Anti-transcription Intermediary Factor 1γ Research Articles

Clinical Features and Immunogenetic Risk Factors Associated With Additional Autoantibodies in Anti-Transcriptional Intermediary Factor 1γ Juvenile-Onset Dermatomyositis.

Novel autoantibody specificities including anti-CCAR1 were recently discovered in adult patients with anti-transcriptional intermediary factor (TIF1)-positive dermatomyositis (DM) and were associated with attenuated cancer emergence. The aims of the present study were to examine whether these autoantibodies occur in patients with juvenile-onset DM (JDM) and to determine their associated features. Sera from 150 patients with anti-TIF1γ autoantibody-positive JDM in a cross-sectional cohort and 90 juvenile healthy controls were assayed for anti-CCAR1, anti-C1Z1, anti-IMMT, anti-TBL1XR1, and anti-Sp4 autoantibodies. Demographics, myositis autoantibodies, clinical features, medications, outcomes, and HLA-DRB1 and HLA-DQA1 alleles were compared between those with and without these autoantibodies. Any one of the anti-TIF1γ-associated autoantibodies was present in 44 patients (29%) overall, including 25 (17%) with anti-Sp4, 22 (15%) with anti-TBL1XR1, 14 (9%) with anti-CCAR1, 2 (1%) with anti-C1Z1, and 2 (1%) with anti-IMMT autoantibodies. These anti-TIF1γ-associated autoantibodies frequently co-occurred. Patients with any of the anti-TIF1γ-associated autoantibodies had less frequent falling (34% [15] vs. 53% [56], P = 0.032) and lower peak muscle enzymes. None of the patients had cancer. Among White patients, HLA-DRB1*03 was protective against an anti-TIF1γ-associated autoantibody (odds ratio 0.20, 95% confidence interval 0.07-0.52). Autoantibodies associated with anti-TIF1γ were found in isolation and in combination among a subset of patients with JDM. Patients with these autoantibodies had less severe muscle disease and were not enriched for HLA-DRB1*03. Additional autoantibodies among patients with positive anti-TIF1γ with JDM likely contribute to the heterogeneity of the anti-TIF1γ serologic subgroup.

Analytic and Clinical Validity of Myositis-Specific Antibodies by Line-Blot Immunoassay Is Essential.

This study assessed the concordance between line blot (LB) and immunoprecipitation (IP) assays for detecting myositis-specific antibodies (MSAs) in idiopathic inflammatory myopathies (IIMs) and their association with IIM subtypes. One hundred patients with IIM were enrolled, and MSA was detected using LB and IP. The IIM subtypes, including immune-mediated necrotizing myopathy-like, anti-tRNA synthetase syndrome-like, and clinically amyopathic dermatomyositis-like, were clinically diagnosed. The validity and reliability of the LB compared with the IP were evaluated. Optimal cutoff levels for LB were determined using various statistical methods including Cohen κ, Gwet's AC, diagnostic odds ratios, and receiver operating characteristic analysis. Line blot exhibited lower specificity and accuracy than IP in predicting IIM subtypes. Some MSAs performed better at higher LB cutoff values. Anti-signal recognition particle antibodies showed poor performance in predicting the immune-mediated necrotizing myopathy-like subtype using LB. Raising the cutoffs improved the reliability of anti-threonyl-tRNA synthetase and anti-signal recognition particle antibodies. Anti-histidyl-tRNA synthetase antibodies performed well at lower positivity, whereas diagnostic odds ratios increased for anti-transcription intermediary factor 1γ and anti-nuclear matrix protein 2 with higher cutoffs. Inconsistencies between LB and IP have been observed in patients with IIM. Individual optimal cutoffs for MSA by LB correlating with IP were determined. Rheumatologists should consider the differences between LB and IP results when classifying IIM subtypes.

Anti-transcriptional intermediary factor 1γ antibody-positive dermatomyositis with intravascular lymphoma.

Anti-transcriptional intermediary factor 1γ antibody-positive dermatomyositis with intravascular lymphoma.

