Features of myositis and myasthenia gravis in patients treated with immune checkpoint inhibitors: a multicentric, retrospective cohort study

Lotta Plomp¹, Hortense Chassepot², Dimitri Psimaras³, Thierry Maisonobe⁴, Eric Mensi⁵, Sarah Leonard-Louis⁶, Isabelle Plu⁶, Antoine Rozes⁷, Florence Tubach⁷, Mehdi Touat³, Celine Anquetil¹, Nadege Wesner¹, Nicolas Champtiaux¹, Aude Rigolet¹, Sophie Demeret³, Nicolas Weiss³, Marie-Alexandra Alyanakian⁸, Rozen Le Panse⁹, Frédérique Truffault⁹, Marie-Agnès Dragon-Durey¹⁰, Lucienne Chatenoud⁸, Baptiste Abbar¹¹, Marie-Claire Bretagne¹², Adrien Procureur¹², Thomas Similowski¹³, Capucine Morelot-Panzini¹³, Martin Dres¹³, Stephane Ederhy¹⁴, Olivier Benveniste¹, Joe-Elie Salem¹², Yves Allenbach¹

Affiliations

¹ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Clinical Immunology and Internal Medicine, INSERM U974, Paris, France.
² University of Picardie Jules Vernes - Amiens Picardie University Hospital, Department of Clinical Immunology and Internal Medicine, Amiens, France.
³ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Neurology, INSERM U974, Paris, France.
⁴ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Clinical Neurophysiology, INSERM U974, Paris, France.
⁵ University of Rennes - Rennes University Hospital, Department of Clinical Immunology and Internal Medicine, Rennes, France.
⁶ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Neuropathology, INSERM U974, Paris, France.
⁷ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Center of Pharmacoepidemiology (Cephepi), INSERM, CIC-1901, Paris, France.
⁸ Paris-Cité University - AP-HP and INEM, Necker-Enfants Malades Hospital, Laboratory of Immunology, Paris, France.
⁹ Sorbonne University - Center of Research in Myology, Institute of Myology, INSERM U974, Paris, France.
¹⁰ Paris-Cité University - AP-HP, Georges Pompidou European Hospital, Laboratory of Immunology, Paris, France.
¹¹ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Oncology, INSERM, Paris, France.
¹² Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology, INSERM, Paris, France.
¹³ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Pneumology, INSERM, Paris, France.
¹⁴ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Cardiology, INSERM, Paris, France.

PMID: 39896961
PMCID: PMC11782875
DOI: 10.1016/j.lanepe.2024.101192

Features of myositis and myasthenia gravis in patients treated with immune checkpoint inhibitors: a multicentric, retrospective cohort study

Lotta Plomp et al. Lancet Reg Health Eur. 2025.

. 2025 Jan 14:50:101192.

doi: 10.1016/j.lanepe.2024.101192. eCollection 2025 Mar.

Authors

Affiliations

¹ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Clinical Immunology and Internal Medicine, INSERM U974, Paris, France.
² University of Picardie Jules Vernes - Amiens Picardie University Hospital, Department of Clinical Immunology and Internal Medicine, Amiens, France.
³ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Neurology, INSERM U974, Paris, France.
⁴ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Clinical Neurophysiology, INSERM U974, Paris, France.
⁵ University of Rennes - Rennes University Hospital, Department of Clinical Immunology and Internal Medicine, Rennes, France.
⁶ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Neuropathology, INSERM U974, Paris, France.
⁷ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Center of Pharmacoepidemiology (Cephepi), INSERM, CIC-1901, Paris, France.
⁸ Paris-Cité University - AP-HP and INEM, Necker-Enfants Malades Hospital, Laboratory of Immunology, Paris, France.
⁹ Sorbonne University - Center of Research in Myology, Institute of Myology, INSERM U974, Paris, France.
¹⁰ Paris-Cité University - AP-HP, Georges Pompidou European Hospital, Laboratory of Immunology, Paris, France.
¹¹ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Oncology, INSERM, Paris, France.
¹² Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology, INSERM, Paris, France.
¹³ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Pneumology, INSERM, Paris, France.
¹⁴ Sorbonne University - AP-HP, Pitié-Salpêtrière Hospital, Department of Cardiology, INSERM, Paris, France.

PMID: 39896961
PMCID: PMC11782875
DOI: 10.1016/j.lanepe.2024.101192

Abstract

Background: Immune checkpoint inhibitors (ICIs) may induce overlapping myositis/myasthenia gravis (MG) features, sparking current debate about pathophysiology and management of this emerging disease entity. We aimed to clarify whether ICI-induced (ir-) myositis and ir-MG represent distinct diseases or exist concurrently.

Methods: We performed a retrospective multicenter cohort study. Using the Paris University Hospitals database (n = 2,910,417), we screened all patients with International Classification of Diseases codes or free text related to myositis/MG signs and ICI (n = 620). 'Ir-MG signs' were defined by fatigability, repetitive nerve stimulation (RNS) decrement, and/or acetylcholine receptor antibodies (AChR Abs).

