Seronegative MG more rare than previously thought: Danish study
These patients have no detectable MG-related antibodies
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- Seronegative myasthenia gravis (MG) is rarer than previously thought.
- Improved testing and retesting can identify antibodies in patients initially deemed seronegative.
- Seronegative MG patients show similar symptoms, demographics, and treatment patterns to those with antibody-positive MG
People with myasthenia gravis (MG) who lack detectable MG-related antibodies, known as seronegative MG, may be rarer than previously suggested, according to a single-center study in Denmark.
Researchers identified seronegative MG in only 4.3% of 350 cases — a percentage lower than the roughly 10% reported in earlier studies. This is likely the result of retesting or improved testing methods, as 20 patients with MG-related antibodies initially tested negative for these antibodies.
In addition, seronegative MG patients showed no significant differences in demographics, symptoms, diagnostic delay, or treatment patterns compared with patients in the more common antibody-positive MG group.
“These findings correspond well with the emerging evidence of a similar [underlying mechanism] in the two groups,” researchers wrote.
The study, “Prevalence and characteristics of patients with seronegative myasthenia gravis,” was published in the Journal of Neurology.
Seronegative MG’s underlying biology remains unclear
MG is a chronic autoimmune disease that disrupts communication between nerves and muscles, leading to muscle weakness that worsens with activity. Symptoms often begin in the eye muscles, causing drooping eyelids or double vision.
Some people have symptoms that remain limited to the eyes, known as ocular MG, while others develop generalized MG, in which weakness affects other muscles, such as those involved in movement, speech, swallowing, or breathing.
In most cases, MG is caused by self-reactive antibodies against the acetylcholine receptor (AChR), a key protein needed for nerve-muscle signaling. Fewer cases have antibodies against other proteins, such as MuSK or LRP4.
However, about 10% of MG patients test negative for antibodies against any of these three proteins and are considered to have seronegative or triple-seronegative MG.
While some studies have suggested that seronegative MG is linked to a higher frequency of ocular MG and milder symptoms relative to AChR-related MG, others have reported no major differences between seronegative and seropositive (antibody-positive) MG.
Still, the underlying biology of seronegative MG remains unclear. Researchers suspect that some patients may have antibody levels too low to detect or antibodies against targets that have not yet been identified.
Most patients were seropositive, primarily for anti-AChR antibodies
MG treatment may include medications that improve nerve-muscle signaling, as well as immune-targeting therapies to reduce disease activity. In more severe cases, doctors may use intravenous immunoglobulin (IVIG), which delivers healthy antibodies to help calm the immune attack, or plasmapheresis, a blood-filtering procedure that removes self-reactive antibodies.
Some patients may also undergo thymectomy, or a surgery to remove the thymus gland, which is thought to play a role in MG.
In this study, a team of researchers aimed to determine how common seronegative MG was among MG patients treated at the Copenhagen Neuromuscular Center in Denmark, and whether these patients differed from antibody-positive MG patients in ways that could affect diagnosis or treatment.
They retrospectively reviewed the clinical records of 350 people with a confirmed MG diagnosis. Of these, 15 people (4.3%) were seronegative, and all but three had been retested for antibody status.
The remaining 335 patients were seropositive, mostly for anti-AChR antibodies (97.3%). Six cases (1.8%) tested positive for anti-MuSK antibodies, and three (0.9%) for anti-LRP4 antibodies.
Repeated and improved testing methods over time reduce the number of seronegative patients.
The proportion of seronegative MG patients was lower than the roughly 10% reported in many earlier studies. Notably, 20 of the seropositive patients “originally tested negative for antibodies, but when retested were found positive in a span of [10 days to more than 10.5 years] after the first negative test,” the team wrote.
This suggests that “repeated and improved testing methods over time reduce the number of seronegative patients,” they added.
Overall, seronegative and seropositive patients looked very similar. There were no significant group differences in age at symptom onset, sex, rates of ocular MG, or rates of thymus abnormalities.
Treatment patterns also did not differ significantly. However, seronegative patients appeared to be more evenly distributed across treatment-intensity groups, while more seropositive patients were represented in higher-intensity treatment categories, including IVIG/plasmapheresis.
There were also no significant differences between the two groups in terms of diagnostic delay or time to reach well-controlled disease.
Overall, the findings of this single-center study showed that seronegative MG patients are largely indistinguishable from seropositive patients across the measures studied.
This suggests that seronegative and seropositive MG may share similar underlying disease mechanisms, and “seronegative MG patients should be managed similarly to seropositive patients,” the researchers wrote.
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