THERAPEUTIC APHERESIS FOR DERMATOLOGY

There are many diseases of skin which are called “skin” only on visible symptoms of the illnesses. In all such cases the valid pathogenetic mechanisms of their development lie inside of an organism. As a rule, the autoimmune, allergic or toxico-allergic frustrations are the reasons of their pathology. And in all these cases therapeutic apheresis has to play a major role in their treatment.
Key words:  Autoimmune skin diseases, allergic dermatitis, Plasmapheresis.


Many skin diseases carry such name only on the manifestation most visible with the naked eye though actually they develop as a result of frustration of structure of the internal environment of an organism.
In particular, the scleroderma (or a systemic sclerosis) is an autoimmune disease and is shown by consolidation (sclerois) of separate parts of face skin, brushes and other parts of a body. Hyperfunction of fibroblast with collagen biosynthesis increase is the cornerstone of generalized fibrosis. The peripheral syndrome of Reynaud – an early and characteristic sign of a scleroderma, has also the internal equivalent in the form of visceral (lungs, heart, kidneys) Reynaud's syndrome. Spasms in combination with defeats of microvessels are the cornerstone of the acro-digital necroses, pulmonary hypertensia, myocardium ischemia. A target organ is microcirculation with damage an endothelium, proliferation of intims and smooth muscles that is followed by microangiopathy and microthromboses. The main triggers of vascular defeats are the increased levels of the antiendothelial antibodies and the VIII and Willebrand factors. With ischemic necroses of fingers found in patients also antibodies against protein annexin-V [1]. 
Combination of a scleroderma to other system autoimmune diseases (polymiositis, SLE), along with the big frequency of detection of autoantibodies, the circulating immune complexes, signs of activation of T-lymphocytes with the high level of cytokins, accurately proves the autoimmune nature and pathogenesis of this disease. Blood plasma of these patients contains antibodies to a wide range of nuclear and cytoplasmatic anti-genes. Except damages of the skin, there are antibodies also against the endothelial cells that defines the accompanying vascular pathology connected with increase in formation of collagen of a fibroblasts with perivascular violations at early stages of an illness. It determines the considerable frequency of a combination of a sclerodermia to damages of kidneys and a myocardium.
The autoimmune nature of an illness also justifies use of a plasma exchange [2]. Z. Szekanecz et al. [3] achieved good clinical effect after a course of the "programmed" plasma exchange with the subsequent introduction of high doses of immunoglobulins performed within a year. There are messages also on efficiency of local ultra-violet radiation of zones of skin damage [4], as well as extracorporeal photochemotherapy [5].
One of types of a scleroderma is the nephrogenic systemic fibrosis known also, as a nephrogenic  fibrous dermopathy. It develops at patients with a renal failure and after transplantation of a liver. It is the possible reason of gadolinum, used for the best contrasting at a magnetic and resonant angiography. It was found in the centers of the corresponding indurative damages of skin [6; 7]. For treatment of such patients with success the plasma exchange was used [8; 9].


Scleromixedema is a system disease with primary generalized damage of skin with papular rash [10]. System manifestations are characterized by damage of lungs, heart, intestines and the central nervous system. In the latter case (a so-called dermato-neuro syndrome) hallucinations, epileptiform spasms, a coma, fevers which are followed by high mortality are observed [11]. As in pathogenesis the essential role is played by autoimmune processes as a monoclonal gammapatiya with hypercoagulation and formation of the neutrophylic aggregates with microcirculation violation, the plasma exchange promoting stop over of neurologic manifestations finds application also [12; 13]


Scleromixedema of Arndt-Gottron is the rare autoimmune disease which is characterized by slow development – in the beginning there are small knots against of skin reddening which progress before drain extensive consolidations of skin with wax-like gloss. At damage of a face rough folds create a mask-like type of facies leonica. At patients lambda-type IgG paraprotheinemia comes to light. Positive results were reached a combination of hormonal therapy against a plasma exchange (to 10 sessions) – the health, the itch, an induration decreased and swelled skin improved [14].


