Relapse of Graves' disease after successful allogeneic bone marrow ...

Bone Marrow Transplantation (2001) 28, 1151–1153  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt

Case report Relapse of Graves’ disease after successful allogeneic bone marrow transplantation L-T Hsiao, J-H Liu, C-C Yen, W-S Wang, FS Fan, T-J Chiou and P-M Chen Division of Medical Oncology, Taipei Veterans General Hospital and National Yang-Ming University, Taiwan, ROC

Summary: As shown in many reports, allogeneic BMT can help cure autoimmune diseases. Conversely, we present a 24year-old woman with Graves’ disease, which was diagnosed just before BMT for CML. The Graves’ disease remitted immediately after BMT but relapsed 18 months later. Since the donor was free from thyroid diseases and the patient showed a rapid shift to complete donor chimerism after BMT, the autoimmune problem seemed neither to arise directly from the donor nor simply from the recipient’s residual lymphocytes. On the contrary, it was most likely compounded by chronic GVHD as suggested by the accompanying GVHD symptoms and the absolute donor karyotype in bone marrow cells. A Graves’ disease-susceptible HLA allele was also shared between recipient and donor, possibly enhancing the chances of this condition developing. Thus, allogeneic BMT may facilitate relapses in autoimmune diseases as well as alleviating them. Bone Marrow Transplantation (2001) 28, 1151–1153. Keywords: allogeneic BMT; chronic GVHD; Graves’ disease; HLA

Autoimmune diseases are thought to be due to defects at the stem cell level, as demonstrated in mouse models.1 Several pre-existing autoimmune diseases have been shown to be cured following allogeneic BMT, which was used to treat a concurrent hematological malignancy or therapyrelated marrow aplasia.2 Conversely, some autoimmune diseases or phenomena have been found to develop after allogeneic BMT. Two mechanisms are known to be involved in this process; these include autoimmunity adopted from the donor, the so-called ‘adoptive autoimmunity’, and mechanisms related to chronic GVHD.3 Here, we describe a patient with CML whose pre-existing Graves’ disease (GD) initially remitted after BMT, but relapsed floridly 18 months after allogeneic BMT. We also discuss the underlying pathogenesis and its clinical impliCorrespondence: Dr J-H Liu, Division of Medical Oncology, Taipei Veterans General Hospital and Yang-Ming University, No. 201, Shih-Pai Road, Sec. 2, Taipei 112, Taiwan, ROC Received 18 December 2000; accepted 2 September 2001

cations. This is the first case reported with pre-existing GD, relapsing after BMT involving lymphocytes most likely derived from the donor. Case report A 24-year-old woman was referred to Taipei Veterans General Hospital in July 1993 with CML and cytogenetic evidence of the Ph chromosome [46, XX, t(9; 22)] in bone marrow cells. She underwent allogeneic BMT in 1994. The BMT donor was her father who was HLA-haploidentical with one DR locus incompatible. However, the mixed lymphocyte culture (MLC) was non-reactive. In detail, the HLA types were A2, A11, Bw46, Bw60, DR8, DR11, DQ1, DQ7, DR52; and A2, A11, Bw46, Bw60, DR8, DR12, DQ1, DQ7,v DR52, for patient and donor, respectively. One month prior to BMT in March 1994, she was coincidentally found to have hyperthyroidism with symptoms of palpitations and heat intolerance and elevated thyroid function by radioimmunoassay: toal serum thyroxine (TT4), 214 nmol/l (reference range, 77 to 155 nmol/l); thyroidstimulating hormone (TSH), 0.02 mU/ml (reference range, 0.4 to 3.1 mU/l); and free thyroxine (FT4), 43 pmol /l (reference range, 9 to 26 pmol/l) (Figure 1). Meanwhile, thyroid sonography revealed a diffusely enlarged gland without nodules. GD was thus confirmed and the patient received anti-thyroid therapy with propylthiouracil (PTU). Tracing her family history, we found a hereditary clustering of GD. Two of her aunts had undergone thyroidectomy for GD in their youth. In April 1994, the patient received a marrow graft from her father with preconditioning regimen of BU/CY. Standard CsA and short-course MTX were used to prevent acute GVHD. A total of 2.9 × 108 per kg unmanipulated nucleated marrow cells were infused. PTU was temporally stopped the day after BMT but reintroduced 1 week after BMT due to persistent hyperthyroidism with a FT4 of 3.73 ng/dl. Acute GVHD grade II developed 2 weeks after BMT, as manifested by generalized skin rash, jaundice and diarrhea; eventually it was controlled using high-dose prednisolone. During the follow-up period, the bone marrow cell karyotype had completely shifted to that of the donor (46,XY) as early as 2 months after BMT. The steroids originally used to control acute GVHD were completely tapered 3

