Search

Proteinase 3 (PR3) is the major antigen for anti-neutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3 anti-neutrophil cytoplasmic antibodies (PR3-ANCAs) recognize different epitopes on PR3. We aimed to study the effect of mutations on PR3 antigenicity.The recombinant PR3 variants, iPR3 (clinically used to detect PR3-ANCAs) and iHm5 (containing three point mutations in Epitope 15 generated for epitope mapping studies, immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) trials were used to screen the differential PR3-ANCA binding. A patient-derived monoclonal ANCA (moANCA518) that selectively binds to iHm5 within the mutation-free Epitope 3 and distant from the point mutations of iHm5 was used as a gauge of remote epitope activation. Selective binding was determined by inhibition experiments.Rather than reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared with 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.The preferential binding of PR3-ANCAs from patients like 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 MCPR-2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding of variable performance characteristics of immunoassays and design of potential novel treatment approaches. This article is protected by copyright. All rights reserved.

ObjectivesSevere infections contribute to morbidity and mortality in antineutrophil cytoplasm antibody-associated vasculitis (AAV). This study aimed to identify risk factors associated with severe infections in participants of the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial.MethodsData on 197 patients recruited into the RAVE trial were analysed. Participants received either rituximab (RTX) or cyclophosphamide (CYC), followed by azathioprine (AZA). Clinical and laboratory data of patients with and without severe infections (≥grade 3, according to the Common Terminology Criteria for Adverse Events version 3.0) were compared. Risk factors for severe infections were investigated using Cox-regression models.ResultsEighteen of 22 (82%) severe infections occurred within 6 months after trial entry, most commonly respiratory tract infections (15/22, 68%). At baseline, lower absolute numbers of CD19+ cells were observed in patients with severe infections either receiving RTX or CYC/AZA at baseline, while CD5+B and CD3+T cells did not differ between groups. In Cox-regression analysis, higher baseline serum immunoglobulin M levels were associated with the risk of severe infections, whereby a higher baseline total CD19+B cell number and prophylaxis againstPneumocystis jiroveciiwith trimethoprim-sulfamethoxazole (TMP/SMX) with decreased risk of severe infections. Use of TMP/SMX was associated with lower risk of severe infections in both groups, receiving either RTX or CYC/AZA.ConclusionsThe use of low-dose TMP/SMX is associated with reduced risk of severe infections in patients with AAV treated with either RTX or CYC/AZA. Reduced B cell subpopulations at start of treatment might be a useful correlate of reduced immunocompetence.

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ., Objective: To develop and validate updated classification criteria for giant cell arteritis (GCA). Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in six phases: (1) identification of candidate items, (2) prospective collection of candidate items present at the time of diagnosis, (3) expert panel review of cases, (4) data-driven reduction of candidate items, (5) derivation of a points-based risk classification score in a development data set and (6) validation in an independent data set. Results: The development data set consisted of 518 cases of GCA and 536 comparators. The validation data set consisted of 238 cases of GCA and 213 comparators. Age ≥50 years at diagnosis was an absolute requirement for classification. The final criteria items and weights were as follows: positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5); erythrocyte sedimentation rate ≥50 mm/hour or C reactive protein ≥10 mg/L (+3); sudden visual loss (+3); morning stiffness in shoulders or neck, jaw or tongue claudication, new temporal headache, scalp tenderness, temporal artery abnormality on vascular examination, bilateral axillary involvement on imaging and fluorodeoxyglucose-positron emission tomography activity throughout the aorta (+2 each). A patient could be classified as having GCA with a cumulative score of ≥6 points. When these criteria were tested in the validation data set, the model area under the curve was 0.91 (95% CI 0.88 to 0.94) with a sensitivity of 87.0% (95% CI 82.0% to 91.0%) and specificity of 94.8% (95% CI 91.0% to 97.4%). Conclusion: The 2022 American College of Rheumatology/EULAR GCA classification criteria are now validated for use in clinical research.

