Niels Rasmussen

2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides

2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides J. Jennette;R. Falk;P. Bacon;N. Basu;M. Cid;F. Ferrario;L. Flores-Suarez;W. Gross;L. Guillevin;E. Hagen;G. Hoffman;D. Jayne;C. Kallenberg;P. Lamprecht;C. Langford;R. Luqmani;A. Mahr;E. Matteson;P. Merkel;S. Ozen;C. Pusey;N. Rasmussen;A. Rees;D. Scott;U. Specks;J. Stone;K. Takahashi;R. Watts; Arthritis & Rheumatism

Randomized Trial of Plasma Exchange or High-Dosage Methylprednisolone as Adjunctive Therapy for Severe Renal Vasculitis

Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.

Pulse Versus Daily Oral Cyclophosphamide for Induction of Remission in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis A Randomized Trial

Context Because cyclophosphamide has many adverse effects, dosing regimens that maintain efficacy but improve safety would be welcome. Contribution In this randomized comparison of pulse and daily oral cyclophosphamide regimens for treatment of ANCA-associated vasculitis, equal proportions of patients had remissions, but the pulse regimen seemed safer, mainly because it caused less leukopenia. Caution Patients and providers were not blinded to the intervention, and the study was not powered to detect differences in relapse rate. Implication The efficacy of pulse cyclophosphamide for treatment of ANCA-associated vasculitis seems no different from that of daily oral treatment and may be safer. The Editors Wegener granulomatosis, microscopic polyangiitis, and the renal-limited variant of microscopic polyangiitis are all associated with antineutrophil cytoplasmic antibodies (ANCAs) and are therefore referred to collectively as ANCA-associated vasculitis. The justification for grouping these diseases together as a single clinical entity goes beyond ANCA seropositivity; they cause similar histologic changes in the kidney, are associated with similar pathogenic autoantibodies, and respond similarly to induction immunosuppressive treatment. However, they also differ in important respects; for example, granuloma formation and relapse after treatment are more common in Wegener granulomatosis (1, 2). Outcomes for these previously fatal diseases improved dramatically with the introduction of daily oral cyclophosphamide therapy (3, 4). However, cyclophosphamide has significant adverse effects that influence long-term morbidity and mortality (5, 6). Strategies to reduce these adverse effects include reducing the duration of cyclophosphamide use to 3 to 6 months (maximum, 9 months) (2) and switching to an alternative immunosuppressive regimen after induction of remission and using methotrexate instead of cyclophosphamide in patients without generalized disease and significantly impaired renal function (7). For many patients, however, cyclophosphamide remains the mainstay of therapy for inducing remission and treating relapse, so regimens that maintain efficacy while minimizing cyclophosphamide dose and maximizing safety would be welcome. Previous studies (8) suggest that pulse cyclophosphamide regimens are safe and provide less cumulative cyclophosphamide exposure than daily oral cyclophosphamide regimens. However, small study sizes and variations in treatment regimens, including the use of treatments alongside cyclophosphamide, make the findings preliminary. We designed this trial to test the hypothesis that a regimen of pulsed intermittent cyclophosphamide would be as effective but less toxic than daily oral cyclophosphamide for inducing remission in patients with generalized ANCA-associated vasculitis with active glomerulonephritis. Methods Trial Design and Participants Our trial was an open-label, multicenter, randomized, controlled trial conducted over 18 months. Patients, providers, and the investigators who assessed trial outcomes were not blinded to treatment assignment. Our inclusion criteria were newly diagnosed Wegener granulomatosis, microscopic polyangiitis, or renal-limited microscopic polyangiitis (diagnostic criteria adapted from the 1992 Chapel Hill consensus conference [9] and our groups previous studies [2, 7, 1012]); renal involvement attributable to active vasculitis (as defined by at least 1 of the following: serum creatinine level >150 mol/L [>1.7 mg/dL] and 500 mol/L [5.7 mg/dL], biopsy demonstrating necrotizing glomerulonephritis, erythrocyte casts, or hematuria [>30 erythrocytes per high-power field] and proteinuria [>1 g/d]); and confirmatory histology or ANCA positivity. Our exclusion criteria were coexistence of other multisystem autoimmune disease; hepatitis B or C virus or HIV infection; serum creatinine level greater than 500 mol/L (>5.7 mg/dL); previous cancer; pregnancy; or age younger than 18 or older than 80 years. We conducted our study according to the Declaration of Helsinki. Informed consent was obtained from each participant, and each participating center reviewed the trial protocol and granted ethical approval. Random Assignment Random assignments were computer-generated and performed centrally by permuted blocks of 4, stratified by country and disease. Patients were enrolled by their treating physician and registered with the central trial coordinating office by fax submission of a form that contained information on center, date of birth, sex, disease, and creatinine level. We randomly assigned