Association of Anti-CCAR1 Autoantibodies With Decreased Cancer Risk Relative to the General Population in Patients With Anti-Transcriptional Intermediary Factor 1γ-Positive Dermatomyositis.

To describe the disease specificity, clinical phenotype, and risk of cancer in dermatomyositis (DM) patients with autoantibodies against cell division cycle and apoptosis regulator protein 1 (anti-CCAR1). The frequency of anti-CCAR1 autoantibodies was measured by enzyme-linked immunosorbent assay in the serum of DM patients from 2 independent cohorts (Johns Hopkins and Stanford), with patients with several other rheumatic diseases and healthy controls used as comparators. Clinical features and the risk of cancer incidence relative to that in the general population were determined in anti-CCAR1-positive DM patients. Anti-CCAR1 antibodies were significantly associated with anti-transcriptional intermediary factor 1γ (anti-TIF1γ) antibodies present in the serum of patients with DM: 80 (32%) of 252 anti-TIF1γ-positive DM patients versus 14 (8%) of 186 anti-TIF1γ-negative DM patients were positive for anti-CCAR1 antibodies (P < 0.001). Anti-CCAR1 antibodies were not detected in any of the 32 serum samples from healthy controls, and were present at very low frequencies in the sera of patients with other rheumatic diseases: 1 (2.3%) of 44 patients with anti-hydroxymethylglutaryl-coenzyme A reductase-positive necrotizing myopathy, 1 (2.3%) of 44 patients with inclusion body myositis, and 3 (6.5%) of 46 patients with systemic lupus erythematosus were positive for anti-CCAR1 antibodies. Upon examining data on occurrence of cancer from the onset of DM onward, the observed number of cancers diagnosed in anti-TIF-1γ-positive DM patients was significantly greater than expected in both cohorts, with a standardized incidence ratio (SIR) of 3.49 (95% confidence interval [95% CI] 2.39-4.92) in the Johns Hopkins cohort and a SIR of 4.54 (95% CI 3.04-6.52) in the Stanford cohort (each P < 0.001). DM patients who were both anti-TIF1γ positive and anti-CCAR1 positive had lower SIRs for cancer, with a SIR of 1.78 (95% CI 0.77-3.51) (P=0.172) in the Johns Hopkins cohort and a SIR of 1.61 (95% CI 0.44-4.13) (P=0.48) in the Stanford cohort. Anti-CCAR1 autoantibodies are specific for anti-TIF1γ-positive DM. Their presence in anti-TIF1γ-positive patients attenuates the risk of cancer to a level comparable to that seen in the general population.

Diagnostic Yield of Computed Tomography for Cancer Detection in a Tertiary Referral Population of Idiopathic Inflammatory Myositis Patients.

To inform guidance for cancer detection in patients with idiopathic inflammatory myopathy (IIM), we evaluated the diagnostic yield of computed tomography (CT) imaging for cancer screening/surveillance within distinct IIM subtypes and myositis-specific autoantibody strata. We conducted a single-center, retrospective cohort study in IIM patients. Overall diagnostic yield (number of cancers diagnosed/number of tests performed), percentage of false positives (number of biopsies performed not leading to cancer diagnosis/number of tests performed), and test characteristics were determined on CT of the chest and abdomen/pelvis. Within the first 3 years since IIM symptom onset, a total of 9 of 1,011 (0.9%) chest CT scans and 12 of 657 (1.8%) abdomen/pelvis CT scans detected cancer. Diagnostic yields for both CT of the chest and CT of the abdomen/pelvis were highest in dermatomyositis, specifically anti-transcription intermediary factor 1γ (2.9% and 2.4% for CT of the chest and abdomen/pelvis, respectively). The highest percentage of false positives was in patients with antisynthetase syndrome (ASyS) (4.4%) and immune-mediated necrotizing myopathy (4.4%) on CT of the chest, and ASyS (3.8%) on CT of the abdomen/pelvis. Patients ages <40 years old at IIM onset had both low diagnostic yields (0% and 0.5%) and high false-positive rates (1.9% and 4.4%) for CT of the chest and abdomen/pelvis, respectively. In a tertiary referral cohort of IIM patients, CT imaging has a wide range of diagnostic yield and frequency of false positives for contemporaneous cancer. These findings suggest that cancer detection strategies targeted according to IIM subtype, autoantibody positivity, and age may maximize cancer detection while minimizing the harms and costs of over-screening.

