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Endocrine Care |
Clinica Neurologica, Dipartimento di Neuroscienze, Universitá di Torino (L.D., B.F., A.O., E.V.); Divisione di Neurologia, Ospedale di Gallarate (A.G., M.Z.); Divisione di Neurologia, Ospedale di Fidenza (E.M.), I-10126 Torino, Italy
Address all correspondence and requests for reprints to: Luca Durelli, M.D., Clinica Neurologica, Dipartimento di Neuroscienze, Universita’ di Torino, Via Cherasco 15, I-10126 Torino, Italy.
Abstract
Thyroid dysfunction and autoimmunity have been reported during type
I interferon therapy, namely interferon-
for chronic hepatitis or
interferon-ß for multiple sclerosis. To define the frequency of
thyroid dysfunction and autoimmunity during interferon-ß treatment,
156 multiple sclerosis patients were prospectively followed up by 18
centers for 1 yr after starting interferon-ß-1b treatment. Serial
clinical assessments and tests of thyroid and liver function and
antithyroid autoantibodies (all performed by the same centralized
laboratory) were conducted every 3 months. TSH and antithyroid
autoantibodies against human TG or thyroid microsomal antigens were
measured by immunoradiometric methods; free T3 and
T4 were measured by chromatographic assays. Longitudinal
occurrence of thyroid or liver alterations or of autoantibodies was
analyzed with the generalized estimating equations method, correcting
for the correlation of repeated measurements of the same subject over
time. Pretreatment comparison with a control group of 437 healthy blood
donors did not show significant differences in the frequency of thyroid
dysfunction or antithyroid autoantibody positivity. During
interferon-ß treatment, the de novo frequency of
thyroid alteration was 8.3%, that of liver alteration was 37.5%, and
that of antithyroid autoantibody was 4.5%. Generalized estimating
equations analysis demonstrated that the frequency of liver alteration
significantly increased during treatment compared with the baseline
value (odds ratio, 7.03; confidence interval, 2.49–19.9), whereas that
of thyroid alteration or of antithyroid autoantibodies did not. The
frequency of thyroid dysfunction during interferon-ß treatment showed
random, nonsignificant changes over time and, in addition, was not
correlated to antithyroid autoantibody positivity.
THYROID DYSFUNCTION and autoimmunity have
been reported during chronic type I interferon (IFN) therapy, more
often in patients positive for antithyroid (AT) autoantibodies (autoAb)
(1, 2, 3, 4, 5). Most reports describe patients treated with IFN
for chronic hepatitis C, a disease that seems to predispose to
autoimmunity (6, 7). In such patients thyroid dysfunction
or autoimmunity would contraindicate IFN treatment (1, 8).
IFNß is the first approved treatment for multiple sclerosis (MS), an
immune-mediated disease (9), and AT autoAb and thyroid
dysfunctions have been recently reported in MS patients treated with
IFNß (10, 11, 12, 13, 14). Most of those reports advise frequent
thyroid function and autoAb testing during IFNß treatment. In
addition, IFNß is being tested in a randomized clinical trial of
chronic hepatitis patients (15, 16).
To define the frequency of thyroid dysfunction and autoimmunity during IFNß treatment, we conducted a multicenter prospective follow-up of MS patients recruited by 18 Italian centers. To take into account the correlation of repeated measurements of the same subject over time, longitudinal data were analyzed with the generalized estimating equations (GEE) method (17).
Subjects and Methods
Subjects and treatment
One hundred and fifty-six patients (101 women and 55 men) with clinically definite relapsing-remitting MS (18), 2 clinically documented exacerbations during the preceding 2 yr, and no exacerbation (and no corticosteroid treatment) for at least 30 d before entry into the study were prospectively included between February 1996 and March 1997 by 18 MS centers representative of northern, central, and southern Italy. Exclusion criteria included pregnancy, lactation, unwillingness to practice acceptable birth control, major depression or suicidal attempt in medical history, and clinically significant heart, liver, renal, or bone marrow disease. The presence of thyroid disease was not an exclusion criteria. IFNß-1b (Betaferon, Schering AG, Berlin, Germany) was given sc on alternate days at a dose of 8 million IU. Patients were examined twice a month during first month, once a month during second and third months, and thereafter every 3 months or in the event of MS exacerbations or side-effects. Follow-up ranged from 12–15 months. Baseline thyroid function and autoimmunity were compared with those of 437 healthy blood donors (162 women). Their serum samples were prospectively collected by blood banks of the hospitals of the 18 MS centers during the same period of MS patient recruitment. Subjects with clinically overt thyroid dysfunction, goiter, or personal or family history of thyroid disease were excluded from the control sample, which was, therefore, a population of clinically normothyroidal individuals. Informed consent was obtained in all cases.
