CE Update

Received 8.7.05 | Revisions Received 10.20.05 | Accepted 10.26.05

Wegeners Granulomatosis: A Review of the Clinical Implications, Diagnosis, and Treatment

Michael K. Ramsey, PhD, MT(ASCP), SH(ASCP), SM(ASCP), Debbie Owens (Department of Clinical Laboratory Science, University of Louisiana at Monroe, Monroe, LA)
DOI: 10.1309/AJBWYYKXJUFB6GPU

Abstract
Wegeners granulomatosis is an autoimmune disorder that results in inflammatory reactions, necrotizing vasculitis and granulomatous lesions in various tissues and organs of the body. In Wegeners granulomatosis, the upper

respiratory tract, lungs, and kidneys are typically involved early in the course of the disease. Microscopic examination of biopsied tissue from an involved organ and the antineutrophil cytoplasmic antibody test (cANCA) are the most reliable diagnostic tests

for Wegeners granulomatosis. Early diagnosis and treatment (ie, combination of cyclophosphamide and prednisone) are imperative in WG since it is an almost invariably fatal condition if left untreated.

After reading this article, the reader should know the most common signs and symptoms of Wegeners granulomatosis as well as the laboratory tests most often used to diagnose this condition.

Immunology exam 40601 questions and corresponding answer form are located after the CE update section on p. 117.

Wegeners granulomatosis (WG) is an autoimmune disorder that results in inflammatory reactions, necrotizing vasculitis, and granulomatous lesions in various tissues and organs of the body.1-3 The typical patient is middle aged (mean age is 40), but this condition can be found in all age groups. It is rarely seen in African-Americans and affects men and women equally. Early diagnosis and proper treatment are imperative since when untreated it is almost invariably fatal.4 Immunosuppressive medications and steroids are currently the therapy of choice. When proper therapy is initiated early in the course of the disease a high rate of remissions can be obtained. Heinz Klinger, a German medical student, described the first case in 1931. Between 1936 and 1939, Friedrich Wegener, a German pathologist, identified 3 additional cases. Wegener determined that this condition was a distinct form of vasculitis involving primarily small blood vessels. He named the condition Wegeners granulomatosis. It is also known as Wegeners arteritis and Wegeners disease.5 Pathology and Pathogenesis The etiology of Wegeners granulomatosis is unknown. The clinical manifestations and laboratory findings suggest an autoimmune disease resulting from a hypersensitivity reaction to some environmental agent (very likely airborne and inhaled by the victim).4 Like other autoimmune conditions there is undoubtedly an underlying genetic predisposition for this disease. The clinical and pathological findings in Wegeners granulomatosis often vary in different patients depending on the stage of the disease and the tissues and organs involved. This condition can mimic many other disease states. This can and often 114
LABMEDICINE Volume 37 Number 2 February 2006

does result in misdiagnosis, mistreatment, and progression of the disease. However, the pathologic triad consists of inflammation of both small arteries and veins (vasculitis), necrotizing granulomas of the lungs and upper respiratory tract, and crescentic glomerulonephritis.4 Pathologic lesions resulting primarily from the vasculitis can appear in virtually any organ of the body (Table 1). The skin, mucous membranes, eyes, nervous system, and the kidneys are affected in the majority of long-term patients. The heart may also be involved but cardiac damage often goes undetected because initially symptoms are often subclinical, vague, and atypical.1 This disease resembles poststreptococcal glomerulonephritis in several respects (ie, autoantibodies, vascular inflammation, and involvement of the respiratory and urinary tracts). Streptococcus pyogenes is the major etiologic agent in this type of glomerulonephritis, whereas Staphylococcus aureus has been implicated in Wegeners granulomatosis, at least in some patients.6 A genetic predisposition, Table 1_Organs Frequently Exhibiting Pathologic Lesions of WG
1. Skin 2. Mucous Membranes 3. Eyes 4. Upper Respiratory Tract (sinuses, trachea, nose) 5. Lungs 6. Kidneys 7. Heart 8. Ears 9. Nervous System 10. Muscles

