eMedicine Specialties > Rheumatology > Vasculitis

Wegener Granulomatosis

Author: Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St. Boniface General Hospital
Contributor Information and Disclosures

Updated: May 26, 2006

Introduction

Background

Wegener granulomatosis (WG) is a systemic vasculitis of the medium and small arteries, venules, arterioles, and, occasionally, large arteries. Initially reported by Klinger in 1931, the condition was later described in more detail by Wegener. In 1954, Goodman and Churg provided the definitive description of WG with their identification of a triad of pathological features, including (1) systemic necrotizing angiitis, (2) necrotizing granulomatous inflammation of the respiratory tract, and (3) necrotizing glomerulonephritis. The largest reported experience with WG is that of Fauci and colleagues at the US National Institutes of Health.

In its classic presentation, WG is a form of systemic vasculitis that primarily involves the upper and lower respiratory tracts and the kidneys. A limited form of WG has clinical findings isolated to the upper respiratory tract and the lungs, although 80% of patients subsequently develop renal involvement.

Pathophysiology

In his publication, Wegener emphasized the vasculitic aspect over the granulomatous character of the disease. However, the earliest lesion of this disorder is injury and necrosis of the vessels that evolves into a necrotizing and palisading granuloma without inflammation. The continuum from granuloma to vasculitis may be an important step in understanding the possible etiology and pathogenesis of WG. Cellular immune processes are likely important in granulomatous inflammation. However, the recent discovery of antibodies to cytoplasmic antigens within neutrophils (antineutrophilic cytoplasmic antibody [ANCA], designated C-ANCA for diffuse cytoplasmic staining and P-ANCA for perinuclear staining by immunofluorescence) in most patients with WG raises the possibility of humoral autoimmunity. This is even more likely with the demonstration of the expression of serine proteinase 3, the predominant antigen for C-ANCA, on the surface of activated endothelial cells.

Tissue injury in WG is a result of interaction between the inflammatory cascade and the pathogenic immune response to the neutrophil granule proteins. Animal studies and indirect evidence from humans indicate that ANCAs are directly involved in the widespread tissue damage characteristic of WG. These antibodies likely induce necrotizing vasculitis and endothelial injury via activation of primed neutrophils, binding of activated neutrophils to the vascular endothelium, degranulation, and release of chemoattractants and other mediators. Further research will advance understanding of the pathogenesis of WG; ANCA involvement is only one piece of a larger puzzle.

Most patients with either classic or limited WG present with upper airway or pulmonary involvement. Renal involvement is also common, manifesting as acute renal failure or acute nephritis, sometimes with nephrotic-range proteinuria. Patients may also present with a clinical picture of rapidly progressive glomerulonephritis. Other organs and systems that may become involved are the joints, eyes, skin, nervous system, heart, and, less commonly, the gastrointestinal tract, subglottis or trachea, lower genital urinary tract, parotid glands, thyroid gland, and liver. WG-related CNS involvement can manifest as chronic hypertrophic pachymeningitis, pituitary involvement, and cerebral vasculitis. CNS involvement may be present at disease onset or could develop several years after WG diagnosis.

Pathologically, the pulmonary features of WG are necrotizing granulomatous pulmonary inflammation and, occasionally, alveolar capillaritis. The former results in nodular densities and lung infiltrates, and the latter results in diffuse pulmonary hemorrhage. The glomerulonephritis is characterized by focal necrosis and crescent formation without immunoglobulin or complement deposition, also called pauci-immune glomerulonephritis. Note that more accurate terminology would be pauci-immune complex because, as described above, immune processes may be involved in the pathogenesis of WG.

Frequency

International

A population-based study reported a prevalence of 8.5 cases per million population in Norfolk, England.

Mortality/Morbidity

WG is associated with a very high (>90%) mortality rate if it remains untreated. With aggressive therapy, mortality rates improve.

  • A 1992 study by Hoffman et al noted a mortality rate of 13% at 8 years.
  • In a 1996 study, Matteson et al noted mortality rates of 28% at 5 years and 36% at 10 years.
  • A retrospective study by Booth et al from 2003 demonstrated a cumulative 5-year survival rate of 76% and a 1-year mortality rate of 18%.

Race

WG affects persons of all races.

Sex

WG has a slight male predominance.

Age

WG has been described in persons of all ages, from young children to elderly adults.

Clinical

History

Patients may present with a wide range of clinical manifestations, defined chiefly by the primary anatomic site of involvement.

