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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4133-4137
Copyright © 2005 by The Endocrine Society

BRIEF REPORT

Long-Term Follow-Up of 106 Multiple Sclerosis Patients Undergoing Interferon-ß 1a or 1b Therapy: Predictive Factors of Thyroid Disease Development and Duration

N. Caraccio, A. Dardano, F. Manfredonia, L. Manca, L. Pasquali, A. Iudice, L. Murri, E. Ferrannini and F. Monzani

Departments of Internal Medicine (N.C., A.D., E.F., F.Mo.) and Neuroscience (F.Ma., L.Ma., L.P., A.I., L.Mu.), University of Pisa, 56126 Pisa, Italy

Address all correspondence and requests for reprints to: Fabio Monzani, M.D., Department of Internal Medicine, University of Pisa, via Roma 67, 56126 Pisa, Italy. E-mail: fmonzani{at}med.unipi.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Conflicting data have been reported on the association between interferon (IFN)-ß therapy of multiple sclerosis (MS) patients and thyroid disease development.

Aims: The goals of this study are as follows: to assess the actual occurrence of thyroid dysfunction and autoimmunity during long-term IFN-ß therapy; to establish the possible presence of predictive factors for thyroid dysfunction development and duration; and to suggest an effective follow-up protocol for patients receiving long-term IFN-ß therapy.

Study Protocol: A total of 106 MS patients (76 women) underwent IFN-ß 1a or 1b therapy for up to 84 months (median, 42 months). Thyroid function and autoimmunity were assessed at baseline and every 3–6 months throughout the treatment course.

Results: Baseline thyroid autoimmunity was detected in 8.5% of patients and hypothyroidism in 2.8%. Thyroid dysfunction (80% hypothyroidism, 92% subclinical, 56% transient) developed in 24% (68% with autoimmunity) of patients and autoimmunity in 22.7% (45.5% with dysfunction), without significant differences between the two cytokines; 68% of dysfunctions occurred within the first year. Autoimmunity emerged as the only predictive factor for dysfunction development (relative risk, 8.9), whereas sustained disease was significantly associated with male gender (P < 0.003).

Conclusions: Both incident thyroid autoimmunity and dysfunction frequently occur in MS patients during IFN-ß therapy, particularly within the first year of treatment. Thyroid dysfunction is generally subclinical and transient in over than half of cases; preexisting or incident autoimmunity emerged as the only significant predictive factor for thyroid dysfunction development. Thyroid function and autoimmunity assessment is mandatory within the first year of IFN-ß therapy; thereafter, serum TSH measurement only in patients with thyroid disease could be sufficient.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
INTERFERON-ß (IFN-ß) IS effectively used for the treatment of patients with multiple sclerosis (MS) (1, 2, 3, 4). Thyroid dysfunction has been reported in patients treated with both IFN-ß 1b (a modified not glycosylated recombinant molecule) and 1a (a natural-sequence recombinant cytokine), especially in those with preexisting autoimmunity (5, 6). In a small group of MS patients treated for up to 3 yr, incident thyroid disease developed only during the first year of IFN-ß therapy (7), although sporadic cases of late onset of dysfunction have been reported subsequently (8, 9).

Aims of the present study, performed in a large cohort of MS patients followed up to 7 yr, were as follows: 1) to assess the actual incidence of thyroid dysfunction and autoimmunity during IFN-ß 1a or 1b therapy; 2) to verify whether incident thyroid disease is or is not an early phenomenon; 3) to possibly elucidate factors predicting thyroid disease development and duration; and 4) to suggest an effective follow-up protocol.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
We studied 106 patients (76 females; mean age, 36.5 ± 9.2 yr) affected by relapsing-remitting MS (10). Inclusion criteria were as follows: 1) patients with at least two acute exacerbations in the previous 2 yr but clinically stable; 2) off corticosteroid treatment for at least 30 d and off immunosuppressant therapy for at least 6 months; and 3) a rating score on the Expanded Disability Status Scale (11) ranging from 1 to 3.5. The local ethical committee approved the study protocol; all patients gave written informed consent.