labmedicine.com

CE Update along with some environmental cofactor or stimulus appears to be involved in the etiology of both conditions. Clinical Course The clinical course of Wegeners granulomatosis can vary significantly from one patient to another. One or several areas of the body can be involved initially or several. Onset of symptoms can be insidious or acute. The patients complaints and disease progression gradually increase over time. In the majority of cases, however, presenting complaints are referable to the upper respiratory tract and include cough, hemoptysis, severe rhinorrhea, otitis media with hearing loss and paranasal sinusitis. Inflammation of the nose with frequent nose bleeds, erosion, and perforation of the nasal septum resulting in collapse of the bridge of the nose (saddle-nose deformity) may occur. Other initial symptoms often include malaise, fever, skin lesions, ocular disorders, and anorexia with weight loss. After a period of time, usually weeks or months, a disseminated vascular phase develops that frequently results in diffuse vasculitis, necrotizing skin lesions, pulmonary lesions with nodules and cavitation and renal involvement that may progress to glomerulonephritis. Renal disease is the hallmark of generalized disease. Without treatment, the prognosis is poor. In these cases, the disease usually spreads, the symptoms worsen and the patients often die. The average lifespan in untreated patients is 1 to 2 years. With modern therapy, the relentless progression of this condition can be slowed and long-term remissions obtained in a large number of these patients.7 Diagnosis The diagnosis of Wegeners granulomatosis is based on the clinical, radiological, serological, and histopathological evaluation of the patient. Since this condition can mimic various other disease states, a variety of test procedures is necessary for definitive diagnosis. The radiology department is often involved in the diagnostic workup of these patients. Routine chest radiographs and computed tomography (CT) scans are used to screen for the granulomas that are the hallmark of this disease. Magnetic resonance imaging (MRI) and CT radiographic scans are more sensitive than routine x-ray procedures. Smaller lesions (ie, granulomas and vasculitis) are often detected by the MRI that would be missed by traditional radiography. The antineutrophil cytoplasmic antibody test (ANCA) is a serological test that became an important adjunct in the diagnostic workup of WG in the 1980s. Today, it is one of the most popular procedures used to help diagnose this condition. Antineutrophil cytoplasmic antibodies are autoantibodies to cytoplasmic components of neutrophils. Two types of ANCAs have been discovered, the cANCA and the pANCA. The cANCA is an autoantibody directed against the neutrophil serine protease PR3. The cANCA fluorescent test pattern appears as a diffuse granular staining of the cytoplasm of neutrophils. The pANCA is an autoantibody directed against myeloperoxidase (MPO) causing a fluorescent staining pattern around the nucleus of the neutrophil (ie, perinuclear). The cANCA test has a high sensitivity (92%) and high specificity (96%) for WG.8 Therefore, the cANCA test is the screening test of choice for this condition. The use of this test allows for earlier diagnosis and earlier treatment of these patients.
labmedicine.com

It is useful for establishing the initial diagnosis, monitoring the effectiveness of therapy, and for detecting remission relapse. Histopathologic examination of biopsied tissue from an involved organ and the antineutrophil cytoplasmic antibody test (cANCA) are the most reliable diagnostic procedures for WG. Tissue for histologic examination is usually taken from the upper respiratory tract and lung and occasionally the kidney. The pathologic triad of necrotizing granulomas in the upper respiratory tract and lungs, vasculitis of small blood vessels, and crescentic glomerulonephritis often establishes the diagnosis.4 Other laboratory procedures that may be used to follow the course of the disease and therapeutic effectiveness include the erythrocyte sedimentation rate (ESR) and the C-reactive protein test. Both procedures are nonspecific tests that are often used to detect inflammation in various disease states. Since they are nonspecific in nature, they play little or no role in the diagnosis of WG. Their utility rests on their ability to detect inflammatory reactions and therefore flare-ups in WG that has previously been in remission and in following the effectiveness of therapy. Their low cost, ease of performance, and fast turnaround time make them attractive for physician office laboratories as well as hospital laboratories. Therapy Until the 1970s the therapeutic protocol for WG was limited and fairly ineffective. Prednisone and other steroids were the mainstay of treatment at this time. Steroids did help to prolong the patients lives but most patients eventually died of their disease. During the late 1960s and early 1970s cyclophosphamide was first used to treat these patients. When used in combination with prednisone, the prognosis improved dramatically. More than 90% of the patients with severe disease respond to this combination and up to 75% achieve long term remissions.5 Unfortunately, approximately 50% of these patients will experience recurrence of their disease.5 Recurrences are usually treated with this same combination of medications. Today, cyclophosphamide and prednisone are still the most effective therapeutic regimen in the majority of patients. Since both medications predispose the patient to several life-threatening complications, close medical supervision of this therapy is imperative. Long-term cyclophosphamide therapy is associated with various cytotoxic effects (ie, infections, cytopenia, etc) and increased risk of various types of malignancies (ie, bladder cancer and lymphomas). Prednisone and other steroids decrease the immune response which may lead to infection or cancer. Therefore, once remission is achieved with cyclophosphamide, many clinicians continue the regimen for 6 to 12 months at which time the patient is switched to a less toxic medication such as methotrexate or azathioprine (Imuran). These medications are usually able to maintain the remission for a certain period of time.9 Trimethoprim/sulfamethoxazole (Bactrim) has also been found to be beneficial in some patients, especially when only the respiratory tract is involved. It is used primarily to prevent Pneumocystis carinii infection of the lung and also S. aureus infections. There is some evidence to suggest that S. aureus may be involved in the etiology of WG in some patients or at least to serve as a trigger for flares in this condition.6 Prognosis The prognosis of patients with Wegeners granulomatosis has improved greatly since the early 1970s when cyclophosphamide
February 2006 Volume 37 Number 2 LABMEDICINE

