Lupus erythematosus and lupus nephritis

Systemic lupus erythematosus is the most common disease from the group of diffuse connective tissue diseases that develops on the basis of genetic imperfection of the immune system and is characterized by the production of a wide range of autoantibodies to the components of the cell nucleus and cytoplasm, a violation of the cellular immunity, leading to the development of immunocomplex inflammation.

[1], [2]

Epidemiology

The prevalence of systemic lupus erythematosus in Europe is 40 per 100 000 population, and the incidence is 5-7 cases per 100 000 population, and these indicators depend on race, age and sex. More than 70% of patients fall ill at the age of 14-40 years, the peak incidence falls on 14-25 years. Systemic lupus erythematosus in women of childbearing age develops 7-9 times more often than men.

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

Causes of the lupus erythematosus and lupus nephritis

The cause of systemic lupus erythematosus is not known, and at present it is considered as a multi-genic disease, as a number of factors (genetic, sexual, environmental factors) are established that play a role in the development of immune disorders that underlie the disease.

• The significance of genetic factors is confirmed by the racial features of the disease, the high rate of development of pathology in persons with certain haplotypes of the HLA system, its high prevalence among relatives of patients, as well as in persons with a deficiency of the early components of the complement system (especially the C2-component).
• The role of sex hormones in etiology is evidenced by a significant predominance among women with systemic lupus erythematosus, which is associated with the ability of estrogens to suppress immune tolerance and the clearance of circulating immune complexes by mononuclear phagocytes. The importance of hyperestrogenemia is emphasized by the high incidence of onset and exacerbation of systemic lupus erythematosus during pregnancy and after childbirth, as well as the recent increase in the incidence of postmenopausal women taking hormone replacement therapy with preparations containing estrogens.
• Among environmental factors, the greatest importance is attached to ultraviolet radiation (debut or exacerbation of the disease after insolation). The reason for this is not clear, but it is suggested that skin damage caused by exposure to this radiation enhances the expression of autoantigens and, consequently, the immune response.
• Other exogenous factors, often causing the development of the disease, are drugs (hydralazine, isoniazid, methyldopa) and infections (including viral).

Lupus nephritis is a typical immunocomplex nephritis, the development mechanism of which reflects the pathogenesis of systemic lupus erythematosus in general. In systemic lupus erythematosus, polyclonal activation of B cells occurs, which can be caused either by a primary genetic defect or by a violation of T-lymphocyte function and a decrease in the ratio of CD4 ⁺ and CD8 ⁺ cells. The pronounced activation of B-lymphocytes is accompanied by the production of a wide range of autoantibodies (primarily nuclear and cytoplasmic proteins) followed by the formation of immune complexes.

The greatest value in the pathogenesis of lupus nephritis is the antibodies to double-stranded (native) DNA, which correlate with the activity of nephritis, which are detected in the composition of both circulating and fixed in the glomeruli of the kidneys of immune complexes.

The development of antibodies to DNA, which is not present in a free form outside cells (in combination with histones it forms nucleosomes in the complex structure of nuclear chromatin) and, thus, is not accessible to the immune system, becomes possible due to loss of immune tolerance to its own antigen. This phenomenon, in turn, is associated with a violation of the process of apoptosis - the physiological removal of old and damaged cells. Disturbed apoptosis results in the appearance of free nucleosomes, which, as a result of defective phagocytosis, along with other components of the nuclei of dead cells, enter the extracellular environment and stimulate the immune system to produce autoantibodies (primarily antibodies to nucleosomes, some of which are antibodies to DNA) .

In addition to antibodies to DNA, a number of autoantibodies are isolated to various cellular structures, whose role in the pathogenesis of systemic lupus erythematosus is unequal. Some of them have high specificity and pathogenicity. In particular, anti-Sm antibodies are pathognomonic for systemic lupus erythematosus in general and are believed to serve as an early preclinical marker of the disease, and anti-Ro and anti-Clq antibodies are associated with severe kidney damage. The presence of antiphospholipid antibodies is associated with the development of antiphospholipid syndrome in systemic lupus erythematosus (see "Kidney damage in antiphospholipid syndrome").

