ANCA-associated vasculitis : towards patient-tailored therapy

The work presented in this thesis concerns various, mainly clinicopathological, studies of ANCA-associated vasculitis. The first chapter provides a general introduction to the topic and the studies. Chapters 2 and 3 describe long-term patient and renal survival data concerning 535 patients. The emphasis in these chapters is on the results of multivariable models, developed to detect baseline patient characteristics that can provide reliable prognostic information to treating physicians. Chapter 4 comprises a clinicopathological study performed on renal biopsies of patients experimentally treated with a rituximab-based regimen. Specific attention is paid to the presence of B cell, T cell and plasma cell infiltrates in the diagnostic renal biopsy and the relation of these infiltrates to renal outcome under rituximab treatment. Chapter 5 reviews known disturbances in cellular immunity in vasculitis. In chapter 6 the presence of anti-plasminogen antibodies is described in two independent patient cohorts, one from the United Kingdom and one from the Netherlands. Chapter 7 illustrates that a simple classification schema comprising only four histological classes correlates well with renal outcome in a first validation exercise. Finally, the results described in this thesis are summarized and discussed in chapter 8.Astellas Pharma B.V., Friedrich Wegener Stichting, Genzyme Nederland, J.E. Jurriaanse Stichting, Novartis Pharma B.V., Reumafonds, Roche Nederland B.V.UBL - phd migration 201

Investigations in systemic vasculitis - The role of renal pathology

ANCA-associated vasculitis (AAV) describes a group of small-vessel vasculitides with frequent renal involvement. The first description of these conditions can be traced back to the 19th-century paper on necrotizing vasculitis by Kussmaul and Maier. Since then, our understanding of the pathogenesis has improved and the histopathological lesions have been described in detail. Characteristic histologic lesions in ANCA-associated glomerulonephritis (AAGN) are fibrinoid necrosis and crescents, often accompanied by tubulointerstitial inflammation. The discovery of ANCAs has not rendered renal biopsies obsolete in the diagnostic process. Currently, renal biopsies remain the gold standard for the diagnosis of AAV in conjunction with ANCA serology. In addition to diagnosis, renal biopsies are useful for patient prognosis. The evaluation of renal histological samples from patients with new-onset AAV who participated in clinical trials led to the proposal of the histopathological classification for AAGN. The prognostic value of this classification continues to be validated and an update is expected soon. (C) 2018 Elsevier Ltd. All rights reserved.Immunopathology of vascular and renal diseases and of organ and celltransplantationIP1

Twisted intramolecular charge transfer states: Rotationally resolved fluorescence excitation spectra of 4,4 '-dimethylaminobenzonitrile in a molecular beam

Contains fulltext : 33124.pdf (publisher's version ) (Open Access)We report the observation at high resolution of seven vibronic bands that appear within similar to200 cm(-1) of the electronic origin in the S-1-S-0 fluorescence excitation spectrum of 4,4(')-dimethylaminobenzonitrile (DMABN) in a molecular beam. Surprisingly, each band is found to be split into two or more components by a (coordinated) methyl group tunneling motion which significantly complicates the analysis. Despite this fact, high quality [(Observed-Calculated)less than or equal to30 MHz] fits of each of the bands have been obtained, from which the rotational constants, inertial defects, torsion-rotation interaction constants, methyl group torsional barriers, and transition moment orientations of DMABN in both electronic states have been determined. The data show that DMABN is a slightly pyramidalized (similar to1degrees) but otherwise (heavy-atom) planar molecule in its ground S-0 state, and that its electronically excited S-1 state has both a more pyramidalized (similar to3degrees) and twisted (similar to25degrees) dimethylamino group. Large reductions in the methyl group torsional barriers also show that the S-1<--S-0 electronic transition is accompanied by significant charge transfer from the nitrogen atom to the pi(*) orbitals of the aromatic ring. Thereby established is the participation of all three vibrational coordinates in the dynamics leading to the "anomalous" emissive behavior of DMABN in the condensed phase. (C) 2005 American Institute of Physics

Azathioprine-induced eosinophilic myocarditis in a patient with ANCA-associated vasculitis

Cardiolog

Repeat protocol renal biopsy in ANCA-associated renal vasculitis

Immunopathology of vascular and renal diseases and of organ and celltransplantatio

Incidence of Malignancies in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Diagnosed Between 1991 and 2013

Development and application of statistical models for medical scientific researc

Long-term follow-up of a randomised controlled trial of azathioprine/methylprednisolone versus cyclophosphamide in patients with proliferative lupus nephritis

