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1.  A Small n Sequential Multiple Assignment Randomized Trial Design For Use in Rare Disease Research 
Background
Clinical trials in rare diseases are difficult to conduct due to the limited number of patients available with each disorder. We developed a Phase 2 trial which is a small n sequential multiple assignment randomized trial (snSMART) design to test several treatments for a rare disease for which no standard therapy exists.
Purpose
This paper illustrate the design, sample size estimation and operating characteristics of an snSMART.
Methods
We investigate the performance of a class of weighted Z statistics via computer simulations.
Results
We demonstrate the increase in power over traditional single stage designs, and indicate how the power changes as a function of the weight given to each stage.
Conclusion
The snSMART design is promising in a rare diseases setting where several alternative treatments are under consideration and small sample sizes are necessary.
doi:10.1016/j.cct.2015.11.010
PMCID: PMC4695231  PMID: 26586608
re-randomization; binary data; weighted Z statistic
2.  Comparison of Treatment Response in Idiopathic and Connective Tissue Disease–associated Pulmonary Arterial Hypertension 
Rationale: Studies suggest that patients with connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) have a poorer treatment response to therapies for PAH compared with patients with idiopathic PAH (IPAH), but individual randomized controlled trials (RCTs) have been underpowered to examine differences within these subgroups.
Objectives: To compare the effect of therapy for PAH in CTD-PAH versus IPAH.
Methods: We obtained individual participant data from phase III placebo-controlled RCTs of therapies for PAH submitted to the U.S. Food and Drug Administration for drug approval. A treatment-by-diagnosis interaction term evaluated differences in treatment response between CTD-PAH and IPAH. Outcomes included change in 6-minute-walk distance (∆6MWD) from baseline to 12 weeks, clinical worsening, and all-cause mortality.
Measurements and Main Results: The study sample included 827 participants with CTD-PAH and 1,935 with IPAH from 11 RCTs. Patients with CTD-PAH had less improvement in 6MWD when assigned to active treatment versus placebo compared with patients with IPAH (difference in treatment effect on ∆6MWD in CTD-PAH vs. IPAH, −17.3 m; 90% confidence interval, −31.3 to −3.3; P for interaction = 0.043). Treatment was less effective in reducing the occurrence of clinical worsening in CTD-PAH versus IPAH (P for interaction = 0.012), but there was no difference in the placebo-adjusted effect of treatment on mortality (P for interaction = 0.65).
Conclusions: Treatment for PAH was less effective in CTD-PAH compared with IPAH in terms of increasing 6MWD and preventing clinical worsening. The heterogeneity of treatment response supports the need for identifying therapies that are more effective for CTD-PAH.
doi:10.1164/rccm.201507-1456OC
PMCID: PMC4642205  PMID: 26291092
pulmonary hypertension; clinical trial; meta-analysis
3.  Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis 
Annals of the rheumatic diseases  2012;72(8):1342-1350.
Objective
To identify circulating proteins that distinguish between active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner complementary to markers of systemic inflammation.
Methods
Twenty-eight serum proteins representing diverse aspects of the biology of AAV were measured before and 6 months after treatment in a large clinical trial of AAV. Subjects (n=186) enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were available for comparison. The primary outcome was the ability of markers to distinguish severe AAV (Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG)≥3 at screening) from remission (BVAS/WG=0 at month 6), using areas under receiver operating characteristic (ROC) curve (AUC).
Results
All subjects had severe active vasculitis (median BVAS/WG=8) at screening. In the 137 subjects in remission at month 6, 24 of the 28 markers showed significant declines. ROC analysis indicated that levels of CXCL13 (BCA-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) best discriminated active AAV from remission (AUC>0.8) and from healthy controls (AUC>0.9). Correlations among these markers and with ESR or CRP were low.
Conclusions
Many markers are elevated in severe active AAV and decline with treatment, but CXCL13, MMP-3 and TIMP-1 distinguish active AAV from remission better than the other markers studied, including ESR and CRP. These proteins are particularly promising candidates for future studies to address unmet needs in the assessment of patients with AAV.
doi:10.1136/annrheumdis-2012-201981
PMCID: PMC4982463  PMID: 22975753
4.  Measurement of damage in systemic vasculitis: a comparison of the Vasculitis Damage Index with the Combined Damage Assessment Index 
Objectives
To compare the Vasculitis Damage Index (VDI) with the Combined Damage Assessment Index (CDA) as measures of damage from vasculitis.
Methods
A total of 283 patients with vasculitis from 11 European centres were evaluated in a cross-sectional study using the VDI and CDA.
Results
Wegener’s granulomatosis (58.4%) and microscopic polyangiitis (11.0%) were the most common diagnoses. Agreement between VDI and CDA scores (Spearman’s correlation) was 0.90 (95% CI 0.87 to 0.92). There was good correlation between individual comparably evaluated organ systems (Spearman’s correlation 0.70–0.94). Interobserver reliability (assessed by intraclass correlation coefficient (ICC)) was 0.94 (95% CI 0.89 to 0.98) for VDI and 0.78 (95% CI 0.63 to 0.93) for CDA. Intraobserver reliability was 0.92 (95% CI 0.83 to 1.00) for VDI and 0.87 (95% CI 0.75 to 1.00) for CDA. A total of 13 items were not used in the VDI compared to 23 in the CDA. Observers agreed that the CDA covered the full spectrum of damage attributable to vasculitis but was more time consuming and thus possibly less feasible for clinical and research purposes.
