DEFINITION

Wegener's granulomatosis (WG) is an idiopathic, systemic inflammatory disease characterized by the presence of granulomas, necrosis, and/or vasculitis. Although WG typically affects the upper and lower airways and the kidneys, it may involve any organ system.¹ WG is classified with microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS) as a primary systemic small-to medium-sized vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs). However, WG can also affect medium and even large arteries, and may lack an association with ANCAs.²

Analyses from the National Hospital Discharge Survey³ indicate the prevalence of WG in the United States to be about 3 per 100,000 population. Although all age groups can be affected, most patients are adults. The disease most often affects Caucasians (>90%), but also occurs in all other racial groups. Most large series show no significant gender difference.¹

The pathology of WG is characterized by granulomatous inflammation with necrosis and vasculitis. Characteristic histologic features are present in less than one-half of head and neck biopsy specimens, where tissue-sample size limitations influence diagnostic yield.⁴ Typical histologic findings from open lung biopsies (larger specimens) are found in more than 80% of specimens. A focal, segmental, necrotizing, crescentic glomerulonephritis is the classic renal lesion in WG. It is typically associated with scant or no immune-complex deposits.⁵

The histologic hallmark of granulomatous inflammation is tissue infiltration with activated macrophages. Granulomas are small collections of modified macrophages called "epithelioid cells," usually surrounded by a rim of lymphocytes and other cell types. The presence of giant cells formed by the coalescence and fusion of these modified macrophages is a typical feature of granulomas. T-cell-mediated immunity with production of tumor necrosis factor (TNF)-α and γ-interferon is necessary for granuloma formation.

A broad array of immunoreactive and inflammatory cells in WG lesions suggests that many types of immune responses contribute to organ damage. Both cellular and humoral components of immune function participate in the pathogenesis of WG. Neutrophils also play an important role in tissue injury in WG. Inflammatory cytokines, such as TNF-α and IL-8, stimulate surface expression of numerous antigens on activated neutrophils, some of which interact with ANCAs and cause enhanced neutrophil degranulation and generation of toxic oxygen radicals, which may lead to tissue injury. The presence of ANCAs in approximately 90% of patients with severe active WG suggests an important but not yet completely understood pathogenic role for B cells and plasma cells in WG. Conversely, the fact that ~20% of all WG patients do not have ANCAs makes it uncertain that antibodies to PR 3 are essential to disease pathogenesis.⁶

Although there are many variations in disease evolution, the most common initial features are ear, nose, and throat (ENT) symptoms that are unresponsive to conventional therapies for allergy or infection. These may be associated with systemic symptoms, polyarthralgias, myalgias and, in time, lung, renal, skin, neurologic, and peripheral vasculitic features (eg, digital infarcts, rash, and gangrene).

WG is often referred to in the literature as "generalized" or "limited." The term "generalized" indicates the presence of glomerulonephritis. These are potentially misleading terms because they imply that such subclassification confers stability or clinical characteristics when, in fact, WG often changes and progresses. For example, ~20% of patients have glomerulonephritis at onset, but 70% to 80% will eventually develop glomerulonephritis (Table 1). In addition, the term "limited" may be misleading by suggesting that the disease is mild when involvement of organs such as the central nervous system, lungs, heart, and gastrointestinal tract can be severe and life-threatening, even in the absence of glomerulonephritis.

Nasal mucosa inflammation leads to obstruction, crusting, pain, epistaxis, and serosanguinous or purulent discharge. Nasal chondritis may result in facial pain, swelling, and/or collapse of the nasal bridge ("saddle nose"). Sinusitis usually presents with facial pain and nasal discharge. Involvement of the oral cavity and oropharynx may produce ulcerative stomatitis, hyperplastic gingivitis, and lingual ulcerations. Disease affecting the ears and associated structures may lead to chondritis, serous or suppurative otitis media, mastoiditis, vestibular dysfunction (vertigo), and sensorineural deafness. Upper airway symptoms such as pain, dyspnea, cough, stridor, and hoarseness maybe due to subglottic narrowing caused by inflammation and scar formation.

