Graft-Versus-Host Disease

Intra-arterial steroid-injection therapy for steroid-refractory acute graft-versus-host disease with the evaluation of angiography

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Summary:

We treated three patients with steroid-refractory acute graft-versus-host disease (aGVHD) with intra-arterial steroid-injection therapy (IAST). Two patients with gut aGVHD received IAST into both superior and inferior mesenteric arteries, while one patient with liver aGVHD received IAST into the proper hepatic artery. The volume of stools and the bilirubin level improved soon after IAST. Angiography of the superior and inferior mesenteric arteries was performed in the two patients with steroid-refractory gut aGVHD, and identical abnormal findings were obtained. IAST might be an earlier option for steroid-refractory aGVHD.

Main

Patients who do not respond to steroid therapy for acute graft-versus-host disease (aGVHD) are regarded as having steroid-refractory aGVHD, and their mortality is high.1 A variety of salvage regimens, including mega-dose steroid therapy, anti-thymocyte globulin (ATG),2 infliximab,3 and daclizumab,4 have been tried for steroid-refractory aGVHD. However, these agents have proven to be insufficiently effective, and there has been little improvement in the treatment related mortality (TRM). Furthermore, these agents cause profound immunosuppression, often resulting in fatal infections. Therefore, it remains critical to establish more effective treatment for steroid-refractory aGVHD without unwanted sequelae.

Recently, Sato et al.5 and Shapira et al.6 reported that direct infusion of corticosteroid into arteries dominating the regions of the gut or liver was effective in treating steroid-refractory gut and liver aGVHD. Indeed, complete response was obtained in nine of 11 patients with gut aGVHD and three of seven patients with liver aGVHD. Furthermore, this procedure was shown to be safe. Based on the results of these studies, we applied the same approach to three patients with steroid-refractory aGVHD in this study.

Case 1

A 46-year-old man with adult T-cell leukemia (ATL) received peripheral blood stem cell transplantation (PBSCT) from his HLA-matched sister. The patient received donor lymphocyte infusion because of incomplete donor-type chimerism. The patient developed grade II aGVHD in the skin (stage III) and gut (stage I) on day 55 post-transplant. Methylprednisolone (mPSL) (1 mg/kg i.v. every 12 h), high-dose mPSL (20 mg/kg i.v. once daily for 3 days) and infliximab (5 mg/kg i.v. once monthly for 2 months) were all ineffective.

We next performed intra-arterial steroid-injection therapy (IAST) according to the method described below. Briefly, selective angiography of both superior and inferior mesenteric arteries was performed through the femoral artery by Seldinger technique. In all, 30 ml of nonionic contrast media (Iopamiron 300, Nihon Schering, Osaka, Japan) was injected into the superior mesenteric artery at a rate of 6 ml/s, and 15 ml into the inferior mesenteric artery at the rate of 3 ml/s. Following the angiography, 10 ml of 1 mg/kg mPSL, which was diluted by adding physiological saline, was slowly infused for 1 min by hand into both the superior and inferior mesenteric arteries.

The angiographic findings were characterized by hypervascularity of the colon wall and early venous filling. Normal tapering of vasa recta in the colon wall was lost in the patient; a finding that could be a reflection of the nonspecific inflammatory change in the bowel wall. The patient’s stool pattern, particularly the frequency of defecation desire, improved 9 days after the start of IAST (Figure 1a). Unfortunately, the patient died of interstitial pneumonia and infectious complications on day 235.

Figure 1
figure1

The volume of stools after the occurrence of gut GVHD in Cases 1 and 2 are shown in (a) White arrow shows intra-arterial steroid in Case 1, black arrow in Case 2. The time course of total bilirubin level after transplantation in Case 3 is depicted in (b).

Case 2

A 40-year-old woman with lymphoblastic lymphoma received PBSCT from her HLA-matched sister. She developed a grade II aGVHD in the skin (stage II) and gut (stage I) on day 17 and received mPSL at a dose of 2 mg/kg (1 mg/kg i.v. every 12 h). Although her skin lesion improved immediately, her diarrhea was exacerbated to stage IV after 4 days of mPSL (Figure 1a). On day 25, she was given an infusion of mPSL at a dose of 1 mg/kg into both the superior and inferior mesenteric arteries according to the method described above. Angiographic findings were basically the same as in Case 1. After 7 days, defecation frequency and stool appearance were dramatically improved, and her aGVHD symptoms eventually disappeared. She currently remains off all immunosuppressive agents with no evidence of GVHD.