At an autoimmune dermatomyositis, besides skin, also parts of muscular tissue are exposed to degenerate changes. Thus the circulating of the complement fractions (C3b, C4b, C5b-9) and specific immune complexes get into walls of the endomysial capillaries and promote their closing with local ischemia and a necrosis of muscle fibers, a perifascial atrophy. At biochemical research the increased level of a creatininphosphokinase and aldolase in blood serum comes to light.


As well as dermatomyositis, polymyositis can conditionally also be carried in group of skin diseases. Thus there is a damage of muscle fibers by cytotoxic T-lymphocytes, and, perhaps, also antibodies to endogenous muscular anti-genes, mainly to histidyl-tRNK-syntetase (antisyntetase antibodies). By the way, human immunodeficiency viruses also promote migration of lymphocytes in muscle fibers. The autoimmune nature as dermato-, and a polymyositis is proved by detection of anti-Jo-1 and of anti-SSA antibodies, specific to them [15]. It justifies application of a plasma exchange at the myositises [16].


The third form of autoimmune idiopathic inflammatory myopathies is inclusion body myositis, meeting at persons 50-60 years are more senior. It is characterized by eosinophilic  cytoplasmatic inclusions in muscle fibers with emergence in them a bordered vacuoles. It finds also the infiltrates consisting for 30% from macrophages and for 70% from T-cells (CD8). Thus muscular weakness and an atrophy of muscles quadriceps femoris, bend-muscles of forearms (wrists and fingers) develops. Besides the autoimmune mechanism, also hyperproduction of the predecessor beta-amyloid protein which will somehow be transformed in toxic for muscle fibers pathological beta amyloid that reminds also pathogenesis of Alzheimer's disease is possible [17; 18; 19].


Basis of treatment of a dermatomyositis and close to it a polimyositis are corticosteroids, and at resistance cytostatics, and a plasma exchange are added to them also [20; 21; 22; 23]. At a combination of these diseases to other systemic autoimmune processes the plasma exchange is even more necessary. P. Cherin et al. [24] also report about successful experience of use of courses of a massive plasma exchange at 57 such patients. About 15 sessions are done with removal of plasma in volume to 60 ml/kg of body weight with clinical improvement at 54% of patients on average, mainly at the acute or subacute phases of a disease. 
Positive results of treatment of a dermatomyositis by means of a plasma exchange are reached also in our practice that was expressed in reduction of muscular weakness and myalgia, increase in volume of active movements and elimination of a skin itch.


