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. Kidney biopsy is necessary to determine the characteristics of morphological changes in order to select adequate therapy, as well as to assess the prognosis of the disease. The treatment of 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 due to the development of complex therapeutic regimens, including mainly two groups of drugs.

• Glucocorticoids.
  • Intravenous administration of "shock" doses of methylprednisolone or prednisolone (pulse therapy with glucocorticoids) promotes a more rapid achievement of the effect in patients with high disease activity and allows to reduce the duration of oral administration in high doses, which reduces the risk of developing adverse reactions. In the presence of nephrotic syndrome, rapid deterioration of kidney function, or especially in their combination, pulse therapy is justified at the onset of the disease.
  • After pulse therapy, to achieve a stable effect, it is necessary to continue taking glucocorticoids orally at a dose of 0.5-1.0 mg/kg. However, 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 administration of glucocorticoids, since in most cases it serves as a reflection of the activity of the process and disappears during remission of the disease.
• Cytostatics are the second group of drugs whose use is pathogenetically justified in lupus nephritis. Alkylating agents (cyclophosphamide, less often chlorbutin) and antimetabolites (azathioprine) are mainly prescribed. Mycophenolate mofetil has been increasingly used recently.
  • Among cytostatics, preference is given to cyclophosphamide, which is administered orally or intravenously (pulse therapy). Cyclophosphamide therapy is indicated for active forms of lupus nephritis, especially for rapidly progressing lupus nephritis with morphological signs of class IV.
  • Azathioprine is usually used for slowly progressive forms and for maintenance therapy.
  • Mycophenolate mofetil is a selective cytostatic with a clinical effect similar to azathioprine; the drug is prescribed for active lupus nephritis as an alternative to azathioprine and cyclophosphamide.
  • Cyclosporine A is superior to glucocorticoids in clinical effect due to its ability to suppress interleukin-2 production by blocking T-helpers, however, its effect on the synthesis of antibodies to native DNA is minimal. This circumstance, as well as nephrotoxicity, limit the success of its use in acute lupus. Cyclosporine A can be used in slowly progressing forms of lupus nephritis that occur without severe arterial hypertension and pronounced sclerosis of the renal tissue, as well as in maintenance therapy as a drug that allows reducing the dose of glucocorticoids, and to reduce proteinuria in patients with severe nephrotic syndrome.
• The theoretical basis for intravenous administration of y-globulin is considered to be the change in the structure of the anti-idiotype by anti-idiotypic antibodies. These drugs are used only in cases resistant to conventional immunosuppressive therapy. However, after improvement, relapses often develop, and patients with nephrotic syndrome experience a transient deterioration in renal function, in some cases as a result of the osmotic effect of glucose.

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

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Modern treatment of lupus nephritis

Modern treatment of lupus nephritis (both at the onset and during exacerbation) consists of a period of intensive immunosuppressive therapy (induction therapy) and a subsequent period of long-term and less intensive maintenance therapy. The objectives of induction therapy are to slow down the development of damage, restore kidney function and induce remission of lupus nephritis by controlling the immunological activity of the process. To consolidate remission and prevent exacerbations, maintenance therapy is prescribed with drugs or treatment regimens with a lower risk of complications.

Induction therapy of active forms of lupus nephritis consists of the administration of combined pulse therapy with glucocorticoids and cyclophosphamide, and maintenance therapy can be either continuation of pulse therapy with cyclophosphamide in smaller doses and at longer intervals, or replacement of the latter with azathioprine or mycophenolate mofetil. The criteria for response to induction therapy in proliferative forms of lupus nephritis are a decrease in hematuria, leukocyturia and the number of cellular casts in the urine sediment, a decrease or at least stabilization of the concentration of creatinine in the blood (in patients with irreversible morphological changes in the kidney tissue, normalization of 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 the decrease in the "activity" of the urinary sediment and even an improvement in kidney function. Remission of lupus nephritis is defined as "inactive" urinary sediment; blood creatinine concentration of no more than 1.4 mg/dL and daily proteinuria of no more than 330 mg.

In addition to immunosuppressive therapy, renoprotective therapy is also indicated for lupus nephritis, aimed at reducing the risk of non-immune progression of nephritis caused by intraglomerular hypertension in the preserved glomeruli.

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

Treatment of lupus nephritis, especially its active forms, involves the administration of immunosuppressive therapy.

