mocetinostat and Lung-Diseases--Interstitial

This review provides an update on recent advances in the diagnosis, pathogenesis, clinical presentation, histopathological findings, and treatment approaches for antineutrophil cytoplasmic antibody (ANCA) vasculitis-associated interstitial lung disease (AAV-ILD) with a focus on literature published in the last 3 years.. Although there is no validated definition of AAV-ILD, which contributes to some of the heterogeneity seen in study results, there has been an increasing number of publications in recent years on this topic. Most patients with AAV-ILD have MPO-ANCA vasculitis, and this association appears to reduce their 5-year-survival to 60-66% (Sun et al. BMC Pulm Med 21(1), 2021, Maillet et al. J Autoimmun 106, 2020). Median age of diagnosis ranges from mid-60 s to mid-70 s (Ando et al. Respir Med 107(4), 2013), Kagiyama et al. BMJ Open Respir Res 2(1):1-9, 2015, Hozumi et al. Lung 194(2):235-42, 2016, Liu et al. Chest 156(4):715-23, 2019, Maillet et al. J Autoimmun 106, 2020, Wurmann et al. Sarcoidosis Vasc Diffuse Lung Dis 37(1):37-42, 2020, Watanabe et al. BMC Pulm Med 19(1), 2019). Computed tomography (CT) chest imaging for patients with AAV-ILD often shows a usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) pattern (12-58% and 13-61%, respectively) (Sun et al. BMC Pulm Med 21(1), 2021, Maillet et al. J Autoimmun 106, 2020, Wurmann et al. Sarcoidosis Vasc Diffuse Lung Dis 37(1):37-42, 2020, Watanabe et al. BMC Pulm Med 19(1), 2019, Baqir at al. Sarcoidosis Vasc Diffuse Lung Dis Off J WASOG 36(3):195-201, 2019). Additionally, lung biopsies typically do not demonstrate active inflammation, or capillaritis, questioning whether these patients should be treated with either immunotherapy or anti-fibrotic therapy, or both (Hozumi et al. Lung 194(2):235-42, 2016, Liu et al. Chest 156(4):715-23, 2019, Kitching at al. Nat Rev Dis Prim 6(1):71, 2020, Tanaka et al. Respir Med 106(12):1765-70, 2012). Besides immunosuppressive treatments, recent advances in anti-fibrotic therapy may offer patients with progressive AAV-ILD an alternative and/or more effective and individualized treatment option.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Lung; Lung Diseases, Interstitial; Peroxidase; Sarcoidosis

Myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibodies (ANCA) are often detected in association with a variety of lung pathologies, the most common being interstitial lung disease (ILD). A growing cohort of patients are being diagnosed with MPO-ANCA in the context of ILD without ANCA-associated vasculitis. Clinically and radiologically, there is little to differentiate this cohort from MPO-ANCA-negative ILD patients; however, the pathophysiology is likely different and different treatments are likely required. We present here a brief summary of the proposed pathophysiology of MPO-ANCA-positive ILD, and a more detailed review of the latest evidence on management, including monitoring for development of ANCA-associated vasculitis, immunosuppression, anti-fibrotics, and novel agents that have yet to be trialled in human experiments.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antifibrotic Agents; Humans; Immunosuppression Therapy; Lung Diseases, Interstitial; Peroxidase

Over the past three decades, an increasing number of publications have reported the association between interstitial lung disease (ILD) and anti-neutrophil cytoplasmic antibody (ANCA) or ANCA-associated vasculitis (AAV). With this increased awareness, we have reviewed the literature to date and provide an update in this narrative review. The vast majority of cases of ILD have been shown to be in the setting of positive anti-myeloperoxidase antibody and can be present in up to 45% of patients of microscopic polyangiitis, though cases of ILD associated with proteinase 3 ANCA have rarely been reported. Pulmonary fibrosis and ANCA positivity can occur with or without systemic involvement. The pathogenetic mechanisms establishing the relationship between ANCA and the development of pulmonary fibrosis remain unclear. Histologic and radiographic features of ANCA-ILD most commonly reveal usual interstitial pneumonia or non-specific interstitial pneumonia patterns, though other atypical features such as bronchiolitis have been described. ILD in the setting of AAV has been associated with worse outcomes, and thus early identification and treatment in these patients is appropriate. We advocate that ANCA antibody testing be performed as a baseline evaluation in patients presenting with idiopathic interstitial pneumonia. Suggested treatment of ANCA-ILD includes immunosuppression and/or antifibrotic agents, though supporting data and clinical trials to substantiate use of these therapies are needed.

Topics: Antibodies, Antineutrophil Cytoplasmic; Humans; Idiopathic Pulmonary Fibrosis; Lung; Lung Diseases, Interstitial; Peroxidase

We report a 54-year-old woman with systemic sclerosis who presented alveolar hemorrhage. She noticed shortness of breath in May 1997. She was diagnosed having interstitial pneumonitis and systemic sclerosis with sclerodactylia of bilateral fingers in December. She developed bloody sputum and dyspnea suddenly on March 12, 1999. Bloody lavage fluid with hemosiderin-laden macropharge was observed by bronchial fiber scopic examination. The elevated level of MPO-ANCA was detected without anti-DNA antibody. Administration of intravenous methylprednisolone(1g per day, 3 days) followed by 40 mg per day of prednisolone achieved complete response, and MPO-ANCA level was decreased. Mild proteinuria and microhematuria was detected on admission, but renal biopsy revealed no findings of crescent formation or angiitis. With coadministration of oral cyclophosphamide she doesn't have any renal involvement or recurrence of alveolar hemorrhage during these four years. MPO-ANCA level remains negative. Alveolar hemorrhage, which is uncommon pulmonary event in systemic sclerosis, is often coexist with renal angiitis in the context of "pulmo-renal syndrome". MPO-ANCA is said to be related to pulmo-renal syndrome and is sometimes induced by D-penicillamine. This patient is really important in considering the pathogenesis of alveolar hemorrhage because she had no renal vasculitic lesions or D-penicillamine intake.

Topics: Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Chronic Disease; Female; Hemorrhage; Humans; Kidney Diseases; Lung Diseases; Lung Diseases, Interstitial; Middle Aged; Peroxidase; Prednisolone; Pulmonary Alveoli; Scleroderma, Systemic; Treatment Outcome

A 68-year-old man who developed MPO-ANCA-associated glomerulonephritis during propylthiouracil (PTU) treatment is reported. In 1986, he was diagnosed as having interstitial pneumonitis. Although he tested positive for antinuclear antibody and rheumatoid factor, he had no symptoms and was followed up without therapy. Five years later, the diagnosis of Graves's disease was made after complaints of body weight loss, diplopia and exophthalmos. Tests showed positivity for anti-thyroid stimulating hormone (TSH) receptor antibody, antithyroidperoxidase antibody and antithyroglobulin antibody. He was treated with PTU and prednisolone for four years. In November 1995, hematuria and proteinuria developed, and renal function deteriorated rapidly. A renal biopsy revealed crescentic glomerulonephritis and the serum titer of MPO-ANCA was markedly elevated. He was treated with a high dose of prednisolone and cyclophosphamide. Although the serum creatinine level gradually decreased, irreversible renal dysfunction persisted. In this patient, the presence of various autoantibodies had been recognized for several years before MPO-ANCA-associated glomerulonephritis developed. Polyclonal B-cell activation and PTU treatment may have played a role in the pathogenesis of MPO-ANCA-associated glomerulonephritis.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Glomerulonephritis; Graves Disease; Humans; Lung Diseases, Interstitial; Male; Peroxidase; Propylthiouracil

