Treatment of retroperitoneal fibrosis

INTRODUCTION — Retroperitoneal fibrosis (RPF), also referred to as Ormond's disease, is characterized by chronic inflammation, fibroblast proliferation, and extracellular matrix deposition in the retroperitoneum. RPF can lead to venous or arterial occlusion of large abdominal blood vessels and hydronephrosis from ureteral obstruction. Patients may require medical therapy for the RPF and endovascular, urological, or surgical treatment for management of complications. Untreated patients may develop severe complications including progression to end-stage kidney disease [1].

RPF is classified into primary (idiopathic) disease, which can result from immunoglobulin G4–related disease (IgG4-RD) or non-IgG4-RD, and secondary disease. The treatment of non-IgG4-RD and secondary RPF is reviewed here.

The clinical manifestations, pathogenesis, and diagnosis of RPF and all aspects of IgG4-RD are presented separately.

●(See "Clinical manifestations and diagnosis of retroperitoneal fibrosis".)

●(See "Clinical manifestations and diagnosis of IgG4-related disease".)

●(See "Clinical manifestations and diagnosis of IgG4-related disease".)

●(See "Treatment and prognosis of IgG4-related disease".)

PREMANAGEMENT EVALUATION — Patients diagnosed with retroperitoneal fibrosis (RPF) generally have already had computed tomography (CT) of the abdomen without and with contrast (or magnetic resonance imaging [MRI]), a complete blood count, and measurement of blood urea nitrogen, serum creatinine, liver function tests, fasting glucose, lipid profile, urinalysis, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) as part of the diagnostic evaluation. Missing tests should be obtained prior to initiating therapy. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis", section on 'Diagnostic approach'.)

The results of some of these tests serve as a pretreatment baseline and help assess the response to therapy. (See 'Assessing response to initial treatment' below.)

We obtain a baseline fluorodeoxyglucose positron emission tomography (FDG-PET) to assess disease activity and to anticipate response to treatment. In one study, high-grade avidity on the FDG-PET was predictive of response to glucocorticoids compared with low-grade avidity or a negative result (82 versus 12 versus 0 percent, respectively) [2]. However, in our experience, while patients who have high-grade avidity are more likely to respond, a negative FDG-PET does not necessarily predict refractoriness to treatment [3].

MANAGEMENT — The goals of therapy are to treat complications caused by fibrosis, stop the progression of the fibrotic process, and prevent recurrence. The overall management consists of the following aspects (algorithm 1):

●Immediate decompression of the urinary tract in patients with moderate to severe urinary tract obstruction. (See 'Treatment of urinary obstruction' below.)

●Treatment of other complications of retroperitoneal fibrosis (RPF), such as venous or arterial obstruction. (See 'Treatment of vascular obstruction' below.)

●Medical therapy for patients with idiopathic RPF (algorithm 2 and algorithm 3). (See 'Treatment of non-IgG4-related idiopathic disease' below.)

●Cause-specific treatment for patients with secondary RPF, when possible. (See 'Treatment of secondary disease' below.)

●Monitoring in addition to medical therapy for patients with mild hydronephrosis but without compromised kidney function. (See 'Treatment of non-IgG4-related idiopathic disease' below and 'Monitoring after remission' below.)

Urgent treatment of complications — Patients with RPF may present with or develop complications of the RPF, such as ureteral obstruction or vascular insufficiency or obstruction. Treatment of these complications is often necessary before further evaluation and management of the underlying disease (algorithm 1).

Treatment of urinary obstruction — The treatment of urinary obstruction depends upon its severity on imaging, the kidney function, and the underlying cause of RPF.  

●We relieve the obstruction with an interventional procedure among patients who have:

•Idiopathic RPF and moderate to severe hydronephrosis

•Idiopathic RPF and mild hydronephrosis of their only kidney

•Idiopathic RPF and mild hydronephrosis and compromised kidney function

•Secondary RPF due to an irreversible (eg, radiation) or slowly reversible (eg, malignancy) cause and hydronephrosis of any degree

●In patients with idiopathic RPF, two kidneys, normal kidney function, and mild hydronephrosis, we treat with glucocorticoids first. If there is evidence of persistent or worsening obstruction despite approximately four weeks of treatment, then we proceed with an interventional procedure.

