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Recent experimental and genetic studies have implicated the role of programmed cell death protein 1 (PD-1), programmed cell death protein-ligand 1 (PDL-1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in the pathogenesis of medium and large vessel vasculitis. This study sought to evaluate the occurrence and nature of vasculitis associated with cancer treatment using immune checkpoint inhibition (anti-PD-1, anti-PDL-1, and anti-CTLA4). A systematic review of the medical literature was conducted by searching all available clinical data up to February 2018 in several databases and search engines including Cochrane Library, Embase, Google Scholar, Medline, Scopus, Web of Science, and Clinicaltrials.gov. Searches included the following FDA-approved anti-PD1 (nivolumab and pembrolizumab), anti-PDL1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA4 (ipilimumab). The vasculitis cases were compiled and classified based on the 2012 revised Chapel Hill Consensus Conference nomenclature. The clinical feature of the vasculitis cases and their relationship to immune checkpoint inhibition was assessed. There were 53 cases of vasculitis of which 20 were confirmed. The main reported type of vasculitis was large vessel vasculitis and vasculitis of the central and peripheral nervous system. All cases resolved with either holding the immune checkpoint inhibitors and/or administering glucocorticoids. No death related to vasculitis was reported. Vasculitis, namely large vessel and vasculitis of the nervous system, is associated with immune checkpoint inhibition. Results of this study add to the growing evidence regarding the relationship between immune checkpoints and vasculitis and suggest that the pathway may be a therapeutic target.

Background Patients with vasculitis, a set of rare diseases, encounter delays in obtaining an accurate diagnosis which can lead to substantial morbidity and increased mortality. This study sought to describe the diagnostic journey of patients with vasculitis and identify factors associated with time to diagnosis. Methods Patients with vasculitis enrolled in an online registry completed a two-stage study: Stage 1: survey of open-ended questions about patients’ diagnostic journeys and perceived factors associated with rapid or delayed diagnosis; Stage 2: survey with specific questions based on data from Stage 1 and additional investigator-identified factors. Results 375 patients with vasculitis participated in Stage 1; 456 patients participated in Stage 2. 85% of patients were seen by a healthcare provider within 3 months of the onset of symptoms. The median time to diagnosis of vasculitis was 7 months. 313/456 (73%) of patients were misdiagnosed initially. 40% of diagnoses were made in a hospital setting; 2% of diagnoses were made at a specialized vasculitis center. 60% of patients had at least 1 visit to an emergency room prior to diagnosis. Unemployment, time to travel to a medical center > 1 h, initial misdiagnosis, and delays in seeing a specialist were all associated with longer times to diagnosis. 373/456 (82%) of patients reported that a delayed diagnosis had negative consequences on their health. Conclusion Patients with vasculitis encounter substantial delays in achieving an accurate diagnosis and these delays are associated with negative health consequences. Both patient-related factors and healthcare-related factors are associated with diagnostic delays.

Objective To assess markers of neutrophil activation such as calprotectin and N-formyl methionine (fMET) in anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) and large-vessel vasculitis (LVV). Methods Levels of fMET, and calprotectin, were measured in the plasma of healthy controls ( n =30) and patients with AAV (granulomatosis with polyangiitis (GPA, n =123), microscopic polyangiitis (MPA, n =61)), and LVV (Takayasu’s arteritis (TAK, n =58), giant cell arteritis (GCA, n =68)), at times of remission or flare. Disease activity was assessed by physician global assessment. In vitro neutrophil activation assays were performed in the presence or absence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporine H. Results Levels of calprotectin, and fMET were elevated in patients with vasculitis as compared to healthy individuals. Levels of fMET correlated with markers of systemic inflammation: C-reactive protein ( r =0.82, p <0.0001), and erythrocyte sedimentation rate ( r =0.235, p <0.0001). The neutrophil activation marker, calprotectin was not associated with disease activity. Circulating levels of fMET were associated with neutrophil activation ( p <0.01) and were able to induce de novo neutrophil activation via FPR1-mediated signaling. Conclusion Circulating fMET appears to propagate neutrophil activation in AAV and LVV. Inhibition of fMET-mediated FPR1 signaling could be a novel therapeutic intervention for systemic vasculitides.

