Pathology of skeletal muscle in mixed connective tissue disease.

To characterize the pathology of muscle involvement in mixed connective tissue disease (MCTD), skeletal muscle biopsies from 13 patients with MCTD were examined by routine light microscopy, histochemistry, and direct immunofluorescence. The histologic and histochemical changes observed corresponded closely to changes seen in idiopathic polymyositis and the myopathy associated with systemic lupus erythematosus. Eight of 13 cases examined by direct immunofluorescence demonstrated immunoglobulin deposition either within normal appearing vessels, within normal fibers, around or on the sarcoplasmic membrane, or within the perimysial connective tissue. The histologic findings support Sharp's observation of the high incidence of focal inflammatory lesions in skeletal muscle biopsies of patients with MCTD. Immunoglobulin deposition in these muscle biopsies suggests an immunologic basis for the muscular symptomatology in MCTD.     

Nailfold capillary density as a possible indicator of pulmonary capillary loss in systemic lupus erythematosus but not in mixed connective tissue disease.

Nailfold capillary density was measured in 24 patients with systemic lupus erythematosus (SLE), 14 with mixed connective tissue disease (MCTD) and 21 healthy subjects. Pulmonary function tests were performed on all subjects and needle muscle biopsies on 12 patients with SLE and 9 with MCTD. A significant correlation was documented between nailfold capillary density and pulmonary gas transfer (KCO) in patients with SLE (p less than 0.001) but not in patients with MCTD. This suggests that in SLE poor gas transfer may be dependent on alveolar capillary loss and that nailfold capillary density may be a good indicator of alveolar capillary density. There was no significant correlation between skeletal muscle fiber atrophy and nailfold capillary density in SLE or MCTD. Additional studies to optimize the nailfold capillary counting method are described.     

Epidermal nuclear immunoglobulin deposits in some connective tissue diseases: correlation with ENA antibodies.

In-vivo nuclear deposits of IgG were demonstrated by direct immunofluorescence in epidermal cells of normal skin from 6 patients with serum antibodies to an RNase-sensitive extractable nuclear antigen (ENA). Addition of complement to the skin sections showed that C3 could bind to epidermal cells with IgG deposits. A skin biopsy from a patient with polymyositis and serum antibodies to ENA, but without nuclear IgG deposits, showed nuclear binding of C3 after addition of complement to the skin sections. The clinical diagnoses of patients with immunofluorescent staining of epidermal cells were mixed connective tissue disease (MCTD) 4 cases, systemic lupus erythematosus (SLE) 2 cases, and polymyositis 1 case. No epidermal nuclear IgG deposits could be demonstrated in 5 cases of SLE, 2 cases of MCTD, one case of polymyositis, or 15 cases of rheumatoid arthritis without antibodies to ENA.     

Clinical significance of U1-RNP immune complexes in mixed connective tissue disease and systemic lupus erythematosus

Summary We measured U1-RNP: anti-U1-RNP immune complexes (U1-RNP ICs) in patients with mixed connective tissue disease (MCTD) and systemic lupus erythematosus (SLE) to examine the clinical significance of circulating U1-RNP ICs. The level of U1-RNP ICs in 11 patients with MCTD was significantly higher than that in 22 normal subjects and there was a close correlation between the level of U1-RNP ICs and the clinical disease activity index of MCTD. In contrast, the level of U1-RNP ICs in 31 patients with SLE was not significantly higher than that in normal subjects and that was not correlated with the clinical disease activity index of SLE or the renal histologic activity index of lupus nephritis. We conclude that U1-RNP ICs are present in sera of patients with MCTD and SLE, and that the level of U1-RNP ICs may be closely associated with clinical disease activity in patients with MCTD.     

Sj?gren's syndrome and mixed connective tissue disease.

We investigated the clinical significance of the close association of Sj?gren's syndrome (SS) with mixed connective tissue disease (MCTD) by analyzing the clinical manifestations, sialographic findings and immunological parameters of MCTD and primary SS. The prevalence of sialectasia or SS in MCTD was significantly higher than in any other connective tissue diseases. The prevalence of Raynaud's phenomenon, swollen fingers, arthralgias, lymphadenopathy, sclerodactyly, muscle weakness, fever and erythema was significantly higher in MCTD than in primary SS. There were no significant differences between these manifestations in MCTD patients with sialectasia or SS, and those in MCTD patients without sialectasia or SS. Although the levels or prevalence of the erythrocyte sedimentation rate, CRP, antinuclear factor, anti-DNA antibody and anti-RNP antibody were significantly greater in MCTD than in primary SS, there were no significant differences in the levels or the prevalence of laboratory abnormalities between MCTD with sialectasia or SS, and MCTD without sialectasia or SS. Moreover, there was a strict dissociation between the occurrence of anti-RNP antibody and anti-SS-B antibody both in MCTD and primary SS. These results suggest that the association of secondary SS or sialectasia in MCTD, although more common than in other connective tissue diseases, is merely a consequence of MCTD and does not influence the clinical course of MCTD.     