Relapse of Graves’ disease after BMT L-T Hsiao et al

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had signs of thyroid disorder either before BMT or for the 7-year follow-up period, and retrospective analysis of the donor’s serum stored prior to marrow donation did not reveal any detectable thyroid antibodies.

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Figure 1 Chronological activity of Graves’ disease in relation to the administration of immunosuppressants for GVHD. The activity of the patient’s Graves’ disease represented by elevated FT4 remitted after administration of CsA and/or steroids and relapsed after their withdrawal. CsA and steroids were primarily used for GVHD prophylaxis and treatment. (See text for full-length words and reference ranges of FT4, TSH, TRAb, AmiA and ATA; broken line above the figure denotes the period during which azathioprine and low-dose prednisolone were intermittently administered.)

months after BMT. PTU was withdrawn 6 months after BMT in view of a euthyroid status and no detectable thyroid autoantibodies. However, CsA and azathioprine were not discontinued until 12 months after BMT because of limited chronic GVHD manifested by mucosa scaling and dry eyes. Relapse of the GD and chronic GVHD occurred 18 months after BMT. GD relapse manifested by palpitations and hand tremors. Thyroid function studies revealed a high FT4 of 2.79 ng/dl and a depressed TSH of 0.05 ␮IU/ml. Serum anti-thyrotropin receptor antibody (TRAb) determined by a competitive 125I-thyrotropin inhibition binding assay was positive with a titer of 38 U/l (reference range, ⬍10 U/l); serum anti-microsomal antibody (AmiA) and anti-thyroglobulin antibodies (ATA) determined by semi-quantitative agglutination tests (SERODIA-AMC and SERODIA-ATG) were strongly positive with titers of ⬎1:25600 (reference range, ⬍1:100) and of 1:25600 (reference range, ⬍1:100), respectively. She then resumed PTU therapy but the disease was poorly controlled (Figure 1). During the same period, the symptoms of chronic GVHD were relieved by intermittent low-dose prednisolone (0.2 to 0.4 mg/kg) and/or azathioprine. In November 1998 (55 months after BMT), she experienced nephrotic syndrome, as manifested by profound bilateral edema of the lower legs and 8.51 g of protein in a 24-h urine collection. The proteinuria responded to relatively high-dose prednisolone (1 mg/kg) and was reduced to less than 1 g daily after 2 weeks of therapy. Coincidentally with the disappearance of the proteinuria, the hyperthyroidism remitted. Notably, the patient still maintained a complete donor karyotype in her bone marrow cells and demonstrated no minimal residual disease, as was shown using Southern blotting with a bcr probe. Furthermore, the donor had not Bone Marrow Transplantation

