Abstract
We encountered a 57-year-old Japanese woman with encapsulating peritoneal sclerosis (EPS) in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis. The patient was admitted to our hospital because of ascites retention. Administration of tocilizumab, an anti-interleukin-6 receptor antibody, for her RA reduced the refractory ascites remarkably; however, she developed sudden acute gastrointestinal bleeding and died a year later. On autopsy, sclerotic thickening of the peritoneum showed diffuse infiltration of podoplanin-positive fibroblast-like cells, and a diagnosis of EPS was made. EPS rarely occurs in SLE, and tocilizumab may be a new treatment candidate for EPS.
Keywords: encapsulating peritoneal sclerosis, systemic lupus erythematosus, rheumatoid arthritis, tocilizumab, podoplanin
Introduction
Encapsulating peritoneal sclerosis (EPS) is a rare clinical syndrome characterized by an inflammatory fibrocollagenous membrane encasing the small and large intestines, resulting in recurrent intestinal obstruction (1-3). EPS often occurs as refractory ascites retention due to chronic peritonitis (2-6). Eltringham et al. first reported EPS as a side effect of β-blockers in 1977 (7); however, most EPS cases have been described as secondary to peritoneal dialysis (1-3) since this phenomenon was first described by Gandhi et al. in 1980 (8).
Abdominal computed tomography is useful for diagnosing EPS but is often inadequate. The most sensitive and specific method for diagnosing EPS is laparoscopy or laparotomy, which can visualize the peritoneal thickening that encloses the bowels (1-3). In addition, a histopathological diagnosis using a peritoneal biopsy has also been found to be useful (1-3). While there is no established therapy for EPS, nutritional support, antimicrobials, corticosteroids, and surgical intervention have been widely used for many years (1-3).
We herein report a rare case of EPS with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc) with no history of peritoneal dialysis and present the pathophysiological and histopathological diagnoses of EPS with a literature review. We also show the efficacy of tocilizumab on our EPS patient.
Case report
A 57-year-old woman was admitted to our hospital because of abdominal bloating that had lasted for 2 months. Fifteen years before admission, she had been diagnosed with SSc (limited form) at another hospital. Two years before admission, she had been transferred to our hospital and diagnosed with pulmonary arterial hypertension (PAH). She was started on pulmonary vasodilators (such as sildenafil 60 mg/day) and had shown no clinical exacerbation of PAH since then.
On admission, her body weight was 55.0 kg (body mass index 22.9). She had a slight fever (37.7°C), and her blood pressure was 105/78 mmHg. A physical examination revealed an abdominal lump, visible epigastric subcutaneous veins, pitting edema of the bilateral lower legs, Raynaud's phenomenon, cutaneous sclerosis, and polyarthritis. Table 1 shows the results of her laboratory findings. Ascites culture was negative, and cell block specimens showed no evidence of malignancy. Abdominal computed tomography revealed a large amount of ascites in the abdominal cavity, the small intestine was unevenly distributed, and edematous changes and thickening of a part of the wall were observed, but no clear origin of obstruction was detected (Fig. 1A).
Table 1.
Laboratory Data of the Peripheral Blood and Peritoneal Fluid in the Patient on Admission.