Many researchers point to autoimmune nature of development and such widespread disease, as psoriasis, meeting at more than 2% of people in population [25]. Existence is revealed autoantibodies to skin fibroblasts at these patients, and their quantity correlated with severity and extending of damages of skin [26]. Oppression of a cellular link of immunity and phagocytal activity of neutrophils, and also increase of the content of immunoglobulins and the CIC is revealed. Thus in the progressing psoriasis stage in the CIC, IgA, IgM and IgG prevail, and in stationary – the maintenance only of IgM is increased. At psoriatic arthritis in the CIC the maintenance of IgA and IgM is most raised [27]. It is interesting that in the presence of the increased T-supressors level (CD8) their supressors activity was lower, than in control group (11.4% against 18.1% respectively). Increase of the contents and natural killers (CD16) who can participate in injury of skin of patients with psoriasis is noted.
Morphological basis of psoriasis is the accelerated cell fission of epidermis which is combined with violations of microcirculation in the subject skin vessels. Thus the local hypoxia promotes decrease in intensity of peroxidation of lipids and other violations of cells metabolism of skin. Ultra-violet radiation and hemosorption, stimulating oxidizing processes, have thereby therapeutic effect. Ultra-violet radiation influences also processes of a reproduction of DNA. Hemosorption promotes sharp activation of processes of peroxidation of lipids due to destruction of membrane structures of blood cells. Use of special photosensitizers - psoralen (8-metoxypsoralen) with powerful ultra-violet radiation on a wave 365 nanometers (PUVA-therapy) have more essential effect based in touch psoralen with molecules of DNA and accumulation of the oxidized products in skin that inhibits local proliferative processes [28]. Nevertheless, and usual short-wave ultra-violet radiation appeared not less effective, than PUVA-therapy [29].
A. I. Vilshonkov et al. [30], on the contrary, considered necessary to inhibit processes of peroxidation of lipids with activation of system of antioxidant protection at psoriasis. For this purpose they used intravascular laser radiation of blood at the increasing power of a light stream from 1-2 MW to 18-20 MW on the end of the light guide. The special effect was reached at a psoriatic artropaty – pains decreased and mobility of joints improved. Intravascular photomodification of blood with success is used not only at psoriasis, but also at other types of a chronic dermatosis (the piodermitis, atopic dermatitis, an exudative erythema.
Indirect confirmation of the autoimmune nature of psoriasis are often observed accompanying systemic frustrations –  arthritises (mainly knee joints) and even defeats of the heart valves with a productive and destructive vasculitis, including coronary arteries. In pathogenesis of psoriasis and psoriatic arthritis it is considered one of the leading factors TNF-α and other cytokins [31]. The psoriatic arthropaty as a type of chronic inflammatory process, contributes to development also an amyloidosis, and microvascular disorders of skin are followed by the same vascular disorders in the kidney glomeruli of that emphasizes system character of this illness even more [32].
Dependence of an illness on frustration of structure of the internal environment is confirmed also by success of therapeutic apheresis at psoriasis. The course of treatment thus usually consists of a session of hemosorption, four sessions of a plasma exchange which are combined with blood radiation by ultraviolet or red laser rays and the subsequent enterosorption. By our experience, usually only 20% had an effective course of such treatment at the first application, from the others receiving a positive effect required carrying out two or three courses of such therapy then, improvement was observed at 85% of patients. The cascade plasma exchange also was applied to treatment of psoriasis and a psoriatic arthropaty with success [33].
Considering an essential role of leukocytes (both neutrophils and monocytes, and lymphocytes) in genesis of tissue defeats at psoriasis, toxic cytokins (TNF-α) are offered the monoclonal antibodies blocking TNF-α (infliximab) and methods of selective removal of these cells at a blood transmission through the special columns Cellsorba and Adacolumn (Japan Immunoresearch Laboratoroes Co) [34]. However it is necessary to consider risk of emergence of a lymphoma and inflammatory complications after introduction of an infliximab [35], and, on the other hand, rather high cost of procedures of granulocyte-monocyte-adsorption – over two thousand Euros [36].


Pemphigus and its versions (pemphigus vulgaris, pemphigus foliaceus, pemphigoid bullous), represent group of the serious illness of skin connected with emergence the intradermal bullous under action the anti-epidermal autoantibodies of class IgG against BP180 – an anti-gene of a basal membrane of skin [37; 38]. Autoantibody to desmoglein-3 – to the component of desmosomes form contacts between cells of epidermis break communication between cells, as leads to violation of integrity of an epidermal layer. At pemphigus vulgaris mucous membranes are damaged even [39; 40]. Therapeutic apheresis is also able to help to achieve remission at this extremely serious pathology [41; 42; 43,; 44; 45; 46; 47; 48]. It is noted that the plasma exchange allows to reduce considerably doses of steroids [49; 50]. The plasma exchange combination with photohemo-therapy and immunoadsorption also led to success [51]. 
It was used also extracorporeal photopheresis – after per os reception of a 8-methoxypsoralen (0,5-0,6 mg/kg) it was carried out leukapheresis (after centrifugation of 500 ml of blood was removed from a software package of 50 ml of a leukocyte layer for one cycle, on only 6 such cycles a day) and radiation of this cellular mass by ultra-violet beams (334-446 nanometers). The similar session repeated in 4 weeks with achievement of permanent remission of medicamentous and resistant forms of the bullous diseases of skin [52].
Efficiency also the cascade plasma exchange which allowed reduce a dose of steroids by 3 times is shown [53; 54; 55; 56; 57]. Introduction of high doses of immunoglobulins right after a cascade plasma exchange prevents "rebaund-effect" of increase of pathogenic IgG [58]. C. Günter et al. [59] achieved success only after intensive (weekly, then monthly within 18 months) a plasma exchange course with immunosorption. Nevertheless, it should be noted also possibility of excess removal of the factor XIII at a cascade plasma exchange which is shown development of hypodermic hemorrhages [57].


