Efh Van Bommel
email: e.f.h.vanbommel@asz.nl

S J Van Der Veer

T R Hendriksz

G S Bleumink

Persistent chronic peri-aortitis ('inflammatory aneurysm') after abdominal aortic aneurysm repair: systematic review of the literature

Keywords: aortic aneurysm repair, chronic peri-aortitis, endovascular, inflammatory aneurysm, open surgical, peri-aortic fibrosis, ureteral obstruction

Persistent chronic peri-aortitis ('inflammatory aneurysm') after abdominal aortic aneurysm repair:

systematic review of the literature

Introduction

The combined findings of abdominal aortic aneurysm (AAA) and peri-aneurysmal fibrosis, usually described as 'inflammatory aneurysm', is considered one of the manifestations of retroperitoneal fibrosis (RPF) and characterized by chronic nonspecific inflammation of the retroperitoneum, which can entrap and obstruct retroperitoneal structures, notably the ureters. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Bommel | Retroperitoneal fibrosis[END_REF] In idiopathic RPF (i.e. where no causal factor can be identified), an exaggerated inflammatory response to advanced atherosclerosis has been implicated in its pathogenesis. [START_REF] Mitchinson | Retroperitoneal fibrosis revisited[END_REF][START_REF] Parums | The spectrum of chronic peri-aortitis[END_REF][START_REF] Baker | Auto-allergic periaortitis (idiopathic retroperitoneal fibrosis)[END_REF] It is for these reasons that some prefer the term chronic peri-aortitis to encompass idiopathic RPF and peri-aneurysmal fibrosis. [START_REF] Bommel | Retroperitoneal fibrosis[END_REF][START_REF] Mitchinson | Retroperitoneal fibrosis revisited[END_REF][START_REF] Parums | The spectrum of chronic peri-aortitis[END_REF][START_REF] Baker | Auto-allergic periaortitis (idiopathic retroperitoneal fibrosis)[END_REF] Peri-aneurysmal fibrosis may be suspected preoperatively in patients with abdominal, back and/or flank pain, weight loss, constipation, and elevated acute-phase reactants and serum creatinine level. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Baskerville | The diagnosis and treatment of peri-aortic fibrosis ('inflammatory' aneurysms)[END_REF] Contrast-enhanced computed tomographic (CT) scanning usually confirms the presumed diagnosis and is mandatory for proper planning of aneurysm repair. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Bommel | Retroperitoneal fibrosis[END_REF] CT reveals the aneurysm and thickened aortic wall, as well as the often welldelineated peri-aortic soft tissue mass with typical caudad extension to the iliac vessels. The posterior aspect of the aortic wall is usually spared and aortic displacement from the vertebrae is rare. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Bommel | Retroperitoneal fibrosis[END_REF] The mass is isodense to psoas muscle and may enhance after contrast injection. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Bommel | Retroperitoneal fibrosis[END_REF] Despite earlier reports suggesting otherwise, [START_REF] Rastogi | Bilateral obstruction following aortic bypass surgery[END_REF][START_REF] Vandendris | Ureteric obstruction secondary to aortic femoral bypass graft[END_REF][START_REF] Tracy | Ureteral obstruction from vascular prosthetic graft surgery[END_REF] it has long been assumed that surgical aneurysm exclusion will suffice in controlling the inflammatory process. Recently, however, the variable regression of peri-aortic fibrosis after surgical aneurysm exclusion has been noted. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Tang | Inflammatory abdominal aortic aneurysms[END_REF] Because management differs between centres, little is known about the incidence and postoperative course of ureteral obstruction in these patients and whether or not concomittant ureterolysis should be performed. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Tang | Inflammatory abdominal aortic aneurysms[END_REF] This is important as associated urological procedures may increase the risk of postoperative complications. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Bommel | Retroperitoneal fibrosis[END_REF][START_REF] Tang | Inflammatory abdominal aortic aneurysms[END_REF] Because of a lower risk for morbidity and mortality, endovascular aneurysm repair (EVAR) may be an alternative treatment option for high-risk patients with peri-aneurysmal fibrosis. [START_REF] Peterson | Five-year report of a multicenter controlled clinical trial of open versus endovascular treatment of abdominal aortic aneurysms[END_REF][START_REF] Norwood | Endovascular abdominal aortic aneurysm repair[END_REF][START_REF] Teruya | Inflammatory abdominal aortic aneurysm treated by endovascular stent grafting. A case report[END_REF][START_REF] Ruppert | Endovascular repair of inflammatory abdominal aortic aneurysms: a valuable alternative?case report and review of literature[END_REF][START_REF] Rehring | Regression of perianeurysmal fibrosis and ureteral dilatation following endovascular repair of inflammatory abdominal aortic aneurysm[END_REF] While it may have equally good results in terms of aneurysm exclusion and aneurysm rupture prevention, persistent or progressive peri-aortic fibrosis has been reported in patients treated with EVAR. [START_REF] Nevelsteen | Inflammatory abdominal aortic aneurysm and bilateral Persistent chronic peri-aortitis after abdominal aortic aneurysm repair 301 Vascular Medicine 2008; 13: 293-303 complete ureteral obstruction: treatment by endovascular graft and bilateral ureteric stenting[END_REF][START_REF] Barrett | Progression of peri-aortic fibrosis despite endovascular repair of an inflammatory aneurysm[END_REF][START_REF] Simons | Periaortitis with ureteral obstruction after endovascular repair of an abdominal aortic aneurysm. Case report[END_REF][START_REF] Jetty | Aortitis and bilateral ureteral obstruction after endovascular repair of abdominal aortic aneurysm[END_REF] These unclear and controversial issues prompted us to report four cases of persistent chronic periaortitis following surgical and endovascular aneurysm exclusion and to review systematically available data on this particular subject.

Materials and methods

Search strategy

The English, German and French language literature indexed in the PubMed and MEDLINE database was thoroughly searched for pertinent articles on open surgical or endovascular repair of inflammatory AAA from 1970 through October 2007. We used the (combined) Medical Subject Headings or text words 'surgical aneurysm repair', 'aortic bypass surgery', 'endovascular aneurysm repair', 'inflammatory aneurysm', 'peri-aortic fibrosis', 'perianeurysmal fibrosis', and 'chronic peri-aortitis'. We hand-searched reference lists of all identified studies and of review articles on the general topic of inflammatory aneurysm for further references. The titles and abstracts of all articles identified by the search strategy were screened for appropriateness before retrieval of full articles.

