Abstract An unusual sequence of the clinical manifesta-tions of microvascular disease is described in a 15 year-old girl. She initially presented with acute renal failurecaused by a crescentic glomerulonephritis associatedwith positive tests for MPO-ANCA. Eighteen monthslater she had pulmonary hemorrhage and respiratory fail-ure. An open lung biopsy showed granulomas that werediagnostic for Wegener granulomatosis. We discuss thediagnostic dilemmas faced in attempts to distinguish in-fective causes of pulmonary granulomas, such as tuber-culosis or fungi, from granulomas associated with vascu-litis, in a patient previously treated with immunosuppres-sive therapy.

Key words Wegener granulomatosis · Anti-neutrophiliccytoplasmic antibodies · Small-vessel vasculitis

Case presentation

A 15-year-old girl presented to the emergency room of another hospital with abdominal pain, vomiting, andrespiratory distress. She had been well until 2 weeksprior to this, when she developed fatigue and facial edema. There was no history of rash, arthritis, fever, hematuria, or oliguria. She had not taken any medica-tions/drugs and did not smoke. The family history was

negative for renal diseases. Growth and developmentwere normal.

Physical examination revealed pallor, facial and pedaledema, hypertension (150/100 mmHg), tachypnea, dif-fuse rales bilaterally, and a 2/6 precordial ejection sys-tolic murmur. There were no rashes, arthritis, adenopa-thy, fever, or hepatosplenomegaly.

Laboratory investigation revealed: blood urea nitrogen140 mg/dl, and serum potassium 6.8 mEq/l, creatinine10.5 mg/dl, calcium 7.5 mg/dl, and albumin 2.2 g/dl. Thehemoglobin concentration was 3.1 g/dl, the sedimentationrate 46 mm/h, and platelet count 200,000/mm3. Urinaly-sis revealed: 3+ protein, hematuria, red blood cell casts,and tubular epithelial casts.

Chest X-ray revealed cardiomegaly, pulmonary ede-ma, and a small pleural effusion. An echocardiogramshowed normal cardiac function and a small pericardialeffusion. Renal ultrasonography demonstrated normal-sized kidneys with increased echogenicity. She was ad-mitted to the intensive care unit and treated with hemo-dialysis for acute renal failure and intravenous solumed-rol for presumed rapidly progressive glomerulonephri-tis. A renal biopsy was performed on the 2nd hospitalday.

Histopathological findings (Marta Guttenberg, M.D.,Pathologist, The Children’s Hospital of Philadelphia)

Light microscopy of the renal biopsy showed a majorityof the glomeruli with a pattern of proliferative glomeru-lonephritis with cellular and fibrous crescent formation.There was tubular atrophy and an interstitial inflammato-ry infiltrate. Some blood vessels had thickened walls(Figs. 1, 2). Immunofluorescence showed strong mesan-gial and capillary loop staining with IgM and C3 anti-bodies. Extraglomerular blood vessels also stained withC3 antibodies. Electron microscopy showed epithelialand mesangial electron-dense deposits and effacement ofepithelial foot processes. The findings were consistentwith an immune-mediated crescentic glomerulonephritis.

M. Pradhan · K.E.C. Meyers · B.S. KaplanDivision of Nephrology and Department of Pediatrics, The Children’s Hospital of Philadelphia,Pennsylvania, USA

M. GuttenbergDepartment of Pathology, The Children’s Hospital of Philadelphia,Pennsylvania, USA

B.S. Kaplan (✉ )Department of Nephrology, The Children’s Hospital of Philadelphia, University of Pennsylvania, 34th Street and Civic Center Boulevard,Philadelphia, PA19104, USAe-mail: kaplanb@email.chop.eduTel.: +1-215-5902451, Fax: +1-215-5903705

