How is systemic lupus erythematosus treated?

Systemic lupus erythematosus is a chronic disease in which complete and definitive cure can not be achieved. The goals of the treatment are to suppress the activity of the pathological process, to preserve and restore the functional capabilities of the affected organs and systems, to induct and maintain clinical and laboratory remission, to prevent relapses in order to achieve a significant life expectancy of patients and to ensure a sufficiently high quality of it.

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

Indications for consultation of other specialists

• The oculist: specification of a genesis of disturbances of sight.
• Neurologist: clarifying the nature and genesis of the nervous system, selecting symptomatic therapy for the appearance or preservation of neurological symptoms.
• Psychiatrist: determination of the tactics of patient management with the appearance or preservation of psychopathological symptoms, clarification of the genesis of mental disorders (manifestations of the underlying disease, complications of glucocorticosteroids, etc.), the selection of symptomatic therapy.

Indications for hospitalization

In 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 a patient;
• the need for correction of ongoing therapy when it is ineffective or when there are drug complications;
• the emergence of infectious complications;
• 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 follow-up and regular clinical and instrumental examinations and laboratory tests are needed to detect early signs of exacerbation of the disease or development of possible complications.

Non-drug treatment of systemic lupus erythematosus

It is necessary to provide the patient a sparing regimen. Monitor body weight. In order to prevent osteoporosis, it is recommended to prohibit smoking for adolescents, advise to include in the diet products with a high content of calcium and vitamin D. During the remission, it is necessary to conduct physical therapy exercises.

Medicamentous 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 correction of hemostasis. The treatment tactics are determined for each child individually, taking into account its constitutional features, clinical symptoms and activity of systemic lupus erythematosus, the effectiveness of previous treatment and its tolerance to patients, and other parameters.

Treatment of systemic lupus erythematosus is continuous and continuous, it is necessary to alternately alternate intensive and supportive immunosuppressive therapy taking into account the phase of the disease, to carry out constant monitoring of its effectiveness and safety.

Treatment of lupus erythematosus by glucocorticosteroids

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

Principles of systemic treatment of glucocorticosteroids:

• Use of short-acting glucocorticosteroids (prednisolone or methylprednisolone).
• Daily intake of glucocorticosteroids inside (alternating therapy with glucocorticosteroids - taking medications every other day with systemic lupus erythematosus is ineffective, associated with a high risk of relapse, it is poorly tolerated by most patients).
• The intake of glucocorticosteroids mainly in the morning hours (the first half of the day), taking into account the physiological rhythm of their allocation.

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:

• at high and crisis activity of systemic lupus erythematosus 1-1,5 mg / kg per day (but not more than 70-80 mg / day);
• at a moderate activity of systemic lupus erythematosus 0,7-1,0 mg / kg per day;
• at a low activity of systemic lupus erythematosus 0,3-0,5 mg / kg per day.

Treatment with a maximum suppressive dose of glucocorticosteroids is usually carried out for 4-8 weeks before the clinical effect is achieved and the activity of the pathological process decreases, followed by a decrease in the dose of the drug to an individually selected maintenance (> 0.2-0.3 mg / kg per day) to 6-12 months from the beginning of treatment. The dose of glucocorticosteroids is reduced gradually, slowing down the rate of its decrease as the dose decreases (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 a previous decrease in dose and severity side effects of glucocorticosteroids.

It is recommended to take a long-term maintenance dose of glucocorticosteroids, which contributes to the preservation of remission (a violation of the regimen of glucocorticosteroids or their rapid cancellation may lead to an exacerbation of the disease or the development of withdrawal syndrome). Complete cancellation of corticosteroids is possible only with long-term clinical and laboratory remission and the condition of preservation of the functionality of the adrenal glands.

Pulse therapy with glucocorticosteroids suggests 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 causes a faster positive dynamics of the patient's condition compared with ingestion of glucocorticosteroids, in some cases it allows to achieve a positive effect in the treatment of patients resistant to oral glucocorticosteroids, to start reducing the dose faster (steroid-saving effect), which reduces the severity of adverse reactions.

