IgG4‑related retroperitoneal fibrosis: diagnosis is just a first step

To the editor

The diagnosis of IGG4-related diseases proves to be a challenging task in everyday practice, therefore, we have read with interest the case report of retroperitoneal fibrosis (RPF) presented by Semik-Grabarczyk et al.¹ In their paper, the authors conclude that RPF seems to be overlooked in daily clinical practice. From the experience of our Rheumatology Department, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland, the clinical problem in the case of RPF is not the diagnosis of the disease itself, but the required differential diagnosis due to the diverse pathogenesis of the disease and disease complications that may hinder the treatment.

Although RPF is a rare disease, it can be encountered in clinical practice. In the last 5 years, we have treated 6 patients at our center referred with suspected RPF by other specialists, mostly surgeons (Table 1). The etiology of RPF can be idiopathic (related or unrelated to IgG4), but also secondary to malignant disease, drugs, exposure to radiation, or surgery.² Therefore, the exclusion of the secondary nature of RPF is mandatory. Current data show that up to one-third of RPF cases may be secondary to malignancy.² Indeed, in 2 of our patients, we diagnosed malignant tumors: renal cell carcinoma and insulinoma. The disease itself may also be mimicked by other disorders and diagnosing RPF only based on imagining techniques may be misleading. In the early stages of RPF, an inflammatory mass is often located in the periaortal area (periaortitis),² and therefore requires differentiation with aortic inflammation and other forms of vasculitis. In one of our patients, computed tomography and magnetic resonance imaging scans suggested RPF, but the patient was not responding to glucocorticoids and immunomodulatory medications. As the disease progressed, new symptoms appeared, which allowed for clinical reevaluation. Finally, Behçet syndrome was diagnosed. Also, histological examination of retroperitoneal lesions is desired for accurate diagnosis and management. All of our patients had serum IgG4 levels determined and none of them had elevated IgG 4 levels. The only case of IgG4-related RPF was diagnosed after histological re-evaluation of the material taken during the surgery. The diagnosis of IgG4-related RPF does not, however, relieve oncological vigilance: the patient was diagnosed with renal cell carcinoma later in the course of the disease. Finally, we would like to highlight some problems that may be encountered when treating patients with RPF. One of the problems is obstructive uropathy secondary to the ureteral involvement, which may cause urinary retention and recurrent urinary tract infections (usually treated by urologists). In the treatment of RPF, glucocorticoids are the first line of treatment, but if ineffective, immunomodulatory agents such as cyclophosphamide or methotrexate are indicated.² Although usually effective, all these drugs are associated with an increased risk of infections. Two of our patients developed recurrent urinary tract infections: in the first, immunomodulatory treatment was stopped altogether, and in the second, the treatment with cyclophosphamide was switched to less aggressive methotrexate. The other clinical problem is prolonged glucocorticoid treatment (even with tapered doses) associated with adverse effects, including osteoporotic fractures, which we observed in 2 of our patients.

Table 1. Patients with suspected retroperitoneal fibrosis referred to our center

Age	Sex	Symptoms (in chronological order)	Tests leading to a diagnosis	Diagnosis	Treatment	Clinical outcome
66	F	Hematuria, abdominal pain Obstructive uropathy Recurrent urinary tract infections	CT scan of the abdomen	RPF	GCs (24 mg/d tapered to 2 mg/d) MTX 10–20 mg/wk	Partial regression Osteoporosis with T8 fracture
57	M	Hematuria Obstructive uropathy	CT scan of the abdomen Laparotomy, histologic examination	RPF	GCs (16 mg/d tapered to 2 mg/d) CP (summary dose, 8.1 g)	Remission Osteoporosis with L1 fracture
77	M	Abdominal aortic aneurysm (incidental finding) Obstructive uropathy	Abdominal ultrasound CT scan of the abdomen MRI scan of the abdomen EUS	RPF, insulinoma	GCs (60 mg/d tapered to 2 mg/d) CP (summary dose, 4.25 g) MTX 15 mg/week	Partial regression after CP Stabilization after MTX
56	M	Perirenal abscess Obstructive uropathy Recurrent urinary tract infections, including alarm pathogens	CT scan of the abdomen Biopsy, histologic examination	RPF	Disqualified	–
52	F	Jaundice, elevated transaminases Obstructive uropathy	CT scan of the abdomen Laparotomy, histologic examination PET-CT Histologic reevaluation Scintigraphy	IgG4-reated RPF, RCC	GCs (40 mg/d tapered to 6 mg/d) MTX 15 mg/wk	Stabilization Osteoporosis
22	F	Abdominal pain, periaortitis After 2 years: Mouth ulcers Episcleritis Labia ulcers Interstitial lung disease	CT scan of the abdomen MRI scan of the abdomen CT scan of the chest and abdomen Biopsy, histologic examination	Behçet disease	GCs (16–80 mg/d plus pulses) Azathioprine 150 mg/d MTX 15 mg/wk CP (summary dose, 6 g) Cyclosporine 150 mg/d Tocilizumab	Relapses
Abbreviations: CP, cyclophosphamide; CT, computed tomography; EUS, endoscopic ultrasound; F, female; GCs, glucocorticoids; IgG4, immunoglobulin G4; M, male; MRI, magnetic resonance imaging; MTX, methotrexate; PET, positron emission tomography; RCC, renal cell carcinoma; RPF, retroperitoneal fibrosis

In conclusion, making a diagnosis of RPF is only the beginning of the challenges awaiting the clinician caring for a patient with RPF. We encourage the authors to deepen the differential diagnosis, strive for a biopsy, and further carefully observe the patient.