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Yuki Ichimura, Risa Konishi, Miwako Shobo, Sae Inoue, Mari Okune, Akemi Maeda, Ryota Tanaka, Noriko Kubota, Isao Matsumoto, Akiko Ishii, Akira Tamaoka, Asami Shimbo, Masaaki Mori, Tomohiro Morio, Takayuki Kishi, Takako Miyamae, Jantima Tanboon, Michio Inoue, Ichizo Nishino, Manabu Fujimoto, Toshifumi Nomura, Naoko Okiyama, Anti-nuclear matrix protein 2 antibody-positive inflammatory myopathies represent extensive myositis without dermatomyositis-specific rash, Rheumatology, Volume 61, Issue 3, March 2022, Pages 1222–1227, https://doi.org/10.1093/rheumatology/keab518
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Abstract
Myositis-specific autoantibodies (MSAs) define distinct clinical subsets of idiopathic inflammatory myopathies (IIMs). The anti-nuclear matrix protein 2 (NXP2) antibody, a MSA detected in juvenile/adult IIMs, has been reported to be associated with a high risk of subcutaneous calcinosis, subcutaneous oedema and internal malignancies. The study aimed to clarify the clinical features of anti-NXP2 antibody-positive IIMs in detail.
This was a multicentre retrospective observational study on 76 anti-NXP2 antibody-positive patients. The antibody was detected via a serological assay using immunoprecipitation and western blotting. The patients were selected from 162 consecutive Japanese patients with IIMs.
The cohort of anti-NXP2 antibody-positive IIMs included 29 juvenile patients and 47 adult patients. Twenty-seven (35.5%) patients presented with polymyositis phenotype without dermatomyositis-specific skin manifestations (heliotrope rash or Gottron sign/papules); this was more common in the adults than children (48.9% vs 15.8%, P < 0.01). Nine (11.8%) patients had subcutaneous calcinosis, and 20 (26.3%) patients had subcutaneous oedema. In addition, the proportion of patients with muscle weakness extending to the distal limbs was high (36 patients [47.4%]) in this cohort. Adult patients had a higher prevalence of malignancy than the general population (age-standardized incidence ratio of malignancies: 22.4).
Anti-NXP2 antibody-positive IIMs, which include dermatomyositis sine dermatitis, are characterized by atypical skin manifestations and extensive muscular involvement.
Anti-NXP2 antibody is detected in patients of not only dermatomyositis but also polymyositis.
Adult patients with anti-NXP2 antibody tend to present polymyositis phenotype lacking dermatomyositis-specific skin manifestations.
Extensive muscle weakness in patients with anti-NXP2 antibody is correlated with ischaemic histological findings.
Introduction
In DM and PM, which belong to the inflammatory idiopathic myopathies (IIMs), myositis is characterized by a predominance in the proximal limb and trunk muscles with or without DM-specific rashes such as heliotrope rash and Gottron sign/papules [1]. Myositis-specific antibodies (MSAs) have been identified in the sera of DM/PM patients [2], and different MSAs are associated with distinct clinical subsets. Anti-nuclear matrix protein 2 (NXP2) antibody belongs to the MSAs and is called anti-MJ antibody [3]. The population with anti-NXP2 antibody is the second largest (20%) among all juvenile DM cases [4], and 5–30% of adult DM cases are positive for anti-NXP2 antibody [5, 6].
Although subcutaneous calcinosis and oedema have been observed frequently in cases of anti-NXP2 antibody-positive DM [5], anti-NXP2 antibody was also detected in the sera of patients with DM sine dermatitis (DMSD) in whom rashes were not observed, but the muscle pathology suggested DM [7]. A high risk of malignancy was suggested in adults [5, 6]. However, the characteristics of patients clinically diagnosed as PM have not been evaluated, and the differences between juvenile and adult patients were scarcely reported.
Methods
Patients
Japanese patients with IIMs, who fulfilled the 2017 EULAR/ACR classification criteria for IIMs [1] and had been treated at University of Tsukuba Hospital and our collaborating medical centres (Supplementary List) from January 2017 to December 2020, were recruited. As presented in Supplementary Fig. S1, available at Rheumatology online, this case series excluded patients whose serum samples tested positive for anti-transcription intermediatory factor (TIF) 1γ, anti-melanoma differentiation-associated protein 5 (MDA5), anti-Mi-2, and anti-aminoacyl transfer RNA synthetase antibodies, tested using commercially available ELISA kits (Medical & Biological Laboratories, Nagoya, Japan), and anti-small ubiquitin-like modifier activation enzyme (SAE) 1/2 antibody and anti-TIF1β antibody tested using immunoprecipitation and western blotting (IP-WB) assays. Seventy-six patients whose serum samples tested positive for anti-NXP2 antibody by IP-WB were included in this study. The serum samples from 53 patients (69.7%) were collected before immunosuppressive therapies with high-dose steroids were commenced.
Clinical information, including muscle biopsy findings, was collected retrospectively by reviewing patients’ medical charts. This study was approved by the ethics committee of University of Tsukuba Hospital (H29-111).
IP-WB
Twenty microlitres of serum from each patient was mixed with 4 mg of protein A–Sepharose beads (Cytiva, Marlborough, MA, USA) in IPP buffer (10 mM Tris–HCl, pH 8.0, 50 mM NaCl, 0.1% 4-nonylphenyl-polyethylene glycol [BioVision, Milpitas, CA, USA]) for 2 h. Antibody-bound sepharose beads were washed with IPP buffer and incubated with extracts of 1 × 107 K562 cells (ATCC, Manassas, VA, USA) at 4°C for 2 h. The precipitated proteins were fractionated by SDS-PAGE using 10% polyacrylamide gel and then transferred onto nitrocellulose membranes using the Mini Trans-Blot Cell (Bio-Rad Laboratories, Hercules, CA, USA). The membranes were blocked with 5% skim milk, incubated with murine anti-human NXP2 monoclonal antibody (clone 17A9, Medical & Biological Laboratories) overnight at 4°C. They were then incubated with peroxidase-labelled goat anti-mouse IgG polyclonal antibodies (Santa Cruz Biotechnology, Dallas, TX, USA) after washing with Tris-buffered saline with Tween 20. Here we confirmed the utility of this method (Supplementary Table S1, available at Rheumatology online).
Statistical analysis
Statistical analyses were performed using SPSS version 22 (IBM Corp., Armonk, NY, USA). A P-value of <0.05 was considered statistically significant.
Results
Clinical characteristics of patients of anti-NXP2 antibody-positive IIMs
The clinical characteristics of 76 patients with anti-NXP2 antibody are summarized in Table 1. The age distribution was bimodal, including 29 juvenile patients (38.2%; mean age at onset [range], 8 [2–14] years) and 47 adult patients (61.8%; 52 [18–82] years). Twenty-seven (35.5%) patients presented with PM without DM-specific skin manifestations (heliotrope rash or Gottron sign/papules). Of these 27 patients, eight patients (10.5% in total 76 patients) did not have any rashes and 19 (25.0% in total 76 patients) patients presented other non-specific rashes. Nine (11.8% in total 76 patients) patients had subcutaneous calcinosis and 20 (26.3% in total 76 patients) patients had subcutaneous oedema.
Clinical and laboratory characteristics of patients with anti-nuclear matrix protein 2 antibody-positive idiopathic inflammatory myopathies
| Characteristic . | Total (n = 76) . | Juveniles (n = 29) . | Adults (n = 47) . | P-value, between juveniles and adults . |
|---|---|---|---|---|
| Male/female, n | 26/50 | 12/17 | 14/33 | 0.33a |
| Age, mean (range), years | 38 (2–82) | 8 (2–14) | 52 (18–82) | |
| Clinical diagnosis | ||||
| PM, n (%) | 27 (35.5) | 4 (13.8) | 23 (48.9) | <0.01a |
| Without any rashes | 8 (10.5) | 1 (3.4) | 7 (14.9) | |
| With non-specific rashes | 19 (25.0) | 3 (10.3) | 16 (34.0) | |
| DM, n (%) | 49 (64.5) | 25 (86.2) | 24 (51.1) | <0.01a,** |
| Skin manifestations | ||||
| All kinds of rashes, n (%) | 68 (89.5) | 28 (96.6) | 40 (85.1) | 0.15a |
| Heliotrope rash, n (%) | 27 (35.5) | 16 (55.2) | 11 (23.4) | <0.01a,** |
| Gottron sign/papules, n (%) | 45 (59.2) | 21 (72.4) | 24 (51.1) | 0.09a |
| Facial oedema, n (%) | 50 (65.8) | 23 (79.3) | 27 (57.4) | 0.08a |
| Periungual erythema, n (%) | 34 (44.7) | 18 (62.0) | 16 (34.0) | 0.02a,* |