Laboratory methods
Hematological investigations, repeated at baseline and each planned visit for 1 yr, were all performed in the same laboratory (Laboratorio Baldi e Riberi, Ospedale Maggiore S. Giovanni Battista, Torino, Italy).
Thyroid function evaluation. TSH was measured by a sensitive immunoradiometric method (Biocode, Sclessin, Belgium), using mouse antihuman TSH monoclonal antibody (Ab) as substrate, and mouse [125I]antihuman TSH Ab as tracer. Purified human TSH standard solutions were calibrated against the Medical Research Council 80/558 international standard. Samples from patients or standards and a fixed amount of tracer were added to assay tubes coated with mouse antihuman TSH monoclonal Ab. Unbound Ab was then discarded, and the remaining radioactivity was counted. The TSH concentration in the sample was interpolated from the calibration curve and expressed in milliinternational units (mIU) per liter. The intra- and interassay coefficients of variation for the TSH assay were 3.9–6.2% and 4.2–7.1%, respectively. The limit of detectability was 0.02 mIU/liter. The normal range (as derived from the 95% confidence limits of measurements obtained for healthy normothyroidal individuals) was 0.3–3 mIU/liter.
Free T3 (fT3) and T4 (fT4) were measured by chromatographic assays (Technogenetics, Cassina de Pecchi, Italy). Patient serum samples or negative or positive standards were added to chromatographic columns with Sephadex LH-20. Chromatographic separation on Sephadex produces highly purified hormones, giving the assay more specificity compared with methods where unpurified serum is directly added to the RIA (19, 20). Adsorbed hormones were, then, directly collected into LISO-PHASE chromatographic columns containing anti-fT3 or anti-fT4 rabbit Ab bound to Sepharose CL-4B gel as immunoadsorbent. A fixed amount of [125I]fT3 or [125I]fT4, which was used as radioactive tracer, and a fixed amount of anti-fT3 or anti-fT4 Ab, used as immunoreagents, were added. Antigen-Ab complex was bound to the immunoadsorbent by affinity chromatography; unbound hormones were discarded, and the remaining radioactivity was counted. The sample fT3 or fT4 concentration was interpolated from the calibration curves. Intra- and interassay coefficients of variation for the fT3 method were 3.5–5.8% and 6.5–9.8%, respectively (limit of detectability, 0.3 ng/liter). Intra- and interassay coefficients of variation for the fT4 method were 3.7–6.5% and 5–7.5%, respectively (limit of detectability, 3 ng/dl). The normal range (95% confidence limits of measurements obtained for healthy normothyroidal individuals) for fT3 was 2.2–4.4 ng/liter; that for fT4 was 7–19 ng/dl.
AT autoAb against human TG (TGA) or thyroid microsomal antigens (TMA) were detected by the immunoradiometric method (Biocode, Sclessin, Belgium), using purified human TGA or TMA as substrates, and Staphylococcus aureus [125I]protein A as tracer. A fixed amount of a 1:50 dilution in PBS of patient serum samples or of human TGA or TMA serum standard solutions (calibrated against Medical Research Council human TGA 65/93 or human TMA 66/387 international standards) was added to assay tubes coated with highly purified human TGA or TMA. The sample anti-TGA or anti-TMA autoAb concentration was interpolated from the calibration curves and expressed as international units per ml. Intra- and interassay coefficients of variation for the anti-TGA autoAb method were 3.7–7.2% and 7.2–9.2%, respectively (limit of detectability, 3 IU/ml). Intra- and interassay coefficients of variation for the anti-TMA autoAb method were 4.2–8.1% and 7.9–13.8%, respectively (limit of detectability, 2.5 IU/ml). AT autoAb were considered positive when their level was above 100 IU/ml.
