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.
Clinical manifestations
SLE is most common in women of childbearing age, mostly in the 15-45 age group, with a female:male ratio of 7-9:1. The clinical manifestations of SLE are complex and varied. Most of the patients have insidious onset, and only one or two systems are involved at the beginning, showing mild arthritis, rash, occult nephritis, thrombocytopenic purpura, etc. Some patients are stable in subclinical state or mild lupus for a long time, some patients can suddenly change from mild to severe lupus, and more patients gradually develop multi-system damage from mild; some patients have multiple systems involved in one disease, 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 often have fever, which may be a manifestation of SLE activity. 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 is a characteristic change of SLE. Other skin lesions include photosensitivity, alopecia, palmar and perineal erythema, discoid erythema, erythema nodosum, lipofuscinosis, reticular cyanosis, Raynaud’s phenomenon, etc. The SLE rash is not obviously pruritic, but obvious pruritus suggests allergy, and the pruritic rash after immunosuppressive treatment should be noted as fungal infection. SLE patients receiving hormonal and immunosuppressive therapy with 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 polyarticular pain and swelling are often present and usually do not cause bone destruction. myalgia and muscle weakness may occur in SLE, and a few may have an increased muscle enzyme profile. Aseptic femoral head necrosis needs to be excluded in patients with SLE on hormonal therapy who present with vague discomfort in the hip region. For patients taking hormones for a long time, hormone-induced diseases should be excluded.
Renal damage: also known as Lupus nephritis (LN), manifests as proteinuria, hematuria, tubular urine, and even renal failure. 50%-70% of SLE have clinical renal involvement during the course of the disease, and renal biopsy shows that almost all SLE have renal pathological changes.
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 epilepsy can 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, polyneuro and other pathologies. The presence of one or more of the above manifestations, excluding secondary factors such as infection and drugs, combined with imaging, cerebrospinal fluid, electroencephalography and other examinations can diagnose neuropsychiatric lupus.
6. Hematologic manifestations: anemia and/or leukopenia and/or thrombocytopenia are common. Anemia may be chronic disease anemia or nephrogenic anemia. SLE may present with leukopenia, but cytotoxic drugs used to treat SLE also often cause leukopenia and need to be differentiated. Leukopenia due to this disease usually occurs before treatment or when the disease relapses, and most are sensitive to hormone therapy; whereas leukopenia due to cytotoxic drugs occurs in association with drug use and recovery is somewhat regular. Thrombocytopenia is associated with the presence of anti-platelet antibodies and antiphospholipid antibodies in the serum as well as 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. The radiological features of SLE pulmonary infiltrates are more widely distributed and variable shadows, and the cough symptoms of SLE lung damage are relatively mild compared with those of infectious pneumonia with the same degree of x-ray manifestations, with less sputum and generally no yellow mucous sputum. or yellow sputum, suggesting a 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, lung high-resolution CT (HRCT) examinations, combined with sputum, broncho-alveolar lavage fluid smears and cultures, to clarify the diagnosis and provide timely treatment. interstitial lesions of the lung caused by SLE are mainly ground glass-like changes in the acute and subacute phases and fibrosis in the chronic phase, 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: Patients often present with pericarditis, manifesting as pericardial effusion, but pericardial tamponade is rare. In most cases, the myocardial damage of SLE is less severe, but in severe cases, it can be accompanied by cardiac insufficiency, which is an indication of poor prognosis. They do not cause a change in the nature of the heart murmur. SLE can have coronary artery involvement, manifested by angina pectoris and ST-T changes on the ECG, or even acute myocardial infarction. In addition to the possible involvement of coronary arteritis in the pathogenesis, long-term use of glucocorticoids accelerates atherosclerosis and antiphospholipid antibodies lead to arterial thrombosis, which may be the other two main causes of coronary artery lesions.
9, digestive system manifestations: manifestations of nausea, vomiting, abdominal pain, diarrhea or constipation, of which diarrhea is more common, may be accompanied by protein-losing enteritis and cause hypoproteinemia. In the active stage of SLE, mesenteric vasculitis may appear, and its manifestation is similar to 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, pressure pain), after excluding secondary factors such as infection, electrolyte disorders, medications, and combination with other acute abdominal conditions, etc. SLE mesenteric vasculitis is still lack of powerful auxiliary examinations, and abdominal CT may show indirect signs such as thickening of the small intestine wall with edema, dilatation of intestinal collaterals with intensification of mesenteric vessels, etc. SLE can also be complicated by acute pancreatitis. Increased liver enzymes are common, with only a few cases of severe liver damage and jaundice.
