Cancer-associated Dermatomyositis Research Articles

Quid de la détection des anticorps anti-TIF1γ dans les dermatomyosites ?

AbstractThe classification of idiopathic inflammatory myopathies (IBD) is evolving, with the consideration, in addition to clinicopathological criteria, of the presence of autoantibodies specific to myositis for the diagnosis and identification of clinical forms.The diagnosis of dermatomyositis (DM) is based on clinical, histological, imaging criteria and the demonstration of myositis-specific autoantibodies (MSA). Within these antibodies, anti-TIF1γ have a special place due to their high prevalence in juvenile DM and in cancer-associated DM. Anti-TIF1γ antibodies are present in 7-31% of adult DMs. DMs with anti-TIF1γ are associated with cancer in more than half of cases in adults (38-75%), whereas this is not the case in juvenile DMs. The role of the TIF1γ protein in the tumor process and of autoantibodies in the triggering of DM are the subject of numerous hypotheses, but without any definitive conclusion currently.Given the diagnostic and prognostic importance of the presence of anti-TIF1γ antibodies, it is essential to have reliable tests suitable for routine practice to characterize them. The reference technique, immunoprecipitation, is not suitable for the routine laboratory. Immunodots are practical but their performance is not optimal in terms of sensitivity and specificity. Elisa and the particle-based multi-analyte technology (PMAT)-type automated technique seem to present performances close to immunoprecipitation but with a practicability adapted to routine use.

Janus kinase inhibitor for anti-transcription intermediary factor 1-γ positive cancer-associated dermatomyositis.

In this retrospective case series, off-label use of Janus kinase inhibitor rapidly and significantly ameliorated the active cutaneous disease in all five glucocorticoid-resistant patients with cancer-associated dermatomyositis who had anti-transcription intermediary factor 1-γ antibodies, showing a promising steroid-sparing effect and a generally well-tolerated safety profile beyond 1-year follow-up.

Spontaneous intramuscular hemorrhage in cancer-associated dermatomyositis: a case and literature review

BackgroundSpontaneous intramuscular hemorrhage (SIH) is a rare but life-threatening complication of dermatomyositis (DM). The pathogenetic mechanism and management of intramuscular hematoma in these patients remains unclear. Here we discuss a case of recurrent hemorrhage in a patient with cancer-associated DM, and review the relevant literature for timely diagnosis and treatment.Case presentationA 53-year-old male patient presented with rashes, muscle weakness, and dysphagia and was diagnosed with DM. During treatment, he developed SIH of the arm and right psoas major muscle successively. MRI showed extensive edema of the right shoulder girdle muscle and muscle groups of the upper arm. During the second SIH, a CT scan showed new-onset hematoma formation in the right psoas major muscle. The detection of D-dimer, thrombin-antithrombin III complex (TAT), plasmin-α2-plasmininhibitor complex (PIC) and tissue plasminogen activator-inhibitor complex (t-PAIC) indicated predominant hyperfibrinolysis over thrombosis. Blood transfusion and supportive treatment were immediately performed, and the hematoma did not expand. However, his abdominal distension was not relieved after active treatment. Further electronic gastroscopy discovered gastric sinus ulcers, and histopathology of the biopsy confirmed signet-ring cell carcinoma.ConclusionsAlthough patients with cancer-associated DM have an increased risk of thrombosis, prophylactic anticoagulation therapy needs deliberate consideration. It is important to monitor the coagulation parameters dynamically during anticoagulation therapy. Especially when the level of D-dimer is high, and it is uncertain whether the patient is in a state of thrombosis or hyperfibrinolysis, the detection of TAT, PIC, t-PAIC can help to determine whether to initiate anticoagulation therapy.

060 Appropriate therapeutic target of cancer-associated dermatomyositis with anti-transcriptional intermediary factor 1-γ antibody

060 Appropriate therapeutic target of cancer-associated dermatomyositis with anti-transcriptional intermediary factor 1-γ antibody

Features of MRI honeycomb edema signals in cancer-associated dermatomyositis patients: a brief report.

