Association of anti-HMGCR antibodies of the IgM isotype with refractory immune-mediated necrotizing myopathy

Abstract

Objective: Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies are one of the myositis-specific antibodies which is associated with immune-mediated necrotizing myopathy (IMNM). However, the relationship between anti-HMGCR isotypes and prognosis has not yet been fully investigated. This study was conducted to gain insight into the association between anti-HMGCR isotypes and clinical, and prognosis in IMNM patients who were positive for anti-HMGCR antibodies.

Methods: Levels of anti-HMGCR isotypes (IgG, IgA and IgM) were assessed by enzyme-linked immunosorbent assay (ELISA) in 123 consecutive serum samples obtained from 71 patients who were positive for anti-HMGCR IgG at baseline. Disease activity was assessed by manual muscle testing (MMT) 8, Physician's Global Assessment (PGA) visual analog scale (VAS), and muscle VAS.

Results: Baseline anti-HMGCR IgG levels were correlated with PGA VAS (r = 0.24; p = 0.04), muscle VAS (r = 0.32; p < 0.01), and MMT8(r=-0.24; p = 0.04), and baseline anti-HMGCR IgM levels were positively correlated with PGA VAS (r = 0.27, p = 0.02), muscle VAS (r = 0.24, p = 0.04). Anti-HMGCR IgM positive patients had a lower age of onset [29(25,46) vs. 51(33,65), p = 0.006], and a higher proportion of neck weakness (63.5% vs. 34.6%, p = 0.031) compared with anti-HMGCR IgM negative patients. Longitudinal analysis showed that the changes in anti-HMGCR IgG levels were correlated with the changes in the PGA VAS (β = 3.830; p < 0.0001), muscle VAS (β = 2.893; p < 0.0001), MMT8 (β=-19.368; p < 0.0001), and creatine kinase (CK) levels (β = 3900.05, p < 0.0001). Anti-HMGCR IgM levels were weakly correlated with anti-HMGCR IgA levels at baseline (r = 0.33, p < 0.01), and the variations in anti-HMGCR IgA levels were correlated with the changes in anti-HMGCR IgM levels during follow-up (β = 0.885; p < 0.0001). There were more patients with anti-HMGCR IgM who showed a refractory course than those who were with anti-HMGCR IgM negative (polycyclic course: 40% vs. 25%; chronic continuous course: 46.7% vs. 20.5%, p = 0.018).

Conclusion: In anti-HMGCR IgG-positive IMNM patients, the levels of anti-HMGCR IgG are associated with disease activity, and anti-HMGCR IgM is associated with refractory outcome and poor prognosis.

Keywords: Anti-HMGCR; Autoantibodies isotypes; Immune-mediated necrotizing myopathy; Outcome.

Fig. 1

Correlation between baseline anti-HMGCR Ig G (A-C), IgA(D-F), and IgM(G-I) levels and disease activity.Abbreviation: HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; PGA, Physician’s Global Assessment; VAS, Visual Analog Scale; MMT, manual muscle testing

Fig. 2

Changes of anti-HMGCR IgG (A), IgA (B), and IgM (C) during follow-up in 33 patients with one or more follow-up visits. Changes of anti-HMGCR IgG in 10 patients with IgG negative-positive conversion(D), changes of anti-HMGCR IgA in 11 patients with a positive conversion of IgA(E), and changes of anti-HMGCR IgM in 8 patients with negative-positive conversion of the IgM (F) over time. Abbreviations: HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase

Fig. 3

Longitudinal relationship between anti-HMGCR IgM levels (red line) and PGA VAS (dark green line), muscle VAS (blue line) in six anti-HMGCR patients with three or more visits. Abbreviations: HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; PGA, Physician’s Global Assessment; VAS, Visual Analog Scale; GCs, glucocorticosteroid; DMARDS, disease-modifying anti-rheumatic drugs; tac, tacrolimus; IVIG, intravenous. immunoglobulin; MMF, mycophenolate mofetil; CTX, cyclophosphamide; CsA, ciclosporin A; HCQ, Hydroxychloroquine