Activation of a Latent Epitope Causing Differential Binding of Antineutrophil Cytoplasmic Antibodies to Proteinase 3.

OBJECTIVE: Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3-targeting ANCAs (PR3-ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity. METHODS: The recombinant PR3 variants, iPR3 (clinically used to detect PR3-ANCAs) and iHm5 (containing 3 point mutations in epitopes 1 and 5 generated for epitope mapping studies) immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) trials were used to screen for differential PR3-ANCA binding. A patient-derived monoclonal ANCA 518 (moANCA518) that selectively binds to iHm5 within the mutation-free epitope 3 and is distant from the point mutations of iHm5 was used as a gauge for remote epitope activation. Selective binding was determined using inhibition experiments. RESULTS: Rather than reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared to iPR3. This differential binding of PR3-ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3-2 also induced recognition by moANCA518. CONCLUSION: The preferential binding of PR3-ANCAs from patients, such as the selective binding of moANCA518 to iHm5, is conferred by increased antigenicity of epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding variable performance characteristics of immunoassays, and design of potential novel treatment approaches.

Pleuritis and Pericarditis in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

BACKGROUND: Pleural and pericardial involvements are well recognized in eosinophilic granulomatosis with polyangiitis (EGPA) but considered rare manifestations of the other forms of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). RESEARCH QUESTION: What are the frequency and clinical characteristics of pleuritis and pericarditis in AAV? STUDY DESIGN: and Methods: Using an institutional database of 1,830 patients with AAV, we analyzed clinical notes and diagnosis codes for key words related to pleuritis and pericarditis. Chart review to confirm these findings was performed. RESULTS: Eighty-eight of 1,058 patients (8.3%) with granulomatosis with polyangiitis (GPA), 27 of 267 (10.1%) with microscopic polyangiitis (MPA), and 35 of 201 (17.4%) with EGPA had a manifestation of pleuritis and/or pericarditis attributable to vasculitis. There was a higher frequency of pericarditis in EGPA compared with that in the other AAVs (P < .01). There was no difference in the frequency of pleuritis in GPA, MPA, or EGPA. In the 156 patients with AAV with pleuritis and/or pericarditis, this was a presenting feature in 127 (81.4%). Overall, it was a presenting feature in 6.9% of all patients with AAV, including 6.5% with GPA, 8.6% with MPA, and 15.9% with EGPA. INTERPRETATION: Pleuritis and pericarditis occur across all the AAVs and, when present, are commonly presenting features of these diseases. Patients with EGPA have a higher proportion of pericardial involvement compared with pleural involvement, whereas this distribution is more equal in patients with GPA and MPA. Pleuritis and pericarditis are underrecognized features of AAV. All forms of AAV should be considered in the differential diagnosis when evaluating a patient with pleuritis or pericarditis.

Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3 in ANCA-Associated Vasculitis.

Background: The utility of ANCA testing as an indicator of disease activity in ANCA-associated vasculitis (AAV) remains controversial. This study aimed to determine the association of ANCA testing by various methods and subsequent remission and examine the utility of a widely used automated addressable laser-bead immunoassay (ALBIA) to predict disease relapses. Methods: Data from the Rituximab vs. Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. ANCA testing was performed by direct ELISA, capture ELISA, and ALBIA. Cox proportional hazards regression models were used to evaluate the association of PR3-ANCA level and subsequent remission or relapse. The ALBIA results are routinely reported as >8 when the value is high. For this study, samples were further titrated. A decrease and increase in PR3-ANCA were defined as a halving or doubling in value, respectively. Results: A decrease in ANCA by ALBIA at 2 months was associated with shorter time to sustained remission (HR 4.52, p = 0.035). A decrease in ANCA by direct ELISA at 4 months was associated with decreased time to sustained remission (HR 1.77, p = 0.050). There were no other associations between ANCA decreases or negativity and time to remission. An increase in PR3-ANCA by ALBIA was found in 78 of 93 subjects (84%). Eleven (14%) had a PR3-ANCA value which required titration for detection of an increase. An increase of ANCA by ALBIA was associated with severe relapse across various subgroups. Conclusions: A decrease in ANCA by ALBIA at 2 months and by direct ELISA at 4 months may be predictive of subsequent remission. These results should be confirmed in a separate cohort with similarly protocolized sample and clinical data collection. A routinely used automated ALBIA for PR3-ANCA measurement is comparable to direct ELISA in predicting relapse in PR3-AAV. Without titration, 14% of the increases detected by ALBIA would have been missed. Titration is recommended when this assay is used for disease monitoring. The association of an increase in PR3-ANCA with the risk of subsequent relapse remains complex and is affected by disease phenotype and remission induction agent.