Ears, nose, and throat or upper respiratory tract; lungs; and kidneys classification

The broad spectrum of organ involvement of WG has been described as ears, nose, and throat or upper respiratory tract (E); lungs (L); and kidneys (K); ie, the ELK, classification. This classification system suggests that within the spectrum of WG, patients may have involvement of any of the ELK sites singularly or in combination. Under the ELK system, any typical manifestation in E (ears, nose, and throat), L (lungs), or K (kidneys) associated with a typical histopathology or positive C-ANCA findings qualifies for the diagnosis of WG.

  • Ears, nose, and throat
    • The most common symptom is nasal obstruction with serosanguineous discharge. Symptoms of chronic sinusitis may be present.
    • Patients often report deep central facial pain.
    • Middle ear involvement may lead to hearing loss, and patients also may present with hoarseness and stridor because of subglottic stenosis.
  • Lungs
    • Patients may be asymptomatic or may present with cough and occasional hemoptysis.
    • Some patients develop progressive dyspnea and respiratory failure. Massive pulmonary hemorrhage is a rare feature.
  • Kidneys: Patients with kidney involvement generally are asymptomatic, but some patients may notice mild hematuria. Edema secondary to nephrotic syndrome may be present.
  • Nervous system
    • Neurologic involvement occurs in approximately one third of patients.
    • Some patients also develop symptoms of peripheral neuropathy with mononeuritis multiplex or cranial neuropathy involving the second, sixth, and seventh cranial nerves.
  • Skin: Approximately 14% of patients manifest skin involvement, with a purpuric rash over the lower extremities.
  • Eye and orbit: Eye and orbit complications occur in 29% of patients, who may present with red or swollen eyes.
  • Joints: Joint symptoms occur frequently in persons with WG. Usually patients have only arthralgias, but up to 25% of patients may have inflammatory joint involvement. The arthritis may be monoarticular, oligoarticular, or polyarticular with swelling and pain of the joints. The arthritis is not erosive or deforming.

Physical

  • Ear, nose, and throat
    • Destruction of the nasal cartilage may lead to saddle deformity of the nose and a central perforation of the nasal septum.
    • Middle ear involvement may lead to conductive hearing loss.
    • Nasal or oral ulceration and/or tenderness over the maxillary sinuses may be evident.
  • Lung
    • Patients may show signs of atelectasis, including dullness on percussion, decreased breath sounds, and crackles upon auscultation.
    • Lower respiratory tract involvement also may produce signs of pulmonary consolidation, pleural effusion, or both.
  • Nervous system: Examination of the nervous system confirms a pattern of mononeuritis multiplex and findings of cranial nerve paralysis.
  • Skin
    • Dermatological findings are palpable purpura, necrotizing ulcerations, papules, nodules, petechiae, and superficial erosions.
    • Palpable purpura, the most common finding, is pathologically a leukocytoclastic vasculitis and is usually associated with concomitant renal involvement.
  • Eye and orbit
    • Signs of conjunctivitis, episcleritis, and corneal ulceration may be present.
    • Proptosis may also be observed, which results from an inflammatory orbital mass (orbital pseudotumor).
  • Joints: Patients may report joint pain and have signs of monoarticular, oligoarticular, or polyarticular arthritis, which may be symmetric or asymmetric and may be migratory. Usually, no joint erosions or deformities occur.

More on Wegener Granulomatosis

Overview: Wegener Granulomatosis
Differential Diagnoses & Workup: Wegener Granulomatosis
Treatment & Medication: Wegener Granulomatosis
Follow-up: Wegener Granulomatosis
Multimedia: Wegener Granulomatosis
References
[ CLOSE WINDOW ]

References

  1. Aasarod K, Iversen BM, Hammerstrom J, et al. Wegener''s granulomatosis: clinical course in 108 patients with renal involvement. Nephrol Dial Transplant. May 2000;15(5):611-8. [Medline].

  2. Afeltra A, Sebastiani GD, Galeazzi M, et al. Antineutrophil cytoplasmic antibodies in synovial fluid and in serum of patients with rheumatoid arthritis and other types of synovitis. J Rheumatol. Jan 1996;23(1):10-5. [Medline].

  3. Allen A, Pusey C, Gaskin G. Outcome of renal replacement therapy in antineutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol. Jul 1998;9(7):1258-63. [Medline].

  4. Baranger TA, Audrain MA, Castagne A, et al. Absence of antineutrophil cytoplasmic antibodies in giant cell arteritis. J Rheumatol. May 1994;21(5):871-3. [Medline].

  5. Booth AD, Almond MK, Burns A. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis. Apr 2003;41(4):776-84. [Medline].

  6. Clarke AE, Bitton A, Eappen R, et al. Treatment of Wegener''s granulomatosis after renal transplantation: is cyclosporine the preferred treatment?. Transplantation. Dec 1990;50(6):1047-51. [Medline].

