Newer Biological Agents in the Treatment of Severe Asthma: Real-World Results from a Tertiary Referral Center.

PURPOSE: To determine the efficacy of IL-5 inhibitory therapy in severe, refractory asthma in a real-world clinical setting from a tertiary referral center. METHODS: A retrospective chart review of patients with severe asthma treated with IL-5 biologic therapy for ≥ 6 months at Mayo Clinic in Rochester, Minnesota between January 1, 2013 and August 31, 2019. RESULTS: Over the study period, we identified 63 patients with a mean age of 54 who received an IL-5 inhibitor for ≥ 6 months. A total of 55 patients received mepolizumab, 2 received benralizumab, and 9 patients received both. Patients were followed up for a mean of 25 months. The mean number of months of oral prednisone use prior to biologic initiation was 64. There was a significant reduction in the median dose of prednisone in the 24 months after drug initiation (15 mg vs. 0 mg; p = < 0.0001). Similarly; there was a significant decline in the median number of asthma exacerbations in the 24 months before and after drug initiation (7 vs. 2; p = < 0.0001). The mean number of emergency room (ER) visits and hospitalizations decreased from 5.1 and 2.0 to 1.6 and 0.4 in the 24 months before and after therapy initiation (p < 0.0001 and p = 0.007, respectively) CONCLUSIONS: IL-5 inhibitory therapy is associated with significant and long-term sustained reductions in asthma exacerbation frequency, ER visits, hospitalizations, as well as oral steroid usage in a patient population with refractory steroid-dependent asthma referred to a tertiary referral center.

Eosinophilic Granulomatosis With Polyangiitis: Clinical Predictors of Long-term Asthma Severity.

BACKGROUND: The long-term clinical course of asthma in patients with eosinophilic granulomatosis with polyangiitis (EGPA) remains unclear. We aimed to characterize long-term asthma in EGPA and to identify baseline predictors of long-term asthma severity. METHODS: This retrospective cohort study included patients who fulfilled standardized criteria for EGPA who were followed up in a single referral center between 1990 and 2017. Baseline and 3 (± 1) years of follow-up clinical, laboratory, and pulmonary function data were analyzed. RESULTS: Eighty-nine patients with EGPA and a documented asthma assessment at baseline and at 3 years from diagnosis were included. Severe/uncontrolled asthma was observed in 42.7% of patients at diagnosis and was associated with previous history of respiratory allergy (P < .01), elevated serum total IgE levels (P < .05), and increased use of high-dose inhaled corticosteroids (ICSs; P < .05) and oral corticosteroids (OCSs; P < .001) for respiratory symptoms the year before the EGPA diagnosis. During follow-up, an improvement or worsening in asthma severity was noted in 12.3% and 10.1% of patients, respectively. Severe/uncontrolled asthma was present in 40.5% of patients at 3 years and was associated with increased airway resistance on pulmonary function tests (PFTs; P < .05). Long-term PFTs did not improve during long-term follow-up regardless of ICS or OCS therapy. Multivariate binary logistic regression results indicated that severe rhinosinusitis (P = .038), pulmonary infiltrates (P = .011), overweight (BMI ≥ 25 kg/m2; P = .041), and severe/uncontrolled asthma at vasculitis diagnosis (P < .001) independently predicted severe/uncontrolled asthma at the 3-year end point. CONCLUSIONS: In patients with asthma with EGPA, long-term severe/uncontrolled asthma is associated with baseline pulmonary and ear, nose, and throat manifestations but not with clear-cut vasculitic features.

Asthma control in eosinophilic granulomatosis with polyangiitis treated with rituximab.

