Arthritis drug tofacitinib may be effective for hard-to-treat MG: Study
Medication improved patients' muscle strength, quality of life in small trial
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- Tofacitinib improved muscle strength and quality of life for patients with hard-to-treat MG in a small trial.
- This arthritis drug, which targets the JAK-STAT3 pathway, also reduced corticosteroid reliance.
- It also reduced numbers of a type of immune cell associated with disease severity.
Tofacitinib, an approved medication for some types of inflammatory arthritis and inflammatory bowel disease, improves muscle strength, daily functioning, and quality of life in people with hard-to-treat myasthenia gravis (MG), according to a small pilot clinical trial.
Slightly more than half of the participants experienced few or no symptoms after six months of tofacitinib, which was also associated with reduced reliance on standard corticosteroids. The therapy was generally well-tolerated.
Tofacitinib is an oral anti-inflammatory medication sold under the brand names Xeljanz and Xeljanz XR. It targets JAK-STAT3, a signaling pathway involved in regulating immune responses.
Further experiments showed that the therapy reduced numbers of T-helper 17 type 1 (Th17.1) cells, a type of immune cell associated with disease severity and resistance to corticosteroids in people with MG.
“Our results suggest that a novel approach to suppress [disease-causing] Th17.1 cells via the JAK-STAT3 [signaling] pathway with tofacitinib is effective and well-tolerated for treating patients with refractory [treatment-resistant] MG,” researchers wrote, while emphasizing the need for larger studies to confirm the therapy’s safety and efficacy.
The study, “Targeting pathogenic Th17.1 cells via JAK-STAT3 pathway: A novel approach with tofacitinib for refractory myasthenia gravis,” was published in Neurotherapeutics.
Need exists for therapies targeting treatment-resistant MG
MG occurs when self-reactive antibodies disrupt normal communication between nerve and muscle cells, leading to muscle weakness and fatigue that worsen with activity. While current MG treatments have markedly improved the quality of life for many patients, up to 15% are considered refractory, meaning their symptoms persist despite treatment.
As a result, there is “a critical unmet need for effective, accessible, and well-tolerated therapies” for people with MG who do not respond adequately to standard treatments, the researchers wrote.
Previous studies have linked refractory MG to Th17.1, a specific subset of immune T-cells that comprises the predominant self-reactive T-cell population in MG and shows reduced responsiveness to corticosteroids, a class of medications commonly used to suppress immune activity in MG.
The development and activity of Th17.1 cells are regulated in part by the JAK-STAT3 signaling pathway. Tofacitinib, a treatment for several types of inflammatory arthritis, as well as ulcerative colitis, a type of inflammatory bowel disease, blocks this pathway by suppressing JAKs, a family of enzymes that transmit immune signals within cells.
While the therapy’s safety and effectiveness have been established in several autoimmune diseases, its therapeutic benefit in MG remains unclear.
A previous study showed that tofacitinib reduced muscle weakness in a rat model of MG and, in experiments using lab-grown cells from MG patients, it reduced the numbers of pro-inflammatory T-helper cells and antibody-producing immune B-cells.
Improvements in muscle strength, fatigue seen as early as 4 weeks
In this study, a team of researchers conducted a pilot clinical trial (NCT04431895) to test the therapy in adults with refractory MG. A total of 19 participants were enrolled at a single Chinese hospital between June 2020 and July 2023.
Most participants (74%) were women, with a mean age of 44.3 years. The majority (89%) had self-reactive antibodies against the acetylcholine receptor (AChR), the most common MG-causing antibodies.
Participants were treated with 5 mg tofacitinib twice daily for 24 weeks, or about six months, alongside the oral corticosteroid prednisolone (started at 10 mg to 40 mg per day).
Score reductions across multiple measures of MG severity, reflecting less severe disease, were observed as early as four weeks (about one month) after starting tofacitinib and maintained throughout the treatment period.
After six months of treatment, Quantitative Myasthenia Gravis scores, which measure muscle strength and fatigue during physical tasks, decreased by a mean of 6.2 points. MG Activities of Daily Living scores, which assess how MG affects everyday activities, decreased by 3.6 points, while MG Composite scores, a combined measure of muscle strength and symptom severity, decreased by 6.6 points.
Patients’ quality of life also improved after six months, with scores on the Myasthenia Gravis Quality of Life 15-item revised questionnaire increasing by 11 points. Gains were evident as early as two months after treatment initiation.
Levels of anti-AChR antibodies also declined after four months of treatment, although this change did not reach statistical significance.
Over 50% of participants had little or no MG symptoms by study’s end
By the end of the study, 52.6% of participants achieved minimal symptom expression, meaning they had little to no MG symptoms. This included two people with seronegative MG, the hardest-to-treat subtype in which common MG-causing antibodies are not detected in the blood.
Treatment was also associated with reduced reliance on corticosteroids from four months onward. By week 24, the mean daily dose of prednisolone had decreased to 13.68 mg.
No severe adverse events were reported during the study.
Our findings demonstrate that blocking the JAK-STAT3 signaling pathway with tofacitinib improves clinical outcomes and glucocorticoid response in refractory MG.
Further analyses showed that tofacitinib treatment was associated with reduced blood levels of the pro-inflammatory molecules IL-6 and IL-23, which are key drivers of Th17.1 cells’ maturation and activity.
“Together, these results indicate that tofacitinib alleviates MG by [suppressing pro-inflammatory molecules] associated with Th17.1 cell [maturation],” the researchers wrote.
While the number of Th17.1 cells was only slightly reduced after treatment, those of immunosuppressive cells and molecules were significantly increased.
In laboratory experiments, patient-derived T-helper cells grown under conditions that promote Th17.1 maturation showed reduced Th17.1 cell counts and lower IL-17A and GM-CSF levels when treated with tofacitinib. IL-17A and GM-CSF are key pro-inflammatory molecules involved in autoimmunity, including by activating B-cells.
“Our findings demonstrate that blocking [the] JAK-STAT3 signaling pathway with tofacitinib improves clinical outcomes and glucocorticoid response in refractory MG,” wrote the researchers, who described the treatment as promising, effective, and well-tolerated.
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