Anticentromere antibody. Clinical Correlations and association with favorable prognosis in patients with scleroderma variants

The presence of antibody to the chromosomal centromere appears to be associated with a subset of patients with the limited CREST form of scleroderma. To further define the prognostic value of this autoantibody, 27 patients, who were identified as having anticentromere antibody by screening antinuclear antibody tests using HEp-2 cell substrates, were followed clinically and serologically for 2 years. The presence of anticentromere antibody is common in the limited CREST forms of systemic sclerosis, and it is often the only autoantibody specificity present in the sera of patients with the CREST variant. When compared with other patients who exhibit speckled or nucleolar antinuclear antibody patterns, those with anticentromere antibody had significantly less major organ system involvement.     

Anticentromere antibodies in subjects with no apparent connective tissue disease.

OBJECTIVES--To study the association of anticentromere antibodies (ACA) in various diseases. METHODS--A total of 4800 consecutive serum samples were tested for ACA by indirect immunofluorescence using HEp-2 cells as substrates and by immunoblotting of Molt-4 cell mitotic chromosomal antigens and recombinant CENP-B protein. RESULTS--Anticentromere antibodies were identified in the serum samples of 24 subjects, including eight without apparent connective tissue diseases, six with primary biliary cirrhosis, two with diffuse scleroderma, one with pulmonary hypertension, one with primary Raynaud's phenomenon, one with CREST syndrome (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia), and five with other connective tissue diseases. By immunoblotting using Molt-4 cells mitotic chromosomal antigens three centromere antigens were recognised by these serum samples. These were: CENP-A (17 kilodalton recognised by 22 of 24 ACA positive serum samples); CENP-B (80 kilodalton recognised by 22 of 24 ACA positive serum samples); and CENP-C (140 kilodalton recognised by 19 of 24 ACA positive serum samples). There was no specific pattern for serum samples from patients with different groups of diseases on immunoblotting. Recombinant CENP-B proteins were all recognised by these samples. Patients without apparent connective tissue disease often had a lower ACA titre than patients with primary biliary cirrhosis. CONCLUSIONS--These data suggest that a positive result for ACA does not always indicate the presence of a connective tissue disease.     

Patterns of antihistone antibody specificity in systemic rheumatic disease. I. Systemic lupus erythematosus,mixed connective tissue disease,primary sicca syndrome,and rheumatoid arthritis with vasculitis

A new fluorimetric assay was used to measure the relative amounts of antibodies to individual nuclear histones in sera from 102 patients with systemic lupus erythematosus (SLE), mixed connective tissue disease, primary sicca syndrome, and rheumatoid arthritis with vasculitis. In SLE sera, the predominant responses were to histones H-1, H-2B, and H-3, with marked elevations of binding to H-1 and H-2B in one-third of the patients, and to H-3 in one-fourth; antibodies of both the IgG and IgM classes were also detected. In a few SLE sera, the pattern of histone response differed or was restricted to 1 immunoglobulin class. In mixed connective tissue disease, only 2 of 9 sera showed elevated histone binding activity, the response being predominantly to H-3 in 1 patient and to H-1 and H-2B in the other. Binding to H-2B was also prominent in 2 of 3 patients with primary sicca syndrome. The highest antihistone reactivity and the most heterogeneous response patterns were observed in patients who had rheumatoid arthritis with vasculitis; 6 of 8 of those sera had elevated histone reactivity. In SLE, the highest histone binding results were found among patients with a history of photosensitivity. Histones are closely associated with DNA in the nucleosome, and we speculate that antihistone antibodies could arise as a result of damage to DNA, induced by drugs or irradiation.     