Subsets of Idiopathic Inflammatory Myositis Enriched for Contemporaneous Cancer Relative to the General Population.

This study investigates cancer risk in idiopathic inflammatory myopathy (IIM) relative to the general population. We conducted a single-center, retrospective cohort study of IIM patients and malignancy. Myositis-specific and -associated autoantibodies were determined by Euroimmun line blot, enzyme-linked immunosorbent assay, and immunoprecipitation. We calculated standardized prevalence ratios (SPRs) and adjusted for calendar year, age, sex, race, and ethnicity by comparing observed cancers in IIM patients versus expected cancers in the general population using the Surveillance, Epidemiology, and End Results registry. Of 1,172 IIM patients, 203 (17%) patients with a cancer history were studied. Over a median follow-up of 5.2 years, the observed number of IIM patients diagnosed with cancer was increased 1.43-fold (SPR 1.43 [95% confidence interval (95% CI) 1.15-1.77]; P=0.002). Within 3 years of IIM symptom onset, an increased SPR was observed for anti-transcription intermediary factor 1γ (anti-TIF1γ)-positive patients for ovarian and breast cancer (ovarian SPR 18.39 [95% CI 5.01-47.08], P < 0.001; breast SPR 3.84 [95% CI 1.99-6.71], P < 0.001). As expected, anti-TIF1γ positivity was associated with a significantly elevated SPR; however, only 55% (36 of 66) of all cancers within 3 years of dermatomyositis onset were observed in anti-TIF1γ-positive patients. Other myositis-specific autoantibodies, including anti-Mi-2, anti-small ubiquitin-like modifier activating enzyme (SAE), and anti-nuclear matrix protein 2 (NXP-2), accounted for 26% (17 of 66) of cancers diagnosed within 3 years of dermatomyositis onset. No cancer association, positive or negative, was observed for patients with antisynthetase, anti-melanoma differentiation-associated protein 5 (anti-MDA-5), or anti-hydroxymethylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies. In a tertiary referral center population, anti-TIF1γ was most strongly associated with breast and ovarian cancer. Patients with antisynthetase, anti-MDA-5, or anti-HMGCR antibodies had the same cancer risk as the general population.

Myositis-specific antibodies in dermatomyositis: A single-center experience of 33 cases in Taiwan

Dermatomyositis (DM) is a systemic autoimmune disease characterized by unique cutaneous manifestations and inflammatory myopathies. With the discovery of myositis-specific antibodies (MSAs), patients with DM, especially those with a higher risk of life-threatening complications, can be classified according to the MSA type. This retrospective study aimed to investigate the clinical significance of MSAs in patients with DM in Taiwan. A total of 33 patients with DM who underwent the MSA test, including 26 with classic DM and 7 with amyopathic DM, were included. There were 13 men and 20 women, with a mean age at diagnosis of 49.6 years. MSA was detected in 26 (78.8%) of 33 patients with DM. The most frequently detected MSA was anti-melanoma differentiation-associated protein 5 (MDA5) (10/33, 30.3%) followed by anti-transcription intermediary factor-1γ (TIF-1γ) (8/33, 24.2%). Dysphagia was present in 6 (18.2%) of the 33 patients and more frequently developed in patients with anti-TIF-1γ (+) (5/8, 62.5%) than those with anti-TIF-1γ (−) (1/25, 4.0%). Interstitial lung disease was noted in 15 patients (45.5%) and developed more frequently in patients with anti-MDA5 (+) (7/10, 70.0%) than those with anti-MDA5 (−) (8/23, 34.8%). Malignancies were detected in 4 (12.1%) patients, with one each of anti-Mi-2 (+), anti-TIF-1γ (+), anti-ARS (+), and MSA (−). Mortality occurred in 6 (18.2%) patients, of whom 4 were anti-MDA5 (+). Anti-MDA5 and anti-TIF-1γ were the two most commonly detected MSAs. The presence of specific MSAs is associated with a certain phenotype, and integrating MSAs while evaluating DM aids in accurate patient management.

