Kikuchi's disease as a presenting feature of mixed connective tissue disease

Summary Necrotising histiocytic lymphadenitis (Kikuchi's disease) is a recognised cause of benign lymphadenopathy. It has been reported in association with both adult Still's disease, systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD). We report a case of mixed connective tissue disease (MCTD), in which biopsy of enlarged lymph nodes occurring as a presenting feature showed the characteristic features of Kikuchi's disease. This finding supports the belief that Kikuchi's disease and the autoimmune rheumatic disorders may share a common aetiology.     

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.     

Undifferentiated connective tissue disease: analysis of 83 patients with a minimum followup of 5 years

OBJECTIVE: Undifferentiated connective tissue disease (UCTD) refers to a cluster of systemic disorders characterized by a simple clinical and autoantibody profile. Previously, we had described a series of 91 patients with UCTD who were followed at our unit for a minimum period of one year; here we report the extended followup of these patients. METHODS: Of the original 91 patients, 8 were lost to followup; the remaining 83, with a minimum followup of 5 years, were included in our analysis. RESULTS: During the followup 18 patients developed systemic lupus erythematosus (SLE) and one developed Sj?gren's syndrome within a mean period of 54 months after the onset of the disease (range 17-96 mo). On analysis the 18 patients with SLE showed a clinical profile similar to cohorts reported in the literature. In one patient the evolution to SLE occurred during puerperium, but no other triggering factors were observed in our series. The presence of anticardiolipin antibodies and of multiple antibody specificities was significantly correlated with the development of SLE (p < 0.05). CONCLUSION: This analysis confirms the findings of our one year followup study that UCTD comprises a distinct group of mild diseases and that the rate of evolution to defined connective tissue diseases is higher during the first years after its onset. Patients who maintain an undifferentiated profile during the followup seem to run a decreasing risk of developing a defined CTD.     

Bamboo nodes associated with mixed connective tissue disease as a cause of hoarseness

Vocal fold lesions related to autoimmune diseases are rheumatoid nodules and, to a lesser extent, bamboo nodes. Mostly transverse, they are located in the middle third of the vocal cord and exhibit a yellowish appearance. The characteristic shape of these lesions led to their name. These vocal fold deposits may interfere with the normal vibratory cycle during phonation and thus may be an unusual cause of hoarseness. We present a 43-year-old woman with known mixed connective tissue disease and a dysphonia. Laryngostroboscopy showed bamboo nodes as described above. We applied several laryngeal injections of cortisone as described previously in the literature. Since this treatment did not lead to a sufficient voice improvement, we attempted to surgically remove the deposits. After the surgery, the voice improved considerably. In all patients with rheumatic diseases who suffer from a rough, breathy, or unstable voice, a laryngostroboscopic examination should be done. If, however, a bamboo node lesion of the vocal folds is found by the laryngologists, an associated autoimmune disorder must be assumed, and adequate diagnostic procedures have to be initiated. Local laryngeal injections (1–3 times) with steroids should be the first line of therapy. In unsuccessful cases, subsequent surgery can be a useful treatment of bamboo nodes to stabilize and improve voice quality.     

The prognosis of mixed connective tissue disease

The prognosis for patients who have mixed connective tissue disease (MCTD) varies from a benign course to severe progressive disease. In approximately one third of patients the clinical symptoms go into long-term remission and the anti-U1 small nuclear ribonucleoprotein antibodies disappear. One third of patients have a severe, progressive disease course. Persistent morbidity often is attributable to arthritis, easy fatiguability, and dyspnea on exertion. The most severe clinical manifestation is pulmonary hypertension which contributes to premature death in patients who have MCTD. Pulmonary hypertension is associated with proliferative vascular abnormalities that involve small pulmonary vessels, rather than interstitial lung disease.     

Articular manifestations of mixed connective tissue disease

All but one of 28 patients with mixed connective tissue disease (MCTD) who were studied prospectively had arthralgia, and 15 of them had noticed joint swelling. Arthralgia was the first symptom in 14 patients and one of the first two symptoms in 24. Arthralgia was pauciarticular in 4 and polyarticular in 23. Presence of morning stiffness in 15 patients, symmetrical joint swelling in 16, joint deformity in 6, marginal erosions in roentgenograms of the hands of 12, rheumatoid factor in 25, and subcutaneous nodules in 5 caused 24 of the 28 patients with MCTD to fulfill criteria for definite or classic rheumatoid arthritis. All patients, however, also had prominent signs or symptoms of scleroderma, systemic lupus erythematosus, or polymyositis.     

