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Anitschkow cells (AC) are a peculiar type of stromal cells observed in myocardium, cardiac valves and coronary vessels wall whose origin, characterization and role remain controversial. In human heart, they represent a histological hallmark of Aschoff nodules in rheumatic fever, but they have also been observed in other myocardial pathologies. Firstly, they have been considered a myocyte-derived cells, but light microscopy, immunohistochemical and ultrastructural studies pointed out that a macrophagic/histiocytic origin cannot be excluded. Many authors also reported extracardiac AC or an Anitschkow nuclear pattern, thus suggesting that these cells may represent a chromatin pattern rather than a specific cell type. In veterinary medicine, AC were described in myocarditis, myocardial necrosis, degenerative and inflammatory endocardial diseases of several species. Recently, AC have been observed in intramural coronary arteries of different animals (including cattle and fish) affected by arteriosclerotic processes. Stress related to the intensive livestock farming could represent a mechanotransduction promoting factor of arteriosclerotic changes allowing the development of Anitschkow chromatin pattern. Further studies both in human and veterinary medicine are needed to confirm the origin and role of these peculiar cells., (© 2019 Blackwell Verlag GmbH.)

Objective: To determine whether the presence, number, and topography (digit location and symmetry) of Heberden's nodes are associated with the incidence and progression of radiographic osteoarthritis (OA) of the knee., Methods: We analyzed 8,023 knees (with 8 years of follow-up) from the Osteoarthritis Initiative. Cox regression was performed on Heberden's node presence, total number, location, and symmetry (using 2 symmetry index models) obtained at baseline physical examination as well as self-report of Heberden's node presence for evaluation of association with radiographic knee OA incidence (development of a Kellgren/Lawrence grade of ≥2) and progression (worsening in the medial joint space narrowing score of ≥1). Covariate adjustments relevant to OA outcomes were performed., Results: The presence of Heberden's nodes (in 64% of the subjects) at baseline physical examinations, but not subjective self-report of Heberden's nodes, was associated with radiographic knee OA incidence (hazard ratio [HR] 1.19 and 95% confidence interval [95% CI] 1.001-1.402 [approached statistical significance]). Each additional Heberden's node found on physical examination was associated with knee OA incidence (HR 1.03 [95% CI 1.000-1.054] [approached statistical significance]) and progression (HR 1.04 [95% CI 1.016-1.063]). Knee OA incidence and progression were associated with Heberden's nodes located on the third digit (HR 1.26 [95% CI 1.068-1.487] and 1.18 [95% CI 1.019-1.361], respectively) and first digit (HR 1.186 [95% CI 0.992-1.418] [approached statistical significance] and HR 1.26 [95% CI 1.084-1.453], respectively). Heberden's node symmetry was associated with knee OA incidence (model 1 HR 1.09 [95% CI 0.997-1.185] [approached statistical significance]) and progression (model 2 HR 1.13 [95% CI 1.035-1.234])., Conclusion: The number of Heberden's nodes, their locations, and symmetry were associated with knee OA incidence and progression over 8 years., (© 2018, American College of Rheumatology.)

