Systemic lupus erythematosus

Systemic lupus erythematosus is a systemic autoimmune disease of unknown etiology, which is based on a genetically determined disorder of immune regulation, which determines the formation of organ-nonspecific antibodies to cell nuclear antigens with the development of immune inflammation in the tissues of many organs.

Systemic lupus erythematosus (SLE, disseminated lupus erythematosus) is a chronic multisystem inflammatory disease, possibly of autoimmune origin, affecting mainly young women. The disease most often manifests itself as arthralgia and arthritis, skin lesions, mainly of the face, pleurisy or pericarditis, kidney and CNS damage, cytopenia. Diagnosis is established by the presence of clinical manifestations and the results of serological tests. Severe course of the active phase of the disease requires the administration of glucocorticoids, often hydroxychloroquine, and in some cases immunosuppressants.

70-90% of cases of systemic lupus erythematosus occur in women (mainly in their reproductive years), more often in blacks than in Caucasians. However, systemic lupus erythematosus can be diagnosed at any age, even in newborns. The incidence of systemic lupus erythematosus is increasing worldwide, and in some countries the prevalence of systemic lupus erythematosus rivals that of RA. Systemic lupus erythematosus may be caused by as yet unknown trigger factors that initiate autoimmune reactions in genetically predisposed individuals. Some drugs (particularly hydralazine and procainamide) can cause a lupus-like syndrome.

ICD 10 code

• M32.1. Systemic lupus erythematosus.

Epidemiology

Systemic lupus erythematosus is the most common disease from the group of systemic connective tissue diseases. The prevalence of systemic lupus erythematosus in children aged 1 to 9 years is 1.0-6.2 cases, and in children aged 10-19 years - 4.4-31.1 cases per 100,000 children, and the incidence is on average 0.4-0.9 cases per 100,000 children per year.

Systemic lupus erythematosus rarely affects preschool-aged children; an increase in incidence is noted from the age of 8-9 years, the highest rates are recorded at the age of 14-18 years. Systemic lupus erythematosus mainly affects girls, the ratio of sick girls and boys under the age of 15 is on average 4.5:1.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ]

Symptoms systemic lupus erythematosus

The symptoms of systemic lupus erythematosus can vary widely. The disease may develop suddenly, with fever, or subacutely, over months or years, with episodes of arthralgia and malaise. Initial manifestations of the disease may also include vascular headaches, epilepsy, or psychosis, but in general, systemic lupus erythematosus can manifest itself by affecting any organ. The disease typically has a wave-like course with periodic exacerbations.

Articular manifestations, ranging from intermittent arthralgia to acute polyarthritis, are observed in 90% of patients and often precede other manifestations by several years. Most lupus polyarthritis is non-destructive and non-deforming. However, with prolonged disease, deformities may develop (for example, damage to the metacarpophalangeal and interphalangeal joints can lead to ulnar deviation or "swan neck" deformity without erosion of bone and cartilage, which is called Jacot arthritis).

Skin lesions include a butterfly erythema over the malar bones (flat or raised above the skin surface), usually sparing the nasolabial folds. The absence of papules and pustules differentiates the erythema from acne rosacea. Other erythematous, firm, maculopapular lesions may also develop on the face and neck, upper chest, and elbows. Bullae and ulcerations are common, although recurrent ulcerations are more common on the mucous membranes (particularly the central hard palate, near the junction of the hard and soft palate, cheeks, gingiva, and anterior nasal septum). Generalized or focal alopecia are common in systemic lupus erythematosus. Panniculitis may result in subcutaneous nodules. Vascular lesions include erythema migrans of the hands and fingers, periangular erythema, nail plate necrosis, urticaria, and palpable purpura. Petechiae may develop secondarily against the background of thrombocytopenia. Photosensitivity occurs in 40% of patients.

On the part of the cardiovascular and bronchopulmonary systems, recurrent pleurisy is observed, with or without pleural effusion. Pneumonitis is rare, while minimal impairment of pulmonary function is often observed. In rare cases, massive pulmonary hemorrhage develops, leading to the death of patients in 50% of cases. Other complications include pulmonary embolism, pulmonary hypertension, and pneumofibrosis. Serious but rare complications include coronary artery vasculitis and Libman-Sachs endocarditis. Accelerated development of atherosclerosis leads to an increase in the frequency of complications caused by it and mortality. Congenital heart blocks may develop in newborns.