Dermatomyositis (DM) is an autoimmune inflammatory disease that is a possible paraneoplastic phenomenon. The aim of this study was to explore the difference in thigh MRI findings between DM patients with and without cancer to further assist clinicians in the early discovery of underlying malignancy. Thigh muscle MRI with T2 fs/STIR images obtained from 47 patients diagnosed with DM at a single center were retrospectively assessed for the involvement of muscle compartments, as well as the pattern and distribution of the edema signal. Among 47 patients, 14 had cancer within three years of DM diagnosis. Honeycomb edema signals were more frequently observed in cancer patients (10 in the cancer group, 11 in the noncancer group, p = 0.020), while foggy signals were not found in cancer patients. Among patients with honeycomb signals, we found that cancer patients had a relatively longer disease duration (p = 0.012), lower creatine kinase levels (p = 0.011), and barely showed adductor involvement (p = 0.016). Logistic regression analysis identified honeycomb edema signals in the quadriceps without adductor involvement as an independent risk factor for having cancer in DM patients. Honeycomb pattern edema signals showed in quadriceps but not adductors on thigh muscle MRI STIR/T2 fs sequence were more frequently found in cancer-associated DM patients. Key points • MRI honeycomb edema signals in the quadriceps without adductor involvement may be a predictor for underlying cancer in DM patients.

ELISA, protein immunoprecipitation and line blot assays for anti-TIF1-gamma autoantibody detection in cancer-associated dermatomyositis.

Anti-TIF1-gamma autoantibodies can be detected with immunoprecipitation (IP), line blot (LB) and ELISA. We compared assay performance in patients with DM and the potential of these assays to detect anti-TIF1-gamma positive cancer-associated DM (CADM). We included sera from 131 patients with DM followed at Karolinska University Hospital, Stockholm, Sweden and 82 healthy controls. Serum samples taken at DM diagnosis were tested for anti-TIF1-gamma autoantibodies with IP, two ELISAs (in-house and commercial) and LB. Cancer diagnosis and dates were obtained from the Swedish national cancer register. CADM was defined as a malignancy that developed within 3 years of DM diagnosis. Anti-TIF1-gamma autoantibodies were detected in 19/101 (18.8%), 15/113 (13.2%), 34/131 (26%) and 45/131 (34.4%) of the patients with IP, LB, in-house and commercial ELISA, respectively. The anti-TIF1-gamma results from the in-house ELISA were confirmed with IP in 93 of 101 (92%) cases, κ = 0.76, with a commercial ELISA in 110 of 131 (84%) cases, κ = 0.63, and with LB in 101 of 113 (89.3%) cases, κ = 0.67. Anti-TIF1-gamma results with IP were confirmed with LB in 85 of 92 (92.4%) cases, κ = 0.73. For detecting CADM, the anti-TIF1-gamma in-house ELISA had a sensitivity of 58% and specificity of 86%, the commercial ELISA had a sensitivity of 63% and specificity of 82%, IP had a sensitivity of 52% and specificity of 92%, LB had a sensitivity of 40% and specificity of 96%. The two anti-TIF1-gamma ELISA assays had advantages both for autoantibody detection and to identify anti-TIF1-gamma-positive CADM.

Cancer-associated Dermatomyositis with Histiocytic Sarcoma

Cancer-associated Dermatomyositis with Histiocytic Sarcoma

P46-2 A case of cancer-associated dermatomyositis diagnosed after curative therapy for esophageal and oropharyngeal cancers

P46-2 A case of cancer-associated dermatomyositis diagnosed after curative therapy for esophageal and oropharyngeal cancers

TRIM33 gene somatic mutations identified by next generation sequencing in neoplasms of patients with anti-TIF1γ positive cancer-associated dermatomyositis.