| Urinalysis | Reference value | Biochemistry | Reference value | Inflammation and immunological data | Reference value | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Protein | (-) | Total protein (g/dL) | 5.3 | 6.5-8.0 | CRP (mg/dL) | 14.4 | <0.14 | |||
| Blood | (-) | Albumin (g/ dL) |
2.8 | 3.9-4.9 | SAA (μg/mL) | 118.0 | ≤8.0 | |||
| Glucose | (-) | Total bilirubin (mg/dL) | 0.5 | 0.3-1.2 | C3 (mg/dL) | 58.8 | 73-138 | |||
| White blood cell | (-) | CK (U/L) | 45 | 24-195 | C4 (mg/dL) | 12.0 | 11-31 | |||
| Bilirubin | (-) | AST (U/L) | 19 | 10-37 | C1q binding immune complex (μg/mL) | 1.5 | ≤3.0 | |||
| Urobilinogen | Normal | ALT (U/L) | 6 | 5-40 | IgG (mg/dL) | 936 | 870-1700 | |||
| Blood cell count | ALP (U/L) | 383 | 96-284 | IgA (mg/dL) | 225 | 110-410 | ||||
| White blood cell (/µL) | 5,270 | 3,300-8,600 | γ-GTP (U/L) | 108 | 0-73 | IgM (mg/dL) | 306 | 35-220 | ||
| Neutrophils (%) | 69.8 | LD (U/L) | 189 | 107-220 | IL-6 (pg/mL) | 23.0 | ≤4.0 | |||
| Lymphocytes (%) | 22.2 | BUN (mg/dL) | 6.5 | 8.0-20.0 | ANA-FA | 1:1,280 | <40 | |||
| Red blood cell (/μL) | 357×104 | 358-490×104 | Creatinin (mg/dL) | 0.5 | 0.3-0.8 | Anti-ds DNA antibody (IU/mL) | 36.9 | ≤12.0 | ||
| Hemoglobin (g/dL) | 11.5 | 11.6-14.8 | Na (mEq/L) | 134 | 138-147 | Anti-centromere antibody (U/mL) | 207.0 | <7.0 | ||
| MCV (fL) | 93.3 | 83.9-101.8 | K (mEq/L) | 4.2 | 3.3-4.8 | Rheumatoid factor (IU/mL) | 119.0 | <15 | ||
| Hematocrit (%) | 33.3 | 33.4-44.9 | Cl (mEq/L) | 94 | 98-110 | Anti-CCP antibody (U/mL) | 0.70 | ≤4.4 | ||
| Reticulocyte (‰) | 15.8 | 5-20 | Ca (mg/dL) | 8.6 | 8.5-10.5 | ESR (mm/h) | 40 | <15 | ||
| Platelets (×104/µL) | 22.1 | 15.8-34.8 | Ferritin (ng/ mL) |
140 | 3-120 | Ascitic fluid | ||||
| Coagulation | BNP (pg/mL) | 174.0 | 0-18.4 | Total protein (g/dL) | 3.2 | |||||
| PT-INR | 1.2 | 0.9-1.1 | Infection | Albumin (g/dL) | 1.8 | |||||
| APTT (s) | 29.7 | 24-39 | β-D-glucan (pg/mL) | <6.0 | 6-11 | Red blood cell (/µL) | 80 | |||
| Fibrinogen (mg/dL) | 463 | 200-400 | HBs antigen | (-) | White blood cell (/µL) | 70 (Mononuclear cell 68, polynuclear cell 2) |
70 (Mononuclear cell 68, polynuclear cell 2) |
|||
| D-dimer (μg/ mL) |
8.8 | 0-0.99 | Anti-HCV antibody | (-) | ADA (U/L) | 2.8 | ||||
| IGRA | (-) | IL-6 (pg/mL) | 13,300 |
ADA: adenosine deaminase, ANA: anti-nuclear antibody, APTT: activated partial thromboplastin time, BNP: brain natriuretic peptide, C1q: first component of complement q subcomponent, C3: third component of complement, C4: fourth component of complement, CCP: cyclic citrullinated peptide, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, HBs: hepatitis B surface, HCV: hepatitis C virus, FA: fluorescent antibody method, IgA: immunoglobin A, IgG: immunoglobin G, IgM: immunoglobin M, IGRA: interferon-gamma release assay, IL: interleukin, MCV: mean corpuscular volume, PT-INR: prothrombin time-international normalized ratio, SAA: serum amyloid A
Figure 1.
An axial cross-section from computed tomography (CT) of the abdomen shows considerable ascites retention before the administration of tocilizumab. A large amount of ascites in the abdominal cavity, an unevenly distributed small intestine, and edematous changes and dilation of a part of the wall are observed (arrows) (A). Ascites retention was clearly reduced after the fourth administration of tocilizumab (B).
