Wegener's Granulomatosis

Wegener’s granulomatosis is a rare disorder in which granulomas (nodular collections of abnormal cells), associated with areas of chronic tissue inflammation due to vasculitis (inflammation of the blood vessels) develop in the nasal passages, lungs, and kidneys. It is thought that the condition is an autoimmune disorder (in which the body’s natural defences attack its own tissues). It is also known as Wegener's disease.

Symptoms 

Principal symptoms include a bloody nasal discharge, coughing (which sometimes produces bloodstained sputum), breathing difficulty, chest pain, and blood in the urine. There may also be loss of appetite, weight loss, weakness, fatigue, and joint pains.

Treatment 

Treatment of the condition is with immunosuppressant drugs, such as cyclophosphamide or azathioprine, combined with corticosteroids to alleviate symptoms and attempt to bring about a remission.

Outlook

With prompt treatment, most people recover completely from Wegener’s granulomatosis within about a year, but kidney failure occasionally develops. Without treatment, complications may occur, including perforation of the nasal septum, causing deformity of the nose; inflammation of the eyes; rash, nodules, or ulcers on the skin; and damage to the heart muscle, which may be fatal.

Wegener's granulomatosis in detail - technical

Summary

Wegener’s granulomatosis (WG) is a potentially life-threatening chronic inflammatory disease of as yet unknown etiology, characterized by necrotizing granulomatous lesions and an autoimmune vasculitis mediated by antineutrophil cytoplasmatic autoantibody (ANCA). The histopathologic hallmark is the triad of granulomatous inflammation, necrosis and vasculitis. WG usually takes a biphasic course starting in the upper and/or lower respiratory tract (so-called localized WG) with subsequent generalization with prominent clinical features of systemic vasculitis. Approximately 95% of patients with active generalized WG are ANCA positive, which is usually directed against ‘Wegener’s autoantigen’ proteinase 3 (PR3). In vitro and animal models suggest that the interaction of ANCA with cytokine- primed neutrophils results in premature activation, respiratory burst, and degranulation of neutrophil granulocytes with subsequent endothelial cell damage and necrotizing vasculitis.

Altered T-cell responses with predominant Th1-type cytokine release might facilitate autoantigen recognition in WG. WG is a multifocal inflammatory disease that affects most often the upper and lower tract and the kidneys, but involvement of any other organ such as eye, skin, heart, gastrointestinal tract, central and peripheral nervous system may occur and give rise to serious or life-threatening complications. In few cases involvement of the upper and/or lower respiratory tract may be the only manifestation for years (localized WG). Cyclophosphamide plus steroids (NIH-scheme) is the standard therapy for the induction of remission in severe organ- or life threatening disease followed by azathioprine or other drugs for the maintenance of remission. In localized and early systemic WG trimetoprim-sulfamethoxazole and/or less aggressive immunosuppressions (e.g., MTX) can induce remission.

Introduction

Wegener’s disease (WG) is a potentially organ- and life-threatening autoimmune disease of as yet unknown etiology characterized by granulomatous lesions and a necrotizing vasculitis predominantly affecting small vessels, that is, arterioles, capillaries, and venules. A prevalence of 23.7 per million adults has been reported in Europe. The peak incidence is in the fourth and fifth decade of life. The overall incidence ranges between 2.9 and 12/106/year depending on the geographic region. In recent years, early diagnosis has led to the recognition of less aggressive disease courses and even long-term variants restricted to the upper respiratory tract in the absence of kidney involvement.

Fifty years ago, Carrington and Liebow introduced the term ‘limited’ WG in order to define disease stages based on clinical and pathological findings. Today, the European Vasculitis Study Group (EUVAS) distinguishes ‘localized’ (i.e., WG restricted to the respiratory tract) and ‘early systemic’ WG (i.e., nonimminent WG without renal organ involvement) from ‘generalized’ WG. In most patients the disease progresses to generalized WG, but in a smaller fraction of patients the disease remains ‘localized’ or ‘early systemic’ for years. In generalized WG the upper and/or lower respiratory tract and the kidneys are involved in 80% of the patients. Rapidly progressive glomerulonephritis and pulmonary hemorrhage (pulmonary-renal syndrome) are typical symptoms of life-threatening full-blown WG. Highly specific antineutrophil cytoplasmatic autoantibodies targeting ‘Wegener’s autoantigen’ PR3 (PR3-ANCA) are detected in about 95% of patients with generalized WG. A large number of in vitro studies and two recently published in vivo studies provide evidence that systemic vasculitis is induced by antineutrophil cytoplasmatic autoantibody (ANCA).

