Article In Brief
Double-seronegative myasthenia gravis patients (DNMG), who were antibody positive for both lipoprotein receptor-related protein 4 and agrin, had a more severe case of the condition than those who were antibody-negative. Experts discuss whether currently approved treatment options would also benefit DNMG patients who are positive for both antibodies.
Patients with double-seronegative myasthenia gravis (DNMG) who were antibody positive for both lipoprotein receptor-related protein 4 (LRP4) and agrin had a more severe case of the condition than those were antibody-negative, a multicenter study found.
Patients identified as DNMG lack autoantibodies against the nicotinic acetylcholine receptor (AChR)— detected in about 80 percent of patients with generalized MG— and to muscle-specific tyrosine kinase (MuSK) found in about 10 percent of generalized MG cases.
Whether currently approved treatment options would also benefit these DNMG patients who are positive for LRP4 and agrin would be worth examining in future studies, neuromuscular experts not involved with the current research told Neurology Today.
In the study published in the September issue of Muscle and Nerve, the investigators, led by Michael H. Rivner, MD, the Charbonnier professor of neurology and director of electrodiagnostic medicine laboratory at Augusta University in Georgia, and colleagues, sought to identify the clinical characteristics, prognosis, and prevalence of LRP4 or agrin-antibodies in DNMG patients from 16 clinical sites.
Of 181 DNMG patients, 14.9 percent were positive for either agrin or LRP4, and 12.7 percent were positive for both LRP4 and agrin antibodies.
Although antibody-positive patients had more severe disease than antibody-negative patients, most DNMG patients responded to standard therapy regardless of their antibody status, the researchers reported.
Also, 43 percent of antibody-negative patients had ocular or mild generalized symptoms compared with 69 percent of antibody-positive patients, the investigators found.
These findings are similar to the rates seen in other reports, the researchers noted. “Although patients positive for both [LRP4 and agrin] have been reported previously, this is not a commonly observed finding among the few patients who have been tested for both antibodies,” the authors wrote.
“There have been a few papers published in the literature that have looked at MG patients, that were positive for LRP4 and agrin, but the numbers of patients studied were limited,” Dr. Rivner told Neurology Today.
“The prevalence of LRP4 antibodies have been very variable in previous studies reported in the literature. Most of these studies were relatively small; only one study had a sizable number of patients.”
Dr. Rivner noted that the prevalence of LRP4 antibodies in other studies in patients with myasthenia gravis ranged from less than 1 percent to as high as 40 percent. For double negative MG patients, the prevalence rate varied from less than 1 percent to as high as 50 percent. “So pretty much, we really didn't know what the prevalence was.”
“If you look at the situation with agrin, we knew even less,” he added.
Finding these antibodies likely indicates that these patients have a more severe course of the disease, noted Dr. Rivner. “Of course, finding a new antibody makes it a little bit easier to take care of these patients because a lot of times, patients present with vague symptoms. We can do some physiological testing, which is helpful, but finding an antibody is also helpful in diagnosing the disease.”
Study Details, Findings
In the current analysis, all patients showed clinical symptoms of MG, received either rituximab within six months of their antibody test or intravenous immunoglobulin or plasma exchange within six weeks of their antibody test.
Nearly 90 percent of patients who tested positive for LRP4 or agrin developed generalized MG. However, after an average follow-up period of 11 years, 81.5 percent of these antibody-positive patients, who received standard MG therapy, improved on MG rating scales.
“I think the most interesting thing —and something that we didn't know—was that patients who had antibodies for LRP4 or agrin, had a more severe form of myasthenia than patients who did not have antibodies. We termed these as quad-negative patients because they did not have antibodies to acetylcholine, MuSK, LRP4, and agrin, and those patients had a milder course of the disease than the patients who had antibodies to LRP4 and agrin,” Dr. Rivner told Neurology Today.
While the researchers had access to clinical exam data on antibody-positive patients, Dr. Rivner said, “we don't have physical exam findings on antibody-negative patients.”
Having information from exams would allow the investigators to compare antibody positive and negative patients, Dr. Rivner said.
The study focuses on the clinical presentation of patients with agrin and LRP4 antibodies in a more systematic way, said Julie Rowin, MD, FAAN, DABMA, of Integrative Neurology in Westchester, IL.
”It is interesting that the majority of patients in this study had both LRP4 and agrin antibodies (85 percent),” Dr. Rowin told Neurology Today in an email. “The coexistence of these two antibodies in MG patients had not really been assessed previously. Having said that, LRP4 interacts with agrin forming a complex with MuSK, so there are structural relationships between these proteins.”
” In addition,” Dr. Rowin said, “agrin and LRP4 antibodies are present in other neurological disorders such as ALS and MS as well as some AChR and MuSK seropositive patients, so it remains unclear at this point if these antibodies are directly involved in the pathogenesis of MG or are a secondary result of the neuromuscular junction damage that occurs in myasthenic disorders.”
Dr. Rowin said that both the LRP4/agrin antibody-positive patients and the double seronegative patients responded equally well to standard therapy and that the paper does not offer any indication that treatment decisions should be impacted by a patients LRP4/agrin antibody status. “The role of newer therapeutic options in these patients (e.g., complement inhibition) cannot be gleaned from this study,” she added.
“Although the authors recommend testing for LRP4/agrin antibodies in double seronegative patients, at this point, there doesn't appear to be a compelling reason to do this routinely, as the response to standard therapy is no different for LRP4/agrin positive patients versus seronegative patients; the two groups are comparable in the response to standard medical management,” Dr. Rowin said.
The current literature consists mainly of case reports, and the data are inconsistent, but this paper provides us with a more rigorous and consistent approach, agreed Alejandro Tobon, MD, chief of the neurology section at South Texas Veterans Health Care System.
“It was interesting that most patients that tested positive were positive for both LRP4 and agrin,” Dr. Tobon said. “Most of the case reports that we've seen in the literature were either patients that were LRP4 positive or agrin positive and the fact that they found that most patients had both raises interesting questions. We still don't know much, but it may have implications in the future for better diagnostic testing and for treatment possibilities.”
“For example, we have FDA-approved medications such as eculizumab for MG, which is approved only for AChR antibody-positive myasthenia gravis,” said Dr. Tobon. “Now that we have identified another group of patients that are antibody positive, it will be interesting to determine through research whether a medication like eculizumab or others in development affect treatment in this group. It opens the door to see other treatment options that are not routinely available for seronegative myasthenia patients.”
Dr. Rivner disclosed relationships with Allergan, Alexion, Ra Pharmaceuticals, Cytokinetics, Catalyst, Biohaven, UCB, Momenta, Shire Takeda, Mallinckrodt, Seikagaku, Grifols, and Orion. Dr. Rowin disclosed relationships with AveXis and Novartis. Dr. Tobon did not report any conflicts of interest.