COLLAGENIC DISEASES (synonym: collagenoses, diffusion diseases of connecting fabric) — the group concept combining several diseases at which diffusion defeat of connecting fabric and vessels is noted. P. Klemperer with soavt, in 1942 suggested to call a diffusion collagenic disease some diseases which are anatomically characterized by generalized alteration of extracellular components of connecting fabric, first of all collagenic fibers and the protein which is their part collagen (see). This group of diseases included a system lupus erythematosus and a system scleroderma, and later — a dermatomyositis and a nodular periarteritis, a pseudorheumatism and rheumatism, a serum disease. To emphasize truly system character of the first four from them, E. M. Tareev (1962) suggested to call them big collagenoses. In the 70th definition of these diseases as diseases of connecting fabric gains ground, and the system lupus erythematosus, a system scleroderma and a dermatomyositis are carried to diffusion diseases of connecting fabric (The international classification of diseases and causes of death, the IX review). However «diseases of connecting fabric» — a concept wide, including and the numerous inborn diseases caused by defects of various structures connecting fabric (see), and acquired, preferential inflammatory character, followed immunol, disturbances. The last group is made by «diseases of connecting fabric with immune disturbances» [A. I. Strupov et al., 1970; D. L. Gardner, 1965]. This concept, in effect, wider, than «collagenic diseases».
The concept To. played a huge role in development of rheumatology, exerted a great influence on basic researches in the field of pathology and physiology of connecting fabric, drew attention to big group of general diseases, various on an etiology, but relatives on a pathogeny, in particular on disturbances of an immunogenesis, allowed to develop new approaches to treatment of these diseases corticosteroids. Thus, the terms «collagenic diseases», «collagenoses» which are rather seldom used mark a certain stage of development of science.
In development of the concept To. it is possible to allocate several periods. The first of them, morphological, is connected with association by Klemperer of the listed above diseases on the basis of the general for them patogistol, a sign — fibrinoid change of collagenic fibers of connecting fabric. The second period is characterized by drawing attention to studying a wedge, the picture of diseases differing polisistemnostyo and frequent damage of joints, serous covers, skin, internals, a nervous system, etc. The third period matched development of the theory of F. Burnett about the prohibited cellular clones, with the advent of the doctrine about an autoimmunity as the leading mechanism of development almost all To. This direction was fruitful concerning development of the principles of treatment, immunodepressive in essence.
An important incentive for development of the doctrine about pathology of connecting fabric were M. Bish's conclusions about morfol, independence of connecting fabric, I. I. Mechnikov's doctrine about phagocytal ability of connective tissue cells.
However the foundation of the doctrine about diseases of connecting fabric was laid at the end of the last century by Neymann (E. Neumann, 1880) who for the first time described the tinktorialny properties of the struck connecting fabric characteristic of its fibrinoid change. Later in V. T. Talalayev (1929) and Klinge's works (F. Klinge, 1933) it was shown that fibrinoid changes of connecting fabric are connected with a condition of a sensitization and allergic genesis. A. A. Bogomolts created the harmonious concept fiziol. systems of connecting fabric and its important role in protection of a human body. In a wedge, the relation the doctrine about so-called collagenic diseases underwent essential changes. Having arisen as the doctrine about morfol, proximity of two diseases, it considerably extended in connection with inclusion of secondary syndromes, napr, a hemorrhagic vasculitis at tuberculosis, a septic endocarditis, etc. In sovr. a wedge, practice most of clinical physicians with immune disturbances include system in group of diseases of connecting fabric lupus erythematosus (see) and system scleroderma (see), dermatomyositis (see), a nodular periarteritis (see. Periarteritis nodular ), pseudorheumatism (see) and rheumatism (see), an ankylosing spondylarthritis (see. Bekhtereva disease ), Shegren's syndrome (see. Shegrena syndrome ), etc. As in due time it was wrong to formulate the diagnosis a collagenic disease, a kollagenopatiya, undifferentiated collagenoses, so in the 70th the diagnosis a general disease of connecting fabric is inadmissible, i.e. recognition defined nozol, forms is necessary.
the Aetiology is studied insufficiently, can be the factors however provoking, revealing: medicinal intolerance (antibiotics, streptocides), e.g. at a nodular periarteritis, a system lupus erythematosus (a volchanochnopodobny syndrome — lupus-like syndrome); influence physical. factors — cooling, especially long impact of wet cold, excessive insolation, vibration, physical. injury; a mental injury, endocrine influences at abortions, childbirth, pregnancy; vegatativno-neurotrophic and endocrine factors — dysfunction gipotalamo - pituitary and adrenal system.
