mycophenolic-acid and Granulomatosis-with-Polyangiitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by inflammation and destruction of small- and medium-sized blood vessels and the presence of circulating ANCA. Clinical disease phenotypes include granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis. Serologic classification of AAV into proteinase 3-ANCA disease and myeloperoxidase-ANCA disease correlates with a number of disease characteristics. AAV has a predilection for the kidney, with >75% of patients having renal involvement characterized by rapidly progressive glomerulonephritis. The cause and pathogenesis of AAV are multifactorial and influenced by genetics, environmental factors, and responses of the innate and adaptive immune system. Randomized controlled trials in the past 2 decades have refined the therapy of AAV and transformed AAV from a fatal disease to a chronic illness with relapsing course and associated morbidity. This article in AJKD's Core Curriculum in Nephrology series provides a detailed review of the epidemiology, pathogenesis, diagnosis, and advances in the management of AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Cyclophosphamide; Disease Progression; Glomerulonephritis; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Kidney Transplantation; Microscopic Polyangiitis; Mycophenolic Acid; Myeloblastin; Peroxidase; Remission Induction; Renal Dialysis; Rituximab

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystem necrotizing vasculitis associated with eosinophilia and extravascular granuloma and classically involving the upper and lower airways. There have only been a few reported cases of gynecologic involvement in EGPA.. We present an 8-year-old girl diagnosed with EGPA with a vulvar granuloma in what is, to our knowledge, the first reported pediatric gynecologic manifestation of EGPA. Interestingly, the vulvar granuloma did not respond to initial immunosuppressant treatment with prednisone and methotrexate and required treatment regimen modification with mycophenolate mofetil resulting in granuloma resolution.. EGPA in the pediatric population has a relatively high mortality rate compared with in the adult population thus it is important that vulvar granulomas associated with EGPA should be included in the differential diagnosis of a vulvar mass allowing for the prompt diagnosis and treatment of this potentially fatal disease in children.

Topics: Adult; Child; Churg-Strauss Syndrome; Diagnosis, Differential; Female; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Mycophenolic Acid; Vulva

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a complex group of systemic vasculitides that are characterized by primary small-to-medium sized blood vessel inflammation with the presence of autoantibodies known as ANCA. AAV diseases include Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), and Microscopic Polyangiitis (MPA). AAVs are challenging conditions associated with high cumulative disease and treatment related morbidity and mortality. Given its rarity and the resulting paucity of pediatric-specific clinical trial evidence, pediatric rheumatologists have had to often extrapolate from adult literature for management and therapeutic decisions. The aim of this review is to provide a comprehensive overview of the important findings and overall conclusions of critical landmark clinical trials in the induction and maintenance treatments in adult AAV for the pediatric rheumatologist. This review also highlights the outcomes of recent pediatric AAV observational studies and discusses the future research priorities in pediatric AAV management.

Topics: Adult; Anti-Inflammatory Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Azathioprine; Child; Churg-Strauss Syndrome; Cyclophosphamide; Drug Substitution; Drug Therapy, Combination; Forecasting; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Leflunomide; Methotrexate; Mycophenolic Acid; Plasma Exchange; Prednisone; Randomized Controlled Trials as Topic; Recurrence; Retrospective Studies; Rituximab; Severity of Illness Index

The authors review the nomenclature of vasculitides and the classification of antineutrophil cytoplasm antibody associated vasculitides and present the method of measuring disease activity (Five-factor Score, Birmingham Vasculitis Activity Score) and its role in defining therapeutical needs. They discuss the treatment algorithm of antineutrophil cytoplasm antibody associated vasculitides, present the sometimes equipotential medications used during the induction therapy followed by a maintenance regimen, and outline their usage and possible side-effects that may require medical attention. They point out the importance of plasmapheresis as an adjunctive treatment in some cases, as well as indications and possible outcome of kidney transplantation in therapy-resistant cases. Finally, they review several ongoing clinical studies, as their outcome will probably influence therapeutical opportunities of antineutrophil cytoplasm antibody associated vasculitides in the next few years.

