Chronic periaortitis is a fibro-inflammatory disease of unknown aetiology with histopathological and laboratory findings suggesting an IgG₄-related sclerosing disease in a subgroup of patients.1,–,3 Due to its inflammatory character and associated autoimmune phenomena, different immunosuppressive regimens have been suggested for treatment.4,–,9

In this study, we retrospectively examined the response to immunosuppressive treatment of 35 patients with chronic periaortitis applying the same study design as before.5 Imaging studies were performed and serum IgG₄ levels were measured both at the time of diagnosis and during follow-up. Retroperitoneal tissue was examined histologically in four patients. Emphasis has been placed on the evaluation of cyclophosphamide in the induction therapy and the hitherto unknown value of serum IgG₄ measurements in disease monitoring.

The Wilcoxon signed-rank test was used for statistical analysis of the imaging findings before and after induction therapy; for the remaining analyses, the Mann–Whitney U test was used. Data are reported as mean±SD or as median (range).

In 21 patients induction therapy was started with cyclophosphamide, and the remaining patients were initially treated with azathioprine (n=8), mycophenolate mofetil (n=2) or oral corticosteroids only (n=3). One patient did not receive immunosuppressive treatment.

During induction therapy, the monthly administration of intravenous cyclophosphamide (median 6 pulses, range 4–12) and the comedication with low-dosed oral corticosteroids significantly reduced the transverse diameter of the periaortic mantle (figure 1) and shortened the time from insertion until removal of ureteral stents (9.6±4.4 months compared with 19.3±3.2 months in comparator treatment regimens, p=0.025). Cyclophosphamide was not associated with clinically relevant side effects.

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Figure 1

Significant regression of the periaortic mantle during intravenous cyclophosphamide induction therapy. Contrast enhanced MRI findings in patient 32 showing the periaortic mantle (arrow) before (A) and after (B) 5 months of cyclophosphamide induction therapy. (C) Dots connected with a line represent the transverse diameter of the periaortic mantle of each of the 17 patients studied using imaging studies available before (mean 14.3±9.3 mm) and after (mean 5.7±3.5 mm) cyclophosphamide induction therapy, demonstrating a significant reduction (p<0.001) during induction therapy.

After induction therapy, stable clinical and radiological findings were successfully maintained by azathioprine in 14/15 patients and by methotrexate in 7/8 patients over a median period of 18 (range 2–113) and 27 (range 8–68) months, respectively. Azathioprine was discontinued or switched to alternative regimens in six patients because of adverse drug effects (new onset leucocytopenia or elevated liver enzymes) while methotrexate was well tolerated in all patients. In eight patients on azathioprine, no follow-up imaging was available. The remaining patients received mycophenolate mofetil (n=2), ciclosporin (n=1) or no immunosuppressive treatment (n=1).

This response to immunosuppressive treatment was, however, impeded in heavy smokers: the reduction of the periaortic mass during cyclophosphamide induction therapy was significantly less effective and the residual mass after maintenance therapy was significantly greater than in patients who smoked less than 20 packyears (figure 2).

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Figure 2

Impeded response to immunosuppressive treatment in heavy smokers. (A) The reduction of the transverse diameter of the periaortic mantle during cyclophosphamide induction therapy is significantly smaller (p=0.042) in the seven patients who smoked more than 20 packyears (mean 41±15 packyears, mean reduction 45±24%) than in the four patients who smoked less (mean 1.8±3.5 packyears, mean reduction 72±11%). (B) The residual periaortic mass after cyclophosphamide induction therapy and different maintenance therapies is significantly greater (p=0.030) in the 10 patients who smoked more than 20 packyears (mean 44.2±13.8 packyears, mean diameter 4.4±1.7 mm) than in the 4 patients who smoked less (mean 1.8±3.5 packyears, mean diameter 2.5±0.1 mm).

Evaluating serum IgG₄ levels as a biomarker during follow-up, untreated patients (n=5) presented with slightly elevated (median 146.0 mg/dl, range 59.0–236.0, normal range 3.9–86.4) and significantly higher levels than patients under immunosuppressive treatment (n=25, median 15.4 mg/dl, range 1.2–127.0, p<0.001), although the levels were not as high as previously reported.3 10 At follow-up, there was an intraindividual decrease of the IgG₄ levels in most patients but no difference between patients who responded to therapy in terms of imaging findings (median 27.4 mg/dl, range 2.8–163.0) and non-responders (median 24.0 mg/dl, range 1.0–138.0, p=0.898). There was no correlation between imaging findings and serum IgG₄ levels.

All retroperitoneal tissue samples showed an infiltration with CD38⁺, IgG⁺ and IgG₄⁺ plasma cells (data not shown). The tissue of the two untreated patients showed both higher absolute (mean 6±1 cells per high power field) and relative (mean IgG₄⁺:IgG⁺ ratio 48±13%, >30%)10 IgG₄⁺ plasma cell counts compared with the two patients under treatment (mean 2±2 cells per high power field, 16±3%).

In summary, our cohort data suggest that intravenous cyclophosphamide is a highly effective and well-tolerated induction therapy in chronic periaortitis. Both azathioprine and methotrexate can sustain long-term remission. The success of immunosuppressive treatment may be compromised in heavy smokers. Serum IgG₄ levels did not correlate with the radiological improvements at follow-up and therefore do not seem to be a suitable biomarker during follow-up in chronic periaortitis.