Anti-nuclear Matrix Protein Research Articles

Dermatomyositis: Muscle Pathology According to Antibody Subtypes.

Background and ObjectivesDiscoveries of dermatomyositis-specific antibodies (DMSAs) in patients with dermatomyositis raised awareness of various myopathologic features among antibody subtypes. However, only perifascicular atrophy and perifascicular myxovirus resistant protein A (MxA) overexpression were officially included as definitive pathologic criteria for dermatomyositis classification. We aimed to demonstrate myopathologic features in MxA-positive dermatomyositis to determine characteristic myopathologic features in different DMSA subtypes.MethodsWe performed a retrospective pathology review of muscle biopsies of patients with dermatomyositis diagnosed between January 2009 and December 2020 in a tertiary laboratory for muscle diseases. We included all muscle biopsies with sarcoplasmic expression for MxA and seropositivity for DMSAs. MxA-positive muscle biopsies that tested negative for all DMSAs were included as seronegative dermatomyositis. We evaluated histologic features stratified according to 4 pathology domains (muscle fiber, inflammatory, vascular, and connective tissue) and histologic features of interest by histochemistry, enzyme histochemistry, and immunohistochemical study commonly used in the diagnosis of inflammatory myopathy. We performed ultrastructural studies of 54 available specimens.ResultsA total of 256 patients were included. Of these, 249 patients were positive for 1 of the 5 DMSAs (seropositive patients: 87 anti–transcription intermediary factor 1-γ [TIF1-γ], 40 anti–complex nucleosome remodeling histone deacetylase [Mi-2], 29 anti–melanoma differentiation gene 5 [MDA5], 83 anti–nuclear matrix protein 2 [NXP-2], and 10 anti–small ubiquitin-like modifier-activating enzyme [SAE] dermatomyositis) and 7 patients were negative for all 5 DMSAs (seronegative patients). Characteristic myopathologic features in each DMSA subtype were as follows: anti-TIF1-γ with vacuolated/punched out fibers (64.7%; p < 0.001) and perifascicular enhancement in HLA-ABC stain (75.9%; p < 0.001); anti-Mi-2 with prominent muscle fiber damage (score 4.9 ± 2.1; p < 0.001), inflammatory cell infiltration (score 8.0 ± 3.0; p = 0.002), perifascicular atrophy (67.5%; p = 0.02), perifascicular necrosis (52.5%; p < 0.001), increased perimysial alkaline phosphatase activity (70.0%; p < 0.001), central necrotic peripheral regenerating fibers (45.0%; p = 0.002), and sarcolemmal membrane attack complex deposition (67.5%; p < 0.001); anti-MDA5 with scattered/diffuse staining pattern of MxA (65.5%; p < 0.001) with less muscle pathology and inflammatory features; anti-NXP-2 with microinfarction (26.5%; p < 0.001); and anti-SAE and seronegative dermatomyositis with HLA-DR expression (50.0%; p = 0.02 and 57.1%; p = 0.02, respectively).DiscussionWe describe a comprehensive serologic–pathologic correlation of dermatomyositis primarily using MxA expression as an inclusion criterion. In our study, DMSAs were associated with distinctive myopathologic features suggesting different underlying pathobiologic mechanisms in each subtype.

Clinically amyopathic dermatomyositis associated with anti-nuclear matrix protein 2 antibody.

Clinically amyopathic dermatomyositis associated with anti-nuclear matrix protein 2 antibody.

Diffuse Soft-Tissue Swelling in Antinuclear Matrix Protein-2 Antibody-Associated Dermatomyositis Sine Dermatitis

A 66-year-old man presented with progressive weakness and myalgia for 3 months, followed by anasarca and dysphagia. Physical examination showed symmetric limb-girdle weakness and generalized edema without skin rashes. Creatine kinase was 1584 U/L (normal: <308). Muscle biopsy displayed inflammatory myopathy with perifascicular pathology (Figure 1). Myositis-specific antibody panel identified positive antinuclear matrix protein 2 (NXP2) autoantibody. Results of a whole-body computed tomography scan were normal except for subcutaneous and soft-tissue edema (Figure 2).

Anti-nuclear matrix protein 2 antibody-positive inflammatory myopathies represent extensive myositis without dermatomyositis-specific rash.

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.

