Matthew D. Morgan

Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis

BACKGROUND Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens. METHODS We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events. RESULTS The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m(2) of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14). CONCLUSIONS A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)

Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up

Introduction The previously reported randomised controlled trial of a consensus regimen of pulse cyclophosphamide suggested that it was as effective as a daily oral (DO) cyclophosphamide for remission induction of antineutrophil cytoplasm autoantibodies-associated systemic vasculitis when both were combined with the same glucocorticoid protocol (CYCLOPS study (Randomised trial of daily oral versus pulse Cyclophosphamide as therapy for ANCA-associated Systemic Vasculitis published de groot K, harper L et al Ann Int Med 2009)). The study had limited power to detect a difference in relapse. This study describes the long-term outcomes of patients in the CYCLOPS study. Methods Long-term outcomes were ascertained retrospectively from 148 patients previously recruited to the CYCLOPS Trial. Data on survival, relapse, immunosuppressive treatment, cancer incidence, bone fractures, thromboembolic disease and cardiovascular morbidity were collected from physician records retrospectively. All patients were analysed according to the group to which they were randomised. Results Median duration of follow-up was 4.3 years (IQR, 2.95–5.44 years). There was no difference in survival between the two limbs (p=0.92). Fifteen (20.8%) DO and 30 (39.5%) pulse patients had at least one relapse. The risk of relapse was significantly lower in the DO limb than the pulse limb (HR=0.50, 95% CI 0.26 to 0.93; p=0.029). Despite the increased risk of relapse in pulse-treated patients, there was no difference in renal function at study end (p=0.82). There were no differences in adverse events between the treatment limbs. Discussion Pulse cyclophosphamide is associated with a higher relapse risk than DO cyclophosphamide. However, this is not associated with increased mortality or long-term morbidity. Although the study was retrospective, data was returned in 90% of patients from the original trial.

Prediction of ESRD and Death Among People With CKD: The Chronic Renal Impairment in Birmingham (CRIB) Prospective Cohort Study

Background Validated prediction scores are required to assess the risks of end-stage renal disease (ESRD) and death in individuals with chronic kidney disease (CKD). Study Design Prospective cohort study with validation in a separate cohort. Setting & Participants Cox regression was used to assess the relevance of baseline characteristics to risk of ESRD (mean follow-up, 4.1 years) and death (mean follow-up, 6.0 years) in 382 patients with stages 3-5 CKD not initially on dialysis therapy in the Chronic Renal Impairment in Birmingham (CRIB) Study. Resultant risk prediction equations were tested in a separate cohort of 213 patients with CKD (the East Kent cohort). Factors 44 baseline characteristics (including 30 blood and urine assays). Outcomes ESRD and all-cause mortality. Results In the CRIB cohort, 190 patients reached ESRD (12.1%/y) and 150 died (6.5%/y). Each 30% lower baseline estimated glomerular filtration rate was associated with a 3-fold higher ESRD rate and a 1.3-fold higher death rate. After adjustment for each other, only baseline creatinine level, serum phosphate level, urinary albumin-creatinine ratio, and female sex remained strongly (P < 0.01) predictive of ESRD. For death, age, N-terminal pro-brain natriuretic peptide, troponin T level, and cigarette smoking remained strongly predictive of risk. Using these factors to predict outcomes in the East Kent cohort yielded an area under the receiver operating characteristic curve (ie, C statistic) of 0.91 (95% CI, 0.87-0.96) for ESRD and 0.82 (95% CI, 0.75-0.89) for death. Limitations Other important factors may have been missed because of limited study power. Conclusions Simple laboratory measures of kidney and cardiac function plus age, sex, and smoking history can be used to help identify patients with CKD at highest risk of ESRD and death. Larger cohort studies are required to further validate these results.

Anti-Neutrophil Cytoplasm-Associated Glomerulonephritis

Wegeners granulomatosis, microscopic polyangiitis, and renal limited vasculitis are associated with circulating anti-neutrophil cytoplasm antibodies and are an important cause of rapidly progressive glomerulonephritis. This review gives an account of recent advances in the understanding of the pathogenesis underlying these conditions and how these may lead to future treatments. Consideration is given to recent clinical trials in the management of anti-neutrophil cytoplasm antibodies (ANCA)-associated vasculitides.

ANCA induces β2 integrin and CXC chemokine-dependent neutrophil-endothelial cell interactions that mimic those of highly cytokine-activated endothelium

Antineutrophil cytoplasm antibodies (ANCA) activate neutrophils to undergo a series of coordinated interactions, leading to transendothelial migration, eventually culminating in vascular destruction. The molecular events underlying neutrophil recruitment in ANCA‐associated vasculitis need to be defined to enable effective therapeutic manipulation. A flow‐based adhesion ssay was used to investigate the role of β2 integrins (CD11a/CD18 and CD11b/CD18) and chemokine receptors [CXC chemokine receptor (CXCR)1 and CXCR2] in neutrophil migration through the endothelium. Two endothelial models were used: a highly activated model stimulated with 100 U/ml tumor necrosis factor α (TNF‐α) and a minimally activated model stimulated with 2 U/ml TNF‐α and in which ANCA was present as a secondary neutrophil stimulus. CD11a/CD18, CD11b/CD18, and CXCR2 contributed to adhesion and transendothelial migration in both models. However, when the endothelium was minimally activated with TNF‐α, CD11b/CD18 played an important role in stabilizing adhesion induced by ANCA immunoglobulin G (IgG). Analysis of β2 integrins and chemokine receptors demonstrated that ANCA IgG had no effect on expression levels at the neutrophil surface but enabled an active conformational change of CD11b/CD18. Similar molecular mechanisms control neutrophil adhesion and migration through highly or minimally TNF‐α‐activated endothelium. However, the direct ANCA‐mediated neutrophil stimulation is needed to drive migration through minimally activated endothelium, and CD11b/CD18 is recruited for greater stability of adhesion during this process and can undergo an activatory, conformational change in response to ANCA IgG.