Other manifestations of mixed connective tissue disease

This article describes other manifestations of mixed connective tissue disease (MCTD). We focus on inflammatory arthritis, the gastrointestinal tract (the esophagus in particular), the kidney, skin, and hematologic changes such as thrombocytopenia. Due to the complexity of potential organ involvements in MCTD, vigilance with appropriate diagnosis and treatment is warranted.     

Panniculitis in a patient with mixed connective tissue disease

A 51-year-old woman who had been suffering from mixed connective tissue disease (MCTD) for 8 years developed an erythematous rash with pain and tenderness on her left leg. A skin biopsy revealed septal panniculitis with multiple lymphangiectasis. No vasculitis was observed. An increase in her prednisolone dose from 5mg to 20mg/day led to an improvement in these lesions. Panniculitis is very rare in MCTD. The clinical significance of panniculitis in MCTD is also discussed.     

Evaluation of paraoxonase activity in patients with mixed connective tissue disease

OBJECTIVE: Mixed connective tissue disease (MCTD) is a systemic inflammatory autoimmune disease. The connection between inflammatory measures and atherosclerosis in MCTD has not been described. Paraoxonase (PON) is known to have an antioxidant function. We evaluated lipid profiles and PON activity in patients with MCTD. METHODS: Thirty-seven patients with MCTD were enrolled. Patients had taken no antihyperlipidemic drugs in the past 2 months. Thirty healthy individuals served as controls. The mean age of patients was 51.2 +/- 9.5 years; disease duration was 11.0 +/- 7.2 years. PON activity was determined with spectrophotometry, von Willebrand factor (vWF) antigen was investigated with the immunoturbidimetry method, and thrombomodulin and antiendothelial cell antibody (AECA) measurements were carried out by ELISA. RESULTS: PON activity in patients with MCTD was significantly lower than in the controls (patients 118.5 +/- 64.6 U/l, controls 188.0 +/- 77.6; p < 0.001). Arylesterase activity was significantly reduced in patients (p < 0.001). Reduction of PON activity showed a close correlation with the age of the patients, duration of the disease, and vascular events (eye, cardiac, cerebral). There was a close association between the low PON activity and endothelial cell activation markers (thrombomodulin, vWF, AECA). CONCLUSION: Our results indicate that in patients with MCTD there is an increased risk for atherosclerosis. In the development of atherosclerosis, besides the elevated levels of cholesterol and triglyceride, reduced PON concentrations and PON activity may play a crucial role.     

Circulating lupus type anticoagulant and pulmonary hypertension associated with mixed connective tissue disease

Summary We report the case of a young woman, with mixed connective tissue disease (MCTD), associated with disabling pulmonary hypertension and presence of the lupus anticoagulant. The lupus anticoagulant, an antibody directed against phospholipid components, was linked in our patient to extensive thrombophlebitis and premature labor. Raynaud's phenomenon progressed towards finger necrosis in spite of optimal vasodilating treatment. The part played by the lupus anticoagulant in pulmonary hypertension remains to be established. Both these complications responded to prednisolone therapy, but the improvement was limited and short-lived.     

Overlap syndromes and mixed connective tissue disease.

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 Sj?gren'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.     

Serum uric Acid as a prognostic predictor in pulmonary arterial hypertension with connective tissue disease

BACKGROUND: Pulmonary arterial hypertension (PAH) has been identified as a life threatening complication of connective tissue disease. However, the association between serum uric acid (UA) levels and long-term outcome in PAH with connective tissue disease has not been evaluated. We therefore assessed whether serum UA levels are related to the mortality of such patients. METHODS AND RESULTS: We investigated 90 consecutive patients with connective tissue disease who were initially diagnosed with PAH by echocardiography, and assessed the long-term clinical outcome in populations with higher (> or = 4.7 mg/dL) and lower serum UA levels. Kaplan-Meier analysis showed that patients with higher median serum UA values had a significantly worse survival rate for any cause of death (54.5% versus 84.7%, log-rank, P < 0.01) and PAH-related death (72.7% versus 93.4%, log-rank, P < 0.01) than those with low values. Multivariate analysis showed that an elevated serum UA level was an independent predictor for survival (hazard ratio, 1.88, 95% CI [1.24- 2.84], P < 0.01). CONCLUSION: Elevated serum UA levels are associated with a poor prognosis and can serve as a prognostic predictor for patients with PAH secondary to connective tissue disease.     