| Subcutaneous calcinosis, n (%) | 9 (11.8) | 5 (17.2) | 4 (8.5) | 0.29a |
| Subcutaneous oedema, n (%) | 20 (26.3) | 7 (24.1) | 13 (27.7) | 0.79a |
| Muscular symptoms | ||||
| Myalgia, n (%) | 56 (73.7) | 22 (75.9) | 34 (72.3) | 0.79a |
| Muscle weakness, n (%) | 74 (97.4) | 28 (96.6) | 46 (97.9) | 1.00a |
| Muscle weakness extending to distal limbs, n (%) | 36 (47.4%) | 17 (58.6) | 19 (40.4) | 0.16 |
| Neck muscle weakness, n (%) | 45 (59.2) | 16 (55.2) | 29 (61.7) | 0.635 |
| Dysphagia, n (%) | 33 (43.4) | 11 (37.9) | 22 (46.8) | 0.484 |
| Complications | ||||
| Interstitial lung disease, n (%) | 4 (5.3) | 0 0 | 4 (8.5) | 0.29a |
| Malignancy, n (%) | 9 (11.8) | 1 (3.4) | 8 (17.0) | 0.14a |
| Laboratory data | ||||
| Maximum creatine kinase, median (IQR), IU/l | 2609 (1125–6972) | 2594 (954–5652) | 2624 (1322–7340) | 1.00b |
| Positivity of antinuclear antibody (>1:40), n (%) | 30 (39.5) | 11 (37.9) | 19 (40.4) | 1.00a |
| Muscle histology (total 64 patients) | ||||
| Peri-fascicular atrophy, n (%) | 31 (48.4) | 14 (58.3) | 17 (42.5) | 0.30a |
| Microinfarction, n (%) | 11 (17.2) | 7 (29.2) | 4 (10.0) | 0.08a |
| Characteristic . | Total (n = 76) . | Juveniles (n = 29) . | Adults (n = 47) . | P-value, between juveniles and adults . |
|---|---|---|---|---|
| Male/female, n | 26/50 | 12/17 | 14/33 | 0.33a |
| Age, mean (range), years | 38 (2–82) | 8 (2–14) | 52 (18–82) | |
| Clinical diagnosis | ||||
| PM, n (%) | 27 (35.5) | 4 (13.8) | 23 (48.9) | <0.01a |
| Without any rashes | 8 (10.5) | 1 (3.4) | 7 (14.9) | |
| With non-specific rashes | 19 (25.0) | 3 (10.3) | 16 (34.0) | |
| DM, n (%) | 49 (64.5) | 25 (86.2) | 24 (51.1) | <0.01a,** |
| Skin manifestations | ||||
| All kinds of rashes, n (%) | 68 (89.5) | 28 (96.6) | 40 (85.1) | 0.15a |
| Heliotrope rash, n (%) | 27 (35.5) | 16 (55.2) | 11 (23.4) | <0.01a,** |
| Gottron sign/papules, n (%) | 45 (59.2) | 21 (72.4) | 24 (51.1) | 0.09a |
| Facial oedema, n (%) | 50 (65.8) | 23 (79.3) | 27 (57.4) | 0.08a |
| Periungual erythema, n (%) | 34 (44.7) | 18 (62.0) | 16 (34.0) | 0.02a,* |
| Subcutaneous calcinosis, n (%) | 9 (11.8) | 5 (17.2) | 4 (8.5) | 0.29a |
| Subcutaneous oedema, n (%) | 20 (26.3) | 7 (24.1) | 13 (27.7) | 0.79a |
| Muscular symptoms | ||||
| Myalgia, n (%) | 56 (73.7) | 22 (75.9) | 34 (72.3) | 0.79a |
| Muscle weakness, n (%) | 74 (97.4) | 28 (96.6) | 46 (97.9) | 1.00a |
| Muscle weakness extending to distal limbs, n (%) | 36 (47.4%) | 17 (58.6) | 19 (40.4) | 0.16 |
| Neck muscle weakness, n (%) | 45 (59.2) | 16 (55.2) | 29 (61.7) | 0.635 |
| Dysphagia, n (%) | 33 (43.4) | 11 (37.9) | 22 (46.8) | 0.484 |
| Complications | ||||
| Interstitial lung disease, n (%) | 4 (5.3) | 0 0 | 4 (8.5) | 0.29a |
| Malignancy, n (%) | 9 (11.8) | 1 (3.4) | 8 (17.0) | 0.14a |
| Laboratory data | ||||
| Maximum creatine kinase, median (IQR), IU/l | 2609 (1125–6972) | 2594 (954–5652) | 2624 (1322–7340) | 1.00b |
| Positivity of antinuclear antibody (>1:40), n (%) | 30 (39.5) | 11 (37.9) | 19 (40.4) | 1.00a |
| Muscle histology (total 64 patients) | ||||
| Peri-fascicular atrophy, n (%) | 31 (48.4) | 14 (58.3) | 17 (42.5) | 0.30a |
| Microinfarction, n (%) | 11 (17.2) | 7 (29.2) | 4 (10.0) | 0.08a |
Fisher’s exact test. bMann–Whitney U-test. *P < 0.05, **P < 0.01. IQR: interquartile range.
