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****** DATA-MEDICOS **********
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LA ENFERMEDAD MIXTA DEL TEJIDO CONECTIVO
THE MIXED CONNECTIVE TISSUE DISEASE
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****** DERMAGIC-EXPRESS No.48 ******* 
****** 07 ABRIL DE 1.999 ********* 
07 APRIL 1.999
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EDITORIAL ESPAÑOL
=================
Hola amigos DERMAGICOS, el tema de hoy, LA ENFERMEDAD MIXTA DEL TEJIDO CONECTIVO. 
Dentro del tema de las colagenosis muchas escuelas opinan que esta enfermedad es un SINDROME DE OVERLAP, otras las clasifican como entidades distintas en base a la presencia o no de anticuerpos anti Ul-RNP, y otros la consideran como una enfermedad indiferenciada del tejido conectivo. Espero que estas 54 referencias nos aclaren bien el tema. 

Bienvenidos a DERMAGIC: Dr.HonaBeth Holmes (Little Rock, ar), Elizabeth ANne Small
(Springfield, IL USA)

Saludos a TODOS !!!

Dr. Jose Lapenta R.,,,


EDITORIAL ENGLISH
=================
Hello DERMAGICS friends, today's topic, THE MIXED CONNECTIVE TISUE DISEASE. 
Inside the topic of the connective diseases, many schools say that this illness is a OVERLAP SYNDROME, other classify them as different entities based on the presence or not of antibodies anti Ul-RNP. Others prefer to classify MCTD as an undifferentiated connective tissue disease. I hope these 54 references clarify us well the topic. 

Welcome to DERMAGIC: Dr.HonaBeth Holmes (Little Rock, ar), Elizabeth ANne Small
(Springfield, IL USA)

Greetings to ALL, !!


Dr. Jose Lapenta R.,,,
======================================================================
DERMAGIC/EXPRESS(48)
======================================================================
LA ENFERMEDAD MIXTA DEL TEJIDO CONECTIVO 
THE MIXED CONNECTIVE TISSUE DISEASE
========================================================================
1.) MIXED CONNECTIVE TISSUE DISEASE
2.) Effective treatment with low-dose methotrexate pulses of a child of mixed 
connective tissue disease with severe myositis refractory to corticosteroid]
3.) Analysis of human T cell and B cell responses against U small nuclear ribonucleoprotein 70-kd, B, and D polypeptides among patients with systemic lupus 
erythematosus and mixed connective tissue disease.
4.) Mixed connective tissue disease. A clinical, histologic, and immunofluorescence 
study of eight cases.
5.) Internalization of anti-nucleolin antibody into viable HEp-2 cells.
6.) Clinical and immunological aspects of autoantibodies to RA33/hnRNP-A/B proteins--a 
link between RA, SLE and MCTD.
7.) Mixed connective tissue disease. A clinico-serological study of 17 cases.
8.) Mixed connective tissue disease associated with acute polyradiculoneuropathy.
9.) [Successful treatment for pulmonary hypertension with angiotensin 1 converting 
enzyme inhibitor in a patient with mixed connective tissue disease]
10.) Mixed connective tissue disease in childhood: a nationwide retrospective study in 
Japan.
11.) Metaplastic bone formation in the subcutaneous nodule of a patient with mixed 
connective tissue disease.
12.) Anti-RNP antibody in a child with undifferentiated carcinoma and no evidence of 
mixed connective tissue disease.
13.) Antiphospholipid antibodies among anti-U1-70 kDa autoantibody positive patients 
with mixed connective tissue disease.
14.) Comparative study of 4 diagnosis criteria sets for mixed connective tissue disease 
in patients with anti-RNP antibodies. Autoimmunity Group of the Hospitals of Toulouse.
15.) [Pleuropericarditis complicated of tamponade disclosing mixed connective tissue 
disease. Remission with non-steroidal anti-inflammatory agents. Apropos of a case]
16.) Blotting patterns of IgG anti-(U1)RNP antibodies in mixed connective tissue 
disease.
17.) Mixed connective tissue disease and radiation toxicity. A case report.
18.) Neutralization of HIV type 1 infectivity by serum antibodies from a subset of 
autoimmune patients with mixed connective tissue disease.
19.) Predominance of IgM anti-U1RNP antibodies in patients with systemic lupus erythematosus.
20.) Focal myositis presenting as pseudothrombophlebitis of the neck in a patient with mixed connective tissue disease.
21.) [Chronic recurrent subileus due to Strongyloides stercoralis infection under immunosuppressive therapy]
22.) Meningococcal endocarditis presenting as cellulitis.
23.) Autoimmune derived combinatorial phage display libraries: methods in construction of and affinity selection for anti-RNA Fabs.
24.) Mixed connective tissue disease complicated by pneumatosis cystoides intestinalis and malabsorption syndrome: case report and literature review.
25.) Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions I.
26.) A connective tissue disease screening questionnaire for population studies.
27.) [Puerperal secondary pulmonary hypertension in a patient with mixed connective tissue disease]
28.) Transverse myelopathy complicating mixed connective tissue disease.
29.) Plasma endothelin correlates with antiendothelial antibodies in patients with mixed connective tissue disease.
30.) [Two cases with SLE and MCTD developed after a long period of chronic arthritis that was initially diagnosed as JRA]
31.) Anti-endothelial cell antibodies in the sera of patients with mixed connective 
32.) [Newer approach of screening test for antinuclear antibodies: an enzyme-linked immunosorbent assay detecting antinuclear antibodies characteristic of connective tissue diseases]
33.) 'Autoantibody dominance' pattern following idiotypic manipulation of naive mice by immunization with anti-U1RNP antibodies.
34.) Usefulness of antinuclear antibody testing to screen for rheumatic diseases.
35.) Histological evaluation of destructive monoarthropathy in mixed connective tissue disease.
36.) Fulminant hepatic failure due to cardiac tamponade associated with mixed connective tissue disease.
37.) Antibodies to the constitutive 73-kd heat shock protein: a new marker of mixed connective tissue disease?
38.) Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions II.
39.) Hypertrophic cranial pachymeningitis associated with mixed connective tissue disease; a comparison with idiopathic and infectious pachymeningitis.
40.) Juvenile-onset mixed connective tissue disease: longitudinal follow-up.
41.)Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions III.
42.) Mixed connective tissue disease associated with autoimmune hepatitis and thyroiditis.
43.) Differences in HLA antigens between patients with mixed connective tissue disease and systemic lupus erythematosus.
44.) Japanese diagnostic criteria for mixed connective tissue disease in Caucasian patients.
45.) Clinical significance of IgG subclasses of Anti-Sm and U1 ribonucleoprotein antibodies in patients with systemic lupus erythematosus and mixed connective tissue disease.
46.) Overlap syndromes and mixed connective tissue disease.
47.) Use of recombinant RNP peptides 70K and A in an ELISA for measurement of antibodies in mixed connective tissue disease: a longitudinal follow up of 18 patients.
48.) Mixed connective tissue disease after exposure to polyvinyl chloride.
49.) Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients.
50.) Clinical and serologic characteristics of patients with overlap syndrome: is mixed connective tissue disease a distinct clinical entity?
51.) Fluctuations in anti-nRNP levels in patients with mixed connective tissue disease are related to disease activity as part of a polyclonal B cell response.
52.) Immunofluorescence studies in progressive systemic sclerosis (scleroderma) and mixed connective tissue disease.
53.) Mixed connective tissue disease - a subset with sequential clinical and laboratory features.
54.) Raynaud's phenomenon and initially seronegative mixed connective tissue disease.
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1.) MIXED CONNECTIVE TISSUE DISEASE
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Source: Harrison's 14

MCTD is an overlap syndrome characterized by combinations of clinical features of systemic lupus erythematosus (SLE), SSc, polymyositis , and rheumatoid arthrisis and the presence of very high titers of circulating autoantibodies to nuclear RNP antigen. This antibody in high titer, now referred to as anti-U1 RNP, has been a justification for considering MCTD as a distinct clinical entity. MCTD has been challenged as a distinct disorder by those who consider it as a subset of SLE or scleroderma. Others prefer to classify MCTD as an undifferentiated connective tissue disease. MCTD occurs worldwide and in all races. The peak onset of disease is in the second and third decades, but MCTD is seen in children and the elderly. Women are predominantly affected. The pathogenic mechanisms in MCTD reflect the disorders making up this syndrome.

Clinical Features The presenting symptoms of MCTD are most often Raynaud's phenomenon, puffy hands, arthralgias, myalgias, and fatigue. Occasionally, patients may present with the acute onset of high fever, polymyositis, arthritis, and neurologic features such as trigeminal neuralgia and aseptic meningitis. The various features of the connective tissue disorders making up MCTD develop over months and years.

The fingers as well as the entire hand may be puffy, followed later by sclerodactyly. Sclerodermal changes are usually limited to the distal extremities and sometimes the face but spare the trunk. Telangiectasia and calcinosis may develop. Some patients have mucocutaneous features of SLE including a classic malar rash, photosensitivity, discoid lesions, alopecia, and painful oral ulcerations. An erythematous rash over the knuckles, elbows, and knees and heliotropic eyelids, typical of dermatomyositis, are uncommon.

Joint pain, stiffness, and swelling involving the peripheral joints occur frequently. Deformities of the hands similar to those of rheumatoid arthritis may develop but usually without bony erosions. A destructive polyarthritis is occasionally observed. Myalgias are a frequent symptom. Some patients develop typical symptoms of polymyositis with proximal muscle weakness, abnormal electromyographic findings, elevated levels of muscle enzymes, and inflammatory changes on muscle biopsy.

Approximately 85 percent of patients have pulmonary involvement, which is often asymptomatic. Diffusing capacity for carbon monoxide may be the only abnormality. Pleurisy commonly occurs but is seldom associated with large pleural effusions. Some patients develop interstitial lung disease. Pulmonary arterial hypertension is the most common cause of death in MCTD.

Approximately 25 percent of patients develop renal disease. Membranous glomerulonephritis is most common and usually mild but can cause nephrotic syndrome. Diffuse proliferative glomerulonephritis is unusual in MCTD, perhaps because of the protective role played by the high titers of anti-U1 RNP. Renal crisis secondary to malignant renovasculature hypertension, as occurs in scleroderma, is seen in a few patients.

Gastrointestinal involvement is seen in approximately 70 percent of patients. The most common manifestations are esophageal dysmotility, lower esophageal sphincter laxity, and gastroesophageal reflux. Bowel manifestations mimic those of scleroderma bowel disease.

Pericarditis occurs in 30 percent of patients. Other cardiac features include myocarditis, arrhythmia, conduction disturbances, and mitral valve prolapse. Other clinical features of MCTD include trigeminal neuropathy, peripheral neuropathy, aseptic meningitis, lymphadenopathy, and Sjogren's syndrome. The majority of patients have developed, or will develop within 5 years of presentation, diagnostic clinical criteria for one of the overlapping connective tissue diseases, most often SLE or SSc.

Laboratory Findings Anemia of chronic inflammation is seen in the majority of patients. A positive direct Coombs' test is found in about 60 percent of patients, but hemolytic anemia is unusual. Leukopenia, thrombocytopenia, or both are present in some patients. Hypergammaglobulinemia is common, and rheumatoid factor is present in 50 percent of patients.

