Standard treatments don’t always work for triple-seronegative MG

Myasthenia gravis (MG) patients who lack the three most common disease-causing antibodies often respond poorly to standard immunosuppressive medications, with many — especially those with hard-to-treat disease — failing to see their symptoms fully controlled.

That’s according to a single-center study in Greece that also showed that only about half of the so-called triple-seronegative MG (tSNMG) patients reached minimal manifestation status, with no functional limitations from MG.

“Treatment challenges in tSNMG are closely linked to the fact that a high proportion of patients in this subgroup exhibit a suboptimal response to conventional immunosuppressants,” the researchers wrote.

The findings are relevant “in the era of personalized medicine that is aimed at optimizing treatment outcomes by tailoring interventions to each patient’s individual characteristics,” they wrote, adding that these patients need to be included in clinical trials for new treatments.

The study, “Treatment Challenges in Triple Seronegative Myasthenia Gravis: A Single-Center Experience and Narrative Review of the Literature,” was published in Acta Neurologica Scandinavica.

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Antibodies attack proteins

MG is caused when self-reactive antibodies attack proteins involved in nerve-muscle communication, leading to MG symptoms such as muscle weakness and fatigue.  In most patients, these autoimmune attacks target the acetylcholine receptor (AChR) protein.

Antibodies against the muscle-specific kinase or the low-density lipoprotein receptor-related protein 4 are each detected in a small percentage of MG patients. Up to 15% of patients test negative for antibodies against any of these three proteins.

Triple-seronegative MG can be more difficult to diagnose, but these patients show similar disease symptoms and are usually treated with immunosuppressive medications similar to those who test positive for any of the antibodies. Data on tSNMG are limited, “especially in terms of disease severity and progression, as well as treatment response to different [immunosuppressive] regimens,” the researchers wrote.

They retrospectively analyzed data from a subgroup of 26 triple-seronegative patients (13.3%) of the 196 MG patients seen at a center in Greece with at least one year of follow-up.

Most of the 26 patients (61.5%) were men, their median age at disease onset was 43, and they had lived with the disease for a median of six years.

Nine (34.6%) were considered to have treatment-resistant (refractory) disease because they did not respond to corticosteroids and at least another standard immunosuppressant, required frequent rescue medications or prolonged use of high doses, or had severe side effects from medication.

Refractory disease was significantly more common in women than in men (77.8% vs. 14.3%) and in patients with problems in the thymus than in those without (88.9% vs. 28.6%). The thymus is a small gland involved in the immune response, and problems in the thymus are often linked to MG. People with refractory MG also tended to have more severe symptoms.

Nearly half of the patients (46.2%) underwent thymectomy, a surgery to remove the thymus, and half of them showed a favorable response one year after surgery. A favorable response was defined as the presence of no or mild symptoms or functional limitations, with or without the need for medications.

Mestinon (pyridostigmine bromide), a treatment that prevents the destruction of acetylcholine, a signaling molecule that binds to AChRs, was given to all patients, with favorable responses reported in 69.2%.

The corticosteroid prednisone, which was administered to all patients, had the best response rate (76.9%) among immunosuppressive medications. This was followed by azathioprine (sold as Imuran, with generics available) (50%).

Mycophenolate mofetil (sold as CellCept, with generics available) worked in all nonrefractory MG patients and in one-quarter of refractory MG patients who received the therapy.

Rituximab, which works by killing the immune B-cells that produce antibodies, helped two-thirds of nonrefractory patients and none of those with refractory disease who received the treatment.

The researchers reviewed the literature of the past decade regarding treatment responses in triple-seronegative MG patients. Data from eight studies involving 299 patients showed generally adequate responses to standard treatments, but lower rates of minimal manifestation compared with people with AChR-related MG. The definition of treatment response varied between studies, and rates of good response ranged from 0% to 75%.

“It remains unclear whether tSNMG patients constitute a uniform group in terms of disease course and treatment response,” the researchers concluded. “The challenges we observed in managing tSNMG patients emphasize the need to include this patient group in the design of clinical trials for new drugs and to be commented upon in future treatment guidelines.”