Clinical and laboratory characteristics of patients with anti-nuclear matrix protein 2 antibody-positive idiopathic inflammatory myopathies
| Characteristic . | Total (n = 76) . | Juveniles (n = 29) . | Adults (n = 47) . | P-value, between juveniles and adults . |
|---|---|---|---|---|
| Male/female, n | 26/50 | 12/17 | 14/33 | 0.33a |
| Age, mean (range), years | 38 (2–82) | 8 (2–14) | 52 (18–82) | |
| Clinical diagnosis | ||||
| PM, n (%) | 27 (35.5) | 4 (13.8) | 23 (48.9) | <0.01a |
| Without any rashes | 8 (10.5) | 1 (3.4) | 7 (14.9) | |
| With non-specific rashes | 19 (25.0) | 3 (10.3) | 16 (34.0) | |
| DM, n (%) | 49 (64.5) | 25 (86.2) | 24 (51.1) | <0.01a,** |
| Skin manifestations | ||||
| All kinds of rashes, n (%) | 68 (89.5) | 28 (96.6) | 40 (85.1) | 0.15a |
| Heliotrope rash, n (%) | 27 (35.5) | 16 (55.2) | 11 (23.4) | <0.01a,** |
| Gottron sign/papules, n (%) | 45 (59.2) | 21 (72.4) | 24 (51.1) | 0.09a |
| Facial oedema, n (%) | 50 (65.8) | 23 (79.3) | 27 (57.4) | 0.08a |
| Periungual erythema, n (%) | 34 (44.7) | 18 (62.0) | 16 (34.0) | 0.02a,* |
| Subcutaneous calcinosis, n (%) | 9 (11.8) | 5 (17.2) | 4 (8.5) | 0.29a |
| Subcutaneous oedema, n (%) | 20 (26.3) | 7 (24.1) | 13 (27.7) | 0.79a |
| Muscular symptoms | ||||
| Myalgia, n (%) | 56 (73.7) | 22 (75.9) | 34 (72.3) | 0.79a |
| Muscle weakness, n (%) | 74 (97.4) | 28 (96.6) | 46 (97.9) | 1.00a |
| Muscle weakness extending to distal limbs, n (%) | 36 (47.4%) | 17 (58.6) | 19 (40.4) | 0.16 |
| Neck muscle weakness, n (%) | 45 (59.2) | 16 (55.2) | 29 (61.7) | 0.635 |
| Dysphagia, n (%) | 33 (43.4) | 11 (37.9) | 22 (46.8) | 0.484 |
| Complications | ||||
| Interstitial lung disease, n (%) | 4 (5.3) | 0 0 | 4 (8.5) | 0.29a |
| Malignancy, n (%) | 9 (11.8) | 1 (3.4) | 8 (17.0) | 0.14a |
| Laboratory data | ||||
| Maximum creatine kinase, median (IQR), IU/l | 2609 (1125–6972) | 2594 (954–5652) | 2624 (1322–7340) | 1.00b |
| Positivity of antinuclear antibody (>1:40), n (%) | 30 (39.5) | 11 (37.9) | 19 (40.4) | 1.00a |
| Muscle histology (total 64 patients) | ||||
| Peri-fascicular atrophy, n (%) | 31 (48.4) | 14 (58.3) | 17 (42.5) | 0.30a |
| Microinfarction, n (%) | 11 (17.2) | 7 (29.2) | 4 (10.0) | 0.08a |
| Characteristic . | Total (n = 76) . | Juveniles (n = 29) . | Adults (n = 47) . | P-value, between juveniles and adults . |
|---|---|---|---|---|
| Male/female, n | 26/50 | 12/17 | 14/33 | 0.33a |
| Age, mean (range), years | 38 (2–82) | 8 (2–14) | 52 (18–82) | |
| Clinical diagnosis | ||||
| PM, n (%) | 27 (35.5) | 4 (13.8) | 23 (48.9) | <0.01a |
| Without any rashes | 8 (10.5) | 1 (3.4) | 7 (14.9) | |
| With non-specific rashes | 19 (25.0) | 3 (10.3) | 16 (34.0) | |
| DM, n (%) | 49 (64.5) | 25 (86.2) | 24 (51.1) | <0.01a,** |
| Skin manifestations | ||||
| All kinds of rashes, n (%) | 68 (89.5) | 28 (96.6) | 40 (85.1) | 0.15a |