A multianalyte assay for the detection of dermatomyositis-related autoantibodies based on immunoprecipitation combined with immunoblotting.

To develop a multianalyte assay for the detection of dermatomyositis (DM)-related autoantibodies using immunoprecipitation (IP) combined with immunoblotting (IB). Sera from 116 DM patients were subjected to RNA and protein immunoprecipitation assays as well as commercial enzyme-linked immunosorbent assays (ELISAs) for anti-aminoacyl transfer RNA synthetase, anti-melanoma differentiation antigen 5 (MDA5), anti-Mi-2, anti-transcriptional intermediary factor-1γ (TIF-1γ), and anti-U1 ribonucleoprotein antibodies. The IP/IB assay was developed by immunoprecipitation of autoantigens from HeLa cell extracts using patient sera, followed by immunoblotting with an antibody against Mi-2, TIF-1γ, OJ, nuclear matrix protein (NXP)-2, MDA5, PM/Scl, small ubiquitin-like modifier activating enzyme (SAE), or Ku. A multianalyte assay was designed by mixing primary antibodies in the IP/IB assay. IP assays identified any DM-related autoantibodies in 100 patients (86%), of which 82% were covered by commercial ELISAs, with a false-positive result in two sera and a false-negative result in one serum. The results obtained from the multianalyte IP/IB assay and 'gold-standard' IP assays were concordant in terms of the presence or absence of anti-MDA5, anti-TIF-1γ, anti-OJ, anti-NXP-2, anti-PM/Scl, anti-SAE, anti-Mi-2, and anti-Ku antibodies. This multianalyte IP/IB assay combined with commercial ELISAs is an alternative to 'gold-standard' IP assays for the detection of DM-related autoantibodies.

Capillary leak syndrome in a patient with cancer-associated anti-transcriptional intermediary factor 1γ dermatomyositis treated with rituximab

Capillary leak syndrome (CLS) is a rare condition characterised by increased capillary permeability, with subsequent hypoalbuminemia and hypotension, leading to an increased risk of shock and death. We present the case of a patient with anti-transcriptional intermediary factor 1γ dermatomyositis that developed CLS one week after starting treatment with rituximab and prophylactic co-trimoxazole. The patient was admitted to the Intensive Care Unit (ICU), recovered after treatment with intravenous immunoglobulin, albumin, and Ringer lactate, but died a month after the discharge due to a poorly differentiated hepatocarcinoma diagnosed in the ICU.

Presence of anti-TIF-1γ, anti-Ro52, anti-SSA/Ro60 and anti-Su/Ago2 antibodies in breast cancer: a cross-sectional study

Objectives The presence of myositis-specific antibodies (MSA), was recently reported in healthy individuals, cancer patients without myopathy and paraneoplastic rheumatic syndromes. We sought to analyze the frequency of MSA, myositis-associated antibodies (MAA) and autoantibodies related to systemic autoimmune rheumatic diseases (SARD) in breast cancer patients. Methods One hundred fifty-two breast cancer patients were enrolled in a cross-sectional study. Clinical information was collected, and autoantibodies tested by immunoprecipitation of an 35S-methionine-labeled K562 cell extract, enzyme-linked immunosorbent assay (ELISA) and Western blot when indicated. All statistical tests were performed using the software statistical package for the social science (SPSS) ver. 19.0 (IBM Inc., NYSE, USA). Results Autoantibodies associated with SARD: anti-52 kD ribonucleoprotein/tripartite motif-containing 21 (anti-Ro52/TRIM21) was found in 5.9% (9/152), anti-Sjögren syndrome-related antigen A/60 kD ribonucleoprotein antibody (anti-SSA/Ro60) in 3.9% (6/152) and anti-Su antigen/Argonaute 2 antibody (anti-Su/Ago2) in 2.6% (4/152). Meanwhile, anti-transcription intermediary factor-1γ (anti-TIF-1γ, p155/140) antibody was positive in 2 cases and anti-polymyositis/scleroderma antibody was detected in one case. As a whole, 14.47% (22/152) of breast cancer patients showed autoantibodies associated with SARD. These specific autoantibodies were not associated with the presence of rheumatic diseases except one rheumatoid arthritis patient positive for anti-Ro52/TRIM21. Conclusions Autoantibodies to TIF-1γ were found in two patients with breast cancer without dermatomyositis (DM). More common specificities were autoantibodies anti-SSA/Ro60, anti-Ro52/TRIM21 and anti-Su/Ago2. More studies are needed in order to establish the biological meaning of the presence of SARD-associated autoantibodies in breast cancer.

