Summary by Louisa Kent

Publication: In people with statin exposure and muscle symptoms, clinical and laboratory features are key in determining a toxic process from an immune-mediated one (IMNM). Histopathological changes have significant overlap, but certain features can help to distinguish these entities.

Pubmed link

PMID: 40450411

DOI: 10.1016/j.nmd.2025.105386

Clinical pearls and histopathological features help discriminate toxic rhabdomyolysis from immune-mediated necrotising myopathy in statin-exposed patients

Benjamin Ellezam, Yves Troyanov, Océane Landon-Cardinal

Summary

This paper came about due to an increase in muscle biopsy samples received by the authors from people with muscle symptoms and statin exposure. The clinical question was whether they could distinguish toxic rhabdomyolysis (TR) and immune mediated necrotising myopathy (IMNM) histologically. Their cohort consisted of 36 patients with TR and 29 patients with IMNM and histology was reviewed retrospectively.

A small proportion of the samples were easier to distinguish; in the 5% of samples that looked pseudodystrophic all had IMNM. In the 11% that had either absent necrosis or very predominant necrosis (>50% of fibres), all had TR. They used a semi-quantitative necrosis score for the remaining samples, and there was significant overlap between the two groups. Having said that, those with the higher score were more likely to be TR.

Basophilic cuffs were more prevalent in TR. In addition, LC3 and C5b-9 staining was focused on the necrotic fibres in TR whereas in IMNM it was more widespread. These features could give us clues as to whether the process is toxic or immune mediated.

Clinical and laboratory features were helpful. Duration of symptoms was longer in the IMNM group. Peak creatine kinase (CK) was higher in TR, with a CK of over 25,000 IU/L only seen in the TR group. CK normalisation was seen much sooner in the TR group. A useful clinic pearl was highlighted in that acute creatinine rise was seen in 94% of TR and none of the IMNM cases.

There are some limitations of this paper, including the fact this this was a retrospective unblinded study. In addition, LC3 staining is not routinely available in all centres.

In summary, clinical features including duration of symptoms, clinical progression, CK and creatinine are very helpful tools in distinguishing between TR and IMNM. Allowing time rather than biopsy in the acute phase can allow the diagnosis to unfold. If a biopsy is carried out, there are some features that can help to distinguish between the two entities, though there is significant overlap in the extent and stages of necrosis that are observed. This paper is worth reading for its useful clinical application and nice muscle biopsy images. It is a helpful paper for pathologists who receive these samples, as it is likely that many centres have also noticed an increase in biopsies received in this scenario. It is also helpful for clinicians trying to distinguish between TR and IMNM and determine the need and best time for biopsy. This paper would be helpful to share and discuss with colleagues facing this question.

About the author

Benjamin Ellezam completed his neuroscience PhD, MD, and anatomic pathology residency at Université de Montréal, followed by a neuropathology fellowship at MD Anderson Cancer Center/Methodist Hospital and Texas Children’s Hospital in Houston.

Since 2012, he has served as a staff neuropathologist at Sainte-Justine Hospital and an associate clinical professor in the Department of Pathology and Cell Biology at Université de Montréal. His practice focuses on neuromuscular pathology, with more than 200 adult and paediatric muscle biopsies reviewed annually, and his research centres on myositis in mixed connective tissue disease.

He founded and directs the Sainte-Justine Biobank for Research on Diseases of the Nervous System, whose scope was recently expanded to include neuromuscular disorders and expected to include over 1,000 muscle biopsy specimens.

About the reviewer

Louisa Kent completed her undergraduate training at Imperial College, London. She undertook her neurology training in Oxford, UK. During this time she achieved a D Phil in clinical neurosciences for investigating the pathophysiology of ALS. She also completed a neuromuscular fellowship in Oxford focusing on myology, mitochondrial disorders and SMA. During this time, her enthusiasm for learning about muscle disorders grew and she is excited to continue to gain experience in this area. She has recently finished her training and is enjoying working in general neurology and in the Oxford rare mitochondrial disorders service.