The effects of xanthine oxidase inhibitor in patients with chronic heart failure complicated with hyperuricemia: a prospective randomized controlled clinical trial of topiroxostat vs allopurinol-study protocol.

BACKGROUND: Hyperuricemia has a close relationship with cardiovascular diseases including heart failure. However, it is controversial whether xanthine oxidase inhibition has benefits for patients with chronic heart failure. We designed the Effect of Xanthine Oxidase Inhibitor in Chronic Heart Failure Patients Complicated with Hyperuricemia study (Excited-UA study) to compare the beneficial effects between a novel xanthine oxidoreductase inhibitor, topiroxostat, and a conventional agent, allopurinol, in patients with chronic heart failure and hyperuricemia. We focus on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level, echocardiography-based cardiac function, vascular endothelial function, renal function, inflammation, and oxidative stress. METHODS: The excited-UA is a prospective, randomized, open-label, blinded-endpoint clinical trial designed to prove our hypothesis that topiroxostat is more effective than allopurinol in patients with chronic heart failure and hyperuricemia. A total of 140 patients with chronic heart failure and hyperuricemia (plasma brain natriuretic peptide level ≥ 40 pg/mL and serum uric acid level ≥ 7.0 mg/dL) are randomly assigned (ratio 1:1) into either the topiroxostat group (40-160 mg/day) or allopurinol group (100-300 mg/day), to achieve the target uric acid level of 6.0 mg/dL. According to the protocol, all patients are followed up annually for 24 weeks. The primary endpoint is percent change in serum NT-proBNP level at 24 weeks from baseline. CONCLUSIONS: The Excited-UA study would provide novel evidence for the clinical relevancy of xanthine oxidoreductase inhibitor treatment in patients with chronic heart failure and hyperuricemia.

Topiroxostat versus allopurinol in patients with chronic heart failure complicated by hyperuricemia: A prospective, randomized, open-label, blinded-end-point clinical trial.

BACKGROUND: The benefits of xanthine oxidase inhibitors to chronic heart failure (CHF) patients is controversial. We investigated the beneficial effects of a novel xanthine oxidoreductase inhibitor, topiroxostat, in patients with CHF and hyperuricemia (HU), in comparison to allopurinol. METHODS AND RESULTS: The prospective, randomized open-label, blinded-end-point study was performed in 141 patients with CHF and HU at 4 centers. Patients were randomly assigned to either topiroxostat or allopurinol group to achieve target uric acid level ≤6.0 mg/dL. According to the protocol, 140 patients were followed up for 24 weeks. Percent change in ln (N-terminal-proB-type natriuretic peptide) at week 24 (primary endpoint) was comparable between topiroxostat and allopurinol groups (1.6±8.2 versus -0.4±8.0%; P = 0.17). In the limited number of patients with heart failure with reduced ejection fraction (HFrEF) (left ventricle ejection fraction <45%), ratio of peak early diastolic flow velocity at mitral valve leaflet to early diastolic mitral annular motion velocity (E/e') decreased in topiroxostat group, but not in allopurinol group. Urinary 8-hydroxy-2'-deoxyguanosine and L-type fatty acid-binding protein levels increased and osmolality decreased significantly in allopurinol group, while these changes were less or absent in topiroxostat group. In allopurinol group HFrEF patients, additional to the increases in these urinary marker levels, urinary creatinine levels decreased, with no change in clearance, but not in topiroxostat group. CONCLUSIONS: Compared with allopurinol, topiroxostat did not show great benefits in patients with CHF and HU. However, topiroxostat might have potential advantages of reducing left ventricular end-diastolic pressure, not worsening oxidative stress in proximal renal tubule, and renoprotection over allopurinol in HFrEF patients.

Two-dimensional analysis of elements and mononuclear cells in hard metal lung disease.

