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1.  An open-label trial of abatacept (CTLA4-IG) in non-severe relapsing granulomatosis with polyangiitis (Wegener’s) 
Annals of the rheumatic diseases  2013;73(7):1376-1379.
Objectives
To determine the safety and efficacy of abatacept in non-severe relapsing granulomatosis with polyangiitis (Wegener’s)(GPA).
Methods
An open-label trial of intravenous abatacept was conducted in 20 patients with non-severe relapsing GPA. Prednisone up to 30 mg daily was permitted within the first 2 months, and patients on methotrexate, azathioprine, or mycophenolate mofetil continued these agents. Patients remained on study until common closing or early termination.
Results
Of the 20 patients, 18 (90%) had disease improvement, 16 (80%) achieved remission (BVAS/WG=0) at a median of 1.9 months, and 14 (70%) reached common closing. Six patients (30%) met criteria for early termination due to increased disease activity; 3 of 6 achieved remission and relapsed at a median of 8.6 months. The median duration of remission before common closing was 14.4 months, with the median duration of time on study for all patients being 12.3 months (range 2–35 months). Eleven of the 15 (73%) patients on prednisone reached 0 mg. Nine severe adverse events occurred in 7 patients, including 7 infections that were successfully treated.
Conclusions
In this study of patients with non-severe relapsing GPA, abatacept was well tolerated and was associated with a high frequency of disease remission and prednisone discontinuation.
doi:10.1136/annrheumdis-2013-204164
PMCID: PMC4149903  PMID: 24323392
2.  Renal Transplantation in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Multicenter Experience 
Transplantation  2011;91(12):1370-1375.
Background
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a common cause of rapidly progressive glomerulonephritis resulting in end-stage renal disease (ESRD). The optimal timing of kidney transplantation (KTX) for ESRD as a result of AAV and the risk of AAV relapse after KTX are not well defined. We report our experience with AAV patients who underwent KTX at our institutions between 1996 and 2010. Median follow-up was 64 months.
Methods
Retrospective multicenter cohort study.
Results
Eighty-five patients (45 men/40 women; mean age 49 years) received a KTX for ESRD secondary to microscopic polyangiitis (n=43) or Wegener’s granulomatosis (n=42). Twenty-four patients underwent preemptive KTX and 69 received a living-donor KTX. All patients were in remission at the time of KTX. Fifty-eight patients received induction therapy. In 64 patients, maintenance immunosuppression was with prednisone, mycophenolate mofetil, and tacrolimus. At the time of KTX, 29 patients were ANCA-positive. The vasculitis relapse rate was 0.02 per patient-years and was not influenced by disease category, ANCA subtype, or remission duration before KTX. There were 23 rejection episodes in 13 patients with seven graft losses. Median serum creatinine at 1 year was 1.3 mg/dL in 75 patients with more than 1 year follow-up and 1.4 mg/dL at last follow-up. The graft and patient survival rates were 100% at 1 year, 97.9% and 93.4% at 5 years, and 79.0% and 67.4% at 10 years, respectively.
Conclusions
KTX is a safe and an effective option for treating ESRD secondary to AAV. Relapses are rare with current immunosuppression.
doi:10.1097/TP.0b013e31821ab9aa
PMCID: PMC4096966  PMID: 21508899
ANCA vasculitis; Kidney transplantation; Immunosuppression; Outcomes
3.  Clinical characteristics and outcome of pauci-immune glomerulonephritis in African Americans 
Objectives
Pauci-immune glomerulonephritis is rare in African Americans (AA) and the clinical presentation and treatment outcomes of vasculitis have not been well described.
Methods
We identified patients who were 2–92 years of age between 1983 and 2011 with a diagnosis of biopsy-proven pauci-immune glomerulonephritis (GN) at any point during their disease course. Comparing AA to Caucasian patients, we examined demographics, clinical features at presentation, treatment and outcomes of relapse, end-stage renal disease (ESRD), and death.
