Granulomatosis with Polyangiitis (Wegener Granulomatosis) Workup
- Author: Christopher L Tracy, MD; Chief Editor: Herbert S Diamond, MD more...
Routine laboratory tests are nonspecific in granulomatosis with polyangiitis (GPA). Elevated blood urea nitrogen (BUN) and creatinine levels may signal renal involvement. Hypoalbuminemia may be present. Serum complement levels are within the reference range or increased.
Mild normochromic normocytic anemia is present in 50% of patients. A peripheral blood smear may show schistocytes and burr cells. Leukocytosis is also common, with a neutrophil predominance. Eosinophilia is not a feature of GPA but rather of allergic granulomatous angiitis (Churg-Strauss syndrome).
Westergren erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are elevated in 90% of patients with active and generalized disease. They may decrease in response to treatment.
In patients with renal involvement, urinalysis may show non-nephrotic–range to nephrotic-range proteinuria, microscopic hematuria, and the presence of red blood cell (RBC) casts consistent with underlying glomerulonephritis.
Rheumatoid factor is positive in a low titer in two thirds of patients, whereas antinuclear antibody is present in 10-20% of patients. Hypergammaglobulinemia may be present.
Whether tissue diagnosis is always required for GPA remains controversial. As the therapy for severe GPA is not benign, tissue diagnosis is recommended if a biopsy site is available, provided that the patient understands the risks of the procedure.
Antineutrophil cytoplasmic antibodies (ANCAs) can be detected with serologic assays. The 2 types of assays in common use are immunofluorescence (IF) and enzyme immunoassay. Three types of IF patterns are recognized: C-ANCA (cytoplasmic antibody), P-ANCA (perinuclear antibody), and atypical ANCA. (See the images below.)
IF represents a qualitative ANCA assay, and significant inter-reader variability exists. Enzyme-linked immunosorbent assay (ELISA) provides target antigen-specific characterization of ANCA (ie, anti-PR3 and anti-myeloperoxidase [MPO]) and should be used to confirm IF findings. Combining IF and ELISA enhances the sensitivity and specificity of a diagnosis of AAV to 96% and 98.5%, respectively. Only ANCAs directed against PR3 or MPO have been associated with primary vasculitic syndromes.
C-ANCA directed against PR3 is most specific for GPA. According to the WGET trial, IF shows positive C-ANCA results in 88% of all patients with GPA. IF shows positive C-ANCA results in 87% of patients with severe disease and in 90% of those with limited disease. Using both IF and ELISA, ANCA is detectable in nearly 100% of patients with active generalized GPA.
Some patients with GPA express P-ANCA specific for MPO. Analysis of the WGET cohort demonstrated that IF showed positive P-ANCA results in 13% of patients with severe disease; 10%of patients with limited disease were P-ANCA–positive. A few patients with GPA are ANCA-negative, although this fraction appears to be exceedingly small.[11, 19]
Rising C-ANCA titers may herald a relapse in some patients with GPA, but this relationship is unreliable. Thus, patients with rising ANCA titers should not be treated with cytotoxic medications in the absence of signs, symptoms, or other objective evidence of disease relapse.[23, 37]
Further considerations in P-ANCA testing
In contrast to GPA, the indirect IF staining pattern in microscopic polyangiitis and allergic granulomatous angiitis is often perinuclear (P-ANCA). This is an artifactual phenomenon that occurs during the ethanol fixation process of neutrophils, resulting in the displacement of the basic positively charged proteins (eg, MPO, lactoferrin, lysozyme, elastase, cathepsin G) from the cytoplasm to the nuclear region. MPO is the antigen at which these autoantibodies are most often directed in the setting of small-vessel vasculitis. This antibody can be observed in microscopic polyangiitis, allergic granulomatous angiitis, idiopathic crescentic glomerulonephritis, and, occasionally, GPA.
A positive finding on a P-ANCA test alone can be observed in a number of other diseases that would not qualify as small-vessel vasculitis. These include inflammatory bowel disease, Kawasaki disease, polyarteritis nodosa, Felty syndrome, and infections such as human immunodeficiency virus (HIV) infection and endocarditis. Because of the variability of the P-ANCA target antigen, more specific antibody testing is recommended strongly. A positive P-ANCA test result should be used to diagnose small vessel vasculitis only when it is used in conjunction with a positive antimyeloperoxidase titer in the setting of high clinical suspicion.