Etiology

The etiology of Wegener's disease is still subject to intensive research. The detection of ANCA directed to proteinase 3 (PR3-ANCA) is highly specific for WG, but incomplete knowledge is achieved about how granulomatous lesions, autoimmune vasculitis, and PR3- ANCA evolve. Infections and other environmental influences may play a role in triggering or maintaining disease activity on the basis of a genetic predisposition. Recently, a strong association of HLADPB1* 0401 has been reported. Epidemiological studies have revealed an association of noninfectious agents such as silica and exposure to farming with WG. Chronic nasal carriage of Staphylococcus aureus is an independent risk factor for a relapse. Animal models and anecdotal reports suggest that further infectious agents might have a role in triggering disease activity but definitive proof has been lacking so far. The risk of relapses in the respiratory tract can significantly be reduced by the use of trimethoprimsulfamethoxazole.

Pathology

Wegener's granulomatosis is characterized by the classic pathological triad of granulomatous inflammation predominantly of the respiratory tract, necrotizing glomerulonephritis, and systemic vasculitis. The classical triad is most often found in specimens from open lung biopsies. However, not all elements of the triad may be seen and only one or two features may be detected in the biopsies. Renal granulomas are rare and found in o10% of kidney biopsies. Granulomatous lesions are built up by CD4þ and CD8þ T cells, CD28 T cells, histiocytes, CD20þ B lymphocytes, neutrophil granulocytes, macrophages, and multinucleated giant cells surrounding an area of central necrosis. The term ‘geographic’ necrosis is used for a confluent or serpiginous pattern of the central necrosis. ‘Geographic’ necrosis and histiocytes lined up in a pallisading fashion are characteristic morphological features most often found in open lung biopsies. Scattered eosinophils are seen and sometimes may cause difficulties in distinguishing WG from Churg–Strauss syndrome. The necrotizing vasculitis affects predominantly small vessels and mediumsize arteries, that is, capillaries, venules, arterioles, and arteries. Endothelial cells are the target of the initial injury. The earliest changes affect the vascular endothelium with swelling, necrosis, and platelet deposition. In the lung capillaries, venules and arterioles are infiltrated by polymorphonuclear leukocytes.

Pulmonary microvascular necrotizing vasculitis (capillaritis) is the cause of pulmonary hemorrhage. In the kidney, rupture of the basement membrane subsequent to neutrophil degranulation gives rise to glomerular capillary thrombosis followed by segmental necrosis of the tuft. Necrotic material, blood, and fibrin spill into the Bowman’s space. As a consequence, accumulation and proliferation of monocytes and parietal (Bowman’s) epithelial cells with the formation of crescents is seen. The growing crescent compresses the capillary tuft, leading to segmental and global loss of circulation through the glomerulus. In WG, the histological picture of vasculitis is polymorphic. Apart from necrotizing vasculitic lesions, leukocytoclastic vasculitis of the skin may be seen as cutaneous vasculitis manifestation. Necrotizing granulomatous arteritis involving medium-sized vessels is commonly found close to large necrotizing granulomatous foci in the lung. Nongranulomatous fibrinoid necrosis may affect bronchial arteries. Finally, vasculitis morphologically identical to that seen in polyarteritis, both in size of the vessels involved and the presence of fibrinoid necrosis, may also be seen in WG in some cases. No or only a few immunodeposits are detected in glomerular lesions, hence the name ‘pauci-immune’ vasculitis.

Clinical Features

Localized Wegener’s Granulomatosis

Localized WG has been defined by the EUVAS as WG restricted to the upper and/or lower respiratory tract. Retrospective studies revealed that 50% of WG patients initially present with solitary ear, nose, and throat (ENT) involvement. The duration of the localized disease stage may last from months to several years. Typically symptoms are nasal obstruction by mucosal swelling, serosanguinous discharge, and epistaxis. Nasal crusting, mucosal ulcerations, hoarseness, sinusitis, or mastoiditis are further typical symptoms of upper respiratory tract involvement. Persistent disease activity causes saddle- nose deformity, septum perforation, and subglottic tracheal stenosis. Proptosis may be a sign of retrobulbary granuloma, often due to per continuum infiltration from the sinus. Granulomatous inflammation of the lower respiratory tract may lead to bronchus stenosis, atelectasis, and obstructive pneumonia. Localized WG usually progresses to early systemic or generalized WG in over 95% of cases within weeks or months.

