Treating Crohn's disease with hematopoietic stem cell transplantation

APRIL 07, 2008

Linda P. Zhang, MD
Resident in General Surgery Department of Surgery

Randolph M. Steinhagen, MD
Associate Professor of Surgery Chief
Division of Colon and Rectal Surgery Department of Surgery Mount Sinai School of Medicine New York, NY

ABSTRACT
Introduction:
Crohn's disease (CD) is an inflammatory bowel disorder that involves loss of immune tolerance in the gastrointestinal tract and T helper 1 delayed-type hypersensitivity of the gut wall, frequently resulting in granuloma formation. Hematopoietic stem cell transplantation (HSCT) has been used to treat other autoimmune diseases and is being evaluated as an option for patients with CD who fail to respond favorably to standard medical treatment.

Discussion and results: The authors discuss the case of a 25-year-old patient who underwent autologous HSCT to treat his CD as part of a Northwestern Medical Center study and presented 9 months later with abdominal pain and possible intussusception. They also provide a general overview of the current literature and research on HSCT in the treatment of CD.

Conclusion: There have been several reported cases in which autologous HSCT was used to treat patients with refractory CD and cases involving patients with CD who underwent stem cell transplantation for other reasons. These studies showed varying remission of CD, both clinically and histologically. It is unclear exactly how autologous HSCT induces remission, and more clinical trials that examine the effectiveness of autologous and allogeneic HSCT specifically in patients with CD are needed. Clinical trials should include long-term follow-up and provide more endoscopic and histologic indicators of remission.



Crohn's disease (CD) is a relapsing and remitting inflammatory bowel disorder that generally presents in the second or third decade of life. It causes significant life-long impairment and chronic pain. CD is characterized by dysregulat-ed immune response of the intestinal mucosa to luminal antigen, which causes chronic inflammation of the intestines. Patients with CD demonstrate decreased immune tolerance in the gastrointestinal (GI) tract and T helper 1 (Th1) delayed-type hypersensitivity of the gut wall, which can lead to the formulation of granulomas.1 Standard therapy for CD has focused on decreasing inflammation and restoring the unbalanced GI immune reaction by administering 5-aminosalicylic acid, corticosteroids, and antibiotics or suppressing cytokines.

Hematopoietic stem cell transplantation (HSCT) has been used to treat patients with other autoimmune diseases that include loss of immune tolerance or a Th1-predominant immune response.2-4 Recent studies on the use of HSCT for refractory CD and evaluations of patients with CD who have undergone HSCT for other reasons show remission of CD following the transplantation. HSCTs in these cases were either allogeneic or autologous. Allogeneic transplants may help by overcoming CD's genetic predisposition to circulate leukocytes, while autologous transplants may clear the body of committed lymphocyte clones and restore the lymphocytic imbalance in patients with CD. Most patients responded well to HSCT, and some were in complete clinical remission 10 years after transplantation.5

Our patient participated in a study on autologous HSCT that was conducted at Northwestern University 9 months prior to his presentation at our institution. His symptoms improved during the first 7 months after the procedure; then he began to experience severe abdominal pain and anorexia. Radiography suggested intussusception or obstruction, but an exploratory laparotomy failed to find either condition, and the patient continued to experience recurrent symptoms. The etiology of his symptoms remains unclear, and further workup is likely needed, particularly given his status as a post-autologous HSCT patient.

CASE REPORT

A 26-year-old man presented to our institution 9 months after undergoing autologous HSCT. He described experiencing 2 months of severe abdominal pain, anorexia, early satiety, and a 20-lb weight loss. The patient had received a diagnosis of CD at age 13, at which time he was treated with steroids, mesalamine, 6-mercaptopurine, and rotating antibiotic therapy. His symptoms worsened significantly at age 18, and it was discovered that he had extensive Crohn's jejunoileitis. At that time, a resection of the 3 feet of strictured proximal ileum and two stricturoplasties were performed.

