Coexistence of autoimmune diseases and autoantibodies in patients with myasthenia gravis
Background: In this study, we assessed 75 patients with myasthenia gravis (MG) for coexistent autoimmune diseases (ADs) and for the characteristic autoantibodies that are associated with the most relevant forms of ADs.
Keywords: Autoantibodies; autoimmune disorder; myasthenia gravis
Myasthenia gravis (MG) is a rare autoimmune disease (AD) caused by autoantibodies against neuromuscular junction proteins such as the nicotinic acetylcholine receptor (AChR), muscle specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4.,, Clinically, MG is characterized by muscle weakness and rapid fatigue aggravated by exercise and relieved by rest. AChR-specific antibodies are detected in the majority (85%) of patients with MG., Known antibodies cannot be detected in approximately 5–10% of patients; these cases are classified as seronegative MG (SNMG). The onset of MG is influenced by age and gender in a bimodal fashion. Females less than 50 years of age are more commonly affected than are males, and males are slightly more frequently affected by late onset MG. The classification of MG takes into account the nature of the antibodies, the age at onset of the disease, the affected muscles (ocular and/or generalized), and thymic abnormalities.,,,
Approximately 5% of the population is affected by one or more autoimmune disorders, and the prevalence is higher in female than in male patients. Patients who are affected by one autoimmune disorder have a higher risk of developing a second one. Patients with MG have an increased risk of developing other autoimmune disorders when compared with the non-MG population. In patients with MG, the frequency of developing a second autoimmune disorder is in the range of 8.7–25%, with the frequency being highest in female subjects and in individuals with early-onset MG. In a systematic review, autoimmune thyroid disease (AITD) was the most frequent AD associated with MG from amongst 23 associated ADs occurring in 10% of patients with MG. The other common ADs associated with MG are systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)., When multiple ADs are present simultaneously, the patient has specific immunological markers for the simultaneously present diseases. The pathogenesis for the co-occurrence of different varieties of ADs in the same patient is unclear; however, genetic, infectious, and immunological factors have been implicated, and abnormalities in both humoral and cell-mediated immunity have been described. Similar environmental triggers in a genetically susceptible individual may lead to the co-occurrence of different ADs in the same patient.
The aim of this study was to evaluate the clinical and serological features of MG associated with other ADs.
We received permission from our local Ethics Committee to conduct the present study. After obtaining informed consent, we examined 75 patients with MG (36 men and 39 women; age range, 17–81 years) who received treatment at the Dıskapı Yıldırım Beyazıt Training and Research Hospital from 2007 to 2012. To establish the diagnosis of MG, the patients included in this study underwent a neurological assessment, which included a physical examination, a Tensilon (edrophonium) test, and electrophysiological studies.
In this study, patients with MG were subdivided into two groups. Patients were classified as seropositive if an anti-acetylcholine receptor (AChR) or anti-MuSK antibody was detected; patients in whom these antibodies were absent were classified as seronegative. Age, gender, age at the onset of the disease, and the disease duration were recorded. Early-onset MG included patients in whom the disease occurred before the age of 50 years; late-onset MG included patients who developed the disease when they were 50 years of age or older. The clinical type was recorded as ocular or generalized. The severity of MG was classified using the MG Foundation of America criteria. All patients were subjected to computed tomography (CT) of the mediastinum. Thirty of the 75 MG patients with thymic abnormalities (that were visualized on the CT scan) received a thymectomy. A diagnosis of thymic hyperplasia or a thymoma was established on the histological examination.
In all patients, the levels of thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine, antithyroid peroxidase (anti-TPO) antibody, antithyroglobulin (anti-TG) antibody, and rheumatoid factor (RF) were determined. Antinuclear antibody (ANA), antidouble-stranded deoxyribonucleic acid (anti-dsDNA), and antineutrophil cytoplasmic antibodies (ANCA; c-ANCA with a cytoplasmic fluorescence pattern, and p-ANCA with a perinuclear fluorescence pattern) were examined using enzyme-linked immunosorbent assay. Anti-Ro/SSA, anti-La/SSB, anti-Jo-1, and anti-Smith (anti-SM) antibodies were investigated by immunoblotting.
The diagnosis of Hashimoto's thyroiditis (HT) and Graves' disease (GD) was made based on clinical features, physical examination, laboratory findings, and ultrasound of the thyroid. Thyroid scintigraphy and fine-needle aspiration biopsy were performed, whenever necessary. The diagnosis of RA and SLE was made according to the American College of Rheumatology criteria. Lambert–Eaton myasthenic syndrome (LEMS) was diagnosed based on clinical examination and electrophysiological findings. Other ADs were recorded based on whether or not the patient already had an established diagnosis of ADs; if there was a clinical suspicion of their existence; and/or the laboratory abnormalities established their coexistence.
