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Clinical Studies |
Institutes of Endocrinology (M.M., A.P., G.B., L.M., L.C.) and Neurology (R.R., B.R., A.M.), University of Pisa, Pisa; and the Institute of Internal Medicine, University of Cagliari (S.M.), Cagliari, Italy; and the Division of Endocrinology and Metabolism, University of Massachusetts (L.E.B.), Worcester, Massachusetts 01655
Address all correspondence and requests for reprints to: Aldo Pinchera, M.D., Institute of Endocrinology, University of Pisa, Viale del Tirreno 64, 56018 Tirrenia-Pisa, Italy.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Ocular MG (Osserman’s class 1) was more frequent in group A (41.0%)
than in group B (14.2%; P < 0.03) or C (21.4%;
P < 0.03). Severe generalized MG (classes 
2B)
was more frequent in groups B (57.1%; P < 0.03)
and C (51.9%; P < 0.02) than in group A (28.5%).
GD patients with clinical evidence of ophthalmopathy had a higher
frequency (P = 0.05) of ocular MG (57.8%) than GD
patients without clinical ophthalmopathy (16.6%). Thymic disease was
less frequent in group A (26.7%) than in group B (71.4%;
P = 0.001) or C (59.7%; P =
0.001). The prevalence of thymic hyperplasia was 17.8%, 38.0%, and
40.3% in groups A, B, and C, respectively; the prevalence of thymoma
was 8.9%, 33.4%, and 19.4%. When only patients with generalized MG
were considered, thymic disease was less frequent
(P < 0.02) in group A (40.6%) than in the
remaining groups (69.4%). AchRAb was more frequent in groups B
(57.1%) and C (57.6%; P < 0.03) than in group A
(35.7%).
In conclusion, MG associated with AITD has a mild clinical expression, with preferential ocular involvement and lower frequency of thymic disease and AchRAb. This supports the hypothesis that ocular and generalized MG are separate diseases with different spectra of associated diseases. Nonautoimmune thyroid diseases have no influence on the features of MG. The association of ocular MG and AITD might be due to a common autoimmune mechanism and/or a peculiar genetic background.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients with MG may have evidence of coexisting autoimmune thyroid
diseases (AITD) (8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) as well as other autoimmune disorders
(21, 22). Epidemiological studies showed that AITD occur in
approximately 5–10% of MG patients (17, 18), whereas a fairly low
incidence of MG (
0.2%) has been reported in patients with AITD
(18). A higher frequency of thyroid antibodies has been observed in OMG
compared to GMG (8), but this increased association between OMG and
thyroid autoimmunity has not been confirmed (13, 14, 15, 16). Thus, the
question of whether the clinical expression of MG associated with AITD
is different from that observed in MG without thyroid autoimmunity
remains unresolved.
The aim of this study was to evaluate the clinical and serological features of MG associated with AITD in a large number of patients. Results were compared to those found in MG patients with nonautoimmune thyroid diseases (N-AITD) and without thyroid disorders.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A total of 129 MG patients (34 men and 95 women; age range, 11–81 yr) were studied. Ninety-one consecutive patients referred to the Institute of Neurology for MG (18 with OMG and 73 with GMG) were screened for thyroid disease. Among these 91 patients, 39 had thyroid disease (26 AITD and 13 N-AITD). The remaining 38 MG patients (19 with OMG and 19 with GMG) were obtained from approximately 20,000 consecutive patients referred to the Institute of Endocrinology for thyroid disease from 1980 to 1995. Among these 38 patients, 30 had AITD and 8 had N-AITD. Thus, 77 patients had coexistent MG and thyroid disorders. Thirty-seven had a diagnosis of thyroid disease made before the diagnosis of MG (median interval, 20.3 months), whereas 40 patients had a diagnosis of thyroid disease after the recognition of MG (median interval, 28.8 months). When they entered the study, 31 of the 129 MG patients were being treated with pyrodostigmine, 4 were being treated with prednisone, and 83 were being given both drugs. Azathioprine was given to 19 patients.
