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Karsten Conrad, Werner Schler, Falk Hiepe, Marvin J. Fritzler

Autoantibodies in SystemicAutoimmune Diseases

PABST

AUTOANTIGENS, AUTOANTIBODIES, AUTOIMMUNITYVolume 2, second Edition 2007

Autoantibodies are a very heterogeneous group of antibodies withrespect to their specificity, induction, effects, and clinical signifi-cance. Testing for autoantibodies can be helpful or necessary for thediagnosis, differential diagnosis, prognostication, or monitoring ofautoimmune diseases. In case of limited (forme fruste) disease or a

single disease manifestation, the detection of serum autoantibodies can play animportant role in raising the suspicion of evolving disease and forecasting prog-nosis. This book and reference guide is intended to assist the physician in under-standing and interpreting the variety of autoantibodies that are being used asdiagnostic and prognostic tools for patients with systemic rheumatic diseases.Autoantibodies observed in systemic autoimmune diseases are described inalphabetical order in Part 1 of this reference guide. In Part 2, systemic autoim-mune disorders as well as symptoms that indicate the possible presence of anautoimmune disease are listed. Systemic manifestations of organ-specific autoim-mune diseases will not be covered in this volume. Guide marks were inserted toensure fast and easy cross-reference between symptoms, a given autoimmunedisease and associated autoantibodies. Although the landscape of autoantibodytesting continues to change, this information will be a useful and valuable refer-ence for many years to come.

ISBN 978-3-89967-420-0www.pabst-publishers.com

A Diagnostic Reference

2nd edition

umschlag_neutral.qxd 03.10.2007 10:53 Seite 1

Autoantibodies in Systemic Autoimmune DiseasesA Diagnostic Reference

Karsten Conrad, Werner Schler, Falk Hiepe, Marvin J. Fritzler

Gesellschaft zur Frderung der Immundiagnostik e.V.Dresden

http://www.GFID-eV.de

AUTOANTIGENS, AUTOANTIBODIES, AUTOIMMUNITY

Edited by: K. Conrad (Dresden, Germany)U. Sack (Leipzig, Germany)Vol. 2, second Edition 2007

Authors

Dr. Karsten ConradInstitute for ImmunologyMedical Faculty of the Technical University DresdenFetscherstrasse 7401307 Dresden, GERMANYPhone: +49 (0) 351-458-6540Fax: +49 (0) 351-458-6308E-mail: K Conrad@mail.zih.tu-dresden.de

Dr. Werner SchlerRathenaustr. 1216341 Panketal, GERMANYFax: +49 (0) 30-983-119-94E-mail: Dr.Schoessler@arcor.de

Prof. Dr. Falk HiepeCharite University HospitalDepartment of Rheumatology & Clinical ImmunologySchumannstrae 20/2110117 Berlin, GERMANYPhone: +49 (0) 30-450-513012Fax: +49 (0) 30-450-51392E-mail: Falk.Hiepe@charite.de

Marvin J. Fritzler, MD, PhDProfessor of MedicineArthritis Society ChairFaculty of MedicineUniversity of CalgaryCalgary, Alberta, CANADAPhone: +01 403-220-3533Fax: +01 403-283-5666E-mail: Fritzler@ucalgary.ca

Contents

Preface, 2nd edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XVPreface, 1st edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XVI

Notes for the Use of this Book . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Autoantibodies Denitions and Characteristics . . . . . . . . . . . . . 3

Autoantibodies in the Diagnosis of Autoimmune Diseases . . . . . . . . 4

Part 1Autoantibodies in Systemic Autoimmune Diseases

Alanyl-tRNA (tRNAAla) Synthetase Antibodies . . . . . . . . . . . . . . 10Alpha-Actinin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 10Alpha-Enolase Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 10Alpha-Fodrin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 12Aminoacyl-tRNA Synthetase Antibodies . . . . . . . . . . . . . . . . . 13Annexin V Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Antineutrophil Cytoplasmic Antibodies (ANCA) . . . . . . . . . . . . . 16Antinuclear Antibodies (ANA) . . . . . . . . . . . . . . . . . . . . . . . 19ASE-1Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Asparaginyl-tRNA (tRNAAsp) Synthetase Antibodies . . . . . . . . . . . 21Assemblyosome Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 22Azurocidin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Beta-Fodrin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Beta-2 Glycoprotein I (2-GPI) Antibodies . . . . . . . . . . . . . . . . 24BPI Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27C1D Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28C1q Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28CADM-140 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Calpastatin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Calreticulin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32cANCA (C-ANCA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

VI C

Cardiolipin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Cathepsin G Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 37CCP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38CD16 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39CENP-B Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40CENP-C Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40CENP-E Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41CENP-F Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42Centriole Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Centromere Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Centrophilin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 47Centrosome Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 47Chromatin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49Chromo Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Citrullinated Protein/Peptide Antibodies . . . . . . . . . . . . . . . . . . 51Coilin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Collagen Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54CRP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56Cryoglobulins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56Cytoplasmic Linker Protein 170 (CLIP-170) Antibodies . . . . . . . . . 57DEK Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58Double-Stranded DNA (dsDNA) Antibodies . . . . . . . . . . . . . . . 59EEA-1Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62EF1A Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63EJ Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64Elastase Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64ENA Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64Endothelial Cell Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 65EPCR Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Exosome Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Fer Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Ferritin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Fibrillarin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68Fibrillin 1Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69Fibroblast Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70Filaggrin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70Glutaminyl-tRNA (tRNAGlu) Synthetase Antibodies . . . . . . . . . . . 71Glycyl-tRNA (tRNAGly) Synthetase Antibodies . . . . . . . . . . . . . . 71GM1Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72Golgi Apparatus Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 72Gu Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74GWB Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

