Retroperitoneal fibrosis: An extraarticular manifestation of ankylosing spondylitis



Idiopathic retroperitoneal fibrosis (RPF) was first described as a clinical entity in 1948 (1). Most patients with RPF are 30–60 years old, and very few pediatric cases have been reported. Although in most cases the RPF is idiopathic, it may also be secondary to underlying infection, malignancy, drugs, radiation, trauma, or surgery. In most patients, fibrosis is confined to the retroperitoneal region of the lower lumbar spine; however 15% have fibrosis in other organs (2). Spondylarthritis, which may also be complicated by extraarticular fibrosis, has been reported in patients with RPF. We present a case of a 7-year-old boy who originally presented with RPF and was later diagnosed as having spondylarthritis, and discuss the relevance of this association.

Case report

A 19-month-old boy presented with a 6-week history of severe nocturnal leg pain, reduced ambulation, and morning stiffness of 2 hours duration. On examination, there was limited flexion, stress pain of both hips, and tight tendo Achillis, but joint effusions were not detected. Laboratory tests showed hemoglobin (Hgb) 97 gm/dl, Westergren erythrocyte sedimentation rate (ESR) 29 mm/hour, and negative antinuclear antibody (ANA) and rheumatoid factor (RF). Chest, abdominal, and hip radiographs and abdominal ultrasound were normal. The patient was treated with 70 mg/kg/day of aspirin for possible juvenile rheumatoid arthritis, which only improved the stiffness.

At 5 years of age, he developed worsening hip pain and stiffness. Examination showed hip and knee flexion contractures, reduced back flexion, and warm, non-tender ankles, but no effused joints. The Hgb was 85 gm/dl, platelet count 613,000/mm3, and ESR 42 mm/hour. The results of iron studies, albumin, creatinine kinase, urinalysis, and HLA–B27 were either normal or negative. Radiographs of the lumbosacral spine, sacroiliac joints, and hips were reported as normal. Treatment consisted of an injection of triamcinolone hexacetonide in both hips that initiated a dramatic, but short-lived improvement. Subsequently, naproxen (18 mg/kg/day) and oral prednisone (0.6 mg/kg every other day) were initiated.

Two years later the boy developed lower abdominal pain, nausea, vomiting, and anorexia. Hip pain and stiffness recurred despite treatment with prednisone 0.25 mg/kg every 48 hours. Examination revealed a distended abdomen and palpable left kidney. Laboratory evaluation revealed the following findings: Hgb 91 gm/dl (normal 120–160), ESR 45 mm/hour (normal 1–10), urea 7.6 mmol/liter (normal 2.9–7.1), creatinine 94 mol/liter (normal 10–80), and normal urinalysis. Abdominal ultrasound and intravenous pyelogram showed severe bilateral hydronephrosis, with minimal vesicoureteral reflux on voiding cystourethrogram. Extensive fibrotic tissue extending from the pelvic brim to the lower pole of kidneys was seen on abdominal computerized tomography (CT) and at laparotomy (Figure 1A). Subsequently, a right ureterolysis with omental wrap and left ureter bypass surgery using the Boari flap procedure were performed. Microscopic examination revealed dense collagenized fibrosis with chronic inflammatory cells, compatible with retroperitoneal fibrosis (Figure 1B).

Figure 1.

A, Computerized tomography scan at the level of the lower kidneys shows asymmetric ureteral wall thickening, and the start of a retroperitoneal mass (arrow) on the left. B, The ureteric lumen (U) is lined by urothelium, supported by a wall of smooth muscle (S). Increased amounts of dense collagen are seen in the subepithelial region (C1) as well as in the interstitial regions external to the muscle layer (C2) (Masson's trichrome stain).

At 8 years of age the patient developed low back pain and stiffness. Marked hip and knee flexion contractures, and reduced hip and back range of motion were noted, as well as bilaterally tight tendo Achillis requiring heel cord and plantar fascia releases. The neurologic examination was normal. Abdominal CT showed improvement of hydronephrosis and resolution of RPF; the hips appeared normal. Magnetic resonance imaging (MRI) of the spine and spinal cord was normal. Treatment with oral prednisone (15 mg/day) was required to control symptoms and any reduction in dosage caused recurrence of leg and back pains.

