Introduction

Idiopathic inflammatory myopathies (IIMs) refer to a rare group of heterogeneous autoimmune disorders, including polymyositis, immune-mediated necrotizing myopathy, dermatomyositis, and inclusion body myositis (IBM) [1]. Autoimmunity is known to play a key role in the pathogenesis of IIMs and autoantibodies have been found in over 50% of patients [2]. Conventionally, autoantibodies found in patients with IIMs are classified into myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies. MSAs are clinically useful biomarkers with diagnostic and prognostic relevance [3].

Anti-nuclear matrix protein 2 (NXP2) autoantibody, originally termed as anti-MJ autoantibody, is one of the MSAs. The reported frequency of anti-NXP2 autoantibody in juvenile and adult IIMs ranges from 2 to 20% [3]. To date, results pertaining to the diagnostic accuracy of anti-NXP2 autoantibody for IIMs have been largely inconsistent. In addition, there is no clear consensus on the association between anti-NXP2 autoantibody and the clinical signs of IIMs. For example, Bodoki et al. found an association between anti-NXP2 autoantibody and malignancy [4]; however, some studies have found no significant difference in the prevalence of malignancy between patients with and without anti-NXP2 autoantibody [5, 6].

There is no consensus on the diagnostic and prognostic relevance of anti-NXP2 autoantibody for IIMs, as well as on the association between anti-NXP2 autoantibody and the clinical manifestations of patients with IIMs. Therefore, we performed a meta-analysis of studies to assess the correlation of anti-NXP2 autoantibody with IIMs and to assess the diagnostic and prognostic relevance of this autoantibody in the context of IIMs. Moreover, we also investigated the relationship of anti-NXP2 autoantibody with the demographic, clinical, and laboratory characteristics of patients with IIMs.

Methods

Search strategy

The PICO strategy was used to develop the search strategy. A systematic search was performed independently on PubMed, Web of Science, EMBASE, the Cochrane Library, and Scopus databases to identify English-language studies published as of February 29, 2020, by L Li and C Liu. A combination of the following keywords was used to retrieve studies: “myositis,” “myopathy,” “polymyositis,” “immune-mediated necrotizing myopathy,” “inclusion body myositis,” “dermatomyositis,” “nuclear matrix protein 2,” “NXP2,” “MJ,” and “p140.” The reference lists of the retrieved articles were also manually screened independently to identify additional relevant studies (L Li and C Liu). Any discrepancies in selecting articles will be resolved by a third author (L Cheng).

Inclusion and exclusion criteria

Original research articles that qualified the following eligibility criteria were included: (1) patients with IIMs fulfilled the Bohan and Peter criteria [7, 8], Sontheimer criteria [9], the criteria of the European Neuromuscular Centre (ENMC) workshop [10], the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria [11], Griggs diagnostic criteria [12] for inclusion body myositis (IBM), or Connors diagnostic criteria [13] for antisynthetase syndrome; (2) availability of data pertaining to the anti-NXP2 autoantibody status of patients with IIMs; (3) availability of adequate data to calculate the odds ratios (OR) or weighted mean differences and the corresponding 95% confidence intervals (CI); (4) adequate data to evaluate the utility of anti-NXP2 autoantibody in the diagnosis of IIMs. Literature reviews, case reports, commentaries, letters, and meeting abstracts were excluded.

Data extraction

The full texts of potentially eligible articles were reviewed and data from the selected studies were extracted independently using a standardized form by two reviewers (L Li and C Liu). The form included the following information: first author, publication year, diagnosis, age at disease onset, age at disease diagnosis, follow-up period, country or region, ethnicity, detection method, total number of cases and controls, frequency of anti-NXP2 autoantibody in cases and controls, demographics, clinical characteristics, laboratory results, and prognostic information of patients with IIMs. Discrepancies, if any, were resolved through discussion and consensus.

Quality assessment

The Newcastle-Ottawa Scale with a star rating system (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp) was used to evaluate the quality of the included studies. A study is judged based on three criteria: selection of the study groups; comparability of the groups; and ascertainment of either the exposure or outcome of interest for studies. Studies awarded 7–9 stars, 4–6 stars, and < 3 stars were regarded as high-quality, moderate-quality, and low-quality studies, respectively.