Vitiligo is considered an autoimmune disease owing to generation and accumulation autoantibodies against anti-genes of melanocytes that leads to emergence of the areas of skin depigmentation. The role of enzyme of a tirosin who participates in process of a melanogenesis is found. Antitirosin antibodies were found in patients with diffusion and local vitiligo; in the first case the maintenance of these autoantibodies was higher [60]. These autoantibodies are produced also at a melanoma, leading to emergence of spots of a depigmentation, similar vitiligos that stretches a peculiar bridge between these diseases [61].


There is evidence of the immune frustration which are the cornerstone of pathogenesis of an alopecia areata (baldness), caused by both genetic factors, and exogenous triggers. Their communication with T-helpers (CD4) and changes of cytokine structure under the influence of the transforming factor β of growth, TNF-α, interferon-γ, interleukin 1α and 1β with accumulation of the antigen presented cells of Langergans in structure of a matrix and between a hair matrix and a nipple, in the peribulbar lymphocytic infiltrates is supposed. It promotes development of autoimmune process, strengthening of apoptosis in a matrix and to violation of conversion in follicles [62; 63]. Among the major starting and additional factors violations of microcirculation, a blood rheology, a hypoxia, products of peroxidation of lipids and other toxins are assumed [64]. Besides, with a focal alopecia were found in all patients the autoantibodies to different anti-genes of the hair follicles belonging to the classes IgM and IgG. It was possible to find out the autoantibodies to a thyroglobulin, cells of adrenal glands and a thyroid gland, smooth muscles cells in such patients, anti-nuclear antibodies, a rheumatoid factor that confirmed the autoimmune nature of this illness even more convincingly [65].
At research of skin bioptates of patients with a focal alopecia existence is revealed autoantibodies to the whole set of anti-genes of skin. Taking into account high concentration of the CIC in blood serum these data also testify to a role of an autoimmune component in pathogenesis and this illness also [66]. 
Rhynofyma who is followed by the expressed increase in volume of a nose, mainly its tip with dense hilly skin of crimson color, is also an autoimmune disease though surgical methods of removal of such excess growths are most often used [67].




Atopic dermatitis (neurodermatitis) is often accompanied by bronchial asthma and allergic rhinitis. Studies indicate activation of cytokines IL-3, IL-4, IL-5, IL-15. Clinical manifestations largely depend on the reactions to exogenous allergens [68]. However, as antigens there may play a role not only products of external origin but also bacterial, in particular – Staphylococcus aureus, which can be identified in 95% of patients with atopic dermatitis. Such bacterial superantigens can activate both local T-cell mechanisms and produce IgE [69].
Duration course neurodermatitis indirect evidence of the ineffectiveness of traditional treatments designed usually to local places of skin lesions. Even hormonal ointments cause only temporary effects. 
The most reasonable pathogenetic approach to the treatment of this skin disease, only to localize lesions, seems therapeutic apheresis aimed at removing allergens from the body, autoantibodies, immune complexes and other pathological metabolites, create a series of vicious circles that break neither the body nor any medications not be able to. That is, treatment should be directed not so much at the local sites of lesions as to eliminate the conditions of their occurrence and chronicity. And the best way it can be achieved by plasmapheresis. From our own experience the best results are achieved by adding to the rate of 4 operations plasmapheresis and also hemosorption with simultaneous ultraviolet or laser beams blood irradiation and subsequent enterosorption [70].
Allergic dermatitis poses also a risk of pregnancy, when many allergy medications pose a risk to the developing fetus and preferred in such cases are also courses of plasmapheresis [71]. 
Described the so-called "hyper-IgE syndrome" when needed to conduct 60 (!) sessions of plasmapheresis for two years to eliminate manifestations of severe dermatitis, which lasted eight years [72].
Local eczema-like dermatitis also has an allergic nature. In particular, periorbital eczema and eyelids dermatitis are a variety of allergic contact dermatitis. The reasons could be eye ointments, creams, eye shadows and makeup, shampoos and even nail polish [73].