Progress of researches of the second half of 20 century allows to discuss a role of a virus in an etiology of these diseases: value of a surface antigen of hepatitis B and antibodies to it at a nodular periarteritis, RNA viruses, clumsy or korepodobny viruses at a system lupus erythematosus. The possibility of virus genesis and others is not excluded To., as in all struck fabrics at a submicroscopy the tubuloretikulyarny inclusions concerning waste products of viruses are found. At all To. find antibodies to a wide range of the RNA-containing viruses: measles, parainfluenza, flu, etc. Inefficiency of the standard methods of allocation of a virus from an organism of the patient allows to speak about To. as diseases integrative at which integration of a RNA virus and a cell of the owner is noted.
Selective defeat of certain people (e.g., only 0,1 — 3% which had streptococcal quinsy get sick with rheumatism) testifies to value of family and genetic predisposition as etiol, a factor To. More and more data in favor of polygenic inheritance collect To.: higher, than in the general population, prevalence in families of patients, especially among relatives there are I degrees of relationship; big frequency among monozygotic, than dizygotic, twins; bigger empirical risk of a disease for sibs (brothers and sisters) in families of patients in comparison with families of healthy. In families of patients To. various diseases of this group meet more often than in population that allows to assume participation of the general genes in inheritance of these diseases. Data on the bigger frequency of some histocompatibility antigens are of undoubted interest at some To., e.g. HLA V-27 at Bekhterev's disease, etc. Stseplennost of this or that gene of HL — A-systems with hypersensitivity to inf. to agents deserves attention as it is proved that carriers of separate HL — A-antigens are characterized by the person immunol, sensitivity to this or that inf. to the agent. The structural similarity of antigens of a microorganism and HLA causing development of cross-reactions, etc. is supposed. Though for the majority To. specific mechanisms of inheritance of predisposition are not known yet, the fact of aggregation (accumulation) To. in certain families deserves attention from the point of view of a possibility of carrying out preventive measures in these families.
These diseases consider a pathogeny a classical example of organonespetsifichesky autoimmune diseases which characteristic features are: 1) hypergammaglobulinemia; 2) existence of autoantibodies; 3) detection in the center of defeat of complexes antigen — an antibody; 4) accumulation in the struck fabrics of the plasmatic and lymphoid cells concerning products of the circulating antibodies and cellular reactions; 5) efficiency of corticosteroids and (or) other immunodepressants; 6) combination to such autoimmune diseases (syndromes) as Hashimoto's thyroiditis, hemolitic anemia, Werlhof's disease, etc. Initial link of any immunopatol. process stimulation of immunocompetent system any antigen probably various for everyone is To., but Always with participation autoantigen (see), the strengthened development autoantibodies (see) and unambiguous for all To. result — the immune disturbances having the idiosyncrasies at each of them. A big role in emergence of autoantigens at To. play lysosomes (see), carriers of acid hydrolases. Release of acid hydrolases in the centers of disorganization of connecting fabric strengthens hydrolytic decomposition of fabrics and cells, promotes emergence of autoantigens and formation of autoimmune reactions. Electronic microscopic examination shows increase in number of lysosomes in a myocardium at rheumatism, in cells of a synovial membrane at a pseudorheumatism. High activity of lizosomalny enzymes is found in cells of a rheumatic granuloma, in synovial fluid at a pseudorheumatism. Veyssmann (G. Weissmann, 1964) observed provocative action of labilizator of lysosomes (UV rays, vitamin A) in cases of emergence and an aggravation of a system lupus erythematosus — diseases with the most pronounced autoimmune disorders.