Selection and data extraction

Studies were included in the analysis if the following criteria were fulfilled: (1) inflammatory aneurysm was diagnosed according to accepted criteria; [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Mitchinson | Retroperitoneal fibrosis revisited[END_REF][START_REF] Baskerville | The diagnosis and treatment of peri-aortic fibrosis ('inflammatory' aneurysms)[END_REF] (2) open surgical or endovascular aneurysm exclusion was the intended treatment strategy; detailed information was available on at least one of the two primary outcome measures: (3) evolution of peri-aortic fibrosis, including data of repeated (i.e. baseline and follow-up) CT scanning allowing categorization of peri-aortic mass regression; and (4) the evolution of ureteral obstruction. We excluded studies on atherosclerotic (i.e. without inflammation) or mycotic aneurysm repair. Single case reports or data presented as abstracts only were also excluded from the analysis. Twenty-six retrospective and prospective case-series were identified as potentially relevant and full-text articles were retrieved for evaluation. Of these studies, five were excluded because of lack of data or inability to extract data on outcomes of interest. [START_REF] Pennell | Inflammatory abdominal aortic aneurysms: a thirty-year review[END_REF][START_REF] Lindblad | Abdominal aortic aneurysm with perianeurysmal fibrosis: experience from 11 Swedish vascular centers[END_REF][START_REF] Railo | Surgical treatment of inflammatory abdominal aortic aneurysms: a longterm follow-up of 19 patients[END_REF][START_REF] Yusuf | Inflammatory abdominal aortic aneurysm: predictors of long-term outcome in a case-control study[END_REF][START_REF] Todd | Retroperitoneal approach for repair of inflammatory aortic aneurysms[END_REF] Two other articles [START_REF] Puchner | Endovascular therapy of inflammatory aortic aneurysms: a meta-analysis[END_REF][START_REF] Deleersnijder | Endovascular repair of inflammatory abdominal aortic aneurysms with special reference to concomitant ureteric obstruction[END_REF] were excluded because data from these case-series were confirmed to be included in more recent articles. [START_REF] Puchner | Endovascular repair of inflammatory aortic aneurysms: long-term results[END_REF][START_REF] Lange | Results of endovacular repair of inflammatory abdominal aortic aneurysms. A report from the EURO-STAR database[END_REF] Hence, 19 studies were included in our statistical analysis. [START_REF] Plate | Management of inflammatory abdominal aortic aneurysm[END_REF][START_REF] Nachbur | The impact of computed tomography in the diagnosis and postoperative follow-up of ureteric obstruction in aorto-iliac aneurysmal disease[END_REF][START_REF] Stella | Postoperative course of inflammatory abdominal aortic aneurysms[END_REF][START_REF] Nitecki | Inflammatory abdominal aneurysms: a case-control study[END_REF][START_REF] Bitsch | Inflammatory aortic aneurysms: regression of fibrosis after aneurysm surgery[END_REF][START_REF] Koch | Intraoperative findings and postoperative CT-follow-up of inflammatory aortic aneurysms[END_REF][START_REF] Lacquet | Inflammatory abdominal aortic aneurysms. A retrospective study of 110 cases[END_REF][START_REF] Dimakakos | Management of inflammatory abdominal aneurysmsimmediate and late results[END_REF][START_REF] Fritchen | Inflammatory abdominal aortic aneurysm: a postoperative course of retroperitoneal fibrosis[END_REF][START_REF] Speziale | Inflammatory aneurysms of the abdominal aorta involving the ureters: is combined treatment really necessary[END_REF][START_REF] Pistolese | Postoperative regression of retroperitoneal fibrosis in patients with inflammatory abdominal aortic aneurysms. Evaluation with spiral computed tomography[END_REF][START_REF] Arroyo | Management and course of hydronephrosis secondary to inflammatory aneurysms of the abdominal aorta[END_REF][START_REF] Ockert | Long-term outcome of operated inflammatory aortic aneurysms[END_REF][START_REF] Vallabhaneni | Perianeurysmal fibrosis: a relative contra-indication to endovascular repair[END_REF][START_REF] Hinchliffe | Endovascular repair of inflammatory abdominal aortic aneurysms[END_REF][START_REF] Puchner | Endovascular repair of inflammatory aortic aneurysms: long-term results[END_REF][START_REF] Hechelhammer | Endovascular repair of inflammatory abdominal aneurysm: a retrospective analysis of CT follow-up[END_REF][START_REF] Faizer | Midterm followup of inflammatory abdominal aortic aneurysms following endovascular repair[END_REF][START_REF] Lange | Results of endovacular repair of inflammatory abdominal aortic aneurysms. A report from the EURO-STAR database[END_REF] The following data were extracted from each article: number of study patients with inflammatory AAA; age (years) and sex of the patients; followup duration after the intervention (months); number of patients with uni-or bilateral ureteral obstruction at presentation; type of procedure (open surgical or EVAR); number of patients with concurrent ureterolysis during open surgical aneurysm repair; number of patients with pre-operative CT scanning and at follow-up; number of patients with persistent ureteral obstruction after aneurysm repair; CTdocumented evolution of peri-aortic fibrosis (complete, partial or no regression; progression).

If a study reported data related to both atherosclerotic and inflammatory aneurysm repair, we extracted only the data for inflammatory aneurysm repair. [START_REF] Nachbur | The impact of computed tomography in the diagnosis and postoperative follow-up of ureteric obstruction in aorto-iliac aneurysmal disease[END_REF][START_REF] Nitecki | Inflammatory abdominal aneurysms: a case-control study[END_REF] Although not a prerequisite for inclusion, follow-up data on clinical signs and symptoms, which were present at baseline (i.e. number of patients with abdominal, back and/or flank pain; number of patients with a raised ESR and/or impaired renal function) were also extracted. If data could not be extracted with confidence, none was entered.

Statistical analysis

Data from most studies were reported as mean and range. In some instances, results were reported as median and range or mean and standard deviation. In cases where individual patient data were available, we chose to calculate the mean and range for continuous variables. Discrete variables are presented as absolute numbers and proportions (%).

To calculate overall data, patient characteristics of studies were pooled if individual patient data were available. When these data were lacking, study estimates were pooled to calculate the means. Differences in findings between study groups (i.e. open surgical versus EVAR) were assessed by the Fisher exact test for categorical variables and the Mann-Whitney test for continuous variables. Values of follow-up variables (i.e. number of patients with pain, raised ESR and impaired renal function) were compared with baseline values using the Fisher exact test. A two-sided p-value less than 0.05 was considered statistically significant.

Case reports

Case 1 A 45-year-old man was referred to the outpatient department of internal medicine with malaise, anorexia, weight loss and progressive pain in the abdomen and groin, radiating to the lower back. Physical examination revealed no abnormalities. Laboratory investigation showed elevated erythrocyte sedimentation rate (ESR) (49 mm/h) and C-reactive protein (CRP) (25 mg/l); serum creatinine was 79 μmol/l. Abdominal CT scanning showed a retroperitoneal fibrotic mantle enveloping a mildly dilated distal aorta and proximal iliac arteries. Chronic periaortitis was suspected and treatment was started with initial high-dose (60 mg/day) prednisone, which led to rapid relief of symptoms. Follow-up CT scanning at 5 months revealed significant regression of the peri-aortic mass. After tapering the prednisone dose to 15 mg, signs and symptoms recurred. Repeat CT scanning confirmed suspected recurrent disease. Combined therapy with azathioprine (150 mg once daily) and prednisone (60 mg once daily) was initiated, which led to rapid improvement in signs and symptoms. Despite combined immunosuppressive treatment for 1 year, he experienced two more recurrences necessitating repeated courses of combined therapy (azathioprine, prednisone, tamoxifen). Fifty-six months after the initial diagnosis, the patient sought a second opinion elsewhere, where surgical intervention was advocated. After gradually stopping medical treatment, the patient underwent resection of the atherosclerotic aorta with insertion of a tube graft prosthesis. Six months after surgery, signs and symptoms of chronic peri-aortitis recurred. Repeat CT scanning showed a large peri-aortic mass; gallium-67 scanning revealed intense pathologic activity. [START_REF] Van Bommel | Clinical value of gallium-67 SPECT scintigraphy in the diagnostic and therapeutic evaluation of retroperitoneal fibrosis. A prospective study[END_REF] Treatment was started with prednisone and cyclophosphamide, which led to rapid improvement. At the time of his latest follow-up, a second recurrence after surgical intervention necessitated re-introduction of immunosuppressive treatment.

Case 2 A 64-year-old man was referred to our outpatient department for evaluation of chronic kidney disease. Eleven months prior to presentation he underwent open surgical aortic aneurysm repair for inflammatory AAA. The patient experienced dull flank and lower back pain, constipation and weight loss of 4 kg in the last 4 months. Physical examination showed systolic hypertension (180/80), weak peripheral pulses of the lower extremities and a murmur over the femoral arteries. Relevant laboratory investigation included a normal ESR (17 mm/h) and increased serum creatinine (256 μmol/l). An abdominal CT scan showed extensive atherosclerotic dis-ease of the proximal abdominal aorta, prosthesis in situ, and peri-aortic fibrosis extending towards the aortic bifurcation (Figure 1). There was no hydronephrosis. Gallium scanning was negative. [START_REF] Van Bommel | Clinical value of gallium-67 SPECT scintigraphy in the diagnostic and therapeutic evaluation of retroperitoneal fibrosis. A prospective study[END_REF] Recurrent chronic peri-aortitis despite aneurysmectomy was suspected. Chronic kidney disease was thought to be due to chronic hypertension and generalized vascular disease. Treatment was started with tamoxifen 20 mg twice daily, which was well tolerated. Within 2 weeks his complaints improved significantly and pain subsided completely. Follow-up CT scanning at 4 months showed significant regression of the peri-aortic mass (Figure 1B). Tamoxifen treatment was continued for 2 years. At the time of his latest follow-up, 20 months after cessation of tamoxifen, the patient feels well and ESR is within the normal range. His latest CT scan showed stable residual peri-aortic fibrosis.

