How is systemic lupus erythematosus treated?

Systemic lupus erythematosus is a chronic disease, in which complete and final cure is impossible. The goals of treatment are to suppress the activity of the pathological process, preserve and restore the functional capabilities of the affected organs and systems, induce and maintain clinical and laboratory remission, prevent relapses to achieve a significant life expectancy of patients and ensure a sufficiently high quality of life.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ]

Indications for consultation with other specialists

• Ophthalmologist: clarification of the genesis of visual impairment.
• Neurologist: clarification of the nature and genesis of damage to the nervous system, selection of symptomatic therapy when neurological symptoms appear or persist.
• Psychiatrist: determining the tactics of patient management when psychopathological symptoms appear or persist, clarifying the genesis of mental disorders (manifestations of the underlying disease, complications with glucocorticosteroids, etc.), selecting symptomatic therapy.

Indications for hospitalization

During the active period of the disease, patients should be treated in a hospital, if possible in a specialized department. Indications for hospitalization:

• clinical and laboratory signs of activity of systemic lupus erythematosus in the patient;
• the need to correct the therapy if it is ineffective or if drug complications occur;
• occurrence of infectious complications;
• the appearance of signs of antiphospholipid syndrome.

With a decrease in activity and the development of remission, treatment can be continued in an outpatient clinic. Long-term dispensary observation and regular clinical and instrumental examinations and laboratory tests are necessary for the early detection of signs of exacerbation of the disease or the development of possible complications.

Non-drug treatment of systemic lupus erythematosus

It is necessary to provide the patient with a gentle regime. Control body weight. In order to prevent osteoporosis, it is recommended to prohibit smoking in adolescents, advise them to include foods with a high content of calcium and vitamin D in their diet. During the period of remission, therapeutic exercise should be carried out.

Drug treatment of systemic lupus erythematosus

Treatment for systemic lupus erythematosus is based on pathogenetic principles, it is aimed at suppressing the synthesis of autoantibodies, reducing the activity of immune inflammation, and correcting hemostasis. Treatment tactics are determined for each child individually, taking into account their constitutional features, clinical symptoms and activity of systemic lupus erythematosus, the effectiveness of previous treatment and its tolerability by patients, as well as other parameters.

Treatment of systemic lupus erythematosus is long-term and continuous; it is necessary to timely alternate intensive and maintenance immunosuppressive therapy taking into account the phase of the disease, and to constantly monitor its effectiveness and safety.

Treatment of lupus erythematosus with glucocorticosteroids

Glucocorticosteroids are first-line drugs in the treatment of systemic lupus erythematosus; they have anti-inflammatory, immunomodulatory and anti-destructive effects.

Principles of systemic glucocorticosteroid treatment:

• Use of short-acting glucocorticosteroids (prednisolone or methylprednisolone).
• Daily oral administration of glucocorticosteroids (alternating glucocorticosteroid therapy - taking medications every other day for systemic lupus erythematosus - is ineffective, is associated with a high risk of relapse, and is poorly tolerated by most patients).
• Taking glucocorticosteroids primarily in the morning (first half of the day), taking into account the physiological rhythm of their excretion.

The dose of glucocorticosteroids is determined depending on the severity of the condition, activity and leading clinical symptoms of the disease, taking into account the individual characteristics of the child. The dose of prednisolone is:

• for high and crisis activity of systemic lupus erythematosus 1-1.5 mg/kg per day (but not more than 70-80 mg/day);
• for moderate activity of systemic lupus erythematosus 0.7-1.0 mg/kg per day;
• for low activity of systemic lupus erythematosus 0.3-0.5 mg/kg per day.

Treatment with the maximum suppressive dose of glucocorticosteroids is usually carried out for 4-8 weeks until the clinical effect is achieved and the activity of the pathological process is reduced, followed by a reduction in the drug dose to an individually selected maintenance dose (>0.2-0.3 mg/kg per day) by 6-12 months from the start of treatment. The dose of glucocorticosteroids is reduced gradually, slowing the rate of its reduction as the dose is reduced (the principle of reducing the daily dose of the drug by 5-10% every 7, 10, 14, 30 days) depending on the speed of development of the therapeutic effect, the patient's response to the previous dose reduction and the severity of the side effects of glucocorticosteroids.