Generalized Wegener’s Granulomatosis

‘Early systemic’ WG has been defined by the EUVAS as WG with any organ involvement except renal or imminent vital organ failure. ‘Generalized WG’ has been defined as WG including renal involvement and/ or imminent organ failure. Classical WG usually takes a biphasic course, starting in the respiratory tract (localized WG), followed by subsequent generalization of the disease. Generalization is often heralded by constitutional symptoms (weight loss, fever, and night-sweat) and rheumatic complaints such as migratory-arthralgia and myalgia.

Otological manifestations include sensorineural hearing loss, vestibular impairment, and facial nerve palsy due to otitis media, mastoiditis, or neuropathy. Relapsing polychondritis may occasionally be encountered. Retroorbital masses, mostly developing by granulomatous inflammation per continuum of the sinus, may cause proptosis, compression of the optic nerve, and progressive visual loss. Dacryocystoadenitis and nasolacrimal duct inflammation are peculiar organ manifestations of WG and are usually not found in other vasculitides. Episcleritis presenting as ‘red eye’, uveitis, retinal exudates, optic nerve vasculitis, and retinal artery occlusion reflect occular vasculitic lesions.

Pulmonary involvement is one of the cardinal features in WG and occurs in over 80% of cases during the course of the disease. Even if pulmonary symptoms are clinically absent, 30% may have radiographically demonstrable pulmonary lesions. Abnormalities of pulmonary function such as reduced CO diffusion may be early signs of pulmonary involvement. In case of subglottic stenosis an inspiratory stridor or severe dyspnea may be present. Frequently, early complaints related to the lower respiratory tract are cough, dyspnea, pleuritic pain, or hemoptysis. Bland hemoptysis or alveolar hemorrhage with respiratory insufficiency and anemia reflects pulmonary capillaritis and has a high mortality rate. Multiple pulmonary nodules may be asymptomatic; however, solitary granulomatous masses can cause severe bronchial stenosis. Spontaneous pneumothorax may be induced by rupture of a subpleural cavity nodule. Pleural effusions and mediastinal or hilar adenopathy are less common.

Cardiac manifestations are pericarditis with pericardial effusion, myocarditis, and coronaritis with or without myocardial infarction and rarely subsequent cardiomyopathy.

Renal involvement ranges from asymptomatic hematuria to rapidly progressive glomerulonephritis. A nephritic urine sediment (microscopic hematuria with red cell casts and glomerular selective or unselective proteinuria) and reduction of creatinine clearance demonstrate renal involvement.

In over 50% of cases neurological involvement is seen as a consequence of vasculitis or compression by mass-like lesions or frank vasculitis. In most patients, sensory peripheral neuropathy or motor mononeuritis multiplex occurs within the first 2 years. An effect on the CNS is less frequent (about 10%).

Further manifestations, including involvement of the gall bladder, ovaries, parotis, and breast among others, add to the broad spectrum of symptoms.

Pathogenesis

American pathologist Fienberg suggested that WG starts as granulomatous disease in the upper and/or lower respiratory tract with subsequent development of vasculitis. A predominance of T-helper-1 (Th1)- type cytokines is seen in early granulomatous lesions in localized WG whereas this is less evident in generalized WG. Disease progression is associated with a ‘switch’ or further complexity of the collective T-cell response with the appearance of a subset of Th2-type cells. This ‘switch’ or increasing complexity of the cytokine profile might be a consequence of further Bcell expansion and T-cell-dependent PR3-ANCA production during disease progression. Infections such as S. aureus, other environmental influences, or ‘Wegener’s autoantigen’ PR3 itself are thought to play a role in triggering and/or maintaining disease activity in Wegener’s granulomatosis on the basis of a genetic predisposition to an exaggerated Th1-type response early in the disease process. Neutrophils become activated by tumor necrosis factor alpha (TNF-a). Cytokine-primed neutrophils release PR3 from azurophilic granula, and express PR3 on the cell surface. Binding of PR3-ANCA to the membrane-located PR3 induces further premature activation and degranulation of the cells with subsequent endothelial damage and induction of necrotizing vasculitis (ANCA-cytokine- sequence theory) (Figure 4). Recently, murine transfer models showing the in vivo induction of a necrotizing systemic vasculitis and glomerulonephritis by myeloperoxidase-specific (MPO)-ANCA and exacerbation of inflammatory panniculitis by PR3-ANCA have further underscored the pathophysiological role of ANCA in inducing vasculitis.

