Lupus erythematosus and lupus nephritis: treatment

Treatment of lupus erythematosus and lupus nephritis depends on the activity of the disease, clinical and morphological variant of nephritis. Conducting a kidney biopsy is necessary to determine the characteristics of morphological changes in order to choose adequate therapy, as well as to assess the prognosis of the disease. The treatment for lupus nephritis should correspond to the activity of the disease: the higher the activity and the more severe the clinical and morphological signs of the disease, the earlier active therapy should be prescribed. Significant advances in the treatment of lupus nephritis have been achieved over the past 20 years, thanks to the development of complex therapeutic regimens, which include basically two groups of drugs.

• Glucocorticoids.
  • Intravenous injection of "shock" doses of methylprednisolone or prednisolone (pulse-therapy with glucocorticoids) contributes to a faster achievement of the effect in patients with high disease activity and allows to reduce the duration of oral use in high doses, which reduces the risk of adverse reactions. In the presence of nephrotic syndrome, rapid deterioration of kidney function, or even more so when combined, it is justified to perform pulse therapy at the onset of the disease.
  • After pulse therapy to achieve a lasting effect, it is necessary to continue taking glucocorticoids inside at a dose of 0.5-1.0 mg / kg. At the same time, long-term use of glucocorticoids leads to the development of severe, sometimes life-threatening complications.
  • Concomitant severe arterial hypertension is not considered a contraindication to the appointment of glucocorticoids, since it in most cases serves as a reflection of the activity of the process and disappears when the disease is remitted.
• Cytotoxic drugs are the second group of drugs, the use of which is pathogenetically grounded in lupus nephritis. In general, alkylating agents (cyclophosphamide, less often chlorobutin) and antimetabolites (azathioprine) are prescribed. Recently, mycophenolate mycophenolate mofetil is increasingly used.
  • Among cytostatics, cyclophosphamide is preferred, which is administered orally or intravenously (pulse therapy). Cyclophosphamide therapy is indicated in active forms of lupus nephritis, especially with rapidly progressive lupus nephritis with class IV morphological features.
  • Azathioprine is usually used with slowly progressing forms and for maintenance therapy.
  • Mycophenolate mofetil is a selective cytotoxic with a clinical effect similar to azathioprine; the drug is administered with active lupus nephritis as an alternative to azathioprine and cyclophosphamide.
  • Cyclosporine A is superior in clinical effect to glucocorticoids, due to the ability to inhibit the production of interleukin-2 by blocking T-helpers, nevertheless its effect on the synthesis of antibodies to native DNA is minimal. This circumstance, as well as nephrotoxicity, limits the success of its use in acute lupus. Cyclosporine A can be used in slowly progressing forms of lupus nephritis, which occur without severe arterial hypertension and expressed sclerosis of the kidney tissue, and as maintenance therapy as a medicine that allows to reduce the dose of glucocorticoids, and to reduce proteinuria in patients with severe nephrotic syndrome.
• The theoretical basis for the intravenous administration of y-globulin is the change in the anti-idiotype structure by anti-idiotypic antibodies. These drugs are used only in cases that are resistant to conventional immunosuppressive therapy. However, after the improvement, relapses often develop, and in patients with nephrotic syndrome, transient impairment of renal function is noted, in some cases as a result of the osmotic effect of glucose.

Sometimes anticoagulants are used in the complex treatment of lupus nephritis. Aminohinolinovye drugs to suppress the activity of lupus nephritis are ineffective, and they are prescribed only in peripheral forms of systemic lupus erythematosus. NSAIDs that remain relevant for extrarenal manifestations of the disease, with lupus nephritis are not used because these drugs can lead to a decrease in glomerular filtration. Among extracorporeal methods of treatment, plasmapheresis remains topical.

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

Modern treatment of lupus nephritis

Modern treatment of lupus nephritis (both in the debut and during exacerbation) consists of a period of intensive immunosuppressive therapy (induction therapy) and the following period of prolonged and less intensive maintenance therapy. The tasks of induction therapy are to slow down the development of damage, restore kidney function and induce remission of lupus nephritis, controlling the immunological activity of the process. To fix remission and prevent exacerbations, prescribe maintenance therapy with drugs or treatment regimens with less risk of complications.

Induction therapy of active forms of lupus nephritis consists in the appointment of combined pulse therapy with glucocorticoids and cyclophosphamide, and maintenance therapy can be either a continuation of pulse therapy with cyclophosphamide in smaller doses and at longer intervals, or by substitution of mofetil with azathioprine or mycophenolate. The criteria for a response to induction therapy in the proliferative forms of lupus nephritis are the reduction of hematuria, leukocyturia and the number of cell cylinders in the urine sediment, a decrease or at least stabilization of the creatinine concentration in the blood (in patients with irreversible morphological changes in renal tissue normalizing the creatinine content in the blood may not occur), as well as a decrease in proteinuria. However, the maximum decrease in protein excretion occurs after a significantly longer period of time than a decrease in the "activity" of urinary sediment and even an improvement in kidney function. Remission of lupus nephritis is defined as an "inactive" urinary sediment; the concentration of creatinine in the blood - no more than 1.4 mg / dl and daily proteinuria - no more than 330 mg.

In addition to immunosuppressive in lupus nephritis, renoprotective therapy has also been shown, aimed at reducing the risk of non-immune progression of nephritis due to intramural hypertension in the preserved glomeruli.

• For this purpose, ACE inhibitors and angiotensin II receptor blockers are prescribed, in addition to antihypertensive, anti-proteinuric action.
• Another method of renoprotection is the control of hyperlipidemia (the development of which is associated with the presence of a nephrotic syndrome and / or antiphospholipid antibodies), for which hypolipidemic drugs are prescribed.

Treatment of lupus nephritis, especially its active forms, presupposes the appointment of immunosuppressive therapy.

• For the therapy of fast-progressive lupus nephritis, whose prognosis is unfavorable and depends on the timely conduct of the
  most active therapy, cyclophosphamide in the form of pulse therapy is considered the drug of choice.
  • The drugs are administered at a dose of 15-20 mg / kg body weight, adjusted for the creatinine concentration in the blood and GFR (with a creatinine content of 350 μmol / L or more and a 50 ml / min GFR or less, the dose should be halved) 3-4 weeks in combination with glucocorticoid therapy. Pulse therapy with cyclophosphamide should be performed continuously for at least 6 months (one session of pulse therapy per month), and further - depending on the dynamics of clinical and laboratory indicators: with complete restoration of kidney function and minimal manifestations of urinary syndrome (absence of hematuria) can reduce the dose of cyclophosphamide and increase the intervals between sessions of pulse therapy (after 2, then after 3 months) followed by the complete cancellation of drugs.
  • The first session of pulse therapy with cyclophosphamide is desirable to combine with pulse therapy with methylprednisolone (1 g for 3 days), concomitantly with the appointment of prednisolone by mouth at a dose of 1 mg / kg of body weight per day. It is possible to repeat the pulses of methylprednisolone in situations where it becomes necessary to quickly reduce the dose of glucocorticoids administered internally (due to complications), and the activity of the process remains high. After intravenous administration of methylprednisolone, the dose of oral prednisolone can be significantly reduced. Continue the intake of prednisolone inside at a daily dose of 1 mg / kg of body weight per day followed for 6-8 weeks with a gradual decrease to 6 months to 20-30 mg / day and the next 6 months to a maintenance dose of 5-10 mg / day , which should be taken within 2-3 years, and sometimes 5 years and for life. Usually, with such therapy of rapidly progressing lupus nephritis, clinical and laboratory remission is achieved after 1.5-2 years.
  • With rapid progression of renal failure, it is possible to conduct plasmapheresis (3 times a week for 1-3 weeks or 1 to 2 weeks, 6-8 procedures in total), preferably with replacement of the removed plasma with an adequate volume of fresh frozen plasma at the rate of 15-20 mg / kg of body weight. Plasmapheresis is used to remove circulating immunoreactants, but there is no consensus on the advisability of its use in lupus nephritis.
  • If necessary, immunosuppressive therapy should be performed against the background of hemodialysis sessions. In the detection of clinical and laboratory signs of the ICE syndrome, infusions of freshly frozen plasma (or plasmapheresis) in combination with the appointment of anticoagulants (heparin), antiaggregants, proteolysis inhibitors, rheological agents are shown. It is necessary to correct arterial hypertension with mandatory use of ACE inhibitors.
• With a slowly progressing version of lupus nephritis with nephrotic or active urinary syndrome, any morphological variant of the disease is possible.
  • Approaches to treatment for diffuse or focal lupus nephritis and mesangiocapillary glomerulonephritis should be almost as active as in fast-progressive lupus nephritis, as inadequate therapy may progress with the development of renal failure.
  • In other morphological variants (membranous and mesangioproliferative), the immunosuppression regimen may be milder: combined pulse therapy with methylprednisolone and cyclophosphamide at the beginning of treatment with the subsequent prescription of prednisolone at a dose of 0.5 mg / kg of body weight per day, combined with pulse therapy with cyclophosphamide or prednisolone at a dose of 50-60 mg / day + cyclophosphamide at a dose of 100-150 mg / day orally for 2-3 months. Then, daily doses of prednisolone are reduced to 20-30 mg, and cyclophosphamide to 100-50 mg (or replaced with azathioprine in the same dose) and continue treatment until remission is achieved.
  • In the absence of morphological confirmation of lupus nephritis, indications for active therapy are nephrotic syndrome, expressed erythrocyturia, arterial hypertension, signs of impaired renal function. With isolated proteinuria with a slight erythrocyte, less active treatment is possible (monotherapy with prednisolone at a dose of 50-60 mg / day), however, with cure-resistant urinary syndrome (persisting more than 8 weeks), cytotoxic drugs should be added to therapy.

Reduction of the dose of corticosteroids and cytostatics should be carried out very slowly (much slower than with the Bright Jade). After reaching remission, in any case, long-term maintenance therapy is needed. Indication for the abolition of immunosuppressive therapy, regardless of the clinical and morphological form of the disease, is the absence of signs of jade activity (proteinuria not more than 0.5 g / day without erythrocyturia) and serological signs of disease activity for at least 2 years.

Renal therapy with lupus nephritis

At present, only 10-15% of patients with lupus nephritis develop terminal renal failure. With its development, renal replacement therapy is required - dialysis and kidney transplantation.

Approximately 30-35% of patients with lupus nephritis who achieved terminal renal insufficiency report a remission of systemic lupus erythematosus. However, the peculiarity of the terminal stage of lupus nephritis, in contrast to chronic glomerulonephritis, is the high activity of the lupus process, which is preserved in a number of cases, represented by extrarenal symptoms (or isolated laboratory disorders, generally remaining in about 30% of patients undergoing hemodialysis), despite the development of nephrosclerosis , which dictates the need to continue immunosuppressive therapy against hemodialysis. Survival of patients with lupus nephritis, who undergo dialysis, is comparable with the survival of patients with other diseases and varies from 70 to 90% (5-year survival). The type of dialysis therapy (hemodialysis or PD) for survival is not affected.

Kidney transplantation is performed in patients with a developed clinical picture of uremia, necessarily in the absence of signs of activity of systemic lupus erythematosus. The results of transplantation are comparable with those in other groups of patients.