Conclusions
The VDI and CDA capture reliable data on damage among patients with vasculitis. The CDA captures more detail but is more complex and less practical than the VDI. Further evolution of damage assessment in vasculitis is likely to include key elements from both instruments.
doi:10.1136/ard.2009.122952
PMCID: PMC4982462  PMID: 20736392
5.  Vasculitis in patients with inflammatory bowel diseases: A study of 32 patients and systematic review of the literature 
Background
Published small case series suggest that inflammatory bowel disease [IBD; Crohn’s disease (CD) or ulcerative colitis (UC)] and vasculitis co-occur more frequently than would be expected by chance.
Objectives
To describe this association by an analysis of a large cohort of carefully studied patients and through a systematic literature review.
Methods
Patients with both IBD and vasculitis enrolled in the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Studies, followed in Canadian Vasculitis research network (CanVasc) centers and/or in the University of Toronto’s IBD clinic were included in this case series. A systematic literature review of patients with IBD and vasculitis involved a PubMed search through February 2014. The main characteristics of patients with Takayasu arteritis (TAK) and IBD were compared to those in patients with TAK without IBD followed in the VCRC.
Results
The study identified 32 patients with IBD and vasculitis: 13 with large-vessel vasculitis [LVV; 12 with TAK, 1 with giant cell arteritis (GCA); 8 with CD, 5 with UC]; 8 with ANCA-associated vasculitis [AAV; 6 granulomatosis with polyangiitis (GPA), 2 with eosinophilic granulomatosis with polyangiitis (EGPA)]; 5 with isolated cutaneous vasculitis; and 6 with other vasculitides. Patients with LVV and AAV were mostly female (18/21). The diagnosis of IBD preceded that of vasculitis in 12/13 patients with LVV and 8/8 patients with AAV. The review of the literature identified 306 patients with IBD and vasculitis: 144 with LVV (133 TAK; 87 with IBD preceding LVV), 19 with AAV [14 GPA, 1 EGPA, 4 microscopic polyangiitis (MPA)], 66 with isolated cutaneous vasculitis, and 77 with other vasculitides. Patients with IBD and TAK were younger and had more frequent headaches, constitutional symptoms, or gastrointestinal symptoms compared to those patients in the VCRC who had TAK without IBD.
Conclusions
These findings highlight the risk of vasculitis, especially TAK, in patients with IBD (both CD and UC).
doi:10.1016/j.semarthrit.2015.07.006
PMCID: PMC4982464  PMID: 26315859
Vasculitis; Takayasu arteritis; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis
6.  Value of commonly measured laboratory tests as biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis 
Rheumatology (Oxford, England)  2014;54(8):1351-1359.
Objective. The aim of this study was to assess the clinical value of absolute eosinophil count, serum IgE, ESR and CRP as longitudinal biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA).
Methods. Patients were selected from an observational EGPA cohort. Absolute eosinophil count, IgE, ESR and CRP were measured quarterly. Disease activity was defined by validated assessment tools. The association of tests with disease activity was assessed via regression models, adjusting for repeated measures and treatment status. Survival analysis was used to determine if laboratory tests were predictive of the 3 month future flare risk.
Results. Seventy-four per cent of 892 study visits in 141 patients occurred while patients were on treatment, mostly during remission or mild disease activity, defined as a BVAS for Wegener’s granulomatosis (BVAS/WG) of 1 or 2. Correlations between absolute eosinophil count, IgE, ESR and CRP were mostly low or non-significant (r = −0.08 to 0.44). There were few weak associations with disease activity [absolute eosinophil count: OR) 1.01/100 U (95% CI 1.01, 1.02); ESR: OR 1.15/10 mg/l increase (95% CI 1.04, 1.27)]. When BVAS/WG ≥1 defined active disease, the absolute eosinophil count [hazard ratio (HR) 1.01/100 U (95% CI 1.01, 1.02)] was weakly predictive of flare. When BVAS/WG ≥3 defined active disease, ESR was weakly predictive of flare [HR 1.52/10 mm/h increase (95% CI 1.17, 1.67)].
Conclusion. The absolute eosinophil count, IgE, ESR and CRP have limitations as longitudinal biomarkers of disease activity or predictors of flare in EGPA. These findings suggest that novel biomarkers of disease activity for EGPA are needed.
doi:10.1093/rheumatology/keu427
PMCID: PMC4502335  PMID: 25406357
vasculitis; eosinophilic granulomatosis with polyangiitis; Churg–Strauss syndrome; biomarker; eosinophil
7.  Reliability, validity and responsiveness to change of the Saint George’s Respiratory Questionnaire in early diffuse cutaneous systemic sclerosis 
Rheumatology (Oxford, England)  2015;54(8):1369-1379.
Objective. Dyspnoea is a common, multifactorial source of functional impairment among patients with dcSSc. Our objective was to assess the reliability, construct validity and responsiveness to change of the Saint George’s Respiratory Questionnaire (SGRQ) in patients with early dcSSc participating in a multicentre prospective study.