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Heat Shock Protein (Hsp) Antibodies . . . . . . . . . . . . . . . . . . . 76Histidyl-tRNA (tRNAHis) Synthetase (HRS) Antibodies . . . . . . . . . 77Histone Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77HMG Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79HsEg5 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805-HT4 Receptor Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 80Human Neutrophil Elastase (HNE) Antibodies . . . . . . . . . . . . . . 80IFI 16 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81IgA Autoantibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Isoleucyl-tRNA (tRNAIle) Synthetase Antibodies . . . . . . . . . . . . . 83Ja Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83Jo-1Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83Keratin Antibodies (AKA) . . . . . . . . . . . . . . . . . . . . . . . . . . 85Ki Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86Kinectin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87KJ Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87KS Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88Ku Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88L5/5S Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90L7 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91L12 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Lactoferrin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Lamin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92La/SS-B Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92LE Cell Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95LEDGF (Lens Epithelial Derived Growth Factor) Antibodies . . . . . . 96Leucyl-tRNA (tRNALeu) Synthetase Antibodies . . . . . . . . . . . . . . 97Lipoprotein Lipase (LPL) Antibodies . . . . . . . . . . . . . . . . . . . . 97Lupus Anticoagulant (LA) . . . . . . . . . . . . . . . . . . . . . . . . . . 98Lysosome Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100Lysozyme Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101Lysyl-tRNA (tRNALys) Synthetase Antibodies . . . . . . . . . . . . . . . 101M3mAchR (M3R) Antibodies . . . . . . . . . . . . . . . . . . . . . . . . 101Mas Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101MBL Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102MCV Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102Mi-2 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103Midbody Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105MMP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107Mpp1Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107Mpp10 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108MSA Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

VIII C

Myeloperoxidase Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 110Myosin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113Nedd5 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113NMDA Receptor Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 114NOR-90 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115Nucleolar Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117Nucleolin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118Nucleophosmin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 119Nucleosome Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 120NuMA Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122OJ Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124oxLDL Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124pANCA (P-ANCA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126PCNA Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128PDGF Receptor (PDGFR) Antibodies . . . . . . . . . . . . . . . . . . . 129Perinuclear Factors (PNF) . . . . . . . . . . . . . . . . . . . . . . . . . . 130Phosphatidic Acid (PA) Antibodies . . . . . . . . . . . . . . . . . . . . . 130Phosphatidylcholine (PC) Antibodies . . . . . . . . . . . . . . . . . . . . 131Phosphatidylethanolamine (PE) Antibodies . . . . . . . . . . . . . . . . 132Phosphatidylinositol (PI) Antibodies . . . . . . . . . . . . . . . . . . . . 133Phosphatidylserine (PS) Antibodies . . . . . . . . . . . . . . . . . . . . . 134Phospholipid (PL) Antibodies . . . . . . . . . . . . . . . . . . . . . . . . 135PL-7 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139PL-12 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140PM-1Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141PMS1Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142PM/Scl Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142PM/Scl-75 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145PM/Scl-100 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145Poly (ADP-Ribose) Polymerase (PARP) Antibodies . . . . . . . . . . . . 145Proteasome Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146Proteinase 3 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147Protein C Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149Protein S Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Prothrombin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 151RA33 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152Replication Protein A (RPA) Antibodies . . . . . . . . . . . . . . . . . . 155Rheumatoid Factors (RF) . . . . . . . . . . . . . . . . . . . . . . . . . . 156Ribosomal Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157Ribosomal P Protein (RPP) Antibodies . . . . . . . . . . . . . . . . . . . 159Ribosomal RNA Processing (Rrp) Protein Antibodies . . . . . . . . . . 161RNA Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

C IX

RNA Helicase II Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 163RNA Helicase A (RHA) Antibodies . . . . . . . . . . . . . . . . . . . . . 163RNAP-I Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164RNAP-II Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164RNAP-III Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164RNA Polymerase (RNAP) Antibodies . . . . . . . . . . . . . . . . . . . . 164Ro52 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166Ro60 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167Ro/SS-A Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16728S rRNA Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172S10 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172Sa Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172SAP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173SC Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173Scl-70 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173Single-Stranded DNA (ssDNA) Antibodies . . . . . . . . . . . . . . . . 176Sip1Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177Sm Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177snoRNP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179snRNP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179SR Protein Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182SRP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182SS-56 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184SS-A Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185SS-B Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185ssDNA Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185Threonyl-tRNA (tRNAThr) Synthetase Antibodies . . . . . . . . . . . . 185Th/To Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185Thrombomodulin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . 186Topoisomerase I Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 187Topoisomerase II Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 187Trimethylguanosine Antibodies . . . . . . . . . . . . . . . . . . . . . . . 188U1-RNP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188U2-RNP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189U4/U6-RNP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 189U5-RNP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190U7-RNP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190U11-RNP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

X C

Part 2Systemic Autoimmune Diseases Syndromes, Diagnostic Criteria,Symptoms

Abortion, spontaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192Acidosis, renal-tubular . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192Acro-Osteolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192Addisons disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192Adrenocortical failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192Aldolase, elevated in plasma . . . . . . . . . . . . . . . . . . . . . . . . . 192Alopecia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192Alveolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193Amaurosis fugax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193ANCA-associated vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . 193Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193Anti-Jo-1 syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194Antiphospholipid syndrome (APS) . . . . . . . . . . . . . . . . . . . . . 194Anti-SRP syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197Anti-Synthetase syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 197Arthralgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198Behcet disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199Bronchial asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199Budd-Chiari syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 200Buttery rash . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200Calcinosis cutis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

CatastrophicAPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201Cavernous sinus thrombosis . . . . . . . . . . . . . . . . . . . . . . . . 202Cerebral infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202Cerebral ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202Chorea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202Churg-Strauss syndrome (CSS) . . . . . . . . . . . . . . . . . . . . . . . 203Claudication of extremities . . . . . . . . . . . . . . . . . . . . . . . . . 203Claudication of masticatory muscles . . . . . . . . . . . . . . . . . . . . 204Cogans syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204Congenital heart block . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204Conjunctivitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204Connective tissue diseases . . . . . . . . . . . . . . . . . . . . . . . . . . 205Creatine kinase, elevated in plasma . . . . . . . . . . . . . . . . . . . . . 205CREST syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205Cryoglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206Cryoglobulinemic nephropathy . . . . . . . . . . . . . . . . . . . . . . . 206

C XI

Cryoglobulinemic purpura . . . . . . . . . . . . . . . . . . . . . . . . . 206Cryoglobulinemic vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . 206Cutaneous leukocytoclastic vasculitis . . . . . . . . . . . . . . . . . . . . 207Dementia, multi-infarct . . . . . . . . . . . . . . . . . . . . . . . . . . . 207Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207Dermatomyositis, amyopathic . . . . . . . . . . . . . . . . . . . . . . . . 208Discoid lupus erythematosus (DLE) . . . . . . . . . . . . . . . . . . . . 208Drug-induced lupus (DIL) . . . . . . . . . . . . . . . . . . . . . . . . . . 209Eosinophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210Episcleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210Erythema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210Esophageal dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . 210Evans syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211Facial Paresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211Feltys syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211Fingertip necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212Giant cell arteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212Glomerulonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212Glomerulosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213Goodpastures disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213Gottrons sign . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213Guillain-Barre syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 213Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213Hemianopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214Hemorrhagic alveolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214Henoch-Schnlein purpura . . . . . . . . . . . . . . . . . . . . . . . . . 214Hepatic infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215Hepatomegaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215Hortons disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215Hypereosinophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215Hypergammaglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . 216Hypersensitivity vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . 216Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216Hypocomplementemic urticarial vasculitis syndrome (HUVS) . . . . . 217IgA nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218Intestinal necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218Intracardiac thrombus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218Juvenile chronic arthritis (JCA) . . . . . . . . . . . . . . . . . . . . . . . 218Juvenile idiopathic arthritis (JIA) . . . . . . . . . . . . . . . . . . . . . . 222Juvenile rheumatoid arthritis (JRA) . . . . . . . . . . . . . . . . . . . . 222Juvenile scleromyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

XII C

Kawasaki syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222Leukocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Leukocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Libman-Sacks endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . 224Lilac rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224Livedo reticularis/racemosa . . . . . . . . . . . . . . . . . . . . . . . . . 224Lymphadenopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224Lymphocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Malabsorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Mechanics hands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Membranous nephritis/nephropathy (MN) . . . . . . . . . . . . . . . . 225Meningitis, aseptic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226Mesenteric infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226Microscopic polyangiitis (MPA) . . . . . . . . . . . . . . . . . . . . . . . 226Microstomia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226Migraine, atypical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Mixed connective tissue disease (MCTD) . . . . . . . . . . . . . . . . . 227Moschkowitzs syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 229Mucocutaneous lymph node syndrome . . . . . . . . . . . . . . . . . . 230Muscle weakness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230Muscular atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230Myalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230Myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Myoglobin, elevated in plasma . . . . . . . . . . . . . . . . . . . . . . . 231Myositis, idiopathic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Myositis overlap syndromes . . . . . . . . . . . . . . . . . . . . . . . . . 231Neonatal lupus erythematosus (NLE) . . . . . . . . . . . . . . . . . . . 231Neonatal lupus syndromes . . . . . . . . . . . . . . . . . . . . . . . . . 232Nephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Organic brain syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Otitis externa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Otitis media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Overlap syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234Pancreatic infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234Panniculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234Parotitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234Pericardial eusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234Pericarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Peritonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Photosensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

C XIII

Pleuritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Polyarteritis nodosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236Polymyalgia rheumatica (PMR) . . . . . . . . . . . . . . . . . . . . . . 237Polymyositis (PM)/Dermatomyositis (DM) . . . . . . . . . . . . . . . . 237Polymyositis/scleroderma overlap . . . . . . . . . . . . . . . . . . . . . 239Polyneuritis, cranial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240Primary Sjgrens syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 240Proteinuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240Pseudocaverns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240Ptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241Pulmonary brosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241Pulmonary hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . 241Pulmonary arterial hypertension (PAH) . . . . . . . . . . . . . . . . . . 241Pulmonary inltrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242Pulselessness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242Purpura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242Raynauds phenomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . 242Relapsing polychondritis . . . . . . . . . . . . . . . . . . . . . . . . . . 243Retinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243Retinal ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244Rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244Rheumatoid nodules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Rhupus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Saddle nose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Scleritis/Episcleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Sclerodactyly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Scleroderma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Scleroderma/myositis overlap . . . . . . . . . . . . . . . . . . . . . . . . 247Scleroderma spectrum disorder . . . . . . . . . . . . . . . . . . . . . . 247Sclerosis sine scleroderma . . . . . . . . . . . . . . . . . . . . . . . . . . 247Secondary Sjgrens syndrome . . . . . . . . . . . . . . . . . . . . . . . 248Sensorineural hearing loss . . . . . . . . . . . . . . . . . . . . . . . . . . 248Sharp syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248Sinus vein thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248Sinusitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248Sjgrens syndrome (SjS) . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Sneddons syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252Spinal infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252Splenomegaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252Stills disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

