Tamoxifen as off-label treatment for SEP (Sclerosing Encapsulating Peritonitis)

Author: Daigoro Arrue Diaz
Date: 14/12/2014



Sclerosing Encapsulating Peritonitis is the most dangerous complication of peritoneal dialysis (PD). To describe the current status of this issue, just read the recent editorial by Peter Blake titled “The specter of SEP” which tells: "Although often described as a rare condition, SEP has become a very big concern in a number of countries over the past 5 years. There is a perception that cases are increasing in number, particularly post renal transplantation, and for some nephrologists, this perception has raised concerns about the very use of peritoneal dialysis (PD) as a renal replacement therapy. It could therefore be said that the “specter” of SEP is haunting PD".
This review aims to define a SEP treatment to put emphasis on the latest and give a boost to the lines of future research.

Images links
Sclerosing Encapsulating Peritonitis presenting after laparotomy for splenic abscess, 2013
Posttransplant Encapsulating Peritoneal Sclerosis Localized to the Terminal Ileum, 2010


SEP is different from the sclerotic thickening of the peritoneum that appears after many years of peritoneal dialisys, a condition often referred to as simple sclerosis (SS).
1. SS and SEP have different incidence: SS is always present in PD patients, SEP is a rare complication,
2. patological anatomy are so different: on the one hand SS presents a moderate fibrosis, on the other hand SEP a despiscable fibrosis, acute and cronic inflammation, calcifications until ossifications, vascular thickening until cavity occlusion,
3. in animal models, SS can be reproduced with PD; SEP cannot, on the contrary, SEP can be induced by chlorexidine,
4. pathogenesis: there is substantial agreement that the poor biocompatibility of PD (related to glucose, hyperosmolarity, low pH, and lactate buffer) is the main reason why anatomic alterations of the peritoneum are a constant in PD; the poor biocompatibility of dialysate is an obvious potential risk factor for SEP but it needs another risk factors like PD interruption, bacterial infection, mycosis and kidney transplant,
5. SS has not clinical manifestations, but they are present in SEP with a 50% mortality.
Newest works agree fibrocyte stimulated by Transforming Growth Factor-ß is the SEP disease promoter. Fibrocyte originates from submesotelium fibrocytes, mesothelial cells undergone mesothelial-to-mesenchymal transition (MMT), endothelial cells and cells recruited from bone marrow. TGF-ß fibrocyte molecular mechanism suggests p38 has a powerful pro-fibrotic action by directly stimulating collagen production.
So, qualitative and quantitative morphological aspects indicate that there are two nosological entities: simple sclerosis and sclerosing encapsulating peritonitis. SS is a thin (<40-50 microm) layer of submesothelial sclerotic tissue often limited to certain peritoneal areas, with monotonous histology. It is a component of the slight anatomical alterations constantly detectable in peritoneal dialysis patients. SEP is characterized by very thick (1,0004,000 microm) sclerotic tissue involving the whole peritoneal wall, often with inflammatory infiltrates, microabscesses, giant cells of macrophagic origin, calcifications and severe vascular alterations. Intermediate stages between SS and SEP peritonitis have rarely been detected.


The three key points of diagnosis are still represented by clinical, CT and histological evidence.
1. Clinical evidence can go from intestinal disorders (nausea, emesis, diarrhea or constipation) until intestinal obstruction; it can presents also malnutrition, fever, high CRP levels. The onset is often insidious, but it can also occur directly as paralytic ileus without clinical notice.
2. CT is the radiological investigation of election; the use of the contrast medium is suggested, but not authorized representative. These 6 signs are indicative of SEP: peritoneal enhancement, thickening and calcifications, abdominal adhesions, intestinal obstruction and in some cases loculated fluid with septum.
3. In doubtful cases, histological evidence continues to have a decisive value.
Noteworthy is the attempt of English school to develop a specific diagnostic method to SEP using a cine-NMR: various sequences acquisition of abdominal NMR shows that in patients with SEP intestinal motility concerns only subdiaphragmatic areas, while in controls it extends to the lower abdominal wall.

Peritonite Sclerosante Incapsulante, 2013


Tamoxifen is a selective oestrogen receptor modulator (SERM), predominantly used for the treatment of breast cancer.