Thus, autoimmune mechanisms of a pathogeny are characterized by that, something the circulating antibodies, or fabric immunocompetent cells are directed against antigens of own fabrics (see. Autoallergichesky diseases ). At a system lupus erythematosus of an autoantibody are active against native DNA of kernels of cells of any localization, at a pseudorheumatism — against the changed (aggregated) human gamma-globulin, etc. It demonstrates loss of ability of recognition personal and others'. For all To. considerable disturbance of a humoral link of the immunity connected with V-lymphocytes and which is shown impetuous products of various autoantibodies is characteristic. At a system lupus erythematosus, e.g., find autoantibodies not only to native DNA, but also to DNA with the changed secondary structure (one-spiral, with despiralizovanny sites), to nucleoproteid (to the DNA complex + a histone), to integral kernels of cells (the antinuclear factors revealed by method of an immunofluorescence), and also to cytoplasmatic components of a cell, etc. At To. also autoimmune syndromes connected with the circulating antibodies, napr, autoimmune hemolitic anemia or autoimmune thrombocytopenia can develop.
Immunocomplex pathology is the cornerstone immunopatol. the syndromes developing at To. A classical example of immunocomplex pathology is the glomerulonephritis at a system lupus erythematosus (lyupus-nephrite) caused by circulation in blood of sick complexes native DNA — antibodies to DNA — a complement. Complement deflection (integral or its components — the third, fourth, fifth, etc.) leads to activation of system complement (see), to release of factors of a chemotaxis with attraction in the center of an inflammation of polynuclear leukocytes and other cells of an inflammation. At destruction of these cells there is a release of lizosomalny enzymes in extracellular space and development of inflammatory reaction. As the system of a complement plays an important role in formation of cell-bound immune complexes, there is a consumption of a complement and the gipokomplementemiya at lyupus-nephrite develops or decrease in a complement in synovial fluid at a rhematoid synovitis. So considerable disturbance of humoral immunity is caused by disturbance of cellular immunity and its controlling functions concerning humoral immunity. It is supposed that inborn deficit of T lymphocytes takes place; besides, they can collapse under the influence of found in patients To. limfotsitotoksichesky autoantibodies and influence of viruses, etc. Cellular immunity plays an important role at many To.
From other mechanisms of development To. the disturbance of metabolism of collagen inherent to all diseases of this group draws to itself attention. Most brightly this pathology is shown at a system scleroderma and a pseudorheumatism at which the increased speed of biosynthesis of collagen, formation of less steady collagenic structures with the increased disintegration and a tendency of development of excess fibrosis is noted.
the Pathoanatomical basis To. make immunopatomorfol. the changes having allergic genesis (see. Allergy ); defeat of a microcirculator bed (mikroangiopatiya), vessels of small and average caliber; the system progressing disorganization of connecting fabric. The combination of these processes gives a characteristic picture of an inflammation on an immune basis (see. Inflammation ). Changes of connecting fabric at different To. are characterized by various preferential localization patol, process: at rheumatism connecting tissue of heart is surprised, at a pseudorheumatism — joints, at a system scleroderma — skin, a nodular periarteritis — walls of vessels of small and average caliber, at a system lupus erythematosus there is a generalized defeat of connecting fabric. Dermatomyositis (see) not all morphologists carry to group K., since it morfol, a basis are dystrophic changes of skeletal muscles with secondary inflammatory processes in intermuscular connecting fabric though on a nek-eye immunol. to indicators it comes nearer to To.
Intense Immunol. activity at To. it is shown by a row morfol, changes in an adenoid tissue and in patholologically the changed bodies and fabrics and reflects reactions of hypersensitivity both the immediate, and slowed-down type. So, are noted a hyperplasia limf, nodes, spleens, proliferation in them an adenoid tissue with the advent of the germinal centers, revival of macrophagic reaction. In limf, nodes, a spleen, marrow, almonds, a thymus there is a proliferation of plasmablasts and plasmocytes — producers of immunoglobulins that is confirmed by an immunofluorescent research. In the struck bodies and fabrics, napr, in a synovial membrane at a pseudorheumatism, there are infiltrates consisting of immunocompetent cells: lymphocytes, macrophages, plasmocytes (tsvetn. fig. 1); components of cell-bound immune complexes (fig. 1 and 2) are defined by method of an immunofluorescence: immunoglobulins, complement. Degree immunomorfol. changes reflects tension patol, process therefore results of a biopsy limf, nodes, marrow (see. Trepanobiopsiya ) and the struck bodies allow to judge N activity of a disease.