Thyroid function alteration was classified according to the American Thyroid Association guidelines (21, 22): clinically overt hyperthyroidism, undetectable to less than 0.1 mIU/liter TSH, more than 4.4 ng/liter fT3, or more than 19 ng/dl fT4; subclinical hyperthyroidism, undetectable to less than 0.1 mIU/liter TSH and fT3 and fT4 in the normal range without exogenous T4 intake; clinically overt hypothyroidism, TSH above the upper limit of the normal range (3 mIU/liter in our assay) and fT4 below 7 ng/dl; and subclinical hypothyroidism, TSH above the upper limit of the normal range and fT4 in the normal range.
Liver function evaluation included serum bilirubin, hepatic cytolytic
(aspartate and alanine aminotransferases) and cholestatic (
-glutamyl
transpeptidase and alkaline phosphatase) enzymes, and hepatic synthetic
function indicators, such as albumin, fibrinogen, prothrombin time, and
partial thromboplastin time. Markers of viral hepatitis B or C were
tested with immunological sensitive PCR-based assays in patients with
liver function alteration.
Statistical analysis
Baseline comparison with healthy normothyroidal controls. To
carefully compare in MS patients and controls even subtle abnormalities
of thyroid function, cases were stratified for several progressively
decreasing or increasing cut-off values of TSH (0.1, 0.3, 3, and 5
mIU/liter; Table 1
). Due to the different
gender and age distribution of the two groups, odds ratios (ORs) with
95% confidence intervals (CIs) were calculated using logistic
regression with the different TSH cut-off values as dependent variables
and MS, gender, and age as independent variables. In a separate
regression model, anti-TMA autoAb positivity was also added as
independent variable.
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2 test with Yates’
correction for continuity. In addition, the frequency of de
novo occurring alterations during treatment was compared with
baseline frequency for the whole 12-month study period as well as for
each 3-month interval using McNemar’s test. To describe the
association between the occurrence of thyroid function alteration and
the occurrence of AT autoAb, 
correlation coefficients were
calculated. Furthermore, between subgroups of patients with AT autoAb
negativity or positivity at baseline or at any time during study, the
proportion of patients with newly occurring thyroid alterations during
treatment was compared using Fisher’s test or
2 test with Yates’ correction for continuity.
A longitudinal analysis with the GEE approach (17) was
used to address the question of whether the probability of having
liver, thyroid, or autoAb alterations varies with time during treatment
compared with baseline by taking into account the correlation of
repeated observations. Longitudinal data require special statistical
methods because the set of observations of one subject tends to be
intercorrelated. The GEE approach provides asymptotically valid
inference even when the correlation structure of repeated observations
is unknown. We analyzed as a response variable the presence/absence of
liver, thyroid, or autoAb alteration, and the OR was the odds of
alterations among patients at each time point divided by the odds among
patients at baseline. A patient was considered to have liver alteration
when he had at least one liver function parameter altered (increase in
liver enzymes or alteration of hepatic synthetic function indicators
15% out of normal range); a patient was considered to have thyroid
alteration when he had serum TSH levels lower than normal range without
exogenous T4 intake; a patient was considered to
have an AT autoAb abnormality when he was positive for at least one AT
autoAb. Missing observations were interpolated using data collected in
the previous or subsequent month (where present), and only patients
with complete observations after this interpolation were included. The
only case with TSH above the normal range (a case of subclinical
hypothyroidism) was not considered for this analysis, because it was
already present at baseline and did not change status during treatment.
GEE analysis, in fact, calculates probabilities of changing of status
(from negative to positive, from normal to abnormal, and vice
versa) of each serial observation compared with baseline.