OBJECTIVES: Rituximab (RTX) treatment is used for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, but its benefits in eosinophilic granulomatosis with polyangiitis (EGPA) are unclear. Our aim was to characterize asthma control and glucocorticoid (GC) sparing after RTX treatment. METHODS: A retrospective, computer-assisted search was performed to identify patients with EGPA and GC-dependent asthma diagnosed between 2000 and 2017 who received RTX for remission induction. Demographic and clinical features were analyzed. RESULTS: Of the 17 patients included, the majority were myeloperoxidase-ANCA positive (n = 13, 76.5%). Uncontrolled asthma symptoms and atopy were present in 13 patients (76.5%). RTX was used for initial remission induction in patients with new onset of severe disease (n = 5, 29.4%) and after failed remission induction with other immunosuppression (n = 12, 70.6%). It was used for remission maintenance in nine patients (52.9%). GCs were used for maintenance at a median dose of 25 mg/day (interquartile range, 16.25-37.5). At the end of follow-up, 13 patients (76.5%) had non-severe or controlled asthma, and remission was achieved in 12 (70.6%). Median serum eosinophil and C-reactive protein values decreased (1.06 vs 0.10 × 109/L [P = .012] and 27.0 vs 5.0 mg/dL [P = .001], respectively), whereas pulmonary function test results remained unchanged. Median GC dose was significantly reduced at 6, 12, 18, and 24 months (P < .0001). Patients receiving RTX for maintenance required less than 10 mg of GCs for asthma control. CONCLUSION: RTX seems to be safe and have GC-sparing efficacy for asthma control in EGPA. Randomized controlled trials are needed for detailed study of RTX for treating EGPA.Key Points• In this retrospective study we have concluded that rituximab (RTX) might be considered for the control of severe corticosteroid-dependent asthma in eosinophilic granulomatosis polyangiitis (EGPA) patients especially when myeloperoxidase antibodies are positive.• Rituximab has not been studied particularly for asthma control in EGPA patients.• The most noticeable effect of RTX was the decrease in the use of corticosteroids for the control of asthma.

Chronic rhinosinusitis in eosinophilic granulomatosis with polyangiitis: clinical presentation and antineutrophil cytoplasmic antibodies.

BACKGROUND: In this study we aim to describe presenting characteristics and identify prognostic factors for disease resolution in patients with chronic rhinosinusitis (CRS) in the setting of eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: Patients evaluated at a tertiary care center with diagnoses of EGPA and CRS were identified. Descriptive statistics were obtained. Univariate analysis was used to search for prognostic factors associated with higher Lund-Mackay score at presentation and disease resolution. RESULTS: Forty-four patients were included with a mean age of 52.7 (standard deviation, 14) years. Twenty-one patients (47.7%) were female, all had a diagnosis of asthma, and 36 (83.7%) had eosinophils >10%. Common presenting symptoms for CRS included nasal discharge (87.9%) followed by nasal congestion (83.9%) and facial pain and pressure (83.8%). Medical management of CRS included systemic corticosteroids (93.2%) and systemic antibiotics (75%). Surgical intervention occurred in 29 patients (67%). Nine patients (20.5%) had resolution of sinus symptoms, including 4 with imaging confirmation. Fourteen patients (31.8%) had continued CRS, but with improved symptoms, whereas 9 patients (20.5%) had continued CRS with no improvement in symptoms. Eleven patients (25%) were lost to follow-up and 4 (9.1%) died. Univariate analysis did not show antineutrophil cytoplasmic antibody positivity, presence of peripheral eosinophilia, gender, age, or absence of systemic therapy to be predictive of higher Lund-Mackay score at presentation or predictive of disease resolution. CONCLUSION: CRS in patients with EGPA is often refractory to medical and surgical management. Treatment of these patients should occur in a multidisciplinary setting.

Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors. METHODS: VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV). RESULTS: VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566-185.805]; P = 0.005), PR3-ANCA (HR 9.12 [95% CI 1.158-71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453-10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607-75.075]; P < 0.001) remained. CONCLUSION: Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3-ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.

Severe/uncontrolled asthma and overall survival in atopic patients with eosinophilic granulomatosis with polyangiitis.