All patients, by definition of MCTD, have antibodies to U1 RNP. The specificity of this antibody is to the 70-kDa protein complexed to small nuclear RNA. The anti-U1 RNP antibodies are associated with HLA-DR4 but not with -DR2 and -DR3 as found in SLE. Molecular mimicry has been demonstrated between U1 RNP and retroviral antigens by some laboratories.

TREATMENT

The treatment of MCTD is essentially the same as would be indicated for the respective connective tissue diseases defining this syndrome. More than half the patients have a favorable course. The 10-year survival rate overall is approximately 80 percent but varies depending on the connective tissue disease that may eventually develop.^

========================================================================
2.) Effective treatment with low-dose methotrexate pulses of a child of mixed 
connective tissue disease with severe myositis refractory to corticosteroid]
======================================================================== Nakata S; Uematsu K; Mori T; Mitsushita N; Kinoshita T; Ishioka C; Mutou K; Yokota 
S; Hirose Y; Komiyama A
Department of Pediatrics, Shimada Citizen Hospital.
Nihon Rinsho Meneki Gakkai Kaishi (JAPAN) Jun 1997 20 (3) p178-83 ISSN: 0911-
4300
Language: JAPANESE Summary Language: ENGLISH
Document Type: 
JOURNAL ARTICLE English Abstract
Journal Announcement: 9711
Subfile: INDEX MEDICUS
A 13-year-old girl with mixed connective tissue disease (MCTD) was described. She 
visited our hospital with recurrent parotid gland swelling, arthritis, and myositis. 
Sclerodactyly and Raynaud's phenomenon were also defined, and the laboratory findings 
of high titers of antinuclear antibody (speckled type), positive anti-RNP antibody, 
positive rheumatoid factor, and hypergammaglobulinemia suggested the diagnosis of 
MCTD associated with Sjogren syndrome. The muscle weakness and the increased levels 
of CK prompted us to examine the muscle biopsy and to perform the electromyography, 
both of which suggested severe muscle inflammation. The siarography and lip biopsy 
indicated definitively the association of Sjogren syndrome. Corticosteroid therapy 
including methyl-prednisolone pulses was started, but the effects were limited. The 
addition of low-dose methotrexate effectively lowered the levels of CK, and gradually 
improved the muscle strength. Thus, low-dose methotrexate therapy is recommended to 
the patients with MCTD who have severe myositis refractory to corticosteroid.

======================================================================== 
3.) Analysis of human T cell and B cell responses against U small nuclear ribonucleoprotein 70-kd, B, and D polypeptides among patients with systemic lupus 
erythematosus and mixed connective tissue disease.
======================================================================== 
Nakata S; Holyst MM; Hill DL; Hoch SO; Hoffman RW
University of Missouri-Columbia and Harry S Truman Memorial Veterans Hospital, USA.
Arthritis Rheum (UNITED STATES) Aug 1997 40 (8) p1493-503 ISSN: 0004-3591
Contract/Grant No.: AR-41051--AR--NIAMS; AR-43308--AR--NIAMS
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9711
Subfile: AIM; INDEX MEDICUS
OBJECTIVE: To analyze T and B cell reactivity with U small nuclear RNP (snRNP) 70-
kd, B, and D polypeptides among patients with connective tissue disease (CTD) and to 
examine the functional characteristics of snRNP-reactive T cell clones. METHODS: We 
used an snRNP enzyme-linked immunosorbent assay and immunoblotting to characterize 
antibodies in patients' sera. We used human recombinant fusion proteins 70 kd, B, 
and D to stimulate and clone snRNP-reactive T cells from CTD patients. We analyzed 
the cell surface phenotype, antigenic specificity, and cytokine profiles of T cell 
clones. RESULTS: Patients showed T cell responsiveness to snRNP polypeptides that 
paralleled their autoantibody reactivities. A total of 256 clones were generated, 
and clones were identified which were specific for the 70-kd, B, or D polypeptides. 
Clones expressed a T helper cell phenotype, and were found to produce substantial 
quantities of both interleukin-4 (IL-4) and interferon-gamma, and lesser quantities 
of IL-2 and IL-6. CONCLUSION: These results show that CTD patients have clonable 
circulating snRNP-reactive T cells that parallel the specificity of snRNP-reactive 
antibodies in their sera. The snRNP-reactive T cells exhibit a helper cell phenotype 
and produce cytokines which are important in B cell help and differentiation.

======================================================================== 
4.) Mixed connective tissue disease. A clinical, histologic, and immunofluorescence 
study of eight cases.
======================================================================== 
Magro CM; Crowson AN; Regauer S
Department of Pathology, Beth Israel Hospital, Harvard Medical School, Boston, 
Massachusetts, USA.
Am J Dermatopathol (UNITED STATES) Jun 1997 19 (3) p206-13 ISSN: 0193-1091
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9710
Subfile: INDEX MEDICUS
A study of the cutaneous eruptions of eight patients with mixed connective tissue 
disease (MCTD) was performed to better characterize its dermatopathology and to 
explore a role for the membrane attack complex of complement C5b-9 in lesional 
pathogenesis. Nine lesional skin biopsies were obtained from eight patients with 
MCTD and analyzed by conventional light microscopy. Direct immunofluorescence (IF) 
and indirect IF using a monoclonal antibody to C5b-9 were applied in six and five 
cases respectively. The biopsied cutaneous eruptions were characterized clinically 
as photo-distributed erythematosus annular and/or papulosquamous lesions mimnicking 
subacute cutaneous lupus erythematosus (SCLE) in five of eight patients as an ill-
defined, telangiectatic, scaly patch on the face in one patient, palpable purpura in 
one patient, and dorsal hand blisters resembling porphyria cutanea tarda (PCT) in 
another. With the exception of the latter two patients, the histology appeared 
similar, comprising a cell poor and/or lichenoid interface dermatitis with 
suprabasilar exocytosis around necrotic keratinocytes in the absence of deep 
periadnexal or perivascular extension or conspicuous follicular plugging, a pattern 
similar to that of SCLE. However, the lesions differed from SCLE by virtue of 
vasculopathic alterations comprising vascular ectasia, hypovascularity, and/or 
luminal thrombosis confined to the superficial vascular plexus and a sclerodermoid 
tissue reaction, the latter seen in two cases. One biopsy showed a pustular 
leukocytoclastic vasculitis (LCV). In another case, a biopsied hand blister 
demonstrated a PCT-like appearance histologically, namely, pauci-inflammatory 
subepithelial blister formation with hyalinization of dermal papillae capillaries 
accompanied by an LCV. There was nuclear keratinocyte decoration with IgG and C5b-9 
in all cases studied, accompanied by a positive lupus band test in two cases and 
homogenous deposition of immunoreactants along the dermoepidermal junction and within 
vessels in the PCT-like eruption. Granular vascular decoration with immunoreactants 
including C5b-9 was seen in two LCV cases and in two biopsies from rashes clinically 
mimicking SCLE. Although the epidermal pathology of MCTD mimicks that of SCLE, a 
concomitant vasculopathy paralleling that seen in skin lesions of dermatomyositis 
distinquishes the dermatopathology of MCTD from that of SCLE. Corroborating the role 
of microangiopathy in the pathogenesis of the skin lesions of MCTD was the 
demonstration of C5b-9 in blood vessels. The deposition of C5b-9 in keratinocytes 
may explain the pattern Of IgG decoration of keratinocytes; the formation of 
plasmalemmal pores may permit binding of immunoglobulin to antigens in the nucleus 
and/or cytosol. The C 5b-9 complex may be the effector mechanism of epithelial 
and/or endothelial cell injury in MCTD or may serve to augment the effects of 
antibody-dependent cellular cytotoxicity.

======================================================================== 
5.) Internalization of anti-nucleolin antibody into viable HEp-2 cells.
======================================================================== 
Deng JS; Ballou B; Hofmeister JK
Medical Service, Department of Veterans Affairs Medical Center, Pittsburgh, PA 
15240, USA.
Mol Biol Rep (NETHERLANDS) 1996 23 (3-4) p191-5 ISSN: 0301-4851
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9708
Subfile: INDEX MEDICUS
Anti-nucleolin antibodies have been detected in patients with systemic connective 
tissue diseases (SCTD) including systemic sclerosis (SSc) and systemic lupus 
erythematosus (SLE). In vivo bound autoantibodies to nucleoli of epidermal 
keratinocytes have been demonstrated in skin from patients with SCTD. In this study, 
monoclonal antibody to nucleolin (D-3) was used to determine the distribution of 
nucleolin in different culture cells including HEp-2, HepG2, HRCC, Molt-4 and Wil2 
cells. Nucleolin was found to be present on the surface of HEp-2 and HepG2 cells, 
but not on the surface of HRCC and lymphoblastoid (Molt-4 and Wil2) cells; in 
contrast, nucleolin was detected in the nucleoli of all permeabilized cells examined. 
In immunoprecipitation, using extracts from 32P-labeled HEp-2 cells as antigenic 
source, cell membrane as well as nuclear nucleolins were found to be phosphorylated 
with a molecular weight of 105 kDa. Viable HEp-2 and HepG2 cells were cocultured 
with IgG fraction of D-3 in a CO2 incubator for 1 to 24 h, and then permeabilized 
with acetone followed by immunofluorescence staining with FITC-labeled goat anti-
mouse IgG antibodies. Nucleolar staining was observed in cells after 10 h or longer 
of coculture. These data indicated that D-3 antibody reacted with cell membrane 
nucleolin and subsequently gain access into cells in a process related to 
pinocytosis.

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6.) Clinical and immunological aspects of autoantibodies to RA33/hnRNP-A/B proteins--a 
link between RA, SLE and MCTD.
======================================================================== 
Steiner G; Skriner K; Hassfeld W; Smolen JS
Ludwig Boltzmann-Institute for Rheumatology and Balneology, University of Vienna, 
Austria.
Mol Biol Rep (NETHERLANDS) 1996 23 (3-4) p167-71 ISSN: 0301-4851
Language: ENGLISH
Document Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL 
Journal Announcement: 9708
Subfile: INDEX MEDICUS
Heterogeneous nuclear ribonucleoprotein (hnRNP) complexes are major constituents of 
the spliceosome. They are composed of approximately 30 different proteins which can 
bind to nascent pre-mRNA. Among these, the hnRNP-A/B proteins form a subgroup of 
highly related proteins consisting of two adjacent RNA binding domains (RBD) within 
the N-terminal parts, whereas the C-terminal halves contain almost 50% glycine 
residues. These proteins, in particular A2/RA33, are targeted by autoantibodies from 
patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and 
mixed connective tissue disease (MCTD). In SLE anti-hnRNP antibodies frequently 
occur together with antibodies to U1 small nuclear RNP (U1-snRNP) and Sm, other 
proteins of the spliceosome. Preliminary epitope mapping studies have revealed major 
antibody binding sites in the RNA binding regions for all three diseases. 
Nevertheless, there is some indication of disease specific epitope recognition. 
Studies in animal models have demonstrated anti-RA33/hnRNP-A/B antibodies in lupus-
prone mouse strains. Thus, autoantibodies to the spliceosomal hnRNP-A/B proteins are 
a common feature of RA, SLE, and MCTD. However, these diseases differ in their 
reactivities to other spliceosomal proteins, especially anti-U1 snRNP and Sm. 
Therefore, anti-RA33/hnRNP-A/B autoantibodies are not only valuable diagnostic 
markers but may also allow additional insights into the pathogenesis of rheumatic 
autoimmune diseases. (29 References)