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

Contraindications for carrying out pulse therapy with glucocorticosteroids can be: uncontrolled arterial hypertension, uremia, heart failure, acute psychosis.

Cytotoxic agents in the treatment of systemic lupus erythematosus

For adequate control over the course of systemic lupus erythematosus and ensuring a high quality of life for patients, in many cases it is necessary to include cytotoxic agents (CA) that have immunosuppressive activity in therapeutic regimens.

Indications for the use of cytotoxic drugs: high-activity nephritis, severe CNS damage, resistance to prior therapy with glucocorticosteroids, the need to strengthen immunosuppressive therapy with pronounced side effects of glucocorticosteroids, realization of steroid-saving effect, maintenance of more stable remission.

Depending on the severity of the disease and the specificity of organ damage, one of the following cytotoxic agents 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 the meta-review, the advantages of combined therapy with glucocorticosteroids and cyclophosphamide of diffuse proliferative lupus nephritis (Class IV in the WHO classification) as compared with monotherapy with glucocorticosteroids consist in preserving the kidney function, reducing the risk of doubling serum creatinine, increasing renal and overall survival, decreasing mortality and the risk of relapse . Therapy with glucocorticosteroids in combination with cyclophosphamide in comparison with monotherapy with glucocorticosteroids has advantages in terms of effects on proteinuria, hypoalbuminemia and the frequency of relapse, and in membranous lupus nephritis (Class V in the WHO classification). Combination of glucocorticosteroids with cyclophosphamide, contributing to the maintenance of a more stable and prolonged remission, allows to minimize the dose of glucocorticosteroids taken orally (steroid-saving effect).

In clinical practice, two different modes of cyclophosphamide administration are used:

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

Principles of pulse therapy with cyclophosphamide

• The choice of the dose of cyclophosphamide should be carried out 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 10-14th day after the administration of the drug (with a decrease in the leukocyte count <4.0 x 10 ⁹ / L, the following dose should be reduced by 25%).
• It is necessary to increase the interval between the management of cyclophosphamide in the development of infectious complications.

Taking cyclophosphamide and inside is associated with a more frequent development of complications in children, so this method is used less often.

Intermittent pulse therapy with cyclophosphamide in combination with glucocorticosteroids is recognized as the standard for the treatment of proliferative lupus nephritis (III class IV in the WHO classification), however, therapeutic regimens can vary. In severe forms of nephritis after induction pulse therapy with cyclophosphamide for 6 months it is recommended to go first to the administration of the drug every 2 months for the next 6 months and only then to inject the drug once a quarter. To maintain remission, some specialists propose to continue the administration of cyclophosphamide once a quarter for 30 months.

For children, a less aggressive pulse-therapy scheme with cyclophosphamide at a dose of 10 mg / kg once every 2 weeks is suggested until an obvious effect is obtained, followed by a transition to the administration of the drug once a quarter.

It should be noted that statistically significant differences in the effectiveness of pulse therapy with higher or lower doses of cyclophosphamide, as well as long (24 months) or short (6 months) treatment regimens in adults, according to the meta-review (RS Flanc et al., 2005) , not noted.

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

In adults, the effectiveness of a short-term (6 months) pulse-therapy with cyclophosphamide at a dose of 0.5-1.0 g / m ^{2 was} demonstrated in combination with the intake of glucocorticosteroids inside with further transfer of the patient to the basic therapy of mycophenolate with mofetil (0.5-3.0 g / day) or azathioprine (1-3 mg / kg per day) and continued treatment with glucocorticosteroids. In randomized trials in adults with proliferative nephritis (III, IV classes in the WHO classification), short courses of cyclophosphamide (6 pulses) at a dose of 500 mg every 2 weeks followed by azathioprine are as effective as classical treatment, but this method is less toxic.