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ., Objective: To develop and validate new classification criteria for Takayasu arteritis (TAK). Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in six phases: (1) identification of candidate criteria items, (2) collection of candidate items present at diagnosis, (3) expert panel review of cases, (4) data-driven reduction of candidate items, (5) derivation of a points-based classification score in a development data set and (6) validation in an independent data set. Results: The development data set consisted of 316 cases of TAK and 323 comparators. The validation data set consisted of an additional 146 cases of TAK and 127 comparators. Age ≤60 years at diagnosis and imaging evidence of large-vessel vasculitis were absolute requirements to classify a patient as having TAK. The final criteria items and weights were as follows: female sex (+1), angina (+2), limb claudication (+2), arterial bruit (+2), reduced upper extremity pulse (+2), reduced pulse or tenderness of a carotid artery (+2), blood pressure difference between arms of ≥20 mm Hg (+1), number of affected arterial territories (+1 to +3), paired artery involvement (+1) and abdominal aorta plus renal or mesenteric involvement (+3). A patient could be classified as having TAK with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the model area under the curve was 0.97 (95% CI 0.94 to 0.99) with a sensitivity of 93.8% (95% CI 88.6% to 97.1%) and specificity of 99.2% (95% CI 96.7% to 100.0%). Conclusion: The 2022 American College of Rheumatology/EULAR classification criteria for TAK are now validated for use in research.

Biomarkers of eosinophilic disease activity, especially in the context of novel therapies that reduce blood eosinophil counts, are an unmet need. Absolute eosinophil count (AEC) does not accurately reflect tissue eosinophilia or eosinophil activation. Therefore, the aims of this study were to compare the reliability of plasma and urine eosinophil major basic protein 1, eosinophil cationic protein, eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase measurement and to evaluate the usefulness of eosinophil granule protein (EGP) measurement for the assessment of disease activity in patients with eosinophil-associated diseases treated with mepolizumab, benralizumab, or dexpramipexole.Eosinophil granule protein concentrations were measured in serum, plasma, and urine from healthy volunteers and patients with hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic asthma using a multiplex assay.Urine EGP concentrations remained stable, whereas serum and plasma EGP concentrations increased significantly with delayed processing. Plasma (p) EDN, but not urine (u) EDN, concentration correlated with AEC and negatively correlated with prednisone dose. Both pEDN and uEDN decreased significantly following treatment of HES patients with benralizumab and EGPA patients with mepolizumab. uEDN appeared to increase with clinical relapse in both patient groups.Measurement of EGP in urine is noninvasive and unaffected by cellular lysis. Although plasma and urine EDN concentrations showed a similar pattern following benralizumab and mepolizumab treatment, the lack of correlation between AEC or prednisone dose and uEDN concentrations suggests that measurement of uEDN may provide a potential biomarker of disease activity in patients with HES and EGPA.

To assess the perceptions and preferences of telemedicine among patients with autoimmune rheumatic diseases during the COVID-19 pandemic.We conducted an online survey among patients with autoimmune rheumatic diseases. Attitudes about telemedicine (i.e., telemedicine acceptability), evaluated using the validated Telemedicine Perception Questionnaire (TMPQ), and visit satisfaction were assessed for different telemedicine experiences and types of autoimmune rheumatic disease.Of 3,369 invitations, 819 responses were received. Participants had a mean ± SD age of 58.6 ± 11.6 years and were mostly White (n = 759, or 92.7%) and female (n = 702, or 85.7%). Of the 618 participants who said that telemedicine was available to them, 449 (72.7%) reported having a telemedicine visit, with 303 (67.5%) reporting attending a telemedicine video visit. On a 0 to 10 scale, the mean ± SD visit satisfaction score was 7.3 ± 1.8, with 25.8% of respondents being very satisfied (scores of 9 or 10). Video visits and higher TMPQ scores were associated with higher satisfaction. Compared to those who did not experience a telemedicine visit, patients who did were more likely to prefer telemedicine (video or phone) for routine visits (73.7% versus 44.3%; P 0.001), reviewing test results (64.8% versus 53.8%; P 0.001), when considering changing medications (40.5% versus 26.8%; P 0.001), and when starting a new injectable medication (18.9% versus 12.7%; P = 0.02).During the COVID-19 pandemic, patients with autoimmune rheumatic diseases frequently had telemedicine visits, with the majority held via video, and were satisfied with these visits. These results suggest that because patients prefer telemedicine for certain visit reasons, maximizing effective use of telemedicine will require personalized patient scheduling.

