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Arterial Aneurysms in Wegener’sGranulomatosis: Case Report and Literature Review

Jean-Benoit Arlet, MD,* Du Le Thi Huong, MD, PhD,*Antonio Marinho, MD,* Philippe Cluzel, MD,†

Bertrand Wechsler, MD,* and Jean-Charles Piette, MD*

Objective: Arterial aneurysms are characteristic of medium-size vessel vasculitis but are a veryunusual feature of Wegener’s granulomatosis (WG). We describe a typical WG case, complicatedby arterial aneurysms and review previously reported cases.Methods: Medline database search of cases published between January 1978 and July 2006, inEnglish, reporting arterial aneurysms complicating WG.Results: Five years after diagnosis, a 29-year-old man with typical WG developed macro- andmicroaneurysms located on branches of the hepatic and renal arteries during a disease relapse. Themain symptoms were abdominal pain, vomiting, and altered general status. He was successfullytreated by coil embolization in combination with prednisone, intravenous mycophenolate mofetil,and high-dose immunoglobulins. Twelve additional cases of WG complicated by arterial aneu-rysms are reported in the English literature. This represents a life-threatening complication sincerupture occurred in half of the patients.Conclusions: Although small-vessel injury predominates in WG, inflammation of medium-sizearteries may occur and lead to aneurysm formation. Abdominal angiography should be recom-mended when unexplained abdominal pain occurs during a WG flare.© 2008 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 37:265-268Keywords: aneurysm, Wegener’s granulomatosis, intravenous immunoglobulins, intestinal perforation

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egener’s granulomatosis (WG) is a small-vesselvasculitis involving primarily the respiratorytract and kidneys. Histological examination

eveals necrotizing vasculitis affecting mostly small-sizeessels (eg, capillaries, venules, and arterioles). It may alsoffect larger arteries, and thus, the vascular distributionverlaps with that of the medium- and large-size vesselasculitides (1). Chronic inflammation can lead to arterialneurysm formation, a characteristic of medium-size ves-el vasculitis, but a very unusual feature of WG. This caseeport presents a patient with typical WG who developedeveral aneurysms in branches of the hepatic and renalrteries during a relapse.

Department of Internal Medicine, La Pitié-Salpétrière Hospital, Paris, France.†Department of Radiology, La Pitié-Salpétrière Hospital, Paris, France.The authors have no conflicts of interest to disclose.

lAddress reprint requests to: Jean-Benoit Arlet, 15 rue du puits de l’Ermite, 75005

aris, France. E-mail: jb.arlet@libertysurf.fr.

049-0172/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1016/j.semarthrit.2007.07.004

ETHODS

literature survey from January 1978 to July 2006 waserformed using a MEDLINE (PubMed), searching forases with coexisting WG and aneurysm. Only cases pub-ished in English with sufficient clinical data for analysisere reviewed.

ASE REPORT

n Algerian man, born in 1973, was admitted to ourepartment of internal medicine in January 2003, be-ause of weight loss, vomiting, and epigastric pain. Head been diagnosed with WG in May 1997 on the basis ofasal ulcerations with epistaxis, nasal perforation and sad-le-nose deformity, sinusitis, orchitis, polyarthralgias,yalgias, subcutaneous nodules, polyneuropathy, and

cute renal insufficiency related to pauci-immune cres-entic glomerulonephritis. Histological examination ofkeletal muscle biopsy showed medium-size artery vascu-

itis. Cytoplasmic antineutrophilic cytoplasmic antibody

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266 Arterial aneurysms in Wegener’s granulomatosis

ANCA) with antiproteinase-3 (anti-PR-3) specificityas present. Serologic tests for hepatitis B, C, and human

mmunodeficiency virus (HIV) were negative. Remissionas obtained with 1 mg/kg daily prednisone, monthly

ntravenous 1.2 g cyclophosphamide pulses, replaced ineptember 1999, after the ninth pulse, by azathioprine50 mg daily. At that time, daily prednisone dose was 20g, and ANCA testing was negative.In September 2002, while the patient had been receiv-

ng prednisone 10 mg/d, azathioprine 150 mg/d, and

igure 1 Common hepatic artery angiography showed a 2-cm-iameter aneurysm located on the superior pancreatic-duodenalrtery and multiple microaneurysms of the hepatic branches.