• For the treatment of rapidly progressive lupus nephritis, the prognosis of which is unfavorable and depends on the timely implementation of
  maximally 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 of body weight adjusted for the concentration of creatinine in the blood and SCF (if the creatinine content in the blood is 350 μmol/l or more and SCF is 50 ml/min or less, the dose should be reduced by 2 times) at intervals of 3-4 weeks in combination with glucocorticoid therapy. Pulse therapy with cyclophosphamide should be carried out continuously for at least 6 months (one pulse therapy session per month), and then - depending on the dynamics of clinical and laboratory parameters: with complete restoration of renal function and minimal manifestations of urinary syndrome (absence of hematuria), the dose of cyclophosphamide can be reduced and the intervals between pulse therapy sessions can be increased (after 2, then after 3 months) with subsequent complete discontinuation of the drugs.
  • The first session of cyclophosphamide pulse therapy should preferably be combined with methylprednisolone pulse therapy (1 g for 3 days), simultaneously with prescribing prednisolone orally at a dose of 1 mg/kg of body weight per day. Methylprednisolone pulses can be repeated in situations where there is a need to quickly reduce the dose of orally administered glucocorticoids (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. Prednisolone should be continued orally at a daily dose of 1 mg/kg of body weight per day for 6-8 weeks, gradually decreasing it by 6 months to 20-30 mg/day and in the following 6 months to a maintenance dose of 5-10 mg/day, which should be taken for 2-3 years, and sometimes 5 years and for life. Typically, with such therapy for rapidly progressing lupus nephritis, clinical and laboratory remission is achieved within 1.5-2 years.
  • In case of rapid progression of renal failure, plasmapheresis may be performed (3 times a week for 1-3 weeks or once every 2-3 weeks, a total of 6-8 procedures), 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 administered in combination with hemodialysis sessions. If clinical and laboratory signs of DIC syndrome are detected, infusions of fresh frozen plasma (or plasmapheresis) are indicated in combination with the administration of anticoagulants (heparin), antiplatelet agents, proteolysis inhibitors, and rheological agents. It is necessary to correct arterial hypertension with the mandatory use of ACE inhibitors.
• In the case of a slowly progressive variant of lupus nephritis with nephrotic or active urinary syndrome, any morphological variant of the disease is possible.
  • Treatment approaches for diffuse or focal lupus nephritis and mesangiocapillary glomerulonephritis should be almost as aggressive as for rapidly progressive lupus nephritis, since with inadequate therapy the disease can progress to 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, followed by prednisolone at a dose of 0.5 mg/kg of body weight per day, in combination 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 the daily doses of prednisolone are reduced to 20-30 mg, and cyclophosphamide to 100-50 mg (or replaced with azathioprine at the same dose) and treatment is continued until remission is achieved.
  • In the absence of morphological confirmation of lupus nephritis, indications for active therapy include nephrotic syndrome, severe erythrocyturia, arterial hypertension, and signs of renal dysfunction. In the case of isolated proteinuria with minor erythrocyturia, less active treatment is possible (monotherapy with prednisolone at a dose of 50-60 mg/day), but in the case of treatment-resistant urinary syndrome (persisting for more than 8 weeks), cytostatic drugs should be added to the therapy.

The dose of corticosteroids and cytostatics should be reduced very slowly (much slower than in Bright's nephritis). After achieving remission, long-term maintenance therapy is necessary in any case. The indication for discontinuing immunosuppressive therapy, regardless of the clinical and morphological form of the disease, is the absence of signs of nephritis activity (proteinuria no more than 0.5 g/day without erythrocyturia) and serological signs of disease activity for at least 2 years.

Renal replacement therapy for lupus nephritis

Currently, only 10-15% of patients with lupus nephritis develop terminal renal failure. When it develops, renal replacement therapy is necessary - dialysis and kidney transplantation.

Approximately 30-35% of patients with lupus nephritis who have reached terminal renal failure experience remission of systemic lupus erythematosus. However, a feature of the terminal stage of lupus nephritis, in contrast to chronic glomerulonephritis, is the persistent high activity of the lupus process in some cases, represented by extrarenal symptoms (or isolated laboratory abnormalities, generally persisting in approximately 30% of patients undergoing hemodialysis), despite the development of nephrosclerosis, which dictates the need to continue immunosuppressive therapy against the background of hemodialysis. The survival of patients with lupus nephritis undergoing dialysis is comparable to the survival of patients with other diseases and varies from 70 to 90% (5-year survival). The type of dialysis therapy (hemodialysis or PD) does not affect survival.

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