PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-21 (21)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
Document Types
1.  Meta-analysis in granulomatosis with polyangiitis reveals shared susceptibility loci with rheumatoid arthritis 
Arthritis and rheumatism  2012;64(10):3463-3471.
Objectives
To examine the association of previously identified autoimmune disease susceptibility loci with granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis), and determine whether genetic susceptibility profiles of other autoimmune diseases are associated with GPA
Methods
Genetic data from two cohorts were meta-analyzed. Genotypes for 168 previously identified single nucleotide polymorphisms (SNPs) associated with susceptibility to different autoimmune diseases were ascertained for a total of 880 GPA cases and 1969 controls of European descent. Single marker associations were identified using additive logistic regression models. Multi-SNP associations with GPA were assessed using genetic risk scores based on susceptibility loci for Crohn’s disease, type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, celiac disease, and ulcerative colitis. Adjustment for population substructure was performed in all analyses using ancestry informative markers and principal components analysis.
Results
Genetic polymorphisms in CTLA4 were significantly associated with GPA in the single-marker meta-analysis (OR 0.79. 95% CI 0.70–0.89, p=9.8×10−5). A genetic risk score based on rheumatoid arthritis susceptibility markers was significantly associated with GPA (OR 1.05 per 1-unit increase in genetic risk score, 95% CI 1.02–1.08, p=5.1×10−5).
Conclusions
Rheumatoid arthritis and GPA may arise from a similar genetic predisposition. Aside from CTLA4, other loci previously found to be associated with common autoimmune diseases were not statistically associated with GPA in this study.
doi:10.1002/art.34496
PMCID: PMC3425721  PMID: 22508400
genetics; vasculitis; granulomatosis with polyangiitis; rheumatoid arthritis; CTLA4
2.  Association of Vascular Physical Examination Findings and Arteriographic Lesions in Large Vessel Vasculitis 
The Journal of rheumatology  2011;39(2):303-309.
Objective
To assess the utility of the vascular physical examination to detect arteriographic lesions in patients with established large vessel vasculitis (LVV), including Takayasu’s arteritis (TAK) and giant cell arteritis (GCA).
Methods
In total, 100 patients (TAK = 68, GCA = 32) underwent standardized physical examination and angiography of the carotid, subclavian, and axillary arteries. Sensitivity and specificity were calculated for the association between findings on physical examination focusing on the vascular system (absent pulse, bruit, and blood pressure difference) and arteriographic lesions defined as stenosis, occlusion, or aneurysm.
Results
We found 67% of patients had at least 1 abnormality on physical examination (74% TAK, 53% GCA). Arteriographic lesions were seen in 76% of patients (82% TAK, 63% GCA). Individual physical examination findings had poor sensitivity (range 14%–50%) and good-excellent specificity (range 71%–98%) to detect arteriographic lesions. Even when considering physical examination findings in combination, at least 30% of arteriographic lesions were missed. Specificity improved (range 88%–100%) if individual physical examination findings were compared to a broader region of vessels rather than specific anatomically correlated vessels and if ≥ 1 physical examination findings were combined.
Conclusion
In patients with established LVV, physical examination alone is worthwhile to detect arterial disease but does not always localize or reveal the full extent of arteriographic lesions. Abnormal vascular system findings on physical examination are highly associated with the presence of arterial lesions, but normal findings on physical examination do not exclude the possibility of arterial disease. Serial angiographic assessment is advisable to monitor arterial disease in patients with established LVV.
doi:10.3899/jrheum.110652
PMCID: PMC3729730  PMID: 22174204
VASCULITIS; TAKAYASU’S ARTERITIS; GIANT CELL ARTERITIS; ANGIOGRAM; PHYSICAL EXAMINATION
3.  Distribution of arterial lesions in Takayasu’s arteritis and giant cell arteritis 
Annals of the rheumatic diseases  2012;71(8):1329-1334.
Objectives
To compare patterns of arteriographic lesions of the aorta and primary branches in patients with Takayasu’s arteritis (TAK) and giant cell arteritis (GCA).
Methods
Patients were selected from two North American cohorts of TAK and GCA. The frequency of arteriographic lesions was calculated for 15 large arteries. Cluster analysis was used to derive patterns of arterial disease in TAK versus GCA and in patients categorised by age at disease onset. Using latent class analysis, computer derived classification models based upon patterns of arterial disease were compared with traditional classification.