Deposits of immune complexes in the renal glomeruli are formed as a result of local formation or deposition of circulating immune complexes. The formation of deposits is affected by the size, charge, avidity of immune complexes, the ability of mesangium to their elimination and local intrarenal hemodynamic factors. Of definite importance are the number and location of immune deposits, the severity of the inflammatory response in the glomeruli. Calling for the activation of the complement system, immune complexes promote the migration of monocytes and lymphocytes into the glomeruli, which release cytokines and other inflammatory mediators that activate the coagulation cascade, cell proliferation and accumulation of the extracellular matrix.

In addition to immune complexes, other pathogenetic factors also play a role in the progression of lupus nephritis: endothelial damage by antiphospholipid antibodies with subsequent disruption of prostacyclin production and platelet activation, which leads to glomerular capillary microthrombosis, arterial hypertension (whose severity is due to lupus nephritis activity) and hyperlipidemia in the presence of nephrotic syndrome. These factors contribute to further damage to the glomeruli.

[8], [9]

Symptoms of the lupus erythematosus and lupus nephritis

Symptoms of lupus nephritis are polymorphic and are composed of a combination of various symptoms, some of which are specific for systemic lupus erythematosus.

• Increased body temperature (from subfebrile to high fever).
• Skin lesion: the most frequently observed erythema is a person in the form of a "butterfly", discoid rashes, but there are possible erythematous rashes of other localization, as well as more rare types of skin lesions (urticaria, hemorrhagic, papulonecrotic rashes, mesh or dendritic lyvedo with ulceration).
• The defeat of the joints is more often represented by polyartralgia and arthritis of the small joints of the hands, which are seldom accompanied by deformity of the joints.
• Polyserositis (pleurisy,  pericarditis ).
• Peripheral vasculitis: capillary tips of the fingers, rarely palms and soles,  cheilitis  (vasculitis around the red border of the lips), enanthema of the oral mucosa.
• The defeat of the lungs: fibrosing alveolitis, discoid atelectasis, high diaphragm standing, leading to the development of restrictive respiratory failure.

Complications and consequences

The pathological process involves skin, joints, serous membranes, lungs, the heart, but the greatest danger to the life of patients is the defeat of the central nervous system and kidneys. Clinically, kidney damage (lupus nephritis) is detected in 50-70% of patients.

[10], [11], [12], [13], [14]

Diagnostics of the lupus erythematosus and lupus nephritis

With the expanded clinical picture of systemic lupus erythematosus, the diagnosis of lupus nephritis is practically not a problem.

The diagnosis is established if there are any 4 or more of the 11 diagnostic criteria of the American Society of Rheumatologists (1997).

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Treatment of the lupus erythematosus and lupus nephritis

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. Conducted therapy 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 it is necessary to prescribe active therapy. 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.

Forecast

On the course and prognosis of systemic lupus erythematosus and lupus nephritis, in particular, immunosuppressive therapy has had the greatest impact in recent decades. The use of glucocorticoids first and then of cytostatic drugs led to an increase in the 5-year survival of patients with systemic lupus erythematosus in general from 49 to 92% (1960-1995), patients with lupus nephritis - from 44 to 82%, including the heaviest, IV class - from 17 to 82%.

The main factors of adverse renal prognosis in patients with lupus nephritis are an elevated level of blood creatinine in the onset of disease and hypertension. As additional prognostic factors, longer duration of nephritis, delayed immunosuppressive therapy, high proteinuria or nephrotic syndrome, thrombocytopenia, hypocomplexemia, low hematocrit, the debut of systemic lupus erythematosus in childhood or over the age of 55, as well as the Negroid race, smoking, male sex and low social status. The response to immunosuppressive therapy, determined year after year by proteinuria levels and creatinine concentration in the blood, is a convenient indicator in the evaluation of a long-term renal prognosis.

The causes of death of patients with lupus nephritis include kidney failure, as well as infections, including sepsis, vascular diseases (IHD, cerebrovascular complications), thromboembolic complications, partially associated with antiphospholipid syndrome.

[20], [21], [22], [23]