From Big Medical Encyclopedia

SHYOGRENA DISEASE (H. S. Page of Sjogren, Swedish ophthalmologist, sort. in 1899; synonym: the isolated dry syndrome, primary syndrome of Shegren) — the general autoimmune disease which is characterized by the dryness of mucous membranes caused by lymphoid infiltration of excretory glands. Lymphoid infiltration in many cases accepts generalized character with involvement in process of muscles, digestive tract, lungs, kidneys, reticuloendothelial system, with development in nek-ry sick limfoproliferativny diseases (see the Lymphoma).

In the International classification of diseases of the IX review of Sh. it is included in group of diffusion diseases of connecting fabric.

The description of separate clinical displays of a disease appeared at the end of 19 century (see Shegren a syndrome), but only in 1965. Fleas (To. J. Bloch) and sotr. for the first time distinguished from patients with Shegren's syndrome of patients with the so-called isolated dry syndrome, at to-rykh there were no reliable symptoms of any autoimmune disease which is usually found at Shegren's syndrome. It was later many researchers it is shown that the isolated dry syndrome has a number of the clinical, serological and genetic features allowing to distinguish it in the independent nosological form called Shegren's disease.

III. occurs at women by

10 — 25 times more often than at men, usually at the age of 20 — 50 years, preferential at persons 30 years are more senior. Though special researches on studying of prevalence of Sh. it was not carried out, the weight of evidence suggests, that this disease meets at least, and, perhaps, even more often than other diffusion diseases of connecting fabric (see. Collagenic diseases).

The etiology is unknown. A number of researchers would consider Sh. as a result of development of immunopathological reactions to various microbic, viral and other antigens. The virus hypothesis of development of Sh. is known., based on detection of virus-like tubulore-tikulyarny structures in an epithelium of sialadens and identification in blood of patients of the increased level of antibodies to a cytomegalovirus. As assume E. J. Shillitoe with sotr. (1982), the cytomegalovirus can be an etiological factor of development of Sh., however the direct evidence of a virus etiology of a disease it is not obtained yet.

The pathogeny is up to the end not found out. The most recognized would be the hypothesis of autoimmune genesis of Sh., in advantage the cut testifies frequent detection at patients as organospetsifichesky and uto antibodies (to an epithelium of channels of sialadens and a pancreas, covering cells of a stomach, etc.), and organonespetsifichesky, such as rhematoid, antinuclear factors and antibodies to soluble nuclear antigens. One more indirect argument in favor of this hypothesis is frequent defeat of excretory glands at autoimmune diseases, such as a pseudorheumatism, a system lupus erythematosus, chronic active hepatitis, biliary cirrhosis, and also development of manifestations of Sh. at a disease of the New Zealand mice (NZB/NZW), autoimmune genesis the cut is conventional. Description of family cases of III., considerable distribution in sick Sh.' families. other autoimmune diseases, detection of a hypergammaglobulinemia at relatives of patients assumes genetic determinancy of a disease. As it was shown by many researchers, at Sh. histocompatibility antigens of HLA Dw3 and HLA B8 decide on the increased frequency. An essential role in Sh.'s pathogeny. belongs to disturbances in T - and V-kletoch-nykh systems of immunity. R. I. Fox and sotr. (1983) would note at Sh. increase in activity T-helperov that leads to chronic stimulation of V-lymphocytes. The deepest disturbances of T - and V-cellular systems of immunity would be observed at bolyshkh by Sh. with multiple system manifestations. The immunofluorescent research of the material received at a biopsy of sialadens of lungs and kidneys reveals high content of T - and V-lymphocytes, and also plasmocytes. At early stages of a disease in lymphoid infiltrates a large number of V-lymphocytes is found, in later stages the maintenance of T lymphocytes accrues, it is preferential T-helperov. Infiltriruyushchy fabrics, V-limfotsi-ty and plasmocytes produce a large amount of immunoglobulins and rhematoid factors (see). A part of patients can have a malignant proliferation of V-lymphocytes with development of lymphoma eventually.

Pathological anatomy. The main changes come to light in salivary and lacrimal glands. Infiltration of fabric of glands lymphoid, plasmatic and reticular macrophages (fig. 1) is characteristic. The stroma of glands usually remains, the lobular structure them is not broken (it allows to carry out differential diagnosis with an adenosis at lymphoma).

Fig. 1 are noted. Microdrug of small salivary gland of an under lip at a late stage of a disease of Shegren: infiltration of a parenkha

we are glands plasmatic and lymphoid cells (J), proliferation of epithelial and myoepithelial cells of a channel (2) with deformation of its gleam, formation on site of a channel of myoepithelial «islands» (3); coloring hematoxylin-eosine; X 300.

dystrophic changes of the epithelial cells covering channels of salivary and lacrimal glands in gleams of channels the condensed secret is defined. Channels are partially expanded. Proliferation of korzinchaty (myoepithelial) cells is observed that leads to occlusion of channels and formation of so-called myoepithelial «islands». Meet as well eosinophilic leukocytic infiltrates, emergence to-rykh it is connected with accession of consecutive infection. In late stages of a disease the full atrophy of an acinus with substitution of salivary and lacrimal glands fatty tissue can be observed. As a rule, there is a parallelism between lymphocytic infiltration and an atrophy of an acinus though sometimes the expressed infiltration can be combined with almost normality of an acinus and, on the contrary, a considerable atrophy of an acinus — with almost total absence of lymphocytic infiltration. Similar changes are found in glands of a mucous membrane of a nasopharynx, bronchial tubes, a stomach, vagina and sweat glands.

Clinical picture. Clinical manifestations of III. it is possible to divide into two categories: the symptoms connected with hypofunction of excretory glands (dryness of mucous membranes of an oral cavity, nasopharynx, trachea, an eye, vaginas, went. - kish. path); system manifestations (e.g., recurrent not erosive arthritis, miositis, intersticial nephrite, hemorrhagic vasculitis).

The most constant symptom of Sh. the dry keratoconjunctivitis (see Conjunctivitis) caused by decrease in secretion of the lacrimal liquid is. Patients often complain of a burning sensation or a thermalgia, described by them as «scratch» and «sand» in eyes; these feelings amplify at the movement a century. The century, reddening, accumulation viscous white separated in corners of eyes is quite often noted an itch. Later there is a photophobia, narrowing of palpebral fissures and decrease in visual acuity. In hard cases of a dry keratoconjunctivitis extensive helcomas develop that can lead to perforation or to permanent opacification of a cornea (cataract) with total loss of sight. Reduction of quantity or lack of the lacrimal liquid and decrease in the maintenance of a lysozyme in it, and also leads change of structure to constant presence of microflora at conjunctival sacs, Staphylococcus aureus, with development of recurrent or chronic bacterial conjunctivitis is more often. Increase in the lacrimal glands would meet at Sh. seldom. At a number of patients, especially in an early stage, complaints can be absent and dystrophic changes of an epithelium of a conjunctiva and cornea come to light only at purposeful survey of the oculist.

Second basic and constant sign of Sh. the defeat of sialadens leading to development of chronic parenchymatous parotitis (see) is. The recurrent course of parotitis, with the periodic aggravations which are followed by pains, diffuse hypostasis of fabrics of sialadens and temperature increase to 38 — 40 ° is characteristic of a half of patients; with nek-ry — parotid glands remain increased for a long time. As a rule,

Fig. 2. A woman's face with Shegren's disease: significant increase in parotid sialadens.

Fig. 3. Upper foreteeth of the man with a disease Shegren (the upper lip is delayed): multiple cervical caries of teeth.

both parotid glands are involved in process, is more rare — one. At a number of patients increase in parotid sialadens develops gradually, causing characteristic change of a face form (fig. 2), their palpation happens painless or ma-loboleznenny. Increase in submaxillary, hypoglossal and palatal sialadens would occur at 10 — 15% of sick Sh. Gradually the xerostomia develops (see). In the beginning dryness in a mouth appears only at exercise and emotional stress. In the expressed stage of a disease dryness in a mouth becomes a constant, is followed by the need to wash down dry food, desire to moisten a mouth during the long conversation. The mucous membrane of an oral cavity of bright pink color, is easily injured, free saliva is not enough, it foamy or viscous, language dry, lips are covered with crusts, quite often there are «perleches», a glossitis (see), the infection can join secondary, including virus and fungal. A late stage of defeat of sialadens at Sh. it is characterized by sharp dryness of an oral cavity, impossibility to tell, swallow food without addition of liquid. Lips are dry, in cracks, the mucous membrane of an oral cavity with the phenomena of keratinization, language folded, nipples of language of an atrofichna, free saliva in an oral cavity is not present. Decrease in a sialosis, change of a consistence and composition of saliva leads to bystry development of caries of tooth (see), preferential cervical (fig. 3), and full loss of teeth. The heavy xerostomia can promote penetration of an infection on channels in parotid and submaxillary sialadens with development of purulent sialadenites and phlegmons. Dryness of a nasopharynx with formation of the dry crusts closing an Eustachian tube leads to development of recurrent otitis. Dryness of a nasopharynx, throat, trachea, and also phonatory bands causes difficulty of swallowing (see the Dysphagy) and an osiplost of a voice.

The third place on frequency among Sh.'s symptoms. occupies damage of joints. Arthralgias, constraint in the mornings, recurrent arthritises and painful a flexion

DISEASE of SHEGREN of the 387th

contracture, preferential small joints of brushes, come to light at 70 — 80% of patients.

Frequent recurrence and total disappearance of arthritis for the second, third day after purpose of corticosteroid drugs and, the main thing, lack of radiological signs of erosive process in the affected joints are characteristic.

At most of patients Shch. signs of damage

of upper parts are noted went. - kish. a path, shown a dysphagy and gastric dyspepsia (see). At histologic studying of the mucous membrane of a stomach received at a biopsy, sick Sh. chronic atrophic gastritis comes to light (see). Frequency and expressiveness of separate symptoms of gastric dyspepsia, such as feeling of weight and discomfort in epigastric area after food, nausea, an eructation, a loss of appetite, increase with increase in weight of a xerostomia. Pains in epigastric area are less often noted. Decrease kisloto-and pepsinoobrazuyushchy functions of a stomach with development in some cases of the achlorhydria steady against Pentagastrinum is characteristic. At many sick Sh. clinical signs (more often soft) colitis (see) and pancreatitis are noted (see). At a research of juice of a pancreas after stimulation by secretin decrease in its volume and concentration of bicarbonates comes to light.

Dryness of a mucous membrane of a trachea and bronchial tubes at Sh. is the contributing moment for accession of pulmonary infections. At patients develop recuring a tracheobronchitis (see Bronchitis) and pneumonia (see). At Sh. also intersticial lymphocytic pneumonia and in nek-ry cases a fibroziruyushchy alveolitis owing to immune complex deposition on the course of alveolar capillary membranes can develop. At a detailed research of function of external respiration at many patients, even in the absence of clinical signs of defeat of a respiratory path, disturbances of restrictive type come to light (see the Spirography), At a X-ray analysis plevrodiafragmalny, plevroperikardialny commissures and a thickening of an interlobar pleura, however bright clinical signs of dry pleurisy at Sh. are found. develop rather seldom.

Frequent signs of Sh. dryness and a peeling of skin are. Sweating can be absent even at high temperature of the environment. At Sh. the vasculitis of skin in the form of dot heart attacks of nail rollers, hemorrhagic rashes as a purpura can be observed, is more rare than yazvennonekrotichesky changes of skin with formation of trophic ulcers. Hemorrhagic rashes are more often observed on skin of shins. At patients with it is long a recurrent purpura usually the hyperpegmentation of skin owing to adjournment of hemosiderin develops. At sick Sh.' number. the syndrome of Yards-but is observed (see Rae but a disease), at the same time the erased its forms prevail; at 5 — 10% of sick Sh. — mialgiya, the moderate miositis which is followed by increase in level of transaminases and kreatinfosfokinaza in blood.