BACKGROUND: Although asthma, rhinitis/rhinosinusitis and peripheral eosinophilia are present in virtually all patients with eosinophilic granulomatosis with polyangiitis (EGPA), the role of atopy in these patients is not well defined. OBJECTIVE: To clarify the role of atopy in patients affected with EGPA. METHODS: Clinical, laboratory and standard spirometry data have been abstracted from medical records. Only patients who underwent skin and/or specific IgE testing for common aeroallergens before the vasculitic phase were included. RESULTS: Overall, 33.5% (63) of our patients underwent skin and/or specific IgE testing to aeroallergens. Atopy related to aeroallergens was confirmed in 22.3% (two-third of those tested), and was associated with more severe/uncontrolled asthma (p < 0.001), including a greater use of oral glucocorticoids for respiratory manifestations the year before the diagnosis of EGPA (p = 0.013). Atopic patients with EGPA had higher total serum IgE levels and less renal disease at EGPA diagnosis compared to non-atopic patients (p < 0.05). Among atopic patients, the majority had multiple sensitizations (76%); dust mite and grass pollen were the most common respiratory allergens identified. The number of allergens did not correlate with peripheral eosinophilia, total serum IgE, ESR, or measures of airway obstruction (p > 0.05 in all cases). The presence of atopy increased the risk of severe/uncontrolled asthma, but not the risk of severe vasculitis (Five Factor Score≥1). Atopic patients had a better overall survival (p = 0.027). CONCLUSION: In EGPA, atopy is associated with better prognosis and more severe/uncontrolled asthma manifestations in the year before the development of vasculitis, but not with more severe vasculitis at presentation.

Treatment of Interstitial Lung Disease Associated Cough: CHEST Guideline and Expert Panel Report.

BACKGROUND: Chronic cough in interstitial lung disease (ILD) causes significant impairment in quality of life. Effective treatment approaches are needed for cough associated with ILD. METHODS: This systematic review asked: Is there evidence of clinically relevant treatment effects for therapies for cough in ILD? Studies of adults aged > 18 years with a chronic cough ≥ 8 weeks' duration were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on by using CHEST guideline methodology. RESULTS: Eight randomized controlled trials and two case series (≥ 10 patients) were included that reported data on patients with idiopathic pulmonary fibrosis, sarcoidosis, and scleroderma-related ILD who received a variety of interventions. Study quality was high in all eight randomized controlled trials. Inhaled corticosteroids were not supported for cough associated with sarcoidosis. Cyclophosphamide and mycophenolate were not supported for solely treating cough associated with scleroderma-associated ILD. A recommendation for thalidomide to treat cough associated with idiopathic pulmonary fibrosis did not pass the panel vote. In view of the paucity of antitussive treatment options for refractory cough in ILD, the guideline panel suggested that the CHEST unexplained chronic cough guideline be followed by considering options such as the neuromodulator gabapentin and speech pathology management. Opiates were also suggested for patients with cough refractory to alternative therapies. CONCLUSIONS: The evidence supporting the management of chronic cough in ILD is limited. This guideline presents suggestions for managing and treating cough on the best available evidence, but future research is clearly needed.

The Diagnostic Accuracy of Fractional Exhaled Nitric Oxide Testing in Asthma: A Systematic Review and Meta-analyses.

OBJECTIVE: To evaluate the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) measurement in individuals with suspected asthma. METHODS: We searched MEDLINE, EMBASE, PsycINFO, Cochrane databases, and SciVerse Scopus from the databases' inception through April 4, 2017, for studies that enrolled patients aged 5 years and older with suspected asthma and evaluated FeNO diagnostic accuracy. Independent reviewers selected studies and extracted data. We used the symmetric hierarchical summary receiver operating characteristic models to estimate test performance. RESULTS: We included 43 studies with a total of 13,747 patients. In adults, using FeNO cutoffs of less than 20, 20 to 29, 30 to 39, and 40 or more parts per billion, FeNO testing had sensitivities of 0.80, 0.69, 0.53, and 0.41, respectively, and specificities of 0.64, 0.78, 0.85, and 0.93, respectively. In children, using FeNO cutoffs of less than 20 and 20 to 29 parts per billion, FeNO testing had sensitivities of 0.78 and 0.61, respectively, and specificities of 0.79 and 0.89, respectively. Depending on the FeNO cutoff, the posttest odds of having asthma with a positive FeNO test result increased by 2.80- to 7.00-fold. Diagnostic accuracy was modestly better in corticosteroid-naive asthmatics, children, and nonsmokers than in the overall population. CONCLUSION: Fractional exhaled nitric oxide measurement has moderate accuracy to diagnose asthma in individuals aged 5 years and older. Test performance may be modestly better in corticosteroid-naive asthmatics, children, and nonsmokers than in the general population with suspected asthma. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) Identifier: CRD42016047887.