Case 3

A 76-year-old man was referred to our outpatient department with progressive abdominal and lower back pain, weight loss of 10 kg, pollakisuria and extreme tiredness of 9 months duration. Fourteen months before referral he had received an endovascular stent for treatment of an inflammatory infrarenal aortic aneurysm. Additionally, 2 months before referral endovascular stenting of a thoracic aortic aneurysm has been performed, which was complicated by a proximal type I endoleak. There were no abnormal findings on physical examination. Relevant laboratory investigation included an increased ESR (48 mm/h), CRP (80 mg/l) and serum creatinine 173 μmol/l. An abdominal CT scan showed periaortic (Figure 2) and peri-iliacal fibrosis with a normal left kidney and an atrophic hydronephrotic right kidney. Hydronephrosis was not seen on a CT scan performed elsewhere prior to the first endovascular procedure. Gallium-67 scanning showed increased pathologic activity at the level of the peri-aortic mass. Progressive chronic peri-aortitis despite endovascular aneurysmal exclusion was suspected and treatment was started with tamoxifen 20 mg twice daily, which resulted in some improvement of symptoms. Repeated gallium scanning at 3 months showed a decrease in pathologic gallium activity. Laboratory investigation revealed a decrease of the ESR to 15 mm/h and CRP to 11 mg/l, while creatinine remained stable. Follow-up CT scanning at 4 months showed no mass regression. Diseaseresponsiveness to tamoxifen was considered insufficient, upon which azathioprine 100 mg once daily was added to the treatment regimen. At the time of his latest follow-up, the patient feels well without any complaints. ESR and CRP are within the normal range. CT scanning after 8 months of medical treatment showed moderate regression of the fibrotic mass (Figure 2B).

Case 4

This 48-year-old man was referred to our outpatient department with persistent chronic peri-aortitis after aortic bifurcation graft implantation. Five months earlier, the patient was diagnosed in another hospital with peri-aneurysmal fibrosis complicated by bilateral hydronephrosis. He had suffered from fatigue, malaise, back pain, weight loss of 22 kg and fever. Physical examination revealed no abnormalities. The patient was treated with open surgical aneurysm repair combined with bilateral ureteral stenting. Ureteral catheters were removed 2 months later because of local bladder wall irritation. Three months after surgery, symptoms of fatigue and malaise were still very prominent. Lower back pain had diminished to a vague sensation. Fever and weight loss had disappeared. Repeat CT scanning revealed a large periaortic mass and hydronephrosis of the left kidney. The patient was then referred to our centre. At presentation, laboratory investigation showed normal ESR (14 mm/h) and CRP (7 mg/l); serum creatinine was 151 μmol/l. Gallium scanning was negative. Persistent chronic peri-aortitis was suspected and treatment was started with tamoxifen 20 mg twice daily. Additionally, a percutaneous nephrostomy catheter was inserted. Tamoxifen was well tolerated and led to rapid improvement of symptoms. CT scanning 4 months later showed significant regression of periaortic fibrosis. No improvement of renal function was observed, probably because of irreversible obstructive nephropathy.

Results

Characteristics of patients who were treated with open surgical aneurysm repair are depicted in Tables 1 and2. The mean age of the patients was 67 years (28-92), with a male predominance (82%). Follow-up CT data from patients who were treated with open surgical aneurysm repair (Table 2) showed regression of the peri-aortic mass in 86% of patients. Complete mass regression occurred in 52% of patients. Pre-operative ureteral obstruction was present in 103 of 337 (31%) patients from whom this data were available (Table 1). Overall, ureteral obstruction persisted in 27% at follow-up. To observe the natural evolution of ureteral obstruction after open surgical aneurysm repair per se, we excluded patients in whom concurrent ureterolysis was performed during surgery. After exclusion of this factor, persistent ureteral obstruction after open surgical aneurysm repair was present in 32% of patients (Figure 3).

Pooled data from the patients who were treated with the EVAR procedure are depicted in Tables 3 and4. The mean age of the patients was 67 years (range 56-82), with a male predominance (90%). CT follow-up in patients after the EVAR procedure (Table 4) showed regression of the peri-aortic mass in 60% of patients. Complete regression was observed in 14% of the patients. Pre-operative ureteral obstruction was present in 19 of 52 patients (37%). Ureteral obstruction persisted in 10 of these patients at follow-up (53%).

Comparison of both study groups showed no difference between age and sex (Table 5). Overall, follow-up duration did not differ between groups (p = 0.22). The number of patients with ureteral obstruction prior to intervention was also similar in both study groups. More patients treated with EVAR received additional corticosteroids than patients treated with open surgery, but we cannot ascertain if such data were actively searched for by all authors (Tables 1 and3). Comparison of CT follow-up data shows that regression of the periaortic mass not only occurs more frequently after open surgical aneurysm repair compared to EVAR, but also to a greater extent (Table 5).

Although rare, progression of the peri-aortic mass is also observed in some patients after both proce-dures (Table 2 and4). Overall, the number of patients with persistent ureteral obstruction at follow-up was lower in patients treated surgically compared to patients treated with EVAR (Table 5). After exclusion of patients in whom concurrent ureterolysis was performed during or shortly after intervention (open surgery, n = 34; EVAR, n = 1), this difference remained, albeit not statistically significant (Table 5). Few data were available on the evolution of clinical signs and symptoms of chronic peri-aortitis after aneurysm repair. Pooled data from four studies reporting on the short-term evolution of pain after open surgical aneurysm repair [START_REF] Plate | Management of inflammatory abdominal aortic aneurysm[END_REF][START_REF] Stella | Postoperative course of inflammatory abdominal aortic aneurysms[END_REF][START_REF] Nitecki | Inflammatory abdominal aneurysms: a case-control study[END_REF][START_REF] Fritchen | Inflammatory abdominal aortic aneurysm: a postoperative course of retroperitoneal fibrosis[END_REF] suggest that pain subsides in the majority of patients (patients with abdominal, back and/or flank pain: preoperative 67/96 [70%] vs postoperative follow-up 6/94 [6%]; p < 0.0001). Similarly, pooled data from three studies [START_REF] Plate | Management of inflammatory abdominal aortic aneurysm[END_REF][START_REF] Nachbur | The impact of computed tomography in the diagnosis and postoperative follow-up of ureteric obstruction in aorto-iliac aneurysmal disease[END_REF][START_REF] Stella | Postoperative course of inflammatory abdominal aortic aneurysms[END_REF] suggest that the ESR normalizes in the majority of patients after open surgical aneurysm repair (patients with raised ESR: preoperative 25/33 [75%] vs postoperative follow-up 6/32 [19%]; p < 0.001). Pooled data from three studies [START_REF] Plate | Management of inflammatory abdominal aortic aneurysm[END_REF][START_REF] Nitecki | Inflammatory abdominal aneurysms: a case-control study[END_REF][START_REF] Speziale | Inflammatory aneurysms of the abdominal aorta involving the ureters: is combined treatment really necessary[END_REF] showed persistently impaired renal function in a significant number of patients (preoperative 34/49 [69%] vs postoperative follow-up 30/44 [68%]; p = 1.0). Lack of data on the evolution of clinical signs and symptoms after the EVAR procedure precludes the performance of similar exploration.