At 12 years of age, azathioprine was added to the treatment regimen to control persistent symptoms, and growth hormone injections for short stature were started. Six months later, he developed severe nocturnal leg, hip, and flank pain, ascending low back pain, and morning stiffness of 4 hours duration. Height and weight were charted at less than the third percentile. A Schöber test of 12.5 cm, and reduced range of motion of wrists, ankles, knees, hips, and back were noted. No joint effusions were found.

Two years subsequently the patient exhibited reduced range of motion in the wrists, hips, and left elbow, and both ankles were effused. The pelvic radiographs revealed bilateral widening and sclerosis of sacroiliac (SI) joints (Figure 2). MRI demonstrated erosive disease of SI joints. Treatment with indomethacin was reinitiated, and in followup assessments symptomatic improvement was noted; however, the patient continues to have back, leg, and ankle pain.

Figure 2.

Coronal view of the sacroiliac joints with extensive iliac greater than sacral sclerosis and sacroiliac irregularities bilaterally.

Literature review

We performed a MEDLINE search of the English and French language literature from 1966–2000 (3–16) and found 15 reported cases of RPF and spondylarthritis (Table 1). Males were more commonly affected (2:1 ratio). The mean age at diagnosis of RPF or spondylarthritis was 43 years; in all but one case spondylarthritis preceded or occurred simultaneously with RPF. In patients in whom it was reported, axial arthritis occurred in 10 of 14 patients, and peripheral arthritis in 2 of 9 patients. HLA–B27 was present in 7 of 12 patients tested; 60% of those who were HLA–B27–negative were female. Treatment of the RPF was surgical in 3 of 15 (20%), involved systemic corticosteroids or irradiation in 7 of 15 (47%), and both surgical and medical in 4 of 15 (27%). Outcome was significantly improved in 10 of 15 patients, 2 had persistent arthralgia, 2 had recurrent RPF, and 1 died of acute renal failure secondary to hypersensitivity vasculitis. The longest followup was 5 years.

Table 1. Reported patients with retroperitoneal fibrosis and spondylitis
Reference3 19614 19655 19696 19777 19818 19819 198210 198310 198311 198512 198813 198914 199215 199316 1999
  1. NA = not available; SP = spondylarthritis; yrs = years; RPF = retroperitoneal fibrosis; SI = sacroiliac; L = left; R = right; B = bilateral; RF = rheumatoid factor; ANA = antinuclear antibodies; NSAID = nonsteroidal antiinflammatory drug; ASA = aspirin; U = ureterolysis; S = corticosteroids; I = irradiation.

Age at SP diagnosis (yrs)435164542532602834317234283655
Age at RPF diagnosis (yrs)435164542432602834517264635254
X-ray spineNAposnegposnegposnegnegposNAnegposposposneg
Arthritis (axial)NAposnegposnegnegposposposposnegpospospospos
Arthritis (peripheral)NAnegnegnegposnegnegnegnegNAposNANANANA
Treatment (SP)NANSAIDASAIndocidINAIndocidPhenylbuta- zone
Treatment (RPF)UUSI & SSU & SSSUU & SSU & SSI
OutcomeImproved × 3 monthDiedImproved × 3 yrsImproved × 1 yrImproved × 2 yrsRelapse at 5 yrsImproved × 6 weeksArthralgiaArthralgiaImproved × 6 monthImproved × 4 yrsRelapseImproved × 2 yrsImproved × 8 monthImproved × 12 month


In this report, we describe a 12-year-old boy diagnosed as having ankylosing spondylitis (AS) and RPF. Extraarticular fibrotic manifestations are prominent in patients with ankylosing spondylitis. Aortic insufficiency occurs in approximately 5% of affected individuals and is secondary to inflammation and fibrosis of the vasa vasorum (17). Pulmonary fibrosis occurs in about 1% of patients, especially those with long-standing disease. We propose that RPF should be considered as another extraarticular fibrotic manifestation of AS.