P047 An unusual case of dermatomyositis with co-existent anti-GAD and anti-NXP2 antibody positivity

Abstract Background/Aims Dermatomyositis (DM) is a rare disease. We present a case of DM with both anti-nuclear matrix protein 2 antibody (NXP2) as well as anti-glutamic acid decarboxylase antibody (GAD) positivity, the combination of which has yet not been documented in the current literature. Methods The case is described below. Results A 48 year old Caucasian male with no co-morbidities presented with a one-month history of sore throat and lethargy, followed 2 weeks later by muscular pain in his upper arms. On examination, there was erythema to the sun-exposed areas of the face and arms, hoarse voice and Gottron’s papules. He had proximal muscle weakness of 4/5 in his shoulder and hips. His creatinine kinase(CK) was elevated at 2914U/L. He was started on methylprednisolone 1 gram od for 3 days with improvement of his CK to 642U/L. His muscle biopsy showed mild chronic neurogenic changes and upregulation of C5b-9 but no evidence of inflammatory myopathy which was attributed to the steroid use prior to the biopsy. His myositis antibody screen was positive for Anti-Nuclear Matrix Protein antibody 2(NXP2). After 4 days he developed rapid onset dysphagia and a sudden drop in his spirometry readings with a fall in his FEV1from 94% to 85% and a fall in his FVC from 88% to 79%. He became acutely unwell, drowsy with difficulty completing sentences and global weakness. His CK had risen to 1567U/L despite the high dose intravenous methylprednisolone. He was diagnosed with Diabetic ketoacidosis(DKA) with a blood glucose of 32mmol/L , pH of 7.0, and transferred to ITU. Intravenous immunoglobulin (IVIG) was administered with subsequent improvement in all muscle groups. He was then commenced on a subcutaneous insulin regime and pulsed intravenous cyclophosphamide (Eurolupus) as his EMG showed a sensorimotor polyneuropathy as well as an inflammatory myopathy. His serology was negative for infectious aetiology. Malignancy screen including PET scan, oesophagogastroduodenoscopy and colonoscopy were normal however, he was found to be positive for anti-GAD antibody. Conclusion GAD antibodies are known to be associated with many disorders including diabetes and stiff person syndrome and can recognise different epitopes in various diseases. This is the first documented case of GAD occurring in a DM patient, in the presence of NXP2 antibodies. IVIG is used to treat both stiff man syndrome and refractory DM. It is possible that the combination of GAD and NXP2 contributed to the pathogenesis and severity of the clinical presentation in this case. Disclosure K. Beharry: None. G. Barminski: None. D. De Lord: None.

Clinical Problem Solving: An Older Woman With Weakness from Head to Toe.

A 67-year-old woman was admitted to our hospital for progressive weakness, dysphagia, muscle pain, and weight loss. Here we detail the clinical problem solving involved in diagnosing and treating her immune-mediated necrotizing myopathy caused by anti-HMGCoA reductase autoantibodies. Interestingly, this diagnosis coincided with discovery of a gastrointestinal stromal tumor (GIST) and positivity for anti-nuclear matrix protein (anti-NXP2), another myositis specific autoantibody.

Association of anti-NXP2 antibody with clinical characteristics and outcomes in adult dermatomyositis: results from clinical applications based on a myositis-specific antibody.

The aim was to study and compare the clinical manifestations, auxiliary examinations, and therapeutic responses in patients with different myositis-specific antibody (MSA) types. We retrospectively investigated the medical records of 143 hospitalized dermatomyositis patients, all of whom were tested for MSAs, and performed follow-up. Patients were divided into groups with and without anti-nuclear matrix protein 2 (NXP2) antibodies (17 vs 126 patients). Demographic, clinical manifestation (occurring at any time during the disease course), imaging, laboratory, treatment response, and survival data were collected for statistical analyses. Adult dermatomyositis patients with anti-NXP2 antibodies were more prone to dysphagia (P<0.001), had higher levels of muscle injury markers (CK peak, P=0.007; CK peak>1000 IU/L, P<0.001; CK-MB, P=0.002), were younger at onset (P=0.008), and were less likely to present with interstitial lung disease (P=0.016) than the anti-NXP2 antibody-negative subgroup. Multivariable logistic regression analysis showed that onset age (OR=0.96 CI 95%: 0.924-0.999, P=0.043) and dysphagia (OR=7.088, CI 95%: 1.824-27.536, P=0.005) were independent risk factors for anti-NXP2 antibody positivity. Kaplan-Meier survival analysis did not reveal that dermatomyositis patients with anti-NXP2 antibodies have a relatively worse prognosis. However, the disease course was more frequently polycyclic, and 68.75% of patients had a relapsing-remitting disease course. More than half (52.94%) of those who showed no response to treatment used at least 3 disease-modifying antirheumatic drugs. We show the important clinical features of and risk factors for this unique antibody-mediated form of dermatomyositis. Although these patients had a relatively low mortality rate, they were prone to recurrence, and treatment was challenging. Key points • The clinical features and risk factors for adult dermatomyositis patients with anti-NXP2 antibodies. • The impact of anti-NXP2 antibody on survival outcomes.