XIV C

Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253Subacute cutaneous lupus erythematosus (SCLE) . . . . . . . . . . . . 253Systemic lupus erythematosus (SLE) . . . . . . . . . . . . . . . . . . . . 253Systemic sclerosis (SSc) . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Systemic vasculitides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257Takayasu arteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258Teleangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Temporal arteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Thrombocytopenic thrombotic purpura (TTP) . . . . . . . . . . . . . 260Thrombocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260Tolosa-Hunt syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 260Transitory ischemic attacks (TIA) . . . . . . . . . . . . . . . . . . . . . . 260Transverse myelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261Undierentiated connective tissue disease (UCTD) . . . . . . . . . . . 261Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262Valvular heart disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262Vertigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262Wegeners granulomatosis (WG) . . . . . . . . . . . . . . . . . . . . . . 263Xerostomia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265

Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

Preface, 2nd edition

The determination of autoantibodies has become an integral part of the diagnosisand dierential diagnosis, as well as the estimation of the prognosis and devel-opment of autoimmune diseases. Furthermore, because many disease-associatedautoantibodies are detectable in preclinical stages, they have assumed a potentialrole in the very early diagnosis or risk assessment of disease development. Thegrowing knowledge about the pathogenic and diagnostic value of autoantibodiesin systemic diseases, and the discovery of novel autoantibodies and changes inclassication criteria necessitated the publishing of a revised and supplemented2nd edition. Besides the clinically relevant autoantibodies also antibodies that mayserve as tools in molecular, cell and tumor biological studies have been included.However due to the rapid development, the alphabetical catalogue of relevant orpotential relevant autoantibodies is incomplete. Therefore, the authors appreciatehelpful comments for future editions.

Karsten ConradMarvin J. FritzlerFalk HiepeWerner Schler

Preface, 1st edition

Among the challenges facing the new millennium physician are tremendouschanges in biomedical and information technologies that are rapidly changing thenature and complexity of clinical practice. Since the discovery of the LE cell over50 years ago, there has been a logarithmic increase in the description and clinicalapplication of autoantibodies in an ever-widening spectrum of diseases. Systemicrheumatic diseases are among the most complex of these diseases because theclinical presentation and constellation of ndings are in part reected by thespectrum of autoantibodies found in these conditions. The litany of autoantibodyacronyms, designations and descriptors include Sm, dsDNA, SS-A/Ro, SS-B/La,U1RNP, Jo-1, topo-I, CENP, Ku, Ki, Sa, and ribo P, to name a few. This

antibodyalphabet soup has threatened to move clinical diagnostics into a literal Tower ofBabel.

It is important to appreciate how the

antibody alphabet soup can be useful inthe diagnosis and management of systemic rheumatic diseases. The applicationsare as varied and rich as are the multiplicity of the autoantibody specicities. Cer-tainly, autoantibody testing is not required to make a diagnosis in a woman whopresents with a photosensitive skin rash, pericarditis, glomerulonephritis, anemiaand psychosis. This patient clearly has SLE and the detection of autoantibodiesconrms the obvious.What may not be as clear is that the presence of anti-dsDNAcould correlate with nephritis and the presence of anti-ribo P may indicate mani-festations of central nervous system lupus in the presence of confounding factorssuch as infections and drug use. In addition, not all patients present with classical

textbook features of systemic rheumatic diseases. Unfortunately, in many casesthe time interval from the onset of symptoms to a conrmed diagnosis and meet-ing established criteria for the classication of disease, can be measured in decades.Thus,when there is limited (forme fruste) disease or a single disease manifestation,the detection of serum autoantibodies can play an important role in raising thesuspicion of evolving disease and forecasting prognosis. A good example is theuse of autoantibodies in the initial evaluation of Raynauds phenomenon. If theANA and other autoantibody tests are negative, the likelihood that his patient hasprimary Raynauds disease is likely and the concern that the clinical course willtransform into systemic rheumatic disease is lessened. On the other hand, ample

P, 1 XVII

clinical studies have shown that the presence of anti-topo-I (Scl-70) is a harbingerof diuse scleroderma, antibodies to CENP are more predictive of the limitedform of the disease, and the presence of anti-PM/Scl, indicates a scleroderma-polymyositis overlap syndrome. There many other examples of the clinical utilityof autoantibody testing in isolated clinical scenarios such as polyarthritis, myosi-tis, neuropathies, cytopenias, and vasculopathies that are characteristic, but notspecic for, any single systemic rheumatic disease. In many of these instances thepresence of one or more

alphabet soup antibodies can be a prologue to diseasesthat are likely to evolve during patient follow-up.

While the diagnosis of forme fruste disease is an important use of autoantibodytesting,another valuable use is that they provide an understanding of the pathogen-esis. This has been clearly illustrated with the subsets of disease such as neonatallupus syndrome, subacute cutaneous lupus, homozygous C2 deciency, interstitiallung disease, granulocytopenia, and Sjgrens syndrome that are strongly associ-ated with anti-SS-A/Ro.Compelling evidence shows that anti-SS-A/Ro binds withthe cognate antigen in the fetal heart and in keratinocytes exposed to ultravioletlight. On the other hand, it is not clear how or if the same antibody participatesin the development of keratoconjunctivitis sicca. The demonstration that riboso-mal P proteins and other autoantigens are found on the surface of some normaland apoptotic cells may provide an important clue to their potential pathogenicrole. The notion that some autoantibodies may be ngerprints incriminating acause or etiology of the disease are also being claried. For example, antibodiesto brillarin (U3-RNP) are induced in certain strains of mice by heavy metal ex-posure and systemic sclerosis patients with these autoantibodies have high levelsof urinary mercury.

