[Show abstract][Hide abstract] ABSTRACT: Rituximab has enriched our armamentarium in the treatment of anti-neutrophil cytoplasmic antibody (ANCA)-
associated vasculitis. Two randomised controlled trials have shown that rituximab is non-inferior compared with
cyclophosphamide followed by azathioprine for the induction of remission. The newly diagnosed patients in the Rituximab in ANCA-Associated Vasculitis (RAVE) and Rituximab Versus Cyclophosphamide in ANCA-Associated Vasculitis (RITUXVAS) trials had a numerically higher response rate in the cyclophosphamide/azathioprine arm, and the number of such patients treated with rituximab numbered <90.We are arguing that in newly diagnosed patients, the evidence for rituximab requires further confirmation and the length of experience with a cyclophosphamide-based induction therapy supports it continuing as the preferred first choice for induction. Also,
there is an absence of information regarding rituximab as ‘sole’ remission induction along with steroids in patients with advanced renal presentations or lung haemorrhage. Reported side effects were similar in both trials; however, the number of participants with at least one serious adverse event following rituximab induction treatment was numerically higher in the RAVE trial. In addition, hypogammaglobulinaemia with the
need of substitution in some cases and late-onset neutropaenia are complications not seen with cyclophosphamide. Over the longer term it is unclear what relapse prevention strategy should be employed after rituximab, and there was a trend to a higher relapse risk after rituximab in the RITUXVAS trial at 2 years.
Further health economic studies are required to understand all the costs associated with rituximab. In the context of concomitant underlying infectious complications, in terms of fertility concerns, especially in young patients, and when malignancy is underlying we would recommend the use of rituximab as first-line therapy.
[Show abstract][Hide abstract] ABSTRACT: Rituximab (RTX) is approved for remission induction in ANCA associated vasculitis (AAV). However, data on use of RTX in patients with severe renal disease is lacking.
We conducted a retrospective multi-center study to evaluate the efficacy and safety of RTX with glucocorticoids (GC) with and without use of concomitant cyclophosphamide (CYC) for remission induction in patients presenting with e GFR less than 20 ml/min/1.73 m(2). We evaluated outcomes of remission at 6 months (6 M), renal recovery after acute dialysis at diagnosis, e-GFR rise at 6 M, patient and renal survival and adverse events.
A total 37 patients met the inclusion criteria. The median age was 61 years. (55-73), 62 % were males, 78 % had new diagnosis and 59 % were MPO ANCA positive. The median (IQR) e-GFR at diagnosis was 13 ml/min/1.73 m(2) (7-16) and 15 required acute dialysis. Eleven (30 %) had alveolar hemorrhage. Twelve (32 %) received RTX with GC, 25 (68 %) received RTX with GC and CYC and seventeen (46 %) received plasma exchange. The median (IQR) follow up was 973 (200-1656) days. Thirty two of 33 patients (97 %) achieved remission at 6 M and 10 of 15 patients (67 %) requiring dialysis recovered renal function. The median prednisone dose at 6 M was 6 mg/day. The mean (SD) increase in e-GFR at 6 months was 14.5 (22) ml/min/m(2). Twelve patients developed ESRD during follow up. There were 3 deaths in the first 6 months. When stratified by use of concomitant CYC, there were no differences in baseline e GFR, use of plasmapheresis, RTX dosing regimen or median follow up days between the groups. No differences in remission, renal recovery ESRD or death were observed.
This study of AAV patients with severe renal disease demonstrates that the outcomes appear equivalent when treated with RTX and GC with or without concomitant CYC.
Journal of nephrology 05/2015; DOI:10.1007/s40620-015-0208-y · 2.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts.
The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE).
657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6±13.9 vs. 46.8±17.3 years), had higher Birmingham vasculitis activity score (19.5±9.1 vs. 16.9±7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively).
Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations.
[Show abstract][Hide abstract] ABSTRACT: Definitive sample sizes for clinical trials in rare diseases are usually infeasible. Bayesian methodology can be used to maximise what is learnt from clinical trials in these circumstances. We elicited expert prior opinion for a future Bayesian randomised controlled trial for a rare inflammatory paediatric disease, polyarteritis nodosa (MYPAN, Mycophenolate mofetil for polyarteritis nodosa).
A Bayesian prior elicitation meeting was convened. Opinion was sought on the probability that a patient in the MYPAN trial treated with cyclophosphamide would achieve disease remission within 6-months, and on the relative efficacies of mycophenolate mofetil and cyclophosphamide. Expert opinion was combined with previously unseen data from a recently completed randomised controlled trial in ANCA associated vasculitis.
A pan-European group of fifteen experts participated in the elicitation meeting. Consensus expert prior opinion was that the most likely rates of disease remission within 6 months on cyclophosphamide or mycophenolate mofetil were 74% and 71%, respectively. This prior opinion will now be taken forward and will be modified to formulate a Bayesian posterior opinion once the MYPAN trial data from 40 patients randomised 1:1 to either CYC or MMF become available.
We suggest that the methodological template we propose could be applied to trial design for other rare diseases.
PLoS ONE 03/2015; 10(3):e0120981. DOI:10.1371/journal.pone.0120981 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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.