Background: Rheumatic fever and chronic rheumatic heart disease (RHD) remains one of the most important causes of cardiovascular morbidity leading to a major public health problem, especially in developing countries. This was a pilot study to assess the presence of inflammation and expression of adhesion molecules by immunohistochemistry (IHC) in endomyocardial biopsy specimens of patients with chronic RHD., Methods: Endomyocardial biopsy was obtained from 14 patients of chronic RHD with no features of activity clinically. Biopsies were processed for histology and IHC. IHC was carried using monoclonal antibodies against CD3, CD4, CD8, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1., Results: Histomorphologically, varying degree of interstitial and perivascular fibrosis was seen in all the 13 patients (100%). Mild fibrosis (1+) was seen in five patients (38.5%); moderate interstitial fibrosis (2+) was present in four patients (30.8%).There was no Aschoff nodule or evidence of active myocarditis in any of the biopsy specimens. IMMUNOHISTOCHEMISTRY: Moderate positivity of (2+) and intense positivity of (3+) for intercellular adhesion molecule-1 was seen in 11 and 2 patients, respectively. With vascular cell adhesion molecule-1, four showed mild positivity (1+), and three showed intense positivity (3+). The phenotypic analysis of the inflammatory cells in our study revealed CD8(+) cells in 77%, CD4(+) in 23.1%, and CD3(+) in 38.5% of total patients, which suggests chronicity., Conclusion: The nonspecific histomorphological changes and increased adhesion molecules expression could be a part of the ventricular remodeling due to the hemodynamic stress by the stenotic or regurgitant lesions of RHD itself., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Conjunctival nodule is very rarely seen in patients with rheumatoid arthritis. Previously reported cases were associated with the use of methotrexate. Here, we report a conjunctival rheumatoid nodule without such prior treatment. A 49-year-old woman with seropositive rheumatoid arthritis, who was being treated only with oral steroids and hydroxychloroquine, developed diffuse anterior scleritis in the right eye. In addition, examination showed a focal raised yellow/tan conjunctival nodule. The nodule was within the bulbar conjunctiva with no attachments to the underlying tissue, which is different from nodular scleritis. The nodule was not tender on palpation. The patient underwent excisional biopsy of the nodule. Intraoperatively, the lesion was noted to be a firm nodule within substantia propria of the conjunctiva. Hematoxylin-eosin staining of the specimen revealed a central area of necrosis surrounded by palisades of histiocytes. Increased dosage of oral steroid after the biopsy resulted in resolution of the ocular symptoms and signs. In conclusion, rheumatoid nodules may be seen in the conjunctiva even without prior treatment with methotrexate. These nodules may show the severity of the underlying disease and the need for more aggressive treatment.

Rheumatic heart disease is the most severe complication of rheumatic fever. Till date, very few successful animal models of rheumatic valvular disease have been reported. This study aimed at developing a suitable animal model of chronic rheumatic valvulitis for further investigation and prevention of rheumatic heart disease. Lewis rats were immunized with one administration of formalin-killed and sonicated group A streptococci together with Complete Freund's Adjuvant every 7 days for three cycles followed by group A streptococci alone till killing. Control rats were administered adjuvants and saline. Rats in group 1 were killed 12 weeks after the initial injection. Rats in group 2 and control group were killed 24 weeks after the initial injection. Results 62.5% (5/8) of rats in group 1 developed myocarditis and 50% (4/8) developed valvulitis. Histological examination of cardiac sections showed only cellular infiltrates. In contrast, 75% (6/8) of rats in group 2 developed rheumatic-like myocarditis and 62.5% (5/8) developed chronic valvulitis. Histological manifestations of the hearts in group 2 animals involved not only acute damage such as cellular infiltrates, Aschoff-like cells, verrucous vegetation, but also chronic lesions such as fibrosis, vascular neogenesis. None of the rats (0/8) in control group presented myocarditis or valvulitis. Lewis rat repeatedly immunized with formalin-killed GAS may be a suitable animal model of chronic rheumatic valvulitis. It may be useful for future investigation of the pathogenesis and possible preventive strategies of human rheumatic heart disease.

The evaluation of patients with subcutaneous nodules remains a diagnostic challenge. The presence of nodules can be a clue to an underlying systemic disease; however, the varied presentations of nodules and numerous disease associations make the assessment of patients with nodules far from simple. With further investigation into the appearance, location, and symptoms associated with nodules, the clinical significance of these lesions can become clearer and aid in logical diagnostic evaluation. We have reviewed the causes of nodules with emphasis on those associated with rheumatic disease and provide guidelines for nodule evaluation to better characterize disease association and lead to directed diagnostic assessment.