The future of autoantibody testing can be cast into at least four arenas. First,the rapid advancement of new technologies (autoantigen arrays,microuidics andnanotechnology) will change the complexion of the autoantibody testing by pro-viding a wealth of serological information that will almost certainly challengecurrent paradigms and clinical associations. It is now possible to use a drop ofblood to analyze serum for the presence of over 100 dierent autoantibodies in asingle test that can be completed and reported within minutes. Second, it is antici-pated that autoantibody testing will be a critical part of monitoring and evaluatingpatients placed on a variety of the newer biological therapeutics. For example, it isincreasingly clear that interferon and tumor necrosis factor blockade therapies areassociated with the induction of autoantibodies and, in some cases, full blown dis-ease. Interestingly, these observations fall on the historical evidence that drugs suchas procainamide and hydralazine can induce autoantibodies and lupus syndromes.Third, it is likely that autoantibody testing will replace more invasive and costlydiagnostic techniques such as the salivary gland biopsy for Sjgrens syndrome,the small bowel biopsy for coeliac disease, the nerve and skin biopsy for vasculi-tis, the muscle biopsy for myositis, and many others. Fourth, carefully designed

XVIII P, 1

studies that assess the cost eectiveness of autoantibody testing are required. Onone hand, there is the notion that in many patients, including the woman withunequivocal features of SLE described above, that even the relatively inexpensiveautoantibody test is superuous and not cost eective. However, the implicationsof longer term health care costs of missing an early diagnosis in a patient withforme fruste disease must also be carefully considered. A cost-eective and ratio-nal approach to autoantibody testing algorithms and clinical practice guidelinesare overdue.Clinical studies to address these issues will prove worthwhile and savepatients from needless, expensive and invasive tests, and missed diagnosis that canlead to signicant morbidity and mortality.

This book and reference guide is intended to assist the physician understandand interpret the variety of autoantibodies that are being used as diagnostic andprognostic tools for patients with systemic rheumatic diseases.Although the land-scape of autoantibody testing continues to change, this information will be a usefuland valuable reference for many years to come.

Marvin J. Fritzler

Notes for the Use of this Book

This reference book on the serological diagnosis of systemic autoimmune diseasesis divided into two main sections. The autoantibodies observed in autoimmunediseases are described in alphabetical order in Part 1, and autoimmune disordersas well as symptoms that indicate the possible presence of an autoimmune diseaseare listed in Part 2. Guide marks (the symbol ) were inserted to ensure fastand easy cross-reference between symptoms, a given autoimmune disease andassociated autoantibodies. Bibliographic references were omitted due to the broadscope of the subject matter. Only the rst authors of historical or some importantrecent publications have been named.

With some exceptions (e.g., antinuclear antibodies) the prex

anti-was omit-ted for better clarity of alphabetization. Anticentromere antibodies, for example,are listed as

centromere antibodies. In as far as they were known to the authors,synonyms or alternative names for the antibodies were also listed. Obsolete termi-nology is indicated as such, and the names preferred by the authors are used inthe alphabetical index.

The autoantibody description section begins, in some cases, with a brief in-troduction or historical account. This is followed by information on the targetstructures (autoantigens), detection methods, clinical relevance, and indicationsfor testing of the autoantibody.

The authors rating of the clinical relevance of each autoantibody listed in thebook is indicated using variable coloring and lettering.

White Letters onGreen Background

These are autoantibodies of high diagnostic relevance (markers for diagnosis,prognosis or monitoring) that can usually be determined in all laboratories.

2 I

Black Letters onMedium Green Background

These are diagnostically relevant autoantibodies that are not measurable in alllaboratories and therefore are determined in specialized laboratories only.

Black Letters onLight Green Background

The clinical relevance of these antibodies is (still) unclear due to their verylow frequency of detection, discrepancies between the ndings of dierent studies(lack of comparability due to dierences in study design, methodology, ethnic dif-ferences, etc.), methodological problems, or preliminary nature of study ndings.

Black Letters onWhite Background

These autoantibodies are currently not clinically relevant, are no longer clini-cally relevant, or are clinically relevant only in isolated cases. This can also includedisease-specic autoantibodies if their testing does not provide any added diag-nostic advantages over other parameters.

Part 1

Autoantibodies in SystemicAutoimmune Diseases

GWB A 75

GWB Antibodies

Synonym:Anti-GW bodies also referred to as mammalian processing (P) bodies.

Autoantigens

GWB autoantigens include a group of 3 GW proteins referred to as GW182, GW2and GW3 as well as other components such asAgo2, Ge-1/Hedls and RAP55.Theyare localized to discrete cytoplasmic structures that are involved in mRNA process-ing. The GW antigens were so-named because they contain numerous glycine (G)and tryptophan (W) repeats and have a calculated molecular mass of 182 kDa)and they bind to mRNA as well as Ago2, and are key components of the RNA in-terference silencing complex (RISC) (reviewed in Jakymiw et al., 2007). The mostcommon target antigen of GWB antibodies is Ge-1/Hedls followed by GW182(Bhanji et al., 2007).

Detection Methods

IIF using monolayers of tissue culture or tumor cells, e.g., HEp-2 cells (Fig.12).

1

2

Figure 12. IIF pattern on HEp-2 cells (Immuno Concepts Ltd, Sacramento, USA) of ananti-GWB antibody positive serum: distinctive cytoplasmic dots varying in number fromzero in mitotic cells (1) to more than 30 in interphase cells (2).

76 A S A D

N: The frequency of detection of anti-GWB depends on the cell line andtissue that is used for the assay because GWB are most highly expressed inrapidly proliferating cells and in testis and a subset of neural cells. In addition,anti-GWB may be obscured by high titer anti-cytoplasmic antigens such asanti-mitochondrial antibodies.

IIF using monoclonal anti-GW182 for co-localization IB using whole cell extracts or puried GWB fractions. EIA or ALBIA using recombinant GW,Ago2, Ge-1/Hedls and RAP55 proteins. IP of recombinant protein produced by in vitro transcription and translation

of cDNA of respective antigens.

Clinical Relevance

Moderate to high titers of anti-GWB are found in 0.4 % of routine screen-ing using HEp-2 cells (Stinton et al., 2004). They are primarily associated with Sjgrens syndrome, ataxia and other neuropathies, systemic lupus erythe-matosus (SLE), primary biliary cirrhosis (Bloch et al., 2005) and also found inother systemic autoimmune rheumatic diseases.

A systematic study of cohorts of various autoimmune diseases is needed nowthat rapid and sensitive array technology (e.g. ALBIA) is available.

It is important to note that the detection of anti-GWB may be masked by otherautoantibodies (i. e. antimitochondrial antibodies in primary biliary cirrhosis)or overlooked in the presence of strong ANA.

Indications

None currently established.

Comments: If the typical cytoplasmic discrete speckled pattern is found duringscreening with HEp-2 cells, serological follow-up to rule out reactivity with othercytoplasmic antigens that give a similar pattern (i. e. EEA-1, lysosome) is required.This can be partly accomplished by co-localization studies. However, it shouldbe noted that GWB are quite heterogeneous with respect to content of any oneof the components. Thus, analyses of autoantibodies with multiplexed array tech-nologies are preferred once the distinctive staining pattern is identied. At theclinical interface, examinations should be performed, e.g., to detect the potentialdevelopment of connective tissue disease (Sjgrens syndrome) and neurologicalconditions such as ataxia and sensory/motor neuropathies. Cooperation with aresearch laboratory can be useful, e.g., for determination of the specicity andfurther evaluation of the potential clinical relevance of these antibodies.

H-RNA (RNAH) S (HRS) A 77

Heat Shock Protein (Hsp) Antibodies

Collective term for all autoantibodies directed against heat shock proteins/heatstress proteins (Hsp).

Autoantigens

Various heat shock proteins (heat-stress-induced proteins) like Hsp60, Hsp70 andHsp90.

Detection Methods

WB using cell extracts after one- or two-dimensional separation. EIA using biochemically puried or recombinant heat shock proteins.

Clinical Relevance

Hsp antibodies occur in a number of autoimmune and non-autoimmune diseases(especially infections) as well as in healthy individuals.

Indications

None related to systemic autoimmune diseases. The use of Hsp antibodies fordiagnosis of arteriosclerosis and autoimmune diseases of the inner ear is beingevaluated.

Histidyl-tRNA (tRNAHis)Synthetase (HRS) Antibodies

See Jo-1 antibodies, Aminoacyl-tRNA synthetase antibodies.

Histone Antibodies

Synonym: Anti-histone antibodies (AHA).

78 A S A D

History: Histone antibodies appear to be involved in the LE cell phenomenon thatwas rst described in1948.H2A-H2B antibodies and,more recently,H1antibodieshave been implicated in this phenomenon, which was an important milestone inthe discovery of autoantibodies associated with SLE ( LE cell factor).

Autoantigens

Histones can be found in almost all eukaryotic cell nuclei. The histone familycontains the following ve basic proteins: H1 (26.5 kDa), H2A (14 kDa), H2B(13.8 kDa), H3 (15.3 kDa) and H4 (10.2 kDa). Histones form complexes withdouble-stranded DNA, called nucleosomes. The DNA thereby wraps arounddimeric H2A-H2B and H3-H4, while H1 binds to DNA on the surface of thenucleosome. The bead-like nucleosomes help bundle the DNA into a morecompact chromatin structure.All histones and histone complexes can be targetedby autoantibodies.

Detection Methods

IIF using HEp-2 cells: Chromatin can be visualized like the pattern producedby dsDNA antibodies (homogeneous staining of interphase nuclei and of thechromatin region in mitotic cells).N: A negative immunouorescence does not exclude the presence of AHA.

EIA, ALBIA and LIA using isolated histones or histone mixtures. RIA using isolated histones or histone mixtures. WB.

Comments: The conformational epitopes may be altered or destroyed due to solidphase binding (EIA) and/or the use of SDS-polyacrylamide gel electrophoresis(WB).

Clinical Relevance

With the possible exception of anti-H1,AHA are not specic for any one disease,but can be detected in a number of autoimmune diseases, especially rheumaticdisorders: Systemic lupus erythematosus (SLE; 5080 %), drug-inducedlupus (DIL; 9295 %), rheumatoid arthritis (RA; up to 11%), RA vasculitis(up to 75 %), Feltys syndrome (up to 79 %), juvenile idiopathic arthritis(JIA; up to 51%), systemic sclerosis (SSc; up to 30 %),ANA positive undieren-tiated connective tissue diseases (up to 90 %), primary biliary cirrhosis (up to55 %), autoimmune hepatitis (up to 35 %). Furthermore,AHA are detectable inpatients with neoplastic diseases, subacute sensoric neuropathies and infections.

HMG A 79

High titers of AHA are found almost exclusively in patients with SLE and DIL.The detection of high AHA titers in the absence of SLE marker antibodies ischaracteristic of drug-induced lupus.

AHA can be of the IgG, IgM or IgA isotype. IgG AHA appear to be related tothe disease activity of lupus.

In patients with SSc, AHA are associated with lung, heart and kidney involve-ment (Hesselstrand et al., 2003).A strong correlation of AHA with the numberof morphea lesions and the number of involved areas of the body have beendescribed in patients with localized sclerodema (Takehara et al., 2005).

Indications

1. Suspicion of drug-induced lupus (especially after procainamide, hydralazine,isoniazid, chlorpromazine, methyldopa, beta blockers, anticonvulsant, sul-fasalazine or captopril use).N: To establish the diagnosis of drug-induced lupus, the potential presenceof SLE marker antibodies (i. e., dsDNA and Sm antibodies) must be ruledout using the appropriate tests.Antihistone antibodies tend to disappear withinone year of discontinuing the causative drug.

2. Dierential recognition of antinuclear antibodies in sera presenting a typicalchromatin uorescence pattern.

HMG Antibodies

Autoantigens

Chromosomal high mobility group (HMG) proteins.The proteins HMG-1, -2, -14and -17 have been described as target proteins of autoantibodies involved in sys-temic autoimmune diseases. Furthermore, antigens with HMG motifs (HMG-boxproteins such as Sp100, SOX13) can be targeted by antibodies from autoimmunepatients (Fida etal., 2002).

Detection Methods

WB using cell extracts or HMG preparations. EIA using biochemically puried HMG.

Part 2

Systemic Autoimmune Diseases Syndromes, Diagnostic Criteria,Symptoms

192 S A D S, D, S

Abortion, spontaneous

Recurrent spontaneous abortions that generally occur after the 10th week of ges-tation (caused by thrombotic events in the placenta) are a characteristic sign of antiphospholipid syndrome.

Acidosis, renal-tubular

Renal manifestation of Sjgrens syndrome.

Acro-Osteolysis

Occurs as a typical feature of systemic sclerosis and is a reection of a severeacral microcirculatory disorder.

Addisons disease

May be due to thrombosis of the blood vessels of the adrenal glands as a rarecomplication (

A 193

Alopecia

Diuse (alopecia diusa) or localized alopecia (alopecia areata) may occur in cuta-neous lupus erythematosus (ANA negative!) or systemic lupus erythematosus.

Alveolitis

Interstitial lung involvement occurs in:

Systemic lupus erythematosus, Sjgrens syndrome, Polymyositis/dermatomyositis, Systemic sclerosis, Scleroderma/myositis overlap syndrome, Microscopic polyangiitis (hemorrhagic alveolitis is a feared complication!).

Typical feature of:

Anti-Jo-1 syndrome or anti-synthetase syndrome.

See also hemorrhagic alveolitis.

Amaurosis fugax

Reversible, mostly unilateral blindness due to retinal circulatory disorder. Rareophthalmologic manifestation of antiphospholipid syndrome (in 5 %). Alsosymptom of giant cell arteritis (temporal arteritis).

ANCA-associated vasculitis

Groupof primary systemic vasculitides associatedwithANCA ( cANCA/proteinase3 antibodies, pANCA/myeloperoxidase antibodies):

Wegeners granulomatosis (WG), Microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS).

194 S A D S, D, S

Anemia

Anemia may occur in all inammatory diseases and is associated with the degreeof inammatory activity. Coombs-positive autoimmune hemolytic anemia mayoccur in systemic lupus erythematosus and rarely in other connective tissuediseases. Coombs-positive hemolytic anemia occurs in about 9 % of patients with antiphospholipid syndrome.

Anti-Jo-1 syndrome

Original name for anti-synthetase syndrome.

Antiphospholipid syndrome(APS)

Synonyms: Hughes syndrome, anticardiolipin syndrome, phospholipid antibodysyndrome, cardiolipin antibody syndrome

APS is one of the most common autoimmune diseases. Its clinical picture is ex-tremely variable, and the complications arising from the disease may be minimalto life-threatening. The features of APS include venous and arterial thrombosis,recurrent spontaneous abortions, neurological complications and phospholipidantibody expression. APS may occur as an isolated disease entity (formerly pri-mary antiphospholipid syndrome) or in combination with another autoimmunedisease, especially systemic lupus erythematosus (formerly secondary antiphos-pholipid syndrome).

Sneddons syndrome and Budd-Chiari syndrome are partially attributableto APS. The catastrophic antiphospholipid syndrome is a rare form of APScharacterized by extensive vascular occlusions in multiple organ systems, leadingto renal failure and malignant arterial hypertension, severe CNS manifestations,acrocyanosis and gangrene.

A workshop, preceding the Eleventh International Congress on antiphospholipidantibodies (aPL) in Sydney, Australia, considered revisions to the internationalclassication criteria for APS.

A (APS) 195

Revised classication criteria for the APS[according to M et al., 2006]

Clinical criteria

1. Vascular thrombosis*One or more clinical episodes of arterial, venous, or small vessel throm-bosis. Thrombosis must be conrmed by objective validated criteria(i. e.unequivocal ndings of appropriate imaging studies or histopathol-ogy). For histopathologic conrmation, thrombosis should be presentwithout signicant evidence of inammation in the vessel wall.

2. Pregnancy morbiditya) One or more unexplained deaths of a morphologically normal

fetus at or beyond the 10th week of gestation, with normal fetal mor-phology documented by ultrasound or by direct examination of thefetus, or

b) One or more premature births of a morphologically normal neonatebefore the 34th week of gestation because of (i) eclampsia or severepreeclampsia dened according to standard denitions, or (ii) recog-nized features of placental insuciency, or

c) Three or more unexplained consecutive spontaneous abortions be-fore the 10th week of gestation, with maternal anatomic or hormonalabnormalities and paternal and maternal chromosomal causes ex-cluded. In studies of populations of patients who have more than onetype of pregnancy morbidity, investigators are strongly encouragedto stratify groups of subjects according to a, b, or c above.