Studies on von Willebrand factor antigen in endothelial cells and sera of patients with connective tissue diseases]

Von Willebrand factor antigen (vWF: Ag) is known to be produced and excreted by endothelial cells (EC). The influences of interferon (IFN) on surface, excreted and intracellular vWF: Ag amounts of EC were studied by flow cytometry and ELISA. Serum levels of vWF: Ag in patients with connective tissue diseases were also studied by ELISA. Experiments in vitro showed that IFN increased vWF: Ag amounts of EC. Serum levels of vWF: Ag in patients with mixed connective tissue disease (MCTD), systemic lupus erythematosus, progressive systemic sclerosis, polymyositis/dermatomyositis or rheumatoid arthritis (RA) were significantly higher than those of normal subjects, on the other hand, vWF: Ag levels in patients with aortitis syndrome were within normal range. MCTD patients complicated with pulmonary hypertension (PH) [MCTD (PH)] and RA vasculitis (MRA) patients had quite high levels of vWF: Ag. The levels of vWF: Ag seemed to correlate with severity of PH in patients with MCTD (PH). Increased serum levels of vWF: Ag observed in those patients might be induced by EC damaged or influenced by IFN or other cytokines. Monitoring of vWF: Ag levels could be useful to predict the onset and pathologic conditions of MCTD (PH) or related vascular diseases.     

Histopathological study of mixed connective tissue disease from 32 autopsy cases in Japan

In order to identify the histological specificity of newly defined connective tissue disease, we examined 32 autopsy cases of mixed connective tissue disease (MCTD) which fulfilled the disease criteria proposed by the Japanese MCTD Committee. The age of the 32 cases ranged from 19 to 79 with an average age of 43 years. The male: female ratio was 3∶29. The duration of illness was 7.9 years on average. These tendencies were not so specific compared with other connective tissue diseases. In reference to the cause of death, pulmonary hypertension associated with severe pulmonary arterial lesions such as plexogenic arteriopathy and intimal thickening was found in 16 cases, which was 34% of all total autopsy cases. Totally pulmonary diseases including pulmonary hypertension, pulmonary fibrosis and interstitial pneumonitis amounted to half of all fatal cases. Following pulmonary disease, esophageal fibrosis, sialoadenitis and cardiac involvement succeeded. Although clinical signs such as dysphagia or hypomotility did not necessarily present before death, the frequency and severity of histological changes of the esophagus cannot be ignored. Accompanied with sicca syndrome, the salivary gland showed variable stages of inflammatory changes from slight lymphocytic infiltration in the periductal region to severe parenchymatous atrophy with severe fibrosis. Autopsy cases of MCTD disclosed myocardial damage in not a few cases, which were often accompanied with fibrosis, and these features were very similar to the those of esophageal lesions. On the other hand, involvement of the kidney, skin and muscle was very slight in MCTD compared with those of systemic lupus erythematosus, progressive systemic sclerosis and polymyositis/dermatomyositis. The kidney lesion was characterized by membranous glomerulonephritis. Skin continued to be scleroedematous in spite of long term illness. Muscle showed slight lymphocytic infiltration around small vessels and interstitium. In addition to serological and clinical features, histopathological study revealed specific features of MCTD different from other connective tissue diseases. In treatment and follow-up of the patients of MCTD, special care should be paid to the conditions of this disease which reflect the histological changes as presented here.     

Histopathological study of mixed connective tissue disease from 32 autopsy cases in Japan