Urticaria is episodic and transient allergic skin lesions, although described and chronic urticaria, in which are found in the blood of patients with IgG-antibodies against highly IgE-receptors. Removing them using plasmapheresis leads to clinical remission [74, 75, 76]. Application of the IgG-antibody on immunosorbent provided almost complete disappearance of autoantibodies with regressive disease within 8 months. X. Jiang et al. [77] have achieved the considerable success using cascade plasmapheresis in the case of chronic urticaria resistant to treatment of dexamethasone and gamma globulin.
Given the greater frequency of detection of parasites in these patients (giardiasis, opistorhosis, toxocariasis), it is advisable to carry out additional inspection and detection of parasites prescribe appropriate therapy (tiberal, flag, biltritsid, dekaris). Chronic urticaria may be accompanied by diseases caused by hepatitis B and C, HIV, Epstein- Barr virus, coxsackie A and B, infectious mononucleosis. Thus acute urticaria can become chronic. Chronic urticaria often develops on the background of other autoimmune diseases – chronic hepatitis C, autoimmune thyroiditis [78].


Same episodic angioedema clearly limited skin and subcutaneous tissue, usually affects the lips, tongue, throat, tissues of the orbit. Nevertheless, it is sometimes a danger to life in the propagation of the larynx edema on the development of severe dyspnea. This swelling usually idiopathic, but may be triggered also some drugs administration, including nonsteroidal anti-inflammatory drugs. Pathogenetic mechanism may be the accumulation of bradykinin by inhibiting its degradation mechanisms [79].
Another factor in the pathogenesis of this edema is the appearance of autoantibodies against specific protein that inhibits the complement component C1 (C1- inhibitor), the lack of which contributes to suddenly increased vascular permeability of certain local areas of the vascular bed, most often on the face, abdomen and extremities. Until recently, such a sudden edema accompanying upper airway obstruction could be lethal to 50% of patients. Permitting trigger such a reaction may be an increase in the content of vasoactive peptides of kinin cascade, in particular the already mentioned above bradykinin at allergic reactions [80].


Toxic epidermal necrolysis, or Stephen-Jones's illness, is acute severe and potentially deadly pemphigo-like reaction of skin to some substances, most often on medicines (allopurinol, sulfanilamides, antibiotics, phenytoin, phenobarbital, etc.) [81;  82]. Sometimes play a role viral infections and even "graft-versus-host" reactions at transplantation of stem cells. The lethality thus reaches 25-75%.In their treatment with success is used plasmapheresis [83; 84] and even cascade plasma exchange [85]. The isolated use of corticosteroids is fraught with strengthening of septic manifestations, but in combination with a plasma exchange provides the best results [86].


The necrotic pyoderma (idiopathic pyoderma gangrenosum, Sweet syndrome, pustular dermatosis) is characterized as a neutrophilic urticarial dermatosis and is followed by the pains, necrotic ulcers surrounded with eritema zones. Intracutaneous inflammatory infiltrates consist from the mature polymorphic nuclear leukocytes. Method of a choice is corticosteroid therapy, but also the plasma exchange is used [87].

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