Efficacy of Rituximab and Plasma Exchange in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis with Severe Kidney Disease.

BACKGROUND: Treatment of patients with ANCA-associated vasculitis (AAV) and severe renal involvement is not established. We describe outcomes in response to rituximab (RTX) versus cyclophosphamide (CYC) and plasma exchange (PLEX). METHODS: A retrospective cohort study of MPO- or PR3-ANCA-positive patients with AAV (MPA and GPA) and severe kidney disease (eGFR <30 ml/min per 1.73 m2). Remission, relapse, ESKD and death after remission-induction with CYC or RTX, with or without the use of PLEX, were compared. RESULTS: Of 467 patients with active renal involvement, 251 had severe kidney disease. Patients received CYC (n=161) or RTX (n=64) for remission-induction, and 51 were also treated with PLEX. Predictors for ESKD and/or death at 18 months were eGFR <15 ml/min per 1.73 m2 at diagnosis (IRR 3.09 [95% CI 1.49 to 6.40], P=0.002), renal recovery (IRR 0.27 [95% CI 0.12 to 0.64], P=0.003) and renal remission at 6 months (IRR 0.40 [95% CI 0.18 to 0.90], P=0.027). RTX was comparable to CYC in remission-induction (BVAS/WG=0) at 6 months (IRR 1.37 [95% CI 0.91 to 2.08], P=0.132). Addition of PLEX showed no benefit on remission-induction at 6 months (IRR 0.73 [95% CI 0.44 to 1.22], P=0.230), the rate of ESKD and/or death at 18 months (IRR 1.05 [95% CI 0.51 to 2.18], P=0.891), progression to ESKD (IRR 1.06 [95% CI 0.50 to 2.25], P=0.887), and survival at 24 months (IRR 0.54 [95% CI 0.16 to 1.85], P=0.330). CONCLUSIONS: The apparent benefits and risks of using CYC or RTX for the treatment of patients with AAV and severe kidney disease are balanced. The addition of PLEX to standard remission-induction therapy showed no benefit in our cohort. A randomized controlled trial is the only satisfactory means to evaluate efficacy of remission-induction treatments in AAV with severe renal involvement.

Remote Activation of a Latent Epitope in an Autoantigen Decoded With Simulated B-Factors.

Mutants of a catalytically inactive variant of Proteinase 3 (PR3)-iPR3-Val103 possessing a Ser195Ala mutation relative to wild-type PR3-Val103-offer insights into how autoantigen PR3 interacts with antineutrophil cytoplasmic antibodies (ANCAs) in granulomatosis with polyangiitis (GPA) and whether such interactions can be interrupted. Here we report that iHm5-Val103, a triple mutant of iPR3-Val103, bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val103 was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val103 was due to increased main-chain flexibility of the latent epitope caused by remote mutations, suggesting rigidification of epitopes with therapeutics to alter pathogenic PR3·ANCA interactions as new GPA treatments.

Update on the Management of Respiratory Manifestations of the Antineutrophil Cytoplasmic Antibodies-Associated Vasculitides.

Antibody-associated vasculitis comprises 3 small vessel vasculitis syndromes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic polyangiitis (EGPA). This article outlines the major tracheobronchial and pulmonary parenchymal disease manifestations of GPA and MPA and their management, as well as relevant recent advances in the treatment of EGPA. Shared trends in the management of all 3 syndromes are: (1) a focus on glucocorticoid avoidance and (2) an increasing reliance on biologic agents. Evidence from randomized controlled trials and large cohort studies in support of these trends as well as ongoing research efforts are summarized.

A 40-Year-Old Man With Albinism and Progressive Dyspnea.

CASE PRESENTATION: A 40-year-old male subject employed as a grocery store manager presented to a pulmonary clinic with a dry cough and progressive dyspnea of 1 year duration. The patient was previously an avid cyclist and first noted his dyspnea when he was unable to bike as far as before. Bilateral interstitial lung infiltrates were recently noted on chest radiography. At the time of presentation, he could no longer cycle due to dyspnea. The patient's medical history was significant for albinism and severe visual impairment. He had no family history of albinism or pulmonary disorders. He had never smoked, drank alcohol only occasionally, and had no significant environmental exposures.

Resilience Among Medical Students: The Role of Coping Style and Social Support.