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 of anti-transcription intermediary factor 1γ (TIF1γ)-positive dermatomyositis with internal malignancy and investigation of the involvement of TIF1γ expression in tumors in the pathogenesis of cancer-associated dermatomyositis.

Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibody (Ab) is significantly associated with internal malignancies in adult patients with dermatomyositis (DM). Although pathogenesis of cancer-associated DM is unknown, TIF1γ overexpression in tumors has been considered to be critical for the development of DM. The objective of this study was to investigate clinical characteristics of patients with anti-TIF1γ Ab-positive DM and elucidate risk factors that are potentially associated with internal malignancy. In addition, we compared the expression of TIF1γ in tumor tissues of patients with anti-TIF1γ Ab-positive DM, anti-TIF1γ Ab-negative DM and without DM in order to investigate the pathogenesis of cancer-associated DM. We analyzed 77 Japanese patients with DM, and found 19 patients to be positive for anti-TIF1γ Ab. Patients with anti-TIF1γ Ab-positive DM were older and presented heliotrope rash and flagellate erythema more frequently than patients without anti-TIF1γ Ab (P<0.05). Interstitial lung disease (ILD) and rapidly progressive ILD, as well as palmar violaceous erythema, were less frequent in patients with anti-TIF1γ Ab than in patients without. Furthermore, internal malignancy and dysphagia were significantly more frequent in the anti-TIF1γ Ab-positive group (P<0.01). Male sex and dysphagia were significantly associated with internal malignancy in patients with anti-TIF1γ Ab-positive DM (P<0.01 and <0.05, respectively). Using immunohistochemistry, we examined the TIF1γ expression in tumors of 11 patients with cancer-associated DM (anti-TIF1γ Ab-positive, nine; anti-TIF1γ Ab-negative, two) and 25 patients without DM. TIF1γ was highly expressed in all tumors, and there was no significant difference in TIF1γ expression between patients with and without DM. Furthermore, TIF1γ expressions in tumors were similar irrespective of the presence of anti-TIF1γ Ab. These results suggest that anti-TIF1γ antibody may not be simply induced by overexpression of TIF1γ in tumors in patients with DM, but that other mechanisms may exist.

A single-center, retrospective record review of malignancy prevalence in patients with dermatomyositis with anti-transcription intermediary factor 1γ antibodies via line immunoassay versus immunoprecipitation

To the Editor: The association of dermatomyositis (DM) with malignancy has been well established, with a prevalence between 11% and 42%.1 Patients with DM with transcription intermediary factor 1γ (TIF-1γ) antibodies appear to be at greater risk of malignancy than the broader population of patients with DM, with a malignancy prevalence between 42% and 100%.2

Cutaneous manifestations of dermatomyositis characterized by myositis-specific autoantibodies.

Dermatomyositis (DM) is an inflammatory myopathy with characteristic skin manifestations, the pathologies of which are considered autoimmune diseases. DM is a heterogeneous disorder with various phenotypes, including myositis, dermatitis, and interstitial lung disease (ILD). Recently identified myositis-specific autoantibodies have been associated with distinct clinical features. For example, anti-melanoma differentiation-associated protein 5 antibodies have a high specificity for clinically amyopathic DM presenting rapidly progressive ILD. Furthermore, anti-transcriptional intermediary factor 1γ antibodies found in patients with juvenile and adult DM are closely correlated with malignancies, especially in elderly patients. Finally, patients with anti-aminoacyl-transfer RNA synthetase antibodies share characteristic clinical symptoms, including myositis, ILD, arthritis/arthralgia, Raynaud’s phenomenon, and fever; thus, the term “anti-synthetase syndrome” is also used. With a focus on the characteristic cutaneous manifestations in each subgroup classified according to myositis-specific autoantibodies, we introduce the findings of previous reports, including our recent analysis indicating that skin eruptions can be histopathologically classified into myositis-specific autoantibody-associated subgroups and used to determine the systemic pathologies of the different types of antibody-associated DM.