Defeat of vessels of microcirculation, increase in vascular and fabric permeability, development of vasculites is important kliniko-morfol. manifestation To. It is established that damage of walls of terminal vessels is caused by sedimentation (precipitation) in them cell-bound immune complexes. Pathogenic properties of the last are defined by surplus of content of antigen over an antibody, aggregation of molecules of antibodies as a part of a complex and presence of the activated components of a complement having cytopathic and hemotaksichesky property.
At electronic microscopic examination cell-bound immune complexes have an appearance of deposits (fig. 3) localized in membranes of capillaries of balls and vessels of skin (a system lupus erythematosus), synovial fabric (pseudorheumatism) on a sarcolemma of muscle fibers of a myocardium and in a wall of capillaries (rheumatism).
As a result of the damaging action of these complexes vascular permeability increases, there are a plasmorrhagia, fibrinoid changes of walls of vessels, proliferation of an endothelium, spasms and expansion haemo - and limfokapillyar, perivascular lymphoid and macrophagic infiltration (fig. 4), the quantity of mast cells on the course of capillaries increases. So, at To. there are vasculites, capillarites sometimes accepting generalized character. In addition to changes of a microcirculator bed, at To. there are changes of arteries of small and average caliber. Fibrinoid necroses of their walls (fig. 5), fibrinferment of a gleam, a trombarteriita are observed.
The system progressing disorganization of connecting fabric defines morphology To. also develops on the basis of disturbances of an immunogenesis and microcirculation. Disorganization of connecting fabric concerns all its components (fibrous structures, interstitial amorphous substance, cells, vessels of microcirculation, nerve fibrils) with secondary involvement in process of a parenchyma of bodies. Founders of the doctrine about To. Klemperer, Pollack, Rem (P. Klemperer, A. D. Pollack, G. Baehr, 1942) considered that defeat of connecting fabric is limited to its fibrinoid swelling (see. Fibrinoid transformation ). However, as showed the subsequent researches, fibrinoid swelling is not a specific character To. also makes only one of components of disorganization of connecting fabric. Soviet scientific G. V' researches. Oryol (1958), A. I. Strukov and D. G. Beglaryan (1963) it is shown that process of disorganization of connecting fabric has four phases.
First phase — Mucoid swelling. It is characterized by redistribution and accumulation in amorphous substance of connecting fabric of acid mucopolysaccharides — glikozaminoglikan (a hondroitinsulfat, hyaluronic to - you and neutral mucopolysaccharides) in connection with their release from complexes with proteins. Connecting fabric gets at the same time metachromatic (see. Metachromasia ) and hydrophilic properties, it is enriched with water and bulks up (tsvetn. fig. 2).
The ultrastructure of collagenic fibers at mucoid swelling is not damaged that allows to consider this stage as manifestation of superficial disorganization of connecting fabric. Allocation of mucoid swelling is very important since, on observations of specialists, it is a reversible phase of disorganization and at this stage process can spontaneously stop or as a result of treatment.
Second phase — fibrinoid swelling of connecting fabric (emergence of fibrinoid) which is characterized by penetration into fabric owing to its hyperpermeability of proteins of plasma: albumine, globulins, fibrinogen which in fabric quickly turns into fibrin. Acid mucopolysaccharides enter insoluble compounds with fibrinogen upon its transition to fibrin and are laid both on collagenic fibers, and between them. During this process there is patol, a recombination of fabric and plasma proteins and polysaccharides. All this again formed heterogeneous weight impregnating connecting fabric carries the name of fibrinoid; in it it is always possible to find cell-bound immune complexes. The ultrastructure of collagenic fibers is broken up to a fibrinoid necrosis. The described changes have irreversible character.
Third phase — development of the cellular reactions having focal (small knots, granulomas) or diffusion character, which clearly are coming to light at development of fibrinoid swelling and a necrosis. Around the centers of the last proliferation of histiocytes, fibroblasts, macrophages is observed, big and small lymphocytes, plasmocytes appear. At some To. cellular reactions have the features. So, at rheumatism cellular reactions have character of the small, defined under a microscope granulomas arising in okolososudisty connecting tissue of a myocardium and in an endocardium (rheumatic small knots of Ashoff — Talalayeva), at a pseudorheumatism there are large, seen by an eye rhematoid nodes in circumarticular fabric (under a microscope — a fibrinoid necrosis of circumarticular connecting fabric with cellular histiocytic and macrophagic reaction around; tsvetn. fig. 3), is more rare in other fabrics. At a system lupus erythematosus cellular reactions have preferential diffusion plazmokletochny character with impurity in cells of gematoksilinovy little bodies, and in blood — LE cells (fig. 6).