Discussion

The present cases illustrate the sometimes recurring or ongoing inflammatory process in patients with chronic peri-aortitis despite aneurysm exclusion. Our systematic review of the literature indicates that in terms of regression of peri-aortic fibrosis, surgical aneurysm repair is superior to EVAR. However, persistent peri-aortic fibrosis occurs in 14% of patients treated with open surgical aneurysm repair. After the EVAR procedure, up to 40% of patients will not develop regression of peri-aortic fibrosis. There is a time-dependent regression of peri-aortic fibrosis after aneurysm exclusion, usually requiring at least 4-6 months, and the regression rate may be slow but persistent. [START_REF] Plate | Management of inflammatory abdominal aortic aneurysm[END_REF][START_REF] Nitecki | Inflammatory abdominal aneurysms: a case-control study[END_REF][START_REF] Bitsch | Inflammatory aortic aneurysms: regression of fibrosis after aneurysm surgery[END_REF] Better results with open surgery cannot be readily explained by a longer follow-up duration. To what extent the use of additional corticosteroids in some patients contributed to outcomes of interest is unclear. Although rare, de novo peri-aortic fibrosis has been observed after EVAR. [START_REF] Speziale | Inflammatory aneurysms of the abdominal aorta involving the ureters: is combined treatment really necessary[END_REF] Endovascular grafts provoke a foreign body reaction. Therefore, persistence or de novo development may relate to this added stimulus. [START_REF] Barrett | Progression of peri-aortic fibrosis despite endovascular repair of an inflammatory aneurysm[END_REF] Although not our primary outcome of interest and based on few data, the present study suggests that in the majority of patients treated with open surgery pain will subside and ESR values will normalize. However, signs and symptoms may recur or gradually worsen and may develop unrecognized, as illustrated in our cases. It is unknown whether the (sequential) measurement of ESR or CRP is of any value in the diagnosis and follow-up of chronic peri-aortitis. Therefore, additional nuclear imaging with [START_REF] Van Bommel | Tamoxifen therapy for non-malignant retroperitoneal fibrosis[END_REF] Ga-scintigraphy or [START_REF] Simons | Periaortitis with ureteral obstruction after endovascular repair of an abdominal aortic aneurysm. Case report[END_REF] F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) may not only help in establishing (recurrent) active disease, but may also be the only follow-up parameter in monitoring treatment response. [START_REF] Van Bommel | Clinical value of gallium-67 SPECT scintigraphy in the diagnostic and therapeutic evaluation of retroperitoneal fibrosis. A prospective study[END_REF][START_REF] Nakajo | 18F-fluorodeoxyglucose positron emission tomography features of idiopathic retroperitoneal fibrosis[END_REF] If more widely available and less costly, combined [START_REF] Simons | Periaortitis with ureteral obstruction after endovascular repair of an abdominal aortic aneurysm. Case report[END_REF] F-FDG PET-CT scanning may become the most appropriate imaging modality in chronic peri-aortitis.

Persistent ureteral obstruction occurred more frequently after EVAR than after open surgical aneurysm exclusion. Although sometimes advocated, [START_REF] Stella | Postoperative course of inflammatory abdominal aortic aneurysms[END_REF][START_REF] Bitsch | Inflammatory aortic aneurysms: regression of fibrosis after aneurysm surgery[END_REF] performing routine ureterolysis during open surgery seems less obvious as we found that ureteral obstruction subsides in the majority of patients following surgical aneurysm exclusion per se. In addition, extensive ureteral dissection has been associated with short and long-term morbidity (e.g. avascular necrosis or fibrosis of the ureter) and mortality. [START_REF] Stella | Postoperative course of inflammatory abdominal aortic aneurysms[END_REF][START_REF] Lacquet | Inflammatory abdominal aortic aneurysms. A retrospective study of 110 cases[END_REF][START_REF] York | Prevention and management of ureteral injuries during aortic surgery[END_REF] Nevertheless, prolonged ureteral obstruction may add to chronic renal failure due to obstructive nephropathy superimposed on often pre-existing ischaemic nephropathy. Indeed, renal atrophy is a frequent finding upon repeated radiologic investigation in patients with RPF complicated by ureteral obstruction. [START_REF] Nitecki | Inflammatory abdominal aneurysms: a case-control study[END_REF][START_REF] Van Bommel | Long-term renal and patient outcome in idiopathic retroperitoneal fibrosis treated with prednisone[END_REF] Our observation of persistently impaired renal function in 68% of patients following surgery in the present study substantiates this point. The above findings justify the question of whether (urgent) renal drainage through percutaneous nephrostomy (PNS) and/or ureteral stenting combined with medical treatment should be performed prior to planning the surgical procedure in cases with severe and/or bilateral ureteral obstruction.

Repairing AAAs smaller than 55 mm has not been shown to improve survival. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Lederle | Systematic review: repair of unruptured abdominal aortic aneurysm[END_REF] Therefore, primary medical treatment, when needed with renal drainage, is probably the best option in cases with no urgent operation indication. Primary medical treatment may also be preferred in cases of severe inflammation, bilateral ureteral obstruction and/or in the presence of a large peri-aortic mass, thereby achieving symptomatic relief and facilitating otherwise more difficult surgical procedures. [START_REF] Baskerville | The diagnosis and treatment of peri-aortic fibrosis ('inflammatory' aneurysms)[END_REF][START_REF] Clyne | Perianeurysmal retroperitoneal fibrosis: two cases responding to steroids[END_REF][START_REF] Hedges | Resection of inflammatory aneurysm after steroid therapy[END_REF][START_REF] Stotter | The response of perianeurysmalthe 'inflammatory' aneurysmto surgery and steroid therapy[END_REF][START_REF] Soury | Apropos of an inflammatory aneurysm of the abdominal aorta revealed by anuria[END_REF][START_REF] Sumino | Steroid therapy is effective in a young patient with an inflammatory abdominal aortic aneurysm[END_REF][START_REF] Testart | Inflammatory abdominal aortic aneurysm. Role of corticosteroid therapy[END_REF][START_REF] Hoffmeister | Inflammatory aneuysm of the infrarenal aorta[END_REF] In other cases, medical treatment should probably be withheld until close follow-up after the intervention shows on-going inflammation, thereby taking into account the time-dependent regression of fibrosis. However, given the risk of irreversible obstructive nephropathy, we suggest earlier consideration of renal drainage in such cases, thereby recognizing the possible early and late complications of PNS or ureteral stenting, notably the increased risk of urinary infection and bacteremia which could lead to prosthesis infection. [START_REF] Hausegger | Percutaneous nephrostomy and antegrade ureteral stenting: techniqueindications-complications[END_REF][START_REF] Lawrentschuk | Ureteric stenting 25 years on: routine or risky[END_REF] Although rare, longterm indwelling ureteral stents in patients with an endovascular stent or prosthesis in situ have been associated with ureteral leak due to pressure necrosis and uretero-arterial fistila formation. [START_REF] Sacks | Ureteral leak around an aortic bifurcation graft: complication of ureteral stenting[END_REF][START_REF] Meester | Endovascular treatment of a ureteroiliac fistula associated with ureteral double J-stenting and an aortic-bifemoral stent graft for an inflammatory abdominal aortic aneurysm[END_REF][START_REF] Krambeck | Ureteroiliac fistula: diagnosis and treatment algorithm[END_REF] PNS may therefore be the preferred drainage procedure. Irrespective of the urological procedure, close clinical and radiological follow-up is mandatory in these patients.