Results
Of the 672 patients, 75 were AA with the remainder being Caucasian. Compared to Caucasians, disease onset in AA was at an earlier age (52 vs. 57 years, p = 0.05) and was more often myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) positive (71% vs. 54%, p = 0.01). AA patients had a shorter median time between onset of symptoms and biopsy compared to Caucasians [median (IQR): 0.23 (0.00, 1.22) months vs. 0.66 (0.00, 3.62) months, p = 0.003]. Median [Interquartile range (IQR)] follow-up in months was 28 (5, 52) in AA and 26 (10, 55) in Caucasian patients. Median estimated glomerular filtration rate was similar at presentation (21 vs. 22 ml/min/m2). Both groups had similar induction treatment regimens. There was less favorable treatment response among AA compared to Caucasians for initial treatment resistance (28% vs. 18%, p = 0.05) and complete remission (72% vs. 82%, p = 0.05). There were no differences in the number of renal relapses or number of deaths between the 2groups. Overall, in multivariable analyses controlling for age, race, ANCA type, and entry serum creatinine, there were not differences by race in treatment response, renal relapse, ESRD, or death over the entire time of follow-up. Conclusions: AA patients with pauci-immune GN are younger and more often MPO-ANCA positive compared to Caucasians. Despite a shorter time to diagnosis for AA patients, there were no differences compared to Caucasians in treatment response, ESRD, renal relapse, or death rates by race over the entire duration of follow-up.
doi:10.1016/j.semarthrit.2013.11.011
PMCID: PMC4086456  PMID: 24387818
Pauci-immune glomerulonephritis; ANCA vasculitis; African Americans; Treatment outcome
4.  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
5.  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
6.  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
7.  Biologic agents in systemic vasculitis 
The treatment of systemic necrotizing vasculitis has made great strides in both efficacy and outcomes. Standard therapies, however, are associated with numerous side effects, and not all patients will respond to conventional immunosuppression. These realities have prompted the search for safer and more efficacious treatments, most notably among biologic agents. For example, the role of TNF-α in the pathophysiology of several vasculitides has led to the investigation of targeted inhibitors of this cytokine, albeit with mixed results. There have been some disappointing results in the area of giant cell arteritis and Wegener’s granulomatosis (granulomatosis with polygiitis), but anti-TNF therapy has shown promise in the treatment of Takayasu’s arteritis, although additional trials to demonstrate its efficacy are required. Anti-B-cell therapy seems to be the most promising advance in the management of these diseases. Complete and partial responses have been seen in both primary and secondary mixed cryoglobulinemic vasculitis. Recent trials have demonstrated that rituximab is effective for the treatment of Wegener’s granulomatosis and microscopic polyangiitis. These trials have, however, raised concerns regarding the long-term safety of these agents. The future holds promise for additional targeted therapies with improved patient response and fewer side effects.
doi:10.2217/IJR.11.29
PMCID: PMC3684397  PMID: 23785387
ANCA; antineutrophil cytoplasmic autoantibodies; biologic therapies; immunosuppression; rituximab; TNF; vasculitis
8.  Development of Outcome Measures for Large-vessel Vasculitis for Use in Clinical Trials: Opportunities, Challenges, and Research Agenda 
The Journal of rheumatology  2011;38(7):1471-1479.
Giant cell (GCA) and Takayasu’s arteritis (TAK) are 2 forms of large-vessel vasculitis (LVV) that involve the aorta and its major branches. GCA has a predilection for the cranial branches, while TAK tends to affect the extracranial branches. Both disorders may also cause nonspecific constitutional symptoms. Although some clinical features are more common in one or the other disorder and the ages of initial presentation differ substantially, there is enough clinical and histopathologic overlap between these disorders that some investigators suggest GCA and TAK may be 2 processes within the spectrum of a single disease. There have been few randomized therapeutic trials completed in GCA, and none in TAK. The lack of therapeutic trials in LVV is only partially explained by the rarity of these diseases. It is likely that the lack of well validated outcome measures for LVV and uncertainties regarding trial design contribute to the paucity of trials for these diseases. An initiative to develop a core set of outcome measures for use in clinical trials of LVV was launched by the international OMERACT Vasculitis Working Group in 2009 and subsequently endorsed by the OMERACT community at the OMERACT 10 meeting. Aims of this initiative include: (1) to review the literature and existing data related to outcome assessments in LVV; (2) to obtain the opinion of experts and patients on disease content; and (3) to formulate a research agenda to facilitate a more data-based approach to outcomes development.
doi:10.3899/jrheum.110275
PMCID: PMC3653638  PMID: 21724719
VASCULITIS; OUTCOMES; TAKAYASU’S ARTERITIS; GIANT CELL ARTERITIS
9.  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
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.  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
12.  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
13.  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
14.  Patient-Reported Outcome Assessment in Vasculitis May Provide Important Data and a Unique Perspective 
Arthritis care & research  2010;62(11):1639-1645.