Topics: Algorithms; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Azathioprine; Clinical Trials as Topic; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Kidney Transplantation; Methotrexate; Microscopic Polyangiitis; Mycophenolic Acid; Plasmapheresis; Prognosis; Rituximab; Severity of Illness Index; Terminology as Topic

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal, Murine-Derived; Cyclophosphamide; Drug Therapy, Combination; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Laryngostenosis; Long-Term Care; Methotrexate; Mycophenolic Acid; Rituximab; Secondary Prevention

In the past, recommendations for the treatment of Wegener's granulomatosis were primarily based on findings reported from open-label clinical trials. Results from several randomized controlled trials in patients with Wegener's granulomatosis and other antineutrophil cytoplasm antibody-associated vasculitides have recently been reported that have a great impact on patient care.. In view of the considerable toxicity of cyclophosphamide, strategies to limit exposure to it have recently been evaluated. The replacement of cyclophosphamide by azathioprine after the successful induction of remission has been demonstrated not to increase the rate of relapse compared with continued cyclophosphamide. In patients with early antineutrophil cytoplasm antibody-associated vasculitides without critical organ manifestations low-dose methotrexate can replace cyclophosphamide for induction treatment with similar remission rates. As the early discontinuation of immunosuppressive treatment is associated with unacceptably high relapse rates, however, treatment for the maintenance of remission is mandatory. Besides azathioprine, leflunomide and methotrexate were efficacious in preventing relapses in Wegener's granulomatosis. Data on anti-cytokine therapy in Wegener's granulomatosis are controversial, possibly related to differences in study design. Open-label clinical studies suggest a beneficial effect of infliximab in addition to standard therapy in refractory Wegener's granulomatosis. In contrast, a recent randomized controlled trial showed that etanercept in addition to standard therapy, with the subsequent tapering of standard medications, is not effective for the maintenance of remission.. Despite recent progress, the prevention of relapses and treatment of refractory cases remain the greatest challenges in the treatment of Wegener's granulomatosis.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Cyclophosphamide; Etanercept; Granulomatosis with Polyangiitis; Guanidines; Humans; Immunoglobulin G; Immunosuppressive Agents; Isoxazoles; Leflunomide; Methotrexate; Mycophenolic Acid; Plasmapheresis; Receptors, Tumor Necrosis Factor; Recurrence; Rituximab

Progress in understanding the pathogenesis and treatment of rheumatologic and glomerular diseases such as systemic lupus erythematosus and particularly lupus nephritis has been closely linked with the development of newer immunosuppressive agents. With improved patient survival following the institution of cyclophosphamide and corticosteroid therapy, longer-term management issues came to the forefront, especially how to decrease adverse effects of the immunosuppressive regimen. Many of the immunosuppressive regimens used in lupus patients were first established as efficacious and safe through their use in solid organ transplantation. Mycophenolate mofetil (MMF) is now widely used in the field of transplantation. Following anecdotal reports describing benefits of MMF in lupus and lupus nephritis patients, small studies and finally large randomized, controlled trials have established the use of MMF in these patients, particularly those with lupus nephritis. MMF use in other rheumatologic and renal diseases has been evaluated in only smaller studies and very few randomized controlled trials. Nevertheless, many studies currently are ongoing with this immunosuppressive agent. This article will review the published data and the experience of two major New York medical centers with the use of MMF in autoimmune and renal diseases.

Topics: Acute Disease; Autoimmune Diseases; Clinical Trials as Topic; Glomerulonephritis, IGA; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Granulomatosis with Polyangiitis; Humans; Immunosuppression Therapy; Kidney Diseases; Lupus Nephritis; Mycophenolic Acid; Nephritis, Interstitial

Current remission maintenance therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are limited by partial efficacy and toxicity.. To compare the effects of mycophenolate mofetil with azathioprine on the prevention of relapses in patients with AAV.. Open-label randomized controlled trial, International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE), to test the hypothesis that mycophenolate mofetil is more effective than azathioprine for preventing relapses in AAV. The trial was conducted at 42 centers in 11 European countries between April 2002 and January 2009 (42-month study). Eligible patients had newly diagnosed AAV (Wegener granulomatosis or microscopic polyangiitis) and were aged 18 to 75 years at diagnosis.. Patients were randomly assigned to azathioprine (starting at 2 mg/kg/d) or mycophenolate mofetil (starting at 2000 mg/d) after induction of remission with cyclophosphamide and prednisolone.. The primary end point was relapse-free survival, which was assessed using a Cox proportional hazards model. The secondary end points were Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria.. A total of 156 patients were assigned to azathioprine (n = 80) or mycophenolate mofetil (n = 76) and were followed up for a median of 39 months (interquartile range, 0.66-53.6 months). All patients were retained in the analysis by intention to treat. Relapses were more common in the mycophenolate mofetil group (42/76 patients) compared with the azathioprine group (30/80 patients), with an unadjusted hazard ratio (HR) for mycophenolate mofetil of 1.69 (95% confidence interval [CI], 1.06-2.70; P = .03). Severe adverse events did not differ significantly between groups. There were 22 severe adverse events in 13 patients (16%) in the azathioprine group and there were 8 severe adverse events in 8 patients (7.5%) in the mycophenolate mofetil group (HR, 0.53 [95% CI, 0.23-1.18]; P = .12). The secondary outcomes of Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria did not differ significantly between groups.. Among patients with AAV, mycophenolate mofetil was less effective than azathioprine for maintaining disease remission. Both treatments had similar adverse event rates.. clinicaltrials.gov Identifier: NCT00307645.