Along with fibrotic encasement, edema and inflammation of the surrounding tissue, which generally respond to glucocorticoids, also play an important role in causing ureteral obstruction [4-8]. In addition, among patients with mild obstruction and normal kidney function, the benefit of interventions to relieve obstruction may be outweighed by the discomfort and risk of complications associated with intervention [9]. Thus, in cases where there is less urgency to relieve obstruction quickly, it is reasonable to wait up to four weeks to determine if relief of the obstruction occurs with glucocorticoids alone. Patients among whom such an approach is generally chosen are those who have mild obstruction and intact kidney function (with the exception of patients who have a mildly obstructed single kidney). Lack of resolution of hydronephrosis by four weeks suggests mechanical obstruction by fibrotic encasement as the major cause of ureteral obstruction, which should then be relieved by an interventional procedure.

The data in support of this practice are limited to our clinical experience and small case series in which some patients with RPF who had ureteral obstruction and hydronephrosis improved while on immunosuppressive therapy and without procedural relief of obstruction [4-8]. However, there is significant variability between the studies with regards to the severity of obstruction treated with immunosuppressive therapy alone. In addition, many of the studies were performed in an era when open surgical procedures to relieve obstruction were more common, compared with minimally invasive procedures that are common in contemporary urological and interventional radiology practice.

Urinary obstruction can be relieved by one of the following interventions [9]:

●Placement of indwelling ureteral stents – This is preferred treatment because it is the least invasive option that offers the best quality of life relative to other interventions [10]. (See "Placement and management of indwelling ureteral stents", section on 'Ureteral obstruction'.)

●Percutaneous nephrostomy – An advantage of this approach is that it allows for descending ureterography for better monitoring of the disease response to treatment and of relief from obstruction.

●Open surgical approach – The advantage of this approach is the simultaneous ability to perform a tissue biopsy and investigate potential secondary causes for RPF, such as a lymphoma, retroperitoneal cancer, or infection. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis", section on 'Features suggestive of secondary disease'.)

Most patients can experience relief from urinary obstruction with indwelling stents. Open surgery should be reserved for the following settings:

•Technical difficulties or complications both with indwelling stent placement and percutaneous nephrostomy.

•Radiologic, laboratory, or clinical findings suggesting underlying malignancy as a possible secondary cause.

•Lack of regression of the retroperitoneal mass after medical therapy with persistent encasement of the ureters or other structures. (See 'Assessing response to initial treatment' below.)

Open surgery generally entails an exploratory laparotomy or laparoscopy with ureterolysis [11,12]. In addition to ureterolysis, procedures to prevent recurrent ureteral obstruction might be necessary. Different techniques have been used either alone or in combination for this purpose, such as [13]:

●Wrapping the ureters with omental fat. The process of ureterolysis (ie, removing fibrous tissue from around the ureters) strips the ureters of their vascular supply. Omental fat that is wrapped around the ureters serves as a barrier against further encasement by fibrous tissue and promotes revascularization of the ureters [14,15]. This is the preferred adjunctive approach.

●Transposition of the ureters to an intraperitoneal position.

●Transposition of the ureters laterally, with interposition of retroperitoneal fat between the ureters and the fibrous tissue.

The techniques of ureterolysis and ureteral injury repair are discussed separately. (See "Surgical repair of an iatrogenic ureteral injury".)

Relief of obstruction after intervention should be ensured by kidney ultrasound postoperatively, every two to four weeks thereafter for approximately four months, then every two months for one year, and then every six months thereafter.

Treatment of vascular obstruction — RPF can involve large and medium vessels in the thorax and abdomen as part of the disease process. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis", section on 'Clinical features'.)

Percutaneous interventions, such as angioplasty and stenting, or surgical management of acute and chronic vascular obstruction may be needed along with systemic medical therapy in some patients [16,17]. A discussion of the evaluation and management of various vascular complications is presented separately. (See "Acute mesenteric arterial occlusion", section on 'Management' and "Surgical and endovascular techniques for mesenteric revascularization" and "Overview of thoracic central venous obstruction" and "Overview of iliocaval venous obstruction" and "Endovenous intervention for iliocaval venous obstruction".)

Treatment of secondary disease — If the RPF is due to a secondary cause (table 1), treatment is aimed at the underlying etiology, if it is amenable to treatment. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis", section on 'Features suggestive of secondary disease'.)

Among patients with drug-induced RPF, discontinuation of the offending agent often leads to improvement of RPF within a few months. However, in our experience, prednisone treatment can be beneficial among patients who do not respond to drug discontinuation alone or who have severe disease manifestations. Our glucocorticoid regimen for persistent or severe drug-induced RPF is the same as for idiopathic disease. (See 'Treatment of non-IgG4-related idiopathic disease' below.)

