A clinical and immunological study on late onset Myasthenia Gravis

Myasthenia gravis is an autoimmune disorder of neuromuscular transmission caused by antibodies to the acetylcholine receptor and related components on the post synaptic membrane of the neuromuscular junction. Recent evidence has shown that the incidence of late-onset myasthenia gravis, defined as onset at more than 50 years of age, has been increasing. We sought to prospectively recruit patients newly diagnosed with myasthenia gravis and look at their clinical and immunological profile to see if there are any differences between early onset and late-onset myasthenia gravis. Methods: This was a multicentre study across Nottingham, Birmingham and Oxford. We recruited 150 patients with myasthenia gravis across the three sites, newly diagnosed within the preceding 12 months. We did clinical examinations, completed MG composite scores (MGC), MG Quality of life scores (MG QOL), and blood tests including serum for antibodies, and whole blood for PBMC isolation and T-cell studies. These were repeated at annual follow up. The antibody studies were performed at Oxford by radioimmunoassay (RIA) and cell based assays (CBA) for acetylcholine receptor antibodies (AChR), muscle specific kinase (MuSK) and lipoprotein-related protein 4 (LRP4) antibodies. Results: We recruited 150 patients with myasthenia gravis, 76% of whom had LOMG, with a female to male ratio of 1:1.6. EOMG patients more frequently had ocular myasthenia compared to LOMG patients, 94.7% of patients were seropositive for either AChR, MuSK or LRP4 antibodies. T-cell studies showed that the pro-inflammatory and anti-inflammatory cytokine balance is disrupted in all MG patients with decreased Treg percentages and increased production of IL10, IL17 and TNF alpha, which is more pronounced in patients with AChR antibodies. The clinical presentation did not show any difference between the different antibody subgroups, but there was a milder, more indolent course in seronegative patients, and AChR + MuSK double positive patients were more likely to need steroids on generalisation. The majority of the patients responded well to treatment with improvement in MGC, MG QOL and AChR RIA titres with time. Conclusions: To our knowledge, this is the largest prospective study on the clinical and immunological aspects of late-onset myasthenia gravis to date. Further studies on B cells in MG along with micro-RNAs as biomarkers in MG are being done

A clinical and immunological study on late onset Myasthenia Gravis

Myasthenia gravis is an autoimmune disorder of neuromuscular transmission caused by antibodies to the acetylcholine receptor and related components on the post synaptic membrane of the neuromuscular junction. Recent evidence has shown that the incidence of late-onset myasthenia gravis, defined as onset at more than 50 years of age, has been increasing. We sought to prospectively recruit patients newly diagnosed with myasthenia gravis and look at their clinical and immunological profile to see if there are any differences between early onset and late-onset myasthenia gravis. Methods: This was a multicentre study across Nottingham, Birmingham and Oxford. We recruited 150 patients with myasthenia gravis across the three sites, newly diagnosed within the preceding 12 months. We did clinical examinations, completed MG composite scores (MGC), MG Quality of life scores (MG QOL), and blood tests including serum for antibodies, and whole blood for PBMC isolation and T-cell studies. These were repeated at annual follow up. The antibody studies were performed at Oxford by radioimmunoassay (RIA) and cell based assays (CBA) for acetylcholine receptor antibodies (AChR), muscle specific kinase (MuSK) and lipoprotein-related protein 4 (LRP4) antibodies. Results: We recruited 150 patients with myasthenia gravis, 76% of whom had LOMG, with a female to male ratio of 1:1.6. EOMG patients more frequently had ocular myasthenia compared to LOMG patients, 94.7% of patients were seropositive for either AChR, MuSK or LRP4 antibodies. T-cell studies showed that the pro-inflammatory and anti-inflammatory cytokine balance is disrupted in all MG patients with decreased Treg percentages and increased production of IL10, IL17 and TNF alpha, which is more pronounced in patients with AChR antibodies. The clinical presentation did not show any difference between the different antibody subgroups, but there was a milder, more indolent course in seronegative patients, and AChR + MuSK double positive patients were more likely to need steroids on generalisation. The majority of the patients responded well to treatment with improvement in MGC, MG QOL and AChR RIA titres with time. Conclusions: To our knowledge, this is the largest prospective study on the clinical and immunological aspects of late-onset myasthenia gravis to date. Further studies on B cells in MG along with micro-RNAs as biomarkers in MG are being done

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Quantitative Assessment of Response to Long‐Term Treatment with Intravenous Immunoglobulin in Patients with Stiff Person Syndrome