patients on a 1:1 basis to receive pulse or daily oral cyclophosphamide. Data were collected in record books, entered into a central computerized database, and validated against the record books before analysis. Eleven patients withdrew before random assignment; we randomly assigned 149 patients. Interventions We designed the pulse cyclophosphamide regimen by investigator consensus, on the basis of published experience with pulse cyclophosphamide in ANCA-associated vasculitis. Patients received 3 intravenous pulses of cyclophosphamide, 15 mg/kg, given 2 weeks apart, followed by pulses at 3-week intervals (15 mg/kg intravenously or 5 mg/kg orally on 3 consecutive days, at the physicians discretion) until remission, and then for another 3 months. The maximum dose per pulse was 1.2 g. We reduced the cyclophosphamide dose by 2.5 mg/kg per pulse for persons age 60 to 70 years, 5 mg/kg per pulse for persons older than 70 years, and 2.5 mg/kg per pulse for persons with a serum creatinine level of 300 to 500 mol/L (3.4 to 5.7 mg/dL). At minimum, blood counts were checked on day 10 and 14 after each pulse and immediately before the next pulse. We reduced the dose of the subsequent pulse by 20% for patients with a leukocyte nadir of 2 to 3109/L and 40% for those with a nadir of 1 to 2109/L. The daily oral cyclophosphamide group received cyclophosphamide, 2 mg/kg per day, until remission, followed by 1.5 mg/kg per day for another 3 months. The maximum oral dose was 200 mg, and we reduced the dose by 25% for persons older than 60 years and 50% for those older than 70 years. At minimum, blood counts were checked weekly for the first month, twice-weekly for the second month, and monthly thereafter. We withheld cyclophosphamide for persons with a leukocyte count less than 4109/L, then resumed therapy at a dose reduced by 25 mg/d when their count increased to greater than 4109/L. Both groups continued the cyclophosphamide regimens for 3 months after remission, after which all patients received azathioprine, 2 mg/kg per day orally, until month 18 for remission maintenance. The maximum daily oral dose of azathioprine was 200 mg. Both groups also received prednisolone, 1 mg/kg orally, tapered to 12.5 mg at the end of month 3 and to 5 mg at the end of the study (month 18). 2-Mercaptoethanesulfonate sodium was optional in both groups. No patients received plasmapheresis. We recommended prophylaxis for Pneumocystis jiroveci for all patients. Treatment was allowed to follow local practice for patients who did not achieve remission at 9 months. We collected data on these patients but censored them for purposes of this analysis. For more details on the protocol, see Appendix 1. Outcomes and Follow-up We defined outcomes by using the Birmingham Vasculitis Activity Score (BVAS) index, which measures manifestations of active vasculitis during the 28 days before the date of assessment (13). Our primary outcome was time to remission, defined as the absence of new or worse signs of disease activity on the BVAS and no more than 1 item indicating persistent disease activity (BVAS 1). Secondary outcomes included the proportion of patients who achieved remission at 6 and 9 months and the proportion with major and minor relapses. We defined major relapse as the recurrence or first appearance of at least 1 BVAS item indicating threatened vital organ function attributable to active vasculitis. We defined minor relapse as the recurrence or first appearance of at least 3 other BVAS items related to nonvital organs. An investigator classified patients as achieving remission or having relapse, and an independent observer validated these classifications retrospectively. Additional secondary outcomes were death; change in renal function; adverse events, including leukopenia and infection; and the cumulative dose of cyclophosphamide and prednisolone, which we calculated as the total cumulative drug dose at each time point in the study (3, 6, 9, 12, 15, and 18 months) divided by the number of patients in the study at that point. For each time point, we considered only the dose of drug for those patients still in the study. Unless otherwise noted, we assessed these outcomes at baseline; at 1.5, 3, 4.5, 6, 7.5, 9, 12, 15, and 18 months after baseline; and at relapse, on the basis of standard recommendations. Clinical assessments included BVAS measures at every visit and measures of cumulative damage from any cause since disease onset, as scored by the Vasculitis Damage Index (14), at baseline and every 3 months. Laboratory assessments included measures of full blood count, C-reactive protein, alanine transaminase, serum creatinine, and glucose, as well as dipstick urine analysis. We calculated glomerular filtration rate at entry, remission, and study end by using the Modification of Diet in Renal Disease method (15). Statistical Analysis We determined the sample size for the trial by clinical rather than statistical considerations. We set a recruitment goal of 160 patients; we considered that number ambitious, given the rarity of these conditions (12 per 1 million persons) and the need to recruit patients and conduct the trial within a period (5 years) that was reasonable for our resources. We performed analyses by intention to treat. To account for censoring, we compared remission and survival by using survival methods instead of relat