Patients with Wegener's granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells.

An increased proportion of CD4+ CD25+ T cells has been reported in Wegener’s granulomatosis (WG) and may represent an accumulation of regulatory T cells (Treg). CD25 is also expressed on recently activated effector T cells. We have determined the relative proportion of these subsets in a large patient cohort. The fraction of Treg in peripheral blood mononuclear cells from patients and healthy controls was determined by assessment of Foxp3 expression on CD4+ CD25+ T cells. The functional activity of Treg was determined by their ability to suppress proliferation and cytokine production in response to proteinase‐3. Although WG patients demonstrated an increased fraction of CD4+ CD25+ T cells, the percentage of Foxp3‐positive cells was decreased. In addition, the percentage of Treg was inversely related to the rate of disease relapse. CD4+ CD25hi T cells were able to suppress T‐cell proliferation to proteinase‐3 in healthy controls and anti‐neutrophil cytoplasm antibody (ANCA)‐ negative patients (at time of sampling) but not in ANCA‐positive patients. In patients with active disease, an increased proportion of CD4+ Foxp3+ cells was associated with a more rapid disease remission. Patients with WG demonstrate abnormalities in the number and function of Treg and this is most pronounced in those with most active disease. This information is of value in understanding the pathogenesis and potential treatment of this disease.

Increased incidence of cardiovascular events in patients with antineutrophil cytoplasmic antibody–associated vasculitides: A matched-pair cohort study

OBJECTIVE To explore the risk of cardiovascular disease in patients with antineutrophil cytoplasmic antibody-associated vasculitides (AAVs) and to assess contributing risk factors. METHODS In a retrospective matched-pair cohort study, 113 of 131 patients with AAVs from a vasculitis clinic registry were matched 1:1 for renal function, age at diagnosis, sex, smoking status, and previous history of a cardiovascular disease to patients with noninflammatory chronic kidney disease (CKD). Cardiovascular events were defined as acute coronary syndrome, new-onset angina, symptomatic peripheral vascular disease, stroke, and transient ischemic attack. RESULTS Median followup times were 3.4 years for the AAV patients and 4.2 years for the CKD patients. More cardiovascular events occurred in the AAV group (23 of 113) than in the CKD group (16 of 113). Cox regression survival analysis showed a significantly increased risk of a cardiovascular event for AAV patients, with a hazard ratio (HR) of 2.23 (95% confidence interval [95% CI] 1.1-4.4) (P = 0.017). Within the cohort of AAV patients, the most strongly predictive factors were previous history of cardiovascular disease (HR 4 [95% CI 1.7-9.8]), history of dialysis dependency (HR 4.3 [95% CI 1.5-12.1]), ever having smoked (HR 3.9 [95% CI 1.5-10]), age at diagnosis (HR 1.038 [95% CI 1.006-1.072]), estimated glomerular filtration rate at remission (HR 0.977 [95% CI 0.957-0.998]), and serum cholesterol concentration at presentation (HR 0.637 [95% CI 0.441-0.92]). CONCLUSION In this retrospective study, patients with AAVs appear at greater risk of cardiovascular disease, with increased risk in those with a previous history of cardiovascular disease, dialysis dependency, poor renal function at remission, or a history of smoking. Measures to reduce the risk of cardiovascular disease should be integral to the management of systemic vasculitis.

Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial

OBJECTIVES The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12 months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. METHODS Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m(2)/week×4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6 months followed by azathioprine (n=11, control group). RESULTS The primary end point at 24 months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. CONCLUSIONS At 24 months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. TRIAL REGISTRATION NUMBER ISRCTN28528813.

ANCA-associated vasculitis is linked to carriage of the Z allele of α1 antitrypsin and its polymers

Background Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Objective To test the validity and the mechanism of this association between α1AT and AAV. Methods The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. Results were compared between cases and controls using χ2 tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91–3.32) mg/dl vs 0.17 (0.06–0.28) mg/dl, p<0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse. Conclusions The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.

Addition of Infliximab to Standard Therapy for ANCA-Associated Vasculitis

Background: Tumour necrosis factor-α (TNF) is implicated in the pathogenesis of anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). Current immunosuppressive therapy is associated with considerable morbidity and mortality. Anti-TNF antibody therapy (infliximab) may help control AAV by providing more targeted immunosuppression and allow reductions in the use of corticosteroids and cyclophosphamide, thereby reducing the burden of immunosuppression with its associated morbidity and mortality. Methods: 33 patients with active AAV participated in this cohort study. Patients were treated with standard therapy (corticosteroids and cyclophosphamide with additional plasma exchange in the case of life- or organ-threatening disease) or standard therapy + infliximab at weeks 0, 2, 6 and 10. The primary outcome measure was time to remission. Other outcome measures were adverse events, cumulative damage scores and relapse, as well as biomarkers for circulating activated and regulatory T cells. Follow-up was for 12 months. Results: 17 patients received standard therapy alone; 16 patients received additional infliximab. The addition of infliximab to standard therapy did not influence remission rates, adverse events, damage index scores, relapse rates or biomarker levels in this cohort study. Conclusion: The addition of infliximab to standard therapy did not confer clinical benefit for patients with active AAV.