Clinical and histological features of immune-mediated necrotising myopathy: A multi-centre South Australian cohort study
Introduction
The idiopathic inflammatory myopathies (IIMs) are a group of systemic autoimmune diseases characterised primarily by muscle inflammation but also potentially accompanied by a range of extra-muscular manifestations. Dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM) constitute well-characterised subtypes of IIM, with the entity of non-specific idiopathic inflammatory myopathy (NSIIM) being more recently described [1]. Whilst these IIM subtypes are distinguished on clinical, serological and histological grounds, they are unified by the presence of a typically prominent intramuscular lymphocytic infiltrate. However, over the past 15 years, descriptions of a distinct form of proximal myopathy characterised by prominent necrosis, regeneration, myophagocytosis and minimal lymphocytic infiltrate that responds to immunotherapy have emerged [2]. This entity has been termed immune-mediated necrotising myopathy (IMNM; also known as necrotising autoimmune myopathy, NAM) and has been conceptualised within the spectrum of IIM. There is a growing body of literature that seeks to define and characterise this IIM subtype with respect to aetiopathogenesis, environmental and genetic risk factors, autoantibody profiles, clinico-histological features, prognosis and response to treatment [3], [4], [5], [6]. Complicating these endeavours is the heterogeneity of IMNM, the recognition that myonecrosis is a non-specific feature that may result from immune- and non-immune factors, and the fact that IMNM is not necessarily accompanied by detectable autoantibodies or other features of autoimmunity. These uncertainties have implications for the systematic study of these conditions and may hinder accurate diagnosis and treatment. Comprehending what the diagnosis of IMNM means in a local context is important to enable meaningful comparisons with international cohorts.
Herein we systematically describe the clinical and histological features of a consecutive cohort of patients diagnosed with IMNM in order to better understand the spectrum of disease, characterise the features that distinguish it from other forms of IIM, identify distinct phenotypes within South Australia and contribute further to the important Australian research [7], [8], [9], [10], [11] accumulating on this emerging condition. We additionally characterise the features that distinguish IMNM from other forms of IIM and identify factors associated with clinically severe forms of IMNM.
Section snippets
Subjects
Muscle tissue, serological and clinical data were obtained from the South Australian Myositis Database (SAMD), a histologically-defined registry of patients with PM, DM, IBM, NSIIM and ‘necrotising myopathy’. The histological criteria for recruitment to the SAMD has previously been described for PM, DM and IBM [12]. ‘Necrotising myopathy’ is defined as the presence of myofibre necrosis and an absence of features consistent with other forms of myopathy. Of these patients, only those with a
Inter-rater reliability of grading
Inter-rater reliability was acceptable (κ 0.66–0.75) for all histological parameters (Supplementary Table 2).
Clinical features of South Australian IMNM patients
Of the 773 patients in the South Australian Myositis Database (1993 – 2016), 20% were recorded as having a ‘necrotising myopathy’ histologically (Supplementary Figure 1). The remaining patients had histological diagnoses of DM (10%), PM (31%), IBM (23%), NSIIM (10%) and ‘Other (e.g. sarcoidosis, vasculitis; 10%). Consecutive cases of IMNM diagnosed between 2001–2016 are analysed herein
Discussion
Immune-mediated necrotising myopathy is a relatively recently described entity. To our knowledge, this is the largest Australian study to systematically describe the histological spectrum of this disease in a consecutive cohort and determine associations with clinical disease severity. Consistent with previous research, we found that many IMNM patients feature a subacute trajectory, high serum CK levels, profound muscle weakness, few extra-muscular manifestations and evidence of myonecrosis,
Conclusions
Immune-mediated necrotising myopathy is a heterogeneous condition. Most patients have persistent weakness at one year despite immunotherapy. Severity at presentation is closely associated with the degree of necrosis and complement deposition on muscle cells. Aboriginal and Torres Strait Islander peoples appear to present with a more severe form of IMNM, and the mechanisms underlying this should be explored in future research.
Acknowledgments
Professor Peter Blumbergs (SA Pathology, Royal Adelaide Hospital) for hypothesis revision.
Ms Bernice Gutschmidt (SA Pathology) for technical assistance with experimental process.
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