Clinical impact of myositis-specific autoantibodies on long-term prognosis of juvenile idiopathic inflammatory myopathies: multicentre study.

This study aimed to investigate the clinical characteristics, treatment and prognosis of juvenile idiopathic inflammatory myopathies (JIIM) in Japan for each myositis-specific autoantibody (MSA) profile. A multicentre, retrospective study was conducted using data of patients with JIIM at nine paediatric rheumatology centres in Japan. Patients with MSA profiles, determined by immunoprecipitation using stored serum from the active stage, were included. MSA were detected in 85 of 96 cases eligible for the analyses. Over 90% of the patients in this study had one of the following three MSA types: anti-melanoma differentiation-associated protein 5 (MDA5) (n = 31), anti-transcriptional intermediary factor 1 alpha and/or gamma subunits (TIF1γ) (n = 25) and anti-nuclear matrix protein 2 (NXP2) (n = 25) antibodies. Gottron papules and periungual capillary abnormalities were the most common signs of every MSA group in the initial phase. The presence of interstitial lung disease (ILD) was the highest risk factor for patients with anti-MDA5 antibodies. Most patients were administered multiple drug therapies: glucocorticoids and MTX were administered to patients with anti-TIF1γ or anti-NXP2 antibodies. Half of the patients with anti-MDA5 antibodies received more than three medications including i.v. CYC, especially patients with ILD. Patients with anti-MDA5 antibodies were more likely to achieve drug-free remission (29 vs 21%) and less likely to relapse (26 vs 44%) than others. Anti-MDA5 antibodies are the most common MSA type in Japan, and patients with this antibody are characterized by ILD at onset, multiple medications including i.v. CYC, drug-free remission, and a lower frequency of relapse. New therapeutic strategies are required for other MSA types.

Gastrointestinal perforation in anti-NXP2 antibody-associated juvenile dermatomyositis: case reports and a review of the literature

BackgroundTo summarize the characteristics of gastrointestinal (GI) perforation in anti-nuclear matrix protein 2 (NXP2) antibody-associated juvenile dermatomyositis (JDM).MethodsFive patients with GI perforation from a JDM cohort of 120 cases are described. Relevant literature was reviewed.ResultsFive patients, including four females and one male, were included in the study. The age of onset of these patients ranged from 3.3 to 9.5 years with the median age of 5.0 years. When these patients were complicated by GI perforation, childhood myositis assessment score (CMAS) ranged from 1 to 5 with the median score of 2. Myositis-specific antibody (MSA) spectrum analysis indicated that the five patients were anti-NXP2 antibody positive. The initial symptoms of GI perforation were progressive abdominal pain and intermittent fever. Two patients also presented with ureteral calculus with hydronephrosis and ureteral stricture. Surgery was performed in four patients. One patient failed to undergo a repair as the perforation was high in position. For the other three patients, perforation repair was successful, of which two patients failed due to recurrent perforation. At 24 months postoperative follow-up, one patient was in complete remission on prednisone (Pred) and methotrexate (MTX) treatment, and her ureteral stricture had disappeared. The other four patients died. Adding these cases with 16 other patients described in the literature, the symptom at onset was progressive abdominal pain, which often occurred within 10 months after JDM was diagnosed. Perforation most commonly occurred in the duodenum, although it also occurred at multiple sites or was recurrent. The mortality rate of GI perforation in JDM was 38% (8/21).ConclusionsAll the five perforation cases in our study subjected to MSA analysis were anti-NXP2 antibody positive. The symptom at onset was abdominal pain. The most common site of perforation was the duodenum in the retroperitoneum, and the lack of acute abdominal manifestations prevented early diagnosis. GI perforation may be a fatal complication in JDM, and early diagnosis is very important. More research is needed to determine the pathogenesis and predictive factors of GI perforation in JDM.

