Granulomatosis with Polyangiitis (Wegener Granulomatosis) Clinical Presentation: History, Physical Examination

History

Clinician awareness is important to prevent delayed or missed diagnosis. Recurrent respiratory infection in an adult may be an indicator of granulomatosis with polyangiitis (GPA). However, the clinician must remain mindful that GPA has a spectrum of clinical presentations.

Patients may report the following chronic, nonspecific constitutional complaints:

• Fevers, night sweats
• Fatigue, lethargy
• Loss of appetite
• Weight loss

Ophthalmic signs

Ocular involvement occurs in many patients, including the following:

• Conjunctivitis
• Episcleritis
• Uveitis
• Optic nerve vasculitis
• Retinal artery occlusion
• Nasolacrimal duct occlusion
• Proptosis

Ear, nose, and throat manifestations

The symptoms causing pediatric patients to seek medical care are usually attributable to the upper and lower respiratory tract.

Chronic sinusitis is the most common initial complaint (67%); failure to respond to conventional treatment is suggestive. Rhinitis and epistaxis occur in 22% and 11% of patients with GPA, respectively.

The development of a saddle nose deformity caused by collapse of nasal support is common. Serous otitis media and hearing loss are the presenting manifestations of GPA in some patients. Tracheal or subglottic granulomatous masses can cause stridor and lead to respiratory compromise.

Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis). Large ulceration of the pharynx covered with a dense necrotic membrane.

Pulmonary manifestations

Pulmonary involvement can be asymptomatic, insidious in onset, or severe and fulminant. Pulmonary disease may cause any of the following:

• Pulmonary infiltrates (71% of patients)
• Cough (34%)
• Hemoptysis (18%)
• Chest discomfort (8%)
• Dyspnea (7%)
• Diffuse alveolar hemorrhage (DAH) due to alveolar capillaritis (5%-45% )

Musculoskeletal symptoms

Musculoskeletal symptoms are common. Arthralgias are usually polyarticular and symmetric, affecting small and large joints. Arthritis can also occur, and typically affects large joints, but is rarely deforming.

Renal involvement

Renal disease is present in 17% of patients at initial diagnosis and is usually asymptomatic.Renal failure occurs in 11% at presentation.Renal disease manifests as crescentic necrotizing glomerulonephritis characterized by urinary sediment with more than 5 red blood cells per high-power field or erythrocyte casts.

Nervous system involvement

The nervous system is affected in numerous patients. Peripheral nervous system (PNS) involvement may occur in as many as 67% of patients, typically later in the disease course. PNS manifestations include mononeuritis multiplex, sensorimotor polyneuropathy, and cranial nerve palsies. Central nervous system (CNS) manifestations include vasculitis of small to medium–sized vessels of the brain or spinal cord and granulomatous masses that involve the orbit, optic nerve, meninges or brain.

Cutaneous signs

The skin is involved in 45% of patients with GPA due to vasculitis. Cutaneous involvement can lead to palpable purpura or skin ulcers.

Necrotic, purpuric, and blistering plaque on the wrist in a patient with granulomatosis with polyangiitis.

Cardiac involvement

Cardiac involvement most often consists of pericarditis or coronary vasculitis, but myocarditis, endocarditis, conduction system granulomata, and valvular involvement may also occur.Necrotizing vasculitis of the coronary vessels can result in myocardial infarction or sudden death.

Estimates of the frequency of cardiac involvement vary widely, with a North American study reporting a rate of 33.3% and no association with a higher rate of relapse or premature death,while a European study reported cardiac involvement in 46% of GPA patients assessed with electrocardiography and echocardiography, along with increased all-cause and cardiovascular mortality.

Physical Examination

Signs related to the head, ears, eyes, nose, and throat

Sinusitis and disease in the nasal mucosa are the most common findings. Ocular findings include scleritis, episcleritis, keratitis, uveitis, and conjunctivitis. Proptosis may signal a retrobulbar granulomatous mass. Xanthelasma has also been reported.

Otitis media and/or hearing loss may be present. Purulent or serosanguinous nasal discharge may be seen. Saddle nose deformity may be present. (See image below.)

Saddle nose deformity in a 26-year-old man with granulomatosis with polyangiitis. Image courtesy of P. Papadopoulos, MD.

Oral involvement is rare; however, a classic presentation includes "strawberry gingival hyperplasia."

Pulmonary/respiratory signs/symptoms

Pulmonary/respiratory symptoms can include the following:

• Atelectasis - May be present, with examination findings of dullness on percussion, decreased breath sounds, and crackles on auscultation
• Lower respiratory tract involvement - May also produce signs of pulmonary consolidation and/or pleural effusion
• Tracheobronchial disease - May manifest as hoarseness, cough, dyspnea, stridor, and wheezing
• Subglottic or tracheal stenosis – May also manifest as stridor; stenosis may prove fatal if untreated
• Hemoptysis - may result from cavitated pulmonary parenchymal lesions, DAH, or bronchiectasis

Cutaneous findings

Cutaneous findings are variable and nonspecific and usually affect the lower extremities. Palpable purpura, papules, subcutaneous nodules, and ulcerations are the most common findings. Ulcerations may resemble pyoderma gangrenosum.

