RHEUMATIC DISEASES

RHEUMATIC DISEASES

·        Rheumatic diseases are group of collagen or systemic connective tissue diseases including rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, dermatomyositis and polyarteriitis nodosa, and Bechterew’s disease.

·        They are characterized by affect of collagen or connective tissue due to disturbances of immune homeostasis.

·        Disturbances of immune homeostasis, development of autoimmune reactions, formation of the toxic immune complexes and sensibilizated cells, injury of microcirculation with following systemic progressive disorganization of connective tissue are main links of pathogenesis of rheumatic diseases.

General characteristic of rheumatic diseases

·        Presence of chronic infectious focus.

·        Presence of early systemic changes of microcirculation.

·        Presence of hypersensitivity of immediate type with development of exudative – necrotic reactions and hypersensitivity of delayed type with formation cellular infiltration.

·        Systemic progressive disorganization of connective tissue includes mucoid swelling, fibrinoid changes, cellular reactions, sclerosis. Combination of different phases of connective tissue disorganization, which indicates the chronic character of the diseases.

·        Chronic recurrent diseases with alternation of periods of exacerbation and remission

·        Genetic and environmental factors are important for development of these diseases. Thus, rheumatic arthritis has less severe course in the residents of Africa than in those of Europe, Lupus erythematosus is more frequent in Europian countries and USA than in Great Britain.

RHEUMATIC FEVER (RF) and RHEUMATIC HEART DISEASE (RHD)

·        RF is an acute, inflammatory, recurrent disease mainly of children (ages 5 to 15) that typically occurs 1 to 5 weeks after a group A streptococcal infection (usually sore throat).

·        Acute RF occurs after the infection with beta-hemolytic streptococci group A. The various manifestations of the disease in the heart and other regions of the body, excluding the initial infection (tonsillitis, nasopharyngitis), are not the result of a direct infection.

·        Most evidence suggests is secondary to host antistreptococcal antibodies that are cross-reactive to cardiac antigens, but microbe initiated autoimmune reactivity is not ruled out.

·        Rheumatic Fever is thus a disease that involves many regions of the body, but it is not serious import to the patient unless it involves the heart. It has been said, “rheumatic fever licks the joints but bits the heart”.

·        Death is rare during acute RF, being secondary usually to the myocarditis. Typically, the myocarditis and arthritis are transient and largely resolve, but the valvular involement may lead to deformed, scarred valves with permanent dysfunction (chronic RHD) and subsequent CHF.

·        Chronic RHD is more likely to occur when the first attack is in early childhood, when the first bout of RF is severe, or with recurrent attacks.

Diagnosis rests on the clinical history and the presence of five major (Jones) criteria:

1.      Erythema marginatum. Seen in children more often than adults. There is specific skin “rush”, typically in a bathing suit distribution, macular lesions with erythematous rims and central clearing.

2.      Sydenhams chorea. A neurologic disorder with rapid, involuntary, purposeless movements.

3.      Carditis. It may be myo-, endo-, or pericarditis.

4.      Subcutaneos nodules. Seen in children more often than adults. Histologically, giant Aschoff bodies are noted.

5.      Migratory large joint polyarthritis.

Minor criteria:

1.   Fever.

2.   Arthralgia.

3.   Longer PR interval in the ECG.

4.   Leukocytosis.

Also may develop:

·        Rheumatic glomerulonephritis, rheumatic pneumonia is visceral changes.

·        Hyperplasia of lymphatic tissue, marked plasmatization is observed in the immune system.

·        Rheumatic vasculitis with fibrinoid changes of the walls. In the capillaries, there is endothelium proliferation followed by desquamation, so-called rheumatic endotheliosis. Vascular permeability increases sharply. The disease results in vascular sclerosis (arteriolosclerosis, arteriosclerosis, capillarosclerosis).

Pathogenesis and Morphology of RF

A widely accepted concept of the nature of RF is that it is one of the so-called immune disorders of connective tissue, the principal lesions being in the connective tissues throughout the body, especially in the heart. RF has four stages.

·        Mucoid swelling. In the early phase of development of the lesions, edema of the connective tissues is associated with an increase of mucopolysaccharide. The collagen fibers are pushed apart by the accumulating of basophilic ground substance, and subsequently they undergo swelling, fraying, fragmentation, and disintegration.

·        Fibrinoid changes. The affected areas, including collagen fibers and the ground substance, are altered considerably and take on a deeply eosinophilic appearance resembling fibrin; thus, the change is referred to as fibrinoid degeneration or necrosis.

·        Cellular reactions. The early exudative and degenerative features are followed by proliferation, that is, an infiltration by lymphocytes, plasma cells, histiocytes, and fibroblasts. The most distinctive proliferative lesion is the granulematous phase of the Aschoff body.