Pediatr Nephrol (2000) 14:862–871 © IPNA 2000

G R A N D R O U N D S

Madhura Pradhan · Kevin E.C. Meyers Marta Guttenberg · Bernard S. Kaplan

Wegener granulomatosis – an atypical case

Received: 4 August 1999 / Revised: 28 October 1999 / Accepted: 3 January 2000

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After the biopsy results were obtained, additionaltests were performed. The anti-neutrophil cytoplasmicantibody (ANCA) titer was >1:5,000 (perinuclear type).Anti-nuclear antibody was 1: 64, double-stranded DNAantibody was negative, and complement levels were nor-mal. Serum anti-glomerular basement membrane (GBM)antibodies and serological studies for hepatitis B andhepatitis C were negative. She was treated with cyclo-phosphamide (one intravenous dose of 1 g) and oral ste-roids (prednisone 20 mg every other day). She pro-gressed to end-stage renal disease (ESRD) while she wason steroids, and was then maintained on chronic hemodi-alysis. Eleven months later she began to cough andwheeze, and a chest X-ray showed an infiltrate in bothlower lobes. She was treated with bronchodilators andantibiotics.

Subsequent course

Eighteen months after the initial presentation she de-veloped cough, dyspnea, and hemoptysis. A chest film

showed diffuse bilateral infiltrates (Fig. 3) which on com-puted tomographic (CT) scan appeared nodular (Fig. 4).On admission for the above symptoms she developed hyp-oxemia and was given one dose of intravenous methyl-prednisolone (1 g) before further tests were performed. Abronchoscopy and broncho-alveolar lavage (BAL) per-formed on the 2nd hospital day demonstrated inflamed

Fig. 2 The renal interstitium shows tubular atrophy, mixed in-flammatory infiltrate, and thick-walled blood vessel (center), he-matoxylin and eosin (H&E), ×30

Fig. 3 The chest X-ray shows diffuse bilateral infiltrates, whichappear more prominent peripherally

Fig. 4 The computed tomographic scan of the chest shows diffusebilateral nodular lesions

Fig. 1 The glomerulus demonstrates crescentic glomerulonephri-tis with a fibrous crescent, compressed capillary loops, with me-sangial cell and matrix increase, periodic acid-Schiff, ×30

ued. Three months later while the corticosteroids werebeing tapered, she again began to cough up blood, and achest X-ray showed increasing pulmonary infiltrates. Arepeat bronchoscopic study revealed acute pulmonaryhemorrhage. Three doses of intravenous methylprednis-olone (1 g) were given and oral cyclophosphamide (1 mg/kg per day) and prednisone (2 mg/kg per day)were started. She remained asymptomatic while on cy-clophosphamide and tapering doses of steroids for 6months. She has subsequently received a cadaver renalallograft and has no evidence of systemic vasculitis.

Discusssion

This patient had atypical features of a vasculitic syn-drome, which raise important diagnostic and therapeuticquestions. She was initially thought to have microscopicpolyangiitis based on the crescentic glomerulonephritisand the presence of perinuclear staining (p-ANCA). How-ever she later developed pulmonary hemorrhage withgranulomas in her lung, typical of Wegener granulomato-sis. This case is instructive from several standpoints. First,Wegener granulomatosis is uncommon in children and ad-olescents. Second, this presentation with isolated renaldisease with ANCA-positive glomerulonephritis and a re-lapse with pulmonary symptoms 18 months later is atypi-cal. Third, the patient had evidence for Mycobacteriumavium intracellulare in the BAL performed at the time ofthe pulmonary relapse before institution of chronic immu-nosuppression. The patient subsequently had a recurrenceof pulmonary hemorrhage after having received anti-tu-berculous therapy for 2 months, while the corticosteroidswere being tapered, suggesting that the lung disease wasmost likely due to Wegener granulomatosis.

The therapeutic dilemma in this patient when she de-veloped respiratory symptoms with evidence of pulmo-nary hemorrhage was whether to administer corticoste-roids without waiting for the diagnostic tests for infec-tion or whether to treat her for pulmonary infection. Al-though she had a history of ANCA-positive crescenticglomerulonephritis, her disease had been inactive for 18months while she was on hemodialysis, and therefore anew infectious process had to be considered as a possiblecause of her symptoms.

