CLINICAL ADVANCES OF ANTITIF 1 AUTOANTIBODY IN A

CLINICAL ADVANCES OF ANTI-TIF 1Γ AUTOANTIBODY IN A HUNGARIAN MYOSITIS COHORT Melinda Nagy-Vincze 1, Zoltán Griger 1, Levente Bodoki 1, Zsuzsa Szankai 1, Zoe E. Betteridge 2, Katalin Dankó 1 1 University of Debrecen, Division of Clinical Immunology, Dept. of Internal Medicine, Debrecen, Hungary 2 University of Bath, Institute for Rheumatic Diseases, Bath, UK

IDIOPATHIC INFLAMMATORY MYOPATHIES Polymyositis (PM) Dermatomyositis (DM) Juvene PM/DM Inclusion body myositis (IBM) Overlap myositis (OM) Necrotizing autoimmun myopathy (NAM): � � � Cancer associated myositis (CAM) Statin induced myopathy Infection induced myopathy

IDIOPATHIC INFLAMMATORY MYOPATHIES SYMPTOMS Gottron’s sign and papule –SKIN

IDIOPATHIC INFLAMMATORY MYOPATHIES –SKIN SYMPTOMS Heliotrop rash Linear extensor erythema Periungual teleangiectasia

IDIOPATHIC INFLAMMATORY MYOPATHIES –SKIN SYMPTOMS V-sign Facial erythema Shawl sign Periorbital oedema

IDIOPATHIC INFLAMMATORY MYOPATHIES –SKIN SYMPTOMS Calcinosis cutis Alopecia Poikiloderma athrophicans vasculare Livedo reticularis

CAM (CANCER ASSOCIATED MYOSITIS) Frequency 7 -66% Relative risk for malignancy � 3 x in DM � 1, 3 x in PM-ben Tumor types: ovarium, breast, lung, colon, endometrium, nasopharyngeal, lymphoma, prostata) In time: � Before myositis symptoms (> 1 years) � Real paraneoplasia (- 1 – +5 years) � After myositis diagnosis (> 5 years) – role of immunosuppressive therapy? R. Aggarwal, C. V. Oddis Paraneoplastic myalgias and myositis Rheum Dis Clin N Am 2011

CAM - ETIOLOGY Paraneoplasia Cytotoxic/immunesuppressive treatment (Methotrexat, cyclophosphamid) Common trigger (EBV? )

CROSSOVER IMMUNITY IN CAM Cellular Immune response CD 8+ T Ly CD 4+ T Ly B Ly ? MSA MSA D e ag am Cross reactions Stuart M. Levine Curr Opin Rheumatol 2006, 18: 620 -624 MSA

Anti-TIF 1γ o antigen: transcription intermedier factor 1 gamma • 155/140 k. Da protein o 13– 21% in adult and 23– 29% in juvenile DM cases o severe skin symptoms, o high tumor risk in adults

OUR STUDY Autoantibody analysis from IIM patients’ serum (n=202) with ELISA and/or IPP Frequency of anti-TIF 1γ positivity Frequency of TIF 1γ negative CAM Clinical and lab findings associated with anti-TIF 1γ positivity

PARAMETERS Clinical symptoms � Proximal muscle weakness � Distal muscle weakness � Skin rash � Dysphagia � Raynaud phenomen � Arthralgia � ILD � Fever o Lab results: • CK and LDH levels • CRP • ESR • ANF positivity • Tumor markers

TIF 1Γ POSITIVE PATIENTS (N=12) CAM n=3 Real paraneoplasia in DM (n=1) After myositis diagnosis in DM (n=1) and in PM (n=1) Subsets: � DM n=7 � JDM n=4 � PM n=1 Gender: � Female 75% (n= 9) � Male 25 % (n=3)

TIF 1Γ POSITIVE CAM PATIENT – REAL PARANEOPLASIA 34 years old, women First symptoms in April 2007: � Skin rash � Muscle weakness � Dysphagia � Arthralgia In July 2007 – ovarium tumor Histology: adenocarcinoma with peritoneal metastasis Operation and chemotherapy She died in November 2007 due to heart failure

TIF 1Γ NEGATIVE CAM PATIENTS (N=51) Subsets: � DM(n=33) � PM (n=18) Gender: � Female 68% (n= 35) � Male 32 % (n=16) In time: � real paraneoplasia (n=37) - 5 months � before myositis (n=2) - 73, 5 months � After diagnosis (n=12) – 181 months

TIF 1Γ NEGATIVE CAM (N=51) 1 1 2 1 1 3 1 15 2 2 1 6 9 6 breast lung gynecology colon brain skin epipharinx gastric hemat urinary salivary glands pancreas penis prostata

HISTOLOGY 1 adenocc. 3 1 duct. 2 planocellulare 1 lobular invasive 1 1 21 microcellulare melanoma kaposi sc. 4 B-cell lymphoma T-cell lymphoma ependymoma 14 mucoepidermal cc. unknown

ve r 55 Fe rit is e as se 12 rth /a lg ia ra 25 di 37 33 th g a ud na ay R 45 Ar un ia ll tit rs te ag i 37 In ph ys v. in d 10 D rt ea 25 20 H 16 ha n a si ta 25 ni c's ha 50 ec 70 ec gn si V- 33 an gi te le 75 M al ng u ra sh gn si 80 riu 's 40 tro p io el H le 83 on ot tr 60 G 30 pa pu s es kn s 20 's on ot tr ea w ea kn es w 90 G cl e us m e cl m us 100 Pe lis ta is D al is im ox DIFFERENCES IN CLINICAL SYMPTOMS (%) 100 83 75 67 55 50 42 24 TIF 1 y negative 17 14 TIF 1 y positive 6 0 4 0 8

LAB FINDINGS 100 90 80 (%) 90 86 75 75 71 71 75 65 70 55 60 50 50 50 TIF 1 y negative 42 40 TIF 1 y positive 30 20 10 0 CK LHD GOT GPT CRP We o No differences in tumor markers o No differences in other antibodies (ANF, APA)

CONCLUSION TIF 1γ positivity is associated with several and severe skin rashes Tumor specificity did not confirmed Autoantibody tests help us in the diagnosis But tumor searching is necessary, specially in DM

THANKS TO MY COLLEGUES Prof. Dr. Dankó Katalin, Dr. Griger Zoltán, Dr. Bodoki Levente, Szankai Zsuzsa, Zoe E. Betteridge This research was organized within the following program: TÁMOP 4. 2. 4. A/2 -11 -1 -2012 -0001 National Excellence Program—local convergence program providing personnel support in the development and operation for students and researchers. The project was funded by the EU and the European Social Fund. The autoantibody analysis was sponsored by the ESF Eu. Myo. Net Research Networking Programme.

THANKS FOR THE ATTENTION!