Objective
To assess patients’ self-estimates of the burden of disease in vasculitis and to compare data across patient populations from the US, Germany, and the UK. Outcome assessment in vasculitis primarily focuses on physician evaluations of disease activity and damage. Little is known about the patients’ perspectives regarding the burden of disease.
Methods
Patients ranked (scale 0–5) a list of vasculitis-related items to estimate a combination of pain, interference with daily function, discomfort and/or annoyance, anxiety/psychological impact, and medical importance. Patients were also asked to list the 5 most troublesome aspects of the disease.
Results
Data from 264 patients with vasculitis from 3 countries were collected. Wegener’s granulomatosis was the predominant disease, comprising 63% of the cohort. Diagnoses were confirmed by physicians in 98% of cases. The most common item from the free-text sections was fatigue (75%), followed by pain (31%), musculoskeletal symptoms (24%), difficulty breathing (19%), financial aspects (13%), nasal discharge/crusting (14%), and weight gain (10%). Rankings of individual items varied substantially: fatigue (3.5), loss of energy (3.4), weight gain (3.1), joint pain (3.0), and sinusitis (3.0) were the highest-ranked symptoms among those manifestations experienced by at least 50% of patients. Several severe manifestations (e.g., dialysis, seizures, oxygen dependency) were ranked lower (<3.0).
Conclusion
Fatigue and reduced energy level are considered the most important disease burdens by patients with vasculitis; manifestations associated with organ damage were rated lower. The patients’ perspectives of the impact of vasculitis differ from the physicians’ ratings. Future outcome assessment in vasculitis should include the patients’ perspectives.
doi:10.1002/acr.20276
PMCID: PMC3123033  PMID: 20556814
15.  Microscopic Polyangiitis 
Synopsis
In 1923, Friedrich Wohlwill described two patients with a “microscopic form of periarteritis nodosa”, which was distinct from classical polyarteritis nodosa. This disease, now known as microscopic polyangiitis (MPA), is a primary systemic vasculitis characterized by inflammation of the small-caliber blood vessels and the presence of circulating antineutrophil cytoplasmic antibodies (ANCA). Typically, microscopic polyangiitis presents with glomerulonephritis and pulmonary capillaritis, although involvement of the skin, nerves, and gastrointestinal tract is not uncommon. Treatment of MPA generally requires use of a cytotoxic agent (such as cyclophosphamide) in addition to high-dose glucocorticoids. Recent research has focused on identifying alternate treatment strategies that minimize or eliminate exposure to cytotoxic agents. This article will review the history, pathogenesis, clinical manifestations, and treatment of MPA.
doi:10.1016/j.rdc.2010.04.003
PMCID: PMC2917831  PMID: 20688249
16.  Progress Towards a Core Set of Outcome Measures in Small-vessel Vasculitis. Report from OMERACT 9 
The Journal of rheumatology  2009;36(10):2362-2368.
The past decade has seen a substantial increase in the number and quality of clinical trials of new therapies for vasculitis, including randomized, controlled, multicenter trials that have successfully incorporated measures of disease activity and toxicity. However, because current treatment regimens for severe disease effectively induce initial remission and reduce mortality, future trials will focus on any of several goals including: (a) treatment of mild—moderate disease; (b) prevention of chronic damage; (c) reduction in treatment toxicity; or (d) more subtle differences in remission induction or maintenance. Thus, new trials will require outcome measure instruments that are more precise and are better able to detect effective treatments for different disease states and measure chronic manifestations of disease. The OMERACT Vasculitis Working Group comprises international clinical investigators with expertise in vasculitis who, since 2002, have worked collaboratively to advance the refinement of outcome measures in vasculitis, create new measures to address domains of illness not covered by current research approaches, and harmonize outcome assessment in vasculitis. The focus of the OMERACT group to date has been on outcome measures in small-vessel vasculitis with an overall goal of creating a core set of outcome measures for vasculitis, each of which fulfills the OMERACT filter of truth, discrimination, feasibility, and identifying additional domains requiring further research. This process has been informed by several ongoing projects providing data on outcomes of disease activity, disease-related damage, multidimensional health-related quality of life, and patient-reported ratings of the burden of vasculitis.
doi:10.3899/jrheum.090373
PMCID: PMC3142467  PMID: 19820226
VASCULITIS; OUTCOMES; ACTIVITY; DAMAGE
17.  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
19.  Advances in the use of biologic agents for the treatment of systemic vasculitis 
Purpose of review
Due to the well-known toxicities of cyclophosphamide, substantial interest exists in finding other therapies to treat primary systemic vasculitis. Biologic agents have been proposed as an alternative to cyclophosphamide for these disorders because of their recent success in treating other rheumatic diseases. This article reviews the current state-of-the-art with regards to the use of biologic agents as a treatment for systemic vasculitis.