Methods. At enrolment and 1 year, patients completed the SGRQ (a multi-item instrument with four scales: symptoms, activity, impact and total), a visual analogue scale (VAS) for breathing and the HAQ Disability Index (HAQ-DI) and underwent 6 min walk distance and pulmonary function tests, physician and patient global health assessments and high-resolution CT (HRCT). We assessed internal consistency reliability using Cronbach’s α. For validity we examined the ability of the SGRQ to differentiate the presence vs absence of interstitial lung disease (ILD) on HRCT or restrictive lung disease and evaluated the 1 year responsiveness to change using pulmonary function tests and patient- and physician-reported anchors. Correlation coefficients of 0.24–0.36 were considered moderate and >0.37 was considered large.
Results. A total of 177 patients were evaluated. Reliability was satisfactory for all SGRQ scales (0.70–0.93). All scales showed large correlations with the VAS for breathing and diffusing capacity of the lung for carbon monoxide in the overall cohort and in the subgroup with ILD. Three of the four scales in the overall cohort and the total scale in the ILD subgroup showed moderate to large correlation with the HAQ-DI and the predicted forced vital capacity (r = 0.33–0.44). Each scale discriminated between the presence and absence of ILD and restrictive lung disease (P ≤ 0.0001–0.03). At follow-up, all scales were responsive to change using different anchors.
Conclusion. The SGRQ has acceptable reliability, construct validity and responsiveness to change for use in a dcSSc population and differentiates between patients with and without ILD.
doi:10.1093/rheumatology/keu456
PMCID: PMC4502336  PMID: 25667436
scleroderma and related disorders; respiratory; quality of life; patient attitude to health; autoinflammatory conditions; systemic sclerosis; dyspnoea; patient-reported outcomes
8.  Adverse Events in Connective Tissue Disease–Associated Pulmonary Arterial Hypertension 
Objective
Patients with connective tissue disease (CTD)–associated pulmonary arterial hypertension (PAH) have a poorer prognosis compared to those with idiopathic PAH, but little is known about the differences in treatment-related adverse events (AEs) and serious adverse events (SAEs) between these groups. This study was undertaken to characterize these differences.
Methods
Individual patient-level data from 10 randomized controlled trials of therapies for PAH were obtained from the US Food and Drug Administration. Patients diagnosed as having either CTD-associated PAH or idiopathic PAH were included. A treatment-by-diagnosis interaction term was used to examine whether the effect of treatment on occurrence of AEs differed between patients with CTD-associated PAH and those with idiopathic PAH. Studies were pooled using fixed-effect models.
Results
The study sample included 2,370 participants: 716 with CTD-associated PAH and 1,654 with idiopathic PAH. In the active treatment group compared to the placebo group, the risk of AEs was higher among patients with CTD-associated PAH than among those with idiopathic PAH (odds ratio [OR] 1.57, 95% confidence interval [95% CI] 1.00–2.47 versus OR 0.94, 95% CI 0.69–1.26; P for interaction = 0.061), but there was no difference in the risk of SAEs in analyses adjusted for age, race, sex, hemodynamic findings, and laboratory values. Despite the higher occurrence of AEs in patients with CTD-associated PAH assigned to active therapy compared to those receiving placebo, the risk of drug discontinuation due to an AE was similar to that in patients with idiopathic PAH assigned to active therapy (P for interaction = 0.27).
Conclusion
Patients with CTD-associated PAH experienced more treatment-related AEs compared to those with idiopathic PAH in therapeutic clinical trials. These findings suggest that the overall benefit of advanced therapies for PAH may be attenuated by the greater frequency of AEs.
doi:10.1002/art.39220
PMCID: PMC4949955  PMID: 26016953
9.  Exploration, Development, and Validation of Patient-reported Outcomes in Antineutrophil Cytoplasmic Antibody–associated Vasculitis Using the OMERACT Process 
The Journal of rheumatology  2015;42(11):2204-2209.
Objective
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of linked multisystem life- and organ-threatening diseases. The Outcome Measures in Rheumatology (OMERACT) vasculitis working group has been at the forefront of outcome development in the field and has achieved OMERACT endorsement of a core set of outcomes for AAV. Patients with AAV report as important some manifestations of disease not routinely collected through physician-completed outcome tools; and they rate common manifestations differently from investigators. The core set includes the domain of patient-reported outcomes (PRO). However, PRO currently used in clinical trials of AAV do not fully characterize patients’ perspectives on their burden of disease. The OMERACT vasculitis working group is addressing the unmet needs for PRO in AAV.
Methods
Current activities of the working group include (1) evaluating the feasibility and construct validity of instruments within the PROMIS (Patient-Reported Outcome Measurement Information System) to record components of the disease experience among patients with AAV; (2) creating a disease-specific PRO measure for AAV; and (3) applying The International Classification of Functioning, Disability and Health to examine the scope of outcome measures used in AAV.
Results
The working group has developed a comprehensive research strategy, organized an investigative team, included patient research partners, obtained peer-reviewed funding, and is using a considerable research infrastructure to complete these interrelated projects to develop evidence-based validated outcome instruments that meet the OMERACT filter of truth, discrimination, and feasibility.
Conclusion
The OMERACT vasculitis working group is on schedule to achieve its goals of developing validated PRO for use in clinical trials of AAV. (First Release September 1 2015; J Rheumatol 2015;42:2204–9; doi:10.3899/jrheum.141143)
doi:10.3899/jrheum.141143
PMCID: PMC4940036  PMID: 26329344
VASCULITIS; ANCA; OUTCOMES; PATIENTS
10.  Current Status, Goals, and Research Agenda for Outcome Measures Development in Behçet Syndrome: Report from OMERACT 2014 
The Journal of rheumatology  2015;42(12):2436-2441.