Fourth phase — development sclerosis (see) which arises in connection with proliferation of cells of a fibroblastichesky row and the subsequent kollagenoobrazovaniye. Less often the sclerosis develops in the result of fibrinoid change in the way hyalinosis (see). Sclerous changes cause such essential manifestations To., as heart diseases at rheumatism, ankiloza of joints at a pseudorheumatism. Feature of a sclerosis at To. its incomplete character in connection with a defective fibrillogenesis because of what in sites of a sclerosis the aggravation of process is possible is.
For To. simultaneity of manifestations of various phases of disorganization of connecting fabric, existence as fresh changes is characteristic (at an aggravation To.), and older processes. Hron, a wavy current To., constant change of the periods of a zatikhaniye and aggravation of process, a lamination of one phase of disorganization with another create polymorphic morfol, a picture of fabric changes.
Broad use corticosteroids (see) and immunodepressive substances (see) at treatment To. changed as clinical, and morfol, their picture that is pathomorphism (see). Fibrinoid changes, exudative processes quite often are absent or are poorly expressed; strengthening of cellular reactions with development of productive capillarites and vasculites, and also a sclerosis of walls is possible. Reactions of hypersensitivity of the slowed-down type with poorly expressed exudative phenomena begin to prevail over reactions of immediate type.
A clinical picture
Despite a big originality separate nozol, forms, all To. such general are inherent a wedge, symptoms as fever, arthritises (polyarthritises) recuring polyserosites, and also a variety of visceral pathology: myoendocardites, glomerulonephritis (or amyloidosis of kidneys), damage of a liver and hepatolienal syndromes, generalized lymphadenopathy and other syndromes.
A current To. in most cases recuring and progressing. More detailed data about a wedge, manifestations separate nozol, forms are given in the table.
in the presence of classical a kliniko-lab. signs the diagnosis comes easy. It is necessary to emphasize great diagnostic importance of definition of various circulating antibodies — antinuclear and rhematoid factors, antibodies to native DNA, etc.
A certain help in diagnosis To. can render rentgenol. research. Rentgenol, a picture at the first stages of development of a disease can be scanty, in the period of expressed a wedge, manifestations — very various. At To. are observed as the general rentgenol, the signs inherent to all diseases of this group, and private, distinctive, the most characteristic of a specific disease. So, e.g., at defeat of a musculoskeletal system by the general rentgenol, signs for all To. are osteoporosis (see) and narrowing of joint cracks of various degree of manifestation. It is possible to carry an uzuration of joint surfaces at a pseudorheumatism to the distinctive rentgenol, signs developing against the background of these signs (see), enostoza of distal phalanxes and aseptic necroses of joint surfaces of large joints at a system lupus erythematosus (see), ossifluences of distal phalanxes and calcification of soft tissues at system sclerodermas (see). At damage of heart rentgenol. the picture is characterized by change of its configuration, the size, contours, situation and pulsation. Combination rentgenomorfol. and rentgenofunkts. signs, degree of their expressiveness and the loudspeaker are various. The most various and numerous symptomatology is observed at rheumatism (see). At a pseudorheumatism signs appear not at once, are a little expressed. Are characteristic of a system scleroderma rentgeno-funkts. signs — disturbance of sokratitelny ability of a myocardium, etc.
In view of the fact that rentgenol, signs are not specific, clinical and differential and diagnostic value rentgenomorfol. and rentgenofunkts. signs depends not only on degree of their expressiveness, dynamism and a combination among themselves, but also on communication about a wedge, manifestations of a basic disease.
The transitional, combined and boundary forms at which the diagnosis of this or that nozol, forms cannot be put are observed. Boundary options of a pseudorheumatism and a system lupus erythematosus, a dermatomyositis and a system scleroderma or a system lupus erythematosus are that. If at the combined or boundary forms it is about a combination at one patient of syndromes of two (three) diseases, then at transitional are observed immunol, and morfol, decussations, napr, bright antinuclear reactions at a pseudorheumatism.
