¹Department of Internal Medicine, The Catholic University of Korea, College of Medicine, Seoul, Korea

²Hematopoietic Stem Cell Transplantation Center, The Catholic University of Korea, College of Medicine, Seoul, Korea

Correspondence to: Dr M-I Kang, Division of Endocrinology and Metabolism, Department of Internal Medicine, St Mary's Hospital, The Catholic University of Korea, 62 Yoido-dong Youngdeungpo-Gu, Seoul 150-010, Korea

Autoimmune diseases can be transmitted and eliminated by bone marrow transplantation (BMT). There have been several cases of autoimmune thyroid disease (AITD) occurring after BMT, but AITD remission has been rarely reported. We present four cases in which the remission or transfer of AITD occurred after an allogeneic BMT. Two patients with severe aplastic anemia (SAA) showed evidence of remission of Hashimoto's thyroiditis which they had before allogeneic BMT. One patient with SAA, which developed during treatment with propylthiouracil for Graves' disease, underwent allogeneic BMT and showed evidence of Graves' disease remission following BMT. In one patient, new AITD occurred after an allogeneic BMT from an HLA-matched sibling who already had AITD. These cases support the evidence that the immune system is newly reconstituted after BMT, and severe autoimmune disease can be an indication for BMT. To fully understand the real changes in autoimmune status after BMT, long-term prospective studies are necessary. Bone Marrow Transplantation (2001) 28, 63-66.

BMT; autoimmune thyroid disease; adoptive autoimmunity

BMT can both transmit and climinate autoimmune diseases. The transfer of autoimmune thyroid disease (AITD) from donor to recipient without any autoimmune phenomena can occur by the mechanism of adoptive autoimmunity.¹ Conversely, there may be a negative conversion of previously identified autoimmune disease or markers in a recipient with an underlying hematologic disease after an allogeneic BMT. Remission of rheumatoid arthritis or psoriasis after BMT has been reported.^2,3 However, AITD remission following BMT has not been reported, except for one case of remission of Graves' disease.⁴ We performed BMTs on over 1200 cases in a single center and noted four cases of BMT recipients who had a remission of, or developed a new AITD after allogeneic BMT, which we report here.

Case report

Case 1

An 18-year-old woman was diagnosed with SAA in April 1999. She also was suffering from Hashimoto's thyroiditis, allergic rhinitis and conjunctivitis. Prior to the BMT, she had a firm goiter approximately 40 g in weight, a high titer of anti-thyroglobulin Ab (anti-TG, 1:160) and anti-thyroid peroxidase Ab (anti-TPO, 1:1600). Thyroid function test results indicated an euthyroid state (TT3 113 ng/dl, TT4 8.7 g/dl, TSH 0.41 mU/l) and the serum IgE level was 156 IU/ml (normal: 0-380 IU/ml). She underwent an allogeneic BMT from her sibling donor who was HLA-identical and had no AITD in June 1999. Pre-BMT conditioning consisted of cyclophosphamide (2120 mg/day, for 5 days), procarbazine (350 mg/day, for 6 days) and anti-lymphocyte globulin (500 mg/day, for 3 days). Cyclosporin A and methotrexate were given for graft-versus-host disease (GVHD) prophylaxis. There was successful, permanent engraftment of all cell lines and no GVHD developed.

The recipient was free of thyroid autoantibodies in the euthyroid state after examination 3 months and 1 year after the BMT, respectively. Symptoms and signs of allergic rhinitis and conjunctivitis also disappeared. She is currently free of her underlying hematologic disease and allergic rhinitis, in remission of AITD.

