Objective. To assess the therapeutic benefit of mycophenolate mofetil (MMF) in retroperitoneal fibrosis (RF). Methods. MMF 2 g/day and prednisone 1 mg/kg were initiated in nine patients with radiological (9/9) and histological verification (2/9) of idiopathic RF. Out of nine patients, seven needed bilateral ureteral stenting due to extensive hydronephrosis. Results. All patients experienced regression of radiological extension. Out of seven patients, five were free of ureteral catheters after a mean of 5.6 months and two remained on stenting due to secondary stenosis. Within 6 months mean creatinine and CRP fell from 2.5 to 1.2 mg/dl and from 4.0 to 1.4 mg/dl, respectively. MMF was discontinued after a mean of 27 months. Prednisone was tapered to zero after a mean of 7 months. Side-effects were urinary tract infections in 7/9 patients and impaired glucose tolerance in 3/9. No recurrence occurred after withdrawal of glucocorticoids and MMF in 7/9 patients after a mean overall follow-up of 55 months (range 12-120). Conclusions. Treatment with MMF and glucocorticoids was successful in inducing partial or complete and lasting remission in RF. The results suggest the use of MMF as additional immunosuppressive optio

Adler, S.

Gaa, J.

Heemann, U.

Lodermeyer, S.

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Concise ReportSuccessful mycophenolate mofetil therapy in nine patientswith idiopathic retroperitoneal fibrosisS. Adler1,2, S. Lodermeyer1, J. Gaa3 and U. Heemann1Objective. To assess the therapeutic benefit of mycophenolate mofetil (MMF) in retroperitoneal fibrosis (RF).Methods. MMF 2 g/day and prednisone 1 mg/kg were initiated in nine patients with radiological (9/9) and histological verification (2/9)of idiopathic RF. Out of nine patients, seven needed bilateral ureteral stenting due to extensive hydronephrosis.Results. All patients experienced regression of radiological extension. Out of seven patients, five were free of ureteral catheters after a meanof 5.6 months and two remained on stenting due to secondary stenosis. Within 6 months mean creatinine and CRP fell from 2.5 to 1.2 mg/dland from 4.0 to 1.4 mg/dl, respectively. MMF was discontinued after a mean of 27 months. Prednisone was tapered to zero after a mean of7 months. Side-effects were urinary tract infections in 7/9 patients and impaired glucose tolerance in 3/9. No recurrence occurred afterwithdrawal of glucocorticoids and MMF in 7/9 patients after a mean overall follow-up of 55 months (range 12–120).Conclusions. Treatment with MMF and glucocorticoids was successful in inducing partial or complete and lasting remission in RF. Theresults suggest the use of MMF as additional immunosuppressive option.KEY WORDS: Mycophenolate mofetil, Retroperitoneal fibrosis, Glucocorticoids, Connective tissue disease.IntroductionIdiopathic retroperitoneal fibrosis (IRF) is a rare disease with anestimated incidence of 0.2–0.5 per 100 000, first describedby Albarran in 1905 and completely recognized by Ormond in1948 [1, 2].Characteristic finding is a retroperitoneal mass around theaorta mostly extending from the renal hilus to the iliac vessels withpossible extension to extra-abdominal organs [1, 3]. The caval veinand one or both ureters are most often involved in this processleading to obstruction, hydronephrosis and renal insufficiency.CT or MRI are mostly able to distinguish from lymphoma,haemorrhage, other inflammatory processes or tumours [4].Histological examinations show signs of an immune-mediatedorigin with infiltrates of IgG4-positive plasma cells, CD20-positiveB cells and CD4- and CD45-positive T cells in the active phase,finally leading to fibrotic replacement [5, 6]. Meanwhile IRF isdescribed as an autoimmune disease with questionable antigenicinduction [3].Treatment strategy has changed from surgery to immunomo-dulating agents like corticosteroids, cyclosporin, AZA, tamoxifenor in part cyclosphosphamide. Their usefulness is mostly limitedby recurrence or side-effects [3, 7].According to histology of IRF it can be useful to quickly stopthe inflammatory action by the use of glucocorticoids. In order tothen block the T- and B-cell proliferation more specifically, aconcomitant