SPSS 17.0 (IBM corporation) was used for statistical analysis. Age and disease duration were compared using Student t-test. The gender, serological status, age at onset, clinical type, and thymic status were compared using the Chi-square test. P < 0.05 was considered to indicate statistical significance.
As shown in [Table 1], of the 75 patients with MG, 40 (20 men and 20 women; age range, 17–80 years) were seropositive, and 35 (16 men and 19 women; age range, 19–81 years) were seronegative. Among the 40 seropositive patients, 37 were anti-AChR-positive, and 3 were anti-MuSK-positive. The mean ages were 50 ± 18 and 48.7 ± 15 years in the seropositive and seronegative groups, respectively. The disease duration ranged from 15 days to 31 years (median interval: 5.5 years). There were no significant differences in gender, age, duration of the disease, age at onset of the disease, clinical type and severity, or thymic disorders between the seropositive and seronegative groups.
As shown in [Table 2], 18 (24%) patients had coexistent MG and ADs. Ten patients already came with an established diagnosis of ADs before the diagnosis of MG was made; whereas in 8 patients, the diagnosis of AD was made following the recognition of MG which led to the performance of ancillary investigations. Among these 18 patients, 5 (27.7%) had ocular MG, and 13 (72.3%) had generalized MG. When analyzed according to the age of onset of the disease, 13 (72.3%) patients were less than 50 years of age, and 5 (27.7%) patients were over 50 years old. Of the 18 patients, 8 had an abnormal thymus with 7 having a thymic hyperplasia, and 1 having a thymoma. Patients with MG with associated ADs were predominantly female, experienced early-onset symptoms of MG, had a higher frequency of generalized MG, and had SNMG; however, the difference was not significant (P = 0.06).
Twelve patients (16%) were diagnosed with AITD. Among these 12 patients, 5 had hypothyroidism, and 4 had hyperthyroidism. Three of them were euthyroid. In MG patients with AITD, 5 (41.6%) had ocular MG, and 7 (58.4%) had mild, generalized MG (classes IIA, IIB, and IIIB). Five patients had thymic hyperplasia, and one had a thymoma. MG patients with AITD were predominantly female, experienced early-onset MG symptoms, and had a higher frequency of generalized MG; however, the difference was not significant (P = 0.04). Eight had a diagnosis of AITD before the diagnosis of MG, whereas in 4 patients, the diagnosis of AITD was established on performing investigations after the recognition of MG.
Three patients with MG also had RA (4%). All cases were associated with generalized (classes IIA, IIB, and IVB) and early-onset MG. Among the 3 RA patients, 1 patient already had a clinically overt RA when the diagnosis of MG was made, whereas 2 patients were detected to be having RA after the recognition of MG. One of the 3 patients had thymic hyperplasia and a history of thymectomy.
Two patients were diagnosed with SLE (2.6%). Both patients had generalized MG (classes IIB and IIIB) and SNMG. One patient with thymic abnormalities had a history of thymectomy before entering the study. Among the 2 patients with SLE, one experienced early and the other, late onset MG symptoms. One patient already had clinically manifest SLE when the diagnosis of MG was made; the other patient was detected to be having SLE (and fulfilled the diagnostic criteria of the disease) after the onset of MG.
A total of 39 (52%) patients, 19 seropositive and 20 seronegative, were positive for autoantibodies in the sera. The detected autoantibodies included 27 anti-TPO, 17 anti-TG, 17 ANA, 6 RF, 3 anti-TSH receptor, 2 anti-dsDNA, 1 anti-Jo-1, 1 anti-Ro/SSA, and 1 anti-La/SSB. We did not detect any anti-SM or ANCA autoantibodies. The presence of autoantibodies did not differ between the seropositive and seronegative groups. The presence of autoantibodies was higher in female patients (62.5% of females vs. 40% of male patients); however, the difference was not significant (P = 0.052).
The clinical features and electrophysiological findings indicated the coexistence of MG and LEMS in 1 (1.3%) patient. The predominance of oculobulbar symptoms and a positive edrophonium test favored a diagnosis of MG. However, areflexia with facilitation after voluntary contraction is a typical finding in LEMS, and the results of the repetitive nerve stimulation test supported concomitant LEMS. Based on these findings, we believe that this patient had MG and LEMS overlap syndrome. No commercially available autoantibodies were available to detect P/Q-type voltage-gated calcium channels. The myasthenic symptoms were of early-onset and generalized, and the thymus was normal. A tumor was found in the lungs, and the patient died 1-year after the diagnosis had been made.