Objective
There is an unmet need for reliable, validated, and widely accepted outcomes and outcome measures for use in clinical trials in Behçet syndrome (BS). Our report summarizes initial steps taken by the Outcome Measures in Rheumatology (OMERACT) vasculitis working group toward developing a core set of outcome measures for BS according to the OMERACT methodology, including the OMERACT Filter 2.0, and discussions during the first meeting of the BS working group held during OMERACT 12 (2014).
Methods
During OMERACT 12, some of the important challenges in developing outcomes for BS were outlined and discussed, and a research agenda was drafted.
Results
Among topics discussed were the advantages and disadvantages of a composite measure for BS that evaluates several organs/organ systems; bringing patients and physicians together for discussions about how to assess disease activity; use of organ-specific measures developed for other diseases; and the inclusion of generic, disease-specific, or organ-specific measures. The importance of incorporating patients’ perspectives, concerns, and ideas into outcome measure development was emphasized.
Conclusion
The planned research agenda includes conducting a Delphi exercise among physicians from different specialties that are involved in the care of patients with BS and among patients with BS, with the aim of identifying candidate domains and subdomains to be assessed in randomized clinical trials of BS, and candidate items for a composite measure. The ultimate goal of the group is to develop a validated and widely accepted core set of outcomes and outcome measures for use in clinical trials in BS.
doi:10.3899/jrheum.141147
PMCID: PMC4940045  PMID: 26373563
BEHÇET SYNDROME; OUTCOME MEASURES; OUTCOMES
11.  Trends in Bone Mineral Density in Young Adults with Cystic Fibrosis over a 15 Year Period 
Background
Improvements in clinical care have led to increased life expectancy in patients with cystic fibrosis (CF) over the past several decades. Whether these improvements have had significant effects on bone health in patients with CF is unclear.
Methods
This is a cross-sectional study comparing clinical characteristics and bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) in adults with CF evaluated in 1995–1999 to age-, race-, and gender matched patients with CF evaluated in 2011–2013 at the same center on calibrated DXA machines.
Results
The cohorts were similar in terms of age, BMI, pancreatic insufficiency, presence of F508del mutation, and reproductive history. In the most recent cohort, pulmonary function was superior, and fewer patients had vitamin D deficiency or secondary hyperparathyroidism. Areal BMD measures of the PA spine, lateral spine, and distal radius were similarly low in the two cohorts.
Conclusions
Although pulmonary function and vitamin D status were better in patients in the present-day cohort, areal BMD of the spine was reduced in a significant number of patients and was no different in patients with CF today than in the late 1990s. Further attention to optimizing bone health may be necessary to prevent CF-related bone disease.
doi:10.1016/j.jcf.2015.01.011
PMCID: PMC4485936  PMID: 25698451
Cystic fibrosis; osteoporosis; dual energy X-ray absorptiometry; bone turnover markers; vitamin D
12.  Neutrophil-Related Gene Expression And Low-Density Granulocytes Associated with Disease Activity and Response to Treatment in ANCA-Associated Vasculitis 
Objectives
To discover biomarkers involved in the pathophysiology of ANCA-associated vasculitis (AAV) and determine if low-density granulocytes (LDGs) contribute to gene expression signatures in AAV.
Methods
The source of clinical data and linked biospecimens was a randomized controlled treatment trial in AAV. RNA-sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit (BL) and during remission 6 months later (6M). Gene expression was compared between patients who met versus did not meet the primary trial outcome of clinical remission at 6M (responders vs. nonresponders). Measurement of neutrophil-related gene expression was confirmed in PBMCs to validate findings in whole blood. A negative selection strategy isolated LDGs from PBMC fractions.
Results
Differential expression between responders (n=77) and nonresponders (n=35) was detected in 2,346 transcripts at BL visit (p<0.05). Unsupervised hierarchical clustering demonstrated a cluster of granulocyte-related genes, including myeloperoxidase (MPO) and proteinase 3 (PR3). A granulocyte multi-gene composite score was significantly higher in nonresponders than responders (p<0.01) and during active disease compared to remission (p<0.01). This signature strongly overlapped an LDG signature identified previously in lupus (FDRGSEA<0.01). Transcription of PR3 measured in PBMCs was associated with active disease and treatment response (p<0.01). LDGs isolated from patients with AAV spontaneously formed neutrophil extracellular traps containing PR3 and MPO.
Conclusions
In AAV an increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV.
doi:10.1002/art.39153
PMCID: PMC4485551  PMID: 25891759
vasculitis; antineutrophil cytoplasmic antibody (ANCA); proteinase 3; myeloperoxidase; biomarkers; low-density granulocyte (LDG); neutrophil extracellular traps (NETs); granulomatosis with polyangiitis (GPA; Wegener’s); microscopic polyangiitis (MPA)
13.  Update on Outcome Measure Development for Large Vessel Vasculitis: Report from OMERACT 12 
The Journal of rheumatology  2015;42(12):2465-2469.
Objective
The rarity of large vessel vasculitis (LVV) is a major factor limiting randomized controlled trials in LVV, resulting in treatment choices in these diseases that are guided mainly by observational studies and expert opinion. Further complicating trials in LVV is the absence of validated and meaningful outcome measures. The Outcome Measures in Rheumatology (OMERACT) vasculitis working group initiated the Large Vessel Vasculitis task force in 2009 to develop data-driven, validated outcome tools for clinical investigation in LVV. This report summarizes the progress that has been made on a disease activity assessment tool and patient-reported outcomes in LVV as well as the group’s research agenda.
Methods
The OMERACT LVV task force brought an international group of investigators and patient research partners together to work collaboratively on developing outcome tools. The group initially focused on disease activity assessment tools in LVV. Following a systematic literature review, an international Delphi exercise was conducted to obtain expert opinion on principles and domains for disease assessment. The OMERACT vasculitis working group’s LVV task force is also conducting qualitative research with patients, including interviews, focus groups, and engaging patients as research partners, all to ensure that the approach to disease assessment includes measures of patients’ perspectives and that patients have input into the research agenda and process.
Results
The preliminary results of both the Delphi exercise and the qualitative interviews were discussed at the OMERACT 12 (2014) meeting and the completion of the analyses will produce an initial set of domains and instruments to form the basis of next steps in the research agenda.
Conclusion
The research agenda continues to evolve, with the ultimate goal of developing an OMERACT-endorsed core set of outcome measures for use in clinical trials of LVV.
doi:10.3899/jrheum.141144
PMCID: PMC4668221  PMID: 26077399
Vasculitis large vessel; Takayasu arteritis; Giant cell arteritis Outcomes; 
14.  The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network 
Background
Among the unique features of the Rare Diseases Clinical Research Network (RDCRN) Program is the requirement for each Consortium to include patient advocacy groups (PAGs) as research partners. This development has transformed the work of the RDCRN and is a model for collaborative research. This article outlines the roles patients and PAGs play in the RDCRN and reports on the PAGs’ impact on the Network’s success.
Methods
Principal Investigators from the 17 RDCRN Consortia and 28 representatives from 76 PAGs affiliated with these Consortia were contacted by email to provide feedback via an online RDCRN survey. Impact was measured in the key areas of 1) Research logistics; 2) Outreach and communication; and 3) Funding and in-kind support. Rating choices were: 1-very negative, 2-somewhat negative, 3-no impact, 4-somewhat positive, and 5-very positive.
Results
Twenty-seven of the PAGs (96 %) disseminate information about the RDCRN within the patient community. The Consortium Principal Investigators also reported high levels of PAG involvement. Sixteen (94 %) Consortium Principal Investigators and 25 PAGs (89 %) reported PAGs participation in protocol review, study design, Consortium conference calls, attending Consortium meetings, or helping with patient recruitment.
Conclusions
PAGs are actively involved in shaping Consortia’s research agendas, help ensure the feasibility and success of research protocols by assisting with study design and patient recruitment, and support training programs. This extensive PAG-Investigator partnership in the RDCRN has had a strongly positive impact on the success of the Network.
doi:10.1186/s13023-016-0445-8
PMCID: PMC4870759  PMID: 27194034
Rare diseases; Patient engagement; Network
15.  Genome-wide association study identifies susceptibility loci in IL6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 in Takayasu’s arteritis 
Objective
Takayasu’s arteritis is a rare large vessel vasculitis with incompletely understood etiology. We performed the first unbiased genome-wide association study (GWAS) in Takayasu’s arteritis.
Methods
Two independent Takayasu’s arteritis cohorts from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 European-derived patients and 1,047 controls. Genotyping was performed using the Omni1-Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu’s arteritis.
Results
We identified genetic susceptibility loci for Takayasu’s arteritis with a genome-wide level of significance in IL6 (rs2069837, OR= 2.07, P= 6.70×10−9), RPS9/LILRB3 (rs11666543, OR= 1.65, P= 2.34×10−8), and an intergenic locus on chromosome 21q22 (rs2836878, OR= 1.79, P= 3.62×10−10). The genetic susceptibility locus in RPS9/LILRB3 is located within the leukocyte receptor complex (LRC) gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin-like receptor gene LILRB3 (P= 2.29×10−8). In addition, we identified candidate susceptibility genes with suggestive levels of association (P <1×10−5) including PCSK5, LILRA3, PPM1G/NRBP1, and PTK2B in Takayasu’s arteritis.
Conclusion
This study identified novel genetic susceptibility loci for Takayasu’s arteritis and uncovered potentially important aspects in the pathophysiology of this form of vasculitis.
doi:10.1002/art.39035
PMCID: PMC4414813  PMID: 25604533
16.  Defining the Nasal Transcriptome in Granulomatosis with Polyangiitis 
Objectives
To determine whether disease processes related to granulomatosis with polyangiitis (GPA) are reflected in gene expression profiles of nasal mucosa.
Methods
Nasal brushings of the inferior turbinate were obtained from 32 patients with GPA (10 with active nasal disease, 13 with prior nasal disease, 9 with no history of nasal disease) and a composite comparator group with and without inflammatory nasal disease (12 healthy people, 15 with sarcoidosis, 8 with allergic rhinitis). Differential gene expression was assessed between subgroups of GPA and comparators.
Results
339 genes were differentially expressed between the GPA and comparator groups (absolute fold change > 1.5; false discovery rate < 0.05). Top canonical pathways upregulated in nasal brushings from patients with GPA include granulocyte adhesion and diapedesis (p=8.6 E-22), agranulocyte adhesion and diapedesis (p=1.3 E-14), interleukin 10 signaling (3.0 E-11), and TREM1 signaling (9.0 E-11). A set of genes differentially expressed in GPA independent of nasal disease activity status included genes related to epithelial barrier integrity (fibronectin 1, desmosomal proteins) and several matricellular proteins (e.g. osteonectin, osteopontin). Significant overlap of differentially expressed genes was observed between active and prior nasal disease GPA subgroups. Peripheral blood neutrophil and mononuclear gene expression levels associated with GPA were similarly altered in the nasal gene expression profiles of patients with active or prior nasal disease.
Conclusions
Profiling the nasal transcriptome in GPA reveals gene expression signatures related to innate immunity, inflammatory cell chemotaxis, extracellular matrix composition, and epithelial barrier integrity. Airway-based expression profiling is feasible and informative in GPA.
doi:10.1002/art.39185
PMCID: PMC4519398  PMID: 25939343
vasculitis; granulomatosis with polyangiitis (GPA Wegener’s); gene expression; ANCA-associated vasculitis; nasal mucosa
17.  Cardiac Involvement in Granulomatosis with Polyangiitis 
The Journal of rheumatology  2015;42(7):1209-1212.
Objective
To determine frequency and outcomes of granulomatosis with polyangiitis (GPA)–related cardiac disease in a North American GPA cohort.
Methods
Analysis was done of all patients in the Vasculitis Clinical Research Consortium Longitudinal Study of GPA. Demographic and clinical characteristics of patients with and without GPA-related cardiac involvement were compared.
Results
Of 517 patients with GPA, 3.3% had cardiac involvement. No differences were observed between patients with or without cardiac involvement in terms of demographics, antineutrophil cytoplasmic antibody positivity, or relapse rate.
Conclusion
Cardiac involvement in GPA is rare and heterogeneous. In this cohort, cardiac involvement was not associated with a higher rate of relapse or premature death.
doi:10.3899/jrheum.141513
PMCID: PMC4505809  PMID: 25934819
CARDIAC DISEASE; GRANULOMATOSIS WITH POLYANGIITIS; VASCULITIS
18.  Disease Relapses among Patients with Giant Cell Arteritis: A Prospective, Longitudinal Cohort Study 
The Journal of rheumatology  2015;42(7):1213-1217.
Objective
To evaluate the frequency, timing, and clinical features of relapses in giant cell arteritis (GCA).
Methods
Patients with GCA enrolled in a prospective, multicenter, longitudinal study were included in the analysis. Relapse was defined as either new disease activity after a period of remission or worsening disease activity.
Results
The study included 128 subjects: 102 women (80%) and 26 men (20%). Mean ± SD age at diagnosis of GCA was 69.9 ± 8.6 years. Mean followup for the cohort was 21.4 ± 13.9 months. Median (interquartile range) duration of disease at study enrollment was 4.6 months (1.2, 16.8). During followup, 59 relapses were observed in 44 patients (34%). Ten patients (8%) experienced 2 or more relapses. The most common symptoms at relapse were headache (42%) and polymyalgia rheumatica (51%), but ischemic (some transient) manifestations (visual symptoms, tongue or jaw claudication, and/or limb claudication) occurred in 29% of relapses (12% cohort). Forty-three relapses (73%) occurred while patients were taking glucocorticoid therapy at a median (range) prednisone dose of 7.5 (0–35) mg. In 21% of relapses, both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were normal. Among 69 patients enrolled in the cohort with newly diagnosed disease, 24% experienced a first relapse within 12 months after diagnosis.
Conclusion
Among patients with GCA, relapses are common, often occurring during treatment. ESR and CRP are frequently normal at times of clinical relapse, highlighting the need for better biomarkers to assess disease activity in GCA. There remains a need for effective therapeutic alternatives to glucocorticoids in GCA.
doi:10.3899/jrheum.141347
PMCID: PMC4505815  PMID: 25877501
GIANT CELL ARTERITIS; RELAPSES; DISEASE ACTIVITY; COHORT STUDY
19.  Mapping of the Outcome Measures in Rheumatology Core Set for Antineutrophil Cytoplasmic Antibody–Associated Vasculitis to the International Classification of Function, Disability and Health 
Arthritis care & research  2015;67(2):255-263.
Objective
The International Classification of Functioning, Disability and Health (ICF) is a framework and classification of health that describes health along 4 components: body functions, body structures, activities and participation, and contextual factors. This study examined the content of instruments that constitute the Outcome Measures in Rheumatology (OMERACT) core set of outcome measures for antineutrophil cytoplasmic antibody–associated vasculitis (AAV) by “mapping” them to the ICF.
Methods
The content of the instruments included in the AAV core set were linked to the ICF by 2 independent investigators according to previously established ICF linkage rules.
Results
The AAV core set includes 3 measures of disease activity (3 versions of the Birmingham Vasculitis Activity Score), 1 damage measure (Vasculitis Damage Index), 1 patient-reported outcome (Short Form 36 health survey), and death. Linking these instruments to the ICF revealed comprehensive coverage of the ICF components body functions and body structures, limited coverage of the ICF component activities and participation, and complete absence of coverage of contextual factors.
Conclusion
ICF was found to be useful for thematic characterization of a heterogeneous group of outcome measures for AAV, i.e., a group of complex medical conditions. Linking of the instruments selected for the OMERACT AAV core set of outcome measures to the ICF classification revealed limitations in the representation of constructs related to life impact of AAV, represented by the ICF components activities and participation and contextual factors. Further research and methods development are needed to better incorporate important aspects of functioning and health relevant to patients into clinical trials of AAV.
doi:10.1002/acr.22414
PMCID: PMC4505813  PMID: 25048363
20.  Peripheral CD5+ B Cells in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis 
Objective
CD5+ B cells have been conceptualized as a possible surrogate for Breg cells. The aim of the present study was to determine the utility of CD5+ B cells as biomarkers in antineutrophil cytoplasmic antibody–associated vasculitis (AAV).
Methods
The absolute and relative numbers (percentages) of CD5+ B cells (explanatory variables) were measured longitudinally during 18 months in 197 patients randomized to receive either rituximab (RTX) or cyclophosphamide (CYC) followed by azathioprine (AZA) for the treatment of AAV (Rituximab in ANCA-Associated Vasculitis [RAVE] trial). Outcome variables included disease activity (status of active disease versus complete remission), responsiveness to induction therapy, disease relapse, disease severity, and, in RTX-treated patients, relapse-free survival according to the percentage of CD5+ B cells detected upon B cell repopulation.
Results
CD5+ B cell numbers were comparable between the treatment groups at baseline. After an initial decline, absolute CD5+ B cell numbers progressively increased in patients in the RTX treatment arm, but remained low in CYC/AZA-treated patients. In both groups, the percentage of CD5+ B cells increased during remission induction and slowly declined thereafter. During relapse, the percentage of CD5+ B cells correlated inversely with disease activity in RTX-treated patients, but not in patients who received CYC/AZA. No significant association was observed between the numbers of CD5+ B cells and induction treatment failure or disease severity. The dynamics of the CD5+ B cell compartment did not anticipate disease relapse. Following B cell repopulation, the percentage of CD5+ B cells was not predictive of time to flare in RTX-treated patients.
Conclusion
The percentage of peripheral CD5+ B cells might reflect disease activity in RTX-treated patients. However, sole staining for CD5 as a putative surrogate marker for Breg cells did not identify a subpopulation of B cells with clear potential for meaningful clinical use. Adequate phenotyping of Breg cells is required to further explore the value of these cells as biomarkers in AAV.
doi:10.1002/art.38916
PMCID: PMC4497572  PMID: 25332071
21.  The informational needs of patients with ANCA-associated vasculitis—development of an informational needs questionnaire 
Rheumatology (Oxford, England)  2014;53(8):1414-1421.
Objective. The aim of the study was to compare the informational needs of patients with ANCA-associated vasculitis (AAV).
Methods. We developed a Vasculitis Informational Needs Questionnaire that was distributed to members of Vasculitis UK (VUK) by mail and registrants of the Vasculitis Clinical Research Consortium (VCRC) online registry with self-reported AAV. Patients were asked to use a 5-point scale (1 = not important, 5 = extremely important) to rank aspects of information in the following domains: disease, investigations, medication, disease management and psychosocial care. The source and preferred method of educational delivery were recorded.
Results. There were 314 VUK and 273 VCRC respondents. Respondents rated information on diagnosis, prognosis, investigations, treatment and side effects as extremely important. Information on patient support groups and psychosocial care was less important. There was no difference in the ratings of needs based on group, sex, age, disease duration, disease or method of questionnaire delivery. The most-preferred methods of providing information for both groups were by a doctor (with or without written material) or web based; educational courses and compact disc/digital video disc (CD/DVD) were the least-preferred methods.
Conclusion. This study demonstrates that people with AAV seek specific information concerning their disease, treatment regimes and side effects and the results of investigations. Individuals preferred to receive this information from a doctor. Patients with AAV should be treated in a similar manner to patients with other chronic illnesses in which patient education is a fundamental part of care.
doi:10.1093/rheumatology/keu026
PMCID: PMC4103516  PMID: 24625507
ANCA-associated vasculitis; granulomatosis with polyangiitis; eosinophilic granulomatosis with polyangiitis; microscopic polyangiitis; vasculitis; informational needs questionnaire
22.  A MODEL TO PREDICT CARDIOVASCULAR EVENTS IN PATIENTS WITH NEWLY DIAGNOSED WEGENER’S GRANULOMATOSIS AND MICROSCOPIC POLYANGIITIS 
Arthritis care & research  2011;63(4):588-596.
Objectives
To create a prognostic tool to quantify the 5 year cardiovascular (CV) risk in patients with newly diagnosed Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) without pre-morbid CV disease.
Methods
We reviewed CV outcomes during the long term follow up of patients in the first 4 European Vasculitis Study Group (EUVAS) trials of WG and MPA. CV events were defined as: CV-death, stroke, myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention. Logistic regression was performed to create a model to predict the absolute risk of a CV event. The model was tested using the Wegener’s Granulomatosis Etanercept Trial (WGET) cohort.
Results
74/535 (13.8%) of the patients with 5 years of follow up from the EUVAS trials had at least one CV event: 33/281 (11.7%) WG vs. 41/254 (16%) MPA. The independent determinants of CV outcomes were; older age [OR 1.45 (95%CI 1.11 – 1.90)]; diastolic hypertension [OR 1.97 (95%CI 0.98 – 3.95)], and positive PR3 ANCA status [OR 0.39 (95%CI 0.20 – 0.74)]. The model was validated using the WGET cohort (Area under ROC curve = 0.80).
Conclusion
Within 5 years of diagnosis of WG or MPA, 14% of patients will have a cardiovascular event. We have constructed and validated a tool to quantify the risk of a cardiovascular event based on age, diastolic hypertension and PR3 ANCA status in patients without prior CV disease. In patients with vasculitis, PR3 ANCA is associated with reduced cardiovascular risk compared to MPO ANCA or negative ANCA status.
doi:10.1002/acr.20433
PMCID: PMC4511092  PMID: 21452269
Vasculitis; Cardiovascular; Wegener’s granulomatosis; microscopic polyangiitis; ANCA; myocardial infarction; stroke
23.  Correlates and Responsiveness to Change of Measures of Skin and Musculoskeletal Disease in Early Diffuse Systemic Sclerosis 
Arthritis care & research  2014;66(11):1731-1739.
Objective
Skin and musculoskeletal involvement are frequently present early in diffuse cutaneous systemic sclerosis (dcSSc). The current study examined the correlates for skin and musculoskeletal measures in a 1-year longitudinal observational study.
Methods
Patients with dcSSc were recruited at 4 US centers and enrolled in a 1-year study. Prespecified and standardized measures included physician and patient assessments of skin involvement, modified Rodnan skin score (MRSS), durometer score, Health Assessment Questionnaire disability index, serum creatine phosphokinase, tender joint counts, and presence/absence of tendon friction rubs, small joint contractures, and large joint contractures. Additionally, physician and patient global health assessments and health-related quality of life assessments were recorded. Correlations were computed among the baseline global assessments, skin variables, and musculoskeletal variables. Using the followup physician and patient anchors, effect sizes were calculated.
Results
A total of 200 patients were studied: 75% were women, mean ± SD age was 50.0 ± 11.9 years, and mean ± SD disease duration from first non–Raynaud’s phenomenon symptom was 1.6 ± 1.4 years. Physician global health assessment had large correlations with MRSS (r = 0.60) and physician-reported skin involvement visual analog scale in the last month (r = 0.74), whereas patient global assessment had large correlations with MRSS, the Short Form 36 health survey physical component scale, skin interference, and skin involvement in the last month (r = 0.37–0.72). Four of 9 skin variables had moderate to large effect sizes (0.51–1.09).
Conclusion
Physician and patient global assessments have larger correlations with skin measures compared to musculoskeletal measures. From a clinical trial perspective, skin variables were more responsive to change than musculoskeletal variables over a 1-year period, although both provide complementary information.
doi:10.1002/acr.22339
PMCID: PMC4511097  PMID: 24692361
24.  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Oral Type I Collagen Treatment in Patients With Diffuse Cutaneous Systemic Sclerosis 
Arthritis and rheumatism  2008;58(6):1810-1822.
Objective
To investigate the safety and efficacy of oral bovine type I collagen (CI) treatment in patients who have had diffuse cutaneous systemic sclerosis (dc-SSc; scleroderma) for ≤10 years.
Methods
One hundred sixty-eight patients with dcSSc were enrolled in a double-blind, placebo-controlled trial of oral CI (500 µg/day) or placebo administered over 12 months, with a followup visit at month 15. The primary outcome was the modified Rodnan skin thickness score (MRSS). Other clinical and immune system parameters were also assessed.
Results
Intent-to-treat and modified intent-to-treat analyses showed that for the total population of patients with dcSSc, there were no significant differences in the mean change in MRSS or other key clinical parameters between the CI and placebo treatment groups at 12 months or at 15 months. However, in a subanalysis of the available data at month 15, the CI-treated group of patients with late-phase dcSSc experienced a significant reduction in the MRSS compared with that in the placebo-treated patients with late-phase dcSSc (change in MRSS at month 15 –7.9 versus −2.9; P = 0.0063).
Conclusion
Although the results from this trial did not meet the primary outcome goals, the findings from exploratory analyses indicated that CI treatment may benefit patients with late-phase dcSSc. This new treatment strategy and preliminary clinical observations in patients with dcSSc need to be corroborated.
doi:10.1002/art.23501
PMCID: PMC4511098  PMID: 18512816
25.  Current Status of Outcome Measure Development in Vasculitis 
The Journal of rheumatology  2014;41(3):593-598.
The conduct of randomized controlled trials for vasculitis, especially for the antineutrophil cytoplasmic antibody-associated vasculitides [AAV, granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis], has been greatly advanced by the development, use, and acceptance of validated outcome measures. Trials have subsequently provided the opportunity to validate and refine reliable, valid outcome measures for these multisystemic and relapsing rare diseases. The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group was formed in 2004 to foster development of validated and widely accepted outcomes in vasculitis using data-driven analyses, a dedication to building consensus, and adherence to, and guidance by, the principles of the OMERACT approach. This work led to the endorsement by OMERACT of the core set of domains and associated outcome measures for AAV. Next steps for the study of existing outcome tools in AAV include better definition of response criteria through development of more data-driven weighting of the elements of activity and damage assessment. The Working Group is now also embarking on a series of linked projects to develop validated patient-reported outcomes for use in clinical research in vasculitis. Additionally, the Working Group is studying how current methods of disease assessment and plans for new outcomes can be informed by the conceptual framework of the International Classification of Function of the World Health Organization. The success of the Group’s work in AAV has also led to a formal process for developing outcomes for the large vessel vasculitides (Takayasu arteritis and giant cell arteritis) and Behçet disease.
doi:10.3899/jrheum.131248
PMCID: PMC4507266  PMID: 24429177
OUTCOMES; VASCULITIS; ASSESSMENT

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