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PLASMAPHERESIS FOR AUTOIMMUNITY


Voinov V.A.
I.P.Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia.
Abstract
Autoimmune 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.
Key words: autoimmune diseases, plasmapheresis.
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

2
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.

3
The most common tactic for treatment of autoimmune diseases is based on a twodrug 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
efferent therapy 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
our country, 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.

4
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

5
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 efferent therapy 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, efferent
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 efferent therapy can
slow the progression, push the onset of irreversible organ and systems damage.

6
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, has 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 allowed to
stabilize or improve the process for kidney and increase survival of patients (12).
Especially

shown

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, even their number reaches 10 million people
(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
immunopathogenicity 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 sharp 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

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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 phenomenon,
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
efferent 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

8
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 efferent 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 heavy progressive nervous disease are based on an autoimmune
pathogenesis, which is considered essential in myasthenia gravis, Guillain-Barr
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 efferent therapy also takes a
significant place in their treatment (27).

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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 sharply 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 [29].
In diabetes type 2 also revealed pronounced metabolic changes in these patients
are prone to obesity [30]. 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 efferent 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 [33]
A.O.Gavrilov et al. [34] 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
[35].
At autoimmune thyroiditis the thyroid gland there is exposed autoantibodies and
immune inflammation occurs with initial excitation of its functions and phenomena
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

10
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
efferent 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, and 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.

11
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, not effective, and able to plasmapheresis at least
slow the progression of these processes in myocardium.
Thus, as a result of disorders of individual 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 efferent 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 efferent 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 efferent therapy possibilities not only treatment, but
prevention of widespread autoimmune diseases.

12

References
1. Chereshnev V.A., Yushkov B.G., Gavrilova T.V. et al. [From immunophysiology to
immunopatophysiology] // Allergology and immunology (Rus) - 2006. - Vol. 7, 3. - P.
242-243.
2. Lyutfalieva G.T., Dobrodeeva L.K., Petrenya N.N., Moser A.A. [On the physiological
role autoantibody formation] // Allergology and immunology (Rus). - 2006. - Vol. 7, 3.
-P.253-254.
3. Zaichik A.S., Churilov L.P. [General pathophysiology of the basics of
immunopathology]. - St. Petersburg: St. Petersburg-Albee. (Rus) - 2008. - 624 p.
4. Barnabe V., Sinigaglia F. Molecular mimicry and T cell-mediated autoimmune disease
// J. Exp. Med., 1997, V. 185, 9, P. 1529-1531.
5. Boye J., Elter T., Engert A. An overview of the current clinical use of anti-CD20
monoclonal antibody rituximab // Ann. Oncol. 2003. Vol. 14. P. 520-535.
6. Rodriquez-Ferrero M., Ampuero J., Anaya F. Rituximab and chronic plasmapheresis
therapy of nephrotic syndrome in renal transplantation patients with recurrent focal
segmental glomerulosclerosis // Transplant. Rroc. 2009. Vol. 41, 6. P. 24062408.
7. Ruch J., McMahon B., Ramsey G., Kwaan H.C. Catastrophic multiple organ ischemia
due to an anti-Pr cold agglutinin developing in a patient with mixed cryoglobulinemia
after treatment with rituximab // Am. J. Hematol. 2009. Vol. 84, 2. P. 120-122.
8. Kim Y.J., Song M., Ryu J.C. Mechanism underlying methotrexate-induced pulmonary
toxicity // Expert. Opin. Drug. Saf. 2009. Vol. 8, 4. P. 451-458.
9. Voinov V.A. [Efferent therapy. Membrane plasmapheresis] / Moscow, 2010. 400 p.
(Rus).
10. Voinov V.A., Dzadzua D.V., Zakharova A.C. et al. [Efferent therapy of fibrosing
alveolitis] // Efferent and Physicochemical Medicine (Rus). - 2009, 1. - P. 71-73.
11. [Disseminated pulmonary disease] / ed. M.M.Ilkovich. - M., "Geoetar Media ."
2011. 470 p. (Rus).
12. Komyagin Yu.V., Milovanov Yu.S. [Plasmapheresis in the treatment of patients with
rapidly progressive glomerulonephritis in systemic diseases] // Proc. of reports. VIII
Conference of Moscow. society Hemapheresis. - M., 2000 - P.31 (Rus).
13. Shelukhin V.A., Kostjuchenko A.L. [Efferent therapy in renal diseases and damages]
// Efferent therapy / Ed. A..L.Kostyuchenko. - St. Petersburg: Folio, 2003. - P. 268-302.
(Rus).
14. Schechtman M.M. [Acute viral hepatitis: perinatal outcomes] // Obstetrics and
Gynecology. (Rus) - 2000. - 4. - P. 3-6.

