Diagnostic modelling and therapeutic monitoring of immune-mediated necrotizing myopathy: role of electrical myotonia

Abstract

Delayed diagnosis of immune mediated necrotizing myopathy (IMNM) leads to increased morbidity. Patients with chronic course without HMGCR-IgG (3-hydroxy-3-methylglutaryl-coenzyme-A reductase) or SRP54-IgGs (signal recognition particle) are often challenging to diagnose. Immunotherapy response can also be difficult to assess. We created a statistical model to assist IMNM diagnosis. Electrical myotonia vs fibrillations were reviewed as biomarkers for immunotherapy treatment response. Identified were 119 IMNM cases and 938 other-myopathy patients. Inclusion criteria included all having electrophysiological evaluations, muscle biopsies showing inflammatory/necrotizing myopathies, comprehensively recorded neurological examinations, and creatine kinase values. Electrical myotonia was recorded in 56% (67/119) of retrospective and 67% (20/30) of our validation IMNM cohorts, and significantly (p < 0.001) favored IMNM over other myopathies: sporadic inclusion body myositis (odds ratio = 4.78); dermatomyositis (odds ratio = 10.61); nonspecific inflammatory myopathies (odds ratio = 8.46); limb-girdle muscular dystrophies (odds ratio = 5.34) or mitochondrial myopathies (odds ratio = 14.17). Electrical myotonia occurred in IMNM seropositive (HMGCR-IgG 70%, 37/53; SRP-IgG 29%, 5/17) and seronegative (51%, 25/49). Multivariate regression analysis of 20 variables identified 8 (including electrical myotonia) in combination accurately predicted IMNM (97.1% area-under-curve). The model was validated in a separate cohort of 30 IMNM cases. Delayed diagnosis of cases with electrical myotonia occurred in 24% (16/67, mean 8 months; range 0-194). Half (8/19) had chronic course and were seronegative, with high model prediction (>86%) at first visit. Inherited myopathies were commonly first suspected in them. Follow-up evaluation in patients with electrical myotonia on immunotherapy was available in 19 (median 21 months, range 2-124) which reduced from 36% (58/162) of muscles to 7% (8/121; p < 0.001). Reduced myotonia correlated with immunotherapy response in 64% (9/14) as well as with median creatine kinase reduction of 1779 U/L (range 401–9238, p < 0.001). Modeling clinical features with electrical myotonia is especially helpful in IMNM diagnostic suspicion among chronic indolent and seronegative cases. Electrical myotonia favors IMNM diagnosis and can serve as an adjuvant immunotherapy biomarker.

Electrocardiogram-Artificial Intelligence and Immune-Mediated Necrotizing Myopathy: Predicting Left Ventricular Dysfunction and Clinical Outcomes

“…7 This AI-ECG algorithm may provide a potential new tool to assist monitoring beyond CK values, direct manual strength, and electromyographic testing. 8 Specifically, we note a significant improvement of AI-ECG-predicted LVD probability scores in patients while on immunotherapy. However, our study has limitations to address this point given the lack of uniform follow-up with echocardiograms in all patients.…”

“…7 The decision to escalate immunotherapy is complex but can be guided by the level of muscle breakdown creatine kinase (CK) enzyme, electromyographic findings (fibrillations and myotonia) and direct manual muscle testing. 8 Patients with cardiorespiratory involvement are likely to benefit from early and more aggressive immunotherapy given the risk of development of cardiac fibrosis, which is irreversible. 9,10 International guidelines have now recommended that all patients with IIM undergo electrocardiogram (ECG), with echocardiograms reserved for those with orthopnea, chest pain, or syncope.…”

Diagnostic delay of myositis: an integrated systematic review

“…The 27 studies included in the review consisted of seventeen non-comparative studies (nine descriptive cross-sectional studies [ 9 , 14 , 16 , 17 , 22 , 23 , 29 , 36 , 38 ], seven case reports [ 27 , 28 , 31 – 35 ] and one case series [ 30 ]), six analytical cross-sectional studies [ 15 , 18 – 20 , 24 , 37 ], one time series with comparison group [ 21 ] and three retrospective cohort studies [ 25 , 26 , 41 ]. Studies were from multiple countries, including nine from Europe [ 9 , 15 , 16 , 25 , 27 , 31 , 35 , 37 , 38 ], eight from the United States [ 20 , 21 , 24 , 29 , 30 , 33 , 34 , 41 ], three from Australia [ 19 , 22 , 23 ], one from New Zealand [ 14 ], two from Asia [ 28 , 32 ], and one from South America [ 26 ]. Two studies were multi-national [ 18 , 36 ].…”

“…Two studies were multi-national [ 18 , 36 ]. Studies reported diagnostic delay in all IIM subtypes; DM [ 28 , 29 , 33 ] (n = 3 studies), IBM [ 9 , 14 , 16 , 17 , 21 – 24 , 27 , 30 , 34 – 36 ] (n = 13 studies), ASS [ 18 , 26 , 31 , 32 ] (n = 4 studies), JDM [ 15 , 20 ] (n = 2 studies), NM [ 41 ] (n = 1 study) and mixed or all types of IIM [ 19 , 21 , 25 , 38 ] (n = 4 studies). In total, based on the IIM subtypes, the systematic review included a sample size of 1827 with the highest sample size for IBM (n = 1262 people) [ 9 , 14 , 16 , 21 – 24 , 27 , 30 , 34 – 36 ] and the lowest for NM [ 41 ] (n = 67 people).…”

“…In total, based on the IIM subtypes, the systematic review included a sample size of 1827 with the highest sample size for IBM (n = 1262 people) [ 9 , 14 , 16 , 21 – 24 , 27 , 30 , 34 – 36 ] and the lowest for NM [ 41 ] (n = 67 people).…”