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7.) Mixed connective tissue disease. A clinico-serological study of 17 cases.
======================================================================== 
Garcia-de la Torre I; Salazar-Paramo M; Salmon-de la Torre G
C.U.C.S., University of Guadalajara, Jalisco, Mexico.
Mol Biol Rep (NETHERLANDS) 1996 23 (3-4) p153-7 ISSN: 0301-4851
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9708
Subfile: INDEX MEDICUS
Mixed connective tissue disease (MCTD) was described as a distinct clinical 
syndrome in 1972. Since then many cases have been reported in the literature 
worldwide. In this study we present our experience with a group of 17 Mexican 
patients with this syndrome, and we analyze their clinical and serological features, 
as well as the causes of death in these patients. The patients are Mexican mestizos 
living in Guadalajara and most of them have been followed-up at Hospital General de 
Occidente for a period of 1-10 years. The female/male ratio was 16:1, and their age 
ranged from 14-55 years with a mean of 29 years. The disease duration has ranged 
from 1-17 years, with a mean of 6 years. Among the clinical manifestations we have 
found a high frequency of lymphadenopathy when compared with published series (13/17 
or 76%), and the laboratory findings in our patients included a very high polyclonal 
increase of gammaglobulins (93%), lymphopenia (76%), direct immunofluorescence 
speckled nuclear epidermal deposits in skin biopsies (75%) and positive rheumatoid 
factor (65%). Other clinical and serological features were similar to those reported 
in other series of patients with MCTD. Six of the 17 patients have died (35%), and 
in 3 of them (17.5%) the cause of death was due to an infectious disease that 
suddenly presented, and apparently was not related to a concomitant high dose of 
steroids or malnutrition in the patients. It seems that in addition to the already 
well known autoimmune abnormalities that occur in MCTD, there are other features like 
the presence of lymphadenopathy, the high polyclonal increase of gammaglobulins, and 
the lymphopenia, that reflect the profound disturbance of the immune system in this 
syndrome, possibly contributing to the sudden appearance of a severe infectious 
disease in some of our patients.

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8.) Mixed connective tissue disease associated with acute polyradiculoneuropathy.
======================================================================== 
Katada E; Ojika K; Uemura M; Maeno K; Mitake S; Tsugu Y; Otsuka Y; Iwase T
Second Department of Internal Medicine, Nagoya City University Medical School.
Intern Med (JAPAN) Feb 1997 36 (2) p118-24 ISSN: 0918-2918
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9708
Subfile: INDEX MEDICUS
A rare case of mixed connective tissue disease (MCTD) with acute 
polyradiculoneuropathy is reported. A 23-year-old woman presented with high body 
temperature, arthralgia and a headache, and developed gait disturbance two weeks 
later. She had many clinical features common to patients with MCTD. Her 
neurological manifestations were diagnosed as acute polyradiculoneuropathy based on 
the clinical picture, combined with supportive ancillary data, including 
cerebrospinal fluid (CSF) analysis, electrophysiological evaluation, sural nerve 
biopsy, peroneus brevis muscle biopsy, and magnetic resonance imaging (MRI). Her 
neurologic deficits, as well as associated laboratory findings, were improved by 
corticosteroid therapy.

======================================================================== 
9.) [Successful treatment for pulmonary hypertension with angiotensin 1 converting 
enzyme inhibitor in a patient with mixed connective tissue disease]
======================================================================== 
Maekawa K; Fujimoto T; Uemura S; Kanauchi M; Dohi K
First Department of Internal Medicine, Nara Medical University.
Nihon Rinsho Meneki Gakkai Kaishi (JAPAN) Feb 1997 20 (1) p79-85 ISSN: 0911-
4300
Language: JAPANESE Summary Language: ENGLISH
Document Type: 
JOURNAL ARTICLE English Abstract
Journal Announcement: 9708
Subfile: INDEX MEDICUS
This report described a 44 years-old female mixed connective tissue disease (MCTD) 
patient presenting pulmonary hypertension, successfully treated with angiotensin I 
converting enzyme (ACE) inhibitor. The patient was diagnosed as having MCTD because 
of Raynaud's phenomenon, swollen hand, and elevated level of anti-U 1 RNP antibodies. 
She was admitted to our hospital one year after the diagnosis of MCTD, because she 
experienced dyspnea and pretibial edema. A diagnosis of pulmonary hypertension was 
made by echocardiography and catheterization study. Pulmonary artery pressure and 
pulmonary artery resistance declined and returned gradually to normal during a period 
of three months with prednisolone and enalapril (10 mg/day) therapy. Pulmonary 
hypertension is one of fetal complications with MCTD, and 5 year mortality rate is 
reported less than 50%. However, a successful therapy for the pulmonary hypertension 
with MCTD has not been established yet. We considered that ACE inhibitor might be 
useful to control the pulmonary hypertension with MCTD and could improve the 
prognosis of MCTD.

======================================================================== 
10.) Mixed connective tissue disease in childhood: a nationwide retrospective study in 
Japan.
======================================================================== 
Yokota S; Imagawa T; Katakura S; Itoh SI; Mitsuda T; Fujikawa S; Aihara Y
Department of Pediatrics, Yokohama City University School of Medicine, Japan.
Acta Paediatr Jpn (AUSTRALIA) Apr 1997 39 (2) p273-6 ISSN: 0374-5600
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9707
Subfile: INDEX MEDICUS
Sixty-six children with mixed connective tissue disease (MCTD) were analyzed by a 
nationwide prospective study. The diagnostic significance of Raynaud's phenomenon 
and positive anti-RNP antibody was confirmed, and additional symptoms including 
swelling of fingers, facial erythema, and polyarthralgia, and laboratory findings 
such as positive rheumatoid factor, hypergammaglobulinemia, and increased levels of 
myogenic enzymes, were variably positive. These clinical and laboratory 
characteristics of MCTD were critically different from those of systemic lupus 
erythematosus, indicating that MCTD is an independent entity of disease.

======================================================================== 
11.) Metaplastic bone formation in the subcutaneous nodule of a patient with mixed 
connective tissue disease.
======================================================================== 
Nakagawa S; Tagami H
Department of Dermatology, Tohoku University School of Medicine, Sendai, Japan.
Acta Derm Venereol (NORWAY) Jan 1997 77 (1) p64-5 ISSN: 0001-5555
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9707
Subfile: INDEX MEDICUS
Cutaneous ossification is a rare phenomenon in collagen diseases, despite the 
rather frequent occurrence in these diseases of dystrophic calcinosis. We observed 
metaplastic woven bone formation associated with calcification in biopsy material 
obtained from a 49-year-old woman suffering from mixed connective tissue disease 
together with multiple subcutaneous indurations. This is the first case of the 
presence of metaplastic bone formation in a patient with mixed connective tissue 
disease.

======================================================================== 
12.) Anti-RNP antibody in a child with undifferentiated carcinoma and no evidence of 
mixed connective tissue disease.
======================================================================== 
Foster HE; Malleson PN; Petty RE; Cabral DA
Department of Rheumatology, Freeman Hospital, Newcastle upon, Tyne.
Br J Rheumatol (ENGLAND) Feb 1997 36 (2) p289-91 ISSN: 0263-7103
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9707
Subfile: AIM; INDEX MEDICUS
We describe a young girl who presented with musculoskeletal symptoms and who was 
found to have high titres of antinuclear antibody with anti-RNP antibody. She was 
initially suspected of having mixed connective tissue disease, but ultimately was 
found to have metastatic undifferentiated carcinoma with an unknown primary site. 
This is a very uncommon malignancy of childhood and an association with anti-RNP 
antibody has, to our knowledge, not been described. The clinical significance of 
this finding is discussed.

======================================================================== 
13.) Antiphospholipid antibodies among anti-U1-70 kDa autoantibody positive patients 
with mixed connective tissue disease.
======================================================================== 
Komatireddy GR; Wang GS; Sharp GC; Hoffman RW
Department of Internal Medicine, University of Missouri, Columbia 65212, USA.
J Rheumatol (CANADA) Feb 1997 24 (2) p319-22 ISSN: 0315-162X
Contract/Grant No.: AR41051--AR--NIAMS
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9707
Subfile: INDEX MEDICUS
OBJECTIVE: The association between antiphospholipid antibodies (aPL) and recurrent 
venous and/or arterial thrombotic events, fetal loss, and thrombocytopenia in 
systemic lupus erythematosus (SLE) has been well documented. Such an association has 
not been carefully assessed in mixed connective tissue disease (MCTD). Our aim was 
to assess the prevalence and clinical significance of aPL in anti-U1-70 kDa 
autoantibody positive patients with MCTD. METHODS: We compared 48 consecutive anti-
U1-70 kDa autoantibody positive patients with MCTD versus 59 consecutive anti-U1-70 
kDa autoantibody negative patients with SLE to determine the frequency of aPL and 
clinical features of the aPL syndrome. RESULTS: Among the patients with MCTD 7/48 
(15%) had anticardiolipin antibodies (aCL) versus 24/59 (41%) patients with SLE (p < 
0.005) and versus 2/150 (1%) apparently healthy blood donors (p < 0.001). Among 
patients with MCTD with aPL, 2 were IgG, 3 IgM, and 2 both IgG and IgM isotypes; 
among patients with SLE 5 were IgG, 11 IgM, and 8 both IgG and IgM isotypes. No 
clotting events or other features of the aPL syndrome were found among the patients 
with MCTD compared with 26 events documented among the group of aCL positive patients 
with SLE (p < 0.001). There were 10 patients with SLE with deep vein thrombosis, one 
with a pulmonary embolism, 2 with recurrent fetal loss, one with chorea, 2 with 
livedo reticularis, one with severe thrombocytopenia, and one with avascular necrosis. 
CONCLUSION: aCL were increased in patients with MCTD compared to controls. 
Furthermore, aCL were increased in SLE compared with both patients with MCTD and 
controls. Finally, while clotting events and other manifestations of the aPL 
syndrome occurred among the group of aCL positive patients with SLE these were 
distinctly absent from the aCL positive MCTD group.

======================================================================== 
14.) Comparative study of 4 diagnosis criteria sets for mixed connective tissue disease 
in patients with anti-RNP antibodies. Autoimmunity Group of the Hospitals of Toulouse.
======================================================================== 
Amigues JM; Cantagrel A; Abbal M; Mazieres B
Rheumatology Department, Rangueil University Hospital, Toulouse, France.
J Rheumatol (CANADA) Dec 1996 23 (12) p2055-62 ISSN: 0315-162X
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9705
Subfile: INDEX MEDICUS
OBJECTIVE: To evaluate the performances of 4 sets of criteria proposed to define 
mixed connective tissue disease (MCTD): the criteria of Sharp, Alarcon-Segovia, 
Kasukawa, and Kahn. As anti-U1-RNP antibodies appear indispensable to establish the 
diagnosis of MCTD, we wished to reevaluate these sets of criteria in patients who all 
had anti-U1-RNP antibodies. METHODS: We analyzed clinical and biological data to 
find which diagnostic criteria were met by 45 patients with anti-U1-RNP antibodies. 
We tested criteria for rheumatoid arthritis, systemic lupus erythematosus, systemic 
sclerosis, polymyositis, Sjogren's syndrome, and 4 sets of criteria for MCTD. 
RESULTS: The criteria that best identified patients with MCTD were those proposed by 
Alarcon-Segovia, with 62.5% sensitivity and 86.2% specificity, comparable to Kahn's 
criteria. The overlap with other connective tissue diseases was found to be 16%. 
These results could be improved by using the term "myalgia" instead of "myositis" in 
the definition. This increased sensitivity to 81.3%, with no decrease in specificity. 
CONCLUSION: Alarcon-Segovia's and Kahn's criteria are the best classification 
criteria to define MCTD.

