Maintenance treatment with infliximab for ulcerative ileitis after intestinal transplantation: A case report.

BACKGROUND: Evidence has been published on the successful applications of the anti-tumor necrosis factor alpha antibody infliximab, such as induction therapy, salvage treatment for acute cellular rejection, and treatment for chronic ulcerative inflammation, in intestinal transplant recipients. However, the optimal protocol for the effective use of infliximab remains largely undetermined due to scarcity of available clinical data. We report a continuative application of infliximab as maintenance therapy for recurrent chronic ulcerative ileitis in a recipient of isolated intestinal transplantation (ITx). CASE
SUMMARY: The patient was a 11-year-old boy with intestinal motility disorder classified as a hypogenic type of intestinal dysganglionosis. The patient underwent living-donor related intestinal transplant. His immunosuppression regimen consisted of daclizumab, tacrolimus, and steroids. Although he did not show rejection while on tacrolimus monotherapy, routine screening endoscopy showed several ulcerative lesions in the distal end of the graft 2 years after the intestinal transplant. Endoscopic work up to evaluate the progression of anemia revealed stenosis with ulcerative inflammatory changes and multiple longitudinal ulcers in the graft. Since the endoscopic findings suggested ulcerative lesions in Crohn's disease, infliximab treatment was considered. Treatment with infliximab and a small dose of oral prednisolone afforded successful withdrawal of total parenteral nutrition and maintenance of a well-functioning graft without infectious complications for 5 years since the administration of the first dose of infliximab.
CONCLUSION: Infliximab is effective as maintenance therapy for recurrent chronic ulcerative ileitis in an isolated ITx patient. ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.

Core Tip: Infliximab binds to soluble and transmembrane forms of human tumor necrosis factor alpha (TNF-α). Ulcerative inflammatory changes in the graft under intestinal transplantation (ITx) is an often-encountered finding. However, it does not meet the criteria for so-called rejection and is close to the pathology of Crohn’s disease. Studies in Crohn’s disease patients revealed that anti-TNF-α therapy provides better outcomes when combined with immunomodulatory agents and that therapeutic drug monitoring might help optimize dosing. Infliximab may be effective as a treatment for ulcerative inflammation in the intestinal graft that does not meet the criteria for acute cellular rejection not improved by immunosuppressant conditioning. The optimal management for recurrent ulcerative inflammation under ITx settings by using anti-TNF-α therapy needs further elucidation.

INTRODUCTION

Tumor necrosis factor alpha (TNF-α) is one of the central cytokines in the pathogenesis of mucosal inflammation in inflammatory bowel disease (IBD) and has been the primary target of biologic therapies. Although TNF is mainly produced by monocytes, macrophages, and T lymphocytes, it is also produced by mast cells, granulocytes, fibroblasts, and several other cell types[1]. TNF is a highly pro-inflammatory cytokine that is involved in key processes in inflammation, including the activation of coagulation and fibrinolytic responses, promotion of the development of the neutrophil-endothelial adhesion necessary for recruitment to inflammation sites[2-4], and promotion of granulomatous inflammation through its role in the recruitment of T lymphocytes, monocytes, and macrophages[5-7].

Infliximab is a chimeric immunoglobulin G1 monoclonal antibody that binds to soluble and transmembrane forms of human TNF-α. It was approved by the United States Food and Drug Administration in 1998 for Crohn’s disease and in 1999 for rheumatoid arthritis. Later, the approval was broadened for the treatment of various autoimmune diseases including diseases in pediatric patients. The advent of anti-TNF-α antibodies has resulted in a paradigm shift in the treatment of IBD. Anti-TNF-α antibodies are thought to have multiple mechanisms of action, including neutralization of TNF-α, reverse signaling, apoptosis, and cytotoxicity[8], and have a predilection and efficiency for distribution into inflamed tissue[9]. Anti-TNF-α antibodies also induce the apoptosis of activated lamina propria T lymphocytes[10], which is contradictory to a proposed pathological mechanism in Crohn’s disease, where mucosal T cell proliferation exceeds T cell apoptosis[11]. In addition, anti-TNF-α therapies are capable of inducing antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity[9].