| Heliotrope rash, n (%) | 27 (35.5) | 16 (55.2) | 11 (23.4) | <0.01a,** |
| Gottron sign/papules, n (%) | 45 (59.2) | 21 (72.4) | 24 (51.1) | 0.09a |
| Facial oedema, n (%) | 50 (65.8) | 23 (79.3) | 27 (57.4) | 0.08a |
| Periungual erythema, n (%) | 34 (44.7) | 18 (62.0) | 16 (34.0) | 0.02a,* |
| Subcutaneous calcinosis, n (%) | 9 (11.8) | 5 (17.2) | 4 (8.5) | 0.29a |
| Subcutaneous oedema, n (%) | 20 (26.3) | 7 (24.1) | 13 (27.7) | 0.79a |
| Muscular symptoms | ||||
| Myalgia, n (%) | 56 (73.7) | 22 (75.9) | 34 (72.3) | 0.79a |
| Muscle weakness, n (%) | 74 (97.4) | 28 (96.6) | 46 (97.9) | 1.00a |
| Muscle weakness extending to distal limbs, n (%) | 36 (47.4%) | 17 (58.6) | 19 (40.4) | 0.16 |
| Neck muscle weakness, n (%) | 45 (59.2) | 16 (55.2) | 29 (61.7) | 0.635 |
| Dysphagia, n (%) | 33 (43.4) | 11 (37.9) | 22 (46.8) | 0.484 |
| Complications | ||||
| Interstitial lung disease, n (%) | 4 (5.3) | 0 0 | 4 (8.5) | 0.29a |
| Malignancy, n (%) | 9 (11.8) | 1 (3.4) | 8 (17.0) | 0.14a |
| Laboratory data | ||||
| Maximum creatine kinase, median (IQR), IU/l | 2609 (1125–6972) | 2594 (954–5652) | 2624 (1322–7340) | 1.00b |
| Positivity of antinuclear antibody (>1:40), n (%) | 30 (39.5) | 11 (37.9) | 19 (40.4) | 1.00a |
| Muscle histology (total 64 patients) | ||||
| Peri-fascicular atrophy, n (%) | 31 (48.4) | 14 (58.3) | 17 (42.5) | 0.30a |
| Microinfarction, n (%) | 11 (17.2) | 7 (29.2) | 4 (10.0) | 0.08a |
Fisher’s exact test. bMann–Whitney U-test. *P < 0.05, **P < 0.01. IQR: interquartile range.
All patients except one had muscle pain and/or weakness. Thirty-six (47.4%) patients demonstrated muscle weakness of the distal limbs in addition to that of the proximal limbs. Forty-five (59.2%) patients showed neck muscle weakness, and 33 (43.4%) patients developed dysphagia. Muscle biopsy samples were histologically evaluated in 64 patients—31 (48.4%) patients had perifascicular atrophy (PFA) and 11 (17.2%) patients had evident microinfarction. The median (interquartile range [IQR]) creatine kinase (CK) level was 2609 (1125–6972) IU/l, with six patients (three juveniles and three adults) having normal serum CK levels.
Four (5.3%) patients, including two with DM phenotype and two with PM phenotype, showed interstitial lung disease (ILD). Nine (11.8%) patients, including three with DM phenotype and six with PM phenotype, had malignancy.
ANA was positive in 30 (39.5%) patients; the range of ANA titre was 1:80 to >1:2560.
Facial oedema and subcutaneous calcinosis were significantly frequently observed in patients with the DM phenotype compared with those with the PM phenotype. In addition, patients with the DM phenotype were significantly younger than those with the PM phenotype (Supplementary Table S2, available at Rheumatology online).