Ocular disease is commonly manifested by conjunctivitis, uveitis, dacrocystitis, retinitis, and/or proptosis due to orbital pseudotumor, which may cause loss of vision in approximately 50% of patients with this complication.⁷

Lung involvement may include focal or diffuse infiltrates, nodules that may cavitate, endobronchial stenoses, and pleurisy. Any of these features can be subclinical, minimally symptomatic, or severe. Computed tomography of the chest should always be part of disease assessment. Asymptomatic pulmonary findings are likely to influence assessment of disease severity and treatment. The most severe pulmonary features are a result of diffuse capillaritis usually associated with dyspnea, hemoptysis, and anemia. It can rapidly lead to ventilator dependency and death if appropriate treatment is not immediately provided.

Nervous system disease is not common at presentation, but mononeuritis multiplex may develop later in ~15% of patients and can result in significant disability.⁷ Lesions in the central nervous system may be from vasculitis, inflammatory mass lesions, or extension of lesions from contiguous sites, such as the sinuses.

More than 60% of patients have myalgias and arthralgias. Frank arthritis and myositis may also be seen. Arthalgias commonly have a migratory pattern. In some, an additive symmetric pattern can mimic rheumatoid arthritis.

Skin manifestations include palpable purpura due to leukocytoclastic vasculitis, tender subcutaneous nodules, vesicles, ulcers, papules, livedo reticularis, digital infarcts, and gangrene.

The most common cardiac feature is pericarditis. Less common sites of disease are the parotid glands, pulmonary artery, breast, penis, urethra, cervix, and vagina.

The diagnosis of WG is based on a combination of clinical, laboratory and, if necessary, pathologic features. If a typical clinical picture is associated with a positive ANCA finding with specificity for proteinase 3 (PR3), the diagnosis of WG can be presumed. It remains incumbent for the clinician to be certain that WG "mimics," especially granulomatous infection, are not present. In the setting of only a moderate suspicion of WG and a negative ANCA result, it would be judicious to pursue histologic support for the diagnosis.

In 1990, the American College of Rheumatology (ACR) proposed specific criteria for the classification of WG.⁸ The criteria were not intended for clinical practice; they were designed for clinical trials. The four criteria are (1) an abnormal urinary sediment (red-cell casts or >5 red blood cells per high-power field); (2) abnormal findings on chest radiograph (nodules, cavities, or infiltrates); (3) oral ulcers or nasal discharge; and (4) granulomatous inflammation on biopsy. The presence of two or more of those four criteria was associated with a sensitivity of 88.2% and a specificity of 92% in distinguishing WG from other forms of vasculitis.⁸ However, the exercise leading to the ACR criteria did not assess specificity in reference to nonvasculitic diseases and did not incorporate the utility of ANCA in making an initial diagnosis.

ANCAs have two distinct patterns: cANCA indicates cytoplasmic staining and refers to a coarse, granular, centrally accentuated, cytoplasmic fluorescence pattern, whereas pANCA refers to a perinuclear fluorescence pattern. The ability to generate these different patterns results from an artifact of ethanol fixation that allows migration of cytoplasmic proteins with a strong positive charge (eg, myeloperoxidase [MPO], elastase, cathepsin G, lactoferrin) to move to the negatively charged nuclear membrane. In formalin-fixed neutrophils, this artifact does not occur, and all ANCAs are cytoplasmic in appearance.⁶ The cANCA pattern (in ethanol-fixed neutrophils) is usually caused by antibodies against PR3. This molecule and others that are weak cations or neutral remain in the cytoplasm after ethanol fixation. Thus, antibodies to them generate a c pattern. Antibodies to MPO are the most common cause for pANCA (MPO-ANCA). About 80% to 90% of all ANCA found in WG are cANCA- and PR3-specific. About 10% to 20% of ANCA in WG may be pANCA- and MPO-specific. The sensitivity of PR3-ANCA in WG depends in part on disease severity and activity. About 80% to 95% of patients with severe active disease and from 55% to 75% with milder limited active disease are ANCA-positive.⁶ The combined use of indirect immunofluorescence and enzyme-linked immunosorbent assay for identification of antigen results in diagnostic specificity of up to 98%.⁹ ANCA is a useful adjunct to clinical diagnosis; however, its presence per se is not diagnostic. ANCA, usually with other than PR3 targeting, may be present in various other diseases including inflammatory bowel disease, autoimmune liver disease, infections, malignancies, rheumatic diseases other than the vasculitides, and other illnesses.^10-14 Cases of endocarditis and systemic amebiasis have, in fact, been associated with ANCA positivity and specificity for PR3.