THEORY: Although medical students begin medical school with better mental health than their peers, during medical school students have a higher prevalence of psychological distress. Medical students often do not seek help for mental health concerns. The use of approach coping strategies and social support has been shown in other populations to be related to mental health resiliency. HYPOTHESES: The rates of depression and burnout in this medical student population are expected to be high, with the majority not seeking help for their psychological distress in accordance with studies of medical students across the nation. Perceptions of stigma are hypothesized to be a potential source of this lack of care-seeking behavior. Approach coping strategies and social support are speculated to have an inverse relationship with the prevalence of depression and burnout in the medical student population. METHOD: Validated measures of depression and burnout along with items pertaining to diagnosis and treatment of mental health issues, specific coping strategies used during stressful times, and perceptions of social support were used in a cross-sectional study of students at the University of North Dakota School of Medicine and Health Sciences (UND SMHS). RESULTS: The overall survey response rate was 64%. Seventeen percent had moderate to severe depression, and 49% had burnout. Of depressed respondents, 81% were undiagnosed. When asked why depression develops, 23% responded that it was due to an inability to cope. A significantly greater risk of depression was associated with inadequate support from family and friends (p = .002), fellow medical students (p = .01), and the UND SMHS (p = .003). Greater use of approach-oriented coping strategies than avoidant-oriented strategies was associated with significantly decreased risk of burnout (p = .02) and was inversely correlated with depression (rs = -0.27, n = 153, p = .001). CONCLUSIONS: This study outlines associations among approach-oriented coping strategies, social support, and resiliency to mental health issues among medical students. This study also supports the existing literature that stigma regarding mental health issues is present in the medical community. Further multi-institutional, longitudinal research to delineate whether interventions that promote approach coping style and utilization of social support lead to decreased rates of mental health issues is necessary. The development of these interventions will need to be a multifaceted approach that includes promotion of care-taking behaviors but also focuses on institutional cultural change in order to empower students to participate in these resiliency strategies.

Biopsy-proven pulmonary capillaritis: A retrospective study of aetiologies including an in-depth look at isolated pulmonary capillaritis.

BACKGROUND AND OBJECTIVE: Pulmonary capillaritis is generally secondary to a systemic autoimmune process. Little is known regarding other causes of pulmonary capillaritis, particularly isolated pulmonary capillaritis (IPC). IPC is defined as pulmonary capillaritis in the absence of evidence of a systemic disease. We aim to describe the aetiology of biopsy-proven pulmonary capillaritis to add to the existing knowledge on aetiologies of pulmonary capillaritis and provide a more detailed description of IPC cases. METHODS: A retrospective cohort of biopsy-proven pulmonary capillaritis was conducted at the Mayo Clinic, Rochester over a 17-year period. Histologic slides were re-reviewed by a lung pathologist. Medical records were reviewed to identify a possible aetiology of the pulmonary capillaritis. A subset analysis of patients identified with IPC was then performed. RESULTS: Thirty-six cases of biopsy-proven pulmonary capillaritis were identified. The majority of cases were secondary to a systemic autoimmune disease, most commonly granulomatosis with polyangiitis. There were four cases of IPC in this cohort. Median follow-up was 116.5 months with no evidence of systemic disease development. No risk factors for IPC were identified. All patients presented sub-acutely with haemoptysis and diffuse alveolar haemorrhage with a delay in diagnosis. After initiation of immunosuppression, most patients obtained remission with a benign clinical course. CONCLUSION: Pulmonary capillaritis is most commonly secondary to systemic autoimmune disorders, predominantly ANCA-associated vasculitis. IPC is a rare form of pulmonary capillaritis with very few cases described in the literature, the availability of effective treatment makes this rare disease important to recognize.

Does Cervical Screening in Young Women Aged 20-25 Years Lead to Unnecessary and Harmful Interventions?