Long-term patient survival in ANCA-associated vasculitis

Background Wegeners granulomatosis and microscopic polyangiitis are antineutrophil cytoplasm antibodies (ANCA)-associated vasculitides with significant morbidity and mortality. The long-term survival of patients with ANCA associated vasculitis treated with current regimens is uncertain. Objective To describe the long-term patient survival and possible prognostic factors at presentation in an international, multicentre, prospectively recruited representative patient cohort who were treated according to strictly defined protocols at presentation and included the full spectrum of ANCA-associated vasculitis disease. Methods Outcome data were collected for 535 patients who had been recruited at the time of diagnosis to four randomised controlled trials between 1995 and 2002. Trial eligibility was defined by disease severity and extent, covered the spectrum of severity of ANCA-associated vasculitis and used consistent diagnostic criteria. Demographic, clinical and laboratory parameters at trial entry were tested as potential prognostic factors in multivariable models. Results The median duration of follow-up was 5.2 years and 133 (25%) deaths were recorded. Compared with an age- and sex-matched general population there was a mortality ratio of 2.6 (95% CI 2.2 to 3.1). Main causes of death within the first year were infection (48%) and active vasculitis (19%). After the first year the major causes of death were cardiovascular disease (26%), malignancy (22%) and infection (20%). Multivariable analysis showed an estimated glomerular filtration rate <15 ml/min, advancing age, higher Birmingham Vasculitis Activity Score, lower haemoglobin and higher white cell count were significant negative prognostic factors for patient survival. Conclusion Patients with ANCA-associated vasculitis treated with conventional regimens are at increased risk of death compared with an age- and sex-matched population.

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.

Clinical and Histologic Determinants of Renal Outcome in ANCA-Associated Vasculitis: A Prospective Analysis of 100 Patients with Severe Renal Involvement