Retroperitoneal fibrosis is a rare disorder in which fibrous tissue is deposited in the lower lumbar retroperitoneal region. It commonly involves the ureters, aorta, vena cava, and common iliac vessels. Presenting features may include back pain, and constitutional symptoms such as fatigue, weight loss, and low grade fever. If allowed to progress, compression of the ureters, lymphatics, and blood vessels can result in renal failure, edema, ischemia, and venous thrombosis, respectively. Up to 15% of patients with RPF have additional fibrosis outside the retroperitoneum including sclerosing cholangitis, constrictive pericarditis, superior vena cava syndrome, pulmonary fibrosis, fibrosing thyroiditis, orbital/sinus pseudotumors, and possibly Dupuytren's contracture (2). Although RPF has been precipitated by medications, trauma, infection, and malignancy, 70% of cases are idiopathic. Some adult patients with RPF have atherosclerotic disease with perivascular fibrosis (18). Others may have concurrent inflammatory or autoimmune diseases such as systemic lupus erythematosus, scleroderma, glomerulonephritis, panniculitis, and AS. With appropriate early treatment the prognosis for patients with RPF is generally excellent (2).

Although the clinical report cited above suggests a relationship between RPF and AS, limitations in our current knowledge of the pathogenesis of each condition restrict our ability to transfer mechanistic models to the alternative disease. In both cases, there is a paucity of information on the target tissues, reflecting the relative inaccessibility of these sites. Hughes and Buckley reported that the cellular infiltrate in RPF was predominantly a macrophage-like cell that expressed CD4, CD11, CD25, CD45, CD68, and HLA–DR (19). The cellular infiltrate in SI joint inflammation is a mixed population, but certainly there are cells which similarly express CD4 and CD45 (20). Ramshaw et al (21) reported on the cytokine gene expression of adventitial inflammation in a precursor of RPF. They observed abundant interferon-γ, interleukin-(IL)1α, IL-2, IL-2 receptor, and IL-4 polymerase chain reaction products, whereas little tumor necrosis factor (TNF)α was detected. Braun et al examined cytokine expression in SI joint biopsies in patients with AS (20) and found TNF-α and transforming growth factor β expressed at sites of inflammation. It is difficult to resolve whether there is sufficient information on cytokines to develop treatment strategies at this point. Certainly the results to date with anti-TNF therapy in AS have been encouraging (22). Although cyclosporin (23), mycophenolate mofetil (24), and tamoxifen (25) have been used in RPF, there is certainly a need for innovative approaches to treatment, and the clinical association with AS may alone warrant a trial of anti-TNF therapy in this disease.

The role that HLA–B27 may play in the pathogenesis of RPF may have to await the clarification of B27 in the pathogenesis of AS, for which there is no consensus at the present time. The canonical role for HLA–B27 is a restricting element in mounting a CD8–positive CTL response to self or foreign antigens. The argument from the cellular immunology perspective comes down to characterizing the “arthritogenic” peptide, which initiates and perpetuates the B27-orchestrated immune response. The identity of such peptides has proved elusive, at least in terms of establishing pathogenicity. The link between B27 and infectious triggers has also invoked molecular mimicry in a pathogenic role, suggesting that shared homology between B27 and certain pathogens may lead to an autoimmune response in the course of host immune response to such cross-reactive microbial antigens. This theory, however, has not been rigorously proven (26). Any or all of the putative roles for B27 in AS could have relevance for the pathogenesis of RPF, but further studies on the immunology of the latter will be needed to answer this question.

RPF has rarely been reported in childhood. Hip or gluteal pain is more common in this age group than adults (27). As in adults, RPF is idiopathic in most cases although associations with lupus, Henoch-Schönlein purpura, relapsing polychondritis, osteomyelitis, and juvenile chronic arthritis have been documented (28). To our knowledge, this is the first reported pediatric case of RPF with associated sacroiliitis. Rheumatologists should be aware of the association of RPF and spondylarthropathies in order to make an accurate diagnosis and institute early treatment.