To deep sequence the TRIM33 gene in tumours from patients with cancer-associated anti-TIF1γ autoantibody-positive dermatomyositis (DM) as TRIM33 somatic mutations in tumours may trigger this auto-immune disease. Next generation sequencing of tumour DNA samples from patients with cancer-associated anti-TIF1γ autoantibody-positive DM. Fourteen tumours from 13 anti-TIF1γ autoantibody-positive DM individuals were sequenced along with two control tumours from non-DM individuals. Fourteen probable somatic variants from four tumours were identified in the TRIM33 gene. These results are in accordance with the previous report of Pinal-Fernandez et al. and support the hypothesis of a role of TRIM33 gene mutations in the pathophysiology of anti-TIF1γ autoantibody-positive DM.

Anti-transcription intermediary factor 1 gamma (TIF1\u03b3) antibody-positive dermatomyositis associated with ascending colon cancer: a case report and review of the\xa0literature

BackgroundAnti-transcriptional intermediary factor 1 gamma (TIF1γ) antibody is a marker for predicting cancer association in patients with dermatomyositis (DM). The overall survival rate in DM patients with cancer was reported to be considerably worse than that in DM patients without cancer. However, the treatment for cancer-associated DM remains controversial, because the treatment priority between surgical resection for the tumor and internal treatments, including glucocorticoids, immunosuppressive agents, and intravenous immune globulin, has not been established.Case presentationWe report the case of a 57-year-old Japanese man diagnosed with anti-TIF1γ antibody-positive DM associated with ascending colon cancer. His clinical symptoms included facial and brachial edema, muscle weakness, dysphagia, myalgia, and rash. Physical examination revealed periorbital edema and Gottron's papules over his knuckles with brachial edema, and tenderness and weakness of the proximal limb muscles. The findings of hyperintense muscles in T2-weighted sequences of brachial contrast-enhanced magnetic resonance imaging and the infiltration of lymphocytic cells and CD4-positive lymphocytes from muscle biopsy were compatible with the diagnostic criteria for dermatomyositis. Anti-TIF1γ antibody was positive by immunoprecipitation assay. He first started internal treatment including intravenous immunoglobulin, steroid pulse, prednisolone, and azathioprine, followed by surgical resection for the tumor because of the elevation of creatine kinase and progression of dysphagia. However, clinical symptoms did not improve, and the patient died 6 months later.ConclusionsWe faced difficulties in determining the treatment priority between surgical resection and internal treatment for our case; therefore, this case would be educational for readers. We searched PubMed to identify English-language case reports of anti-TIF1γ antibody-positive dermatomyositis with malignancy and found 21 reported cases. We herein review and summarize previously reported cases of anti-TIF1γ antibody-positive DM with malignancy. Cancer screening is essential in patients with anti-TIF1γ antibody-positive dermatomyositis because it is associated with a high prevalence of malignancies. Our review revealed that initial surgical treatment should be recommended for better prognosis if the general condition allows.

Myositis autoantibodies: recent perspectives.

To provide an overview of recent discoveries related to myositis-specific autoantibodies (MSAs) and assays used for their measurement. New autoantibody specificities have been reported including a MSA directed against eukaryotic initiation factor 3 and a myositis-associated autoantibody directed against heat shock factor 1. The association of anti-TIF1γ with cancer-associated dermatomyositis dependent on age has been confirmed in several large cohorts. Despite MSAs being almost entirely mutually exclusive, several myositis autoantigens are overexpressed in regenerating muscle and do not correlate with the corresponding MSA in any one patient. Further mechanisms may determine the final MSA specificity and are likely to include the need for autoantigen processing and presentation with adaptive T-cell help. The presence of CD4-positive T cells specific for histidyl tRNA synthetase protein in bronchial lavage fluid from antisynthetase patients lends support to this view. Finally, it is widely held that MSA do play an important role in clinical practice among some evidence and concern about commercial assay reliability. MSAs continue to provide important tools for clinical diagnosis and management as well as insights into disease mechanisms. Further improvement in the standardization and reliability of routine detection of MSAs is a high priority.

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.