Case 2

A 21-year-old woman was diagnosed as having SAA in November 1997. She also had high titers of thyroid autoantibodies with other autoimmune markers such as FANA, anti-ds DNA Ab, anti-cardiolipin Ab, and lupus anticoagulant (Table 1). However, she did not meet the criteria for SLE, and was thus diagnosed as SAA with an autoimmune background. Thyroid function tests showed mild subclinical hypothyroidism (TT3 103 ng/dl, TT4 5.31 g/dl, TSH 4.63 mU/l). In 1998, she underwent an allogeneic BMT from an HLA-identical sibling who had no AITD. She was conditioned with high-dose cyclophosphamide (3125 mg/day, for 4 days), procarbazine (390 mg/day, for 6 days) and anti-thymocyte globulin (78 mg/day, for 3 days). GVHD prophylaxis consisted of cyclosporin A and methotrexate. There was no evidence of either acute or chronic GVHD.

Two months after BMT, titers of the autoantibodies decreased and thyroid autoantibodies, FANA, and anti-ds DNA Ab became negative in the recipient 9 months after BMT. She is currently in hematologic remission without any autoimmune phenomena.

Case 3

A 23-year-old woman was diagnosed with SAA in December 1988 and treated with anti-lymphocyte globulin (ALG) therapy. Allogeneic BMT was performed from a HLA-matched sibling donor in April 1997. Pre-BMT conditioning consisted of cyclophosphamide (3400 mg/day, for 4 days), procarbazine (425 mg/day, for 6 days) and anti-thymocyte globulin (85 mg/day, for 3 days). Cyclosporin A and methotrexate were given for GVHD prophylaxis. At day 14 post BMT, mild (grade I) skin GVHD developed, but resolved after 4 days of pulsed steroid therapy. Bone marrow engraftment was confirmed on marrow aspiration at day +21. Three months after BMT, results of RFLP (restriction fragment length polymorphism) showed complete donor chimerism.

Before BMT, the recipient had no evidence of AITD with no thyroid autoantibodies, but the donor was suffering from Hashimoto's thyroiditis. In the donor, thyroid function tests were euthyroid, but high titers of thyroid autoantibodies were present (anti-TPO 1:102400, anti-TG 1:80). One year after the BMT, anti-TPO Ab and anti-TG Ab (anti-TPO 1:1600, anti-TG 1:40) appeared with elevation of TSH (TT3 122 ng/dl, TT4 9.25 g/dl, TSH 9.25 mU/l) in the recipient. She is currently being followed up regarding her thyroid function while in hematologic remission.

Case 4

A 24-year-old man had been diagnosed with Graves' disease in 1996 and was treated with propylthiouracil for 3 years. In 1999, a pancytopenia was detected and a BM biopsy revealed SAA, which had not recovered after a 6-month observation period. An allogeneic BMT was performed from a HLA-identical sibling donor in November 1999. He was conditioned with cyclophosphamide (2400 mg/day, for 5 days), procarbazine (400 mg/day, for 6 days) and anti-thymocyte globulin (75 mg/day, for 3 days). Cyclosporin A and methotrexate were given for GVHD prophylaxis. One month after BMT, complete donor chimerism was documented by RFLP. Mild (grade II) gut GVHD developed 35 days post BMT, but resolved after short-term treatment with methylprednisolone.

Immediately before the transplant, he had mild exophthalmos and was in a state of subclinical hyperthyroidism. (TT3 155 ng/dl, TT4 9.34 g/dl, TSH 0.01 mU/l, TBII 8.1%). Two months after the BMT, thyroid function tests showed no evidence of hyperthyroidism despite no anti-thyroid treatment being administered during the pre- and post-BMT period. He is currently being followed up and to date is in good condition.