Topics: Adult; Aged; Antirheumatic Agents; Azathioprine; Cyclophosphamide; Female; Glomerular Filtration Rate; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Microscopic Polyangiitis; Middle Aged; Mycophenolic Acid; Prednisolone; Proteinuria; Secondary Prevention

Endothelial vasomotor dysfunction and markers of systemic inflammation are independent determinants of cardiovascular risk. However, the link between clinical inflammation and endothelial dysfunction is unclear. The aim of this study was to use anti-neutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) as a model of systemic inflammation in which to test the hypothesis that inflammation is associated with endothelial dysfunction and can be reversed with anti-tumor necrosis factor-alpha (TNF-alpha) therapy.. Fourteen patients with active AASV and 21 age-matched control subjects were studied. Endothelial function was assessed through the use of forearm plethysmography and related to clinical disease activity: Birmingham Vasculitis Activity Score (BVAS) and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-alpha. The effects of anti-TNF-alpha therapy (infliximab), either alone (n=6) or in combination with standard treatment (n=4), on endothelial function were subsequently determined. Patients had a mean BVAS of 11+/-1, and CRP and IL-6 were higher in the AASV group than in control subjects (34.8+/-10.5 versus 1.6+/-0.2 pg/mL, P<0.001; 9.0+/-0.7 versus 6.7+/-0.6 pg/mL, P=0.02). Forearm blood flow response to acetylcholine (ACh) was reduced in the patients compared with control subjects (P=0.002), but sodium nitroprusside (SNP) responses were not (P=0.3). The response to ACh improved with infliximab treatment (P=0.004) in particular, with infliximab alone (P=0.03).. AASV is associated with endothelial dysfunction. Anti-TNF-alpha therapy, alone or in combination with standard treatment, results in clinical remission, reduced inflammation, and improved endothelium-dependent vasomotor responses.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal; Autoimmune Diseases; C-Reactive Protein; Churg-Strauss Syndrome; Cohort Studies; Cyclophosphamide; Drug Therapy, Combination; Endothelium, Vascular; Enzyme Inhibitors; Female; Forearm; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Infliximab; Interleukin-6; Male; Middle Aged; Mycophenolic Acid; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; omega-N-Methylarginine; Pilot Projects; Plethysmography; Prednisolone; Regional Blood Flow; Tumor Necrosis Factor-alpha; Vasculitis

To examine the safety of mycophenolate mofetil (MMF) for remission maintenance in patients with Wegener's granulomatosis (WG) who had been treated with daily cyclophosphamide (CYC) and glucocorticoids to induce remission.. Fourteen patients were treated for active WG using a standardized regimen of CYC and glucocorticoids for induction of remission and MMF for remission maintenance. Outcome was assessed using predetermined definitions based on clinical characteristics and pathologic, laboratory, and radiographic findings.. Remission occurred in all 14 patients (100%) at a median time of 3 months. The median time to discontinuation of glucocorticoids was 8 months. No patients died during protocol treatment and 6 patients (43%) relapsed at a median of 10 months after achieving remission. MMF was well tolerated and no patients had to be withdrawn as a result of medication toxicity.. The use of CYC and glucocorticoids for induction of remission and MMF for remission maintenance was well tolerated, but disease relapses were observed.

Topics: Adult; Aged; Female; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Recurrence; Remission Induction; Treatment Outcome

This study describes the pharmacokinetics of mycophenolate mofetil (MMF) in 15 pediatric patients with vasculitis and connective tissue disease involving the kidney. Patients included 10 with systemic lupus erythematosus (SLE), 1 with antiphospholipid antibody syndrome, 2 with Wegener granulomatosis, and 1 each with Goodpasture syndrome, Henoch-Schönlein-associated nephritis, and 1 with severe tubulointerstitial nephritis and uveitis. All patients were treated with steroids and additional therapy prior to treatment with MMF, which was administered for a median of 491 days. Mean starting dose of MMF was 974+/-282 mg/m(2 )in two divided doses. Pharmacokinetic monitoring of the active compound of MMF, mycophenolic acid (MPA), was performed using an EMIT assay. The mean MPA AUC after a median of 39 days was 61.8+/-31.0 micro gxh/ml, median time to maximum concentration was 60 min, and mean maximum concentration was 18.5+/-8.4 micro g/ml. At last follow-up, mean MMF dose was 900+/-341 mg/m(2) per day, and mean trough MPA concentration was 3.1+/-1.1 (range 0.6-4.6) micro g/ml. Therapy was effective in inducing remission in 4 of 9 patients with active disease. Only 1 of the 5 other patients relapsed. All 6 patients with controlled disease maintained remission. There were few side effects: one episode each of diarrhea and leukocytopenia and two viral infections. We conclude that MMF at 900 mg/m(2) per day appears to be effective in these patients.