The IgG2 Isotype of Anti-Transcription Intermediary Factor 1γ Autoantibodies Is a Biomarker of Cancer and Mortality in Adult Dermatomyositis.

Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibodies are the main predictors of cancer in dermatomyositis (DM). Yet, a substantial proportion of anti-TIF1γ-positive DM patients do not develop cancer. This study was undertaken to identify biomarkers to better evaluate the risk of cancer and mortality in DM. This multicenter study was conducted in adult anti-TIF1γ-positive DM patients from August 2013 to August 2017. Anti-TIF1γ autoantibody levels and IgG subclasses were identified using a newly developed quantitative immunoassay. Age, sex, DM signs and activity, malignancy, and creatine kinase (CK) level were recorded. Risk factors were determined by univariate and multivariate analysis according to a Cox proportional hazards regression model. Among the 51 adult patients enrolled (mean ± SD age 61 ± 17 years; ratio of men to women 0.65), 40 (78%) had cancer and 21 (41%) died, with a mean ± SD survival time of 10 ± 6 months. Detection of anti-TIF1γ IgG2 was significantly associated with mortality (P = 0.0011) and occurrence of cancer during follow-up (P < 0.0001), with a 100% positive predictive value for cancer when the mean fluorescence intensity of anti-TIF1γ IgG2 was >385. None of the patients developed cancer after 24 months of follow-up. Univariate survival analyses showed that mortality was also associated with age >60 years (P = 0.0003), active DM (P = 0.0042), cancer (P = 0.0031), male sex (P = 0.011), and CK level >1,084 units/liter (P = 0.005). Multivariate analysis revealed that age >60 years (P = 0.015) and the presence of anti-TIF1γ IgG2 (P = 0.048) were independently associated with mortality. Our findings indicate that anti-TIF1γ IgG2 is a potential new biomarker of cancer that should be helpful in identifying the risk of mortality in anti-TIF1γ-positive DM patients.

Use of Anti-transcriptional Intermediary Factor-1 Gamma Autoantibody in Identifying Adult Dermatomyositis Patients with Cancer: A Systematic Review and Meta-analysis.

Anti-transcriptional intermediary factor-1γ (TIF-1γ) autoantibody may be associated with cancer in adult patients with dermatomyositis. The aim of this study was to evaluate the risk of cancer in the presence of anti-TIF-1γ autoantibody in adult dermatomyositis. A comprehensive database search of EMBASE, MEDLINE and the Cochrane Library up to May 2018 was performed using the main key words "dermatomyositis", ""myositis", "inflammatory myopathies" and "anti-TIF-1". Eighteen studies, with a total of 1,962 dermatomyositis, were included in the meta-analysis. The pooled prevalence of cancer-associated dermatomyositis in patients with anti-TIF-1γ autoantibody was 0.41 (95% confidence interval (CI) 0.36-0.45). In the presence of anti-TIF-1γ autoantibody, the overall diagnostic odds ratio of cancer was 9.37 (95% CI 5.37-16.34) with low heterogeneity (Cochran's Q: 14.88 (df = 17, p = 0.604); I2 = 0%). The results of this systematic review confirm that detection of anti-TIF-1γ autoantibody is a valuable tool to identify a subset of adult dermatomyositis patients with higher risk of cancer.

New insights in myositis-specific autoantibodies.

