In summary, idiopathic retroperitoneal fibrosis, as distinguished from histopathologically documented IgG4-related retroperitoneal fibrosis, appears to have a similar response to rituximab treatment. There was a non-statistically significant improvement in the CRP, GFR, and creatinine values post-therapy, potentially attributable to such a small sample size. When comparing iRPF diameter on imaging pre and post-rituximab, there was a statistically significant reduction in both axial and coronal planes. It is unknown how the efficacy of rituximab compares to prednisone alone, DMARDs or placebo in this observational case series.
A more recent study of rituximab therapy in RPF looked at 26 patients, 7 of whom were diagnosed with iRPF [12]. The remaining 19 patients had IgG4-RD. Treatment response was defined as either improvement in RPF symptoms, shrinkage of RPF on imaging, or resolution of laboratory markers (IgG4, CRP or ESR). On post-treatment imaging, 21 of the 25 patients (84%) had treatment response, as defined by improvement in RPF size in at least 2 imaging planes. This study, however, chose not to delineate improvement in the iRPF patient population from those with IgG4-RD. Another recent study by Urban et. al. [13] looked at 20 iRPF patients with relapsing/refractory disease or with contraindications to glucocorticoids, of which 8 patients were biopsy proven. At 6 months following treatment with rituximab, a significant reduction in periaortic and peri-iliac thickness, and CRP was found. These findings are consistent with those of our study, although our CRP reduction did not reach statistical significance, likely due to a small sample size. This study also found a statistically significant reduction in ureteral involvement. In our study, pre and post-rituximab imaging was used to determine the number of patients with ureter involvement, vessel involvement, and renal stents. The pre-treatment imaging was often done months prior to start of treatment, and therefore may not have accurately reflected the true ureter and vessel involvement prior to treatment. On chart review, it was found that the patients had less ureteral stents following rituximab (3 unilateral, 1 bilateral) than prior to treatment (2 unilateral, 2 bilateral), which suggests that the imaging data likely overestimated the progression of ureter involvement despite treatment with rituximab.
We noted several interesting trends in our study. Firstly, there was one patient who was previously treated with steroids and still benefitted from rituximab therapy, with further improvement seen on imaging post-treatment. It was also noted that 3 patients were on concurrent prednisone at time of RTX treatment. Two of these patients had the best radiological response post-RTX, with 1 achieving complete resolution on imaging, while the other improved by over 50% when reviewing maximal aortic thickness on post-treatment imaging. The third patient on concurrent steroids, who had been successfully treated with steroids in the past, had a less impressive improvement in RPF thickness, of approximately 18%.
Based on this study, there appears to be a role for rituximab in treating idiopathic RPF. While there were statistically significant changes in disease on imaging post-treatment, the clinical improvement of patients was more difficult to assess. Although patients seemed to have some improvement based on clinical records, it is our suspicion that RPF may cause lumbosacral plexus nerve damage given the proximity of those nerves that may result in chronic pain. More studies are needed to assess patients’ long-term outcomes.
This study focused on rituximab as a treatment for idiopathic RPF and did not explore the efficacy of disease modifying antirheumatic drugs (DMARDs) in treating this condition. There is likely a role for DMARDs in idiopathic RPF, but this is yet to be established through further research. One strength of rituximab that was noted in this study was its favorable side effect profile. Only two patients had an allergic reaction during their infusion, but this was quickly mitigated with diphenhydramine and both patients were able to complete treatment. The patient who developed a more severe reaction initially took prednisone 50 mg orally in the evening prior to the first infusion. During the infusion, the patient received diphenhydramine 50 mg IV over 2–3 minutes followed by hydrocortisone 100 mg IV to mitigate the allergic reaction. Prior to the second infusion, this patient took the prednisone 50 mg orally in the morning prior to infusion and was then able to tolerate the infusion well.
There were several limitations to this study. As RPF is a fairly rare condition, the study was only able to include 10 patients who met iRPF criteria. Patients were ruled out to have IgG4-related disease using the histopathological classification by Deshpande et. al. [11]. Since the writing of this manuscript, new consensus guidelines have been published [14]. As a retrospective study, there was no opportunity to have a control group of iRPF patients. Future research comparing iRPF patients on prednisone to patients treated with rituximab would provide valuable information on the efficacy of rituximab in comparison to the current standard first-line treatment. There was variation in disease duration prior to treatment as well as previous therapies that were trialed prior to rituximab. In addition, this study included patients who were previously treated with prednisone, as well as patients on concurrent prednisone. Therefore, the effects of prednisone versus rituximab are not fully clear. Again, future studies that include comparison of prednisone to rituximab are needed to further understand the roles of prednisone and rituximab in treating iRPF.
Some questions about rituximab in iRPF still remain. At this time, it is unclear how long to continue treatment with rituximab for iRPF patients who have seen benefit from treatment and when the medication can be stopped. The most feared complication of untreated retroperitoneal fibrosis is end stage renal disease [11]. Re-treatment should be considered with the goal of preventing persistent hydronephrosis and reflux nephropathy. Although stenting and ureterolysis are utilized to treat hydronephrosis, the added role of medical therapy is not known at this time.
There are several strengths to this study. This study specifically selected for idiopathic RPF patients, with most having biopsies showing no evidence of any other etiology. As far as we are aware, this is the largest study to date of rituximab in an iRPF population. The primary outcome, improvement of disease by imaging as an objective measure of disease progression, showed a significant response to rituximab.