Tamoxifen, 2014

Queen Alexandra Hospital, UK

In Wessex Renal and Transplantation Unit and Dep. of Radiology, Queen Alexandra Hospital, Hampshire, UK, Mohmed Eltoum and his team have treated with tamoxifen four cases of SEP that have presented to his unit since 1999, and we reporte the favorable outcome here. The 4 patients were seriously ill with total SBO (Small Bowel Obstrucion) and infection, raising the major concern of exacerbating their condition by introducing steroids or immunosuppressants. They all received tamoxifen 20 mg once per day and resolved completely. The unit provides renal replacement therapy for a population of about 2 million.
All patients underwent abdominal CT scan, which demonstrated classic peritoneal thickening and calcification, with loculated collection and dilatation of the small bowel (see example of Patient 2 in Figure 3). Figure 4 shows resolution of these conditions in the same patient after 6 months of treatment with tamoxifen.

All patients underwent laparotomy/laparoscopy, which revealed typical SEP features. Limited division of adhesions was attempted in 2 patients, whereas Patient 3 was considered inoperable. The 2 patients on PD at the time of presentation were switched immediately to hemodialysis. All patients received the appropriate antibiotics and total parenteral nutrition. Tamoxifen treatment was started after several months in the early patients but immediately in the later patients.
These 4 patients with SEP presented with a life-threatening acute inflammatory state and SBO. They were characterized by long duration of PD (mean duration 58 months) but relatively few episodes of prior peritonitis. All patients had evidence of ultrafiltration failure, demanding a switch to hemodialysis or major modification of their PD regime. Surgery provided confirmation of the diagnosis of SEP but in no case provided useful relief of SBO. Parenteral nutrition was essential in all cases. After the introduction of tamoxifen therapy, major benefit was seen in all cases. It was possible to discontinue total parenteral nutrition within, at most, 2 months. All patients are now on a normal diet and the nutritional and inflammatory markers have all returned to normal. In three cases, relatively mild episodes of subacute SBO have subsequently settled with conservative management. Tamoxifen is not licensed for SEP treatment. However, it has been used for its antifibrotic effect in steroid-resistant Riedel’s disease and in retroperitoneal fibrosis. So, they describe its use in patients with fulminant SEP and high mortality expectation. In their experience, tamoxifen has been highly effective. The optimum duration of treatment remains to be determined.

Four consecutive cases of peritoneal dialysis-related encapsulating peritoneal sclerosis treated successfully with tamoxifen, 2006

Dutch Multicentre SEP Study

In another work, results of the Dutch Multicentre SEP Study validate Tamoxifen is associated with lower mortality of encapsulating peritoneal sclerosis.


There is no clear consensus on the treatment of SEP, but anecdotal reports indicate improvement in SEP patients treated with tamoxifen.

Recently, they performed a large multicentre study to investigate the incidence of SEP in recent years. As part of this study, they investigated the survival of SEP patients treated with tamoxifen in comparison with not-treated patients in the period of 1997–2007.


This study is a retrospective analysis of survival in SEP patients as part of the Dutch multicentre SEP study in the period January 1996 to July 2007. Sixty-three patients with severe SEP were followed up until August 2008. Demographic, patient and PD-related variables of SEP patients were investigated. Patients treated with tamoxifen were compared to patients not treated with tamoxifen. Survival was analysed with multivariate Cox regression analysis.


Patient characteristics

In the period 1 January 1996 until 1 July 2007, 63 cases of SEP occurred in the participating centres. All 63 patients had objective symptoms of bowel obstruction, underwent abdominal CT scanning and were diagnosed with SEP according the ISPD (International Society for Peritoneal Dialysis) criteria. Twenty-four patients were treated with tamoxifen, and 39 patients were not treated with tamoxifen.
There were no significant differences between the two groups in ages at start of PD, at SEP diagnosis, at last kidney transplantation or at death. The groups were also comparable concerning follow-up time and the type of renal replacement at the time of the diagnosis (Table 1).