Advances in treatment for IBD provide an insight into the potential mechanism to control immune responses in intestinal transplantation (ITx). The first case report about the use of infliximab in the ITx setting dates back to 2003[12]. The report describes two adult patients who were successfully treated for cellular rejection refractory to anti-CD3 monoclonal antibody (OKT3) treatment. Since then, 22 published cases related to “intestinal transplant and infliximab” have been found in PubMed. Studies in rodents suggested promising complementary effects of infliximab addition to conventional immunosuppressive regimens not only in terms of alleviation of ischemic reperfusion injury but also attenuation of acute cellular rejection (ACR)[13,14]. However, despite some promising clinical evidence available from both animal and human studies, little is known about the optimal protocol and safety of infliximab use in the ITx setting. Herein, we report the detailed clinical course with serial serum TNF-α levels of an intestinal transplant recipient for a prolonged period and discuss future prospects of infliximab treatment based on a literature review.

CASE PRESENTATION

Chief complaints

Routine screening endoscopy showed several ulcerative lesions in the distal end of the graft 2 years after ITx. The patient developed anorexia, showed weight loss, and experienced intermittent abdominal pain.

History of present illness

A patient was an 11-year-old boy with intestinal motility disorder classified as a hypogenic type of intestinal dysganglionosis. The patient underwent living-donor related ITx from his father because of a lack of vascular access and growth retardation due to malnutrition. The graft was 110 cm of donor ileum from a point 20 cm proximal to the Bauhin valve. His initial immunosuppression regimen consisted of daclizumab as induction therapy, tacrolimus, and steroids. Daclizumab was continued until 12 wk after ITx as the maintenance treatment. Tacrolimus was started on the day of surgery after reperfusion. It was initially administered in a continuous intravenous manner, before switching to oral administration 2 wk after the transplant. The target trough level was between 20 and 25 ng/mL for the first month, 15-20 ng/mL for the next 2 mo, 10-15 ng/mL for the next 3 mo, and 10 ng/mL thereafter. Despite two episodes of steroid-responsive mild ACR and cytomegalovirus (CMV) infection within the first year after ITx, he was free of rejection on tacrolimus monotherapy.

History of past illness

Hypogenic type of intestinal dysganglionosis.

Personal and family history

There was no relevant family history.

Physical examination

Routine screening endoscopy showed several ulcerative lesions in the distal end of the graft 2 years after ITx. Partial resection of the small intestine including the ulcerative lesions was performed when he underwent revision of the stoma (Bishop-Koop procedure) in preparation for a complete reversal of ileostomy at the age of 13 years. Histological analysis of the ulcerative lesion revealed non-specific inflammatory changes. However, the patient developed anorexia, showed weight loss, and experienced intermittent abdominal pain several months after the previous operation. These symptoms persisted on and off over several months.

Laboratory examinations

Regular blood tests revealed hypoalbuminemia, a low total cholesterol level, and anemia; the other findings were unremarkable, including C-reactive protein level, erythrocyte sedimentation rate, and white blood cell count.

Imaging examinations

The endoscopic work up to evaluate the progression of anemia revealed stenosis with ulcerative inflammatory changes in the proximal part of the anastomosis and multiple longitudinal ulcers in the graft near the distal anastomosis site (Figure 1A and B). Computed tomography showed thickened intestinal walls with inflamed fat tissue.

Figure 1

Ulcerative lesion in graft before and after administration infliximab. A: The location of the diseases in the graft; B and C: Stenosis with inflammation in the proximal anastomosis between the graft and the original intestine (B, indicated by a white diamond in A), and a longitudinal ulcerative lesion in the distal end of the graft (C, indicated by a black diamond in A); D and E: Mucosal healing was observed in the distal ulcerative lesion after the administration of two doses of infliximab. IFN: Infliximab.

Pathological examinations

Mucosal biopsy showed non-specific inflammation of the mucosa, which did not fulfill the criteria of ACR or chronic rejection (CR). C4d staining was negative; the anti-donor human leukocyte antigen antibody was absent in the patient’s serum. Polymerase chain reaction performed using the mucosal specimen was negative for CMV and Epstein-Barr virus (EBV).

FINAL DIAGNOSIS

The final diagnosis was suggested to be ulcerative lesions in Crohn’s disease.