At least in the short and mid-term, the recently developed EVAR procedure seems to have equally good results as the long-established technique of open surgical aneurysm repair in terms of rupture prevention, which is usually considered the best marker of successful treatment of both inflammatory and non-inflammatory aortic aneurysms. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Tang | Inflammatory abdominal aortic aneurysms[END_REF][START_REF] Norwood | Endovascular abdominal aortic aneurysm repair[END_REF][START_REF] Eliason | Current management of infrarenal abdominal aortic aneurysms[END_REF] In atherosclerotic aortic aneurysm, EVAR is associated with lower operative mortality than open surgery. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Tang | Inflammatory abdominal aortic aneurysms[END_REF][START_REF] Norwood | Endovascular abdominal aortic aneurysm repair[END_REF][START_REF] Eliason | Current management of infrarenal abdominal aortic aneurysms[END_REF] In a controlled trial, 5-year survival was similar for EVAR compared to open surgery, but with less morbidity despite the need for late reinterventions. [START_REF] Peterson | Five-year report of a multicenter controlled clinical trial of open versus endovascular treatment of abdominal aortic aneurysms[END_REF] Early mortality rate with open surgery in inflammatory aneurysm is slightly higher than in atherosclerotic aneurysm and ranges from 6.8% to 11%. [START_REF] Pennell | Inflammatory abdominal aortic aneurysms: a thirty-year review[END_REF][START_REF] Lindblad | Abdominal aortic aneurysm with perianeurysmal fibrosis: experience from 11 Swedish vascular centers[END_REF][START_REF] Railo | Surgical treatment of inflammatory abdominal aortic aneurysms: a longterm follow-up of 19 patients[END_REF][START_REF] Yusuf | Inflammatory abdominal aortic aneurysm: predictors of long-term outcome in a case-control study[END_REF][START_REF] Nitecki | Inflammatory abdominal aneurysms: a case-control study[END_REF][START_REF] Lacquet | Inflammatory abdominal aortic aneurysms. A retrospective study of 110 cases[END_REF][START_REF] Ockert | Long-term outcome of operated inflammatory aortic aneurysms[END_REF] Early mortality rate in inflammatory aneurysm with EVAR appears low and similar to that reported with EVAR in atherosclerotic aneurysm (1.9% vs 1.8%). [START_REF] Lange | Results of endovacular repair of inflammatory abdominal aortic aneurysms. A report from the EURO-STAR database[END_REF][START_REF] Brewster | Long-term outcomes after endovascular abdominal aortic aneurysm repair: the first decade[END_REF] Although these data need to be confirmed, EVAR seems associated with a lower early mortality than open surgery in inflammatory aneurysm.

However, regression of peri-aortic fibrosis and resolution of ureteral obstruction in patients with inflammatory aortic aneurysms should also be considered important treatment goals. Indeed, postoperative persisting fibrosis with ureteral entrapment and postoperative chronic renal failure were recently shown to be independent risk factors for death. [START_REF] Todd | Retroperitoneal approach for repair of inflammatory aortic aneurysms[END_REF] Hence, the debate as to whether EVAR should be considered a safer option in (selected) patients with peri-aneurysmal fibrosis as opposed to open surgery should include the less satisfactory results in terms of peri-aortic mass regression and resolution of ureteral obstruction. Therefore, additional medical treatment may need to be considered at an earlier stage with EVAR than with open surgical aneurysm repair, in which a 'wait and see' policy after surgery seems justified in cases without extensive disease.

It has long been recognized that treatment with corticosteroids may facilitate successful resection of an inflammatory aneurysm in patients who were initially considered unfit for surgery. [START_REF] Bommel | Retroperitoneal fibrosis[END_REF][START_REF] Baskerville | The diagnosis and treatment of peri-aortic fibrosis ('inflammatory' aneurysms)[END_REF][START_REF] Lederle | Systematic review: repair of unruptured abdominal aortic aneurysm[END_REF][START_REF] Clyne | Perianeurysmal retroperitoneal fibrosis: two cases responding to steroids[END_REF][START_REF] Hedges | Resection of inflammatory aneurysm after steroid therapy[END_REF][START_REF] Stotter | The response of perianeurysmalthe 'inflammatory' aneurysmto surgery and steroid therapy[END_REF][START_REF] Soury | Apropos of an inflammatory aneurysm of the abdominal aorta revealed by anuria[END_REF][START_REF] Sumino | Steroid therapy is effective in a young patient with an inflammatory abdominal aortic aneurysm[END_REF][START_REF] Testart | Inflammatory abdominal aortic aneurysm. Role of corticosteroid therapy[END_REF][START_REF] Hoffmeister | Inflammatory aneuysm of the infrarenal aorta[END_REF] Despite these early reports, no (controlled) studies exist on the role of steroids and/or other medical therapy in addition to aneurysm exclusion. Steroids act through reduction of inflammation and oedema, inhibition of fibroblastic proliferation, and immunosuppression. [START_REF] Mitchinson | Retroperitoneal fibrosis revisited[END_REF][START_REF] Van Bommel | Long-term renal and patient outcome in idiopathic retroperitoneal fibrosis treated with prednisone[END_REF] Although steroids do not reverse established fibrosis, further fibroblastic proliferation may be slowed and symptomatology reversed. The use of corticosteroids is not without hazard. As a lower rupture rate is reported for inflammatory compared with non-inflammatory aneurysms, some assume that peri-aortic fibrosis actually protects against rupture. [START_REF] Tang | Inflammatory abdominal aortic aneurysms[END_REF][START_REF] Hinchliffe | Endovascular repair of inflammatory abdominal aortic aneurysms[END_REF] In rare cases, actual rupture follows shortly after commencing corticosteroid treatment. [START_REF] Baskerville | The diagnosis and treatment of peri-aortic fibrosis ('inflammatory' aneurysms)[END_REF][START_REF] Thompson | Non-operative management of perianeurysmal fibrosis[END_REF] Therefore, if corticosteroid therapy is initiated, patients should be carefully followed and if signs of impending rupture such as increasing size or aortic wall thinning are demonstrated, surgical aneurysm repair should be undertaken. [START_REF] Baskerville | The diagnosis and treatment of peri-aortic fibrosis ('inflammatory' aneurysms)[END_REF][START_REF] Hedges | Resection of inflammatory aneurysm after steroid therapy[END_REF][START_REF] Thompson | Non-operative management of perianeurysmal fibrosis[END_REF] Another consideration is the increased risk of postoperative morbidity with prolonged corticosteroid use, notably through increased risk of infection and depressed wound healing. In addition, its long-term use is associated with accelerated atherosclerosis and an increased risk of cardiovascular death. [START_REF] Wei | Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease[END_REF] If (additional) medical treatment is considered, we prefer tamoxifen in patients with aneurysmal chronic peri-aortitis. [START_REF] Van Bommel | Tamoxifen therapy for non-malignant retroperitoneal fibrosis[END_REF] Contrary to corticosteroids, tamoxifen does not appear to have significant side effects which could complicate surgery and it may even have significant long-term cardioprotective effects. [START_REF] Grainger | Tamoxifen for the prevention of myocardial infarction in humans: preclinical and early clinical evidence[END_REF][START_REF] Van Bommel | Tamoxifen therapy for non-malignant retroperitoneal fibrosis[END_REF] The pathophysiologic pathway by which tamoxifen exerts its effects in chronic peri-aortitis is unknown but is probably hormonal-independent. [START_REF] Van Bommel | Tamoxifen therapy for non-malignant retroperitoneal fibrosis[END_REF] Tamoxifen may alter the balance of growth factors such that fibroblast proliferation is inhibited. [START_REF] Van Bommel | Tamoxifen therapy for non-malignant retroperitoneal fibrosis[END_REF] The anti-oestrogen tamoxifen may also act as anti-inflammatory/ immunosuppressive therapy, which would explain the observed decrease in acute-phase reactants and disappearance of pathologic Ga 67 activity. [START_REF] Van Bommel | Clinical value of gallium-67 SPECT scintigraphy in the diagnostic and therapeutic evaluation of retroperitoneal fibrosis. A prospective study[END_REF][START_REF] Van Bommel | Tamoxifen therapy for non-malignant retroperitoneal fibrosis[END_REF] Its anti-oxidant and anti-angiogenic properties may also contribute to its efficacy. [START_REF] Van Bommel | Tamoxifen therapy for non-malignant retroperitoneal fibrosis[END_REF][START_REF] Grainger | Tamoxifen for the prevention of myocardial infarction in humans: preclinical and early clinical evidence[END_REF][START_REF] Van Bommel | Tamoxifen therapy for non-malignant retroperitoneal fibrosis[END_REF] Experimentally, tamoxifen has been shown to attenuate development of AAAs. [START_REF] Grigoryants | Tamoxifen upregulates catalase production, inhibits vessel wall neutrophil infiltration, and attenuates development of experimental abdominal aortic aneurysms[END_REF] However, as illustrated in case 1, chronic peri-aortitis may have a chronic-relapsing course and we do not yet have data on the long-term safety and efficacy of tamoxifen.