Autoimmunity occurs due to an inappropriate response against tissue elements that are normally present, leading to chronic diseases characterized by the loss of immune tolerance to self-antigens.,,, Like most ADs, MG is caused by a complex interaction among multiple genotypes of low penetrance and various environmental factors including pathogenic exposure. The latter conditions include exposure to Epstein–Barr virus,, administration of sex hormones, low vitamin D levels, and lifestyle disorders such as cigarette smoking.,,
Most autoimmune disorders appear with increased frequency in patients with MG. The prevalence of ADs in patients with MG ranges from 8.7% to 25% in the literature. In a systematic review of 25 studies, the frequency of ADs was 13%. However, only four of these 25 studies provided a diagnostic criteria that could detect the associated presence of ADs. We included the assessment of the recommended diagnostic criteria in our study and found a 24% incidence of association of ADs with MG. This finding is consistent with the previously published studies.
The comorbidity due to autoimmunity varies between the MG subgroups. In early-onset MG, all ADs appear more frequently than expected, particularly in female patients. Late-onset MG has a lower frequency of autoimmune overlap than do the other MG subgroups., A thymectomy per se does not seem to be influencing the development of a second autoimmune disorder. However, thymectomy may induce a breakdown in self-tolerance and be a risk factor for the development of systemic autoimmune disorders, such as SLE and neuromyelitis optica (NMO), in patients with MG.,
A systematic review of the frequency of ADs in patients with MG showed that AITD was the most common disease that coexisted with MG. The incidence of AITD was 16% in our study: HT was predominant (12%) followed by GD (4%). MG combined with AITD tends to be a milder form of the disease. Ocular MG has a special link to thyroid disease. The reason for the association between AITD and ocular MG is unknown, but several hypotheses may be considered. First, ocular MG and generalized MG might actually represent separate diseases with different spectra of associated conditions. Second, immunological cross-reactivity against epitopes or auto-antigens shared by the thyroid and eye muscles might be the basis for this association. A third explanation for the higher frequency of ocular MG in AITD could be that these disorders have a common genetic background., In our study, we showed that the clinical features of patients with MG and AITD had an early-onset, mild clinical expression, with a lower frequency of thymic abnormalities.
The coexistence of SLE and MG has rarely been reported, and most of the published studies are case reports. In our study, 2 of 75 MG patients had SLE. The prevalence of SLE in our study was 2.6%. A higher prevalence of SLE in patients with MG (7.7%; 78 patients) was reported by Sthoeger et al. In accordance with previous reports, the majority of patients who had combined manifestations of MG-SLE were female. In our patients, the clinical manifestations of patients with SLE and MG were less severe than that encountered when either of them is present individually. Whether thymectomy precipitates SLE is still controversial; however, the co-occurrence of these two diseases (i.e., patients who had SLE before the onset of MG) cannot be explained by this hypothesis. The co-occurrence of SLE and MG may be due to a common genetic predisposition as well as coexisting immunological abnormalities.
In our study, 2 of the 75 MG patients had RA (4%). The previous studies have reported a prevalence of 4.2%, a figure that was similar to that seen in our study. Cases where MG may occur in patients treated with penicillamine for RA have been reported in the literature. None of our cases had received treatment with penicillamine. Similar to the findings observed in patients with SLE, the manifestations of RA were also classically less severe.
Due to the chronic nature of most ADs, autoantibodies may appear before clinical symptoms manifest and could provide a good predictive marker for the potential development of the disease. The presence of autoantibodies was much more than that the incidence of clinically manifest ADs in our study. Thyroid autoantibodies and ANA positivity had the highest prevalence in this cohort of patients. TPO was the most frequent autoantibody encountered alone. ANA was frequently detected with other autoantibodies. The clinical characteristics of the patients did not differ according to the type of autoantibody positivity. To predict the development of the disease, prospective studies are needed that systematically follow up patients who are positive for autoantibodies until they develop clinically manifest ADs.
A rare case of coexistence of NMO and MG was documented recently. McKeon et al., reported their findings on four (2%) patients of NMO with MG, and an 11% prevalence of muscle AChR antibodies in their database of 177 patients with NMO. This high prevalence suggests that the coexistence of MG and NMO might not be coincidental. Both disorders may share a common immunopathogenesis. The coexistence of MG and NMO has mainly been reported in patients who underwent a thymectomy months to years before the development of NMO. Leite et al., reported that patients with MG in association with NMO were predominantly female, had early-onset AChR-MG, had mostly mild, generalized disease, and had achieved remission in a large proportion of cases. Visual and motor symptoms caused by MG are usually easily distinguishable on clinical grounds from those caused by optic neuritis and myelitis, respectively. Our patients had no history of optic neuritis or a longitudinally extensive transverse myelitis.
Our study supports the concept that patients with MG have an increased frequency of coexisting ADs. Autoantibodies can also be detected even when the diagnosis of ADs is not established. The presence of autoantibodies may result in the subsequent development of ADs during the follow-up of patients with MG.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2]