TREATMENT

Several attempts to dilate the stenotic lesions with a balloon only provided transient relief. Anorexia, pain, and anemia were progressive. Since the endoscopic findings suggested ulcerative lesions in Crohn’s disease, infliximab treatment was considered. Before the initiation of infliximab treatment, screening tests for malignancy and latent infections, including tuberculosis and infections with EBV, CMV, and hepatitis B virus, were performed, all of which were negative.

The initial, second, third, and subsequent doses of infliximab were administered on day 0, day 14, day 42, and every 8 wk thereafter, respectively.

OUTCOME AND FOLLOW-UP

The patient’s oral intake was restored immediately after the first infusion of infliximab, and abdominal pain alleviated. Endoscopy, which was performed after the administration of the second dose of infliximab, showed mucosal healing of the ulcerative lesions (Figure 1C-E). However, the effect was only transient, the symptoms relapsed, and ulcerative inflammation recurred within several weeks. Furthermore, the effect of infliximab was attenuated; thus, repetitive infusion of infliximab was required in shorter intervals. The dosage was also increased to 7.5 mg/kg, and mycophenolate mofetil (MMF, 20 mg/kg) was added to prevent the production of neutralizing antibodies against infliximab. Later, MMF was switched with 5 mg of prednisolone, which helped reduce the dosage and frequency. Treatment with 5 mg/kg infliximab every 8 wk and 5 mg of oral prednisolone allowed the maintenance of remission for the following 2 years. Since the ulcerative lesion persisted despite symptom relief, another partial resection of the intestinal part with longitudinal ulcerative lesions was performed at the same time as ileostomy reversal 11 years after ITx (when the patient was 22 years old). The serum level of TNF-α and changes in body weight are shown in Figure 2. The trough serum TNF-α levels ranged from 14.8 to 246 pg/mL, which rapidly declined to 0.55-4.17 pg/mL (immediately after each infusion). The resected specimen of the graft revealed no clinical features of ACR or CR (such as submucosal vasculopathy, intimal thickening, or fibrosis) (Figure 3). Endoscopy performed for surveillance 3 mo after the resection showed the recurrence of several ulcerative lesions in the graft, which prompted the resumption of treatment with infliximab (5 mg/kg) followed by symptom-based administration. Currently, the patient is successfully off parenteral nutrition. Infliximab is being administered as needed (average 8-10 wk), and the patient’s condition has been stable without any obvious adverse events for 5 years since the first administration infliximab. The test for neutralizing antibodies against infliximab has been negative to date.

Figure 2

Clinical course during infliximab administration. A: Height and body weight indicating a steady growth, in line with the initiation of infliximab (5 mg/kg). Hemoglobin (g/dL) level rapidly recovered. Following attenuation in the clinical response, the dose was increased to 7.5 mg/kg and immunomodulatory agents were added (mycophenolate mofetil was later switched with oral prednisolone); B: Dots (●) indicate the trough serum tissue necrosis factor alpha level, which declined immediately after each infliximab infusion (indicated by squares). In contrast, almost normal white blood cell counts and C-reactive protein level were observed throughout the course of treatment. Partial resection and stoma reversal were performed (indicated by dotted lines). IFN: Infliximab; MMF: Mycophenolate mofetil; PSL: Prednisolone; TAC: Tacrolimus; Hb: Hemoglobin.

Figure 3

Pathological findings of the ulcerative lesion. A: The resected specimen of the graft showing ulcerative inflammation with fibrotic tissue; B: No signs of chronic rejection are observed.

DISCUSSION

The four major indications of infliximab for ITx can be considered as follows: (1) Induction therapy; (2) Salvage treatment for rejection refractory to treatment with lymphocyte-depleting antibodies [anti-thymocyte globulin (ATG) or OKT3]; (3) Preemptive treatment for steroid-refractory rejection to avoid the use of treatment with lymphocyte-depleting antibodies; and (4) Treatment for ulcerative inflammation not meeting the criteria for rejection. Regarding indication I, some treatment centers use infliximab as part of induction therapy based on results of animal studies[13-15]. however, thus far, clear benefits in human studies remain to be elucidated[16]. The data of 22 ITx patients treated with infliximab due to indications 2, 3, and 4 are summarized in Table 1[17-23]. Ten patients received infliximab after being treated with lymphocyte-depleting antibodies (indication 2), six received infliximab before treatment with lymphocyte-depleting antibodies or did not receive lymphocyte-depleting antibodies (indication 3), and two received infliximab for chronic ulcerative conditions, which did not meet the criteria for ACR (indication 4). No clinical details were available for four patients[24].

