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Does Interferon-B Therapy Induce Thyroid Autoimmune Phenomena? M. C. Pagliacci, G. Pelicci, M. Schippa, A. M. Liberati and I. Nicoletti Istituto di Clinica Medica I, Universita di Perugia, Perugia, Italy

Table 1 Thyroid function parameters (mean±SE) in patients on IFN-p.

Thyroid function abnormalities have been reported Basal During IFN1 After IFN2 during IFN-a treatment and the detection of anti-thyroid autoantibodies in patients so treated would seem to indicate an autoimmune TT4 (ng/dl) 7.5 + 0.5 8.5 ±0.4 7.8 ±0.9 pathogenesis (Fentiman, Thomas, Balkwill, Rubens and Hayward 0.6 ±0.1 TT3 (ng/ml) 0.9 ±0.1* 1.0±0.1* 1985; Burman, Tottermann, Oberg and Karlsson 1986). The expres- FT4 (pg/ml) 8.6 + 0.4 9.6 + 0.6 8.8 ±0.4 sion of Class II MHC Antigens (HLA-DR) has been demonstrated in 3.7 + 0.2 FT3 (pg/ml) 4.3 + 0.2* 4.6 + 0.3* thyroid glands affected by Graves' Disease and Hashimoto's thyroidi1.5 ±0.2 TSH (uU/ml) 1.6 ±0.2 1.5 ±0.2 tis (Hanafusa, Chiovato, Doniach, Pujol-Borrell, Russel and Bottazzo RT3 (ng/dl) 15.2 ±2.0 19.6 ±3.3 17.4 ±2.7 1983). Since IFN-y is able to induce the aberrant expression of HLA- TBG (ug/ml) 27.1 ±2.6 25.4 ±1.7 25.3 ±2.7 DR antigens on cultured thyroid follicular cells (Iwatani, Iitaka, Gerstein, Row and Volpe 1987; Piccinini, Mackenzie, Platzer and Davies *P < 0.05 vs basal (by Kruskall-Wallis' analysis of the variance) Results at the XII week of IFN (20 patients) 1987) and IFN-a and IFN-p increase the synthesis of both Class I and 2 Class II histocompatibility antigens in vitro and in vivo (Spear, Paul- results 6 weeks after the end of therapy (10 patients) nock, Jordan, Meltzer, Merrit and Borden 1987), it has been hypothesized that autoimmune disorders may be induced by IFN therapy. The aim of this study was to evaluate whether thyroid-specific autoimResults mune disorders may complicate the treatment with IFN-p. None of the patients displayed clinical signs of thyroid dysfunction during the whole period of the investigation. Patients and Methods Thyroid function parameters were analyzed and thyroid-specific autoantibody levels, determined in 20 patients (13 male and 7 female, mean age 59 years range 28 — 73 years) treated with IFNp, 8 for hairy cell leukemia, 10 multiple myeloma, and one each nonHodgkin's lymphoma and chronic myeloid leukemia. Six x 10 IU/sm IFN-P (FRONE, Serono) was infused iv for 7 days alternate weeks for a total of 3 cycles and then continued at the same dose twice weekly for 24 weeks. Thyroid function indexes (TT3, TT4, FT3, FT4, RT3, TSH, TBG, anti-TG and anti-TM autoantibodies) were evaluated in serum samples. Specific radioimmunoassays were used to determinate TT3, TT4, FT3, FT4 and RT3 and an immuno-radiometric assay for TSH (Pagliacci, Pelicci, Francisci, Giammartino, Fedeli, Stagni and Nicoletti 1989). The serum binding capacity of thyroid hormone was evaluated directly by specific RIA measurement of TBG. Anti-thyroid antibodies were detected by both immunofluorescence and RIA methods. The sensitivity of RIA (Biodata, Milan, Italy) was 20 IU/ml for anti-TG and 1.5 IU/ml for anti-TM autoantibodies. All sera that had autoantibody titers < 1:20 in the immunofluorescence assay also had values > 100 IU/ml for anti-TG and 50 IU/ml for antiTM in the RIA. These RIA values were therefore taken as cut-off between negative and positive patients. Blood samples were obtained every six weeks during, and at the end of therapy, for a total of six tests. All patients completed at least the first 3 tests; however, due to progression of the disease or death, only ten patients completed all programmed tests. Kruskall-Wallis' analysis of the variance was used for the statistical evaluation of the data.

