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Thyroid eye disease in patients with multiple sclerosis who have been exposed to immune reconstitution therapies

This study reports the first documented cases of thyroid eye disease following autologous haematopoietic stem cell transplantation for multiple sclerosis, highlighting that while patients often present with low clinical activity scores, the condition frequently progresses to moderate-to-severe disease, necessitating prolonged multidisciplinary surveillance and careful consideration of future biologic therapies.

Original authors: Vickie Lee, Mohammud Musleh, Kunwar Bhatia, Richard Nicholas, Sandhi Nyunt, Claire Feeney, Karim Meeran

Published 2026-07-08

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CC BY 4.0

Original authors: Vickie Lee, Mohammud Musleh, Kunwar Bhatia, Richard Nicholas, Sandhi Nyunt, Claire Feeney, Karim Meeran

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

The Big Picture: Resetting the System

Imagine the immune system as a highly trained security team for the body. In Multiple Sclerosis (MS), this security team gets confused and starts attacking the body's own "wiring" (the nerves).

To fix this, doctors sometimes use Immune Reconstitution Therapy (IRT). Think of this as hitting a "factory reset" button on the security team. They wipe out the old, confused guards and let a brand new team grow back. The two main ways they do this in this study are:

Alemtuzumab: A drug that acts like a "reset button" for the immune system.
AHSCT (Stem Cell Transplant): A more intense "factory reset" where the body's immune system is wiped out and rebuilt from scratch using the patient's own stem cells.

The Surprise: While this "reset" works well for stopping MS, the paper reports that sometimes, the new security team gets confused in a different way. Instead of attacking the nerves, it starts attacking the thyroid gland and the eyes.

The Story of the Patients

The researchers looked back at eight women who had MS and went through these "reset" therapies. Here is what happened to them:

The First Glitch (The Thyroid): About 3 years after the "reset," all the women developed Graves' Hyperthyroidism. Imagine the thyroid gland as a thermostat. Suddenly, the new security team turned the thermostat way up, making the body run too hot.
The Second Glitch (The Eyes): About a year after the thyroid went haywire, Thyroid Eye Disease (TED) started.
- What is TED? Imagine the space behind your eyes is a small room filled with fat and muscles that move your eyes. In TED, the immune system sends in a construction crew that puffs up the fat and swells the muscles. This pushes the eyes forward (proptosis), makes them look bulgy, and can cause double vision.

Key Findings: The "Silent" Danger

The most interesting part of this paper is a warning about how TED looks in these patients.

The "Calm" Surface: When these women first went to the doctor, their eyes didn't look very angry or inflamed. Their "Clinical Activity Score" (a measure of how active the inflammation is) was low. It was like a volcano that looked quiet on the outside.
The "Storm" Inside: Despite looking calm, the disease was actually quite severe. By the time the doctors finished following them, all eight women had moderate-to-severe eye disease.
The Metaphor: It's like a house with a quiet exterior but a foundation that is crumbling. The doctors realized that just because the eyes don't look red or angry, it doesn't mean the damage isn't happening deep inside.

The "Moving Target" Problem

The researchers used MRI scans (like high-tech X-rays) to look inside the eye sockets. They found something strange: the disease was shifty.

In one patient, the swelling moved from the right eye to the left eye over time.
In another, the swelling appeared in the fat but not the muscles, then later in the muscles.
The Analogy: Imagine a game of "Whac-A-Mole." The immune system keeps popping up in different spots behind the eyes, making it hard to predict where the next problem will be.

The Treatment Struggle

Treating these patients was like trying to fix a leaky roof while the house is still being rebuilt.

The Conflict: The doctors had to balance treating the eye disease without messing up the MS treatment.
The Surprise Reactivation: One patient had her eye disease under control for four years. Then, she started a new MS drug (ofatumumab) to keep her MS in check. Suddenly, her eye disease "woke up" and got worse again.
The Lesson: Changing the MS medication can sometimes trigger the eye disease to flare up again, even years later.

The Bottom Line

This paper reports the first time anyone has seen Thyroid Eye Disease happen after a Stem Cell Transplant (AHSCT) for MS.

The main takeaways are:

Watch out for the Thyroid: If you have MS and get a "reset" therapy, your thyroid might go haywire later.
Don't be fooled by calm eyes: Even if the eyes look normal, the disease inside can be severe.
Long-term vigilance is needed: Doctors need to keep checking these patients' eyes and thyroids for a very long time, because the disease can change or flare up years after the initial treatment.
Teamwork is essential: You need eye doctors, thyroid doctors, and neurologists talking to each other to manage this complex puzzle.

The authors conclude that while these therapies are great for MS, they bring a new set of challenges that require careful, long-term monitoring.