Table 1

Summary of the literature related to treatment with infliximab for ulcerative lesion after intestinal transplantation

Ref.	Number of patients	Age of the patients at the time of events (yr)	Disease	Baseline immunosuppressive therapy at the time of the event	Indications	Serum TNF-α (pg/mL)	Dose	Number of infusions	Interval after ITx	Outcome	Adverse events and F/u
Fishbein et al[17], 2006	4	N/A	N/A	N/A	Late-onset resistant rejection (no details available)	N/A	N/A	N/A	N/A	Full recovery	N/A
Giovanelli et al[18], 2008	1	11 (m)	Chronic intestinal pseudo-obstruction	Tacrolimus, sirolimus	Steroid-resistant ACR	N/A	N/A	1	18 mo	No response, remission after OKT3 treatment	EBV viremia, graft loss due to chronic rejection in 5 mo
Gerlach et al[19], 2011	9	27-44 (7: m 2: f)	Short bowel syndrome, chronic intestinal pseudo-obstruction	Steroid, tacrolimus, ATG, daclizumab, alemtuzumab, sirolimus, MMF	Late-onset OKT3-resistant ACR (2), early-onset OKT3-resistant ACR, humoral rejection (1), early-onset OKT3-resistant ACR (1), steroid-resistant ACR (3), chronic ulcerative ileitis/anastomositis (2)	Late-onset OKT3-resistant ACR (60-170), steroid-resistant ACR (80-140), chronic ulcerative ileitis (60-114), early-onset OKT3-resistant rejection (100-167)	5 mg/kg	12 ± 11.3	0-40 mo (18.2 + 14.1 mo)	6/9 sustained remission, 2/9 repeated transient remission, 1/9 graft loss	EBV infection (3), cutaneous mycosis, pneumonia, 6 mo to 10 yr
De Greef et al[20], 2012	2	13 (m), 5 (f)	Microvillous inclusion disease, short bowel syndrome	Tacrolimus monotherapy, rapamycin + daclizumab + steroid	Steroid- and ATG-resistant ACR	N/A	5 mg/kg, 4 mg/kg + 3 mg/kg 2-wk interval	1, 3	5 yr and 6 mo	Complete remission	27/22 mo
Avsar et al[21], 2014	1	52 (f)	Short bowel syndrome	Steroid, tacrolimus, everolimus, daclizumab, MMF	Graft rejection after CMV infection	N/A	5 mg/kg	1	6 mo	No response, graft explantation (no ATG)	Graft loss
Rao et al[22], 2016	1	38 (f)	Crohn’s disease	Steroid, tacrolimus	Late-onset steroid- and ATG-resistant ACR	N/A	Adalimumab	< 2	10 mo	Remission with maintenance adalimumab treatment	6 mo
Narang et al[23], 2019	1	20 (f)	Total intestinal aganglionosis + solitary kidney	Steroid, tacrolimus	Late-onset steroid-resistant ACR (moderate to severe), ulcerative ileitis	N/A	5 mg/kg, 10 mg/kg	More than 3	13 yr	No response with 5 mg/kg, remission after ATG, 10 mg/kg induced remission for another ACR episode later	PTLD (remission), 2 yr
Current case, 2020	1	20 (m)	Isolated hypoganglionosis	Tacrolimus	Chronic ulcerative ileitis, anastomositis	14.8-246 pg/mL	5-7.5 mg/kg	> 17	6 yr	Repeated transient remission	5 yr

TNF-α: Tissue necrosis factor alpha; ITx: Intestinal transplantation; ACR: Acute cellular rejection; OKT3: Anti-CD3 monoclonal antibody; EBV: Epstein-Barr virus; ATG: Anti-thymocyte globulin; MMF: Mycophenolate mofetil; CMV: Cytomegalovirus; PTLD: Posttransplant lymphoproliferative disorder; N/A: Not available.