Horm.metab.Res.23(1991) 196-197 © Georg Thieme Verlag Stuttgart -New York

Thyroid function indexes (mean + SE values) did not show any major difference at any time during the study (Table 1). TT3 and FT3 serum levels slightly but significantly increased during IFN therapy. The more logical explanation for this datum is the improved clinical and nutritional status induced by the medical treatment. It should be noted that the ten patients who died during the study had the lowest TT3 and FT3 levels before treatment. One patient was positive for anti-TG and anti-TM thyroid autoantibodies at the basal evaluation; IFN therapy provoked no increase in antibody titre in this patient. None of the pretreatment antibody-negative patients developed anti-TM or anti-TG autoantibodies either during, or after completing therapy. Discussion The results of this longitudinal study do not support the proposal that thyroid autoimmune disease is a frequent side effect of IFN-P treatment, but rather indicate that there is little or no relationship between the enhancement of Class II MHC antigens induced on patients' PBMC during IFN-p treatment (Spear et al. 1987) and thyroid autoimmune phenomena. Our results do not confirm the high incidence (15—40%) of thyroid specific autoimmune phenomena reported by others in IFN-treated patients (Fentimam et al. 1985; Burman et al. 1986). Although a number of reasons (sex of examined patients, impact of the malignancy on immune function, time and schedule of treatment) can contribute to explain this discrepancy it is likely that the different IFN preparation we used accounts for the low incidence of thyroid dysfunction in our study.

Received: 24 July 1990

Accepted: 12 Dec. 1990

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Introduction

Does Interferon-B Therapy Induce Thyroid Autoimmune

Phenomena?

Harm. metab. Res. 23 (1991)

197

It should be noted that IFN-y, but not IFN-p (WeetHanafusa, T, L. Chiovato, D. Doniach, R. Pujol-Borrell, R. C. G. Russel, G. F. Bottazzo: Lancet ii: 1111-1115 (1983) man, Volkman, Burman, Gerrard and Fauci 1985) is able to induce abIwatani, Y., M. litaka, H. C. Gerstein, V. V. Row, R. Volpe: J. Clin. Enerrant expression of HLA-DR antigen on cultured thyroid follicular docrinol. Metab. 64:1302-1308 (1987) cells. The thyroid-specific immune phenomena reported in patients Mandelli, F., G. Avvisati, S. Amadori, M. Boccadow, A. Gernone, V. M. treated with natural IFN-a may depend on the additional proteins and Lauta, F. Marmont, M. T. Petrucci, M. Tribalto, M. L. Vegna, F. IFN-y that are detectable in some of these early leukocyte-derived Dammacco, A. Pileri:N. Engl. J. Med. 322:1430-1434 (1990) preparations (Burman et al. 1986; Fentiman et al. 1985). This idea is Padmanabhan, N., F. R. Balkwill, J. G. Bodmer, R. D. Rubens: Br. J. indirectly supported by the finding that patients treated with recombiCancer51:55-60(1985) nant IFN-a (rIFN-a) do not develop thyroid autoimmune complications (Padmanabhan, Balkwill, Bodmer and Rubens 1985; Mandelli, Pagliacci, M. C., G. Pelicci, D. Francisci, C. Giammartino, L. Fedeli, G. Stagni,I.Nicoletti. Endocrinol. Invest. 12:149-153 (1989) Avvisati, Amadori, Boccadoro, Gernone, Lauta, Marmont, Petrucci, Tribalto, Vegna, Dammacco and Pileri 1990) and by the demonstration Piccinini, L. A., W. A. Mackenzie, M. Platzer, T. F. Davies: J. Clin. Endocrinol. Metab. 64:543-548 (1987) that in vitro incubation with rIFN-a does not induce HLA-DR anSpear, G. T, D. M. Paulnock, R. L. Jordan, D. M. Meltzer, J. A. Merrit, tigens on thyroid follicular cells (Burman et al. 1986). E. C.Borden:Clin.Exp. Immunol. 69: 107-115(1987) Weetman, A. P., D. J. Volkman, K. D. Burman, T L. Gerrard, A. S. It would therefore seem that the IFN-P, at the schedFauci:J. Clin. Endocrinol. Metab. 61:817-823 (1985) ule used in our study, is unlikely to give rise to immune side effects and that thyroid specific autoimmune phenomena are a very rare complication of IFN-P therapy. Requests for reprints should be addressed to: Ildo Nicoletti M. D. Istituto di Clinica Medica I Burman, P., T. H. Tottermann, K. Oberg, F. A. Karlsson: J. Clin. EnUniversita di Perugia docrinol. Metab. 63:1086-1090(1986) Policlinico Monteluce Fentiman, I. S., B. S. Thomas, F. R. Balkwill, R. D. Rubens, J. L. Hay- 1-06100 Perugia (Italy) warrf/Lanceti: 1166-1167(1985)

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References