APS1 Case Report Supports Early Immunosuppressive Treatment

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by Marta Figueiredo PhD |

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Starting immunosuppressive treatment early in the disease course normalized some signs of autoimmunity, halted the development of additional autoimmune diseases, and reversed total body hair loss in a girl with autoimmune polyglandular syndrome type 1 (APS1), a case study shows.

While immunosuppressive therapies have been generally reserved for life-threatening features of APS1, this case suggests that physicians should consider initiating such treatments early, as they may result in significant benefits to these patients, the researchers noted.

The case report, “Attenuation of Autoimmune Phenomena in a Patient with Autoimmune Polyglandular Syndrome Type 1,” was published in the journal Case Reports in Endocrinology.

In APS1, the immune system abnormally recognizes cells in multiple organs and glands as foreign, mounting antibody-based immune attacks against them that result in tissue damage.

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This rare, inherited autoimmune disorder is caused by mutations in both copies of the autoimmune regulator (AIRE) gene. AIRE is involved in the development of self-tolerance, a process by which immune cells recognize the body’s molecules and cells as not threats, thereby not driving immune responses against them.

ASP1 is clinically defined by the presence of at least two of the three core features: hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis (CMC), which is an infection of the skin, mucous membranes, and nails.

Hypoparathyroidism is caused by abnormally low levels of the parathyroid hormone (produced by the parathyroid glands), which results in vitamin D deficiency, low levels of calcium, and high levels of phosphorus in the blood.

Adrenal insufficiency, also called Addison’s disease, is a condition in which the adrenal glands, which sit on top of the kidneys, become unable to produce two key hormones, called cortisol and aldosterone.

Treatment with ASP1 is generally “directed toward replacing the hormones that are deficient as a direct result of the autoimmune processes,” the researchers wrote.

These include calcium supplements and activated forms of vitamin D for hypoparathyroidism, and glucocorticoid and mineralocorticoid replacement for adrenal insufficiency.

“When immunosuppressive therapies have been used, it is often in the setting of life-threatening features of APS1,” the researchers added.

Now, a team of researchers at Children’s Mercy Hospital, in Kansas, and the University of Kansas School of Medicine described the case of a girl whose APS1 was progressing rapidly until she was initiated on immunosuppressive therapies.

At 6 years of age, the girl experienced a grand mal seizure, characterized by loss of consciousness and violent muscle contractions. She temporarily stopped breathing and was therefore transported to the hospital.

She had no family history of hormone-related or immune-related disorders, and her physical examination was unremarkable expect for short stature for her age (104.6 centimeters or 3.43 feet).

Lab results showed she had lower-than-normal levels of calcium and parathyroid hormone and higher-than-normal phosphorus levels, prompting the diagnosis of hypoparathyroidism, whose associated calcium deficiency likely caused the seizure.

Further hormone-related tests showed features consistent with autoimmune-induced spleen dysfunction, a condition frequently seen in APS1. This led to the hypothesis that the girl could have APS1, which was confirmed through genetic testing. She carried two known disease-causing AIRE mutations (R257X and c.967 979del13).

Additional blood tests revealed the presence of antibodies against adrenal and stomach glands. Until the age of 11, and at a consistent rate of nearly once per year, she developed antibodies associated with autoimmunity-induced liver damage, diabetes, and Sjögren’s syndrome.

Sjögren’s is an autoimmune disease characterized by immune attacks to glands that produce fluids, such as tears and saliva.

She developed elevated liver enzymes, suggestive of liver damage, and adrenal insufficiency, for which she was started on replacement therapy with hydrocortisone (a glucocorticoid) and fludrocortisone (a mineralocorticoid).

Shortly afterward, her liver enzymes normalized, and the levels of both liver damage-inducing antibodies and Sjögren’s antibodies began to decline. The researchers hypothesized that these benefits may have been related to hydrocortisone treatment, even at physiologic doses, as the therapy is known to have immunosuppressive effects.

At age 12, she began to show areas without any hair, which prompted a more aggressive treatment in an attempt to prevent further hair loss. She received two doses of rituximab, a therapy that targets B-cells, the immune cells responsible for antibody production.

However, soon after treatment she lost all hair on her head and started losing her body hair too, at which time methotrexate, an immunosuppressive oral treatment, was initiated, along with folic acid and vitamin B12, which are commonly used to promote healthy hair growth.

Within a year, she experienced a complete hair regrowth.

While hair loss “worsened in close temporal proximity to the rituximab injections, it is impossible to say whether the rituximab exacerbated her symptoms or contributed to her later improvement,” the team wrote.

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Hypoparathyroidism Not Always Seen in APS1, Case Study Suggests

When she was 18, she developed multisystem inflammatory syndrome in children, a rare condition that can occur after COVID-19 infection and is characterized by inflammation in different organs, such as the heart, lungs, and kidneys.

She needed intensive care support and recovered uneventfully from the condition, although she remained with high levels of a heart damage biomarker.

“For the past 7 years while on glucocorticoid and methotrexate treatment, our patient has displayed normalization of 2 antibodies, a lack of progression to additional autoimmune diseases, and experienced reversal of alopecia universalis [loss of all body hair],” the researchers wrote.

“We are not aware of any reports in the literature of such attenuation of APS1,” they added.

This case suggests that “early consideration of immunosuppressive agents may be warranted” and that “early testing for adrenal insufficiency may justify early use of glucocorticoids and mineralocorticoids,” the team wrote.