use of MMF appears to be a promising option. MMFhas shown to be effective as antilymphocytic proliferative drug.It is clinically used in the prevention of transplant rejection and inautoimmune diseases like lupus nephritis and vasculitides [8, 9].The use in IRF patients was described in a few single-case reportsfor initiation as well as maintenance therapy and in two recentlyreported cohorts for observational periods of <10 yrs [10–14].We describe our experiences with a combination therapy ofcorticosteroids and MMF in nine patients with IRF since 1996.Patients and methodsBetween 1996 and 2005, nine patients (seven males and twofemales, age at diagnosis 41–75 yrs, mean age 58.5 yrs) werereferred to our outpatient clinic with either confirmed or suspectedIRF. One patient had already been treated with a 4-month cycle ofprednisone and presented another 4 months after cessation oftherapy with the recurrence of ureteral obstruction.All patients showed signs of systemic inflammation with eitherpositive CRP (maximum 13.3mg/dl, minimum 0.5mg/dl; normalrange <0.5mg/dl) or ESR (maximum 70mm/1 h) or both.Creatinine values ranged from 12.8 to 0.8 mg/dl prior to therapy.Thorough clinical examination and additional chest X-ray wasperformed in all patients to rule out additional malignancy. Out ofnine patients, six had been treated with antihypertensive medica-tion consisting of -blockers in two of six patients and calciumchannel blockers and diuretics in three patients; one patient waswithout antihypertensive therapy. There was no history ofmethyldopa, ergotamine, radiation, surgery except in one (seesubsequently) or asbestos exposure.This case series meets and is in compliance with ethicalstandards in medicine and informed consent was obtained fromall patients. For patient overview please see Table 1.BiopsiesHistology in 2/9 patients during laparotomy ruled out malignancyin one patient with a history of bladder cancer and an abdominalaortic aneurysm in a second one. It showed signs of IRF withproliferating B- and T-cell infiltrates.Radiological diagnosisAbdominal ultrasound showed signs of an undefined periaorticmass. There was mild hydronephrosis in one and moderate tosevere hydronephrosis in seven patients. All patients underwenteither abdominal CT between 1996 and 2001 or MRI thereafter fordiagnosis and follow-up. It initially showed periaortic inflamma-tory tissue beginning inferior to the renal hili and extending to theiliac vessels with various extensions into the retroperitoneal area.1Department of Internal Medicine II/Nephrology, Technical University of Munich,Munich, Germany, 2Department of Rheumatology and Clinical Immunology/Allergology, Inselspital, University of Bern, Bern, Switzerland and 3Department ofRadiology, Technical University of Munich, Munich, Germany.Submitted 13 April 2008; revised version accepted 25 June 2008.Correspondence to: S. Adler, Department of Rheumatology and ClinicalImmunology/Allergology, Inselspital, University of Bern, Freiburgstrasse 3010,Bern, Switzerland. E-mail: sabine.adler@lrz.tu-muenchen.deRheumatology 2008;47:1535–1538 doi:10.1093/rheumatology/ken291Advance Access publication 7 August 20081535 The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.orgInitial diagnosis and follow-up considered the grade of inflamma-tion as radiological enhancement as well as the extension andregression of RF.Ureteral stentingSeven patients with moderate to severe hydronephrosis underwentbilateral double-J stenting of both their ureters. Two patientswithout hydronephrosis did not need any stenting.MedicationPharmacological treatment consisted of oral prednisone in adosage of 1 mg/kg bodyweight for 2 months and was then taperedto zero within the next 4 months to a planned overall duration of6 months. MMF was started concomitantly in a dosage of 1 gtwice daily.Follow-upDuring therapy and after cessation of immunosuppression itconsisted of serum creatinine, blood urea nitrogen, electrolytes,blood glucose, CRP, lipase, ALT, AST, ESR, blood smear,urinalysis and abdominal ultrasound. Within the first 6 monthsafter initiation of therapy, intervals of investigation were 2 weeks,gradually extending to every 3 months