For the purpose of this study patients with MG were subdivided into 3 groups. Group A consisted of 56 MG patients with AITD (9 men and 47 women; age range, 13–81 yr). Twenty-five patients had autoimmune thyroiditis (AT); 22 had typical Hashimoto’s thyroiditis [HT; 15 untreated at entry (8 euthyroid and 7 with clinical or subclinical hypothyroidism) and 7 treated with L-T4 (2 euthyroid and 5 hypothyroid], and 3 had euthyroid nodular goiter with focal autoimmune thyroiditis and were not treated. Thirty-one patients had Graves’ disease (GD); 3 were untreated hyperthyroid, 14 were euthyroid receiving methimazole, 10 were euthyroid receiving L-T4 therapy after thyroidectomy or radioiodine treatment, and 4 had euthyroid GD (Graves’ ophthalmopathy with no evidence of hyperthyroidism). Among GD patients, 19 had clinical evidence of Graves’ ophthalmopathy, as assessed by physical examination. Clinical ophthalmopathy was characterized in all cases by moderate or severe exophthalmos associated with signs and symptoms of soft tissue inflammation. Eye muscles were enlarged in all patients with clinical ophthalmopathy, as assessed by orbital computerized tomography (CT). Diplopia was present in 16 patients. Involvement of optical nerves at CT was present in 4 patients. In the 12 GD patients with no clinical evidence of ophthalmopathy, orbital CT was not performed. Therefore, for the purpose of the present study, Graves’ ophthalmopathy was defined as a clinically detectable condition.
Group B consisted of 21 MG patients with associated N-AITD (5 men and 16 women; age range, 22–77 yr). Two had toxic adenoma and were euthyroid after radioiodine treatment, and 19 had nontoxic nodular goiter (13 untreated and 6 receiving L-T4).
Group C consisted of 52 MG patients with no evidence of associated thyroid disorders (20 men and 32 women; age range, 11–76 yr).
Clinical and serological investigation
Neurological evaluation. All patients underwent neurological assessment, which included physical examination and a Tensilon (edrophonium) test. A repetitive nerve stimulation test (Desmedt test) was performed when necessary. All patients had CT or magnetic resonance imaging (MRI) of the mediastinum performed. Patients with thymic enlargement at CT or MRI were submitted to thymectomy. The diagnosis of thymic hyperplasia or thymoma was based on histological findings. AchRAb was assayed in all patients using a commercial kit (acetylcholine receptor autoantibodies, Immuno Biological Laboratories, Hamburg, Germany).
Thyroid evaluation. All patients underwent a thyroid evaluation, which included physical examination, thyroid ultrasonography, and the following thyroid tests: free thyroid hormones (free T4 and free T3 RIA, Lysophase, Technogenetics, Milan, Italy), TSH (Ultrasensitive-TSH immunoradiometric assay, Delfia, Wallac, Finland), antithyroglobulin autoantibodies (TgAb; anti-Tg MELISA, Byk Gulden, Milan, Italy), and antithyroperoxidase autoantibodies (TPOAb; anti-TPO RIA, Sorin Biomedica, Saluggia, Italy). The following tests were also carried out when necessary: anti-TSH receptor autoantibodies (TRAb; TRAb immunoradiometric assay, Henning, Berlin, Germany), thyroid scan, and thyroid fine needle aspiration biopsy. Patients with clinical evidence of Graves’ ophthalmopathy had an orbital CT performed.
Diagnostic criteria
The diagnosis of MG was based on the presence of muscular weakness and abnormal fatigability aggravated by exercise and was confirmed by the Tensilon and Desmedt tests (1). GMG was diagnosed in patients with systemic muscle involvement in whom iv edrophonium administration was associated with unequivocal improvement in an objectively weak muscle (1, 23). The Desmedt test confirmed the diagnosis of GMG in patients showing an equivocal response to the Tensilon test (1, 24). OMG was diagnosed in patients with restricted ocular symptoms (diplopia and palpebral ptosis) and a clear improvement in eye muscle weakness a few seconds after the iv administration of edrophonium (1, 23). None of the OMG patients had generalized muscle involvement during a follow-up period of almost 2 yr. The diagnosis of both OMG and GMG was confirmed by the amelioration of muscle weakness during chronic treatment with pyridostigmine. The severity of MG was ranked according to the Osserman score (4): class 1, OMG; class 2A, GMG with no bulbar involvement; class 2B, GMG with bulbar involvement; class 3, acute rapidly progressive GMG; and class 4, severe GMG with myopathy.