Treatment of IgG4-related disease — The treatment of immunoglobulin G4-related disease (IgG4-RD) is discussed at length elsewhere. (See "Treatment and prognosis of IgG4-related disease".)

Treatment of non-IgG4-related idiopathic disease — A variety of immunosuppressive agents, used alone or in combination, are available to treat idiopathic RPF (algorithm 4).

Initial treatment — Glucocorticoids are the mainstay of therapy for idiopathic RPF [1,5,11,18-20]. However, among patients with relative contraindications to glucocorticoids, they should be used for the shortest possible duration and at a lower dose (prednisone 25 mg per day), in combination with other immunosuppressive medications (algorithm 2 and algorithm 3).

Preferred treatment with high-dose glucocorticoids — We initiate therapy with glucocorticoids as soon as an empiric diagnosis of idiopathic RPF is made (algorithm 4). We treat with prednisone at a dose of 1 mg/kg per day (maximum 80 mg per day) for four weeks. This is usually followed by an assessment of the response to initial therapy and decision-making regarding further treatment (algorithm 2). (See 'Assessing response to initial treatment' below and 'Responders to initial treatment' below and 'Nonresponders to initial treatment' below.)  

Our glucocorticoid dosing regimen is based upon our clinical experience [1,21]. However, other initial dosing regimens that have been successfully applied include: 60 mg once daily for six weeks [6]; or 60 mg every other day for two months [22].

There are no clinical trials to guide the initial management of RPF. The initial treatment of RPF with high-dose glucocorticoids is based largely upon small observational studies, our clinical experience, and biological rationale (ie, RPF is an immune-mediated fibroinflammatory process). Glucocorticoids alone are effective in the majority of patients with response rates ranging from 75 to 90 percent depending upon the dose and duration of therapy [4-8,20-23].

There are no trials comparing glucocorticoids with other immunosuppressive agents for initial management. However, in one trial, compared with patients who switched to tamoxifen after initial therapy with prednisone, patients who continued long-term treatment with prednisone had a lower risk of relapse [21].

Several aspects related to long-term therapy with glucocorticoids are presented elsewhere. (See "Major adverse effects of systemic glucocorticoids", section on 'General treatment considerations and monitoring' and "Major adverse effects of systemic glucocorticoids", section on 'Factors related to glucocorticoid toxicity' and "Major adverse effects of systemic glucocorticoids", section on 'Organ-based toxicity of systemic glucocorticoids' and "Determinants of glucocorticoid dosing", section on 'Drug interactions'.)

Patients with contraindications to high-dose glucocorticoids — We treat patients who have relative contraindications to long-term, high-dose glucocorticoids with alternative immunosuppressants, such as rituximab, methotrexate, or mycophenolate mofetil in combination with low-dose glucocorticoids (prednisone 25 mg/day) (algorithm 4 and algorithm 3). This ensures that the total glucocorticoid dose can be minimized in such patients. Alternatively, if glucocorticoids must be completely avoided, we treat patients with rituximab monotherapy. (See "Major adverse effects of systemic glucocorticoids", section on 'General treatment considerations and monitoring'.)

We prefer to use glucocorticoids in combination with alternative immunosuppressive medications rather than alternative immunosuppressive medications alone. This is because of the rapidity and durability of response noted with glucocorticoids (high dose) as compared with the slower response with alternative immunosuppressive agents, especially rituximab. (See 'Preferred treatment with high-dose glucocorticoids' above and 'Assessing response to initial treatment' below.)

There are limited data available with regards to the success of rituximab, methotrexate, and mycophenolate mofetil in RPF. The choice between these agents may depend upon presence or absence of relative or absolute contraindications to these individual agents (algorithm 4). The data in support of and contraindications to individual agents are discussed below:

●Rituximab – We administer rituximab at a dose of 375 mg/m² per week for four consecutive weeks or two infusions of 1000 mg each two weeks apart. The data in support of rituximab use is based on small case series (the series is repeated at six months among those who respond) [24-27]. In the largest of these case series, 22 patients who had relapsing or refractory disease or who had contraindications to standard-dose glucocorticoids were treated with rituximab. At a median follow-up of approximately three years, 75 percent of patients had achieved remission. Treatment was generally well tolerated.

