Identification and management of relapsing disease 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
- Section Editors
- Richard J Glassock, MD, MACP
Richard J Glassock, MD, MACP
- Editor-in-Chief — Nephrology
- Section Editor — Glomerular Diseases
- Emeritus Professor
- The David Geffen School of Medicine at UCLA
- Gerald B Appel, MD
Gerald B Appel, MD
- Section Editor — Glomerular Diseases
- Professor of Medicine
- Columbia University College of Physicians and Surgeons
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]. This change reflects a plan to gradually shift from honorific eponyms to a disease-descriptive or etiology-based nomenclature.
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related systemic vasculitides . Both are associated with antineutrophil cytoplasmic autoantibodies (ANCA), and both have similar features on renal histology (eg, a focal necrotizing, pauci-immune glomerulonephritis). However, there are several differences between these disorders. (See "Clinical manifestations and diagnosis of granulomatosis with polyangiitis and microscopic polyangiitis".)
Patients who have vasculitis associated with ANCA (ie, GPA and MPA) can also be distinguished according to the two most prominent ANCA serotypes, specifically, proteinase-3 (PR3) and myeloperoxidase (MPO). The ANCA serotype may have more prognostic significance than the terms "MPA" and "GPA" with respect to response to therapy, propensity for relapse, and patient outcome. In addition, genetic variants that are associated with ANCA disease are more specifically linked with the antigen (PR3 versus MPO) rather than with the clinical phenotype. (See "Clinical manifestations and diagnosis of granulomatosis with polyangiitis and microscopic polyangiitis", section on 'Limitations of classification algorithms'.)
Between 70 and 90 percent of patients with GPA or MPA attain clinical remission with initial immunosuppressive therapy (typically, cyclophosphamide or rituximab in combination with glucocorticoids). They are then treated with maintenance immunosuppressive therapy, usually with azathioprine, rituximab, or methotrexate, for a period that is typically 12 to 18 months. However, relapses are common, and some patients have frequent relapses. In addition, among patients who progress to end-stage renal disease, nonrenal relapses can occur in patients treated with maintenance hemodialysis or renal transplantation, and renal manifestations can recur in the transplanted kidney.
Issues related to relapsing disease in patients with GPA or MPA will be reviewed here. This includes patients who have progressed to end-stage renal disease and are on chronic renal replacement therapy.
- 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. 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. Ann Rheum Dis 2011; 70:704.
- Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1.
- Hogan SL, Falk RJ, Chin H, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med 2005; 143:621.
- Nachman PH, Hogan SL, Jennette JC, Falk RJ. Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol 1996; 7:33.
- Chen M, Yu F, Zhao MH. Relapses in patients with antineutrophil cytoplasmic autoantibody-associated vasculitis: likely to begin with the same organ as initial onset. J Rheumatol 2008; 35:448.
- Harper L, Morgan MD, Walsh M, et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis 2012; 71:955.
- Specks U, Merkel PA, Seo P, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med 2013; 369:417.
- Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005; 352:351.
- Savage CO, Winearls CG, Evans DJ, et al. Microscopic polyarteritis: presentation, pathology and prognosis. Q J Med 1985; 56:467.
- 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.
- Lionaki S, Blyth ER, Hogan SL, et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum 2012; 64:3452.
- Seo P, Min YI, Holbrook JT, et al. Damage caused by Wegener's granulomatosis and its treatment: prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET). Arthritis Rheum 2005; 52:2168.
- 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.
- Geffriaud-Ricouard C, Noël LH, Chauveau D, et al. Clinical spectrum associated with ANCA of defined antigen specificities in 98 selected patients. Clin Nephrol 1993; 39:125.
- Jayne DR, Gaskin G, Pusey CD, Lockwood CM. ANCA and predicting relapse in systemic vasculitis. QJM 1995; 88:127.
- Stegeman CA, Tervaert JW, Sluiter WJ, et al. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 1994; 120:12.
- Kyndt X, Reumaux D, Bridoux F, et al. Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with systemic vasculitis. Am J Med 1999; 106:527.
- Pettersson E, Heigl Z. Antineutrophil cytoplasmic antibody (cANCA and pANCA) titers in relation to disease activity in patients with necrotizing vasculitis: a longitudinal study. Clin Nephrol 1992; 37:219.
- Finkielman JD, Merkel PA, Schroeder D, et al. Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann Intern Med 2007; 147:611.
- Boomsma MM, Stegeman CA, van der Leij MJ, et al. Prediction of relapses in Wegener's granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum 2000; 43:2025.
- Kerr GS, Fleisher TA, Hallahan CW, et al. Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener's granulomatosis. Arthritis Rheum 1993; 36:365.