Generalized lymphadenopathy is common, especially in children, young patients, and blacks. Splenomegaly is reported in 10% of patients. Splenic fibrosis may develop.

Neurological disorders may occur as a result of involvement of various parts of the central or peripheral nervous system in the pathological process or the development of meningitis. These include mild changes in cognitive functions, headache, personality changes, ischemic strokes, subarachnoid hemorrhages, seizures, psychosis, aseptic meningitis, peripheral neuropathy, transverse myelitis, and cerebellar disorders.

Kidney damage may develop at any stage of the disease and be the only manifestation of systemic lupus erythematosus. Its course may vary from benign and asymptomatic to rapidly progressive and fatal. Kidney damage may range from focal, usually benign glomerulitis to diffuse, potentially fatal proliferative glomerulonephritis. Most often, this is accompanied by proteinuria, changes in microscopic examination of urine sediment containing leached erythrocytes and leukocytes, arterial hypertension, and edema.

In systemic lupus erythematosus, the frequency of miscarriages increases in early and late stages. However, a successful resolution of pregnancy is also possible, especially after a remission lasting from 6 to 12 months.

Hematologic manifestations of systemic lupus erythematosus include anemia (often autoimmune hemolytic), leukopenia (including lymphopenia with a decrease in the lymphocyte count to <1500 cells/μl), thrombocytopenia (sometimes life-threatening autoimmune thrombocytopenia). Recurrent arterial and venous thromboses, thrombocytopenia, and a high probability of obstetric pathology occur in the development of antiphospholipid syndrome, which is characterized by the detection of antiphospholipid antibodies. Thrombosis is probably the cause of many complications of systemic lupus erythematosus, including obstetric pathology.

Gastrointestinal manifestations develop as a result of both intestinal vasculitis and impaired intestinal peristalsis. Pancreatitis may develop (caused either directly by systemic lupus erythematosus or by treatment with glucocorticoids or azathioprine). Clinical manifestations of this condition include abdominal pain due to serositis, nausea, vomiting, signs characteristic of intestinal perforation and obstructive intestinal obstruction. In systemic lupus erythematosus, the liver parenchyma is often affected.

Symptoms of Systemic Lupus Erythematosus

Forms

Discoid lupus erythematosus (DLE)

Discoid lupus erythematosus, sometimes called cutaneous lupus, is a skin disorder that may or may not involve systemic manifestations. Skin lesions begin as erythematous plaques that progress to atrophic cicatricial changes. These changes occur on exposed areas of skin that are exposed to light, including the face, scalp, and ears. If untreated, the skin lesions result in atrophy and scarring and may become widespread, leading to cicatricial alopecia. Sometimes, the main manifestation of the disease may be mucosal lesions, especially in the oral cavity.

Patients with typical discoid skin lesions should be examined to exclude systemic lupus erythematosus. Antibodies to double-stranded DNA are almost always undetectable in patients with DLE. Biopsy of the edges of skin lesions does not differentiate DLE from systemic lupus erythematosus, although it helps to exclude other diseases (eg, lymphoma or sarcoidosis).

Early treatment may help prevent atrophy by minimizing exposure to sunlight or ultraviolet light (eg, by wearing protective clothing outdoors). Topical glucocorticoid ointments (especially for dry skin) or creams (less greasy than ointments) applied 3 to 4 times daily (eg, triamcinolone acetonide 0.1% or 0.5%; fluocinolone 0.025% or 0.2%; flurandrenolide 0.05%, betamethasone valerate 0.1%, and especially betamethasone dipropionate 0.05%) usually promote involution of small skin lesions. However, excessive use on the face (where it may cause skin atrophy) should be avoided. Recalcitrant lesions may be covered with a flurandrenolide dressing. Alternative therapy may include intradermal injections of 0.1% triamcinolone acetonide suspension (<0.1 ml per site), but this treatment often results in secondary skin atrophy. Antimalarials (eg, hydroxychloroquine 200 mg orally once or twice daily) may be useful. In cases resistant to therapy, long-term (months to years) combination therapy (eg, hydroxychloroquine 200 mg/day and quinacrine 50-100 mg orally once daily) may be required.