·        Sclerosis. Aschoff bodies or diffuse inflammatory cellular infiltration are slowly replaced by fibrous scar mainly about the vessels.

Pathognomonic focal inflammatory nodules called Aschoff bodies are the most characteristic in the heart, but similar lesions may occur elsewhere. Three phases or stages in the development of the Aschoff body are recognized:

1. Early (exudative, degenerative, or alterative) phase. These constitute foci of fibrinoid necrosis, initially surrounded by lymphocytes, macrophages and a few plasma cells. The early phase of the life cycle of the Aschoff body occur up to the fourth week of acute RF.

2.       Intermediate (proliferative or granulematous) phase. In the intermediate phase, which is evident during the fourth to the thirteenth week of the disease, cellular proliferation is the dominant feature. Distinctive plump histiocytes (Aschoff or Anitschkow cells), some of which are multinucleated (Aschoff multinucleated giant cells with abundant basophilic cytoplasm), appear in periphery of nodules. Anitschkow cells are mononuclear cells. They have a moderate amount of faintly stained cytoplasm with vaguely defined borders. Their nuclei are large and vesicular and contain a prominent central chromatin mass that longitudinal section is serrated (caterpillar-like). In cross section a halo is observed about the chromatin bar so that the nucleus has an “owl-eye” appearance.

3. Late (senescent, fibrous, healing, or healed) phase. In 3 to 4 months, the healing phase is reached, characterized by regression and fibrosis of the nodule. The collagenous fibers fuse to form dense collagenous bindles, resulting in small scars between the muscle bundles, frequently perivascularly.

Clinical-anatomical forms of Rheumatic Fever:

1. Cardiovascular form occurs endocarditis, myocarditis, pericarditis.
2. Polyarthritic form occurs migratory large joint polyarthritis (knee, cubital, humeral, hip joint, ankle-joint). It is characterized by serous or serous-fibrinous inflammation. In the synovial membrane the mucoid swelling develops. Articular cartilage is safe, therefore deformation and ankylosis is absent.
3. Nodular (nodules around vessels) form occurs deposition of giant Aschoff bodies under skin and may develop perivascular sclerosis.
4. Cerebral form occurs chorea. The damage of the brain is connected with rheumatic vasculitis. Nervous cells degeneration, brain destruction and hemorrhages occur in the brain. If these changes are clearly marked, they may cause chorea minor (in children).

Cardiovascular form

The cardiac involvement in RF is that of a pancarditis; that is, there is endocarditis, myocarditis, and pericarditis.

Endocarditis (valvulitis)

·        The most prominent changes develop in mitral and aortic valves. Lesions may also be present on the chordae tendineae, particularly at their attachment to the leaflets, and are rarely on the papillary muscles of the left ventricle.

·        According to A.I. Abrikosov, valvular endocarditis is classified as follows:

1. Diffuse or valvulitis. In the active acute stage of the disease the valve leaflets or cusps are thickened and lose their transparency. Edema with swelling of the leaflet, an increased number of capillaries, and an infiltration by lymphocytes and occasionally by neutrophils are seen. Plasma cells and fibroblasts may be present. In some instances, this nonspecific inflammatory reaction may be all that occurs. Usually, however, there is also an increase in acid mucopolysaccharide, with alteration of collagen and the fibrinoid change near the surface of the valve and with surface deposition of fibrin from the blood in the ventricular cavity.
2. Acute verrucous endocarditis. This is followed by the appearance of characteristic wartlike nodules (verrucae) ranging from 1 to 3 mm in diameter, mainly along the line of closure of the cusps. It may lead to thickening, shortening, and blunting of valvular leaflets. Microscopically: fibrinoid necrosis with thrombotic masses.

3.       Fibroblastic or healing of the rheumatic valvulitis. The following changes take place:

a)      Fibroblastic proliferation and collagen formation throughout the valve with scarring, thickening, and rigidity of the leaflets.

b)      Organization of the vegetations, with greater thickening along the line of closure.

c)       Adhesions between the lateral portions of the cusps, particularly in the region of the commisures.

d)      Thickening, shortening, and fusion of the chordae tendineae.

e)      Frequently, calcification, with contributes to the rigidity of the valve.

4. Relapsing verrucous endocarditis.

·        The result is deformity of one or more valves, especially mitral or aortic.

·        In the chronic or recurrent condition, the functionally important lesions are those of the valves, which result in heart failure because of the increased work of the heart caused by the valvular stenosis of insufficiency.

Mitral insufficiency

·        The pathophysiology of mitral regurgitation is complex.

·        Proper closure of the mitral valve depends not only on the mitral valve leaflets by themselves but also on several additional functional components of the mitral valve apparatus, namely, the chordae tendineae, the papillary muscles, and the left ventricle.