10. Other: Ocular involvement includes conjunctivitis, uveitis, fundus changes, optic neuropathy, etc. SLE is often accompanied by secondary dry syndrome with exocrine gland involvement, manifested as dry mouth and dry eyes, and often positive serum anti-SSB and anti-SSA antibodies.
11. Immunological 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 sera of other connective tissue diseases, and low titers of ANAs can be seen in some chronic infections.ANAs include a series of autoantibodies directed against antigenic components in the nucleus. Among them, anti-double-stranded DNA (ds-DNA) antibody has 95% specificity and 70% sensitivity for SLE, and it is related to disease activity and prognosis; anti-Sm antibody has 99% specificity but only 25% sensitivity, and the presence of this antibody is not significantly related to disease activity.
Diagnostic points
1. With the manifestation of multisystem involvement (with symptoms of more than two systems mentioned above) and evidence of autoimmunity, lupus should be alerted. Early atypical SLE may manifest as: recurrent fever of unknown cause, anti-inflammatory and antipyretic treatment is often ineffective; multiple and recurrent arthralgia and arthritis, often lasting for years without producing deformity; persistent or recurrent pleurisy, pericarditis; pneumonia that cannot be cured by antibiotic or anti-TB treatment; rash that cannot be explained by other causes, reticular cyanosis, Raynaud’s phenomenon; renal disease or persistent unexplained proteinuria of unknown origin; thrombocytopenic purpura or hemolytic anemia; unexplained hepatitis; recurrent spontaneous abortions or deep vein thrombosis or stroke episodes, etc. For these may be early manifestations of atypical SLE, it is necessary to be vigilant to avoid the delay of diagnosis and treatment.
2. Diagnostic criteria: The classification criteria of SLE recommended by the American College of Rheumatology (ACR) in 1997 are commonly used (Table 1). The sensitivity and specificity are 95% and 85% respectively. It is important to emphasize that patients may not initially have four of the classification criteria, and that other items may appear as the disease progresses. 11 of the classification criteria are more diagnostic in terms of immunologic abnormalities and high titers of antinuclear antibodies. Once a patient has immunological abnormalities, even if the clinical diagnosis is not sufficient, close follow-up should be performed to allow for early diagnosis and timely treatment.
Table 1, American College of Rheumatology (ACR) recommended classification criteria for SLE in 1997
1.Erythema of the cheek
Fixed erythema, flat or elevated, in the prominent part of both cheekbones
2.Disciform erythema
Flaky erythema raised above the skin, with adherent keratinous debridement and hair follicle plugs; old lesions may occur as atrophic scarring
3.Photosensitivity
Significant reaction to sunlight, causing rash, known from medical history or observed by doctors
4.Mouth ulcers
Ulcers in the mouth or nasopharynx observed by a physician, usually painless
5.Arthritis
Non-erosive arthritis involving 2 or more peripheral joints with pressure pain, swelling or fluid accumulation
6.Plasmacytitis
Pleurisy or pericarditis
7.Nephritic 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.Hematological disorders
Hemolytic anemia, or leukopenia, or lymphopenia, or thrombocytopenia
10. Immunologic abnormalities
Positive anti-ds-DNA antibody, or positive anti-Sm antibody, or positive antiphospholipid antibody (including one of anti-cardiolipin antibody, or lupus anticoagulant, or false positive syphilis serologic test of at least 6 months duration)
11. Antinuclear antibodies
Abnormal titers of antinuclear antibodies at any time and in the absence of drug-induced “drug lupus”
Treatment
1. General treatment
(1) Patient education: Properly understand the disease, eliminate fear, understand the significance of regular medication, learn to recognize the signs of disease activity, cooperate with treatment, follow medical advice, and follow up regularly. Understand the necessity of long-term follow-up. Avoid excessive exposure to ultraviolet light, use UV protection (sunscreen, etc.) and avoid overexertion.
(2) Treat symptomatically and remove various factors that affect the prognosis of the disease, such as paying attention to controlling hypertension and preventing various infections.
2, drug treatment: there is no cure, but proper treatment can enable most patients to achieve complete remission of the disease. SLE is a highly heterogeneous disease, and clinicians should master the risk-benefit ratio of treatment according to the severity of the disease. It is important to understand both the toxic side effects of drugs and the vitality they bring to patients.
(1) Pharmacological treatment of mild SLE.
Patients have disease activity but mild symptoms, manifesting only photosensitivity, rash, arthritis or mild pluritis, without significant visceral damage. Pharmacological treatment includes.
① Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to control arthritis. Attention should be paid to the side effects of peptic ulcers, bleeding, renal and liver function.