On a re-evaluation after hospitalization, the patient was diagnosed with SLE based on the findings of serositis (pleuritis and ascites) and arthritis; positive antinuclear antibody and anti-double stranded DNA IgG antibody tests; and hypocomplementemia, which met the 2012 Systemic Lupus International Collaboration Clinics classification criteria for SLE (9). In addition, she was diagnosed with RA (Steinbrocker class II, stage II) based on the findings of polyarthritis predominantly in the small joints, rheumatoid factor positivity, and elevated C-reactive protein levels, which met the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for RA (10) and 1987 ACR classification criteria for RA (11).
Her ascites retention was resistant to diuretics, glucocorticoids (including methylprednisolone 500 mg/day for 3 days), ascites puncture, and cell-free and concentrated ascites reinfusion therapy. On the 118th day of hospitalization, she received intravenous tocilizumab (8 mg/kg, monthly) against increased RA disease activity [disease activity score for 28 joints ESR (DAS28-ESR): 4.64, indicating moderate disease activity] and high levels of IL-6 in the serum and ascites. After the therapy, her polyarthritis gradually improved, and her ascites obviously decreased (Fig. 1B). On the 140th day of hospitalization, she was transferred to another hospital for rehabilitation to return home.
After the fourth administration of tocilizumab, her abdominal bloating was ameliorated, and the DAS28-ESR was 0.63, indicating the achievement of clinical remission. Thus, tocilizumab remarkably improved the DAS28-ESR (-4.01) in this patient (Fig. 2). Tocilizumab was continued for 14 months, and the patient did not re-accumulate ascites. Unfortunately, however, the patient suddenly developed acute gastrointestinal bleeding the following year and eventually died.
Figure 2.
Clinical course of the patient, including symptoms, disease activity score 28, serum C-reactive protein levels, and immunosuppressive therapy during hospitalization. CRP: C-reactive protein, DAS28-ESR: disease activity score for 28 joints erythrocyte sedimentation rate, mPSL: methylprednisolone, PSL: prednisolone
Postmortem autopsy was performed three hours after the death of the patient. Macroscopically, blood retention was observed in the esophagus and stomach, on which there was a finding of acute gastric mucosal lesion (AGML). A large amount of pleural effusion and ascites were observed. In addition, dense peritoneal adhesion covering all of the bowel in the abdomen was observed, suggesting characteristic findings of EPS (Fig. 3A). A microscopic evaluation revealed marked fibrous thickening of the visceral side peritoneum of the large and small intestine tissue specimens, which also showed fibroblast swelling, peritoneal denudation, angiogenesis and mononuclear cell infiltration (Fig. 3B, C). These findings are common in EPS (12).
Figure 3.
In autopsy, macroscopic findings show diffuse fibrotic thickening of the peritoneum on both the visceral and wall sides and an intestinal tract that had turned into a mass in the abdomen (A). Histopathological findings of the visceral side peritoneum of the large intestine tissue specimens show marked thickening of the intestinal serosa with collagen fibers with fibroblast hyperplasia and lymphocyte infiltration (B, C: Hematoxylin and Eosin staining). The visceral side peritoneum of the large intestine tissue specimens shows the extensive presence of podoplanin-positive cells. Staining with brown is podoplanin-positive cells (D, E: Immunohistochemistry staining).
We performed immunohistochemical staining of the peritoneum of the large intestine tissue specimens with a monoclonal antibody D2-40 against podoplanin. As a result, podoplanin-positive cells were extensively observed in the thickened peritoneum (Fig. 3D, E), which were reported to be a hallmark of EPS (13). In addition, Congo red staining of the large and small intestine tissues was negative, and no tumor cells were observed in the peritoneum. Finally, the histopathological findings revealed that the cause of ascites retention was EPS in SLE, RA, and SSc. No clear association was found between AGML and EPS. Her primary cause of death was acute hypoxemic respiratory failure due to pleural effusion and ascites, pulmonary congestive edema, and bronchial pneumonia.