Diagnosis

Diagnosis of WG is based on clinical manifestations, serological parameters, and histomorphological findings. The classification criteria of the American College of Rheumatology (ACR), defining clinical criteria for distinguishing patients with WG from those with other vasculitides, were proposed in 1990 before the implementation of ANCA as a routine diagnostic procedure and are not intended to be used as diagnostic criteria.

Non-specific serological parameters indicative of inflammation such as elevated erythrocyte sedimentation rate and C-reactive protein are usually found. With regard to ANCA highest specificity (99%) and sensitivity (73%) can be reached when the results of the immunofluorescence (IFT) and enzyme-linked immunosorbent assay (ELISA) technique are combined. In IFT a cytoplasmic pattern C-ANCA is found in 50% of patients with localized WG and in 95% with generalized WG. The target autoantigen detected by ELISA is PR3 in X95% of WG patients. Few patients (p5%) present with an MPO-ANCA. Tissue biopsies should be obtained from easily accessible symptomatic organs such as the upper or lower respiratory tract. Transbronchial biopsies are seldom representative, whereas nasal biopsies produce a much higher yield of representative biopsies. However, most often specimens from open lung biopsies exhibit the classic pathological triad of granulomatous inflammation, necrosis, and vasculitis. Kidney biopsies typically provide evidence of segmental necrotizing glomerulonephritis with little or no immunoglobulin deposition (pauciimmune) which is characteristic of ANCA-associated vasculitis.

Disease activity, extent, and damage can be scored with validated instruments such as the Birmingham vasculitis activity score (BVAS), the disease extent index (DEI), and the vasculitis damage index (VDI). ANCA titers can be used for the follow-up of patients: a fourfold or greater rise in the titer may indicate an imminent relapse and should be followed by close monitoring of the patient for clinical signs of WG activity.

Therapy

In severe organ- and life-threatening WG induction of remission with the NIH-standard or so-called ‘Fauci’s scheme’ remains the gold standard, with oral cyclophosphamide (2 mg kg1 day1 po for 3 days) and steroids (initially 1–2mg kg1 day1 prednisolone iv or orally, with subsequent tapering of dose) given for 3–6 months. Data from a recent EUVAS trial (CYCAZAREM) provided evidence that azathioprine is equally effective for the maintenance of remission. Therefore, azathioprine should be regarded as the treatment of choice for maintenance therapy. The use of mesna is recommended for prophylaxis of the cyclophosphamide urotoxicity. Several trials analyzed the potential benefit of plasmapheresis in patients with severe renal involvement. Preliminary data from the latest EUVAS trial (MEPEX) analyzing initial plasmapheresis versus intravenous high-dose methyl-prednisolone (1 g) in addition to standard treatment with cyclophosphamide and steroids showed higher efficacy of plasmapheresis in patients with a creatinine of 4500 mmol l1. Disease and treatment-related mortality was shown to be high in the subgroup of patients in this trial.

In non-life-threatening, nonrenal ‘early systemic’ WG, MTX can be used. The efficacy of other agents (leflunomide, mycophenolate mofetil, and cyclosporin A) has been reported in case reports or smaller case series. The optimal duration of maintenance therapy is the subject of another presently ongoing EUVAS study (REMAIN) comparing 2 years versus 5 years of maintenance remission with azathioprine.

For prophylaxis, treatment with trimetoprim-sulfamethoxazole reduces S. areus colonization in the respiratory tract and thereby reduces the risk of respiratory relapses. Trimetoprim-sulfamethoxazole also induces remission in localized WG.