Unlabelled: Rheumatic diseases usually promote several systemic disorders, which can affect blood vessels, mucosa and serosa of the aerodigestive tract. Scarce laryngeal involvement has been described in these patients and this study aims at investigating laryngeal alterations found in patients with rheumatic diseases., Study Design: Transversal cohort., Material and Method: A transversal study was developed with systemic lupus erythematous, systemic sclerosis and mixed connective tissue disease's patients. They were evaluated by means of clinical examinations and videolaryngoestroboscopy., Results: Twenty-seven patients were included in the study, 26 succeeded in completing the videolaryngoestroboscopy. Laryngeal abnormalities were seen in 11 of 12 patients with lupus, in all 11 patients with sclerodermia and in 3 patients with mixed connective tissue disease. Vocal fold bamboo node was observed in 5 patients and 92.3% of all patients presented laryngeal signs of gastroesophageal reflux disease., Conclusion: We noticed 5 vocal fold bamboo nodes and gastroesophageal reflux disease in almost all patients.

The caterpillar chromatin pattern of the nucleus in longitudinal section and owl-eye appearance in transverse section characterize the Anitschkow cell of Aschoff bodies in rheumatic heart disease. Determining whether it is of muscle origin or cardiac histiocyte has been a source of controversy for many years. In a study of fetal and neonatal hearts from humans, vesicular nuclei often displaying the Anitschkow chromatin pattern were the predominant cell type in the myocardium. Because a similar pattern was also observed in two cell types related to laryngeal cartilage and the neighbouring fibrous tissue in a six week old neonate, it was concluded that the Anitschkow chromatin pattern probably indicates cellular immaturity rather than any specific cell type.

Aims: A recent immunohistochemical analysis of the Aschoff lesions in rheumatic fever, combining immunohistochemical analysis with comparative morphology, permitted the division of the Aschoff nodules into three stages: (1) Aschoff nodule without admixed lymphocytes, (2) Aschoff nodules with a few T lymphocytes, and (3) Aschoff nodules containing many admixed lymphocytes of both B- and T-cell phenotype. It was postulated that the order of progression was from stage 1 with macrophages only, to accumulation of first T lymphocytes (stage 2) and then B lymphocytes (stage 3). This study was undertaken to determine the role and distribution of interleukin 1 (IL-1), interleukin 2 (IL-2) and tumour necrosis factor alpha (TNF alpha) in the various stages of the rheumatic Aschoff nodule to investigate our hypothesis on the progression of these nodules., Methods and Results: Sixteen fresh valve specimens from patients with acute rheumatic fever undergoing valve surgery were obtained. Tissue sections from 14 specimens identified as containing Aschoff nodules were subjected to immunohistochemistry for (1) T and B lymphocytes, to stage the lesions according to our previously proposed criteria; (2) IL-1, IL-2 and TNF alpha; and (3) CD4 and CD8 to phenotype the T lymphocytes. The stage 1 and 2 lesions expressed IL-1 and TNF alpha in the macrophages. The stage 3 lesions showed more variable expression of all three cytokines including IL-2 within T lymphocytes., Conclusion: TNF alpha and IL-1 secretion in macrophages is required for T and B lymphocytes activation and aggregation; suggesting that macrophages arrive at the scene of rheumatic injury prior to the lymphocytes. IL-2 is usually expressed later in the inflammatory process and was found only in the lymphoid aggregates. This study therefore produces corroborative evidence for our previously proposed developmental stages of the Aschoff nodule.

A 36-old-woman was admitted with an infectious syndrome, respiratory insufficiency and vasculitis. There was a history of chronic intravenous drug abuse, sexual promiscuity and rheumatic heart disease. She had HIV positive tests. The vasculitis and heart failure worsened and the patient died of stroke. At autopsy it was found histologic evidence of AIDS, rheumatic heart disease with Aschoff nodes, infective endocarditis with cerebral abscesses and thalamic infarction.

