of cyclosporine on LN is not as good as cyclophosphamide shock therapy, and it is expensive, has more toxic side effects, and the disease is easy to rebound after stopping the drug.
(6) Mycophenolate esters: Inhibitors of hypoxanthine mononucleotide dehydrogenase, which inhibit the purine de novo synthesis pathway and thus lymphocyte activation. Mycophenolate mofetil is effective in the treatment of lupus nephritis and can effectively control type IV LN activity. The daily dose is 10-30 mg/kg body weight, divided into 2 oral doses.
(3) Treatment of lupus crisis: The treatment aims to save life, protect the involved organs and prevent sequelae. High-dose methylprednisolone shock therapy, symptomatic treatment for the involved organs and supportive therapy are usually required to help patients survive the crisis. Subsequent treatment may follow the principles of heavy SLE, with continued induction of remission and maintenance consolidation therapy.
(1) Acute glomerulonephritis: presents with acute progressive oliguria, swelling, proteinuria/hematuria, hypoproteinemia, anemia, progressive decline in renal function, increased blood pressure, hyperkalemia, metabolic acidosis, etc. Ultrasound renal volume is often increased and renal pathology often shows crescentic nephritis, mostly consistent with WHO type IV of LN. Treatment includes correction of disorders of water-electrolyte acid-base balance, hypoproteinemia, prevention and control of infection, correction of hypertension, heart failure and other comorbidities, protection of vital organs, and if necessary, dialysis support therapy. While assessing the activity and systemic condition of SLE and the presence of treatment counter indications, the timing of renal puncture should be grasped to determine the type of pathology and acute and chronic indications and to develop a treatment plan. In patients with markedly active, non-renal fibrosis/sclerosis and other predominantly irreversible lesions, hormones (prednisone ≥2 mg/kg/d) should be used aggressively, and high-dose MP shock therapy may be used. CYC 0.4-0.8 q2w shock therapy can also be added.
②Neuropsychiatric lupus: central nervous system infections such as septic meningitis, tuberculous meningitis, cryptococcal meningitis, and viral meningoencephalitis must be excluded. In diffuse neuropsychiatric lupus, symptomatic treatment is emphasized on the basis of drugs for controlling SLE, including antipsychotic drugs (in cooperation with psychiatrists), active antiepileptic treatment is required in cases of grand mal seizures or persistent status epilepticus, and attention is paid to enhancing care. for ACL-related neuropsychiatric lupus, anticoagulant and antiplatelet aggregation drugs should be added. With clear evidence of active systemic vasculitis manifestations, apply high-dose methylprednisolone shock therapy. Central lupus including transverse myelitis can be treated with a trial of dexamethasone 10 mg plus methotrexate intrathecal injection/wk for 2-3 times.
③Severe thrombocytopenic purpura: platelets <20,000/mm3, with spontaneous bleeding tendency, conventional hormone therapy is ineffective (1mg/kg/d), the hormone dosage should be increased to more than 2mg/kg/d. Intravenous vincristine (VcR) 1mg, qwk×3-6 times can also be administered. Intravenous infusion of high-dose human immunoglobulin (IVIG) is effective in severe thrombocytopenic purpura, and the standard IVIG therapy is: daily dose 0.4g/kg body weight, intravenous drip, for 5 consecutive days as a course of treatment. IVIG has immunotherapeutic effect on SLE itself on the one hand, and non-specific anti-infective effect on the other hand, and can be used against the combination of high-dose MP and cyclophosphamide immune contusion caused by shock therapy, and can significantly improve the success rate of treatment of various lupus crises. Severe thrombocytopenic purpura without myeloproliferative hypoplasia can also be tried with other immunosuppressive agents such as CYC and cyclosporine. Other drugs include Danazol, triamcinolone, vitamin C, etc. Splenectomy may be considered if conservative medical treatment is ineffective.
Diffuse hemorrhagic alveolitis and acute severe interstitial lung disease: Some patients with diffuse hemorrhagic alveolitis may start without hemoptysis, and bronchoscopy can help to make a clear diagnosis. The disease is highly susceptible to co-infection, often accompanied by massive proteinuria, and has a very poor prognosis. There are no good treatment options. Pulmonary involvement in SLE should be vigilant and combined with systematic assessment of SLE disease, imaging, blood gas analysis, and fibrinoscopy for early detection and timely diagnosis. Treatment includes oxygen therapy, mechanical ventilation if necessary, infection control and supportive therapy. High-dose MP shock therapy, IVIG, plasma exchange, etc. can be tried.
⑤ Severe mesenteric vasculitis: a daily hormone dose of 2 mg/kg/d or more is often required to control the disease. Attention should be paid to water-electrolyte acid-base balance, strengthening parenteral nutrition support, preventing and controlling co-infection, and avoiding unnecessary surgery and exploration. Once the complication of intestinal necrosis, perforation, toxic intestinal paralysis, should be promptly surgical treatment.
3, special treatment: plasma exchange and other treatment of SLE, should not be included in the treatment routine, should be applied depending on the specific circumstances of the patient.
4, pregnancy and childbirth: in the past, pregnancy and childbirth were once listed as a contraindication to SLE. Nowadays, most of the SLE patients can safely become pregnant and have children after the disease is controlled. Generally speaking, when there is no important organ damage, the disease is stable for one year or more, cytotoxic immunosuppressants (cyclophosphamide, methotrexate, etc.) are discontinued for six months, and only small doses of hormones are needed before pregnancy, most of them can be safely pregnant and childbirth. Pregnancy with SLE not in remission carries the risk of miscarriage, preterm delivery, stillbirth and induced worsening of maternal SLE disease. After pregnancy, both obstetric and rheumatologic follow-up is required. Prednisolone is inactivated when passing through the placenta, but dexamethasone and betamethasone can pass through the placental barrier and affect the fetus. Immunosuppressants such as cyclophosphamide and methotrexate are contraindicated from the first trimester to the gestation period as they may affect fetal growth and development leading to malformations. For pregnant women with a history of habitual abortion and positive antiphospholipid antibodies, oral low-dose aspirin (50 mg/d) and/or low-dose heparin anticoagulation is recommended to prevent miscarriage or stillbirth.
V. Prognosis
Irregular follow-up, non-compliance with medical advice and non-standard treatment are important causes of mortality. In recent years, the prognosis of SLE has improved significantly compared with that of the past due to better patient education and improved diagnosis and treatment. With regular treatment, the 1-year survival rate is 96%, the 5-year survival rate is 85%, and the 10-year survival rate has exceeded 75%. The main causes of death in patients in the acute stage are severe multi-organ damage and infection in SLE, especially those with severe neuropsychiatric lupus and acute nephritis; chronic renal insufficiency, poor response to drugs (especially long-term use of high-dose hormones) and coronary atherosclerotic heart disease are the main causes of death in the distant stage of SLE.