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1.  Experience with rituximab in the treatment of antineutrophil cytoplasmic antibody associated vasculitis 
Prior to the 1970s, severe cases of antineutrophil cytoplasmic antibody associated vasculitis (AAV) were thought to be invariably fatal. However, the use of cyclophosphamide-based treatment regimens fundamentally altered disease outcomes, transforming AAV into a manageable, chronic illness. Despite the tremendous success of cyclophosphamide in the treatment of AAV, there remained a need for alternative therapies, due to high rates of treatment failures and significant toxicities. In recent years, with the introduction of targeted biologic response modifiers into clinical practice, many have hoped that the treatment options for AAV could be expanded. Rituximab, a chimeric monoclonal antibody directed against the B-lymphocyte protein CD20, has been the most successful biologic response modifier to be used in AAV. Following the first report of its use in AAV in 2001, experience with rituximab for treatment of AAV has rapidly expanded. Rituximab, in combination with glucocorticosteroids, is now well established as a safe and effective alternative to cyclophosphamide for remission induction for severe manifestations of granulomatosis with polyangiitis and microscopic polyangiitis. In addition, initial experiences with rituximab for remission maintenance in these diseases have been favorable, as have experiences for remission induction in eosinophilic granulomatosis with polyangiitis.
doi:10.1177/1759720X13516239
PMCID: PMC3956138  PMID: 24688606
antineutrophil cytoplasmic antibody; antineutrophil cytoplasmic antibody associated vasculitis; eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome); granulomatosis with polyangiitis (Wegener’s granulomatosis); microscopic polyangiitis; rituximab; vasculitis
2.  Update on Diffuse Alveolar Hemorrhage and Pulmonary Vasculitis 
doi:10.1016/j.iac.2012.08.001
PMCID: PMC3483562  PMID: 23102067
Pulmonary vasculitis; diffuse alveolar hemorrhage; ANCA-associated vasculitis; granulomatosis with polyangiitis; microscopic polyangiitis; eosinophilic granulomatosis with polyangiitis
3.  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
4.  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
5.  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
6.  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
7.  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
8.  Pathogenesis of ANCA-Associated Vasculitis 
Antineutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) are a group of systemic vasculitis characterized by inflammation and necrosis of blood vessel walls. Genetic, epigenetic and environmental factors contribute to the etiology and pathogenesis of AAV. Based on currently available clinical and experimental evidence, it is reasonable to conceptualize that in predisposed patients, different triggers can lead to the production of autoantibodies (ANCA) that in the context of an inflammatory environment can cause tissue inflammation and vascular injury. Several different pathways and mechanisms in the pathogenesis of AAV are described in this contemporary review.
doi:10.1016/j.rdc.2010.05.006
PMCID: PMC3486518  PMID: 20688244
ANCA; ANCA-associated vasculitis; Granulomatosis with polyangiitis; Microscopic polyangiitis; Eosinophilic granulomatosis with polyangiitis; Pathogenesis; Etiology
9.  Rituximab for the treatment of Churg–Strauss syndrome with renal involvement 
Nephrology Dialysis Transplantation  2011;26(9):2865-2871.
Introduction. Churg–Strauss syndrome (CSS) is a small vessel systemic vasculitis associated with asthma and eosinophilia that causes glomerulonephritis (GN) in ∼25% of patients. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody that depletes B cells and is effective in numerous autoimmune diseases including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We aim to evaluate the safety and efficacy of RTX in inducing remission of renal disease activity in patients with CSS.
Methods. We conducted a single-center, open-label pilot study using RTX (375 mg/m2/week × 4) for induction of remission in CSS patients with renal involvement [defined as having >25% dysmorphic red cells, red blood cell casts or pauci-immune GN on biopsy]. Written informed consent was obtained from all individuals. Patients were eligible if they were untreated, had failed glucocorticoid therapy or had failed glucocorticoid dose reductions because of disease relapses. The primary outcome was remission of renal disease activity defined as stability or improvement of creatinine clearance, absence of active urinary sediment and reduction of the glucocorticoid dose to <50% of the average dose received over 3 months before enrollment or <10 mg/day (whichever is smaller) at 6 months. Patients were followed up for 1 year.
