Biomarkers for fatigue in patients with Myasthenia Gravis

Myasthenia Gravis (MG) is a chronic autoimmune disease affecting the
neuromuscular junction. Although a hallmark of MG is muscle fatigability due to
dysfunction of the neuromuscular junction (peripheral fatigue), a large number
of MG patients also report symptoms of central/ cognitive fatigue, defined as
an experienced lack of energy, physically and/or mentally. In October 2019 we
performed a cross-sectional survey study (P15.287) among 420 Dutch MG patients
showing a clinically relevant fatigue rate of 62% on the Checklist Individual
Strength-Fatigue subscale (CIS-f). Its pathophysiology is likely multifactorial
in nature but there are some unanswered questions.

the main objective is to investigate if there are potential biomarkers for
cognitive fatigue in MG. With this biomarker we aim to gain insight in the
pathophysiology of fatigue. A biomarker could potentially be helpful in
diagnostics, treatment and longitudinal follow-up of fatigue.
We hypothesize that the elevated serum biomarker has its origin in the affected
muscles.

Exploratory study (phase 1) with the option for a longitudinal design (phase
2). We have chosen a longitudinal design to investigate the effect of change in
central fatigue scores on the potential biomarkers. However, we will only carry
out phase II if the first part of the study yields biomarkers that can be used
in a longitudinal follow-up study. Therefore, after the final inclusion in part
I of the study, the results will be analysed. If there are biomarkers which
have a significant association with fatigue, we will continue the study and
perform part 2. If there are no biomarkers associated with fatigue, the study
will end after part 1.

Patients are informed that they will not likely profit directly from
participation in this study. The insights that can be obtained through this
study can be used as a step towards a diagnostic tool for fatigue in MG.
The study will consist out of 1 visit of approximately 2-3 hours.

Risks
• The risk of venous blood withdrawal is that the puncture can be painful and/
or a hematoma at the puncture site can arise, causing minor discomfort. The
amount of blood to be withdrawn is small, approximately 225-385cc and is not
expected to give any problems.
• Performing a QMG will take 10 minutes and consists of an assessment of muscle
fatigability. There are no risks involved, except for a minor risk of
discomfort when patients with difficulties swallowing are asked to drink half a
cup of water. This risk will be minimized by leaving out this item when known
difficulties with swallowing are present, as is common clinical practice.
• A muscle biopsy is performed under local anaesthesia. It does not require the
patient to stay in the hospital after the procedure and does not impair normal
daily activities afterwards. The complication risk is low and limited to a
small possibility of development of a hematoma, which generally does not need
treatment or hospital admission. Separate informed consent forms for muscle
biopsies must be signed before muscle biopsies can be performed.