Abstract

In order to identify the histological specificity of newly defined connective tissue disease, we examined 32 autopsy cases of mixed connective tissue disease (MCTD) which fulfilled the disease criteria proposed by the Japanese MCTD Committee. The age of the 32 cases ranged from 19 to 79 with an average age of 43 years. The male: female ratio was 3∶29. The duration of illness was 7.9 years on average. These tendencies were not so specific compared with other connective tissue diseases. In reference to the cause of death, pulmonary hypertension associated with severe pulmonary arterial lesions such as plexogenic arteriopathy and intimal thickening was found in 16 cases, which was 34% of all total autopsy cases. Totally pulmonary diseases including pulmonary hypertension, pulmonary fibrosis and interstitial pneumonitis amounted to half of all fatal cases. Following pulmonary disease, esophageal fibrosis, sialoadenitis and cardiac involvement succeeded. Although clinical signs such as dysphagia or hypomotility did not necessarily present before death, the frequency and severity of histological changes of the esophagus cannot be ignored. Accompanied with sicca syndrome, the salivary gland showed variable stages of inflammatory changes from slight lymphocytic infiltration in the periductal region to severe parenchymatous atrophy with severe fibrosis. Autopsy cases of MCTD disclosed myocardial damage in not a few cases, which were often accompanied with fibrosis, and these features were very similar to the those of esophageal lesions. On the other hand, involvement of the kidney, skin and muscle was very slight in MCTD compared with those of systemic lupus erythematosus, progressive systemic sclerosis and polymyositis/dermatomyositis. The kidney lesion was characterized by membranous glomerulonephritis. Skin continued to be scleroedematous in spite of long term illness. Muscle showed slight lymphocytic infiltration around small vessels and interstitium. In addition to serological and clinical features, histopathological study revealed specific features of MCTD different from other connective tissue diseases. In treatment and follow-up of the patients of MCTD, special care should be paid to the conditions of this disease which reflect the histological changes as presented here.     

Esophageal dysfunction in patients with progressive systemic sclerosis and mixed connective tissue diseases

Esophageal motility was studied in 37 patients with progressive systemic sclerosis (PSS), 12 patients with mixed connective tissue disease (MCTD) and 40 controls by the manometry method, using an open tube and continuous perfusion, and by radiological examination. Radiology was normal in 17 patients with PSS and five patients with MCTD, and abnormal in 15 patients with PSS and three with MCTD. The most frequent abnormality was slow transit time of barium. Manometry of the esophageal body was normal in 20 patients with PSS and six patients with MCTD, and abnormal in 17 patients with PSS and six with MCTD. Lack of contraction in the middle lower segments of the esophagus was the abnormality most frequently observed. Lower esophageal sphincter pressure was significantly lower among patients with PSS and MCTD than among the controls. Dysphagia was reported by ten patients with PSS and by six patients with MCTD. Radiology and manometry showed similar changes in PSS and MCTD, but dysphagia was more frequent among patients with MCTD.     

Scleroderma renal crisis and concurrent isolated pulmonary hypertension in mixed connective tissue disease and overlap syndrome: report of two cases

We here report on scleroderma renal crisis (SRC) appearing concurrently with isolated pulmonary hypertension (IPHT), that is, pulmonary hypertension without interstitial lung disease with fibrosis, in a patient with mixed connective tissue disease (MCTD) and in one with overlap syndrome or undifferentiated connective tissue disease (UCTD). To the best of our knowledge there are only five previous reports on SRC in MCTD and UCTD. The unexpected appearance of SRC in the setting of concomitant IPHT and limited or absent scleroderma skin changes is discussed. Received: 26 January 2001 / Accepted: 13 July 2001     

Rheumatoid factor isotypes in mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a connective tissue disorder that is often accompanied by various immunological abnormalities. In this study, we analyzed serum levels of rheumatoid factor (RF) isotypes in patients with MCTD and in normal controls to determine if any of these isotypes reflects the severity of the disease. IgM-RF, IgG-RF, and IgA-RF were positive in 48, 38, and 33% of the patients, respectively. The frequency of positive anti-SS-A antibody and decrease in white blood cell counts were significantly greater in patients with elevated IgA-RF levels than that in those with normal levels. These results suggest that the presence of RF isotypes can be regarded as one of the various immunological abnormalities of MCTD.     

Ultrastructure of lung in Legionnaires' disease. Observations of three biopsies done during the Vermont epidemic.

Open lung biopsies from three patients with Legionnaires' disease were examined by light and transmission electron microscopy. The patients had serious underlying disease. All developed a rapidly progressive pneumonia unresponsive to penicillin, oxacillin, and gentamicin. One patient, who received erythromycin, survived. Light microscopy in all three showed severe acute bronchopneumonia. The Legionnaires' disease bacterium was seen in tissue sections and confirmed by direct immunofluorescence. Transmission electron microscopy showed numerous rod-shaped intracellular organisms that were morphologically similar to other gram-negative bacteria and the Rickettsieae. They were within phagolysosomes, free in the cytoplasm, and rarely within structures resembling dilated rough endoplasmic reticulum. Lung tissue changes included marked detachment and necrosis of alveolar pneumocytes, septal and alveolar exudate with lysis, and prominent endothelial cell swelling and degeneration. Capillary and epithelial basement membranes were consistently intact, suggesting that the tissue changes are potentially capable of reverting to normal structure and function.     

MCTD: is it rare in India?