======================================================================== 
15.) [Pleuropericarditis complicated of tamponade disclosing mixed connective tissue 
disease. Remission with non-steroidal anti-inflammatory agents. Apropos of a case]
Pleuropericardite compliquee d'une tamponnade revelatrice d'une connectivite mixte. 
Regression sous anti-inflammatoires non steroidiens. A propos d'un cas.
Richard P; Sabouret P; Vayre F; Desrame J; Ollivier JP
======================================================================== 
Service de Cardiologie, Hopital du Val-de-Grace, Paris.
Ann Cardiol Angeiol (Paris) (FRANCE) Nov 1996 45 (9) p513-5 ISSN: 0003-3928
Language: FRENCH Summary Language: ENGLISH
Document Type: 
JOURNAL ARTICLE English Abstract
Journal Announcement: 9705
Subfile: INDEX MEDICUS
Mixed connective tissue diseases or Sharp's syndrome are inflammatory diseases 
essentially presenting in the form of joint, muscle and skin manifestations. 
Pleuropericardial involvement is uncommon and rarely the presenting sign, and 
tamponade is exceptional. This clinical report concerns a case of pleuropericarditis 
complicated by tamponade in a 22-year-old man, constituting the presenting sign of 
Sharp's syndrome. The diagnosis of mixed connective tissue disease was based on the 
combination of clinical signs and a high serum anti-RNP antinuclear antibody titre. 
The treatment of the pericarditis is base on prescription of corticosteroids, but non-
steroidal anti-inflammatory drugs were sufficient in our case. Larger effusions may 
require corticosteroids and pericardial drainage. We report the value of 
immunological assays in the aetiological assessment of pleuropericarditis in young 
subjects.

======================================================================== 
16.) Blotting patterns of IgG anti-(U1)RNP antibodies in mixed connective tissue 
disease.
======================================================================== 
Ghirardello A; Doria A; Vesco P; Vaccaro E; Bernardi C; Catani C; Fagiolo U; 
Gambari PF
Division of Rheumatology, University of Padova, Italy.
Rheumatol Int (GERMANY) 1996 16 (4) p145-50 ISSN: 0172-8172
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9705
Subfile: INDEX MEDICUS
Serum reactivities towards individual U1 snRNP proteins were determined by 
immunoblotting in 32 patients with mixed connective tissue disease (MCTD). Time 
persistence of immunoblot profiles and clinical significance of anti-(U1)RNP antibody 
specificities were also investigated. IgG anti-(U1)RNP antibodies were found in the 
sera of 29 out of 32 patients (90.6%): 21 (65.6%) reacted with the 70-kD protein, 25 
(78.1%) with A, 23 (71.9%) with C and 20 (62.5%) with B/B' proteins. None were 
reactive with the Sm-D peptide. Seventy kilodalton antibody specificity was strongly 
associated with a higher antinuclear antibody titre (> 160) and slightly associated 
with disease activity; anti-B/B' specificity was associated with lymphadenopathy. 
Anti-A, -C and -B/B' antibodies were negatively associated with systemic lupus 
erythematosus (SLE) skin rashes. Two types of anti-(U1)RNP blotting patterns were 
selected: "full spectrum" (53.1% of cases) and a "partially/no reactive" one (46.9%). 
Such patterns were unchanged over time in 14 out of 16 cases prospectively examined 
(87.5%), while the pattern shifted from "full spectrum" to "partially/no reactive" in 
2 cases (12.5%): in 1 after a prolonged clinical remission (> or = 4 years) and in 
the other following immunosuppressive therapy. The anti-(U1)RNP antibody immunoblot 
profile in MCTD patients consisted of various reactivities and remained unchanged 
over time in most cases. Antibody reactivity against the 70-kD protein represented 
the major U1 snRNP specificity. The various anti-(U1)RNP specific reactivities 
demonstrated poor clinical significance within MCTD. Thus, MCTD seems to be 
characterized by a longstanding serological heterogeneity whose reactivities do not 
apparently correspond to distinct features within the broad clinical spectrum of 
MCTD.

======================================================================== 
17.) Mixed connective tissue disease and radiation toxicity. A case report.
======================================================================== 
Mayr NA; Riggs CE Jr; Saag KG; Wen BC; Pennington EC; Hussey DH
Department of Radiology, University of Iowa College of Medicine, Iowa City, USA.
Cancer (UNITED STATES) Feb 1 1997 79 (3) p612-8 ISSN: 0008-543X
Language: ENGLISH
Document Type: JOURNAL ARTICLE; REVIEW; REVIEW OF REPORTED CASES 
Journal Announcement: 9705
Subfile: AIM; INDEX MEDICUS
BACKGROUND: Several cases of long term radiation sequelae have been reported in 
patients with lupus erythematosus and systemic sclerosis after breast or chest wall 
irradiation. To the authors' knowledge, no experience with such complications in 
patients with mixed connective tissue disease (MCTD) has been reported previously. 
METHODS: A case of a woman with occult breast carcinoma metastatic to the axilla and 
preexisting MCTD is presented. To the authors' knowledge, this is the first case 
report of the adverse effects of breast irradiation in a patient with MCTD. The 
pathophysiology of such radiation injury to specific anatomic structures and 
technical dosimetric considerations of the radiation therapy and radiation dose are 
analyzed. The relevant literature on other collagen vascular diseases with features 
related to MCTD is reviewed. RESULTS: A moderate dose of radiation to the breast and 
regional lymphatics resulted in marked early and late toxicity to skin and 
subcutaneous tissues. The tissue injury was similar to that observed in patients 
with lupus erythematosus and systemic sclerosis. The early skin reaction (moist 
desquamation) was related to the daily radiation dose delivered at the depth of the 
epidermis, and the late reaction (subcutaneous fibrosis) was related to the dose at 
the depth of the dermal capillaries and dermal connective tissue. CONCLUSIONS: 
Patients with MCTD may develop exaggerated radiation reactions similar to those in 
patients with lupus erythematosus and systemic sclerosis. Although the incidence of 
such radiation reactions in patients with MCTD is difficult to assess, the risks and 
benefits of radiation therapy should be carefully weighed in these patients, 
particularly if an alternative therapy is available. If there is no alternative, 
judicious attention to radiotherapy technique may reduce or prevent skin toxicity. 
(12 References)

======================================================================== 
18.) Neutralization of HIV type 1 infectivity by serum antibodies from a subset of 
autoimmune patients with mixed connective tissue disease.
======================================================================== 
Douvas A; Takehana Y; Ehresmann G; Chernyovskiy T; Daar ES
Department of Medicine, University of Southern California School of Medicine, Los 
Angeles 90033, USA.
AIDS Res Hum Retroviruses (UNITED STATES) Nov 1 1996 12 (16) p1509-17 ISSN: 
0889-2229
Language: ENGLISH
Document Type: JOURNAL ARTICLE 
Journal Announcement: 9705
Subfile: INDEX MEDICUS
Mixed connective tissue disease (MCTD) is a rheumatic disorder with clinical 
similarities to HIV-1 infection, and with characteristic autoimmune anti-RNP 
antibodies specific for the U1 snRNP splicing complex. Anti-RNP antibodies cross-
react with the HIV-1 surface, owing to multiple homologies between the gp120/41 
envelope complex and the 70K protein of U1 snRNP. A key epitope of 70K, its RNA-
binding site, is homologous to a dominant B and T cell epitope in the third variable 
loop (V3) of gp120. In this study, we tested the ability of anti-RNP sera to inhibit 
HIV-1 infectivity in vitro. Of nine sera tested, five were 70-99% effective in 
neutralizing one or more HIV-1 strains. One serum was > 99% effective in 
neutralizing HIV-1MN, and 86 and 77% effective against the primary isolates HIV-1(CO) 
and HIV-1(JR-FL), respectively, an efficacy equal to that of a pool of broadly 
neutralizing antibodies from HIV-1-infected subjects (HIVIG). The mean neutralizing 
titer of anti-RNP sera against HIV-1(JR-FL) was 3.9-fold higher than that of HIVIG. 
Neutralizing potency was associated with high reactivity to gp120 by ELISA, and with 
the presence of serum rheumatoid factor, known to enhance antibody neutralization of 
other viruses. The current findings provide further evidence that individuals 
unexposed to HIV-1 may develop immunologic resistance by alternative mechanisms, 
possibly including molecular mimicry, or exposure to as yet unidentified retroviruses. 
Thus MCTD, which involves both B and T cell reactivity to self-epitopes homologous to 
HIV-1, may elucidate new strategies for generating protective immunity to this virus.

======================================================================== 
19.) Predominance of IgM anti-U1RNP antibodies in patients with systemic lupus erythematosus.
======================================================================== 
AU: Vlachoyiannopoulos-PG; Guialis-A; Tzioufas-G; Moutsopoulos-HM
SO: Br-J-Rheumatol. 1996 Jun; 35(6): 534-41
ISSN: 0263-7103
LA: ENGLISH
CP: ENGLAND
AB: Anti-U1RNP antibodies occur in patients with mixed connective tissue disease (MCTD), systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other ill-defined connective tissue diseases. To associate the isotypes of anti-U1RNP antibodies with the diagnosis of the disease, namely SLE or MCTD, sequential sera of patients positive for anti-U1RNP antibodies by counterimmunoelectrophoresis (CIE) (32 with SLE, 35 with MCTD) were tested for IgG and IgM anti-U1RNP antibodies by enzyme-linked immunosorbent assay (ELISA) using affinity-purified U1snRNP complexes. Results from ELISA were confirmed by RNA precipitation. IgG RNA precipitation of HeLa cellular extracts was performed using the bulk of the IgG fraction removed from each serum after binding to protein A-Sepharose beads. IgM RNA precipitation was carried out on the IgM fraction of the serum bound to protein A-Sepharose-rabbit anti-human IgM immune complexes. RNAs were electrophoresed in 10.5% acrylamide-7 M urea gels and detected with the silver stain. ELISA showed that all sera were positive to IgG anti-U1RNP, while 12 of the 35 MCTD and 21 of the 32 SLE patients possessed IgM anti-U1RNP (P < 0.025). IgM anti-U1RNP reactivity was found during the follow-up in 20% of 44 sera from 17 MCTD patients and 68% of 112 sera from 23 SLE patients (P < 0.0001). IgG from all the sera precipitated U1RNPs. Eight of the MCTD sera also precipitated U2RNPs and 14 of the SLE sera U2 and/or U4/U6, U5 RNPs. IgM from MCTD sera did not precipitate URNPs, while IgM from SLE sera precipitated predominantly U1RNPs. These data suggest that IgM anti-U1RNP antibodies occur predominantly in patients with SLE. The occurrence of IgG anti-U1RNP without IgM is more frequent in MCTD.

======================================================================== 
20.) Focal myositis presenting as pseudothrombophlebitis of the neck in a patient with mixed connective tissue disease.
======================================================================== 
AU: Rivest-C; Miller-FW; Love-LA; Turgeon-PP; Blier-C; Senecal-JL
SO: Arthritis-Rheum. 1996 Jul; 39(7): 1254-8
ISSN: 0004-3591
LA: ENGLISH
CP: UNITED-STATES
AB: This report describes a case of focal myositis in a patient with mixed connective tissue disease. The patient presented with diffuse neck swelling and pseudothrombophlebitis of the left internal jugular vein. Other clinical features included a high fever, elevated erythrocyte sedimentation rate, and prompt improvement after administration of high-dose intravenous corticosteroid therapy. Criteria for polymyositis were absent, serum levels of creatine kinase remained normal, and there was no sign of recurrence during 3 years of followup. Results of immunoprecipitation for anti-Jo-1 and other myositis-specific autoantibodies remained negative in serial serum samples obtained before, during, and after the episode.

======================================================================== 
21.) [Chronic recurrent subileus due to Strongyloides stercoralis infection under immunosuppressive therapy]
======================================================================== 
AU: Birck-R; Braun-C; Back-W; Gottstein-T; Rohmeiss-P; Manegold-BC; Strauch-M; Gretz-N
SO: Dtsch-Med-Wochenschr. 1996 May 31; 121(22): 723-6
ISSN: 0012-0472
LA: GERMAN; NON-ENGLISH
CP: GERMANY
AB: HISTORY AND CLINICAL FINDINGS: A 33-year-old woman from Laos was admitted due to recurrent vomiting and weight loss. Since one year, she was receiving immunosuppressive therapy (azathioprine 50 mg/d and methylprednisolone 18 mg/d) for a mixed connective tissue disease. Because of a drug induced Stevens-Johnson-Syndrome one month earlier high doses of methylprednisolone (100 mg/d intravenously) had been administered. The patient's general condition was reduced. Examination elicited a mild pain in the middle abdomen on palpation but no resistance or tumour. The differential diagnosis included obstructive and (or) inflammatory disease of the gastrointestinal tract. INVESTIGATIONS: Elevated IgE-levels (1111 IU/ml; normal up to 100 IU/ml) and eosinophilia (8%) lead to the suspicion of a helminthiasis. Oesophagogastroduodenoscopy showed a significant duodenal stenosis. Duodenal biopsy revealed a severe infestation with Strongyloides stercoralis. Stool examinations were negative though. TREATMENT AND COURSE: With administration of thiabendazole (2 g/d) a rapid recovery was noted. A second oesophagogastroduodenoscopy one week after the onset of therapy revealed no further stenosis. Since there was no activity of the mixed connective tissue disease the methylprednisolone dosage was reduced and the administration of azathioprine was ceased. 3 weeks after beginning of treatment the patient was discharged in improved condition. CONCLUSION: In immunocompromised patients suffering from gastrointestinal complaints who have been in endemic areas an infection with Strongyloides stercoralis should be excluded. Without treatment, this helminthiasis may be fatal.

======================================================================== 
22.) Meningococcal endocarditis presenting as cellulitis.
======================================================================== 
AU: Lin-VH; Parekh-RS; McQuillan-MA; Braun-DK; Markovitz-DM
SO: Clin-Infect-Dis. 1995 Oct; 21(4): 1023-5
ISSN: 1058-4838
LA: ENGLISH
CP: UNITED-STATES
AB: We report the case of a patient with mixed connective tissue disease who presented with two very unusual manifestations of meningococcal disease, cellulitis and endocarditis, concurrently. We also review the literature concerning Neisseria meningitidis as a causative agent of cellulitis or endocarditis. While meningococcal endocarditis or cellulitis is very rare, autoimmune disease predisposes patients to meningococcal infection. Therefore, unusual infections with this organism should be considered in the differential diagnosis of fever and rash in patients with connective tissue diseases.

======================================================================== 
23.) Autoimmune derived combinatorial phage display libraries: methods in construction of and affinity selection for anti-RNA Fabs.
======================================================================== 
AU: Marchbank-MT; Deutscher-SL
SO: Nucleic-Acids-Symp-Ser. 1995(33): 120-2
ISSN: 0261-3166
LA: ENGLISH
CP: ENGLAND
AB: Display of antibody fragments (Fab) on the surface of filamentous bacteriophage and selection of phage that bind to a particular antigen has enabled the isolation of Fab with numerous specificities. We have examined the possibility of isolating RNA-binding Fab by constructing and screening combinatorial libraries of phage displaying Fab derived from the antibody repertoires of autoimmune humans. The genes and corresponding Fabs will allow for examination of the mechanism by which antibodies recognize RNA. Patients selected exhibit mixed connective tissue disease (MCTD), which is a subset of systemic lupus erythematosus (SLE), MCTD patients contain antibodies reactive against various nucleic acid, protein, and nucleoprotein complexes, most notably those involved in RNA processing. The cDNA libraries were constructed from total RNA derived from leukophoresed patient samples and the resulting Fab genes were expressed in E. oli using the pComb system1. Affinity selection procedures have been designed to isolate anti-RNA Fabs from these libraries. Results demonstrate the ability to enrich for anti-RNA Fabs using biotinylated RNA-streptavidin capture methodologies.

======================================================================== 
24.) Mixed connective tissue disease complicated by pneumatosis cystoides intestinalis and malabsorption syndrome: case report and literature review.
======================================================================== 
AU: Wakamatsu-M; Inada-K; Tsutsumi-Y
SO: Pathol-Int. 1995 Nov; 45(11): 875-8
ISSN: 1320-5463
LA: ENGLISH
CP: AUSTRALIA
AB: A case of mixed connective tissue disease (MCTD) in a female with positive ribonucleoprotein antibody and overlapped manifestations of systemic lupus erythematosus and dermatomyositis is presented. During the last 9 years of her 13 year clinical course, she repeatedly manifested abdominal distension, pneumoperitoneum and malabsorption syndrome. She died, aged 54 years, of respiratory failure secondary to pulmonary compression from marked abdominal distention. Autopsy revealed esophageal fibrosis with ulceration and the typical appearance of pneumatosis cystoides intestinalis (PCI), in association with atrophy and fibrosis of the inner circular muscle layer of the small bowel. The association of PCI with MCTD is reviewed briefly.

======================================================================== 
25.) Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions.
======================================================================== 
AU: Kallenberg-CG
SO: Curr-Opin-Rheumatol. 1995 Nov; 7(6): 568-73
ISSN: 1040-8711
LA: ENGLISH
CP: UNITED-STATES
AB: Connective tissue diseases (CTDs) frequently present with one or only a few symptoms, which does not allow prompt diagnosis. Raynaud's phenomenon is one of those symptoms. However, only a minority of patients who present with Raynaud's phenomenon develop a CTD. Prognostic factors for the future development of CTD in such patients are older age at presentation, more severe Raynaud's phenomenon, the presence of antinuclear antibodies, and abnormal patterns on nailfold capillary microscopy. Some patients have overlapping symptoms of various CTDs. Mixed connective tissue disease (MCTD) is the prototype of such an overlapping syndrome. However, during follow-up, most patients with MCTD develop a specific CTD, either scleroderma, systemic lupus erythematosus, rheumatoid arthritis, or combinations of those illnesses. Primary pulmonary hypertension is one of the leading causes of death in MCTD. Its treatment is insufficient, although continuous prostacyclin infusion may provide some relief. New therapies such as nitric oxide and combined heart-lung transplantation in an early stage should be explored. The autoimmune response to small nuclear ribonucleoproteins, which is highly characteristic for MCTD, interestingly shows cross-reactivity with retroviral antigens, and the cooccurrence of human T cell lymphotropic virus type I and HIV infection with MCTD has been reported. This suggests that those viruses, possibly by molecular mimicry, play a role in the induction of the disease. Fibrotic conditions related to silicone exposure still evoke much interest. However, most recent data do not substantiate a role for silicone gel breast implants in the development of autoimmune CTDs.

======================================================================== 
26.) A connective tissue disease screening questionnaire for population studies.
======================================================================== 
AU: Karlson-EW; Sanchez-Guerrero-J; Wright-EA; Lew-RA; Daltroy-LH; Katz-JN; Liang-MH
SO: Ann-Epidemiol. 1995 Jul; 5(4): 297-302
ISSN: 1047-2797
LA: ENGLISH
CP: UNITED-STATES
AB: To develop a technique to screen populations for potential connective tissue disease (CTD), we mailed a 30-item questionnaire to 253 randomly selected patients with systemic lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis, dermatomyositis, mixed connective tissue disease (MCTD), or Sjogren's syndrome and to 340 randomly selected control subjects. The response rate after four mailings was 71% for case subjects and 54% for control subjects. Test-retest reliability for detection of any CTD was 0.82. Sensitivity for specific CTDs was 83 to 96% and specificity was 83 to 93%. The positive predictive value for any CTD (assuming an overall prevalence of 1.3%) was 5.5%; negative predictive value was 99.7%. The CTD Screening Questionnaire has high sensitivity and specificity for screening large populations.

======================================================================== 
27.) [Puerperal secondary pulmonary hypertension in a patient with mixed connective tissue disease]
======================================================================== 
AU: Watanabe-R; Tatsumi-K; Uchiyama-T; Kato-K; Okada-O; Nagao-K; Kuriyama-T
SO: Nippon-Kyobu-Shikkan-Gakkai-Zasshi. 1995 Aug; 33(8): 883-7
ISSN: 0301-1542
LA: JAPANESE; NON-ENGLISH
CP: JAPAN
AB: A woman with mixed connective tissue disease (MCTD) developed pulmonary hypertension after delivery of a child, but had little evidence of parenchymal lung disease. This 29-year-old woman had been given a diagnosis of MCTD when she was 19 years old. She was admitted to our department two days after delivery of a child, because of dyspnea on exertion. Acute thromboembolism was suspected because of: (1) chest roentgenogram showing cardiomegaly and enlargement of the left main pulmonary artery, (2) a lung perfusion scan showing a segmental defect in the left S6 and S8 areas, (3) laboratory studies showing abnormally high WBC, LDH, FDP, and D-D dimer, and (4) arterial blood gas analyses showing mild hypoxemia and hypocapnia. Thrombolytic therapy with heparin and urokinase was begun, and was followed by a loop diurtic and anticoagulation with warfarin. One month after admission, cardiac enlargement and the A-aDO2 were found to have decreased. At that time, cardiac catheterization was done and revealed pulmonary hypertension (mean PA pressure: 45 mmHg) and low cardiac output with no detectable thrombosis in the left pulmonary artery. The patient was subsequently treated with a calcium antagonist and a prostacyclin derivative, and her condition was stable for 5 months. Then her exercise tolerance gradually decreased due to shortness of breath, and cardiomegaly gradually increased over the next 3 months. Eight months after delivery of the child, the patient died of right heart failure. In clinically stable patients with MCTD, delivery of a child may lead to pulmonary thromboembolism and pulmonary hypertension.

======================================================================== 
28.) Transverse myelopathy complicating mixed connective tissue disease.
======================================================================== 
AU: Mok-CC; Lau-CS
SO: Clin-Neurol-Neurosurg. 1995 Aug; 97(3): 259-60
ISSN: 0303-8467
LA: ENGLISH
CP: NETHERLANDS
AB: We report the case of a 46-year-old female patient with transverse myelitis complicating mixed connective tissue disease (MCTD). She responded well to steroid and immunosuppressive therapy. Unlike in systemic lupus erythematosus (SLE), transverse myelopathy in association with MCTD is very rarely described. The mechanisms, diagnosis and treatment of transverse myelitis in MCTD are briefly discussed.

======================================================================== 
29.) Plasma endothelin correlates with antiendothelial antibodies in patients with mixed connective tissue disease.
======================================================================== 
AU: Filep-JG; Bodolay-E; Sipka-S; Gyimesi-E; Csipo-I; Szegedi-G
SO: Circulation. 1995 Nov 15; 92(10): 2969-74
ISSN: 0009-7322
LA: ENGLISH
CP: UNITED-STATES
AB: BACKGROUND: Elevated circulating levels of the vasoactive peptide endothelin-1 have been reported in various cardiovascular disorders. Because these conditions are frequently associated with endothelial dysfunction and damage and the vasoconstrictor effect of endothelin-1 is believed to be produced at the local vascular level, it is uncertain whether circulating endothelin-1 is a causal factor in enhanced vascular tone or instead a marker of endothelial injury. METHODS AND RESULTS: We tested whether elevated immunoreactive endothelin-1 could be detected by radioimmunoassay in plasma and whether endothelin-1 levels correlated with antiendothelial autoantibodies in patients with mixed connective tissue disease. Venous blood samples were collected from 21 patients in the morning after an overnight fast and before medication. The plasma immunoreactive endothelin-1 level was 2.7 +/- 0.5 pg/mL (range, 1.1 to 5.2 pg/ml; n = 9) and 7.3 +/- 1.5 pg/mL (range, 2.8 to 20.7 pg/mL; n = 12) in patients who had no antiendothelial antibodies and in patients with antiendothelial antibodies, respectively. These latter values were significantly (P < .001) increased compared with 10 age-matched healthy volunteers (2.0 +/- 0.3 pg/mL; range, 0.5 to 3.0 pg/mL). Plasma endothelin-1 level strongly correlated with antiendothelial antibodies (rs = .836, n = 21, P < .001), whereas there was no correlation between age, systolic and diastolic blood pressures, antinuclear antibodies, and duration of the disease and endothelin-1 values. The incidence of Raynaud's phenomenon and angina did not differ significantly in patients with low and high endothelin-1 levels. CONCLUSIONS: This study showed that mixed connective tissue disease is associated with elevated plasma immunoreactive endothelin-1 and that endothelin-1 levels significantly correlate with antiendothelial autoantibodies. These findings suggest that increases in plasma endothelin-1 concentration may be secondary to vascular injury and do not necessarily represent enhanced susceptibility to vasoconstriction.

======================================================================== 
30.) [Two cases with SLE and MCTD developed after a long period of chronic arthritis that was initially diagnosed as JRA]
======================================================================== 
AU: Takei-S; Maeno-N; Shigemori-M; Nakae-Y; Mori-H; Nerome-Y; Imanaka-H; Hokonohara-M; Miyata-K
SO: Ryumachi. 1997 Oct; 37(5): 702-8
ISSN: 0300-9157
LA: JAPANESE; NON-ENGLISH
CP: JAPAN
AB: In order to discuss the diversity of clinical features and the difficulty in diagnosis of children with juvenile rheumatoid arthritis (JRA), we present two cases who have documented the development of systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) after a long period of disease characterized only by arthritis that was initially diagnosed as JRA. The first case was a girl diagnosed for her arthritic joints as polyarticular JRA at 15 years of age. At onset, she had Raynaud phenomenon but autoantibodies such as anti-nuclear antibody (ANA), anti-DNA antibody, and rheumatoid factor were negative. Five years after onset, she became ANA positive and 3 years later she became pregnant. During her pregnancy, she became positive for anti-DNA antibody without any signs of nephritis. One month after the delivery, however, she developed butterfly rash, carditis, nephritis, and was diagnosed as SLE. No destructive changes were observed in her joints though arthritis continued for 8 years form onset to pregnancy. The second case was a 3 years old girl who was diagnosed as polyarticular JRA. Treatment by aspirin induced complate remission after one year from the onset. However, 10 years after that remission, she developed Raynaud phenomenon and arthralgia in her knees and hip joints. Her laboratory findings showed hypergammaglobulinemia, positive ANA, positive anti-DNA antibody, positive anti-RNP antibody. She was eventually diagnosed as MCTD when she was found to have polymyositis by EMG and serum CK. In the present paper, two cases imply the difficulty in diagnosing JRA and diversity of rheumatic diseases such as JRA, SLE and MCTD. Closer and longer period of observation is essential for the JRA patients with nondestructive arthritis.

======================================================================== 
31.) Anti-endothelial cell antibodies in the sera of patients with mixed connective ======================================================================== 
tissue disease--the clinical significance.
AU: Watanabe-H; Kaise-S; Takeda-I; Matsuzaki-H; Kobayashi-H; Nishimaki-T; Kasukawa-R
SO: Fukushima-J-Med-Sci. 1997 Jun; 43(1): 13-28
ISSN: 0016-2590
LA: ENGLISH
CP: JAPAN
AB: To determine the clinical significance of anti-endothelial cell antibodies in mixed connective tissue disease (MCTD), we measured the titers of antibodies to both untreated and cytokine-treated endothelial cells (EC) in the sera of the MCTD patients by means of an enzyme linked immunosorbent assay. The mean titer of antibodies to untreated EC (aEC) in the sera of the MCTD patients was significantly higher than that for the healthy subjects. The mean titer of antibody to EC treated with IFN gamma, IL1 (aIL1-EC) or TNF alpha (aTNF-EC) was significantly higher than that of aEC in the sera of the MCTD patients with proteinuria, and the mean titer of aTNF-EC was significantly higher than that of aEC in the sea of the MCTD patients with pulmonary fibrosis. Furthermore, the mean titers of aIL1-EC and aTNF-EC in the sera of the MCTD patients with pulmonary fibrosis were significantly higher than those of aIL1-EC and aTNF-EC in the sera of the MCTD patients without pulmonary fibrosis. These results suggest that antibodies to cytokine-treated EC may play a more important role in the manifestation of renal or pulmonary lesions in MCTD patients than aEC.

======================================================================== 
32.) [Newer approach of screening test for antinuclear antibodies: an enzyme-linked immunosorbent assay detecting antinuclear antibodies characteristic of connective tissue diseases]
======================================================================== 
AU: Asanuma-H; Miyake-J; Miyawaki-S
SO: Nihon-Rinsho-Meneki-Gakkai-Kaishi. 1997 Oct; 20(5): 417-27
ISSN: 0911-4300
LA: JAPANESE; NON-ENGLISH
CP: JAPAN
AB: An enzyme-linked immunosorbent assay (ELISA) has been developed for the detection of antinuclear antibodies (ANAs) previously established as diagnostic and/or prognostic marker ANAs for various connective tissue diseases. The antigen used in ELISA is a mixture of purified recombinant or natural antigens including single-and double-stranded DNA, RNP, Sm, SS-A/Ro, SS-B/La, centromere, topoisomerase I and Jo-1 antigens. Thirty hundred and fifty nine patients sera from a variety of connective tissue diseases and 113 normal human sera (NHS) were examined. ELISA ANAs were positive in 3.5% of NHS and 80.2% of patients sera at cut off index 11.5, whereas indirect immunofluorescent antinuclear antibodies (FANAs) using HEp-2 cells were positive in 9.7% of NHS and 92.5% of patients sera at 1:160 serum dilution. More than 80% of sera from systemic lupus erythematosus, mixed connective tissue disease and primary Sjogrens disease were ELISA ANAs positive. Mean value of ELISA ANAs was highest in sera of patients with MCTD. ELISA ANAs were positive in 92.5% of sera with marker ANAs for connective tissue diseases. Mean value of ELISA ANAs was higher in sera with more than two marker ANAs than in sera with a single ANA or in sera without marker ANAs. In contrast incidence and mean value of ELISA ANAs were low in sera positive for anti topoisomerase I antibody or anti Jo-1 antibody. Sensitivity, specificity and agreement (accuracy) for connective tissue diseases with marker ANAs were as follows: ELISA ANAs (at index 11.5): 92.5%, 88.3% and 90.9%: FANAs (at 1:160 serum dilution): 99.0%, 70.4% and 88.1%, respectively. ELISA ANAs, thus, are specific for connective tissue diseases when compared to FANAs and previous ELISA for the detection of total ANAs. Moreover, ELISA ANAs are able to measure precise ANAs titers and are much less labor intensive when screening a large number of clinical specimens.

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33.) 'Autoantibody dominance' pattern following idiotypic manipulation of naive mice by immunization with anti-U1RNP antibodies.
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AU: George-J; Gilburd-B; Levy-Y; Afec-A; Damianovich-M; Ghirardello-A; Doria-A; Todesco-S; Shoenfeld-Y
SO: Pathobiology. 1997; 65(4): 204-9
ISSN: 1015-2008
LA: ENGLISH
CP: SWITZERLAND
AB: OBJECTIVE: To study the immune response and clinical findings in mice immunized with different epitope-specific anti-U1RNP antibodies purified from the sera of mixed connective tissue disease (MCTD) patients with various clinical manifestations. METHODS: BALB/c mice were immunized with anti-U1RNP-IgG preparations from 3 patients with MCTD. Group 1 was immunized with U1 70 kD A-positive IgG, group 2 with U1 70 kD-negative, U1A, U1C, B-B'-positive IgG and group 3 with U1 70 kD, U1A, U1C-positive IgG. The induced autoantibody response in the mice was studied by ELISA and immunoblots and the clinical findings of MCTD in humans were assessed. RESULTS: Immunoblot assays showed that mice immunized with different human anti-U1RNP antibodies developed predominantly autoantibodies directed against U1 68-70 kD epitope. This 'autoantibody dominance' pattern was not associated with clinical findings. CONCLUSIONS: The restricted murine autoimmune response may provide clues to the diversified autoantibody production in autoimmune diseases and explain in part the changing patterns of clinical findings in individuals with MCTD.

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34.) Usefulness of antinuclear antibody testing to screen for rheumatic diseases.
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AU: Malleson-PN; Sailer-M; Mackinnon-MJ
SO: Arch-Dis-Child. 1997 Oct; 77(4): 299-304
ISSN: 0003-9888
LA: ENGLISH
CP: ENGLAND
AB: OBJECTIVE: To assess the usefulness of the indirect immunofluorescence antinuclear antibody test (FANA) using human laryngeal epithelial carcinoma cells as nuclear substrate, to screen for childhood rheumatic diseases. STUDY DESIGN: A review of all FANA tests performed on children at British Columbia's Children's Hospital between 7 March 1991 and 31 July 1995. RESULTS: FANA tests were positive at titres of 1:20 or greater in 41% of all subjects tested, and in 65% of all subjects in whom the diagnosis was obtained. FANA positivity occurred in 67% of those with a rheumatic disease, compared with 64% of those with a non-rheumatic disease (p = 0.4). More girls had high titre FANA positivity than boys independent of whether or not they had a rheumatic disease (p = 0.05). At a screening serum dilution of 1:40 a positive test has a sensitivity of only 0.63, and a positive predictive value of only 0.33 for any rheumatic disease. For systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), or overlap syndrome at a screening dilution of 1:40 the test has a very high sensitivity of 0.98, but a very low positive predictive value of only 0.10, the test having slightly better characteristics for boys than girls. CONCLUSION: Although a negative FANA test makes a diagnosis of SLE or MCTD extremely unlikely, a positive test even at moderately high titres of 1:160 or higher is found so frequently in children without a rheumatic disease that a positive result has little or no diagnostic value. It is suggested that a screening serum dilution of 1:160 or 1:320 would increase the usefulness of the test, by decreasing false positive tests, without significantly increasing false negative tests for SLE or MCTD, and would have the potential for considerable cost savings.