Two-sided descriptive P values are given as indicators of
statistical significance. Results
Demographic characteristics of the study groups
MS patients. The female to male ratio was 2:1; the age at study entry was 32.2 ± 6.5 yr (mean ± SD; range, 18–49); the age at disease onset was 21.6 ± 8.1 yr (range, 14–42); disease duration was 10.5 ± 5.4 yr (range, 2–27); the Expanded Disability Status Scale (23) score was 2.4 ± 1.2 (range, 1.5–3.5).
Healthy controls. The female to male ratio was 1:1.7; the age at entry was 42 ± 15.3 yr (range, 17–93).
Baseline comparison of thyroid function and autoimmunity with
healthy normothyroidal controls (Table 1
)
Baseline thyroid function evaluation of 152 of the 156 MS patients recruited was available. Two cases (1.3%) of clinically overt hyperthyroidism (1 AT autoAb positive), 2 patients with goiter (1.3%) and 3 with thyroid nodules (2%; all without thyroid function alterations), and 6 patients with a family history of thyroid disease (4%; all without thyroid function alteration, one anti-TMA autoAb positive) were excluded from the comparison with healthy normothyroidal controls. No cases below the lowest (0.1 mIU/liter) or above the highest (5 mIU/liter) TSH cut-off were found in MS patients. The risk of having a TSH level below 0.3 mIU/liter (OR, 0.84; CI, 0.32–2.19) or above 3.0 mIU/liter (OR, 0.37; CI, 0.05–3.01) was not significantly increased in MS patients. Adding anti-TMA autoAb positivity as an independent variable did not change the risk for MS patients of having a TSH level either below 0.3 mIU/liter (OR, 0.85; CI, 0.33–2.23) or above 3.0 mIU/liter (OR, 0.35; CI, 0.04–3.00). MS patients do not have an increased risk of having an abnormal TSH value even if they are anti-TMA autoAb positive. The frequency of subclinical hypothyroidism and that of anti-TMA autoAb positivity were slightly higher in MS patients, although not significantly so.
Longitudinal evaluation during IFNß treatment
Thyroid function alterations. No case of clinically overt
hypothyroidism and 1 case of subclinical hypothyroidism was observed in
the study. The latter was a man with subclinical hypothyroidism already
present at baseline and persisting during treatment, with a transient
subclinical worsening at months 6–9 (TSH increase from 3.7 to 6.3
mIU/liter). The patient was negative for AT autoAb both at baseline and
during IFN treatment, and his hypothyroidism was the result of subacute
thyroiditis. Two patients (of 152, 1.3%) at baseline had clinically
overt hyperthyroidism, diffuse toxic goiter without AT autoAb, and
toxic adenoma with anti-TMA and anti-TGA autoAb, respectively. Two
patients (of 144, 1.4%) developed clinically overt hyperthyroidism
de novo during IFNß treatment, in 1 case after 3 months of
IFN treatment, returning to normothyroidal status by month 6 and after
12 months of treatment in the other. Both patients had subacute
thyroiditis with low radioactive iodine uptake and were anti-TMA and
anti-TGA autoAb negative during the entire study. A patient with
subclinical hyperthyroidism at baseline developed clinically overt
hyperthyroidism (toxic nodular goiter with high radioactive iodine
uptake) at 3–6 months of treatment, returning to subclinical
hyperthyroidism by the ninth month. He was AT autoAb negative during
the entire study. Excluding the 2 cases with hyperthyroidism at
baseline, 3 of 154 patients (1.9%) had clinical hyperthyroidism
de novo during IFNß treatment, a figure not significantly
different from that at baseline. No case of clinical hyperthyroidism
de novo occurring during treatment was associated with AT
autoAb positivity either at baseline or during treatment. The frequency
of cases with TSH below the normal range (clinical hyperthyroidism
included) was 5.3% at baseline (8 of 152 patients, in 1 case
associated with anti-TMA and anti-TGA autoAb) and 8.3% de
novo during IFNß treatment (12 of 144, in 1 case with anti-TGA
autoAb at baseline, in another with anti-TMA autoAb de novo
during treatment), without a statistically significant difference. The
frequency of hyperthyroidism occurrence in each 3-month period during
treatment pointed to random fluctuations throughout the study (Table 2), and GEE analysis showed that the
probability of having a TSH level below the normal range at each time
point analyzed during treatment was never significantly different from
that at baseline (Table 3).