Data analysis

This meta-analysis was performed using Stata 12.0 software (Stata Corporation, College Station, TX, USA). The overall odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the association between anti-NXP2 autoantibody and IIMs, as well as characteristics. The overall relative risk (RR) with 95% CIs was calculated to evaluate the prognostic value. Heterogeneity among the included studies was evaluated using the Cochrane Q test and I2 statistics. In the event of significant heterogeneity (P ≤ 0.1 for the Cochrane Q test or I2 ≥ 50%), a sensitivity analysis was conducted to assess the stability of the combined results by sequential omission of individual studies, and the random-effects model was used to calculate the summary ORs and corresponding 95% CIs; otherwise, a fixed-effects model was used. The pooled sensitivity, specificity, and area under the curve (AUC) of anti-NXP2 autoantibody for IIMs were assessed using the Meta-DiSc statistical software (version 1.4, Unit of Clinical Biostatistics, Ramon y Cajal Hospital, Madrid, Spain).

Results

Characteristics and quality of the included studies

As shown in Fig. 1, a total of 2143 studies were retrieved on search of the databases. Twenty-eight studies [4,5,6, 14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38] with a combined study population of 4764 patients with IIMs and 1981 controls (including 369 healthy controls, 183 systemic lupus erythematosus, 577 systemic sclerosis, 414 juvenile idiopathic arthritis, 27 muscular dystrophies, 25 rheumatoid arthritis, 25 Sjögren syndrome, 124 idiopathic pulmonary fibrosis, 47 genetic muscle disease, 45 Behcet’s disease, 145 psoriatic arthritis) qualified the inclusion criteria and were included in the meta-analysis. Fourteen studies [16,17,18, 22, 23, 26, 27, 29,30,31, 34, 36,37,38] with a combined study population of 2877 patients with IIMs and 1981 controls were assessed for the association between anti-NXP2 autoantibody and IIMs, as well as the diagnostic accuracy of anti-NXP2 autoantibody for IIMs. Twenty-three studies [4,5,6, 14,15,16,17,18,19,20,21,22, 24,25,26, 28, 30,31,32,33,34,35,36] (3538 patients with IIMs) were evaluated for the correlation of anti-NXP2 autoantibody with two demographic (male and female), 18 clinical (edema, muscle weakness, myalgia/myodynia, arthritis/arthralgia, interstitial lung disease, dysphagia, malignancy, heliotrope rash, Gottron’s sign or papules, mechanics hand, skin ulcers, calcinosis, alopecia, Raynaud’s phenomenon, lateral hip rash, facial erythema, palmar papules, and heart involvement), and one laboratory (elevation of creatine kinase (CK)) characteristics. Two studies [19, 33] enrolling 74 patients with IIMs were used to assess the prognostic value of anti-NXP2 autoantibody for IIMs. The characteristics of the 28 eligible studies are presented in Table 1. All the included studies showed moderate-quality or high-quality scores.

Fig. 1
figure 1

Illustration of the literature search and study selection criteria

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Table 1 The main characteristics of the 28 studies included in this meta-analysis
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Heterogeneity test

The results of the heterogeneity tests are summarized in Table 2. No significant heterogeneity (I2 < 50% and P > 0.1) was observed during the assessment of the association between anti-NXP2 autoantibody and IIMs (including subgroup analysis according to control group, age, and region); the relationship between anti-NXP2 autoantibody and two demographic features, 15 clinical manifestations, and one laboratory result; and the correlation between anti-NXP2 autoantibody and mortality. Significant heterogeneity (I2 ≥ 50% and P ≤ 0.1) was observed for three clinical manifestations (arthritis/arthralgia, malignancy, and calcinosis). Owing to no significant heterogeneity, a fixed-effects model was used to calculate the overall ORs or the overall RR. A random-effects model was used to calculate the overall ORs between anti-NXP2 autoantibody and arthritis/arthralgia, malignancy, and calcinosis, respectively (Table 2). Sensitivity analyses showed that the combined results of association between anti-NXP2 autoantibody and arthritis/arthralgia, malignancy, and calcinosis were stable (data not shown).

Table 2 The results of the heterogeneity tests in this meta-analysis
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Association between anti-NXP2 autoantibody and IIMs

On comparing 2877 patients with IIMs and 1981 controls from 13 studies, the frequency of anti-NXP2 autoantibody in patients with IIMs was significantly greater than that in controls (OR = 26.36, 95% CI: 12.05–57.67, P < 0.001) (Table 3).

