anca associated vasculitis
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ANCA-associated vasculitis Dr. Aris Tsalouchos
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Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis Small vessel vasculitis Wegener’s granulomatosis Churg-Strauss syndrome Microscopic polyangiitis Henoch-Schonlein purpura Essential cryoglobulinemic vasculitis Cutaneous leukocytoclastic angiitis Medium-sized vessel vasculitis Polyarteritis nodosa Kawasaki disease Large-vessel vasculitis Giant cell (temporal) arteritis Takayasu arteritis
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Jennette JC, Falk RJ. Renal involvement in systemic vasculitis. In: Greenberg A, Cheung AK, Coffman TM, et al, eds. National Kidney Foundation Nephrology Primer. 4th ed. Philadelphia: WB Saunders; 2005:226-233.
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ANCA Associated vasculitis Wegener’s granulomatosis (newly renamed granulomatosis with polyangiitis [WG/GPA]) Microscopic polyangiitis Renal limited (pauci-immune) vasculitis Churg-Strauss syndrome Drug-induced ANCA-associated vasculitis PTU, Hydralazine, Minocycline
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Epidemiology (WG) Wegener granulomatosis (WG) is a rare disease with an as yet undetermined incidence. The prevalence of WG in the United States is estimated to be 3 cases per 100,000 people. The incidence and prevalence of WG in the United Kingdom is estimated at 10.2 cases and 250 cases per million population, respectively. Race-, sex-, and age-related demographics WG is more common in individuals of northern European descent (approximately 90%); it occurs less commonly in blacks. In European populations, WG is slightly more common in men, with a male-to-female ratio of 1.5:1. Women are more likely to have limited disease. The onset of WG may occur at any age, although patients typically present at age 35-55 years. WG is rare in childhood. Patricia J Papadopoulos,et al. Wegener Granulomatosis. Medscape. Updated: Jan 24, 2012
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Epidemiology (MPA) Frequency United States The annual incidence of MPA is 3.6 cases per million persons. Prevalence is 1-3 cases per 100,000 population. International Incidence is approximately 2 cases per 100,000 persons in the United Kingdom and approximately 1 case in 100,000 persons in Sweden. Mortality/Morbidity Renal failure and pulmonary involvement are the major causes of morbidity and mortality. Race In the United States, MPA is more frequent among white persons than black persons. Sex Males are affected slightly more frequently than females. Age The age of onset is approximately 50 years. Mehran Farid-Moayer, et al. Microscopic Polyangiitis. Medscape. Updated: Jan 24, 2012
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Genetic Factors HLA-DPB1*0401 alleles conferred an increased risk of WG in a German population, and a study from the Netherlands suggested that HLA-DR4 and HLA-DR13(6) are associated with WG. Heckmann, M. et al. Ann. Rheum.Dis. 67, 972-979 (2008). Stassen, P M. et al. Rheumatology (Oxford) 48, 622-625 (2009) HLA-DRB4 might be a genetic risk factor for CSS. Vaglio, A. et al. Arthritis Rheum. 56, 3159-3166 (2007). A study of a Japanese population found HLA-DRB1*0901 to be associated with MPA. Tsuchiya, N. et al. J. Rheumatol. 30, 1534-1540 (2003).
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Genetic Factors Genes encoding CD226 antigen, PTPN22 protein and interleukin (IL)-10 might contribute to AAV. Wieczorek, S. et al. Genes Immun. 10, 591-595 (2009). Carr, E. J. et al. BMC Med. Genet. 10, 121 (2009). Wieczorek, S. et al. Arthritis Rheum. 58, 1839-1848 (2008). Single-nucleotide polymorphisms in CTLA4 and PTPN22 are associated with AAV (similarly to type 1 diabetes). Carr, E. J. et al. BMC Med. Genet. 10, 121 (2009).
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Silica Several case-control studies have shown that 22-46% of patients with ANCA-associated vasculitis were previously exposed to silica. Hogan, S. L. et al. J. Am. Soc. Nephrol. 12, 134-142 (2001). Beaudreuil, S. et al. Kidney Int. 67, 1961-1966 (2005). Accelerated apoptosis of polymorphonuclear leukocytes and macrophages might act as a trigger in the development of AAV; indeed, accelerated apoptosis of neutrophils has been induced in an animal model through intratracheal instillation of silica in a dose-dependent manner. Leigh, J. et al. Environ. Health Perspect. 105 (Suppl. 5), 1241-1245 (1997). In vitro studies have shown that silica can induce apoptosis in human peripheral blood lymphocytes, with an increase in Fas (CD95, also known as tumor necrosis factor [TNF] receptor superfamily, member 6)-mediated cell death. Aikoh, T. et al. Int. J. Oncol. 12, 1355-1359 (1998).