At To. early recognition defined nozol, forms of a disease and an initiation of treatment in the earliest period of a course of a disease when it gives the best effect is especially important. Treatment shall be strictly individual, based on the diagnosis, assessment of sharpness of a current (option of disease), its stages and activity patol, process.
The philosophy of treatment is staging: a hospital — out-patient clinic — sanatorium (local, climatic, balneal); at the same time at the first stage carry out antiinflammatory and immunodepressive therapy, become the attempt of appointment immunostimulating (stimulation of T lymphocytes) therapies. At the second stage carry out a maintenance therapy, and on the last — rehabilitation. For antiinflammatory therapy use the numerous drugs suppressing various links of a pathogeny. Along with salicylates and pyrazolon drugs indometacin, derivatives alpha-toluic were widely adopted to - you are (Brufenum). Immunodepressive therapy is also various. Classical immunodepressants are the glucocorticosteroids possessing a broad spectrum of activity including and on metabolism of connecting fabric; they are shown at inefficiency of antiinflammatory therapy, high activity of process and bystry progressing of a disease, heavy visceral processes, especially at defeat of nights, c. N of page. At inefficiency of glucocorticosteroids appoint immunodepressants of cytotoxic action of the alkylating row (cyclophosphamide) or metabolites (Azathioprinum). However cytotoxic drugs are appointed also according to special indications: at the expressed side effects of glucocorticoids and need to continue immunodepressive therapy; at hypersensitivity to kortikoida, quite often observable at women in a climacteric and at teenagers; at corticosteroid dependence. At a pseudorheumatism and a system scleroderma the D-Penicillaminum suppressing formation of a rhematoid factor and influencing metabolism of collagen, etc. can be means of the choice. Basic therapy by gold (is of great importance at a pseudorheumatism), and also aminoquinolinic derivatives. Physiotherapeutic treatment is shown at all low-active forms K., especially at a pseudorheumatism, the system scleroderma, Bekhterev's disease, but is not recommended at a system lupus erythematosus and a dermatomyositis, and also a nodular periarteritis at which the aggravation can develop. Treatment in local sanatoria is shown, indications at the direction are more limited on klimatobalneol. resorts. Treatment in these resorts is recommended by a sick pseudorheumatism, Bekhterev's disease, a system scleroderma in a stage a wedge, remissions or with signs of the I degree of activity. It is important not to interrupt at this stage of drug treatment because of danger of development of a balneoreaktion and a heavy exacerbation of a disease.
Timely, correct, complex therapy, including and rehabilitation (to lay down. the gymnastics, corrective procedures, employment, psikhol, and social rehabilitation), allows is long to keep rather satisfactory condition of patients and even working capacity.
Primary prevention is not developed, however it is reasonable to allocate group of the increased risk — members of families of patients To. the lake, especially what have small symptoms of a disease (hypersensitivity to drugs, insolation, cooling, a leukopenia, inexplicable acceleration of ROE, Reynaud's syndrome, etc.) and to recommend them the guarding mode. The aggravation and progressing of a disease can be prevented by long continuous immunodepressive or antiinflammatory therapy on condition of systematic observation at the rheumatologist, consecutive performing the appointed treatment, observance of a work-rest schedule.
It is reasonable to recommend to patients to keep the diary of the health and dosages of the medicines used by them, the Doctor in turn shall make annually on each patient a stage epicrisis with the detailed characteristic of a condition of the patient within a year: existence of aggravations, the postponed intercurrent infections and stressful situations, working capacity, changes in treatment, data a kliniko-lab. researches. The entire period of hormonal and cytotoxic treatment patients shall be under constant observation of the doctor. At achievement of full remission glucocorticosteroids cancel, however patients are surveyed within 2 — 3 years; once in a year carry out by him antirecurrent treatment to the autumn and spring periods (anti-malarial drugs, vitamins intramusculary and inside).
At diseases in which pathogeny the infection (e.g., streptococcal matters at rheumatism) prevention consists in elimination of a possibility of its emergence or an aggravation.
Table. Short etiological, pathogenetic, morphological and clinical characteristic of collagenic diseases
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V. A. Nasonova; A. I. Strukov (stalemate. An), Yu. S. Homyakov (rents.), author of the tab. V. A. Nasonova.