One year after surgery, the patient developed a perforation at the site of one of the stricturoplasties, and this area was resected. Over the next 4 years, the patient's condition progressively worsened. He developed abdominal pain, rectal bleeding, persistent anemia, weight loss, and diarrhea. He had minimal response to treatment with azathioprine, methotrexate, prednisone, a combination of balsalazide and mesalamine, cyclosporine, and infliximab. At age 22, the patient underwent a third resection to remove the fibrostenotic anastomosis, and he was left with short bowel syndrome. His symptoms continued to worsen.

At age 25, the patient enrolled in the first series of autologous HSCT, which took place at Northwestern University Medical Center in Chicago. He was one of 12 participants, all of whom had chronic, active, refractory CD and a CD Activity Index (CDAI) between 250 and 400 despite therapy. Peripheral blood stem cells were mobilized using cyclophosphamide and granulocyte colony-stimulating factors and procured for the procedure. T-cell depletion was done by enrichment of CD34 .

Patients underwent an immune ablative regimen, which entailed cyclophosphamide and equine antithy-mocyte globulin. On admission, patients were started on a low microbial diet and given additional supportive care against infections, including metronidazole, ciprofloxacin if neutropenia occurred, and parental piperacillin/tazobactam until neutrophil recovery. Our patient tolerated HSCT well and had no immediate post-procedural complications. Fluconazole and vala-cyclovir were continued for 6 to 12 months after HSCT, and trimethoprim/sulfamethoxazole was given for 6 months after engraftment.6

The patient stated that he felt somewhat better after the transplant. He became dependent on large doses of narcotics, however, and required inpatient detoxification 6 months after HSCT. Seven months after the initial procedure, he experienced a 2-month period of severe abdominal pain, postprandial distress, incomplete emptying, cramping, and hematochezia, and he lost 20 lb.

When he presented to our institution 9 months after HSCT, we performed a computed tomography (CT) scan of his abdomen that suggested proximal small bowel intussusception at the proximal to mid-jejunum. A small area of focal wall thickening observed in the distal small bowel at the level of the anastomosis was suspicious for recurrent CD (Figure). It was difficult to differentiate whether the patient's symptoms were attributable to narcotics withdrawal, irritable bowel syndrome, or active CD, but the radiographic findings suggested surgical intervention was needed, and the patient underwent exploratory laparotomy. There was no visible inflammation of the small intestine, and no palpable masses were found. The patient was discharged on postoperative day 7 but readmitted 2 days later with severe abdominal pain and obstruction. The patient's condition improved over the next few days with bowel rest and bowel decompression by nasogastric tube, and he was again discharged.

 
 

DISCUSSION

In the past, standard treatment of CD primarily has entailed controlling the inflammatory response and inhibiting the aberrant T-cells using anti-inflammatory and chemotherapy-like agents. Recent studies on CD have focused on identifying and altering the genetic constitutes of the disease through allogeneic and autologous HSCT.

Allogeneic HSCT

Since the early 1990s, it has been observed that some patients with CD who undergo allogeneic HSCT for other conditions experience remission of CD after transplantation. The earliest reported case was in 1993, when a patient's CD symptoms improved after allogeneic HSCT for lymphoma.7 In 1998, 3 of 5 CD patients who underwent allogeneic transplantation for other medical reasons achieved remission of their CD for up to 10 years following transplantation.8 A German study pooled 11 CD patients, 6 of whom had active disease and 4 who were taking medication.9 Of the original 11 patients, 1 died and the remaining 10 found that their CD became inactive following allogeneic HSCT for other medical reasons. Patients were followed up at a median interval of 34 months, and their CD remained in remission.

Allogeneic HSCT alters the genetic mechanisms responsible for the exaggerated immune responses to luminal antigens and has been used on this basis. Its full benefit is not solely its ability to switch the genetic pool of T-cells available completely. It also stimulates donor lymphocyte-induced recipient T-cell aplasia, a process called graft-versus-autoimmunity. The donor lymphocytes attack the recipient's aberrant T-cells, resulting in complete depletion of the former immune system.10 This is the presumed mechanism of allogeneic HSCT's superior, long-lasting effect when compared with autologous HSCT in treating hematologic malignancy concomitant with autoimmune disease.11 An allogeneic transplantation should be considered if the immune hyperactivity is presumed to result from underlying genetic abnormality manifested in bone marrow-derived cells. In comparison with autologous HSCT, the abnormality is presumed to be secondary to proliferation of aberrant peripheral T-cells hypersensitive to luminal antigen.