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Bacterial Infections Bacterial infections have been associated with the initiation and relapse of WG. S. aureus seems to have the strongest association with WG. Stegeman, C. A. et al. N. Engl. J. Med. 335, 16-20 (1996). Stegeman, C. A. et al. Ann. Intern. Med. 120, 12-17 (1994). Peptides from cPR3 are homologous to peptides from S. aureus, suggesting that S. aureus can induce PR3-ANCAs. Kallenberg, C. G. & Tadema, H. Autoimmun. Rev. 8, 29-32 (2008). About 90% of patients with active ANCA-associated necrotizing crescentic glomerulonephritis (NCGN) had autoantibodies to human lysosomal membrane protein 2 ( LAMP-2) Kain, R. et al J.. Exp. Med. 181, 585-597 (1995). A major epitope of LAMP-2 (designated P41-49) is homologous to the bacterial adhesin protein FimH, which is found in Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae. Kain, R. et al. Nat. Med. 14, 1088-1096 (2008).
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Nat Med 2008;14:1018-1019
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Drugs A variety of drugs can cause AAV, including propyl-thiouracil (the most common cause of drug-induced AAV), hydralazine, D-penicillamine and minocycline. The reported prevalence of propylthiouracil-induced ANCA expression ranges from 4% to 46%. Slot, M. C. et al. Arthritis Rheum. 53, 108-113 (2005). Zhao, M. H. et al. Kidney Int. 69, 1477-1481 (2006). In the presence of hydrogen peroxidase, propyl-thiouracil can be transformed into cytotoxic metabolites by neutrophil-derived MPO. The converted drug and its metabolites could then stimulate T cells to activate B-cell production of ANCAs. Jiang, X.et al Science 266, 810-813 (1994). von Schmiedeberg S.et al. Science 268, 585-586 (1995).
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ANCAS IN THE PATHOGENESIS OF AAV Evidence from Clinical Studies Development of glomerulonephritis and pulmonary hemorrhage in a neonate caused by transplacental transfer of ANCA IgG from the mother with anti-MPO-antibody-positive MPA Bansal, P. J. & Tobin, M. C. Ann. Allergy Asthma Immunol. 93, 398-401 (2004). Clinical remission is often accompanied by a decrease in ANCA levels. Falk, R. J.et al. Semin. Nephrol. 20, 233-243 (2000). Savage, C. O.et al. Kidney Int. 60, 1614-1627 (2001). The predictive value of ANCA levels for relapse remains questionable. Stegeman, C. A.et al. Nephrol. Dial. Transplant. 17, 2077-2080 (2002). A multicenter prospective cohort study of 156 patients with active WG observed that decreases in PR3-ANCA levels were not associated with a shorter time to remission, and increases in PR3-ANCA levels were not associated with relapse. Finkielman, J. D. et al. Ann. Intern. Med. 147, 611-619 (2007).
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ANCAS IN THE PATHOGENESIS OF AAV Evidence from in vitro Studies Stimulation of neutrophils with TNF induces the migration of ANCA target antigens from the cytoplasm to the neutrophil surface. Here, ANCAs stimulate primed neutrophils to undergo a respiratory burst and degranulate primary granular constituents. Falk, R. J.et al. Proc. Natl Acad. Sci. USA 87, 4115-4119 (1990). Fc? receptors (in particular, Fc?RIIa and Fc?RIIb) are involved. Rarok AA.et al. J Leukoc Biol 2003, 74:3–15. phosphoinositol 3-kinase–? mediates ANCA-induced degranulation; a specific inhibitor of this enzyme abrogated these processes in vitro and protected mice against the development of necrotizing glomerulonephritis in a murine model of MPO-ANCA–associated glomerulonephritis. Schreiber A.et al. Kidney Int 2010,77:118–128.
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. Morgan M D et al. JASN 2006;17:1224-1234 ©2006 by American Society of Nephrology
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ANCAS IN THE PATHOGENESIS OF AAV Evidence from in vitro Studies In vitro studies have shown that ANCAs stimulate neutrophil-induced cytotoxicity toward endothelial cells. Ewert BH.et al. Kidney Int 1992, 41:375–383. In an in vitro flow system, ANCAs induce conversion of rolling of neutrophils to firm integrin-mediated adhesion. Adhesion could be blocked by inhibiting monoclonal antibodies to the Fc?RIIa receptor and to CD11b. Radford DJ.et al Arthritis Rheum 2000, 43:1337–1345.
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ANCAS IN THE PATHOGENESIS OF AAV Evidence from in vivo Studies Xiao et al. immunized MPO-knockout mice with purified mouse MPO, resulting in the production of anti-MPO IgG or the generation of MPO-reacting splenocytes, each of which was transferred into recipient mice. Mice that received anti-MPO IgG developed pauci-immune NCGN after 6 days. Xiao, H. et al. J. Clin. Invest. 110, 955-963 (2002). MPO knockout (Mpo-/-) mice immunized with mouse MPO were irradiated and received a bone marrow transplant from Mpo+/+ or Mpo-/- mice. Engraftment of Mpo+/+ bone marrow cells in Mpo-/- mice with circulating anti-MPO resulted in the development of pauci-immune NCGN. By contrast, transfer of Mpo-/- bone marrow cells into irradiated Mpo+/+ mice did not lead to disease induction. Schreiber, A, J. Am. Soc. Nephrol. 17, 3355-3364 (2006). Passive transfer of anti-PR3 antibodies into recipient mice did not lead to a relevant animal model of WG, indicating possible differences in pathogenic potential between anti-PR3 antibodies and anti-MPO antibodies. Pfister, H. et al. Blood 104, 1411-1418 (2004). van der Geld, Y. M. et al. Ann. Rheum. Dis. 66, 1679-1682 (2007).