Fifty-seven patients (42 women; mean age, 35.5 ± 9.3 yr) received IFN-ß 1a treatment, whereas 49 (34 women; mean age, 37.4 ± 9.2 yr) received IFN-ß 1b. IFN-ß 1a (Avonex; Biogen, Cambridge, MA) was administered im weekly (6 x 106 IU), whereas IFN-ß 1b (Betaferon; Schering, Berlin, Germany) was given sc on alternative days (8 x 106 IU). Serum TSH, free T4 (FT4), free T3 (FT3), anti-thyroglobulin antibody (Tg-Ab), anti-thyroid peroxidase antibody (TPO-Ab), and anti-TSH receptor antibody (TR-Ab) levels were assessed at baseline and during IFN-ß therapy (every 3 months up to 1 yr and every 6 months thereafter). Patients developing hyperthyroidism were submitted to technetium-99m (Tc99m) thyroid scan.

Thyroid dysfunction was defined as follows: 1) overt hyperthyroidism, TSH less than 0.30 mIU/liter, FT4 more than 15.0 pg/ml, and/or FT3 more than 5.6 pg/ml; 2) subclinical hyperthyroidism, TSH less than 0.30 mIU/liter and free thyroid hormones within the normal range; 3) overt hypothyroidism, TSH more than 3.6 mIU/liter, FT4 less than 5.6 pg/ml, and/or FT3 less than 2.1 pg/ml; and 4) subclinical hypothyroidism, TSH more than 3.6 mIU/liter and free thyroid hormones within the normal range. FT4, FT3, TPO-Ab, and TR-Ab levels were measured by specific RIAs (DiaSorin, Saluggia, Italy), TgAb levels by specific immunoradiometric assay (MP Biomedicals, Asse-Relegem, Belgium), and TSH by an ultrasensitive immunoradiometric method (Incstar, Stillwater, MN). The assay sensitivity was 0.4 and 0.05 pg/ml for FT4 and FT3, respectively, and 0.009 mIU/liter for TSH. Normal ranges (from 400 blood donors) were as follows: FT4, 5.6–15.0 pg/ml (7.2–19.3 pmol/liter); FT3, 2.1–5.6 pg/ml (3.2–8.6 pmol/liter); TSH, 0.3–3.6 mIU/liter; TPO-Ab, less than 10 IU/ml; Tg-Ab less than 50 IU/ml; and TR-Ab, less than 1 IU/ml.

Mean values and percentages were compared by Mann-Whitney U test, Kruskal-Wallis test, and {chi}2 test as appropriate. The relative risk of developing thyroid dysfunction has been also estimated for the following parameters: sex, age, and baseline or incident autoimmunity. Unless otherwise stated, data are reported as mean ± SD. Statistical significance was assigned for P < 0.05. SPSS for Windows XP (SPSS, Chicago, IL) was used as statistical software.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
MS patients received continuous IFN-ß 1a or 1b therapy for up to 84 months (median, 42; range, 12–84); the two treatment groups were comparable for both patients’ gender and age, whereas the median follow-up was significantly longer (P = 0.0002), with IFN-ß 1b longer than 1a (54 and 30 months, respectively). At baseline, the prevalence of thyroid autoimmunity was 8.5%, without significant difference between IFN-ß 1a and 1b treatment groups (7.0 and 10.2%, respectively); three patients (2.8%) suffered from subclinical hypothyroidism, one with positive TPO-Ab titer (Fig. 1Go).



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  		FIG. 1. Demographic and clinical features of the whole cohort of MS patients at baseline and throughout the IFN-ß (1a and 1b) treatment course. sHT, Subclinical hypothyroidism; M, male; F, female.

 
Thyroid dysfunction developed in 25 of 103 patients (24%, 21 women), without significant difference between IFN-ß 1a and 1b treatment groups (22 and 27%, respectively). Hypothyroidism developed in nine patients (19%) receiving IFN-ß 1b (eight subclinical, six with permanent dysfunction) and in 11 (20%) receiving IFN-ß 1a (all subclinical, five with permanent dysfunction). Hyperthyroidism, always transient, developed in five patients (4.9%, four subclinical), and only one (subclinical) was treated with IFN-ß 1a; all of these patients had a reduced or absent radioactive uptake at Tc99m scintiscan (data not shown). Moreover, three of them showed a biphasic thyroid hormone pattern with transient hyperthyroidism, followed by sustained hypothyroidism. Overall, incident thyroid dysfunction was transient in 14 of 25 cases (56%) and was generally (92%) subclinical. It was never necessary to stop IFN treatment: ß-blocker therapy was successfully given (1 month) to the patient with overt hyperthyroidism, and permanent hypothyroidism was effectively treated by levothyroxine replacement.

