The case, published in Frontiers in Drug Discovery by Ju Hye Kim, Ji Yeon Chung, and Jeong Bin Bong, centers on a 65-year-old man with a layered oncological history. Twelve years before presentation he had undergone a total thyroidectomy for thyroid cancer and a thymectomy for thymoma, a tumor of the thymus gland that sits behind the sternum and plays a central role in immune education. One year before the current episode he was diagnosed with bladder cancer, treated with a radical cystectomy, and started on adjuvant pembrolizumab every three weeks. Four weeks after the first infusion, roughly a week after his second dose, he began to notice double vision, slurred speech, difficulty swallowing, and shortness of breath. Over the following two months these symptoms progressed steadily, interfering with eating and sleeping, until he required hospital admission.

Neurological examination on admission revealed a pattern classic for myasthenia gravis but with an unusual distribution. The patient displayed external ophthalmoplegia, meaning his eyes could not move normally in any direction, along with bilateral ptosis, or drooping of both eyelids. His speech was dysarthric and his swallowing impaired, yet his limb strength was essentially preserved and deep tendon reflexes were normal. Arterial blood gas analysis showed a low partial pressure of oxygen at 68.6 mmHg against a normal range of 83 to 108 mmHg, with oxygen saturation of 93.2 percent, indicating respiratory compromise despite normal carbon dioxide clearance. Pulmonary function testing was more alarming still: forced vital capacity had fallen to 40 percent of predicted and forced expiratory volume in one second to 44 percent of predicted, a pattern consistent with severe neuromuscular respiratory weakness rather than intrinsic lung disease.

The diagnostic workup then took a decisive turn. Creatine kinase, the enzyme that rises when skeletal muscle is destroyed, measured 185 U/L, comfortably within the reference range of 37 to 212 U/L. Cardiac injury markers told a similar story: creatine kinase-MB at 2.31 ng/mL, myoglobin at 33.56 ng/mL, and troponin I below 0.01 ng/mL were all normal, and both the electrocardiogram and transthoracic echocardiography, which showed an ejection fraction of 64 percent, were unremarkable. This combination effectively excluded myositis and myocarditis, the inflammatory muscle and heart conditions that frequently overlap with checkpoint inhibitor-induced myasthenia and account for much of its mortality. Cerebrospinal fluid analysis showed only a mildly elevated protein of 79.8 mg/dL, brain magnetic resonance imaging was unremarkable, and nerve conduction studies demonstrated normal conduction velocities and amplitudes without abnormal spontaneous activity on electromyography.

Electrophysiological testing did, however, capture the signature of the neuromuscular junction. Repetitive nerve stimulation revealed a mild decremental response of 14 percent at low-frequency stimulation, but only in the trapezius muscle; the orbicularis oculi and abductor digiti minimi muscles showed no significant decrement. The ice-cube test, a bedside maneuver in which cooling temporarily improves myasthenic weakness, was negative, while the neostigmine test produced a modest improvement in bilateral ptosis. On the second day of hospitalization the patient’s breathing deteriorated to the point that he required transfer to the intensive care unit and initiation of noninvasive positive-pressure ventilation. Clinicians suspected pembrolizumab-induced myasthenia gravis and began a three-day course of 500 mg of intravenous methylprednisolone.

Serological testing then revealed the feature that makes this case exceptional. Antibodies against the acetylcholine receptor, the most common target in myasthenia gravis, were negative, as were antibodies against muscle-specific kinase, or MuSK, and against gangliosides. But the paraneoplastic syndrome panel returned a positive result for anti-titin antibodies, autoantibodies directed against titin, an enormous structural protein that provides skeletal muscle with its elastic properties. Anti-titin antibodies belong to the heterogeneous family of anti-striational antibodies, which also include antibodies against ryanodine receptors and the voltage-gated potassium channel Kv1.4. They are classically associated with thymoma-related myasthenia gravis and have been linked to more severe disease progression and greater muscle involvement, yet in this patient they appeared in complete isolation, without the muscle destruction that their presence might have predicted.