The aim of this study was to provide the most recent evidence on clinical utility of myositis-specific autoantibodies (MSAs) in the management of patients with myositis. In the last few years, several evidences have emerged on the clinical and pathogenetic role of established and novel MSA. Antisynthetase antibodies represent a reliable biomarker for pulmonary involvement also in patients with connective tissue diseases other than myositis. Antisignal recognition particle and antihydroxy-3-methylglutaryl coenzyme A reductase autoantibodies are able to induce complement-dependent muscle damage. Dermatomyositis-specific antibodies are useful indicators of clinical diversity. The pivotal role of antitranscription intermediary factor 1γ autoimmune response in adult-age paraneoplastic dermatomyositis has been further asserted. AnticN1A and antifour-and-a-half LIM protein 1 antibodies are newly conceived myositis-related antibody specificities, which can contribute to patients' stratification into more homogeneous groups. Distinct autoantibody-associated clinical phenotypes can be predicted by extended MSA testing in serum. Standardization and validation of MSA laboratory detection methods is strongly recommended for better supporting myositis diagnosis, management and prognosis definition.

Development of a New Classification System for Idiopathic Inflammatory Myopathies Based on Clinical Manifestations and Myositis-Specific Autoantibodies

Idiopathic inflammatory myopathies are heterogeneous in their pathophysiologic features and prognosis. The emergence of myositis-specific autoantibodies suggests that subgroups of patients exist. To develop a new classification scheme for idiopathic inflammatory myopathies based on phenotypic, biological, and immunologic criteria. An observational, retrospective cohort study was performed using a database of the French myositis network. Patients identified from referral centers for neuromuscular diseases were included from January 1, 2003, to February 1, 2016. Of 445 initial patients, 185 patients were excluded and 260 adult patients with myositis who had complete data and defined historical classifications for polymyositis, dermatomyositis, and inclusion body myositis were enrolled. All patients were tested for anti-histidyl-ARN-t- synthetase (Jo1), anti-threonine-ARN-t-synthetase (PL7), anti-alanine-ARN-t-synthetase (PL12), anti-complex nucleosome remodeling histone deacetylase (Mi2), anti-Ku, anti-polymyositis/systemic scleroderma (PMScl), anti-topoisomerase 1 (Scl70), and anti-signal recognition particle (SRP) antibodies. A total of 708 variables were collected per patient (eg, cancer, lung involvement, and myositis-specific antibodies). Unsupervised multiple correspondence analysis and hierarchical clustering analysis to aggregate patients in subgroups. Among 260 participants (163 [62.7%] women; mean age, 59.7 years; median age [range], 61.5 years [48-71 years]), 4 clusters of patients emerged. Cluster 1 (n = 77) included patients who were male, white, and older than 60 years and had finger flexor and quadriceps weakness and findings of vacuolated fibers and mitochondrial abnormalities. Cluster 1 regrouped patients who had inclusion body myositis (72 of 77 patients [93.5%]; 95% CI, 85.5%-97.8%; P < .001). Cluster 2 (n = 91) regrouped patients who were women and had high creatine phosphokinase levels, necrosis without inflammation, and anti-SRP or anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies corresponding to immune-mediated necrotizing myopathy (53 of 91 [58.2%]; 95% CI, 47.4%-68.5%; P < .001). Cluster 3 (n = 52) regrouped patients who had dermatomyositis rash and anti-Mi2, anti-melanoma differentiation-associated protein 5 (MDA5), or anti-transcription intermediary factor-1γ (TIF1γ) antibodies, mainly corresponding with patients who had dermatomyositis (43 of 52 [82.7%]; 95% CI, 69.7%-91.8%; P < .001). Cluster 4 (n = 40) was defined by the presence of anti-Jo1 or anti-PL7 antibodies corresponding to antisynthetase syndrome (36 of 40 [90.0%]; 95% CI, 76.3%-97.2%; P < .001). The classification of an independent cohort (n = 50) confirmed the 4 clusters (Cohen κ light, 0.8; 95% CI, 0.6-0.9). These findings suggest a classification of idiopathic inflammatory myopathies with 4 subgroups: dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome. This classification system suggests that a targeted clinical-serologic approach for identifying idiopathic inflammatory myopathies may be warranted.

Association of Anti-Transcription Intermediary Factor 1γ Antibodies With Paraneoplastic Rheumatic Syndromes Other Than Dermatomyositis.

