J Am Soc Nephrol 2012; 23:313. 136. Mekhail TM, Hoffman GS. Longterm outcome of Wegener's granulomatosis in patients with renal disease requiring dialysis. J Rheumatol 2000; 27:1237. 137. Glassock RJ. Intensive plasma exchange in crescentic glomerulonephritis: help or no help? Am J Kidney Dis 1992; 20:270. 138. Cole E, Cattran D, Magil A, et al. A prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis. The Canadian Apheresis Study Group. Am J Kidney Dis 1992; 20:261. 139. Geffriaud-Ricouard C, No l LH, Chauveau D, et al. Clinical spectrum associated with ANCA of defined antigen specificities in 98 selected patients. Clin Nephrol 1993; 39:125. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 44/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 140. Berti A, Matteson EL, Crowson CS, et al. Risk of Cardiovascular Disease and Venous Thromboembolism Among Patients With Incident ANCA-Associated Vasculitis: A 20-Year Population-Based Cohort Study. Mayo Clin Proc 2018; 93:597. 141. Houben E, Penne EL, Voskuyl AE, et al. Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis of observational studies. Rheumatology (Oxford) 2018; 57:555. 142. Nygaard L, Polcwiartek C, Nelveg-Kristensen KE, et al. Long-term cardiovascular outcomes and temporal trends in patients diagnosed with ANCA-associated vasculitis: a Danish nationwide registry study. Rheumatology (Oxford) 2023; 62:735. 143. Liapi M, Jayne D, Merkel PA, et al. Venous thromboembolism in ANCA-associated vasculitis: a population-based cohort study. Rheumatology (Oxford) 2021; 60:4616. 144. Kronbichler A, Leierer J, Shin JI, et al. Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol 2019; 71:1888. 145. Englund M, Merkel PA, Tomasson G, et al. Comorbidities in Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis versus the General Population. J Rheumatol 2016; 43:1553. 146. Merkel PA, Lo GH, Holbrook JT, et al. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener's Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann Intern Med 2005; 142:620. 147. Moiseev S, Bulanov N, Crnogorac M, et al. Traditional and Disease-Specific Risk Factors for Cardiovascular Events in ANCA-Associated Vasculitis: A Multinational Retrospective Study. J Rheumatol 2023. Topic 3105 Version 59.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 45/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate GRAPHICS Phase-contrast micrograph showing dysmorphic RBCs in urine sediment Phase-contrast microscopy showing dysmorphic red blood cells (RBCs) and acanthocytes in the urinary sediment of a patient with glomerular hematuria. Acanthocytes (arrows) can be recognized as ring forms with vesicle-shaped protrusions. Courtesy of Juan Carlos Q Velez, MD. Graphic 130438 Version 1.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 46/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Scanning electron micrograph showing dysmorphic red cells in urine sediment Scanning microscopy showing dysmorphic red cells in a patient with glomerular bleeding. Acanthocytes can be recognized as ring forms with vesicle-shaped protrusions (arrows). Courtesy of Hans K hler, MD. Graphic 62064 Version 3.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 47/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Initial induction and maintenance therapy in patients with a diagnosis of GPA or MPA This treatment algorithm applies to patients who are not pregnant. Induction therapy in pregnant patients requires modification due to the potential risk of fetal harm associated with some agents. Refer to UpToDate content on initial immunosuppressive therapy in pregnant patients with GPA or MPA. GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; GBM: glomerular basement membrane; ANCA: antineutrophil cytoplasmic autoantibodies; eGFR: estimated glomerular filtration rate. Refer to UpToDate content on the use of rituximab or cyclophosphamide as induction therapy for patients with GPA or MPA who have organ- or life-threatening disease. The role of plasma exchange, in addition to glucocorticoids and either cyclophosphamide or rituximab, among patients with GPA or MPA is controversial. Refer to UpToDate content on plasma exchange in patients with GPA or MPA. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 48/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Contraindications to methotrexate include, but are not limited to, heavy alcohol use, chronic liver 2 disease, eGFR <60 mL/min/1.73 m , or evidence of renal vasculitis. Refer to UpToDate content on management of non-organ- and non-life-threatening GPA or MPA. Rituximab is preferred for most patients who achieve remission after induction therapy. Azathioprine, methotrexate, and mycophenolate are reasonable alternatives to rituximab and may be preferred based on other patient-specific factors, such as a prior history of toxicity from a certain drug and/or a comorbid condition that increases the risk of toxicity with a specific agent. Refer to UpToDate content on the choice of maintenance therapy in patients with GPA or MPA. Graphic 111371 Version 3.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 49/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Adjusting oral cyclophosphamide dose for adult patients with kidney function impairment Cyclophosphamide (CYC) oral dose Creatinine clearance* (mL/minute) (mg/kg/day) >100 2 50 to 99 1.5 25 to 49 1.2 15 to 24 1 <15 or dialysis 0.8 Initial 2 mg/kg per day dose and adjustments for kidney function impairment are for daily oral administration of "low-dose" cyclophosphamide therapy in rheumatic diseases. For approach, other dose adjustments that may be needed, and duration of therapy, refer to UpToDate topics on the use of cyclophosphamide in rheumatic diseases. CYC: cyclophosphamde; Clcr: creatinine clearance. Can be estimated by using the Cockroft-Gault equation. Clcr = [140-age] * weight (kg)/serum Cr in mg/dL * 72. Multiply result by 0.85 for women. Separate calculators for creatinine clearance using conventional and SI units are available in UpToDate. Usual maximum daily dose is 200 mg. For patients who are overweight or obese, an estimate of ideal or lean body weight is used for estimating Clcr and determining daily CYC weight-based dose. Calculators are available in UpToDate. CYC is variably dialyzable (approximately 20 to 50 percent). Dose may require further adjustment depending upon type of dialysis. For intermittent hemodialysis, give dose after session on dialysis days. Adapted with permission from: Rheumatic Disease Clinics of North America 2001. 27(4):863. Copyright 2001 Elsevier Science. Additional information from de Groot et al. Ann Intern Med 2009. 150(10):670. Graphic 60883 Version 9.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 50/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Reduced-dose glucocorticoid tapering regimen for patients with GPA and MPA Patient weight Week <50 kg 50 to 75 kg >75 kg 1 50 60 75 2 25 30 40 3 to 4 20 25 30 5 to 6 15 20 25 7 to 8 12.5 15 20 9 to 10 10 12.5 15 11 to 12 7.5 10 12.5 13 to 14 6 7.5 10 15 to 16 5 5 7.5 17 to 18 5 5 7.5 19 to 20 5 5 5 21 to 22 5 5 5 This table provides an example of a reduced-dose, oral glucocorticoid-tapering regimen for a patient with new-onset or relapsing GPA or MPA. Depending on the management by the treating clinicians, it can be initiated immediately or after a course of IV glucocorticoids. After week 22, further reduction in glucocorticoid dose is individualized based on treating provider and patient preference. GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; IV: intravenous. From: Walsh M, Merkel PA, Peh CA et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med 2020; 382:622. Copyright 2020 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Graphic 129362 Version 1.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 51/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and Conivaptan Lumacaftor Dexamethasone cobicistat- containing Crizotinib Lumacaftor- Dipyrone ivacaftor Cyclosporine Efavirenz coformulations Mitotane Diltiazem Elagolix, estradiol, Darunavir Phenobarbital and norethindrone Duvelisib Idelalisib therapy pack Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin Fedratinib Ketoconazole (rifampicin) Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- Mifepristone* Pexidartinib palonosetron Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- Sotorasib Isavuconazole ritonavir (isavuconazonium St. John's wort Ombitasvir- sulfate) paritaprevir- Lefamulin ritonavir Letermovir Ombitasvir- Netupitant paritaprevir- Nilotinib ritonavir plus Ribociclib dasabuvir Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 52/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. [1,2] These classifications are based upon US Food and Drug Administration (FDA) guidance. sources may use a different classification system resulting in some agents being classified Other differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 53/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Contributor Disclosures Peter A Merkel, MD, MPH Equity Ownership/Stock Options: Kyverna [Systemic lupus erythematosus]. Grant/Research/Clinical Trial Support: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; Electra [Vasculitis]; Genentech/Roche [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Sanofi [Vasculitis]; Takeda [Vasculitis]. Consultant/Advisory Boards: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; CSL Behring [Scleroderma, vasculitis]; Dynacure [Vasculitis]; EMDSerono [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Janssen [Vasculitis]; Kyverna [Scleroderma, vasculitis]; MiroBio [Vasculitis]; Neutrolis [Vasculitis]; Novartis [Vasculitis]; NS Pharma [Vasculitis]; Otsuka [Vasculitis]; Q32 [Vasculitis]; Regeneron [Vasculitis]; Sparrow [Vasculitis]; Takeda [Vasculitis]. All of the relevant financial relationships listed have been mitigated. Andre A Kaplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Ronald J Falk, MD Grant/Research/Clinical Trial Support: National Institutes of Health [ANCA vasculitis, IgA, minimal change, focal segmental glomerulosclerosis, membranous glomerulonephritis, T32 training]. Consultant/Advisory Boards: Vertex Pharmaceuticals Inc [Focal segmental glomerulosclerosis]. All of the relevant financial relationships listed have been mitigated. Gerald B Appel, MD Grant/Research/Clinical Trial Support: Alexion [C3 glomerulopathies]; Calliditas [IgA nephropathy]; ChemoCentryx [C3 glomerulopathies]; Equillium [Lupus nephritis]; Goldfinch [FSGS]; Mallinckrodt [Fibrillary glomerulonephritis]; Novartis [C3GN, IgAN]; Reata [Alport syndrome]; Roche [Glomerular diseases, glomerulonephritis, and lupus nephritis]; Sanofi [Alport syndrome]; Travere [FSGS, IgAN]. Consultant/Advisory Boards: Alexion [Glomerular diseases, glomerulonephritis, lupus nephritis]; Arrowhead [Glomerulonephritis]; Aurinia [Glomerular diseases, glomerulonephritis, lupus nephritis]; Callidaitas [IgAN]; ChemoCentryx [Immunosuppressives]; KIRA Pharma [New immunosuppressives in glomerular kidney disease]; Mallinckrodt [Glomerular diseases, glomerulonephritis, lupus nephritis]; Merck [Glomerular diseases, glomerulonephritis, lupus nephritis]; Novartis [Glomerulonephritis]; Pfizer [Glomerular diseases, glomerulonephritis, lupus nephritis]; Reata [Glomerulonephritis]; Roche [Glomerular diseases, glomerulonephritis, lupus nephritis]; Sanofi [Glomerular diseases, glomerulonephritis,]; Steritas [Reduction of corticosteroid use in clinical practice of treating kidney disease]; Travere [IgAN]. Speaker's Bureau: Aurinia [Lupus nephritis]; GlaxoSmithKline [Lupus nephritis]. All of the relevant financial relationships listed have been mitigated. Fernando C Fervenza, MD, PhD Grant/Research/Clinical Trial Support: Genentech [Membranous nephropathy, fibrillary GN]; Janssen Pharmaceutical [Monoclonal protein-mediated kidney diseases, lupus nephritis]; Morphosys AG [IgA nephropathy]. Consultant/Advisory Boards: Alexion [C3 glomerulopathy, IgA nephropathy]; BioCrystal Pharmaceuticals [C3 glomerulopathy]; ChemoCentryx, Inc [ANCA associated vasculitis]; Equilium, Inc [Lupus nephritis]; Galapagos [Focal segmental glomerulosclerosis]; GlaxoSmithKline [Lupus nephritis]; Novartis [IgA Nephropathy]; Otsuka [IgA nephropathy]; Takeda [IgA nephropathy]; Zyversa Therapeutics [FSGS]. All of the relevant financial relationships listed have been mitigated. Albert Q Lam, MD No relevant financial relationship(s) with ineligible companies to disclose. Philip Seo, MD, MHS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 54/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 55/55