after having achieved astable situation. Additional CT or MRI scans were performedevery 4–6 months during therapy and every 12 months aftercessation of immunosuppression. Ureteral stents were removedaccording to radiological regression of IRF extension andreinserted in case of recurrent hydronephrosis after removal.ResultsAll patients experienced regression of IRF on CT or MRI that ledto removal of ureteral catheters in five of seven stented patientswith a mean duration of 5.6 months (range 3–8). The tworemaining patients have repeatedly been stented due to recurrenceof hydronephrosis after stent removal. Patient 7 is free of hisinitially mild hydronephrosis. Creatinine declined from 2.8 to1.3mg/dl mean.MMF treatment was discontinued after a mean of 27 months,range 11–96 months.Corticosteroid treatment was discontinued after a mean of7 months, range 3–24 months. CRP declined from a mean of 5.5(range 0.5–13.3mg/dl) to 0.8 mg/dl (range <0.5–1.8, normalvalues <0.5mg/dl), ESR values declined from a mean of 36 to9 mm/first hour.Special patient characteristicsPatient 1 was planned for operative lateralization of her uretersdue to extreme hydronephrosis but refused surgical treatment.With recurrent intermittent stenting and a continuous MMFtreatment her renal function remained stable with a creatinineof 1.2 mg/dl despite a remnant kidney function of 10% on the leftside. In order to avoid surgery she refused to stop MMF for 8 yrs.Patient 3 presented with extensive hydronephrosis and acreatinine level of 3.6mg/dl. Under immunosuppression andconcomitant ureteral stenting he experienced a marked regressionof IRF and then stopped corticosteroids after 3 months in fear ofside-effects. He repeatedly became hydronephrotic after stentremoval and underwent surgical ureterolysis 5 months afterinitiation of medical treatment with immediate postoperative reliefof hydronephrosis. MMF was continued for 2 yrs due to the factof a monotherapy in an extensive disease. Creatinine fell to 1.4mg/dl.Patient 9 underwent emergency admission to a tertiary carecentre due to abdominal pain and radiological suspicion of anextensive abdominal aortic aneurysm. Emergency surgery the nextday did not show an aortic aneurysm. Fast-track histologyrevealed signs of RF. Surgery was discontinued without anyfurther procedure and the patient was transferred for medicaltreatment. Immunosuppression was begun after completion ofwound healing. Radiological regression of IRF is shown priorto immunosuppression and 4 months after initiation of therapy(Figs 1 and 2).Side-effectsDuring ureteral stenting all seven patients experienced recurrenturinary tract infections and were sufficiently treated withantibiotics according to microbial testing. Three patients werefound to have abnormal glucose tolerance within the first3 months. Corticosteroids were therefore reduced prior toschedule in combination with dietary modification and part-timeoral antidiabetics. Due to unspecific upper gastroinstestinaldisturbance in one patient, MMF was given in four applicationsper day and finally had to be reduced to 50%, which was welltolerated.No side-effects were seen with regard to the haematopoieticsystem or tumour induction in the long run.Overall follow-up ranged from 2 to 11 yrs with respect to thetime of diagnosis and from 1 to 4 yrs after cessation ofimmunosuppression.DiscussionWe could demonstrate the effectiveness of MMF and corticoste-roids in the induction and maintenance therapy of IRF in ninepatients over the last 10 yrs with minor side-effects and no case ofrecurrence after cessation of therapy.Suspecting an autoimmune-mediated disease with immunohisto-chemistry of CD20þ B lymphocytes and some CD4þ andCD45þ T lymphocytes, MMF in this case appears to be a specificantiproliferative drug. As there is evidence that MMF is able tohave additional direct antifibrotic effects this explains its use inthe early phase to stop the B- and T-cell cycle as well as initiatingTABLE 1. Overview of patient characteristicsPatient Sex Age at Leading Initial Double J Duration of Radiological Histology Steroids MMF Creatinine Side-effects/number diagnosis symptom(s) hydronephrosis stenting stenting diagnosis