Technical Summary: Thyroid Eye Disease in Multiple Sclerosis Patients Following Immune Reconstitution Therapies

Problem Statement
Immune reconstitution therapies (IRT), specifically alemtuzumab and autologous haematopoietic stem cell transplantation (AHSCT), are effective treatments for multiple sclerosis (MS) that function by ablating immunity to reset pathogenic autoimmunity. However, these therapies carry a well-characterized risk of inducing secondary autoimmune diseases, most notably Graves' hyperthyroidism (GH). While the association between IRT and thyroid dysfunction is established, the development of Thyroid Eye Disease (TED) following AHSCT has not been previously described in the literature. Furthermore, the natural history, radiological heterogeneity, and optimal management of TED in patients with MS who have undergone these complex immune-modifying therapies remain unclear.

Methodology
This study presents a retrospective case series of eight female patients with MS and TED managed at a tertiary center (Imperial College Healthcare NHS Trust) between January 2015 and 2026.

Cohort Identification: Patients were identified from a multidisciplinary thyroid eye clinic database. All had a history of MS and developed TED following IRT (alemtuzumab, AHSCT, or both).
Clinical Assessment: Patients underwent comprehensive endocrine evaluation and ophthalmic assessment, including Clinical Activity Score (CAS), EUGOGO severity score (ESS), Gorman diplopia grades, and Graves' Orbitopathy Quality of Life (GO-QoL) scores.
Imaging: Orbital MRI was performed using a dedicated TED protocol (axial/coronal T2 STIR, pre/post-contrast T1, and diffusion-weighted imaging with ADC mapping).
Management: Treatment decisions were made via multidisciplinary team (MDT) consensus, adhering to EUGOGO guidelines. Interventions ranged from smoking cessation and selenium for mild cases to intravenous methylprednisolone, triamcinolone injections, and rehabilitative surgery (decompression, strabismus, eyelid surgery) for moderate-to-severe active disease.
Data Analysis: Data were extracted from electronic health records and analyzed using descriptive statistics. The study was non-interventional and did not require formal research ethics approval.

Key Results

Patient Demographics: The cohort consisted of eight women (median age at MS diagnosis: 29.8 years; range 23–43). The ethnic distribution included 50% non-Caucasian patients.
Therapy Exposure: All patients received IRT: alemtuzumab ( $n=6$ ), AHSCT ( $n=3$ ), with one patient receiving both.
Disease Timeline:
- All patients were euthyroid prior to IRT.
- GH developed a median of 34.5 months (range 12–49) post-IRT.
- TED developed a median of 12 months (range 2–35) after the onset of GH.
- Five patients had TRAb levels exceeding 30 IU/L; one AHSCT patient had a lower titre (3.2 IU/L).
Clinical Presentation and Course:
- Despite predominantly low Clinical Activity Scores (CAS $\le$ 2) at presentation (7/8 patients), all patients progressed to EUGOGO moderate-to-severe TED by final review.
- GO-QoL scores (appearance and visual function) remained low (<75) at both baseline and final follow-up.
- One patient (Case 3) experienced TED reactivation seven months after starting ofatumumab (an anti-CD20 therapy), despite a four-year period of quiescence.
Radiological Findings: Orbital MRI revealed marked heterogeneity. Findings included apical crowding, extraocular muscle (EOM) enlargement, and fat-predominant disease. Notably, radiological changes (e.g., EOM involvement) could occur in patients with low clinical activity scores, and temporal changes in muscle involvement were observed even in clinically stable patients.
Outcomes: Treatments included intravenous methylprednisolone ( $n=4$ ), local triamcinolone ( $n=3$ ), and various surgical interventions ( $n=5$ total procedures across the cohort). One patient required tocilizumab for refractory disease.

Key Contributions

First Report of AHSCT-Associated TED: This study reports the first documented cases of TED following AHSCT for MS in patients without prior alemtuzumab exposure.
Characterization of Disease Course: The authors highlight a discordance between low initial clinical activity scores (CAS) and the eventual progression to moderate-to-severe disease, suggesting that low CAS at presentation may not predict a benign course in this specific cohort.
Radiological Heterogeneity: The study documents significant variability in MRI phenotypes (fat vs. muscle involvement) and temporal evolution of radiological signs, even in the absence of overt clinical inflammation.
Complexity of Sequential Therapies: The case of TED reactivation following ofatumumab initiation underscores the complexity of managing TED in patients receiving sequential or overlapping biologic therapies for MS.

Significance and Claims
The authors claim that GH and TED are late complications of both alemtuzumab and AHSCT. They emphasize that despite low initial CAS scores, the disease course in this cohort tends toward moderate-to-severe TED. Consequently, the paper advocates for prolonged, multidisciplinary vigilance (endocrine, ophthalmic, and neurological) with concordant radiological surveillance for patients undergoing these therapies.

The study also raises questions regarding the use of newer biologic therapies for both MS and TED (e.g., teprotumumab, veligrotug) in patients with complex immune-modifying histories, noting that while anti-CD20 therapies are used to treat TED, they may not prevent autoantibody production due to the sparing of plasma cells. The authors conclude that referral bias and the retrospective nature of the study limit generalizability, but the findings necessitate extended monitoring for this specific patient population.