Clinical and immunological characteristics of myositis complicated with thromboembolism

OBJECTIVE To investigate and analyse the clinical and immunological features of patients with myositis complicated with thromboembolism. METHODS We identified a cohort of 390 myositis patients diagnosed with myositis admitted to People's Hospital of Peking University from 2003 to 2019. The patients were retrospectively enrolled in this investigation. According to the outcome of the color Doppler ultrasound, CT pulmonary angiography, pulmonary ventilation and perfusion scan patients were divided into myositis with and without thromboembolism group. Demographic, clinical (heliotrope rash, Gottron's sign/papules, periungual erythema, skin ulceration, subcutaneous calcinosis, Mechanic's hands, myalgia, interstitial lung disease, pulmonary arterial hypertension), laboratory, immunological [anti-autoantibodies including melanoma differentiation associated gene 5 (anti-MDA5), anti-Mi-2, anti-transcription intermediary factor-1γ (anti-TIF-1γ, anti-nuclear matrix protein 2 (anti-NXP2), anti-small ubiquitin-like modifier activating enzyme (anti-SAE), anti-synthetase], imaging and therapeutic status data of the patients at the diagnosis of myositis with and without thromboembolism were collected and the differences in these data were analyzed. Logistic regressive analysis was used to identify the risk factors of thromboembolism. RESULTS In the retrospective study, 390 myositis patients were investigated. The mean age of onset was (49.6±13.4) years, male to female ratio was 0.31 :1. Thromboembolism was identified in 4.62% (18/390) of the myositis patients, which was lower than the published reports. Out of 18 patients with thromboembolism, 55.6% (10/18) of them were deep venous thrombosis, followed by cerebral infarction (22.2%, 4/18), pulmonary embolism (11.1%, 2/18), renal artery embolism (5.6%, 1/18) and embolism of upper extremity (5.6%, 1/18). Fifty percent of thromboembolism events occurred 6 months after the diagnosis of myositis, 38.9% of thromboembolism events occurred 6 months within the diagnosis of myositis, 11.1% of thromboembolism events occurred 6 months before the diagnosis of myositis. As compared with the myositis patients without thromboembolism, the myositis patients complicated with thromboembolism were older [(58.3±11.7) years vs. (49.3±13.4) years, P=0.006]. C-reaction protein (CRP) (12.2 mg/L vs. 4.1 mg/L, P < 0.001), ferritin (20 085.5 μg/L vs. 216.6 μg/L, P < 0.001) and D-dimer (529.0 μg/L vs. 268.0 μg/L, P=0.002) were significantly higher in thromboembolism group. Diabetes (44.4% vs. 16.4%, P=0.006), coronary heart disease (22.2% vs. 3.0%, P=0.003) and surgery (16.7% vs. 3.5%, P=0.032) were observed more common in thromboembolism group than those without thromboembolism. Activated partial thromboplastin time (APTT) (26.9 s vs. 28.7 s, P=0.049) and albumin (32.4 g/L vs. 36.5 g/L, P=0.002) was lower in thromboembolism group. The risk factors of thromboembolism in the myositis patients were low level of albumin (OR=0.831, 95%CI: 0.736-0.939, P=0.003), diabetes (OR=4.468, 95%CI: 1.382-14.448, P=0.012), and coronary heart disease (OR=22.079, 95%CI: 3.589-135.837, P=0.001) were independent significant risk factors for thromboembolism in the patients with myositis. There was no significant difference in clinical manifestations, myositis-specific antibodies or myositis-associated antibodies between the two groups. CONCLUSION Thromboembolism is a complication of myositis. Lower levels of albumin, diabetes, and coronary heart disease might be risk factors of thromboembolism in myositis patients.

Clinical features, treatments and outcomes of calcinosis in adult patients with dermatomyositis: a single cohort study.