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35.) Histological evaluation of destructive monoarthropathy in mixed connective tissue disease.
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AU: Fujinami-M; Saito-K; Okawa-Takatsuji-M; Kotajima-L; Kinoshita-M; Sumiya-M; Sato-K; Himeno-S; Aotsuka-S
SO: Scand-J-Rheumatol. 1997; 26(5): 395-8
ISSN: 0300-9742
LA: ENGLISH
CP: NORWAY
AB: The synovium from a patient with mixed connective tissue disease and destructive ankle monoarthritis was studied in detail to determine its immunohistological characteristics. Fibrinoid necrotic tissue on the surface of the synovium, multi-layered lining cells, increased numbers of capillaries, interstitial edema, infiltration of macrophages, relatively small numbers of lympho-plasma cells and polymorphonuclear leukocytes, scattered bone fragments, and multinucleated giant cells were observed. Many cells in the lining and sublining area were positive for CD68 and MAC387. Lower layers of increased lining cells which had a spindle shape were positively stained with anti-HLA-DR antibody. The small arteries in the deeper part of the synovium revealed obstruction or highly stenotic change. These findings suggest that obstructive circulatory disturbance due to endothelial injury might influence the progression of arthritis.

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36.) Fulminant hepatic failure due to cardiac tamponade associated with mixed connective tissue disease.
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AU: Inoue-T; Kamishirado-H; Ishiyama-E; Hayashi-T; Morooka-S
SO: J-Med. 1997; 28(3-4): 129-35
ISSN: 0025-7850
LA: ENGLISH
CP: UNITED-STATES
AB: We describe a 42-year old Japanese woman with mixed connective tissue disease (MCTD) who developed fulminant hepatic failure and hepatic encephalopathy. Massive pericardial effusion accompanying cardiac tamponade was shown by echocardiography. The hepatic failure was considered to be caused by a low cardiac output state because of cardiac tamponade, which might be due to cardiac involvement of MCTD. This is a rare case, showing an unusual progressive course in MCTD.

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37.) Antibodies to the constitutive 73-kd heat shock protein: a new marker of mixed connective tissue disease?
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SO - Am J Med 1993 Dec;95(6):595-600
AU - Mairesse N; Kahn MF; Appelboom T
PT - JOURNAL ARTICLE
AB - PURPOSE, PATIENTS, AND METHODS: This report documents the finding of an elevated titer of IgG reacting with the constitutive bovine 73-kd heat shock protein (HSP) in the serum of patients with rheumatoid arthritis, scleroderma, and mixed connective tissue disease (MCTD). RESULTS AND CONCLUSIONS: Further characterization of antibodies from patients with MCTD showed that the antibodies also recognize the human constitutive 73-kd HSP, but not the inducible 72-kd isoform. Very high levels of antibodies appeared to be specific for MCTD; the differences between levels in patients with MCTD and those in healthy subjects (blood donors) were highly significant (p 10(-8)), with no values in this group of patients overlapping with those in the controls. This parameter might therefore represent a new diagnostic marker for this disease.

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38.) Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions.
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SO - Curr Opin Rheumatol 1993 Nov;5(6):809-15
AU - Kallenberg CG
PT - JOURNAL ARTICLE; REVIEW (29 references); REVIEW, TUTORIAL
AB - Connective tissue diseases (CTDs) frequently present as undifferentiated disorders that may or may not develop into one of the well defined CTDs. The natural evolution of the early undifferentiated CTDs is not well known. Some years ago a cooperative study was started on 410 patients with early CTD; within this group, 48 patients had early scleroderma. Raynaud's phenomenon has been recognized as an early sign of CTD. Several studies on Raynaud's phenomenon patients have shown that abnormal nailfold capillary patterns have prognostic significance for evolution to a CTD, particularly scleroderma. Mixed connective tissue disease (MCTD) is the prototype of an overlap syndrome. The relevance of defining MCTD as a separate disease entity has been challenged. Follow-up studies show that many patients originally diagnosed with MCTD develop a definite CTD, particularly scleroderma or systemic lupus erythematosus, within a few years. In patients with MCTD, primary pulmonary hypertension is an important cause of death. This condition seems to be associated with anticardiolipin antibodies. A number of case reports suggest that immunosuppressive treatment is of benefit in this almost always fatal condition. The main reason for describing MCTD as a separate entity is its association with antibodies to U1-RNP. Recent studies have suggested that the production of anti-U1-RNP is an antigen-driven process, but the nature of the trigger for its production has not been elucidated. Retroviral proteins do not appear to be involved. Antibodies to the protein part of the U1-RNP complex and antibodies to the RNA component have been described. Levels of anti-RNA antibodies seem to parallel disease activity in MCTD patients.(ABSTRACT TRUNCATED AT 250 WORDS).

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39.) Hypertrophic cranial pachymeningitis associated with mixed connective tissue disease; a comparison with idiopathic and infectious pachymeningitis.
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SO - Intern Med 1993 Jun;32(6):510-2
AU - Fujimoto M; Kira J; Murai H; Yoshimura T; Takizawa K; Goto I
PT - JOURNAL ARTICLE
AB - This is the first report describing hypertrophic cranial pachymeningitis which developed in association with mixed connective tissue disease (MCTD). A 56-year-old man with a two-year history of MCTD gradually developed symptoms of headache and blurred vision. Bilateral papilledema and increased opening pressure and mild pleocytosis of the cerebrospinal fluid were noted. Magnetic resonance imaging of the brain revealed a diffuse thickening and a gadolinium-enhancement of the cranial dura mater. While five previous patients, diagnosed as idiopathic or infectious hypertrophic cranial pachymeningitis in our department, had either otitis media or sinusitis and showed multiple cranial nerve involvement, the present patient had neither otitis media nor sinusitis and did not show any cranial nerve involvement other than papilledema.

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40.) Juvenile-onset mixed connective tissue disease: longitudinal follow-up.
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SO - J Pediatr 1993 Feb;122(2):191-7
AU - Tiddens HA; van der Net JJ; de Graeff-Meeder ER; Fiselier TJ; de Rooij DJ; van Luijk WH; Herzberger R; van Suijlekom LW; van Venrooij WJ; Zegers BJ; et al
PT - JOURNAL ARTICLE
AB - To establish the symptoms and clinical course of juvenile-onset mixed connective tissue disease, we studied 14 patients, classified according the criteria of Kasukawa et al. The patient records were studied retrospectively and all patients were examined in a 1-day follow-up program. Systemic lupus erythematosus and polymyositis/dermatomyositis-like symptoms disappeared in time, whereas scleroderma-like symptoms (such as in the Raynaud phenomenon) and joint abnormalities persisted. Extensive limitation of joint function was found in four patients. At the time of follow-up, no active renal disease was found. Thrombocytopenia was still present in one of the three patients who had had this feature. All patients had abnormalities of esophageal motility. Long-term corticosteroid treatment was associated with aseptic bone necrosis in three patients and growth retardation in one. We conclude that the Kasukawa criteria are easy to apply to children, and that juvenile-onset mixed connective tissue disease has many similarities to the adult form of the disease.

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41.) Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions. III
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SO - Curr Opin Rheumatol 1992 Dec;4(6):837-42
AU - Kallenberg CG
PT - JOURNAL ARTICLE; REVIEW (22 references); REVIEW, TUTORIAL
AB - Many patients presenting with symptoms suggestive of a connective tissue disease do not fulfill criteria for a specific connective tissue disease at initial presentation. Some of these patients with undifferentiated connective tissue disease eventually develop a specific connective tissue disease. Recently, a large cohort of 213 patients from different centers with undifferentiated connective tissue disease of early onset were enrolled in a prospective protocoled study. Baseline characteristics, including antinuclear antibody profiles, were reported. The aim of this study was to define predictors for the development of specific organ-system involvement and connective tissue diseases in early undifferentiated connective tissue disease. Many patients show overlapping features of two or more connective tissue diseases. The presence of autoantibodies to U1-ribonucleoproteins has been associated with a particular overlap syndrome, mixed connective tissue disease. Most anti-U1-ribonucleoprotein-positive patients with undifferentiated connective tissue disease at presentation appear to develop mixed connective tissue disease over the course of disease. Although levels of anti-U1-ribonucleoprotein do not seem to be related to disease activity, this association suggests a pathogenetic relationship between anti-U1-ribonucleoprotein and mixed connective tissue disease. Genetic studies have shown that patients with antibodies against the 70-kD component of U1-ribonucleoprotein share a common epitope within the groove of their DR molecules at antigen-binding region, pointing to a particular antigen involved in the induction of these antibodies that may be relevant in the etiopathogenesis of associated disease.

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42.) Mixed connective tissue disease associated with autoimmune hepatitis and thyroiditis.
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SO - Ann Rheum Dis 1992 Apr;51(4):544-6
AU - Tomsic M; Ferlan-Marolt V; Kveder T; Hojker S; Rozman B
PT - JOURNAL ARTICLE
AB - The case is reported of a 27 year old woman who had mixed connective tissue disease (MCTD) associated with chronic active hepatitis and thyroiditis. Although hepatomegaly is sometimes observed in MCTD, only four cases of MCTD and chronic active hepatitis have been described. It is thought that this is the first report of an association between MCTD, chronic active hepatitis and thyroiditis.

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43.) Differences in HLA antigens between patients with mixed connective tissue disease and systemic lupus erythematosus.
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SO - Ann Rheum Dis 1992 Jan;51(1):52-5
AU - Ruuska P; Hameenkorpi R; Forsberg S; Julkunen H; Makitalo R; Ilonen J; Tiilikainen A
PT - JOURNAL ARTICLE
AB - Patients with mixed connective tissue disease (MCTD, n = 32) or systemic lupus erythematosus (SLE, n = 60) were typed for HLA-A, B, C, Dw, and DR antigens. All patients with SLE fulfilled at least four criteria of SLE and the patients with MCTD met the criteria proposed by Alarcon-Segovia (1989). The presence of antibodies to Sm was not considered as an exclusion for MCTD. In the patients with SLE, Dw3, DR3, and the associated B8 and A1 antigens were increased, whereas in the patients with MCTD an increased frequency of Dw4 was found (45 v 18% in controls v 14% in SLE). Of the subtypes of DR4, Dw4 was present in all but one of the DR4 positive patients. The frequency of DR4 in patients with MCTD (52%) differed significantly from that of controls (28%). The strong association of MCTD to one DR4 subtype was further seen in the significantly increased frequency of the B15, DR4 combination. Thus the genetic background seems to be different in patients with MCTD from that in patients with SLE. This could partly explain the clinical differences between these diseases.