Cancer in myositis

There is an intriguing relationship between cancer and myositis. The immunosuppressive agents commonly used to treat myositis patients are known to favor the development of cancer, but this factor does not seem to be the main cause of the association. Most myositis patients who develop cancer are considered to have cancer-associated myositis, which suggests that there are some types of etiopathogenic relationship between these two conditions. The malignancy usually appears within 3 years of the myositis diagnosis, and the risk of cancer depends on the myositis phenotype, with classic or amyopathic dermatomyositis (DM) and immune-mediated necrotizing myopathy being the main associated phenotypes. Several considerations regarding the pathogenesis of this association and strategies to detect occult malignancy in these patients are discussed here, with special emphasis on the role of autoantibodies as markers of this condition. Anti- TIF1g (Transcription Intermediary Factor 1 gamma) antibodies have been extensively studied in patients with cancer-associated DM. In addition, we discuss the peculiarities of treating patients with cancer-associated myositis and suggest some good treatment options, and finally, we examine the cancer–myositis relationship with regard to the recently described concept of myositis as an immune-related adverse event derived from the use of checkpoint immune inhibitors to treat cancer.

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.

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.

Detection of autoantibodies in dermatomyositis

Some autoantibodies have been identified to be closely associated with the clinical phenotypes and prognosis of dermatomyositis, such as anti-melanoma differentiation-associated gene 5 (MDA5) antibody, anti-transcriptional intermediary factor 1-γ (TIF-1γ) antibody, anti-nuclear matrix protein-2 (NXP-2) antibody, anti-glycyl-tRNA synthetase (anti-EJ) antibody, anti-nucleosome remodelling and histone deacetylase complex (anti-Mi-2) antibody, anti-histidyl-tRNA synthetase (anti-Jo-1) antibody, and so on. Anti-MDA5, anti-EJ and anti-Jo-1 antibodies are all related to dermatomyositis complicated by interstitial lung disease, especially anti-MDA5 antibody, which is significantly associated with the occurrence, disease activity and high mortality of dermatomyositis complicated by interstitial lung disease. Usually, anti-MDA5 antibody-positive patients have poor response to conventional immunosuppressive treatments. Anti-TIF-1γ and anti-NXP-2 antibodies are related to cancer-associated dermatomyositis. Moreover, anti-TIF-1γ and anti-NXP-2 antibodies are linked to some other distinctive clinical phenotypes of dermatomyositis. For example, obviously increased occurrence of psoriasis-like lesions and hyperkeratotic papules of palms is observed in anti-TIF-1γ antibody-positive patients, while muscle weakness in the forearms, lower legs and neck occurs more commonly in anti-NXP-2 antibody-positive patients. However, anti-Mi-2 antibody-positive patients have significantly decreased risk of interstitial lung disease and prolonged duration of treatment. Thus, wide application of the detection of these autoantibodies will be helpful to guide the diagnosis and treatment of dermatomyositis. Key words: Dermatomyositis; Autoantibodies; Antibodies, anti-MDA5; Antibodies, anti-TIF-lγ; Antibodies, anti- NXP-2; Antibodies, anti-EJ; Antibodies, anti- Mi-2; Antibodies, anti- Jo-1

Myositis-specific autoantibodies and their association with malignancy in Italian patients with polymyositis and dermatomyositis.

This study aims to characterize myositis-specific antibodies in a well-defined cohort of patients with idiopathic inflammatory myopathy and to determine their association with cancer. Sera from 40 patients with polymyositis, dermatomyositis, and controls were tested by protein and RNA immunoprecipitation to detect autoantibodies, and immunoprecipitation-Western blot was used for anti-MJ/NXP-2, anti-MDA5, and anti-TIF1γ/α identification. Medical records were re-evaluated with specific focus on cancer. Anti-MJ/NXP-2 and anti-TIF1γ/α were the most common antibodies in dermatomyositis. In six dermatomyositis cases, we found five solid forms of cancer and one Hodgkin's lymphoma in long-term remission. Among patients with cancer-associated dermatomyositis, three were positive for anti-TIF1γ/α, two for anti-Mi-2, and one for anti-MJ/NXP-2. The strongest positivity of anti-TIF1γ was seen in two active forms of cancer, and this antibody was either negative or positive at low titers in the absence of cancer or in the 7-year remission Hodgkin's lymphoma. Four out of twenty (20%) patients with polymyositis had solid cancer, but no specific association with autoantibodies was identified; further, none of the four cases of antisynthetase syndrome had a history of cancer. No serum myositis-associated autoantibody was observed in control sera, resulting in positive predictive value 75%, negative predictive value 78.5%, sensitivity 50%, specificity 92%, and area under the ROC curve 0.7083 for the risk of paraneoplastic DM in anti-TIF1γ/α (+) patients. Myositis-specific autoantibodies can be identified thanks to the use of immunoprecipitation, and their association with cancer is particularly clear for anti-TIF1γ/α in dermatomyositis. This association should be evaluated in a prospective study by immunoprecipitation in clinical practice.