Thyroid autoimmunity developed in 22 of 97 patients (22.7%), without significant difference between IFN-ß 1a and 1b treatment groups (20.8 and 25%, respectively) (Fig. 1Go). Ten patients developed positive serum Tg-Ab titer, nine TPO-Ab, two both, and one TR-Ab (IFN-ß 1b). Incident autoimmunity was transient in 13 of 22 patients (59.1%), with no significant difference between IFN-ß 1a and 1b treatment groups (54.5 and 63.6%, respectively). Twelve patients (54.5%) with incident autoimmunity remained euthyroid, although 10 also developed thyroid dysfunction (three hyperthyroidism, seven hypothyroidism). Both thyroid dysfunction and autoimmunity developed mainly within the first year of treatment (68 and 76%, respectively), without significant differences between IFN-ß 1a and 1b (Fig. 2Go). The only case of late onset (60 months) of hyperthyroidism was characterized by the concomitant development of transient (lasting 3 months) positive TR-Ab titer.



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  		FIG. 2. Time course of serum TPO-Ab (A) or Tg-Ab (B) titer in patients developing thyroid dysfunction during IFN-ß (1a and 1b) therapy. Filled circles represent patients with incident hypothyroidism, and open squares represent those with incident hyperthyroidism. Time of onset of incident thyroid dysfunction in the whole cohort of MS patients undergoing IFN-ß (1a and 1b) therapy. Filled bars represent patients developing hyperthyroidism, and hatched bars represent those developing hypothyroidism (C). Time of onset of incident thyroid autoimmunity in the whole cohort of MS patients undergoing IFN-ß (1a and 1b) therapy. Filled bars represent patients with positive serum Tg-Ab titer, and hatched bars represent those with positive serum TPO-Ab or both TPO-Ab and Tg-Ab (D) titers. The patient who developed transient positive serum TR-Ab titer at 60 months is not reported.

 
No age difference was observed between patients either with or without incident thyroid dysfunction (34.8 ± 8.9 and 37.0 ± 9.3 yr, respectively) or those with transient or permanent disease (34.0 ± 9.6 and 34.5 ± 8.6 yr, respectively). Although not reaching statistical significance, thyroid dysfunction developed more frequently in women than men (28 vs. 15%), in whom, however, sustained disease was more common (P < 0.003).

Overall, incident dysfunction was associated with thyroid autoimmunity in 17 of 25 patients: seven with baseline autoimmunity (three receiving IFN-ß 1a) and 10 with incident autoimmunity (five receiving IFN-ß 1a), which developed earlier (median, 9 months; range, 3–12) than dysfunction (median, 18 months; range, 3–66). Both baseline and incident autoimmunity emerged as significant risk factors for thyroid dysfunction development (P = 0.001, risk ratio of 8.9, 95% confidence interval of 3.2–24.4; and P = 0.003, risk ratio of 5.4; 95% confidence interval of 1.8–16.4, respectively). Moreover, incident dysfunction was 2-fold prevalent among patients with serum TPO-Ab level more than 50 and/or Tg-Ab level more than 100 U/liter (72.2%) than in those with lower antibody titer (31%; P < 0.05). Thyroid autoimmunity was 2-fold frequent in patients with sustained hypothyroidism than in those with transient hypothyroidism (82 vs. 44%, respectively; P = 0.07), and incident autoantibody titers remained positive in 85% of hypothyroid patients but never in hyperthyroid patients (P = 0.03) (Fig. 2Go).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The association between MS and thyroid autoimmunity varies widely from 4–22% (5). In the current study, baseline thyroid autoimmunity was detected in 8.5% of patients, whereas 2.8% suffered from subclinical hypothyroidism. The prevalence of positive anti-thyroid autoantibody titer in healthy subjects varies from 1–30%, increasing with age; similarly, the prevalence of subclinical hypothyroidism reaches 21% in elderly women (12, 13). Therefore, according to a recent report (14), our series of MS patients shows a prevalence of thyroid autoimmunity and dysfunction comparable with the general population. The overall described prevalence of the association between IFN-ß therapy and incident thyroid disease is almost 8%, but it varies widely from 0–34% (5, 15, 16, 17, 18, 19, 20). Differences in study protocol, duration of follow-up, and data presentation may account, at least in part, for the high variability of prevalence, time of onset, duration, and severity of IFN-associated thyroid disease (5, 21, 22).