Azithromycin for the Treatment of Obliterative Bronchiolitis after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.

Obliterative bronchiolitis (OB) is a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Our objective was to perform a systematic review and meta-analysis of the impact of azithromycin on change in forced expiratory volume in 1 second (FEV1). We searched MEDLINE, EMBASE, Web of Science, Cochrane CENTRAL and Scopus databases and included studies that compared azithromycin with placebo or no intervention in the treatment of OB or bronchiolitis obliterans syndrome (BOS) in patients who had undergone allogeneic HSCT. Ninety-one unique publications were identified, and 4 studies met inclusion criteria, with a total of 90 patients. Changes in FEV1 were measured between 12 and 24 weeks after initiation of treatment. The meta-analysis demonstrated a mean increase in FEV1 of 30 mL (95% confidence interval, -260 to +330 mL; P = .82) after initiation of azithromycin. One patient death was reported but not attributed to azithromycin therapy. In conclusion, current evidence can neither support nor refute the use of azithromycin in the treatment of patients who develop OB/BOS after HSCT. Further studies are needed to determine whether azithromycin is beneficial for the treatment of OB/BOS in this setting.

Bilateral Thyroarytenoid Botulinum Toxin Type A Injection for the Treatment of Refractory Chronic Cough.

IMPORTANCE: Refractory chronic cough is a debilitating condition with limited therapeutic options. Laryngeal botulinum toxin type A (BtxA) has been anecdotally reported to benefit patients with chronic cough. We report on our experience with the use of BtxA for the treatment of patients with refractory chronic cough. OBJECTIVE: To describe the effects of electromyography (EMG)-guided thyroarytenoid (TA) BtxA injection for the treatment of refractory chronic cough. DESIGN, SETTING, AND PARTICIPANTS: For this single tertiary referral center retrospective case series, we included all patients with refractory chronic cough who received bilateral EMG-guided TA BtxA injections (n = 22) between July 1, 2013, and July 31, 2014, at the Mayo Clinic in Rochester, Minnesota. INTERVENTION: Bilateral TA BtxA injection. MAIN OUTCOMES AND MEASURES: The primary outcome is a self-reported improvement of 50% or more in cough severity and/or symptoms by a 2-month follow-up telephone call. Adverse events and patient-reported quality measures were also assessed. RESULTS: A total of 22 patients (median [interquartile range] age 61 [57.5-85] years; 19 of 22 women) underwent 31 distinct laryngeal BtxA treatment sessions. The primary outcome of self-reported improvement of 50% or more of cough severity and/or symptoms was achieved in 16 of 31 (52%) treatment sessions. Eleven patients (50%) reported greater than 50% improvement after the first BtxA injection. No major complications occurred. Postprocedural liquid dysphagia had a positive predictive value of 84% and negative predictive value of 100% for response to therapy. CONCLUSIONS AND RELEVANCE: In this case series, laryngeal BtxA injection was well tolerated in patients with refractory chronic cough with half of participants experiencing at least short-term improvement in their cough. The occurrence of liquid dysphagia after a BtxA injection appeared to be predictive of a beneficial response. The durability of response, patient selection criteria, and optimal BtxA dosage remains to be determined.

Somatic Cough Syndrome (Previously Referred to as Psychogenic Cough) and Tic Cough (Previously Referred to as Habit Cough) in Adults and Children: CHEST Guideline and Expert Panel Report.