ObjectivesPrior studies have suggested a potential link between nasal microbes and granulomatosis with polyangiitis (GPA; Wegener’s), but these studies relied on culture-dependent methods. This study comprehensively examined the entire community of nasal microbiota (bacteria and fungi) in participants with GPA compared with healthy controls using deep sequencing methods.Methods16S rRNA and internal transcribed spacer gene sequencing were performed on nasal microbial DNA isolated from nasal swabs of 60 participants with GPA and 41 healthy controls. Alpha and beta diversity were assessed as well as the relative abundance of the most abundant bacterial and fungal taxa. The effects of covariates including disease activity and immunosuppressive therapies on microbial composition were evaluated.ResultsCompared with controls, participants with GPA had a significantly different microbial composition (weighted UniFrac p=0.04) and lower relative abundance of Propionibacterium acnes and Staphylococcus epidermidis (for both, false discovery rate-corrected p=0.02). Disease activity in GPA was associated with a lower abundance of fungal order Malasseziales compared with participants with GPA in remission (p=0.04) and controls (p=0.01). Use of non-glucocorticoid immunosuppressive therapy was associated with ‘healthy’ nasal microbiota while participants with GPA who were off immunosuppressive therapy had more dysbiosis (weighted UniFrac p=0.01). No difference in the relative abundance of Staphylococcus aureus was observed between GPA and controls.ConclusionsGPA is associated with an altered nasal microbial composition, at both the bacterial and fungal levels. Use of immunosuppressive therapies and disease remission are associated with healthy microbial communities.

Identification of a biomarker for disease activity in eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss) remains an unmet need. This study examined the value of serum periostin, a marker of type 2 inflammation, as a measure of disease activity in patients with EGPA. Participants enrolled in a multicenter, prospective cohort of patients with EGPA were included in this study if they had disease activity (defined as Birmingham Vasculitis Activity Score [BVAS] > 0) during follow-up. Serum levels of periostin were measured at flare visit as well as two pre- and two post-flare visits, if available. The outcome of disease activity was assessed either with BVAS or Physician Global Assessment (PGA). Mixed-effect models were used to examine the association between periostin levels and disease activity. Comparisons were made with a historical cohort of healthy individuals and patients with asthma. In the 49 patients included in the study, the median periostin level was 60 ng/ml (IQR 50 to 73) in all visits and did not significantly change across visits. Multivariate analyses found no association between periostin level and presence or absence of flare according to the BVAS (adjusted OR 1.00 [95% CI 0.98 to 1.02], p = 0.98) but an increase in periostin level was significantly associated with greater disease severity during a flare according to the PGA (adjusted beta-coefficient 0.02 [95% CI 0.004 to 0.03], p = 0.01). Periostin levels in EGPA were significantly higher than previously studied healthy controls and patients with asthma. In EGPA serum periostin level is modestly associated with greater disease severity during a flare but does not discriminate active from inactive disease. Periostin levels in EGPA are higher than in other previously studied cohorts, including healthy populations and patients with asthma, and are relatively stable over time.

Objective To describe clinical manifestations and outcomes in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in North America. Methods Analysis of patients aged 18 years or older who fulfilled the 1990 American College of Rheumatology Classification Criteria for EGPA enrolled in the Vasculitis Clinical Research Consortium from 2003 to 2019. Main clinical characteristics, treatments, outcomes, and accumulated damage were studied. Results The cohort included 354 patients; 59% female; age at diagnosis of 50.0 (±14) years; 39% were antineutrophil cytoplasm antibody (ANCA) positive. Time from diagnosis to last follow‐up was 7.0 (±6.2) years; 49.4% had one or more relapse. Patients positive for ANCA more commonly had neurological and kidney involvement when compared with patients negative for ANCA, who had more cardiac and lung manifestations. At last study visit, only 35 (12.6%) patients had been off all therapy for more than 2 years during their follow‐up. The overall mortality rate was 4.0% and did not differ by ANCA status or cyclophosphamide use. Scores on the Vasculitis Damage Index (VDI) for 134 patients with two or more visits and more than 1 year of follow‐up increased from 1.7 (±1.8) at enrollment (3.7 [±5.1] years after diagnosis) to 3.35 (±2.1) at last follow‐up (7.5 [±5.8] years after diagnosis), mainly represented by chronic asthma (67.5%), peripheral neuropathy (49.6%), and chronic sinusitis (31.3%). Longer duration of glucocorticoid use and relapse were associated with higher VDI scores. Conclusion This analysis describes the many clinical manifestations and varied outcomes of EGPA and highlights the ongoing need to attain more sustained, long‐term remission to limit the accrual of disease‐related damage.

