Immune Profiles in Myasthenia Gravis

Comparison of Lymphocyte Subset, Cytokine and Complement Profiles in Myasthenia Gravis of Different Severity, Disease Time-points, and Treatment History

The investigators aim to better describe the immune profile in myasthenia gravis (MG), including lymphocyte subset, cytokine and complement profiles; how they differ between patients of different severity, at times of disease exacerbation, and with different immunosuppressive treatments. The investigators hope to build a clearer picture of how different immune measures vary in MG, contributing to the understanding of the patho[physiology of the disease, and working towards a biomarker that might help clinicians optimise an individual's treatment.

the investigators aim to take into account the heterogeneity of MG by taking into account age of onset of MG (early vs late onset) and focussing on acetylcholine receptor antibody (AChR) positive, non-thymomatous MG aged 18-80.

Study Overview

• Status: Not yet recruiting
• Conditions: Myasthenia Gravis

Detailed Description

This study is designed to confirm and refine the knowledge around these changes in the immune profile, including lymphocyte subsets, and complement analysis, between different subgroups of patients with MG of different severity, different levels of immunosuppressive treatment, and at different time points in the disease course, ensuring these are put into the context of the patient's disease subtype (late-onset (LOMG) vs early-onset (EOMG)). This should enable us to understand more about the underlying immune changes in MG, how they relate to disease activity or severity, how this is impacted upon by immunosuppression, and guide us towards a markers for disease severity and effective immunosuppression that could be used in clinical practice, and help guide treatment decisions. One of the challenges in studying patients with MG with the relatively low prevalence of the condition, meaning it can be difficult to recruit large enough numbers of patients; the investigators will work with other tertiary neurology centres throughout England in order to meet recruitment targets.

The research project will consist of three work streams:

1. A one-off observational comparison of the immune profile of patients with different MG severity and in comparison to healthy controls.
2. A prospective observational study examining changes in lymphocyte subset, cytokine and complement profiles associated with clinical exacerbation of myasthenia gravis.
3. A prospective cohort study comparing lymphocyte subset, cytokine and complement profile with disease activity following B cell depletion for refractory myasthenia gravis.

• Study Type: Observational
• Enrollment (Anticipated): 163

Contacts and Locations

• Study Contact: Name: Katherine Dodd, MBChB MRCP; Phone Number: 07599 072993; Email: katherine.dodd-3@postgrad.manchester.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Acetylcholine receptor antibody positive myasthenia gravis

Description

Inclusion Criteria:

• All participants:
• Are able to give valid written consent
• are aged between the ages of 18 and 80

Stable Immunosuppressed

• Have a diagnosis of AChR positive myasthenia gravis (can be ocular, bulbar or generalised)
• MGFA Post-intervention Status MM or better with no clinical relapse for 2 years
• On either azathioprine or MMF along with ≤5mg/day of prednisolone
• No prednisolone dose increase or decrease in past 12 months
• No increase in azathioprine or MMF dose for 2 years (allowing for cessation for up to 1 month)

Stable Non-Immunosuppressed

• have a diagnosis of AChR positive myasthenia gravis (can be ocular, bulbar or generalised)
• MGFA Post-intervention Status MM or better on only low-dose cholinesterase inhibitors (≤<120 mg pyridostigmine/day) for over two years and ≤5mg/day of prednisolone for over two years.
• No prednisolone dose increase or decrease in past 12 months

Refractory

• have a diagnosis of AChR positive myasthenia gravis (can be ocular, bulbar or generalised)
• have been deemed eligible to be refractory to standard treatment and eligible for rituximab as per the NHS England criteria.

Exclusion Criteria for all participants:

• Are unable to give valid consent
• Co-existing autoimmune condition for which azathioprine or mycophenolate mofetil are treatments (e.g. inflammatory bowel disease, rheumatoid arthritis, neuromyotonia)
• Currently undergoing treatment for solid organ or haematological malignancy, or previous thymoma
• Clinical frailty scale ≥6

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Stable Immunosuppressed; Acetylcholine repector antibody positvie myasthenia gravis, stable for two years on prednsiolone <5mg/day and azathioprine or mycophenolate.
Stable Non-immunosuppressed; Acetylcholine repector antibody positvie myasthenia gravis, stable for two years on ≤120mg pyridostigmine/day and no immunosuppression.
Refractory; Acetylcholine repector antibody positvie myasthenia gravis, meeting the NHS England criteria for Rituximab
Healthy Controls; No autoimmune disease or current solid organ or haematological malignancy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary outcome work stream 1	Difference in CD19 count between cohorts	Baseline
Primary outcome work stream 2	● CD27 frequency (% of peripheral blood mononuclear cells) at clinical exacerbation of MG compared to when that patient was clinically stable.	Relapse within 18 months of recrutiment
Primary outcome work stream 3	● CD27+ frequency (% of peripheral blood mononuclear cells) in MG patients who are symptomatic compared to those who are asymptomatic 12 months following B cell depletion.	12 months after B cell depletion

Secondary Outcome Measures

Outcome Measure	Time Frame
MG Composite Score	Baseline, at any clinical relapse within 18 months, 3,6 months after relapse in stable groups or 4 weeks, 6 and 12 months post rituximab in refractory groups,
MGFA - Post Intervention status	Baseline, at any clinical relapse within 18 months, 3,6 months after relapse in stable groups or 4 weeks, 6 and 12 months post rituximab in refractory groups
MG QOL-15r	Baseline, at any clinical relapse within 18 months, 3,6 months after relapse in stable groups or 4 weeks, 6 and 12 months post rituximab in refractory groups
Acetylcholine receptor antibody titre	Baseline, at any clinical relapse within 18 months, 3,6 months after relapse in stable groups or 4 weeks, 6 and 12 months post rituximab in refractory groups
Lymphocyte Count	Baseline, at any clinical relapse within 18 months, 3,6 months after relapse in stable groups or 4 weeks, 6 and 12 months post rituximab in refractory groups
Number of relapses requiring hospital admission or rescue therapy	Baseline, at any clinical relapse within 18 months, 3,6 months after relapse in stable groups or 4 weeks, 6 and 12 months post rituximab in refractory groups
Average daily dose of prednisolone over the three months prior to review	Baseline, at any clinical relapse within 18 months, 3,6 months after relapse in stable groups or 4 weeks, 6 and 12 months post rituximab in refractory groups

Collaborators and Investigators

• Sponsor: University of Manchester
• Collaborators: King's College Hospital NHS Trust; Cardiff University; University College London Hospitals; Northern Care Alliance NHS Foundation Trust; Nottingham University Hospitals NHS Trust; University Hospital Birmingham NHS Foundation Trust; University Hospital Southampton NHS Foundation Trust; Newcastle-upon-Tyne Hospitals NHS Trust; Oxford University Hospitals NHS Trust; Imperial College Healthcare NHS Trust; Walton Centre NHS Foundation Trust
• Investigators: Principal Investigator: Katherine Dodd, MBChB MRCP, University of Manchester

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2021
• Primary Completion (Anticipated): April 1, 2024
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: September 28, 2021
• First Submitted That Met QC Criteria: October 13, 2021
• First Posted (Actual): October 27, 2021

Study Record Updates

• Last Update Posted (Actual): October 27, 2021
• Last Update Submitted That Met QC Criteria: October 13, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Neoplasms by Site; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuromuscular Junction Diseases; Muscle Weakness; Myasthenia Gravis
• Other Study ID Numbers: NHS001843

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No