BACKGROUND: We conducted a systematic review on the management of psychogenic cough, habit cough, and tic cough to update the recommendations and suggestions of the 2006 guideline on this topic. METHODS: We followed the American College of Chest Physicians (CHEST) methodologic guidelines and the Grading of Recommendations, Assessment, Development, and Evaluation framework. The Expert Cough Panel based their recommendations on data from the systematic review, patients' values and preferences, and the clinical context. Final grading was reached by consensus according to Delphi methodology. RESULTS: The results of the systematic review revealed only low-quality evidence to support how to define or diagnose psychogenic or habit cough with no validated diagnostic criteria. With respect to treatment, low-quality evidence allowed the committee to only suggest therapy for children believed to have psychogenic cough. Such therapy might consist of nonpharmacologic trials of hypnosis or suggestion therapy, or combinations of reassurance, counseling, and referral to a psychologist, psychotherapy, and appropriate psychotropic medications. Based on multiple resources and contemporary psychologic, psychiatric, and neurologic criteria (Diagnostic and Statistical Manual of Mental Disorders, 5th edition and tic disorder guidelines), the committee suggests that the terms psychogenic and habit cough are out of date and inaccurate. CONCLUSIONS: Compared with the 2006 CHEST Cough Guidelines, the major change in suggestions is that the terms psychogenic and habit cough be abandoned in favor of somatic cough syndrome and tic cough, respectively, even though the evidence to do so at this time is of low quality.

Assessment of Intervention Fidelity and Recommendations for Researchers Conducting Studies on the Diagnosis and Treatment of Chronic Cough in the Adult: CHEST Guideline and Expert Panel Report.

BACKGROUND: Successful management of chronic cough has varied in the primary research studies in the reported literature. One of the potential reasons relates to a lack of intervention fidelity to the core elements of the diagnostic and/or therapeutic interventions that were meant to be used by the investigators. METHODS: We conducted a systematic review to summarize the evidence supporting intervention fidelity as an important methodologic consideration in assessing the effectiveness of clinical practice guidelines used for the diagnosis and management of chronic cough. We developed and used a tool to assess for five areas of intervention fidelity. Medline (PubMed), Scopus, and the Cochrane Database of Systematic Reviews were searched from January 1998 to May 2014. Guideline recommendations and suggestions for those conducting research using guidelines or protocols to diagnose and manage chronic cough in the adult were developed and voted upon using CHEST Organization methodology. RESULTS: A total of 23 studies (17 uncontrolled prospective observational, two randomized controlled, and four retrospective observational) met our inclusion criteria. These articles included 3,636 patients. Data could not be pooled for meta-analysis because of heterogeneity. Findings related to the five areas of intervention fidelity included three areas primarily related to the provider and two primarily related to the patients. In the area of study design, 11 of 23 studies appeared to be underpinned by a single guideline/protocol; for training of providers, two of 23 studies reported training, and zero of 23 reported the use of an intervention manual; and for the area of delivery of treatment, when assessing the treatment of gastroesophageal reflux disease, three of 23 studies appeared consistent with the most recent guideline/protocol referenced by the authors. For receipt of treatment, zero of 23 studies mentioned measuring concordance of patient-interventionist understanding of the treatment recommended, and zero of 23 mentioned measuring enactment of treatment, with three of 23 measuring side effects and two of 23 measuring adherence. The overall average intervention fidelity score for all 23 studies was poor (20.74 out of 48). CONCLUSIONS: Only low-quality evidence supports that intervention fidelity strategies were used when conducting primary research in diagnosing and managing chronic cough in adults. This supports the contention that some of the variability in the reporting of patients with unexplained or unresolved chronic cough may be due to lack of intervention fidelity. By following the recommendations and suggestions in this article, researchers will likely be better able to incorporate strategies to address intervention fidelity, thereby strengthening the validity and generalizability of their results that provide the basis for the development of trustworthy guidelines.

Primary antiphospholipid syndrome-associated diffuse alveolar hemorrhage.