PD and kidney transplantation-related variables

There were no significant differences between the treated and not-treated groups of SEP patients with regards to the cumulative period on PD, the episodes of peritonitis, the number of transplanted patients and the number of transplantations per transplanted patient. Overall, 47 transplanted patients developed SEP after the last kidney transplantation with a mean of 50.8 ± 69.8 months after the last kidney transplantation. Mean age at the last transplantation was 36.4 ± 13.4 years. Twenty-one patients with a kidney transplant (44.7% of the total 47 transplanted patients) developed SEP within 2 years after the last kidney transplantation (Table 2).

Among the 47 patients with SEP after transplantation, 18 patients had a functioning kidney transplant at the time of SEP diagnosis (Table 1). None of the patients was transplanted because of SEP symptoms.

SEP treatment

There were no differences between the groups of SEP patients with respect to the treatment with TPN (Total Parenteral Nutrition) or prednisone. The total number of patients using prednisone (patients using prednisone for the treatment of SEP or as part of post-transplant regimen combined) was also not different between the groups. In each group, one patient treated was also treated with azathioprine (Table 3). Treatment with tamoxifen was started by the treating physician. Dosages of tamoxifen varied in time from 10 mg once a day to 20 mg twice a day. All patients in the treatment group were treated with tamoxifen for at least 4 weeks. There was no enterolysis performed in any of the patients.


The overall mortality rate was lower in tamoxifen-treated patients compared to the patients not treated with tamoxifen, respectively, 11 out of 24 and 29 out of 39 patients (45.8% vs 74.4%), P = 0.03. Estimated survival analysed with Kaplan–Meier showed better survival in the group treated with tamoxifen (P = 0.07, Figure 5). Univariate Cox regression analysis confirmed this trend with a hazard risk (HR) of 0.54 (P = 0.08). Multivariate Cox regression analysis with adjustment for age, year of diagnosis, presence of a functioning kidney transplant at time of diagnosis, PD centre, use of concomitant prednisone and the use of TPN also showed a trend to an improved survival in the tamoxifen-treated group, although the level of statistical significance did not reach the predefined limit of <0.05 (HR 0.39, P = 0.056).


The present study shows that mortality rate is lower in tamoxifen-treated SEP patients compared to SEP patients not treated with tamoxifen with both groups having comparable demographic and clinical characteristics. More importantly, treatment of SEP patients with tamoxifen was associated with a trend to an improved survival, independent of other possible beneficial treatment options. In accordance with previous studies, the results identify SEP as a life-threatening condition with a very high mortality.
At present, there are no randomized controlled trials that have shown the efficacy of any given drug for SEP. Because there is a presumed inflammatory response in the early development of SEP, corticosteroids are often given. Nevertheless, in this study, they could not identify a beneficial effect of prednisone on survival of SEP patients. Therefore, the effect of immunosuppressive medication for the treatment of SEP remains to be proven.
The antifibrotic effects of tamoxifen seem to be related to the influence of TGF-β and inhibition of angiogenesis. In other diseases with excessive collagen deposition and involvement of TGF-β, like Dupuytren’s, tamoxifen was able to downregulate the TGF-β production. In oncology, levels of vascular endothelial growth factor (VEGF) are associated with the extent of angiogenesis and have prognostic value. Tamoxifen decreased extracellular VEGF level in solid tumours and attenuated VEGF-mediated angiogenesis. Extrapolating these findings, tamoxifen might ameliorate the process of peritoneal fibrosis by downregulating TGF-β and decrease VEGF levels, thereby inhibiting angiogenesis.
When tamoxifen is considered as part of the treatment of SEP, potential adverse effects of the drug must be taken into account. Most reported adverse effects are thromboembolism, endometrial carcinoma or strokes. Due to the morbidity and the limited life expectancy of SEP patients, the benefits of tamoxifen outweigh the potential risks.

Tamoxifen is associated with lower mortality of encapsulating peritoneal sclerosis: results of the Dutch Multicentre EPS Study, 2011


In conclusion, tamoxifen has demonstrated effectiveness on fibroblast activity in vitro and in vivo. But above all, tamoxifen treatment is associated with a lower mortality and shows a trend to a higher multivariate-adjusted survival of SEP patients. In addition to supportive therapy, tamoxifen may therefore improve the prospect of this severe condition.

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