Maintenance immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis
- Ronald J Falk, MD
Ronald J Falk, MD
- Nan and Hugh Cullman Eminent Professor of Nephrology
- Chair, Department of Medicine
- Director, UNC Kidney Center
- University of North Carolina-Chapel Hill
- Peter A Merkel, MD, MPH
Peter A Merkel, MD, MPH
- Section Editor — Vasculitis
- Chief, Division of Rheumatology
- University of Pennsylvania
- Section Editors
- Gerald B Appel, MD
Gerald B Appel, MD
- Section Editor — Glomerular Diseases
- Professor of Medicine
- Columbia University College of Physicians and Surgeons
- Fernando C Fervenza, MD, PhD
Fernando C Fervenza, MD, PhD
- Section Editor — Glomerular Diseases
- Professor of Medicine
- Mayo Clinic College of Medicine
In January 2011, the Boards of Directors of the American College of Rheumatology (ACR), the American Society of Nephrology (ASN), and the European League Against Rheumatism (EULAR) recommended that the name "Wegener's granulomatosis" be changed to "granulomatosis with polyangiitis," abbreviated as GPA [1-3].
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related systemic vasculitides. Both are associated with antineutrophil cytoplasmic autoantibodies (ANCA), have similar clinical manifestations and features on renal histology (eg, a focal necrotizing, pauci-immune glomerulonephritis), and have similar therapies. There are, however, several differences between these disorders. (See "Clinical manifestations and diagnosis of granulomatosis with polyangiitis and microscopic polyangiitis", section on 'Clinical presentation'.)
Therapy of GPA and MPA has two components: induction of remission with initial immunosuppressive therapy and maintenance immunosuppressive therapy for a variable period to prevent relapse.
Maintenance immunosuppressive therapy of GPA and MPA will be reviewed here. Initial immunosuppressive therapy, the treatment of resistant or relapsing disease, clinical manifestations and diagnosis, and prognosis are discussed elsewhere. (See "Initial immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis" and "Treatment-resistant granulomatosis with polyangiitis and microscopic polyangiitis" and "Identification and management of relapsing disease in granulomatosis with polyangiitis and microscopic polyangiitis" and "Clinical manifestations and diagnosis of granulomatosis with polyangiitis and microscopic polyangiitis" and "Prognosis in granulomatosis with polyangiitis and microscopic polyangiitis, and management of those who develop end-stage renal disease".)
GOAL OF MAINTENANCE THERAPY
After attainment of remission with initial immunosuppressive therapy, almost all patients with GPA or MPA are switched to a maintenance regimen, most often azathioprine, rituximab, or methotrexate. Some may not require maintenance therapy, including those with drug-induced vasculitis and some who are myeloperoxidase (MPO)-antineutrophil cytoplasmic autoantibody (ANCA) positive and have a clinical remission after induction therapy for their initial presentation with vasculitis. (See 'Patients with drug-induced ANCA-associated vasculitis' below and 'MPO-ANCA-positive patients' below.)
- Falk RJ, Gross WL, Guillevin L, et al. Granulomatosis with polyangiitis (Wegener's): an alternative name for Wegener's granulomatosis. J Am Soc Nephrol 2011; 22:587.
- Falk RJ, Gross WL, Guillevin L, et al. Granulomatosis with polyangiitis (Wegener's): an alternative name for Wegener's granulomatosis. Arthritis Rheum 2011; 63:863.
- Falk RJ, Gross WL, Guillevin L, et al. Granulomatosis with polyangiitis (Wegener's): an alternative name for Wegener's granulomatosis. Ann Rheum Dis 2011; 70:704.
- Mahr AD, Neogi T, Lavalley MP, et al. Assessment of the item selection and weighting in the Birmingham vasculitis activity score for Wegener's granulomatosis. Arthritis Rheum 2008; 59:884.
- Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005; 352:351.
- Tomasson G, Davis JC, Hoffman GS, et al. Brief report: The value of a patient global assessment of disease activity in granulomatosis with polyangiitis (Wegener's). Arthritis Rheumatol 2014; 66:428.
- Walsh M, Merkel PA, Mahr A, Jayne D. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: A meta-analysis. Arthritis Care Res (Hoboken) 2010; 62:1166.
- Langford CA, Talar-Williams C, Sneller MC. Use of methotrexate and glucocorticoids in the treatment of Wegener's granulomatosis. Long-term renal outcome in patients with glomerulonephritis. Arthritis Rheum 2000; 43:1836.
- McGregor JG, Hogan SL, Hu Y, et al. Glucocorticoids and relapse and infection rates in anti-neutrophil cytoplasmic antibody disease. Clin J Am Soc Nephrol 2012; 7:240.
