Background/Purpose:  Autoantibodies (Abs) to 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase (HMGCR) identified in adult myositis patients with immune-mediated necrotizing myopathies (IMNM) have been associated with severe weakness, HLA DRB1*11, and statin use. The prevalence and features of juvenile idiopathic inflammatory myopathies (JIIM) patients with this myositis autoantibody (MSA) have not previously been described. Our purpose was to evaluate the prevalence, clinical features and outcomes of JIIM with anti-HMGCR Abs.

Methods:  We examined the prevalence of HMGCR Abs in the Childhood Myositis Heterogeneity Study, a nationwide registry of JIIM patients. We also examined demographics and clinical features, outcomes, responses to therapy and associated HLA alleles for this MSA, and whether this MSA can be distinguished from other MSAs in children with myositis.

Results:  Of the 441 JIIM patients tested, anti-HMGCR Abs were detected in the serum of 5 patients (1.1%) by ELISA and confirmed by immunoprecipitation. Among these 5 patients, 3 had juvenile dermatomyositis (JDM) and 2 had juvenile polymyositis (JPM). Median age at diagnosis was 8.1 years, 60% were female, 3 were Caucasian, 1 each was Black and Hispanic. HLA typing revealed the DRB1*0701-DQA1*0201 haplotype in 4 patients, and DRB1*0701 allele alone in the 5th (OR =1.4X10⁷, P≤0.001 vs. healthy controls). None of the patients had a documented statin exposure. All patients had severe disease and were hospitalized at onset, and 2 used a wheelchair. Proximal and distal weakness, falling episodes, muscle atrophy, joint contractures and arthralgias were uniformly present in JIIM patients with anti-HMGCR Abs, and most of these were increased in frequency compared to other MSAs, including anti-synthetase (ARS), p155/140, MJ, and MSA-negative (p = 0.038 – 0.005), but not different from those with anti-SRP Abs. The median highest serum CK in patients with HMGCR Abs was 17,000 U/L [IQ range 441– 17,112 U/L]. Two patients’ muscle biopsies showed prominent myonecrosis, myophagocytosis, degeneration, fiber size variation, and mild mononuclear cell infiltration. In 2/3 JDM patients, rashes were frequently mild and improved quickly. Other frequent features were fatigue (5/5), weight loss (4/5), dysphagia, regurgitation, dyspnea (3/5 each), while interstitial lung disease, cardiac involvement and Raynaud’s were absent or infrequent, differing from anti-SRP and ARS Abs. The median number of drug received was 8.0 [IQ range 4.0-9.0] in patients with HMGCR Abs, with a median of 9 treatment trials and 2.6 drug therapies per trial over 22 months. All patients received oral prednisone and MTX; 4 IV methylprednisolone, 3 IVIG, 2 cyclophosphamide, and 2 biologics. Patients had partial responses to many of these, and none entered remission. Four patients had a chronic and 1 had polycyclic disease course. On final evaluation, 3 had continued weakness, 2 had elevated serum CK.

Conclusion:  Anti-HMGCR Ab is an uncommon MSA in patients with JIIM, and as in adults, is associated with severe weakness, a necrotizing myopathy, and treatment-refractory disease. Interestingly, unlike adults, statin use has not been identified and a different HLA allele, HLA DRB1*0701, is associated in JIIM cases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-anti-3-hydroxy-3-methylglutaryl-coenzyme-a-reductase-autoantibodies-in-juvenile-idiopathic-inflammatory-myopathies/