Citations

Abstract Rationale Standard therapy for Wegener's granulomatosis is fraught with substantial toxicity and not always effective. B lymphocytes have been implicated in the pathogenesis of Wegener's granulomatosis. Their depletion has been proposed as salvage therapy for refractory disease. Earlier encouraging reports are confounded by concomitant immunosuppressive medications and include only limited available biomarker data. Objectives To evaluate the efficacy and safety of rituximab for remission induction in refractory Wegener's granulomatosis. Methods A prospective open-label pilot trial was conducted with 10 patients monitored for 1 yr. Included were patients with active severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, ANCA positivity, and resistance to (or intolerance of) cyclophosphamide. The remission induction regimen consisted of oral prednisone (1 mg/kg/d) and four weekly infusions of rituximab (375 mg/m2). Prednisone was tapered and discontinued over 5 mo. Failure to achieve remission, a clinical flare in the absence of B lymphocytes, and inability to complete the glucocorticoid taper were considered treatment failures. Main Results Three women and seven men (median age, 57 yr; range, 25–72 yr) were enrolled. All had ANCA reacting with proteinase-3. The median activity score at enrollment was 6 (range, 5–10). All patients tolerated rituximab well, achieved swift B-lymphocyte depletion and complete clinical remission (activity score, 0) by 3 mo, and were tapered off glucocorticoids by 6 mo. Five patients were retreated with rituximab alone for recurring/rising ANCA titers according to protocol. One patient experienced a clinical flare after B lymphocyte reconstitution. Conclusion In this cohort, rituximab was a well-tolerated and effective remission induction agent for severe refractory Wegener's granulomatosis.

Background— The objective of this study was to address the feasibility and the biological activity of orally administered human brain natriuretic peptide (hBNP). Proprietary technology has been developed in which short, amphiphilic oligomers are covalently attached to peptides. The conjugated peptides are intended to have an improved pharmacokinetic profile and to enable oral administration. We hypothesized that novel oral conjugated hBNP (CONJ-hBNP) increases plasma hBNP, activates cGMP, and reduces mean arterial pressure (MAP). Methods and Results— This randomized crossover-designed study tested the biological activity of oral CONJ-hBNP compared with oral native hBNP in normal conscious dogs. Measurements of MAP, plasma hBNP, and cGMP were made at baseline (BL) and repeated at 10, 30, 60, 120, 180, and 240 minutes after oral administration. Plasma hBNP was not detectable in dogs at BL. Plasma hBNP was detected after native hBNP and CONJ-HBNP administration. However, plasma hBNP concentration was significantly higher after CONJ-hBNP than after native hBNP administration ( P =0.0374 between groups). Plasma cGMP increased after CONJ-hBNP for 60 minutes (from 10.8±3 to 36.8±26 pmol/mL; P <0.05), whereas it did not change after native hBNP ( P =0.001 between groups). MAP decreased at 10 minutes and remained decreased for 60 minutes after CONJ-hBNP (from 113±8 to 101±12 mm Hg after 10 minutes to 97.5±10 mm Hg after 30 minutes to 99±13 mm Hg after 60 minutes) while remaining unchanged after native hBNP ( P =0.0387 between groups). Conclusions— This study reports for the first time that novel conjugated oral BNP activates cGMP and significantly reduces MAP, thus implying an efficacious coupling of CONJ-hBNP to the natriuretic receptor-A. These data advance a new concept of orally administered chronic BNP therapy for cardiovascular diseases.

Abstract Current guidelines recommend that the clinician, radiologist, and pathologist work together to establish a diagnosis of idiopathic interstitial pneumonia. Three clinicians, two radiologists, and two pathologists reviewed 58 consecutive cases of suspected idiopathic interstitial pneumonia. Each participant was provided information in a sequential manner and was asked to record their diagnostic impression and level of confidence at each step. Interobserver agreement improved from the beginning to the end of the review. After the presentation of histopathologic information, radiologists changed their diagnostic impression more often than did clinicians. In general, as more information was provided the confidence level for a given diagnosis improved, and the diagnoses rendered with a high level of confidence were more likely congruent with the final pathologic consensus diagnosis. The final consensus pathologist diagnosis was idiopathic pulmonary fibrosis in 30 cases. Clinicians identified 75% and radiologists identified 48% of these cases before presentation of the histopathologic information. Histopathologic information has the greatest impact on the final diagnosis, especially when the initial clinical/radiographic diagnosis is not idiopathic pulmonary fibrosis. We conclude that dynamic interactions between clinicians, radiologists, and pathologists improve interobserver agreement and diagnostic confidence.

Abstract Chemokines are increased and may exert effects on both inflammatory and remodeling events in idiopathic pulmonary pneumonia (IIP). Accordingly, we examined the concomitant expression of inflammatory CC chemotactic cytokines or chemokines and their corresponding receptors in surgical lung biopsies obtained at the time of disease diagnosis and pulmonary fibroblasts grown from these biopsies. By gene array analysis, upper and lower lobe biopsies and primary fibroblast lines from patients with usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia, and respiratory bronchiolitis-interstitial lung disease, but not patients without IIP, exhibited CCL7 gene expression. TAQMAN, immunohistochemical, and ELISA analyses confirmed that CCL7 was expressed at significantly higher levels in UIP lung biopsies compared with biopsies from patients with nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, and from patients without IIP. Higher levels of CCL7 were present in cultures of IIP fibroblasts compared with non-IIP fibroblasts, and CCL5, a CCR5 agonist, significantly increased the synthesis of CCL7 by UIP fibroblasts. Together, these data suggest that CCL7 is highly expressed in biopsies and pulmonary fibroblast lines obtained from patients with UIP relative to patients with other IIP and patients without IIP, and that this CC chemokine may have a major role in the progression of fibrosis in this IIP patient group.