To evaluate the prevalence, clinical and radiographic features, and long-term outcomes of interstitial lung disease (ILD) in a United States-based ANCA-associated vasculitis (AAV) cohort.. In this retrospective cohort study, we identified cases of ILD within the 2002-2019 Mass General Brigham AAV Cohort, a consecutive inception cohort of PR3- or MPO-ANCA+ AAV patients. ILD diagnosis and classification as fibrotic or non-fibrotic were confirmed by review of available chest imaging by two board-certified radiologists. Cox proportional hazard models, with age as the time scale, were used to estimate the association of AAV-ILD with all-cause mortality.. Of 684 patients in the MGB AAV Cohort, 91 (13%) had ILD which preceded the diagnosis of AAV by a mean of 2.2 years. AAV-ILD patients were older (67 vs 60 years, P < 0.001) than patients without ILD but the distribution of sex and race was similar. AAV-ILD patients were more often MPO-ANCA+ (93% vs 65%, P < 0.001); among MPO-ANCA+ patients (n = 470), 85 (18%) had ILD. The majority of ILD was fibrotic (76%) and UIP was the most common ILD pattern (42%). The baseline forced vital capacity (FVC) % predicted among ILD patients was 81 ± 20%. Fibrotic AAV-ILD was associated with a 58% higher risk of death (aHR 1.58, 95% CI 1.06, 2.37) compared with AAV patients without ILD.. ILD is a frequent complication of AAV, especially MPO-ANCA+ AAV, often preceding recognition of AAV. Fibrotic AAV-ILD is associated with a higher risk of death than AAV without ILD.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Lung Diseases, Interstitial; Peroxidase; Retrospective Studies

Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and idiopathic interstitial lung diseases (IIPs) are positive for myeloperoxidase (MPO)-ANCA. MPO-ANCA-positive vasculitis mainly comprises microscopic polyangiitis (MPA) and unclassifiable vasculitis. These diseases are frequently complicated by interstitial lung disease (ILD). Few studies have reported the clinical differences between the subtypes of MPO-ANCA-positive ILD. Therefore, this study aimed to examine the clinical findings and courses of MPO-ANCA-positive ILD.. This retrospective study enrolled 100 patients with MPO-ANCA-positive ILD who were categorized into three groups: MPA (n = 44), unclassifiable vasculitis (n = 29), and IIP (n = 27). Our study compared the clinical findings and prognosis of these patients and analyzed the poor prognostic factors. Furthermore, we assessed the association between the patients with and without acute exacerbation of ILD (AE-ILD).. Our study found clinical differences in serum markers, clinical symptoms, and treatment regimens among the three groups. ILD complications, as the main cause of death, differed among the three groups (P = 0.04). Patients with unclassifiable vasculitis showed higher survival rates than those with IIP (P = 0.046). Patients with AE-ILD showed fewer general symptoms (P = 0.02) and lower survival rates (P < 0.01) than those without AE-ILD. In multivariate analysis, AE-ILD development was a strong poor prognostic factor for MPO-ANCA-positive ILD.. The subtypes of MPO-ANCA-positive ILD have different clinical features and prognoses. Patients who develop AE-ILD require careful evaluation of clinical courses. Key Points • In myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive interstitial lung disease (ILD), patients with unclassifiable vasculitis showed a better prognosis than those with idiopathic ILD.. • Development of acute exacerbation in ILD was a strong poor prognostic factor in patients with MPO-ANCA-positive ILD..

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Lung Diseases, Interstitial; Microscopic Polyangiitis; Peroxidase; Retrospective Studies

Interstitial lung disease (ILD) has been described as a possible pulmonary involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV), mainly granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Aim of this cross-sectional Italian national study was to describe demographic, clinical and serological profile of ILD related to MPA and GPA and investigate possible correlations between radiologic patterns of ILD and vasculitis features.. We enrolled 95 consecutive patients with AAV-ILD, 56 affected by MPA (58.9%) and 39 by GPA (41.1%).. NSIP was the most frequently detected ILD pattern, observed in c-ANCA patients in 60.9% of cases, followed by UIP pattern mainly observed in p-ANCA patients (47.7%, p=0.03). ILD represented the first clinical manifestation, preceding vasculitis diagnosis in 22.1% of cases and, globally, ILD was already detectable at AAV diagnosis in 66.3% of patients. The diagnosis of ILD preceded that of AAV in 85.7% of p-ANCA positive-patients, while only one patient with c-ANCA developed ILD before AAV (p= 0.039). Multivariate analysis confirmed the correlation of UIP pattern with p-ANCA-positivity and a diagnosis of ILD before AAV, also when adjusted for age and sex.. Our study confirms that UIP is a frequent pattern of lung disease in AAVILD patients. Our results also suggest that ILD can represent an early complication of AAV but also occur in the course of the disease, suggesting the need of a careful evaluation by both pulmonologist and rheumatologist to achieve an early diagnosis. Further prospective studies are needed to define ILD prevalence and evolution in AAV patients.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cross-Sectional Studies; Demography; Granulomatosis with Polyangiitis; Humans; Lung Diseases, Interstitial; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Rheumatology

To explore in myeloperoxidase-antineutrophil cytoplasmic autoantibody-associated vasculitis (MPO-AAV) the value of circulating oncomarkers in identifying interstitial lung disease (ILD) and predicting prognosis.. Newly diagnosed MPO-AAV patients were evaluated retrospectively at a single center. The serum levels of carbohydrate antigen (CA) 19-9, CA125, cytokeratin fraction 21-1 (CYFRA21-1), carcinoembryonic antigen, squamous cell carcinoma antigen, and neuron-specific enolase were compared between patients with and without ILD. The strength of the oncomarkers in identifying ILD was assessed through logistic regression and receiver operating characteristic (ROC) curves. Correlation analysis was applied to detect the associations between oncomarkers and ILD severity. The significance of serum oncomarkers as prognosis predictors for MPO-AAV associated ILD was evaluated by survival analysis.. 169 MPO-AAV patients were included and ILD was found in 101 patients. Serum CA125, CA19-9, and CYFRA21-1 were significantly higher in patients with ILD than those without ILD. The area under the ROC curve of CA19-9, CA125, and CYFRA21-1 for identifying ILD was 0.701, 0.660, and 0.711, respectively. A specificity of 98.5% for diagnosing ILD was found for CA19-9 at the recommended normal level. CA19-9 was positively correlated with HRCT fibrosis score (r = 0.498, p < 0.001) and CYFRA21-1 was correlated with ground-glass score (r = 0.316, p = 0.002). Both CA19-9 and CYFRA21-1 were independent risk factors for all-cause mortality in patients with ILD.. Serum CA19-9 and CYFRA21-1 might be useful markers in the diagnosis, disease severity evaluation, and prognosis prediction of MPO-AAV-associated ILD.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antigens, Neoplasm; CA-125 Antigen; CA-19-9 Antigen; Humans; Keratin-19; Lung Diseases, Interstitial; Peroxidase; Prognosis; Retrospective Studies; Vasculitis

Antisynthetase syndrome (ASS) and dermatomyositis (DM) are serious autoimmune diseases, with lungs being the most frequently involved organ and sometimes fatal. This study is aimed at clarifying the role of neutrophil-associated biological markers in suggesting ASS and DM-associated respiratory infections and interstitial lung diseases.. We carried out a retrospective review of the medical records of 46 cases of ASS and DM diagnosed at the Second Hospital of Zhejiang University College of Medicine, between January 2017 and December 2020. Serum myeloperoxidase (MPO), neutrophil elastase (NE),. Gottron's sign is characteristic of dermatomyositis, while polyarthritis is more characteristic of ASS. Pulmonary function is worse in ASS than in DM patients. Patients with ASS and DM had abnormal lymphocyte and neutrophil counts compared to healthy subjects, but not in relation to lung function and rapid progression of interstitial lung disease (RP-ILD). Elevated serum NE, MPO, and IL-6 levels are suggestive of respiratory infections, whereas decreased circulating IL-6 is predictive of RP-ILD.. Our study identified the neutrophil-associated biomarkers MPO, NE, and IL-6 as promising indicators with different suggestive roles in respiratory infections and interstitial lung diseases in patients with ASS and DM.