We avoid rituximab in patients with history of recurrent severe infections or proven hypersensitivity to rituximab. (See "Overview of biologic agents in the rheumatic diseases", section on 'Rituximab' and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Contraindications'.)

●Methotrexate – We administer methotrexate at a dose of 7.5 to 10 mg per week, increased by 2.5 mg every week for a maximum of 20 mg/week. We administer methotrexate in combination with prednisone 25 mg/day. Limited data in support of this combined regimen show that 79 percent patients with RPF achieved remission at a median follow-up of 24 months [28].

We avoid methotrexate among patients with a preexisting condition that may predispose patients to severe adverse effects (eg, advanced liver disease, severe acute or chronic kidney disease with an estimated glomerular filtration rate of <30 mL/min/1.73 m²). (See "Major side effects of low-dose methotrexate", section on 'Potential severe adverse effects'.)

●Mycophenolate mofetil – We administer mycophenolate mofetil at a dose of 1000 mg twice daily in combination with prednisone 25 mg/day.

The best data in support comes from one study of 28 treatment-naïve patients with RPF who received mycophenolate mofetil and prednisone as initial therapy [29]. At a mean follow-up of over two years, approximately 89 percent had clinical improvement. The rate of relapse was approximately 7 percent (2 of 28 patients).

We avoid mycophenolate mofetil among patients with leukopenia or severe gastrointestinal diseases. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Contraindications'.)

Other therapies, such as tamoxifen, azathioprine, and colchicine have limited efficacy against RPF. We generally do not use these therapies in our practice [30,31].

Assessing response to initial treatment — Within a few days of beginning glucocorticoid-based therapy, even when given at a low dose, pain and constitutional symptoms usually improve, and the erythrocyte sedimentation rate (ESR) falls dramatically. The response to rituximab monotherapy may be slower compared with regimens that include glucocorticoids.

Among patients who did not receive an initial intervention to relieve urinary obstruction, improvement in the obstruction (by symptoms or imaging) may be observed within a few weeks. The resolution of the mass by computed tomography (CT) or magnetic resonance imaging (MRI) may begin within a few weeks of initiating medical therapy [20].

We monitor patients initiated on immunosuppression as follows, usually four to eight weeks after initiation of immunosuppressive agents:

●Clinical evaluation – By four weeks, we expect to see resolution of pain and urinary obstruction. Clinical response may be delayed among patients who do not receive glucocorticoids as part of their treatment.

●Laboratory evaluation – We expect to see improvement in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and serum creatinine concentration (if it was previously elevated). Inflammatory markers (ESR and CRP) don’t always correlate with response to treatment or with subsequent flares [32]. Thus, ESR and CRP are assessed in combination with clinical evaluation and imaging findings, rather than in isolation.

●Radiological evaluation – We obtain a CT scan without and with contrast (or an MRI if an MRI was the test used during the diagnostic evaluation) after one and four months of therapy among patients who received a glucocorticoid-based regimen. Among patients who received rituximab monotherapy, we expect the radiologic response to be slower, and therefore, we delay the first imaging study to the third month. The subsequent study is performed four to six months after the one performed in the third month.  

Failure to detect clinical or radiologic improvement within four weeks of initiation of medical therapy should prompt a repeat evaluation with CT scan after another four to six weeks, with the exception of patients treated with rituximab monotherapy, who can have a delayed response (by approximately 12 weeks). In addition, a biopsy, if not already obtained for initial diagnosis, should be performed to confirm the diagnosis. (See 'Biopsy to confirm the diagnosis (if not already done)' below.)

●We define response to therapy as:

•Resolution of symptoms

•Resolution of obstructive complications (by imaging)

In addition, there may be improvement in ESR and CRP (normalization or return to <30 percent of normal values). However, such an improvement is not required to consider patients in remission because of their suboptimal sensitivity and specificity [2]. Similarly, reduction of the mass by imaging is supportive but not required to deem a patient as being in remission. This is because some patients have sclerotic masses that fail to shrink despite response to therapy (based upon symptom resolution and improvement in ESR and CRP).

Responders to initial treatment — Among patients who have a demonstrable response to high-dose prednisone therapy (see 'Assessing response to initial treatment' above), we typically taper the prednisone in the months after remission as follows [21]:

●0.5 mg/kg daily for one month, then

●0.25 mg/kg daily for two months, then

●0.2 mg/kg daily for one month, then

●0.15 mg/kg daily for one month, then

●7.5 mg daily for one month, then

●5 mg daily for one month, then

●2.5 mg daily for two weeks, then

●2.5 mg every other day for two weeks

Among patients taking an alternative immunosuppressant in combination with low-dose prednisone (ie, 25 mg daily), we slowly taper the prednisone over the same eight-month period.