Autologous HSCT

Although autologous transplantation does not incorporate complete removal of the patient's genetic predisposition for CD, it has been shown to induce remission of the disease. It is associated with less morbidity and lower mortality risks than allogeneic HSCT and is a valid alternative to allogeneic HSCT. There have been several reported cases of CD remission in patients who underwent autologous HSCT for other conditions. One patient had autologous HSCT for non-Hodgkin's lymphoma and had no clinical or laboratory evidence of recurrent CD 7 years later.11 Another patient had CD with diffuse pancolitis before transplantation but became asymptomatic for 3 years after the transplant.12 A handful of studies in Europe show similar results.13-16 Overall, most patients achieved clinical improvement following mobilization; however, maintaining complete histological remission after transplantation required additional treatment.

The Northwestern Medical Center study that our patient participated in was the first and only reported case series of autologous HSCT specifically for patients with CD. All 12 participants had chronic, active, refractory CD and a CDAI between 250 and 400 despite therapy. The study found that 11 of the 12 patients, including our patient, sustained remission as defined by a CDAI lower than 150 without any immunosuppressive drugs after a median follow-up of 18.5 months (range, 7-37 months). The only patient who developed a recurrence experienced abdominal pain and diarrhea 15 months' post-HSCT. Although this study shows promising results in the short-term, only 2 patients achieved a treatment-free clinical remission that exceeded 3 years. On colonoscopy during follow-up, the patients exhibited minor ulcerations, indicating that a complete structural remission did not occur within the time frame of this study.

Autologous HSCT induces remission by eradicating activated clones of aberrant T-cells and recovering na?ve T-cells that recognize other epitopes. The exact mechanism behind autologous HSCT-induced remission remains unclear, but there are a few theories. One theory suggests that autologous HSCT allows more potent immunosuppression than would otherwise be possible, resulting in immune ablation of nearly all aberrant T-cells. The autologous stem cell infusion would then be done only to shorten the post-HSCT neutropenic interval.17 This potent immunosuppression can offer long-term benefits that would not be seen with less intensive chemotherapy. Despite this, complete immune ablation is not possible with autologous HSCT, as shown in the use of autologous HSCT to treat malignant disease. There is no graft-versus-autoimmune effect to eliminate the last resting memory lymphocyte, however, and patients have increased risk of recurrence when compared with those who undergo allogeneic HSCT.11

A second theory presumes that CD hypersensitivity results from an imbalance between normal and aberrant T-cells. The conditioning regimen is not intended to destroy every aberrant immune cell but rather to eliminate enough of them to restore the dynamic immune "balance." Another theory proposes that bowel flora plays a role in the heterogeneous pathogenesis of CD and suggests that the prophylactic medications given in autologous HSCT alter the bowel flora and, thus, the natural progression of CD. This theory is applicable to the Northwestern study, which administered extensive broad prophylaxis to counter potential neutropenic infections immediately after transplantation.

CONCLUSION

The future of autologous and allogeneic HSCT in treating CD depends on more extensive clinical trials of HSCT that target patients with CD. At present, there have been few allogeneic HSCT trials specifically for patients with CD, and Northwestern has conducted the only non-case-based study of autologous HSCT18 Future trials need longer follow-up and to supply more endoscopic and histologic indicators of remission. Recent research on "minitransplantations" for autoimmune diseases may open a new venue for allogeneic-HSCT treatment of CD. Experimental data has shown successful remission of systemic sclerosis and severe graft-versus-host disease using allogeneic HSCT that specifically replaces endothelial cells, fibroblasts, and mesenchymal stem cells.19,20 In the future, these minitransplants of non-myeloablative HSCT may constitute safer and more "curative" HSCTs for autoimmune illnesses such as CD.21

Disclosure

The authors have no relationship with any commercial entity that might represent a conflict of interest with the content of this article and attest that the data meet the requirements for informed consent and for the Institutional Review Boards.


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