Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): ten-year experience at a single center.

OBJECTIVE: This study was conducted to evaluate the efficacy and safety of repeated and prolonged B cell depletion with rituximab (RTX) for the maintenance of long-term remission in patients with chronic relapsing granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: We conducted a single-center observational study of all patients with chronic relapsing GPA treated with at least 2 courses of RTX between January 1, 2000 and May 31, 2010. Participants in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were excluded from this analysis. Data were abstracted from electronic medical records. RESULTS: Fifty-three patients with refractory GPA (median age 46 years [interquartile range (IQR) 30-61 years]; 53% women) received at least 2 courses of RTX to treat GPA relapses or to maintain remission. All but 1 patient had antineutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3). These patients received a median of 4 courses of RTX (IQR 3-5); all had depletion of B cells, and the median time to return of B cells was 8.5 months (IQR 6-11 months). All observed relapses occurred after reconstitution of B cells and were accompanied or preceded by an increase in ANCA levels, except for the 1 ANCA-negative patient. Infusion-related adverse events occurred in 16 patients. During the period of B cell depletion, 30 infections requiring antimicrobial therapy were recorded. CONCLUSION: RTX appeared to be effective and safe for the induction and maintenance of remission in patients with chronic relapsing GPA. Repeated depletion of B lymphocytes seems to be associated with a low risk of infections. Preemptive re-treatment decisions can be individualized based on serial B lymphocyte and PR3 ANCA monitoring. The use of RTX for the maintenance of long-term remission merits further formal investigation.

High-resolution CT findings of parenchymal fibrosis correlate with prognosis in hypersensitivity pneumonitis.

BACKGROUND: Histopathologic evidence of fibrosis on surgical lung biopsy has been associated with reduced survival in patients with hypersensitivity pneumonitis (HP). Changes of pulmonary fibrosis detected on CT may also correlate with prognosis in patients with HP. METHODS: We identified 69 consecutive patients with HP diagnosed between January 1997 and December 2002 at Mayo Clinic, Rochester, MN. Patients were stratified into fibrotic and nonfibrotic groups based on the CT findings. Fibrosis was defined by the presence of irregular linear opacities, traction bronchiectasis, or honeycombing. MEASUREMENTS AND MAIN RESULTS: Of 69 patients, 26 were classified as fibrotic and 43 as nonfibrotic. Patients in the fibrotic group were older, had longer symptom duration, were more likely to have crackles on auscultation, more likely to be exposed to avian antigen, and had greater restrictive lung impairment (p<0.05 for all comparisons). There were 11 deaths in the fibrotic group and 1 death in the nonfibrotic group (p<0.0001). In the regression analysis, CT evidence of fibrosis, more severe pulmonary function abnormalities, and the presence of crackles on auscultation were predictive of reduced survival (p<0.05 for all). The presence as well as the extent of fibrosis on CT was associated with increased mortality. The age-adjusted hazard ratio for mortality in patients with fibrosis was 4.6 (95% confidence interval, 2.0 to 20.1; p<0.0001). CONCLUSION: CT findings of parenchymal fibrosis are associated with reduced survival in patients with HP and may serve as a useful prognostic indicator.

Causes and presenting features in 85 consecutive patients with hypersensitivity pneumonitis.

OBJECTIVE: To assess the current spectrum of causes and clinical features associated with hypersensitivity pneumonitis (HP). PATIENTS AND METHODS: We studied consecutive patients with HP diagnosed at the Mayo Clinic in Rochester, Minn, from January 1, 1997, through December 31, 2002. Diagnostic criteria for HP included the following: (1) presence of respiratory symptoms, (2) radiologic evidence of diffuse lung disease, (3) known exposure or a positive serologic test result to an inciting antigen, and (4) no other identifiable cause for the lung disease. If there was no identifiable inciting antigen, 1 of the following 2 criteria was required: (1) lung biopsy specimen that demonstrated features of HP or (2) bronchoalveolar lavage lymphocytosis and high-resolution computed tomographic evidence of ground-glass opacities or centrilobular nodules bilaterally. RESULTS: The mean +/- SD age of the 85 study patients was 53 +/- 14 years; 53 patients (62%) were women. Only 2 patients (2%) were current smokers. Chronic (> or = 4 months) respiratory symptoms were present in 66 patients (78%). Histopathologic confirmation was obtained in 64 patients (75%). The cause was identified in 64 patients (75%), and the most common causes were avian antigens (34%) and Mycobacterium avium complex in hot tub water (21%). Farmer's lung disease accounted for 11% of cases, and an additional 9% were related to household mold exposure. The inciting antigen was not identifiable in 25% of patients. CONCLUSION: Most patients with HP seen at this tertiary care referral center in the Midwest region of the United States had chronic HP, and the most common causes were exposure to birds and exposure to hot tubs.

Targeting B lymphocytes as therapy for ANCA-associated vasculitis.

This article focuses on the initial results achieved with the more selective immunosuppressive approach of B-lymphocyte depletion in patients who fail cyclophosphamide or have contraindications for its use in the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This novel approach has sparked hope for patients and physicians in their search for effective, well-tolerated therapy for AAV. B-cell depletion is now undergoing rigorous investigation in randomized clinical trials.

