Retroperitoneal Fibrosis

Driving a paradigm shift in retroperitoneal fibrosis: Medical management with combined prednisone/MMF therapy

Retroperitoneal fibrosis (RPF) is a condition marked by inflammation and fibrosis within the retroperitoneal space, including the infrarenal aorta as well as other surrounding structures. As the fibrosis spreads inferiorly and laterally, it leads to ureteral obstruction and acute renal failure. Although there is limited data on disease incidence and prevalence, RPF typically emerges in the fifth, sixth, and seventh decades of life (with a mean age of 54 years), and there is a slight male-to-female predominance. 

Little is known about what causes RPF, and there has been significant ambiguity around diagnostic criteria (see sidebar), which has further hampered formal studies of the disease and its optimal treatment. Historically, treatment has focused on relieving ureteral obstruction, using stents followed by open or laparoscopic ureterolysis to relocate the ureter. But that approach does not address systemic symptoms, such as pain, weight loss, and anemia, or the disease’s underlying causes—inflammation and fibrosis.

In the last decade, early reports of successful, nonsurgical treatment with various immunosuppressive agents have spurred a new therapeutic approach to RPF, pioneered by Paul Scheel, M.D., M.B.A., director of the Division of Nephrology at Johns Hopkins. This novel treatment, which combines prednisone and mycophenolate mofetil (MMF), can treat the underlying inflammation and fibrosis, and has been shown to reduce or eliminate disease symptoms in 95% of patients, with a recurrence rate of 5%.

Early prospective study reveals drugs’ effectiveness in RPF

Scheel began his work on RPF 15 years ago, as he searched the medical literature for a potential treatment for a patient with inoperable disease. Based on case reports of patients with RPF and animal models of fibrosis, he proposed a drug combination, combining the anti-inflammatory drug prednisone with MMF, which has both antifibrotic and immunosuppressive properties. The initial results were striking,1 and Scheel and his colleagues subsequently expanded their work to a rospective series of 31 patients with RPF.

The drug regimen includes 1,000 mg of MMF administered orally twice a day and continued for 6 months following resolution of systemic symptoms and extubation of affected ureters. (In some patients, particularly African-Americans, who metabolize MMF more rapidly than others, the dose may be increased to 1,500 mg twice a day.) Therapy also includes 40 mg of prednisone administered daily with a gradual taper over 6 months. In patients receiving this combination treatment, the investigators measured various outcomes, including laboratory tests indicative of inflammation, CT scanning to assess fibrosis around the infrarenal aorta, and the removal of ureteral stents. In this 31-patient study, systemic symptoms resolved and laboratory values returned to normal in all patients. Eighty-nine percent of patients had a 25% or greater reduction in periaortic mass. Of the 32 obstructed ureters (representing 18 patients), 30 were free of obstruction after an average of 513 days of therapy.

Drug combination transforms RPF treatment 

Following their initial studies, Scheel and his colleagues have now treated a total of 234 RPF patients with the prednisone/MMF combination therapy (unpublished). These patients have a response rate of 95% and a recurrence rate of 5% following cessation of therapy. Although this approach has not been directly compared to other medical treatments for RPF (including prednisone alone and prednisone combined with tamoxifen), the response rate is higher and the recurrence rate is markedly lower.

The prednisone/MMF drug combination has sparked a paradigm shift in the treatment of RPF. The disorder, which was treated for many years with surgery alone, was associated with significant morbidity. It can now be treated medically, resulting in a complete resolution of disease in the vast majority of cases and with few side effects. 

Toward a deeper knowledge of retroperitoneal diseases

As Scheel and his colleagues have emerged as world leaders in the clinical care of RPF, they are now turning their attention to the disease’s root causes. Using blood collected from RPF patients, they are working with collaborators in Italy to uncover the genetic basis of the disorder. They have also expanded their clinical practice to include other diseases of the retroperitoneum. For example, the Johns Hopkins Division of Nephrology is one of three national centers of excellence in managing patients with Erdheim-Chester disease (ECD), a rare non-Langerhans histiocytosis. Historically, this disease was considered to be highly aggressive and responded poorly to therapy. Now, with a clearer molecular picture of ECD, including the finding of the BRAFV600E mutation in more than 50% of patients3, a promising new treatment has emerged. 

Scheel PJ Jr, Piccini J, Rahman MH, Lawler L, Jarrett T. Combined prednisone and mycophenolate mofetil treatment for retroperitoneal fibrosis. Journal of Urology 2007 Jul;178(1):140-3 

Scheel PJ Jr, Sozio SM, Feeley N. Medical management of retroperitoneal fibrosis. Transactions of the American Clinical and Climatological Association 2012;123:283-290 

Scheel P, Feeley N, Sozio S. Combined prednisone and mycophenolate mofetil for retroperitoneal fibrosis: A case series. Annals of Internal Medicine 2011;154(1):31-36

Scheel P, Feeley N. The clinical, laboratory and radiographic presentation of retroperitoneal fibrosis. Medicine 2009;88:202-207

Scheel P, Feeley N. Retroperitoneal fibrosis. Rheumatic Disease Clinics of North America 2013;39(2):365-381

Swartz R, Scheel P. Retroperitoneal fibrosis: Gaining traction on an enigma. The Lancet 2011;378(9788):294-296

Haroche J, Charlotte F, Arnaud L et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 2012;120(13):2700-2703

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