BACKGROUND: Stiff person syndrome (SPS) is an autoimmune condition involving antibodies against several components of the inhibitory synapse in the spinal cord, with glutamic acid decarboxylase antibodies being the predominant immune marker. SPS affects approximately 1 patient per million population per year. The effect of intravenous immunoglobulin (IVIG) has been established, but studies on the long‐term efficacy of regular IVIG are limited. OBJECTIVES: To review clinical details and long‐term treatment response using a patient‐reported questionnaire in SPS and related syndromes. METHODS: Patients were identified from a tertiary neuroimmunology clinic based on classical clinical symptoms, autoimmune profiles, and neurophysiological changes (Dalakas criteria). They were followed up after treatment to assess the response to IVIG. RESULTS: A total of 23 patients fulfilled the selection criteria. Patients' demographic profiles and clinical presentations were akin to that reported in literature. There was significant improvement in the functional ability (assessed by the modified Rankin scale [mRS]) and quality of life (QoL) following treatment with IVIG within 4 to 10 weeks (pre‐mRS vs. post‐mRS, P < 0.0001; pre‐QoL vs. post‐QoL, P = 0.0003) and sustained after 5 years of treatment (pre‐mRS vs. present mRS, P = 0.0003; pre‐QoL vs. present QoL, P = 0.0002). CONCLUSIONS: This article describes one of the largest single‐center experiences of 23 patients with SPS and related syndromes and is the first to establish the long‐term efficacy of regular IVIG using a patient‐reported scoring system (Birmingham Response to Immunomodulatory Therapy [BRIT]). Consistent improvement in QoL and functional scores were seen over nearly 5 years after regular use of IVIG. It is recommended to use BRIT scores to assess the initial response as well as to monitor continued improvement to immunomodulation in SPS

False-positive acetylcholine receptor antibody results in patients without myasthenia gravis.

Acetylcholine receptor antibodies are very specific for myasthenia. During a large prospective cohort study of myasthenia, we encountered five patients, positive for acetylcholine receptor (AChR) antibodies by radioimmunoprecipitation assay (RIA), whose clinical course revealed diagnoses other than myasthenia. Two patients had transiently raised AChR antibodies associated with Guillain-Barré syndrome. Antibodies to clustered AChRs, in a live cell-based assay, were negative in all five patients, suggesting that results from the RIAs were false-positives. It is possible that the AChR antibodies detected by RIA in these cases were non-pathogenic, and directed to intracellular epitopes of the AChR

Circulating microRNA miR-21-5p, miR-150-5p and miR-30e-5p correlate with clinical status in late onset myasthenia gravis

There are no biomarkers for late onset myasthenia gravis (LOMG; onset &gt; 50 years). We evaluated circulating microRNA in a discovery cohort of 4 LOMG patients and 4 healthy controls and in a prospective diagnostic validation cohort of 73 LOMG patients (48 male) with longitudinal follow-up samples. In immunosuppression naive patients, levels of miRNAs miR-150-5p, miR-21-5p and miR-30e-5p decreased in parallel with clinical improvement after initiation of immunosuppression and their levels positively correlated with the clinical MG composite score. Levels of miR-150-5p and miR-21-5p were lower in patients with ocular compared to generalized LOMG. Circulating miR-150-5p, miR-21-5p and miR-30e-5p correlate with the clinical course in LOMG

miR-30e-5p as predictor of generalization in ocular myasthenia gravis

Objective: To determine a predictive factor for the risk of conversion from ocular myasthenia gravis (OMG) to generalized MG (GMG) in a prospective study. Methods: RNA was isolated from serum samples and detection of microRNA (miRNA) expression analyzed with qPCR. In the discovery set, 179 human miRNAs were assayed for profiling of five OMG patients and four age- and gender-matched healthy controls. Based on the specific accumulation pattern of 19 miRNAs from the discovery set, in addition to miRNAs previously found elevated in generalized MG (GMG; miR-150-5p and miR-30e-5p), 21 miRNAs were subsequently analyzed in a validation cohort of 83 OMG patients (82 immunosuppression treatment naive; 49 male) within 3 months of diagnosis and at a follow-up visit (median duration 28 months from first visit). Results: Thirteen patients generalized 14.8 +/- 12.0 months after the diagnosis and the majority (85%) belonged to the late onset MG group. Two miRNAs were significantly higher in secondary GMG (SGMG) patients compared to OMG patients with late onset MG: miR-30e-5p (9.1 +/- 0.5 vs. 6.3 +/- 0.9; P &lt; 0.0001) and miR-150-5p (7.4 +/- 1.1 vs. 6.4 +/- 1.1; P = 0.01). The sensitivity for miR-30e-5p in differentiating OMG and SGMG was 96% in all OMG patients and 100% in late onset OMG patients. Interpretation: This is the first study to describe a potential predictive factor associated with the risk of generalization for patients with OMG. Raised levels (&gt;8) of miR-30e-5p at initial presentation in patients with ocular MG symptoms, give a predictive cut-off for subsequent generalization of 96-100%