RATIONALE: Hard metal lung disease is caused by exposure to hard metal, a synthetic compound that combines tungsten carbide with cobalt as well as a number of other metals. Interstitial lung disease caused by hard metal is uniquely characterized by giant cell interstitial pneumonia. The pathogenesis of hard metal lung disease is unclear. OBJECTIVES: To elucidate the distribution of inhaled hard metal and reactive inflammatory cells in biopsy lung tissue from patients with hard metal lung disease. METHODS: Seventeen patients with interstitial lung disease in which tungsten was detected and five control subjects were studied. Detection and mapping of elements were performed with an electron probe microanalyzer equipped with a wavelength dispersive spectrometer. We immunohistochemically stained mononuclear cells, in tissue samples available from five patients, with anti-human CD4, CD8, CD20, CD68, and CD163 antibodies, and compared the distribution of positive cells with hard metal elements. MEASUREMENTS AND MAIN RESULTS: Thirteen of 17 patients were pathologically diagnosed as having giant cell interstitial pneumonia. Tungsten and cobalt were accumulated in the centrilobular fibrotic lesions, but were never found in the control lungs. CD8+ lymphocytes and CD163+ monocyte-macrophages were distributed predominantly in centrilobular fibrotic lesions around the hard metal elements. CD163+ colocalized with tungsten. Small numbers of CD8+ and CD163+ cells were also immunohistochemically shown in peribronchiolar areas and alveolar walls. CONCLUSIONS: Macrophages may phagocytose inhaled tungsten via CD163 and play an important role in forming the fibrotic lesion of hard metal lung disease with cytotoxic T lymphocytes.

Non-paraneoplastic autoimmune subepidermal bullous disease associated with fatal bronchiolitis obliterans.

Bronchiolitis obliterans is a small-airway obstructive lung disease for which immunologically mediated pathogenesis is supposed. Frequent association of bronchiolitis obliterans with paraneoplastic pemphigus is well known, but its association with other autoimmune bullous diseases has not been reported except for a case of anti-laminin-332-type mucous membrane pemphigoid in a patient with chronic graft-versus-host disease. We report a case of non-paraneoplastic autoimmune subepidermal bullous disease associated with fatal bronchiolitis obliterans in a patient without transplantation. Although the patient's serum contained immunoglobulin (Ig)A antibodies to the 180-kDa bullous pemphigoid antigen/type XVII collagen and IgG antibodies to laminin-332, diagnosis of either linear IgA bullous dermatosis or mucous membrane pemphigoid could not be made because of the failure to detect linear IgA deposition at the basement membrane zone by direct immunofluorescence and the lack of mucous membrane lesions. Physicians should be aware that autoimmune bullous diseases other than paraneoplastic pemphigus can also associate with this rare but potentially fatal lung disease.

Inflammatory cells in lung disease associated with rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with numerous pulmonary manifestations. However, the inflammatory mechanism remains undetermined. We studied the features of inflammatory cells in bronchoalveolar lavage (BAL) fluid and biopsy lung tissue from patients with RA-associated lung disease. METHODS: BAL findings were statistically compared between diseases. We divided RA patients into two groups, airway lesion group (AW) and interstitial lesion group (INT) according to predominant HRCT findings and compared the BAL findings. We immunohistochemically stained lung tissue for CD4, CD8, CD20, and CD163 and counted the immunopositive cells in five different regions. PATIENTS: Twenty patients fulfilling the Japanese criteria for RA, 13 patients with systemic sclerosis (SSc), and 21 patients with polymyositis and dermatomyositis (PM-DM) with pulmonary disease detected by high-resolution CT (HRCT) were enrolled in this study. RESULTS: As for BAL in RA, we found a lower lymphocyte frequency with higher CD4/8 ratio compared with PM-DM and a higher neutrophil percentage than both PM-DM and SSc. Nine and eleven patients with RA were classified into AW and INT groups, respectively. BAL findings did not differ between the two groups. Immunohistochemically, most CD4(+) and CD20(+) lymphocytes were accumulated in lymphoid follicles and in the alveolar wall and T-lymphocytes; in particular CD8(+) lymphocytes were predominant in lung interstitium. CONCLUSION: These results suggest that 1) neutrophils may play an important role, 2) the inflammatory mechanism may be similar between airway lesion and interstitial pneumonia, and 3) CD8(+) lymphocytes may be major inflammatory cells in lung interstitium in RA-associated interstitial lung disease.

Isolation and immunophenotyping of mononuclear cells from human lung tissue.