Comparison between juvenile and adult patients
As presented in Table 1, adult patients with anti-NXP2 antibody-positive IIMs more frequently presented the PM phenotype than juveniles (n = 23, 48.9% vs n = 4, 13.8%; P < 0.01 by Fisher’s exact test). In other words, DM-specific skin manifestations, especially heliotrope rashes, were more prevalent among the juvenile patients than among adults (n = 25, 86.2% vs n = 24, 51.1%; P<0.01; Table 1). Periungual erythema was also more common in juvenile patients than in adults (n = 18, 62.0% vs n = 16, 34.0%; P = 0.02 by Fisher’s exact test).
Muscular manifestations were not significantly different between juvenile and adult patients. The median CK levels were also similar between juvenile and adult patients (2596 vs 2624 IU/l; P = 1.00 by Mann–Whitney U-test).
Four (8.5%) adult patients had ILD, while no juvenile patients had ILD (0%). Malignancies were diagnosed in eight (17.0%) adult patients, including cervical cancer in two patients, colon cancer in one patient, gastric cancer in two patients, breast cancer in one patient, uterine cancer in one patient, and cutaneous squamous cell carcinoma on the cheek in one patient. Because the age-standardized incidence ratio of malignancies calculated using Cancer Statistics 2016 and 2017 by the National Cancer Registry (Ministry of Health, Labour and Welfare, Japan, Tokyo, Japan) was 22.4, the malignancy rate in anti-NXP2 antibody-positive adults was definitely high. In contrast, only one (3.4%) juvenile patient was diagnosed with mature B cell lymphoma at the time of the PM diagnosis.
Relative factors of extensive muscle weakness
As presented in Table 2, 36 (47.4%) patients with muscle weakness extending to the distal limbs showed equal elevation of serum CK levels (median [IQR], 2205 [820–5986] U/l), while 40 patients with muscle weakness in the proximal limbs showed equal elevation of serum CK levels (3543 [1470–7247] U/l; P = 0.79 by Mann–Whitney U-test). The frequency of neck muscle weakness was significantly higher in patients with muscle weakness extending to the distal limbs than patients without muscle weakness in the distal limbs (75% vs 45%; P = 0.01 by Fisher’s exact test). Among patients with DM-suggestive histopathological findings on muscle biopsy, microinfarction was more frequently observed in patients with extended muscle weakness than in the other patients (28.1% vs 6.3%; P = 0.043 by Fisher’s exact test).
Muscular involvement in patients with anti-nuclear matrix protein 2 antibody-positive idiopathic inflammatory myopathies
| . | Total number of patients (n = 76) . | Limited muscle weakness (within the proximal limbs) (n = 40) . | Extended muscle weakness (to the distal limbs) (n = 36) . | P-value, between limited and extended muscle weakness . |
|---|---|---|---|---|
| Male/female (n) | 26/50 | 13/27 | 13/23 | 0.464a |
| Involvement of trunk muscles | ||||
| Neck muscle weakness, n (%) | 45 (59.2) | 18 (45.0) | 27 (75.0) | 0.01a,* |
| Dysphagia, n (%) | 33 (43.4) | 19 (47.5) | 14 (38.9) | 0.30a |
| Laboratory data | ||||
| Maximum creatine kinase, median (IQR), IU/l | 2609 (1125–6972) | 3543 (1470–7247) | 2205 (820–5986) | 0.141b |
| Positivity of antinuclear antibody (>1:40), n (%) | 30 (39.5) | 13 (32.5) | 17 (47.2) | 0.141a |
| Muscle histology (total 64 patients) | ||||
| Peri-fascicular atrophy, n (%) | 31 (48.4) | 15 (46.9) | 16 (50.0) | 1.00a |
| Microinfarction, n (%) | 11 (17.2) | 2 (6.3) | 9 (28.1) | 0.04a,* |
| . | Total number of patients (n = 76) . | Limited muscle weakness (within the proximal limbs) (n = 40) . | Extended muscle weakness (to the distal limbs) (n = 36) . | P-value, between limited and extended muscle weakness . |
|---|---|---|---|---|
| Male/female (n) | 26/50 | 13/27 | 13/23 | 0.464a |
| Involvement of trunk muscles | ||||
| Neck muscle weakness, n (%) | 45 (59.2) | 18 (45.0) | 27 (75.0) | 0.01a,* |
| Dysphagia, n (%) | 33 (43.4) | 19 (47.5) | 14 (38.9) | 0.30a |
| Laboratory data | ||||
| Maximum creatine kinase, median (IQR), IU/l | 2609 (1125–6972) | 3543 (1470–7247) | 2205 (820–5986) | 0.141b |
| Positivity of antinuclear antibody (>1:40), n (%) | 30 (39.5) | 13 (32.5) | 17 (47.2) | 0.141a |
| Muscle histology (total 64 patients) | ||||
| Peri-fascicular atrophy, n (%) | 31 (48.4) | 15 (46.9) | 16 (50.0) | 1.00a |
| Microinfarction, n (%) | 11 (17.2) | 2 (6.3) | 9 (28.1) | 0.04a,* |
Fisher’s exact test. bMann–Whitney U-test. *P < 0.05; **P < 0.01. IQR: interquartile range.