Mixed connective tissue disease (MCTD) has been rarely reported from India. Thus, we did a retrospective analysis of cases of MCTD seen at our hospital during the last 13 years. We found 16 cases among 441 patients with connective tissue disease. All the 16 patients (15 females) of MCTD fulfilled classification criteria by Kasukawa and at least one of the other two (Sharp's and Alarcon-Sergovia). Raynaud's phenomenon, sclerodactyly, puffy fingers, esophageal hypomotility, and pulmonary disease were the most common manifestations. At a median follow-up of 12 months (1-172), 12 patients developed features of limited scleroderma and three patients had pulmonary hypertension.     

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.     

Mixed connective tissue disease developing into MPO-ANCA-positive polyangiitis

Renal involvement of mixed connective tissue disease (MCTD) shows systemic lupus erythematosus (SLE)-like immune complex glomerulonephritis. The prognosis of this condition is generally good. We report the case of an elderly female patient with MCTD who developed autoimmune pleurisy and rapidly progressive glomerulonephritis. Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) was positive with a titer of 59.0 EU. Anti-DNA antibody and complement levels were normal. Renal biopsy revealed crescentic glomerulonephritis and mild mesangial proliferation. However, immunofluorescence examination revealed immune-complex glomerulonephritis. These findings suggest that the renal involvement of MCTD developed concurrently with MPO-ANCA-related glomerulonephritis.     

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.     

Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients

We tested patients with a well defined connective tissue disease (CTD) against 3 different sets of criteria for mixed connective tissue disease (MCTD). Included were 200 patients with systemic lupus erythematosus (SLE), 80 with MCTD, 100 with rheumatoid arthritis (RA), 80 with scleroderma, 53 with dermato/polymyositis (DM/PM) and 80 with primary Sj?gren's syndrome (SS). The 3 sets of criteria fared similarly in capturing nearly all MCTD patients. They also were similar in ruling out most of the other CTD except for 11 patients with SLE, 36 with scleroderma, 13 with DM/PM and 3 with SS who fulfilled the category of possible MCTD included in the set of criteria proposed by Sharp. Because the set of criteria we proposed includes only 5 clinical manifestations (edema of the hands, synovitis, myositis, Raynaud's phenomenon, and acrosclerosis) whereas the other 2 sets include 15 and 13, respectively, it would seem that the 5 included in our criteria are core manifestations of MCTD. Of the 80 patients with MCTD 32 had all 5, 38 had 4, and 10 had 3 of these manifestations. The sensitivity of 3 or more of these clinical criteria for MCTD was 100%, whereas the specificity which, with the clinical criteria was 91.8%, rose to 99.6% with the presence of anti-RNP antibody. However, because testing of our criteria was made internally, they should be further tested, along with the other 2 sets of criteria by unrelated groups of clinical investigators, perhaps in a multicenter study.     

Immunohistological analysis of CD59 and membrane attack complex of complement in muscle in juvenile dermatomyositis

OBJECTIVE: To assess the presence of CD59 and the deposition of membrane attack complex (MAC) of complement system in skeletal muscle from patients with juvenile dermatomyositis (JDM), in comparison to patients with muscular dystrophies (MD) and children with normal muscle biopsies. METHODS: Muscle specimens obtained for diagnostic purposes from 10 patients with JDM, 6 with MD, and 7 children whose biopsies showed normal histology were analyzed. Immunohistological staining was performed using Mab against CD59 (YTH 53.1) and MAC (WU 7.2). RESULTS: Immunohistochemical staining for CD59 was weak and irregularly distributed on muscle fibers of all patients with JDM. Two of the 9 biopsies that allowed analysis of vessels showed negative CD59 staining in all vessels; in the remaining 7 patients, there was weak staining in a proportion of the vessels. In contrast, uniform and strong or moderate immunoreactivity was detected on the sarcolemma and in intramuscular endothelium in all normal and MD samples. Immunostaining for MAC was strong in JDM muscle vessels, and weak in normal or MD muscle. An inverse relation was found between MAC deposition and presence of CD59 in vessels in 6/9 JDM biopsies and in all normal and MD samples. CONCLUSION: Decreased CD59 expression in JDM muscle fibers and vessels may be associated with muscle lesions mediated by deposition of MAC of complement in JDM.     

ACUTE SCLERODERMA IN STABLE MIXED CONNECTIVE TISSUE DISEASE: TREATMENT BY PLASMAPHERESIS

Abstract This report describes a case of stable mixed connective tissue disease (MCTD) with development of acute scleroderma with hypertension, oliguric renal failure, microangiopathic hemolytic anemia, and pulmonary infiltrates. The renal histology in the acute episode was that of scleroderma with intimal sclerosis and ‘onion skinning’ of vessels and glomerular ischemic injury but with no evidence of damage by immune complexes either histologically or by immunofluorescence. Improvement occurred after treatment with plasmapheresis, cyclosphamide, and captopril with return of near normal renal function.