Thymus changes may play larger role in late-onset myasthenia gravis

Adults with late-onset myasthenia gravis (LOMG), when symptoms begin at age 50 or later, showed advanced fatty replacement of the thymus gland, while a separate group of LOMG patients showed reduced production of new immune cells, according to a new study.

Abnormalities in the thymus gland are well established in early-onset MG (EOMG), in which symptoms arise before age 50. The new findings suggest the thymus also may play a larger role in LOMG than previously thought.

The study, “Exaggerated thymic involution in late-onset myasthenia gravis: clinical and immunological evidence,” was published in Immunity & Ageing.

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How the thymus may be involved in myasthenia gravis

In myasthenia gravis (MG), a self-directed immune attack disrupts the communication between nerves and the muscles they control, causing muscle weakness that fluctuates over time.

The thymus gland, located in the chest, is an immune organ where T-cells mature. These immune cells can kill infected or abnormal cells and help regulate other parts of the immune system. As people age, the thymus naturally shrinks and is gradually replaced by fatty tissue, a process called thymic involution.

Thymus abnormalities are thought to play a central role in MG. Thymic hyperplasia, in which the gland becomes enlarged, has long been linked to early-onset MG, but the thymus’s role in late-onset MG has been less clear.

To investigate further, a team of researchers in China examined chest CT scans taken when 75 adults were diagnosed with MG and before immunotherapy treatment began. Of these patients, 59 had LOMG and 16 had EOMG. All tested positive for self-reactive antibodies against the acetylcholine receptor protein, the most common target of MG-driving antibodies. People with thymoma, a tumor of the thymus, were excluded from the study.

The researchers compared the patients’ scans with those of 225 people without diseases potentially affecting the thymus. The controls were matched for age, sex, diabetes status, and BMI category. Body mass index (BMI) is a measure based on height and weight.

Radiologists used the scans to build three-dimensional models of each person’s thymus and measure its volume, surface area, and gray value. A lower gray value indicates that more of the thymus has been replaced by fat.

CT scans reveal distinct thymus changes in late-onset MG

In both MG patients and controls, gray value “declined steeply before the age of 50 and plateaued thereafter,” the researchers wrote. However, LOMG patients had a significantly lower median thymic gray value than controls, indicating greater fatty replacement of thymic tissue.

LOMG patients also had a significantly larger median thymic volume (45,356 vs. 17,156 cubic mm) and surface area (11,462.5 vs. 5,401 square mm) than controls.

In contrast, EOMG patients had higher median gray values, or less fatty replacement, than controls (98.97 vs. 86.73), although this difference did not reach statistical significance. These patients did have significantly larger thymic volume (24,312 vs. 9,971 cubic mm) and surface area (7,291.5 vs. 3,974 square mm) compared with controls.

While both patient groups had larger thymuses than controls, the team noted that those with LOMG had more severe fatty replacement than controls, whereas those with EOMG had a lower degree of fatty replacement than controls.

In a multivariable analysis, thymic volume, surface area, and gray value were each independently associated with LOMG status.

In an exploratory analysis of how well the imaging measures could distinguish LOMG patients from controls, thymic volume had an area under the curve (AUC) of 0.85 and surface area had an AUC of 0.87. AUC is a measure of how well a test distinguishes between two groups, with higher values indicating better discrimination.

“Thymic volume and surface area can serve as useful parameters for differentiating the LOMG thymus from the normal thymus,” the researchers wrote.

When analyzed alongside clinical data, LOMG patients with diabetes had significantly larger thymic volume and surface area than those without. Higher values in both measures were significantly associated with a higher BMI. Among the controls, thymic volume and surface area did not differ significantly based on diabetes status, but both were also significantly associated with higher BMI.

Blood tests point to reduced thymic output in LOMG

Researchers then measured naïve T-cells and recent thymic emigrants (RTEs) in blood samples collected from a separate group of 20 LOMG patients and 27 age- and sex-matched healthy controls. RTEs are newly formed T-cells that have recently left the thymus, so their levels can indicate how actively the gland is producing new immune cells.

The proportions of naïve CD4-positive and CD8-positive T-cells were similar between LOMG patients and controls. CD4 T-cells help coordinate immune responses, while CD8 T-cells can kill infected or abnormal cells.

However, CD4-positive RTEs were significantly less common in LOMG patients than in controls. CD8-positive RTEs were also less common in the LOMG group, but that difference was not statistically significant and could have occurred by chance.

“These findings suggest that thymic output function is impaired in LOMG patients,” the researchers wrote.

“Patients with LOMG showed exaggerated thymic involution and reduced thymic output, supporting potential thymic involvement in the [disease process] of LOMG,” the team concluded. “Thymic volume and surface area may help differentiate LOMG-associated thymic changes from thymic features observed in healthy controls.”

The researchers noted that because the CT scans and immune-cell analyses involved separate groups of patients, the study cannot directly link structural thymus changes to reduced thymic output in the same individuals.