Topics: Biomarkers; Dermatomyositis; Humans; Interleukin-6; Leukocyte Elastase; Lung Diseases, Interstitial; Myositis; Neutrophils; Peroxidase; Respiratory Tract Infections; Retrospective Studies

Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is often positive in patients with interstitial lung disease (ILD), which is also often present in patients with microscopic polyangiitis (MPA). A possible association between MPO-ANCA, MPA, and idiopathic ILD remains unclear. The objective of this study was to determine whether high-resolution computed tomography (HRCT) classification based on recent idiopathic pulmonary fibrosis guideline and specific CT findings can obtain new knowledge of prognostic factors in all MPO-ANCA-positive patients with ILD including both idiopathic ILD and MPA-ILD.. We analyzed 101 consecutive MPO-ANCA-positive patients with respiratory disease. We assessed the diagnostic accuracy of CT findings, HRCT pattern, and specific radiological signs. Prognostic predictors were determined using Cox regression models.. Subjects with chronic ILD included 22 patients with MPA-ILD and 39 patients with ILD but without MPA. A quarter of the patients were radiological indeterminate for usual interstitial pneumonia (UIP) pattern, which resulted in a better prognosis than that for UIP pattern. "Increased attenuation around honeycomb and traction bronchiectasis" and "anterior upper lobe honeycomb-like lesion" were found to be highly frequent radiological findings (39% and 30%, respectively). In addition, the latter finding was a significant negative prognostic factor.. Radiological indeterminate for UIP was a useful HRCT classification in MPO-ANCA-positive patients with ILD. In addition, anterior upper lobe honeycomb-like lesion was found to be specific radiological finding that was a significant prognostic factor. The present results might aid in the assessment of appropriate strategies of diagnosis in these patients.

Topics: Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Chronic Disease; Female; Humans; Idiopathic Pulmonary Fibrosis; Japan; Lung Diseases, Interstitial; Male; Middle Aged; Peroxidase; Prognosis

The prognosis of microscopic polyangiitis (MPA) with interstitial lung disease (ILD) is significantly worse than that of MPA without ILD. However, the clinical characteristics in MPA-ILD, especially poor prognostic factors, are not elucidated. We evaluated demographic, clinical, laboratory, and radiological findings, treatments, and outcomes of 80 patients with MPA, and investigated prognostic factors of respiratory-related death in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) positive MPA-ILD. Ground-glass opacity and fibrosis were evaluated as scores on high-resolution computed tomography (HRCT). The presence of ILD was consistent with a high risk of respiratory-related death (hazard ratio, 4.8; P = 0.04). Multivariable logistic regression analyses using propensity scoring showed right or left lower lobe fibrosis score to be significantly associated with respiratory-related death (P = 0.0005 and 0.0045, respectively). A right or left lower lobe fibrosis score ≥ 2, indicating the presence of honeycombing at 1 cm above the diaphragm, was determined to be the best cut-off value indicating a poor prognosis. The 5-year survival rate was significantly lower in patients with right or left lower lobe fibrosis score ≥ 2 (survival rates: 37% and 19%, respectively) than those with a score < 2 (71% and 68%, respectively) (P = 0.002 and 0.0007, respectively). These findings suggest that the presence of honeycomb lesions in bilateral lower lobes on chest HRCT was associated with respiratory-related death in patients with MPO-ANCA positive MPA-ILD.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Japan; Lung; Lung Diseases, Interstitial; Male; Microscopic Polyangiitis; Peroxidase; Prognosis; Proportional Hazards Models; Retrospective Studies; Survival Rate; Tomography, X-Ray Computed

Polyangiitis overlap syndrome (POS) is a diagnostic term coined by Leavitt and Fauci that characterises patients with overlapping features of more than one vasculitis. Prior case studies of antineutrophil cytoplasmic antibodies (ANCA)-associated POS have only been published in patients with eosinophilic granulomatosis with polyangiitis (EGPA) and granulomatosis with polyangiitis alongside proteinase-3/cytoplasmic (C)-ANCA positivity. We present a case of a 60-year-old woman with dyspnoea, hemoptysis, positive perinuclear-ANCA and renal biopsy demonstrating evidence of microscopic polyangiitis. In addition, our patient also had asthma, mononeuritis multiplex, eosinophilia and migratory pulmonary infiltrates, thus fulfilling the criteria for EGPA. This novel case report suggests that POS is not limited to C-ANCA positivity and has variable presentations.

Topics: Antibodies, Antineutrophil Cytoplasmic; Azathioprine; Churg-Strauss Syndrome; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Microscopic Polyangiitis; Middle Aged; Mononeuropathies; Peroxidase; Prednisone; Renal Insufficiency, Chronic; Tomography, X-Ray Computed

The concept of otitis media with ANCA-associated vasculitis (OMAAV) was recently proposed by the study group of the Japan Otological Society. However, little is known about the effect of ear involvement on the clinical features and prognosis of AAV. We investigate this issue in this study.. We retrospectively examined 36 patients diagnosed with OMAAV and 44 patients diagnosed with AAV without ear involvement (non-OMAAV) at Ehime University Hospital from 2013 to 2018. We collected serological findings including ANCA type and titer, C-reactive protein (CRP), serum creatinine level, organ involved at initial diagnosis, treatment, remission, disease relapse, and mortality from medical records. We investigated whether clinical features and outcomes differed between the OMAAV and non-OMAAV groups.. Age, ANCA titer, and CRP at initial diagnosis were not significantly different between the two groups, and the rate of intravenous cyclophosphamide (IVCY) use also did not differ. The proportions of patients with concurrent eye involvement, facial palsy (FP), and hypertrophic pachymeningitis (HCP) were significantly higher in the OMAAV than in the non-OMAAV group (p = 0.005, 0.005 and 0.049, respectively), while both renal and peripheral nerve involvement were significantly less common in OMAAV patients (p = 0.04). Among the 30 patients with renal involvement, serum creatinine level at diagnosis was significantly lower in the OMAAV group (p = 0.04). The mortality rate was 8.3% in OMAAV and 6.8% in non-OMAAV cases, but this difference was not significant. The rate of relapse was 33.3% in OMAAV and 13.6% in non-OMAAV cases; this difference was significant (p = 0.04).. Serological measurements of disease activity did not differ between the groups. Eye involvement, FP, and HCP, however, were significantly more common in AAV with ear involvement. In addition, renal involvement was less common and renal impairment was milder in AAV with ear involvement. These findings can be considered clinical features. The relapse rate was significantly higher in AAV with ear involvement.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; C-Reactive Protein; Cyclophosphamide; Eye Diseases; Facial Paralysis; Female; Glucocorticoids; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Diseases; Lung Diseases, Interstitial; Male; Meningitis; Methylprednisolone; Myeloblastin; Otitis Media; Peripheral Nervous System Diseases; Peroxidase; Prognosis; Rituximab