Classification of vasculitis

Wegener granulomatosis is classified as a small-vesselvasculitis (SVV) that includes microscopic polyangiitisand Churg-Strauss syndrome. In 1993 the Chapel HillConsensus Conference for the nomenclature of systemicvasculitis agreed on the names and definitions of many ofthe vasculitides that affect the kidney (Table 1). Patientswith SVV have a high frequency of ANCA that react withcytoplasmic constituents of neutrophils and monocytes [1–4]. Approximately 90% of cytoplasmic staining ANCA(c-ANCA) react with the serine proteinase called protein-

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mucosa, and microscopy revealed hemosiderin-ladenmacrophages. An open lung biopsy was performed on the3rd hospital day.

Histopathological findings (Marta Guttenberg, M.D.)

A wedge biopsy of the lung showed multiple necrotizingand non-necrotizing granulomas, and evidence of vasculitiswith irregular endothelial cell proliferation (Figs. 5, 6). Spe-cial stains for fungi and acid-fast organisms were negative.

Cultures from the lung biopsy were negative for bac-teria, fungi, viruses, and Pneumocystis carinii. TheANCA titer was 1:80. A CT scan of the sinuses was nor-mal. She was treated with oral corticosteroids (1.5 mg/kgper day) as well as isoniazid, rifampicin, pyrazinamide,and ethambutol for possible pulmonary tuberculosis. Amonth later a specimen of respiratory secretions from theBAL performed on the 2nd hospital day (at that time shehad received a single dose of methylprednisolone) grewMycobacterium avium intracellulare, and the treatmentwas modified for atypical mycobacteria (azithromycinand rifampicin) but corticosteroid treatment was contin-

Fig. 5 A distal airway that shows a non-caseating granuloma,H&E, ×15

Fig. 6 The small pulmonary artery shows cellular proliferation ofan endothelial cushion, consistent with healing vasculitis, tri-chrome, ×15

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ase 3 (PR3-ANCA) and 90% of the p-ANCA react withmyeloperoxidase (MPO-ANCA). c-ANCA are detectedmost commonly in patients with Wegener granulomatosisbut are not specific for this disease; 65% of patients withWegener granulomatosis have c-ANCA and 20% have p-ANCA [5]. p-ANCA are more commonly seen in micro-scopic polyangiitis. ANCA positivity in a patient with thesigns and symptoms of SVV confirms the presence ofsome form of ANCA-associated SVV. The characteristicpathological lesion of ANCA-associated vasculitis is focalfibrinoid necrosis of vessels with associated leukocyte in-filtration and necrotizing crescentic glomerulonephritis.Wegener granulomatosis is distinguished by the presenceof necrotizing granulomatous inflammation, Churg-Strauss by the presence of asthma and eosinophilia, andmicroscopic polyangiitis by the absence of granulomatousinflammation and asthma. ANCA-SVV is typically pauci-immune. However, in half the patients, variable degrees ofmesangial and/or parietal deposition of C3 and IgG areseen without features of any of the well-classified primaryimmune complex-mediated glomerulonephritides [6]. Falkand Jennette [5] evaluated 213 patients with glomerulone-phritis and crescent formation. They concluded that to beat least 80% predictive of ANCA disease, “pauci-im-mune” should be defined as 2+ or less staining for any im-munoglobulin and the absence of immune complex-typeelectron-dense deposits by electron microscopy [5, Fig. 7].

Table 1 Names and definitions of vasculitis adopted by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitisa

Large-vessel vasculitsGiant-cell (temporal) arteritis Granulomatous arteritis of the aorta and its major branches, with a predilection for the extra-

cranial branches of the carotid artery. Often involves the temporal artery. Usually occursin patients over 50 years and is often associated with polymyalgia rheumatica

Takayasu arteritis Granulomatous inflammation of the aorta and its major branches. Usually occurs in patientsunder 50 years

Medium vessel vasculitisPolyarteritis nodosa Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis

or vasculitis in arterioles, capillaries, or venulesKawasaki disease Arteritis involving large, medium-sized, and small arteries, and associated with mucocutaneous

lymph node syndrome. Coronary arteries are often involved. Aorta and veins may be involved.Usually occurs in children

Small-vessel vasculitisWegener granulomatosis Granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting

small- to medium-sized vessels, e.g., capillaries, venules, arterioles, and arteries. Necrotizingglomerulonephritis is common

Churg-Strauss syndrome Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizingvasculitis affecting small- to medium-sized vessels, and associated with asthma and blood eosinophilia