Discussion
In the present case, we encountered a case of EPS with refractory ascites in SLE, RA, and SSc in a patient with no history of peritoneal dialysis. To our knowledge, two cases of EPS with SLE have previously been reported (Table 2); however, there have been no reports of EPS present with other connective tissue diseases, such as RA or SSc. Ichinose et al. and Pepels et al. reported EPS occurring during the course of SLE without a history of peritoneal dialysis (14,15). Ichinose et al. described a 57-year-old man with EPS in lupus nephritis on maintenance hemodialysis (14). The patient was diagnosed with EPS based on fibroblast proliferation and inflammatory cell infiltration in the peritoneal tissue collected during synechiotomy. After undergoing synechiotomy, the patient had no recurrence. The authors considered chronic lupus peritonitis to be involved in the development of EPS. In addition, Pepels et al. reported a 62-year-old woman with ESP in SLE (15). Abdominal laparotomy revealed a stiff omentum, and a pathological examination of the thickened peritoneum showed chronic fibrous inflammation surrounding the proliferation of capillaries and fibromyoblasts, leading to a diagnosis of EPS. The authors suggested that chronic lupus peritonitis may have progressed to EPS.
Table 2.
Previous Case Reports of Systemic Lupus Erythematosus with Encapsulating Peritoneal Sclerosis.
| No. | Age/sex | SLE clinical and serological findings | EPS clinical findings | EPS histopathological findings in peritoneum | Therapy | Outcome | Reference |
|---|---|---|---|---|---|---|---|
| 1 | 57/Male | Lupus nephritis, hypocomplementemia, positive for ANA and anti-dsDNA antibody, immune complex elevation | Vomiting, abdominal pain, relapses of ileus | Collagen fibers with fibroblast and lymphocyte infiltration and calcification | Synechiotomy | Recovered | (14) |
| 2 | 62/Female | Hemolytic anemia, serositis (pleuritis and ascites), positive for lupus anticoagulant, positive for ANA and anti-dsDNA antibody | Anorexia, weigh gain, abdominal distension | Chronic fibrosing inflammation with a lot of histiocytic multinucleated giant cells | Prednisone, azathioprine | Recovered | (15) |
| 3 | 57/Female | Arthritis serositis (pleuritis and ascites), positive for ANA and anti-dsDNA antibody, hypocomplementemia | Anorexia, weigh gain, abdominal distension | Collagen fibers with fibroblast hyperplasia and lymphocyte infiltration, podoplanin-positive cells in the peritoneal sclerosis area | MP pulse-therapy, CART therapy, tocilizumab | Recovered | Our case |
ANA: antinuclear antibody, anti-dsDNA antibody: anti-double stranded DNA antibody, CART: cell-free and concentrated ascites reinfusion therapy, EPS: encapsulating peritoneal sclerosis, MP pulse therapy: methylprednisolone pulse therapy, SLE: systemic lupus erythematosus
During hospitalization of our patient, the cause of refractory ascites was not fully understood. In general, lupus peritonitis is less common (16,17) and is reported to occur in approximately 8-11% (18). In our case, the presence of chronic lupus peritonitis was suspected because of increased exudative ascites with serological activity, such as elevated anti-double stranded DNA IgG antibody titer and hypocomplementemia. In the present case, autopsy revealed macroscopic findings showing diffuse fibrotic thickening of the visceral and parietal peritoneum, and the intestinal tract had formed a mass. Furthermore, immunohistochemistry of the visceral peritoneum of the large intestine showed a population of cells that were positive for podoplanin. Braun et al. previously reported that the detection ratio of podoplanin-positive cells, which morphologically present as fibroblasts, in peritoneal biopsy specimens from EPS patients was 83.3% (15/18 cases), with no such cells observed in patients with control biopsies taken at the time of appendectomy or hernia repair (n=20 or 15, respectively), suggesting that the presence of podoplanin-positive cells in the peritoneum is a hallmark of EPS (13). In our case, the histopathological identification of podoplanin-positive cells in the peritoneal tissue was useful in the diagnosis of EPS in SLE along with macroscopic findings.