13
15. Rakhmanova A.G., Belyakov N.A., Vinogradova T.N., Volkova G.V. [Service
development of HIV and chronic viral hepatitis in St. Petersburg for 20 years] // HIV
infection and immunosuppression. (Rus) - 2010. - Vol. 2, 1. - P. 7-15.
16. Demchilo A.P., Javoronkova S.V. [Organ-specific and organ-nonspecific
autoantibodies in chronic HCV-infection] // Allergology and immunology. (Rus) - 2006. Vol.7, 3. - P. 397-398.
17. Wilson L.E., Widman D., Dikman S.H., Gorevic P.D. Autoimmune disease
complicating antiviral therapy for hepatitis C virus infection // Semin. Arthritis Rheum.
2002. Vol. 32, 3. P. 163-173.
18. Puncher K.P., Berg T. Extrahepatic manifestations of chronic hepatitis C virus
infection // Z. Gastroenterol. 2009. Vol. 47, 5. P. 446-456.
19. Voinov V.A. [Autoimmune mechanisms of chronic hepatitis and indications for
efferent therapy] // Efferent Therapy (Rus). - 2000. - Vol. 6, 2. - P. 36-39.
20. Stuckov B.V., Portnoy O.A., Popov D.V., Gluschenko G.P. at al. [Extracorporeal
blood correction in patients with severe chronic hepatitis] // In: "Efferent and physicochemical methods of therapy", Mogilev, 1998 - P. 81-83 (Rus).
21. Poletaev A.B. [Immunology of pregnancy and embryotropic autoantibodies[ // Herald
"MEDSI." (Rus) - 2010. - 8. - P. 38-44.
22. Makatsaria A.D., Bizadze V.O. [Thrombophilia and antithrombotic therapy in
obstetric practice]. - M.: " Triada- X ", 2003. 904 p.(Rus).
23. Morozov B.N., Mogireva I.A., Mebonia N.C. et al. [The effectiveness of
plasmapheresis in microvascular angina and radioisotope research methods] // Proc . of
reports.of XIV Conference of Moskow. Hemapheresis society. - M., 2006. - P. 27.
24. Mukhtyar C., Brogan P., Lugmani R. Cardiovascular involvment in primary systemic
vasculitis // Best Pract. Res. Clin. Rheymatol. - 2009 . - Vol. 23 , 3 . - P. 419-428 .
25. Konyaev B.V. [Antiphospholipid syndrome] // Clin. Med. (Rus) - 1997, 4 - P.52
-54.
26. Glueck C.J., Lang J.E., Tracy T. et al. Evidence that anticardiolipin antibodies are
independent risk factors for atherosclerosic vascular disease // Am. J. Cardiol. - 1999 . Vol. 83 , 10 . - P. 1490-1494 .
27. Linker R.A., Gold R. Use of intravenous immunoglobulin and plasma exchange in
neurological disease / / Curr Opin Neurol. - 2008 . - Vol. 21 , 3 . - P. 358-365.
28. Kostjuchenko A.L. [Extracorporeal haemocorrection in endocrinology] // Efferent
therapy / Ed. A.L.Kostyuchenko . - St. Petersburg: Folio, 2003 . - P. 303-338. (Pus)
29. Nagornev V.A., Denisenko A.D. [Diabetes mellitus and atherosclerosis] // Med.
Acad. J. (Rus) - 2008. - Vol. 8, 1. - P. 159-167.
30. Prins J.B., Niesler C.U., Winterford C.M. et al. Tumor necrosis factor- induces
apoptosis of human adipose cells // Diabetes. - 1997. - Vol. 46, 12. - P. 1939-1940.
31 Kivva V.N., Anoufrienko V.F., Redkina L.V., Cherkashina S.F. [Application of
plasmapheresis in the complex therapy of metabolic syndrome X] // Proc. of reports. VII
Conference. Of Moskow. Hemapheresis society. (Rus) - M., 1999. - P. 72.
32. Grundy S.M. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome //
Am. J. Cardiol. 1999. Vol. 83, 9B. P. 25-29.
33. Shelukhin V.A., Kostjuchenko A.L. [Efferent therapy in diseases and damages renal]
// In: Efferent Therapy/ Ed. A.L.Kostyuchenko. (Rus) - St. Petersburg: Folio, 2003. - P.
268-302.
34. Gavrilov A.O., Yepifanova N.Y., Korolev M.L. [Regulation and other systemic
disorders of blood aggregation in patients of elderly and senile age]. (Rus) - Moscow,
2003. - 113 p.

14
35. Voinov A.V., Voinov V.A., Karchevskii K.S., Libov I.V. [Plasmapheresis in the
treatment of diabetic angiopathy] // Proc. of reports. XI Conference of Moskow
Hemapheresis society. - M., 2003 - P. 20. (Rus).
36. Lopukhin Y.M. [Efferent therapy and the problem of longevity] // Efferent Therapy
(Rus). - 1996, Volume 2, 1. - P. 3-7