Bone Marrow Transplantation (2015) 50, 1365–1366
© 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15
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LETTER TO THE EDITOR
Inflammatory bowel disease after allogeneic stem cell
transplantation
Bone Marrow Transplantation (2015) 50, 1365–1366; doi:10.1038/
bmt.2015.138; published online 8 June 2015
Gastrointestinal (GI) disorders frequently occur after allogeneic
stem cell transplantation (allo-SCT), infections and GvHD represent
the most frequent events. They develop as a consequence of
tissue damage, particularly in the GI tract, induced by the
conditioning regimen. Release of damage-associated molecular
pattern molecules and pathogen-associated molecular pattern
molecules after conditioning induces the activation of the innate
and adaptive immune responses leading to GI GvHD. Despite
sharing common pathophysiology pathways with GI GvHD,
inflammatory bowel disease (IBD) has been occasionally described
after allo-SCT.
We report here a case of IBD occurring 1 year after allo-SCT in
the context of post-transplant immune dysfunction.
A 57-year-old Caucasian woman without medical history was
diagnosed in September 2011 with myelodysplasia/myelofibrosis
disease. Bone marrow biopsy showed 19.5% blasts with a normal
karyotype. She received one course of induction chemotherapy
with idarubicin and cytosine–arabinoside leading to CR. She then
received two consolidation courses based on the same schedule.
She proceeded to undergo allo-SCT from an HLA-identical
sister (HLA A*01-02/B*08-57/C*06-07/DRB1*03-07/DQB1*02-03).
Conditioning regimen included fludarabine 30 mg/m2/day for
5 days, IV busulfan 3.2 mg/kg/day for 3 days and thymoglobulin
2.5 mg/kg/day for 2 days. The PBSC graft contained
4.7 × 106 CD34+ and 26.1 × 107 CD3+ cells/kg of recipient’s
body weight. Post-transplant GvHD prophylaxis consisted of
cyclosporine-A (CsA).
After transplantation, she presented two episodes of CMV
reactivation on day 30 and at 5 months, both treated by
valgancyclovir. By day 40, EBV reactivation was treated by two
weekly courses of rituximab at 375 mg/m2/day. At day 100, there
Figure 1. Microscopic examination of the colonic biopsy.
Hematoxilyn–eosin stain, decreased crypt density, distortion and
branching of crypts and irregular mucosal surface. Original
magnification × 50.
was full donor chimerism in whole blood and in the CD3+ cell
fraction, and she was in complete cytologic remission.
In the absence of acute GvHD, CsA was tapered between 2 and
3 months post transplantation. At 4 months, she developed
cutaneous grade II acute GvHD treated with CsA and systemic oral
steroids at 2 mg/kg/day. She had no GI symptoms at that time. At
7 months, steroids could be stopped but CsA was maintained
because of the persistence of histologically proven skin manifestations of chronic GvHD. These consisted in follicular lichen papules
of the face and the axillae, as well as lichenoid alopecic plaques of
the scalp and the eyebrows. These lesions were treated with
topical steroids and topical tacrolimus. She also presented dry eye
syndrome treated with eye drops (carmellose sodium 1%).
At 1 year and 4 months after transplantation, although different
types of cutaneous lesions consisting of ‘psoriasis-like’ umbilical
and peri-anal lesions developed, she presented diarrhea,
abdominal pain and with 5-kg weight loss. Diarrhea consisted of
2–3 soft stools per day without fever or mucous stools.
A colonoscopy was performed up to right colon, which showed
diffuse edematous and congestive lesions consistent with colitis.
Biopsies showed inflammation of the mucosa with crypt distortion
and irregular mucosal surface (Figure 1). Crypt abscesses were
sometimes seen (Figure 2). There was no sign of GvHD and,
especially, no apoptotic criteria, gland destruction or submucosal
fibrosis. There was also no evidence of infectious agents,
particularly of CMV. The final diagnosis was IBD and, more likely,
ulcerative colitis, given the absence of mucin depletion and the
presence of crypt abcesses and diffuse inflammation. She was
treated with oral budesonide and mesalazine with rapid clinical
improvement. One year later, clinical symptoms completely
resolved and she recovered normal weight under maintenance
treatment with mesalazine.
Patients often experience diarrhea after allo-SCT. The diagnosis
of GvHD must be invoked but it is not the only possibility. In these
cases, the anatomopathological findings have an important place.
Here we report the case of a female patient who presented an
Figure 2. Microscopic examination of the colonic biopsy. Hematoxilyn–eosin stain and crypt abscesses signing the activity of IBD.