BACKGROUND: Cervical human papillomavirus (HPV) infection among young women (20-25 years of age) is common and normally transient. There are growing concerns that referral to a colposcopy clinic may lead to unnecessary treatment with an increased risk of obstetric complications. Therefore, the purpose of this study was to determine the level of intervention for cervical abnormalities in this age group of the Northern Ireland population. MATERIALS AND METHODS: A review of all serial new patients under 25 years of age, who were referred to colposcopy clinics in Northern Ireland between January 1, 2009 to June 30, 2009 formed the basis of this study. RESULTS: During the study period, a total of 4,767 women under 25 years of age were screened. Two-hundred-and- thirty-four (4.9%) cases were referred to the colposcopy clinics. The cervical cytology results were: high-grade abnormality in 35%, and low-grade abnormality in 31% of these cases. One-hundred-and-seventy-eight (76%) of the referred women received at least one treatment. One-hundred-and-twenty-one of 234 (51.5%) women underwent an excisional treatment with histology showing the presence of high-grade abnormalities (CIN2-3) in 52%, CIN1 in 28%, and Koilocytosis or normal tissue in 20% of this sub-group of cases. CONCLUSIONS: Screening women under the age of 25 years cause unnecessary referral for colposcopy. This may also result in considerable anxiety and psychosexual morbidity. It leads to an over-treatment with a potential of negative impact on the future pregnancy outcomes (including pre-term delivery, low birth weight, and pre-term premature rupture of membranes).

Isolated pauciimmune pulmonary capillaritis successfully treated with rituximab.

Diffuse alveolar hemorrhage (DAH) is a syndrome caused by different mechanisms, including capillary stress failure, diffuse alveolar damage, and capillaritis. Capillaritis is the most common cause and is often associated with systemic autoimmune disorders, most commonly antineutrophilic cytoplasmic antibody-associated vasculitis. The occurrence of DAH with underlying pulmonary capillaritis but without clinical or serologic findings of an associated underlying systemic disorder is known as isolated pauciimmune pulmonary capillaritis (IPPC), and only eight cases have been described in the literature. The mainstay of treatment of this rare condition has been cyclophosphamide and glucocorticoids. When cases are unresponsive to cyclophosphamide, there is no known alternative treatment. Herein, we describe a case of IPPC that failed cyclophosphamide treatment with recurrent DAH. Rituximab therapy was then initiated with no further evidence of recurrence. This case report suggests that rituximab could be considered an alternative therapy to induce remission in patients with IPPC.

Impact of the Electronic Medical Record on Mortality, Length of Stay, and Cost in the Hospital and ICU: A Systematic Review and Metaanalysis.

OBJECTIVE: To evaluate effects of health information technology in the inpatient and ICU on mortality, length of stay, and cost. Methodical evaluation of the impact of health information technology on outcomes is essential for institutions to make informed decisions regarding implementation. DATA SOURCES: EMBASE, Scopus, Medline, the Cochrane Review database, and Web of Science were searched from database inception through July 2013. Manual review of references of identified articles was also completed. STUDY SELECTION: Selection criteria included a health information technology intervention such as computerized physician order entry, clinical decision support systems, and surveillance systems, an inpatient setting, and endpoints of mortality, length of stay, or cost. Studies were screened by three reviewers. Of the 2,803 studies screened, 45 met selection criteria (1.6%). DATA EXTRACTION: Data were abstracted on the year, design, intervention type, system used, comparator, sample sizes, and effect on outcomes. Studies were abstracted independently by three reviewers. DATA SYNTHESIS: There was a significant effect of surveillance systems on in-hospital mortality (odds ratio, 0.85; 95% CI, 0.76-0.94; I=59%). All other quantitative analyses of health information technology interventions effect on mortality and length of stay were not statistically significant. Cost was unable to be quantitatively evaluated. Qualitative synthesis of studies of each outcome demonstrated significant study heterogeneity and small clinical effects. CONCLUSIONS: Electronic interventions were not shown to have a substantial effect on mortality, length of stay, or cost. This may be due to the small number of studies that were able to be aggregately analyzed due to the heterogeneity of study populations, interventions, and endpoints. Better evidence is needed to identify the most meaningful ways to implement and use health information technology and before a statement of the effect of these systems on patient outcomes can be made.

Novice nurses' first death in critical care.

BACKGROUND: The curative focus of critical care and the advanced technology may overshadow the fact that critically ill patients die. Research investigating critical care nurses involvement with death has predominately focused on experienced nurses, but these findings may not be applicable to novice nurses. Increasingly, novice nurses are beginning their careers in critical care and there is minimal research describing their experiences with death. PURPOSE: To explore the experiences of novice nurses with their first patient death in critical care. METHOD: Approval was received by the University of Alberta Health Research Ethics Board and the health region's Nursing Division Administration to conduct a qualitative research study. Five nurses, employed in a medical-surgical intensive care unit, participated in the study. Data collection involved an unstructured interview with each participant. FINDINGS: Analysis of the data revealed five themes: anticipating death, transition from life to death, the moment of death, being with the family, and carrying on. These findings are discussed with implications for academic and clinical settings and suggestions for future nursing research.