Microscopic polyangiitis Necrotizing vasculitis with a few or no immune deposits, affecting small vessels, i.e., capillaries, venules, or arterioles. Necrotizing arteritis involving small- to medium-sized arteriesmay be present. Necrotizing glomerulonephritis is very common. Pulmonary capilllaritis oftenoccurs

Henoch-Schönlein purpura Vasculitis with immunoglobulin A-dominant immune deposits, affecting small vessels, i.e., capillaries, venules, or arterioles. Typically involves skin, gut, and glomeruli, and is associatedwith arthralgias or arthritis

Essential cryoglobulinemic vasculitis Vasculitis with cryoglobulin immune deposits, affecting small vessels, i.e., capillaries, venules,or arterioles, and associated with cryoglobulins in serum. Skin and glomeruli are often involved

Cutaneous leukocytoclastic angiitis Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis

a Printed with permission from reference [1]

Fig. 7 Graph showing the frequency of anti-neutrophil cytoplas-mic antibody (ANCA) positivity as a function of the intensity ofglomerular staining for immunoglobulin. The data were obtainedfrom 213 patients with glomerular crescent formation. Patientswith anti-glomerular basement membrane antibodies and lupusglomerulonephritis patients were excluded (IF immunofluores-cence, ELISA enzyme-linked immunosorbent assay). Printed withpermission from reference [5]

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Patients with anti-GBM glomerulonephritis and immunecomplex crescentic glomerulonephritis have a higher fre-quency of ANCA positivity than healthy controls [7, 8].ANCA, by acting in a synergistic manner with localizedimmune complex deposition, induce more severe inflam-mation in those patients with anti-GBM disease [7, 8].

Clinical manifestations of Wegener granulomatosis in children

Wegener granulomatosis is a necrotizing granulomatousvasculitis of the upper and lower respiratory tract that isassociated with variable degrees of SVV that can involvejoints, skin, eyes, and ears [9]. Glomerulonephritis isseen in 77% of patients and completes the triad of upperand lower airway disease and kidney involvement; how-ever, renal disease is not a pre-requisite for the diagnosis[10]. The mean age of presentation is in the 4th to 5thdecade and presentation in childhood is uncommon. Ananalysis of 23 children with Wegener granulomatosis fol-lowed for up to 18 years revealed the following differ-ences between children and adults [10]:

• Lung involvement at onset was significantly lesscommon in children (22% of children vs. 49% of adults),although the frequency during the course of the illnesswas not significantly different (74% in children vs. 87%in adults).• A third of the abnormal radiographs were from pa-tients without pulmonary symptoms.• Nasal deformity and subglottic stenosis was commonin childhood-onset Wegener granulomatosis.• No childhood-onset patient developed cyclophospha-mide-related malignancies, although the duration oftreatment and follow-up was the same in the concurrent-ly studied 135 adult-onset patients.

Significance and pathogenesis of ANCA

Although p-ANCA and c-ANCA are present predomi-nantly in microscopic polyangiitis and Wegener granulo-matosis respectively, neither subtype is specific for dif-ferentiation among the different phenotypes of ANCA-SVV. For ANCA to cause segmental fibrinoid necrosisof vessel walls, neutrophil and monocyte infiltrationwith leukocytoclasia, they must induce the following se-quence of events:

1. leukocyte margination, adherence and diapedesis2. leukocyte activation with degranulation and genera-tion of toxic oxygen metabolites3. vascular necrosis resulting in karyorrhexis and fibrin-ous insudation [11].

Experimental data suggest that ANCA can induce all ofthese events in vitro [12, 13] (Table 2), yet their exactrole in pathogenesis is unclear. Most of the evidencesupporting a biological effect and a possible pathologicalrole for ANCA is derived from in vitro studies. There areno experimental models that closely resemble pauci-immune ANCA-vasculitis or glomerulonephritis, al-though there are an increasing number of models thatsimulate certain ANCA-positive disease states. Brouweret al. [14] have developed a rat model of glomerulone-phritis and vasculitis by immunizing with human MPO.Once circulating anti-MPO antibodies were present,MPO and hydrogen peroxide were perfused in the renalartery to form MPO-anti-MPO complexes. This led tothe development of a crescentic glomerulonephritis, al-though the immune complexes later disappeared. In thismodel the target antigen was purposefully planted in theglomerulus, which is different from spontaneous ANCA-associated glomerulonephritis. Kobayashi et al. [15] andHeeringa et al. [16] further observed that rats injectedwith low doses of anti-GBM antibodies along with anti-

