Plasmapheresis for autoimmunityAutoimmune diseases have a major difficulty in their treatment. Traditional drug therapy of hormones poses new threat to health disorders – Cushing's syndrome, hypertension, diabetes, osteoporosis, all of which require additional therapy. Pathogenetically more justified is efferent therapy, plasmapheresis is mainly, focused on removal of autoantibodies, immune complexes and other pathological metabolites. Their timely removal allows a more stable remission at half the level of drug therapy.
Over the past four decades, increased awareness that many human diseases are linked, at least partly, with disorders of the immune system, which functions instead of inherent protection of health and life itself of the body, allows self-destructive immune processes.
There is plenty evidence confirming that autoimmune concept. Well known and triggers that provoke these processes – such as infections, foods and even drugs. The antibodies and lymphocytes in patients show responses to specific structures of the body, such as cell nuclei and the receptors or tissue, such as collagen, or muscle.
Immune complexes were detected in the circulation and in certain places, especially in the vascular wall, are the initiators of the immune response to inflammation or atopy. Some etiological mechanisms such as endocrine, genetic, infectious, environmental, as well as the aging process, are participants in the development of the set of autoimmune diseases (1).
The very fact of the appearance of autoantibodies, ie antibodies against self antigens – components of various tissues of the body, is a biological mystery. This process is not peculiar to the normal body as uncontrolled destruction threatens its own tissues for no apparent reason, and even its complete destruction. Therefore, there is blocked the appearance of antibodies to self antigens.
However, to completely disclaim the physiological role of antibody against its own self-antigens would not be entirely correct. The appearance of antibodies against damaged by any reason of their own cells plays even kind sanitation role because it allows to remove them faster from the body. This is evidenced by the facts of the sharp increase in the level of autoantibodies in patients operated on in the early postoperative period (2). However, such an arrangement is beneficial to the body only within certain limits. Too strong, unbalanced immune response causes the body more harm than good (3). In those cases where antibodies start and continue its action against unmodified cells, this process has become abnormal, since it leads to autoimmune disorders their self progressive.
The fundamental laws of immunology were based on the postulate that autoreactive lymphocyte clones already eliminated during ontogeny. However, it may result in some sort of mutation may be a clone of immune cells (B-lymphocytes), which does not block the ability of such antibody to self antigens .
Another trigger may be an infection. The toxin can be superimposed on any part of the cell and make it supposedly alien, which can already be produced antibody. Even some drugs can take the cells and make them strangers. Thus, quinidine can cause the appearance of autoantibodies against their own platelets and cause thrombocytopenia. Viruses, especially retroviruses, are long regarded as etiologic factors responsible for the development of systemic autoimmune diseases. It is very likely that the intracellular viruses can use some self-antigens or parts thereof for their reproduction and growth. There is a possiblity to form a complex between the virus and the autoantigen, thereby violating the tolerance of the immune system to its own autoantigens.
Some foreign antigens can have properties close to some own antigens, and antibodies raised against the first logical can erroneously react with such autoantigens. Under the influence of any infectious agent can occur "molecular mimicry" activating clonal expansion of autoreactive T-cells, which in their turn is activated by microbial peptides (antigens) and begin to cross-react with the elements of some own tissues (epitopes of antigens). It contributes to the development and consolidation of autoimmune processes (4).
Usually the introduction of a foreign antigen to the body there is an episode, and antibodies destroying these antigens may consider their mission accomplished. But staying in it for a certain period, they provide that acquired immunity, which facilitates the struggle with the same antigen, if it ever attempts to enter the body.
There is another thing in the formation, even mistakenly or accidentally autoantibodies. Since self-antigens for life remain in their place, and then the process of antibodies production against them will be with varying intensity as last a lifetime. And depending on the intensity of this will manifest sharpness and scale caused by artificial pathology – an autoimmune disease.