The occurrence of calcinosis cutis as a clinical feature of dermatomyositis in adult patients is not well understood. Cohort studies of adult patients with calcinosis are rare. We systematically describe the clinical features, treatments and outcomes of adult patients with calcinosis. We initially enrolled 627 adult DM patients. Of those enrolled, 35 (5.6%) were found to have calcinosis. We analysed the clinical features associated with calcinosis in this subgroup. The risk factors associated with calcinosis were analysed using the Poisson regression model. Multivariate analysis showed that a younger age at disease onset [odds ratio (OR) = 0.945, 95% CI 0.925, 0.966, P < 0.001], dysphagia (OR = 2.609, 95% CI 1.189, 5.728, P = 0.017), skin ulcer (OR = 5.705, 95% CI 3.041, 10.705, P < 0.001) and the presence of anti-nuclear matrix protein 2 antibody (OR = 5.917, 95% CI 2.754, 12.714, P < 0.001) were independently associated with calcinosis. In both the low- and high-dose prednisone treatment groups, no difference in treatment response was seen between the bisphosphonate treatment group and the group not receiving bisphosphonate treatment (P = 1.000 and P = 0.375, respectively). A follow-up study revealed that the mortality rate of the calcinosis group was 5.7%. Additionally, 60.6% of the cases had a chronic polycyclic disease course and 17.1% had mild complications secondary to calcinosis. Calcinosis is an uncommon, but significant clinical feature in adult patients with DM. Bisphosphonates were not found to effectively treat calcinosis, however, the overall health outcomes of adult DM patients with calcinosis were favourable.

Anti-MDA5 autoantibodies associated with juvenile dermatomyositis constitute a distinct phenotype in North America.

Myositis-specific autoantibodies have defined distinct phenotypes of patients with juvenile myositis (JIIM). We assessed the frequency and clinical significance of anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody-associated JIIM in a North American registry. Retrospective examination of the characteristics of 35 JIIM patients with anti-MDA5 autoantibodies was performed, and differences from other myositis-specific autoantibody groups were evaluated. Anti-MDA5 autoantibodies were present in 35/453 (7.7%) of JIIM patients and associated with older age at diagnosis, and lower serum creatine kinase and aldolase levels. Patients with anti-MDA5 autoantibodies had more frequent weight loss, adenopathy, arthritis, interstitial lung disease (ILD), and less frequent falling compared with anti-transcriptional intermediary factor 1 (TIF1), anti-nuclear matrix protein 2 (NXP2)and myositis-specific autoantibody/myositis-associated autoantibody-negative patients. They had a different season of diagnosis and less frequent mechanic's hands and ILD compared with those with anti-synthetase autoantibodies. Anti-MDA5 patients received fewer medications compared with anti-TIF1, and corticosteroid treatment was shorter compared with anti-TIF1 and anti-nuclear matrix protein 2 autoantibody groups. The frequency of remission was higher in anti-MDA5 than anti-synthetase autoantibody-positive JIIM. In multivariable analyses, weight loss, arthritis and arthralgia were most strongly associated with anti-MDA5 autoantibody-positive JIIM. Anti-MDA5 JIIM is a distinct subset, with frequent arthritis, weight loss, adenopathy and less severe myositis, and is also associated with ILD. Anti-MDA5 is distinguished from anti-synthetase autoantibody-positive JIIM by less frequent ILD, lower creatine kinase levels and differing seasons of diagnosis. Anti-MDA5 has comparable outcomes, but with the ability to discontinue steroids more rapidly and less frequent flares compared with anti-TIF1 autoantibodies, and more frequent remission compared with anti-synthetase JIIM patients.

Assessment of diagnostic utility, clinical phenotypic associations, and prognostic significance of anti-NXP2 autoantibody in patients with idiopathic inflammatory myopathies: a systematic review and meta-analysis.