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44.) Japanese diagnostic criteria for mixed connective tissue disease in Caucasian patients.
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SO - J Rheumatol 1992 Feb;19(2):259-64
AU - Doria A; Ghirardello A; de Zambiasi P; Ruffatti A; Gambari PF
PT - JOURNAL ARTICLE
AB - Preliminary Japanese diagnostic criteria for the classification of mixed connective tissue disease (MCTD) were tested in a group of 32 Caucasian patients with this disease. Many clinical and laboratory similarities were found between Caucasian and Japanese patients. However, polyarthritis was more frequent in the Caucasians, while finger and hand swelling, DLCO reduction and muscle involvement were more frequent in the Japanese. In Caucasians the sensitivity of this criteria set was 87%, very similar to that found in the Japanese group (88%), and the specificity was 94%, higher than that of Japanese (87%). The difference resulted from the higher specificity of anti-nRNP antibody positivity in the Caucasian patients, probably due to the use of counterimmunoelectrophoresis in the detection of this antibody. The Japanese criteria seem more useful than others because they allow the use of techniques other than passive hemagglutination in detecting the anti-nRNP antibody. In our experience, such criteria also contribute to a better definition of MCTD in Caucasian patients.

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45.) Clinical significance of IgG subclasses of Anti-Sm and U1 ribonucleoprotein antibodies in patients with systemic lupus erythematosus and mixed connective tissue disease.
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SO - J Clin Immunol 1991 Nov;11(6):317-25
AU - Tokano Y; Yasuma M; Harada S; Takasaki Y; Hashimoto H; Okumura K; Hirose S
PT - JOURNAL ARTICLE
AB - IgG subclasses of anti-Sm and anti-U1 ribonucleoprotein (U1 RNP) antibodies were determined using a new clone of the anti-IgG2 antibody (HG2-56F). Although the predominance of IgG1 coincided with previous reports, IgG2 anti-Sm and U1 RNP antibodies were detected in numerous patients. IgG3 anti-Sm antibody significantly correlates with joint involvement and a high titer of anti-DNA antibody. On the other hand, IgG4 anti-U1 RNP antibody significantly correlated with esophageal dilation and muscular involvement. These results may suggest that some IgG subclasses are related to a specific clinical feature or manifestation.

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46.) Overlap syndromes and mixed connective tissue disease.
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SO - Curr Opin Rheumatol 1991 Dec;3(6):995-1000
AU - Maddison PJ
PT - JOURNAL ARTICLE; REVIEW (25 references); REVIEW, TUTORIAL
AB - While the etiology of connective tissue diseases remains unknown, the classification of individual cases will continue to depend on identifying certain patterns of clinical and laboratory features. As many as 25% of connective tissue disease patients present with an overlap syndrome with features of systemic lupus erythematosus, systemic sclerosis, polymyositis, or dermatomyositis, with rheumatoid arthritis and Sjogren's syndrome evolving concurrently or consecutively during the course of the disease. The term overlap syndrome is applied to what appears to be a heterogeneous group of disorders, but in recent years there have been attempts to identify antibody markers within this population to identify subsets with particular patterns of disease expression. Thus, anti-U1-ribonucleoprotein is associated with overlap syndromes in which features of systemic lupus erythematosus are accompanied by features of systemic sclerosis or myositis; antibodies to polymyositis-scleroderma, Ku, and U2-ribonucleoprotein are associated with overlaps of systemic sclerosis and polymyositis, and anti-Jo-1 is associated with polymyositis and pulmonary fibrosis. A practical reason for subdividing cases in this way relates to prognosis and treatment, but at a more fundamental level it is hoped that the study of the origin of these antibodies and their antigen targets will provide clues to pathogenesis and even etiology.

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47.) Use of recombinant RNP peptides 70K and A in an ELISA for measurement of antibodies in mixed connective tissue disease: a longitudinal follow up of 18 patients.
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SO - Ann Rheum Dis 1990 Jun;49(6):391-5
AU - de Rooij DJ; Habets WJ; van de Putte LB; Hoet MH; Verbeek AL; van Venrooij WJ
PT - JOURNAL ARTICLE
AB - In a three year prospective study disease activity variables and levels of antibody against the RNP-peptides 70K and A were measured in 18 patients with mixed connective tissue disease. Antibody measurement entailed use of cloned autoantigens in an enzyme linked immunosorbent assay (ELISA). Fluctuations in antibody levels against 70K and A were most commonly noted in patients who also had changes in disease activity, but these changes in serology and disease activity were synchronous in only a minority of the episodes. Even major disease flares were associated with changes in anti-A levels in only a few, and with changes in anti-70K levels in none of the episodes. The data indicate that measurements of anti-70K and anti-A levels are not useful in monitoring disease activity or response to treatment in mixed connective tissue disease, and suggest that these antibody specificities do not play a direct part in the pathogenesis of disease manifestations.

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48.) Mixed connective tissue disease after exposure to polyvinyl chloride.
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SO - J Rheumatol 1989 Apr;16(4):533-5
AU - Kahn MF; Bourgeois P; Aeschlimann A; de Truchis P
PT - JOURNAL ARTICLE
AB - We present 4 patients fulfilling criteria for mixed connective tissue disease (MCTD) with anti-RNP antibodies, who had been previously exposed, in 4 different professions, to polyvinyl chloride. This presentation is clinically and serologically different from the classical polyvinyl chloride disease in which no such antibody can be found. Already observed in patients after cosmetic surgery, MCTD could also be a result of toxic exposure.

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49.) Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients.
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SO - J Rheumatol 1989 Mar;16(3):328-34
AU - Alarcon-Segovia D; Cardiel MH
PT - JOURNAL ARTICLE
AB - 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 Sjogren'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.

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50.) Clinical and serologic characteristics of patients with overlap syndrome: is mixed connective tissue disease a distinct clinical entity?
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SO - Medicine (Baltimore) 1989 Jan;68(1):58-65
AU - Lazaro MA; Maldonado Cocco JA; Catoggio LJ; Babini SM; Messina OD; Garcia Morteo O
PT - JOURNAL ARTICLE; REVIEW (79 references); REVIEW, ACADEMIC
AB - We discuss the clinical and serologic features of 27 patients with overlap syndrome followed prospectively by our group. The findings are similar to those of other reports, but we have drawn attention to the presence of peritendinous nodules in these patients and mentioned some peculiar neurologic manifestations. Rheumatoid arthritis was the most common diagnosis in our patients. The presence of high-titer antibodies against the nuclear ribonucleoprotein fraction of extractable nuclear antigen (nRNP) did not allow the identification of a particular subgroup. However, patients with this antibody tended to fulfill more criteria of more diseases than those without it. The findings lead us to conclude that antibodies to nRNP do not identify a particular subgroup within the overlap syndromes and that mixed connective tissue disease does not appear to be a distinct entity.

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51.) Fluctuations in anti-nRNP levels in patients with mixed connective tissue disease are related to disease activity as part of a polyclonal B cell response.
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SO - Ann Rheum Dis 1986 Oct;45(10):800-8
AU - Houtman PM; Kallenberg CG; Limburg PC; van Leeuwen MA; van Rijswijk MH; The TH
PT - JOURNAL ARTICLE
AB - In a follow up study of 11 patients with mixed connective tissue disease the levels of antibodies to nuclear ribonucleoprotein (nRNP) as measured by an enzyme linked immunosorbent assay (ELISA) were related to clinical activity of disease. To assess the relation between anti-nRNP levels and disease activity the levels of total immunoglobulin G, IgM rheumatoid factor (IgM RF), and antibodies to an unrelated antigen (tetanus toxoid) were determined simultaneously. No significant changes in anti-nRNP levels were noted in four patients with minor activity of disease. Major flares of disease were observed in seven patients. Clinical symptoms were preceded by a rise in anti-nRNP level in these patients unless they received immunosuppressive agents before the exacerbation. Conversely, when a rise in anti-nRNP level occurred a major flare of disease was followed in all but one case. Anti-nRNP levels fell during clinical improvement whether or not immunosuppressive treatment was given. All patients showed parallel fluctuations in anti-nRNP, IgM RF, and total immunoglobulin G levels. Furthermore, parallel fluctuations were seen in the levels of anti-nRNP and antibodies to tetanus toxoid except in one patient. We conclude that measurement of anti-nRNP by ELISA may be a guide for disease activity in connective tissue disease. Fluctuations of anti-nRNP are not restricted to this antibody, however, but are part of a more polyclonal activity of the B lymphocyte system.

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52.) Immunofluorescence studies in progressive systemic sclerosis (scleroderma) and mixed connective tissue disease.
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SO - Br J Dermatol 1983 Jul;109(1):27-36
AU - Reimer G; Huschka U; Keller J; Kammerer R; Hornstein OP
PT - JOURNAL ARTICLE
AB - Immunofluorescence (IF) investigations of the skin were performed in thirty patients with progressive systemic sclerosis (scleroderma) and eight patients with mixed connective tissue disease (MCTD). The results show that speckled epidermal nuclear immunoglobulin deposition occurs not only in MCTD but also in true scleroderma. Granular IgM deposition at the dermo-epidermal junction of light-exposed skin was detected in both groups of patients, but six of eight MCTD patients also showed a granular IgM band in non-exposed skin. Antinuclear antibodies (ANA) were demonstrated in the sera of 96% and 100% of patients with scleroderma and MCTD respectively. The pattern of nuclear IF staining in scleroderma included dense fine speckles, large coarse speckles, threads, nucleolar and centromere staining. In MCTD, by contrast, the ANA staining pattern consisted of threads. The significance of ANA titres and immunological specificities for the in vivo reaction of serum ANA with epidermal nuclear antigens is discussed.

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53.) Mixed connective tissue disease - a subset with sequential clinical and laboratory features.
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SO - J Rheumatol 1981 Jul-Aug;8(4):587-98
AU - Grant KD; Adams LE; Hess EV
PT - JOURNAL ARTICLE
AB - Twenty-three patients who lacked the full picture of mixed connective tissue disease (MCTD) initially, developed new findings or experienced regression of initial features with time. Each patient had at least 1 extractable nuclear antigen (ENA) antibody titer greater than or equal to 1:10,000 composed exclusively of ribonucleoprotein; but variation in titer occurred in 9 and Sm antibody was transiently found in 3 patients. Four initially had other diagnoses and negative antinuclear antibody tests (ANA) before developing speckled ANAs. Eleven patients had consistently speckled ANAs. As suggested by earlier clinical observations, MCTD can change clinically and serologically. This study demonstrates the sequential development of the features of SLE, polymyositis, rheumatoid arthritis and in addition emphasizes the serologic studies may also vary over time in these patients.

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54.) Raynaud's phenomenon and initially seronegative mixed connective tissue disease.
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SO - J Rheumatol 1981 Jul-Aug;8(4):632-4
AU - Ellman MH; Pachman L; Medof ME
PT - JOURNAL ARTICLE
AB - We report 2 young women with Raynaud's phenomenon who later developed the laboratory and clinical features of mixed connective tissue disease (MCTD). Antibodies to extractable nuclear antigens were initially negative and remained so far several years before becoming positive. Raynaud's phenomenon is common in MCTD, but laboratory and clinical evidence of the latter may not be present initially.
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DATA-MEDICOS/DERMAGIC-EXPRESS No (48) 07/04/99 DR. JOSE LAPENTA R. 
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