Case 3

A 43-year-old man who was diagnosed as having myelodysplastic syndrome with refractory anemia with excess blasts underwent allogeneic bone marrow transplantation from an HLA 1-allele (DR locus)-mismatched unrelated donor. This patient developed a grade III aGVHD in the skin (stage III) and liver (stage II) on day 23, and received mPSL at a dose of 2 mg/kg (1 mg/kg i.v. every 12 h). However, the skin and liver aGVHD progressed to stages IV and III, respectively and stage III gut aGVHD occurred on day 26. He was given high-dose mPSL at a dose of 20 mg/kg (20 mg/kg i.v. once daily) for 3 days. The skin and gut aGVHD improved but the liver aGVHD progressed to stage IV on day 33 (Figure 1b). The patient then received IAST consisting of 10 ml of 3 mg/kg mPSL, which was diluted by adding physiological saline. This was slowly infused for 1 min by hand into the proper hepatic artery. The bilirubin level started to decline 4 days after IAST, but stage III gut aGVHD recurred. The patient died of multiple organ failure induced by prolonged liver and gut aGVHD on day 65.

Discussion

In this study, although IAST partially improved the gut or liver aGVHD in Cases 1 and 3, these two patients eventually died of unwanted complications caused by the persisting advanced stage of aGVHD and profound and long-term immunosuppression induced by prior megadose steroid therapy and/or administration of infliximab. In contrast, IAST controlled gut aGVHD in case 2 and no infectious complications were observed. In this case, IAST was performed as the first salvage therapy after the diagnosis that the patient's aGVHD was steroid-refractory. In view of these findings, it may be important to make an early evaluation of whether the aGVHD is steroid-refractory and then to promptly adopt IAST for such patients.

We performed angiography of selective mesenteric arteries before the infusion of mPSL in Cases 1 and 2. To our knowledge, this is the first report that evaluates the angiography of steroid-refractory gut aGVHD. The two cases in this study showed identical abnormal angiography. Interestingly, the angiographic findings were similar to those of ulcerative colitis (UC),7 a chronic inflammatory bowel disease (IBD) of unknown etiology. In view of this similarity between aGVHD and UC, it is interesting to note that IAST was significantly effective in nine of 11 patients with steroid-refractory UC.8

It is currently unknown why topical infusion of steroids, but not systemic steroid administration, even in high doses, may be effective in treating gut or liver aGVHD. Several studies suggest that the number of steroid receptors and the affinity of the receptors to steroids are both decreased in the inflammatory mucosa of IBD such as UC.9,10 Direct intra-arterial steroid infusion may expose topical inflammatory mucosa to high concentrations of steroids and thus overcome the ineffectiveness of steroids caused by the decrease in the number of receptors and their affinity.

In conclusion, this study showed that IAST can be safe and effective in treating steroid-refractory aGVHD, particularly of the gut. However, to obtain maximal benefit from this therapy, it may be critical to diagnose the steroid-refractoriness of aGVHD quickly and to apply this therapy immediately after the diagnosis. Although the biological mechanism of IAST remains to be elucidated, it could become an early option for steroid-refractory aGVHD of the gut or liver. Further case studies will establish the clinical significance of this therapy.

References

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Acknowledgements

We are grateful to Miss Tomoko Masuda for her secretarial work.

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Correspondence to K Nakai.

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Nakai, K., Tajima, K., Tanigawa, N. et al. Intra-arterial steroid-injection therapy for steroid-refractory acute graft-versus-host disease with the evaluation of angiography. Bone Marrow Transplant 33, 1231–1233 (2004) doi:10.1038/sj.bmt.1704523

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Keywords

  • intra-arterial steroid-injection therapy
  • steroid-refractory acute graft-versus-host disease
  • angiography

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