Clinical and immunologic manifestations of mixed connective tissue disease in a Miami population compared to a Midwestern US Caucasian population

OBJECTIVE: A cross-sectional study of mixed connective tissue disease (MCTD) was performed to determine if there were identifiable differences in the clinical expression of MCTD associated with race or ethnicity. METHODS: Miami, Florida, and Midwestern US (Missouri) Caucasian MCTD cohorts were studied. Clinical and laboratory features of the 2 MCTD cohorts were compared. A concurrently collected cohort of Sm-positive patients with systemic lupus erythematosus (SLE) was studied as a control. Disease activity and severity and functional status were measured. CD4+CD25(high)-expressing T-regulatory cells were enumerated and serum soluble L selectin was measured as biomarkers of disease activity. RESULTS: The Miami and Missouri Caucasian MCTD groups, while differing from the SLE group, were largely similar; however, gastroesophageal reflux, sclerodactyly, and malar rash were significantly more frequent in the Missouri MCTD group and alopecia was more frequent in the Miami MCTD group. Significant clinical and laboratory differences were found between the Miami MCTD and Miami SLE groups despite similar disease duration, activity, severity and functional status. Raynaud's phenomenon (RP), hand swelling, synovitis, myositis, and sclerodactyly were all significantly more common in RNP-positive MCTD versus Sm-positive SLE subjects. CONCLUSION Ethnic differences were observed in the frequency of end-organ involvement in the Miami MCTD versus the Missouri Caucasian MCTD groups. Clinical and laboratory features of all MCTD groups were clearly different from the SLE group, despite similar disease activity, disease severity, and functional status. Disease activity measures appeared to behave similarly as valid measures of disease activity in SLE and MCTD.     

Mixed connective tissue disease

A defining feature of mixed connective tissue disease (MCTD) is the presence of antibodies against the U1-ribonucleoprotein (RNP) complex, but other autoantibodies in MCTD have recently been described. Research has also further elucidated the immune responses directed against U1-RNP in humans and in murine models of disease. Hypotheses implicating modified self-antigens and/or infectious agents in the pathogenesis of MCTD have been advanced. Links between the immunologic and clinical phenomena in MCTD are emerging. Longitudinal study of patients with MCTD highlights the impact of pulmonary hypertension on disease outcome.     

Severe mixed connective tissue disease in a woman with pure gonadal dysgenesis: estrogens do not influence disease expression

Mixed connective tissue disease (MCTD) is more prevalent in women during the child bearing years, suggesting that estrogens may play a role in disease expression. We describe a woman who developed MCTD despite pure gonadal dysgenesis, i.e., a disease associated with permanently very low plasma levels of estrogens. The onset of MCTD and subsequent life threatening disease course over 15 years occurred while she declined exogenous hormonal replacement therapy. Concurrent presence of estrogens is not necessary for onset, persistence, or exacerbation of severe MCTD.     

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

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

Mixed connective tissue disease

The concept of mixed connective tissue disease (MCTD) as a separate connective tissue disease (CTD) has persisted for more than four decades. High titers of antibodies targeting the U1 small nuclear ribonucleoprotein particle (U1 snRNP) in peripheral blood are a sine qua non for the diagnosis of MCTD, in addition to distinct clinical features including Raynaud's phenomenon (RP), “puffy hands,” arthritis, myositis, pleuritis, pericarditis, interstitial lung disease (ILD), and pulmonary hypertension (PH). Recently, population-based epidemiology data from Norway estimated the point prevalence of adult-onset MCTD to be 3.8 per 100,000 and the mean annual incidence to be 2.1 per million per year, supporting the notion that MCTD is the least common CTD. Little is known about the etiology of MCTD, but recent genetic studies have confirmed that MCTD is a strongly HLA (​human leukocyte antigen)-linked disease, as the HLA profiles of MCTD differ distinctly from the corresponding profiles of ethnically matched healthy controls and other CTDs.In the first section of this review, we provide an update on the clinical, immunological, and genetic features of MCTD and discuss the relationship between MCTD and the other CTDs. Then we proceed to discuss the recent advances in therapy and our current understanding of prognosis and prognostic factors, especially those that are associated with the more serious pulmonary and cardiovascular complications of the disease. In the final section, we discuss some of the key, unresolved questions related to anti-RNP-associated diseases and indicate how these questions may be approached in future studies.     

An adult case of mixed connective tissue disease associated with perimyocarditis and massive pericardial effusion

We report the case of a 55-year-old woman with mixed connective tissue disease (MCTD), who developed perimyocarditis associated with massive pericardial effusion. The diagnosis of MCTD was based on clinical and serological findings. We confirmed myocarditis by right ventricular endomyocardial biopsy. The pericardial effusion gradually disappeared after the administration of prednisolone. Although there have been several reports of cardiac disease in adult MCTD, few cases of adult MCTD having perimyocarditis associated with massive pericardial effusion have been reported.     