Petechiae, vesicles, pustules, hemorrhagic bullae, livedo reticularis, digital necrosis, subungual splinter hemorrhages, and genital ulcers resembling squamous cell carcinoma have been reported.

Several necrotic, purpuric, and blistering papules and plaques on the hands in a patient with granulomatosis with polyangiitis.

Additional findings

Other symptoms may include the following:

• General - Patients may be febrile and appear ill
• Cardiac - Pericardial rub may occur with pericarditis
• Gastrointestinal - Abdominal pain may be present with splanchnic vasculitis
• Musculoskeletal - Large- and medium-joint arthritis; polyarticular, symmetrical small- and medium-joint arthralgias; and myalgias may be appreciated
• Neurologic - Examination of the nervous system may confirm a pattern of mononeuritis multiplex, polyneuropathy, or cranial nerve paralysis

Differential Diagnoses



Christopher L Tracy, MD Associate Program Director, Rheumatology Fellowship Program, Walter Reed National Military Medical Center

Christopher L Tracy, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Medical Association

Coauthor(s)

Patricia J Papadopoulos, MD Staff Rheumatologist, MultiCare Rheumatology Specialists

Patricia J Papadopoulos, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American College of Rheumatology

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Acknowledgements

Michael R Bye, MD Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia University College of Physicians and Surgeons; Attending Physician, Pediatric Pulmonary Medicine, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center

Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Heidi Connolly, MD Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center

Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Robert John O'Brian, MD Staff Rheumatologist, National Naval Medical Center

Robert John O'Brian, MD is a member of the following medical societies: American College of Rheumatology

Girish D Sharma, MD Associate Professor of Pediatrics, Rush Medical College; Director, Section of Pediatric Pulmonology and Rush Cystic Fibrosis Center, Rush University Medical Center

Girish D Sharma, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Royal College of Physicians of Ireland

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Debbie S Toder, MD Director of Cystic Fibrosis Center, Department of Pediatrics, Division of Pulmonary Medicine, Assistant Professor, Wayne State University and Children's Hospital of Michigan

Debbie S Toder, MD is a member of the following medical societies: American Academy of Pediatrics and American Thoracic Society

Disclosure: Nothing to disclose.

Rudolph P Valentini, MD Director of Dialysis Services, Associate Professor, Department of Pediatrics, Division of Pediatric Nephrology, Wayne State University; Vice Chief of Staff, Children's Hospital of Michigan

Rudolph P Valentini, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Robert E Wolf, MD, PhD Professor Emeritus, Department of Medicine, Louisiana State University Health Sciences Center at Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Administration Medical Center of Shreveport

Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, and Society for Leukocyte Biology

Disclosure: Nothing to disclose.

Acknowledgments

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the US Government. Additionally, this publication does not imply the Federal or Department of Defense endorsement of any product.

References

1. 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].
2. 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].
3. 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].
4. Holle JU, Gross WL. Neurological involvement in Wegener's granulomatosis. Curr Opin Rheumatol. 2011 Jan. 23(1):7-11. [Medline].
5. 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].
6. 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].
7. 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].
8. 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].
9. 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].
10. 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].
11. 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].
12. 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].
13. 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].
14. 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].
15. 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].
16. 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].
17. 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].
18. 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].
19. Kallenberg CGM. Pathogenesis of PR3-ANCA associated vasculitis. J Autoimmun. February-March 2008. 30:29-36. [Medline].
20. 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.
21. Kallenberg CGM. Pathophysiology of ANCA-associated small vessel vasculitis. Curr Rheumatol Rep. December 2010. 12(6):399-405. [Medline].
22. 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].
23. 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].
24. Moosig F, Lamprecht P, Gross WL. Wegener's Granulomatosis: the current view. Clin Rev Allergy Immunol. October 2008. 35(1-2):19-21. [Medline].
25. 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].
26. 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].
27. 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].
28. 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].
29. 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].
30. 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].
31. 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].
32. Watts RA, Lane SE, Koldingsnes W, et al. Epidemiology of vasculitis in Europe. Ann Rheum Dis. December 2001. 60(12):1156-7. [Medline].
33. Lane SE, Watts R, Scott DGI. Epidemiology of systemic vasculitis. Curr Rheumatol Rep. August 2005. 7:270-275. [Medline].
34. 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].
35. 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].
36. 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].
37. Renaudineau Y, Le Meur Y. Renal involvement in Wegener's Granulomatosis. Clinic Rev Allerg Immunol. October 2008. 35:22-29. [Medline].
38. 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].
39. Phillip R, Luqmani R. Mortality in systemic vasculitis: a systematic review. Clin Exp Rheumatol. September-October 2008. 26:S94-S104. [Medline].
40. 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].
41. 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].
42. 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].
43. 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].
44. 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].
45. 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].
46. 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].
47. 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].
48. 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].
49. Frankel SK, Cosgrove GP, Fischer A. Update in the diagnosis and management of pulmonary vasculitis. Chest. February 2006. 129(2):452-65. [Medline].
50. 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].
51. 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].
52. 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].
53. 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].
54. 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].
55. 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].
56. 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].
57. Langford CA. Cyclophosphamide as induction therapy for Wegener's granulomatosis and microscopic polyangiitis. Clin Exp Immunol. May 2011. 164 (Suppl 1):31-4. [Medline].
58. 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].
59. 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].
60. 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].
61. 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].
62. 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].
63. 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].
64. 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].
65. 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].
66. 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].
67. 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].
68. 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].
69. 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].
70. 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].
71. 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].
72. 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].
73. 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].
74. 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].
75. 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].
76. 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].
77. 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].
78. 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].
79. Guillevin L, et al; French Vasculitis Study Group. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov 6. 371 (19):1771-80. [Medline]. [Full Text].
80. 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].
81. 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].
82. 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].
83. 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].
84. 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].
85. Koukoulaki M, Jayne DR. Mycophenolate mofetil in anti-neutrophil cytoplasm antibodies-associated systemic vasculitis. Nephron Clin Pract. 2006. 102(3-4):c100-7. [Medline].
86. 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].
87. 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].
88. 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].
89. 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].
90. Lee RW, D'Cruz DP. Novel therapies for anti-neutrophil cytoplasmic antibody-associated vasculitis. Drugs. 2008. 68:747-770. [Medline].
91. 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].
92. Hinze CH, Colbert RA. B-cell depletion in Wegener's Granulomatosis. Clin Rev Allergy Immunol. June 2008. 34:372-379. [Medline].
93. 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].
94. 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].
95. 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].
96. 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].
97. 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].
98. 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].
99. 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].
100. 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].
101. 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].
102. 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].

