Anti-HMGCR Antibody-Positive Myopathy Shows Bcl-2-Positive Inflammation and Lymphocytic Accumulations

Abstract

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and antisignal recognition particle (SRP) antibodies are frequently associated with immune-mediated necrotizing myopathy (IMNM). However, the difference in clinical manifestations between anti-HMGCR and anti-SRP antibodies is unclear. HMGCR is an essential enzyme for cholesterol biosynthesis and is inhibited by statins that regulate apoptosis of Bcl-2-positive and beta chemokine receptor 4 (CCR4)-positive lymphoma cells. In this study, we aimed to clarify Bcl-2 and CCR4 expressions of lymphocytes in anti-HMGCR antibody-positive IMNM and explore the difference between anti-HMGCR antibody-positive myopathy and other inflammatory myopathies. We retrospectively examined Bcl-2- and CCR4-positive lymphocyte infiltrations in muscle and skin biopsy specimens from 19 anti-HMGCR antibody-positive patients and 75 other idiopathic inflammatory myopathies (IIMs) patients. A higher incidence of Bcl-2- and CCR4-positive lymphocytes was detected in the muscle and skin of anti-HMGCR antibody-positive IMNM patients (p < 0.001). In 5 patients with anti-HMGCR antibodies, Bcl-2-positive lymphocytes formed lymphocytic accumulations, which were not observed in other IIMs. Low-density lipoprotein cholesterol levels were not increased except for patients with Bcl-2-positive lymphocytic accumulations (p = 0.010). Bcl-2 and CCR4 lymphocyte infiltrations could be a pathological characteristic of anti-HMGCR antibody-positive IMNM.

Keywords: 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR); Bcl-2; Hyperlipidemia; Immune-mediated necrotizing myopathy.

FIGURE 1.

Pathological changes in anti-HMGCR antibody-positive necrotizing myopathy patients showing muscular Bcl-2-positive lymphocyte infiltration and lymphoid follicle-like structures. (A) Inflammatory cell infiltrates to the endomysium and perivascular areas. (B, C) CD4-positive/CD8-positive lymphocytes infiltrated to the perivascular area and endomysium. (D) CD20-positive lymphocytes were rarely observed in mild cases with anti-HMGCR antibody-positive myopathy. (E) Bcl-2-positive lymphocytes are observed in the perivascular area. (F) Bcl-2-positive lymphocytes infiltrate to endomysium. (G) CCR4-positive lymphocytes were scattered in both perimysium and endomysium. (H) Lymphocytic accumulations were scattered in severe cases with anti HMGCR antibody-positive myopathy. (I, J) Lymphocytes were positive for CD3 and CD20 in these accumulations. (K) Lymphocytes were positive for Bcl-2 in lymphocytic accumulations. (L) CCR4-positive lymphocytes were observed in both endomysium and lymphocytic accumulations. (M) α-SMA was negative. (N) Bcl-2 indexes in anti-HMGCR antibody-positive myopathy were significantly highest in each group. (O) CCR4 indexes were highest in anti-HMGCR antibody-positive myopathy cases (***p < 0.001). (A–G) Patient 12. (H–K, M) Patient 11. (L) Patient 18. Scale bar: 100 µm.

FIGURE 2.

Bcl-2 and CCR4 immunopositivity in muscle of other IIMs. (A, B) Focal endomysial Bcl-2- and CD45-positive lymphocytes infiltrations forming hotspot were observed, especially in sIBM cases. (C) The muscle biopsy specimen of sIBM patient with HTLV-1 infection showed aberrant CCR4-positive lymphocytes. (D) Bcl-2-positive perivascular cuffings were scattered most frequently in cases with antimitochondria M2 antibody-positive myositis. (E) Superficial perivascular dermatitis in cases without anti-HMGCR antibody. (F) CD45-positive lymphocytes infiltrated mainly in perivascular areas. (G) Bcl-2-positive lymphocytes are scattered. (H) CCR4-positive cells were not observed. Scale bar: 100 µm.

FIGURE 3.

Pathological changes in skin of anti-HMGCR antibody-positive necrotizing myopathy patients also showed Bcl-2-positive lymphocyte infiltration and lymphocytic accumulations. (A) Skin biopsy specimens show superficial perivascular dermatitis. (B) CD3-positive lymphocytes are observed in epidermis and dermis. (C) CD20-positive lymphocytes are not observed. (D) Lymphocytes infiltrating skin are positive for Bcl-2. (E) In severe cases, lymphocytic accumulations are observed in dermis. (F, G) CD3-positive/CD20-positive lymphocytes infiltrate to cutis including these accumulations. (H) Bcl-2-positive lymphocytes were diffusely observed in skin tissues including these accumulations. (I) CCR4-positive lymphocytes were also scattered. (J) α-SMA was negative except for vessels. (K) Bcl-2 indexes of skin in anti-HMGCR antibody-positive myopathy were significantly highest in each group (***p < 0.001). (L) CCR4-positive lymphocytes were observed only in anti-HMGCR antibody-positive myopathy (***p < 0.001). (A–E) Patient 14. (F–J) Patient 10. Scale Bars: (A–E) 100 µm, (F–H, J) 500 µm, (I) 50 µm.

FIGURE 4.

Cholesterol levels and lymphoid follicle-like structures. (A–C) There were no significant differences in cholesterol levels in each group. (D) Anti-HMGCR antibody-positive myopathy patients with lymphocytic accumulations had higher levels of LDL cholesterol than patients without these accumulations (*p = 0.01).