In summary, be cautious not to equate a positive ANCA test result with disease. When used appropriately, the ANCA test is a very powerful test with high degrees of sensitivity and specificity; however, when used in the wrong setting, it can lead to misdiagnosis with resultant inappropriate treatment using potentially toxic therapy. Indeed, a positive C-ANCA test result in patients with only sinusitis has a posttest probability of 7-16% of correctly diagnosing GPA. In patients with sinusitis, pulmonary infiltrates or nodules, and active urinary sediment with RBC casts, a positive C-ANCA test finding has a posttest probability of GPA of 98%. Moreover, ANCA tests should not be used to correlate with clinical disease in patients with established diagnoses of vasculitis.
Radiography and CT Scanning
Findings on chest radiography are abnormal in two thirds of adults with GPA. The most common radiologic findings are single or multiple nodules and masses. Nodules are typically diffuse, and approximately 50% are cavitated. (See the images below.)
Diffuse alveolar opacities due to diffuse alveolar hemorrhage (DAH), atelectasis, and obstructive pneumonia caused by bronchial stenosis may also be seen. Findings on computed tomography (CT) scans and high-resolution CT (HRCT) scans include consolidation, patchy or diffuse ground-glass opacities, or both. (See the images below.)
Additional CT scan findings include stenoses of the larynx or tracheobronchial tree, bronchial wall thickening, bronchiectasis, pleural thickening or effusion, and lymphadenopathy.
Opacification, bony destruction, and mucosal thickening are reported, but these signs are not specific to GPA. (See the image below.)
Sinus CT scanning
This is the radiographic test of choice to evaluate sinus disease. Findings on thin-section sinus CT scans are abnormal in more than 90% of adults with GPA. A similar number would be expected in the pediatric population, based on an 83% incidence of sinusitis reported by Rottem et al.
In patients old enough to cooperate, spirometry, plethysmography, and diffusing capacity should be performed as soon as possible to identify abnormalities and provide a baseline.
Good inspiratory and expiratory loops should be obtained. If these are flattened, subglottic stenosis or other causes for central airway obstruction should be suspected.
Because most pediatric subglottic stenosis is not found initially, spirometry, particularly with a good baseline flow volume loop, can be used to screen noninvasively for this development.
Spirometry may show either restrictive or obstructive patterns, and the diffusing capacity of lung for carbon monoxide (DLCO) may be decreased or increased, as in the case of DAH.
Although a decreased diffusing capacity is a common finding in GPA, it may still fall within the reference range. In alveolar hemorrhage, the single-breath diffusing capacity is increased.
In adults, limitation to flow and decrease of the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) are the most common pulmonary function test abnormalities. Focal and interstitial infiltrates and peripheral mass lesions produce decreased lung volumes.
This study is helpful in the evaluation of alveolar hemorrhage, infection, airway disease, and endobronchial lesions.
Transbronchial biopsy in diffuse lung disease has a low yield of diagnostic findings, presumably because of the geographic nature of the granulomatous inflammation. Bronchoscopy may also be used as needed for palliative measures for narrowed airways (ie, stents).
The diagnosis of GPA is generally confirmed with tissue biopsy from a site of active disease, and renal and lung biopsies are most specific for GPA. However, sampling error may occur, and histopathologic findings can be nonspecific. Tissue diagnosis may not be required if the clinical gestalt is convincing and a site for biopsy is not apparent or would be too invasive to obtain. For example, the finding of leukocytoclastic vasculitis in the setting of pulmonary nodules and PR3-ANCA may be sufficient for the diagnosis.
Renal biopsy may be easier to perform than lung biopsy and has a greater diagnostic yield. The typical renal lesion of GPA is segmental crescentic necrotizing glomerulonephritis with little or no immunoglobulin or complement deposition (pauci-immune). Generally, vasculitis is not observed, but this histology helps in establishing the diagnosis. Renal biopsy findings cannot be used to distinguish between GPA and microscopic polyarteritis. (See the image below.)