The diagnosis of GD was based on the presence of hyperthyroidism (25) and/or Graves’ ophthalmopathy associated with diffuse goiter and circulating thyroid antibodies including TRAb (26). The diagnosis of ophthalmopathy in all GD patients with clinical evidence of Graves’ ophthalmopathy was confirmed by the presence of eye muscle enlargement and an increase in fibroadipose retrobulbar tissue determined by CT (27). Euthyroid GD was diagnosed in patients with Graves’ ophthalmopathy who did not have previous or actual clinical and biochemical evidence of hyperthyroidism. This was always associated with small diffuse goiter, circulating thyroid antibodies (including TRAb), and undetectable TSH. Patients with clearly diagnosed Graves’ ophthalmopathy who had an unequivocal improvement of palpebral ptosis and diplopia after the iv administration of edrophonium were diagnosed as having coexistent Graves’ ophthalmopathy and OMG. The improvement of diplopia, but not of palpebral ptosis, after the Tensilon administration was not considered a sufficient criterion for the diagnosis of OMG in patients with Graves’ ophthalmopathy. All patients with primary hypothyroidism associated with positive TgAb/TPOAb were considered to have HT. The diagnosis of HT was also made in patients with positive TgAb/TPOAb associated with a firm goiter and a hypoechogenic pattern on ultrasound examination of the gland and/or lymphocytic infiltration at fine needle aspiration biopsy (28, 29, 30, 31). Patients with nodular goiter and circulating TPOAb at high levels (range, 277-2000 U/mL) were considered to have nodular goiter with focal autoimmune thyroiditis (28) and were included in group 1. Five euthyroid patients with nodular goiter and circulating TPOAb at low levels (range, 12–47 U/mL) did not have a hypoechogenic pattern on ultrasound examination or lymphocytic infiltration on fine needle aspiration biopsy. Furthermore, none of them had a family history of AITD. Therefore, for the purpose of the present study, these 5 patients were considered to have N-AITD (32) and were included in group B.
Statistical analysis
Results were analyzed by 
2 test, using a personal
computer software (Stat-View, Abacus Concepts, Berkeley, CA).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As shown in Table 1
and Fig. 1, OMG
(class 1) was more frequent in group A (41.0%) than in group B
(14.2%; P < 0.03) or C (21.4%; P <
0.03). The frequency of mild GMG (class 2A) was similar among the three
groups. The frequency of bulbar, acute, and severe GMG (classes 2B, 3,
and 4 grouped together) was higher in groups B (57.1%;
P < 0.03) and C (51.9%; P < 0.02)
than in group A (28.5%). Classes 3 and 4 were observed only in group C
(two and one patients, respectively). No difference was observed
between groups B and C and in group A between GD (with or without
ophthalmopathy) and AT (data not shown). GD patients with clinical
evidence of ophthalmopathy had a higher frequency (P =
0.05) of ocular MG (57.8%) than GD patients without clinical
ophthalmopathy (16.6%).
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Sixty-one of 129 patients had an abnormal thymus; 39 patients had thymic hyperplasia, and 22 had thymoma. Fifty-four of the 61 patients with thymic abnormalities had a thymectomy before entering the study, and the remaining 7 underwent thymectomy after entering the study. No evidence of thymic enlargement was detected by CT or MRI in the remaining 68 patients. As expected, the frequency of thymic disease was lower in patients with OMG (8.8%) than in those with GMG (63.0%).
Thymic disease was less frequently observed in group A (26.7%) than in
groups B (71.4%; P = 0.001) and C (59.7%;
P = 0.001; Fig. 2). When the frequencies
of various thymic diseases were analyzed (Table 1
and Fig. 2), a lower
prevalence of thymic hyperplasia was observed in group A (17.8%) than
in group B (38.0%) or C (40.3%); the difference was statistically
significant between groups A and C (P < 0.01).
Similarly, the prevalence of thymoma was lower in group A (8.9%) than
in group B (33.4%) or C (19.4%), with a statistically significant
difference between groups A and B (P < 0.01). The
frequency of thymic disease did not differ between groups B and C or in
group A between GD and AT (data not shown). No difference in thymic
disease was observed between GD patients with or without ophthalmopathy
(data not shown). Among patients with GMG (Osserman classes >1), the
frequency of thymic disease was significantly lower (P
< 0.005) in patients in group A (40.0%) than in those in groups B and
C taken together (69.0%; Fig. 2).
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As expected, the frequency of TgAb and TPOAb was higher in group A
(TgAb, 37.5%; TPOAb, 78.5%) than in groups B (TgAb 0%; TPOAb 8.7%)
and C (TgAb, 0%; TPOAb, 15.3%; Table 1 and Fig. 3).
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As expected, AchRAb was less frequent in patients with OMG (8.1%)
than in those with GMG (64.1%). As shown in Table 1 and in Fig. 3, the
prevalence of AchRAb was higher in groups B (57.1%) and C (57.6%)
than in group A (35.7%), with a statistically significant difference
between groups A and C (P < 0.03). No difference was
observed between groups B and C.