Original magnification × 50.
Letter to the Editor
1366
association of immune dysfunction symptoms after allo-SCT, with
dry eye syndrome, psoriasis-like skin lesions and IBD. These
manifestations occurred while she was receiving immunosuppressive treatment for chronic GvHD. There is only one similar case in
the literature.1 Sonwalkar et al.1 reported a case of Crohn’s colitis
occurring after myeloablative conditioning allo-SCT for Hodgkin
lymphoma.
IBD is a multifactorial disease with environmental, microbial,
immunologic and genetic factors. It is now well established that
dysfunctions in genes involved in host–microbe interactions have
an important role in the development of these diseases.2,3
However, although many genetic polymorphisms are associated
with IBD on genes such as NOD2, MICB, IBD 1 or 3, no causal
mutations have been pointed out.4,5 Since the discovery of these
mutations in susceptibility genes, many authors have raised the
hypothesis of adoptive transfer of genetic susceptibility in IBD,1,4
especially after transplantation. The onset of IBD after transplantation has been more frequently described in the field of solid
organs such as liver.6 Nevertheless, the reported cases were
recipients with history of primary sclerosing cholangitis or
autoimmune hepatitis, which are by themselves associated with
IBD.7 In the study by Sonwalkar et al., the donor, but not the
recipient, exhibited a 5′UTR polymorphism of NOD2/CARD15 that
might be associated with Crohn’s disease. There were also
haplotype mismatches between the donor and the recipient at
the IBD3 locus. These genetic abnormalities highlight the
possibility of adoptive gene transfer.
We performed detailed genetic analysis of the NOD2 locus in
our case. We did not find the NOD2 polymorphisms rs2066844,
rs2066845 or rs2066847, which are the most frequently associated
polymorphisms with IBD, in the donor or the recipient. However,
we did not analyze all susceptibility genes described in the
literature.
In the majority of case reports of post-transplantation IBD, the
donor had no signs of this disease. This highlights the fact that
other factors have a role in the IBD onset after transplantation,
such as alterations of the intestinal microbiota after the
conditioning regimen, antibiotics, immunosuppressive treatment
or interaction with the non myeloid cells and particularly epithelial
cells.1,2
Stabilization or even remission of IBD after allo-SCT has been
well described.8,9 However, its onset in a recipient who had no
signs before the procedure is rare. These reports allow us to better
explore the complex physiopathology of this disease, and raise the
question of a systematic screening of the donors for any gut
symptoms.2,8
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
We thank the nursing staff for providing excellent care for our patients, the transplant
coordination nurses and the following physicians: P Coppo, JP Marie, R Dulery,
Bone Marrow Transplantation (2015) 1365 – 1366
NC Gorin, AL Ruggeri, M Aoudjhane, L Garderet, F Isnard, MP Lemonnier, E Corre,
A Gomez, S Lapusan, O Legrand, AC Mamez, E Brissot, A Vekhoff, Z Marjanovic,
R Adaeva, H Benredouane, M Labopin and R Belhocine for their dedicated patient
care. IB was supported by educational grants from the ‘Association for Training,
Education and Research in Hematology, Immunology and Transplantation’ (ATERHIT).
Our group is supported by several grants from the French National Cancer Institute
(PHRC, INCa to MM).
I Boussen1,2, H Sokol2,3, S Aractingi4,5, O Georges2,6, N HoyeauIdrissi2,7, JP Hugot8,9, M Mohty1,2 and MT Rubio1,2
1
Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint
Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP),
Paris, France;
2
Université Pierre et Marie Curie, UPMC Univ Paris 06, Paris, France;
3
Service de Gastroentérologie et Nutrition, Hôpital Saint Antoine,
Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France;
4
Service de Dermatologie, Hôpital Cochin, Assistance Publique
Hôpitaux de Paris (AP-HP), Paris, France;
5
Université Paris Descartes, Univ Paris 05, Paris, France;
6
Laboratoire d’Anatomo-Cyto-Pathologie, Hôpital Tenon, Assistance
Publique-Hôpitaux de Paris (AP-HP), Paris, France;
7
Laboratoire d’Anatomo-Cyto-Pathologie, Hôpital Saint Antoine,
Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France;
8
Service des maladies digestives et respiratoires de l’enfant, Hôpital
Robert Debré, Assistance Publique-Hôpitaux de Paris (AP-HP),
Paris, France and
9
Centre de recherche sur l’inflammation, UMR 1149,
Inserm - Université Paris Diderot, Univ Paris 07, Paris, France
E-mail: [email protected]
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