Table 3 The summary of ORs in IIMs patients versus controls and in subgroup analysis
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Subgroup analyses were performed disaggregated by the type of control group (healthy control and disease control), age (adult and juvenile), and region (Asia, Europe, and North America) (Table 3). In the subgroup analysis disaggregated by the type of control group, 11 studies (2268 IIMs versus 369 healthy controls) as well as 7 studies (1449 IIMs versus 1612 disease controls) were assessed. The overall OR was 10.72 (95% CI: 4.55–25.22, P < 0.001) for the healthy control subgroup and 40.39 (95% CI: 13.62–119.80, P < 0.001) for the disease control subgroup. On subgroup analysis disaggregated by age, the overall OR from eight studies of 1251 adult IIMs versus 1284 controls was 11.81 (95% CI: 4.01–34.78, P < 0.001), and the overall OR from six studies of 874 juvenile IIMs versus 1373 controls was 62.48 (95% CI: 16.97–229.98, P < 0.001). Subgroup analysis disaggregated by region involved six studies of 1631 IIMs versus 963 controls in Asia, five studies of 942 IIMs versus 951 controls in Europe, and two studies of 304 IIMs versus 67 controls in North America. The frequency of anti-NXP2 autoantibody in IIMs was significantly greater than that in controls in Asia (OR = 11.03, 95% CI: 3.40–35.76, P < 0.001), in Europe (OR = 58.70, 95% CI: 15.85–217.33, P < 0.001), and in North America (OR = 14.35, 95% CI: 1.96–105.28, P = 0.009).

Diagnostic ability of anti-NXP2 autoantibody for IIMs

The pooled sensitivity, specificity, and AUC of the summary receiver operating characteristic curve of anti-NXP2 autoantibody for IIMs versus controls were 0.11 (95% CI = 0.10–0.12), 1.00 (95% CI = 1.00–1.00), and 0.91, respectively (Table 3).

The diagnostic accuracy of anti-NXP2 autoantibody for IIMs versus controls was calculated in the subgroup analysis disaggregated by the type of control group (healthy control and disease control), age (adult and juvenile), and region (Asia, Europe, and North America) (Table 3). In the subgroup analysis by control group, the pooled sensitivity, specificity, and AUC values of anti-NXP2 autoantibody were 0.13 (95% CI = 0.11–0.14), 1.00 (95% CI = 0.99–1.00), and 0.83 in IIMs versus healthy controls, and 0.10 (95% CI = 0.08–0.11), 1.00 (95% CI = 1.00–1.00), and 0.93 in IIMs versus disease controls, respectively. On subgroup analysis disaggregated by age, the pooled sensitivity, specificity, and AUC values of anti-NXP2 autoantibody, respectively, were 0.07 (95% CI = 0.06–0.09), 1.00 (95% CI = 1.00–1.00), and 0.84 in adult IIMs versus controls, and 0.19 (95% CI = 0.16–0.21), 1.00 (95% CI = 1.00–1.00), and 0.95 in juvenile IIMs versus controls. On subgroup analysis disaggregated by region, the pooled sensitivity for diagnosing IIMs was 0.06 (95% CI = 0.05–0.07) in Asia, 0.17 (95% CI = 0.15–0.20) in Europe, and 0.18 (95% CI = 0.14–0.23) in North America. The pooled specificity for diagnosis of IIMs was 1.00 (95% CI = 1.00–1.00) both in Asia and Europe, and 1.00 (95% CI = 0.95–1.00) in North America. The AUC values were 0.83 and 0.95 for IIM diagnosis in Asia and Europe, respectively. The AUC value for diagnosis of IIMs in North America was not evaluated due to the small sample size of participants examined.

Association of anti-NXP2 autoantibody with demographic, clinical, and laboratory characteristics

The association of anti-NXP2 autoantibody with demographic, clinical, and laboratory characteristics is shown in Table 4. Five clinical features showed a positive association with anti-NXP2 autoantibody. The overall ORs, 95% CIs, and the associated P values were as follows: edema (four studies with 1147 IIMs patients) (OR = 3.94, 95% CI = 2.63–5.91, P < 0.001); muscle weakness (three studies with 1211 IIMs patients) (OR = 9.89, 95% CI = 4.55–21.50, P < 0.001); myalgia/myodynia (three studies with 1122 IIMs patients) (OR = 2.97, 95% CI = 1.97–4.46, P < 0.001); dysphagia (five studies with 1719 IIMs patients) (OR = 3.81, 95% CI = 2.71–5.36, P < 0.001); calcinosis (15 studies with 2633 IIMs patients) (OR = 4.19, 95% CI = 2.44–7.18, P < 0.001). Based on the analysis of 14 studies (2371 IIMs patients), anti-NXP2 autoantibody was negatively associated with interstitial lung disease (ILD) (OR = 0.26, 95% CI = 0.18–0.38, P < 0.001).