months months pre- and post- complications(months) treatment (mg/dl)1 F 57 Abdominal pain Severe Yes Ongoing CT and MRI No 24 96 1.2–1.3 UTI2 M 61 Back pain Moderate to severe Yes 3 CT Yes 6 36 0.8–0.8 UTI3 M 58 Malaise Severe Yes 8 CT No 3 24 4.3–1.6 UTI4 M 55 Back pain Moderate to severe Yes 5 MRI No 4 11 1.0–0.9 UTI5 M 41 Malaise Severe Yes Ongoing MRI No 3 24 12.8–2.6 UTI, diabetes6 M 53 Back pain Moderate Yes 6 MRI No 8 12 2.0–1.1 UTI7 M 74 Malaise Mild No No MRI No 6 14 0.9–1.1 None8 F 75 Malaise Moderate to severe Yes 6 MRI No 4 12 1.2–1.2 UTI, diabetesconjunctivitis9 M 53 Abdominal pain None No No MRI Yes 5 12 1.1–1.1 DiabetesF: female; M: male; UTI: urinary tract infection.1536 S. Adler et al.it at any time of disease activity to reduce fibrogenesis [15].Furthermore, we learned from organ transplantation that due to itshigh immunosuppressive potency the use of MMF can lead to afaster reduction of concomitant steroids that appears useful withregard to Patients 5, 8 and 9 who all experienced an intermittentdiabetic situation [8].Mean duration of MMF application in our patient group was27 months, which is in congruence with the data from Scheel et al.[12] taking into account Patient 1 who refused to stop MMF formany years in fear of surgical ureterolysis. Furthermore, it seemsreasonable to continue on MMF for more than 12 months inpatients with a suspected long-standing or severe extension ofdisease like in Patients 1 and 5 or in patients with MMFmonotherapy due to early corticosteroid cessation.For an unspecific fast reduction of acute inflammation itappears reasonable to begin MMF in combination with cortico-steroids and reduce or even stop the steroid application afterabout 3 months when MMF should have developed antiprolif-erative potency. We would not suggest starting with corticosteroidtherapy alone. Apart from high recurrence rates, a high dosageappears to be necessary to control inflammation that goes alongwith known side-effects [16]. This is in accordance with Patient 8who after a 4-month cycle of corticosteroids relapsed early aftercessation and experienced a diabetic situation after initiation ofcombination treatment.In retrospect, the overall dosage and duration of glucocorti-coids might have been too high and too long in a combinationtherapy with a high immunosuppressive potency. Therefore, earlyreduction of glucocorticoids in a controlled and reducedinflammational situation might be more reasonable in favour ofa longer duration of MMF where necessary.Whether ESR and CRP levels are reliable parameters forsurveillance remains a matter of debate. Whereas Warnatz et al.[17] could not find a good correlation of disease activity with CRPlevels but with radiology, Scheel et al. [12] demonstrated a positivecorrelation of ESR as well as CRP. We could not find a reliablecourse as some patients had normal CRP values despiteradiologically detectable inflammation and a good response toimmunosuppressive treatment.With regard to the side-effects we emphasize the need for ashort duration of ureteral stenting as all stented patientsexperienced urinary tract infections. In patients with mildhydronephrosis, without elevation of creatinine a ureteral stentingmight be unneccessary like in Patient 7.As CT and MRI are able to identify RF we suggest histologyfor query cases only keeping in mind a possibly misleadingcytology of fine needle aspirates and the risk of intervention itself[18]. A PET might be helpful in the future for differentiation andfollow-up of inflammation vs remnant scar tissue [19].Combination with CT or MRI might verify ureteral fibrosis dueto repeated ureteral stenting and lead to surgical treatment—asprobably will become necessary in Patients 1 and 5.A future steroid-sparing option could be the use of other anti-inflammatory drugs for induction therapy like TNF- inhibitorsor anti-CD20 drugs. Yet for the time being, we would favour thecombination of MMF and corticosteroids as optional therapy atany stage of IRF leaving surgery for insufficient treatmentresponses or secondary distal ureteral stenoses. As our study—like many others—is limited by the number of patients we ask forthe establishment of a multicentre-driven