  7. Cordier JF, Valeyre D, Guillevin L, et al. Pulmonary Wegener''s granulomatosis. A clinical and imaging study of 77 cases. Chest. Apr 1990;97(4):906-12. [Medline].

  8. DeRemee RA. The treatment of Wegener''s granulomatosis. Clin Exp Immunol. Jul 1995;101 Suppl 1:23-6. [Medline].

  9. Duna GF, Galperin C, Hoffman GS. Wegener''s granulomatosis. Rheum Dis Clin North Am. Nov 1995;21(4):949-86. [Medline].

  10. Esnault VL, Ronda N, Jayne DR, Lockwood CM. Association of ANCA isotype and affinity with disease expression. J Autoimmun. Apr 1993;6(2):197-205. [Medline].

  11. Frankel SK, Cosgrove GP, Fischer A. Update in the diagnosis and management of pulmonary vasculitis. Chest. Feb 2006;129(2):452-65.

  12. Gross WL. New developments in the treatment of systemic vasculitis. Curr Opin Rheumatol. Jan 1994;6(1):11-9. [Medline].

  13. Guillevin L, Cordier JF, Lhote F, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener''s granulomatosis. Arthritis Rheum. Dec 1997;40(12):2187-98. [Medline].

  14. Habib A, MacKay K, Abrons HL. Wegener''s granulomatosis complicating pregnancy: presentation of two patients and review of the literature. Clin Nephrol. Nov 1996;46(5):332-6. [Medline].

  15. Hagen EC, Daha MR, Hermans J, et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int. Mar 1998;53(3):743-53. [Medline].

  16. Haubitz M, Koch KM, Brunkhorst R. Survival and vasculitis activity in patients with end-stage renal disease due to Wegener''s granulomatosis. Nephrol Dial Transplant. Jul 1998;13(7):1713-8. [Medline].

  17. Hellmich B, Lamprecht P, Gross WL. Advances in the therapy of Wegener''s granulomatosis. Curr Opin Rheumatol. Jan 2006;18(1):25-32.

  18. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. Mar 15 1992;116(6):488-98. [Medline].

  19. Hoffman GS, Specks U. Antineutrophil cytoplasmic antibodies. Arthritis Rheum. Sep 1998;41(9):1521-37. [Medline].

  20. Jayne D. Current attitudes to the therapy of vasculitis. Kidney Blood Press Res. 2003;26(4):231-9. [Medline].

  21. 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. Jul 3 2003;349(1):36-44. [Medline].

  22. Kallenberg CG, Brouwer E, Weening JJ, Tervaert JW. Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int. Jul 1994;46(1):1-15. [Medline].

  23. 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. Mar 1993;36(3):365-71. [Medline].

  24. Kitahara T, Hiromura K, Maezawa A, et al. Case of propylthiouracil-induced vasculitis associated with anti- neutrophil cytoplasmic antibody (ANCA); review of literature. Clin Nephrol. May 1997;47(5):336-40. [Medline].

  25. Langford CA. Treatment of ANCA-associated vasculitis. N Engl J Med. Jul 3 2003;349(1):3-4. [Medline].

  26. 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. Dec 1999;42(12):2666-73. [Medline].

  27. Langford CA. 15. Vasculitis. J Allergy Clin Immunol. Feb 2003;111(2 Suppl):S602-12. [Medline].

  28. Lockwood CM, Thiru S, Isaacs JD, et al. Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet. Jun 26 1993;341(8861):1620-2. [Medline].

  29. Matteson EL, Gold KN, Bloch DA, Hunder GG. Long-term survival of patients with Wegener''s granulomatosis from the American College of Rheumatology Wegener''s Granulomatosis Classification Criteria Cohort. Am J Med. Aug 1996;101(2):129-34. [Medline].

  30. Mulder AH, Horst G, Haagsma EB, et al. Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology. Mar 1993;17(3):411-7. [Medline].

  31. Mustila A, Korpela M, Mustonen J, et al. Perinuclear antineutrophil cytoplasmic antibody in rheumatoid arthritis: a marker of severe disease with associated nephropathy. Arthritis Rheum. Apr 1997;40(4):710-7. [Medline].

  32. Nachman PH, Segelmark M, Westman K, et al. Recurrent ANCA-associated small vessel vasculitis after transplantation: A pooled analysis. Kidney Int. Oct 1999;56(4):1544-50. [Medline].

  33. Nolle B, Specks U, Ludemann J, et al. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener granulomatosis. Ann Intern Med. Jul 1 1989;111(1):28-40. [Medline].

  34. 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. May 1992;37(5):219-28. [Medline].