Results. Only three patients (two females; ages 54, 55 and 65) were enrolled. All patients had positive myeloperoxidase-ANCA and renal involvement. Two patients had biopsy-proven pauci-immune crescentic GN. All achieved the primary end point of renal remission within the first 3 months and remained in renal remission during the year following RTX treatment. One patient experienced a nonrenal relapse (eye and joint involvement) at 6 months coinciding with the reconstitution of CD19+ cells and eosinophilia. He was retreated with RTX and achieved remission within 6 weeks. No major adverse effects were recorded.
Conclusions. In this pilot study, RTX was safe and successful in controlling renal disease activity in three patients with CSS. This agent deserves further study in CSS.
doi:10.1093/ndt/gfq852
PMCID: PMC3218640  PMID: 21325353
ANCA vasculitis; Churg–Strauss syndrome; glomerulonephritis; rituximab
10.  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
11.  Histopathologic Overlap between Fibrosing Mediastinitis and IgG4-Related Disease 
Fibrosing mediastinitis (FM) and IgG4-related disease (IgG4-RD) are two fibroinflammatory disorders with potentially overlapping clinical and radiological features. In this paper, we looked for histopathologic features of IgG4-RD and enumerated infiltrating IgG4-positive plasma cells within mediastinal tissue biopsies from FM patients. We identified 15 consecutive FM surgical mediastinal tissue biopsies between 1985 and 2006. All patients satisfied the clinical and radiological diagnostic criteria for FM. All patients had either serological or radiological evidence of prior histoplasmosis or granulomatous disease, respectively. Formalin-fixed paraffin-embedded tissue sections of all patients were stained for H&E, IgG, and IgG4. Three samples met the predefined diagnostic criteria for IgG4-RD. In addition, characteristic histopathologic changes of IgG4-RD in the absence of diagnostic numbers of tissue infiltrating IgG4-positive plasma cells were seen in a number of additional cases (storiform cell-rich fibrosis in 11 cases, lymphoplasmacytic infiltrate in 7 cases, and obliterative phlebitis/arteritis in 2 cases). We conclude that up to one-third of histoplasmosis or granulomatous-disease-associated FM cases demonstrate histopathological features of IgG4-RD spectrum. Whether these changes occur as the host immune response against Histoplasma or represent a manifestation of IgG4-RD remains to be determined. Studies to prospectively identify these cases and evaluate their therapeutic responses to glucocorticoids and/or other immunosuppressive agents such as rituximab are warranted.
doi:10.1155/2012/207056
PMCID: PMC3357960  PMID: 22654916
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.  Discrimination and Variable Impact of ANCA Binding to Different Surface Epitopes on Proteinase 3, the Wegener’s Autoantigen 
Journal of autoimmunity  2010;35(4):299-308.
Proteinase 3 (PR3)-specific antineutrophil cytoplasmic antibodies (ANCA) are highly specific for the autoimmune small vessel vasculitis, Wegener’s granulomatosis (WG). PR3-ANCA have proven diagnostic value but their pathogenic potential and utility as a biomarker for disease activity remain unclear. PR3-ANCA recognize conformational epitopes, and epitope-specific PR3-ANCA subsets with variable impact on biological functions of PR3 have been postulated. The aims of this study were to identify specific PR3 surface epitopes recognized by monoclonal antibodies (moAbs) and to determine whether the findings can be used to measure the functional impact of epitope-specific PR3-ANCA and their potential relationship to disease activity. We used a novel flow cytometry assay based on TALON-beads coated with recombinant human (H) and murine (M) PR3 and 10 custom-designed chimeric human/mouse rPR3-variants (Hm1–5/Mh1–5) identifying 5 separate non-conserved PR3 surface epitopes. Anti-PR3 moAbs recognize 4 major surface epitopes, and we identified the specific surface location of 3 of these with the chimeric rPR3-variants. The ability of PR3-ANCA to inhibit the enzymatic activity of PR3 was measured indirectly using a capture-ELISA system based on the different epitopes recognized by capturing moAbs. Epitope-specific PR3-ANCA capture-ELISA results obtained from patient plasma (n=27) correlated with the inhibition of enzymatic activity of PR3 by paired IgG preparations (r=0.7, P<0.01). The capture-ELISA results also seem to reflect disease activity. In conclusion, insights about epitopes recognized by anti-PR3 moAbs can be applied to separate PR3-ANCA subsets with predictable functional qualities. The ability of PR3-ANCA to inhibit the enzymatic activity of PR3, a property linked to disease activity, can now be gauged using a simple epitope-based capture-ELISA system.