Topics: Adolescent; Anti-Glomerular Basement Membrane Disease; Antiphospholipid Syndrome; Autoimmune Diseases; Child; Female; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Mycophenolic Acid; Nephritis, Interstitial; Remission Induction; Treatment Outcome

Topics: Adult; Female; Glomerulonephritis, IGA; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Treatment Outcome; Vasculitis

Torasemide is a loop diuretic with a molecule that is chemically similar to the sulphonamides described as eosinophilic granulomatosis with polyangiitis (EGPA) triggering drugs. The presented case is probably the first description of torasemide-induced vascular purpura in the course of EGPA. Any diagnosis of vasculitis should be followed by an identification of drugs that may aggravate the disease. A 74-year-old patient was admitted to the Department of Dermatology with purpura-like skin lesions on the upper, and lower extremities, including the buttocks. The lesions had appeared around the ankles 7 days before admission to the hospital and then started to progress upwards. The patient complained on lower limb paresthesia and pain. Other comorbidities included bronchial asthma, chronic sinusitis, ischemic heart disease, mild aortic stenosis, arterial hypertension, and degenerative thoracic spine disease. The woman had previously undergone nasal polypectomy twice. She was on a constant regimen of oral rosuvastatin 5 mg per day, spironolactone 50 mg per day, metoprolol 150 mg per day, inhaled formoterol 12 μg per day, and ipratropium bromide 20 μg per day. Ten days prior to admission, she was commenced on torasemide at a dose of 50 mg per day prescribed by a general practitioner due to high blood pressure. Doppler ultrasound upon admission to the hospital excluded deep venal thrombosis. The laboratory tests revealed leukocytosis (17.1 thousand per mm3) with eosinophilia (38.6%), elevated plasma level of C-reactive protein (119 mg per L) and D-dimers (2657 ng per mm3). Indirect immunofluorescent test identified a low titer (1:80) of antinuclear antibodies, but elevated (1:160) antineutrophil cytoplasmic antibodies (ANCA) in the patient's serum. Immunoblot found them to be aimed against myeloperoxidase (pANCA). A chest X-ray showed increased vascular lung markings, while high-resolution computed tomography revealed peribronchial glass-ground opacities. Microscopic evaluation of skin biopsy taken from the lower limbs showed perivascular infiltrates consisting of eosinophils and neutrophils, fragments of neutrophil nuclei, and fibrinous necrosis of small vessels. Electromyography performed in the lower limbs because of their weakness highlighted a loss of response from both sural nerves, as well as slowed conduction velocity of the right tibial nerve and in both common peroneal nerves. Both clinical characteristics of skin lesions and histopathology suggested a

Topics: Adolescent; Aged; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Antihypertensive Agents; Asthma; C-Reactive Protein; Churg-Strauss Syndrome; Eosinophilia; Female; Formoterol Fumarate; Granulomatosis with Polyangiitis; Humans; IgA Vasculitis; Inflammation; Ipratropium; Leukotriene Antagonists; Metoprolol; Mycophenolic Acid; Peroxidase; Prednisone; Purpura; Receptors, Fc; Rosuvastatin Calcium; Sodium Potassium Chloride Symporter Inhibitors; Spironolactone; Sulfanilamides; Torsemide

Infectious scleritis is a rare but important cause of scleral inflammation. It is usually associated with an underlying ocular (prior ocular surgery or trauma) or systemic risk factor. A 53-year-old apparently systemically healthy woman presenting with spontaneous-onset pain, redness and watering in the left eye for 10 days was diagnosed with culture-proven

Topics: Anti-Bacterial Agents; Autoimmune Diseases; Cefazolin; Diagnosis, Differential; Female; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Polymyxin B; Pseudomonas aeruginosa; Pseudomonas Infections; Scleritis; Tropanes