Long-term use of a maintenance dose of glucocorticosteroids is recommended, which helps maintain remission (violation of the glucocorticosteroid regimen or their rapid withdrawal may lead to an exacerbation of the disease or the development of withdrawal syndrome). Complete withdrawal of corticosteroids is possible only with long-term clinical and laboratory remission and the preservation of the functional capabilities of the adrenal glands.

Glucocorticosteroid pulse therapy involves intravenous administration of ultra-high doses of methylprednisolone (10-30 mg/kg per day, but not more than 1000 mg/day; the dose for adult patients is usually 500-1000 mg/day) for 3 days.

Pulse therapy results in faster positive dynamics of the patient's condition compared to oral administration of glucocorticosteroids, in some cases it allows achieving a positive effect in the treatment of patients resistant to oral glucocorticosteroids, and to start reducing the dose more quickly (steroid-sparing effect), which allows to reduce the severity of side effects.

Pulse therapy with glucocorticosteroids is indicated for the relief of crisis conditions and the treatment of severe forms of systemic lupus erythematosus with highly active nephritis, severe CNS damage, active vasculitis, exudative pleurisy and pericarditis, thrombocytopenia, hemolytic anemia, etc.

Contraindications for pulse therapy with glucocorticosteroids may include: uncontrolled arterial hypertension, uremia, heart failure, acute psychosis.

Cytotoxic agents in the treatment of systemic lupus erythematosus

To adequately control the course of systemic lupus erythematosus and ensure a high quality of life for patients, in many cases it is necessary to include cytotoxic agents (CA) with immunosuppressive activity in therapeutic regimens.

Indications for the use of cytotoxic agents: highly active nephritis, severe CNS damage, resistance to previous glucocorticosteroid therapy, the need to enhance immunosuppressive therapy in the case of severe side effects of glucocorticosteroids, the implementation of a steroid-sparing effect, maintaining a more stable remission.

Depending on the severity of the disease and the specific organ damage, one of the following cytostatics should be used: cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil and methotrexate.

Cyclophosphamide is the drug of choice among cytostatics, primarily for the treatment of active lupus nephritis. According to a meta-review, the advantages of combination therapy with glucocorticosteroids and cyclophosphamide in diffuse proliferative lupus nephritis (WHO class IV) compared to glucocorticosteroid monotherapy include preservation of renal function, reduced risk of doubling of serum creatinine, increased renal and overall survival, decreased mortality and the risk of relapse. Glucocorticosteroid therapy in combination with cyclophosphamide compared to glucocorticosteroid monotherapy has advantages in terms of impact on proteinuria, hypoalbuminemia and the frequency of relapses in membranous lupus nephritis (WHO class V). The combination of glucocorticosteroids with cyclophosphamide, while helping to maintain a more stable and long-term remission, allows for a maximum reduction in the dose of glucocorticosteroids taken orally (steroid-sparing effect).

In clinical practice, 2 different regimens of cyclophosphamide administration are used:

• daily oral administration at a dose of 1.0-2.5 mg/kg per day in order to reduce the number of leukocytes in the peripheral blood to 3.5-4.0x10 ⁹ /l (>3.0x10 ⁹ /l) for several months;
• pulse therapy - periodic intravenous administration of ultra-high doses of the drug. A common scheme is to administer cyclophosphamide once a month in doses of 0.5 (0.75-1.0) g/m2, ^taking into account tolerability, for 6 months, followed by administration of the drug once every 3 months for 2 years.

Principles of cyclophosphamide pulse therapy

• The dose of cyclophosphamide should be selected in accordance with the value of glomerular filtration (if it falls below 30 ml/min, the dose of the drug should be reduced).
• The number of leukocytes in the blood should be monitored on the 10th-14th day after administration of the drug (if the level of leukocytes decreases to <4.0x10 ⁹ /l, the next dose should be reduced by 25%).
• It is necessary to increase the interval between cyclophosphamide administration if infectious complications develop.

Taking cyclophosphamide orally is associated with a higher incidence of complications in children, so this method is used less frequently.

Intermittent pulse therapy with cyclophosphamide in combination with glucocorticosteroids is recognized as the standard treatment for proliferative lupus nephritis (WHO classes III. IV), but therapeutic regimens may vary. In severe forms of nephritis, after induction pulse therapy with cyclophosphamide for 6 months, it is recommended to first switch to administering the drug once every 2 months for the next 6 months and only then administering the drug once per quarter. To maintain remission, some experts suggest continuing to administer cyclophosphamide once per quarter for 30 months.