Results
Arteriographic lesions were identified in 145 patients with TAK and 62 patients with GCA. Cluster analysis demonstrated that arterial involvement was contiguous in the aorta and usually symmetric in paired branch vessels for TAK and GCA. There was significantly more left carotid (p=0.03) and mesenteric (p=0.02) artery disease in TAK and more left and right axillary (p<0.01) artery disease in GCA. Subclavian disease clustered asymmetrically in TAK and in patients ≤55 years at disease onset and clustered symmetrically in GCA and patients >55 years at disease onset. Computer derived classification models distinguished TAK from GCA in two subgroups, defining 26% and 18% of the study sample; however, 56% of patients were classified into a subgroup that did not strongly differentiate between TAK and GCA.
Conclusions
Strong similarities and subtle differences in the distribution of arterial disease were observed between TAK and GCA. These findings suggest that TAK and GCA may exist on a spectrum within the same disease.
doi:10.1136/annrheumdis-2011-200795
PMCID: PMC3729734  PMID: 22328740
4.  A Genetic Progression Model of BrafV600E-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention 
Cancer Cell  2013;24(1):15-29.
Summary
We show that BRAFV600E initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic BrafV600E expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition.
Graphical Abstract
Highlights
•We present a progression model of BrafV600E-initiated serrated intestinal cancer•Stage-specific genetic alterations drive sequential tumorigenesis•Oncogenic signaling triggered by mutant Braf displays dose-dependent effects•Large-scale pharmacologic profiling reveals new approaches for therapeutic targeting
doi:10.1016/j.ccr.2013.05.014
PMCID: PMC3706745  PMID: 23845441
5.  Relationship Between Markers of Platelet Activation and Inflammation with Disease Activity in Wegener’s Granulomatosis 
The Journal of rheumatology  2011;38(6):1048-1054.
Objective
There remains a need for biomarkers to guide therapy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Our objective was to determine whether measures of platelet activation or inflammation are associated with disease activity in Wegener’s granulomatosis (WG).
Methods
Study subjects were participants in a clinical trial. Soluble CD40 ligand (sCD40L), C-reactive protein, interleukin 6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1), P-selectin, vascular endothelial growth factor, and proteinase 3 (PR3)-specific ANCA were measured by ELISA using plasma samples obtained at baseline (active disease), at remission, and prior to, during, and after first flares. Disease activity was assessed by the Birmingham Vasculitis Activity Score for WG (BVAS/WG). Association of biomarkers with disease activity was determined with conditional logistic and linear regression.
Results
Over a mean followup of 27 months, 180 subjects underwent 2044 visits; markers were measured in 563 samples. Longitudinally, all markers other than IL-6 were associated with disease activity. The strongest associations for active disease at baseline versus remission were observed for sCD40L (OR 4.72, 95% CI 2.47–9.03), P-selectin (OR 6.26, 95% CI 2.78–14.10), PR3-ANCA (OR 9.41, 4.03–21.99), and inversely for MCP-1 (OR 0.36, 95% CI 0.22–0.57). BVAS/WG increased by 0.80 (95% CI 0.44–1.16), 0.83 (95% CI 0.42–1.25), and 0.81 (95% CI 0.48–1.15) per unit-increase in PR3-ANCA, sCD40L, and P-selectin, respectively; and decreased by 1.54 (95% CI 0.96–2.12) per unit-increase in MCP-1.
Conclusion
Cytokines arising from within the circulation, including those of platelet activation, correlate with disease activity in WG.
doi:10.3899/jrheum.100735
PMCID: PMC3653633  PMID: 21411717
VASCULITIS; BIOMARKERS; DISEASE ACTIVITY; WEGENER’S GRANULOMATOSIS
6.  OPTIMAL DNA TIER FOR THE IRT/DNA ALGORITHM DETERMINED BY CFTR MUTATION RESULTS OVER 14 YEARS OF NEWBORN SCREENING 
Background
There has been great variation and uncertainty about how many and what CFTR mutations to include in cystic fibrosis (CF) newborn screening algorithms, and very little research on this topic using large populations of newborns.
Methods
We reviewed Wisconsin screening results for 1994–2008 to identify an ideal panel.