Discussion

In the four cases reviewed here, not only was remission of a pre-existing AITD observed in a recipient, but it was also demonstrated that transfer of new thyroid diseases or autoantibodies is possible following an allogeneic BMT (Table 2). In one patient, subclinical hypothyroidism developed with the emergence of new thyroid autoantibodies after BMT. Hypothyroidism is one of the most common endocrine disorders that occurs after BMT. There are possible explanations for this. Radiation to the head and neck is a well-known cause of hypothyroidism and more profound hypothyroidism develops with increasing radiation doses.⁵ However, hypothyroidism can occur without total body irradiation (TBI), and the patient in case 3 who developed autoimmune thyroiditis following BMT had not received TBI. Thus, other etiologies for post-BMT hypothyroidism may play a role. One is the development of an autoimmune process in which adoptive transfer of pathogenic lymphoid clones from the donor may take place. The pathogenesis of Hashimoto's thyroiditis (a form of chronic autoimmune thyroiditis) is complex. The mechanism underlying the initial activation of T cells is not clear, but direct killing of thyroid cells by cytotoxic T cells is believed to be the main mechanism responsible for the hypothyroidism secondary to Hashimoto's thyroiditis.⁶ It is reported that even low numbers of lymphocytes are capable of transferring autoimmune disorders following allogeneic BMT⁷ and there have been several reports on the adoptive transfer of autoimmune thyroid diseases following allogeneic BMT.^{7,8,9,10,11,12} However, such adoptive transfer is a minor component of the many etiologies. Most cases of post-BMT autoimmunity are known to result from an immunologic dysregulation ('immunologic chaos').¹³ In case 3, adoptive autoimmunity is more probable as a possible mechanism in the development of new AITD rather than 'immunologic chaos' because the donor had already had the same kind of AITD and thyroid autoantibodies that later developed in the recipient. It has been suggested that chronic GVHD is related to post-BMT autoimmune disease, but the patient in case 3 had only a mild degree of acute GVHD which disappeared rapidly after steroid pulse therapy. Chronic GVHD has clinical and pathogenic characteristics similar to autoimmune disease such as Sjogren's syndrome and scleroderma. It is suggested that thymic damage induced by acute GVHD may contribute to both the immunodeficiency and autoimmunity characterising chronic GVHD.¹³

There have been several cases where AITD developed after BMT.^{7,8,9,10,11,12} In particular, post-transplant adoptive hyperthyroidism is rarer than adoptive hypothyroidism, and in total, eight case reports have been published including the latest one by Berisso et al.¹² However, to our knowledge, no cases have been described in which a pre-existing AITD disappeared following BMT with the exception of one case of Graves' disease which remitted.⁴ Remission of previous, clinically unidentified AITDs may have occurred more frequently than was found in this study. Moreover, this could be due partly to inattention to subtle changes in thyroid autoimmunity following BMT. BMT can cure patients with autoimmune diseases, as is clear from many animal models and human case reports.⁷ This is because both the hematologic and immune systems are newly reconstituted after a BMT. In this context, if the basic defect of an autoimmune disease is related to abnormal stem cells, it may be cured by a BMT. If the primary defect is an aberrant immune reaction to a self antigen, then tolerance may be acquired after a BMT.⁸ Because the pathogenesis of AITD begins with the activation of self-reactive T helper lymphocytes, in particular thyroid antigen specificity, the remission of AITD in our patients appears to be related to an immune tolerance which developed after the BMT. Replacement of stem cells, T cells, and B cells responsible for AITD by means of allogeneic BMT could ameliorate previous aberrant organ-specific immune reactions with the introduction of immune tolerance. In addition, the disappearance of symptoms and signs of allergic rhinitis and conjunctivitis were also observed in case 1. In case 2, the disappearance of not only the AITD but also the autoimmune markers including anti-dsDNA Ab, anti-cardiolipin Ab and lupus anticoagulant was observed. These findings further support the hypothesis that autoimmune diseases can be cured following BMT by the replacement of the lymphohematopoietic system. The contribution of high-dose cyclophosphamide therapy to the long-term remission of AITD seems small.

In conclusion, although AITDs are not lethal and do not usually necessitate BMT, our cases further support the use of BMT for the treatment of severe autoimmune diseases.

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Table 1 The change in the level of autoimmune markers in case 2

Table 2 Summary of the four cases