Objectives To systematically review the psychometric properties of outcome measurement instruments used in ANCA-associated vasculitis (AAV). Methods Medline, EMBASE, Cochrane, Scopus and Web of Science were searched from inception to 14 July 2020 for validation studies of instruments used in AAV. Following the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) and OMERACT frameworks, different psychometric properties (validity, reliability, responsiveness and feasibility) were summarized. Risk of bias was assessed according to the COSMIN checklist. Results From 2505 articles identified, 32 met the predefined selection criteria, providing information on 22 instruments assessing disease activity (n = 7), damage (n = 2), activity and damage (n = 1), health-related quality of life (HRQoL; n = 9) and function (n = 3). Most of the instruments were tested in AAV as a group or in granulomatosis with polyangiitis only. The BVAS, any version, the Vasculitis Damage Index (VDI) and the AAV-Patient-Reported Outcome (AAV-PRO) have been more extensively validated than the other instruments. BVAS for Wegener Granulomatosis (BVAS/WG) has been shown to be valid for measuring disease activity [correlation with Physician global assessment (r = 0.90)], reliability (inter-observer intraclass correlation coefficient = 0.97), responsiveness and feasibility. For damage, VDI was shown to be moderately valid (correlations with BVAS version 3 at 6 months r = 0.14, BVAS/WG at 1 year r = 0.40 and 5 years r = 0.20), and feasible. For HRQoL, AAV-PRO demonstrated validity (correlations of the six AAV-PRO domains with EQ-5D-5L: −0.78 to −0.55; discrimination between active disease and remission, P Conclusion Among the 22 outcome measurement instruments used for AAV, BVAS (any version), VDI and AAV-PRO had the strongest psychometric properties.

© Published by Oxford University Press on behalf of the British Society for Rheumatology 2022. This work is written by US Government employees and is in the public domain in the US., Objectives: To assess whether data from 18F-fluorodeoxyglucose (FDG) PET should be incorporated into eligibility criteria for clinical trials in Takayasu's arteritis (TAK). Methods: The study was conducted in two parts. Part one was an international online survey among physicians with experience managing TAK to determine, using clinical vignettes, whether FDG-PET data influence decisions about enrolment in trials. Part two used patient data from an observational cohort study in TAK to assess agreement regarding decisions about enrolment into trials, based on clinical assessment with and without incorporation of FDG-PET data. Results: In part one, 68 physicians responded to the survey. Most physicians had used FDG-PET to diagnose TAK (82%) or monitor disease activity (66%). In vignettes representing active clinical disease, FDG-PET findings increased physician confidence in disease assessment and reduced outlier assessments. The greatest variability in decisions regarding enrolment into trials was observed in vignettes representing constitutional symptoms alone and elevated acute-phase reactants. In these cases, FDG-PET findings influenced decisions about enrolment and improved physician confidence. In multivariable models, FDG-PET findings were 1.29 times more strongly associated with enrolment decisions compared with levels of acute-phase reactants. In part two, incorporation of FDG-PET data significantly improved agreement about enrolment decisions between raters [inter-rater reliability (IRR) = 0.68 (95% CI 0.67, 0.69) to IRR = 0.88 (95% CI 0.87, 0.89); P < 0.01]. Conclusions: Incorporation of FDG-PET data into assessment of TAK influences decisions about enrolment of patients into trials, improves physician confidence about clinical assessment and could help reduce variability in study populations. Future trials in TAK should consider incorporating FDG-PET data into eligibility criteria.