Results
Upon analyzing approximately 1 million screening results, we found it optimal to use a 23 CFTR mutation panel as a second tier when an immunoreactive trypsinogen (IRT)/DNA algorithm was applied for CF screening. This panel in association with a 96th percentile IRT cutoff gave a sensitivity of 97.3%, but restricting the DNA tier to F508del was associated with 90% (P<.0001).
Conclusions
Although CFTR panel selection has been challenging, our data show that a 23 mutation method optimizes sensitivity and is practically advantageous. The IRT cutoff value, however, is actually more critical than DNA in determining CF newborn screening sensitivity.
doi:10.1016/j.jcf.2011.02.001
PMCID: PMC3650906  PMID: 21388895
Cystic Fibrosis Transmembrane Conductance Regulator; immunoreactive trypsinogen; sensitivity
7.  Improving Communication between Doctors and Parents after Newborn Screening 
Background
Newborn screening (NBS) enables early treatment and some consider it a natural vehicle for genetic screening. Bioethicists argue for caution since families of carrier infants can develop psychosocial complications. This paper describes methods and feasibility of our statewide project for quality improvement of communication and psychosocial outcomes after NBS.
Methods
When NBS identifies carrier status for cystic fibrosis or sickle cell, we contact primary care providers (PCPs), answer questions, and invite them to rehearse informing the parents. Three months later we telephone parents, assess knowledge and psychosocial outcomes, provide counseling, and assist with self-referral to further resources. Afterwards, anonymous evaluation surveys are provided.
Results
Birthing facilities provided accurate PCP names for 73% of 817 infants meeting inclusion criteria; we identified PCPs for 21% more. We reached 47.3% of PCPs in time to invite a rehearsal; 60% of these accepted. We successfully called 50.2% of eligible parents; 61% recalled a PCP explanation and 48.5% evaluated the explanation favorably. Evaluations by parents with limited health literacy were less favorable.
Conclusion
It is feasible to follow parents for psychosocial outcomes after NBS. Preliminary data about communication is mixed, but further data will soon describe psychosocial outcomes, and investigate outcomes’ associations with communication.
PMCID: PMC3594768  PMID: 22164579
Newborn Screening; Genetic counseling; Genetic screening; Cystic fibrosis; Sickle cell trait; Provider-patient communication; Communication quality assurance
8.  Assessment of Health Related Quality of Life as an Outcome Measure in Granulomatosis with Polyangiitis (Wegener's) 
Arthritis care & research  2012;64(2):273-279.
Objective
Assess a generic measure of health-related quality of life (HRQOL) as an outcome measure in granulomatosis with polyangiitis (Wegener's, GPA)
Methods
Subjects were participants in the Wegener’s Granulomatosis Etanercept Trial (WGET) or the Vasculitis Clinical Research Consortium Longitudinal Study (VCRC-LS). HRQOL was assessed with the Short Form 36 Health Survey (SF-36) that includes physical and mental component summary scores (PCS and MCS). Disease activity was assessed with the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG).
Results
Data from 180 subjects in the WGET (median follow-up = 2.3 years, mean number of visits = 10) and 237 subjects in the VCRC-LS (median follow-up = 2.0 years, mean number of visits = 8) were analyzed. One unit increase in BVAS/WG corresponded to a 1.15 unit (95%CI: 1.02; 1.29) decrease in PCS and a 0.93 (95%CI: 0.78; 1.07) decrease in MCS in the WGET and by 1.16 for PCS (95%CI: 0.94; 1.39) and 0.79 for MCS (95%CI: 0.51; 1.39) in the VCRC-LS. In both arms of the WGET study, SF-36 measures improved rapidly during the first 6 weeks of treatment followed by gradual improvement among patients achieving sustained remission (0.5 improvement in PCS per three months), but worsened slightly (0.03 decrease in PCS per three months) among patients not achieving sustained remission (p = 0.005).
Conclusion
HRQOL, as measured by SF-36, is reduced among patients with GPA. SF-36 measures are modestly associated with other disease outcomes and discriminate between disease states of importance in GPA.
doi:10.1002/acr.20649
PMCID: PMC3250569  PMID: 21954229
vasculitis; health-related quality of life; outcome measures
9.  A Decision-Tree Approach to Cost Comparison of Newborn Screening Strategies for Cystic Fibrosis 
Pediatrics  2012;129(2):e339-e347.