Anticyclic citrullinated peptide antibodies in patients with mixed connective tissue disease

Abstract

The clinical significance of anticyclic citrullinated peptide (CCP) antibodies in patients with mixed connective tissue disease (MCTD) was assessed. Altogether, 86 sera from MCTD patients, 96 from rheumatoid arthritis (RA) patients, 42 from systemic lupus erythematosus (SLE) patients, 23 from systemic sclerosis (SSc) patients, 21 from poymyositis/dermatomyositis (PM/DM) patients, and 17 from those with Sjögren’s syndrome (SjS) were tested for anti-CCP antibodies using an enzyme-lined immunosorbent assay. Among the 96 RA patients, anti-CCP antibodies were detected in 85%, with the frequency being significantly higher than in MCTD, SLE, SSc, PM/DM, and SjS patients (9%, 14%, 13%, 14%, and 18%, respectively; P < 0.001). Among eight MCTD patients who fulfilled the diagnostic criteria for RA, only 50% had anti-CCP antibodies, and the prevalence was significantly lower than for all RA patients (p < 0.01). All eight patients who fulfilled the criteria for RA had overlap of SLE and SSc, except one patient, whereas the four anti-CCP-positive patients who did not fulfill the criteria for RA had SjS without overlapping features of SLE and SSc; moreover, most of their antibody titers were low. These results suggested that anti-CCP antibodies are associated with RA in MCTD patients, but careful diagnosis of RA is required if patients with low titers of anti-CCP antibodies lack overlapping SLE and SSc.     

Anticyclic citrullinated peptide antibodies in patients with mixed connective tissue disease

The clinical significance of anticyclic citrullinated peptide (CCP) antibodies in patients with mixed connective tissue disease (MCTD) was assessed. Altogether, 86 sera from MCTD patients, 96 from rheumatoid arthritis (RA) patients, 42 from systemic lupus erythematosus (SLE) patients, 23 from systemic sclerosis (SSc) patients, 21 from poymyositis/dermatomyositis (PM/DM) patients, and 17 from those with Sjögrens syndrome (SjS) were tested for anti-CCP antibodies using an enzyme-lined immunosorbent assay. Among the 96 RA patients, anti-CCP antibodies were detected in 85%, with the frequency being significantly higher than in MCTD, SLE, SSc, PM/DM, and SjS patients (9%, 14%, 13%, 14%, and 18%, respectively; P < 0.001). Among eight MCTD patients who fulfilled the diagnostic criteria for RA, only 50% had anti-CCP antibodies, and the prevalence was significantly lower than for all RA patients (p < 0.01). All eight patients who fulfilled the criteria for RA had overlap of SLE and SSc, except one patient, whereas the four anti-CCP-positive patients who did not fulfill the criteria for RA had SjS without overlapping features of SLE and SSc; moreover, most of their antibody titers were low. These results suggested that anti-CCP antibodies are associated with RA in MCTD patients, but careful diagnosis of RA is required if patients with low titers of anti-CCP antibodies lack overlapping SLE and SSc.     

Free serum ribonucleoprotein in mixed connective tissue disease and other connective tissue diseases.

Free ribonucleoprotein (RNP) was found by means of a hemagglutination inhibition assay in 21 sera from 11 of 25 patients with mixed connective tissue disease (MCTD) who had 299 sera studied. Free RNP tended to appear when anti-RNP antibody titers fell or when prednisone was initiated or increased. Five of 72 SLE patients (211 sera) had free RNP in at least one serum. Three of them had anti-RNP antibodies in other sera. Free serum RNP was found in one of 20 patients with scleroderma and in two of seven patients with connective tissue disease "overlap" syndromes without anti-RNP.     

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.