Long-term tacrolimus safe, effective in pediatric MG patients: Study

Drug's use would cut down on need for prednisone, which can cause side effects

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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About two years treatment with the immunosuppressant tacrolimus safely and effectively eases symptoms in children and adolescents with myasthenia gravis (MG) while cutting down the need for oral prednisone, according to a small study in China.

Corticosteroids like prednisone, often used when other medications fail to control symptoms of MG, can cause serious side effects when taken for a long time or at a high dose. As such, tacrolimus’ steroid-sparing effect may further help improve the health and life of pediatric MG patients.

“This study adds to the research on the efficacy and side effects of tacrolimus in the treatment of young children with MG,” the researchers wrote, adding, however, that “more studies, especially [appropriately-controlled] trials and comparative studies, are needed to verify its efficacy and safety.”

The study, “Long-term efficacy and safety of tacrolimus in young children with myasthenia gravis,” was published in the Journal of Clinical Neuroscience.

MG occurs when the immune system mistakenly damages the communication route between the nerves and the muscles. As a result, the muscles become weak and easily tired over time.

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Treating myasthenia gravis

The first approach to treatment is usually with pyridostigmine bromide (sold under the brand name Mestinon and with generics available), which helps electrical signals travel between the nerves and the muscles, thereby easing muscle weakness and fatigue.

Corticosteroids also are commonly prescribed as first-line treatment for MG due to their anti-inflammatory and immunosuppressive effects. But given that long-term treatment and high doses of these medications are associated with serious side effects, their dose is gradually lowered as much as possible once symptoms are under control.

Still, “some patients are unable to achieve remission even after administration of CSs [corticosteroids] or to tolerate CSs,” the researchers wrote, adding that that’s when immunosuppressive therapies are prescribed to MG patients.

“Immunosuppressants may be introduced when there is no response to steroids, there is an inability to wean steroids to a reasonable minimum effective dose, or if side-effects of steroid treatment become intolerable,” the researchers wrote.

Tacrolimus, sold as Prograf and other brand names, and also available as generics, is an immunosuppressant that works by blocking the activation of a type of immune cell called T-cells. Originally used to prevent organ rejection in transplant patients, tacrolimus has been increasingly used off-label in people with autoimmune diseases, including MG.

Previous research suggested that the medication is safe and effective on its own to treat MG in adults. However, less is known about its use in children and adolescents with the disease.

To know more about the therapy’s long-term effects in pediatric MG patients, a team of researchers in China reviewed the records of 21 children and adolescents (13 girls and eight boys) with MG who were treated with tacrolimus between June 2012 and June 2020 at the researchers’ hospital. All patients were followed for at least a year.

More than half of the patients (52.4%) were dependent of corticosteroids, meaning they were taking this type of medication for more than six months but required additional treatment with an immunosuppressant to control symptoms or reduce side effects.

Among the 10 remaining patients, half did not respond well to corticosteroids and required additional treatment with an immunosuppressant, while the other half did not tolerate corticosteroids’ side effects.

Patients initiated tacrolimus treatment at a median age of 8.7 years, at a median of four years after disease onset. Treatment lasted a median of 2.5 years (range, 1.7-5.8 years) at a median initial dose of 1 mg and a median maintenance dose of 2 mg.

Symptoms minimal in majority of patients prior to tacrolimus

Before tacrolimus, most patients (71.4%) had minimal symptoms, according to the MG Foundation of America (MGFA) classification, which rates how severe MG is. Two other patients had mild symptoms, two had moderate disease, and the remaining two had severe symptoms.

At their last post-tacrolimus visit, 14 patients (66.6%) had achieved pharmacological remission and one (7.1%) had attained minimal symptoms. Symptom were reduced in two patients (9.5%) and unchanged in four (19.1%).

The researchers also looked at changes in the MG Activities of Daily Living (MG-ADL) score, which assesses the impact of MG on daily functions. The total score ranges from 0 to 24, with higher scores indicating more severe symptoms.

Before starting on tacrolimus, patients had a median MG-ADL score of five, which dropped significantly to a median of three after one month of treatment and to zero after six months and up until the last visit.

Patients were defined as responders if they had a reduction of two points or more in the MG-ADL score. Compared with the 16 responders (76.2%), the five non-responders (23.8%) had a significantly lower MG-ADL score (three vs. six), suggesting that the less severe disease in these patients may have hindered the detection of greater score difference.

No other significant differences were detected between responders and non-responders.

Tacrolimus also helped reduce the dose of oral prednisone, a corticosteroid, over time, and significantly so as early as three months. Prednisone was stopped altogether in three patients (14.3%) at six months and in 13 (61.9%) at the last visit.

“The steroid-sparing effect of long-term tacrolimus therapy in this study is encouraging,” the researchers wrote.

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Prior to treatment with tacrolimus, most children and adolescents (80.9%) had side effects related to long-term use of prednisone. The most common were symptoms of Cushing’s syndrome (71.4%), obesity (52.4%), high blood pressure in the eyes (19%), and short stature (14.3%).

With prednisone-sparing tacrolimus, Cushing’s symptoms resolved in 13 of the 15 patients and eased in the remaining two. Also, high blood pressure in the eye resolved in all four patients, and two of the three patients with short stature reached their normal height for age. One of the 11 patients with obesity returned to normal weight for age.

“Toxicity from long-term use of tacrolimus was mild in this study,” the researchers wrote, adding that no patient “discontinued tacrolimus due to safety concerns, suggesting that long-term tacrolimus usage in young children is relatively safe.”

These findings highlight that “a course of tacrolimus of more than one year was effective and well-tolerated in young children with MG, and tacrolimus improved MG symptoms and reduced the dose and adverse events of oral prednisone,” the team wrote.

Larger studies, following patients over time, are needed to confirm these findings.