OBJECTIVE Little is known about temporal changes in nasal bacteria in granulomatosis with polyangiitis (GPA). This study was undertaken to examine longitudinal changes in the nasal microbiome in association with relapse in GPA patients. METHODS Bacterial 16S ribosomal RNA gene sequencing was performed on nasal swabs from 19 patients with GPA who were followed up longitudinally for a total of 78 visits, including 9 patients who experienced a relapse and 10 patients who remained in remission. Relative abundance of bacteria and ratios between bacteria were examined. Generalized estimating equation models were used to evaluate the association between bacterial composition and 1) disease activity and 2) levels of antineutrophil cytoplasmic antibody (ANCA) with specificity for proteinase 3 (PR3), adjusted for medication. RESULTS Corynebacterium and Staphylococcus were the most abundant bacterial genera across all nasal samples. Patients with quiescent disease maintained a stable ratio of Corynebacterium to Staphylococcus across visits. In contrast, in patients who experienced a relapse, a significantly lower ratio was observed at the visit prior to relapse, followed by a higher ratio at the time of relapse (adjusted P < 0.01). Species-level analysis identified an association between a higher abundance of nasal Corynebacterium tuberculostearicum and 1) relapse (adjusted P = 0.04) and 2) higher PR3-ANCA levels (adjusted P = 0.02). CONCLUSION In GPA, significant changes occur in the nasal microbiome over time and are associated with disease activity. The occurrence of these changes months prior to the onset of relapse supports a pathogenic role of nasal bacteria in GPA. Our results uphold existing hypotheses implicating Staphylococcus as an instigator of disease and have generated a novel finding involving Corynebacterium as a potential mediator of disease in GPA.

Objective To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Methods Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel. Results We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations. Conclusion This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.

Objective To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis. Methods Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel. Results We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions. Conclusion These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.

Patient-Powered Research Networks (PPRNs) are US-based registry infrastructures co-created by advocacy groups, patient research partners, academic investigators, and other healthcare stakeholders. Patient-Powered Research Networks collect information directly from patients to conduct and disseminate the results of patient-centered/powered research that helps patients make more informed decisions about their healthcare. Patient-Powered Research Networks gather and utilize real-world data and patient-reported outcomes to conduct comparative effectiveness, safety, and other research, and leverage the Internet to accomplish this effectively and efficiently. Four PPRNs focused on autoimmune and immune-mediated conditions formed the Autoimmune Research Collaborative: ArthritisPower (rheumatoid arthritis, spondyloarthritis, and other rheumatic and musculoskeletal diseases), IBD Partners (inflammatory bowel disease), iConquerMS (multiple sclerosis), and the Vasculitis PPRN (vasculitis). The Autoimmune Research Collaborative aims to inform the healthcare decision making of patients, care partners, and other stakeholders, such as clinicians, regulators, and payers. Illustrated by practical applications from the Autoimmune Research Collaborative and its constituent PPRNs, this article discusses the shared capacities and challenges of the PPRN model, and the opportunities presented by collaborating across autoimmune conditions to design, conduct, and disseminate patient-centered outcomes research.

We report a 57-year-old man with recurrent meningoencephalitis resulting in bouts of altered consciousness, encephalopathy, tremors, focal seizures, and paraparesis. The neurological manifestations were accompanied by fever and leukocytosis in the absence of other systemic manifestations. MRI abnormalities of the brain, brainstem, spinal cord and meninges and CSF pleocytosis and elevated protein were observed. Exhaustive studies failed to reveal an etiology. Brain biopsy revealed nodules of neutrophils and macrophages, but no vasculitis. The lesions were not vasocentric as would be expected with neuro-Behcet's disease and neuro-Sweet's disease. The disorder was responsive to high-dose corticosteroid therapy and, ultimately, to anakinra, an IL-1α and IL-1β receptor antagonist.