An association between cancer and dermatomyositis (DM) is well recognized. The high frequency of malignancies detected close to DM diagnosis suggest that DM can be a paraneoplastic syndrome. Recently, anti-transcription intermediary factor 1γ (anti-TIF1γ) has been discovered to be associated with cancer and with DM. A meta-analysis reported the pooled sensitivity of anti-p155 for diagnosing cancer-associated DM to be 78% and the specificity to be 89%. Thus, anti-TIF1γ has shown promising results as a marker for cancer-associated DM. However, none of the studies evaluated the association of anti-TIF1γ with cancer with or without rheumatic diseases other than DM. To clarify the specificity of anti-TIF1γ antibodies as a biomarker for cancer-associated DM, we analyzed the frequency of anti-TIF1γ antibodies in other cancer-associated rheumatic syndromes, as well as in cancer patients and healthy controls. Sera from patients with paraneoplastic rheumatic syndrome (n = 91), patients with solid cancer (n = 95), and healthy controls (n = 80) were analyzed for the frequency of anti-TIF1γ IgG by enzyme-linked immunosorbent assay using a commercially available recombinant TIF1γ protein as coating antigen. The cutoff value was calculated by adding 2 SD to the mean optical density value of 80 healthy controls. The rate of anti-TIF1γ IgG positivity was 3.3% (n = 3) in patients with paraneoplastic rheumatic syndrome, 3.1% (n = 3) in cancer patients, and 1.3% (n = 1) in healthy controls. There were no significant differences in positivity between the groups (P < 0.05). Anti-TIF1γ antibodies are rarely present in patients with solid cancers or paraneoplastic rheumatic syndromes. This finding strengthens the approach to using anti-TIF1γ IgG as a marker for cancer-associated DM.

Muscle Biopsy Findings in Combination With Myositis-Specific Autoantibodies Aid Prediction of Outcomes in Juvenile Dermatomyositis.

ObjectiveJuvenile dermatomyositis (DM) is a rare and severe autoimmune condition characterized by rash and proximal muscle weakness. While some patients respond to standard treatment, others do not. This study was carried out to investigate whether histopathologic findings and myositis‐specific autoantibodies (MSAs) have prognostic significance in juvenile DM.MethodsMuscle biopsy samples (n = 101) from patients in the UK Juvenile Dermatomyositis Cohort and Biomarker Study were stained, analyzed, and scored for severity of histopathologic features. In addition, autoantibodies were measured in the serum or plasma of patients (n = 90) and longitudinal clinical data were collected (median duration of follow‐up 4.9 years). Long‐term treatment status (on or off medication over time) was modeled using generalized estimating equations.ResultsMuscle biopsy scores differed according to MSA subgroup. When the effects of MSA subgroup were accounted for, increased severity of muscle histopathologic features was predictive of an increased risk of remaining on treatment over time: for the global pathology score (histopathologist's visual analog scale [hVAS] score), 1.48‐fold higher odds (95% confidence interval [95% CI] 1.12–1.96; P = 0.0058), and for the total biopsy score (determined with the standardized score tool), 1.10‐fold higher odds (95% CI 1.01–1.21; P = 0.038). A protective effect was identified in patients with anti–Mi‐2 autoantibodies, in whom the odds of remaining on treatment were 7.06‐fold lower (95% CI 1.41–35.36; P = 0.018) despite muscle biopsy scores indicating more severe disease. In patients with anti–nuclear matrix protein 2 autoantibodies, anti–transcription intermediary factor 1γ autoantibodies, or no detectable autoantibody, increased histopathologic severity alone, without adjustment for the effect of MSA subtype, was predictive of the risk of remaining on treatment: for the hVAS global pathology score, 1.61‐fold higher odds (95% CI 1.16–2.22; P = 0.004), and for the total biopsy score, 1.13‐fold higher odds (95% CI 1.03–1.24; P = 0.013).ConclusionHistopathologic severity, in combination with MSA subtype, is predictive of the risk of remaining on treatment in patients with juvenile DM and may be useful for discussing probable treatment length with parents and patients. Understanding these associations may identify patients at greater risk of severe disease.