Table 2 Clinical, pathological, and experimental evidence of pathogenesis of vasculitis due to anti-neutrophil cytoplasmic antibodies(ANCA) (GBM glomerular basement membrane, MPO myeloperoxidase)a

Clinical and pathological evidence:ANCA are very frequent in patients with necrotizing glomerulonephritis and vasculitisANCA-disease responds to immunosuppressive treatmentANCA titers correlate with disease activityThere is no evidence for anti-GBM or immune complex mediation of pauci-immune ANCA vasculitisDrug-induced ANCA are associated with pauci-immune necrotizing vasculitis that disappears with discontinuation of the drug

In vivo experimental evidence:Animals with genetically determined or drug induced polyclonal B cell activation develop ANCA along with other autoantibodies, and

develop glomerulonephritis and vasculitisRats immunized with human MPO develop anti-MPO that cross-reacts with rat MPO. Subsequent renal perfusion with MPO results in

glomerulonephritis and vasculitisRats injected with subnephritogenic doses of anti-GBM in the presence of anti-MPO develop glomerulonephritisANCA are induced in mice by an anti-idiotype network response to human c-ANCA and develop pulmonary inflammation

In vitro experimental evidence:ANCA stimulate cytokine-primed neutrophils to degranulate and release toxic oxygen metabolitesANCA-activated neutrophils kill cultured endothelial cellsANCA-antigens adsorb to endothelial cells where they could participate in immune complex formationEndothelial cells may synthesize PR3

a Printed with permission from reference [11]

MPO antibodies developed a more-severe glomerular in-flammation than if injected with anti-MPO antibodiesalone.

Experimental data suggest that the activation of neu-trophils by ANCA probably involves multiple synergis-tic events, including translocation of the major target an-tigens, MPO and PR3, to the outer cell surface when thecells are activated with cytokines [interleukin-1 (IL-1),tumor necrosis factor-α] or as they undergo apoptosis[17]. If cytokine-primed leukocytes are then exposed toanti-MPO or anti-PR3, the antibodies bind the antigen,cross link Fcγ II receptors, and cause the cells to degran-ulate, undergo a respiratory burst, and damage co-cul-tured endothelial cells [18, 19]. Cockwell et al. [20] haveshown that ANCA also stimulate the release of IL-8 andthey have identified IL-8 mRNA in the inflamed glomer-uli of patients with ANCA-associated glomerulonephritisat segmental, crescentic, and parietal epithelial sites. Itseems that some yet unknown stimulus leads to the initi-ation of vascular damage and production of circulatingANCA autoantibodies. It is possible that locally activat-ed leukocytes with exposed antigen are engaged by cir-culating ANCA, leading to degranulation and release ofproteases, reactive oxygen species, and lipid mediators,with the simultaneous release of IL-8 and other chemo-kines setting up a paracrine loop thereby amplifying in-flammation [21]. It is conceivable that ANCA are theconsequence and not the cause of the inflammatory re-sponse.

The value of using ANCA titers to monitor the natu-ral history of renal vasculitis and help in the early diag-nosis of clinical relapses is controversial [12, 22]. Inmost patients the titers decrease during effective immu-nosuppressive treatment, although in 22%–55% whoachieve remission, ANCA positivity persists at a low tointermediate titer [23, 24, 25]. Patients with a persistent-ly elevated ANCA titer at clinical remission tend to havehigher relapse rates [24, 25].

Can pulmonary disease present asynchronously after isolated renal manifestations of Wegener granulomatosis?