The present study compared the efficacy of mycophenolate mofetil (MMF) with that of azathioprine (AZA) in Korean patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA).. The medical records of 69 patients with MPA and GPA who received cyclophosphamide and subsequently received AZA or MMF for remission maintenance therapy were reviewed. All-cause mortality, relapse, end-stage renal disease (ESRD), cerebrovascular accident, and cardiovascular disease were evaluated as poor outcomes. Having a lower Birmingham Vasculitis Activity Score (BVAS) was defined as the lowest tertile of BVAS (BVAS ≤11 in this study).. In comparative analysis of the occurrence of poor outcomes among patients taking AZA only, MMF only, and MMF after AZA, patients taking MMF only exhibited a significantly lower cumulative ESRD-free survival rate than patients taking AZA only (. With regard to ESRD occurrence, the efficacy of MMF in remission maintenance therapy was less effective than AZA in patients with MPA and GPA. However, among patients with lower BVAS, there was no difference in the occurrence of poor outcomes between patients taking MMF and those taking AZA.

Topics: Azathioprine; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Microscopic Polyangiitis; Mycophenolic Acid; Treatment Outcome

Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of ANCA-associated vasculitis (AAV). Clinical trials demonstrating the efficacy of mycophenolate mofetil (MMF) for remission induction in AAV excluded patients with EGPA. Despite this, MMF is commonly used in these patients. The objective of this study was to evaluate, for the first time, the effectiveness and tolerance of MMF in EGPA remission induction. A retrospective, two-center, real-world study was conducted in patients with EGPA who received MMF in addition to prednisolone for newly diagnosed or relapsing disease between 2009 and 2019. Baseline, 3-, 6- and 12-month outcome data were extracted from electronic health records. The primary outcome was disease remission, defined as a Birmingham Vasculitis Activity Score of 0 at 6 months. Secondary outcomes included disease relapse, median prednisolone dose at 12 months and drug tolerance. In total, 15 patients (73% male, median age 57) with EGPA (11 newly diagnosed/4 relapsing) were identified. At 6 months, 67% had achieved disease remission. At 12 months, this was maintained (66.7%) and 4 patients had relapsed. All but one patient remained on MMF at study completion and all patients tolerated MMF. Our real-world data suggest that MMF is an effective and well-tolerated agent for achieving disease remission in EGPA. A future randomized controlled trial of MMF in this neglected orphan disease is now warranted.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Female; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Recurrence; Remission Induction; Retrospective Studies

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms u

Topics: Adult; Aged; Azathioprine; B-Lymphocyte Subsets; B-Lymphocytes; Cell Proliferation; Cytokines; Female; Flow Cytometry; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Interleukin-6; Male; Mercaptopurine; Middle Aged; Mycophenolic Acid

Granulomatosis with polyangiitis (GPA), extremely rare in children, is a disease characterized by granulomatous inflammation and necrotizing vasculitis that involves medium and small vessels. Central nervous system (CNS) involvement in GPA is not common and often appears at a later stage of the disease. The CNS manifestation of pediatric GPA was fragmentally discussed. Herein, we reported a case of relapsing-remitting pediatric GPA with prominent CNS involvement as initial symptoms.. The patient was a 9-year-old female. The first episode manifested as uroclepsia and bilateral lower extremity weakness, resulting from diffused dot-enhanced large lesions within bilateral anterior cerebral artery territory on magnetic resonance (MR). This was followed by three recurring episodes of visual impairment as a result of optic neuritis. MR in the last episode indicated bilateral sphenoid sinus inflammation adjacent to the left optical nerve. All four episodes were combined with upper respiratory tract symptoms and slight urine abnormality. She responded well to large doses of corticosteroids and immunoglobulins. However, the patient had long been suspected of having multiple sclerosis and had not received appropriate maintenance treatment.. After being diagnosed with GPA, the patient received small doses of glucocorticoids and mycophenolate mofetil for maintenance, which generated a favorable outcome.. CNS involvement in pediatric GPA is rare. Single large or multifocal insults involving one or more lobes consistent with the distribution of cerebral arteries could be a typical feature on MR. Early diagnosis and proper treatments help to improve the prognosis.

Topics: Central Nervous System Diseases; Child; Enzyme Inhibitors; Female; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Magnetic Resonance Imaging; Mycophenolic Acid

To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA).. The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons.. In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil.. Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

Topics: Adolescent; Adrenal Cortex Hormones; Age Distribution; Antibodies, Antineutrophil Cytoplasmic; Asia; Azathioprine; Canada; Child; Child, Preschool; Cohort Studies; Cyclophosphamide; Drug Therapy, Combination; Europe; Female; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Immunosuppressive Agents; Infant; Kidney Failure, Chronic; Lung Diseases; Male; Methotrexate; Microscopic Polyangiitis; Mycophenolic Acid; Nephrotic Syndrome; Oxygen Inhalation Therapy; Plasmapheresis; Proteinuria; Renal Dialysis; Respiratory Insufficiency; Rituximab; United States