Rheumatic fever is still the leading cause of acquired heart disease in children and young adults in developing countries. Recent reports have documented a rising incidence of rheumatic fever in both the USA and Europe. The disease is characterized by specific lesions in the heart muscle and valves called Aschoff nodules. The Aschoff nodule has been neglected in the last few decades as most of the studies were conducted in the 1960s on autopsy tissues. This study examines Aschoff nodules using heart valve material obtained at valve surgery with updated commercially available immunohistochemical antibodies to determine the phenotypic characteristics of the cells involved in the formation of these lesions. Fifteen cases of rheumatic valvulitis, as indicated by the presence of Aschoff nodules, were examined. The Anitschkow and Aschoff cells stained prominently with macrophage markers. Three stages of nodules with Aschoff and Anitschkow cells were identified: stage 1, central fibrinoid necrosis without lymphocytes, stage 2 with occasional T lymphocytes (< 10) and stage 3 with lymphoid aggregates containing both T- and B-lymphocytes (with occasional admixed macrophages). We propose that the stage 1 lesion is the earliest granulomatous stage with the lymphoid aggregates being a later stage in the development of Aschoff nodules. The Aschoff and Anitschkow cells demonstrated mitotic activity and stained with antibodies to the proliferation cell nuclear antigen (PCNA) suggesting that the multinucleated giant cells may be formed, at least partially, by nuclear division rather than fusion.

Forty-four left auricular appendages removed from patients presenting clinically as rheumatic heart disease (RHD) were subjected to histopathologic examination. The aim was to identify the changes so far reported in RHD. It was found that Aschoff's nodules, though specific for RHD, are much less frequent than the other changes reported. Viewing the histopathologic alterations in the perspective of clinical data is important in identifying the rheumatic process.

This two-part article examines the histologic and morphologic basis for stenotic and purely regurgitant mitral valves. In Part I, conditions producing mitral valve stenosis are reviewed. In over 99% of stenotic mitral valves, the etiology is rheumatic disease. Other rare causes of mitral stenosis include congenital malformed valves, active infective endocarditis, massive annular calcium, and metabolic or enzymatic abnormalities. In Part II, conditions producing pure mitral regurgitation will be discussed. In contrast to the few causes of mitral stenosis, the causes of pure (no element of stenosis) mitral regurgitation are multiple. Some of the conditions producing pure regurgitation include floppy mitral valves, infective endocarditis, papillary muscle dysfunction, rheumatic disease, and ruptured chordae tendinae.

Heart transplantation as a treatment for end-stage heart failure has spawned numerous important challenges in patient care. A heart transplant patient with clinically unsuspected acute rheumatic carditis had an ultimately fatal course marked by refractory rejection and early death after transplantation. The patient had several immune abnormalities. Peripheral blood T lymphocytes (CD2+) were significantly elevated (p < 0.05) by flow cytometry in active rheumatic carditis versus 76 healthy individuals. The CD4+:CD8+ T-cell ratio was 5.5:1 in rheumatic disease and only 2.7:1 in healthy individuals. Numbers of peripheral blood B lymphocytes (CD19+), macrophages (CD14+), and interleukin-2 receptor-positive cells (CD25+) were also elevated in rheumatic disease. Natural killer cells (CD16+) were slightly reduced in number and appeared functionally deficient, and antibody-dependent cellular cytotoxicity was also reduced. Immunohistochemically, infiltrating cells in Aschoff lesions of the rheumatic native heart were mainly T cells, with putative TH/I cells predominating. The striking immune accompaniments of acute rheumatic fever may have heralded profound immune-mediated allograft intolerance leading to the patient's demise. Considering the recrudescence of rheumatic heart disease in this country and its remaining worldwide importance, such patients as the one discussed offer daunting clinical challenges when transplantation is an obvious management choice for severe, end-stage dilated cardiomyopathy.