[ 8 ], [ 9 ], [ 10 ], [ 11 ], [ 12 ]

Subacute cutaneous lupus erythematosus

In this variant of systemic lupus erythematosus, severe recurrent skin lesions come first. Annular or papular-squamous eruptions may be noted on the face, arms, and trunk. The lesions are usually photosensitive and may lead to hypopigmentation of the skin and, in rare cases, to the development of atrophic scars. Arthritis and increased fatigue are often present, but there is no damage to the nervous system and kidneys. Depending on the fact of detection of antinuclear antibodies, all patients are divided into ANA-positive and ANA-negative. Most patients have antibodies to the Ro antigen (SSA). Children whose mothers have antibodies to the Ro antigen may suffer from congenital subacute cutaneous lupus erythematosus or congenital heart block. Treatment for this condition is similar to that for SLE.

Diagnostics systemic lupus erythematosus

Systemic lupus erythematosus should be suspected, especially in young women, if symptoms consistent with it are present. In the early stages, systemic lupus erythematosus may resemble other connective tissue diseases (or other pathologies), including RA, if the joint syndrome predominates. Systemic lupus erythematosus may resemble mixed connective tissue disease, systemic sclerosis, rheumatoid polyarthritis, polymyositis, or dermatomyositis. Infections resulting from immunosuppressive therapy may also mimic the manifestations of systemic lupus erythematosus.

Laboratory tests can differentiate systemic lupus erythematosus from other connective tissue diseases; this requires determination of the antinuclear antibody titer, white blood cell count, general urinalysis, and assessment of renal and hepatic function. The diagnosis of systemic lupus erythematosus is highly probable if the patient has had 4 or more criteria at any time during the disease, but is not excluded if fewer than 4 criteria are detected. If the diagnosis is suspected but not proven, additional tests for autoantibodies should be performed. In addition, verification of the diagnosis

[ 13 ], [ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ]

Diagnostic criteria for systemic lupus erythematosus ¹

To diagnose systemic lupus erythematosus, at least 4 of the following symptoms are required:

1. Butterfly-wing rash on the face
2. Discoid rash
3. Photosensitization
4. Oral ulcers
5. Arthritis
6. Serositis
7. Kidney damage
8. Leukopenia (<4000 µL), lymphopenia (<1500 µL), hemolytic anemia or thrombocytopenia (<100,000 µL)
9. Neurological disorders
10. Detection of antibodies to DNA, Sm-antigen, false positive Wasserman reaction
11. Elevated titer of antinuclear antibodies

¹ These 11 criteria are proposed by the American College of Rheumatology and are often used for diagnostic purposes. Although the presence of at least 4 of these criteria in a patient is not absolutely specific for the diagnosis of systemic lupus erythematosus, they help to recognize the manifestations of the disease.

Diagnosis of systemic lupus erythematosus may require repeat testing after months or even years. The best test for diagnosing systemic lupus erythematosus is immunofluorescence detection of antinuclear antibodies; a positive result (usually high titers, >1:80) is determined in more than 98% of patients. However, this test may be false-positive in patients with RA, other connective tissue diseases, malignancies, and even in 1% of healthy individuals. Drugs such as hydralazine, procainamide, beta-blockers, tumor necrosis factor alpha (TNF-a) antagonists can cause lupus-like syndromes and lead to false-positive laboratory results; however, in this case, seroconversion occurs when these drugs are discontinued. If antinuclear antibodies are detected, a study of autoantibodies to the DNA double helix, high titers of which are specific for systemic lupus erythematosus, should be performed.

Other tests for antinuclear and anticytoplasmic antibodies [eg, Ro (SSA), La (SSB), Sm, RNP, Jo-1] should be performed when the diagnosis of systemic lupus erythematosus remains unclear. The Ro antigen is predominantly cytoplasmic; anti-Ro antibodies are occasionally found in patients who do not produce antinuclear autoantibodies and who have chronic cutaneous forms of lupus. They are also characteristic of neonatal lupus and of children with congenital heart block. Anti-Sm is highly specific for systemic lupus erythematosus but, like the autoantibodies to the DNA double helix, has low sensitivity.