The objectives of this study are to analyze the association between anti-nuclear matrix protein 2 (NXP2) autoantibody and idiopathic inflammatory myopathies (IIMs) and to assess the diagnostic and prognostic relevance of anti-NXP2 autoantibody in patients with IIMs. A systematic search was performed in PubMed, Web of Science, EMBASE, the Cochrane Library, and Scopus to identify studies published as of February 29, 2020. Data was analyzed using Stata 12.0 and Meta-DiSc 1.4. Twenty-eight studies (4764 patients with IIMs and 1981 controls) were included in the meta-analysis. Anti-NXP2 autoantibody showed a significant association with IIMs (odds ratio (OR) = 26.36, 95% confidence interval (CI): 12.05-57.67, P < 0.001), especially juvenile IIMs (OR = 62.48, 95% CI: 16.97-229.98, P < 0.001). The pooled sensitivity, specificity, and area under the curve were 0.19 (95% CI = 0.16-0.21), 1.00 (95% CI = 1.00-1.00), and 0.95 for patients with juvenile IIMs versus controls. Anti-NXP2 autoantibody was associated with an increased risk of developing five characteristics (edema, muscle weakness, myalgia/myodynia, dysphagia, and calcinosis) and reduced risk of interstitial lung disease (ILD) (P < 0.001). Anti-NXP2 autoantibody showed no association with increased risk of death in IIMs (P = 0.463). These findings suggest that anti-NXP2 autoantibody is specially related to IIMs and is related to edema, muscle weakness, myalgia/myodynia, dysphagia, calcinosis, and ILD in patients with IIMs. However, there is no evidence to suggest that the presence of anti-NXP2 autoantibody confers a poor prognosis with respect to overall survival. Key Points • This study summarized the diagnostic and prognostic accuracies of anti-NXP2 autoantibody for patients with IIMs. Anti-NXP2 autoantibody is related to edema, muscle weakness, myalgia/myodynia, dysphagia, calcinosis, and ILD in patients with IIMs.

A Clinically and Biologically Based Subclassification of the Idiopathic Inflammatory Myopathies Using Machine Learning.

ObjectivePublished predictive models of disease outcomes in idiopathic inflammatory myopathies (IIMs) are sparse and of limited accuracy due to disease heterogeneity. Computational methods may address this heterogeneity by partitioning patients based on clinical and biological phenotype.MethodsTo identify new patient groups, we applied similarity network fusion (SNF) to clinical and biological data from 168 patients with myositis (64 adult polymyositis [PM], 65 adult dermatomyositis [DM], and 39 juvenile DM [JDM]) in the Rituximab in Myositis trial. We generated a sparse proof‐of‐concept bedside classifier using multinomial regression and identified characteristics that distinguished these groups. We conducted χ2 tests to link new patient groups with the myositis subtypes.Results SNF identified five patient groups in the discovery cohort that subdivided the myositis subtypes. The sparse multinomial regressor to predict patient group assignments (areas under the receiver operating characteristic curve = [0.78, 0.97]; areas under the precision‐recall curve = [0.55, 0.96]) found that autoantibody enrichment defined four of these groups: anti–Mi‐2, anti–signal recognition peptide (SRP), anti–nuclear matrix protein 2 (NXP2), and anti‐synthetase (Syn). Depletion of immunoglobulin M (IgM) defined the fifth group. Each group was associated with one subtype, with adult DM being associated with anti–Mi‐2 and anti‐Syn autoantibodies, JDM being associated with anti‐NXP2 autoantibodies, and adult PM being associated with IgM depletion and anti‐SRP autoantibodies. These associations enabled us to further resolve the current myositis subtypes.ConclusionUsing unsupervised machine learning, we identified clinically and biologically homogeneous groups of patients with IIMs, forming the basis of an integrated disease classification based on both clinical and biological phenotype, thus validating other approaches and what has been previously described.

An Unusual Cause of Dysphagia

An Unusual Cause of Dysphagia

Association of anti-nuclear matrix protein 2 antibody with complications in patients with idiopathic inflammatory myopathies: A meta-analysis of 20 cohorts

