Four dermatomyositis-specific autoantibodies—anti-TIF1γ, anti-NXP2, anti-SAE and anti-MDA5—in adult and juvenile patients with idiopathic inflammatory myopathies in a Hungarian cohort

Highlights

• Authors evaluated MSAs and their association with clinical symptoms.

• 133 of 337 myositis patients had MSA; within 12 anti-TIF1γ, 4 anti-NXP2, 4 anti-SAE.

• Clinical findings of patients with anti-TIF1γ, -NXP2, -SAE, and -MDA5 positivity

• The relevant results were similar to those seen in previously published reports.

Abstract

Idiopathic inflammatory myopathies (IIMs) are chronic systemic autoimmune diseases characterised by symmetrical, proximal muscle weakness. Dermatomyositis represents one subset of IIMs, in which skin rashes are present in addition to muscle weakness. Myositis-specific antibodies can only be detected in myositis, and they are directed against specific proteins found in the cytoplasm or in the nucleus of cells. With this case-based article, we introduce the recently detected anti-TIF1γ, anti-NXP2, anti-SAE and anti-MDA5 antibodies that form various clinical groups. These antibodies could be detected in patients with dermatomyositis. The myositis-specific autoantibodies of three hundred and thirty-seven Hungarian patients with IIM were detected. Retrospective analysis of the clinical findings has also been introduced by revision of the medical history. We had twelve patients with anti-TIF1γ positivity, four patients with anti-NXP2 positivity and four patients with anti-SAE positivity. We did not have any positive anti-MDA5 patients. The most relevant clinical findings were similar to those seen in previously published reports. Eleven of the twelve patients with anti-TIF1γ positivity had classical dermatomyositis. Three of the twelve anti-TIF1γ patients had cancer during the disease progression. This was two out of four for the anti-NXP2 subgroup and one in four for the anti-SAE subgroup. In two juvenile dermatomyositis cases, typical ulceration was seen in patients with anti-TIF1γ positivity. The frequency of pulmonary fibrosis during the disease progression was 2/12, 1/4 and 1/4 in anti-TIF1γ, anti-NXP2 and anti-SAE, respectively. Other extra-muscular manifestations, such as arthralgia, dysphagia, dysphonia and dyspnoea, were also detectable. The myositis subgroups determined by these myositis-specific autoantibodies differ from each other in their symptoms, prognosis and therapy responsiveness. Their detection is helpful for the preparation of an adequate treatment, but in daily diagnostic methods, these antibodies cannot be detected. By presenting our anti-TIF1γ, anti-NXP2 and anti-SAE cases, we would like to highlight the clinical role of these antibodies.

Introduction

Idiopathic inflammatory myopathies (IIMs) are systemic autoimmune diseases characterised by symmetrical, proximal muscle weakness. The most commonly used criteria for the classification of IIMs are those that were proposed by Bohan and Peter in 1975 [1]. From a clinico-pathological perspective, the IIMs fall into six categories: (1) dermatomyositis (DM; juvenile, adult), (2) polymyositis (PM; T-cell mediated, eosinophilic, granulomatous), (3) overlap syndromes (with DM, with PM, with sIBM/hIBM), (4) cancer-associated myositis, (5) inclusion body myositis (IBM), and (6) other forms (focal: orbital myositis, localised nodular myositis, inflammatory pseudotumor; diffuse: macrophagic myofasciitis, necrotizing autoimmune myopathy (NAM), infantile myositis) [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Although this clinico-pathological subdivision has a predictive value in prognosis and in therapy, according to our rising knowledge of the autoantibodies, this system seems to be worn out. Frequently, it generates heterogeneous disease groups; the definition of the criteria is indefinite. The degree of abnormality for the muscle enzymes, electromyography and histopathological alterations is not precise defined [17].