We investigated the clinical implication of ANCA positivity at diagnosis on the poor outcomes in patients with Sjögren's syndrome. The medical records of 606 Korean patients with Sjögren's syndrome were retrospectively reviewed. The results of perinuclear (P)-ANCA, myeloperoxidase (MPO)-ANCA, cytoplasmic (C)-ANCA, and proteinase 3 (PR3)-ANCA were collected and the frequencies of all-cause mortality, interstitial lung disease (ILD), end-stage renal disease (ESRD), and lymphoma were assessed as the poor outcomes of Sjögren's syndrome. Comparison of the cumulative patient survivals between the two groups was analysed by the Kaplan-Meier survival analysis. Of the 606 patients, ANCA was detected in 10.2% of Sjögren's syndrome patients without AAV. Twenty-one patients (3.5%) died, 99 patients (16.3%) suffered from ILD, and 8 patients had ESRD. Lymphoma occurred in 5 patients (0.8%) during 37.5 months. Sjögren's syndrome patients with ANCA positivity exhibited a lower cumulative ILD-free survival rate than those with ANCA negativity (P = 0.001). Sjögren's syndrome patients with P-ANCA positivity and those with MPO-ANCA (or P-ANCA) positivity showed a lower cumulative ILD-free survival rate than those without (P = 0.012 and P < 0.001). Also, Sjögren's syndrome patients with P-ANCA positivity exhibited a lower cumulative ESRD-free survival rate than those without (P = 0.043). ANCA positivity was associated with neither all-cause mortality nor lymphoma in Sjögren's syndrome patients. ANCA positivity and MPO-ANCA (or P-ANCA) positivity at diagnosis was associated with the development of ILD during follow-up in patients with Sjögren's syndrome.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Cause of Death; Female; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Lung Diseases, Interstitial; Lymphoma; Male; Middle Aged; Mortality; Myeloblastin; Peroxidase; Prognosis; Republic of Korea; Retrospective Studies; Sjogren's Syndrome

Damage to the vascular endothelium is strongly implicated in the pathogenesis of idiopathic inflammatory myopathies (IIM). Normally, high-density lipoprotein (HDL) protects the vascular endothelium from damage from oxidized phospholipids, which accumulate under conditions of oxidative stress. The current work evaluated the antioxidant function of HDL in IIM patients.. HDL's antioxidant function was measured in IIM patients using a cell-free assay, which assesses the ability of isolated patient HDL to inhibit oxidation of low-density lipoproteins and is reported as the HDL inflammatory index (HII). Cholesterol profiles were measured for all patients, and subgroup analysis included assessment of oxidized fatty acids in HDL and plasma MPO activity. A subgroup of IIM patients was compared with healthy controls.. The antioxidant function of HDL was significantly worse in patients with IIM (n = 95) compared with healthy controls (n = 41) [mean (S.d.) HII 1.12 (0.61) vs 0.82 (0.13), P < 0.0001]. Higher HII associated with higher plasma MPO activity [mean (S.d.) 13.2 (9.1) vs 9.1 (4.6), P = 0.0006] and higher oxidized fatty acids in HDL. Higher 5-hydroxyeicosatetraenoic acid in HDL correlated with worse diffusion capacity in patients with interstitial lung disease (r = -0.58, P = 0.02), and HDL's antioxidant function was most impaired in patients with autoantibodies against melanoma differentiation-associated protein 5 (MDA5) or anti-synthetase antibodies. In multivariate analysis including 182 IIM patients, higher HII was associated with higher disease activity and DM diagnosis.. The antioxidant function of HDL is abnormal in IIM patients and may warrant further investigation for its role in propagating microvascular inflammation and damage in this patient population.

Topics: Adult; Aged; Amino Acyl-tRNA Synthetases; Autoantibodies; Case-Control Studies; Chromatography, Liquid; Dermatomyositis; Endothelium, Vascular; Fatty Acids; Female; Glucocorticoids; Humans; Hydroxyeicosatetraenoic Acids; Immunologic Factors; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lipoproteins, HDL; Lipoproteins, LDL; Lung Diseases, Interstitial; Male; Middle Aged; Myositis; Myositis, Inclusion Body; Oxidation-Reduction; Peroxidase; Polymyositis; Pulmonary Diffusing Capacity; Spectrometry, Mass, Electrospray Ionization

To describe the clinical and serological patients characteristics with Microscopic Polyangiitis (MPA) and Interstitial lung disease (ILD).. Of all the patients with AAV diagnosed between 2007-2017 at the Hospital Clinico Universidad de Chile, those with MPA and ILD were selected and studied retrospectively.. All patients were Hispanic; median age at diagnosis 65 years (32-84). 59% were female. All were positive for p-ANCA, 16 patients for MPO. Most common manifestations were constitutional symptoms, weight loss and fever. CT-Scans patterns were Usual Interstitial Pneumonia (UIP) in 10 patients, Nonspecific Interstitial Pneumonia (NSIP) in 6 and fibrosis not UIP or NSIP pattern in 1. In 6 cases, ILD was diagnosed 0.5-14 years before MPA and concomitantly in 11.. Although infrequent, Microscopic Polyangiitis should be suspected in patients with ILD particularly if extra-pulmonary manifestations that rise the possibility of a systemic illness are present, regardless of the time elapsed between the latter and the diagnosis of this type of lung involvement.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Chile; Female; Humans; Lung Diseases, Interstitial; Male; Microscopic Polyangiitis; Middle Aged; Peroxidase; Predictive Value of Tests; Prognosis; Retrospective Studies; Serologic Tests; Tomography, X-Ray Computed

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Female; Hemorrhage; Humans; Lung Diseases, Interstitial; Male; Microscopic Polyangiitis; Middle Aged; Peroxidase

The association between interstitial lung disease (ILD) and myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCAs) has been described, but pathologic characteristics are not well characterized.. We assessed the radiologic and pathologic characteristics of ILD in MPO-ANCA-positive patients and the association between ILD and vasculitis, particularly microscopic polyangiitis (MPA).. We retrospectively searched electronic health records to identify MPO-ANCA-positive patients with ILD who underwent surgical lung biopsy at our institution from January 1997 through August 2017. Demographic, clinical, imaging, and pathologic characteristics were analyzed.. We identified 18 MPO-ANCA-positive patients with ILD. The median (range) age was 58 (43-75) years, and the cohort included 10 men (56%), 10 former smokers (56%), and 11 patients (61%) had clinical evidence of systemic vasculitis (MPA) at the time of diagnosis of ILD. On high-resolution computed tomography, the most common radiologic pattern was "inconsistent with usual interstitial pneumonia" (UIP) (n=14 [78%]); the other 4 patients (22%) fulfilled the radiologic criteria for the UIP pattern. Honeycombing was seen in 15 patients (83%). Ten patients (56%) had the UIP pattern on biopsy: 4 of these patients had additional inflammatory changes that were not typical of UIP (as seen in patients with idiopathic pulmonary fibrosis), and the other 6 patients had other inflammatory patterns or findings. The presence or absence of MPA did not correlate with pathologic findings.. MPO-ANCA-positive patients with ILD do not show the typical UIP pattern as seen in patients with idiopathic pulmonary fibrosis on surgical lung biopsy.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Biopsy; Electronic Health Records; Female; Humans; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Peroxidase; Predictive Value of Tests; Prognosis; Retrospective Studies; Tomography, X-Ray Computed

A 70-year-old man presented with 1 month of haematuria and mild right-sided flank pain with no other symptoms. Diagnostic workup included serum studies which showed the presence of antimyeloperoxidase antibodies, a kidney biopsy which demonstrated necrotising crescentic glomerulonephritis with linear immunofluorescence of the basement membrane, and electron microscopy which exhibited thickening of the glomerular basement membrane. Incidentally, the patient was discovered to have a latent hepatitis B infection, which complicated immunosuppressive therapy. He was treated with a course of plasmapheresis and methylprednisolone, followed by entecavir for hepatitis B prophylaxis, and finally by rituximab. This case of glomerulonephritis was notable for its resemblance to the better known Goodpasture's disease. Typically, Goodpasture's syndrome exists on a spectrum from seronegative disease to double-positive disease that presents with both anti-glomerular basement membrane (anti-GBM) and cytoplasmic-antineutrophil cytoplasmic antibodies/antiproteinase 3 antibodies (c-ANCA/anti-PR3). However, this patient's glomerulonephritis was unique because he presented negative for anti-GBM antibodies and positive for perinuclear-antineutrophil cytoplasmic antibodies/antimyeloperoxidase antibodies (p-ANCA/anti-MPO).