OBJECTIVE:
Because cystic fibrosis can be difficult to diagnose and treat early, newborn screening programs have rapidly developed nationwide but methods vary widely. We therefore investigated the costs and consequences or specific outcomes of the 2 most commonly used methods.
METHODS:
With available data on screening and follow-up, we used a simulation approach with decision trees to compare immunoreactive trypsinogen (IRT) screening followed by a second IRT test against an IRT/DNA analysis. By using a Monte Carlo simulation program, variation in the model parameters for counts at various nodes of the decision trees, as well as for costs, are included and applied to fictional cohorts of 100 000 newborns. The outcome measures included the numbers of newborns given a diagnosis of cystic fibrosis and costs of screening strategy at each branch and cost per newborn.
RESULTS:
Simulations revealed a substantial number of potential missed diagnoses for the IRT/IRT system versus IRT/DNA. Although the IRT/IRT strategy with commonly used cutoff values offers an average overall cost savings of $2.30 per newborn, a breakdown of costs by societal segments demonstrated higher out-of-pocket costs for families. Two potential system failures causing delayed diagnoses were identified relating to the screening protocols and the follow-up system.
CONCLUSIONS:
The IRT/IRT screening algorithm reduces the costs to laboratories and insurance companies but has more system failures. IRT/DNA offers other advantages, including fewer delayed diagnoses and lower out-of-pocket costs to families.
doi:10.1542/peds.2011-0096
PMCID: PMC3269109  PMID: 22291119
cystic fibrosis; immunoreactive trypsinogen; DNA; newborn screening; costs; sensitivity
10.  Circulating Markers of Vascular Injury and Angiogenesis in ANCA-Associated Vasculitis 
Arthritis and rheumatism  2011;63(12):3988-3997.
Objective
To identify biomarkers that distinguish between active ANCA-associated vasculitis (AAV) and remission in a manner superior or complementary to established markers of systemic inflammation.
Methods
Markers of vascular injury and angiogenesis were measured before and after treatment in a large clinical trial in AAV. 163 subjects enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Serum levels of E-selectin, ICAM-3, MMP1, MMP3, MMP9, P-selectin, thrombomodulin, and VEGF were measured at study screening (time of active disease) and at month 6. ESR and CRP levels had been measured at the time of the clinical visit. The primary outcome was the difference in marker level between screening and month 6 among patients in remission (BVAS/WG score of 0) at month 6.
Results
All subjects had severe active vasculitis (mean BVAS/WG score 8.6 +/− 3.2 SD) at screening. Among the 123 subjects clinically in remission at month 6, levels of all markers except E-selectin showed significant declines. MMP3 levels were also higher among the 23 subjects with active disease at month 6 than among the 123 subjects in remission. MMP3 levels correlated weakly with ESR and CRP.
Conclusion
Many markers of vascular injury and angiogenesis are elevated in severe active AAV and decline with treatment, but MMP3 appears to distinguish active AAV from remission better than the other markers studied. Further study of MMP3 is warranted to determine its clinical utility in combination with conventional markers of inflammation and ANCA titers.
doi:10.1002/art.30615
PMCID: PMC3227746  PMID: 21953143
biomarkers; vasculitis; ANCA
11.  Oral Cyclophosphamide Therapy Diminishes Ovarian Reserve in Women with Granulomatosis with Polyangiitis 
Arthritis care & research  2011;63(12):1777-1781.
Objective
Standard treatment for severe granulomatosis with polyangiitis (GPA, previously Wegener’s granulomatosis) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX).
Methods
Patients in the Wegener’s Granulomatosis Etanercept Trial received either daily CYC or weekly MTX and were randomized to etanercept or placebo. For all women under 50, plasma samples taken at baseline or early in the study were evaluated against samples taken later in the study to compare levels of anti-Müllerian hormone (AMH) and follicle stimulating hormone (FSH), endocrine markers of remaining egg supply. Diminished ovarian reserve was defined as AMH<1.0ng/ml.
Results
Of 42 women in this analysis (mean age 35), 24 had CYC exposure prior to enrollment and 28 received the drug during the study. At study entry, women with prior CYC exposure had significantly lower AMH, higher FSH, and a higher rate of early menstruation cessation. For women with normal baseline ovarian function, 6/8 who received CYC during the trial developed diminished ovarian reserve, compared to 0/4 who did not receive CYC (p<0.05). Changes in AMH correlated inversely with cumulative CYC dose (p=0.01), with a 0.74ng/ml decline in AMH for each 10g of CYC.
Conclusion
Daily oral CYC, even when administered for less than 6 months, causes diminished ovarian reserve, as indicated by low AMH levels. These data highlight the need for alternative treatments for GPA in women of childbearing age.
doi:10.1002/acr.20605
PMCID: PMC3306000  PMID: 22127969
Granulomatosis with polyangiitis; fertility; cyclophosphamide; anti-Müllerian hormone; ovarian function
12.  Solid Malignancies Among Patients with Wegener’s Granulomatosis Treated with Etanercept: Long-term Follow-up of a Multicenter Longitudinal Cohort 
Arthritis and rheumatism  2011;63(8):2495-2503.
Purpose
An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener’s Granulomatosis Etanercept Trial (WGET). The present study was conducted to determine the malignancy risk beyond the exposure to study therapy.
Methods
The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic reports, and therapeutic interventions. The SEER database was used to estimate a standardized incidence rate (SIR) for solid malignancies.
Results
The median post-trial follow-up available for 153 patients (85% of the original cohort) was 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographics between etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept and 5 in the placebo group. The risk of solid malignancies in the etanercept group was increased compared to the general population (SIR=3.92; 95% CI 1.69–7.72), but not different from that of the placebo group (SIR=2.89; 95% CI 0.94–6.73, p=0.39). All solid malignancies occurred in patients exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post-trial follow-up.
Conclusions
The incidence of solid malignancy remained increased during long-term follow-up of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti-TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with WG treated with cytotoxic therapy and should be avoided in such patients.
doi:10.1002/art.30394
PMCID: PMC3149780  PMID: 21484770
Wegener’s granulomatosis; vasculitis; etanercept; malignancy; cancer
13.  Circulating Angiopoietin-2 as a Biomarker in ANCA-Associated Vasculitis 
PLoS ONE  2012;7(1):e30197.
The endothelial-specific Angiopoietin-Tie2 ligand-receptor system is an important regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to Tie2 receptor renders the endothelial barrier responsive to pro-inflammatory cytokines. We previously showed that circulating Ang-2 correlated with disease severity in a small cohort of critically ill patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The current study reassessed Ang-2 as a biomarker of disease activity and relapse in AAV. Circulating Ang-2 was measured in 162 patients with severe AAV (BVAS/WG≥3, with or without glomerulonephritis) in a clinical trial. Ang-2 levels during active AAV were compared to levels in the same patients during remission (BVAS/WG = 0). Levels in clinical subsets of AAV were compared, and association with future disease course was assessed. Ang-2 levels were elevated in severe disease (median 3.0 ng/ml, interquartile range 1.9–4.4) compared to healthy controls (1.2, 0.9–1.5). However, they did not reliably decline with successful treatment (median 2.6 ng/ml, interquartile range 1.9–3.8, median change −0.1). Ang-2 correlated weakly with BVAS/WG score (r = 0.17), moderately with markers of systemic inflammation (r = 0.25–0.41), and inversely with renal function (r = −0.36). Levels were higher in patients with glomerulonephritis, but levels adjusted for renal dysfunction were no different in patients with or without glomerulonephritis. Levels were higher in patients with newly diagnosed AAV and lower in patients in whom treatment had recently been started. Ang-2 levels during active disease did not predict response to treatment, and Ang-2 levels in remission did not predict time to flare. Thus, Ang-2 appears to have limited practical value in AAV as a biomarker of disease activity at time of measurement or for predicting future activity.
doi:10.1371/journal.pone.0030197
PMCID: PMC3261176  PMID: 22279570
14.  Alpha1-Antitrypsin Deficiency–Related Alleles Z and S and the Risk of Wegener’s Granulomatosis 
Arthritis and rheumatism  2010;62(12):3760-3767.
Objective
Deficiency of α1-antitrypsin (α1AT) may be a determinant of susceptibility to Wegener’s granulomatosis (WG). Several previous, mainly small, case–control studies have shown that 5–27% of patients with WG carried the α1AT deficiency Z allele. It is not clear whether the S allele, the other major α1AT deficiency variant, is associated with WG. This study investigated the relationship of the α1AT deficiency Z and S alleles with the risk of developing WG in a large cohort.