It should be noted that some use the term 'perianeurysmal fibrosis', where others use the term 'inflammatory aneurysm'. It is now clear that it is not aneurysmal formation per se but the presence of severe atherosclerosis that is the prerequisite to develop peri-aortic fibrosis in such patients. [START_REF] Bommel | Retroperitoneal fibrosis[END_REF][START_REF] Mitchinson | Retroperitoneal fibrosis revisited[END_REF][START_REF] Parums | The spectrum of chronic peri-aortitis[END_REF][START_REF] Baker | Auto-allergic periaortitis (idiopathic retroperitoneal fibrosis)[END_REF] Idiopathic RPF and peri-aneurysmal fibrosis share similar clinical and histopathological features and are both thought to result from an exaggerated inflammatory response to advanced atherosclerosis. [START_REF] Mitchinson | Retroperitoneal fibrosis revisited[END_REF][START_REF] Parums | The spectrum of chronic peri-aortitis[END_REF][START_REF] Baker | Auto-allergic periaortitis (idiopathic retroperitoneal fibrosis)[END_REF] It is for these reasons that some prefer the term chronic peri-aortitis to encompass idiopathic RPF and perianeurysmal fibrosis. [START_REF] Bommel | Retroperitoneal fibrosis[END_REF][START_REF] Mitchinson | Retroperitoneal fibrosis revisited[END_REF][START_REF] Parums | The spectrum of chronic peri-aortitis[END_REF][START_REF] Baker | Auto-allergic periaortitis (idiopathic retroperitoneal fibrosis)[END_REF] Perhaps most appropriately, conditions may be referred to as non-aneurysmal chronic peri-aortitis and aneurysmal chronic periaortitis. The increased incidence of RPF in men may well be explained by the higher incidence of symptomatic atherosclerotic disease in men. Some even suggest that the future of this disorder lies in the prevention and treatment of atherosclerosis. [START_REF] Baker | Auto-allergic periaortitis (idiopathic retroperitoneal fibrosis)[END_REF] Smoking, a major risk factor for atherosclerotic AAA, has been shown to be an even stronger risk factor for the inflammatory variant. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Nitecki | Inflammatory abdominal aneurysms: a case-control study[END_REF] Cessation of smoking should therefore be strongly encouraged in all cases of chronic peri-aortitis. [START_REF] Hellman | Inflammatory abdominal aortic aneurysm[END_REF][START_REF] Nitecki | Inflammatory abdominal aneurysms: a case-control study[END_REF] In conclusion, open surgical aneurysm exclusion is superior to EVAR in achieving regression of periaortic fibrosis and resolution of ureteral obstruction in patients with aneurysmal chronic peri-aortitis. After excluding patients in whom concurrent ureterolysis was performed, the frequency of persistent ureteral obstruction remained lower in patients treated surgically compared to EVAR but was still relevant. Additional medical treatment, combined with renal drainage when needed, should be considered in selected cases of aneurysmal chronic peri-aortitis, particularly when severe and/or bilateral ureteral obstruction and/or a large peri-aortic mass is (remains) present. This decision should probably also depend on the type of procedure (i.e. earlier with EVAR than with open surgery).

Figure 1 (

 1 Figure 1 (A) Eleven-month postoperative CT scan in a 64-year-old man shows the aortic bypass graft and a peri-aneurysmal soft tissue mass with limited involvement of inferior caval vein (C). (B) Note that the posterior aortic wall is spared. A follow-up CT scan after 4 months of tamoxifen treatment shows regression of the periaortic mass.

Figure 2 (

 2 Figure 2 (A) Contrast-enhanced CT scan 14 months post-EVAR in a 76-year-old man shows the two patent limbs of the endovascular graft (Excluder ® graft) and a well-delineated peri-aneurysmal soft tissue mass extending to the right psoas muscle. There is some narrowing of the inferior caval vein (C). The posterior aortic wall is spared. (B) A follow-up CT scan after 8 months of treatment with tamoxifen and azathioprine shows regression of the peri-aortic soft tissue mass.

Figure 3

 3 Figure 3 Depiction of the number of patients with preoperative ureteral obstruction in whom ureteral obstruction did not resolve after open surgical aneurysm exclusion per se (i.e. without concurrent ureterolysis). Data from refs 27-31,33-38.

Table 1

 1 Characteristics of study patients treated with open surgical aortic aneurysm repair No. of patients (percentage) with pre-operative uni-or bilateral ureteral obstruction due to peri-aortic fibrosis.

	Author, year [ref]	Patients, n Mean age, years	Male sex, n (%) Ureteral	Mean follow-up
			(range)		obstruction a , n (%)	months (range)
	Plate, 1988 27	6 b	70 (63-78)	4 (80)	4 (50)	7 (6-17) c
	Nachbur, 1989 28	8 b	62 (50-77)	7 (100)	8 (100)	N/A (4-60)
	Stella, 1993 29	19	65 (38-76)	18 (95)	10 (53)	21 (N/A) c
	Nitecki, 1996 30	29	72 (N/A)	24 (83)	9 (31)	13 (3-51)
	Bitsch, 1997 31	21	64 (47-78)	19 (90)	7 (33)	36 (4-108)
	Lacquet, 1997 33	110 b	67 (49-84)	101 (92)	23 (21)	54 (6-180)
	Koch, 1998 32	49	65 (28-92)	46 (94)	N/A	30 (N/A)
	Von Fritchen, 1999 35	42	71 (N/A)	40 (95)	9 (21)	36 (10-91) c
	Dimakakos, 1999 34	15	66 (58-78)	15 (100)	3 (20)	N/A (4-120)
	Speziale, 2001 36	14 b	66 (58-72)	10 (77)	14 (100)	48 (3-60)
	Pistolese, 2002 37	21	66 (49-76)	19 (90)	5 (24)	10 (4-18)
	Arroyo, 2003 38	52	66 (53-76)	10 (91)	11 (21)	55 (12-96)
	Ockert, 2006 39	40	67 (51-86)	38 (96)	N/A	32 (N/A)
	Overall	426	67 (28-92)	351 (82)	103 (31)	35 (3-120)
	N/A, not applicable or not available.

a b Some patients received additional corticosteroids (Plate, n = 1; Nachbur, n = 2; Lacquet, n = 1; Speziale, n = 1). c Values are median and range.

Table 2

 2 Evolution of peri-aortic fibrosis after open surgical aortic aneurysm repair in study patients with CT follow-up

	Author, year [ref]	Patients with CT		CT findings
		follow-up, n
			CR, n (%)	PR, n (%)	NR, n (%)
	Plate, 1988 27	5	5 (100)	0 (0)	0 (0)
	Nachbur, 1989 28	7	4 (57)	3 (43)	0 (0)
	Stella, 1993 29	19	9 (47)	4 (21)	6 (32)
	Nitecki, 1996 30	19	10 (53)	9 (47)	0 (0)
	Bitsch, 1997 31	21	6 (29)	12 (57)	3 (14)
	Koch, 1998 32	49	42 (85)	5 (11)	2 (4)
	Von Fritchen, 1999 35	26	6 (23)	9 (35)	11 (42) a
	Dimakakos, 1999 34	10	7 (70)	3 (30)	0 (0)
	Speziale, 2001 36	12	6 (50)	3 (25)	3 (25) a
	Pistolese, 2002 37	21	5 (24)	14 (67)	2 (9)
	Ockert, 2006 39	19	9 (47)	8 (42)	2 (11)
	Overall	208	109 (52)	70 (34)	29 (14)

CT, computed tomographic; CR, complete regression; PR, partial regression; NR, no regression. a Progressive fibrosis was observed in some of these patients (von Fritchen, n = 1; Speziale, no. of patients not specified).