This study aimed to identify clinical and histologic prognostic indicators of renal outcome in patients with ANCA-associated vasculitis and severe renal involvement (serum creatinine >500 micromol/L). One hundred patients who were enrolled in an international, randomized, clinical trial to compare plasma exchange with intravenous methylprednisolone as an additional initial treatment were analyzed prospectively. Diagnostic renal biopsies were performed upon entry into the study. Thirty-nine histologic and nine clinical parameters were determined as candidate predictors of renal outcome. The end points were renal function at the time of diagnosis (GFR0) and 12 mo after diagnosis (GFR12), dialysis at entry and 12 mo after diagnosis, and death. Multivariate analyses were performed. Predictive of GFR0 were age (r = -0.40, P = 0.04), arteriosclerosis (r = -0.53, P = 0.01), segmental crescents (r = 0.35, P = 0.07), and eosinophilic infiltrate (r = -0.41, P = 0.04). Prognostic indicators for GFR12 were age (r = -0.32, P = 0.01), normal glomeruli (r = 0.24, P = 0.04), tubular atrophy (r = -0.28, P = 0.02), intraepithelial infiltrate (r = -0.26, P = 0.03), and GFR0 (r = 0.29, P = 0.01). Fibrous crescents (r = 0.22, P = 0.03) were predictive of dialysis at entry. Normal glomeruli (r = -0.30, P = 0.01) and treatment arm (r = -0.28, P = 0.02) were predictive of dialysis after 12 mo. No parameter predicted death. Both chronic and acute tubulointerstitial lesions predicted GFR12 in severe ANCA-associated glomerulonephritis, whereas plasma exchange was a positive predictor of dialysis independence after 12 mo for the entire patient group. Plasma exchange remained a positive predictor when patients who were dialysis dependent at presentation were analyzed separately (r = -0.36, P = 0.01). Normal glomeruli were a positive predictor of dialysis independence and improved renal function after 12 mo, indicating that the unaffected part of the kidney is vital in determining renal outcome.

The value of indirect immunofluorescence and solid phase techniques for ANCA detection: A report on the first phase of an international cooperative study on the standardization of ANCA assays

This study describes the results of phase I of an international effort to develop and standardize assays for the detection of anti-neutrophil cytoplasmic antibodies (ANCA). 12 sera, four of which were selected for their potential to cause problems in the detection of various ANCA specificities, were analyzed in the standard indirect immunofluorescence (IIF) test and in ELISAs for ANCA routinely performed in the seven participating laboratories. The IIF methodology differed with respect to the dilution of the serum being screened and the concentration of the conjugate used. Results from sera with high ANCA titers were similar, although the quantitative values could not be compared. In sera containing rheumatoid factor and anti-nuclear antibodies (ANA), ANCA-unrelated staining patterns were observed. Six antigen preparations were used in ELISA for the detection of cANCA. In ELISA with purified proteinase-3 all three cANCA sera were positive, but not anti-myeloperoxidase (MPO) or anti-lactoferrin (LF) positive sera. The other assays were less sensitive or gave inconsistent results. Various preparations of purified MPO and LF used in ELISA were readily recognized by anti-MPO and anti-LF positive sera. From this study it can be concluded that the IIF test, although performed with different methods, shows comparable results using strongly positive sera. In general solid phase assays for cANCA detection are not well standardized and need improvement although the purified proteinase-3 ELISA is possibly an exception. MPO and LF can be used in ELISA procedures for the detection of pANCA-related antibodies.

Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis

Background Granulomatosis with polyangiitis (Wegeners) (GPA) and microscopic polyangiitis (MPA) are subgroups of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) defined historically by clinical and histological features. GPA and MPA are heterogeneous entities with overlapping phenotypes. To identify novel subgroupings, cluster analysis was used to explore the phenotypic spectrum of AAV. Methods This study used a dataset of patients newly diagnosed as having GPA and MPA enrolled in five clinical trials. One cluster model included nine clinical baseline variables as input variables, and a second cluster model additionally included ANCA specificities. The clustering process involved multiple correspondence analyses followed by hierarchical ascendant cluster analysis. The clinical relevance of the generated clusters was analysed by their summary characteristics and outcomes. Results The analyses involved data for 673 subjects: 396 (59%) with GPA and 277 (41%) with MPA. Both cluster models resulted in five partially redundant clusters of subjects, and the model including ANCA resulted in more pertinent separations. These clusters were named ‘renal AAV with proteinase 3 (PR3)-ANCA’ (40% of subjects), ‘renal AAV without PR3-ANCA’ (32%) and ‘non-renal AAV’ (12%), ‘cardiovascular AAV’ (9%) and ‘gastrointestinal AAV’ (7%). The five clusters had distinct death and relapse rates. On the basis of 4 variables, 651 subjects (97%) could be accurately allocated to 1 of the 5 classes. Conclusions This analysis suggests that AAV encompasses five classes associated with different outcomes. As compared with the traditional GPA–MPA separation, this classification system may better reflect the phenotypic spectrum of AAV.

