Amelia Evoli

Guidelines for treatment of autoimmune neuromuscular transmission disorders

Background:  Important progress has been made in our understanding of the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert–Eaton myasthenic syndrome (LEMS) and neuromyotonia (Isaacs’ syndrome).

ANTI-MuSK ANTIBODY MYASTHENIA GRAVIS: CLINICAL FINDINGS AND RESPONSE TO TREATMENT IN TWO LARGE COHORTS

Introduction: Myasthenia gravis (MG) patients with autoantibodies to muscle‐specific tyrosine kinase (MuSK) represent a distinct subset of those with this disease. Treatment and outcomes data in these patients are limited and conflicting. Methods: We reviewed 110 MuSK‐MG patients from two large clinics in Italy and the USA. Results: Thirty‐nine to 49% of patients with generalized, acetylcholine receptor antibody (AChR‐Ab)–negative MG had MuSK‐MG. Eighty‐five percent were female, with disease onset typically in the fourth decade. Ocular and/or bulbar symptoms were present at onset in 79% of those studied. Eighty‐five percent were MGFA class III or greater, and crisis occurred in 28%. Plasma exchange (PLEX) produced improvement in 93%, whereas only 61% improved after intravenous immunoglobulin. Long‐term outcomes were comparable to those of patients with AChR‐Ab–positive MG. Conclusions: MuSK‐MG has a marked female predominance with frequent oculobulbar weakness and crises. Many patients deteriorate rapidly early in the disease, and PLEX is usually the preferred treatment. Long‐term outcomes are similar to those of patients with AChR‐Ab+ MG. Muscle Nerve 44: 36–40, 2011

Randomized Trial of Thymectomy in Myasthenia Gravis

BACKGROUND Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Thymus changes in anti-MuSK-positive and -negative myasthenia gravis

Morphologic findings of thymuses from 32 anti-acetylcholine receptor (AChR)-negative myasthenia gravis patients, 12 with and 20 without antibodies against the muscle-specific kinase (MuSK), were compared with those from 30 AChR-positive subjects. In contrast with the high frequency of thymic hyperplastic changes in AChR-positive patients, in MuSK-positive subjects histologic alterations were minimal, arguing against an intrathymic disease pathogenesis. Since hyperplastic changes were seen in 35% of MuSK-negative patients, the thymus could be involved in some of these cases.

Course and treatment of myasthenia gravis during pregnancy

Objective: To evaluate the influence of myasthenia gravis (MG) on pregnancy and potential treatment risks for infants and mothers. Background: MG frequently affects young women in the second and third decades of life, overlapping with the childbearing years. Knowledge of the potential effects of 1) pregnancy on the course of MG and 2) the use of immunosuppressive drugs during pregnancy is limited, rendering decision-making difficult for both patient and physician. Methods: We studied 47 women who became pregnant after the onset of MG. Immunosuppressive drugs were administered when MG symptoms were not controlled with anticholinesterases. Sixty-four pregnancies resulted in 55 children and 10 abortions. Results: During pregnancy, MG relapsed in 4 of 23 (17%) asymptomatic patients who were not on therapy before conception; in patients taking therapy, MG symptoms improved in 12 of 31 pregnancies (39%), remained unchanged in 13 (42%), and deteriorated in 6 (19%). MG symptoms worsened after delivery in 15 of 54 (28%) pregnancies. Anti-acetylcholine receptor antibody (anti-AChR ab) was positive in 40 of 47 mothers and was assayed in 30 of 55 newborns; 13 were positive and 5 of 55 (9%) showed signs of neonatal MG (NMG). All affected babies were seropositive. Conclusions: Pregnancy does not worsen the long-term outcome of MG. The course of the disease is highly variable and unpredictable during gestation and can change in subsequent pregnancies. The occurrence of NMG does not correlate with either maternal disease severity or anti-AChR antibody titer. Immunosuppressive therapy, plasmapheresis, and IV human immunoglobulins can be administered safely if needed.

A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis.

Double-seronegative myasthenia gravis (dSN-MG, without detectable AChR and MuSK antibodies) presents a serious gap in MG diagnosis and understanding. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) have been identified in several dSN-MG sera, but with dramatic frequency variation (∼2-50%). We have developed a cell based assay (CBA) based on human LRP4 expressing HEK293 cells, for the reliable and efficient detection of LRP4 antibodies. We have screened about 800 MG patient sera from 10 countries for LRP4 antibodies. The overall frequency of LRP4-MG in the dSN-MG group (635 patients) was 18.7% but with variations among different populations (range 7-32.7%). Interestingly, we also identified double positive sera: 8/107 anti-AChR positive and 10/67 anti-MuSK positive sera also had detectable LRP4 antibodies, predominantly originating from only two of the participating groups. No LRP4 antibodies were identified in sera from 56 healthy controls tested, while 4/110 from patients with other neuroimmune diseases were positive. The clinical data, when available, for the LRP4-MG patients were then studied. At disease onset symptoms were mild (81% had MGFA grade I or II), with some identified thymic changes (32% hyperplasia, none with thymoma). On the other hand, double positive patients (AChR/LRP4-MG and MuSK/LRP4-MG) had more severe symptoms at onset compared with any single positive MG subgroup. Contrary to MuSK-MG, 27% of ocular dSN-MG patients were LRP4 antibody positive. Similarly, contrary to MuSK antibodies, which are predominantly of the IgG4 subtype, LRP4 antibodies were predominantly of the IgG1 and IgG2 subtypes. The prevalence was higher in women than in men (female/male ratio 2.5/1), with an average disease onset at ages 33.4 for females and 41.9 for males. Overall, the response of LRP4-MG patients to treatment was similar to published responses of AChR-MG rather than to MuSK-MG patients.