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The role of complement in AAVs Supernatants from ANCA-activated neutrophils activated the complement system via the alternative pathway ,leading to C5a production. C5a subsequently primed neutrophils for the ANCA-induced respiratory burst, but blockade of the neutrophil C5aR prevented neutrophils from priming—a prerequisite for the ANCA-induced respiratory burst. C5a and the neutrophil C5aR, therefore, might comprise an amplification loop for ANCA-mediated neutrophil activation. Schreiber, A. et al. J. Am. Soc. Nephrol. 20, 289-298 (2009). The complement components membrane attack complex, C3d, and factor B could be detected in diseased glomeruli of patients with AAVs. Xing, G. Q. et al. J. Clin. Immunol. 29, 282-291 (2009). In a mouse model of AAV, C5-deficient or factor-B-deficient mice were completely protected from disease development. Xiao, H. et al. Am. J. Pathol. 170, 52-64 (2007). Mice receiving C5-inhibiting monoclonal antibodies before disease induction were protected from anti-MPO-IgG-induced NCGN. If anti-C5 monoclonal antibodies were administered 1 day after disease induction, glom-erular crescent formation in these mice was reduced by 80%. Huugen, D. et al. Kidney Int. 71, 646-654 (2007).
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Cellular Immunity in the Pathogenesis of AAV Neutrophils In an Mpo-/- mouse model of AAV, neutrophil depletion could prevent anti-MPO-antibody-induced NCGN in recipient mice Xiao, H. et al. J. Clin. Invest. 110, 955-963 (2002). The circulating level of neutrophil-gelatinase-associated lipocalin, a biomarker of neutrophil degranulation, is also useful for assessing disease activity of AAV. Chen, M.et al.Rheumatology (Oxford) 48, 355-358 (2009). ANCA-mediated neutrophil activation induces the generation of neutrophil extracellular traps (NETs) containing PR3 and MPO. NETs can adhere to the endothelium causing damage, and they might also activate plasmacytoid dendritic cells and B cells to produce interferon and ANCAs, respectively. Kessenbrock, K. et al.Nat. Med.15, 623-625 (2009). Chen, M. & Kallenberg, C. G.Nephrol. Dial. Transplant. 24, 3618-3620 (2009).
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Cellular Immunity in the Pathogenesis of AAV B cells B cells have a role in the pathogenesis of AAV, primarily through the production of ANCAs. Indeed, rituximab, a chimeric monoclonal antibody directed against B cells is a useful treatment for AAV. Stone, J. H. et al.N. Engl. J. Med. 363, 221-232 (2010). Jones, R. B. et al.N. Engl. J. Med. 363, 211-220 (2010). B cells can act as antigen-presenting cells and interact with T cells; abnormal T-cell activity in AAV, therefore, might depend on B-cell function ion. Shlomchik, M. J.et al.Nat. Rev. Immunol. 1, 147-153 (2001). Voswinkel et al.studied B cells in nasal biopsy samples of patients with WG and observed that selection and affinity maturation of autoreactive B cells can begin in granulomatous lesions, thereby contributing to disease progression from localized to generalized WG. Voswinkel, J. et al. Ann. Rheum. Dis. 65, 859-864 (2006).
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Cellular Immunity in the Pathogenesis of AAV T cells Nogueira et al. reported elevated levels of IL-17 and IL-23, as well as autoantigen-specific T-helper type 17 (Th17) cells in the peripheral blood of AAV patients. Nogueira, E. et al.Nephrol. Dial. Transplant. 25, 2209-2217 (2010). IL-17A and IL-23 levels are elevated in active AAV and might remain elevated during remission. Nogueira, E. et al.Nephrol. Dial. Transplant. 25, 2209-2217 (2010). In an animal model of anti-MPO glomerulonephritis, Gan et al. found that Th17 cells were instrumental in orchestrating renal injury. Gan PY.et al. J Am Soc Nephrol 2010, 21:925–931. A numerical and functional defect in PR3-specific TREG cells occurs in patients with WG, and that the percentage of TREG cells is inversely related to the rate of disease relapse. Morgan, M. D. et al. Immunology 130, 64-73 (2010). Chavele et al.found a numerical deficiency rather than a functional deficiency in MPO-specific TREG cells in AAV, which they suggest is possibly related to increased tryptophan degradation. Chavele, K. M. et al. Arthritis Rheum. 62, 1539-1548 (2010).
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Gary S. Hoffman, MD, MS. Medscape Education © 2011 Medscape, LLC
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Mukhtyar C, Guillevin L, Cid MC et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009; 68: 310–317.
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Clinical Features (Systemic) The most common prodrome of ANCA-associated vasculitis is flulike symptoms characterized by: malaise fever arthralgias myalgias anorexia and weight loss This occurs in more than 90% of patients and can occur within days to months of the onset of nephritis or other manifestations of vasculitis. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Clinical Features (Musculoskeletal) Pain and elevation in tissue enzyme levels can result from inflammation in the arteries of skeletal muscle. Musculoskeletal involvement is present in 60% of patients with ANCA-associated disease. Arthritis is a very common symptom. It is usually symmetrical and migratory and usually involves the small joints. Arthralgias are also common, but this is not considered a marker of active vasculitis. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Clinical Features (ENT) Mild symptoms of rhinitis, epistaxis, otitis media and sinusitis are compatible with a diagnosis of MPA but severe destructive disease, infiltrative, or granulomatous disease is not seen and its occurrence is highly suggestive of WG. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Wegener granulomatosis. Large ulceration of the pharynx covered with a dense necrotic membrane. Rheumatology,5th Edition Marc C. Hochberg, MD, MPH,et al. MOSBY Elsevier 2011
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Nasal bridge collapse in a patient with Wegener’s granulomatosis MRI T1W images showing sinusitis due to granulomatous tissue. Vasculitis in Clinical Practice. Richard A. Watts · David G. I. Scott Editors. Springer-Verlag London Limited 2010
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Subglottic stenosis. A web of scar tissue is evident just below the vocal chords, leading to narrowing of the subglottic area and inspiratory stridor. Three-dimensional shaded-surface display of the trachea shows eccentric narrowing of the subglottic trachea in this patient with airway involvement from Wegener granulomatosis. Rheumatology,5th Edition Marc C. Hochberg, MD, MPH,et al. MOSBY Elsevier 2011
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Clinical Features (Pulmonary) Pulmonary manifestations range from fleeting focal infiltrates to hemorrhagic alveolar capillaritis resulting in massive pulmonary hemorrhage and hemoptysis. This is the most deadly complication of ANCA disease. The prevalence rate of pulmonary findings is 50% in those with microscopic polyangiitis, 90% in those with Wegener granulomatosis, and 80% in those with Churg-Strauss disease. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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pulmonary hemorrhage : MPA or GPA ? nodular granuloma formations in GPA Rheumatology,5th Edition Marc C. Hochberg, MD, MPH,et al. MOSBY Elsevier 2011 Vasculitis in Clinical Practice. Richard A. Watts · David G. I. Scott Editors. Springer-Verlag London Limited 2010
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Alveolar hemorrhage in a patient with Wegener granulomatosis. This has resulted in rapidly changing pulmonary infiltrates. There is also a nodular lesion in the right lung. Computed tomography scan of the chest in Wegener granulomatosis. Multiple bilateral pulmonary nodules can be seen, many of which have cavitated. Rheumatology,5th Edition Marc C. Hochberg, MD, MPH,et al. MOSBY Elsevier 2011 Vasculitis in Clinical Practice. Richard A. Watts · David G. I. Scott Editors. Springer-Verlag London Limited 2010
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Clinical Features (Skin) Leukocytoclastic vasculitis is common (40-60%) and usually affects the lower extremities. Necrotizing arteritis can result in painful erythematous nodules, focal necrosis, ulceration, and livedo reticularis. Patients with Wegener granulomatosis or Churg-Strauss syndrome can also have granulomatous cutaneous nodules. Nail fold infarcts can be present. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Skin rash in a patient with Wegener’s granulomatosis. Vasculitis in Clinical Practice. Richard A. Watts · David G. I. Scott Editors. Springer-Verlag London Limited 2010 Leukocytoclastic angiitis in Microscopic Polyangiitis
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Clinical Features (Ocular) Iritis, uveitis, and conjunctivitis are the most common ocular manifestations of ANCA. The most serious ocular complication/involvement associated with Wegener’s granulomatosis is proptosis due to retro-orbital granuloma formation, which can lead to blindness. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Active scleral inflammation, associated with substantial eye pain. Healed scleritis, with resultant scleral thinning. The bluish-colored choroid is evident beneath the scleral layer. Rheumatology,5th Edition Marc C. Hochberg, MD, MPH,et al. MOSBY Elsevier 2011
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CT of a patient with WG and a left orbital mass. This was causing proptosis and visual loss through compression of the optic nerve. Exophthalmos (patient’s right eye). resulting from orbitalpseudotumors Rheumatology,5th Edition Marc C. Hochberg, MD, MPH,et al. MOSBY Elsevier 2011
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Clinical Features (Nervous system) Mononeuritis multiplex is the most common nervous system manifestation of ANCA-associated disease. This condition is caused by inflammation of the epineural arteries and arterioles, which results in ischemia of the nerve tissue. Central nervous system disease can result from involvement of meningeal vessels and manifest as generalized seizures. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Mononeuritis multiplex. Wasting of the interosseous muscle between the thumb and first finger, caused by peripheral nerve infarction. Rheumatology,5th Edition Marc C. Hochberg, MD, MPH,et al. MOSBY Elsevier 2011 Mononeuritis multiplex. A patient with weakness bilaterally of foot dorsiflexion (“foot drop”), left greater than right.
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Magnetic resonance imaging study revealing pachymeningitis in a patient with Wegener granulomatosis. Rheumatology,5th Edition Marc C. Hochberg, MD, MPH,et al. MOSBY Elsevier 2011
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Clinical Features Gastrointestinal GI involvement occurs in 50% of patients with ANCA. Arteritis can result in ischemic ulceration in the GI tract, causing pain and bleeding, which is usually occult. The most serious complications of GI ischemia are intussusception and pancreatitis. Cardiac involvement Is rare (3%) but pericarditis, myocarditis, arythmias and myocardial infarction have been reported. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012 Vasculitis in Clinical Practice. Richard A. Watts · David G. I. Scott Editors. Springer-Verlag London Limited 2010
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Clinical Features (Renal involvement) The most common renal manifestations are caused by glomerular involvement and include hematuria, proteinuria, and renal failure. Hypertension can be present but is not common. If overt renal disease is not present upon presentation, then the most common finding is microscopic hematuria. The diagnostic biopsy finding is proliferative necrotizing crescentic glomerulonephritis. The prevalence rate of renal disease is 90% for those with microscopic polyangiitis, 80% for those with Wegener granulomatosis, and 45% for those with Churg-Strauss disease. The renal failure has the characteristics of Rapidly progressive glomerulonephritis (RPGN). James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Rapidly Progressive Glomerulonephritis (RPGN) is a disease of the kidney characterized clinically by a rapid decrease in the glomerular filtration rate (GFR) of at least 50% over a short period, from a few days to 3 months. Rapidly progressive glomerulonephritis is classified pathologically into 3 categories, as follows: (1) anti-GBM antibody disease (approximately 3% of cases) (2) immune complex disease (45% of cases) (3) pauci-immune disease (50% of cases) Immunologic classification is based on the presence or absence of ANCAs. The disorders are also classified based on their clinical presentation. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Differential Diagnosis Anti-GBM antibody Goodpasture syndrome (lung and kidney involvement) Anti-GBM disease (only kidney involvement) Note: 10-40% of patients may be ANCA positive. Immune complex Postinfectious (staphylococci/streptococci) Collagen-vascular disease Lupus nephritis Henoch-Schönlein purpura (immunoglobulin A and systemic vasculitis) Immunoglobulin A nephropathy (no vasculitis) Mixed cryoglobulinemia Primary renal disease Membranoproliferative glomerulonephritis Fibrillary glomerulonephritis Idiopathic Note: Of all patients with crescentic immune complex glomerulonephritis, 25% are ANCA positive; however, less than 5% of patients with noncrescentic immune complex glomerulonephritis are ANCA positive. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Anti-neutrophil cytoplasmic autoantibodies Serologic testing for ANCA is useful diagnostic test, but should be interpreted in the context of other patient characteristics Testing should include both indirect immunoflourescence microscopy (IFA) and enzyme immunoassay (EIA) Because the sensitivity and the specificity of ANCA testing for pauci-immune glomerulonephritis is only 80-90%, a renal biopsy is recommended to be performed on patients with rapidly progressive glomerulonephritis to establish a definite diagnosis and to determine the severity of the disease. The initiation of therapy should not be delayed for biopsy results to be obtained. ¼- 1/3 of patients with anti-GBM crescentic GN and ¼ of patients with idiopathic immune-complex crescentic GN are ANCA positive Pts with concurrent ANCA and anti-GBM antibodies have worse prognosis than those with ANCA alone James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Antineutrophil cytoplasmic antibodies staining patterns
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ANCA antigens ANCA specific for various proteins, mostly enzymes, localized in the cytoplasmic lyzosomes of neutrophils and monocytes. Major target antigens for ANCA in patients with pauci-immune small vessel vasculitides : Myeloperoxidase (MPO) – epitope expressed by 130 kDa native molecule in the azurophilic granules Proteinase 3 (PR3) – 28 kDa serine proteinase, colocalized with MPO in the azurophilic granules James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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ANCA antigens Other ANCA antigens: lactoferrin, elastase, lysozyme, cathepsin G, azurocidin, bactericidal permeability increasing protein (BPI), alpha-enolase, defensin, unknown human lysosomal-associated membrane protein 2 (h-lamp-2) - homologous to bacterial protein FimH Kain, R. et al J.. Exp. Med. 181, 585-597 (1995).