Analysis of MG features in AITD patients according to their referral to different institutions
To determine whether the referral of patients to two different
institutions influenced our results, patients with MG and AITD were
subdivided according to their referral to the Institute of Neurology or
to the Institute of Endocrinology. As shown in Table 2,
no difference was observed for any of the clinical or serological
features of MG between the two referral sites.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the present study we evaluated the clinical and serological features of MG associated with AITD compared with those found in MG patients with N-AITD or without thyroid disease. The clinical presentation of MG associated with AITD was characterized by neuromuscular involvement, frequently restricted to the eye muscles. In contrast, GMG was more frequent in MG patients with N-AITD and in those without thyroid disease. Thymic abnormalities were less frequent in MG associated with AITD than in MG without thyroid autoimmunity. This lower frequency of thymic abnormalities in AITD patients was also present when only OMG patients were considered. Moreover, the prevalence of serum AchRAb was lower in patients with AITD than in the other groups of MG patients. The majority of MG patients without thyroid autoimmunity had GMG and were receiving immunosuppressive therapy when they entered the study. Therefore, this difference in circulating AchRAb is almost certainly greater in untreated patients.
Our finding of an increased association between OMG and thyroid autoimmunity supports the observation of Garlepp et al. (8), who reported a greater frequency of thyroid antibodies in OMG than in GMG. On the other hand, a higher frequency of associated autoimmune disorders (including AITD) in GMG compared to OMG has been observed by others (13, 14, 15, 16). This discrepancy might be due to the different diagnostic criteria employed and/or the limited number of patients studied. Furthermore, several earlier studies on the association of MG with thyroid disease failed to distinguish between autoimmune and nonautoimmune thyroid disorders (10, 11, 21, 22). In the present study a large number of patients with MG have been evaluated and subdivided on the basis of strict diagnostic criteria for their thyroid disorder. Patients with coexisting AITD or N-AITD have been studied. Our data clearly demonstrate that a milder clinical expression of MG occurs in patients with associated AITD than in those without thyroid autoimmunity. No difference was observed in any of the clinical and laboratory findings between MG patients with coexistent N-AITD and those without thyroid disease. This suggests that the mild clinical expression of MG associated with AITD is not related to the presence of a thyroid disorder per se, but to the presence of thyroid autoimmunity. In agreement, the coexistence of N-AITD has no effect on the type or the clinical course of MG, and the presence of goiter in MG patients should be considered a random association. The study was carried out in an Italian population from Tuscany, where mild to moderate iodine deficiency is still present, and the prevalence of endemic goiter ranges from 22–59% (33).
The reason for the association of AITD with ocular MG is unknown, but several hypotheses can be considered. First, OMG and GMG might actually represent separate diseases (5, 6, 7, 8, 9) with different spectra of associated diseases. Second, an immunological cross-reactivity against epitopes or autoantigens shared by the thyroid and the eye muscles might be the basis of this association. Several experimental data suggest that thyroid antigens are present in ocular tissues (34, 35, 36, 37, 38, 39, 40, 41, 42). Circulating autoantibodies directed to eye muscle components have been identified in GD and HT (36, 37, 43, 44) and recently also in GD patients with associated MG (45). Further studies are needed to clarify whether autoantibodies against antigens shared by the thyroid and the eye muscles are present in sera from patients with MG and AITD. In particular, it would be useful to evaluate the presence of autoantibodies directed against a membrane 64-kDa protein that has been suggested to play an important role in the pathogenesis of Graves’ ophthalmopathy (46, 47). A third explanation for the higher frequency of OMG in AITD could be that these disorders have a common genetic background. Among the various major histocompatibility complex (MHC) haplotypes associated with AITD and MG (48, 49, 50, 51, 52, 53), a high frequency of human leukocyte antigen-B8 and -DR3 has been reported in both disorders (48, 49, 50). A difference in the MHC repertoire was also found between OMG and GMG (6, 12, 54, 55), supporting the hypothesis that they are separate entities. Further studies are needed to evaluate the MHC repertoire in MG patients with associated AITD compared to MG patients without associated AITD.
In conclusion, MG associated with AITD has a mild clinical expression characterized by preferential involvement of the eye muscles. This is consistent with the hypothesis that OMG and GMG are separate diseases with different spectra of associated diseases and different immunogenetic backgrounds. The association of OMG with AITD might also be due to a common immunopathogenetic mechanisms acting through antigens shared by the eye muscles and the thyroid. Further immunological and genetic studies are needed to verify these hypotheses. The important clinical implication of this study is that the coexistence of MG with thyroid autoimmunity might have prognostic relevance in the identification of a subgroup of MG patients with a mild form of the disease.
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Footnotes |
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Received May 8, 1996.
Revised September 4, 1996.
Accepted October 18, 1996.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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