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Thyroid function alteration in patients with baseline thyroid
disease or a family history of thyroid disease (Table 4). The 2 cases of clinically overt
hyperthyroidism persisted during treatment without worsening. The
anti-TMA autoAb concentration increased (in the autoAb-positive case)
from 145 to 331 IU/ml, and that of anti-TGA autoAb from 405 to 1102
IU/ml at months 3–6, then returned to values similar to baseline. The
other patient remained AT autoAb negative for the entire study. Five
patients had baseline thyroid disease (2 with goiters and 3 with
thyroid nodules) without thyroid function alteration. One of the
patients with goiter had de novo occurrence of anti-TGA
autoAb at the third month of IFN treatment; the anti-TGA autoAb
concentration progressively rose to 1335 IU/ml and persisted until the
twelfth month; thyroid function, however, remained normal. The second
patient with goiter developed transient clinical hyperthyroidism at the
third month, which disappeared thereafter, and had no AT autoAb. Of the
3 patients with thyroid nodules, 2 developed transient subclinical
hyperthyroidism, respectively, at the third and sixth to ninth months
of IFN treatment, which disappeared thereafter; the latter remained
normothyroidal. All 3 patients with thyroid nodules remained free of AT
autoAb during the entire study. Five of the 6 patients with a family
history of thyroid disease never had AT autoAb (either at baseline or
during treatment), 3 remained normothyroidal, and 2 developed
subclinical hyperthyroidism at the twelfth month of treatment. The
remaining patient with a positive family history was baseline positive
for anti-TMA autoAb. The autoAb concentration decreased below the
positivity threshold by the twelfth month of treatment, and her thyroid
function remained normal throughout the study. Comparing patients with
and without goiter, thyroid nodules, or a family history of thyroid
disease, 3 of 5 patients with and 9 of 139 patients without goiter or
nodules developed hyperthyroidism during IFNß treatment
(P < 0.001); 2 of 6 with and 10 of 138 without a
family history of thyroid disease developed hyperthyroidism during
treatment (P = 0.1). Patients with preexisting goiter
or thyroid nodules seem to be at risk for developing transient thyroid
dysfunction during IFNß treatment.
|
). The
frequency of liver alteration was definitely higher during treatment
than at baseline (P < 0.0001). Most de novo
cases of liver alteration occurred during the first 3-month interval
(Table 2), and GEE analysis showed that the probability of having liver
alteration changed significantly with time (Table 3). In particular, it
was significantly higher (P 
0.002) at the third and
sixth months compared with baseline, returning to values no longer
significantly different from baseline by the ninth month. Baseline liver alteration persisted (in at least 2 determinations) during treatment in most cases (5 of 7, 71.4%). Liver alteration occurring de novo during IFNß treatment persisted in only 13 of 57 (22.8%) cases, less frequently than alteration present at baseline (P < 0.02).
Occurrence of AT autoAb. AT autoAb was detected in 15 of 149
patients (10.1%) at baseline and in 20 of 155 (12.9%) during IFNß
treatment; anti-TMA autoAb was found in 11 of 149 (7.4%) at baseline
and in 15 of 155 (9.7%) during treatment; anti-TGA autoAb was detected
in 5 of 149 (3.3%) at baseline and in 9 of 155 (5.8%) during
treatment. AT autoAb was detected de novo during treatment
in 6 of 134 patients (4.5%; anti-TMA autoAb in 5 of 138, 3.6%;
anti-TGA autoAb in 4 of 144, 2.8%), with random, nonsignificant
frequency changes at each 3-month study period (Table 2). GEE analysis
showed that the probability of having AT or anti-TMA autoAb positivity
during IFNß treatment did not change significantly with time (Table 3).
Baseline AT autoAb positivity persisted (at least once during treatment) in most cases (13 of 15, 86.7%). AT autoAb positivity occurring de novo during IFNß treatment persisted in only 2 of 6 cases (33%), less frequently than autoAb positivity present at baseline (P < 0.05).