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COMPREHENSIVE CLINICAL NEPHROLOGY Copyright © 2010,
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CBC count with differential: Full blood count may show a normochromic, normocytic anemia. White count is usually normal or slightly raised, but leucopaenia is very unusual. Serum electrolytes, BUN, creatinine, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and liver function tests: The most common abnormality is an increased serum creatinine level. However, the level can be normal at presentation. Tissue enzyme (ie, lactate dehydrogenase, creatine kinase) levels may be elevated if the amount of inflammation is significant enough to result in myalgias. Erythrocyte sedimentation and C-reactive protein: Levels are elevated and correspond with disease activity. Urinalysis with microscopy: Proteinuria is almost always present but is rarely greater than 2-3 g in 24 hours. Microscopic hematuria is invariably present and may be the only clue to renal disease at presentation. The presence of red cell casts indicates glomerular inflammation and is a very helpful clue. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012 Laboratory Studies
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Cryoglobulins: The symptoms of cryoglobulinemia are very similar to those of ANCA-related disease. However, in persons with ANCA-related diseases, the cryoglobulin titer result should be negative. Urine and serum protein electrophoresis: Perform this in any middle-aged or elderly person presenting with rapidly progressive glomerulonephritis to exclude the presence of light-chain disease or overt multiple myeloma as a cause of the clinical findings. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012 Laboratory Studies
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Imaging Studies A renal ultrasound should be done to rule out obstructive uropathy in any patient with acute renal failure. In patients with rapidly progressive glomerulonephritis, a renal ultrasound is done to establish the presence of 2 functioning kidneys prior to a percutaneous renal biopsy. James W Lohr, et al. Rapidly Progressive Glomerulonephritis Clinical Presentation.Medscape. Updated: Mar 1, 2012
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Necrotizing arteritis in an interlobular artery from a patient with antineutrophil cytoplasmic antibody (ANCA)–associated small-vessel vasculitis. The fibrinoid necrosis is accentuated by the red staining of the trichrome stain. (Masson trichrome; original magnification ×100.) COMPREHENSIVE CLINICAL NEPHROLOGY Copyright © 2010,
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Segmental glomerular necrosis and crescent formation in a patient with antineutrophil cytoplasmic antibody (ANCA)–associated small-vessel vasculitis. The fibrinoid material is red. The uninvolved segments appear normal. (Masson trichrome; original magnification ×150.) COMPREHENSIVE CLINICAL NEPHROLOGY Copyright © 2010,
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Massive necrosis is usually associated to diffuse circumferential extracapillary proliferation Ferrario F, Rastaldi MP. In: Pusey C, Rees A, eds. "Rapidly Progressive Glomerulonephritis." Oxford University Press 1998;
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ANCA-associated renal vasculitis are by definition"pauci-immune“ glomerulonephritis. Immunofluorescence can be either negative or characterized by scattered C3 granular deposition. in 20% of cases, a more consistent mesangial and parietal deposition of C3 can be observed. Ferrario F, Rastaldi MP. In: Pusey C, Rees A, eds. "Rapidly Progressive Glomerulonephritis." Oxford University Press 1998;
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In active lesions, fibrin deposition is invariably present and its entity and distribution are related to the entity of glomerular damage Ferrario F, Rastaldi MP. In: Pusey C, Rees A, eds. "Rapidly Progressive Glomerulonephritis." Oxford University Press 1998;
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Q J Med 2005;98:97-112
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Am J Kidney Dis 2003;41:776-784.
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Serum creatinine, ANCA titer, and acute phase response all usually improve with induction treatment Sally Hamour. et al.Therapeutics and Clinical Risk Management 2010:6 253–264
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Am J Kidney Dis 2003;41:776-784
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Recurrent Disease in Kidney Transplantation A pooled analysis of 127 patients, has largely clarified the behavior of this group of disorders after transplantation. Disease recurrence was detected in 17% of cases after 4 to 89 months of follow-up, with renal involvement demonstrated in approximately 60% of these recurrences and graft losses reported in a minority of these. Kidney transplantation for ANCA-associated vasculitis is associated with a reduction in the frequency of disease relapse by approximately 50% compared with patients remaining on dialysis, and patient and graft survival after transplantation is similar to that of other transplant recipients. Westman KWA,et al. J Am Soc Nephrol. 1998;9:842-852.
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Recurrent Disease in Kidney Transplantation Pretransplantation disease course, duration of dialysis, ANCA titers at time of transplantation and during follow-up, c-ANCA or p-ANCA specificity, disease subtype (Wegener’s granulomatosis, microscopic polyangiitis, or renal-limited vasculitis), and donor source had no significant impact on recurrence rate. In the absence of evidence, the authors recommend that clinical remission be maintained for at least 6 months before transplantation to reduce the risk of recurrence Patients with renal relapses have generally been managed with cyclophosphamide-based regimens as used for renal vasculitis in native kidneys, reported o be successful in inducing a remission in 11 of 16 (69%) cases. Westman KWA,et al. J Am Soc Nephrol. 1998;9:842-852.
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TREATMENT OF AAV
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Induction of Remission
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Methotrexate in Early Systemic AAV A randomized controlled trial, called the NORAM study, was initiated by EUVAS to test the hypothesis that methotrexate could replace cyclophosphamide as the induction treatment of AAV. Overall, 100 patients without renal involvement or with only mild renal involvement (creatinine levels <150 µmol/l) were randomly assigned to one of two groups for induction of remission, and received glucocorticoids in combination with either oral cyclophosphamide (2 mg/kg per day) or oral methotrexate (initially 15 mg per week, then increased to 20-25 mg per week) for 12 months. No significant difference in remission rates was observed between the two groups; however, the relapse rate at 18 months was significantly higher in the methotrexate group than in the cyclophosphamide group (69.5% versus 46.5%, P=0.023). On the basis of the results from the NORAM study, EUVAS and EULAR recommend methotrexate as an alternative to cyclophosphamide for induction of remission in non-organ-threatening or non-life-threatening AAV. De Groot, K. et al..Arthritis Rheum. 52, 2461-2469 (2005). Mukhtyar, C. et al. Ann. Rheum. Dis. 68, 310-317 (2009).
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NORAM study by EUVAS
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NORAM study by EUVAS
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NORAM study by EUVAS
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Induction of Remission in Generalized AAV ( Combined treatment with corticosteroid and cyclophosphamide ) A typical regimen for induction therapy of severe ANCA-positive rapidly progressive GN might include IV pulse methylprednisolone (7 mg/kg, to a maximum dose of 500–1000 mg) for 3 consecutive days followed by daily oral prednisone 1 mg/kg (to a maximum of 60–80 mg/day) for the first month with subsequent tapering of the dose. Cyclophosphamide may be given orally or intravenously (daily oral 2 mg/kg or IV pulses at 2- or 3- week intervals at a dose of 15 mg/kg) . Cyclophosphamide dose should be tapered to maintain total white cell count above 4_109/l and neutrophils >2.0_109 to reduce risk of infection . Cyclophosphamide dosage should be reduced for age and renal function . Current clinical practice with these protocols for remission induction are associated with an expected remission rate of 80% at 3 months and 90% at 6 months Mukhtyar C, Guillevin L, Cid MC et al. Ann Rheum Dis 2009; 68: 310–317. C. Lapraik, R. Watts.et al.Rheumatology 2007;46:1–11.
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Induction of Remission in Generalized AAV (Daily oral cyclophosphamide versus pulse intravenous cyclophosphamide) Both regimens are associated with a similar rate of remission, but intravenous cyclophosphamide therapy resulted in a lower cumulative dose and less adverse effects. Adu, D. et al. QJM 90, 401-409 (1997). Guillevin, L. et al. Arthritis Rheum. 40, 2187-2198 (1997). A randomized controlled trial by EUVAS, termed CYCLOPS (149 patiens), compared pulse cyclophosphamide with daily oral cyclophosphamide. Similar rates of remission were noted with both regimens, but the pulse regimen was associated with a lower cumulative dose of the drug, and fewer episodes of leukopenia, than the oral regimen. Relapses were more frequent following pulse therapy than oral therapy, although the study was not powered to detect significant differences in relapse rate; therefore, oral cyclophosphamide can still be considered for use in patients with AAV who experience frequent relapses. de Groot, K. et al. Ann. Intern. Med. 150, 670-680 (2009)
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de Groot, K. et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann. Intern. Med. 150, 670-680 (2009). CYCLOPS study by EUVAS CYCLOPS study by EUVAS
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de Groot, K. et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann. Intern. Med. 150, 670-680 (2009). The betweengroup difference in the proportion of patients who had relapse was not statistically significant, CYCLOPS study by EUVAS
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de Groot, K. et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann. Intern. Med. 150, 670-680 (2009). CYCLOPS study by EUVAS
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de Groot, K. et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann. Intern. Med. 150, 670-680 (2009). CYCLOPS study by EUVAS
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Induction of Remission in Generalized AAV (Randomized controlled trials of rituximab for induction of remission) RITUXVAS Trial compared a regimen of cyclophosphamide plus glucocorticoids (n = 11) with cyclophosphamide plus glucocorticoids and rituximab (n = 33) for induction of remission in generalized AAV (both regimens were followed by maintenance therapy with azathioprine). The rituximab group received four infusions of rituximab 375 mg/m2 plus two infusions of intravenous cyclophosphamide 15 mg/kg. The cyclophosphamide group received between six and ten infusions of cyclophosphamide 15 mg/kg. The study's primary end point—sustained remission at 12 months— was achieved by 76% of patients in the rituximab group and by 82% of patients in the cyclophosphamide group. Jones, R. B. et al.N. Engl. J. Med. 363, 211-220 (2010).