Findings: Ir-MG signs were never observed in the absence of ir-myositis (pathological diagnosis (n = 12/14) or CK levels >8000 U/L (n = 2/14)). Among ir-myositis patients, fatigability (2%; n = 1/62) and RNS decrement (2%; n = 1/41) were demonstrated only in one patient with pre-existing MG. AChR Abs testing yielded positive results in 26% of ir-myositis patients (n = 14/53). We revealed that test results were already positive prior to ICI therapy (n = 8/9). Clinically, ir-myositis frequently presented with "MG-like" oculomotor disease (50%; n = 31/62), bulbar dysfunction affecting speech (29%; n = 18/62) and swallowing (42%; n = 26/62), and respiratory disorders (53%; n = 33/62). Extraocular and diaphragm muscles necropsies disclosed intense muscle inflammation (100%; n = 5/5).

Interpretation: In our extensive database, we found no evidence of isolated ir-MG, nor of clear neuromuscular junction dysfunction in ir-myositis. These findings suggest that patients with ir-MG suspicion frequently have ir-myositis and ir-MG might be rare. "MG-like" symptoms may stem from ir-myositis-specific predilection for oculo-bulbo-respiratory musculature. Indeed, we revealed florid inflammatory infiltration of the oculomotor and respiratory muscles. Additional studies are needed to confirm these results and to elucidate the role of pre-existing AChR Abs in ir-myositis.

Funding: None.

Keywords: Acetylcholine receptor antibodies; Autoimmunity; Biomarker; Immune checkpoint inhibitor; Immune checkpoint inhibitor-induced myasthenia gravis; Immune checkpoint inhibitor-induced myositis; Immune-related adverse event; Immunotherapy; Myasthenia gravis; Myositis.

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Conflict of interest statement

None of the authors received financial support for the submitted work. CA reports one patent planned in the field of management of immune checkpoint inhibitors toxicities. BA reports a research grant from MSD Avenir, consulting fees from Novartis, Astellas, and Sanofi, personal honorarium from Sanofi, AstraZeneca, BMS, MSD and Astellas, and support for attending meetings and/or travel from Janssen, MSD, Pfizer, IPSEN Pharma and Takeda. MT reports a grant from Sanofi, consulting fees from Servier, Novocure and NH TherAguiX, personal honorarium from Servier, Novocure and ONO, and support for attending meetings and/or travel from Servier. MT participated on a Data Safety Monitoring or Advisory Board for Servier. MCB reports personal honorarium, and support for attending meetings and/or travel from Novartis. SE reports consulting fees from Bayer, Amgen and Ipsen, and personal honorarium from AstraZeneca, BMS, Philips, General Electric, and Eisai. FT reports non-personal consulting fees from MSD, Novartis, and GSK. JES reports personal consulting fees from AstraZeneca, BeiGene, BMS and Novartis, several patents planned, issued or pending in the field of management of immune checkpoint inhibitors toxicities. YA received research funding from Sanofi and Association Recherche contre le Cancer, consulting fees from BMS, personal honorarium from RE-IMAGINE Health Agency and CSL Behring SA, and support for attending meetings and/or travel from CSL Behring SA and Boehringer Ingelheim France. YA had several patents planned, issued or pending in the field of management of immune checkpoint inhibitors toxicities.

Figures

**Fig. 2**
AChR Abs titer evolution pre-/post-**ICI exposure.** Spaghetti plot of AChR Abs titer (log2 scale, nmol/L) dynamics in patients with ir-myositis ± MG, showing evolution between last available AChR Abs titer before and first available AChR Abs titer after ICI exposure (black, n = 10) or, in patients without available pre-ICI AChR Abs testing, solely showing first available AChR Abs titer after ICI exposure (grey, n = 5). The dotted vertical red line indicates time of ICI exposure. The dotted horizontal black line denotes the threshold titer at which an AChR Abs test result was considered positive (0·5 nmol/L).

**Fig. 3**
**Oculomotor, neck/limb, and respiratory muscles: frequency of clinical involvement (n = 62, left) and typical histopathology on biopsy and necropsy (right) in ir-myositis ± MG patients.** Left: Frequency of clinically significant oculomotor (50%; n = 31/62), neck/limb (82%; n = 51/62), and respiratory (53%; n = 33/62) muscle involvement in our cohort of ir-myositis ± MG patients (n = 62). Details in Table 2. Right: Representative histopathological findings on biopsy and necropsy of oculomotor (a, lateral rectus muscle, H&E, 100× magnification), neck/limb (b, deltoid muscle, H&E, 100× magnification), and respiratory (c, diaphragm, H&E, 25× magnification) muscles, showing florid, multifocal inflammatory cell densities (of CD68+ and CD8+ predominance, immunohistochemistry shown in Fig. 4) and necrosis. Other universal features included MHC class I upregulation and C5b-9 deposition on necrotic and non-necrotic fibers (not shown here).

**Fig. 4**
**Typical myopathology on diaphragm necropsy in ir-myositis ± MG patients: CD68+ and CD8+ cells.** Immunohistochemistry reveals that inflammatory infiltrates in ir-myositis ± MG are composed mainly of macrophages (a, diaphragm, CD68, 100× magnification) and CD8+ T-cells (b, diaphragm, CD8, 100× magnification).

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Features of myositis and myasthenia gravis in patients treated with immune checkpoint inhibitors: a multicentric, retrospective cohort study

Affiliations

Features of myositis and myasthenia gravis in patients treated with immune checkpoint inhibitors: a multicentric, retrospective cohort study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources

Research Materials