Topics: Antirheumatic Agents; Azathioprine; Drug Administration Schedule; Drug Therapy, Combination; Granulomatosis with Polyangiitis; Humans; Methotrexate; Mycophenolic Acid; Remission Induction; Rituximab; Treatment Outcome

Topics: Antibodies, Monoclonal, Murine-Derived; Azathioprine; Female; Granulomatosis with Polyangiitis; Humans; Immunologic Factors; Male; Methotrexate; Mycophenolic Acid

Topics: Antibodies, Monoclonal, Murine-Derived; Azathioprine; Female; Granulomatosis with Polyangiitis; Humans; Immunologic Factors; Male; Methotrexate; Mycophenolic Acid

ANCA-associated vasculitis (AAV) with renal involvement is not uncommon in older individuals. Unfortunately, this can be catastrophic requiring hemodialysis (HD) and may lead to end stage renal disease (ESRD). However, more than 50 % of patients with AAV who require HD initially have renal recovery and discontinue HD. The aim of this study was to describe a retrospective cohort of older patients with AAV and severe renal involvement which required hemodialysis.. Between 1995 and 2013 a total of 30 patients with histologic evidence of pauci-immune glomerulonephritis who required HD were evaluated at a single university center. The association of demographic and clinical parameters with age was assessed. Older age of disease onset was defined as age ≥ 60 years. The risk of developing ESRD at 3 months was examined using univariate logistic regression analysis.. Among 30 patients with AAV who required HD, the mean age of disease onset was 59 ± 17 years (range 22-88 years). Twelve patients were in the older age group, and 18 were in the younger group. Three months after diagnosis, 43 % of the cohort had ESRD with a statistically similar proportion of older (n = 9, 50 %) versus younger (n = 4, 33 %) patients (p = 0.367). Most patients (93 %) received immunosuppressive therapy. There was not a statistically significant association between age and ESRD.. These data suggest that age alone does not predict renal recovery among individuals on HD due to AAV. Renal recovery is a realistic expectation and outcome, if patients are treated, even among older patients with AAV who require HD initially.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; Cyclophosphamide; Disease Progression; Female; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Microscopic Polyangiitis; Middle Aged; Mycophenolic Acid; Renal Dialysis; Retrospective Studies; Rituximab; Young Adult

To determine the safety and efficacy of abatacept in non-severe relapsing granulomatosis with polyangiitis (Wegener's)(GPA).. An open-label trial of intravenous abatacept was conducted in 20 patients with non-severe relapsing GPA. Prednisone up to 30 mg daily was permitted within the first 2 months, and patients on methotrexate, azathioprine, or mycophenolate mofetil continued these agents. Patients remained on study until common closing or early termination.. Of the 20 patients, 18 (90%) had disease improvement, 16 (80%) achieved remission (BVAS/WG=0) at a median of 1.9 months, and 14 (70%) reached common closing. Six patients (30%) met criteria for early termination due to increased disease activity; 3 of 6 achieved remission and relapsed at a median of 8.6 months. The median duration of remission before common closing was 14.4 months, with the median duration of time on study for all patients being 12.3 months (range 2-35 months). Eleven of the 15 (73%) patients on prednisone reached 0 mg. Nine severe adverse events occurred in 7 patients, including 7 infections that were successfully treated.. In this study of patients with non-severe relapsing GPA, abatacept was well tolerated and was associated with a high frequency of disease remission and prednisone discontinuation.

Topics: Abatacept; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Azathioprine; Cohort Studies; Drug Therapy, Combination; Female; Granulomatosis with Polyangiitis; Humans; Immunoconjugates; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Recurrence; Remission Induction; Severity of Illness Index; Treatment Outcome; Young Adult