The current study is the first performed in a large cohort of MS patients in whom thyroid function and autoimmunity were regularly assessed during long-term IFN-ß therapy (up to 7 yr). Thyroid autoimmunity and dysfunction both developed in almost one fourth of MS patients, regardless of the type of IFN-ß given. Although sporadic cases of late onset of dysfunction have been described (8, 9), we reported previously, in a small group of MS patients followed up to 3 yr, that thyroid dysfunction occurred always within the first year of IFN treatment (7). In the current study, one third of patients showed a late onset of thyroid dysfunction; incident hypothyroidism was 4-fold more frequent than hyperthyroidism, and both conditions were generally subclinical. Hyperthyroidism was characterized by early transient thyrotoxicosis, followed by hypothyroidism in 60% of cases and always by low/absent Tc99m uptake at scintiscan, thus suggesting destructive thyroiditis rather than thyroid cell hyperfunction (17, 23, 24). Accordingly, four patients showed also transient positive anti-thyroid antibody titers, as reported in association with other clinical conditions, sharing a common pattern of damage to the thyroid gland (25, 26).

Incident hypothyroidism is reported twice as frequent as thyrotoxicosis and transient in almost half of cases, with sustained disease being found mainly in patients with preexisting autoimmunity (5, 27). Similarly, in the current study, sustained hypothyroidism accounted for 55% of cases and was more likely associated with thyroid autoimmunity than the transient form, in which, however, dysfunction occasionally takes up to several months to resolve. Therefore, replacement levothyroxine therapy should be given only to patients with symptomatic hypothyroidism, and periodic withdrawal of treatment and evaluation of thyroid function while off therapy should be performed to verify the possible recovery of thyroid function. It should be not overlooked that thyroid dysfunction could improve after stopping the drug, although IFN-ß is generally given chronically.

Preexisting but not incident autoimmunity has been reported as a significant risk factor for thyroid dysfunction development during IFN-ß therapy (5, 28). At partial variance, our data show that both baseline and incident autoimmunity act as significant risk factors for thyroid dysfunction development, with serum anti-thyroid antibody titer ensuing as an additional predictive feature. Although the prevalence of incident thyroid dysfunction was almost double in women than in men, neither age nor female gender emerged as significant risk factors. Moreover, men were at high risk of developing permanent thyroid dysfunction. These data partly disagree with most previous studies in which women are reported to be three times more susceptible to IFN-induced thyroid disorders than men, although, in some reports, gender did not emerge as a significant risk factor (5, 22, 29).

In conclusion, both incident thyroid autoimmunity and dysfunction frequently occur in MS patients during IFN-ß (1a and 1b) therapy, particularly within the first year of treatment. However, thyroid dysfunction is generally subclinical and transient in more than half of cases, with sustained disease being more likely associated with positive serum anti-thyroid antibody titer and male gender. Although incident thyroid dysfunction is more frequently observed in women, preexisting or incident thyroid autoimmunity (particularly at high titer) emerged as the only significant predictive factor for thyroid dysfunction development. Therefore, we suggest to assess both serum TSH and anti-thyroid antibody levels every 3 months in the first year of IFN therapy, whereas TSH measurement every 6 to 12 months only in patients with thyroid dysfunction or autoimmunity could be sufficient during the following treatment course.


   Acknowledgments
 
We thank Dr. G. Meucci, Dr. F. Lombardo, and Dr. C. Davino for their valuable assistance in the follow-up of patients.


   Footnotes
 
The study was partly supported by grants from Ministero Istruzione, Università e Ricerca Scientifica (Rome, Italy).

First Published Online April 5, 2005

Abbreviations: FT3, Free T3; FT4, free T4; IFN, interferon; MS, multiple sclerosis; Tc99m, technetium-99m; Tg-Ab, anti-thyroglobulin antibody; TPO-Ab, anti-thyroid peroxidase antibody; TR-Ab, anti-TSH receptor antibody.

Received November 29, 2004.

Accepted March 29, 2005.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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