Clinical and histological features of immune-mediated necrotising myopathy: A multi-centre South Australian cohort study

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Highlights

  • Immune-mediated necrotising myopathy is clinically and histologically heterogeneous.

  • Many patients present with severe weakness and few recover full power by one year.

  • Complement deposition on myofibres closely correlates with clinical severity.

  • Aboriginal and Torres Strait islander patients present with a severe phenotype.

Abstract

Immune-mediated necrotising myopathy (IMNM) is a recently described entity. We describe a cohort of South Australian IMNM patients in order to define the spectrum of disease, characterise features that distinguish IMNM from other idiopathic inflammatory myopathy (IIM) subtypes and identify factors associated with clinically severe disease. Subjects were identified from the South Australian Myositis Database (SAMD), a histologically defined registry. Consecutive muscle sections from patients with IMNM (n = 62), other forms of IIM (n = 60) and histologically normal muscle (n = 17) were stained using immunohistochemistry and graded. Clinical information was collected from the SAMD and through retrospective chart review. IMNM patients displayed clinical and histological heterogeneity. While most (67%) were profoundly weak at presentation, 24% exhibited mild to moderate weakness and 9% had normal power. Histological myonecrosis ranged from minor to florid. The amount of myofibre complement deposition was closely associated with clinical severity. Patients of Aboriginal and Torres Strait Islander heritage and those with anti-SRP autoantibodies present with a severe phenotype. Despite intense immunotherapy, few IMNM patients recovered full power at one year follow up. The identification of clinical, serological and histological features which are associated with severe forms of the disease may have diagnostic and therapeutic utility.

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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