ANCA-SVV has a predilection for the capillary beds ofthe respiratory tract [2, 26, 27]. Fifty percent of patientswith ANCA-positive glomerulonephritis have a spec-trum of pulmonary disease from severe life-threateningpulmonary hemorrhage to alveolar infiltrates. Pulmonaryinvolvement without renal manifestations is common atthe onset of SVV. Among the 158 patients studied at theNational Institutes of Health (NIH), 18% of those withWegener granulomatosis presented with evidence of glo-merulonephritis, but renal disease eventually occurred in77%, usually in the first 2 years of the illness [28]. How-ever, a delayed variant of Wegener granulomatosis hasbeen noted in 19 patients in whom typical respiratorymanifestations became apparent 1–7 years after the onsetof glomerulonephritis [29]. These patients presentedwith acute nephritis without the typical respiratory mani-

festations of Wegener granulomatosis. There were 13 fe-males and the age of onset ranged from 12 to 65 years.The renal findings in the classical and delayed formswere similar. The delayed variant was usually diagnosedas microscopic polyangiitis or idiopathic glomerulone-phritis. It is difficult to avoid a misdiagnosis because theglomerular lesion is not specific and renal granulomassuggestive of Wegener granulomatosis are rarely seen in kidney biopsy specimens. A specific diagnosis of Wegener granulomatosis helps in the institution and con-tinuance of immunosuppressive treatment, despite pro-gression of the rapidly progressive glomerulonephritis toESRD. Specific treatment may be started early during apulmonary relapse if clinicians are aware that Wegenergranulomatosis may present with primary glomerulone-phritis and become active again during chronic renalfailure and while on dialysis. There is a perception thatthe activity of Wegener granulomatosis in patients withESRD is suppressed [30, 31, 32], but continued diseaseactivity occurs during regular hemodialysis [33, 34]. It isunclear whether periods of low or absent disease activityin some patients on dialysis are due to the waxing andwaning nature of Wegener granulomatosis or a result ofthe temporary suppression of the disease by the immunedysfunction of uremia [35, 36, 37]. A retrospective anal-ysis of the clinical course of 35 patients with Wegenergranulomatosis and ESRD during chronic dialysis re-vealed patient survival rates of 93% after 2 years and79% after 5 years [38]. This yielded a relapse rate of0.24/patient per year. The authors concluded that the re-lapse rate was no different from that of non-dialyzed pa-tients and emphasized the need to maintain treatment forlong-term remission in dialysis patients.

Optimal therapy for the ANCA-associated vasculitis

Treatment of ANCA-associated vasculitis generally con-sists of corticosteroids and cyclophosphamide. Inductiontherapy can be started while awaiting the results of therenal biopsy. Most nephrologists prescribe three intrave-nous infusions of methylprednisolone before starting oralcorticosteroids, although no controlled trials have beenperformed to demonstrate the advantages of this more-aggressive approach [6]. Induction therapy generallyconsists of cyclophosphamide, although plasmapheresishas been used for fulminant disease. Pusey et al. [39]performed a randomized control trial to determine ifplasma exchange was of additional benefit in patientstreated with oral immunosuppressive drugs for focal ne-crotizing glomerulonephritis. They noted that patientswho were initially dialysis dependent were more likelyto have recovered renal function if treated with plasmaexchange as well as drugs.

Cyclophosphamide is administered either intrave-nously or orally. Intravenous cyclophosphamide can begiven at monthly intervals in a dose of 0.5 g/m2, with ad-justment of the dose upward on the basis of a 2-weekleukocyte count [40, 41]. “Fauci scheme” uses an oral

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dose of cyclophosphamide of 2 mg/kg per day for activedisease and 3–4mg/kg per day for progressive or fulmi-nant disease [42], which is maintained until remission isachieved and is always combined with corticosteroids.The optimal duration of cyclophosphamide therapy re-mains undetermined. In adults, prolonged oral cyclo-phosphamide treatment is associated with serious risks,such as transitional cell carcinoma and lymphoma, theoncogenic potential in children is unknown [10, 43]. Talar-Williams et al. [43] reported an incidence of 5%for bladder cancer in adults 10 years after exposure tocyclophosphamide. Treatment can be stopped in patientswho achieve complete remission within 6 months ofstarting therapy [5] with close follow-up. Patients withpersistently active disease should be treated for at least12 months. Intravenous cyclophosphamide was intro-duced for the therapy of ANCA-associated SVV to re-duce the cumulative toxicity of the drug. In an analysisof 43 patients, pulse cyclophosphamide appeared to beeffective in moderately active and limited disease, butnot in the very ill [25]. However, two groups of nephrol-ogists reported that the outcome of pulse cyclophospha-mide was comparable to daily administration [40, 44]. Acontrolled trial of pulse versus oral continuous cyclo-phoshamide showed a slightly higher incidence of leuko-penia in patients on oral continuous cyclophosphamide[45]. Gonadal toxicity was studied with different modesof cyclophosphamide therapy in men with vasculitis orminimal change glomerulonephritis by measurement oflevels of follicle-stimulating hormone and in Lewis ratsby studying testicular histology [46]. A higher incidenceof gonadal toxicity was found after oral treatment.

