TY - JOUR
T1 - Diagnostic modelling and therapeutic monitoring of immune-mediated necrotizing myopathy
T2 - Role of electrical myotonia
AU - Triplett, James D.
AU - Shelly, Shahar
AU - Livne, Guy
AU - Milone, Margherita
AU - Kassardjian, Charles D.
AU - Liewluck, Teerin
AU - Kelly, Cecilia
AU - Naddaf, Elie
AU - Laughlin, Ruple S.
AU - Lamb, Christopher J.
AU - Rubin, Devon
AU - Dimberg, Elliot L.
AU - Dubey, Divanshu
AU - Mills, John R.
AU - Mandrekar, Jay
AU - Klein, Christopher J.
N1 - Publisher Copyright:
© 2020 The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2020
Y1 - 2020
N2 - Delayed diagnosis of immune-mediated necrotizing myopathy leads to increased morbidity. Patients with the chronic course without 3-hydroxy-3-methylglutaryl-coenzyme-A reductase-IgG or signal recognition particle-IgG are often challenging to diagnose. Immunotherapy response can also be difficult to assess. We created a statistical model to assist immune-mediated necrotizing myopathy diagnosis. Electrical myotonia versus fibrillations were reviewed as biomarkers for immunotherapy treatment response. Identified were 119 immune-mediated necrotizing myopathy 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 immune-mediated necrotizing myopathy cohorts, and significantly (P < 0.001) favoured immune-mediated necrotizing myopathy over other myopathies: sporadic inclusion body myositis (odds ratio = 4.78); dermatomyositis (odds ratio = 10.61); non-specific 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 immune-mediated necrotizing myopathy seropositive (3-hydroxy-3-methylglutaryl-coenzyme-A reductase-IgG 70%, 37/53; signal recognition particle-IgG 29%, 5/17) and seronegative (51%, 25/49). Multivariate regression analysis of 20 variables identified 8 (including electrical myotonia) in combination accurately predicted immune-mediated necrotizing myopathy (97.1% area-under-curve). The model was validated in a separate cohort of 30 immune-mediated necrotizing myopathy cases. Delayed diagnosis of cases with electrical myotonia occurred in 24% (16/67, mean 8 months; range 0-194). Half (8/19) had a chronic course and were seronegative, with high model prediction (>86%) at the 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). Modelling clinical features with electrical myotonia is especially helpful in immune-mediated necrotizing myopathy diagnostic suspicion among chronic indolent and seronegative cases. Electrical myotonia favours immune-mediated necrotizing myopathy diagnosis and can serve as an adjuvant immunotherapy biomarker.
AB - Delayed diagnosis of immune-mediated necrotizing myopathy leads to increased morbidity. Patients with the chronic course without 3-hydroxy-3-methylglutaryl-coenzyme-A reductase-IgG or signal recognition particle-IgG are often challenging to diagnose. Immunotherapy response can also be difficult to assess. We created a statistical model to assist immune-mediated necrotizing myopathy diagnosis. Electrical myotonia versus fibrillations were reviewed as biomarkers for immunotherapy treatment response. Identified were 119 immune-mediated necrotizing myopathy 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 immune-mediated necrotizing myopathy cohorts, and significantly (P < 0.001) favoured immune-mediated necrotizing myopathy over other myopathies: sporadic inclusion body myositis (odds ratio = 4.78); dermatomyositis (odds ratio = 10.61); non-specific 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 immune-mediated necrotizing myopathy seropositive (3-hydroxy-3-methylglutaryl-coenzyme-A reductase-IgG 70%, 37/53; signal recognition particle-IgG 29%, 5/17) and seronegative (51%, 25/49). Multivariate regression analysis of 20 variables identified 8 (including electrical myotonia) in combination accurately predicted immune-mediated necrotizing myopathy (97.1% area-under-curve). The model was validated in a separate cohort of 30 immune-mediated necrotizing myopathy cases. Delayed diagnosis of cases with electrical myotonia occurred in 24% (16/67, mean 8 months; range 0-194). Half (8/19) had a chronic course and were seronegative, with high model prediction (>86%) at the 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). Modelling clinical features with electrical myotonia is especially helpful in immune-mediated necrotizing myopathy diagnostic suspicion among chronic indolent and seronegative cases. Electrical myotonia favours immune-mediated necrotizing myopathy diagnosis and can serve as an adjuvant immunotherapy biomarker.
KW - HMGCR
KW - SRP54
KW - immune-mediated necrotizing myopathy
KW - myositis
KW - myotonia
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U2 - 10.1093/braincomms/fcaa191
DO - 10.1093/braincomms/fcaa191
M3 - Article
AN - SCOPUS:85116800405
SN - 2632-1297
VL - 2
JO - Brain Communications
JF - Brain Communications
IS - 2
M1 - fcaa191
ER -