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Diagnosis, Differential; Glomerulonephritis; Guanine; Humans; Lung Diseases, Interstitial; Male; Methylprednisolone; Microscopy, Electron; Peroxidase; Plasmapheresis; Rituximab; Treatment Outcome

To determine the prevalence of lung abnormalities on chest computed tomography (CT) in patients with microscopic polyangiitis (MPA), to assess the responsiveness of such abnormalities to initial treatment, and to assess associations between these abnormalities and patient and disease characteristics and mortality.. We retrospectively identified 167 consecutive hospital-based patients with MPA in 3 hospitals in Japan. We longitudinally collected clinical information for 150 of these patients, for whom CT images obtained before treatment were available. We then determined the presence of 22 imaging components of lung abnormalities in these patients.. The vast majority of patients (97%) had at least 1 lung abnormality on chest CT images, including interstitial lung lesions (66%), airway lesions (66%), pleural lesions (53%), and emphysematous lesions (37%). In multivariate analyses, ground-glass opacity was associated with the Birmingham Vasculitis Activity Score, whereas 3 of 4 airway lesions were associated with myeloperoxidase-antineutrophil cytoplasmic antibodies. Latent class analysis identified a distinct group of patients with airway-predominant lung lesions. Airway lesions such as bronchiolitis and bronchovascular bundle thickening were among the components that showed improvement within 3 months of the initial treatment. An idiopathic pulmonary fibrosis pattern was the only chest CT variable that was independently associated with shorter survival.. Abnormalities in a wide range of anatomic areas, including the whole airway, can be identified in the lungs of patients with MPA before treatment. The prevalence, clustering patterns, and responsiveness to treatment of individual lung abnormalities provide groundwork for informing future studies to understand the pathophysiology of MPA.

Topics: Adult; Aged; Aged, 80 and over; Airway Obstruction; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Idiopathic Pulmonary Fibrosis; Immunosuppressive Agents; Longitudinal Studies; Lung Diseases; Lung Diseases, Interstitial; Male; Microscopic Polyangiitis; Middle Aged; Multivariate Analysis; Peroxidase; Pleural Diseases; Pulmonary Emphysema; Radiography, Thoracic; Retrospective Studies; Tomography, X-Ray Computed

Granulomatosis with polyangiitis (GPA) is a rare systemic vasculitis that often involves the lung. However, interstitial pneumonia (IP) is rarely seen in GPA patients. We herein report 3 cases of IP associated with GPA diagnosed by surgical lung biopsy. High-resolution CT showed uniform subpleural reticular opacity with traction bronchiectasis. Biopsies from all 3 patients revealed neutrophilic capillaritis, microabscesses with giant cells, and coexisting histological findings of usual IP pattern or fibrosing nonspecific IP pattern. All 3 patients had elevated levels of serum myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), but not proteinase 3-ANCA. We diagnosed GPA and treated with corticosteroid and cyclophosphamide. Follow-up CT showed improvement of the lesions in all patients. Surgical lung biopsy specimens which revealed GPA enabled us to conduct the most suitable therapy. This report indicates the importance of surgical lung biopsy for differentiating idiopathic IPs from GPA-associated IP and suggests a relationship between MPO-ANCA and IP in GPA.

Topics: Adrenal Cortex Hormones; Aged; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Cyclophosphamide; Female; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Middle Aged; Peroxidase; Tomography, X-Ray Computed

We studied the clinico-pathological differences among PR3-ANCA-positive granulomatosis with polyangiitis (PR3-GPA), MPO-ANCA-positive GPA (MPO-GPA) and microscopic polyangiitis (MPA). ANCA-associated vasculitis (AAV) was classified using the European Medicines Agency classification. We retrospectively analyzed 38 patients with GPA and 41 with MPA treated in eight hospitals in Japan. Of the patients with GPA, 17 were positive for MPO-ANCA, and 15 for PR3-ANCA. All patients with MPA were MPO-ANCA positive. The mean ages of those with MPO-GPA were 69.6 years old, 10 years older than those with PR3-GPA. The majority (82 %) of patients with MPO-GPA were woman, a significantly greater proportion than for PR3-GPA. We also found that ear, nose and throat (ENT), nervous system involvement were significantly more common in MPO-GPA, but renal function was less impaired than those with MPA. Both PR3-GPA and MPO-GPA relapsed more frequently than MPA, but overall survival was significantly better (P < 0.01 and P < 0.05, respectively). Univariate analysis identified the following factors as predictors of a poor prognosis: MPA (P < 0.01), pulmonary UIP pattern (P < 0.005) Cr ≥ 1.7 mg/dl (P < 0.01) and absence of ENT involvement (P < 0.05), which were characteristics of MPA. In our cohort, MPO-GPA was most likely to affect older women and was associated with otitis media, nervous system involvement, mild renal impairment and more favorable outcome. It is clinically useful to differentiate MPO-GPA from MPA and PR3-GPA in patients with AAV.

Topics: Age Factors; Aged; Antibodies, Antineutrophil Cytoplasmic; Female; Granulomatosis with Polyangiitis; Humans; Japan; Lung Diseases, Interstitial; Male; Middle Aged; Myeloblastin; Otitis Media; Peroxidase; Recurrence; Retrospective Studies; Sex Factors; Vasculitis, Central Nervous System

The effect of betanin on a rat paraquat-induced acute lung injury (ALI) model was investigated. Paraquat was injected intraperitoneally at a single dose of 20 mg/kg body weight, and betanin (25 and 100 mg/kg/d) was orally administered 3 days before and 2 days after paraquat administration. Rats were sacrificed 24 hours after the last betanin dosage, and lung tissue and bronchoalveolar lavage fluid (BALF) were collected. In rats treated only with paraquat, extensive lung injury characteristic of ALI was observed, including histological changes, elevation of lung : body weight ratio, increased lung permeability, increased lung neutrophilia infiltration, increased malondialdehyde (MDA) and myeloperoxidase (MPO) activity, reduced superoxide dismutase (SOD) activity, reduced claudin-4 and zonula occluden-1 protein levels, increased BALF interleukin (IL-1) and tumor necrosis factor (TNF)-α levels, reduced BALF IL-10 levels, and increased lung nuclear factor kappa (NF-κB) activity. In rats treated with betanin, paraquat-induced ALI was attenuated in a dose-dependent manner. In conclusion, our results indicate that betanin attenuates paraquat-induced ALI possibly via antioxidant and anti-inflammatory mechanisms. Thus, the potential for using betanin as an auxilliary therapy for ALI should be explored further.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Betacyanins; Bronchoalveolar Lavage Fluid; Claudin-4; Interleukin-1; Interleukin-10; Lung; Lung Diseases, Interstitial; Male; Malondialdehyde; Neutrophil Infiltration; NF-kappa B; Paraquat; Permeability; Peroxidase; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Zonula Occludens-1 Protein

Myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) is a well known marker for small vessel vasculitis. Recent reports have demonstrated that interstitial pneumonia (IP) may rarely be associated with serum MPO-ANCA. Yet, little is known about the histological features. We reviewed surgical lung biopsy from nine patients with IP of uncertain etiology with serum MPO-ANCA. There was a male predominance (6:3) with a median age of 62.1. Histologically, eight patients presented with a usual interstitial pneumonia (UIP) pattern of pulmonary fibrosis, frequently accompanied by areas of nonspecific interstitial pneumonia (NSIP) pattern. One patient showed diffuse alveolar damage (DAD), and two patients showed mixture of UIP and DAD reflecting acute exacerbation of UIP. Microscopic honeycomb cysts were common, but fibroblastic foci were inconspicuous. The most frequent additional findings were small airway disease (9/9), and lymphoid follicles (7/9). Neither capillaritis nor vasculitis was seen in any of our cases. Three patients had microscopic hematuria, but none progressed to microscopic polyangiitis during the follow up. Mortality rate was 44% (median follow up 39.1 months). IP associated with MPO-ANCA showed characteristic histology dominated by UIP pattern. Vasculitis was not identified in our cohort, but small airways disease and lymphoid follicles were present in most cases. IP associated with MPO-ANCA may be a histologically distinctive disease from idiopathic pulmonary fibrosis. Mortality was relatively high and life threatening acute exacerbation may occur.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Kaplan-Meier Estimate; Lung Diseases, Interstitial; Male; Middle Aged; Peroxidase; Prognosis

A 65-year-old man who was occupationally exposed to asbestos for 40 years was admitted to our hospital with fever and cough. Chest CT revealed paraseptal emphysema, subpleural fibrosis in both lungs, and pleural plaques. On bronchoalveolar lavage fluid contained elevated levels of lymphocytes and neutrophils (15% and 17%, respectively), and asbestos bodies were also found. Because serum MPO-ANCA titer was elevated to 188 EU, we suspected ANCA-associated disease with interstitial pneumonia. Prednisolone was begun at 30 mg/day and his lung opacities partially disappeared. Six weeks later, he complained of headache, dysphagia and hoarseness, and was admitted to the neurology department of the hospital. Under a diagnosis of either hypertrophic pachymeningitis or neuritis due to angiitis of the lower cranial nerves, steroid pulse therapy was performed. Asbestos exposure may have been a contributing factor for ANCA generation in this case. Furthermore, the fact that cranial nerves palsy occurred in spite of steroid therapy may also be important.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Asbestos; Cranial Nerve Diseases; Humans; Lung Diseases, Interstitial; Male; Methylprednisolone; Occupational Exposure; Peroxidase; Prednisolone; Pulse Therapy, Drug

A 67-year-old woman, suffering from continuous hemoptysis, was admitted to our hospital where she was managed with mechanical ventilation. Computed tomography of the chest demonstrated bilateral massive alveolar hemorrhage without evidence of infectious disease. She was diagnosed with anti-myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated diffuse alveolar hemorrhage because a high titer of MPO-ANCA was found in the serum. Plasmapheresis as well as methylprednisolone pulse therapy were initiated, followed by intravenous administration of cyclophosphamide. Tacrolimus was employed for the maintenance therapy, and the oral prednisolone dosage could successfully be tapered without recurrence, along with the decrement of the titer of MPO-ANCA.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Combined Modality Therapy; Cyclophosphamide; Drug Therapy, Combination; Female; Glucocorticoids; Hemorrhage; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Peroxidase; Plasmapheresis; Prednisolone; Pulmonary Alveoli; Radiography, Thoracic; Tacrolimus; Treatment Outcome

Transmigration of phagocytic leukocytes (PLCs) from the peripheral blood into injured lung requires a conversion of the microvascular endothelial cells (ECs) to the proinflammatory phenotypes and spatiotemporal interplay of different types of cell adhesion molecules (CAMs) on PLC and endothelium. The present report is focused on involvement of iron-dependent redox signaling in spatial coordination of lung CAM due to either a pulmonary trauma or endotracheal iron administration in rats. Redox alterations, deposition of 3-nitrotyrosine, expression of VE-cadherin, ICAM-1, and the PLC integrins, and the status of thioredoxin, Ref-1, NF-kappaB and Nrf2 redox-sensitive elements in the alveolar microvasculature were assessed with EPR spectroscopy, immunobloting, and confocal microscopy. We demonstrated for the first time in vivo that the presence of catalytically active iron, deposition of myeloperoxidase, and induction of the oxidative stress in the lung-injury models were accompanied by (a) downregulation of VE-cadherin, (b) upregulation and polarization of ICAM-1 and the PLC integrins, and (c) nuclear translocation and interaction of thioredoxin, Ref-1, and NF-kappaB and complex structural changes in EC and PLC at the sites of their contacts. The studies suggested that a part of the proinflammatory action of iron in the lung resulted from its stimulation of the redox-sensitive factors.

Topics: Animals; Antigens, CD; Cadherins; Cell Adhesion Molecules; DNA-(Apurinic or Apyrimidinic Site) Lyase; Electron Spin Resonance Spectroscopy; Endothelial Cells; Immunoblotting; Integrins; Intercellular Adhesion Molecule-1; Iron; Leukocytes; Lung; Lung Diseases, Interstitial; Male; Microcirculation; Microscopy, Confocal; NF-kappa B; Oxidation-Reduction; Peroxidase; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Signal Transduction; Thioredoxins

We encountered a case of interstitial pneumonia preceding microscopic polyangiitis (MPA). A 64-year-old asymptomatic woman was found to have interstitial pneumonia on a chest radiograph taken during a work-up before an operation for cataract. Six months later she presented with non-productive cough, low grade fever and renal dysfunction. Interstitial pneumonia worsened with new lesions. The test for MPO-ANCA was positive, though it had been negative six months previously. The histopathology of the lung by video-assisted lung biopsy showed the usual interstitial pneumonitis pattern and small vessel pulmonary vasculitis. Renal biopsy showed necrotizing glomerulonephritis. She was given a diagnosis of MPA and was immediately treated with methylprednisolone pulse therapy and a combination of prednisolone and cyclophosphamide. She has remained stable for two years. This positive inversion of MPO-ANCA, while interstitial pneumonia advanced, was of interest concerning the etiology of MPA. We discuss the important topic of the mechanism of the development of MPA.

Topics: Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Lung Diseases, Interstitial; Middle Aged; Peroxidase; Polyarteritis Nodosa

Myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) is an autoantibody that is frequently found in patients with vasculitides. We encountered some MPO-ANCA positive patients with interstitial pneumonia who lacked vasculitides, but its meaning remains unclear. We measured MPO-ANCA titers in 69 patients with interstitial pneumonia (IP) who did not have collagen vascular diseases and observed their outcome. MPO-ANCA was positive in 5 patients and its prevalence was 7.2%. Patients with MPO-ANCA positive showed higher positivity in rheumatoid factor (RF) than patients with MPO-ANCA negative. The sensitivity and specificity of a combination of anti-nuclear antibody-negative and RF-positive were 80.0% and 87.7%, respectively. Two patients were accompanied by microscopic polyangiitis and the 3-year survival rate was 40% in all patients with MPO-ANCA. Measurement of MPO-ANCA titers in patients with IPs is meaningful for determining therapeutic strategy.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Lung Diseases, Interstitial; Male; Peroxidase

A 72-year-old woman was admitted complaining of productive cough. She had worked for an asbestos factory for twenty years. She was positive for MPO-ANCA. The chest HRCT showed interstitial pneumonia without any UIP pattern. A specimen obtained by video-assisted thoracoscopic lung biopsy revealed chronic interstitial pneumonia associated with an asbestos body. Although the interstitial pneumonia improved after the administration of a corticosteroid and an immunosuppressive agent, hematuria and renal dysfunction developed about nine months later. The serum MPO-ANCA titer was elevated and the renal biopsy specimen revealed the presence of vasculitis. As the interstitial pneumonia improved after this treatment, the correct diagnosis may have been, not asbestosis, but MPO-ANCA-related interstitial pneumonia.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Asbestosis; Disease Progression; Female; Humans; Kidney Diseases; Lung Diseases, Interstitial; Occupational Exposure; Peroxidase; Vasculitis