The most common tactic for treatment of autoimmune diseases is based on a two-drug therapy – corticosteroids and cytostatics agents. In recent years, has become commonly used intravenous administration of high doses of immunoglobulins (IVIG) lead to a significant reduction in the pathological autoantibody and inhibitors, and the effect of this is greater than period of the immunoglobulins lifetime, which means a more significant correction regulatory autoimmune pathological processes in the body of patients.
In recent years, became widespread treatment of autoimmune diseases with rituximab – chimeric monoclonal antibody to the CD20 antigen of B-lymphocytes, which should reduce the production of autoantibodies (5, 6). Nevertheless, there described and complications such treatment until the development of multiple organ failure (7).
Often used in the treatment of rheumatoid arthritis and other inflammatory diseases methotrexate is toxic to the lungs and the frequent combination of various systemic diseases with the development of pulmonary fibrosis also causes cautious approach to their medical treatment (8).
However, this therapy is not without a large number of side reactions. Corticosteroids cause Cushingoid syndrome, cytostatics – to significant metabolic disorders, including healthy organs and systems, high doses of immunoglobulins, in addition to the high cost of such treatments are fraught with the danger of transmission of viral diseases.
In most cases, treatment is symptomatic, it is aimed at the elimination of visible clinical manifestations, hormone therapy only reduces autoantibodies to tissue reaction, leaving them in circulation and target organs "for life." A truly pathogenetic can only be therapeutic apheresis for the removal of the body of autoantibodies, immune complexes and other pathological metabolites. This is best achieved by means of plasmapheresis.
There are two main methods of plasmapheresis – centrifugal and filtration.
First by using continuously-flowing or fractional centrifugation special apparatuses of firms Gambro, Fresenius, Cobe, Dideco, Terumo or packages (bottles) into a centrifuge.
The second method is more physiologic. It is based on filtering the blood in special plasma filters. The same companies produced plasma filter of porous hollow fibers. In Russia, launched production of the plasma filter PFM-TT "Rosa" from flat "track" porous membranes by "Trackpore Technology Corp." (Moscow), the functional characteristics of which are the best foreign samples, which allowed us to obtain EU certificates of CE.
In any of the methods after removing plasma thickened blood cell mass ("packed red blood cells") diluted with isotonic sodium chloride solution, or other plasma expanders and returned to the patient. During one session can thus be removed from 1/3 to 1/2 of circulating plasma volume (CPV), constituting the adult "medium weight" 2.0-2.5 liters. Removing 700-900 ml of plasma seems to be quite safe, even when compensating only crystalloid solutions (9).
After a session of plasmapheresis can observe a significant decrease in the concentration of pathological products, but after a few hours of their content in the blood is already close to the original level. This suggests that in the bloodstream enter substances that were before in the interstitium, or even in the cells (which is the main task of efferent therapy – removal of autoantibodies from target organs). Subsequent sessions of plasmapheresis contribute to the removal of these substances also, which leads to a full sanitation throughout the internal environment, given that the bulk of harmful products are in the extravascular spaces.
However, in the body there is a "dynamic equilibrium" concentrations of various substances in the intracellular, extracellular (interstitial) and intravascular spaces. Changing the content of one of these spaces (in this case – the intravascular) implies their redistribution in the other. Thus can be removed from the body and there are xenobiotics long received from the environment and natural abnormal metabolites.
This "soft" technique of plasmapheresis, which does not require replenishment removed plasma protein preparations or donor plasma, it is more preferred. For patients addicted to allergic reactions, the introduction of any protein product poses a threat to anaphylaxis, up to heavy terminal shock. In autoimmune diseases, we are also more than half of the cases of donor plasma observed certain allergic or autonomic responses (9).