Bronchoalveolar lavage fluid cells in mixed connective tissue disease

OBJECTIVE: Patients with mixed connective tissue disease (MCTD) exhibit clinical features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and polymyositis and dermatomyositis (PM-DM). The objective of this study was to clarify differences in BAL findings and immunophenotypes of BAL fluid (BALF) cells of patients with interstitial lung disease associated with these diseases. METHODOLOGY: We were unable to recruit a sufficient number of SLE patients with lung disease. We compared immunophenotypes of lymphocytes and alveolar macrophages (AM) in BALF of 20 MCTD patients with those of 21 SSc and 27 PM-DM patients and tested the relationships between immunophenotypes and pulmonary function in MCTD. RESULTS: MCTD patients had a significantly higher CD4/CD8 ratio with more CD4 positive lymphocytes than PM-DM patients (P = 0.025). In AM phenotypes, MCTD patients had a significantly lower percentage of CD71 positive AM compared with SSc patients (P = 0.023). DLCO was negatively related to absolute numbers of CD8 positive lymphocytes (R = -0.517, P= 0.033). CONCLUSIONS: CD4 positive lymphocytes in BALF were increased in MCTD compared to PM-DM patients, while CD71 positive AM were decreased in MCTD compared to SSc patients. CD8 positive lymphocytes correlated negatively with DLCO measurements in MCTD patients.     

Pulmonary veno-occlusive disease as a primary cause of pulmonary hypertension in a patient with mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a systemic disease seen in a group of patients with overlapping clinical features of lupus, scleroderma, polymyositis, and rheumatoid arthritis. A defining feature of MCTD is the presence of antibodies against the U1-ribonucleoprotein (U1-RNP) complex. Pulmonary hypertension is the major cause of death in MCTD. We report an autopsy case of MCTD with pulmonary hypertension. The U1-RNP antibody of this patient was 171.9 U (normal < 25.0 U). The immediate cause of death was attributed to acute pulmonary embolism at left lower lobe. A severe vasculopathy characterized by fibrotic occlusion of small veins and venules, associated with prominent capillary congestion, was consistent with pulmonary veno-occlusive disease (PVOD). This is the first case reported in which PVOD is the primary cause of pulmonary hypertension in MCTD.     

Pleuritis-pericarditis--an unusual initial manifestation of mixed connective tissue disease.

Cardiac involvement has been reported in mixed connective tissue disease (MCTD). We describe a 16-year-old girl in whom pleuritis and pericarditis occurred as the initial clinical manifestations of MCTD. Although pleuritis and pericarditis form a common clinical entity in MCTD, it is rarely seen as an initial manifestation. If MCTD is suspected, the diagnosis can be made by the clinical findings and the occurrence of a high titre of antibody against ribonuclease-sensitive ribonucleoprotein (RNP). This report emphasizes the importance of screening for connective tissue disease in patients with pericarditis/pleuritis.     

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

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

Pediatric-onset mixed connective tissue disease

This article discusses the literature on pediatric-onset mixed connective tissue disease (MCTD) and adds 34 new cases. Although not benign, pediatric-onset MCTD carries less mortality than adult-onset disease.     

Mixed connective tissue disease associated with autoimmune hepatitis and thyroiditis.

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.     

Pregnancy in mixed connective tissue disease: comparison with systemic lupus erythematosus

The risk of pregnancy was evaluated in 31 patients with mixed connective tissue disease (MCTD), 31 patients with systemic lupus erythematosus (SLE) and 51 controls. The fertility rates in MCTD and SLE were unaltered by disease; however, parity was decreased and fetal wastage was increased both before and even more so after onset. It is our observation that pregnancy carries the same risks in MCTD as it does in SLE.     

Serum cytokine levels and type 1 and type 2 intracellular T cell cytokine profiles in mixed connective tissue disease

OBJECTIVE: To determine serum cytokine concentrations and intracellular cytokine production of CD4+ and CD8+ T cells in 20 patients with mixed connective tissue disease (MCTD). METHODS: Detailed analysis of cytokine production; 8 patients were in the active stage, 12 in the inactive stage of the disease. Serum concentrations of interferon-gamma (IFN-gamma), interleukin 4 (IL-4), and IL-10 were assessed by ELISA. Intracellular content of IFN-gamma, IL-4, and IL-10 in CD4+ and CD8+ peripheral blood T cell and lymphocyte subsets was determined by flow cytometry. RESULTS: Serum concentrations of both type 1 and type 2 cytokines were significantly higher in patients with MCTD than in healthy controls. IFN-gamma expression of CD4+ and CD8+ T cells did not differ comparing all patients to controls. In patients with active MCTD, the percentage of CD8+/IFN-gamma+ Tc1 cells was significantly increased compared to inactive disease or to controls (p < 0.05). IL-4 expression of CD4+ T cells was scarcely detectable in MCTD, while a subpopulation of CD8+ Tc2 cells produced IL-4. A higher percentage of these CD8+/IL-4+ Tc2 cells were detected in patients with MCTD, especially in active disease, compared to controls (p < 0.05). The percentage of IL-10-expressing CD4+ and CD8+ T cells was higher in patients than in controls (p < 0.05). Again, CD4+ and CD8+ T cells from patients with active MCTD produced significantly more IL-10 than cells in patients with inactive disease or in controls (p < 0.05). CONCLUSION: Our results suggest that MCTD is associated with increased production of both type 1 (IFN-gamma) and type 2 cytokines (IL-4, IL-10). Cytokine production is usually higher in active MCTD than in inactive disease. CD8+ T cells may produce more IFN-gamma and IL-10 in comparison to CD4+ T cells. Patients with active disease have more IL-4-expressing Tc2 cells and IL-10-expressing Th2 and Tc2 cells than patients with inactive MCTD or controls. In MCTD, increased IL-10 production by Th2 and Tc2 cells may be an attempt by the immune system to downregulate the inflammatory reaction, although this effect may not be sufficient to restore the physiological Th1/Th2 balance in MCTD.     

Immune complex nephropathy in mixed connective tissue disease.

Initial reports on the clinical spectrum of mixed connective tissue disease (MCTD) indicated that renal involvement was uncommon. Four of 20 patients with MCTD underwent renal biopsy and all showed evidence of immune complex trapping with a membranous glomerulonephritis in three patients. Clinically evident renal disease was absent in two patients. These findings suggest that renal involvement in MCTD may be more prevalent than previously indicated.     

Osteoporosis in mixed connective tissue disease

The existence of osteoporosis in 58 postmenopausal women with mixed connective tissue disease (MCTD) was investigated. The mean bone mineral density assessed by dual energy X-ray absorptiometry in the lumbar spine was decreased in 25.8% of the patients, reflecting osteoporosis (T score < –2.5). In the femoral neck there was no significant difference between the BMD of MCTD patients and that of age-matched, healthy postmenopausal women. Low bone mineral density was found among patients on, as well as off, corticosteroids. The extent of bone loss was associated with disease duration, as well as corticosteroid therapy. Serum osteocalcin levels were lower in MCTD patients than in controls. Lower serum oestradiol, testosterone and dehydroepiandrosterone sulphate levels were detected in MCTD patients than in controls. Thus, MCTD may be associated with increased bone loss. Pathogenic factors may include the disease itself, corticosteroid therapy, impaired osteoblast function, and low serum sex hormone levels.     

Treatment of mixed connective tissue disease

Mixed connective tissue disease (MCTD) is believed to be incurable and seems to have a variable prognosis. Some patients have a mild self-limited disease, whereas others develop major organ involvement that requires aggressive treatment. Because no controlled clinical trials have been performed to guide therapy in MCTD, treatment strategies must rely largely upon the conventional therapies that are used for similar problems in other rheumatic conditions (systemic lupus erythematosus, scleroderma, polymyositis). Given the heterogeneous clinical course of MCTD, therapy should be individualized to address the specific organ involved and the severity of underlying disease activity. Corticosteroids, antimalarials, methotrexate, cytotoxics (most often cyclophosphamide), and vasodilators have been used in the treatment of MCTD with varying degrees of success.     

Outcome of pregnancies complicated by systemic sclerosis and mixed connective tissue disease

Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are rare autoimmune diseases which share the common feature of non-inflammatory vasculopathy. Studies evaluating pregnancy outcomes in these patients have yielded conflicting results. We sought to describe the outcomes of pregnancies associated with SSc and MCTD followed at our center utilizing a retrospective review of all pregnant women with SSc and MCTD followed at Stanford University from 1993 to 2003. We identified 20 pregnancies occurring in 13 women with SSc or MCTD. Twelve pregnancies occurred in seven women with SSc and eight pregnancies occurred in six women with MCTD. The overall preterm delivery rate was 39% and small for gestational age infants occurred in 50% and 63% of pregnancies associated with SSc and MCTD, respectively. Fetal loss complicated two pregnancies in women with severe diffuse SSc and the antiphospholipid antibody syndrome. There were no cases of congenital heartblock among infants, and only one case of pre-eclampsia was observed. Maternal flares of disease during pregnancy were generally mild. Most pregnancies in women with SSc and MCTD in this cohort were uncomplicated. The high rates of prematurity and small for gestational age infants underscore the risk for growth restriction consistent with the vasculopathy associated with these diseases.