Autoantibodies are of great importance for the diagnosis of many systemic autoimmune rheumatic diseases, including IIMs. Autoantibodies can be specific markers for myositis. They can be divided into two parts. The first is the group of myositis-associated autoantibodies (MAAs), for example anti-PM-Scl, anti-U1, U2-, U3-RNP, anti-Ku, anti-SSA/Ro and anti-SSB/La. These can be found in overlapping cases. Many studies highlight the importance of MAAs. It was reported that anti-U1-RNP was associated with active mixed connective tissue disease (MCTD) and with myositis and esophageal hypomotility [18]. We know that patients with anti-synthetase syndrome (ASS) are more frequently associated with anti-Ro/SSA antibody than PM/DM patients without ASS [19]. Our workgroup also reported previously that the co-existence of anti-SSA and anti-Jo-1 antibodies seems to be a predictor for relatively severe interstitial lung disease (ILD) in IIM patients [20]. In American patients anti-Ku antibody tends to be detected mainly in lupus patients [21], while in Europe it appears to be associated with overlap syndromes and certain clinical symptoms such as arthralgia and Raynaud's phenomenon [22], [23].

The other category is the group of the myositis-specific autoantibodies (MSAs). The MSAs are directed against specific proteins that can be found in the cytoplasm or in the nucleus of the cells. MSAs are useful in the diagnosis of IIMs and in the precise definition of disease subsets. Approximately 38% of IIM patients have MSAs in their sera [24], and, to our knowledge, the co-existence of two MSAs is considered extremely rare [25]. The presence of the MSA, in many cases, can be detected in the sera some months before clinical manifestation of the symptoms; the serum level may correlate with disease activity. If the MSA disappears, it could be the sign of remission, so they can serve as prognostic markers. With the help of the MSAs, we can make different disease phenotypes that could be important in diagnosis, therapy and prognosis [26]. The most relevant MSAs are the following. A meta-analysis from 2014 reviewed the clinical symptoms of patients with anti-aminoacyl-transfer RNA-synthetase (anti-ARS) autoantibody. According to recent research anti-ARS autoantibodies include anti-Jo1, anti-PL-7, anti-PL-12, anti-OJ, anti-EJ, anti-KS, anti-SC, anti-JS, anti-Ha and anti-Zo autoantibodies [27]. Autoantibodies found in patients with NAM are anti-SRP and the recently recognised anti-HMGCR and anti-200/100 [28], [29], [30]. The statin-induced form of NAM is associated with the presence of anti-HMGCR autoantibodies [31]. Anti-Mi-2 is a DM-associated MSA [32].

Novel MSAs targeting intracellular proteins have recently been detected in patients with DM, namely anti-TIF1γ, anti-NXP2, anti-SAE and anti-MDA5.

According to previous reports, we can summarise that the frequency of anti-TIF1γ is 13–21% in adult and 23–29% in juvenile IIM cases [33]. The antigen is a 155 kDa antigen (the transcriptional intermediary factor 1 gamma—TIF1γ). Clinical representation of patients with anti-TIF1γ is DM together with malignancy in adult patients. In juvenile DM patients, antibodies for TIF-1γ are not associated with malignancy, but rather, with skin ulcerations and more extensive cutaneous diseases [33].

The frequency of this antibody in adult cases is less than 5% and in JDM within 23–25% [33]. Nuclear matrix protein 2 (NXP2) was identified as the auto-antigen target [34]. Similar to anti-TIF1γ positivity, we can state that the adult and juvenile IIM cases also have different phenotypes when this antibody is present. The disease course is severe; in adult patients, DM and malignancy might be typical, whereas in juvenile cases, DM with specific skin symptoms such as calcinosis can appear [33].

The frequency of this antibody is less than 5% in adult and less than 1% in juvenile IIM cases [33]. The antigen is the small ubiquitin-like modifier activating enzyme (SAE). It is associated with severe DM and, in adult patients, dysphagia can appear [33].

In a Japanese study, the frequency of this antibody was 11% in DM patients, whereas, in a retrospective study from the USA, it was 13% [35], [36]. The antigen is the melanoma differentiation-associated gene 5 (MDA5). Patients from the USA with anti-MDA5 positivity are reported to have mild muscle symptoms and DM is associated with ulcers; they often have arthritis and ILD. Patients from the East Asian population are reported to have clinically amyopathic dermatomyositis (CADM), rapidly progressive ILD and poor prognosis [33].

In this study, after giving an overview of the MAAs and MSAs, we highlight the importance of our clinical findings in positive anti-TIF1γ, anti-NXP2, anti-SAE and anti-MDA5 adult and juvenile patients with IIM in a Hungarian cohort. Our aim was to evaluate the prevalence of these MSAs in IIM and their association with clinical characteristics and the disease course.