Although findings on a renal biopsy are often negative for the presence of granulomas in GPA, renal biopsy is nonetheless a very useful diagnostic tool, especially in the setting of pulmonary-renal syndrome.
Importantly, renal biopsy with indirect immunofluorescent staining allows exclusion of anti–glomerular basement membrane (GBM) antibody disease in the setting of a pulmonary renal syndrome. Because of the importance of treating anti-GBM with plasma exchange, this therapy is often started empirically and continued until this disease can be ruled out.
Lung biopsy is performed in the absence of renal involvement by either open or thoracoscopic lung biopsy. Biopsy may reveal the entire histologic spectrum of GPA to include vasculitis and granulomatous inflammation. Chronic infections should be excluded.
In the setting of pulmonary hemorrhage, pulmonary biopsy is much more risky. If the cause of a new infiltrate is unclear, bronchoscopy can be used to confirm the presence of blood. Lavage fluid is bloody and contains hemosiderin-laden macrophages. Stains and cultures should be obtained to rule out infection.
Upper respiratory tract tissue biopsies (nose, sinuses, subglottic region) are frequently nondiagnostic, yielding only nonspecific acute and chronic inflammation in up to 50% of biopsy samples. Upper respiratory tract biopsies demonstrate the full pathologic triad of granulomatous inflammation, vasculitis, and necrosis in only about 15% of cases. However, in the correct clinical context, finding only parts of this triad in an upper respiratory tract biopsy may support the diagnosis of GPA.
Peripheral nerve biopsy can be considered if signs or symptoms such as paresthesias or mononeuritis multiplex are present.
A retrospective study suggested that even in the absence of myalgias or creatine kinase elevation, a muscle biopsy can aid in the diagnosis of systemic vasculitides because biopsy findings can reveal necrotizing or nonnecrotizing vasculitis. A prospective study found that muscle biopsy is a safe method for diagnosing small- or medium-vessel vasculitis, with a sensitivity of 57% overall, and sensitivity of 75% in patients presenting with peripheral neuropathy.
Histologic examination of lung samples may reveal the classic triad of parenchymal necrosis, vasculitis, and granulomatous inflammation characterized by an inflammatory infiltrate composed of neutrophils, lymphocytes, plasma cells, histiocytes, and eosinophils. (See the images below.)
Pulmonary vasculitis may affect arteries, veins, and capillaries, is pauci-immune, and can be granulomatous or nongranulomatous. Vasculitis causes vessel wall necrosis with infiltration by neutrophils, which degenerate and become surrounded by palisading histiocytes and multinucleated giant cells. The neutrophilic debris coalesces into irregularly bordered microabscesses, which can become extensive areas of "geographic" necrosis.
Segmental pauci-immune crescentic necrotizing glomerulonephritis is typically seen. The earliest histologic abnormalities include thrombotic changes in the glomerular capillary loops. The finding of granulomatous inflammation in renal biopsy samples is unusual. Generally, vasculitis is not observed in renal biopsy specimens. (See the image below.)
Leukocytoclastic vasculitis is most commonly reported.
Fauci AS, Haynes BS, Katz P, Wolff SM. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. January 1983. 98(1):76-85. [Medline].
Manganelli P, Fietta P, Carotti M, Pesci A, Salaffi F. Respiratory system involvement in systemic vasculitis. Clin Exp Rheumatol. March-April 2006. 24:S48-S59. [Medline].
Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992 Mar 15. 116(6):488-98. [Medline].
Holle JU, Gross WL. Neurological involvement in Wegener's granulomatosis. Curr Opin Rheumatol. 2011 Jan. 23(1):7-11. [Medline].
Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. March 2009. 68:310-317. [Medline].
Jayne D, Rasmussen N, Andrassey K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic antibodies. N Engl J Med. July 2003. 349(1):36-44. [Medline].
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). July 2007. 46(7):1087-1091. [Medline].
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. [Medline].
Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum. August 1990. 33(8):1101-1107. [Medline].
Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Limited versus severe Wegener's granulomatosis: baseline patient data on patients in the Wegener's granulomatosis etanercept trial. Arthritis Rheum. August 2003. 48(8):2299-2309. [Medline].
Finkielman JD, Lee AS, Hummel AM, et al. ANCA are detectable in nearly all patients with active severe Wegener's Granulomatosis. Am J Med. July 2007. 120:643.e9-14. [Medline].