However, the total duration of therapy may be varied based upon the severity of disease (size and extent of the retroperitoneal mass) and the response to therapy. As an example, patients with mild disease who rapidly respond to prednisone may be treated for a shorter duration (eg, a total of six months). On the other hand, patients with an extensive retroperitoneal mass that regresses slowly may require prolonged therapy. In such patients, a slow taper of prednisone over the course of a year or longer would be appropriate.

Among patients treated with a combination of mycophenolate mofetil and prednisone therapy, we continue mycophenolate mofetil at the same dose of 1000 mg twice daily until the last month of therapy, when it is tapered to 500 mg twice a day before being stopped. Among patients treated with methotrexate in combination with prednisone, we reduce the methotrexate to one-half the dose in the last month of therapy before stopping it.

We monitor the response to therapy by:

●Clinical evaluation every two to three months or more frequently as dictated by symptoms.

●Laboratory evaluation with a serum creatinine, ESR, and CRP monthly for two months, then every two to three months.

●Radiological evaluation with a CT scan without and with iodinated contrast (or MRI, if appropriate) approximately every four to six months (after the initial CT at four weeks showing response) to follow the size of the fibrotic mass. A reduction of the mass size by at least 20 percent indicates a response. Resolution of the mass or lack of a further reduction in size on serial CTs provides guidance regarding duration of immunosuppressive therapy. In addition, an increase in the size of the mass or a new complication (eg, hydronephrosis or vascular insufficiency) related to the mass may prompt surgical intervention. Full resolution of the fibrotic plaque may never occur.

●In patients with equivocal findings on serial CTs, a 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) may be useful to assess the metabolic activity of the residual retroperitoneal tissue [33].  

The best data supporting the use of glucocorticoids as a maintenance regimen come from a trial in which 36 patients with idiopathic RPF who responded to prednisone induction therapy (1 mg/kg per day for one month) were randomly assigned to a tapering dose of prednisone or a fixed dose of tamoxifen for eight months [21]. The primary endpoint was relapse of disease, defined as the new onset or recurrence of one or more of: hydronephrosis; a 20 percent or larger increase in the size of a retroperitoneal mass; or symptoms (eg, back or abdominal pain, constipation) in combination with a 50 percent or greater increase in CRP or ESR. At eight months, the relapse rate was lower in patients who received prednisone compared with tamoxifen (6 versus 39 percent). Five of the seven patients who relapsed on tamoxifen were switched to prednisone, later on leading to remission. All patients were followed for an additional 18 months after termination of all therapy. At 26 months, the relapse rate was lower among patients treated with prednisone compared with tamoxifen (17 versus 50 percent). Although the relapse rate was lower, prednisone was associated with significantly more adverse effects, including cushingoid changes, weight gain, and hyperlipidemia.

Some patients with RPF appear to derive greater benefit from glucocorticoid therapy than others; such patients may have a greater degree of edema and inflammation, which is responsive to glucocorticoids, within and surrounding their diseased tissue [4-8,34].  

Nonresponders to initial treatment — Patients who receive glucocorticoids (alone or in combination with another agent) as initial treatment and who do not have clinical and radiologic improvement by four weeks are considered nonresponders to initial treatment (algorithm 2 and algorithm 3). Patients who receive rituximab monotherapy may take longer to respond to treatment, and such patients are considered nonresponders if they have not had clinical and radiologic improvement by nine to twelve weeks.

The lack of expected response should prompt a repeat evaluation with CT scan and biopsy (if not already performed) to ascertain that the diagnosis is correct (eg, not a misdiagnosed infection or malignancy). (See 'Assessing response to initial treatment' above.)

However, some cases of correctly diagnosed idiopathic RPF may be intrinsically resistant to glucocorticoids, possibly because such patients have masses that have a greater proportion of fibrotic rather than inflammatory tissue.

Biopsy to confirm the diagnosis (if not already done) — We attempt a biopsy of the suspected RPF tissue for histopathologic confirmation, if possible, among patients who had the initial diagnosis made by imaging alone (CT or MRI) and have not responded to initial treatment. Details regarding the biopsy are presented separately. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis", section on 'Indications for a biopsy and diagnostic histopathology'.)