Table 1 Large- and Medium-Size Vessels Aneurysms in We

ReferencesGenderAge (y) Criteria for Diagno

Sieber (3) M/59 Clinical picture, NGV, cANBlockmans (4) M/42 Clinical picture, NGV, PR3Carels (5) M/63 Clinical picture, NGV, MPShirit (6) M/58 Clinical picture, pulmonar

MPO-ANCA �Senf (7) M/35 Clinical picture, NGV, PR3

Backer (8) M/24 Clinical picture, NGVMoutsopoulos (9) M/30 Clinical picture, NGV

F/53 Clinical pictureFamularo (10) M/67 Clinical picture, NGV, PR3Aoki (2) M/56 Clinical picture, NGV, PR3Den Bakker (11) M/55 Clinical picture, NGV, PR3Takei (12) M/34 Clinical picture, PR3-cANCPresent study M/29 Clinical picture, NGV, PR3

M, male; F, female; WG, Wegener’s granulomatosis; NGV, bioppauci-immune crescentic glomerulonephritis; PR3-cANCA, cytopla

ANCA, myeloperoxidase-ANCA; CY, cyclophosphamide; NS, not stated, I

rimethoprim-sulfamethoxazole, he developed rhinitis,odular lesions of the elbows and ear lobe, myalgias, hema-uria, and proteinuria (1.2 g/24 hour). Histological exami-ation of skin nodules showed perivascular giant-cell granu-

oma and necrotizing vasculitis involving small arteries.nti-PR3 antibody titer was 35 IU/mL (N � 10). The pa-

ient received prednisone 35 mg daily (patient declined a 1g/kg/d dosage) and 3 methylprednisolone pulses, alongith monthly 1.4 g intravenous cyclophosphamide pulses.In January 2003, while on a prednisone dose of 27.5g daily, he complained of persistent epigastric pain,

omiting, a 15-kg weight loss during the previous 3onths, and rhinitis. His abdomen was moderately ten-

er in the epigastric quadrant, without rigidity. Nodularkin lesions located on the elbows and ears persisted, andower limb purpura and left big toe ischemia appeared.aboratory tests showed the following: leukocyte count,0,000/mm3; hemoglobin, 9.9 g/dL; C-reactive protein,57 mg/L; serum albumin, 24 g/L; normal serum lipase,icroscopic hematuria, proteinuria 2.3 g/24 hour; serum

reatinine, 127 �mol/L; and anti-PR3 ANCA antibodies,5 IU/mL. Sinus computed tomography (CT) scanhowed left maxillary sinusitis and chest CT scan wasormal. Upper digestive fibroscopy revealed oesophagitisnd abdominal echography showed a 2 � 2 � 3 cmneurysm near the pancreas head. Abdominal CT scanonfirmed the presence of a 2-cm-diameter aneurysm lo-ated on the superior pancreatic-duodenal artery andultiple microaneurysms in the hepatic and renal arteries

ranches (Fig. 1), parietal thickening of the small bowel,nd splenic infarction.

The patient was then treated by coil embolization ofhe largest aneurysm and methylprednisolone pulses (1g

s Granulomatosis: Literature Review

WG

Duration BetweenAneurysm andWG Diagnosis Involved Artery

9 months before AortaA � PICG Concomitant Aorta

CA � Concomitant Aortaillaritis, Concomitant Subclavian

A � 1 month after Hepatic, renal,splanchnic

Concomitant Renal4 months after Renal1 month after Renal

A � PICG 1 month after Pancreatic-duodenalA � Concomitant Left gastricA � PICG 15 days after HepaticICG 1 year before IntracranialA � PICG 5 years after Pancreatic-duodenal,

hepatic, renal

ven necrotizing granulomatous vasculitis; PICG, biopsy-provenntineutrophil cytoplasmic antibody with anti-proteinase 3; MPO-

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VIg, intravenous immunoglobulin; MMF, mycophenolate mofetil.

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aily for 3 days) were resumed, followed by 60 mg dailyrednisone. Intravenous cyclophosphamide was stoppednd replaced by intravenous mycophenolate mofetil (2.5daily). High-dose intravenous immunoglobulin (1g/kgaily) was given for 2 days every 3 weeks.In March 2003, acute abdominal pain and shock oc-

urred, a result of peritonitis secondary to small bowelerforation. A resection of 25 cm of ileum was followedy an ileostomy. Histological examination showed necro-izing vasculitis of small- and medium-size arteries with-ut active inflammation. ANCA testing was negative.bdominal CT scan did not show a recurrence of mac-

oaneuryms.A high fever (39°C) appeared in April with an increase

f C-reactive protein from 6 to 84 mg/L. Chest CT scanevealed multiple nodular opacities, while ANCA testingas negative. Bronchoscopy showed granulomatous le-