OBJECTIVE: Diffuse alveolar hemorrhage (DAH) is an uncommon complication of primary antiphospholipid syndrome (APS). We aimed to describe the clinical characteristics, treatment, and outcomes of primary APS-associated DAH in a single center. METHODS: We conducted a retrospective review of all adults with primary APS-associated DAH evaluated at Mayo Clinic over a 15-year period. DAH was defined as bilateral pulmonary infiltrates and bronchoalveolar lavage (BAL) fluid documenting progressively bloody returns and/or the presence of >20% hemosiderin-laden macrophages. Patients with other causes of DAH were excluded. RESULTS: Eighteen patients were identified (median age 43 years). Capillaritis was present in surgical lung biopsy samples of 3 patients. BAL differential cell counts revealed predominantly neutrophils. All patients were treated initially with glucocorticoids. Cyclophosphamide (CYC) was used in 8 patients; complete remission was achieved in 3 patients treated with CYC alone and in 1 patient receiving combination therapy with rituximab (RTX). RTX was used in 9 patients; 2 patients achieved remission with RTX alone, whereas 3 patients required combination therapy with CYC or mycophenolate mofetil (MMF). No patient achieved complete remission while receiving single therapy with MMF, azathioprine, or plasma exchange. Intravenous gamma globulin therapy was administered in 5 patients; no patient achieved control of the disease. Six patients died, all because of complications related to uncontrolled DAH or its therapy. CONCLUSION: We present the largest case series of primary APS-associated DAH reported in the literature. DAH carries a very poor prognosis and therapeutic options are limited. Immunosuppression with either CYC or RTX is associated with the highest likelihood of remission induction and should be considered early.

IgG4-positive plasma cells in granulomatosis with polyangiitis (Wegener's): a clinicopathologic and immunohistochemical study on 43 granulomatosis with polyangiitis and 20 control cases.

Granulomatosis with polyangiitis (GPA) (Wegener's) may mimic IgG4-related disease (IgG4-RD) on histologic examination of some biopsies, especially those from head and neck sites. IgG4 immunostaining is often performed in this context for differential diagnosis with IgG4-RD. Herein, we report the results of IgG4-positive (IgG4+) cells in 43 cases of GPA including 26 previously published cases as well as the newly added cases from the lung and kidney. We also included 20 control cases without any clinical evidence of GPA or IgG4-RD that consisted of chalazion (n = 8), chronic sinusitis (n = 8), and chronic tonsillitis (n = 4). Forty-three biopsies diagnosed as GPA were from sinonasal mucosa/oral cavity/nasopharynx (n = 14), orbit/periorbital tissue (n = 7), lung/pleura (n = 14), kidney (n = 4), skin (n = 3), and dura (n = 1). Of 43 biopsies, 8 (18.6%) revealed increased IgG4+ cells (>30 per high-power field and >40% in IgG4+/IgG+ ratio) and originated from sinonasal (n = 4) or orbital/periorbital (n = 4) regions. The IgG4+ cells and IgG4+/IgG+ ratio in these cases ranged from 37 to 139 per high-power field and 44% to 83%, respectively. None of the control cases had increased IgG4+ cells. In conclusion, increased IgG4+ cells can be seen in sinonasal or orbital/periorbital biopsies of GPA, which could pose as a pitfall in the diagnosis of IgG4-RD. However, GPA in other organs and controls did not show increased IgG4+ cells when using the above threshold. The biologic or clinical importance of increased IgG4+ cells in GPA cases involving head and neck region is uncertain, and a further study might be warranted to address the potential pathogenic relationship between IgG4-RD and GPA in those cases.

Efficacy of remission-induction regimens for ANCA-associated vasculitis.

BACKGROUND: The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is unknown. METHODS: In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months. RESULTS: A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide-azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P=0.01) and at 12 months (P=0.009) but not at 18 months (P=0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. CONCLUSIONS: In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

Long-term safety of nebulized lidocaine for adults with difficult-to-control chronic cough: a case series.