Muscular involvement in patients with anti-nuclear matrix protein 2 antibody-positive idiopathic inflammatory myopathies
| . | Total number of patients (n = 76) . | Limited muscle weakness (within the proximal limbs) (n = 40) . | Extended muscle weakness (to the distal limbs) (n = 36) . | P-value, between limited and extended muscle weakness . |
|---|---|---|---|---|
| Male/female (n) | 26/50 | 13/27 | 13/23 | 0.464a |
| Involvement of trunk muscles | ||||
| Neck muscle weakness, n (%) | 45 (59.2) | 18 (45.0) | 27 (75.0) | 0.01a,* |
| Dysphagia, n (%) | 33 (43.4) | 19 (47.5) | 14 (38.9) | 0.30a |
| Laboratory data | ||||
| Maximum creatine kinase, median (IQR), IU/l | 2609 (1125–6972) | 3543 (1470–7247) | 2205 (820–5986) | 0.141b |
| Positivity of antinuclear antibody (>1:40), n (%) | 30 (39.5) | 13 (32.5) | 17 (47.2) | 0.141a |
| Muscle histology (total 64 patients) | ||||
| Peri-fascicular atrophy, n (%) | 31 (48.4) | 15 (46.9) | 16 (50.0) | 1.00a |
| Microinfarction, n (%) | 11 (17.2) | 2 (6.3) | 9 (28.1) | 0.04a,* |
| . | Total number of patients (n = 76) . | Limited muscle weakness (within the proximal limbs) (n = 40) . | Extended muscle weakness (to the distal limbs) (n = 36) . | P-value, between limited and extended muscle weakness . |
|---|---|---|---|---|
| Male/female (n) | 26/50 | 13/27 | 13/23 | 0.464a |
| Involvement of trunk muscles | ||||
| Neck muscle weakness, n (%) | 45 (59.2) | 18 (45.0) | 27 (75.0) | 0.01a,* |
| Dysphagia, n (%) | 33 (43.4) | 19 (47.5) | 14 (38.9) | 0.30a |
| Laboratory data | ||||
| Maximum creatine kinase, median (IQR), IU/l | 2609 (1125–6972) | 3543 (1470–7247) | 2205 (820–5986) | 0.141b |
| Positivity of antinuclear antibody (>1:40), n (%) | 30 (39.5) | 13 (32.5) | 17 (47.2) | 0.141a |
| Muscle histology (total 64 patients) | ||||
| Peri-fascicular atrophy, n (%) | 31 (48.4) | 15 (46.9) | 16 (50.0) | 1.00a |
| Microinfarction, n (%) | 11 (17.2) | 2 (6.3) | 9 (28.1) | 0.04a,* |
Fisher’s exact test. bMann–Whitney U-test. *P < 0.05; **P < 0.01. IQR: interquartile range.
Discussion
The present study revealed that 35.5% of all patients with anti-NXP2 antibody-positive IIMs present with PM without DM-specific skin manifestations and that 70.4% of these patients had non-specific skin manifestations. Adult patients tended to present with PM phenotype more frequently than juvenile patients. These patients would have been diagnosed with PM according to the 2017 EULAR/ACR classification criteria for IIMs. However, the results of this study suggest that these patients should be treated for DM phenotype, with consideration to the possibility of complications, including internal malignancy and ILD, especially in adult patients. The Skin Myositis Delphi Group identified DM-favourite cutaneous manifestations other than heliotrope rash and Gottron sign/papules [8]. Collectively, EULAR/ACR classification criteria for IIMs might have to be changed to ensure that even patients without heliotrope rash or Gottron sign/papules could be identified as having DM by the presence of MSAs.