Treatment regimens for active lupus nephritis

Phase induction of remission	The phase of maintaining remission
Pulsed therapy with methylprednisolone, glucocorticosteroids inside at a dose of 0.5 mg / kg per day + pulse therapy with cyclophosphamide (7 IV injections) J times a month for 6 months at a dose of 0.5-1 g / m 2 (possible combination with pulse therapy with methylprednisolone). If there is evidence, you can extend the monthly administration of cyclophosphamide up to 9-12 months	Glucocorticosteroids inside in a reduced dose + pulse-therapy with cyclophosphamide at a dose of 0.5-1.0 g / m 2 every 3 months to 24 months
Pulse therapy with methylprednisolone 750 mg / day for 3 days, glucocorticosteroids inside 0.5 mg / kg per day (1 mg / kg per day) 4 weeks + pulse therapy with cyclophosphamide (6 IV injections), 1 time per month for 6 months at a dose of 0.5 g / m 2 (then 0.75 and 1.0 g / m 2, taking into account the tolerability of the drug, but not more than 1.5 g for administration)	Glucocorticosteroids orally (2.5 mg / day dose reduction 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 (decrease up to 1 mg / kg per day, taking into account the tolerability of the drug)
Pulse therapy with methylprednisolone 750 mg / day for 3 days, glucocorticosteroids inside at a dose of 0.5 mg / kg per day (1 mg / kg per day) 4 weeks + pulse therapy with cyclophosphamide (6 injections of 500 mg every 2 week - the total dose of cyclophosphamide 3.0 g)	Glucocorticosteroids orally (2.5 mg / day dose reduction every 2 weeks to maintain) + azathioprine 2 weeks after cyclophosphamide at a starting dose of 2 mg / kg per day (decrease to 1 mg / kg per day, taking into account drug tolerance)
Pulse therapy with methylprednisolone 750 mg / day for 3 days, glucocorticosteroids inside at a dose of 0.5-1.0 mg / kg per day + pulse therapy with cyclophosphamide (6 IV) once a month for 6 months in a dose of 0.5-1.0 g / m 2 (but not more than 1.5 g per administration)	Glucocorticosteroids inside in a reduced dose + mycophenolate mofetil inside at a dose of 0.5-3.0 g / day
Pulse therapy with methylprednisolone, then glucocorticosteroids inside + cyclophosphamide at a dose of 2 mg / kg per day for 3 months	Glucocorticosteroids inside + azathioprine for 21 months

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

High-dose therapy with cyclophosphamide (followed by stem cell transplantation or without it) has been proposed for the treatment of the most severe patients with systemic lupus erythematosus, resistant to combined therapy with glucocorticosteroids and cytostatics, but is associated with a high risk of complications (agranulocytosis, sepsis, etc.). The treatment regimen included pulse therapy with cyclophosphamide at a dose of 50 mg / kg per day for 4 consecutive days, followed by the administration of G-CSF until neutrophil count reached at least 1.0 × ^{10 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 the remission of lupus nephritis induced by cyclophosphamide or other cytostatics, and is used to treat steroid-dependent and steroid-resistant patients with less severe variants of systemic lupus erythematosus, including thrombocytopenia, a pronounced and widespread skin syndrome, which reduces the activity of the process, reduces the recurrence of the disease and allows to reduce the need of patients in glucocorticosteroids (steroid-saving 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 less than 5.0 × ^{10 9} / L). The effect of treatment develops slowly and distinctly expressed after 5-12 months.

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

Cyclosporine can be used as an alternative drug when traditional alkylating drugs or antimetabolites can not be used due to cytopenia. There is evidence of the effectiveness of cyclosporine in thrombocytopenia.

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 at the 2 nd 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 maintenance (2.5 mg / kg per day on average). Taking into account the possible development of dependence on cyclosporine after discontinuation of the drug, azathioprine or cyclophosphamide can be recommended.

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

Mycophenolic acid preparations

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

Mycophenolate mofetil can be used to induce the remission of lupus nephritis resistant to cyclophosphamide, it is prescribed if it is not possible to treat with cyclophosphamide due to the development of side effects or the patient's reluctance. Mycophenolate mofetil can be used to relieve extrarenal symptoms of systemic lupus erythematosus with resistance to other cytotoxic agents. Mycophenolate mofetil is also recommended for maintenance of remission induced by cyclophosphamide.