Change to alternative immunosuppression (if diagnosis is correct) — Among patients who have not responded to initial glucocorticoid therapy, we usually continue prednisone at a high dose (1 mg/kg per day) for another month. We then initiate a taper over the subsequent two to four months. If the disease does not adequately respond to prednisone alone despite the additional month of treatment with prednisone, other drugs can be added to improve the response or to reduce the cumulative exposure to high-dose prednisone. We prefer to add methotrexate, mycophenolate mofetil, or rituximab to prednisone therapy. The choice among these three options depends upon presence or absence of relative or absolute contraindications to these individual agents. Among patients who have not responded to an alternative immunosuppressive therapy, we change the therapy to a different regimen (eg, patients nonresponsive to methotrexate and prednisone can be switched to a regimen of rituximab and prednisone or mycophenolate mofetil and prednisone). (See 'Patients with contraindications to high-dose glucocorticoids' above.)

The data in support of methotrexate as an adjunct immunosuppressant to prednisone come from its demonstrated efficacy in other immune-mediated diseases that have a chronic clinical course, such as giant-cell arteritis or rheumatoid arthritis [35]. We administer methotrexate at a starting dose of 7.5 mg/week and increase it by 2.5 mg weekly, until there is either notable improvement or dose-limiting toxicity, for a maximum of 20 mg/week. Once methotrexate is initiated, we begin a prednisone taper to a goal of 5 mg/day within four to six months. The total duration of therapy (prednisone in combination with methotrexate) is based upon clinical and radiographic response, but is usually at least 8 to 10 months. A review of dosing and monitoring can be found elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)

Due to the risk of toxicity in those with kidney disease, methotrexate should not be administered to patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m². In addition, we avoid methotrexate among patients with liver disease. Instead, we use mycophenolate mofetil 1 g twice daily and prednisone among such patients [29,36-38]. As for the methotrexate-based regimen, upon initiation of mycophenolate mofetil, we taper off prednisone over four to six months, with a total duration of treatment of approximately 8 to 10 months. The best data in support of this regimen come from a series of 28 patients with idiopathic RPF who were treated with mycophenolate mofetil 1g twice daily in combination with prednisone 40 mg daily tapered over six months [29]. At a mean follow-up of two years, all patients had resolution of symptoms and normalization of inflammatory markers, and 89 percent of patients had a substantial reduction (>25 percent) in their periaortic mass.

Among patients who have contraindications to the methotrexate and mycophenolate mofetil or among patients who have failed to respond to methotrexate or mycophenolate mofetil, we give rituximab (either 375 mg/m² weekly for four weeks or 1 g, twice, two weeks apart) with or without prednisone. An additional course of rituximab is often necessary after 6 to 12 months. In one case series of 20 patients who either had relapsing or refractory disease or contraindications to standard-dose glucocorticoids, rituximab led to effective disease control. These patients were able to tolerate a substantial reduction of the glucocorticoid dose, had improvement in FDG uptake on PET, and had periaortic tissue reduction by CT or MRI [24].

Among patients in whom contraindications preclude use of both glucocorticoids and rituximab, monotherapy with tocilizumab, a recombinant monoclonal antibody to interleukin-6, is an alternative to rituximab. Tocilizumab is administered at a dose of 8 mg/kg/month for six months (maximum dose 800 mg/month). Evidence in favor of tocilizumab remains limited to case reports [39].

Other therapies that have been tried, in combination with glucocorticoids, include azathioprine, cyclophosphamide, cyclosporine, and infliximab [19,40-42].

Monitoring after remission — Following discontinuation of glucocorticoids (or other immunosuppressive agents), we suggest monitoring for disease relapse for 10 years after the last episode. We perform the following assessments:

●Clinical and laboratory monitoring of serum creatinine, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) every three to six months in the first year and every six to twelve months thereafter.

●Monitoring with an abdominal ultrasound every three to four months (to detect relapse in the form of hydronephrosis) and computed tomography (CT) scan or magnetic resonance imaging (MRI) every six months for the first year and every one to two years thereafter.

We define disease relapse by presence of at least one of the following criteria:

●Mass enlargement by CT or MRI (defined by ≥20 percent increase in mean maximal thickness as compared with the prior scans).

●New-onset hydronephrosis or worsening of prior hydronephrosis.

●Recurrent or new-onset of disease-related symptoms (see "Clinical manifestations and diagnosis of retroperitoneal fibrosis", section on 'Clinical features') and an increase in ESR or CRP values (≥50 percent of the values recorded at the previous visit).