Eight out of the 10 patients (dosage: 3 mg/kg to 5 mg/kg) treated for indication 2 achieved complete remission, one was in transient remission and being treated, and one lost the graft. The patient who lost the graft had developed severe exfoliative ACR accompanied by humoral rejection 15 d after transplantation. The graft did not recover even after the administration of seven doses of infliximab along with plasma pheresis and intravenous immunoglobulin (high dose). Although based on only a single case, it can be speculated that infliximab may have a limited effect on humoral rejection. Among the 10 rejection episodes, two occurred early after ITx (1 d and 15 d) and the other eight episodes occurred 6 mo to 5 years after ITx.

Among six patients who received infliximab for indication III, graft recovery was achieved in three patients (dosage: 5 mg/kg) without the need for treatment with lymphocyte-depleting antibodies. Two patients needed ATG/OKT-3 treatment and achieved remission, and one lost the graft without receiving ATG because of underlying CMV disease. Whether earlier treatment with infliximab might have prevented the need for treatment with lymphocyte-depleting antibodies remains unclear, because, unfortunately, data on the interval between the onset of ACR and infliximab administration were unavailable. For now, early application of infliximab in cases of steroid-resistant ACR with an aim to avoid treatment with lymphocyte-depleting antibodies remains controversial and should be prudent because a delay in treatment with ATG might have detrimental effects.

Only three patients, including our current patient, received infliximab for indication 4, known as ulcerative ileititis/anastomositis, which is clearly distinct from ACR. Results of histological analyses were consistent in three individuals, and were characterized as an ulcer with granulation tissue and fibrinoid necrosis on the surface. The events occurred 17, 24, and 72 mo after ITx. Of note, although one patient achieved complete remission after two infusions of infliximab, the other two patients continue to be treated for recurrent ulcerative lesions at the time of submission. One patient received regular treatment every 6 mo[19], and our patient receives the treatment every 8-10 wk as of now. The macroscopic findings and the clinical response induced by infliximab led us to speculate about the potential commonality of immune responses in the transplanted intestine and consider IBD. The first description of such similarity was reported by Fishbein et al[25]. They reported that 10% of 30 ITx recipients showed gross features of graft ulceration and a reduction in the number of Paneth cells on histological examination, and required on average 6 wk of infliximab treatment until remission; the success rate was 75%. A subsequent study reported the potential underlying mechanism of NOD2 polymorphism in such inflammatory lesions[25].

The optimal management for recurrent ulcerative inflammation under ITx settings by using anti-TNF-α therapy needs further elucidation. Previous studies in patients with Crohn’s disease revealed that anti-TNF-α therapy provides better outcomes when used in combination with immunomodulatory agents and that therapeutic drug monitoring might help optimization of dosing[26]. Our patient received MMF (500 mg) for 6 mo without additional improvement. MMF has since been switched with 5 mg of prednisolone. The dose was once escalated to 7.5 mg/kg based on clinical symptoms. Five years have passed since the patient was first administered infliximab, and treatment has been effective thus far. Options for future treatment include dose escalation or short-interval based on therapeutic drug monitoring, combination treatment with other immunomodulatory agents (such as azathioprine), and switching to other anti-TNF antibodies (such as adalimumab)[23]. With regard to the safety of infliximab addition in highly immunocompromised recipients, EBV viremia and cutaneous mycosis have been reported as adverse events. Studies on the addition of anti-TNF-α treatment for immunosuppression maintenance among other solid-organ transplant recipients, the indications for which mostly included coexistent IBD and rheumatoid arthritis, showed essentially no additional risk of infectious complications and malignancy in liver transplant[27,28] and kidney transplant patients[29]. Nevertheless, as stated in the guideline for Crohn’s disease management, a thorough assessment for opportunistic infections and malignancy is necessary among ITx recipients before the initiation of anti-TNF-α therapy.

CONCLUSION

Treatment with infliximab and immunomodulatory agents in addition to conventional immunosuppressive therapy is safe and effective for chronic ulcerative conditions after ITx. Anti-TNF-α therapy should be considered as a powerful option in immunosuppressive treatment strategy against various conditions associated with immunologically challenging ITx.