The therapeutic dose of mycophenolate mofetil for adults is 2-3 g / day, it is administered internally in 2 doses. Children are recommended doses of mycophenolate mofetil from the calculation of 600 mg / m ² 2 times a day.

An enteric- soluble form of delivery of mycophenolic acid ( Mayrotic preparation ) is proposed, the effectiveness of which is similar to the efficacy of mycophenolate mofetil at a lower incidence of dyspeptic adverse reactions. The daily therapeutic dose of mayforth for adults is 1,440 mg (720 mg 2 times a day). Dosage regimen for children: 450 mg / m ² 2 times a day inside.

Plasmapheresis combined 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 cris activity, accompanied by pronounced endogenous intoxication; high-activity nephritis with renal insufficiency (in particular, fast-progressive lupus nephritis); severe CNS damage; absence of the effect of combined pulse therapy with glucocorticosteroids and cytostatics; cryoglobulinemia; The presence of antiphospholipid syndrome, resistant to standard therapy.

Methotrexate is recommended for use in the treatment of non-severe "non-invasive" variants of systemic lupus erythematosus with resistant cutaneous and articular-muscular syndromes for more rapid remission and lowering of glucocorticosteroid doses.

Methotrexate is usually given orally once a week at a dose of 7.5-10.0 mg / m ² for 6 months or more. The effect of treatment is assessed no earlier than 4-8 weeks.

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

Aminoquinoline preparations

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

Aminoquinoline preparations are usually used in systemic lupus erythematosus of low activity. These drugs contribute to the disappearance of skin rashes and joint lesions in the cutaneous-articular form of systemic lupus erythematosus; reduce the risk of developing severe exacerbations of the disease, reduce the need for patients in glucocorticosteroids. Aminohinolinovye drugs are connected to treatment in order to maintain remission and prevent relapses with reduced doses of glucocorticosteroids or cytostatics. In combination with antiplatelet agents, aminoquinoline preparations 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 month with a subsequent decrease in 2 times apply for a long time, for 1-2 years or more. The initial therapeutic effect from the use of aminoquinoline drugs is achieved on average 6 weeks later, the maximum after 3-6 months, and after cancellation it persists for another 1-3 months.

Taking into account the possibility of developing "ophthalmologic" side effects (accommodation defects and convergence, AHP deposits in the cornea or toxic lesions of the retina), a regular examination of patients should be performed at least once a year.

Intravenous immunoglobulin is used to treat patients with systemic lupus erythematosus with severe exacerbations and non-natal pathology, thrombocytopenia, CNS damage, widespread skin and mucosal 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.

The methods of using intravenous immunoglobulin are not standardized. The course dose of 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 infections in systemic lupus erythematosus, which occurs with moderate activity, a dose of 0.4-0.5 g / kg is sufficient.

Along with the basic immunosuppressive therapy in the treatment of systemic lupus erythematosus, direct and indirect anticoagulants, antiaggregants, antihypertensives, diuretics, antibiotics, preparations for the prevention and treatment of osteoporosis and other symptomatic medicines are used according to indications.

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

Surgical treatment of systemic lupus erythematosus

Conducted at the testimony and build on generally accepted principles.

Prognosis of systemic lupus erythematosus

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

Prognostically unfavorable factors are: male sex, onset of disease before the age of 20, nephritis in the onset of the disease, diffuse proliferative nephritis (class IV), decreased creatinine clearance, detection of fibrinoid necrosis, interstitial fibrosis, tubular atrophy in biopsy specimens, arterial hypertension, high titers AT to DNA and low S3, attachment of infection, CNS damage, a significant increase in the index of organ damage (ACR damage score index) from 1 to 3 years of the disease, the presence of lupus anticoagulant and cryoglobulinemia , thrombosis.