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By Anne Hartenhauer
Myasthenia gravis is an autoimmune disease with an estimated prevalence of 14-20/100,000 population in the U.S.1 and 1-9 /100,000 population in Europe.2 Many affected individuals go undiagnosed. Myasthenia gravis can cause severe muscle weakness and greatly impact quality of life. Diagnosis can be difficult, but state-of-the-art disease biomarkers and targeted assays are available to increase the likelihood that a patient with myasthenia gravis is diagnosed early and can be treated appropriately. How can these biomarkers and use of the correct assays also help clinicians monitor therapeutic efficacy and support better treatment outcomes for their patients?
Myasthenia gravis causes muscle weakness when autoantibodies against acetylcholine or muscle-specific receptor tyrosine kinase block transmission of electrical signals from nerve endings to muscles.
Myasthenia gravis symptoms
In myasthenia gravis, the body’s own immune system produces antibodies that attack the skeletal muscles responsible for breathing and various other movements. Patients typically experience muscle weakness following activity that improves with rest. Certain key muscle groups are commonly affected. Early and accurate diagnosis of myasthenia gravis is important because, despite the absence of a cure, there are effective treatments that can help control symptoms and improve a patient’s quality of life.3
In most cases of myasthenia gravis, autoantibodies target the receptors for acetylcholine, a neurotransmitter that carries electrical signals between nerve endings and acetylcholine receptors. These receptors are transmembrane proteins present on muscle cells. The electrical signals stimulate the muscles to contract. Acetylcholine receptor autoantibodies (ARAbs) produced in myasthenia gravis patients prevent acetylcholine from binding to its receptor and block normal muscle contractions.
About 85 % of patients with myasthenia gravis express ARAbs. The other 15 % of cases are known as seronegative myasthenia gravis. In patients with seronegative myasthenia gravis, there are clear clinical symptoms, but no detectable autoantibodies against the acetylcholine receptor. Approximately half of these ARAb-seronegative patients will express autoantibodies against another myasthenia gravis-related protein called muscle-specific tyrosine kinase (MuSK). This protein plays a key role in cross-linking the acetylcholine receptor to the musculature. Patients expressing MuSK autoantibodies tend to have a more severe form of myasthenia gravis, with worse symptoms.
What makes myasthenia gravis diagnosis so complex?
ARAb and MuSK autoantibodies are the gold standard biomarkers for diagnosing myasthenia gravis. To achieve an early and accurate diagnosis requires applying the correct assay strategy. The first step is an assay to detect ARAbs. For this assay, an ELISA is not sufficient, and will yield too many false positive results. To maximize the sensitivity and specificity of ARAb detection, laboratories should use a radioreceptor assay (RRA). The RRA is the test of choice because, unlike an ELISA, it maintains the three-dimensional structure of the acetylcholine receptor, which is necessary for antibody recognition.
If the RRA result for ARAbs is positive, a diagnosis of myasthenia gravis can be confirmed. In the setting of a negative RRA, the clinician should consider the 15 % of affected patients who may have been missed – those with seronegative myasthenia gravis. Follow-up with a MuSK ELISA will make it possible to identify about 50 % of these patients. A quantitative MuSK ELISA is the preferred test.
A quantitative MuSK-Ab assay enables therapeutic monitoring
Patients with MuSK autoantibodies not only have a more severe form of the disease, but the therapy they receive also tends to be more intensive, commonly involving rituximab immunosuppression to achieve B-cell depletion. In the treatment of myasthenia gravis, the target reduction of ARAbs is 50 %, whereas the clinical goal of treatment in MuSK-positive patients is complete elimination of the MuSK autoantibodies. To determine this, and to do so most efficiently, requires a highly sensitive and quantitative assay, rather than relying on qualitative results.
In addition, since therapy may require some time to take effect, by using a sensitive, quantitative assay, clinicians can carefully monitor the efficacy of myasthenia gravis treatment. They can detect increases or decreases in MuSK autoantibody levels, and modify both treatment and therapeutic decision-making as needed to achieve optimal patient outcomes.
An example of a robust diagnostic protocol for myasthenia gravis is the LAB Maastricht approach used at Maastricht University Medical Center in The Netherlands. They have a special interest in myasthenia gravis clinical practice and research, including an advanced therapeutic program, and they use a combination of an RRA for ARAbs detection followed by quantitative MuSK-Ab ELISA for diagnosis.
Are you using state-of-the-art assays and biomarkers for myasthenia gravis detection and treatment monitoring? To learn more, read the Tecan Journal article “Correct Identification of Autoimmune Diseases”
1 Myasthenia Gravis Foundation of America. Available at: www.myasthenia.org.
2 The Portal for Rare Diseases and Orphan Drugs. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=589
3 National Institute of Neurological Disorders and Stroke. National Institutes of Health. Myasthenia Gravis. Available at: www. Ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Myasthenia-Fravis-Fact-Sheet