Serum levels of tissue inhibitor of metalloproteinases in patients with mixed connective tissue disease

OBJECTIVE: To determine serum tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 levels in patients with mixed connective tissue disease (MCTD) and investigate whether these levels were correlated with the clinical or serological features of this disease. METHODS: Serum TIMP-1 and TIMP-2 levels were measured with specific enzyme-linked immunosorbent assays. Serum samples from 26 patients with MCTD and 18 healthy individuals were examined. RESULTS; Serum levels of TIMP-1 were significantly higher in patients with MCTD than those in healthy individuals (mean +/- SD: 218.9 +/- 50.8 ng/ml versus 160.0 +/- 38.7 ng/ml, P < 0.0001). MCTD patients with elevated TIMP-1 had esophageal involvement at a significantly higher incidence than those without (77.8% versus 35.3%, p < 0.05). There was no difference in serum TIMP-2 levels between patients with MCTD and healthy controls (75.6 - 11.9 ng/ml versus 77.3 +/- 10.7 ng/ml). CONCLUSION: These results suggest that TIMP-1 is involved in the pathogenesis of MCTD, and that TIMP-1 may be a serological marker for the presence of esophageal involvement in these patients.     

Pure red cell aplasia in mixed connective tissue disease

We describe a patient with mixed connective tissue disease (MCTD), who developed pure red cell aplasia which responded favorably during treatment with corticosteroids. Pure red cell aplasia has been described in a few patients with rheumatoid arthritis and systemic lupus erythematosus, but, to our knowledge, this is the first report of an association between it and MCTD.     

Suppressor cell loss and dysfunction in mixed connective tissue disease

Of 11 patients with untreated mixed connective tissue disease (MCTD) who were studied, all had decreased circulating T gamma cells, and all but one had decreased suppressor cell function of T cells on B cells, determined by a reverse hemolytic plaque-cell assay. Results in 21 normal subjects were significantly, different. Incubation of mononuclear cells from MCTD patients in purified anti-ribonucleoprotein (anti-RNP) IgG resulted in further decrease in their suppressor function. Decrease of T gamma cells and their suppressor function may be due to in vivo penetration of anti-RNP antibody into T gamma cells, causing their deletion.     

Th1 and Th2 cytokine profiles in sickle cell disease

We have investigated the levels of Th1 (IL-2 and IFN-gamma) and Th2 (IL-4) cytokines in the plasma and supernatants following peripheral blood mononuclear cell culture and mitogen stimulation in a group of 39 patients with sickle cell disease (SCD) made up of 29 SS, 8 Sbeta-thal and 2 Hb SD in steady state. Five SS patients were studied during 7 episodes of vaso-occlusive crisis. Twenty-four control (3 Hb AS and 21 Hb AA) were also studied; 10 were acutely ill while 14 were healthy at the time of the study. The plasma levels of IL-2 and IFN-gamma were similar in the patients and the controls. However, plasma IL-4 was significantly higher among the steady-state SS patients than in the controls. While there was no significant difference in cytokine levels following mitogen stimulation in the different groups, plasma IL-2 to IL-4 and IFN-gamma to IL-4 ratios were significantly lower among the steady-state SS patients, indicating a possible Th2 bias in our sickle cell patients and suggesting a possible mechanism to explain the predisposition of SCD patients to bacterial infections. However, SS patients with good splenic function showed a relative Th1 bias, which may be an additional explanation for the protection against bacterial infections in such patients.     

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.     

Pregnancy in mixed connective tissue disease

This article discusses fetal and maternal morbidity in women who have mixed connective tissue disease.     

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.     

Myocarditis in mixed connective tissue disease

A young black woman with clinical and serologic features of mixed connective tissue disease (MCTD) developed myocarditis with congestive heart failure and ventricular ectopic activity. Despite treatment with steroids and cyclophosphamide, progressive myocarditis resulted in death 20 months after cardiomegaly first developed. Necropsy findings in the myocardium included multiple areas of extensive lymphocytic infiltration and patches of fibrosis. Myocarditis has not previously been described in the adult with MCTD but may be an important complication in patients with a high titer of antibody to nuclear ribonucleoprotein.     

Raynaud's phenomenon in mixed connective tissue disease

Raynaud's phenomenon affects most patients who have mixed connective tissue disease (MCTD) and frequently represents the initial manifestation of the disease. It is the cutaneous symptom of a systemic vasculopathy that is characterized by intimal fibrosis and blood vessel obliteration that frequently leads to visceral involvement, particularly pulmonary hypertension. An association between Raynaud's phenomenon and the characteristic autoantibody in MCTD, anti-U1-RNP (ribonucleoprotein), is found across the spectrum of rheumatic diseases, including undifferentiated connective tissue disease, scleroderma, and systemic lupus erythematosus. Capillary nailfold examination represents a valuable tool to identify patients who are at risk for MCTD. The goal in the therapy of Raynaud's phenomenon in MCTD is to decrease the frequency of attacks, to prevent digital ulceration, and to limit progressive vascular damage. Therapeutic regimens include the traditional use of calcium channel blockers and novel vascular therapies.     

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.     

Esophageal involvement in mixed connective tissue disease

A study of esophageal symptoms and function was performed in 21 patients with mixed connective tissue disease (MCTD). Esophageal involvement was found in 18 cases (85%), in 14 (66%) with typical symptoms, in 15 (71%) with manometric abnormalities and in 11 (57%) with both. The manometric pattern was characterized by reduction of amplitude and coordination of peristaltic waves throughout the esophageal body and reduction of lower esophageal sphincter (LES) competency. In comparison, 38 patients with systemic sclerosis showed a similar but more severe pattern, particularly at the level of the distal esophagus and LES. Thus, although similar, the esophageal involvement in MCTD was not exactly the same as that of systemic sclerosis. Furthermore, in MCTD a correlation between manometric abnormalities and cutaneous involvement was lacking, and this suggests that esophageal disorders are not always linked with clinically evident scleroderma-like features of this disease. Since the diagnosis of MCTD is made in the presence of the clinical picture of more than one connective tissue disease, the detection of esophageal involvement by a sensitive technique such as esophageal manometry in a patient with suspected MCTD may be a useful diagnostic aid.     

Cardiac abnormalities in mixed connective tissue disease

Sixteen patients with mixed connective tissue disease (MCTD) were studied using noninvasive cardiovascular techniques. Cardiovascular abnormalities including pericarditis, asymmetric septal hypertrophy, and LV dilatation were found in 38 percent of the study group. Borderline ECG and echocardiographic abnormalities were present in 31 percent of the study group, and the remaining 31 percent were normal by all study techniques. MCTD patients have a high prevalence of cardiovascular abnormalities when studied noninvasively. The most common clinical abnormality is a steroid-responsive pericarditis, present in 25 percent of our series.     

Ibuprofen-induced meningitis in mixed connective tissue disease

Summary A young Black woman with mixed connective tissue disease (MCTD) developed an aseptic meningitis after receiving ibuprofen. The meningeal reaction, reported infrequently in systemic lupus erythematosus (SLE) and only once previously in MCTD, was characterized by a predominantly polymorphonu-clear cerebrospinal fluid (CSF) pleocytosis and depression of CSF glucose. Reversible renal insuffiency also occurred. Features suggestive of a hypersensitivity reaction included pruritus, conjunctivitis, facial oedema, desquamation of the palms and soles, and subsequent near total alopecia. Meningeal signs responded rapidly to systemic corticosteroid therapy. Patients with MCTD as well as those with SLE may be at peculiar risk of developing this uncommon reaction to ibuprofen.     

Lungs in mixed connective tissue disease.

Patients with mixed connective tissue disease (MCTD) exhibit clinical features of systemic lupus erythematosus (SLE), progressive systemic sclerosis or scleroderma (PSS), and polymyositis-dermatomyositis (PM-DM). In their sera is an unusually high titer of a circulating antinuclear antibody with specificity for a nuclear ribonucleoprotein antigen. Pleuropulmonary manifestations are common in MCTD and the incidence varies from 20% to 85%. The pleuropulmonary complications include pleural effusion, interstitial pulmonary processes, pulmonary arterial hypertension (PAH), pulmonary vasculitis, pulmonary thromboembolic phenomena, aspiration pneumonia, and hypoventilatory failure. Pulmonary vascular pathology with progressive PAH and cor pulmonale is the most serious complication of MCTD. The pleuropulmonary manifestations in MCTD are similar to the respiratory problems well recorded in SLE, PSS, and PM-DM. Even though the pleuropulmonary complications are common in MCTD, they may remain clinically inapparent until fatal complications ensue.     

Transverse myelitis in mixed connective tissue disease

A case of transverse myelitis in a 16-year-old woman with mixed connective tissue disease is described. After treatment with azathioprine and prednisolone complete recovery was obtained.