115

CE Update and prednisone became the standard therapy. Long-term remissions are able to be achieved in many of these patients with as many as 90% surviving more than 20 years.10 A good prognosis is often associated with a young age at diagnosis, early detection, limitation of the disease to fewer body sites, absence of renal involvement, and tolerance and effectiveness to the therapy. A poor prognosis is often associated with dissemination of the disease to multiple body sites, an older age group, renal involvement, delay in diagnosis and medication intolerance or ineffectiveness. The main cause of death in patients with WG is uncontrolled sepsis rather than uncontrolled disease.10,11 Summary Wegeners granulomatosis is a rare, autoimmune disorder of unknown etiology. Without treatment most patients will eventually die of their disease. In the early 1970s cyclophosphamide (Cytoxan) and prednisone were first used in combination to treat WG patients. Since that time this combination of medications has become the therapy of choice for most WG patients. Due to the potential side effects of these immunosuppressive medications, alternative medications (ie, methotrexate and azathioprine) are often substituted once remission is achieved and maintained for a certain period of time (usually 1 year). With early diagnosis and treatment the prognosis for these patients has improved significantly. Further research is needed to identify the environmental cofactors and the genetic link for this potentially fatal disease. LM
1. Korantzopoulos P, Papaioannides D, Siogas K. The heart in Wegeners granulomatosis. Cardiology. 2004;102:7-10. 2. Restrepo S, Rojas I, Villamil M, et al. Wegeners granulomatosis of the nasal cavity. Ear, Nose and Throat Journal. 2003:82:100-101. 3. Lamprecht P, Gross W. Wegeners granulomatosis. Herz. 2004;29:47-56. 4. Fitzpatrick T, Johnson R, Wolff K, et al. Color Atlas and Synopsis of Clinical Dermatology, 4th ed., Wegeners Granulomatosis. The McGraw Hill Companies, Inc. 2001:386-389. 5. Types of Vasculitis: Wegeners Granulomatosis. The Johns Hopkins Vasculitis Center Web site. Available at: http://vasculitis.med.jhu.edu/typesof/ wegeners.html. Accessed June 3, 2005. 6. Popa ER, Tervaert JW. The Relation between Staphylococcus aureus and Wegeners granulomatosis: Current knowledge and future directions. Internal Medicine. 2003;42:771-780. 7. Jacob S, Martin L, Kerdel F. Cutaneous Wegeners granulomatosis (malignant pyoderma) in a patient with Crohns disease. Internat J Derm. 2003:42:896898. 8. Sadiq S, Jennings C, Jones N, et al. Wegeners granulomatosis: The ocular manifestations revisited. Orbit. 2000;19:253-261. 9. Metzler C, Fink C, Lamprecht P, et al. Maintenance of remission with leflunomide in Wegeners granulomatosis. Rheumatology. 2004;43:315-320. 10. Atula T, Honkanen V, Tarkkanen J, et al. Otitis media as a sign of Wegeners granulomatosis in childhood. ACTA Otolaryngology. 2000;543:48-50. 11. Koldingsnes W, Nossent H. Predictors of survival and organ damage in Wegeners granulomatosis. Rheumatology. 2002;41:572-581.

116

LABMEDICINE Volume 37 Number 2 February 2006

labmedicine.com