Methods
We studied the distribution of the α1AT deficiency alleles Z and S in 433 unrelated Caucasian patients with WG and 421 ethnically matched controls. Genotyping was performed using an allele discrimination assay. Results were compared between cases and controls using exact statistical methods.
Results
Among the patients with WG, the allele carriage frequencies of Z and S were 7.4% and 11.5%, respectively. The frequencies of the 6 possible genotypes differed in a statistically significant manner between cases and controls (P = 0.01). The general genetic 2-parameter codominant model provided the best fit to the data. Compared with the normal MM genotype, the odds ratio (OR) for MZ or MS genotypes was 1.47 (95% confidence interval [95% CI] 0.98–2.22), and the OR for ZZ, SS, or SZ genotypes was 14.58 (95% CI 2.33–∞). ORs of similar direction and magnitude were observed within the restricted cohorts that excluded cases and controls carrying ≥1 Z or ≥1 S allele.
Conclusion
Both Z and S alleles display associations with risk of WG in a codominant genetic pattern. These findings strengthen the evidence of a causal link between α1AT deficiency and susceptibility to WG.
doi:10.1002/art.27742
PMCID: PMC3123032  PMID: 20827781
15.  Tissue and serum markers of inflammation during the follow-up of patients with giant-cell arteritis—a prospective longitudinal study 
Rheumatology (Oxford, England)  2011;50(11):2061-2070.
Objective. To evaluate the association between inflammatory markers and relapse in GCA patients longitudinally assessed in a clinical trial of infliximab and glucocorticosteroids.
Methods. Forty-four newly diagnosed GCA patients in glucocorticosteroid-induced remission were randomized to receive infliximab 5 mg/kg or placebo plus daily glucocorticosteroids, tapered using a standardized schedule. Sera were analysed for inflammatory markers at multiple, pre-defined time points. Temporal artery biopsies were performed in four patients before and after treatment to analyse changes in inflammatory and vascular remodelling marker expression.
Results. Thirteen of 44 patients relapsed. Similar proportions of relapsed patients were present in both treatment arms. ESR, CRP, intercellular adhesion molecule (ICAM)-1, TNF-α, and IL-12p40 were significantly elevated near relapse. In post-treatment biopsies, mRNA expression of pro-inflammatory cytokines decreased, while vascular remodelling factors increased relative to baseline biopsies. Tissue IL-12p40 and IFN-γ mRNA remained elevated in relapsing vs remitting patients.
Conclusion. Despite prior findings of high concentrations of TNF-α in temporal artery biopsies of GCA patients, infliximab plus glucocorticosteroids did not result in improved clinical outcomes. Increased measures of this biomarker did not provide useful insight into the relative importance of TNF-α in the pathogenesis of GCA. Gene expression analysis in paired temporal artery biopsies pre- and post-treatment revealed decreased inflammatory activity and active vascular remodelling following treatment. In relapsing patients, increased expression of IFN-γ and IL-12p40 in post-treatment biopsies suggests a role in sustaining disease and setting the stage for relapse during treatment withdrawal.
Trial registration. ClinicalTrials.gov; http://www.clinicaltrials.gov; NCT00076726.
doi:10.1093/rheumatology/ker163
PMCID: PMC3198905  PMID: 21873264
Serum markers; Giant cell arteritis; Relapse; Remission; Cytokines
16.  Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis 
The New England journal of medicine  2010;363(3):221-232.
BACKGROUND
Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen.
METHODS
We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months.
RESULTS
Nine centers enrolled 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events.
CONCLUSIONS
Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)
doi:10.1056/NEJMoa0909905
PMCID: PMC3137658  PMID: 20647199
17.  Junior doctor titles following implementation of Modernising Medical Careers in the UK 
JRSM Short Reports  2011;2(3):22.
Objective
Recent changes in postgraduate medical training in the UK collectively organized under the auspices of Modernising Medical Careers (MMC) have created new labels for junior doctors in training. It would appear that many nurses and other health workers do not understand the new terminology. We aimed to investigate the knowledge of nursing staff about new junior doctor titles in a district general hospital. As far as we are aware, this is the first survey to determine the views and knowledge of the new terms among staff working in the NHS.
Design
Questionnaire study.
Setting
District general hospital, West Midlands, UK.
Participants
Fifty-five randomly selected staff nurses working in the surgical directorate.
Main outcome measure
Questions were asked about their views and knowledge of the current nomenclature. To objectively assess knowledge of the new titles respondents were asked to match equivalent positions with those based on the old system.
Results
Only 22% (n = 12) of respondents felt that they fully understand current terms in usage. Seventy-six percent (n = 42) felt that it was ‘very important’ that titles accurately convey role and seniority of the doctor. The most common titles correctly matched were FY1 and House Officer (n = 45, 81%) and FY2 and First Year Senior House Officer (n = 35, 64%). Only 9% (n = 5) of staff nurses correctly matched ST3 to Junior Registrar and 13% (n = 7) correctly matched ST7 to Senior Registrar. Ward-based staff nurses demonstrated greater familiarity with titles when compared to nurses who work mainly in the outpatient clinic and theatre setting (p = 0.017). We did not identify a statistically significant association with demographic characteristics (age, gender, experience) and knowledge of the new terms (p > 0.05). Approximately 98% (n = 54) of the staff surveyed felt that terms are confusing to nurses and need to be simplified.
Conclusions
Our survey revealed that nursing staff lacked knowledge of the current terminology to describe doctors in training. This may have implications for staff expectations regarding specific role of junior doctor in terms of clinical decision-making, working relationships and communication between team members, and ultimately patient care.
doi:10.1258/shorts.2011.010110
PMCID: PMC3086326  PMID: 21541090
18.  Two rare causes of frey syndrome 
doi:10.1007/s12663-010-0004-0
PMCID: PMC3453682  PMID: 23139585
19.  Multiplexed Genetic Analysis Using an Expanded Genetic Alphabet 
Clinical chemistry  2004;50(11):2019-2027.
Background
All states require some kind of testing for newborns, but the policies are far from standardized. In some states, newborn screening may include genetic tests for a wide range of targets, but the costs and complexities of the newer genetic tests inhibit expansion of newborn screening. We describe the development and technical evaluation of a multiplex platform that may foster increased newborn genetic screening.
Methods
MultiCode® PLx involves three major steps: PCR, target-specific extension, and liquid chip decoding. Each step is performed in the same reaction vessel, and the test is completed in ~3 h. For site-specific labeling and room-temperature decoding, we use an additional base pair constructed from isoguanosine and isocytidine. We used the method to test for mutations within the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The developed test was performed manually and by automated liquid handling. Initially, 225 samples with a range of genotypes were tested retrospectively with the method. A prospective study used samples from >400 newborns.
Results
In the retrospective study, 99.1% of samples were correctly genotyped with no incorrect calls made. In the perspective study, 95% of the samples were correctly genotyped for all targets, and there were no incorrect calls.
Conclusions
The unique genetic multiplexing platform was successfully able to test for 31 targets within the CFTR gene and provides accurate genotype assignments in a clinical setting.
doi:10.1373/clinchem.2004.034330
PMCID: PMC1592527  PMID: 15319316
20.  Determinants of Vessel Targeting in Vasculitis 
Studies of autoimmune diseases have not yet elucidated why certain organs or vessels become the objects of injury while others are spared. This paper will explore the hypothesis that important differences exist in regions of the aorta that determine vulnerability to diseases, such as atherosclerosis, aortitis, giant cell arteritis and Takayasu's disease. The reader is invited to reassess; (1) whether the aorta is indeed a single homogeneous structure, and (2) whether the initial stage of aortitis (and indeed other diseases considered “autoimmune”) may be primarily due to acquired alterations of substrate, that influence unique immune profiles, which by themselves may not be pathogenic. Disease susceptibility and patterns are influenced by many factors that are inborn and acquired. Examples include genetic background, gender, ethnicity, aging, prior and concomitant illnesses, habits, diet, toxin and environmental exposures. Studies of vascular diseases must assess how such variables may affect regional differences in endothelial cells, subendothelial matrix, vascular smooth muscle and the response of each to a variety of stimuli.
doi:10.1080/17402520400001652
PMCID: PMC2486329  PMID: 15559374

Results 1-21 (21)