Leukopenia is a common manifestation of the disease; lymphopenia may develop in the active phase. Hemolytic anemia may also be observed. Thrombocytopenia in systemic lupus erythematosus is difficult, and sometimes impossible, to differentiate from idiopathic thrombocytopenic purpura, with the exception of patients with antinuclear antibodies. False-positive serologic reactions to syphilis are observed in 5-10% of patients with systemic lupus erythematosus. This is believed to be due to the lupus anticoagulant and prolongation of prothrombin time. Therefore, pathological values of one or more of these parameters indicate the presence of antiphospholipid antibodies (for example, antibodies to cardiolipin), which can be detected by the enzyme immunoassay. Detection of antibodies to beta ₂ -glycoprotein I is perhaps more informative. The presence of antiphospholipid antibodies allows us to predict the development of arterial and venous thrombosis, thrombocytopenia and, during pregnancy, spontaneous abortions and intrauterine fetal death.

Other studies help to assess the nature of the disease and the need for specific therapy. Concentrations of complement components (C3, C4) in the blood serum often decrease in the active phase of the disease, particularly in patients with active nephritis. An increase in ESR always indicates an active phase of the disease. In contrast, determining the concentration of C-reactive protein is not necessary: it can be extremely low in systemic lupus erythematosus, even with ESR values over 100 mm/h.

Evaluation of renal involvement begins with a urinalysis. Red blood cells and hyaline casts suggest active nephritis. Urinalysis should be performed periodically, at intervals of approximately 6 months, even during remission. However, urine test results may be normal even with repeated tests, despite renal involvement verified by histological examination of biopsy material. Renal biopsy is usually not required for the diagnosis of systemic lupus erythematosus, but it helps to assess their condition (eg, acute inflammation or postinflammatory sclerosis) and to choose adequate therapy. In patients with chronic renal failure and severe glomerulosclerosis, the advisability of aggressive immunosuppressive therapy is questionable.

Diagnosis of systemic lupus erythematosus

[ 19 ], [ 20 ], [ 21 ], [ 22 ], [ 23 ], [ 24 ]

Treatment systemic lupus erythematosus

To simplify the understanding of treatment principles, the course of systemic lupus erythematosus can be classified as mild (eg, fever, arthritis, pleurisy, pericarditis, headache, rash) or severe (eg, hemolytic anemia, thrombocytopenic purpura, massive pleural and pericardial lesions, severe renal impairment, acute vasculitis of the extremities or gastrointestinal tract, CNS involvement).

Mild and remitting course of the disease

No or minimal drug therapy is required ¹. Arthralgias are usually well controlled with NSAIDs. Aspirin (80 to 325 mg once daily) is indicated in patients with a tendency to thrombosis who have anticardiolipin antibodies but have not had thrombosis before; it should be remembered that high doses of aspirin in systemic lupus erythematosus may be hepatotoxic. Antimalarial drugs may be useful when skin and joint manifestations predominate. In such cases, hydroxychloroquine (200 mg orally once or twice daily) or a combination of chloroquine (250 mg orally once daily) and quinacrine (50 to 100 mg orally once daily) are used. It should be remembered that hydroxychloroquine has a toxic effect on the retina, which requires an ophthalmological examination every 6 months.

[ 25 ], [ 26 ], [ 27 ], [ 28 ], [ 29 ], [ 30 ]

Severe course

Glucocorticoids are the first-line therapy. Combination of prednisolone with immunosuppressants is recommended for CNS lesions, vasculitis, especially of internal organs, and active lupus nephritis. Prednisolone is usually prescribed orally at a dose of 40-60 mg once a day, but the dose depends on the severity of the manifestations of systemic lupus erythematosus. Oral azathioprine (in doses of 1 to 2.5 mg/kg once a day) or oral cyclophosphamide (CPh in doses of 1 to 4 mg/kg once a day) can be used as immunosuppressants.

Pulse therapy regimen with cyclophosphamide in combination with intravenous mesna

The patient must be under constant observation for tolerance of the treatment during the entire procedure.

1. Dilute 10 mg of ondansetron and 10 mg of dexamethasone in 50 ml of saline solution and administer intravenously by drip over 10-30 minutes.
2. Dilute 250 mg of mesna in 250 ml of saline solution and administer the resulting solution intravenously by drip over 1 hour.
3. Dilute cyclophosphamide in 250 ml of physiological solution at a dose of 8 to 20 mg/kg, administer the resulting solution intravenously by drip over 1 hour. The next mesna infusion is administered after 2 hours.
4. Dilute 250 mg of mesna in 250 ml of saline solution, administer the resulting solution intravenously by drip over 1 hour. In parallel, using another intravenous access, administer 500 ml of saline solution by drip.
5. The next morning, patients should take ondansetron (orally at a dose of 8 mg).

In case of CNS damage and other critical conditions, the initial therapy is intravenous drip (over 1 hour) administration of methylprednisolone at a dose of 1 g for three subsequent days, after which intravenous administration of cyclophosphamide is used according to the scheme described above. As an alternative to cyclophosphamide in case of kidney damage, mycophenolate mofetil (orally in doses from 500 to 1000 mg 1-2 times a day) can be used. Intravenous administration of immunoglobulin G (IgG) at a dose of 400 mg/kg for 5 consecutive days is performed in case of refractory thrombocytopenia. For the treatment of refractory systemic lupus erythematosus, stem cell transplantation methods after preliminary intravenous administration of cyclophosphamide at a dose of 2 g/m2 are currently being studied. In case of terminal renal failure, kidney transplantation is performed.

Improvement in severe systemic lupus erythematosus occurs within 4-12 weeks and may not be evident until the glucocorticoid dose is tapered. Thrombosis and embolism of the brain, lungs, and placenta require short-term heparin administration and long-term (sometimes lifelong) warfarin therapy until an INR of 3 is achieved.

Suppressive therapy

In most patients, the risk of exacerbations can be reduced without long-term high-dose glucocorticoid therapy. Chronic disease requires low-dose glucocorticoid therapy or other anti-inflammatory agents (eg, antimalarials or low-dose immunosuppressants). Treatment should be guided by the main manifestations of the disease, as well as the titer of antibodies to double-stranded DNA and the concentration of complement. Patients receiving long-term glucocorticoid therapy should be prescribed calcium, vitamin D, and bisphosphonates.

Local complications and concomitant pathology

Long-term anticoagulant therapy is indicated for patients who have been diagnosed with antiphospholipid antibodies and recurrent thromboses.

If antiphospholipid antibodies are detected in a pregnant woman, thrombotic complications are prevented by prescribing glucocorticoids (prednisolone at a dose of <30 mg once daily), low doses of aspirin, or anticoagulant therapy with heparin. The most effective preventive therapy is considered to be subcutaneous administration of heparin in combination with aspirin during the second and third trimesters of pregnancy or as monotherapy.

How is systemic lupus erythematosus treated?

Prevention

Primary prevention has not been developed, since the etiology of systemic lupus erythematosus has not been fully established. In order to prevent exacerbations of the disease, insolation and ultraviolet radiation (UVR) should be avoided: use sunscreens; wear clothing that covers the skin as much as possible, hats with brims; avoid traveling to regions with high levels of insolation.

It is necessary to reduce psycho-emotional and physical stress: children should be taught at home (they can attend school only if they develop stable clinical and laboratory remission), and their social circle should be limited to reduce the risk of developing infectious diseases.

Vaccination of children is carried out only during the period of complete remission of the disease according to an individual schedule. Gamma globulin can be administered only if there are absolute indications.

Forecast

Systemic lupus erythematosus is usually characterized by a chronic, relapsing, and unpredictable course. Remission can last for years. If the primary acute phase of the disease is adequately controlled, even in very severe cases (e.g., with cerebral vascular thrombosis or severe nephritis), the long-term prognosis is usually favorable: ten-year survival in developed countries exceeds 95%. Improved prognosis is associated, in particular, with early diagnosis and more effective therapy. Severe disease requires more toxic therapy, which increases the risk of death (in particular, as a result of infections associated with immunosuppressive therapy, coronary vascular pathology, or osteoporosis with long-term use of glucocorticoids).