Blood proteins may predict success of gMG treatments
Higher NfL, CLP levels linked to poor response to Ultomiris, Vyvgart
Measuring changes in blood levels of two proteins — neurofilament light chain (NfL) and calprotectin (CLP) — may show how well people with generalized myasthenia gravis (gMG) respond to Ultomiris (ravulizumab) and Vyvgart (efgartigimod).
That’s according to a small, real-world study in Germany that found that rising levels of NfL and CLP were associated with poor treatment response.
“Our preliminary findings suggest that markers of systemic [body-wide] inflammation (such as [blood CLP]) and local destruction of the neuromuscular junction (such as [blood NfL]) may assist in treatment decision-making for gMG patients,” the researchers wrote.
The study, “Calprotectin and neurofilament serum levels correlate with treatment response in myasthenia gravis under intensified therapy–A pilot study,” was published in the Journal of Autoimmunity.
Myasthenia gravis is caused by the immune system’s wrongful production of self-reactive antibodies that attack proteins essential for the proper functioning of the neuromuscular junction, the point where nerve cells communicate with muscles to coordinate voluntary movements. The disease results in MG symptoms of fatigue and muscle weakness that, in people with the gMG form, affect multiple parts of the body.
Biomarkers may aid disease monitoring, treatment
In most MG cases, the antibodies target acetylcholine receptor proteins (AChRs) on muscle cells. Ultomiris and Vyvgart, which work through distinct mechanisms to target these antibody-mediated immune mechanisms, are approved to treat MG patients with anti-AChR antibodies.
“However, there is no established biomarker for monitoring disease activity and supporting treatment decisions,” the researchers wrote.
The team set out to determine whether changes in the circulating levels of CLP and NfL could serve as biomarkers of response to Ultomiris and Vyvgart in people with AChR-related gMG.
Recent studies have shown that blood levels of NfL are elevated in MG patients testing positive for anti-AChR antibodies. NfL is an established marker of nerve cell damage, and in MG a potential indicator of neuromuscular junction damage. CLP, a marker of body-wide inflammation, has been used to assess treatment response in other autoimmune diseases.
A total of 22 people with AChR-related gMG who had not received previous treatment with Ultomiris, Vyvgart, or others with a similar mechanism of action were enrolled between January and December 2023.
Participants had to be on a stable immunosuppressive treatment regimen for at least six months at study’s start (baseline). Nearly a third (32%) met predetermined criteria for refractory status, indicating a failure to respond to prior standard therapies.
Twelve people were treated with Ultomiris (median age 69; 58% women) and 10 with Vyvgart (median age 75; 60% women). Ninety-two percent of Ultomiris-treated people and 50% of Vyvgart-treated people had undergone surgery to remove the thymus gland, which is thought to contribute to the production of MG-driving self-reactive antibodies.
Blood levels of CLP and NfL were measured immediately before starting treatment, and again before re-treatment with Ultomiris maintenance dosage (week eight) or before the second cycle of Vyvgart (week 10).
At baseline, participants in each treatment group showed higher-than-normal levels of CLP and NfL in the blood, with no differences between the groups. In follow-up measurements, there were no significant changes in the median values of either protein.
However, 33% of patients treated with Ultomiris and 40% of those treated with Vyvgart experienced clinically meaningful improvements — defined as a decrease of at least two points on the MG-specific Activities of Daily Living scale.
Further statistical analyses showed that in both treatment groups, clinical responses significantly correlated with changes in blood CLP and NfL levels. Participants showing clinically meaningful improvements had reductions in CLP and NfL levels, while those without improvement showed increases in these proteins.
“A clinical deterioration under treatment with [Ultomiris] and [Vyvgart] seems to be associated with an increase in [blood CLP and NfL] levels,” the team wrote.
The researchers examined whether corticosteroid tapering during follow-up could have affected CLP and NfL levels, as corticosteroids like prednisolone are commonly used in MG treatment. They found, however, that the median change in prednisolone dosage for both groups was 0 mg/day, indicating a stable corticosteroid treatment regimen.
The findings support the potential of blood changes in NfL and CLP levels as “biomarkers to guide therapeutic decisions,” the researchers wrote. “However, their clinical utility must be confirmed in large, multicenter studies with extended follow-up periods to validate these preliminary findings.”
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