Chances of renal recovery for dialysis-dependent ANCA-associated glomerulonephritis.

In patients who have anti-neutrophil cytoplasm autoantibody (ANCA)-associated glomerulonephritis and are on dialysis at time of diagnosis, renal function is sometimes insufficiently restored by immunosuppressive treatment, which often coincides with potentially lethal adverse effects. This study investigated the clinical and histologic variables that determine the chances of dialysis independence, dialysis dependence, or death after 12 mo in these patients. Sixty-nine patients who had ANCA-associated glomerulonephritis and were dialysis dependent at diagnosis received uniform, standard immunosuppressive therapy plus either intravenous methylprednisolone or plasma exchange. Eleven clinical and histologic variables were assessed. Univariate and binary logistic regression analyses were performed. Predictive parameters were entered into a two-step binary logistic regression analysis to differentiate among the outcomes of dialysis independence, dialysis dependence, or death. The point at which the chance of therapy-related death exceeded the chance of dialysis independence was determined. The chance of recovery exceeded the chance of dying in most cases. Intravenous methylprednisolone as adjunctive therapy plus <18% normal glomeruli and severe tubular atrophy increased the chance of therapy-related death over the chance of dialysis independence. Plasma exchange treatment plus severe tubular atrophy and <2% normal glomeruli increased the chance of therapy-related death over that of dialysis independence. Even with ominous histologic findings, the chance of renal recovery exceeds the chance of therapy-related death when these patients are treated with plasma exchange as adjunctive therapy.

Brief Report: Long-term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody–associated vasculitis

OBJECTIVE The NORAM (Nonrenal Wegeners Granulomatosis Treated Alternatively with Methotrexate [MTX]) trial demonstrated that MTX can replace cyclophosphamide (CYC) as remission-inducing treatment for patients with newly diagnosed early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Duration of relapse-free survival was longer among CYC-treated patients than among MTX-treated patients during short-term followup. The aim of the present study was to describe the long-term outcome in patients enrolled in the randomized clinical trial. METHODS Outcome questionnaires were sent to investigators who had recruited patients for the NORAM trial. Patients treated with MTX for induction of remission (n = 49) were compared to CYC-treated patients (n = 46) with respect to immunosuppressive therapy during followup, relapse-free survival, mortality, and occurrence of other clinical events. RESULTS The median duration of followup was 6 years (range 0.1-10.8 years). One patient developed end-stage renal disease, and 11 died. The number of patients affected by serious infection, malignancy, or severe organ failure did not differ between treatment groups, and no difference in survival rate was observed. The duration of corticosteroid therapy was longer in the MTX group during the 18 months of the trial (P = 0.005). During subsequent followup, patients who were in the MTX group in the NORAM trial received corticosteroids, CYC, and other immunosuppressive agents (azathioprine, MTX, and/or mycophenolate mofetil) for longer periods than those who were in the CYC group (P = 0.004, P = 0.037, and P = 0.031, respectively). The cumulative relapse-free survival tended to be lower in the MTX group (P = 0.056). CONCLUSION In the NORAM cohort, no difference in occurrence of major adverse events was observed between treatment groups during long-term followup. However, first-line treatment with MTX was associated with less effective disease control than CYC-based induction therapy.