To evaluate the efficacy and safety of rituximab (RTX) induction therapy and the duration of remission, when RTX is used with or without a conventional maintenance agent, in a cohort of patients with granulomatosis with polyangiitis (Wegener's) (GPA).. This was a retrospective, single-center study of patients with relapsing GPA treated with at least 1 course of RTX (4 weekly doses of 375 mg/m(2) intravenously [IV] or 2 fixed doses of 1,000 mg IV 2 weeks apart). Complete remission was defined as the absence of disease activity measured by a Birmingham Vasculitis Activity Score for Wegener's granulomatosis of 0 and not qualified by the prednisone dosage at the time.. Eighty-nine patients achieved remission after their first course of RTX and were not re-treated preemptively with RTX to maintain remission of their disease during followup. Among these patients, relapse-free survival was significantly higher in those who received a conventional maintenance agent (azathioprine, methotrexate, or mycophenolate mofetil) in conjunction with RTX and glucocorticoids (n = 47) than in those who received no additional immunosuppressive agent (n = 42) (P = 0.04). The hazard ratio of relapse in those receiving a maintenance agent was 0.53 (95% confidence interval 0.29-0.97). Serious adverse events did not differ between the 2 groups. Within a subset of 15 patients in the cohort who were relapse free 2 years after 1 course of RTX, remissions endured for 2-6 years in 8 patients.. RTX is an effective remission-inducing agent in GPA. The addition of a conventional maintenance agent to RTX and glucocorticoids decreased the incidence of relapse and did not result in a higher incidence of adverse events.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Drug Therapy, Combination; Female; Granulomatosis with Polyangiitis; Humans; Immunologic Factors; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Remission Induction; Retrospective Studies; Rituximab; Treatment Outcome

Topics: Adenocarcinoma; Adult; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Murine-Derived; Autoantigens; Cyclophosphamide; Disease Susceptibility; Drug Resistance; Granulomatosis with Polyangiitis; Hemoptysis; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Male; Methylprednisolone; Mycophenolic Acid; Myeloblastin; Prednisone; Rectal Neoplasms; Recurrence; Rituximab

Topics: Antirheumatic Agents; Azathioprine; Clinical Trials as Topic; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Microscopic Polyangiitis; Mycophenolic Acid

A long-term female hemodialysis patient with end-stage renal disease due to Wegener's granulomatosis (WG) experienced a severe relapse when immunosuppressive therapy was switched from prednisone and cyclophosphamide to azathioprine maintenance therapy. Ten courses of protein A immunoadsorption therapy and switching immunosuppressive therapy to mycophenolate mofetil have proved to be very successful and free of side effects. The patient has fully recovered from all clinical WG symptoms and is still in remission ten months after the treatment.

Topics: Adult; Azathioprine; Cyclophosphamide; Female; Granulomatosis with Polyangiitis; Humans; Immunosorbent Techniques; Immunosuppressive Agents; Kidney Failure, Chronic; Mycophenolic Acid; Prednisone; Remission Induction; Renal Dialysis; Staphylococcal Protein A

A 40-year-old man was referred to a specialist vasculitis center 4 years after being diagnosed with Wegener's granulomatosis. At the time of diagnosis he had presented with skin, ear, nose and throat involvement, pulmonary hemorrhage, and microscopic hematuria. Remission was achieved with plasma exchange and with daily oral prednisolone and cyclophosphamide. The patient was switched to maintenance treatment with azathioprine and prednisolone but suffered a relapse shortly afterwards. Further treatment with cyclophosphamide achieved a second remission, but the patient relapsed again despite remission-maintaining treatment with mycophenolate mofetil.. Physical examination, laboratory testing, serological testing, culture of eye swabs and sputum, chest X-ray, chest CT scan, head MRI scan, bronchoscopy and bronchoalveolar lavage, and consultation with ophthalmological and otorhinolaryngological specialists.. Refractory Wegener's granulomatosis with involvement of the eyes, upper and lower respiratory tracts, and kidneys.. Disease activity was controlled following treatment with deoxyspergualin and oral steroids in addition to aggressive management of intercurrent infections with repeated courses of oral and intravenous antibiotics. Relapses that occurred when deoxyspergualin was discontinued were treated with repeated courses of deoxyspergualin or with pulsed intravenous cyclophosphamide. Remission was achieved with rituximab. Pulmonary disease was closely monitored with repeated bronchoscopy.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Cyclophosphamide; Drug Therapy, Combination; Granulomatosis with Polyangiitis; Guanidines; Humans; Immunologic Factors; Immunosuppressive Agents; Male; Mycophenolic Acid; Plasma Exchange; Prednisolone; Recurrence; Remission Induction; Rituximab

Topics: Aged; Granulomatosis with Polyangiitis; Herpes Zoster; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Mycophenolic Acid; Skin Diseases

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Remission Induction

Topics: Cyclophosphamide; Drug Therapy, Combination; Glucocorticoids; Granuloma; Granulomatosis with Polyangiitis; Humans; Injections, Intravenous; Male; Methotrexate; Methylprednisolone; Middle Aged; Mycophenolic Acid; Prednisone; Pulse Therapy, Drug; Remission Induction; Uveitis, Anterior