Thymoma in patients with MG: Characteristics and long-term outcome

Objective: To examine the characteristics of thymoma when associated with MG and to evaluate those conditions that can complicate management and affect survival. Methods: The study includes 207 myasthenic patients who were operated on for thymoma, with at least 1-year follow-up from surgery. MG severity and response to treatment, the occurrence of paraneoplastic diseases and extrathymic malignancies, thymoma histologic types and stages, adjuvant therapy, tumor recurrences, and causes of death were recorded. Results: MG-associated thymoma was predominantly of B type and was invasive in the majority of patients. MG was generally severe, and most patients remained dependent on immunosuppressive therapy. Other paraneoplastic disorders and extrathymic malignancies were found in 9.66 and 11.11% of patients. Thymoma recurrences occurred in 18 of 115 patients with invasive tumors (15.65%) and were often associated with the onset/aggravation of autoimmune diseases. On completion of the study, MG and thymoma accounted for a similar mortality rate. Conclusions: Thymoma should be considered as a potentially malignant tumor requiring prolonged follow-up. The presence of myasthenic weakness can still complicate its management. Thymoma-related deaths are bound to outnumber those due to MG in the future.

Circulating and thymic CD4+ CD25+ T regulatory cells in myasthenia gravis: effect of immunosuppressive treatment

Accumulating evidence indicates an immunosuppressive role of the thymus‐derived CD4+ T‐cell population constitutively expressing high level of CD25, T regulatory (Treg) cells, in autoimmune diseases. Here we show that the number of Treg cells in the blood is significantly lower in untreated myasthenia gravis patients than in age‐matched healthy subjects, whereas it is normal or elevated in patients on immunosuppressive therapy (prednisone frequently associated with azathioprine). Therapeutic thymectomy (Tx) for either the thymoma or non‐neoplastic thymic alterations that are often associated with myasthenia gravis provided unique material for studying intrathymic Treg cells and correlating them with their peripheral counterparts. We observed that Tx prevents the increase of Treg cells in the circulation that follows immunosuppressive therapy (particularly evident if the thymus is not neoplastic), indicating that the thymus contributes to Treg‐cell normalization. However, thymic Treg cells are not modulated by immunosuppressive therapy and even in thymectomized patients Treg‐cell numbers in the blood eventually recover. The present findings suggest that a deficiency in Treg cells favours the development of myasthenia gravis and that their normalization is an important clinical benefit of immunosuppressive therapy. Treg normalization appears to be largely thymus independent and possibly reflects the reported capacity of corticosteroids to promote Treg‐cell development.

Anti-P110 Autoantibodies Identify a Subtype of “Seronegative” Myasthenia Gravis with Prominent Oculobulbar Involvement

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and pathogenetic autoantibodies directed against the nicotinic acetylcholine receptor (seropositive myasthenia gravis; SPMG). Nearly 15% to 20% of MG patients do not have these antibodies (seronegative myasthenia gravis; SNMG), but several evidence indicate that these patients have circulating pathogenic autoantibodies directed against other muscle antigens. Using the TE671 rhabdomyosarcoma cell line as an antigen source, we analyzed sera from 63 SNMG and 26 SPMG patients and 26 healthy blood donors by FACS analysis. We found that 40 of 63 SNMG patients and only 1 of 26 SPMG patients had IgG binding to the TE671 cell line. None of the sera bound to the unrelated MRC5 cell line. To identify the antigen, we analyzed sera immunoreactivity in more detail by immunoprecipitation of biotinylated membrane proteins from TE671 cells. When the immunoprecipitated proteins were separated by SDS-PAGE electrophoresis and then transferred to nitrocellulose membranes, we found that SNMG IgG identify a band corresponding to a protein with a molecular weight of 110 kDa (P110), which is not recognized by seropositive MG sera. This anti-P110 immunoreactivity is significantly associated with a distinct clinical picture characterized by a prominent involvement of ocular and bulbar muscles, with frequent respiratory problems (p < 0.005), and is recognized by a specific antimuscle specific kinase (MuSK) antiserum. In a recent article, the presence of anti-MuSK antibodies was described in SNMG. Our results confirm the presence of these antibodies in SNMG and suggest that anti-P110/MuSK autoantibodies identify a subtype of SNMG in which the different pathogenesis induces the distinct clinical picture.

Prognosis of myasthenia gravis: A multicenter follow-up study of 844 patients

The prognosis of myasthenia gravis (MG) was assessed retrospectively using life-table analysis in 844 patients followed up for a mean period of 5 years in 3 major Italian centers. The chance of achieving at least a 1-year remission after treatment withdrawal (complete remission) was assessed as a specific end-point in the whole population and in selected subgroups with reference to the principal prognostic variables. The cumulative probability of complete remission was 1% by 1 year, 8% by 3 years, 13% by 5 years, and 21% by 10 years. The only variables correlated to the chance of complete remission were younger age at onset of MG, lower severity of symptoms at onset and nadir, and shorter disease duration at diagnosis. In addition, thymectomy and early surgery seemed to influence the chance of remission. Other factors (including the presence of thymoma) did not significantly influence the outcome of the disease.