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.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Annals of the Rheumatic Diseases 03/2015; 74(6). DOI:10.1136/annrheumdis-2014-206404 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective. Takayasu arteritis (TAK) and giant cell arteritis (GCA) are 2 major variants of large vessel vasculitis (LVV). The frequent involvement of large vessels in GCA has raised the possibility that TAK and GCA should be regarded as 1 disease. By detailed phenotyping of a single-center cohort, we aimed to define the differences between TAK and GCA. Methods. Forty-five patients (23 TAK, 22 GCA) were identified. Baseline characteristics, clinical symptoms, laboratory data, enhanced computed tomography/magnetic resonance imaging, treatments, and clinical courses were retrospectively assessed with descriptive statistics. In addition, latent class analysis of the 45 patients was performed to explore phenotypic differences. Results. Patients with GCA had more frequent headache (p < 0.01), higher C-reactive protein levels (p = 0.01), and higher erythrocyte sedimentation rates (p = 0.03) than did patients with TAK at diagnosis. With the exception of subdiaphragmatic lesions, the distributions of vessel lesions were not different between TAK and GCA. However, focusing on subclavian and carotid arteries, long tapered-type stenotic lesions were more frequent in GCA than in TAK (p < 0.01). The proportion of patients without relapse was higher in GCA (60%) than in TAK (22%, p = 0.01). Latent class analysis also divided patients with LVV into 2 separate groups consistent with TAK and GCA. Conclusion. The differences observed in clinical symptoms, inflammatory markers, radiological findings, and clinical courses suggested that TAK and GCA were 2 different diseases. Latent class analysis supported these results. The shape of stenotic lesions in the subclavian and carotid arteries is a useful discriminator between TAK and GCA.
The Journal of Rheumatology 11/2014; 42(2). DOI:10.3899/jrheum.140562 · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Importance
Airway stenosis occurs in patients with granulomatosis with polyangiitis (GPA or Wegener granulomatosis). It produces significant morbidity and contributes to mortality.Objective
To investigate the frequency and distribution of airway stenoses in GPA and evaluate the efficacy of local interventions in maintaining airway patency.Design, Setting, and Participants
A retrospective single-center study of 44 patients with GPA and airway stenosis assessed and treated as needed by a multidisciplinary team at a university medical center between 1997 and 2012. The median duration of observation for each patient from the time of diagnosis was 146 months.Interventions
Patients who had critical stenoses underwent either dilatation or laser radial cuts to the lesion. In some cases, intralesional administration of steroids or topical mitomycin C was used.Main Outcomes and Measures
The main outcome measure was airway patency for at least 12 months and the number of interventions required to achieve this end point. Details of patients and interventions were recorded at baseline and at each treatment.Results
The median age at diagnosis was 37.6 years; 73% of patients were women (n = 34). The median follow-up after the initial intervention was 62.5 months. Subglottic stenosis was found in 36 patients, lower airway stenosis in 30. There were 213 interventions in 39 patients, including balloon and bougie dilatation and laser treatment. Adjuvant local treatment was used in 71 interventions. A 12-month period of airway stability was achieved in 34 of 36 cases (97%) (5 had no procedures and 3 had follow-up shorter than 12 months). The median interval between procedures was 4.9 months, and after the last intervention recorded, patients had at least 27 months of airway stability. Fourteen adverse events were recorded (6.6%).Conclusions and Relevance
The frequency and distribution of airway stenoses in 44 patients with GPA has been described. In the 39 patients who required intervention, multiple procedures were required, but 97% then achieved a prolonged period of airway patency. The procedures and adjuvant treatments were found to be safe. Our experience with a variety of techniques in this rare presentation has permitted design of a structured approach and an algorithm to manage and evaluate airway stenosis in GPA.
JAMA Otolaryngology - Head and Neck Surgery 10/2014; 140(11). DOI:10.1001/jamaoto.2014.2430
[Show abstract][Hide abstract] ABSTRACT: Background The use of mycophenolate mofetil (MMF) in autoimmune disease is often limited by adverse effects. In this single-centre, open label, parallel design study, we investigated whether enteric-coated mycophenolate sodium (MS) is better tolerated and therefore more efficacious than MMF in primary systemic vasculitis (PSV) and systemic lupus erythematosus (SLE).
Methods Forty patients with vasculitis or systemic lupus erythematosus (SLE) due to commence MMF for active disease or remission maintenance were randomized to receive either 1440 mg/day MS or 2000 mg/day MMF (18 PSV, 2 SLE per group) in addition to corticosteroids. Random allocation was performed by minimization for age, diagnosis and renal function using a computer algorithm. Twenty-five were treated for active disease (5 first-line therapy, 20 salvage therapy) and 15 for remission maintenance. The composite primary end point was treatment failure and/or drug intolerance over 12 months. Treatment failure was defined as failure to achieve remission by 6 months or disease relapse and treatment intolerance was defined as inability to tolerate and maintain the target dose of MS or MMF within 12 months.
Results Forty patients were included in the analyses. MS was associated with a lower primary end point rate [hazard ratio (HR) 0.37; 95% CI 0.17–0.80; P = 0.012] (11/20, 55% patients) compared with MMF (17/20, 85% patients). Treatment failure alone was less common in the MS group (HR 0.28; 95% CI 0.095–0.82; P = 0.020), although drug intolerance did not differ between groups (HR 0.53; 95% CI 0.20–1.42; P = 0.21). Despite randomization, patients in the MMF group may have had a higher baseline risk for treatment failure; more MMF patients had refractory disease and granulomatosis with polyangiitis (Wegener's). A glomerular filtration rate (GFR) ≤40 mL/min was associated with intolerance. Serious adverse events were common (55% MMF and 45% MS patients).
Conclusions No differences in treatment tolerance were observed between the MS and MMF groups. Despite similar treatment intolerance, MS was associated with improved efficacy in PSV and SLE compared with MMF. However, baseline group imbalances in factors potentially affecting remission and relapse may have influenced the results. Treatment intolerance was common and strongly associated with low GFR. Further treatment trials are warranted to investigate the effect of GFR on mycophenolic acid pharmacokinetics and clinical outcomes (ISRCTN83027184; EUDRACT 2005-002207-16; Funding Novartis UK).