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. September 2000. 43(9):2025-33. [Medline].
Finkielman JD, Merkel PA, Schroeder D, et al. Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann Intern Med. November 2007. 147(9):611-9. [Medline].
Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's Granulomatosis. N Engl J Med. 2005 Jan 27. 352(4):351-61. [Medline].
Schlieben DJ, Korbet SM, Kimura RE, Schwartz MM, Lewis EJ. Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs. Am J Kidney Dis. 2005 Apr. 45(4):758-61. [Medline].
Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CG. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med. January 1994. 120(1):12-17. [Medline].
Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15. 363(3):221-32. [Medline].
Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. July 2010. 363(3):211-20. [Medline].
Kallenberg CGM. Pathogenesis of PR3-ANCA associated vasculitis. J Autoimmun. February-March 2008. 30:29-36. [Medline].
Falk RJ, Terrell RS, Charles LA, Jennett C. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils todegranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci USA. June 1990. 87:4115-4119.
Kallenberg CGM. Pathophysiology of ANCA-associated small vessel vasculitis. Curr Rheumatol Rep. December 2010. 12(6):399-405. [Medline].
Xiao H, Heeringa P, Liu Z, et al. The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. Am J Pathol. July 2005. 167(1):39-45. [Medline].
Kallenberg CGM, Heeringa P, Stegeman CA. Mechanisms of disease: pathogenesis and treatment of ANCA-associated vasculitis. Nat Clin Pract Rheumatol. December 2006. 2:661-670. [Medline].
Moosig F, Lamprecht P, Gross WL. Wegener's Granulomatosis: the current view. Clin Rev Allergy Immunol. October 2008. 35(1-2):19-21. [Medline].
Spagnolo P, Richeldi L, DuBois RM. Environmental triggers and susceptibility factors in idiopathic granulomatous diseases. Semin Respir Crit Care Med. December 2008. 29:610-619. [Medline].
Carr EJ, Niederer HA, Williams J, et al. Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis. BMC Med Genet. December 2009. 10:121. [Medline].
Jagiello P, Aries P, Arning L, et al. The PTPN22 620W allele is a risk factor for Wegener's granulomatosis. Arthritis Rheum. December 2005. 52(12):4039-43. [Medline].
Heckmann M, Holle JU, Arning L, et al. The Wegener's granulomatosis quantitative trait locus on chromosome 6p21.3 as characterised by tagSNP genotyping. Ann Rheum Dis. July 2008. 67(7):972-9. [Medline].
Pendergraft WF 3rd, Preston GA, Shah RR, et al. Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3. Nat Med. January 2004. 10(1):72-9. [Medline].
Kain R, Exner M, Brandes R, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med. October 2008. 14(10):1088-96. [Medline].
Hogan SL, Cooper GS, Savitz DA, et al. Association of silica exposure with anti-neutrophil cytoplasmic autoantibody small-vessel vasculitis: a population-based, case-control study. Clin J Am Soc Nephrol. March 2007. 2(2):290-9. [Medline].
Watts RA, Lane SE, Koldingsnes W, et al. Epidemiology of vasculitis in Europe. Ann Rheum Dis. December 2001. 60(12):1156-7. [Medline].
Lane SE, Watts R, Scott DGI. Epidemiology of systemic vasculitis. Curr Rheumatol Rep. August 2005. 7:270-275. [Medline].
Mukhtyar C, Flossmann O, Hellmich B, et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis. July 2008. 67:1004-1010. [Medline].
Haroun MK, Stone JH, Nair R, Racusen L, Hellmann DB, Eustace JA. Correlation of percentage of normal glomeruli with renal outcome in Wegener's granulomatosis. Am J Nephrol. September-December 2002. 22(5-6):497-503. [Medline].
Hauer HA, Bajema IM, Van Houwelingen HC, et al. Determinants of outcome in ANCA-associated glomerulonephritis: a prospective clinico-histopathological analysis of 96 patients. Kidney Int. November 2002. 62(5):1732-1742. [Medline].
Renaudineau Y, Le Meur Y. Renal involvement in Wegener's Granulomatosis. Clinic Rev Allerg Immunol. October 2008. 35:22-29. [Medline].
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 Aug. 62(8):1166-73. [Medline].
Phillip R, Luqmani R. Mortality in systemic vasculitis: a systematic review. Clin Exp Rheumatol. September-October 2008. 26:S94-S104. [Medline].
Seo P, Min Y-I, 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. July 2005. 52:2168-2178. [Medline].
Le Guenno G, Mahr A, Pagnoux C, Dhote R, Guillevin L. Incidence and predictors of urotoxic adverse events in cyclophosphamide-treated patients with systemic necrotizing vasculitides. Arthritis Rheum. 2011 Feb 17. [Medline].
Heijl C, Harper L, Flossmann O, et al. Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials. Ann Rheum Dis. August 2011. 70(8):1415-1421. [Medline].
Suppiah R, Judge A, Batra R, et al. A model to predict cardiovascular events in patients with newly diagnosed wegener's granulomatosis and microscopic polyangiitis. Arthritis Care Res (Hoboken). 2011 Jan 14. [Medline].
Little MA, Nightingale P, Verburgh CA, et al. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann Rheum Dis. June 2010. 69(6):1036-43. [Medline].
Florian A, Slavich M, Blockmans D, Dymarkowski S, Bogaert J. Cardiac involvement in granulomatosis with polyangiitis (Wegener granulomatosis). Circulation. 2011 Sep 27. 124 (13):e342-4. [Medline].
McGeoch L, Carette S, Cuthbertson D, Hoffman GS, Khalidi N, Koening CL, et al. Cardiac Involvement in Granulomatosis with Polyangiitis. J Rheumatol. 2015 Jul. 42 (7):1209-12. [Medline].
Hazebroek MR, Kemna MJ, Schalla S, Sanders-van Wijk S, Gerretsen SC, Dennert R, et al. Prevalence and prognostic relevance of cardiac involvement in ANCA-associated vasculitis: Eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis. Int J Cardiol. 2015 Nov 15. 199:170-9. [Medline].
Al-Hakeem DA, Fedele S, Carlos R, Porter S. Extranodal NK/T-cell lymphoma, nasal type. Oral Oncol. January 2007. 43(1):4-14. [Medline].
Frankel SK, Cosgrove GP, Fischer A. Update in the diagnosis and management of pulmonary vasculitis. Chest. February 2006. 129(2):452-65. [Medline].
Rottem M, Fauci AS, Hallahan CW, Kerr GS, Lebovics R, Leavitt RY, et al. Wegener granulomatosis in children and adolescents: clinical presentation and outcome. J Pediatr. 1993 Jan. 122(1):26-31. [Medline].
Polychronopoulos VS, Prakash UBS, Golbin JM, Edell ES, Specks U. Airway involvement in Wegener's Granulomatosis. Rheum Dis Clin N Am. November 2007. 33:755-775. [Medline].
Hervier B, Durant C, Masseau A, Ponge T, Hamidou M, Mussini JM. Use of muscle biopsies for diagnosis of systemic vasculitides. J Rheumatol. 2011 Mar. 38(3):470-4. [Medline].
Nunokawa T, Yokogawa N, Shimada K, Enatsu K, Sugii S. The use of muscle biopsy in the diagnosis of systemic vasculitis affecting small to medium-sized vessels: a prospective evaluation in Japan. Scand J Rheumatol. 2015 Oct 8. 1-5. [Medline].
DeGroot K, Harper L, Jayne DRW, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. May 2009. 150:670-680. [Medline].
Monach PA, Arnold LM, Merkel PA. Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review. Arthritis Rheum. 2010 Jan. 62(1):9-21. [Medline].
Clowse ME, Copland SC, Hsieh TC, Chow SC, Hoffman GS, Merkel PA, et al. Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's). Arthritis Care Res (Hoboken). 2011 Dec. 63(12):1777-81. [Medline].
Langford CA. Cyclophosphamide as induction therapy for Wegener's granulomatosis and microscopic polyangiitis. Clin Exp Immunol. May 2011. 164 (Suppl 1):31-4. [Medline].
Garcia-Valladares I, Espinoza LR. Is rituximab superior to cyclophosphamide for ANCA-associated vasculitis for induction of remission, and with a better safety profile?. Curr Rheumatol Rep. December 2010. 12(6):395-8. [Medline].