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RITUXVAS - Baseline Characteristics Jones, New Engl J Med 2010
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RITUXVAS – remission (BVAS = 0 for 6 months) Jones, New Engl J Med 2010 Time to Remission
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RITUXVAS -Relapse Jones, ACR/ASN 2010
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Induction of Remission in Generalized AAV (Randomized controlled trials of rituximab for induction of remission) RAVE Overall, 197 patients with AAV were randomly assigned to receive corticosteroids plus either rituximab (375 mg/m2 per week for four weeks; n = 99) or cyclophosphamide (2 mg/ kg per day; n = 97). Complete remission was acheived in 64% of patients in the rituximab group and 53% in the cyclophosphamide group. Furthermore, rituximab was more effective than cyclophosphamide for induction of remission in the subgroup of patients with relapsing disease (n = 101). Stone, J. H. et al.N. Engl. J. Med. 363, 221-232 (2010).
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Curr Opin Rheumatol. 2011;23(1):12-17. © 2011 Lippincott Williams & Wilkins
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Curr Opin Rheumatol. 2011;23(1):12-17. © 2011 Lippincott Williams & Wilkins
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Plasma Exchange in Life-threatening AAV. (A trial from EUVAS, termed MEPEX) A total of 137 patients with a new diagnosis of AAV (and serum creatinine level >500 µmol/l) were randomly assigned to receive seven plasma exchanges (n = 70) or three infusions of 1 g methylprednisolone pulse therapy (n = 67). Both groups also received oral prednisolone and cyclophosphamide. At 3 months of follow-up, renal recovery rate was significantly higher in the plasma exchange group than in the intravenous methylprednisolone group (69% versus 49%, P = 0.02). Furthermore, at 12 months of follow-up, plasma exchange was associated with a 24% reduction in the risk of end-stage renal disease in comparison with intravenous methylprednisolone treatment. Jayne, D. R. et al.J. Am. Soc. Nephrol.18, 2180-2188 (2007).
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Curr Opin Rheumatol. 2011;23(1):12-17. © 2011 Lippincott Williams & Wilkins MEPEX study
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Maintenance of Remission
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Maintenance of Remission (The CYCAZAREM study by EUVAS) Randomly assigned 144 patients with AAV (who achieved remission by receiving oral cyclophosphamide and prednisolone) to receive either azathioprine (2 mg/kg per day; n = 71) or to continue taking cyclophosphamide (1.5 mg/kg per day; n = 73). Both treatment groups continued to receive prednisolone (7.5 mg per day). At 18 months of follow-up, relapses had occurred in 15.5% and 13.7% of patients in the azathioprine and cyclophosphamide group, respectively,suggesting that azathioprine is as effective as cyclophosphamide for maintaining remission in AAV. Adverse events were comparable between the two treatment groups. Jayne, D. et al. N. Engl. J. Med. 349, 36-44 (2003).
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CYCAZAREM study by EUVAS
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Maintenance of Remission (A randomized controlled trial by the French Vasculitis Study Group) 126 patients with WG or MPA were randomly assigned to receive either oral azathioprine (2 mg/kg per day; n = 63) or methotrexate (0.3 mg/kg per week, progressively increased to 25 mg per week; n = 63) for 12 months after induction therapy. No significant difference was found between the two groups in terms of relapse-free survival and toxicity at a follow-up period of 29 ± 13 months. Pagnoux, C. et al. N. Engl. J. Med. 359, 2790-2803 (2008).
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French Vasculitis Study Group
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Pagnoux, C. et al. N. Engl. J. Med. 359, 2790-2803 (2008).
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Maintenance of Remission (randomized controlled clinical trial by EUVAS, termed IMPROVE) Comparing MMF with azathioprine for maintenance of remission in renal vasculitis. The results suggest that MMF is less effective than azathioprine; therefore, Azathioprine and methotrexate are the preferred drugs for maintenance of remission in AAV. Hiestra TF.et al.JAMA.2010;304:2381-8
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RELAPSE THERAPY The best treatment for relapses is unsettled. Reinstitution of treatment similar to an induction regimen is used most often, but less intensive or less toxic therapy may be adequate. A number of therapies have been used, including cyclophosphamide, rituximab, intravenous immune globulin, and MMF in combination with methotrexate or azathioprine, and combinations of these drugs must be tailored to the individual patient with recalcitrant disease Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009;68:310-317.
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PROPHYLACTIC TREATMENT IN CHRONIC NASAL CARRIERS OF S. AUREUS Stegeman et al. first noted that 63% of patients with WG were chronic nasal carriers of S. aureus and that S. aureus carriage was associated with a higher relapse rate, with an adjusted relative risk of 7.16. Stegeman CA, et al. Ann Intern Med 1994, 120:12–17 . Furthermore, they showed that prophylactic treatment with cotrimoxazole could prevent the occurrence of relapse. 82 percent of the patients in the co-trimoxazole group remained in remission at 24 months, as compared with 60 percent of those in the placebo group (relative risk of relapse, 0.40; 95 percent confidence interval, 0.17 to 0.98). Stegeman CA,et al. N Engl J Med 1996, 335:16–20.
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Stegeman CA,et al. N Engl J Med 1996, 335:16–20.
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