[Case 1]: An 81-year old man was referred to our hospital with dyspnea and bloody sputum. Computed tomography with contrast medium for the evaluation of metastasis of urinary bladder carcinoma had been performed 4 months previously. On admission, his serum creatinine and potassium were 15.3 mg/dl and 6.9 mEq/l, respectively. His chest X ray revealed cardiomegaly, butterfly shadow and interstitial change, indicating congestive heart failure and interstitial pneumonia. His electrocardiogram showed that he was on the brink of cardiac arrest due to hyperkalemia. Mechanical ventilation and hemodialysis were initiated. Myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) was highly positive(321 EU), leading to the diagnosis of MPO-ANCA-associated rapidly progressive glomerulonephritis (RPGN) with interstitial pneumonia. Treatment with pulse methylprednisolone was not effective and he died. Autopsy findings showed crescentic glomerulonephritis, alveolar hemorrhage and interstitial pneumonia with honeycomb formation. [Case 2]: A 73-year old man was referred to our hospital with rapid deterioration of his renal function. He had received a cardiac catheter examination 3 weeks previously. On admission, his serum creatinine was 4.5 mg/dl. His chest X ray showed cardiomegaly and interstitial change. Renal biopsy findings showed crescentic formation in the glomeruli. Moreover, MPO-ANCA was 494 EU, leading to the diagnosis of MPO-ANCA-associated RPGN with interstitial pneumonia. Treatment with pulse methylprednisolone and cyclophosphamide was not effective and he died. Autopsy findings revealed crescentic glomerulonephritis and interstitial pneumonia with honeycomb formation. Here we described two cases of ANCA-associated RPGN complicated by microscopic polyantitis and interstitial pneumonia after the use of contrast medium. The relation between ANCA-associated RPGN and the contrast medium was unclear. However, in the case of rapid deterioration of renal function, MPO-ANCA should be measured even after the use of contrast medium. The complication of lung diseases, especially interstitial pneumonia, should be investigated simultaneously.

Topics: Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Autopsy; Contrast Media; Fatal Outcome; Glomerulonephritis; Humans; Lung Diseases, Interstitial; Male; Peroxidase

The purpose of this study is to evaluate pulmonary involvement in rapidly progressive glomerulonephritis (RPGN). Of 71 patients in whom RPGN was diagnosed, 32 (45.1%) had pulmonary involvement: 12, alveolar hemorrhage (AH) (16.9%); 10, interstitial pneumonia (IP) (14.1%); four, chronic bronchial lesions (5.6%); two, consolidation (2.8%), and four, old inflammatory lesions (5.6%). Investigation of which organ of the twelve AH patients, the kidney or the lung, was the first to be involved, showed that the lung preceded in one patient, the kidney was first in three, and the lung and kidney occurred at the same time in the other eight. Of the ten IP patients, the lung preceded in eight, the kidney was ahead in two, and lung and kidney were simultaneous in one. Three patients had a history of pneumoconiosis, and two had acute progressive IP. Seventeen (45.9%) of 37 patients who tested positive for antineutrophil cytoplasmic autoantibodies (MPO-ANCA) had lung involvement, and three (30.0%) of the ten patients who tested negative for MPO-ANCA, PR 3-ANCA and anti-GBM antibody also had lung involvement.

Topics: Aged; Anti-Glomerular Basement Membrane Disease; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Female; Glomerulonephritis; Hemorrhage; Humans; Lung Diseases; Lung Diseases, Interstitial; Male; Middle Aged; Peroxidase; Retrospective Studies

KL-6 is reported to be excreted from the lung alveolar and bronchial epithelial cells and may be a good marker for monitoring disease activity of interstitial pneumonia. This study was designed to ascertain the clinical significance of serum KL-6 levels in interstitial pneumonia associated with anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis.. Serum KL-6 levels were determined by an enzyme-linked immunosorbent assay.. We examined 20 healthy subjects, 13 patients with perinuclear (myeloperoxidase, MPO) ANCA-related vasculitis and 12 dermatomyositis (DM)/polymyositis (PM) patients as disease controls in this study. Six out of 13 patients with ANCA-related vasculitis had interstitial pneumonia.. Serum levels of KL-6 in ANCA-positive patients with interstitial pneumonia were significantly elevated, while they remained as low as those of healthy subjects in ANCA-positive patients without interstitial pneumonia. Similarly, KL-6 levels in sera were higher in 12 dermatomyositis/polymyositis patients with interstitial pneumonia, while they remained low in DM/PM patients without interstitial pneumonia. Moreover, the elevated serum KL-6 level was reduced during the convalescence induced by glucocorticoid therapy and reflected the disease activity of interstitial pneumonia associated with ANCA-related vasculitis.. These data suggest that the measurement of serum KL-6 levels may be a good monitoring system for the diagnosis and follow-up of interstitial pneumonia of patients with ANCA-related vasculitis.

Topics: Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Antigens; Antigens, Neoplasm; Biomarkers; Female; Glycoproteins; Humans; Lung Diseases, Interstitial; Male; Middle Aged; Mucin-1; Mucins; Peroxidase; Predictive Value of Tests; Severity of Illness Index; Vasculitis

The main target organs of myeloperoxidase (MPO) antineutrophil cytoplasmic antibodies (ANCA)-related disease are the kidney and lung. This report describes a 71-year-old man with rapidly progressive glomerulonephritis (RPGN) and interstitial pneumonitis associated with MPO ANCA. The patient was admitted to our hospital because of bloody sputum, low grade fever and appetite loss on October, 1998. He was diagnosed as having interstitial pneumonitis from the findings of chest X-ray and CT examinations. Moderate proteinuria and hematuria, renal dysfunction(serum creatinine: 5.6 mg/dl, BUN: 58.0 mg/dl) and positivity for MPO ANCA were noted. He was negative for anti-glomerular antibody and PR3-ANCA. Renal biopsy was performed and revealed crescentic glomerulonephritis without deposition of immunoglobulins. Therefore, the diagnosis of pauci immune type RPGN was made. Pulse therapy with methylprednisolone(1.0 g/day x 3 days) following oral administration of prednisolone (60 mg/day) found marked improvement of renal function maintenance and interstitial pneumonitis, respectively. However, he died because of lung tuberculosis and acute tuberculous pericarditis during treatment with prednisolone. In this case, MPO ANCA might have been directly associated with both RPGN and interstitial pneumonitis. Furthermore, chronic lung disease, such as interstitial pneumonitis, is important as a preceding disease of RPGN. MPO ANCA-related disease is more frequent in aged persons, therefore particular attention should be paid during their treatment with an immunosuppressant.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Fatal Outcome; Glomerulonephritis; Humans; Immunocompromised Host; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Pericarditis, Tuberculous; Peroxidase; Tuberculosis, Pulmonary

We reported two cases of silicosis exhibiting MPO-ANCA associated disorder. Case 1 was a 69 year-old man with silicosis and chronic interstitial pneumonia. He was admitted because of fever, dry cough, left chest pain, dyspnea and body weight loss. He was diagnosed as acute exacerbation of interstitial pneumonia, pericarditis and gastrointestinal bleeding. Case 2 was a 67 year-old man with silicosis. He repeated attack of fever, hoarseness, dysphagia and headache. The cell counts of cerebrospinal fluid increased and the thickness of cerebellar tent and left dura mater was observed in the brain MRI. Therefore, he was diagnosed as pachymeningitis and neuropathy of cranial nerves. Both cases were complicated by silicosis and the laboratory findings showed high serum levels of P-ANCA, ANA and rheumatoid factor and inflammatory responses, indicating they were suspected vasculitis. The two cases were treated by steroid and immunosuppressive therapy and had good clinical response. Silicosis may affect multiple organ involvement associated with P-ANCA.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Humans; Lung Diseases, Interstitial; Male; Meningitis; Methylprednisolone; Peripheral Nervous System Diseases; Peroxidase; Prednisolone; Pulse Therapy, Drug; Silicosis; Treatment Outcome; Vasculitis