Patterns of antihistone antibody specificity in systemic rheumatic disease. I Systemic lupus erythematosus, mixed connective tissue disease, primary sicca syndrome, and rheumatoid arthritis with vasculitis

A new fluorimetric assay was used to measure the relative amounts of antibodies to individual nuclear histones in sera from 102 patients with systemic lupus erythematosus (SLE), mixed connective tissue disease, primary sicca syndrome, and rheumatoid arthritis with vasculitis. In SLE sera, the predominant responses were to histones H-1, H-2B, and H-3, with marked elevations of binding to H-1 and H-2B in one-third of the patients, and to H-3 in one-fourth; antibodies of both the IgG and IgM classes were also detected. In a few SLE sera, the pattern of histone response differed or was restricted to 1 immunoglobulin class. In mixed connective tissue disease, only 2 of 9 sera showed elevated histone binding activity, the response being predominantly to H-3 in 1 patient and to H-1 and H-2B in the other. Binding to H-2B was also prominent in 2 of 3 patients with primary sicca syndrome. The highest antihistone reactivity and the most heterogeneous response patterns were observed in patients who had rheumatoid arthritis with vasculitis; 6 of 8 of those sera had elevated histone reactivity. In SLE, the highest histone binding results were found among patients with a history of photosensitivity. Histones are closely associated with DNA in the nucleosome, and we speculate that antihistone antibodies could arise as a result of damage to DNA, induced by drugs or irradiation.     

Anticentromere antibody positive CREST syndrome associated with polyarthritis,renal impairment and mixed cryoglobulinaemia

Summary We describe a 63-year-old female who developed the CREST syndrome within two years. Even though she was anticentromere antibody positive, her illness followed a very aggressive course and was associated with severe polyarthritis, renal impairment, hypocomplementaemia and mixed cryoglobulinaemia.     

Antiendothelial cell antibodies in vasculitis and connective tissue disease

Antiendothelial cell antibodies (AECA) are a heterogeneous family of antibodies reacting with endothelial cell antigens. These antibodies are found in various diseases and recognise several antigen determinants. Different pathophysiological effects have been observed in in vitro experiments, which include direct or indirect cytotoxicity and endothelial cell apoptosis. Furthermore, some AECA activate endothelial cells, resulting in increased leucocyte adhesiveness, activation of coagulation and vascular thrombosis. In animal models, it has been shown that AECA could promote vascular damage. Neither the endothelial cell antigens nor their precise role in the pathogenecity of different diseases in which AECA are found is well characterised. Nowadays, it is not known whether AECA are an epiphenomenon accompanying vascular injury or whether they are pathogenic. It is controversial whether fluctuations in AECA titres are associated with disease activity during follow-up studies. This review summarises the present knowledge about AECA, AECA antigens and their potential role in the pathogenecity of vasculitis and connective tissue diseases.     

Anticentromere antibody as a predictor of digital ischemic loss in patients with systemic sclerosis.

OBJECTIVE. To determine the clinical and serologic risk factors for digital ischemic events in patients with systemic sclerosis (SSc). METHODS. Retrospective review of clinical and laboratory data and review of current clinical status of 98 patients with SSc, seen between 1985 and 1990. RESULTS. Amputation of 1 or more digits due to ischemia occurred in 20.4% of the patients; 9.2% had multiple digit loss. Sclerodactyly alone and anticentromere antibody (ACA) were associated with loss of 1 or more digits. Age, smoking status, duration of disease, or duration of Raynaud's phenomenon were not predictive for loss of digits. CONCLUSION. Patients with limited SSc who are positive for ACA have an increased risk of major peripheral vascular occlusive disease.     

Large vessel occlusive disease associated with CREST syndrome and scleroderma.

OBJECTIVES--To report the cases of three patients with CREST syndrome and one patient with diffuse scleroderma who had severe macrovascular disease and only minimal vascular risk factors. METHODS--The medical histories, physical examinations, and results of clinical investigations were reviewed in four patients. RESULTS--These four patients had severe morbidity from macrovascular disease of the arms and legs in the presence of minimal underlying vascular risk factors. These patients represent 11% of the women with scleroderma seen at our hospital since 1974. This is a greater than threefold increase above the expected proportion of symptomatic vascular disease seen in population studies. In the patients with CREST syndrome, large vessel disease was first seen more than 10 years after the onset of Raynaud's phenomenon, which was the first manifestation of the disease. A pathological specimen of the ulnar artery from one patient showed severe luminal narrowing by an acellular material with no evidence of atheroma. CONCLUSIONS--These cases suggest an association of both the CREST syndrome and scleroderma with macrovascular disease.     