Saddle nose deformity in a 26-year-old man with granulomatosis with polyangiitis. Image courtesy of P. Papadopoulos, MD.

Necrotic, purpuric, and blistering plaque on the wrist in a patient with granulomatosis with polyangiitis.

Several necrotic, purpuric, and blistering papules and plaques on the hands in a patient with granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis). Large ulceration of the pharynx covered with a dense necrotic membrane.

Extensive thickening of the maxillary sinuses in a patient with granulomatosis with polyangiitis. The patient also had intermittent epistaxis.

Granulomatosis with polyangiitis. Bilateral nodules observed on a plain chest radiograph in a patient with hemoptysis and hematuria. Image courtesy of G. Eschun, MD.

This 42-year-old man presented with hemoptysis, weight loss, and night sweats. He was diagnosed with the limited form of granulomatosis with polyangiitis.

Bilateral cavitating nodules in a patient with granulomatosis with polyangiitis.

Granulomatosis with polyangiitis. This patient presented with massive hemoptysis. No nodules are identified on the chest radiograph, although a subsequent CT scan showed several noncavitating nodules.

Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. Image courtesy of the US Government.

Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. Image courtesy of the US Government.

Shown is a chest radiograph of an 11-year-old girl who presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month, followed by an abrupt presentation with pallor, hemoptysis, and hypertension. Her bilateral fluffy infiltrates are suggestive of a pulmonary hemorrhage. She had an antineutrophil cytoplasmic autoantibody (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis associated with her pulmonary hemorrhage. Supportive therapy consisted of mechanical ventilation and hemodialysis along with immunosuppressive therapy. Her anti–glomerular basement membrane antibody test result was negative. Nearly 2 years later, she had a serum creatinine of 0.7mg/dL and no residual pulmonary disease.

An 11-year-old girl presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. She had an antineutrophil cytoplasmic autoantibody (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis associated with her pulmonary hemorrhage. A follow-up chest radiograph obtained several days later shows a complete resolution of her pulmonary infiltrates. This rapid resolution is more consistent with hemorrhage than with pneumonia.

A renal biopsy specimen from a 13-year-old girl with antineutrophil cytoplasmic antibody (C-ANCA)–positive pulmonary renal syndrome. Seven weeks after presenting with sinusitis, she presented with an acute abdomen, pulmonary hemorrhage, and acute renal failure (creatinine 4.9mg/dL). This biopsy specimen shows a necrotizing and crescentic glomerulonephritis (Silver stain).

Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.

Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.

Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of granulomatosis with polyangiitis.

C-ANCA immunofluorescence pattern. Staining for antineutrophil cytoplasmic antibody by indirect immunofluorescence shows heavy cytoplasmic staining, whereas nuclei are nonreactive. Image courtesy of K. Orr, MD.

P-ANCA immunofluorescence pattern. Perinuclear antineutrophil cytoplasmic antibody staining pattern by indirect immunofluorescence shows perinuclear staining, whereas cytoplasm is nonreactive. Image courtesy of K. Orr, MD.

Goodpasture syndrome: Linear deposition of immunoglobulin G and C3 are observed on a renal biopsy specimen from a patient with Goodpasture syndrome. Immunofluorescence staining. Image courtesy of K. Orr, MD.