Aries PM, Hellmich B, Voswinkel J, et al. Lack of efficacy of rituximab in Wegener's granulomatosis with refractory granulomatous manifestations. Ann Rheum Dis. July 2006. 65(7):853-858. [Medline].
Seo P, Specks U, Keogh KA. Efficacy of rituximab in limited Wegener's granulomatosis with refractory granulomatous manifestations. J Rheumatol. October 2008. 35(10):2017-2023. [Medline].
Gottenberg JE, Ravaud P, Bardin T, et al. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum. 2010 Sep. 62(9):2625-32. [Medline].
Jones RB, Ferraro AJ, Chaudhry AN, et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009 Jul. 60(7):2156-68. [Medline].
Tesfa D, Ajeganova S, Hägglund H, et al. Late-onset neutropenia following rituximab therapy in rheumatic diseases: Association with B lymphocyte depletion and infections. Arthritis Rheum. August 2011. 63(8):2209-2214. [Medline].
McGregor JG, Hogan SL, Hu Y, Jennette CE, Falk RJ, Nachman PH. Glucocorticoids and relapse and infection rates in anti-neutrophil cytoplasmic antibody disease. Clin J Am Soc Nephrol. 2012 Feb. 7(2):240-7. [Medline]. [Full Text].
Klemmer PJ, Chalermskulrat W, Reif MS, Hogan SL, Henke DC, Falk RJ. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis. December 2003. 42(6):1149-1153. [Medline].
Pusey CD, Rees AJ, Evans DJ, Peters DK, Lockwood CM. Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies. Kidney Int. October 1991. 40(4):757-763. [Medline].
Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. July 2007. 18(7):2180-2188. [Medline].
Casian A, Jayne D. Plasma exchange in the treatment of Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal limited vasculitis. Curr Opin Rheumatol. 2011 Jan. 23(1):12-7. [Medline].
DeGroot 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. August 2005. 52:2461-2469. [Medline].
Rhee EP, Laliberte KA, Niles JL. Rituximab as maintenance therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis. Clin J Am Soc Nephrol. 2010 Aug. 5(8):1394-400. [Medline]. [Full Text].
Sanders JS, Slot MC, Stegeman CA. Maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. November 2003. 349(21):2072-2073. [Medline].
Slot MC, Tervaert JW, Boomsma MM, Stegeman CA. Positive classic antineutrophil cytoplasmic antibody (C-ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3-related vasculitis. Arthritis Rheum. April 2004. 51(2):269-273. [Medline].
Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. December 2008. 359:2790-2803. [Medline].
Puéchal X, Pagnoux C, Perrodeau É, Hamidou M, Boffa JJ, et al. Long-term outcomes of the WEGENT trial on remission-maintenance for granulomatosis with polyangiitis or microscopic polyangiitis. Arthritis Rheumatol. 2015 Oct 16. [Medline].
Reinhold-Keller E, Fink CO, Herlyn K, Gross WL, De Groot K. High rate of renal relapse in 71 patients with Wegener's granulomatosis under maintenance of remission with low-dose methotrexate. Arthritis Rheum. June 2002. 47(3):326-32. [Medline].
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. April 2003. 114(6):463-9. [Medline].
Langford CA, Talar-Williams C, Barron KS, Sneller MC. A staged approach to the treatment of Wegener's granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance. Arthritis Rheum. December 1999. 42(12):2666-73. [Medline].
Sneller MC, Hoffman GS, Talar-Williams C, Kerr GS, Hallahan CW, Fauci AS. An analysis of forty-two Wegener's granulomatosis patients treated with methotrexate and prednisone. Arthritis Rheum. May 1995. 38(5):608-13. [Medline].
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 Jul 4. 335(1):16-20. [Medline].
Bosch X, Guilabert A, Espinosa G, Mirapeix E. Treatment of antineutrophil cytoplasmic antibody-associated vasculitis: a systematic review. JAMA. August 2007. 298:655-669. [Medline].
Martinez V, Cohen P, Pagnoux C, et al. Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patients. Arthritis Rheum. January 2008. 58(1):308-371. [Medline].