·        Valvular insufficiency may result because of retraction of the scarred leaflets in the vertical direction leading to shortening of the cusps.

·         Changing hemodynamic conditions may dramatically improve or worsen the degree of mitral regurgitation.

·        Mitral insufficiency and stenosis are commonly combined.

·        When mitral insufficiency is the main alteration, the effects are the follows:

a)      Dilatation and hypertrophy of the left ventricle.

b)      Dilatation and hypertrophy of the left atrium, often greater than in mitral stenosis.

c)      Effects on the right side of the heart as in mitral stenosis after left-sided failure.

Mitral stenosis

·        The most characteristic type of deformity causes mitral stenosis.

·        Mitral stenosis is the result of rheumatic endocarditis or bacterial endocarditis.

·        The gross appearance of the stenotic valve varies greatly according to the degree of involvement.

·        Fibrous adhesion at the comissures may be slight or extensive.

·        The leaflets are fibrotic and thickened, especially toward the closing edges.

·        Contraction of scar tissue takes place, the valve leaflets become more rigid, and calcification of the mitral cusps and ring frequently is present to a greater or lesser degree.

·        Ulceration of the thickest part of deformed valve is a common occurrence.

·        The orifice becomes considerably narrowed.

·        When the valves are less extensively involved and the bases of the leaflets are still somewhat pliable, the narrowed opening is surrounded but puckered, thickened tissue, so-called purse-string puckering. As the entire valve becomes more rigid it takes on appearance of a fixed diaphragm with a narrow oval or curved opening, a “buttonhole” or “fish-mouth” orifice.

·        The effects of mitral stenosis develop as a consequence of obstruction to the outflow of blood from the left atrium and include the following:

a)      Dilatation and hypertrophy of the left atrium, which occasionally appears as a huge saclike structure (so-called giant left atrium).

b)      Endocardial fibrous thickening of the left atrium.

c)      Pronounced chronic passive congestion of the lungs; eventual pulmonary-arteriolar thickening.

d)      Hypertrophy and dilatation of the right ventricle as a result of pulmonary hypertension

e)      Dilatation of the right atrium as a right-sided heart failure develops.

f)       A normal-sized left ventricle or, in prolonged mitral stenosis, atrophic left ventricle caused by reduced inflow of blood, with possible hypertrophy of this ventricle if mitral insufficiency or aortic stenosis is present.

·        One of the complications that may occur in mitral stenosis and the consequent atrial dilatation is atrial fibrillation. Atrial fibrillation contributes to blood stasis and predisposes to development of thrombosis, especially in the left atrial appendage; systemic embolism may result.

Myocarditis

Rheumatic myocarditis is characterized by the presence of

1. Granulematous myocarditis. It is characterized by the presence of specific Aschoff bodies. There is gradual subsidence of the inflammatory reaction, and the Aschoff bodies are converted into small scars.
2. Nonspecific exudative interstitial myocarditis. It is characterized by diffuse or focal lymphohistiocytic infiltration and vasculitis. In the later stages of the disease may diffuse small-focal cardiosclerosis.
3. Parenchymal damage may lead to acute cardiac insufficiency and to death in early stages of disease or to chronic ischemic heart disease.

Pericarditis

·        The tendency to affect serous membranes is one of the distinctive features of RF, and fibrinous pericarditis is a prominent part of the picture of acute rheumatic heart disease.

·        The exudate varies from a thin film of fibrin to a shaggy coat with adhesions between the layers of the pericardium, thus the designation of “shaggy” heart, or “cor villosum”.

·        Microscopically, fibrin is seen as a shaggy layer on the surface of the epicardium and an infiltrate of lymphocytes, plasma cells, histiosytes, and occasionally neutrophils are present.

·        Subsequently, organization of the fibrin by vascularized connective tissue may be observed. This may lead to fibrous thickening and adhesions of the visceral and parietal layers, to partial or complete obliteration of the pericardial cavity, and to a “chronic adhesive pericarditis”.

·        Although pericarditis may be the most prominent gross manifestation of the acute disease, it is usually a little physiologic significance and does not usually affect the clinical course of the patient.

Postmorten diagnosis of old rheumatic disease is based on the following marks:

1. Chronic adhesive pericarditis, especially circumscribed obliteration of the cardiac sac nears the apex.
2. Fibrous thickening of the valve leaflets, especially at the line of closure.
3. Valvular deformities, especially aortic or mitral stenosis of insufficiency and, more significantly, involvement of both the aortic and mitral valves.
4. Thickening, shortening, and adhesions of the chordal tendineae.
5. Microscopic changes, including foci of perivascular interstitial fibrosis and vascularization of the valves.
6. The chief causes of death in RF patients are cardiac failure, infective endocarditis, and embolism. Death may, however, be attributable to various conditions such as pneumonia.