Correlation between AT autoAb positivity and thyroid function
alteration (Table 5). De
novo thyroid function alteration (clinically overt hyperthyroidism
or TSH below the normal range) during IFNß occurred in 1 of the 15
patients with AT autoAb at baseline and in 11 (with 2 cases of clinical
hyperthyroidism) of the 134 patients without AT autoAb at baseline
(2 = 0.00; P = NS; Table 5).
De novo thyroid function alteration occurred in 1 of the 6
patients with de novo AT autoAb and in 10 (with 2 cases of
clinical hyperthyroidism) of the 134 who never had AT autoAb (neither
at baseline or during IFNß; 2 = 0.00;
P = NS; Table 5). Statistical analysis did not show any
significant correlation between the development of thyroid function
alteration during IFNß treatment and AT autoAb positivity either at
baseline (r = 0.047) or during treatment (r = 0.134).
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Thyroid function alteration and autoimmunity have been reported in
2–10% patients treated with type I IFN (1, 2, 3, 4). They are
considered contraindications to IFN treatment (1, 8), and
frequent thyroid function assessments during IFN treatment are advised
(1, 24, 25). Most reports describe patients treated with
IFN for chronic hepatitis C, a disease that seems to predispose to
autoimmunity (6, 7). MS patients, too, may be predisposed
to develop thyroid function alteration or autoimmunity during IFN
treatment. The prevalence of thyroid dysfunction in MS patients ranges
from 2–11%, and that of AT autoAb from 4–22% (26, 27, 28, 29, 30, 31)
(Table 6). In some reports the prevalence
is higher than that in the healthy control group, whereas in others it
is not. Subjects positive for AT autoAb or with abnormal TSH level have
an increased risk to develop thyroid dysfunctions
(32, 33, 34), and some reports of thyroid dysfunction during
IFNß treatment for MS (10, 11, 12, 13, 14) have, in fact, appeared.
They are summarized in Table 7. The
frequency of thyroid dysfunction during IFNß ranges from 1–13%, and
that of AT autoAb ranges from 22–43%. Thyroid dysfunction and
autoimmunity occur more often during first year of treatment (10, 12) and are almost always reversible (12). Anti-TMA
autoAb is the AT autoAb most frequently studied in studies of MS
patients as well as in those of patients treated with IFN
(1, 2, 3, 4). Anti-TMA and anti-TGA autoAb have been studied in
powerful long-term epidemiological surveys (32, 33, 34), and
anti-TMA autoAb positivity correlates well to the occurrence of thyroid
dysfunction both in subjects free of any treatment (32, 35) as well as in those treated with IFN (5).
Antithyroid peroxidase (anti-TPO) autoAb has been also studied in
some reports dealing with MS patients (12, 13, 29).
TPO is identical to or at least the major antigenic protein component
of TMA (36), and lymphocytes producing anti-TMA autoAb
also produce anti-TPO autoAb in patients with thyroid autoimmune
disease (37).
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The frequency of clinical or subclinical thyroid dysfunction during
IFN treatment ranges from 2.5–31% (1, 2, 3, 4), somewhat
higher than that during IFNß treatment (ranging 1–13%)
(10, 11, 12, 13, 14). IFN binds to type I IFN-specific cell surface
receptor with an affinity 1000-fold higher than that of IFNß
(44) and has biological effects different from those of
IFNß (45, 46). The frequency of AT autoAb is even more
variable; it is reported in up to 70% of patients treated with IFN
(4) and in 22–43% of patients treated with IFNß
(10, 11, 12, 13, 47, 48). Some reports showed an increased
frequency of thyroid dysfunction or of AT autoAb during IFNß
treatment compared with baseline, and others did not (Table 7). In our
study the frequency of clinical and subclinical thyroid dysfunction
during IFNß treatment was 8.3%; that of AT autoAb was 13%. The
values are not significantly different from baseline frequency. All
previous reports are cross-sectional studies of patient samples
recruited in a single center and did not use a longitudinal statistical
approach correcting for the correlation of repeated measurements of the
same subject over time. Multicenter studies like ours reduce sampling
bias due, for example, to ethnic or geographic origin, which is deemed
important for thyroid dysfunction, and are more representative of the
overall disease population. Therefore, the results of multicenter and
single center studies may be different. The statistical approach we
used (prospective, multicenter, with longitudinal analysis)
demonstrated, during IFNß treatment, a significantly increased
frequency of liver function alteration, but not of thyroid function or
autoimmunity abnormalities. Most de novo alterations
occurring during IFNß treatment (of liver or thyroid function as well
as of autoAb positivity) were, eventually, transient, rarely persisting
at the end of the year of follow-up. From the results of our analysis,
there is no need for repeated assessment of thyroid function and
autoimmunity in all MS patients treated with IFNß, probably only in
those with preexisting thyroid autoimmunity, goiter, or thyroid
nodules. Ongoing trials with IFNß in other diseases should further
address this question with a thorough methodological approach.