The primary goal of all therapies is to achieve remission. Using the BVAS, remission is defined as the absence of signs of new or worse disease activity and persistent disease activity for no more then one item on the BVAS evaluation form. Some disease manifestations regress completely, but others do not such as nasal septal perforation or persistent ‘defect’ proteinuria after glomerulonephritis. Despite the efficacy of the above-mentioned regimen in the majority of patients, up to 10% achieve no complete remission and/or early relapses occur in up to 50% of patients.

Thus, the aim of new treatment options is to combine improved efficacy with less toxicity. TNF-a inhibitors infiximab and etanercept, anti-CD20 antibody rituximab, azathioprine pulse therapy, highdose cyclophosphamide, anti-thymocyte globin, intravenous immunoglobulins, 15-deoxyspergualin, and humanized monoclonal anti-CD52 or anti-CD4 antibodies have been reported to be beneficial in refractory WG in smaller case series. One trial found no significant differences between the addition of etanercept to standard treatment and standard treatment alone in the rates of sustained remission in nonrefractory WG (WGET study by eight American centers). However, it has been shown that TNF-a production is elevated in active and refractory WG. TNF-a levels are normalized with successful standard treatment. Therefore, as suggested by these in vitro data, patients responding to standard treatment will have no further benefit from the addition of a TNF-a blocking agent, whereas patients refractory to standard treatment will benefit from the addition of a TNF-a inhibitor. In line with this consideration are data from an open-label, multicenter, prospective clinical trial by Booth, et al. who successfully induced remission with infliximab in addition to standard or existing treatment regimens both in active and refractory patients (n¼32). Further, higher rates of nonsustained remission in the WGET trial might have been caused by early tapering of steroids in that study.

Further Reading

Jagiello P, Gencik M, Arning L, et al. (2004) New genomic region for Wegener’s granulomatosis as revealed by an extended association screen with 202 apoptosis-related genes. Human Genetics 114: 468–477.

Jayne D for the European Vasculitis Study Group (EUVAS) (2001) Update on the European Vasculitis Study Group trials. Current Opinion in Rheumatology 13: 48–55.

Jayne D, Rasmussen N, Andrassy K, et al., for the European Vasculitis Study Group (2003) A randomized trial of maintenance therapy for vasculitis associated with antineutrophil autoantibodies. New England Journal of Medicine 349: 36–44.

Jennette JC and Falk RJ (1997) Small-vessel vasculitis. New England Journal of Medicine 337: 1512–1523.

Jennette JC, Falk RJ, Andrassy K, et al. (1994) Nomenclature of systemic vasculitides. Proposal of an International Consensus Conference. Arthritis and Rheumatism 37: 187–192.

Komocsi A, Lamprecht P, Csernok E, et al. (2002) Peripheral blood and granuloma CD4þCD28 T-cells are a major source of IFN-g and TNF-a in Wegener’s granulomatosis. American Journal of Pathology 160: 1717–1724.

Lamprecht P, Erdmann A, Muller A, et al. (2003) Heterogeneity of CD4þ and CD8þ memory T cells in localized and generalized Wegener’s granulomatosis. Arthritis Research and Therapy 5: R25–R31.

Leavitt RY, Fauci AS, Bloch DA, et al. (1990) The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis and Rheumatism 33: 1101–1107.

Pfister H, Ollert M, Frohlich LF, et al. (2004) Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo. Blood 104: 1411–1418.

Popa ER, Stegeman CA, Kallenberg CGM, and Cohen Tervaert JW (2002) Staphylococcus aureus and Wegener’s granulomatosis. Arthritis Research 4: 77–79.

Reinhold-Keller E, Beuge N, Latza U, et al. (2000) An interdisciplinary approach to the care of patients with Wegener’s granulomatosis. Long-term outcome in 155 patients. Arthritis and Rheumatism 43: 1021–1032.

Stone JH, Hoffman GS, Merkel PA, et al. for the International Network for the Study of the Systemic Vasculitides (INSSYS) (2001) A disease-specific activity index for Wegener’s granulomatosis: modification of the Birmingham Vasculitis Activity Score. Arthritis and Rheumatism 44: 912–920.

Xiao H, Heeringa P, Hu P, et al. (2002) Jennette: antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. Journal of Clinical Investigation 110: 955–963.

Relevant Website

http://www.vasculitis.org – Homepage of the ‘The European Vasculitis Study Group (EUVAS)’ with information about trial protocols, trial progress, meetings, nomenclature, disease scoring and ANCA-testing.