For children, a less aggressive regimen of pulse therapy with cyclophosphamide at a dose of 10 mg/kg once every 2 weeks until an obvious effect is achieved, followed by a transition to administering the drug once a quarter, has been proposed.

It should be noted that, according to a meta-review (RS Flanc et al., 2005), no statistically significant differences were observed in the effectiveness of pulse therapy when using high or lower doses of cyclophosphamide, as well as long (24 months) or short (6 months) courses of treatment in adults.

The risk of developing side effects during treatment with cyclophosphamide depends on the total course dose of the drug: if the dose does not exceed 200 mg/kg, the probability of severe side effects is low, but it increases significantly with a cumulative dose of more than 700 mg/kg. In view of this, combined treatment regimens are being developed in which cyclophosphamide is replaced with less toxic cytostatics after remission is achieved.

In adults, the effectiveness of short-term (6 months) pulse therapy with cyclophosphamide at a dose of 0.5-1.0 g / m ² in combination with oral glucocorticosteroids with subsequent transfer of the patient to basic therapy with mycophenolate mofetil (0.5-3.0 g / day) or azathioprine (1-3 mg / kg per day) and continuation of glucocorticosteroid treatment has been demonstrated. Randomized studies in adults with proliferative nephritis (III, IV classes in the WHO classification) showed that short courses of cyclophosphamide (6 pulses) at a dose of 500 mg every 2 weeks with a subsequent transition to azathioprine are as effective as treatment according to the classical scheme, but this method is less toxic.

Treatment regimens for active lupus nephritis

Remission induction phase	Remission maintenance phase
Pulse therapy with methylprednisolone, glucocorticosteroids orally at a dose of 0.5 mg/kg per day + pulse therapy with cyclophosphamide (7 intravenous injections) J once a month for 6 months at a dose of 0.5-1 g/m2 ( combination with pulse therapy with methylprednisolone is possible). If indicated, monthly administration of cyclophosphamide can be extended to 9-12 months	Glucocorticosteroids orally in a decreasing dose + pulse therapy with cyclophosphamide at a dose of 0.5-1.0 g/m2 once every 3 months up to 24 months
Pulse therapy with methylprednisolone at a dose of 750 mg/day for 3 days, glucocorticosteroids orally 0.5 mg/kg per day (1 mg/kg per day) for 4 weeks + pulse therapy with cyclophosphamide (6 intravenous injections), once a month for 6 months at a dose of 0.5 g/m2 ( then 0.75 and 1.0 g/ m2 taking into account the tolerability of the drug, but not more than 1.5 g per injection)	Oral glucocorticosteroids (reduce the dose by 2.5 mg/day every 2 weeks to maintenance) + pulse therapy with cyclophosphamide (2 injections once a quarter), then azathioprine 2 weeks after cyclophosphamide at a starting dose of 2 mg/kg per day (reduce to 1 mg/kg per day taking into account the tolerability of the drug)
Pulse therapy with methylprednisolone at a dose of 750 mg/day for 3 days, glucocorticosteroids orally at a dose of 0.5 mg/kg per day (1 mg/kg per day) for 4 weeks + pulse therapy with cyclophosphamide (6 injections of 500 mg every 2 weeks - total dose of cyclophosphamide 3.0 g)	Oral glucocorticosteroids (reduce the dose by 2.5 mg/day every 2 weeks to maintenance) + azathioprine 2 weeks after cyclophosphamide at a starting dose of 2 mg/kg per day (reduce to 1 mg/kg per day taking into account the tolerability of the drug)
Pulse therapy with methylprednisolone at a dose of 750 mg/day for 3 days, glucocorticosteroids orally at a dose of 0.5-1.0 mg/kg per day + pulse therapy with cyclophosphamide (6 intravenous injections) once a month for 6 months at a dose of 0.5-1.0 g/m2 ( but not more than 1.5 g per injection)	Glucocorticosteroids orally in a decreasing dose + mycophenolate mofetil orally in a dose of 0.5-3.0 g/day
Pulse therapy with methylprednisolone, then oral glucocorticosteroids + cyclophosphamide at a dose of 2 mg/kg per day for 3 months	Oral glucocorticosteroids + azathioprine for 21 months

Pulse therapy with cyclophosphamide also allows control of extrarenal symptoms of highly active systemic lupus erythematosus: it is more effective and safer in severe CNS damage than pulse therapy with methylprednisolone, and is indicated for steroid-resistant or steroid-dependent thrombocytopenia, active vasculitis, pulmonary hemorrhages, interstitial pulmonary fibrosis, and in the treatment of highly active systemic lupus erythematosus with antiphospholipid syndrome.

Pulse therapy with cyclophosphamide allows to overcome resistance to traditional glucocorticosteroid therapy and can also be used as an alternative method when active treatment with glucocorticosteroids is necessary in patients with severe complications.

High-dose cyclophosphamide therapy (with or without subsequent stem cell transplantation) is proposed for the treatment of the most severe patients with systemic lupus erythematosus who are resistant to combined therapy with glucocorticosteroids and cytostatics, but is associated with a high risk of complications (agranulocytosis, sepsis, etc.). The treatment regimen includes pulse therapy with cyclophosphamide at a dose of 50 mg/kg per day for 4 consecutive days, followed by the introduction of G-CSF until the neutrophil count is at least 1.0x10 ⁹ /l for 2 consecutive days.

Azathioprine is less effective than cyclophosphamide in the treatment of proliferative lupus nephritis. The drug is used to maintain cyclophosphamide-induced or other cytostatic remission of lupus nephritis, and is used to treat steroid-dependent and steroid-resistant patients with less severe forms of systemic lupus erythematosus, including those with thrombocytopenia, severe and widespread skin syndrome, which helps to reduce the activity of the process, reduce the number of relapses of the disease, and reduce the need for glucocorticosteroids in patients (steroid-sparing effect).

The therapeutic dose of azathioprine is 1.0-3.0 mg/kg per day (the number of leukocytes in the blood should not be lower than 5.0x10 ⁹ /l). The effect of treatment develops slowly and is clearly expressed after 5-12 months.

Cyclosporine in combination with glucocorticosteroids significantly reduces the level of proteinuria, but is potentially nephrotoxic, which limits the possibility of its use in patients with impaired renal function. The indication for the use of cyclosporine is the presence of steroid-resistant or recurrent steroid-dependent diabetes insipidus caused by membranous lupus nephritis (class V).

Cyclosporine can be used as an alternative drug when traditional alkylating agents or antimetabolites cannot be used due to cytopenia. There are data on the effectiveness of cyclosporine in thrombocytopenia.

The therapeutic dose of cyclosporine is 3-5 mg/kg per day, its concentration in the blood should not exceed 150 ng/ml. The clinical effect is usually noted in the 2nd month of treatment. When remission is achieved, the dose of cyclosporine is gradually reduced by 0.5-1.0 mg/kg per day/month to a maintenance dose (on average 2.5 mg/kg per day). Taking into account the possible development of cyclosporine dependence after drug withdrawal, azathioprine or cyclophosphamide can be recommended.

[ 10 ], [ 11 ], [ 12 ], [ 13 ]

Mycophenolic acid preparations

Mycophenolate mofetil is a selective immunosuppressant. According to a meta-analysis (Moore and Deny, 2006), mycophenolate mofetil in combination with glucocorticosteroids is comparable in efficacy to pulse therapy with cyclophosphamide in combination with glucocorticosteroids, is less toxic and less likely to cause infectious complications in adults when this drug is used to treat proliferative and membranous lupus nephritis for induction of remission.

Mycophenolate mofetil can be used to induce remission of cyclophosphamide-resistant lupus nephritis; it is prescribed when cyclophosphamide treatment is impossible due to the development of side effects or the patient's unwillingness. Mycophenolate mofetil can be used to relieve extrarenal symptoms of systemic lupus erythematosus when it is resistant to other cytotoxic agents. Mycophenolate mofetil is also recommended for maintenance of cyclophosphamide-induced remission.

The therapeutic dose of mycophenolate mofetil for adults is 2-3 g/day, administered orally in 2 doses. For children, the recommended dose is 600 mg/m2 ² times a day.

An enteric-coated form of mycophenolic acid delivery (the drug Myfortic ) has been proposed, the effectiveness of which is similar to that of mycophenolate mofetil with a lower incidence of dyspeptic side effects. The daily therapeutic dose of Myfortic for adults is 1440 mg (720 mg 2 times a day). Dosage regimen for children: 450 mg/m2 ² times a day orally.

Plasmapheresis in combination with pulse therapy with methylprednisolone and cyclophosphamide ("synchronous" therapy) is one of the most intensive treatment methods used to treat the most severe patients with systemic lupus erythematosus.

Indications for "synchronous" therapy: systemic lupus erythematosus of high or crisis activity, accompanied by severe endogenous intoxication; highly active nephritis with renal failure (especially rapidly progressive lupus nephritis); severe CNS damage; lack of effect of combined pulse therapy with glucocorticosteroids and cytostatics; cryoglobulinemia; presence of antiphospholipid syndrome resistant to standard therapy.

Methotrexate is recommended for use in the treatment of mild "non-renal" variants of systemic lupus erythematosus with resistant skin and joint-muscular syndromes to more quickly achieve remission and reduce the dose of glucocorticosteroids.

Methotrexate is usually prescribed orally once a week at a dose of 7.5-10.0 mg/ ^m2 for 6 months or more. The effect of treatment is assessed no earlier than after 4-8 weeks.

To reduce the frequency and severity of adverse reactions associated with folate deficiency, patients are recommended to take folic acid.

Aminoquinoline drugs

Hydroxychloroquine and chloroquine are similar in clinical efficacy, but the latter is significantly more toxic.

Aminoquinoline drugs are usually used for low-activity systemic lupus erythematosus. These drugs help eliminate skin rashes and joint lesions in the cutaneous and articular form of systemic lupus erythematosus; reduce the risk of severe exacerbations of the disease, and reduce the need for glucocorticosteroids in patients. Aminoquinoline drugs are included in treatment to maintain remission and prevent relapses when reducing glucocorticosteroid doses or discontinuing cytostatics. In combination with antiplatelet agents, aminoquinoline drugs are used to prevent thrombotic complications in patients with systemic lupus erythematosus and antiphospholipid syndrome.

Hydroxychloroquine at a maximum dose of 0.1-0.4 g/day (up to 5 mg/kg per day) and chloroquine at a maximum dose of 0.125-0.25 g/day (up to 4 mg/kg per day) for 2-4 months with subsequent reduction by 2 times are used for a long time, for 1-2 years or more. The initial therapeutic effect from the use of aminoquinoline drugs is achieved on average after 6 weeks, the maximum - after 3-6 months, and after cancellation it remains for another 1-3 months.

Taking into account the possibility of developing “ophthalmological” side effects (accommodation and convergence defects, deposits of ACP in the cornea or toxic damage to the retina), it is necessary to conduct regular examination of patients at least once a year.

Intravenous immunoglobulin is used to treat patients with systemic lupus erythematosus with severe exacerbations and nonrenal pathology, thrombocytopenia, CNS damage, widespread skin and mucous membrane damage, antiphospholipid syndrome, pneumonitis, including those resistant to glucocorticosteroids and cytostatics. In addition, intravenous immunoglobulin in systemic lupus erythematosus is actively used to treat and prevent infectious complications.

Methods for the use of intravenous immunoglobulin are not standardized. The course dose of the drugs is 0.8-2.0 g/kg, it is usually administered intravenously in 2-3 doses for 2-3 consecutive days or every other day. For the prevention and treatment of opportunistic infection in systemic lupus erythematosus, occurring with moderate activity, a dose of 0.4-0.5 g/kg is sufficient.

Along with basic immunosuppressive therapy, direct and indirect anticoagulants, antiplatelet agents, antihypertensive drugs, diuretics, antibiotics, drugs for the prevention and treatment of osteoporosis and other symptomatic drugs are used in the treatment of systemic lupus erythematosus as indicated.

[ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ]

Surgical treatment of systemic lupus erythematosus

They are carried out when indicated and are based on generally accepted principles.

Prognosis of systemic lupus erythematosus

With early diagnosis and long-term treatment, 5-year survival rates for patients with systemic lupus erythematosus reach 95-100%, and 10-year survival rates are more than 80%.

The following factors are considered to be prognostically unfavorable: male gender, onset of the disease before the age of 20, nephritis at the onset of the disease, diffuse proliferative nephritis (class IV), decreased creatinine clearance, detection of fibrinoid necrosis, interstitial fibrosis, tubular atrophy in biopsies, arterial hypertension, high titers of AT to DNA and low SZ, addition of infection, CNS damage, significant increase in the organ damage index (ACR damage score index) from the 1st to the 3rd year of the disease, the presence of lupus anticoagulant and cryoglobulinemia, thrombosis.