Acknowledgments
The Betaferon Safety Trial study group includes M. Trojano and F. Giuliani (Clinica Neurologica, Bari); F. Salvi (Dipartimento di Scienze Neurologiche, Ospedale Bellaria, Bologna); S. Stecchi (Centro Sclerosi Multipla, Azienda USL Cittá di Bologna, Bologna); A. Reggio and E. Reggio (Clinica Neurologica, Catania); E. Montanari, G. Negri, and L. Ludovico (Divisione di Neurologia, Fidenza); A. Ghezzi and M. Zaffaroni (Divisione di Neurologia, Gallarate); G. L. Mancardi and M. Inglese (Clinica Neurologica, Genova); A. Carolei and R. Totaro (Clinica Neurologica, L’Aquila); C. Milanese and L. La Mantia (Divisione di Neurologia, Istituto Neurologico Besta, Milan); D.Caputo and M. Mini (Divisione di Neurologia, Istituto Don Gnocchi, Milan); R. Cotrufo and G. Lus (Clinica Neurologica, Naples); V. Cosi and A. Romani (Clinica Neurologica, Pavia); V. Gallai and P. Sarchielli (Clinica Neurologica, Perugia); U. Nocentini and B. Rizzato (Clinica Neurologica, Universitá Tor Vergata, Rome); P. A. Tonali and A. R. Massaro (Clinica Neurologica, Universitá Cattolica, Rome); G. Rosati and S. Sotgiu (Clinica Neurologica, Sassari); P. Annunziata (Clinica Neurologica, Siena); F. Bortolon and G. Stenta (Divisione di Neurologia, Vicenza); M. P. Sormani (Unitá di Epidemiologia Clinica e Trials, Istituto Nazionale per la Ricerca sul Cancro, Genova); K. Beckmann (Schering AG, Berlin, Germany); P. C. Brossa, E. Ghigo, and M. Maccario (Dipartimento di Medicina Interna, Universitá di Torino, Torino); F. Faggiano (Dipartimento di Sanitá Pubblica, Universitá di Torino); U. Ecari and M. Ciampini (Farmades, SpA, Rome). Coordinating center: Clinica Neurologica, Dipartimento di Neuroscienze, Universitá di Torino (Torino): L. Durelli, B. Ferrero, A. Oggero, E. Verdun, P. Barbero, A. Pipieri, A. Ricci, A. Bosio, M. A. Cucci, and B. Bergamasco. Coordinating center for laboratory investigations: Laboratorio Baldi e Riberi, Ospedale Maggiore S. Giovanni Battista (Torino): G. Aimo and L. Giorda.
Footnotes
This work was supported in part by Farmades, SpA (Rome, Italy).
Abbreviations: Ab, Antibody; AT, antithyroid; autoAb, autoantibodies; CI, confidence interval; fT3, free T3; fT4, free T4; GEE, generalized estimating equations; IFN, interferon; MS, multiple sclerosis; OR, odds ratio; TGA, autoAb against TG; TMA, autoAb against thyroid microsomal antigens; TPO, thyroid peroxidase.
Received December 17, 2000.
Accepted April 9, 2001.
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