Treatment unfolded in a way that carries practical lessons. High-dose corticosteroids failed to produce meaningful clinical improvement, but intravenous immunoglobulin, administered at 2 g/kg over five days, led to visible clinical benefit by the third day of infusion. The patient was discharged with gradual improvement and continued on oral prednisolone, though steroid therapy ultimately had to be discontinued when bleeding from a duodenal ulcer, considered steroid-related, intervened. He has since remained on monthly intravenous immunoglobulin as maintenance therapy, and at five-month follow-up his Myasthenia Gravis-Activities of Daily Living score stood at 7, reflecting sustained overall clinical improvement. The authors note that while no conclusions about treatment efficacy can be drawn from a single patient, this experience supports prior reports suggesting that early use of intravenous immunoglobulin or plasma exchange may benefit selected patients with checkpoint inhibitor-related myasthenia gravis.

To place their patient in context, the team systematically reviewed published cases of checkpoint inhibitor-related myasthenia gravis with anti-striational antibody positivity, compiling twelve cases including their own. The picture that emerged was sobering. In the majority of reported cases there was no history of thymoma, and several patients presented with the dreaded overlap of myasthenia gravis, myositis, and myocarditis, a triad associated with rapid deterioration and death within days to weeks. Of the twelve patients, four died, including a 77-year-old woman treated with nivolumab who succumbed 29 days after presentation and an 87-year-old man treated with atezolizumab who died within three days. Only one other case, described by Lara and colleagues in 2019, involved a patient with a remote thymectomy, and in that instance only a generic anti-striational antibody titer was reported without specification of the anti-titin subtype. No previously published case combined anti-titin antibody positivity with a documented thymoma history, making the present report the first of its kind.

The temporal relationship between thymectomy and disease onset raises deep immunological questions. The thymus is the site where T cells learn to distinguish self from non-self, and thymomas disrupt this process in ways that predispose to autoimmunity. Approximately 20 percent of patients diagnosed with thymoma have myasthenia gravis, and conversely, thymoma is frequently discovered during the evaluation of newly diagnosed myasthenia. Rare reports have documented myasthenia gravis appearing years after thymectomy for thymoma, and the authors of the present case propose that autoreactive T cells or long-lived plasma cells may persist in the periphery long after the thymoma is removed, remaining dormant until PD-1 blockade removes the inhibitory signals that keep them in check. A previous report described pembrolizumab-induced myasthenia gravis occurring fifteen years after thymectomy, lending plausibility to this model of reactivation after prolonged quiescence.

The authors are careful to acknowledge the limits of a single case. Causality between isolated anti-titin antibody positivity and the clinical phenotype cannot be established from one patient, and the anti-titin antibody testing was qualitative, precluding any assessment of whether antibody titers tracked with disease activity. Nevertheless, the case expands the recognized immunological spectrum of checkpoint inhibitor-related myasthenia gravis and carries a clear clinical message: patients with a history of thymoma who receive immune checkpoint inhibitors warrant careful neurological vigilance, and clinicians should consider anti-striational antibody testing, including anti-titin antibodies, when myasthenic symptoms emerge in this population, even when conventional acetylcholine receptor and MuSK assays come back negative. As checkpoint inhibitors continue to expand across tumor types, the population of thymectomy survivors exposed to these drugs will only grow, and this case suggests that the immunological legacy of the thymus can resurface with surprising force, more than a decade after the gland itself is gone.

Subject of Research: Pembrolizumab-induced myasthenia gravis with isolated anti-titin antibody positivity after thymectomy for thymoma

Article Title: Case Report: Pembrolizumab–induced myasthenia gravis with isolated anti-titin antibody positivity after thymectomy for thymoma

Article References: Kim, J. H., Chung, J. Y., & Bong, J. B. (2026). Case Report: Pembrolizumab–induced myasthenia gravis with isolated anti-titin antibody positivity after thymectomy for thymoma. Frontiers in Drug Discovery, 6, Article 1932554. https://doi.org/10.3389/fddsv.2026.1932554

Image Credits: AI Generated

DOI: 10.3389/fddsv.2026.1932554

Keywords: pembrolizumab, immune checkpoint inhibitors, myasthenia gravis, anti-titin antibody, thymoma, thymectomy, immune-related adverse events, PD-1 inhibitor, intravenous immunoglobulin, neuromuscular junction, paraneoplastic antibodies, bladder cancer