Abstract Exercise-induced hypoxia is an index of the severity of interstitial lung disease. We hypothesized that desaturation during a 6-minute walk test would predict mortality for patients with usual interstitial pneumonia (n = 83) and nonspecific interstitial pneumonia (n = 22). Consecutive patients with biopsy-proven disease performed a 6-minute walk test between January 1996 and December 2001. Desaturation was defined as a fall in oxygen saturation to 88% or less during the 6-minute walk test. Desaturation was common (44 of 83 usual interstitial pneumonia and 8 of 22 nonspecific interstitial pneumonia; chi square, p = 0.39). Patients with usual interstitial pneumonia or nonspecific interstitial pneumonia who desaturated had a significantly higher mortality than patients who did not desaturate (respective log-rank tests, p = 0.0018, p = 0.0089). In patients with usual interstitial pneumonia, the presence of desaturation was associated with an increased hazard of death (hazard ratio, 4.2; 95% confidence interval, 1.40, 12.56; p = 0.01) after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, FVC, and resting saturation. We conclude that knowledge of desaturation during a 6-minute walk test adds prognostic information for patients with usual interstitial pneumonia and nonspecific interstitial pneumonia.

Abstract Idiopathic interstitial pneumonias are a diverse group of lung diseases with varied prognoses. We hypothesized that changes in physiologic and radiographic parameters would predict survival. We retrospectively examined 80 patients with usual interstitial pneumonia and 29 patients with nonspecific interstitial pneumonia. Baseline characteristics were examined together with 6-month change in forced vital capacity, diffusing capacity for carbon monoxide, and ground glass infiltrate and fibrosis on high resolution computed tomography. Patients with usual interstitial pneumonia were more likely to have a statistically significant or marginally significant decline in lung volume, diffusing capacity for carbon monoxide, and an increase in ground glass infiltrates (p ⩽ 0.08) compared with patients with nonspecific interstitial pneumonia. For patients with usual interstitial pneumonia, change in forced vital capacity was the best physiologic predictor of mortality (p = 0.05). In a multivariate Cox proportional hazards model controlling for histopathologic diagnosis, gender, smoking history, baseline forced vital capacity, and 6-month change in forced vital capacity, a decrease in forced vital capacity remained an independent risk factor for mortality (decrease &gt; 10%; hazard ratio 2.47; 95% confidence interval 1.29, 4.73; p = 0.006). We conclude that a 6-month change in forced vital capacity gives additional prognostic information to baseline features for patients with idiopathic interstitial pneumonia.

Abstract A histologic feature of usual interstitial pneumonia is the presence of fibroblastic foci. As some patients with usual interstitial pneumonia and an underlying collagen vascular disease have a better prognosis, we hypothesized that they would have fewer fibroblastic foci. Pathologists reviewed surgical lung biopsies from 108 patients with usual interstitial pneumonia (nine with collagen vascular disease) and assigned a score (absent 0, mild 1, moderate 2, and marked 3) for fibroblastic foci. Patients with idiopathic usual interstitial pneumonia had a higher median profusion of fibroblastic foci (1.75 vs. 1.0, p = 0.003). Baseline characteristics were similar, although patients with a collagen vascular disease were younger, had a shorter duration of symptoms, and had a higher percentage of predicted total lung capacity. Profusion of fibroblastic foci was the most discriminative feature for separating idiopathic from collagen vascular disease–associated usual interstitial pneumonia (odds ratio 8.31; 95% confidence interval, 1.98, 59.42; p = 0.002 for a one-unit increase in fibroblastic foci score). No deaths were noted in the collagen vascular disease–associated usual interstitial pneumonia group; 52 deaths occurred in the idiopathic usual interstitial pneumonia group (log rank; p = 0.005). We conclude that patients with collagen vascular disease–associated usual interstitial pneumonia have fewer fibroblastic foci and improved survival.

Conformationally altered proteins and protein fragments derived from the extracellular matrix and hemostatic system may function as naturally occurring angiogenesis inhibitors. One example of such a protein is cleaved high molecular weight kininogen (HKa). HKa inhibits angiogenesis by inducing apoptosis of proliferating endothelial cells, effects mediated largely by HKa domain 5. However, the mechanisms underlying the antiangiogenic activity of HKa have not been characterized, and its binding site on proliferating endothelial cells has not been defined. Here, we report that the induction of endothelial cell apoptosis by HKa, as well as the antiangiogenic activity of HKa in the chick chorioallantoic membrane, was inhibited completely by antitropomyosin monoclonal antibody TM-311. TM-311 also blocked the high-affinity Zn 2+ -dependent binding of HKa to both purified tropomyosin and proliferating endothelial cells. Confocal microscopic analysis of endothelial cells stained with monoclonal antibody TM-311, as well as biotin labeling of cell surface proteins on intact endothelial cells, revealed that tropomyosin exposure was enhanced on the surface of proliferating cells. These studies demonstrate that the antiangiogenic effects of HKa depend on high-affinity binding to endothelial cell tropomyosin.