Table 3

 3 Characteristics of study patients treated with endovascular aortic aneurysm repair No. of patients (percentage) with pre-operative uni-or bilateral ureteral obstruction due to peri-aortic fibrosis. b Some patients received additional corticosteroids (Vallabhaneni, n = 2; Hinchliffe, n = 1; Hechelhammer, n = 4).

	Author, year [ref]	Patients, n Mean age, years	Male sex, n	Ureteral	Mean follow-up
			(range)	(%)	obstruction a , n	months (range)
					(%)
	Vallabhaneni, 2001 40	6 b	66 (56-76)	5 (83)	2 (33)	19 (6-36)
	Hinchliffe, 2002 41	11 b	69 (60-78)	11 (100)	6 (55)	29 (11-73)
	Faizer, 2005 44	6	6 7( 5 8 -77)	5 (83)	1 (17)	25 (4-56)
	Lange, 2005 45	11	66 ± 10.1 (SD)	10 (91)	5 (45)	N/A
	Hechelhammer, 2005 43	10 b	64 (57-80)	8 (80)	3 (30)	33 (13-59)
	Puchner, 2006 42	8	6 9( 5 5 -82)	8 (100)	2 (25)	24 (1-109)
	Overall	52	67 (56-82)	47 (90)	19 (37)	26 (1-109)
	SD, standard deviation; N/A, not applicable or not available.

a

Table 4

 4 Evolution of peri-aortic fibrosis and ureteral obstruction after endovascular aortic aneurysm repair in study patients No. of patients (percentage) with persistent uni-or bilateral ureteral obstruction at follow-up. b Progressive fibrosis was observed in some patients in these series (Vallabhaneni, n = 2; Lange, number of patients not specified). c Ureterolysis was performed in one patient post-EVAR (endovascular aortic aneurysm repair).

	Author, year [ref]		CT findings		Persistent ureteral
					obstruction a , n (%)
		CR, n (%)	PR, n (%)	NR, n (%)
	Vallabhaneni, 2001 40	0 (0)	0 (0)	6 (100) b	1/2 (50)
	Hinchliffe, 2002 41	2 (18)	3 (27)	6 (55)	5/6 (83)
	Faizer, 2005 44	0 (0)	6 (100)	0 (0)	0/1 (0)
	Lange, 2005 45	0 (0)	6 (55)	5 (45) b	3/5 (60) c
	Hechelhammer, 2005 43	2 (20)	7 (70)	1 (10)	0/3 (0)
	Puchner, 2006 42	3 (38)	2 (24)	3 (38)	1/2 (50)
	Overall	7 (14)	24 (46)	21 (40)	10/19 (56)
	CT, computed tomographic; CR, complete regression; PR, partial regression; NR, no regression.

a

Table 5

 5 Comparison of the evolution of peri-aortic fibrosis (PAF) and ureteral obstruction after open surgical or endovascular aortic aneurysm repair in study patients

	Variable	Open surgical	Endovascular	p-value a
		aneurysm repair	aneurysm repair
			(EVAR)
	Clinical characteristics
	Mean age, years (range)	67 (28-92)	67 (56-80)	0.79
	Male sex, n (%)	351/426 (82)	47/52 (90)	0.17
	Ureteral obstruction, n (%)	103/337 (31)	19/52 (37)	0.42
	Outcome
	Regression of PAF, n (%)	179/208 (86)	31/52 (60)	<0.0001
	Complete regression, n (%)	109/208 (52)	7/52 (14)	<0.0001
	Persistent ureteral obstruction, n (%)
	All patients with follow-up	25/97 (27)	10/19 (53)	0.02
	Patients without ureterolysis b	20/63 (32)	10/18 (56)	0.09

a Mann-Whitney test or Fisher exact test, where appropriate. b Patients in whom concurrent ureterolysis was performed during or shortly after aneurysm repair were excluded from this analysis (open surgery, n = 34; EVAR, n = 1).

Vascular Medicine 2008; 13: 293-303

Acknowledgement

Conflict of interest: none.


Editorial

Why cost-of-illness studies are important and inform policy Costs of illness studies are becoming more popular in industry, with the academic community and with the government. The issues raised are why these studies are important, why they are difficult to perform and how they can be useful to the healthcare community.

Why it is important

Cost-of-illness studies provide information at the micro-and macroeconomic levels, to help determine the acceptable price of innovations in the diagnosis and treatment of illness and to estimate appropriate funding for health policies. The target audiences of cost-of-illness studies are predominantly public or private institutions that decide to allocate resources to treat or prevent specific disorders. Therefore, it would be expected that researchers would preferably concentrate on key illnesses that represent an important burden both in direct and indirect costs. At the microeconomic level, researchers use costof-illness data in cost-effectiveness models: the price of an innovation that prevents or limits the progression of a disease can be estimated from the cost savings (by how much is the cost of the disease reduced) and the medical benefits. At the macroeconomic level, policy-makers look for information on how the healthcare money is spent or, in a more prospective fashion, on where to invest and what can be the expected returns on investment. [START_REF] Rice | The economic costs of illness: A replication and update[END_REF] The use of cost-of-illness studies by policy-makers has been, to date, rather limited, because of the limited trust in the methods and the results as well as limitations of the budgeting process at government level. Governments may be drawn to prioritize funding for basic research rather than for diseasespecific research, have election-driven agendas, and an annual budget setting, which conflicts with the need for long-term commitment of resources to finding ways to reduce the cost of illness. [START_REF] Kirschstein | Disease-specific estimates of direct and indirect cost of illness and NIH support -Fiscal year 2000 update[END_REF][START_REF] Goddard | Priority setting in healtha political economy perspective[END_REF] For example, the breakdown of total costs into hospital, ambulatory, physicians, tests, drugs and nursing can draw attention to possible reorganizations of inputs that would be more efficient. This is particularly true if international comparisons are available. An example of such research would be studies of how care can be provided on an outpatient rather than inpatient basis or by nurses or podiatrists rather than physicians.

Why it is difficult

A 2008 review 4 identified an average of 140-150 cost-of-illness studies for the United States published each year since 2000. Of these, few had adopted the Medicare perspective, as they seldom considered conditions affecting predominantly the elderly with the notable exception of Alzheimer's disease. This review identifies the methodological limitations of many cost-of-illness studies, including flaws in the identification of patients, and incomplete reporting of costs, use of costs and charges.

Cost-of-illness studies are still relatively scarce compared with economic evaluations in general and epidemiological studies. The reasons for this scarcity might be in part the difficulty of linking diagnoses to resource utilization and to identifying costs outside the healthcare system. Cost-of-illness studies that use insurance claims have at least two limitations in addition to methodological difficulties that exist with most administrative databases. The first one is data linkage in countries such as the United States where a patient can have several insurers over time depending on age and work status. An incisive description of the US healthcare system and its fragmentation, with consequences that reach further than the scope of cost-of-illness studies, was provided by economist Henry Aaron and applies to studies that use Medicare data:

"like many other observers, I look at the US health care system and see an administrative monstrosity, a truly bizarre mélange of thousands of payers with payment systems that differ for no socially beneficial reason, as well as staggeringly complex public systems with mind-boggling administered prices and other rules expressing distinctions that can only be regarded as weird. Consider Medicare's different rules for 'Qualified Medicare Beneficiaries,' 'Specified Low-Income Medicare Beneficiaries,' and 'Qualifying Individuals' and I rest my case. [START_REF] Aaron | The cost of health care administration in the United States and Canadaquestionable answers to a questionable question[END_REF] " Such a system does not favour the use of an administrative or insurance database for one thing and does not create an environment where stakeholders can share information and budgets. The second limitation is the limited information on indirect costs such as absence from work, reduced productivity and cost to the family.