The treatment approaches to antineutrophil cytoplasmic autoantibody (ANCA) small vessel vasculitis expose patients to the risks associated with long-term use of corticosteroids and cytotoxic agents. In an effort to explore approaches to minimize risks, we conducted a pilot efficacy and safety study of mycophenolate mofetil (MMF) in the treatment of subjects with nonlife-threatening recurrent or cyclophosphamide-resistant ANCA-vasculitis.. MMF was initiated at 500 mg orally twice daily and gradually increased to a target dose of 1000 mg twice daily for a duration of 24 weeks. Concomitant therapy with corticosteroids was allowed. The Birmingham Vasculitis Activity Score (BVAS) was used to assess disease activity and treatment efficacy. ANCA titres, serum creatinine and adverse events were secondary measures of efficacy and/or toxicity.. Twelve subjects were enrolled in the study. Treatment with MMF led to an improvement in disease activity as measured by the BVAS at 24 weeks (P = 0.0013) and 52 weeks (P = 0.0044) as compared to baseline. The BVAS decreased from an average of 9.1+/-3.5 at baseline (range, 3-17) to an average of 2.8+/-1.9 (range, 1-6) at 24 weeks and to 2.8+/-4.3 (range, 0-13) at 52 weeks. Early and sustained reductions in BVAS occurred in subjects initially classified as disease relapses vs those with treatment resistance. Side effect profile was consistent with the mechanism of action and pharmacokinetic disposition of MMF.. MMF is a reasonable option in the treatment of non-life-threatening recurrent or resistant vasculitis and may obviate the immediate need for recurrent use of cytotoxic agents.

Topics: Administration, Oral; Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Disease Progression; Feasibility Studies; Female; Follow-Up Studies; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prodrugs; Recurrence; Treatment Outcome

Topics: Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Remission Induction

Topics: Adult; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Pyoderma Gangrenosum

Mycophenolate mofetil (MMF) is increasingly used for prevention of allograft rejection and to treat immune disorders. We report the development of an acute inflammatory syndrome in two patients with Wegener's granulomatosis after MMF was introduced, because of persistent renal and systemic disease activity despite cyclophosphamide treatment. Within 1 week both patients developed an acute inflammatory syndrome, characterized by fever, arthralgias and muscle pain. No infection could be detected and no indications for increased Wegener's activity were present. MMF was stopped resulting in a rapid and complete resolution of the syndrome. A rechallenge with 2 g of MMF in the second patient resulted in a relapse of the syndrome within 4 days. There was an association between symptoms and increased levels of mycophenolic acid (MPA) acyl glucuronide and serum interleukin-6, suggesting the induction of inflammatory cytokines by MPA acyl glucuronide as the cause of the syndrome. Therefore, special attention should be given to side effects such as fever, arthralgias and muscle pain when treating patients with Wegener's granulomatosis during the active phase. Because this side effect of MMF may also occur after solid organ transplantation and in other immune disorders, pharmacokinetic profiling of MPA and MPA acyl glucuronide is needed in future studies with MMF.

Topics: Acute Disease; Arthralgia; Female; Fever; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Inflammation; Male; Middle Aged; Muscles; Mycophenolic Acid; Pain; Syndrome

Topics: Antibodies, Antineutrophil Cytoplasmic; Antilymphocyte Serum; Cyclosporine; Follow-Up Studies; Granulomatosis with Polyangiitis; Guanidines; Immunosuppressive Agents; Mycophenolic Acid; Time Factors

Successful maintenance therapy with mycophenolate mofetil (MMF) 2 g/d and low-dose oral corticosteroids (OCS) over a period of 15 mo was given to patients with Wegener's granulomatosis (WG) (n = 9) and microscopic polyangiitis (MPA) (n = 2). All patients had severe generalized disease with pauci-immune necrotizing glomerulonephritis and received standard induction therapy with oral cyclophosphamide and OCS for a mean of 14 wk until remission was achieved. Of 11 patients, only one WG patient relapsed in the 14th month of maintenance therapy. Maintenance therapy with MMF was able to further reduce grumbling disease activity as measured by the Birmingham vasculitis activity score (BVAS2) and proteinuria that were still present by the end of induction therapy. OCS could be reduced to a median daily dose of 5 mg and discontinued in three patients. Possible drug-related adverse effects were transient and included abdominal pain, respiratory infection, diarrhea, leukopenia, and a cytomegalovirus-colitis in one patient that was successfully treated with ganciclovir. It is concluded that MMF in combination with low-dose OCS is well tolerated and effective for maintenance therapy of WG and MPA. Long-term treatment with MMF in these diseases is attractive because of its low toxicity. MMF will have to be studied further and compared with cyclophosphamide or azathioprine maintenance therapy in randomized trials.

Topics: Adrenal Cortex Hormones; Adult; Aged; Cyclophosphamide; Female; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prospective Studies; Vasculitis