An isolated increase in ESR or CRP values is not sufficient to diagnose relapse. In addition, development of hydrocele, varicocele, and erectile dysfunction are not part of the criteria for diagnosis of relapse because they can develop independent of the progression of RPF.

The rate of disease recurrence varies widely between studies, ranging from less than 10 percent to over 70 percent [6,7,19,43,44]. This reported variation is likely due to differences between studies in the treatment schedules, total duration of treatment, and length of follow-up. Because of such lack of uniformity, it is unclear whether the reported recurrence rates represent true resurgence of the disease or regrowth of partially treated masses.

Management of relapse — In patients who relapse after remitting with high-dose prednisone therapy, we usually initiate a combination of prednisone and methotrexate to limit the cumulative exposure to glucocorticoids. In patients who have contraindications to methotrexate (eg, liver disease), we treat with mycophenolate mofetil or rituximab in combination with prednisone. In patients who have previously responded to an alternative initial therapy regimen (eg, prednisone and mycophenolate mofetil), we repeat the same regimen for the treatment of relapse.

The dosing of alternative immunosuppressive medications is similar to that used for patients with contraindications to glucocorticoids. (See 'Patients with contraindications to high-dose glucocorticoids' above.)

The dose of prednisone varies and can be as high as 1 mg/kg per day, depending upon the severity of the flare and whether or not there are relative contraindications to high-dose glucocorticoids. Among patients with no contraindications to high-dose glucocorticoids, we use the higher dose of prednisone among patients who have a severe flare, characterized by presence of disease-related symptoms that significantly affect the patient's quality of life (eg, kidney function impairment from urinary tract obstruction). We use a lower dose of prednisone among patients who have a mild flare characterized by mild disease-related symptoms and urinary tract obstruction without impairment of kidney function. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis", section on 'Clinical features'.)

We gradually taper prednisone over the course of 12 months while maintaining methotrexate at the same dose, until the last month when it is reduced by one-half before being stopped [13]. Mycophenolate mofetil is maintained at the same dose until the last month of therapy when it is halved before discontinuation. Rarely, patients require extension of this regimen beyond 12 months for up to 18 to 24 months.

This regimen with prednisone and methotrexate was effective in one study in which 16 patients were treated for relapsed disease [28]. At one year, 11 of 16 achieved remission. Of the 11, four discontinued treatment at one year and relapsed shortly afterwards; seven continued treatment and remained in remission. One patient discontinued treatment because of sepsis and liver toxicity, one temporarily interrupted treatment, and another one required a dose reduction because of adverse effects.

PROGNOSIS — In patients who respond to glucocorticoids, mortality is less than 10 percent over many years of follow-up (excluding cases associated with malignancy) [4,20]. Complete resolution of the manifestations of retroperitoneal fibrosis may depend, in part, on the duration of entrapment. In approximately one-third of patients, chronic kidney function impairment with associated hypertension and/or anemia may persist, despite relief of obstruction, if there has been permanent kidney parenchymal damage [45]. However, development of end-stage kidney disease is rare.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults" and "Society guideline links: IgG4-related disease".)

SUMMARY AND RECOMMENDATIONS

●Retroperitoneal fibrosis and goals of therapy – Retroperitoneal fibrosis (RPF) is characterized by chronic inflammation, fibroblast proliferation, and extracellular matrix deposition in the retroperitoneum, which can lead to venous or arterial occlusion of large abdominal blood vessels and hydronephrosis from ureteral obstruction. The goals of therapy are to relieve obstruction, stop the progression, and prevent recurrence of RPF. (See 'Introduction' above.)

●Premanagement evaluation – Prior to initiating treatment, patients who have not already had the following tests should proceed to have them completed: computed tomography (CT) of the abdomen (or magnetic resonance imaging [MRI]), a complete blood count, blood urea nitrogen, serum creatinine, liver function tests, fasting glucose, lipid profile, urinalysis, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) (algorithm 1). (See 'Premanagement evaluation' above.)