ions in the right bronchus but histological study uncov-red only nonspecific inflammation. Bronchoalveolar la-age showed intraalveolar hemorrhage. Another chest CTcan was performed 15 days later as the fever persistedespite 2 g daily of mycophenolate mofetil, intravenous

mmunoglobulins and high-dose prednisone, and the ad-ition of 100 mg daily oral cyclophosphamide. It showedilateral pleuritis, necrotic mediastinal lymphadenopa-hy, and multiple excavated pulmonary nodules. A secondronchoscopy showed the disappearance of granuloma-ous lesions. Bacteriologic study of the bronchoalveolaravage showed Pseudomonas aeruginosa resistant to tazocil-in, and Mycobacterium tuberculosis resistant to rifampi-in, ethambutol, izoniazid, and streptomycin. Cyclo-hosphamide and mycophenolate mofetil were stopped,ut intravenous immunoglobulins and prednisone were

Table 1 Large- and Medium-Size Vessels Aneurysms in We

Presentation

Abdominal pain, weight loss, nauseaAbdominal pain, weight loss, nauseaLow back pain, weight loss, feverIschemic painful hand

Left flank pain, shock, perinephritic hematoma

Right flank pain, shock, perinephritic hematomaNSSystematic renal angiographyAbdominal pain, shock, intraperitoneal hemorrhageShock, cardiac arrest, intraperitoneal hemorrhageRight upper quadrant pain, intraperitoneal hemorrhage, caSubarachnoid hemorrhageAbdominal pain, weight loss, vomiting

aintained. Antituberculous therapy included amikacing every 72 hours for 1 month, and daily doses of pyra-

inamide 1.5 g, moxifloxacin 400 mg, and ethionamideg for 2.5 years.In July 2004, intestinal continuity was restored, while

he daily prednisone dose was 20 mg. In September 2005,zathioprine 100 mg daily was started and the intravenousmmunoglobulin dose was progressively tapered. In

arch 2007, the patient was still in remission on azathio-rine 100 mg daily, 1 g/kg monthly intravenous immu-oglobulin, and prednisone 15 mg daily. ANCA testingas negative.

ISCUSSION

e report an unusual and severe case of WG with multipleneurysms located on medium-sized arteries. The diagnosisf WG was based on typical characteristics: rhinitis and si-usitis, pauci-immune crescentic glomerulonephritis, in-raalveolar hemorrhage, and polyneuropathy. Histologicaltudies showed giant-cell granuloma and/or necrotizingranulomatous inflammation of medium and small vesselsn the skin, muscle, and gastrointestinal tract. Anti-PR3 an-ibodies were present.

Aneurysms are an uncommon feature of WG, althoughhey are present in 50 to 60% of the cases of polyarteritisodosa (PAN). By definition, PAN does not involve smallessels or glomeruli and there are no granuloma. Neitheraddle-nose deformity nor c-ANCA are features of PAN. Byefinition, WG can involve small- and medium-size vessels1). Hence, we do not believe that our patient suffered frompolyangiitis overlap syndrome” (2), but that the aneurysmsere a specific complication of WG.

s Granulomatosis: Literature Review (continued)

Therapy Outcome

Dacron bypass RecoveryAortoiliac bypass, steroids, CY RecoveryAorto-iliac bypass, steroids RecoveryStent, prostacyclin, anticoagulation

Supportive therapy, steroids, CY,plasmapheresis

Recovery

Gelfoam embolization, steroids, CY RecoverySteroids, CY NSSteroids, CY NSRupture repair DeathResuscitation Death

arrest Resuscitation DeathClip RecoveryCoil embolization, steroids, CY,

IVIg, MMFRecovery

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268 Arterial aneurysms in Wegener’s granulomatosis

A MEDLINE search of the medical literature revealedother cases of WG complicated with aneurysms locatedn large vessels (3-6), and 8 cases of aneurysms located onedium-size vessels (2, 7-12): branches of renal (n � 4),

epatic (n � 3), gastric (n � 2), splanchnic (n � 1), anderebral (n � 1) arteries (Table 1) Large- and medium-ize vessel aneurysms were observed more commonly inen (n � 11) and occurred at the onset (n � 10) rather

han during the course of the disease (2, 4-9, 11). How-ver, in our patient aneurysms occurred 5 years after di-gnosis, and 4 months after the onset of a severe poorlyontrolled relapse. In only 2 cases, aneurysms were dis-overed before the onset of manifestations resulting frommall-size vessel involvement, such as pulmonary capil-aritis and glomerulonephritis (3, 12). All these patientsad diffuse disease with marked weight loss, upper and

ower respiratory tract involvement, and glomerulone-hritis. Abdominal pain was the most common warningign of intraabdominal arterial aneurysm.

