Anti-HMGCR Autoantibodies in Juvenile Idiopathic Inflammatory Myopathies Identify a Rare but Clinically Important Subset of Patients

Tansley, Sarah; Betteridge, Zoë; Simou, Stefania; Jacques, Thomas S.; Pilkington, Clarissa; Wood, Mark; Warrier, Kishore; Wedderburn, Lucy R.; McHugh, Neil

doi:10.3899/jrheum.160871

Cited by 55 publications

(46 citation statements)

References 13 publications

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“…As will be discussed in more detail, both anti-SRP and anti-HMGCR myopathies can occur in children [17••, 18••, 19•, 20]. Among adult patients, those with anti-SRP myopathy tend to be younger [16••] than those with anti-HMGCR myopathy (~ 40 vs. ~ 55 years of age).…”

Section: Epidemiologymentioning

confidence: 99%

“…Thus, testing for these autoantibodies should be an essential part of the evaluation of children thought to have a muscular dystrophy but who have no family history or genetically confirmed diagnosis [17••, 18••, 19•, 20, 28, 29•]. …”

Section: Clinical Featuresmentioning

confidence: 99%

“…In both groups, younger age seems to be the factor most closely associated with a worse prognosis. In this regard, some reports of IMNM in children have suggested that juvenile forms of this disease may be considerably resistant to treatment [17••, 18••, 19•, 20]. However, a recent case report and small case series have shown that children with anti-HMGCR and anti-SRP myopathy, respectively, can have a dramatic improvement with immunosuppressive therapy [28, 29•].…”

Section: Prognosismentioning

confidence: 99%

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Immune-Mediated Necrotizing Myopathy

2018

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Purpose of Review Immune-mediated necrotizing myopathy (IMNM) is a type of autoimmune myopathy characterized by relatively severe proximal weakness, myofiber necrosis with minimal inflammatory cell infiltrate on muscle biopsy, and infrequent extra-muscular involvement. Here, we will review the characteristics of patients with IMNM. Recent Findings Anti-signal recognition particle (SRP) and anti-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies are closely associated with IMNM and define unique subtypes of patients. Importantly, the new European Neuromuscular Centre criteria recognize anti-SRP myopathy, anti-HMGCR myopathy, and autoantibody-negative IMNM as three distinct subtypes of IMNM. Anti-SRP myopathy patients have more severe muscle involvement, have more common extra-muscular features, and may respond best to immunosuppressive regimens that include rituximab. In contrast, anti-HMGCR myopathy is often associated with statin exposure and intravenous immunoglobulin treatment may be an effective treatment, even as monotherapy. Both anti-SRP and anti-HMGCR myopathy tend to be most severe in younger patients. Furthermore, children with these forms of IMNM may present with dystrophy-like features which are potentially reversible with immunosuppressant treatment. IMNM patients with either autoantibody may experience fatty replacement of muscle soon after disease onset, suggesting that intense and early immunosuppressant therapy may provide the best chance to avoid long-term disability. Summary IMNM is composed of anti-SRP myopathy, anti-HMGCR myopathy, and autoantibody-negative IMNM. Both anti-SRP and anti-HMGCR myopathy can cause severe weakness, especially in younger patients. Anti-SRP myopathy patients tend to have the most severe weakness and most prevalent extra-muscular features. Autoantibody-negative IMNM remains poorly described.

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Section: Epidemiologymentioning

confidence: 99%

Section: Clinical Featuresmentioning

confidence: 99%

Section: Prognosismentioning

confidence: 99%

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Immune-Mediated Necrotizing Myopathy

2018

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“…The percentage of unexposed patients is even higher in other series, such as the largest cohort of European patients, in which 45.6% of patients with anti-HMGCR-associated myopathy were statin-naïve [32]. Furthermore, in recent reports including children with inflammatory myopathy, some of them misdiagnosed as having dystrophy, none of the children had received statins [34,47,48]. Therefore, a relevant question remains: Is the clinical management of anti-HMGCR-associated myopathy the same in patients who have been exposed to statins and those who have not?…”

Section: Defining Clinical Phenotypesmentioning

confidence: 99%

Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations

Selva-O’Callaghan

Alvarado-Cárdenas

Pinal‐Fernandez

et al. 2018

Expert Review of Clinical Immunology

141

128

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Introduction Musculoskeletal manifestations are well-recognized side effects of treatment with statins. New advances in this field have appeared in recent years. This review focuses on the diagnosis of these conditions and their underlying pathogenesis, in particular immune-mediated necrotizing myopathy. Areas covered Clinical phenotypes including rhabdomyolysis, myalgia and/or mild hyperCKemia, self-limited toxin statin myopathy, and immune-mediated necrotizing myopathy are herein described. Therapeutic recommendations and a diagnostic algorithm in statin-associated myopathy are also proposed. The etiology and pathogenesis of statin-induced myopathy has mainly focused on the anti-HMGCR antibodies and the responsibility of the immune-mediated necrotizing myopathy is discussed. The fact that patients who have not been exposed to statins may develop statin-associated autoimmune myopathy with anti-HMGCR antibodies is also addressed. The literature search strategy included terms identified by searches of PubMed between 1969 and December 2017. The search terms ‘myositis’, ‘statin-induced autoimmune myopathy’, ‘immunemediate necrotizing myopathy’, ‘statins’, ‘muscular manifestations’, and ‘anti-HMGCR antibodies’ were used. Expert commentary Full characterization of the known phenotypes of statin toxicity and the specific role of the anti-HMGCR in those exposed and not exposed (i.e. juvenile forms) to statins and in some types of neoplasms is of paramount relevance.

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“…Our group has previously shown differences in histopathological severity between the MDA5 and Mi2 serological groups and described distinctive features of the paediatric patients positive for MDA5 . SRP and HMGCR serological groups appear to be associated with necrotizing myopathies in children as they are in adults . Detailed histological studies in large serologically well‐defined cohorts have not been published to date, partly due to the rarity of such cohorts.…”

Section: Introductionmentioning

confidence: 97%

Histological heterogeneity in a large clinical cohort of juvenile idiopathic inflammatory myopathy: analysis by myositis autoantibody and pathological features

Yasin¹,

Schütz²,

Deakin³

et al. 2019

Neuropathology Appl Neurobio

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Aim Juvenile idiopathic inflammatory myopathies have been recently reclassified into clinico‐serological subgroups. Myopathological correlates of the subgroups are incompletely understood. Methods We studied muscle biopsies from 101 children with clinically and serologically defined juvenile idiopathic inflammatory myopathies from the UK JDM Cohort and Biomarker Study by applying the international JDM score tool, myopathological review and C5b‐9 complement analysis. Results Autoantibody data were available for 90/101 cases with 18/90 cases positive for anti‐TIF1γ, 15/90 anti‐NXP2, 11/90 anti‐MDA5, 5/90 anti‐Mi2 and 6/90 anti‐PmScl. JDM biopsy severity scores were consistently low in the anti‐MDA5 group, high in the anti‐Mi2 group, and widely distributed in the other groups. Biopsies were classified histologically as perifascicular atrophy (22/101), macrophage‐rich necrosis (6/101), scattered necrosis (2/101), clustered necrosis (2/101), inflammatory fibre invasion (2/101), chronic myopathic change (1/101), diffuse endomysial macrophage infiltrates (40/101) and minimal change (24/101). MDA5 cases segregated with the minimal change group and showed no capillary C5b‐9‐deposition. The Mi2 group displayed high severity scores and a tendency towards sarcolemmal complement deposition. NXP2 and TIF1γ groups showed a variety of pathologies with a high proportion of diffuse endomysial macrophage infiltrates and a high proportion of capillary C5b‐9 deposition. Conclusion We have shown that juvenile idiopathic inflammatory myopathies have a spectrum of histopathological phenotypes and show distinct complement attack complex deposition patterns. Both correlate in some cases with the serological subtypes. Most cases do not show typical histological features associated with dermatomyositis (e.g. perifascicular atrophy). In contrast, more than half show relatively mild histopathological changes.

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Anti-HMGCR Autoantibodies in Juvenile Idiopathic Inflammatory Myopathies Identify a Rare but Clinically Important Subset of Patients

Cited by 55 publications

References 13 publications

Immune-Mediated Necrotizing Myopathy

Immune-Mediated Necrotizing Myopathy

Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations

Histological heterogeneity in a large clinical cohort of juvenile idiopathic inflammatory myopathy: analysis by myositis autoantibody and pathological features

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