Laboratory criteria**

1. Lupus anticoagulant (LA) present in plasma, on two or more occa-sions at least 12 weeks apart, detected according to the guidelines ofthe International Society on Thrombosis and Haemostasis (ScienticSubcommittee on LAs/phospholipid-dependent antibodies) (Brandt etal., 1995, Wislo et al., 2002). See Lupus anticoagulant.

2. Anticardiolipin (aCL) antibody of IgG and/or IgM isotype in serum orplasma, present in medium or high titer (i. e. > 40 GPL or MPL, or >the 99th percentile), on two or more occasions, at least l2 weeks apart,measured by a standardized EIA (Tincani et al., 2001;Harris et al., 2002;Wong et al., 2004). See Cardiolipin antibodies.

196 S A D S, D, S

3. Anti- 2 glycoprotein I antibody of IgG and/or IgM isotype in serumor plasma (in titer > the 99th percentile), present on two or moreoccasions, at least 12 weeks apart, measured by a standardized EIA,according to recommended procedures (Reber et al., 2004). See 2glycoprotein I antibodies.DeniteAPS is considered to be present if at least one of the clinicalcriteria and one of the laboratory criteria are met.

It must be pointed out that the classication of APS should be avoidedif less than 12 weeks or more than 5 years separate the positive aPL testand the clinical manifestation.

Coexisting inherited or acquired factors for thrombosis are not reasons for ex-cluding patients fromAPS trials.However, two subgroups ofAPS patients shouldbe recognized, according to: (a) the presence, and (b) the absence of additionalrisk factors for thrombosis. Indicative (but not exhaustive) such cases include:age (> 55 in men,and > 65 in women), and the presence of any of the establishedrisk factors for cardiovascular disease (hypertension, diabetes mellitus, elevatedLDL or low HDL cholesterol, cigarette smoking, family history of premature car-diovascular disease,body mass index 30 kg m2, microalbuminuria, estimatedCFR < 60 m min1), inherited thrombophilias, oral contraceptives, nephroticsyndrome, malignancy, immobilization, and surgery. Thus, patients who fullcriteria should be stratied according to contributing causes of thrombosis.

Investigators are strongly advised to classify APS patients in studies into oneof the following categories: I, more than one laboratory criteria present (anycombination); IIa, LA present alone; IIb, aCL antibody present alone; IIc, anti-2 glycoprotein I antibody present alone.

Features associated with APS but not included in the revised criteria:

heart valve disease (Libman-Sacks endocarditis; rheumatic fever and septic en-docarditis have to be excluded)

livedo reticularis thrombocytopenia nephropathy neurological manifestations (cognitive dysfunction, transient cerebral ischemia

and stroke, dementia, transverse myelopathy, seizure) IgA aCL IgA anti- 2GPI antibodies against phosphatidylserine antibodies against phosphatidylethanolamine

A-SRP 197

antibodies against prothrombin alone antibodies to the phophatidylserine-prothrombin complex

Autoantibodies: Phospholipid antibodies (see also appendix VI)

Anti-SRP syndrome

A subtype of idiopathic myositis (see Polymyositis).

Characteristic features:

Predominantly occurs in women of black African descent Acute/subacute onset with severe polymyositis Cardiac involvement frequently occurs Severe myonecrosis with only minimal inammation Responds poorly to immunosuppressive therapy; very poor prognosis (5-year

mortality of 75 %!)

Comment: In rare cases atypical clinical manifestations may occur in the presenceof necrotizing myopathy (Dimitri et al., 2007).

Autoantibodies: SRP antibodies serve as diagnostic marker. Ro52 antibodiescan be found but did not have any diagnostic or prognostic relevance.

Anti-Synthetase syndrome

Synonym: Anti-Jo-1 syndrome.

Subtype of idiopathic myositis (see Polymyositis) characterized by the addi-tional occurrence of arthralgia/arthritis and interstitial lung involvement (alveoli-tis, pulmonary brosis) and the detection of autoantibodies that react with tRNAsynthetases (especially Jo-1).

Major criteria of the anti-synthetase syndrome

1. Polymyositis2. Polysynovitis (arthralgia, arthritis, tenosynovitis)

198 S A D S, D, S

3. Interstitial lung disease (brosing alveolitis)4. Aminoacyl-tRNA synthetase antibodies

Additional associations

Rhagades and keratoses of the hands (mechanics hands) Raynauds phenomenon Acrosclerosis Sicca symptoms Dermatomyositis-like skin manifestations

Autoantibodies: Aminoacyl-tRNA synthetase antibodies are diagnostic mark-ers. Among these, Jo-1 antibody is the most common detectable biomarker. Ro52 antibodies are found at high frequencies but without aid in diagnosingthis type of autoimmune myositis.

Arthralgia

Common feature of all degenerative and inammatory rheumatic diseases; fre-quently occurs as a manifestation of systemic and organ-specic autoimmunediseases.

Autoantibodies: Patients suspicious for inammatory rheumatic disease shouldbe screened for antinuclear antibodies (ANA), antineutrophil cytoplasmic an-tibodies (ANCA), CCP/citrullinated protein/peptide antibodies and rheuma-toid factor (RF).

Arthritis

Characteristic feature of inammatory joint diseases: HLA-B27 associatedspondylarthropathia, juvenile chronic arthritis (JIA), rheumatoid arthritis(RA).

Common symptom of systemic autoimmune diseases: Connective tissuediseases, systemic vasculitides, relapsing polychondritis, hypocomple-mentemic urticarial vasculitis syndrome.

Autoantibodies: Patients suspicious for inammatory rheumatic diseases shouldbe screened for antinuclear antibodies (ANA), antineutrophil cytoplasmic