study protocol compar-ing various immunosuppressive regimen to optimize therapeuticoutcome.Disclosure statement: The authors have declared no conflicts ofinterest.References1 Monev S. Idiopathic retroperitoneal fibrosis: prompt diagnosis preserves organfunction. Cleve Clin J Med 2002;69:160–6.2 Ormond JK. Bilateral ureteral obstruction due to envelopment and compression byan inflammatory retroperitoneal process. J Urol 1948;59:1072–9.3 Vaglio A, Salvarani C, Buzio C. Retroperitoneal fibrosis. Lancet 2006;367:241–51.4 Engelken JD, Ross PR. Retroperitoneal MR imaging. MRI Clin North Am1997;5:165–78.5 Zen Y, Sawazaki A, Miyayama S, Notsumata K, Tanaka N, Nakanuma Y. A case ofretroperitoneal and mediastinal fibrosis exhibiting elevated levels of IgG 4 in theabsence of sclerosing pancreatitis (autoimmune pancreatitis). Hum Pathol2006;37:239–43.6 Dash C, Liu K, Sheafor D, Dodd L. Fine-needle aspiration findings in idiopathicretroperitoneal fibrosis. Diagn Cytopathol 1999;21:22–6.7 Marcolongo R, Tavolini IM, Laveder F et al. Immunosuppressive therapy foridiopathic retroperitoneal fibrosis: a retrospective analysis of 26 cases. Am J Med2004;116:194–7.Rheumatology key message A combination therapy of glucocorticoids and MMF could reduceextension and inflammation in IRF with few side-effects. Therewere no recurrences after cessation of immunosuppression.FIG. 2. Abdominal MRI 4 months after initiation of MMF and glucocorticoidtreatment showing regression of the periaortic mass to a minimal extent. Inferiorcaval vein and left ureter are almost free of surrounding tissue (one section distalin comparison with Fig. 1 due to technical reasons). Please note the scar tissuein both the figures after surgery for a questionable abdominal aortic aneurysm.FIG. 1. Abdominal MRI pre-treatment showing a periaortic mass encoating aorta,inferior caval vein and in part the left ureter.Mycophenolate mofetil therapy in IRF 15378 Hamour IM, Lyster HS, Burke MM, Rose ML, Banner NR. Mycophenolate mofetilmay allow cyclosporine and steroid sparing in de novo heart transplant patients.Transplantation 2007;83:570–6.9 Koukoulaki M, Jayne DR. Mycophenolate mofetil in anti-neutrophil cyto-plasm antibodies-associated systemic vasculitis. Nephron Clin Pract 2006;102:c100–7.10 Grotz W, von Zedwitz I, Andre M, Schollmeyer P. Treatment of retro-peritoneal fibrosis by mycophenolate mofetil and corticosteroids. Lancet1998;352:1195.11 Jois RN, Kerrigan N, Scott DGI. Mycophenolate mofetil for maintenance of remissionin idiopathic retroperitoneal fibrosis. Rheumatology 2007;46:718–9.12 Scheel P, Piccini J, Rahman M, Lawler L, Jarett T. Combined prednisoneand mycophenolate mofetil treatment for retroperitoneal fibrosis. J Urol 2007;178:140–4.13 Khalil F, Mir MA, Venuto RC. Mycophenolate mofetil in the treatment of retro-peritoneal fibrosis. Clin Rheumatol 2008;27:679–81.14 Swartz RD, Lake AM, Roberts WW, Faerber GJ, Wolf JS Jr. Idiopathic retro-peritoneal fibrosis: a role for mycophenolate mofetil. Clin Nephrol 2008;69:260–8.15 Roos N, Poulalhon N, Farge D, Madeleine I, Mauviel A, Verrecchia F. In vitroevidence for a direct antifibrotic role of the immunosuppressive drug mycophenolatemofetil. J Pharmacol Exp Ther 2007;321:583–9.16 Van Bommel EF, Siemes C, Hak LE, van der Veer SJ, Hendricksz TR. Long-termrenal and patient outcome in idiopathic retroperitoneal fibrosis treated withprednisone. Am J Kidney Dis 2007;49:615–25.17 Warnatz K, Keskin AG, Uhl M et al. Immunosuppressive treatment of chronicperiaortitis: a retrospective study of 20 patients with chronic periaortitis and a reviewof the literature. Ann Rheum Dis 2005;64:828–3.18 Jogai S, Al-Jassar A, Temmim L. Idiopathic retroperitoneal fibrosis – a potential pitfallfor fine needle aspiration cytology. Cytopathology 2005;16:49–50.19 Vaglio A, Versari A, Fraternali A, Ferozzi F, Salvarani C, Buzio C. 18F-Fluoro-deoxyglucose positron emission tomography in the diagnosis and follow-up ofidiopathic retroperitoneal diagnosis. Arthritis Rheum 2005;53:122–5.1538 S. Adler et al.

Successful mycophenolate mofetil therapy in nine patients with idiopathic retroperitoneal fibrosis

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