The first limitation can be overcome by using models or databases of patient populations that will not likely change insurer. For diseases such as PAD that have costs fluctuating over time and varying by severity level, the absence of data linkage over time is a real issue. Cost of PAD studies produced by health plans use cross-sectional data that can be entered into a disease model. [START_REF] Margolis | Health care resources and costs for treating peripheral artery disease in a managed care population: results from analysis of administrative claims data[END_REF] Data linkage over a long period of time is possible in the Veterans Administration population and the Medicare population. [START_REF] Hirsch | National healthcare costs of peripheral arterial disease in the Medicare population[END_REF] The external validity of the results (i.e. are the results relevant to populations other than the one included?), however, remains fragile. Thus, surveys on representative samples of the population are useful, although expensive. [START_REF] Hodgson | Medical care expenditures for selected circulatory diseases: opportunities for reducing national health expenditures[END_REF] The second limitation can be partly controlled when the health insurance also pays leave of absence and unemployment benefits.

How cost-of-illness studies can be useful to the community

In the United States, the segmentation of health insurance makes a consistent policy of investment in health more difficult than in other countries. Diseases such as PAD or other cardiovascular diseases affect predominantly the elderly but their preven-tion concerns the younger population in the workforce. The paradox is that employers' insurance should make the investment in prevention while Medicare would benefit from its return. This obviously is more difficult to achieve with multiple insurer systems than in unified systems with a national health service. [START_REF] Migliaccio-Walle | Costs and medical care consequences associated with the diagnosis of peripheral arterial disease[END_REF] Another difficulty relates to the viewpoint chosen for the computation of costs. Healthcare systems in developed countries involve at least three stakeholders: the providers, the payers, and the patients. The costs for one stakeholder are the revenue for another; the charges that are often used for cost-of-illness studies based on insurance claims differ from the costs to the healthcare providers. This may create confusion and inconsistencies. It also creates incentives and disincentives. For example, a medical or surgical specialty that benefits from the high reimbursement of a procedure will oppose the diffusion of a more efficient substitute, or a government agency will welcome an investment in prevention if it increases its budget but oppose it if it benefits a rival agency. [START_REF] Goddard | Priority setting in healtha political economy perspective[END_REF] The global model that would inform decisionmakers on where to spend prevention money and how to reorganize the inputs for the production of health and healthcare is illustrated in Figure 1. [START_REF] Paris | Des comptes de la santé par pathologie: un prototype pour l'année 1998[END_REF] Cost-of-illness studies contribute to this model by informing decision-makers on the cost of NOT making a decision to act upon risk factors compared with the cost of other prevention measures. [START_REF] Asaria | Chronic disease prevention: health effects and financial costs of strategies to reduce salt and control tobacco use[END_REF] There could be a debate among vascular physicians as to the best strategy to draw the attention of policy-makers and payers to PAD. Cost-of-illness data could be presented either isolated from the cost of the other circulatory disorders, which is what Hirsch, et al. have done in their article that appears in this issue, or together with the costs for all circulatory diseases. The relative importance of each vascular disorder was described by the TASC statement. [START_REF] Norgren | Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)[END_REF] The first option creates the possibility to channel resources directly to vascular departments and therefore might seem attractive. The risk, however, is that the cost of PAD looks small in comparison with cardiac and cerebrovascular diseases, which would be counterproductive. Hodgson and Cohen in 1999 estimated the total expenditure on circulatory disorders at $129 billion USD, [START_REF] Hodgson | Medical care expenditures for selected circulatory diseases: opportunities for reducing national health expenditures[END_REF] Kirschstein cited a cost of $43.3 billion for cerebrovascular and $183.1 billion for heart diseases in 2000, 2 while Hirsch, et al., in this issue of Vascular Medicine, estimate the cost of PAD at $4.3 billion for the Medicare population. [START_REF] Hirsch | National healthcare costs of peripheral arterial disease in the Medicare population[END_REF] The authors attribute this low cost in part to underdiagnosis and undertreatment of PAD. This is an important message because it could result in a recommendation of more active case-finding among Medicare beneficiaries. To draw the attention of policy-makers to the need for investments in the prevention of PAD, one possibility is to use the Saskatchewan data which shows that the burden of PAD is comparable with the burden of acute myocardial infarction. [START_REF] Migliaccio-Walle | Costs and medical care consequences associated with the diagnosis of peripheral arterial disease[END_REF] Another is to use the global model (Figure 1) and estimate the expected return on an investment in prevention and early treatment.

Patients should also be a target audience for costof-illness studies. In countries with high copayments, patients have a direct interest in supporting investments in prevention and, on a more individual basis, to invest in healthy lifestyles. In countries with no or limited co-payments, the insurance theory of moral hazard predicts that patients may engage in risky behaviours if they do not bear the financial burden of its outcomes. In the case of diseases, however, money is not the sole issue and patients will also consider the loss of quality of life.

Thus, cost-of-illness studies need to be contextualized with information on research opportunities, opportunities for the reorganization of inputs, for the use of new technologies and, ultimately, added value to the healthcare system.

Figure 1

 1 Figure 1 The global model for relating health determinants to cost of illness. Reproduced with permission from ref. 10.

Vascular Medicine 2008; 13: 251-253 © 2008 SAGE Publications, Los Angeles, London, New Delhi and Singapore 10.1177/1358863X08091738


Suman Rathbun
email: suman-rathbun@ouhsc.edu

Panel A Panel

Images in vascular medicine

The venoarterial reflex Suman Rathbun, P Jay Heath and Thomas Whitsett

The venoarterial reflex, or postural vasoconstriction reflex, is the decline in limb blood flow in the dependent position due to an increase in pre-capillary vascular resistance. [START_REF] Hassan | Mechanism of the postural vasoconstrictor response in the human foot[END_REF] Impairment of the venoarterial reflex may be a cause of unexplained leg swelling.

The venoarterial reflex prevents loss of fluid to the extravascular space when the legs are dependent. Testing of this reflex evaluates the ability of the cutaneous pre-capillary sphincters to constrict in response to dependency or elevated venous pressure and modulate the hydrostatic pressure. [START_REF] Hassan | Mechanism of the postural vasoconstrictor response in the human foot[END_REF] The mechanism of this autoregulation is threefold: a local sympathetic axonal reflex, an arteriolar-mediated myogenic response, and a minor central sympathetic efferent nerve component. [START_REF] Hassan | Mechanism of the postural vasoconstrictor response in the human foot[END_REF] The impaired venoarterial reflex may explain swelling in patients receiving calcium channel blockers. [START_REF] Pedrinelli | Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension[END_REF] It is a cause of swelling in diabetics or patients with spinal degeneration that have neuropathy. [START_REF] Rayman | Blood flow in the skin of the foot related to posture in diabetes mellitus[END_REF] It may explain edema in women during the luteal phase of their menstrual cycle. [START_REF] Hassan | Postural vasoconstriction in women during the normal cycle[END_REF] Attenuation of the reflex with higher skin temperatures may contribute to swelling experienced in hot climates. [START_REF] Hassan | Effect of changes in local skin temperature on postural vasoconstriction in man[END_REF] With the patient in a supine position, photoplethysmography (PPG) probes are applied to the great toe (Panel A) to monitor capillary flow at baseline showing normal amplitude pulsatile flow. One leg is then lowered 50 cm off the side of the exam table (Panel B). If the reflex is intact, there is an immediate reduction in the amplitude of the PPG pulsations (Panel C). If the reflex is absent or impaired, there will be no appreciable reduction in the pulsations (Panel D) compared to the supine leg position.

Treatment of leg swelling caused by an impaired venoarterial reflex is application of prescription knee length compression hose (20-30 mmHg) daily. Use of diuretics is minimally helpful. Evaluation of the venoarterial reflex is an inexpensive, simple test for excluding this abnormality as a cause of otherwise unexplained leg swelling.

Vascular Medicine 2008; 13: 315-316