- McGregor JG, Negrete-Lopez R, Poulton CJ, et al. Adverse events and infectious burden, microbes and temporal outline from immunosuppressive therapy in antineutrophil cytoplasmic antibody-associated vasculitis with native renal function. Nephrol Dial Transplant 2015; 30 Suppl 1:i171.
- McGregor JG, Hogan SL, Kotzen ES, et al. Rituximab as an immunosuppressant in antineutrophil cytoplasmic antibody-associated vasculitis. Nephrol Dial Transplant 2015; 30 Suppl 1:i123.
- Lee T, Gasim A, Derebail VK, et al. Predictors of treatment outcomes in ANCA-associated vasculitis with severe kidney failure. Clin J Am Soc Nephrol 2014; 9:905.
- Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:36.
- Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med 2008; 359:2790.
- Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014; 371:1771.
- https://clinicaltrials.gov/ct2/show/NCT01697267?term=RITAZAREM&rank=1 (Accessed on April 08, 2014).
- Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA 2010; 304:2381.
- de Groot K, Reinhold-Keller E, Tatsis E, et al. Therapy for the maintenance of remission in sixty-five patients with generalized Wegener's granulomatosis. Methotrexate versus trimethoprim/sulfamethoxazole. Arthritis Rheum 1996; 39:2052.
- Metzler C, Miehle N, Manger K, et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis. Rheumatology (Oxford) 2007; 46:1087.
- Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med 1996; 335:16.
- Knight A, Hallenberg H, Baecklund E. Efficacy and safety of rituximab as maintenance therapy for relapsing granulomatosis with polyangiitis—a case series. Clin Rheumatol 2014; 33:841.
- Besada E, Koldingsnes W, Nossent JC. Long-term efficacy and safety of pre-emptive maintenance therapy with rituximab in granulomatosis with polyangiitis: results from a single centre. Rheumatology (Oxford) 2013; 52:2041.
- Charles P, Néel A, Tieulié N, et al. Rituximab for induction and maintenance treatment of ANCA-associated vasculitides: a multicentre retrospective study on 80 patients. Rheumatology (Oxford) 2014; 53:532.
- Pendergraft WF 3rd, Cortazar FB, Wenger J, et al. Long-term maintenance therapy using rituximab-induced continuous B-cell depletion in patients with ANCA vasculitis. Clin J Am Soc Nephrol 2014; 9:736.
- McAdoo SP, Pusey CD. Should rituximab be used to prevent relapse in patients with ANCA-associated vasculitis? Clin J Am Soc Nephrol 2014; 9:641.
- Smith RM, Jones RB, Guerry MJ, et al. Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2012; 64:3760.
- Reinhold-Keller E, Fink CO, Herlyn K, et al. High rate of renal relapse in 71 patients with Wegener's granulomatosis under maintenance of remission with low-dose methotrexate. Arthritis Rheum 2002; 47:326.
- Alberici F, Smith RM, Jones RB, et al. Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for ANCA-associated vasculitis. Rheumatology (Oxford) 2015; 54:1153.
- Pagnoux C, Guillevin L, French Vasculitis Study Group, MAINRITSAN investigators. Rituximab or azathioprine maintenance in ANCA-associated vasculitis. N Engl J Med 2015; 372:386.
- Cartin-Ceba R, Golbin JM, Keogh KA, et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): ten-year experience at a single center. Arthritis Rheum 2012; 64:3770.
- Langford CA, Talar-Williams C, Barron KS, Sneller MC. Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener's granulomatosis: extended follow-up and rate of relapse. Am J Med 2003; 114:463.
- GOAL OF MAINTENANCE THERAPY
- WHEN TO START MAINTENANCE THERAPY
- If cyclophosphamide is used for induction
- If rituximab is used for induction
- SELECTING A REGIMEN FOR MAINTENANCE THERAPY
- General principles
- - Choosing a maintenance drug
- - Tapering of glucocorticoids started during induction
- - Prophylaxis against infection
- - Patients who require dialysis
- - Patients with drug-induced ANCA-associated vasculitis
- Newly diagnosed patients
- - PR3-ANCA-positive patients
- - MPO-ANCA-positive patients
- Patients who have had one or more relapses
- - Relapse occurred during maintenance therapy
- - Relapse occurred after completion of maintenance therapy
- DOSING OF MAINTENANCE THERAPY
- Azathioprine dosing
- Rituximab dosing
- Methotrexate dosing
- Mycophenolate mofetil dosing
- WHEN TO STOP MAINTENANCE THERAPY
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS