Late-onset Myasthenia Gravis Patients Research Articles

Therapeutic and prognostic features in myasthenia gravis patients followed in a tertiary neuromuscular diseases center in Turkey.

In this study, we aim to evaluate the treatment responses and prognostic characteristics of Myasthenia Gravis (MG) patients followed in a tertiary neuromuscular diseases center in Turkey. One hundred seventy four MG patients (between years 2011 and 2022) in Antalya, Turkey were diagnosed, and evaluated on a classification of MG was based on Myasthenia. Gravis Foundation of America (MGFA) clinical classification. Exclusion of other possible diseases in the differential diagnosis and support by beneficial response to treatment with acetylcholinesterase inhibitors were also taken into consideration. Mean age of participants was 54.86 (SD = 14.856; min-max = 22-84). Ninety (51.7%) were female. MG was more common in women under the age of 65 (58%) and in men over the age of 65 (64%). Generalized MG was seen in 75.3% of the patients. Anti-AChR positivities were detected in 52.3%, Anti-MuSK positivity in 4.6%, and seronegativity in 22.4%. Thymoma was detected in nearly 9.8% and thymectomy was performed in 28.7 percent. Most of the patients (57.5%) were using corticosteroids. Azathioprine was used by 39% and mycophenolate mofetil by 10.3% of patients. Mortality was higher and disease was more severe in late-onset (>50 years) MG patients (especially in the COVID-19 pandemic). Eight patients (four women, four men, mean age 75.5 years) died during follow-up. None of them died due to myasthenic worsening, two died due to malignancy and two due to infection. During the COVID pandemic, 16 patients (9.2%) had COVID infection. Four patients died due to COVID-19 infection, these four patients had serious comorbidities, and three of them were elderly (>75 years). In conclusion, MG is more common in women between the ages of 20-40 and in men over the age of 65. The use of corticosteroids was more common under the age of 50, and the use of non-steroidal immunosuppressant agents was more common over the age of 50. Thymectomy is still an important supportive treatment approach in anti-AChR positive and seronegative generalized patients under 50 years of age. IVIG and plasmapheresis are effective treatments during acute exacerbations and bridging periods of treatments. Specific treatments are needed especially for resistant group of patients.

Clinical characteristics and prognosis of very late-onset myasthenia gravis in China

Alteration in onset-age distribution in myasthenia gravis (MG) and its increasing prevalence among the elderly underscores the need for a better understanding of the clinical course of MG and the establishment of personalized treatment. In this study we reviewed the demographics, clinical profile, and treatment of MG. Based on onset age, eligible patients were classified as early-onset MG (onset age ≥18 and <50 years), late-onset MG (onset age ≥50 and <65 years), and very late-onset MG (onset age ≥65 years). Overall, 1160 eligible patients were enrolled. Patients with late- and very late-onset MG showed a male predominance (P=0.02), ocular MG subtype (P=0.001), and seropositivity for acetylcholine receptors and titin antibodies (P<0.001). In very late-onset MG, a lower proportion of patients retained minimal manifestations status or better, a higher proportion of patients had MG-related deaths (P<0.001), and a shorter maintenance time of minimal manifestation status or better was seen at the last follow-up (P=0.007) than that in patients with early- and late-onset MG. Non-immunotherapy may associated with a poor prognosis in patients in the very late-onset group. Further studies on very late-onset MG patients should be performed to evaluate the relationship between immunotherapy and prognosis.

Aberrant Dendritic Cell Subsets in Patients with Myasthenia Gravis and Related Clinical Features

Introduction: Dendritic cells (DCs) play critical roles in the pathogenesis of myasthenia gravis (MG), and a series of DC-based experimental strategies for MG have recently been developed. However, the definite roles of different DC subsets in the mechanism of MG have scarcely been covered by previous studies. The present study aimed to investigate the levels of three main DC subsets, plasmacytoid DCs (pDCs) (CD303 positive) and two distinct subsets of conventional DCs (cDCs), namely CD1c⁺ cDCs and CD141⁺ cDCs, in MG patients and analyze related clinical features. Methods: From January 2016 to December 2020, 160 newly diagnosed MG patients and matched healthy controls (n = 160) were included in the study, and their clinical data were collected. The blood samples from MG patients before treatment and controls were collected for flow cytometry analysis. A total of 14 MG thymoma, 24 control thymoma, and 3 thymic cysts were used to immunostain the DC subsets. Results: The flow cytometry analysis showed a significantly higher frequency of circulating pDCs, CD1c⁺ cDCs, and CD141⁺ cDCs in MG patients than in healthy controls (p < 0.001 for all). Patients with early-onset MG (<50 years old) had a lower frequency of circulating pDCs but a higher frequency of circulating CD1c⁺ cDCs than those with late-onset MG (≥50 years old) (p = 0.014 and p = 0.025, respectively). The frequency of circulating pDCs was positively associated with the clinical severity of late-onset MG patients (r = 0.613, p < 0.001). 64.3% (9/14) of MG thymoma is of type B2 under the World Health Organization classification, which is higher than that in control thymoma (33.3%, 8/24) (p = 0.019). For type B2 thymoma, there were significantly more pDCs but fewer CD1c⁺ cDCs in MG thymoma than in the controls. Conclusion: The distribution of aberrant pDCs, CD1c⁺ cDCs, and CD141⁺ cDCs in MG patients displayed age- and thymoma-related differences, which may contribute to the impaired immune tolerance and lead to the onset of MG.

Studying the relationship between clinical features and mental health among late-onset myasthenia gravis patients.

BACKGROUNDMental disorders are common comorbidities among individuals with neurological diseases, and the prevalence of depressive and anxiety-related symptoms in newly referred patients at neurology outpatient clinics is high. There have been few studies on the mental health of patients with late-onset myasthenia gravis (MG).AIMTo examine the relationship between clinical features and the mental health symptoms within late-onset MG patients.METHODSA total of 105 patients diagnosed with MG were recruited consecutively from a neuromuscular outpatient clinic between December 2020 and February 2021. Patients were classified into two groups: early-onset MG (age at onset < 50 years, n = 63) and late-onset MG (age at onset ≥ 50 years, n = 42). Social demographic data and information about marital status, education level, clinical symptoms, serum antibody levels, and therapies used were collected for all participants. Participants were also evaluated using the Myasthenia Gravis Composite scale, the Myasthenia Gravis Activities of Daily Living scale, the Myasthenia Gravis Quality of Life 15 (MG-QOL-15) questionnaire, the 17-item version of the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). The relationship between clinical features and mental health in late-onset MG patients was examined using multivariate logistic regression analyses. RESULTSLate-onset MG patients were more prone to dyspnea, had higher levels of serum anti-acetylcholine receptor antibodies, and higher total scores on the MG-QOL-15, HAM-D, and HAM-A questionnaires, than early-onset MG patients had (P < 0.05). Among those with late-onset MG, female patients had higher total HAM-D and HAM-A scores than male patients had (P < 0.05). High scores on the QOL-15 questionnaire were associated with higher incidences of anxiety and depression, and the association was found to be independent after adjusting for confounding risk factors. In the late-onset subgroup, the areas under the receiver operating characteristic curves for the MG-QOL-15 score-based diagnostic accuracy for anxiety and depression state were 0.816 (P = 0.001) and 0.983 (P < 0.001), respectively.CONCLUSIONHigher MG-QOL-15 scores were a risk factor for anxiety and depression in late-onset MG, and women with late-onset MG were more likely to have anxiety and depression than men were.

Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations.

Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein sequence level. Consequently, genetic variants in noncoding and untranslated HLA gene segments have not been fully explored but could also be important determinants for MG. To gain further insight into the role of HLA in MG, we applied next-generation sequencing to analyze sequence variation at eleven HLA genes in early-onset (EO) and late-onset (LO) non-thymomatous MG patients positive for the acetylcholine receptor (AChR) antibodies and ethnically matched controls from Italy, Norway, and Sweden. For all three populations, alleles and haplotype blocks present on the ancestral haplotype AH8.1 were associated with risk in AChR-EOMG patients. HLA-B*08:01:01:01 was the dominant risk allele in Italians (OR = 3.28, P = 1.83E−05), Norwegians (OR = 3.52, P = 4.41E−16), and in Swedes HLA-B*08:01 was the primary risk allele (OR = 4.24, P <2.2E-16). Protective alleles and haplotype blocks were identified on the HLA-DRB7, and HLA-DRB13.1 class II haplotypes in Italians and Norwegians, whereas in Swedes HLA-DRB7 exhibited the main protective effect. For AChR-LOMG patients, the HLA-DRB15.1 haplotype and associated alleles were significantly associated with susceptibility in all groups. The HLA-DR13–HLA-DR–HLA-DQ haplotype was associated with protection in all AChR-LOMG groups. This study has confirmed and extended previous findings that the immunogenetic predisposition profiles for EOMG and LOMG are distinct. In addition, the results are consistent with a role for non-coding HLA genetic variants in the pathogenesis of MG.

Rituximab for the treatment of generalised myasthenia gravis: experience in clinical practice

Rituximab (RTX) is an anti-CD20 monoclonal antibody that has been used in cases of refractory myasthenia gravis (MG). The aim of this work is to analyse the efficacy and safety of RTX in MG in real clinical practice in a tertiary hospital. A retrospective study was conducted with patients with MG treated with RTX in our centre from March 2014 to September 2020. Demographic and serological data, together with information about previous immunomodulatory treatment, clinical response and adverse effects are collected. Twenty patients with MG - 100% generalised: 70% late-onset MG (LOMG) and 30% early-onset MG (EOMG) - were given RTX (mean age: 66.8 years; 70% male). A total of 90% are seropositive, 16 of them with positive anti-acetylcholine receptor antibodies and two with positive muscle-specific tyrosine kinase (anti-MuSK) antibodies. All had failed previous treatments: 100% with steroids, 100% with intravenous immunoglobulins and/or plasmapheresis, 55% with other immunosuppressants (25% with one previous immunosuppressant, 10% with two, 15% with three and 5% with four) and 35% with thymectomy. After RTX, 75% of patients showed a clinical response (12 patients with complete remission and the possibility of steroid withdrawal without recurrence; and three patients with partial remission and the possible reduction of steroid dosage) and 25% therapeutic failure; in all these cases RTX was withdrawn. All the anti-MuSK+ patients (100%) and 92.8% of the LOMG patients responded to RTX, while 66% of EOMG patients failed. Only three patients reported adverse effects, all of which were mild and did not require RTX withdrawal. In our experience, rituximab is a safe and effective treatment in aggressive generalised MG with anti-MuSK or late-onset MG (LOMG).

Determinants of Quality of Life in Myasthenia Gravis Patients.

Background: Although approximately half of myasthenia gravis (MG) patents achieve remission, for the remaining group MG is often a life-long disease. Better understanding of the determinants of Quality of Life (QoL) in MG is needed to optimize treatment goals in chronic cases.Materials and Methods: We performed a single center cross-sectional study in 339 MG adult patients (64.9% women), with ocular or generalized disease. SF-36 and a structured questionnaire was administered, including information on previous and current MG severity, medications, comorbidities, education, occupation and BMI of the patient. Mean disease duration was 7.5 + 9.3 years. Current age was 51.6 + 18.3 years, 55% had Early-Onset (<50 years) MG.Results: There were no statistically significant differences in mean SF-36 subscores between women and men. Worse MGFA class was related to lower QoL in physical (PCS) and mental (MCS) subscore (p = 0.000 for both). Patients with MGFA I-II class had significantly better QoL in physical and mental subscores than patients with more severe MG (p < 0.005). Late-onset MG patients had worse QoL than EOMG in physical score domain PCS (p = 0.049). Overweight and obese patients had lower PCS (p = 0.002) and MCS (p = 0.038) than patients with normal BMI. University education was related to statistically higher PCS (p = 0.015) and MCS (p = 0.006). QoL in currently employed was better in PCS and MCS (p = 0.000), with white collar workers reporting higher PCS (p = 0.049) than the remaining group. Patients living with family evaluated their MCS (p = 0.015) better than living alone. Moderate physical activity (twice a week) improved PCS (p = 0.045).Conclusion: Our study confirmed that greater severity of symptoms, age, age of onset but also BMI, type of work, education status and physical activity affect QoL in MG.

Role of miRNAs in Normal and Myasthenia Gravis Thymus.

The thymus, a primary lymphoid organ, provides a complex environment essential for the generation of the T-cell repertoire. Thymic alterations occur during life either in the context of thymic involution upon aging or the pathophysiological context of Myasthenia Gravis (MG). These changes involve complicated regulatory networks, in which microRNAs (miRNAs) are key players. Here, we analyzed the role of miRNAs in thymocyte maturation and differentiation sustained by thymic epithelial cells. We compared data from the literature regarding the role of mouse thymic miRNAs and original data obtained from a human thymic miRnome study. We identified a set of highly expressed miRNAs defined as ThymiRs and investigated miRNA expression in infants as compared to adults to determine those associated with human thymic involution. Thymic changes are also frequently observed in MG, an autoimmune disease which results in the production of anti-acetylcholine receptor (AChR) antibodies that lead to muscle weaknesses. Alterations such as thymoma in late-onset MG patients and hyperplasia with ectopic germinal centers (GCs) in early-onset (EOMG) patients are found. Thymic miRNA expression has been studied in AChR-MG patients both in thymoma-associated MG (TAMG) and EOMG, and their function through their mRNA targets investigated. Most of the dysregulated thymic miRNAs in EOMG are associated with GC development, such as miR-7, miR-24, miR-139, miR-143, miR-145, miR-146, miR-150, miR-452, miR-548 or thymic inflammation, such as miR-125b, miR-146, or miR-29. Understanding these pathways may provide therapeutic targets or biomarkers of disease manifestations.

Evidence for association of STAT4 and IL12RB2 variants with Myasthenia gravis susceptibility: What is the effect on gene expression in thymus?

Myasthenia gravis (MG) is an autoimmune disease mediated by the presence of autoantibodies that bind mainly to the acetylcholine receptor (AChR) in the neuromuscular junction. In our case-control association study, we analyzed common variants located in genes of the IL12/STAT4 and IL10/STAT3 signaling pathways. A total of 175 sporadic MG patients of Greek descent, positively detected with anti-AChR autoantibodies and 84 ethnically-matched, healthy volunteers were enrolled in the study. Thymus samples were obtained from 16 non-MG individuals for relative gene expression analysis. The strongest signals of association were observed in the cases of rs6679356 between the late-onset MG patients and controls and rs7574865 between early-onset MG and controls. Our investigation of the correlation between the MG-associated variants and the expression levels of each gene in thymus did not result in significant differences.

Effect of ethnic origin and gender on the clinical manifestations of myasthenia gravis among the Jewish population in Israel

Reports on patients with myasthenia gravis (MG) of different ethnic origins demonstrated differences in weakness distribution and serological results. We studied MG characteristics in a cohort of Ashkenazi (ASH) and non-Ashkenazi (NASH) Jewish origin according to their ethnic origins and gender. The frequency of age of MG onset was distributed in a bi-modal fashion in the female patients and increased gradually over time, with a peak around 70years of age in the male patients. Ocular MG was more frequent in males and ASH patients. Unlike previous reports, our male patients had a higher proportion of positive serum anti-acetyl choline receptor (AChR) than female patients, with no ethnic-based differences in the rates of anti-AChR or anti-muscle specific kinase. Comorbidity with another autoimmune disease was more frequent among female patients with late-onset MG and NASH patients (mainly Israel-born). Male MG patients tended to have more malignant comorbidities than female MG patients. These results demonstrate the effect of ethnicity on clinical aspects of MG within the Jewish population in Israel, and reveal novel effects of gender-associated comorbidities in patients with MG.

Late-onset myasthenia gravis is predisposed to become generalized in the elderly.

ObjectiveThe continuous increase in the number of patients presenting with late-onset myasthenia gravis (LOMG) underscores the need for a better understanding of the clinical course and the establishment of an optimal therapeutic strategy. We aimed to clarify factors associated with clinical outcomes in LOMG.MethodsWe retrospectively reviewed the clinical profiles of 40 patients with early-onset MG (EOMG) (onset age: 49 years or younger), 30 patients with non-elderly LOMG (onset age: 50–64 years), and 28 patients with elderly LOMG (onset age: 65 years or older) and compared the subgroups according to onset age and thymus status. The evaluated parameters were MGFA classification before treatment, MG-ADL score, complicating diseases, antibody titer, treatment, and MGFA post-intervention status.ResultsElderly LOMG patients showed transition to generalized symptoms at a higher frequency and underwent thymectomy less frequently than EOMG and non-elderly LOMG patients (p < 0.001). The frequencies of crisis and plasmapheresis were significantly lower in thymectomized LOMG patients without thymoma than in thymectomized LOMG patients with thymoma or non-thymectomized LOMG patients (p < 0.01, P < 0.05, respectively). However, the outcome was not significantly different. All of the thymectomized LOMG patients without thymoma presenting with hyperplasia or thymic cyst had a favorable clinical course.ConclusionsOur study showed that elderly LOMG patients are more prone to severity, suggesting that they require aggressive immunomodulatory therapy.

Two-year outcome of thymectomy in non-thymomatous late-onset myasthenia gravis.

Thymectomy is an effective treatment for myasthenia gravis (MG). However, there is limited data on its effectiveness in non-thymomatous late-onset MG (LOMG). The aim of this study was to analyze the effects of thymectomy in LOMG. We retrospectively reviewed the 2-year post-thymectomy prognosis in 39 consecutive patients with non-thymomatous, anti-acetylcholine receptor antibody positive, and generalized LOMG (age at onset ≥ 50 years). The MG foundation of America (MGFA) classification, MGFA post-intervention status, dosage of prednisolone and pyridostigmine, and anti-acetylcholine receptor antibody titers were evaluated. Among the 39 LOMG patients, thymic hyperplasia was seen in 5 (12.8%). MGFA classification and prednisolone dosage before thymectomy were similar between the LOMG with thymic hyperplasia group (n = 5) and the LOMG with involuted thymus group (n = 34). Two years after thymectomy, the LOMG patients with thymic hyperplasia showed higher proportion of remission (60 vs. 26%) and received lower prednisolone dosage compared to patients with involuted thymus (0.8 vs. 4.0 mg/day). Notably, the proportion of patients with minimal manifestation or better status with receiving ≤ 5 mg/day prednisolone was much higher in the thymic hyperplasia group than in the involuted thymus group (100 vs. 62%). In conclusion, thymectomy could have beneficial effects in generalized LOMG, particularly in patients with thymic hyperplasia.

Late-onset myasthenia gravis – CTLA4low genotype association and low-for-age thymic output of naïve T cells

Late-onset myasthenia gravis (LOMG) has become the largest MG subgroup, but the underlying pathogenetic mechanisms remain mysterious. Among the few etiological clues are the almost unique serologic parallels between LOMG and thymoma-associated MG (TAMG), notably autoantibodies against acetylcholine receptors, titin, ryanodine receptor, type I interferons or IL-12. This is why we checked LOMG patients for two further peculiar features of TAMG – its associations with the CTLA4high/gain-of-function +49A/A genotype and with increased thymic export of naïve T cells into the blood, possibly after defective negative selection in AIRE-deficient thymomas. We analyzed genomic DNA from 116 Caucasian LOMG patients for CTLA4 alleles by PCR/restriction fragment length polymorphism, and blood mononuclear cells for recent thymic emigrants by quantitative PCR for T cell receptor excision circles. In sharp contrast with TAMG, we now find that: i) CTLA4low +49G(+) genotypes were more frequent (p = 0.0029) among the 69 LOMG patients with age at onset ≥60 years compared with 172 healthy controls; ii) thymic export of naïve T cells from the non-neoplastic thymuses of 36 LOMG patients was lower (p = 0.0058) at diagnosis than in 77 age-matched controls. These new findings are important because they suggest distinct initiating mechanisms in TAMG and LOMG and hint at aberrant immuno-regulation in the periphery in LOMG. We therefore propose alternate defects in central thymic or peripheral tolerance induction in TAMG and LOMG converging on similar final outcomes. In addition, our data support a 60-year-threshold for onset of ‘true LOMG’ and an LOMG/early-onset MG overlapping group of patients between 40 and 60.

Genetics of Myasthenia Gravis: A Case-Control Association Study in the Hellenic Population

Myasthenia gravis (MG) is an heterogeneous autoimmune disease characterized by the production of autoantibodies against proteins of the postsynaptic membrane, in the neuromuscular junction. The contribution of genetic factors to MG susceptibility has been evaluated through family and twin studies however, the precise genetic background of the disease remains elusive. We conducted a case-control association study in 101 unrelated MG patients of Hellenic origin and 101 healthy volunteers in order to assess the involvement of common genetic variants in susceptibility to MG. We focused on three candidate genes which have been clearly associated with several autoimmune diseases, aiming to investigate their potential implication in MG pathogenesis. These are interferon regulatory factor 5 (IRF-5), TNFα-induced protein 3 (TNFAIP3), also known as A20, and interleukin-10 (IL-10), key molecules in the regulation of immune function. A statistical trend of association (P = 0.068) between IL-10 promoter single nucleotide polymorphisms (SNPs) and the subgroups of early and late-onset MG patients was revealed. No statistically significant differences were observed in the rest of the variants examined. As far as we are aware, this is the first worldwide attempt to address the possible association between IRF-5 and TNFAIP3 common genetic variants and the genetic basis of MG.

Comparing the Autoantibody Levels and Clinical Efficacy of Double Filtration Plasmapheresis, Immunoadsorption, and Intravenous Immunoglobulin for the Treatment of Late‐onset Myasthenia Gravis

The aim of this study was to investigate the effects of double-filtration plasmapheresis (DFPP), immunoadsorption (IA) and intravenous immunoglobulin (IVIg) in the treatment of late-onset myasthenia gravis (MG). A total of 40 late-onset MG patients were randomly divided into three groups: 15 patients were treated with DFPP; 10 patients were treated with IA; and 15 patients received IVIg. The titers of titin antibodies (Titin-ab), acetylcholine receptor antibodies (AChR-ab), presynaptic membrane antibody (Prsm-ab) were detected before and after the treatment, and the quantitative MG score (QMG score) was assessed by blinded examiners before and immediately after the entire course of treatment. The clinical efficacy, duration of respiratory support, hospital stay, and the correlation between the three antibodies and the QMG score were also analyzed. Compared to pre-treatment, the values of Titin-ab, AChR-ab, and PrsmR-ab were all dramatically decreased (P < 0.05); meanwhile the value of Titin-ab in the DFPP and IA groups decreased much more than in the IVIg group (P < 0.01); however, no statistical difference was found between the DFPP and IA groups (P > 0.05). Although the QMG score significantly improved in all three groups, it decreased much more in both the DFPP and IA groups than that in the IVIg group (P < 0.01). Symptoms were also effectively ameliorated by all treatments, but the clinical efficacy of the DFPP and IA groups was higher than the IVIg group (P < 0.05), as was the remission time (P < 0.01), the duration of hospital stay (P < 0.05), and the number of respiratory supports required (P < 0.05). Using Pearson's correlation, the decrease of Titin-ab showed a longitudinal correlation with the decrease of QMG score (r = 0.6107, P < 0.01). Both DFPP and IA showed better short-term clinical effectiveness than immunoglobulin transfusion, rapidly and effectively clearing the pathogenic antibodies in late-onset MG patients, especially for Titin-ab.

Titin and ryanodine receptor antibodies in myasthenia gravis

Some myasthenia gravis (MG) patients have antibodies against skeletal muscle antigens in addition to the acetylcholine receptor (AChR). Two major antigens for non-AchR antibodies in MG are the Ca(2+) release channel of the sarcoplasmic reticulum, the ryanodine receptor (RyR) and titin, a gigantic filamentous muscle protein essential for muscle structure, function and development. RyR and titin antibodies are found mainly in thymoma MG patients and in a few late-onset MG patients and correlate with a severe MG disease. The presence of titin antibodies, which bind to key regions near the A/I junction and in the central I-band, correlates with myopathy. The immunosuppressant (FK506), which enhances Ca(2+) release from the RyR, seems to have a symptomatic effect on MG patients with RyR antibodies. The RyR antibodies recognize a region near the N-terminus important for channel regulation and inhibit Ca(2+) release in vitro. However, evidence that antibodies against the intracellular antigens RyR and titin are pathogenic in vivo is still missing.

The role of complement in myasthenia gravis: serological evidence of complement consumption in vivo

Background Antibodies to the acetylcholine receptor (AChR) titin and the ryanodine receptor (RyR) occur in myasthenia gravis (MG). These antibodies are capable of complement activation in vitro. The involvement of the complement system should cause consumption of complement components such as C3 and C4 in vivo. Materials and methods Complement components C3 and C4 were assayed in sera from 78 AChR antibody-positive MG patients and 52 healthy controls. Forty-eight of the patient sera contained titin antibodies as well, and 20 were also RyR antibody-positive. Results MG patients with AChR antibody concentrations above the median (11.2 nmol/l) had significantly lower mean C3 and C4 concentrations in serum compared to those with AChR antibody concentrations below the median. Titin antibody-positive MG patients, titin antibody-negative early-onset MG patients, titin antibody-negative late-onset MG patients, and controls had similar C3 and C4 concentrations. Nor did mean C3 and C4 concentrations differ in MG patients with RyR antibodies. Patients with severe MG (grades 4 and 5) had similar C3 and similar C4 levels compared to those with mild MG (grades 1 and 2). Conclusion An increased in vivo complement consumption was detected in MG patients with high AChR antibody concentrations, unrelated to MG severity and non-AChR muscle antibodies.

Different age-related effects of thymectomy in myasthenia gravis: role of thymoma, zinc, thymulin, IL-2 and IL-6

Different age-related immune pathogenetic mechanisms in myasthenia gravis (MG) have been suggested because of restoration after thymectomy (Tx) of altered zinc, thymulin (TH) and T-cell subsets exclusively in early-onset patients (younger <50 years), not in late-onset patients (older >50 years). In this context interleukin-2 (IL-2), interleukin-6 (IL-6) and thymoma are crucial because both involved in MG pathogenesis and correlated with acetylcholine receptors (AchRs) Ab production. Moreover, IL-2 and IL-6 are zinc-dependent, are altered in aging and related with zinc and TH age-dependent declines. Moreover, zinc is relevant for immune efficiency. In order to confirm these different age-related pathogenetic mechanisms further, the role of thymoma, zinc, TH, IL-2 and IL-6 is studied in MG patients with generalized MG with and without thymoma before and 1 month and 1 year after Tx. The high IL-2, IL-6, zinc, and AChR Ab levels observed before Tx are significantly correlated each other in younger MG patients (<50 years) independently by thymoma and in older MG patients (>50 years) with thymoma. No correlations exist in older MG patients without thymoma. Thymulin is not correlated with other parameters considered to be both in younger and older MG patients independently by the thymoma. Thymectomy restores zinc; immune parameters and AChR Ab are exclusively in the younger group, not in the older one. These findings suggest that IL-2 and IL-6, via zinc, rather than TH, may be involved in different age-related pathogenetic mechanisms mainly in early-onset MG. By contrast, thymoma may be involved in MG etiology in late-onset representing, as such, a useful discriminant tool for MG etiology between early and late-onset MG patients. Because autoimmune phenomena may rise in aging, a parallelism with altered immune functions during aging is discussed.

Striational autoantibodies in myasthenia gravis patients recognize I-band titin epitopes

Myasthenia gravis (MG) patients develop autoantibodies primarily against the acetylcholine receptor in the motor endplate, but also against intracellular striated muscle proteins, notably titin, the giant elastic protein of the myofibrillar cytoskeleton. Titin antibodies have previously been shown to be directed against a single epitope on the molecule, located at the A-band/I-band junction and referred to as the main immunogenic region (MIR) of titin. By using immunofluorescence microscopy on stretched single myofibrils, we now report that ∼40% of the sera from 18 MG/thymoma patients and 8 late-onset MG patients with thymus atrophy contain antibodies that bind to a more central I-band titin region. This region consists of homologous immunoglobulin domains and is known to be differentially spliced dependent on muscle type. All patients with I-band titin antibodies also had antibodies against the MIR. Although a statistically significant correlation between the occurrence of I-band titin antibodies and MG severity was not apparent, the results could hint at an initial immunoreactivity to titin's MIR, followed by reactivity along the titin molecule in the course of the disease.

Late onset myasthenia gravis

Late onset myasthenia gravis (MG) is defined as the onset of the disease after the age of 50 in a patient with no clinical or paraclinical evidence of a thymoma. Myasthenia gravis has a bimodal appearance for both sexes with a peak age of onset located in the early onset group and another peak for late onset of MG. Early onset of MG in men is approximately 10 years later than in females. In late onset MG, the thymus is smaller than in early onset and much of the lymphoid tissue has been substituted with fat. There is no morphological evidence that the thymus atrophy seen in late onset MG is any different from the thymus involution which is age‐related. The AChR antibody concentration is lower in cases with late onset MG than it is in early onset and in thymoma‐associated MG. Sera from late onset MG patients can be divided in 2 groups; those with and those without striated muscle (MGT 30) antibodies. Their presence is not an effect of age since they are not detected among old healthy individuals. Nor is it an effect of long MG duration, since there is no relation between titre and duration. Non‐thymoma MG patients who demonstrate an immune response to titin identical to that observed in thymoma, have a worse prognosis and seem to do less well after thymectomy than late onset MG patients without muscle antiboides.