case report

Immune-Mediated Necrotizing Myopathy with Anti-Ku Antibodies and Simultaneous Papillary Thyroid Tumour: A Case Report

Teresa Franco-Leyva1*τ, Anaís Mariscal, Andrés Baucells1, Esther Ortiz1, Victoria Fuste2, Jose-Luis Tandaipan3, Iván Castellví3, Montse Olivé4, Eduard Gallardo5

1Immunology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain

2Pathology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain

3Rheumatology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain

4Neurology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain

5Neuromuscular Disorders Laboratory, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain τContributed equally

*Corresponding author: Teresa Franco-Leyva, Immunology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain

Received Date: 25 January 2023

Accepted Date: 30 January 2023

Published Date: 01 February 2023

Citation: Franco-Leyva T, Mariscal A, Baucells A, Ortiz E, Fuste V, et al (2023) Immune-Mediated Necrotizing Myopathy with Anti-Ku Antibodies and Simultaneous Papillary Thyroid Tumour: A Case Report. Ann Case Report. 8: 1149. DOI: https://doi.org/10.29011/2574- 7754.101149

 

Abstract

Objectives: Anti-Ku antibodies have been described in idiopathic inflammatory myopathies, where a high percentage met the criteria for immune-mediated necrotizing myopathy (IMNM). Furthermore, patients with anti-Ku or seronegative IMNM have a higher rate of malignancy. We report a patient with Rheumatoid Arthritis (RA) that developed IMNM with anti-Ku and a simultaneous diagnosis of papillary thyroid carcinoma. We aimed to elucidate the association between IMNM with anti-Ku and cancer in this patient.

Methods: We diagnosed IMNM with anti-Ku in a patient with RA. Anti-Ku positivity was confirmed by protein immunoprecipitation western-blot. To study Ku expression in the muscle and the tumour, we performed immunohistochemical staining of Ku70 in our patient’s muscle and tumour biopsy as well as in two control muscle biopsies and three other papillary thyroid carcinoma biopsies.

Results: In the muscle, Ku70 was homogeneously expressed in some fibres in the healthy controls. However, in our patient, Ku70 presented a stronger expression in the subsarcolemmal region. In the tumour, Ku70 was heterogeneously expressed in the nuclei and homogeneously in the cytoplasm of the controls. Interestingly, our patient had strong homogeneous expression of Ku70 in the nuclei and little or no staining in the cytoplasm.

Conclusion: We report Ku expression and localization in both muscle and papillary thyroid carcinomas. Our patient showed differential Ku expression in both her muscle and tumour. Thus, anti-Ku antibodies could be a paraneoplastic phenomenon linking cancer to the development of IMNM.

Keywords: Myositis and Muscle Disease; Neoplasia, Autoantigens and Autoantibodies; Muscle; Histopathology

Introduction

Idiopathic inflammatory myopathies (IIM) are clinically and serologically heterogeneous autoimmune diseases characterized by inflammation in striated muscles. They present with muscle weakness, myalgia, elevated serum creatine kinase (CK) levels and myopathic pattern in the electromyogram (EMG). Symptoms develop over weeks or months, often first involving proximal muscles. Some IIM are associated with extra muscular manifestations including skin rashes, or interstitial lung disease (ILD) [1].There are five types among IIM: dermatomycosis’s (DM), immune-mediated necrotizing myopathy (IMNM), sporadic inclusion-body myositis (IBM), overlap myositis and polymyositis1. Each IIM type has characteristic clinical, laboratory and histopathological findings. Thus, screening for autoantibodies and muscle biopsy are recommended for diagnosis. Accurate identification of the IIM is relevant to treatments, complications, outcomes and prognosis. Myositis-specific autoantibodies (MSA) allow classifying patients affected with similar phenotypic subsets. IMNM is characterized by progressive and often severe muscle weakness, very high serum CK levels, minimal extra-muscular manifestations, and muscle biopsy findings with prominent fibre necrosis and scarce inflammation [1,2]. Around two thirds of patients with IMNM have autoantibodies recognizing either SRP or HMGCR, the latter frequently seen in patients treated with statins1. However, differences between these two subtypes have been reported. For instance, patients with anti-SRP can have cardiac involvement and ILD, while patients with anti-HMGCR, as well as with seronegative IMNM, have an increased risk of malignancy [3]. Myositis-associated autoantibodies (MAA) are not specific to myositis and may be found in other autoimmune rheumatic diseases. MAA include anti-Pm-Scl, associated with systemic sclerosis (SSc) and myositis; anti-U1RNP and U3RNP associated with overlap syndromes often with myositis; and antiKu, usually found in systemic lupus erythematosus (SLE) and SSc but also in patients with overlap myositis with ILD [4]. The Ku protein is a heterodimer formed by the Ku70 and the Ku80 subunits that can bind to dsDNA and participates in its repair processes [5]. Interestingly, patients with anti-Ku are more likely to have a history of malignancy at the moment of SSc diagnosis compared with anti-Ku-negative patients [6]. There is an increased risk of malignancy in patients with IIM compared to the general population [7]. For instance, 32% of patients with DM have an associated cancer diagnosis. Most of cancer-associated myopathies appear to be paraneoplastic syndromes (PNS), which are complications of cancer caused by multiple mechanisms, one being immune-mediated. The most accepted hypothesis is that the immune response against the tumour is misdirected against healthy tissues due to cross-reactivity with tumoral antigens [7]. We report a 74-year-old woman who presented with severe myocarditis and IMNM. Screening for MSA and MAA revealed anti-Ku as the only autoantibody. Simultaneously, the patient was diagnosed with a papillary thyroid tumour. Thus, we investigated the presence of anti-Ku autoantibodies as a paraneoplastic phenomenon.