Objectives: Methotrexate is successfully used in the treatment of arthritis but little is known about its effects on extra-articular manifestations of rheumatoid arthritis. We focused this work on the incidence and clinical course of extra-articular manifestations during long-term treatment with methotrexate., Methods: The effect of methotrexate on extra-articular manifestations was investigated in 176 patients with rheumatoid arthritis who had obtained, in a prospective study, a good clinical response to methotrexate (10 mg/week) taken for 33 months (range 4-68)., Results: Before taking methotrexate, 44 patients (25.1%) had extra-articular manifestations: nodules (n = 40) and vasculitis (n = 9). With methotrexate, nodulosis and vasculitis were stable in 31 cases, improved in 3 and worsened in 10 (23%). Among the 132 patients without extra-articular manifestations before methotrexate therapy, 15 (11%) developed accelerated nodulosis preferentially located on the fingers, 7 had a vasculitis and 3 a pericarditis during methotrexate therapy. Extra-articular manifestations occurred between 1 and 24 months of initiating methotrexate therapy. Rheumatoid factor was positive in 88% of the patients with extra-articular manifestations. No relationship was noted between extra-articular manifestations and HLA type or antinuclear antibodies. In 3 out of 4 patients who developed accelerated nodulosis while taking methotrexate, the addition of hydroxychloroquine (400 mg/day) resulted in a significant reduction in the number and size of the nodules within 3 to 10 months after starting combined therapy., Conclusion: These data suggest that methotrexate is not effective in the treatment of extra-articular manifestations in rheumatoid arthritis and that nodulosis may occur in about 11% of patients taking methotrexate therapy for rheumatoid arthritis. The combination of hydroxychloroquine and methotrexate may have a beneficial effect on nodulosis that needs to be evaluated.

Endomyocardial biopsy (EMB) specimens obtained from ventricles in 10 patients with rheumatic heart disease were examined under light microscope. The results showed that typical Aschoff bodies and Anitschkow cells were found in 5 cases and Anitschkow cells only in other 2 cases. The positive detecting rate of active rheumatic lesion was 70 per cent. Active rheumatism was suggested clinically in 4 out of 7 cases with positive rheumatic lesions, whereas no clinical active rheumatism was suggested in the remaining three. The present study indicates that the active rheumatism lesions are frequently present in patients with rheumatic heart disease. Among the 3 cases without active rheumatic lesions, clinical active rheumatism was suggested in one, but no active clinical rheumatic evidence in the remaining two. In conclusion, the EMB technique gives limited value in assessing clinical active rheumatism in patients with rheumatic heart disease.

The presence of clinically palpable finger joint nodules (Heberden's and Bouchard's nodes) was documented in 123 consecutive cases with diffuse idiopathic skeletal hyperostosis (DISH) of the thoracic spine and 191 matched DISH negative controls. The prevalence of palpable finger joint nodules was almost twice as frequent in cases with spinal DISH compared to controls (46% versus 31%, chi 2 = 7.67, P less than 0.01; multivariate adjusted odds ratio OR = 1.84; 95% CI: 1.14-2.98). This increase was most marked at the proximal interphalangeal joint, in males and in patients up to the age of 65 years. In addition and independent of other variables such as hyperostotic features, age and sex, the prevalence of palpable finger joint nodules was about twice as high in probands with a history of physically heavy work compared to those without (43% versus 26%, chi = 9.18, P less than 0.005; multivariate adjusted odds ratio OR = 2.10; 95% CI: 1.26-3.52). From these results we conclude that DISH should be considered as an independent risk factor in the development of finger joint nodules.