悪性腫瘍随伴皮膚筋炎を伴った胸腺癌の1例

背景．胸腺癌は悪性腫瘍関連皮膚筋炎の原因となり得る．症例．73歳，女性．皮膚筋炎を急速に発症し，ステロイド治療を開始された．症状が安定しないため悪性腫瘍合併を疑った．精査時に胸部CTにて前縦隔に長径42 mmの分葉状の結節および縦隔，鎖骨上窩リンパ節腫大を指摘された．診断と治療を兼ねた胸骨正中切開前縦隔腫瘍切除術，拡大胸腺摘出術，心膜・縦隔胸膜・左腕頭静脈合併切除術，リンパ節郭清術が行われた．病理組織検査ではリンパ節転移を伴う胸腺原発扁平上皮癌（pT1aN2M0，stage IVb）と診断された．皮膚筋炎症状は術後速やかに改善したが，術後4か月後に肝転移再発を認め，以後皮膚症状が再増悪した．結語．本症例の皮膚筋炎は，突然の発症，切除後の改善，再発時の再増悪のため，胸腺癌に随伴する病態と考えた．

AB0611 Recurrent Cutaneous Ulcers and Interstitial Lung Disease in Dermatomyositis with Positive Anti-P155/140 Autoantibodies: an Atypical Case

BackgroundAnti-P155/140 autoantibodies (anti-TIF1) have been reported to be associated with malignancy1; whereas melanoma differentiation-associated gene 5 (MDA5) has been identified as a DM specified autoantigen that appears to be targeted...

Comparison of radioimmunoprecipitation versus antigen-specific assays for identification of myositis-specific autoantibodies in dermatomyositis patients

Background. To confirm the antigen specificities of autoantibodies that precipitate 140-kDa (anti-p140) or 155/140-kDa polypeptides (anti-p155/140) previously identified by radioimmunoprecipitation in Korean patients with dermatomyositis (DM) and to look into the relationship between each MSA and clinical features of DM.Methods. Seventeen serum samples of classic DM patients who had been found to have either anti-p140 antibodies (n = 9) or anti-p155/140 (n = 8) antibodies in our previous study were examined using enzyme-linked immunosorbent assay (for anti-MDA5 antibodies) and immunoblotting (for anti-MJ/NXP-2 and anti-TIF-1γ antibodies).Results. Seven out of nine anti-p140 antibody positive patients were found to have anti-MDA5 antibodies. Two out of nine had anti-MJ/NXP-2 antibodies with no interstitial lung disease (ILD). All eight anti-p155/140 antibody positive patients were found to have anti-TIF-1γ antibodies. Anti-TIF-1γ and anti-MDA5 antibodies were simultaneously detected in one patient with anti-p155/140 antibody, who suffered HIV infection and non-Hodgkin's lymphoma. The associations between anti-MDA5 antibody and rapidly progressive ILD and between anti-TIF-1γ antibody and cancer-associated DM were confirmed to be significant.Conclusions. Although radioimmunoprecipitation still looks to be a good screening tool, confirmation with antigen-specific assays seems mandatory. The associations between anti-MDA5 and rapidly progressive ILD and between anti-TIF-1γ and cancer-associated DM were confirmed in Korean patients with DM.