●Urgent treatment of complications – Treatment of complications of RPF, such as vascular or urinary tract obstruction, is often required before management of the underlying disease. The treatment of urinary obstruction depends upon its severity on imaging, the kidney function, and the underlying cause of RPF (see 'Urgent treatment of complications' above):

•Relief of urinary tract obstruction with an interventional procedure is required among patients who have one of the following (see 'Treatment of urinary obstruction' above):

-Idiopathic RPF and moderate to severe hydronephrosis

-Idiopathic RPF and mild hydronephrosis of their only kidney

-Idiopathic RPF and mild hydronephrosis and compromised kidney function

-Secondary RPF due to an irreversible (eg, radiation) or slowly reversible (eg, malignancy) cause and hydronephrosis of any degree

•However, in patients with idiopathic RPF, two kidneys, normal kidney function, and mild hydronephrosis, we suggest that the patient receive medical treatment (eg, glucocorticoids) first, and defer an interventional procedure to relieve the obstruction, rather than proceeding immediately with an interventional procedure (Grade 2C). This is due to the likelihood that the obstruction will be relieved with medical therapy alone. However, if there is evidence of persistent or worsening obstruction despite approximately four weeks of treatment, then we proceed with an interventional procedure to relieve the obstruction. (See 'Treatment of urinary obstruction' above.)

●Treatment of secondary disease – If the RPF is due to a secondary cause (table 1), treatment is aimed at the underlying etiology, if it is amenable to treatment. (See 'Treatment of secondary disease' above.)

●Treatment of IgG4-related disease – The treatment of immunoglobulin G4–related disease is discussed in detail elsewhere. (See "Treatment and prognosis of IgG4-related disease".)

●Treatment of non-IgG4-related disease – A variety of immunosuppressive agents, used alone or in combination, are available to treat idiopathic RPF (algorithm 4). (See 'Treatment of non-IgG4-related idiopathic disease' above.)

•Initial treatment – Glucocorticoids are the mainstay of therapy for idiopathic RPF. However, among patients with relative contraindications to glucocorticoids, they should be used for the shortest possible duration and at a lower dose in combination with other immunosuppressive medications:

-Among patients with idiopathic RPF, we suggest high-dose glucocorticoids as initial treatment rather than alternative immunosuppressive medications alone or in combination with low-dose glucocorticoids (algorithm 2) (Grade 2C). We typically administer prednisone at 1 mg/kg/day (maximum 80 mg daily) for four to eight weeks. (See 'Preferred treatment with high-dose glucocorticoids' above.)

-Among patients with relative contraindications to long-term, high-dose glucocorticoids, we suggest treatment with low-dose glucocorticoids in combination with alternative immunosuppressive medications, such as rituximab, methotrexate, or mycophenolate mofetil, rather than a regimen that does not include glucocorticoids (algorithm 3) (Grade 2C). This ensures that the total glucocorticoid dose can be minimized in such patients. Alternatively, if glucocorticoids must be completely avoided, we treat patients with rituximab monotherapy. The choice of therapy between rituximab, methotrexate, and mycophenolate mofetil depends upon presence or absence of relative or absolute contraindications to these individual agents. (See 'Patients with contraindications to high-dose glucocorticoids' above.)

•Assessing response – At four to eight weeks after initiation of treatment, we assess response to therapy and define this as resolution of symptoms and of urinary outflow obstruction (on imaging), if applicable. Improvement in ESR and CRP may be noted but are not required to assess response. (See 'Assessing response to initial treatment' above.)

•Responders to initial treatment – Among patients who have a demonstrable response to high-dose prednisone therapy or to alternative immunosuppressive medications in combination with prednisone, we typically taper the prednisone in the months after remission. (See 'Responders to initial treatment' above.)

•Nonresponders to initial treatment – Among nonresponders to initial treatment, we perform a biopsy to confirm the diagnosis (if not already performed). Once the diagnosis is confirmed, we change the treatment to a regimen different from the one originally chosen, depending upon presence or absence of contraindications to individual agents. (See 'Nonresponders to initial treatment' above.)

•Monitoring after remission – Following discontinuation of glucocorticoids (or other immunosuppressive agents), we monitor for disease relapse by laboratory and radiographic tests for 10 years after the last episode. (See 'Monitoring after remission' above.)

•Management of relapse – In patients who relapse after remitting with high-dose prednisone therapy, we suggest treating with a combination of prednisone and methotrexate, rather than high-dose prednisone alone or other immunosuppressive approaches (Grade 2C). This can limit the cumulative exposure to glucocorticoids. In patients who have contraindications to methotrexate (eg, liver disease), we treat with mycophenolate mofetil or rituximab in combination with prednisone. In patients who relapse after remitting to an alternative initial therapy regimen (eg, combination of prednisone and mycophenolate mofetil), we suggest repeating the same regimen for the treatment of relapse (Grade 2C). (See 'Management of relapse' above.)