Aneurysm formation in WG is a life-threatening com-lication since rupture occurred in half of the patientsn � 6), leading to death from abdominal bleeding in 32, 10, 11). Autopsy showed granuloma involving theneurysm wall in 1 case (10). In the other 3 patients thaturvived, aneurysm rupture led to subarachnoid hemorrhagereated by clip (12), perinephritic hematoma with shockreated by embolization (8), or supportive therapy (7). In theemaining 6 patients who did not experience aneurysm rup-ure, disease remission was obtained with prednisone andyclophosphamide (3-6, 9).

Our patient also developed intestinal ischemia leadingo perforation. Intestinal ischemia is uncommonly re-orted in WG, although gut involvement was detected atecropsy in 24% of cases in previous studies (13). Store-und and coworkers (14) identified only 6 cases of WGith intestinal ischemia in the medical literature in 1998.

ntestinal manifestations appeared during the first 2 yearsf WG and were reported exclusively in patients exhibit-ng lung and kidney involvement. Intestinal ischemia re-urred 9 years later in 1 patient. Acute abdominal painnd peritonitis were the main manifestations. Four casesere complicated by intestinal perforation; both small

nd large bowel may be involved. In only 3 histologicaltudies did biopsy prove bowel vasculitis involving small- oredium-sized arteries (14). Five of 6 patients underwent

urgery successfully and 1 patient died from sepsis. Pred-isolone associated with cyclophosphamide, chlorambucil,r azathioprine was used (14).

In summary, abdominal pain occurring during a WGare may result from intestinal vasculitis, which may

ause rare life-threatening disease complications (ie, arte-

ial aneurysms and/or perforation/hemorrhage). After anbdominal echography, a CT scan should be rapidly per-ormed to search for bowel parietal thickening or abdom-nal aneurysms. If the imaging is not conclusive, angiog-aphy should be considered. Treatment of aneurysmalasculitis should combine aneurysm embolization whenossible, with prompt high-dose prednisone and immu-osuppressive agents to prevent life-threatening rupture.

CKNOWLEDGMENT

e thank Jacques Pouchot, MD, for critically reviewinghe manuscript.

EFERENCES

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3. Sieber SC, Cuello B, Gelfman NA, Garfinkel HB. Pulmonarycapillaritis and glomerulonephritis in an antineutrophil cytoplas-mic antibody-positive patient with prior granulomatous aortitis.Arch Pathol Lab Med 1990;114:1223-6.

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5. Carels T, Verbeken E, Blockmans D. p-ANCA-associated peri-aortitis with histological proof of Wegener’s granulomatosis: casereport. Clin Rheumatol 2005;24:83-6.

6. Shitrit D, Shitrit AB, Starobin D, Izbicki G, Belenky A, KaufmanN, et al. Large vessel aneurysms in Wegener’s granulomatosis. JVasc Surg 2002;36:856-8.

7. Senf R, Jurgensen JS, Teichgraber U, Kampf D, Schindler R.Ruptured arterial aneurysm of the kidney in a patient with We-gener’s granulomatosis. Nephrol Dial Transplant 2003;18:2671-3.

8. Baker SB, Robinson DR. Unusual renal manifestations of Wege-ner’s granulomatosis. Report of two cases. Am J Med 1978;64:883-9.

9. Moutsopoulos HM, Avgerinos PC, Tsampoulas CG, KatsiotisPA. Selective renal angiography in Wegener’s granulomatosis.Ann Rheum Dis 1983;42:192-5.

0. Famularo G, De Cata A, Bracci M, Minisola G, De Simone C,Nicotra GC. Fatal rupture of an inflammatory arterial aneurysmin a patient with Wegener’s granulomatosis. Scand J Rheumatol2004;33:277-9.

1. den Bakker MA, Tangkau PL, Steffens TW, Tjiam SL, van derLoo EM. Rupture of a hepatic artery aneurysm caused by Wege-ner’s granulomatosis. Pathol Res Pract 1997;193:61-6.

2. Takei H, Komaba Y, Kitamura H, Hayama N, Osawa H, Fu-rukawa T, et al. Aneurysmal subarachnoid hemorrhage in a pa-tient with Wegener’s granulomatosis. Clin Exp Nephrol 2004;8:274-8.

3. Walton EW. Giant cell granuloma of the respiratory tract (We-gener’s granulomatosis). BMJ 1958;2:265-70.

4. Storesund B, Gran JT, Koldingsnes W. Severe intestinal involve-ment in Wegener’s granulomatosis: report of two cases and review

of the literature. Br J Rheumatol 1998;37:387-90.