Silva F, Specks U, Kalra S, et al. Mycophenolate mofetil for induction and maintenance of remission in microscopic polyangiitis with mild to moderate renal involvement--a prospective, open-label pilot trial. Clin J Am Soc Nephrol. March 2010. 5(3):445-53. [Medline].
Joy MS, Hogan SL, Jennette JC, Falk RJ, Nachman PH. A pilot study using mycophenolate mofetil in relapsing or resistant ANCA small vessel vasculitis. Nephrol Dial Transplant. December 2005. 20(12):2725-2732. [Medline].
Koukoulaki M, Jayne DR. Mycophenolate mofetil in anti-neutrophil cytoplasm antibodies-associated systemic vasculitis. Nephron Clin Pract. 2006. 102(3-4):c100-7. [Medline].
Nowack R, Göbel U, Klooker P, Hergesell O, Andrassy K, van der Woude FJ. Mycophenolate mofetil for maintenance therapy of Wegener's granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement. J Am Soc Nephrol. 1999 Sep. 10(9):1965-71. [Medline].
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. December 2010. 304(21):2381-2388. [Medline].
Stone JH, Uhlfelder ML, Hellmann DB, Crook S, Bedocs NM, Hoffman GS. Etanercept combined with conventional treatment in Wegener's granulomatosis: a six-month open-label trial to evaluate safety. Arthritis Rheum. May 2001. 44(5):1149-1154. [Medline].
Booth A, Harper L, Hammad T, Bacon P, Griffith M, Levy J, et al. Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol. 2004 Mar. 15(3):717-21. [Medline].
Lee RW, D'Cruz DP. Novel therapies for anti-neutrophil cytoplasmic antibody-associated vasculitis. Drugs. 2008. 68:747-770. [Medline].
Sangle SR, Hughes GR, D'Cruz DP. Infliximab in patients with systemic vasculitis that is difficult to treat: poor outcome and significant adverse effects. Ann Rheum Dis. April 2007. 66(4):564-565. [Medline].
Hinze CH, Colbert RA. B-cell depletion in Wegener's Granulomatosis. Clin Rev Allergy Immunol. June 2008. 34:372-379. [Medline].
Schmitt WH, Birck R, Heinzel PA, et al. Prolonged treatment of refractory Wegener's granulomatosis with 15-deoxyspergualin: an open study in seven patients. Nephrol Dial Transplant. June 2005. 20(6):1083-1092. [Medline].
Birck R, Warnatz K, Lorenz HM, et al. 15-Deoxyspergualin in patients with refractory ANCA-associated systemic vasculitis: a six-month open-label trial to evaluate safety and efficacy. J Am Soc Nephrol. February 2003. 14(2):440-7. [Medline].
Schmitt WH, Hagen EC, Neumann I, et al. Treatment of refractory Wegener's granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients. Kidney Int. April 2004. 65(4):1440-1448. [Medline].
Walsh M, Chaudhry A, Jayne D. Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H). Ann Rheum Dis. September 2008. 67(9):1322-1327. [Medline].
Reynolds J, Tam FW, Chandraker A, et al. CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis. J Clin Invest. March 2000. 105(5):643-51. [Medline].
Girard C, Charles P, Terrier B, Bussonne G, Cohen P, Pagnoux C, et al. Tracheobronchial Stenoses in Granulomatosis With Polyangiitis (Wegener's): A Report on 26 Cases. Medicine (Baltimore). 2015 Aug. 94 (32):e1088. [Medline].
Hoffman GS, Thomas-Golbanov CK, Chan J, Akst LM, Eliachar I. Treatment of subglottic stenosis, due to Wegener's granulomatosis, with intralesional corticosteroids and dilation. J Rheumatol. May 2003. 30(5):1017-21. [Medline].
Langford CA, Sneller MC, Hallahan CW, et al. Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis. Arthritis Rheum. October 1996. 39(10):1754-60. [Medline].
Martinez Del Pero M, Jayne D, Chaudhry A, Sivasothy P, Jani P. Long-term outcome of airway stenosis in granulomatosis with polyangiitis (Wegener granulomatosis): an observational study. JAMA Otolaryngol Head Neck Surg. 2014 Nov. 140 (11):1038-44. [Medline].
Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013 Aug 1. 369(5):417-27. [Medline].