At the same time it must be recognized that overseas operations are usually used with a more massive removal of plasma – up to two CPV, which of course, is impossible without the use of donor plasma. In addition to a much greater cost of such an operation (up to $2000), the replacement for the removed plasma of donor eliminates reflex disaster recovery plasma and CBV in general "suction" fluid from the tissues, which is cleansed the last of pathological substances. This should occurs even conditions to remove "fixed" before the pathological products in tissue structures. If, however, would be used to fill protein preparations, then no changes oncotic pressure or CBV not generally occur. Therefore, the alignment of the various concentrations of the ingredients in the vascular and extravascular spaces occur more slowly, during more longer hours and days.
Creation of "artificial hypovolemia" launches the most ancient and powerful reflex recovery priority circulating volume and a "jerk" of tissue fluid helps equalize concentrations in these spaces during the next hours.
This provides the opportunity for subsequent sessions in a day, which reduces the treatment to a period not exceeding two weeks. Therefore, the recommended method here seems to be more acceptable and functional, and economic and organizational sides.
For a complete reorganization of the internal environment it is usually requires 4 sessions of plasmapheresis, which is removed for a total of 1-1.5 CPV. After the fourth session is no significant release of pathological products in circulation and fails, so to achieve a balance of interests – their elimination as possible with minimum negative effects of plasmapheresis. However, as a rule, it is impossible to completely block autoantibody production process. But, given a sufficiently slow rate of accumulation of autoantibodies – for weeks and even months, then periodically, usually twice a year, courses of efferent therapy, you can achieve quite stable and manageable remission timely warning crises severe exacerbations. Our experience shows that after six months the content of autoantibodies and circulating immune complexes, although rises but does not reach the initial level (10).
Naturally, the therapeutic apheresis is not an alternative treatment and does not replace conventional medical therapy, but it allows your doctor to significantly reduce the dose maintenance therapy. For example, in the treatment of idiopathic pulmonary fibrosis we can reduce the dose of hormonal drugs by 40%, do not lead to Cushingoid phenomena, and almost completely dispense with cytostatics. More remission at a smaller level of maintenance therapy provides a better "quality of life", while maintaining their operability. And even the life expectancy of these patients does not exceed 5 years earlier (since diagnosis) increased to more than 10 years (11).
Given the nature of autoimmune diseases, for they are constantly progressing with increasing destructive processes in the target organs and the body in general, apheresis therapy should be administered as soon as possible. We must remember that change has already organic begun it is not possible to recover virtually, but apheresist therapy can slow the progression, push the onset of irreversible organ and systems damage.
So, if at the initial stage of formation of glomerulonephritis, one of the most striking examples of autoimmune diseases, autoantibodies removed from the body, it is possible to prevent damage to the basement membrane of the nephron, or at least mitigate its organic disorders. Repeated courses of plasmapheresis in subsequent exacerbations will also contribute to a distant prospect transfer patients on hemodialysis and kidney transplantation even coming. In practice, however, we meet with plasmapheresis only for hormone resistant forms of glomerulonephritis, have already come under severe kidney disorders, although excluded in the future such "malignant" course of the disease in its early stages is almost impossible. Still less, including plasmapheresis in patients with rapidly progressive glomerulonephritis it is allowed to stabilize or improve the process for kidney and increase survival of patients (12). Especially there is shown success by the inclusion of plasmapheresis in the treatment of glomerulonephritis on a background of nephrotic syndrome (13).
Dire problem is the treatment of chronic hepatitis. It is known that after the acute hepatitis B its chronicity occurs in 5-10% of patients, and served the American statistics in the U.S. the number of patients with chronic hepatitis B was 1.25 million. Even more serious consequences of hepatitis C, chronic forms which in the U.S. are affected about 4.5 million people, and in Russia, their number reaches 10 million people even (14). In St. Petersburg, such patients, about 200,000 people (15). At the same time, the hepatitis C virus has the highest potential chronicity it has the main reason for the formation of the whole group of chronic liver disease – chronic hepatitis, cirrhosis and hepatocellular carcinoma.
There is a lot of evidence that such viral infection causes a cascade of immune pathogenicity reactions, leading eventually to the formation of autoimmune hepatitis. In particular, one-third of such patients show autoantibodies to specific human hepatic lipoprotein (16).
It was established that interferon is widely used in the treatment of viral infections may even induce autoimmune processes and cause exacerbations in 4-19% of patients (17). Moreover, in patients with autoimmune predisposition interferon can trigger the development of autoimmune thyroiditis (18). But we must not forget that in the coming years, millions of carriers of hepatitis C virus become seriously ill with a significant increase in mortality from chronic hepatitis and cirrhosis.
All the above facts convincingly prove autoimmune nature of chronic hepatitis, almost naturally developing after suffering a viral hepatitis B, C and D, and if so, it only plasmapheresis helps to mitigate its manifestations and postpone the inevitable outcome. This raises the question of the appointment of preventive courses of plasmapheresis immediately after detection of hepatitis C virus infection, because there is no guarantee that will avoid chronic process. Given the same factual incurable viral infection of this kind, even when 10-20 years asymptomatic develop signs of chronic liver disease, it becomes necessary to repeat such courses of plasmapheresis at least once a year for the rest of life (19).
But against the background of developing cirrhosis with severe chronic liver disease courses of plasmapheresis also contribute some stabilization of the patients (20). As a result, such treatment can stop of hepatic encephalopathy signs, decreased ascites, decreased level of cholestasis, prothrombin index rose more than 60% and even increase the level of total protein in the blood.
With respect to the so-called systemic diseases, collagen diseases (rheumatoid arthritis, systemic lupus erythematosus, vasculitis, granulomatosis and so on) tactics of apheresis therapy is greater understanding, but not always, these courses are held regularly, which nullifies the results and even their discredit. We should never forget that these diseases are incurable and only regular courses of plasmapheresis able to hold these patients in remission. The task is to prevent the accumulation of autoantibodies and immune complexes to a level where their "quantity turns into quality ", ie leads to an exacerbation of autoimmune process. And here we should start all over again.
Unfortunately, this has to make in these difficult times, when due to the known economic reasons these patients are unable to arrive in time for the passage of a repeated course of plasmapheresis. Doctors are forced to increase their dose of hormonal drugs and cytostatics, which are not significantly preventing the progression of organic disorders, led to the concomitant secondary complications.
Recently, there is growing the interest in antiphospholipid syndrome – an autoimmune vascular disease, manifested the development of recurrent thrombosis in the venous and arterial systems of various organs. Elevated levels of autoantibodies to the antigen ANCA – a component of the cytoplasm of neutrophils and vascular endothelial cells promotes various types vasculopathies with an increased tendency to thrombosis (21). Among other manifestations there are deep vein thrombosis marked with episodes of pulmonary embolism, and spontaneous abortion ("habitual miscarriage") (22).
Nevertheless, autoimmune factors play some role in the pathogenesis of atherosclerosis. This primarily refers to the anticardiolipin antibodies. Furthermore, there are detected IgG-antibodies to vascular endothelium, cardiomyocytes, fibers conducting system of the heart and the smooth muscle (23). In patients with various types of systemic vasculitis has a greater predisposition to atherosclerosis with occlusive lesions of the coronary, cerebral and peripheral arteries (24, 25).
There is most dangerous cerebral vascular thrombosis with the occurrence of stroke. 25% of young stroke patients can detect anticardiolipin antibodies (26). Antiphospholipid antibodies may cause of coronary artery disease and myocardial infarction.
Autoimmune mechanisms are involved in the pathogenesis and myocardial infarction, ischemic myocardium which throws into the bloodstream their damaged proteins – actin and tropomyosin, which, while not constant blood ingredients, are perceived by the immune system as foreign antigens and there is starts the reproduction mechanism of antibodies against these proteins during the first two weeks after a heart attack and this level is maintained for at least three months (27). These facts are additional justification for the use of plasmapheresis to remove such antibodies as in the acute phase of myocardial infarction, and in the period of rehabilitation.
Many skin diseases are such a name only the most visible manifestation of the naked eye, although in reality they are developing as a result of disorders of the internal environment. These include, in particular, pemphigus, scleroderma, dermatomyositis, polymyositis, in which treatment has been successfully used plasmapheresis (17).
Many researchers point to the autoimmune nature of the development and spread disease such as psoriasis, which is often accompanied by a number of systemic disorders (mainly psoriatic arthritis). Dependence of the disease from disorders of the internal environment is confirmed the success of apheresis therapy in psoriasis. In our practice such treatment usually consists of a session hemosorption and four sessions of plasmapheresis, combined with ultraviolet blood irradiation or laser beams and subsequent enterosorption.
Several severe progressive nervous disease are based on an autoimmune pathogenesis, which is considered essential in myasthenia gravis, Guillain-Barré syndrome, IgM monoclonal and chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, multiple sclerosis, inflammatory myopathies, stiffness syndrome (stiff-person syndrome), autoimmune neyromiotonia and nervous diseases associated with systemic vasculitis and viral infection. In these diseases autoantibodies affect glial cells, myelin, axon, calcium channels, and apheresis therapy also takes a significant place in their treatment (27).
Insulin-dependent diabetes mellitus in the modern view is a chronic autoimmune disease with a fairly long pre-clinical prodromal period. During this phase (months to several years), it is characterized by undulating recurrent autoimmune "attack" with destruction and progressive decrease in the mass of insulin-producing -cells of Langerhans’ islets of the pancreas. There are many signs that the nature of the damage has -cell autoimmune nature. There is possible impact of some external factors, which can be as initiators of autoimmune processes and boost the already arrived earlier. The activity of autoimmune processes begins much earlier than the first signs of the disease, so when they are detected timely plasmapheresis would be able to inhibit them (28).
In diabetes has increased significantly production of modified glycated low-density lipoproteins (LDL). Formation of immune complexes with glycated LDL increases their atherogenicity and contributes to the progression of atherosclerosis .
In diabetes type 2 also revealed pronounced metabolic changes in these patients are prone to obesity . It should be borne in mind that the characteristic of diabetes type 2 so-called metabolic syndrome or insulin resistance syndrome naturally accompanied not only impaired glucose tolerance, but also dyslipidemia, arterial hypertension, visceral obesity, and prothrombotic status [31, 32].
Thus, the presence of both immune and metabolic changes in this form of diabetes makes reasonable use of apheresis therapy at all stages of the disease. It is practically the only way to correct these complications – elimination of secondary metabolic disorders. Only by plasmapheresis we can remove many damaging factors such as the circulating immune complexes, glycoproteins, lipids, uric acid, endothelins, antibodies to insulin and others 
A.O.Gavrilov et al.  reported about the recovery of microcirculatory disorders after courses of plasmapheresis with increasing pain-free walking distance, healing of trophic ulcers or amputations suspended with gangrene of the toes. This confirms also our own experience of using membrane plasmapheresis in diabetic microangiopathy .
At autoimmune thyroiditis the thyroid gland there is exposed autoantibodies and immune inflammation occurs with initial excitation of its functions and signs of thyrotoxicosis successive cancellation function and the development of resistant hypothyroidism (9). But also in the pathogenesis of diffuse toxic goiter autoimmune components can clearly be seen also. It is characterized by autoantibodies to three thyroid antigens – thyroglobulin, peroxidase and thyroid-stimulating hormone. All this makes it necessary the efferent therapy in this pathology.
Allergies can also be considered a type of autoimmune disease and in the treatment of their manifestations such as bronchial asthma and atopic dermatitis apheresis therapy plays an important role (9).
Now we can assume the presence of well-established facts of autoreactive T-cells and autoreactive antibody-secreting B-cells in healthy individuals. Natural autoantibodies of IgM, IgG and IgA isotypes present in normal plasma, reacting with a wide range of self antigens, including nucleus and cytoplasm, cell membrane components, and circulating plasma proteins.