Airway involvement in Wegener's granulomatosis.

Wegener's granulomatosis is characterized by necrotizing granulomatous inflammation and necrotizing vasculitis affecting predominantly small arteries, arterioles, capillaries, and venules. In contrast to the well-described pulmonary parenchymal involvement of Wegener's granulomatosis, the lower airway (tracheobronchial) disease manifestations are less well recognized by clinicians. Consequently, mild disease of the airways is easily missed. There is a relative paucity of published information on various tracheobronchial manifestations of Wegener's granulomatosis. This article provides a comprehensive review of the diagnosis and management of the infraglottic tracheobronchial disease manifestations.

Portopulmonary hypertension.

As a result of the success of orthotopic liver transplantation, there has been increasing interest in the diagnosis and therapeutic options for the pulmonary vascular complications of hepatic disease. These pulmonary vascular complications range from the hepatopulmonary syndrome, which is characterized by intrapulmonary vascular dilatations, to portopulmonary hypertension (POPH), which is characterized by an elevated pulmonary vascular resistance as a consequence of obstruction to pulmonary arterial blood flow. This review concentrates on POPH.

Intrathoracic manifestations of Rosai-Dorfman disease.

INTRODUCTION: Rosai-Dorfman Disease (RDD), also known as Sinus Histiocytosis with Massive Lymphadenopathy (SHML), is a rare monocyte/macrophage proliferative disorder of varied biological behavior. Although cutaneous and lymph node involvement are relatively well-described, intrathoracic manifestations of RDD have only occasionally been reported. METHODS: We conducted a retrospective computer-assisted search of the Mayo Clinic record from 1976 to 2005 for patients with histopathologic evidence of RDD on organ biopsy. Clinical characteristics were abstracted from charts and thoracic manifestations recorded. Survival was estimated using the national social security database. RESULTS: A total of 21 patients were diagnosed with RDD over a period of 30 years; 9 had intrathoracic manifestations (43%). Main pulmonary symptoms included dyspnea and cough. Age at the time of diagnosis, gender, race, smoking history, mortality and time of survival after diagnosis were no different between RDD patients with and without intrathoracic manifestations. The most common radiographic thoracic manifestation was mediastinal lymphadenopathy (6 patients). Cystic change, interstitial lung disease, and airway disease were radiographically evident in 4 patients. Seven patients were treated at some point in the course of their disease, most commonly with oral corticosteroids. At the time of last follow-up 87% were alive, with a median (IQR) time interval since diagnosis of 8 years (4-9.7). CONCLUSIONS: Intrathoracic manifestations of RDD are relatively common and include mediastinal lymphadenopathy, airway disease, pleural effusion, cystic and interstitial lung disease. Although limited in size, this series suggests the prognosis of patients with RDD and intrathoracic manifestations is relatively good.

Obstructive sleep apnea, cardiovascular disease, and pulmonary hypertension.

With the growing epidemic of obesity in an aging population, obstructive sleep apnea (OSA) is increasingly encountered in clinical practice. Given the acute cardiopulmonary stressors consequent to repetitive upper airway collapse, as well as evidence for cardiovascular homeostatic dysregulation in subjects with sleep apnea, there is ample biologic plausibility that OSA imparts increased cardiovascular risk, independent of comorbid disease. Indeed, observational studies have suggested strong associations with multiple disorders, such as systemic hypertension, heart failure, cardiac arrhythmias, and pulmonary hypertension. Further data in the form of longitudinal cohort studies and randomized controlled trials are accruing to add to the body of evidence. This review examines pathophysiologic mechanisms and explores current concepts regarding the impact of OSA and its treatment on selected clinical disease states.

Moving beyond empiric continuous positive airway pressure (CPAP) trials for central sleep apnea: a multi-modality titration study.

There is no universally accepted method to determine effective therapy for central sleep apnea (CSA). Continuous positive airway pressure (CPAP) applied acutely most often does not eliminate apneas and hypopneas. We hypothesized that the application of two or more therapeutic modalities after the diagnostic phase of polysomnography, a multi-modality titration study (MMTS), would identify a successful CSA treatment more often than a standard split-night study (SNS) and obviate the need for additional polysomnograms to determine a successful therapy. We retrospectively analyzed polysomnograms of patients diagnosed with CSA at our Sleep Disorders Center. We defined a therapy trial that resulted in an apnea-hypopnea index < 10 with at least one treatment modality as a therapeutic success. One hundred fifteen patients with CSA were studied. Sixty-six patients (57.4%) underwent a SNS, and 49 patients (42.6%) underwent a MMTS. SNS yielded only 8/66 (12.1%) successes on the first night, whereas a MMTS yielded 19/49 (38.8%) successes (p = 0.001, two-tailed Fishers exact). Patients who underwent a SNS eventually had similar rate of success as patients studied with MMTS (60.6 vs 63.3%, NS), but required more testing. Adaptive servo-ventilation was the most successful modality tested, yielding 36/46 (78.3%) successes. Trials of additional modalities following a failed trial of CPAP often produce a successful option that may guide therapy in patients with CSA. This approach may lead to establishing the diagnosis and treatment plans faster, while reducing unnecessary testing.