We have evaluated the nature of Aschoff cells within Aschoff bodies seen in 35 of 100 excised left atrial appendages from cases of rheumatic mitral stenosis who underwent closed mitral valvotomy. These were tested using a panel of monoclonal and polyclonal antisera by the indirect immunoperoxidase staining for leucocyte common antigen, macrophage, desmin, vimentin, alpha-1-antitrypsin, alpha-1-antichymotrypsin, lysozyme, acid phosphatase and nonspecific esterase. The Aschoff cell gave strong reactivity with monoclonal antisera to vimentin, macrophage and variable reaction with polyclonal antisera known to recognise macrophages/histiocytes in tissues, namely alpha-1-antitrypsin, alpha-1-antichymotrypsin and lysozyme. These were also strongly positive for acid phosphatase and nonspecific esterase. The Aschoff cell lacked affinity for desmin and only an occasional cell in 4 out of 20 and 6 out of 35 cases showed a weak reaction with myoglobin and leucocyte common antigen, respectively. Intense consistent reactivity with several histiocytic markers affirms the genesis of these cells from macrophages/histiocytes and not muscle cells; a controversy which must be laid to rest!

The frequency and patho-histological characteristics of pulmonary changes were studied on the autopsy material of 100 patients with rheumatoid arthritis (RA). The formal pathogenesis and different stages of vasculitis, rheumatoid nodule, interstitial pneumonia, rheumatoid pleuritis, obliterative bronchiolitis, amyloidosis and the so-called rheumatoid pneumonia in the lungs is discussed. The rheumatoid pneumonia is a disseminating inflammatory lobular-sublobular process, not described previously. The frequency of rheumatoid pneumonia was 4%. The rheumatoid pneumonia is characterized by the necrotic vasculitis, fibrinoid necrosis or thrombovasculitis of the pulmonary and bronchial arterioles, and of small arteries. Because of the diminished blood supply distal to the vascular changes inflammatory foci may develop, more or less respecting the anatomic borders of pulmonary tissue. The lobular-sublobular inflammation is basically of non haemorrhagic character. Because of the recurrent nature of vasculitis, foci of inflammation in different stages can be observed in the lungs simultaneously side by side. Clinically the rheumatoid pneumonia was accompanied by severe RA, according to the frequency and severity of acute exacerbations. In all 4 cases of rheumatoid pneumonia the pulmonary process had been proven clinically and radiologically. Rheumatoid pneumonia occurred subsequent to recurrent arthritis following steroid withdrawal, and it was resistant to antibiotics.

Electron microscopic evaluation of subcutaneous nodules excised from two cases of acute rheumatic fever showed an electron dense and smudgy material which had a distinct filamentous appearance in places. The latter was recognized as collagen. This corresponded to the fibrinoid necrosis seen under the light microscope. In addition, several histiomonocytic cells and fibroblasts were seen. A large number of cells were degenerated. A fair degree of resemblance of the nodule both by light and electron microscopy to the rheumatoid nodule was noted.

The histologic findings of 325 necropsies of rheumatic patients at the National Institute of Cardiology in Mexico, between 1980-1985 were studied forty five of them had Aschoff nodules plus valvular inflammation-Out of these 45 cases two groups were formed: children-adolescent group (24 cases) and an adult group (21 cases). The clinical, histologic and laboratory findings were compared. Clinical records were reviewed searching for history of rheumatic fever. Active rheumatic fever was suspected in 16 patients in the younger group (67%) and only in 3 adults (14.2%). As far as Jones' criteria is concerned, the most common finding was carditis, principally in the younger group (83%). In the adult group, it appeared in 50% of the patients. All other criteria were only occasionally seen or could not be identified during the patients lifetime. The most common laboratory finding which could suggest active rheumatic fever were: a high levels of anti-streptolysin in younger patients (95%) and elevation of erythro-sedimentation in adults (83%). We conclude that in active rheumatic fever of the adult; Jones criteria are not met, so the illness is difficult to recognize, and there is clinical-histologic discrepancy. In this context the disease has a "silent" evolution.