Background Traditional medical research infrastructures relying on the Centers of Excellence (CoE) model (an infrastructure or shared facility providing high standards of research excellence and resources to advance scientific knowledge) are often limited by geographic reach regarding patient accessibility, presenting challenges for study recruitment and accrual. Thus, the development of novel, patient-centered (PC) strategies (e.g., the use of online technologies) to support recruitment and streamline study procedures are necessary. This research focused on an implementation evaluation of a design innovation with implementation outcomes as communicated by study staff and patients for CoE and PC approaches for a randomized controlled trial (RCT) for patients with vasculitis. Methods In-depth qualitative interviews were conducted with 32 individuals (17 study team members, 15 patients). Transcripts were coded using the Consolidated Framework for Implementation Research (CFIR). Results The following CFIR elements emerged: characteristics of the intervention, inner setting, characteristics of individuals, and process . From the staff perspective, the communication of the PC approach was a major challenge, but should have been used as an opportunity to identify one “point person” in charge of all communicative elements among the study team. Study staff from both arms were highly supportive of the PC approach and saw its promise, particularly regarding online consent procedures. Patients reported high self-efficacy in reference to the PC approach and utilization of online technologies. Local physicians were integral for making patients feel comfortable about participation in research studies. Conclusions The complexity of replicating the interpersonal nature of the CoE model in the virtual setting is substantial, meaning the PC approach should be viewed as a hybrid strategy that integrates online and face-to-face practices. Trial registrations 1) Name: The Assessment of Prednisone In Remission Trial – Centers of Excellence Approach (TAPIR). Trial registration number: ClinicalTrials.gov NCT01940094 . Date of registration: September 10, 2013. 2) Name: The Assessment of Prednisone In Remission Trial – Patient Centric Approach (TAPIR). Trial registration number: Clinical Trials.gov NCT01933724 . Date of registration: September 2, 2013.

The objective of this study was to determine health-related quality of life (HRQoL) in patients with ANCA-associated vasculitis (AAV) as measured by the “routine assessment of patient index data 3” (RAPID3) and whether RAPID3 is correlated with disease activity as determined by the Birmingham Vasculitis Activity Score (BVAS). Data from patients at an academic institution vasculitis clinic seen between Jan 2010 and Jan 2012 were collected using chart review. BVAS and RAPID3 scores were calculated at each patient visit. RAPID3 was compared between patients in remission (BVAS = 0) and patients with active disease (BVAS > =1) at all visits for four consecutive visits, when data available, at least 3 months apart during the period mentioned. Robust generalized estimating equations (GEE) in linear regression models evaluated associations between the RAPID3 and BVAS over all available observations, adjusting for intra-subject correlations. Thirty-four patients were included in the study, 26 had granulomatosis with polyangiitis (GPA), five microscopic polyangiitis (MPA), and three eosinophilic granulomatosis with polyangiitis (EGPA). Patients at first visit had impaired HRQoL as measured by RAPID3 [6.8 (3.1–12.6)]. The median RAPID3 scores were higher in patients with active disease as compared to patients in remission (7.0 vs. 3.0, p  = 0.115; 8.8 vs. 1.0, p  = 0.011; 6.1 vs. 2.0, p  = 0.032; and 11.7 vs. 2.0, p  = 0.128 for visits 1, 2, 3, and 4, respectively). In longitudinal GEE models incorporating all observations there was a strong association between the RAPID3 (per 1 unit) and BVAS (per 1 unit) [β 0.21 (0.10, 0.32) p  < 0.001]. RAPID3 can be used to measure HRQoL in patients with AAV. RAPID3 correlated significantly with BVAS. RAPID3 can discriminate between disease states in AAV. This instrument may help document patient experience and add to clinical decisions.

Objective Our objective was to describe characteristics and compare clinical and patient‐reported outcomes (PROs) for disease‐modifying antirheumatic drug (DMARD)–naive patients with psoriatic arthritis (PsA) who initiate DMARD therapy early versus late. Methods Patients with PsA from the CorEvitas PsA/Spondyloarthritis Registry were classified by reported time between diagnosis and DMARD initiation. Early and late initiators were patients whose first DMARD treatment occurred ≤1 year or >1 year, respectively, following PsA diagnosis. Change in disease activity and PRO measures from initiation to the six‐month follow‐up was calculated for each group; mean change for each continuous outcome and proportion achieving binary outcomes were reported for early and late initiators. Associations of early versus late DMARD initiation with disease activity and PROs at six months were calculated using adjusted linear and Poisson regressions. Results The mean patient age was 53 years, more than half of patients were female, and 90% of patients were White. Mean time from diagnosis to DMARD initiation was 0.2 years in early initiators (n = 229, 79%) and 8.6 years in late initiators (n = 62, 21%). In adjusted analyses, achievement of minimal disease activity (adjusted risk ratio 2.01, 95% confidence interval [CI] 1.03–4.40) and mean change in Clinical Disease Activity Index (β −3.4, 95% CI −6.2 to −0.49) were statistically different between early and late initiators. Conclusion Among patients from the PsA registry, those who had both early and late initiation of DMARD therapy experienced improvements throughout all disease activity and PROs across six months of treatment. Minimal disease activity, a key treatment target, was more likely observed in early initiators, highlighting the value of early identification and treatment. Early Treatment With DMARDs in Psoriatic Arthritis: The CorEvitas Psoriatic Arthritis/Spondyloarthritis Registry