Case Description

A 74-year-old woman was admitted to our hospital with malaise, asthenia, muscular weakness, dysphagia and dyspnoea. The symptoms had begun 3 months before with increasing intensity and had been accompanied by unintentional 10kg weight loss in 4 months. The patient had a history of Rheumatoid Arthritis (RA) untreated due to intolerance to Methotrexate. The physical examination revealed proximal muscular weakness: 4/5 in shoulder girdle, 2/5 in pelvic girdle and 4/5 in neck flexors. Deep tendon reflexes were preserved. Sensory examination was normal. She showed oedema in lower extremities with bilateral positive fovea sign. Lung auscultation revealed bibasilar rales with left predominance. The initial blood tests are detailed in Supplementary Table S1. Electrocardiogram (ECG) showed sinusal rhythm with supraventricular extra systoles, without repolarization abnormalities, and no signs of left-sided heart failure but low voltages in II, aVR, aVF and precordial derivations, suggesting pericardial effusion. Chest radiography showed signs of pleuro-pericardial effusion. A PET-CT scan revealed a pseudo nodular hyper metabolic lesion in the anterior cervical region, suggesting a thyroidal nodule. A fine needle aspiration puncture was performed, compatible with papillary thyroid carcinoma (Bethesda V). Initially, the patient’s condition was considered an IIM associated with my pericarditis. The pericardial effusion evolved to cardiac tamponade that required pericardiocentesis. The diaphragm weakness led to restrictive respiratory insufficiency requiring non-invasive mechanic ventilation at intensive care unit. She was treated with methylprednisolone 1mg/kg/day for 4 days and intravenous immunoglobulin for 5 days, with good response. A month after admission, the patient was discharged with residual muscle weakness. She continued tacrolimus 2mg/12h and prednisone 60mg/day as maintenance treatment. A month later, a hemi thyroidectomy was performed. Its biopsy confirmed a papillary carcinoma stage pT1bN0 with G2 histological grade. The indirect immunofluorescence on HEp-2 cells showed a speckled pattern (AC-4,5) at 1/1280 titter. Anti-Ro60, anti-La, anti-Sm and anti-U1RNP were negative. She was screened for MSA/ MAA with EUROLINE-profile-16Ag (IgG) (Lübeck, Germany). She was also tested for anti-HMGCR by ELISA (Inova, Bedford, USA) and for anti-MDA5, TIF-1γ and nucleotidase-1A (cN1A) using a homemade western-blot as previously described8. Only anti-Ku autoantibodies were positive, confirmed by protein immunoprecipitation western blot, recognizing 70 and 80 KDa bands (Supplementary Data S1). Muscle biopsy was from the right biceps was performed. It showed variable fibre size, increased internal nuclei, and abundant necrotic and split fibres with phagocytosis. Moreover, there were endomysia inflammatory infiltrates that were immunophenotyped (anti-CD68, antiCD4, anti-CD8, anti-CD20, anti-CD138, anti-C5b9, anti-HLAABC, and HLA-DR). Infiltrates were composed of B cells with occasional plasma cells, macrophages, and isolated T CD4 and CD8 cells. There were membrane attack complex (MAC) deposits in capillary walls and at the sarcolemma of muscle fibres. We did not observe class I or II HLA expression. These pathological features were compatible with IMNM (Supplementary Figure S1). Immunohistochemistry against Ku70 (Santa Cruz Biotechnology, Dallas, USA) was performed in the muscle biopsy. The patient’s sample was processed in parallel with a healthy individual and another patient with IMNM but with anti-HMGCR as controls [8]. Both controls showed homogeneous staining of some muscle fibres. However, our patient showed different staining pattern, with redistribution of Ku towards the sarcolemma (Figure 1). Immunohistochemistry against Ku70 was also performed on the patient’s thyroid tumour, a normal thyroid sample, and three other samples from same-stage papillary carcinomas as controls. The healthy control showed homogeneous staining of the nuclei of follicular cells and little or no staining of the cytoplasm, similar to what was seen in the patient’s healthy thyroid tissue (not shown). The control papillary carcinomas showed two different nuclear patterns: one with weak homogeneous staining and one with perinuclear staining. Additionally, we observed some immunoreaction at the cytoplasm in all the cells. However, our patient showed a strong homogeneous Ku70 staining in the nuclei of nearly all cells, and little or no staining within the cytoplasm (Figure 2).

 

Figure 1: (A) Immunohistochemistry of the muscle with antiKu70 antibodies. Both the healthy control at x10 (B) and x40 (C) and a patient with immune mediated necrotizing myopathy (IMNM) and anti-HMGCR autoantibodies at x10 (D) and x40 (E) show Ku positive fibres with homogeneous staining. Our patient with IMNM and anti-Ku antibodies shows a distinctive pattern with greater intensity at its outer rim membrane x10 (F) and x40.