Table 4 Results of the meta-analysis showing the association of anti-NXP2 antibody with demographic, clinical, and laboratory features
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Anti-NXP2 autoantibody showed no correlation with sex, 12 clinical manifestations (arthritis/arthralgia, malignancy, heliotrope rash, Gottron’s sign or papules, mechanics hand, skin ulcers, alopecia, Raynaud’s phenomenon, lateral hip rash, facial erythema, palmar papules and heart involvement), and one laboratory characteristic (elevated CK level) (all P > 0.05).

Prognostic relevance of anti-NXP2 autoantibody for IIMs

The overall RR determined from two studies (74 patients with IIMs) was 1.83 (95% CI = 0.36–9.21, P = 0.463).

Discussion

Nuclear matrix protein 2 (NXP2) is a protein involved in the regulation of transcriptional and RNA metabolism [39]. Anti-NXP2 autoantibody was first identified in 1997 in childhood myositis [40] and was regarded as a key biomarker for diagnosis of IIMs. A previous meta-analysis evaluated the association of anti-NXP2 autoantibody with calcinosis, ILD, and malignancy in IIM patients [41]. However, the association of anti-NXP2 autoantibody with other demographic, clinical, and laboratory characteristics as well as the diagnostic and prognostic relevance of anti-NXP2 autoantibodies for IIMs is worth studying. Thus, we included a greater number of studies and performed a meta-analysis to analyze the diagnostic accuracy, clinical phenotypic association, and prognostic significance of anti-NXP2 autoantibody for IIMs.

This meta-analysis showed that the frequency of anti-NXP2 autoantibody was specific to IIMs. Based on the overall ORs, the anti-NXP2 autoantibody showed a stronger association with juvenile IIMs than adults IIMs (62.48 vs. 11.81). Anti-NXP2 autoantibody showed the strongest association with IIMs among European patients as compared with that in Asian and North American patients (overall ORs: 58.70 vs. 11.03 vs. 14.35). However, further studies are required to confirm the correlation between anti-NXP2 autoantibody and patients with IIMs in North America due to the small sample size. Additionally, related studies conducted in other regions are few or absent; therefore, we could not evaluate the association between anti-NXP2 autoantibody and IIMs in other geographical regions. Analysis of the diagnostic indices demonstrated that anti-NXP2 autoantibody had good specificity but low sensitivity for diagnosis of IIMs. The frequency of anti-NXP2 autoantibody ranged from 1.2 to 64.3% [4,5,6, 14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38], but was absent in the sera of healthy controls and disease controls.

The association of anti-NXP2 autoantibodies with demographic, clinical, and laboratory features is conflicting. In particular, contradictory results have been reported with respect to the relationship of anti-NXP2 autoantibody with malignancy and calcinosis [3]. Our meta-analysis showed that anti-NXP2 autoantibody increased the risk of calcinosis. However, there was no association between anti-NXP2 autoantibody and malignancy. These results are consistent with those of a previous study [41]. In addition, we also found a relation of anti-NXP2 autoantibody with edema, muscle weakness, myalgia/myodynia, dysphagia, and ILD.

The prognostic relevance of anti-NXP2 autoantibodies was also analyzed in the current meta-analysis. We found no connection between the presence of anti-NXP2 autoantibody and poor prognosis of patients with IIMs. However, due to the small number of patients examined, the result should be interpreted with caution and additional studies are required to confirm this outcome.

Some limitations of this meta-analysis should be acknowledged. Due to the small sample size of studies conducted in North America, further studies are required to obtain more definitive evidence. In addition, the relationship of anti-NXP2 autoantibody with other demographic, clinical, and laboratory characteristics was not investigated because of the limited number of studies available.

In conclusion, our findings indicate that anti-NXP2 autoantibody has a high specificity and low sensitivity for diagnosis of IIMs. Anti-NXP2 autoantibody is related to edema, muscle weakness, myalgia/myodynia, dysphagia, calcinosis, and ILD in patients with IIMs, but is not associated with overall survival of these patients.