Although anti-NXP2 antibody and other MSAs such as anti-TIF1γ, anti-Mi-2, anti-MDA5 and anti-SAE antibodies are reported to be strongly associated with DM-specific rashes [9, 10], a European cohort study revealed that anti-TIF1γ, anti-MDA5 and anti-SAE antibodies showed a stronger correlation with DM-specific rashes, with odds ratio (OR) with 95% CI of 42.68 (17.22, 105.83), 43.12 (5.76, 322.62) and 42.04 (10.0, 175.15), respectively, than anti-NXP2 antibody (OR [95% CI], 7.70 [3.29, 17.29]) [9]. Another study showed that 10–12.5% patients with anti-NXP2 antibody were diagnosed with PM [6], while almost all the patients with anti-TIF1γ and anti-SAE antibodies were diagnosed with DM [10]. In our previous study, anti-NXP2 antibody was frequently observed in cases of DMSD, which is defined as DM based on histological features of muscle biopsies, but without any skin manifestations [7]. The present study also showed that 35.5% of anti-NXP2 antibody-positive patients were classified as having PM according to the 2017 EULAR/ACR classification criteria for IIMs. Moreover, there were PM phenotype patients without any other skin manifestations, including periungual erythema and facial erythema, who could be diagnosed with DMSD.
It has been reported that 10–37% and 35–36% anti-NXP2 antibody-positive patients had the complications of subcutaneous calcinosis and oedema, respectively [3, 5, 11, 12]. The present study also showed that 11.6% and 26.3% of patients had subcutaneous calcinosis and oedema, respectively, which represented lower frequencies than those reported in previous studies. The patients in this study were all Japanese; therefore, these differences may be partially explained by the genetic background and/or accessibility of medical specialists in Japan.
The muscular manifestation of IIMs with anti-NXP2 antibody is known to be severe, with a high incidence of dysphagia [5, 9, 11] and muscle weakness of the distal extremities [5]. The present study also showed that almost half of the patients had dysphagia and muscle weakness of the neck and distal extremities. We also found that the extent of muscle weakness was not related to serum CK levels. To the best of our knowledge, no previous study has reported this point. Our results from another study indicated that microinfarction, but not PFA, was a predominant muscle pathology in anti-NXP2 antibody-positive IIMs compared with other MSA-related IIMs (submitted). The present study revealed that microinfarction, detected on the muscle biopsy, was associated with the extent of the muscle weakness. In a previous study, muscle ischaemic findings were often observed in patients with anti-NXP2 antibody-positive juvenile DM and these patients tended to develop more severe myopathies than others without muscle ischaemia [13]. These results suggest that muscle ischaemia, but not muscle inflammation, may be directly correlated with muscle weakness, as shown in a murine model of spontaneous autoimmune myositis in major histocompatibility complex class I-transgenic mice due to endoplasmic reticulum stress, which could be caused by ischaemia [14].
The clinical characteristics of juvenile and adult patients were not significantly different, except for the frequency of DM-specific skin manifestations. It has been reported that juvenile DM patients more frequently present with calcinosis and less frequently present with ILD and internal malignancy than adult patients [15]. These trends were also observed in the present study. This study also confirmed that adult patients with anti-NXP2 antibody-positive IIMs had a higher prevalence of malignancy than the general population. The complication rate of malignancy has previously been reported to be 9.0–37.5% [5, 6, 11]. Collectively, the presence of anti-NXP2 antibody, as well as anti-TIF1γ antibody, may enhance the risk of malignancy.
The limitations of this study include a cohort of Japanese only, although we first demonstrated the clinical characteristics of juvenile and adult patients with anti-NXP2 antibody-positive IIMs. Large populations lacking DM-specific skin manifestations in adult patients, and extensive muscle weakness as correlated with ischaemic histological findings in muscle biopsies were especially remarkable. Future studies are needed to evaluate and establish these characteristics in large international cohorts.
Acknowledgements
We appreciate the help of members of the different departments in collecting patients’ clinical data, as shown in the supplementary material.
Funding: Supported by KAKENHI from the Japan Society for the Promotion of Science (JSPS, 18K08263 for Naoko Okiyama).
Disclosure statement: M.M.: Grant from Chugai Pharmaceutical Co., Ltd, UCB Japan Co. Ltd, CSL Behring, Abbvie Japan Co., Ltd, Japan Blood Products Organization, Ayumi Pharmaceutical Co., Nippon Kayaku Co., Ltd, Asahikasei Pharmaceutical Co.; consulting fees from Daiichi Sankyo Co., Ltd and Taisho Pharmaceutical Co., Ltd; and lecture fees from SD K.K. The other authors have declared no conflicts of interest.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supplementary data
Supplementary data are available at Rheumatology online.
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