The presence of red blood-cell casts in the urine sediment can be used as a reliable surrogate marker for the diagnosis of glomerulonephritis and may eliminate the need for renal biopsy in some patients.

Differential Diagnosis:

The differential diagnosis of WG depends on the clinical presentation. When pulmonary-renal syndrome is the presenting clinical feature, WG needs to be distinguished from Goodpasture's syndrome (GPS), MPA, CSS, and systemic lupus erythematous (SLE). These features plus a prior or persistent history of upper airway disease and PR3-ANCA positivity make the diagnosis of WG very likely. The presence within a biopsy of granulomatous inflammation, although not an absolute requirement for diagnosis in WG, represents an important distinction between that disease and MPA.² Pulmonary nodules are common in WG and can coexist with infiltrates, whereas nodules are almost always absent in GPS, SLE, MPA, and CSS, where infiltrates are the rule.

The diagnosis may be much less evident in patients with disease limited to ENT symptoms for a prolonged period. In this situation, the diagnosis is usually delayed until the onset of other organ involvement (eg, lungs or kidneys), or the finding of biopsy features of WG from a surgical procedure. The differential diagnosis of granulomas in ENT biopsies includes chronic infections such as tuberculosis and syphilis, and sarcoidosis. The differential diagnosis of septal perforation is not very broad and includes infections, cocaine use, sarcoidosis, SLE, angiocentric lymphoma-lymphomatoid granulomatosis, and excessive use of intranasal corticosteroids.

The outcome of WG has been dramatically altered by treatment with glucocorticoids (GCs) and cyclophosphamide (CP). In the first 40 years after its initial description, the disease was recognized as uniformly fatal. In its severe form, untreated WG has a 5-month mortality rate of 50% and a 1-year mortality rate of greater than 80%. Treatment with GCs alone resulted in only modestly improved outcome, with a mean survival time of 12.5 months.¹⁵ The combination of CP and GC treatment in the early 1970s had a major impact, changing the prognosis of a disease once typically fatal to a disease in which marked improvement occurs in >90% of cases, and remission can be induced in at least 75% of patients. Mortality has also been dramatically reduced.^16-18 The initial protocol, introduced by Fauci at the National Institutes of Health, consisted of CP 2 mg/kg/day together with the GC prednisone 1 mg/kg/day.^1,7,16 At the end of 1 month, if there was evidence of improvement, the prednisone dose was slowly tapered and discontinued over 6 to 9 months. CP was maintained for 1 year after remission was achieved, then tapered and discontinued. Despite the great efficacy of this combination therapy, significant morbidity due to treatment toxicity was observed, and relapses occurred in ~50% of cases. Chronic CP therapy carries the risk of significant toxicity such as hemorrhagic cystitis, severe infections, sterility, myelodysplasia, and bladder cancer.^8,19 The current standard of care limits the use of CP to 3 to 6 months followed by "remission-maintenance" therapy with agents such as methotrexate (MTX) or azathioprine (AZA). Leukopenia is not necessary for achieving disease remission and should be avoided because it increases the risk of infection.^16-18,20