BackgroundSeveral complications like calcinosis, interstitial lung disease (ILD) or malignancy, are primary causes leading to poor outcomes in idiopathic inflammatory myopathies (IIM) patients. Specific antibodies might help to indicate the occurrence or absence of these complications. ObjectiveThe aim of this study was to evaluate the association of anti-nuclear matrix protein 2 antibody (anti-NXP2) with calcinosis, ILD and malignancy in IIM patients. MethodsTwo investigators independently searched literature about the relation of anti-NXP2 with calcinosis, ILD, malignancy in IIM patients in PubMed, EMBASE, Web of Science databases, then selected eligible articles and extracted data from the included studies. The association between anti-NXP2 and these complications was assessed by odds ratios (OR) and 95% confidence intervals (95% CI). Further quantitative meta-analysis, subgroup analysis, sensitivity analysis and publication bias analysis were conducted with STATA 14.0 software (Stata Corp.; College Station, Texas, USA). A fixed-effects model (the Mantel-Haenszel method) was employed when I2 < 25%, otherwise a random-effects model (the Mantel-Haenszel method) was used. ResultsTwenty cohorts with 3064 IIM patients were included in this meta-analysis, among which 9 were about calcinosis in adults, 6 about calcinosis in juvenile patients, 9 about ILD in adults, 3 about ILD in juvenile patients, while 13 about malignancy in adult patients. Anti-NXP2 was more common in patients with calcinosis than those without calcinosis (pooled OR = 4.00, 95% CI: 2.65–6.06 in adults; pooled OR = 1.62, 95% CI: 1.14–2.30 in juvenile patients). On the contrary, this antibody was less common in adult patients with ILD than those without ILD (pooled OR: 0.33, 95% CI: 0.19–0.56). No significant difference concerning the incidence of anti-NXP2 antibody was found in IIM patients between those with and without cancer (pooled OR = 1.42, 95% CI: 0.69–2.91). ConclusionThe present study indicates that anti-NXP2 autoantibody is a risk factor for development into calcinosis both in adult and juvenile patients, while a protective factor for ILD in adult patients. Anti-NXP2 had no relation with malignancy in adult patients.

Investigation of myositis and scleroderma specific autoantibodies in patients with lung cancer

BackgroundThe close temporal association between onset of some connective tissue diseases and cancer suggests a paraneoplastic association. Adult patients with scleroderma with anti-RNA polymerase III autoantibodies and adult patients with dermatomyositis with anti-transcriptional intermediary factor 1 (anti-TIF1) or anti-nuclear matrix protein 2 (anti-NXP2) autoantibodies have a significantly increased risk of developing cancer. Autoantibodies may serve as biomarkers for early detection of cancer and also could be relevant for prediction of responses to immune therapies. We aimed to test whether myositis and scleroderma specific or associated autoantibodies are detectable in individuals with lung cancer.MethodsSerum from 60 Caucasian patients with lung cancer (30 with small cell lung cancer, 30 with non-small cell lung cancer) was screened for myositis and scleroderma specific and associated autoantibodies by radiolabelled immunoprecipitation.ResultsAnti-TIF1, anti-NXP2 or anti-RNA polymerase III autoantibodies were not detected in any of the 60 patients with lung cancer. Anti-glycyl-transfer RNA (tRNA) synthetase (anti-EJ) autoantibodies were detected in one patient with non-small cell lung cancer. No other known myositis or scleroderma autoantibodies were identified.ConclusionsMyositis and scleroderma specific autoantibodies, including anti-TIF1, anti-NXP2 and anti-RNA polymerase III, are rare in patients with lung cancer without an autoimmune disease. We report here the first case of anti-EJ autoantibodies being detected in a patient with lung cancer without clinical or radiographic evidence of the anti-synthetase syndrome.

Calcinosis and malignancy are rare in Chinese adult patients with myositis and nuclear matrix protein 2 antibodies identified by an unlabeled immunoprecipitation assay.

Autoantibodies in patients with myositis may associate with specific clinical manifestations. This study aimed to identify a subset of patients with myositis carrying antinuclear matrix protein 2 (anti-NXP-2) antibodies using an unlabeled immunoprecipitation (IP) assay, and clarify the features of these patients in a Chinese cohort. We developed novel methods for unlabeled protein IP and immunoblotting of Myc-tagged truncated NXP-2 fragments for anti-NXP-2 detection. The sera of 120 Chinese adult patients with myositis were screened for anti-NXP-2 by IP and immunoblot. Anti-NXP-2 antibodies were detected in 10 of the 120 patients (8.3%) using the established unlabeled protein IP and immunoblotting, with 70% (7/10) exhibiting either heliotrope rash or Gottron's papules. All 10 anti-NXP-2-positive patients exhibited myopathy and 60% complained of dysphagia. Severe diffuse calcinosis (10%) and nasopharyngeal carcinoma (10%) were each only present in single anti-NXP-2-positive patients with myositis. Antibodies against Ro-52 were found in four living but not in three deceased anti-NXP-2-positive patients. A comprehensive review of 13 anti-NXP-2 studies demonstrated markedly lower anti-NXP-2 prevalence among adult patients with myositis and lower association of anti-NXP-2 with calcinosis in Japan, China, and Hungary than in the USA and Italy. Anti-NXP-2 antibody association with internal malignancy in adult patients varied from 0 to 50% across different studies. A novel IP assay was developed to detect patients with myositis expressing anti-NXP-2. Calcinosis and malignancy are rare in Chinese adult patients with myositis positive for anti-NXP-2. Literature review indicated highest anti-NXP-2 prevalence and association of anti-NXP-2 with calcinosis in US and Italian myositis cohorts.