Prednisone is used with cyclophosphamide, generallyat a dose of 1 mg/kg per day for the 1st month and thentapered to alternate-day therapy in the 2nd month, withcessation of therapy at the end of the 3rd to 4th month[5].

Methotrexate has been used in Wegener granulomato-sis, especially in patients who have near-normal renalfunction and in patients with vasculitides predominantlyconfined to the kidneys [47]. Trimethoprim-sulfameth-oxazole, methotrexate, azathioprine, and cyclosporinehave all been used for maintenance of remission [42]. Intravenous immunoglobulins, monoclonal antibodies(anti-CD4+), and anti-thymocyte globulin have beenused to treat refractory disease [42].

Treatment of relapses

Most cases of ANCA-associated SVV treated with eitherintravenous or oral cyclophosphamide have a long-termremission rate of 60%–85%. Relapses occur in up to40% of patients within a mean of 18 months of stoppingtherapy [5]. Full-blown vasculitic relapse should betreated with a repeat course of prednisone and cyclo-phosphamide, followed by maintenance immunosuppres-sion.

Treatment of dialysis-dependent patients

Up to 20% of patients with ANCA-SVV and glomeru-lonephritis require dialysis at the time of diagnosis, andhalf may come off dialysis within 8–12 weeks. Dialy-sis-dependent patients were treated for at least 8–12weeks with pulse methylprednisone and oral predni-sone, in patients whose renal function improved cor-ticosteroids were continued and cyclophosphamide wasstarted [5].

Role of trimethoprim-sulfamethoxazole in preventing relapse of Wegener granulomatosis

De Renee et al. [48] suggested that local regional diseaseof the upper respiratory tract should be treated first withtrimethoprim-sulfamethoxazole and then with corticoste-roids in the event of unsuccessful antibacterial therapy.This approach was based on the fact that chronic nasalcarriage of Staphylococcus aureus is a risk factor for re-lapses in Wegener granulomatosis [49]. Of 100 patients,11 improved on trimethoprim-sulfamethoxazole, and 4of those were not on any immunosuppressive agents.Similar results were found in 19 patients with Wegenergranulomatosis restricted to the upper and lower airways[50]. A prospective placebo-controlled trial with trimeth-oprim-sulfamethaxozole (960 mg twice daily) in 81 pa-tients showed a statistically significant reduction in thenumber of relapses limited to the upper respiratory tract[51]. However, conflicting data emerged from a random-ized trial comparing methotrexate and trimethoprim-sul-famethaxozole for maintenance of remission in 65 pa-tients with Wegener granulomatosis in whom trimetho-prim-sulfamethaxozole and prednisone together seemedto increase the chance of relapse [52]. As a result its usein Wegener granulomatosis remains controversial.

The timing of transplant in Wegener granulomatosis

Patients with end-stage disease caused by ANCA-asso-ciated vasculitis were once considered unsuitable fortransplantation. However, it is now accepted that ANCA-SVV rarely recurs after renal transplantation [5]. Trans-plantation may proceed in patients in clinical remissionwith negative ANCA titers. Transplantation may be de-ferred in patients who have had a persistently negativeANCA titer who then develop a marked rise in titer.However, in patients who have persistently high ANCAtiters but no clinical evidence of disease, it is reasonableto proceed with transplantation. Disease frequently re-curs following transplantation in organs other than thekidney [53, 54, 55, 56]. The relapse rate for Wegenergranulomatosis was appreciably lower in patients receiv-ing azathioprine than in those treated with cyclosporine(20% vs. 71%) [55], and a lower recurrence rate wasfound with a triple regimen in which azathioprine or cy-clophosphamide were added to cyclosporine and steroids

[56]. Relapse of the vasculitis (in all organs) occurs in-frequently (12%), despite the persistence of positiveANCA titers [57]. None of the 13 patients with Wegenergranulomatosis who received 14 renal transplants (10 ca-daveric, 4 living-related) over 50 months developed re-currence [58].