  35. Rao JK, Weinberger M, Oddone EZ, et al. The role of antineutrophil cytoplasmic antibody (c-ANCA) testing in the diagnosis of Wegener granulomatosis. A literature review and meta- analysis. Ann Intern Med. Dec 15 1995;123(12):925-32. [Medline].

  36. Rao JK, Allen NB, Feussner JR, Weinberger M. A prospective study of antineutrophil cytoplasmic antibody (c-ANCA) and clinical criteria in diagnosing Wegener''s granulomatosis. Lancet. Oct 7 1995;346(8980):926-31. [Medline].

  37. Rasmussen N, Sjolin C, Isaksson B, et al. An ELISA for the detection of anti-neutrophil cytoplasm antibodies (ANCA). J Immunol Methods. Feb 20 1990;127(1):139-45. [Medline].

  38. Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary approach to the care of patients with Wegener''s granulomatosis: long-term outcome in 155 patients. Arthritis Rheum. May 2000;43(5):1021-32. [Medline].

  39. Rojo-Leyva F, Ratliff NB, Cosgrove DM 3rd, Hoffman GS. Study of 52 patients with idiopathic aortitis from a cohort of 1,204 surgical cases. Arthritis Rheum. Apr 2000;43(4):901-7. [Medline].

  40. Rostaing L, Modesto A, Oksman F, et al. Outcome of patients with antineutrophil cytoplasmic autoantibody-associated vasculitis following cadaveric kidney transplantation. Am J Kidney Dis. Jan 1997;29(1):96-102. [Medline].

  41. Rother E, Schochat T, Peter HH. Antineutrophil cytoplasmic antibodies (ANCA) in rheumatoid arthritis: a prospective study. Rheumatol Int. 1996;15(6):231-7. [Medline].

  42. Savige J, Davies D, Falk RJ, et al. Antineutrophil cytoplasmic antibodies and associated diseases: a review of the clinical and laboratory features. Kidney Int. Mar 2000;57(3):846-62. [Medline].

  43. Seror R, Mahr A, Ramanoelina J. Central nervous system involvement in Wegener granulomatosis. Medicine (Baltimore). Jan 2006;85(1):54-65.

  44. Spronk PE, Bootsma H, Horst G, et al. Antineutrophil cytoplasmic antibodies in systemic lupus erythematosus. Br J Rheumatol. Jul 1996;35(7):625-31. [Medline].

  45. Stasi R, Stipa E, Poeta GD. Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology (Oxford). Apr 21 2006.

  46. 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. Jul 4 1996;335(1):16-20. [Medline].

  47. Tanemoto M, Miyakawa H, Hanai J, et al. Myeloperoxidase-antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis complicating the course of Graves'' disease: report of three adult cases. Am J Kidney Dis. Nov 1995;26(5):774-80. [Medline].

  48. Weber MF, Andrassy K, Pullig O, et al. Antineutrophil-cytoplasmic antibodies and antiglomerular basement membrane antibodies in Goodpasture''s syndrome and in Wegener''s granulomatosis. J Am Soc Nephrol. Jan 1992;2(7):1227-34. [Medline].

  49. Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. Jan 27 2005;352(4):351-61. [Medline].

  50. Woywodt A, Haubitz M, Haller H. Wegener''s granulomatosis. Lancet. Apr 22 2006;367(9519):1362-6.

  51. de Bandt M, Meyer O, Haim T, Kahn MF. Antineutrophil cytoplasmic antibodies in rheumatoid arthritis patients. Br J Rheumatol. Jan 1996;35(1):38-43. [Medline].

  52. van der Woude FJ, Rasmussen N, Lobatto S, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener''s granulomatosis. Lancet. Feb 23 1985;1(8426):425-9. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

WG, Wegener's granulomatosis, Wegener's disease, Wegener disease, systemic vasculitis, systemic necrotizing angiitis, necrotizing granulomatous inflammation of the respiratory tract, necrotizing glomerulonephritis, rapidly progressive glomerulonephritis, RPGN, necrotizing granulomatous pulmonary inflammation, occasionally, alveolar capillaritis, glomerulonephritis, GN, pauci-immune complex, pauci-immune glomerulonephritis, ELK classification

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St. Boniface General Hospital
Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association
Disclosure: Nothing to disclose.

Medical Editor

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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; 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, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; Merck, Amgen, Biogen, Zimmer, Wyeth, Johnson&Johnson, Stryker, Medtronic, Zimmer.Abbott,  Ownership interest Other; West Penn Allegheny Health System Consulting fee Consulting; Alpharma Honoraria Consulting; Proctor&Gamble Grant/research funds Independent contractor

CME Editor

Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Arthur Weinstein, MD, Professor of Medicine, Georgetown University Medical Center; Associate Chairman, Department of Medicine, Director, Section of Rheumatology, Washington Hospital Center
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.