OBJECTIVE: To quantitatively isolate and immunologically phenotype mononuclear cells contained in human lung tissue. METHODS: Normal appearing lung tissue as far distal to the resected lesion as possible was obtained from lung cancer patients. Lung tissue was thoroughly washed and cut into small pieces and digested with collagenase. Peripheral blood mononuclear cells (PBMNC) were prepared from controls using Ficoll gradient. Isolated cells and PBMNC were analyzed by flow cytometry. We immunohistochemically stained snap-frozen lung tissue with anti-CD3, CD4, CD8, CD20, and CD161 antibodies. PARTICIPANTS: Nineteen patients with lung cancer who underwent lobectomy were enrolled. Twelve healthy volunteers also participated as controls for flow cytometric analysis of PBMNC. RESULTS: In forward scatter vs side scatter, 92.1+/-7.8% of isolated cells in the lymphoid population expressed leukocyte common antigen, CD45. The frequency of CD45-positive cells in the lymphoid population from lung tissue was as high as that from PBMNC (p=0.118). CD45-positive cells were successfully further extended by anti-CD3, CD4, CD8, CD19, and CD161 antibodies. Monocyte-macrophages bearing CD68 were also detected. CD68-positive alveolar macrophages disappeared from alveolar spaces after thorough washing by immunohistochemical staining. Mononuclear cells in the interstitium were positively stained by anti-CD3, CD4, CD8, CD20, and CD161 monoclonal antibodies. CONCLUSIONS: We could isolate interstitial cells and analyze cell surface markers via flow cytometry from fresh lung specimens by collagenase digestion without further purification. Immunohistochemistry confirmed the presence of the cells detected by flow cytometry in the lung interstitium.

Analysis of the effect of surgical lung biopsy on serum KL-6 Levels in patients with interstitial pneumonia: surgical lung biopsy does not elevate serum KL-6 levels.

OBJECTIVE: It is well known that the serum level of KL-6 can be an indicator of disease activity in patients with interstitial pneumonia (IP). However, surgical lung biopsy is often required for the diagnosis of IP, although this can result in IP exacerbation. METHODS: The effect of surgical lung biopsy on the serum level of KL-6 in patients with IP was analyzed. Thirty-two cases of IP were examined in this study. There were no cases showing exacerbation of IP. RESULTS: The serum level of KL-6 demonstrated 1067+/-550 U/ml (mean+/-SD) before lung biopsy, 991+/-471 U/ml a day, 824+/-377 U/ml 4 days and 826+/-384 U/ml 7 days after lung biopsy. The serum KL-6 levels on the 1st, 4th, 7th day after the lung biopsy were significantly lower than that before the lung biopsy (P<0.05, P<0.01 and P<0.01, respectively). The percent decrease of the serum KL-6 levels on the 4th day (the lowest level) was dependent on the urine volume, and the analysis of the urinary levels of KL-6 showed a transient increase in urinary KL-6 excretion, suggesting that the decrease in serum KL-6 levels associated with surgical lung biopsy may be caused by this increase in urinary KL-6 excretion. CONCLUSION: Surgical lung biopsy of patients with IP has little effect on the increase in serum KL-6 levels. An elevation of serum KL-6 after surgical lung biopsy may indicate exacerbation of IP.

Pulmonary artery involvement in Takayasu's arteritis with lung infarction and pulmonary aspergillosis.

We describe a patient with a chronic case of pulmonary involvement of Takayasu's arteritis in the resected lung. A 49-year-old woman was first diagnosed with Takayasu's arteritis at age 30 years. On her first admission, she presented with Takayasu's arteritis and pneumonia with cavitation in the left lung. After recovering from pneumonia, she was treated initially with prednisolone, 30 mg/day, and remained well until she developed hemoptysis at age 34 years. Findings suggesting aspergilloma were found in the same lobe on chest x-ray film when she was 46 years of age. By age 49 years, the hemoptysis became massive, and she was admitted for surgery. Left upper lobectomy and partial resection of S6 and S8 pulmonary segments were performed. Histologic analysis of the resected lung revealed typical pathologic findings of pulmonary artery involvement in Takayasu's arteritis, such as stenosis recanalization and a vessel-in-vessel feature, but not active vasculitis. Infection probably occurred in the cavity of the infarcted tissue. Pulmonary artery involvement is common in Takayasu's arteritis, but the aspergilloma in this corticosteroid-treated patient is an uncommon complication.