Cutaneous and Systemic Findings Associated With Nuclear Matrix Protein 2 Antibodies in Adult Dermatomyositis Patients

To characterize the cutaneous and systemic clinical phenotype of dermatomyositis patients with antinuclear matrix protein 2 (anti-NXP-2) antibodies. We conducted a retrospective cohort analysis of 178 dermatomyositis patients seen at the Stanford University Clinic. An electronic chart review employing a keyword search strategy was performed to collect clinical and laboratory data. Anti-NXP-2 antibodies were assayed by immunoprecipitation using NXP-2 produced by invitro transcription/translation. Antibodies to NXP-2 were detected in 20 of the 178 patients (11%). Anti-NXP-2 antibodies were associated with male sex (50% versus 25%; P = 0.02), dysphagia (74% versus 39%; P = 0.006), myalgia (89% versus 52%; P = 0.002), peripheral edema (35% versus 11%; P = 0.016), and calcinosis (37% versus 11%; P = 0.007). These patients were less likely to be clinically amyopathic (5% versus 23%; P = 0.08). Five of the 20 patients with anti-NXP-2 antibodies (25%) had an associated internal malignancy. No other cutaneous characteristics were associated with anti-NXP-2 antibodies, except a decreased frequency of Gottron's sign (44% versus 75%; P = 0.012) and a greater likelihood of having mild skin disease. Dermatomyositis patients with anti-NXP-2 antibodies have a distinct and often severe systemic phenotype that includes myalgia, peripheral edema, and significant dysphagia, despite having milder inflammatory skin disease.

Antinuclear Matrix Protein 2 Autoantibodies and Edema, Muscle Disease, and Malignancy Risk in Dermatomyositis Patients.

Dermatomyositis (DM) patients typically present with proximal weakness and autoantibodies that are associated with distinct clinical phenotypes. We observed that DM patients with autoantibodies recognizing the nuclear matrix protein NXP-2 often presented with especially severe weakness. The aim of this study was to characterize the clinical features associated with anti-NXP-2 autoantibodies. There were 235 DM patients who underwent testing for anti-NXP-2 autoantibodies. Patient characteristics, including muscle strength, were compared between those with and without these autoantibodies. The number of cancer cases observed in anti-NXP-2-positive subjects was compared with the number expected in the general population. Of the DM patients, 56 (23.8%) were anti-NXP-2-positive. There was no significant difference in the prevalence of proximal extremity weakness in patients with and without anti-NXP-2. In contrast, anti-NXP-2-positive patients had more prevalent weakness in the distal arms (35% versus 20%; P = 0.02), distal legs (25% versus 8%; P < 0.001), and neck (48% versus 23%; P < 0.001). Anti-NXP-2-positive subjects were also more likely to have dysphagia (62% versus 35%; P < 0.001), myalgia (46% versus 25%; P = 0.002), calcinosis (30% versus 17%; P = 0.02), and subcutaneous edema (36% versus 19%; P = 0.01) than anti-NXP-2-negative patients. Five anti-NXP-2-positive subjects (9%) had cancer-associated myositis, representing a 3.68-fold increased risk (95% confidence interval 1.2-8.6) compared to the expected prevalence in the general population. In DM, anti-NXP-2 autoantibodies are associated with subcutaneous edema, calcinosis, and a muscle phenotype characterized by myalgia, proximal and distal weakness, and dysphagia. As anti-NXP-2-positive patients have an increased risk of cancer, we suggest that they undergo comprehensive cancer screening.