Pregnancy in mixed connective tissue disease, poly/dermatomyositis and scleroderma

Pregnancy related problems in mixed connective tissue disease, polydermatomyositis and scleroderma are analysed. Particular attention is also elevated to the therapeutical approach to these diseases during pregnancy and delivery.     

Retinal vasculitis in mixed connective tissue disease. A fluoroangiographic study

The eyes of 20 consecutive patients with mixed connective tissue disease (MCTD) were studied by ophthalmologic and retinal fluoroangiographic examinations (RFA) and compared with the findings in 18 consecutive patients with primary Sj?gren's syndrome (SS) and 50 with systemic lupus erythematosus (SLE). Six of the 20 MCTD patients had abnormal RFA with thickening of capillary walls that stained and progressively leaked fluorescein. None of these lesions could be seen in ophthalmoscopy, where only one patient had cotton wool spots that in RFA were found to correspond to focal areas of ischemia, probably resulting from capillary lesions. Only one patient with primary SS showed capillary leakage, whereas 13 patients with SLE had RFA abnormalities that included microaneurysms in 9, capillary lesions in 6 and drusen in one. No microaneurysms were found in MCTD patients. The differences between MCTD, SLE and SS patients may reflect differences in the quality, quantity, frequency and chronicity of immune complex formation and deposition in these 3 diseases.     

Urticarial vasculitis in a connective tissue disease clinic: patterns, presentations, and treatment

Findings in 27 patients with typical skin lesions of urticarial vasculitis (UV) who were seen at a connective tissue disease clinic over a 5-year period (1986 to 1990) are reviewed. The majority suffered from systemic lupus erythematosus (SLE) or from "lupus-like" disease (18 patients), 1 from "mixed" connective tissue disease (MCTD), and 5 from primary UV. All of the latter patients had normal serum complement levels (normocomplementemic urticarial vasculitic syndrome; NUVS). No patients with hypocomplementemic UV were encountered. Two patients suffered from necrotizing vasculitis (polyarteritis nodosa, Wegener's granulomatosis); one had a C1-esterase inhibitor deficiency and also demonstrated an immunoglobulin G paraproteinemia. Angioedema occurred in many patients and could not be used as a differential diagnostic feature. The course of the illness was chronic in most patients, lasting for up to 23 years, and the response to therapy was unpredictable, erratic, and unsustained. The use of intravenous "pulse" methylprednisolone, cyclophosphamide, or high-dose oral steroids helped selected patients. Colchicine was dramatically effective in one patient with NUVS of 15 years duration. Azathioprine was not beneficial. None of the five patients with NUVS suffered from severe systemic involvement or renal disease, confirming observations by others that this form of UV represents a milder example of the condition.     

Anticentromere antibody as a predictor of digital ischemic loss in patients with systemic sclerosis

Objective. To determine the clinical and serologic risk factors for digital ischemic events in patients with systemic sclerosis (SSc). Methods. Retrospective review of clinical and laboratory data and review of current clinical status of 98 patients with SSc, seen between 1985 and 1990. Results. Amputation of 1 or more digits due to ischemia occurred in 20.4% of the patients; 9.2% had multiple digit loss. Sclerodactyly alone and anticentromere antibody (ACA) were associated with loss of 1 or more digits. Age, smoking status, duration of disease, or duration of Raynaud's phenomenon were not predictive for loss of digits. Conclusion. Patients with limited SSc who are positive for ACA have an increased risk of major peripheral vascular occlusive disease.     

Morphoea (localised scleroderma) in a patient with mixed connective tissue disease.

An 18 year old girl concurrently developed skin lesions of morphoea (localised scleroderma) and pain and swelling of the hands and fingers. There were no dermatological or systemic signs of systemic sclerosis. The immunological features (high titred speckled antinuclear antibody, negative DNA binding, high titred positive anti-RNP and negative anti-Sm antibodies, speckled nuclear Ig fluorescence in the epidermis of the skin lesions) were consistent with mixed connective tissue disease, and it is suggested that the morphoea represented a component of this condition.     