At all sick Sh. the regional lymphadenopathy (increase in submaxillary, cervical, occipital, supraclavicular lymph nodes) is noted; at a third of patients — a generalized lymphadenopathy. Increase in a liver and spleen is quite often observed. Frequency of emergence of these signs increases with development of a hemorrhagic vasculitis, and also limfoproliferativny diseases.

At 4 — 5% of sick Sh. after 10 — 15-year disease limfoproliferativny diseases develop, lymphoma of various types and a macroglobulinemia Wal-denstrema are more often (see. In an aljdenstrem a disease). It is necessary to remember that the roentgenotherapy of sialadens sharply would increase risk of development of lymphoma at Sh. In nek-ry cases signs psevdolimfo-we are found. In the material received at a biopsy of lymph nodes, easy and other bodies tumorous accumulations of lymphoid cells without the histologic signs of a zlokachestvennost synthesizing a large amount of polyclonals are found. At development of a malignant lymphoma the producing monoclonal IgM is noted that would indicate development of lymphoma at Sh. from V-lymphocytes.

At Sh. damages of kidneys come to light, is more often than the canalicular device — canalicular acidosis (see), a generalized aminoaciduria (see) and a fos-faturiya (see) with development in nek-ry cases of nephrogenic diabetes (see Diabetes renal). Decrease in concentration ability of kidneys, osteomalacy, nephrocalcinosis and the hypopotassemia resulting in muscular weakness can be a consequence of canalicular acidosis. At a biopsy of nights the changes characteristic of chronic intersticial nephrite (see), and limfoplazmotsitarny infiltration are found. Intersticial nephrite can progress with development, in some cases a renal failure (see) and uraemias (see). Much more rare at Sh. the diffusion glomerulonephritis of hymenoid and proliferative or hymenoid type is observed. As showed Mut-sopulos (H. M of Moutsopoulos) and sotr. (1978), a glomerulonephritis at III. is immunocomplex.

Are quite often observed disturbance of sensitivity of distal departments of extremities as «socks» and «gloves» and paresthesia; sometimes heavy polyneurites develop (see). Neuritis of facial and trigeminal nerves can come to light (see. Facial nerve, Trifacial).

At Sh. often apocrenic glands of external genitals are surprised. Skin and a mucous membrane of external genitals and a vagina become dry and atrofichny that is followed by thermalgias and emergence of an itch.

Clinical signs of damage of a thyroid gland (see the Thyroiditis) occur at 10 — 14% of patients. Autoantibodies to thyreoglobulin and tissue of a thyroid gland come to light in blood much more often.

At Sh. allergic reactions are often observed, and the polyvalent medicinal allergy comes to light at a half of patients.

Diagnosis. Sh.'s diagnosis. is based on identification of simultaneous damage of eyes (a dry keratoconjunctivitis) and sialadens (parenchymatous parotitis, withprovozhdayushchiysya xerostomia). The diagnosis of a dry keratoconjunctivitis is confirmed by decrease in lacrimation, and also data of oftalmoskopiya using methods of coloring of an epithelium of a conjunctiva and a cornea (Bengalese pink and flyuo-restseiny), at a cut the wedge, a picture comes to light typical for a keratoconjunctivitis (see the Keratitis, Conjunctivitis). Reduction of release of the lacrimal liquid (see the Xerophthalmia) comes to light by Shirmer's test. The test is considered positive if the strip of filter paper 4 mm wide and the about 5 — 8 cm long, put in the lower conjunctival sac after stimulation secretions of the lacrimal liquid steam inhalation of spirit of ammonia, is moistened no more than on 1 cm of Sialografiya (see) is the most available and informative diagnostic method of defeat of sialadens. Assessment sialogramm is carried out on a condition of a parenchyma of sialadens, existence of cavities of various size in it, a condition of channels. Characteristic sialografichesky signs of Sh. narrowing of channels of sialadens and a gnezdny atrophy of their parenchyma are. Sialografiya and a sia-lometriya (see Salivation) allow to estimate a stage of defeat of sialadens at III. (initial, expressed, late). As a rule, the stages of defeat of sialadens revealed by a sialogra-fiya correspond to degree of manifestation of the functional insufficiency determined by a sialo-metriya, and also a stsintigrafiya of sialadens with radioactive technetium (see Stsintigrafiya). The biopsy of slkshny glands has additional value (usually small, located in the field of an under lip).

At laboratory researches at a third of patients moderate normokhromny anemia, seldom hemolitic anemia and thrombocytopenia comes to light. The leukopenia is found in most of patients, the leukopoiesis at the same time is not oppressed. At a part of patients the eosinophilia and a lymphocytosis is observed. At most of patients considerable acceleration of ROE (30 — 80 mm/hour), a hyperproteinemia with a moderate hypoalbuminemia and a considerable hypergammaglobulinemia due to increase in content of immunoglobulins of all classes is noted. In nek-ry cases the monoclonal gammapathy can take place. Viscosity of blood owing to existence in it krio globulins or the circulating IgG-rhematoid factor and antibodies to it is often increased. Practically at all patients high credits of a rhematoid factor in blood serum come to light. Antinuclear antibodies of homogeneous and speckled types of a luminescence, just as precipitant antibodies to fabric nuclear antigens (SS-A and SS-B), are found in 65 — 70% of patients, and an antibody, according to Elspo (T. A. Alspa-ugh, 1976) and sotr., would be highly specific for Sh. also are not found at other diseases. So often cell-bound immune complexes come to light. Various organospetsifichesky antibodies — antibodies to an epithelium of channels of a pancreas and sialadens, thyreoglobulin, a microsome of l of ny fraction of a thyroid gland, to smooth and cross-striped muscles, covering cells of a stomach, cellular membranes of a liver, etc. — would come to light at sick Sh.' quarter. LE cells and antibodies to native DNA are found exclusively seldom. At a research of saliva the increased content of seromukoidny proteins and r2-microglobulin, and also emergence of immunoglobulins of three classes and a rhematoid factor comes to light. In the lacrimal liquid of patients of III. considerable decrease or total absence of a lysozyme is defined. Confirmation of the diagnosis is detection in blood of antibodies, specific to Shegren SS-A i SS-B's disease, to fabric nuclear antigens.

The differential diagnosis should be carried out with a pseudorheumatism (see), a system lupus erythematosus (see), autoimmune gepa-tobiliarny diseases (see Hepatitis, Cirrhosis). At sick Sh. unlike patients with a pseudorheumatism deformations, despite a long current of a joint syndrome and constant existence of a rhematoid factor in blood do not develop, on roentgenograms signs of erosive damage of joints are not found; arthritis at Sh. usually completely disappears on 2 — the 3rd day after purpose of small doses of corticosteroids. For a system lupus erythematosus unlike Sh. erythematic rashes in the form of «butterfly», an endocarditis, exudative pleurisy and a pericardis, existence in blood of LE cells and antibodies to native DNA are characteristic. At chronic active hepatitis, biliary cirrhosis unlike Sh. disturbances of functional trials of a liver are often observed, in blood markers of a virus of serumal hepatitis, including HBs Ag, in the material received at a biopsy of a liver — the characteristic morphological changes which are not observed at Sh. are found. The separate symptoms taking place at Sh., can be observed at a large number of various diseases. So, increase in sialadens is noted at primary tumors of sialadens, malignant lymphoma, a sarcoidosis, tuberculosis, syphilis, an actinomycosis, an acute bacterial and virus sialadenitis, chronic parenchymatous parotitis, a lipidemia, a diabetes mellitus, exhaustion. Reduction of release of the lacrimal liquid can be a consequence of a senile atrophy of the lacrimal glands, inflammatory states (a sarcoidosis, tuberculosis) and tumoral processes. Keratoconjunctivitis (however without characteristic of Sh. decrease in the lacrimal secretion) can meet at a pemphigus, an epidemic keratoconjunctivitis, virus, fungal, bacterial, neurogenic infection of eyes, at avitaminosis. To distinguish these diseases from Sh. absence allows at them the consensual defeat of salivary and lacrimal glands proceeding with decrease in allocation of their secret, absence or the atypical nature of «extra ferruterous» manifestations.

Treatment of a dry keratoconjunctivitis consists in purpose of replacement therapy (instillation of 0,5% of solution of methyl cellulose, Polyglucinum, the salt solutions prepared from 0,1 g of hydrosodium carbonate and 0,1 g of sodium chloride on 10 ml of a distilled water), the eye drops containing vitamins (katakhry, solution of citral with Riboflavinum), antiinflammatory drops (solutions of citral, Furacilin, levomycetinum and sul-fatsil-sodium), and also means reducing dystrophy and improving regeneration of an epithelium of a conjunctiva and cornea (the drop prepared from donor serum, metiluratsilovy, solkoserilovy and tiaminovy ointments). Frequency of use of drops depends on weight of a current of a dry keratoconjunctivitis. There are data indicating efficiency of cauterization of the lacrimal channels. At severe forms of a keratoconjunctivitis for protection of a conjunctiva soft contact lenses are used.

In complex treatment of chronic parotitis at Sh. use the drugs reducing permeability of channels: gluconate of calcium, ascorbic acid, novocainic blockade of parotid sialadens, and also applications of 30% of solution of Dimexidum. The xerostomia will most difficult respond to treatment. Apply weak saline solutions to moistening of an oral cavity. At initial and moderate forms of a xerostomia the positive effect is observed from rinsings of 1% by solution of Pilocarpinum (1 — 3 drops), caramel with Dekaminum and intramuscular introductions of 0,5% of solution of Galantaminum of hydrobromide. Use of oils (peach, a dogrose, a sea-buckthorn), giving temporary improvement, further only increases dryness of a mouth. At a xeromycteria apply frequent applications by saline solutions. Use of Solutio oleosa should be avoided because of a possibility of development of aspiration pneumonia. Dryness of a vagina decreases at regular greasing by iodide and potassium jelly. In case of accession of consecutive infection with development of a purulent sialadenitis, aphthous or fungal stomatitis, sinusitis, otitis, a tracheobronchitis, pneumonia the appropriate chemotherapeutic means are applied. There are data indicating high performance of corticosteroids and especially cytotoxic immunodepressants in treatment of damages of an oral cavity and an eye at Sh., however the issue of use of these drugs in therapy of defeat of excretory glands is not resolved yet. Corticosteroids (usually) or corticosteroids in combination with immunodepressants (usually Chlorbutinum in an initial dose of 4 — 6 mg a day), as a rule, would appoint Prednisolonum in an initial dose of 15 — 20 mg a day by sick Sh. in the presence «extra ferruterous» (system) manifestations. Treatment by these means is carried out is long, for years, with gradual (in process of reduction of expressiveness of clinical manifestations) decrease in initial doses and selection of supporting. There are messages on good effect of use of corticosteroids together with Cyclophosphanum or Chlorbutinum at development of intersticial nephrite, limfoplazmotsi-tare infiltration of lungs, a glomerulonephritis, krioglobulinemi-chesky purpura and polyneuritis. At the expressed joint syndrome and an exacerbation of parenchymatous parotitis non-steroidal anti-inflammatory drugs in a complex with corticosteroids are shown.

The forecast at Sh. for life favorable. At timely begun treatment the disease gets more high-quality long current with the subsequent recovery of working ability of patients. Late begun treatment leads usually to bystry development of heavy ophthalmologic, dental, system displays of a disease and disability. The forecast becomes adverse at development of malignant lymphoma and other limfoproliferativny diseases.

Prevention is not developed. The prevention of aggravations and progressing of a disease provides early diagnosis, timely purpose of replacement therapy, active treatment in a hospital, and further dispensary observation for patients. Nek-ry patients need transfer into disability or employment with restriction of exercise stresses and loads of organs of sight, and also with an exception to an aller-gizir of lean factors. Sick Sh. vaccination are absolutely contraindicated, physiotherapeutic and thermal procedures, especially in the period of high activity of a disease carefully shall be applied, and also to be appointed any new pharmaceuticals. Timely sanitation and denture treatment is necessary.

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