- Gaskin G, Savage CO, Ryan JJ, et al. Anti-neutrophil cytoplasmic antibodies and disease activity during long-term follow-up of 70 patients with systemic vasculitis. Nephrol Dial Transplant 1991; 6:689.
- Tervaert JW, Huitema MG, Hené RJ, et al. Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet 1990; 336:709.
- Russell KA, Fass DN, Specks U. Antineutrophil cytoplasmic antibodies reacting with the pro form of proteinase 3 and disease activity in patients with Wegener's granulomatosis and microscopic polyangiitis. Arthritis Rheum 2001; 44:463.
- Pagnoux C, Hogan SL, Chin H, et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts. Arthritis Rheum 2008; 58:2908.
- Cao Y, Tian Z, Li W, et al. Predictors of treatment resistance and relapse in Chinese patients with antineutrophil cytoplasmic antibody-associated disease. J Rheumatol 2014; 41:916.
- Miloslavsky EM, Specks U, Merkel PA, et al. Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2013; 65:2441.
- Kemna MJ, Damoiseaux J, Austen J, et al. ANCA as a predictor of relapse: useful in patients with renal involvement but not in patients with nonrenal disease. J Am Soc Nephrol 2015; 26:537.
- Gayraud M, Guillevin L, le Toumelin P, et al. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum 2001; 44:666.
- Bacon PA. The spectrum of Wegener's granulomatosis and disease relapse. N Engl J Med 2005; 352:330.
- Rarok AA, Stegeman CA, Limburg PC, Kallenberg CG. Neutrophil membrane expression of proteinase 3 (PR3) is related to relapse in PR3-ANCA-associated vasculitis. J Am Soc Nephrol 2002; 13:2232.
- Popa ER, Tervaert JW. The relation between Staphylococcus aureus and Wegener's granulomatosis: current knowledge and future directions. Intern Med 2003; 42:771.
- Popa ER, Stegeman CA, Abdulahad WH, et al. Staphylococcal toxic-shock-syndrome-toxin-1 as a risk factor for disease relapse in Wegener's granulomatosis. Rheumatology (Oxford) 2007; 46:1029.
- De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005; 52:2461.
- Goek ON, Stone JH. Randomized controlled trials in vasculitis associated with anti-neutrophil cytoplasmic antibodies. Curr Opin Rheumatol 2005; 17:257.
- Andrassy K, Waldherr R, Erb A, Ritz E. De novo glomerulonephritis in patients during remission from Wegener's granulomatosis. Clin Nephrol 1992; 38:295.
- Haas M, Jafri J, Bartosh SM, et al. ANCA-associated crescentic glomerulonephritis with mesangial IgA deposits. Am J Kidney Dis 2000; 36:709.
- Bantis C, Stangou M, Schlaugat C, et al. Is presence of ANCA in crescentic IgA nephropathy a coincidence or novel clinical entity? A case series. Am J Kidney Dis 2010; 55:259.
- Miloslavsky EM, Specks U, Merkel PA, et al. Rituximab for the treatment of relapses in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 2014; 66:3151.
- Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010; 363:221.
- Hogan J, Avasare R, Radhakrishnan J. Is newer safer? Adverse events associated with first-line therapies for ANCA-associated vasculitis and lupus nephritis. Clin J Am Soc Nephrol 2014; 9:1657.
- Jindal KK. Management of idiopathic crescentic and diffuse proliferative glomerulonephritis: evidence-based recommendations. Kidney Int Suppl 1999; 70:S33.
- Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med 2004; 117:39.
- Stassen PM, Tervaert JW, Stegeman CA. Induction of remission in active anti-neutrophil cytoplasmic antibody-associated vasculitis with mycophenolate mofetil in patients who cannot be treated with cyclophosphamide. Ann Rheum Dis 2007; 66:798.
- 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.
- NEW TERMINOLOGY
- DEFINITION OF RELAPSING DISEASE
- IDENTIFYING PATIENTS WITH RELAPSING DISEASE
- Monitoring for relapse
- - Patient self-monitoring
- - Monitoring by the clinician
- ANCA titers
- Risk factors for relapse
- Precipitants of relapse
- Diagnosis of relapsing disease
- - Differential diagnosis
- TREATMENT OF RELAPSING DISEASE
- Overall approach
- Treatment of a severe relapse
- Treatment of a mild relapse
- - Disease limited to the upper respiratory tract
- Patients who have multiple relapses
- Maintenance therapy after reinduction for a severe relapse
- EFFECT OF RELAPSE ON PROGNOSIS
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS