Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

New diagnostics for the spectrum of asymptomatic TB: from infection to subclinical disease.

TB remains a leading cause of morbidity and mortality worldwide. However, most infected immunocompetent individuals are asymptomatic and only 5-10% of these will eventually develop active TB during their lifetime (typically within 2 years after exposure). Therefore, rapid diagnosis and efficient management of asymptomatic infected individuals who are at the highest risk of progression and transmission remain major clinical and public health challenges. In recent years, there has been important scientific progress in our understanding of the spectrum of asymptomatic Mycobacterium tuberculosis (Mtb) infections that not only includes the dynamic state of latent TB infection (LTBI), but also the preclinical state of incipient and subclinical TB. The latter is possibly as prevalent as symptomatically active TB and potentially contributes to global Mtb transmission in various settings. We summarize the latest developments and current challenges of the existing testing tools for LTBI and describe promising biomarkers and diagnostics for the spectrum of asymptomatic TB. Following the negative results of a recent clinical trial for a biomarker-guided preventive therapy approach, we also suggest some treatment options for incipient TB.

Glycosylation of proteinase 3 (PR3) is not required for its reactivity with antineutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis.

OBJECTIVE: The glycosylation status of autoantigens appears to be crucial for the pathogenesis of some autoimmune diseases, since carbohydrates play a crucial role in the distinction of self from non-self. Proteinase 3 (PR3), the main target antigen for anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener's granulomatosis (WG), contains two Asn-linked glycosylation sites. The present study explores the influence of the glycosylation status of PR3 on the PR3 recognition by ANCA in a well characterized population of patients with WG. METHODS: Forty-four patients with WG (459 serum samples) who participated in a multicenter randomized trial, were tested by capture ELISA for ANCA against PR3 and deglycosylated recombinant variants of PR3. RESULTS: The patients were followed for a median of 27 months, and the median number of serum samples per patient was 10. At baseline, the correlation between the levels of ANCA against PR3 and against all the deglycosylated recombinant variants of PR3 were greater than 0.94 (?<0.001 for all the comparisons). Longitudinal analyses comparing the levels of ANCA against PR3 versus all the deglycosylated recombinant variants of PR3, using linear mixed models, showed no significant statistical differences (rho >or=0.90 in all cases). CONCLUSION: The glycosylation status of PR3 has no impact on its recognition by ANCA in WG.

[Analysis of non-confraternity sports accidents in the surgical department of a former district hospital during the period of 2 years]. / Sportunfallerhebung der Nicht-BG-Fälle einer chirurgischen Abteilung eines ehemaligen Kreiskrankenhauses uber den Zeitraum von zwei Jahren.

This epidemiological study analyses all n = 1,659 outpatient and inpatient non-confraternity sports accidents treated during a 2-year period in a former district hospital. The largest share with 40.6% is soccer, followed by cycling (15%), general fitness sports (7.6%), outdoor sports (6.5%), winter sports (5.5%), and riding (5.2%). Soccer injuries rise steadily until the age of 30. Of 86 horse riding accidents a total of 68 involved women, but only 18 men (ratio 8 : 2). 53% of the horse riding accidents among women concern the age group between 10 and 20 years. 70.6% (79%) of the athletes under (over) 20 years were male, 29.4% (21%) female (p < 0.05). Topographically the lower extremities represent the most affected body region in all sports (runners 84.4%, soccer players 60.2%). Most accidents occur on a Sunday. The most common diagnosis is contusion, most commonly in martial arts (60.8%), followed by horse riding (51%). There is an astonishing dominance of soccer accidents given the fact that this study records all athletes, not just club athletes, unlike insurance studies. Important preventive measures would be a comprehensive biological training prophylaxis and the provision of communication of age-specific accident prevention proposals for the mainly affected sports.

Assessment of current practice in the diagnosis and therapy of idiopathic pulmonary fibrosis.

BACKGROUND: The consensus statement on the Diagnosis and Therapy of Idiopathic Pulmonary Fibrosis (IPF) formulated by the American Thoracic Society/European Respiratory Society (ATS/ERS) was published in 2000. Acceptance and implementation of these guidelines have not been assessed. We surveyed the fellows of the American College of Chest Physicians (FCCP) to establish current practice patterns regarding the diagnosis and therapy of IPF. METHODS: We electronically distributed a 32-item questionnaire to all 6443 pulmonary medicine board-certified Fellows of the American College of Chest Physicians. The response rate was 13%. Demographic characteristics were similar between respondents and non-respondents. RESULTS: Seventy-two percent of respondents were familiar with the ATS/ERS consensus statement and 63% found it clinically useful. However, a similar number of respondents indicated that an update is needed. Bronchoscopy and surgical lung biopsy are used infrequently. Forty-five percent of pulmonary physicians advocate providing only supportive care for patients outside of clinical trials. If pharmacological therapy is recommended, prednisone (either alone or in combination with azathioprine) or off-label agents are preferentially prescribed. Despite physician awareness (79%) of clinical trials, interested patients are not consistently referred (54%). A majority of respondents (61%) felt that lung transplantation represents the only effective therapy for IPF, and 86% refer their patients to lung transplant centers. CONCLUSIONS: There is substantial variability among pulmonary physicians in the diagnosis and management of IPF. This may, in part, reflect the current lack of effective pharmacologic therapy. Updated practice guidelines are needed for the diagnosis and therapy of IPF.

A Single-Institution Experience in Percutaneous Image-Guided Biopsy of Malignant Pleural Mesothelioma.

PURPOSE: Mesothelioma has been considered a difficult pathologic diagnosis to achieve via image-guided core needle biopsy. The purpose of this study was to assess the diagnostic sensitivity of percutaneous image-guided biopsy for diagnosis of pleural mesothelioma. MATERIALS AND METHODS: Retrospective review was performed to identify patients with a confirmed diagnosis of pleural mesothelioma and who underwent image-guided needle biopsy between January 1, 2002, and January 1, 2016. Thirty-two patients with pleural mesothelioma were identified and included for analysis in 33 image-guided biopsy procedures. Patient, procedural, and pathologic characteristics were recorded. Complications were characterized via standardized nomenclature [Common Terminology for Clinically Adverse Events (CTCAE)]. RESULTS: Percutaneous image-guided biopsy was associated with an overall sensitivity of 81%. No CTCAE clinically significant complications were observed. No image-guided procedures were complicated by pneumothorax or necessitated chest tube placement. No patients had tumor seeding of the biopsy tract. CONCLUSION: Percutaneous image-guided biopsy can achieve high sensitivity for pathologic diagnosis of pleural mesothelioma with a low procedural complication rate, potentially obviating need for surgical biopsy.

Rituximab for the treatment of relapses in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. RESULTS: Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). CONCLUSION: Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.

Agreement of anti-neutrophil cytoplasmic antibody measurements obtained from serum and plasma.

Serum and plasma are used interchangeably to measure anti-neutrophil cytoplasmic antibodies (ANCA), even though the release of ANCA target antigens during the preparation of serum could affect ANCA assays and cause discrepancies between the results obtained from serum and plasma. To what extent ANCA test results obtained from serum agree and correlate with results from plasma remains unknown. Therefore, a comprehensive comparison was performed using serum and plasma samples which were collected in 175 patients with active Wegener's granulomatosis at enrollment of a recent randomized trial. These paired serum and plasma samples were subjected to parallel ANCA testing by standard indirect immunofluorescence on ethanol-fixed neutrophils, a direct enzyme-linked immunoassay (ELISA) for proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, and two different capture ELISAs for PR3-ANCA. The concordance of categorical serum and plasma ANCA results was assessed using kappa-coefficients. These were > 0.8 for all assays, indicating a very good concordance between positive and negative serum and plasma results. Spearman's correlation coefficients for serum and plasma PR3-ANCA values obtained by direct ELISA and both capture ELISAs were > or = 0.95 (P < 0.0001). Our study shows that serum and plasma samples can be used interchangeably for measuring ANCA.

[Hair cell function diagram in premature and mature newborn infants]. / Haarzellfunktionsdiagramme bei Früh- und Reifgeborenen.

BACKGROUND: The grade of maturation of the cochlear function must be taken into account when the cochlear function is investigated in premature infants and neonates. Quantitative analysis has not yet been performed. METHODS: Using the otodynamic analyzer ILO 88/92, we therefore determined haircell functional diagrams and the echo 65 dB levels in 35 healthy neonates as well as 30 healthy premature infants with a median gestational age (GA) of 32 weeks (28-35 weeks) 2-3 days post natum. Follow up investigations were performed in 10 neonates and 16 premature infants. RESULTS: The mean echo 65 dB levels were 4.88 +/- 4.22 dB for the right ears and 5.72 +/- 5.16 dB for the left ears in premature infants < or = 32 weeks of GA, 10.25 +/- 3.89 dB and 10.69 +/- 5.55 dB respectively in premature infants > 32 weeks of GA, and 16.01 +/- 4.99 and 14.90 +/- 4.41 dB respectively in neonates. There was no significant difference between neonates at day 2 and 4 post natum. In 16 premature infants the echo 65 dB levels increased from 4.92 dB for the right ears and 4.79 dB for the left ears at the second day of life to 11.72 dB and 11.73 dB respectively at the age of 4 weeks. CONCLUSION: We present therefore strong evidence for a maturation of the cochlear function in premature infants with increasing age. The individual grade of maturation of the cochlea is of relevance for the auditive stimulation of very premature infants.