Item does not contain fulltextOBJECTIVES: The objectives of this study are to analyse the long-term follow-up of a randomised controlled trial of induction treatment with azathioprine/methylprednisolone (AZA/MP) versus high-dose intravenous cyclophosphamide (ivCY) in patients with proliferative lupus nephritis (LN) and to evaluate the predictive value of clinical, laboratory and renal biopsy parameters regarding renal outcome. METHODS: 87 patients with biopsy-proven proliferative LN were treated with either AZA/MP (n=37) or ivCY (n=50), both with oral prednisone. After 2 years, renal biopsy was repeated, and all patients continued with AZA/oral prednisone. The primary study end point was sustained doubling of serum creatinine. Secondary end points included renal relapse, end-stage renal disease and mortality. RESULTS: After a median follow-up of 9.6 years, no significant differences between AZA/MP versus ivCY groups were found in the proportion of patients with sustained doubling of serum creatinine (n=6 (16%) vs n=4 (8%); p=0.313), end-stage renal disease (n=2 (5%) vs n=2 (4%); p=1.000) or mortality (n=6 (16%) vs n=5 (10%); p=0.388). Renal relapses occurred more often in the AZA/MP group (n=14 (38%) vs n=5 (10%); p=0.002, HR: 4.5). Serum creatinine, proteinuria and immunosuppressive treatment regimens at the last follow-up were comparable. Clinical and laboratory parameters at baseline and after 2 years, and renal biopsy parameters (only) at baseline predicted renal outcome. CONCLUSION: Induction treatment with ivCY was superior to AZA/MP in preventing renal relapses, but other parameters for renal function did not differ. AZA/MP can therefore serve as an alternative in patients with proliferative LN who wish to avoid gonadal toxicity of CY. Several prognostic factors of long-term renal outcome were identified.1 juni 201

Dutch guidelines for diagnosis and therapy of proliferative lupus nephritis.

Item does not contain fulltextProliferative lupus nephritis is a strong predictor of morbidity and mortality in patients with systemic lupus erythematosus. Despite improvements in the management of lupus nephritis, a significant number of the patients do not respond to immunosuppressive therapy and progress to end-stage renal failure. In order to optimise the diagnostic strategy and treatment of patients with proliferative lupus nephritis, guidelines are needed. In this review, the Dutch Working Party on Systemic Lupus Erythematosus provides recommendations regarding four important areas in patients with proliferative lupus nephritis: I) indications for a first renal biopsy, II ) definitions of treatment response, III ) selection of treatment options, and IV) indications for a repeat biopsy.1 mei 201

Induction therapy with short-term high-dose intravenous cyclophosphamide followed by mycophenolate mofetil in proliferative lupus nephritis

BACKGROUND: For decades, high-dose intravenous cyclophosphamide (ivCY) given for 24-30 months was regarded as the standard therapy for proliferative lupus nephritis, despite serious side effects. Our aim was to evaluate the effect of induction therapy with short-term high-dose ivCY followed by mycophenolate mofetil (MMF) on disease parameters, mortality and health-related quality of life (HRQoL) in patients with proliferative lupus nephritis. METHODS: Between January 2003 and November 2006, 71 patients with biopsy-proven proliferative lupus nephritis were included in the second Dutch Lupus Nephritis Study. All patients were treated with ivCY (750 mg/m2, six monthly pulses) plus oral prednisone, followed by MMF (2000 mg/day) plus oral prednisone for 18 months, and then azathioprine (2 mg/kg/day) plus oral prednisone. Study endpoints included the occurrence of renal relapse, end-stage renal disease (ESRD) and mortality. RESULTS: After a median follow-up of 3.8 years (range 0.1-4.5), four (5.6%) of the 71 patients had a renal relapse, one (1.4%) failed treatment, one (1.4%) reached ESRD, and two (2.8%) died. Systemic lupus erythematosus (SLE) Disease Activity Index, serum creatinine, proteinuria and antibodies against anti-dsDNA decreased significantly during treatment and serum levels of complement factor 3 and 4 increased significantly. Furthermore, six of eight domains of the Short Form-36 as well as the number of symptoms and total distress level according to the SLE Symptom Checklist improved significantly over time. CONCLUSIONS: This open-label study shows that induction therapy with short-term (six monthly pulses) high-dose ivCY followed by MMF is effective in preventing renal relapses, ESRD and mortality and improving HRQoL in patients with proliferative lupus nephritis