OBJECTIVE. Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of vasculitis that can resemble polyarteritis nodosa (PAN). This study was undertaken to identify potential disease-causing sequence variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA). METHODS. Patients with idiopathic PAN (n = 118) and patients with GPA or MPA (n = 1,107) were screened for rare nonsynonymous variants in ADA2 using DNA sequencing methods. ADA-2 enzyme activity was assessed in selected serum samples. RESULTS. Nine of 118 patients with PAN (7.6%) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4%) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2%) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA-2 enzyme activity. ADA-2 enzyme testing of 86 additional patients revealed 1 individual with strongly reduced ADA-2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant in ADA2, with no other clinical differences noted. None of the patients with GPA or MPA carried biallelic variants in ADA2. CONCLUSION. A subset of patients with idiopathic PAN meet genetic criteria for DADA2. Given that tumor necrosis factor inhibition is efficacious in DADA2 but is not conventional therapy for PAN, these findings suggest that ADA-2 testing should strongly be considered in patients with hepatitis B virus–negative idiopathic PAN.

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 x 10(-s)) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets., National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [R01 AR070148]; National Institute of Arthritis and Musculoskeletal and Skin DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [U54 AR057319, U01 AR51874 04]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [U54 RR019497]; Office of Rare Diseases Research of the National Center for Advancing Translational Sciences; Imperial College, National Institute for Health Research, Biomedical Research Centre; Wellcome TrustWellcome TrustEuropean Commission [WT107881]; Medical Research CouncilUK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission [MC_UU_00002/4], This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health grant R01 AR070148 to A.H.S. The Vasculitis Clinical Research Consortium has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR057319 and U01 AR51874 04), the National Center for Research Resources (U54 RR019497), and the Office of Rare Diseases Research of the National Center for Advancing Translational Sciences. J.C.M., A.P.K., and R.M.M. acknowledge support from the Imperial College, National Institute for Health Research, Biomedical Research Centre. C.W. and G.R. acknowledge support from The Wellcome Trust (WT107881) and the Medical Research Council (MC_UU_00002/4). This work was supported by the use of study data downloaded from the dbGaP website, under dbGaP: phs000272.v1.p1, phs000431.v2.p1, phs000583.v1.p1, and phs000444.v1.p1.

Background Recruitment into clinical trials is a challenging process, with as many as 40% of studies failing to meet their target sample sizes. The principles of direct-to-consumer (DTC) advertising rely upon novel marketing strategies. The ability to reach expansive audiences in the web-based realm presents a unique opportunity for researchers to overcome various barriers to enrollment in clinical trials. Research has investigated the use of individual web-based platforms to aid in recruitment and accrual into trials; however, a gap in the literature exists, whereby multiple mass communication platforms have yet to be investigated across a range of clinical trials. Objective There is a need to better understand how individual factors combine to collectively influence trial recruitment. We aimed to test whether DTC recruitment of potentially eligible study participants via social media platforms (eg, Facebook [Meta Platforms Inc] and Twitter [Twitter Inc]) was an effective strategy or whether this acted as an enhancement to traditional (eg, email via contact registries) recruitment strategies through established clinical research sites. Methods This study tested multiple DTC web-based recruitment efforts (Facebook, Twitter, email, and patient advocacy group [PAG] involvement) across 6 national and international research studies from 5 rare disease consortia. Targeted social media messaging, social media management software, and individual study websites with prescreening questions were used in the Protocol for Increasing Accrual Using Social Media (PRISM). Results In total, 1465 PRISM website referrals occurred across all 6 studies. Organic (unpaid) Facebook posts (676/1465, 46.14%) and Rare Diseases Clinical Research Network patient contact registry emails (461/1465, 31.47%) represented the most successful forms of engagement. PRISM was successful in accumulating a 40.1% (136/339) lead generation (those who screened positive and consented to share their contact information to be contacted by a clinical site coordinator). Despite the large number of leads generated from PRISM recruitment efforts, the number of patients who were subsequently enrolled in studies was low. Across 6 studies, 3 participants were ultimately enrolled, meaning that 97.8% (133/136) of leads dropped off. Conclusions The results indicate that although accrual results were low, this is consistent with previously documented challenges of studying populations with rare diseases. Targeted messaging integrated throughout the recruitment process (eg, referral, lead, and accrual) remains an area for further research. Key elements to consider include structuring the communicative workflow in such a way that PAG involvement is central to the process, with clinical site coordinators actively involved after an individual consents to share their contact information. Customized approaches are needed for each population and research study, with observational studies best suited for social media recruitment. As evidenced by lead generation, results suggest that web-based recruitment efforts, coupled with targeted messaging and PAG partnerships, have the potential to supplement clinical trial accrual.

BACKGROUND More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. METHODS We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of

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

The systemic vasculitides are a group of multisystem diseases, which can be life and organ threatening. High-dose immunosuppressants are required to control inflammation in vital organs, such as the kidneys, lungs, skin, joints, and eyes. Patients report a range of impacts on their health-related quality of life due to symptoms, irreversible damage, and the adverse effects of medications. The measurement of patient perspectives within clinical studies in vasculitis is essential to capture outcomes of greatest importance to patients. Validated generic, disease-specific and symptom-specific patient-reported outcomes available for use in patients with systemic vasculitis are reviewed here.

Glucocorticoids are standard of care for many chronic inflammatory conditions, including juvenile dermatomyositis (JDM) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We sought to define pharmacodynamic biomarkers of therapeutic efficacy and safety concerns of glucocorticoid treatment for these two disorders. Previous proteomic profiling of patients with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease (IBD) treated with glucocorticoids identified candidate biomarkers for efficacy and safety concerns of glucocorticoids. Serial serum samples from patients with AAV (n = 30) and JDM (n = 12) were obtained during active disease, and after treatment with glucocorticoids. For AAV, 8 of 11 biomarkers of the anti-inflammatory response to glucocorticoids were validated (P-value ≤0.05; CD23, macrophage-derived cytokine, interleukin-22 binding protein, matrix metalloproteinase-12, T lymphocyte surface antigen Ly9, fibrinogen gamma chain, angiopoietin-2 [all decreased], and protein C [increased]), as were 5 of 7 safety biomarkers (P-value ≤0.05; afamin, matrix metalloproteinase-3, insulin growth factor binding protein-5, angiotensinogen, leptin [all increased]). For JDM, 10 of 11 efficacy biomarkers were validated (P-value ≤0.05; all proteins except fibrinogen gamma chain) and 6 of 7 safety biomarkers (P-value ≤0.05; AAV proteins plus growth hormone binding protein). The identified efficacy biomarkers may be useful as objective outcome measures for early phase proof-of-concept studies when assessing novel anti-inflammatory drugs in JDM and AAV, and likely in other inflammatory disorders. Similarly, safety biomarkers may also be helpful assessing toxicity of alternatives to glucocorticoids.

Objectives. To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes.Methods. This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m(2)). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission.Results. RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse.Conclusion. Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.

Objectives To assess the clinical value of 18F-flurodeoxyglucose (FDG) positron emission tomography (PET) in a prospective cohort of patients with large-vessel vasculitis (LVV) and disease comparators. Methods Patients with Takayasu's arteritis (TAK) and giant cell arteritis (GCA) were studied, along with a comparator group consisting of patients with hyperlipidemia, diseases that mimic LVV, and healthy controls. Participants underwent clinical evaluation and FDG-PET imaging, and patients with LVV underwent serial imaging at six-month intervals. Performance characteristics of FDG-PET interpretation to differentiate clinically active LVV from disease comparators and from clinical remission were calculated. A qualitative summary score (PETVAS) based on global arterial FDG uptake was used to study associations between PET activity and clinical characteristics and to predict future relapse. Results 170 FDG-PET scans were performed in 115 participants (LVV=56; comparators=59). FDG-PET differentiated patients with clinically active LVV and disease comparators with a sensitivity=85% (95%CI: 69-94%) and specificity=83% (95%CI: 71-91%). FDG-PET scans were interpreted as active vasculitis in most patients with LVV in clinical remission (41 of 71, 58%). Clinical disease activity status, disease duration, body mass index, and glucocorticoid use were independently associated with PET scan activity. Among patients who underwent PET during clinical remission, future clinical relapse was more common in patients with a high versus low PETVAS (45% versus 11%, p=0.03) over a median follow-up of 15 months. Conclusions FDG-PET provides information about vascular inflammation that is complimentary to, and unique from, clinical assessment in LVV. FDG-PET scan activity during clinical remission was associated with future clinical relapse. This article is protected by copyright. All rights reserved.

Objective To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function. Results Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA–DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA–DPB1 gene and HLA–DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)–reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%. Conclusion This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

Summary Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P

Resume Introduction La mucoviscidose s’accompagne d’un risque accru d’osteoporose et d’une augmentation consequente du risque fracturaire. Le but de ce travail etait d’analyser les facteurs independants predictifs, au depart et a deux ans de suivi, d’une modification de la densite minerale osseuse (DMO) chez les adultes mucoviscidosiques. Methodes Soixante-quatre patients adultes atteints de mucoviscidose, âges de 18 a 57 ans, ont ete recrutes dans la clinique de mucoviscidose du Massachussets General Hospital. Une absorptiometrie biphotonique a rayons X (DXA) a ete realisee au rachis et au radius a l’inclusion puis a deux ans (chez 39 sujets). L’indice de masse maigre (IMM) et l’indice de masse grasse (IMG) ont ete estimes a partir du poids, de la taille et de l’impedancemetrie bioelectrique tetrapolaire. Tous les sujets ont ete soumis a une spirometrie pulmonaire dans un delai d’un mois a compter de la visite de suivi. Des modeles de regression lineaire ont permis d’evaluer les variables predictives du Z score de DMO au depart et les modifications du Z score au rachis AP a 2 ans. Deux definitions d’une DMO basse ont ete etudiees a partir du Z score (≤ −1,0 et ≤ −2,0). Resultats Un defaut de mineralisation osseuse a ete retrouve chez 52 % des sujets. Ces derniers etaient majoritairement des hommes (67 % vs. 32 %, p = 0,009), sous traitement par glucocorticoides (21 % vs. 0 %, p Conclusions Le sexe masculin, la petite taille et une insuffisance de masse maigre sont correles a une DMO basse dans la mucoviscidose. L’adiposite elevee et les troubles respiratoires sont predictifs d’une modification negative du Z score de DMO a deux ans de suivi.

Objective. To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: antimyeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA). Methods. We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA). Results. Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P=0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P

Purpose The aim of this study was to develop and validate case-finding algorithms for granulomatosis with polyangiitis (Wegener's, GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (Churg–Strauss, EGPA). Methods Two hundred fifty patients per disease were randomly selected from two large healthcare systems using the International Classification of Diseases version 9 (ICD9) codes for GPA/EGPA (446.4) and MPA (446.0). Sixteen case-finding algorithms were constructed using a combination of ICD9 code, encounter type (inpatient or outpatient), physician specialty, use of immunosuppressive medications, and the anti-neutrophil cytoplasmic antibody type. Algorithms with the highest average positive predictive value (PPV) were validated in a third healthcare system. Results An algorithm excluding patients with eosinophilia or asthma and including the encounter type and physician specialty had the highest PPV for GPA (92.4%). An algorithm including patients with eosinophilia and asthma and the physician specialty had the highest PPV for EGPA (100%). An algorithm including patients with one of the diagnoses (alveolar hemorrhage, interstitial lung disease, glomerulonephritis, and acute or chronic kidney disease), encounter type, physician specialty, and immunosuppressive medications had the highest PPV for MPA (76.2%). When validated in a third healthcare system, these algorithms had high PPV (85.9% for GPA, 85.7% for EGPA, and 61.5% for MPA). Adding the anti-neutrophil cytoplasmic antibody type increased the PPV to 94.4%, 100%, and 81.2% for GPA, EGPA, and MPA, respectively. Conclusion Case-finding algorithms accurately identify patients with GPA, EGPA, and MPA in administrative databases. These algorithms can be used to assemble population-based cohorts and facilitate future research in epidemiology, drug safety, and comparative effectiveness. Copyright © 2016 John Wiley & Sons, Ltd.