BACKGROUND: The long-term safety of patient-administered nebulized lidocaine for control of chronic cough has not been established. METHODS: We performed a retrospective study of adults who received a prescription and nurse education for nebulized lidocaine for chronic cough between 2002 and 2007. A survey questionnaire inquiring about adverse reactions and the effectiveness of nebulized lidocaine was developed and administered to these individuals after the nebulized lidocaine trial. We conducted two mailings and a postmailing phone follow-up to nonresponders. When adverse events were reported in the questionnaire response, a structured phone interview was conducted to obtain additional details. RESULTS: Of 165 eligible patients, 99 (60%) responded to the survey. Responders were a median age of 62 years (range, 29-87 years); 77 (79%) were women, and 80 (82%) were white. The median duration of cough was 5 years before treatment with nebulized lidocaine. Of the patients who used nebulized lidocaine (93% of survey responders), 43% reported an adverse event. However, none of these events required an emergency visit, hospitalization, or antibiotic therapy for aspiration pneumonia. The mean (SD) of the pretreatment cough severity score was 8.4 (1.6) and posttreatment was 5.9 (3.4) (P < .001). Of the patients reporting improvement in cough symptoms (49%), 80% reported improvement within the first 2 weeks. CONCLUSIONS: Adults tolerated self-administration of nebulized lidocaine for difficult-to-control chronic cough. No serious adverse effects occurred while providing symptomatic control in 49% of patients.

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.

Increased IgG4-Positive Plasma Cells in Granulomatosis with Polyangiitis: A Diagnostic Pitfall of IgG4-Related Disease.

Granulomatosis with polyangiitis (Wegener's) (GPA) may mimic IgG4-related disease (IgG4-RD) on histologic examination of some biopsies, especially those from head and neck sites. IgG4 immunostain is often performed in this context for differential diagnosis with IgG4-RD. However, the prevalence of IgG4+ cells in GPA has not been explored. We examined the IgG4+ cells in 26 cases confirmed as GPA by a thorough clinical and pathologic assessment. Twenty-six biopsies consisted of 14 sinonasal/oral cavity/nasopharynx, 7 orbit/periorbital, 3 lung/pleura, 1 iliac fossa/kidney, and 1 dura specimens. Eight of 26 (31%) biopsies revealed increased IgG4+ cells (>30/HPF and >40% in IgG4+/IgG+ ratio). The IgG4+ cells and IgG4+/IgG+ ratio ranged 37-137/hpf and 44-83%, respectively. Eight biopsies with increased IgG4+ cells were from sinonasal (n = 4) or orbital/periorbital (n = 4) sites. In conclusion, increased IgG4+ cells are not uncommonly seen in sinonasal or orbital/periorbital biopsies of GPA, which could pose as a diagnostic pitfall.

Rituximab for the treatment of Churg-Strauss syndrome with renal involvement.

INTRODUCTION: Churg-Strauss syndrome (CSS) is a small vessel systemic vasculitis associated with asthma and eosinophilia that causes glomerulonephritis (GN) in ∼25% of patients. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody that depletes B cells and is effective in numerous autoimmune diseases including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We aim to evaluate the safety and efficacy of RTX in inducing remission of renal disease activity in patients with CSS. METHODS: We conducted a single-center, open-label pilot study using RTX (375 mg/m(2)/week × 4) for induction of remission in CSS patients with renal involvement [defined as having >25% dysmorphic red cells, red blood cell casts or pauci-immune GN on biopsy]. Written informed consent was obtained from all individuals. Patients were eligible if they were untreated, had failed glucocorticoid therapy or had failed glucocorticoid dose reductions because of disease relapses. The primary outcome was remission of renal disease activity defined as stability or improvement of creatinine clearance, absence of active urinary sediment and reduction of the glucocorticoid dose to <50% of the average dose received over 3 months before enrollment or <10 mg/day (whichever is smaller) at 6 months. Patients were followed up for 1 year. RESULTS: Only three patients (two females; ages 54, 55 and 65) were enrolled. All patients had positive myeloperoxidase-ANCA and renal involvement. Two patients had biopsy-proven pauci-immune crescentic GN. All achieved the primary end point of renal remission within the first 3 months and remained in renal remission during the year following RTX treatment. One patient experienced a nonrenal relapse (eye and joint involvement) at 6 months coinciding with the reconstitution of CD19+ cells and eosinophilia. He was retreated with RTX and achieved remission within 6 weeks. No major adverse effects were recorded. CONCLUSIONS: In this pilot study, RTX was safe and successful in controlling renal disease activity in three patients with CSS. This agent deserves further study in CSS.

Rituximab versus cyclophosphamide for ANCA-associated vasculitis.

BACKGROUND: Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS: We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS: Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)