Electrocardiographic findings in patients with connective tissue disease.

ECG changes in 49 patients with rheumatoid arthritis, 18 with ankylosing spondylitis, 47 with systemic lupus erythematosus, 17 with dermatomyositis, 21 with scleroderma and 7 with polyarteritis nodosa were compared with ECG changes in 106 control subjects. The classification of ECG findings was based mainly on the Minnesota Code. Compared with control subjects, pathological Q--QS, ST segment and T wave patterns were more common in all patient groups--including dermatomyositis, in which cardiac involvement has rarely been reported. P terminal force (PTF) was higher in the patient group. Conduction defects were probably more common in connective tissue diseases, whereas differences in ectopic beats, arrhythmias, QRS duration and QRS axis and R wave amplitude were not significant. The only significant difference between the steroid-treated patients and those without such treatment was the higher frequency of ST changes in the steroid-treated group. The results imply that heart affection is common in all connective tissue diseases. The several mechanisms underlying the cardiac involvement are reflected in many ways in the electrocardiograms of these patients, including an increased frequency of ECG changes mimicking those met in coronary heart disease.     

Bronchoalveolar lavage in patients with connective tissue disease.

Bronchoalveolar lavage (BAL) allows the recovery of cellular and fluid constituents that are derived from the epithelial surface of the lower respiratory tract. BAL fluid and cell analysis has become an important tool for understanding human pulmonary disease. Changes in the quantities and patterns of BAL cells and secretions have been described in a number of chronic lung disorders, especially the diffuse interstitial lung diseases. Specific BAL alterations have correlated with patient outcome and response to therapy. The connective tissue diseases have been associated with serious pleural and/or pulmonary pathology and may be a major cause of morbidity and mortality. BAL appears to be a useful semi-invasive tool in the evaluation and management of lung disease in patients with connective tissue diseases. The article describes the BAL findings in various connective tissue diseases and assesses the usefulness of BAL in the clinical management of patients with pulmonary complications.     

Antinuclear antibody profile in Italian patients with connective tissue diseases.

In the present work we report data on the specificity of antinuclear antibodies (ANA) in a large series of Italian patients suffering from a broad spectrum of connective tissue diseases (CTD), by using a series of homogeneous and validated techniques. The present study confirms, on the one hand, generally accepted concepts, i.e. that certain autoantibodies are strictly associated to certain disease states (such as anti-PCNA and anti-Sm in systemic lupus erythematosus, Jo 1 in polymyositis, and ACA and Scl-70 in scleroderma); the presence of 'marker' antibodies is, however, restricted to a relative minority of CTD patients. The application of a new methodological approach that considers the entire profile of ANA can greatly augment their diagnostic relevance and may provide useful indications for their interpretation, allowing us to establish for the first time the diagnostic usefulness not only of marker autoantibodies but also of certain associations between non-marker autoantibodies. Finally, the application of a more appropriate and powerful statistical tool (multiple correspondence analysis) has further emphasized the clear relationship existing between antibody specificities and certain disease states.     

Mixed connective tissue disease: a case with scleroderma renal crisis following abortion

The term mixed connective tissue disease (MCTD) has been applied to a particular subset of patients with overlapping clinical features of systemic sclerosis, systemic lupus erythematosus, and polymyositis. Immune response to U1-ribonucleoprotein is the defining serological feature of MCTD. There are different organ and system involvements in MCTD including the heart, lung, kidney, muscle, joints, gastrointestinal, and hematologic involvements. Reports describing pregnancies in patients with MCTD are rare, and the results have been contradictory: a high risk of fetal loss and of disease exacerbation or no influence on fetus or mother. In MCTD, simultaneous pulmonary and renal involvement is very rare. In this paper, we report a case of MCTD with pulmonary involvement that developed scleroderma renal crisis after an abortion.