Pulmonary renal syndrome is encountered in several diseases such as Goodpasture's syndrome, antineutrophil cytoplasmic antibody (ANCA) associated systemic vasculitis, systemic lupus erythematosus (SLE) and infection-associated or drug-induced glomerulonephritis. To preserve organ function it is of vital importance to make the correct diagnosis and institute adequate therapy early, in the acute phase.. An enzyme-linked immunosorbent assay (ELISA), specially designed as a rapid screening assay for antiglomerular basement membrane (anti-GBM) antibody, proteinase-3 (PR3-) ANCA and myeloperoxidase-(MPO-) ANCA were evaluated from 1060 serum samples drawn from patients with clinically suspected pulmonary renal syndrome or rapidly progressive glomerulonephritis (RPGN).. Of the 1060 serum samples, 142 were positive for anti-GBM antibody (n = 19), PR3-ANCA (n = 60), or MPO-ANCA (n = 73). Of the 142 samples, 10 were double positive. Reanalysis of positive sera with a quantitative ELISA yielded results manifesting good correlation with those of the the rapid screening assay. Of 918 sera found to be negative in the rapid screening assay, 105 were also tested with IIF, 11 being found to be positive. However, these 11 sera manifested no specificity for PR3 or MPO, but some were specific for bactericidal/permeability-increasing proteins, lactoferrin or elastase ANCAs. Two of the patients whose sera yielded negative results in the rapid assay had systemic vasculitis.. The ELISA thus detects the true antibodies to PR3, MPO, and GBM, whereas IIF detects additional specificities. The findings suggest the rapid assay results to be of high positive predictive value, and the assay to be of high diagnostic specificity and sensitivity and thus useful in the diagnostic workup in suspected cases of RPGN or pulmonary renal syndrome.

Topics: Anti-Glomerular Basement Membrane Disease; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Basement Membrane; Diagnosis, Differential; Disease Progression; Enzyme-Linked Immunosorbent Assay; False Negative Reactions; Glomerulonephritis; Humans; Kidney Diseases; Kidney Glomerulus; Lung Diseases, Interstitial; Myeloblastin; Peroxidase; Serine Endopeptidases; Syndrome

A 55-year-old man was admitted to our hospital with of hemoptysis, progression of anemia and renal failure in February, 1996. Idiopathic interstitial pneumonia had been diagnosed and he had been followed at a regional hospital since 1988. On the third day after admission, he suffered from sudden and massive hemoptysis. Goodpasture's syndrome was diagnosed because anti-GBM antibody was detected in serum. A high titer of MPO-ANCA was also recognized simultaneously. Steroid pulse therapy, immunosuppressive therapy, and plasmapheresis were begun, but he died on the 28th hospital day because of severe hypoxemia and multi-organ failure. Histological examination after autopsy revealed crescentic glomerulonephritis with linear deposition of IgG in the glomerular capillary wall, and interstitial pneumonia accompanied by massive alveolar hemorrhage. It was suggested that in this patient, not only anti-GBM antibody but also circulating MPO-ANCA might have participated in the progression of the crescentic glomerulonephritis and alveolar hemorrhage observed in Goodpasture's syndrome.

Topics: Anti-Glomerular Basement Membrane Disease; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Autoantibodies; Chronic Disease; Humans; Lung Diseases, Interstitial; Male; Middle Aged; Peroxidase

We describe two cases (61-year-old female and 71-year-old male) with MPO-ANCA (myeloperoxidase-antineutrophil cytoplasmic antibody) positive who developed severe interstitial pneumonitis. They presented at our hospital with dyspnea and dry cough. The hypoxia and abnormal shadow on chest X-ray led to a diagnosis of interstitial pneumonitis. Serologic studies revealed the high titers of MPO-ANCA in two cases. They were treated with methylprednisolone, immunosuppressant agents and plasma exchange. The pneumonitis and the titers of MPO-ANCA improved on these therapies, The former was introduced continuous hemodialysis therapy and the later continued nephrotic syndrome. These renal damages did not recover, regardless of the reduction of the titers of MPO-ANCA. It is concluded that methylprednisolone pulse therapy, immunosuppressant agents and plasma exchange therapy are useful to interstitial pneumonitis in patient with positive of MPO-ANCA. The measurement of MPO-ANCA is useful to interstitial pneumonitis in patient with positive of MPO-ANCA. The measurement of MPO-ANCA is useful maker of interstitial pneumonitis for unknown causes.

Topics: Aged; Anti-Inflammatory Agents; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Methylprednisolone; Middle Aged; Peroxidase; Plasma Exchange; Serologic Tests

A 78-year-old man was admitted to our hospital in October 1994 because of renal dysfunction. The level of anti-myeloperoxidase antibody in serum was 500 EU/ml, and examination of a specimen obtained by open renal biopsy revealed crescentic glomerulonephritis. A chest roentgenogram revealed no abnormality. Administration of prednisolone was started at 50 mg/day, and the dosage was then tapered. Renal function remained stable, but on interstitial shadow appeared on the chest roentgenogram. Pulmonary function tests showed a restrictive ventilatory abnormality and a low diffusing capacity. A thoracoscopic lung biopsy was done in April 1995, and microscopic examination of the specimen showed interstitial pneumonia with relatively young granulation. The dosage of prednisolone was increased to 50 mg/day, after which the interstitial shadow decreased and pulmonary function improved. The level of anti-myeloperoxydase antibody in serum was 16 EU/ml (weakly positive). Alveolar hemorrhage can occur in cases of rapidly progressive glomerulonephritis. In addition, interstitial pneumonia or pulmonary fibrosis can also complicate this condition. In the present case, glomerulonephritis associated with anti-myeloperoxydase antibody co-existed with interstitial pneumonia. This case is valuable because both renal biopsy and lung biopsy specimens were available.

Topics: Aged; Autoantibodies; Disease Progression; Glomerulonephritis; Humans; Lung Diseases, Interstitial; Male; Peroxidase

A 52-year-old man was admitted to our hospital in July 1995, because of intermittent claudication, paresthesia on foot and gross hematuria. Chest radiograph in 1988 revealed bilateral interstitial shadows and proteinuria had been pointed out since 1992. On admission, chest X-ray and computed tomography showed diffuse interstitial shadow, however it had not been changed for several years. Laboratory tests revealed elevated level of erythrocyte sedimentation rate, C-reactive protein, immunoglobulin, rheumatoid factor, IgG-rheumatoid factor, and immune complex. Serum MPO-ANCA were positive. Although serum creatinine level and renal function test were normal, renal biopsy demonstrated crescentic formation and necrotizing vasculitis. Immunofluorescence and electron microscopy demonstrated no remarkable deposit in glomerulus. A diagnosis of microscopic polyarteritis necrotizing and crescentic glomerulonephritis (NCGN) was made. Treatment was initiated with 30 mg of prednisolone, followed by marked improvement of intermittent claudication, and decreased titer of serum MPO-ANCA. Previous reports have demonstrated the association of MPO-ANCA with rapidly progressive NCGN, microscopic polyarteritis, and occasionally pulmonary hemorrhage recognized as pulmonary-renal syndrome. However, the present case suggests the possibility that another disease subset may also be associated with MPO-ANCA, which is characterized by interstitial pneumonitis and slowly progressive glomerulonephritis.

Topics: Antibodies, Antineutrophil Cytoplasmic; Disease Progression; Glomerulonephritis; Humans; Kidney; Lung Diseases, Interstitial; Male; Middle Aged; Necrosis; Peroxidase