The emergence of GD or an alternative autoimmune thyroiditis (AIT) after allogeneic BMT has rarely been reported. To date, only 10 cases of GD and AIT after allogeneic BMT have been reported in the literature and none had pre-existing GD/AIT.4–6 Complete donor chimerism and no relapses of the underlying hematological disorder were demonstrated in marrow and/or peripheral blood cells in all 10 of the cases, as well as in our case, when GD/AIT emerged. The so-called ‘adoptive autoimmunity’ that transmitted autoreactive lymphocytes from the donor was thought to mediate this process. However, most of the evidence for ‘adoptive autoimmunity’ comes from the fact that donors had pre-existing thyroid autoantibodies or that donors developed GD/AIT at similar times. However, this is not the case in our patient. The possibility of ‘adoptive autoimmunity’ in mediating post-BMT relapse of preexisting GD in our case was ostensibly low. As stated above, the residual autoreactive lymphocytes in the patient could reasonably be suggested to play a role in the relapsed GD. A review of the literature regarding clinical outcomes of pre-existing autoimmune diseases showed only three other patients who relapsed or were not cured after allogeneic BMT, including two with rheumatoid arthritis (RA)2,7 and one with psoriasis.2 Our patient is the first reported case with pre-existing GD which relapsed after allogeneic BMT. Taking all the four cases together, a latent period of at least 1 to 2 years occurred between BMT and relapse. The relapse of our case occurred in the absence of residual bone marrow cells of recipient type, and the relapses of the other three patients occurred in the presence of donor chimerism of bone marrow or peripheral blood cells, evident by DNA typing. The autoimmunity was thus most likely to have been raised by the donor lymphocytes. The intervals between BMT and the relapses in these cases were compatible with that required to allow T cell function and antibody responsiveness to occur after allogeneic BMT.8,9 The possibility of a role played by the recipient’s residual autoreactive lymphocytes was low. These would have had to survive a long latent period in the presence of complete donor chimerism and, in our case, GVHD. It is therefore reasonable to implicate graft-mediated autoimmunity in the relapse of pre-existing autoimmune disease, in our case the autoimmune disease representing an alternative manifestation of GVHD. Fittingly, the nephrotic syndrome in our patient responded well to steroid therapy, which might also have been a manifestation of chronic GVHD as already reported in more than 10 cases.10 Moreover, the clinical course of our patient’s GD relapsing after withdrawal of immunosuppressants but remitting after the reintroduction of adequate immunosuppression might also support a diagnosis of chronic GVHD as opposed to a poor response to conventional anti-thyroid therapy. As discussed above, the autoreactive lymphocytes which

Relapse of Graves’ disease after BMT L-T Hsiao et al

dominate late relapse of autoimmune disease were hypothesized to originate from the donor. Under such circumstances, it is interesting to speculate how the autoreactive lymphocytes of donor origin are ‘primed’ to undergo the autoimmune process, as can those of recipient origin, prior to BMT. In view of the multi-factorial pathogenesis for de novo autoimmune disease, the similar genetic predisposition between recipient and donor might also play a role in the post-BMT setting. The link between susceptibility to autoimmune disease and human leukocyte antigens (HLA) has been known for more than 20 years.11 HLA-associated autoimmune diseases occur when autoreactive T cell clones escape from negative selection of the thymus when some HLA molecules have high binding affinity with selfpeptides.11 Different HLA genotypes have also been implicated in GD among different human populations. For example, the Bw46 allele was associated with GD among the Chinese, DR3 among Caucasians, and Bw35 among Japanese.12 In addition, more than 40% of patients with thyroid disease have a family history, although specific genetic factors have not been clearly defined. In our case and the case reported from Japan with post-BMT GD or AIT, the donor and recipient pairs shared the same susceptible alleles, Bw46 and Bw35, respectively. This might lead to the hypothesis that after BMT T cell clones autoreactive to thyroid tissues which were probably damaged during BMT developed easily by either escaping from the thymic negative selection or by having high binding affinity to the selfpeptides. An RA-susceptible HLA-allele shared with the donor was also reported in one of the two aforementioned patients who had a relapse of RA after BMT.7 The results of our case study have suggested mechanisms whereby chronic GVHD may mediate post-BMT relapse of pre-existing autoimmune disease. It might also forewarn for relapse of pre-existing autoimmune disease after allogeneic BMT especially when a recipient shares an associated HLA-allele with his donor. Measures to prevent relapse of autoimmune disease are required under such a circumstance.

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