Podoplanin is a cell membrane protein that is primarily present in the endothelium of lymphatic vessels (19), type-I pneumocytes (20) and glomerular podocytes (21). In addition, podoplanin was also found in the synovial tissues from the joints of RA patients (22) and in the lung tissues from patients with primary lung squamous cell carcinoma (23). Kerjaschki et al. reported that podoplanin in a complex with lymphatic endothelial cells produced secondary lymphoid tissue chemokine (SLC/CCL21) leading to an increase in lymphatic neoangiogenesis (24). Therefore, podoplanin might induce inflammatory reactions and promote lymphangiogenesis, thus causing persistent chronic peritonitis leading to sclerosing formation on diffuse visceral and parietal peritoneum (12,13). Thus, podoplanin may play a functional role in the pathogenesis process of EPS.
The current case showed increased levels of IL-6 in the ascites. Table 3 shows previous case reports concerning the levels of IL-6 in ascites among patients with various diseases. It was revealed that the levels of IL-6 in the ascites in our present case were relatively high among previously reported cases. To detect IL-6-producing cells in the ascites, we performed immunohistochemical staining of IL-6 using peritoneal tissues from our patient. Interestingly, the IL-6 expression was detected in mononuclear cells from the peritoneal tissue, whereas only a few such cells were found in the peritoneal tissue from a non-EPS peritoneal dialysis patient (Fig. 4). These results indicated that the IL-6-producing cells in ascites were mononuclear cells in the peritoneal tissues from our patient.
Table 3.
Previous Reports of the Levels of Interleukin-6 in Ascitic Fluid on the Patients with Various Disease.
| No. | Disease | Concentration of interleukin-6 in ascitic fluid (pg/mL) | Reference |
|---|---|---|---|
| 1 | Ovarian cancer | 6,419* | (27) |
| 2 | TAFRO syndrome | 3,310 | (28) |
| 3 | Lupus peritonitis | 12,389 | (17) |
| 4 | Lupus peritonitis | 5,486 | (17) |
| 5 | EPS associated with liver cirrhosis | 14,800 | (29) |
| 6 | EPS associated with CAPD | 8,480 | (30) |
| 7 | EPS associated with CAPD | 4,720 | (30) |
| 8 | EPS associated with CAPD | 18,200 | (30) |
| 9 | EPS associated with CAPD | 1,210 | (30) |
| 10 | EPS in SLE, RA, and SSc | 13,300 | Our case |
CAPD: continuous ambulatory peritoneal dialysis, EPS: encapsulating peritoneal sclerosis, SLE: systemic lupus erythematosus, RA: rheumatoid arthritis, SSc: systemic sclerosis, TAFRO: thrombocytopenia, anasarca, fever, reticulin myelofibrosis/renal failure, and organomegaly, *mean concentration of interleukin-6 in patients with ovarian cancer
Figure 4.
Expression of interleukin-6 (IL-6) in the peritoneum tissues. IL-6 expression was detected in mononuclear cells on the peritoneal tissue from the present case (A, B). IL-6 expression was identified in only a few cells in peritoneal tissue from a peritoneal dialysis patient without encapsulating peritoneal sclerosis (C, D). Staining with brown is IL-6-positive cells (A-D: Immunohistochemistry staining).
EPS is a poor prognostic complication that often occurs in patients undergoing long-term peritoneal dialysis. Its annual incidence is reported to be 0.14-2.5% (4,25), and the mortality rate of peritoneal dialysis patients with EPS is approximately 50% within 1 year of the diagnosis (1). Early diagnostic imaging, a histopathological diagnosis, and aggressive therapeutic intervention are essential for improving the prognosis of EPS (1-3). Although it is known that there is no effective treatment for EPS, and the prognosis is poor, there has been one previous case of induction of tocilizumab for refractory ascites caused by idiopathic EPS with high levels of IL-6 in serum that showed a favorable response (26). Therefore, based on the present and previous findings, IL-6 plays an important role in the pathogenesis and progression of EPS.
We encountered a case of EPS in SLE, RA, and SSc with refractory ascites retention. Tocilizumab showed potential efficacy as a new drug candidate for the treatment of EPS.
Informed consent was obtained from the patient's family in the present case.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We would like to thank the patient and her family for their patience and courage and all of the clinicians and medical staff for their enormous efforts in providing medical care. We are also grateful to Toshinori Nagai (Pathology, Saitama Medical University, Saitama, Japan) for providing technical assistance.
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