②Anti-malarials Can control skin rash and reduce photosensitivity, commonly used chloroquine 0.25g
once a day, or hydroxychloroquine 200mg once or twice a day. 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. Those who have significant loss of vision should have their fundus examined to clarify the cause. Those with a history of heart disease, especially those with bradycardia or conduction block, are prohibited from taking antimalarials.
③ Short-term local application of hormones can be used to treat 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 (prednisone ≤10mg/d) can reduce symptoms.
⑤ Weigh the pros and cons and use immunosuppressants such as azathioprine, methotrexate or cyclophosphamide if necessary. It should be noted that light 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 serological indicators, symptoms and functional recovery of damaged organs), but attention should be paid to complications induced by excessive immunosuppression, especially infection and gonadal suppression. At present, most patients need more than six months to one year for induced remission to achieve 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 have inhibitory effects on many functions of immune cells and many aspects of immune response, especially on cellular immunity, and can significantly inhibit humoral immunity and reduce antibody production at high doses, and have direct lymphocytolysis at large doses.
Cyclophosphamide (CYC): Cyclophosphamide 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, and the combination of cyclophosphamide and hormone therapy can effectively induce disease remission, stop and reverse the development of lesions, and improve the long-term prognosis.
(iii) Azathioprine (Azathioprine): a purine analogue that exerts cytotoxic effects on lymphocytes by inhibiting DNA synthesis.
(iv) Methotrexate (MTX): 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.
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.
(6) Mycophenolate: It is an inhibitor of hypoxanthine mononucleotide dehydrogenase, which can inhibit the purine ab initio synthesis pathway and thus inhibit lymphocyte activation. It is effective in the treatment of lupus nephritis and can effectively control type IV LN activity.
(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 can follow the principles of heavy SLE, continue to induce remission and maintain consolidation therapy.
3, special treatment: plasma replacement and other treatments should not be included in the conventional treatment, and should be applied depending on the patient’s specific situation.
Pregnancy and childbirth]: Pregnancy and childbirth were once listed as contraindications to SLE. Nowadays, most SLE patients can be safely pregnant and have children after the disease is controlled. Generally speaking, pregnancy can only occur when there is no significant organ damage, the disease has been stable for one year or more, cytotoxic immunosuppressants (cyclophosphamide, methotrexate, etc.) have been discontinued for six months, and hormones are only maintained in small doses. The risk of miscarriage, preterm delivery, stillbirth, fetal failure (fetal heart block and congenital SLE) and induced deterioration of maternal disease are associated with non-remission SLE pregnancies. After pregnancy, both obstetricians and rheumatologists should follow up the patient. If the disease is active during pregnancy, the decision to terminate the pregnancy should be made on a case-by-case basis. In the first trimester of pregnancy, if the disease is significantly active, termination of pregnancy is recommended.
If the disease is active after the third trimester, glucocorticoids can be added under the guidance of a rheumatologist, but the dose is usually prednisone ≤ 30 mg/d. Because prednisone can be inactivated when passing through the placenta, short-term administration is generally not significant for the fetus, while dexamethasone (betamethasone) can pass through the placental barrier and affect the fetus, so it should not be taken. For those who have reached 28 weeks of pregnancy and are likely to deliver within 7 days, in order to promote fetal lung development and maturity, dexamethasone 6mg intramuscular injection Q12h×4 times, or betamethasone 12mg intramuscular injection Q24h×2 times, after the course of treatment is completed, a cesarean section can be performed so that the fetus can be removed from the adverse maternal environment as soon as possible. If the disease is active in the second trimester, the hormone dose can also be increased for a short period of time according to the condition. If the pregnancy is complicated by pre-eclampsia in the second trimester, it should be differentiated from the deterioration of lupus nephritis.
Immunosuppressants such as cyclophosphamide and methotrexate are prohibited from the first 3 months of pregnancy to the whole gestation period because they may affect the normal growth and development of the fetus and lead 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 low-molecular heparin anticoagulation is recommended to prevent miscarriage or stillbirth. In conclusion, pregnancy, medication during pregnancy, and postpartum follow-up of SLE patients should be jointly handled by rheumatologists and obstetricians.
[Prognosis].
Irregular follow-up, non-compliance with medical advice and non-standardized treatment are important causes of death. In recent years, the prognosis of SLE has improved significantly compared with that of the past due to the strengthening of patient education and the improvement of treatment level. 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 damage to multiple organs and infections in SLE, especially those with severe neuropsychiatric lupus and acute lupus nephritis; chronic renal insufficiency, adverse reactions to drugs (especially long-term use of high-dose hormones) and coronary atherosclerotic heart disease, which are the main causes of death in the distant stage of SLE.