doi:10.1016/j.jaut.2010.06.021
PMCID: PMC2963671  PMID: 20810247
ANCA; proteinase 3; Wegener’s granulomatosis; vasculitis
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.  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
16.  Rituximab for Refractory Wegener's Granulomatosis 
Rationale: Standard therapy for Wegener's granulomatosis is fraught with substantial toxicity and not always effective. B lymphocytes have been implicated in the pathogenesis of Wegener's granulomatosis. Their depletion has been proposed as salvage therapy for refractory disease. Earlier encouraging reports are confounded by concomitant immunosuppressive medications and include only limited available biomarker data.
Objectives: To evaluate the efficacy and safety of rituximab for remission induction in refractory Wegener's granulomatosis.
Methods: A prospective open-label pilot trial was conducted with 10 patients monitored for 1 yr. Included were patients with active severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, ANCA positivity, and resistance to (or intolerance of) cyclophosphamide. The remission induction regimen consisted of oral prednisone (1 mg/kg/d) and four weekly infusions of rituximab (375 mg/m2). Prednisone was tapered and discontinued over 5 mo. Failure to achieve remission, a clinical flare in the absence of B lymphocytes, and inability to complete the glucocorticoid taper were considered treatment failures.
Main Results: Three women and seven men (median age, 57 yr; range, 25–72 yr) were enrolled. All had ANCA reacting with proteinase-3. The median activity score at enrollment was 6 (range, 5–10). All patients tolerated rituximab well, achieved swift B-lymphocyte depletion and complete clinical remission (activity score, 0) by 3 mo, and were tapered off glucocorticoids by 6 mo. Five patients were retreated with rituximab alone for recurring/rising ANCA titers according to protocol. One patient experienced a clinical flare after B lymphocyte reconstitution.
Conclusion: In this cohort, rituximab was a well-tolerated and effective remission induction agent for severe refractory Wegener's granulomatosis.
doi:10.1164/rccm.200507-1144OC
PMCID: PMC2662987  PMID: 16224107
17.  What you should know about PR3-ANCA: Conformational requirements of proteinase 3 (PR3) for enzymatic activity and recognition by PR3-ANCA 
Arthritis Research  2000;2(4):263-267.
The neutrophil azurophil granule constituent proteinase 3 (PR3) is the principal antigen for anti-neutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis. The conformation of the mature PR3 enzyme results from intracellular post-translational processing. The nascent molecule undergoes proteolytic cleavage of the amino-terminal signal peptide and activation dipeptide and of a carboxy-terminal peptide extension. The conformation of PR3 is stabilized by four disulfide bonds and, to a lesser extent, by asparagine-linked glycosylation. Most anti-neutrophil cytoplasmic antibodies directed against proteinase 3 (PR3-ANCA) recognize conformational epitopes. The expression of recombinant PR3 has provided a better understanding of the significance of the various intracellular processing steps for enzymatic activity and recognition by PR3-ANCA.
doi:10.1186/ar99
PMCID: PMC130016  PMID: 11094439
ANCA; proteinase 3; recombinant proteins

Results 1-17 (17)