However, in our opinion, these facts do not rule out that such "healthy" person who found the autoantibodies are in the distant or not so distant future will be candidates for developing relevant autoimmune diseases, since the latter are manifested only after accumulating a certain critical amount of antibodies.
Indeed, with advancing age, there are occur also changes in the immune system, in particular, the attenuation function of the suppressor T-cells, thus giving rise to the "forbidden" at the normal state of lymphoid cell clones responding to the body 's own antigens, which cause different types of autoimmune pathologies. More than 50% of the elderly different autoantibodies can be detected, but not at high concentrations. Therefore, rheumatoid factor causes the emergence of signs of arthritis but not as pronounced as in true rheumatoid arthritis, but a rare person in old age does not suffer from joint pain, considering them only consequence of "salt deposits." Commonly found antinuclear antibodies. It is characterized by the appearance of antibodies to thyroglobulin, causing autoimmune thyroiditis with hypothyroidism. Interestingly, autoantibodies to three major thyroid antigens were found in healthy individuals aged 18-24 years 10.6-14.9% of cases, but in those aged 55-64, this rate increases to 24.2-30.3% (2).
Even senile dementia is a consequence of the appearance of autoantibodies to the elements of the central nervous system. As a result of autoimmune processes appear and symptoms of Parkinson's disease, but also do not reach the intensity observed in Parkinson's disease itself. Autoimmune processes underlie the formation and demyelinating disease with the advent of widespread sclerosis type of multiple sclerosis and muscular dystrophy type myasthenia.
Characteristic of old age is the appearance of signs of paraproteinemia with accumulation of monoclonal immunoglobulin M-components resembling now myeloma.
In the elderly heart failure can not only be ishemic, but also develop as a result of amyloid deposition and fibrosis in the myocardium with the development of its increased rigidity, making it difficult to relax during diastole and reduces cardiac output as a result of "diastolic myocardial dysfunction." In such cases, no medications and surgical procedure, transplantation besides, aren't effective, and able to plasmapheresis at least slow the progression of these processes in myocardium.
Thus, as a result of disorders of certain parts of the immune system in old age there is a wide range of symptoms, more worn out than the corresponding actual nosologic forms of diseases, but it is they who determine the shape of an old man – the slowness of speech and reactions, "absentmindedness and forgetfulness", muscle weakness, stiffness and incoordination movements, etc.
So more and more becomes clearer the picture of disorders of the internal environment, leading to premature aging. Interrupt these vicious circles interdependent violations can only be deletion all pathological products of the body that is able to completely solve only apheresis therapy, mainly – plasmapheresis.
The challenge is to increase the immune potency, which means the extension of the productive middle age while maintaining the level of health and energy, that is, the quality of life on which the creative and physical performance, the opportunity to experience life in all its colors. The challenge is maintaining the "youth to old age," without waiting for the development of the manifesting symptoms of old age prevent their occurrence (29).
As mentioned above, and many autoimmune diseases, as well as old age, creep imperceptibly. For many months, even years growing micro-disorders different units until homeostasis "transition from quantity to quality," when appeared the symptoms of a particular disease. Task is to find these microshears, not turn a blind eye, not regarded as an accident, did not believe that it affects everyone except of ourselves.
Timely primary prevention of diseases will serve as the primary prevention and early aging. And the main point of such prophylaxis is apheresis therapy aimed at removing what can be seen now, and that has not even arisen.
If until recently such procedures plasmapheresis were only available to large specialized centers, but with the advent of Russian plasma filters and affordable portable devices for membrane plasmapheresis “Hemofenix” arises to perform plasmapheresis in any municipal hospital outpatient care, and even in a "day hospital", which significantly expands apheresis therapy possibilities not only treatment, but prevention of widespread autoimmune diseases.