The distinction between mild and severe disease is helpful in deciding which medications to use in the initial treatment. Although the combination of GC with another immunosuppressive drug is necessary to achieve sustained remission in all patients, not all individuals require CP. CP is used to induce remission in all patients with critical organ involvement, life-threatening disease, or disease refractory to other immunosuppressive agents. MTX in combination with GC has been used to induce remission in patients with milder forms of disease.^17,18 When CP has been used for remission-induction, maintenance of remission can be attempted with either weekly MTX or daily AZA.^20-22 MTX is contraindicated in the setting of significant renal impairment (serum creatinine >2.0 mg/dL). Renal failure requires dose adjustments for all cytotoxic agents.

The use of monthly intravenous (IV) CP has been the subject of significant controversy in the literature. The prospective randomized trial by Guillevin and colleagues²³ compared oral CP with pulse CP. Results showed intermittent pulse CP to be as effective as daily oral CP in producing remissions in WG, and pulse CP was associated with fewer side effects. However, a higher rate of relapse was seen in the group treated with monthly IV pulse CP. Most authorities have recommended use of oral daily CP, which allows dose adjustment on a daily basis, if necessary. Conversion to an alternative agent would generally follow within 3 to 6 months.

Because of the high risk of drug toxicity in the setting of renal insufficiency, treatment should be carefully monitored in all patients. AZA is preferred to MTX in patients with serum creatinine >2.0, a setting in which MTX marrow toxicity is less predictable. Because the effects of cytotoxic agents on marrow progenitor cells is cumulative and a significant risk of progressive renal disease is ever present, laboratory parameters should be followed at least once a month. In patients who have a normal urine sediment, surveillance for new-onset glomerulonephritis can be aided by patients themselves checking a urine dipstick for the new occurrence of blood and protein every 1 to 2 weeks.

Relapse of WG occurs within 12 to 18 months in ~50% of patients.^20,24 Relapse usually occurs after tapering or discontinuation of corticosteroid (CS) or cytotoxic agents. The ideal duration of therapy is unknown and is likely to vary for each patient. Consequently, patients should have close, long-term follow-up to allow for early diagnosis and institution or change of treatment at first signs or symptoms of relapse.

What role new biologic agents will have in the treatment of WG is unknown. Studies of anti-TNFα therapies and anti-B-cell therapies are ongoing. To date, adjunctive treatment with anti-TNF therapies have not demonstrated an ability to provide more enduring, CS-independent remissions.²⁵

The use of trimethoprim/sulfamethoxazole (TMP/SMX) in the treatment of WG is still among the most debated issues for treating mild WG. There has been only one prospective study showing positive results, with a decrease in the rate of ENT-related relapses.²⁶ The difficulty in interpreting that study lies in not knowing whether TMP/SMX reduced ENT relapses or ENT infections. It is well known that patients with ENT involvement from WG may have significant anatomic and mucosal damage that leads to recurrent infections.

TMP/SMX should be given for Pneumocystis carinii pneumonia prophylaxis to all patients receiving a combination of CS and cytotoxic agents that are likely to produce sustained lymphopenia. Effective regimens include either one single-strength tablet daily or one double-strength tablet three times a week.

Disease morbidity may be reduced by the ability to detect the earliest signs of disease activity. It would be very advantageous to possess a laboratory surrogate marker of disease that could identify relapse, ideally even when clinically unapparent. It has been suggested that a rise in cANCA (anti-PR3) titers during remission may predict relapse and justify presumptive immunosuppressive therapy.^27,28 The use of a change in ANCA titers in treatment decision making in WG remains controversial. Persistent high titers or rising titers are often associated with disease relapse. However, the timing of relapse based on ANCA titers cannot be predicted. One-third or more of patients with rising or persistently high ANCA titers may not relapse during 1 or more years of follow up.²⁹ Therefore, the use of rising ANCA titer to justify an increase in treatment may result in over-treatment and unnecessary toxicity. ANCA use in this fashion is not recommended.

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