Recent findings
The greatest amount of experience with these agents for the treatment of systemic vasculitis is with anti-tumor necrosis factor agents, pooled intravenous immunoglobulin, and anti-B cell therapies such as rituximab. Intravenous immunoglobulin is already a standard therapy for Kawasaki's disease, but should also be considered for the treatment of ANCA-associated vasculitis when standard therapies are either ineffective or contraindicated. Early experience with tumor necrosis factor inhibitors indicates that they may be effective for the treatment of Takayasu's arteritis, but their role in the treatment of other forms of vasculitis remains controversial. Early experience with rituximab for the treatment of several forms of vasculitis has been quite promising, but must be confirmed by ongoing randomized clinical trials.
Summary
Biologic agents represent the next evolution in treatment for the primary systemic vasculitides. Greater understanding of these diseases has allowed use to move further away from non-specific, highly toxic therapies towards a more directed approach. As our experience with these agents increases, they will likely form the keystone of treatment in the near future.
doi:10.1097/BOR.0b013e32831d28b3
PMCID: PMC2921590  PMID: 19077713
vasculitis; anti-TNF; intravenous immunoglobulin; rituximab
20.  Vasculitis: lessons learned 
doi:10.1097/BOR.0b013e32831e4250
PMCID: PMC2896030  PMID: 19077712
21.  Assessment of damage in vasculitis: expert ratings of damage 
Rheumatology (Oxford, England)  2009;48(7):823-827.
Objectives. Current measures of damage in vasculitis do not account for the possibility that some forms of damage may exert greater impact than others. As part of an international effort to revise how damage is quantified in vasculitis clinical research, an exercise was performed to measure expert ratings of damage items.
Methods. Members of the Vasculitis Clinical Research Consortium and European Vasculitis Study Group were given a list of 129 items of damage related to WG and microscopic polyangiitis (MPA). Participants were asked to rate each item of damage on an integer scale from 0 to 10, where 10 represented the most severe form of damage and 0 indicated ‘no impact’.
Results. A multidisciplinary panel of 50 investigators from North America, Europe and Australia–New Zealand participated. The highest median ratings (8–10) were assigned to items of damage associated with malignancy, tissue ischaemia, the central nervous system and cardiopulmonary manifestations. The mean scores ranged from 1.3 to 9.5. The highest s.d.s (⩾2.5) were associated with forms of damage that may benefit from surgical intervention or may not be causally associated with WG or MPA. Lower scores were assigned by nephrologists in comparison with rheumatologists and by Americans in comparison to Europeans, although the difference in median ranks used by these groups was not statistically significant (P > 0.05 for the comparisons).
Conclusions. This exercise represents an important step in the development of a weighting system that may increase the utility of damage index scores for the assessment of patients with vasculitis.
doi:10.1093/rheumatology/kep103
PMCID: PMC2722812  PMID: 19454608
Damage; Morbidity; Disease assessment; Vasculitis; Wegener's granulomatosis; Microscopic polyangiitis; OMERACT
22.  Development of comprehensive disease assessment in systemic vasculitis 
Annals of the Rheumatic Diseases  2006;66(3):283-292.
The systemic vasculitides are multisystem disorders with considerable mortality and morbidity and frequent relapses. In the absence of reliable serological markers, accurate clinical tools are required to assess disease activity and damage for treatment decisions, and for the performance of clinical trials. This article reviews and summarises the development and use of disease assessment tools for determining activity and damage in systemic vasculitis and reports ongoing initiatives for further development of disease assessment tools. A literature search was conducted using PubMed and reference lists for vasculitis, assessment, clinical trials, outcome and prognosis. The findings indicate that comprehensive disease assessment in vasculitis requires documentation of disease activity, chronic irreversible damage and impairment of function.
doi:10.1136/ard.2005.051078
PMCID: PMC1855994  PMID: 16728460

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