Wegener granulomatosis and tuberculosis

Granulomatous inflammation is seen in pulmonary tuber-culosis and in non-tuberculous mycobacterial infections.Marchevsky et al. [59] evaluated the clinical and patho-logical features of 40 patients in whom non-tuberculousmycobacteria were found in open-lung biopsy specimens.They identified patients with distinct pulmonary lesions,such as solitary pulmonary nodules with granulomas anddiffuse interstitial infiltrates with fibrosis and pneumonia.One of their patients with multiple discrete infiltrates hadnecrotizing granulomatous vasculitis indistinguishablefrom Wegener granulomatosis. This patient was treatedwith cytotoxic medications, with a partial clinical re-sponse. It is possible that in this patient and ours Myco-bacterium avium intracelullare was a commensal, since itwas recovered only from the BAL and not from a tissueculture. A form of vasculitis is also well known in tuber-culosis, and hence it should be considered in the differen-tial diagnosis of granulomatous necrotizing pulmonary le-sions with vasculitis.

Questions and answers

Q. Does the eosinophilic infiltration resolve with thetreatment of Wegener granulomatosis? (Kathy Jabs,M.D., Assistant Professor of Pediatrics, The Children’sHospital of Philadelphia)A. The eosinophilic infiltration in Wegener granulomato-sis is not as marked as in Churg-Strauss syndrome. It con-tributes to granuloma formation and disappears with glu-cocorticoid therapy as the eosinophils undergo apoptosis.Q. Which diseases are associated with positive ANCA ti-ters? (Madhura Pradhan, M.D., Renal Fellow, The Chil-dren’s Hospital of Philadelphia)A. ANCA are found in a number of diseases includingWegener granulomatosis, microscopic polyangiitis, idio-pathic pauci-immune crescentic glomerulonephritis, Anti-GBM disease, Churg-Strauss syndrome, Kawasaki dis-ease, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease (prevalence is 50%–80% inulcerative colitis and 10%–40% in Crohn disease), pri-mary sclerosing cholangitis, chronic active hepatitis, andhuman immunodeficiency virus infection.Q. Why do ANCA titers have such an inconsistent corre-lation with disease activity? (Jarred Scott, M.D., RenalFellow, Hospital of the University of Pennsylvania)A. It is unclear why ANCA titers are useful in monitor-ing disease activity in some patients but not in others.Various longitudinal studies have shown that titers of

ANCA rise prior to a relapse of vasculitis [24]. Howeverthese data were challenged by a report from NIH [60].Persistently or intermittently positive tests for ANCA inpatients who go into remission have been shown to be arisk factor for an ensuing relapse. Treatment cannot bebased on a rise in ANCA titers.Q. Can one use mycophenolate mofetil (MMF) to main-tain a clinical remission in Wegener granulomatosis?(Roy Bloom, M.D., Assistant Professor of Medicine,Hospital of the University of Pennsylvania)A. There is growing evidence that MMF can be used tomaintain remission in patients with systemic vasculitis.It acts by impairment of de novo purine synthesis. It isrelatively selective for lymphocytes and inhibits anti-body production by B cells more than other immunosup-pressants. Nowack et al. [61] treated four patients withsystemic vasculitis with 2 g MMF daily in combinationwith oral corticosteroids after standard induction therapy.They found no relapses of vasculitis and a decrease inANCA titers in all four patients.Q. What is the incidence of post-transplant lymphopro-liferative disease (PTLD) in patients with Wegener gran-ulomatosis and renal allografts? (Robert Grossman,M.D., Professor of Medicine, Hospital of the Universityof Pennsylvania)A. Patients with Wegener granulomatosis have renal al-lograft survival at 1 and 3 years that is comparable toother allograft recipients. The incidence of PTLD in thispopulation is unknown.

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