Presence of Aschoff nodules and other chronic inflammatory cells in the left atrial appendage even in the absence of rheumatic activity has been reported in a high percentage of patients with chronic rheumatic valvular heart disease. This study was conducted on 37 left atrial appendages resected at the time of closed mitral valvotomy. Aschoff nodules were present in 61.2 percent of resected appendages, positivity being 71.4 percent in the age group of 20 years of less and 53.3 percent in patients more than 20 years of age. The histological findings did not change significantly in the presence of activity. The frequency of Aschoff nodules and chronic inflammatory cells and their subtypes also did not show any correlation with age, sex, duration of symptoms or severity of mitral stenosis.

Fc-receptors for IgG (Fc gamma R) are important triggers of effector function in macrophages. We have investigated the distribution of cells bearing Fc gamma R I, Fc gamma R II, and Fc gamma R III in 14 synovia and 3 nodules from rheumatoid arthritis (RA) patients, using monoclonal antibodies on serial cryostat sections. 8 osteoarthritis (OA), 2 ankylosing spondylitis (AS) patients and one sarcoid patient were also studied. Significant numbers of macrophages bearing Fc gamma R were present in inflamed synovial tissue with no significant difference in relative frequency between RA and OA. There was no correlation with the degree of lymphocytic infiltration. Distinctive staining patterns for the three Fc-receptors suggest differential regulation of these molecules on macrophages in synovium.

Autopsy study of 60 cases of rheumatic heart disease is presented, demonstrating an increased incidence of panvalvulitis in our series. The presence of Aschoff bodies is correlated with the clinical and laboratory parameters of activity and their significance is discussed.

Histo-morphological changes of the coronary vessels in cases of rheumatic heart disease (RHD) have been studied in 60 cases. Involvement of intramyocardial branches of coronary vessels in the form of active rheumatic vasculitis or inactive lesions characterized by medial hypertrophy and replacement fibrosis was seen in 15 of 60 cases. These lesions may affect myocardial function. Atherosclerosis of the pulmonary trunk and its branches was frequently seen in these hearts, indicating that this may be an important index of pulmonary hypertension. An unusual association of bicuspid aortic stenosis and RHD was seen in one case. Another case showed acute myocardial infarction due to coronary embolism from bacterial vegetation of bacterial endocarditis.

Exanthematous skin eruptions in an acute attack of polyarthritis histologically showed Aschoff's nodules or rheumatic granulomas, which are usually found in the myocardium but not in the skin.

In acute rheumatic fever, various types of myocardial degeneration and subsequent transformation of the damaged muscle fibers into a variety of cells, classified and unclassified, are described from microscopic examination of autopsy specimens. This study suggests that in the origin of Aschoff bodies, the diagnostic feature of rheumatic fever, there are three different pathways (Types A, B and C) for cytogenesis of Aschoff cells from altered muscle fibers. Type A cytogenesis takes place through the stage of Anitschkow myocytes of cardiac muscle origin (McDONALD 1963), and the Type B pathway, through the stage of dedifferentiated cells arising in lysing cardiac muscle fibers. These dedifferentiated cells with capacity for regeneration of regular cardiac muscle fibers (McDONALD 1975), show abortive or atypical development of muscle cells through the Aschoff cell stage. The Type C cytogenesis of Aschoff cells takes place through direct transformation of cardiac muscle fibers which show central hyalinization of myoplasm and changes in nuclei from normal to single or multinucleated large vesicular forms. The fibrinoid material of Aschoff bodies is shown to be the product of muscle origin. The mechanism of formation of fibrous scars in the myocardium and fibrous thickening of subendocardium are explained on the basis of fibrous transformation of cardiac muscle. Altered muscle fibers have been shown to give rise to cells which simulate inflammatory cells and others which cannot be classified.

The commonest extra-articular symptoms of rheumatoid arthritis include nodules, vasculitis, neuro-muscular involvement and keratoconjunctivitis sicca with dry mouth, characteristic of Sjögren's syndrome. However, laboratory tests demonstrate that there is a high percentage of pericarditis and involvement of the lungs, liver and pancreas, which are clinically silent. Personal statistics on extra-articular symptoms in 110 cases of classic rheumatoid arthritis are presented.