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Seite 1

Autoantibodies in Systemic Autoimmune Diseases

Autoantibodies are a very heterogeneous group of antibodies with

respect to their specificity, induction, effects, and clinical significance. Testing for autoantibodies can be helpful or necessary for the
diagnosis, differential diagnosis, prognostication, or monitoring of
autoimmune diseases. In case of limited (forme fruste) disease or a
single disease manifestation, the detection of serum autoantibodies can play an
important role in raising the suspicion of evolving disease and forecasting prognosis. This book and reference guide is intended to assist the physician in understanding and interpreting the variety of autoantibodies that are being used as
diagnostic and prognostic tools for patients with systemic rheumatic diseases.
Autoantibodies observed in systemic autoimmune diseases are described in
alphabetical order in Part 1 of this reference guide. In Part 2, systemic autoimmune disorders as well as symptoms that indicate the possible presence of an
autoimmune disease are listed. Systemic manifestations of organ-specific autoimmune diseases will not be covered in this volume. Guide marks were inserted to
ensure fast and easy cross-reference between symptoms, a given autoimmune
disease and associated autoantibodies. Although the landscape of autoantibody
testing continues to change, this information will be a useful and valuable reference for many years to come.

K. Conrad, W. Schler, F. Hiepe, M. J. Fritzler

2n
d

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

Autoantibodies in Systemic
Autoimmune Diseases
A Diagnostic Reference

AUTOANTIGENS, AUTOANTIBODIES, AUTOIMMUNITY

Volume 2, second Edition 2007

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

ed
itio
n

PABST

Autoantibodies in Systemic Autoimmune Diseases

A 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 Conrad
Institute for Immunology
Medical Faculty of the Technical University Dresden
Fetscherstrasse 74
01307 Dresden, GERMANY
Phone: +49 (0) 351-458-6540
Fax: +49 (0) 351-458-6308
E-mail: K Conrad@mail.zih.tu-dresden.de
Dr. Werner Schler
Rathenaustr. 12
16341 Panketal, GERMANY
Fax: +49 (0) 30-983-119-94
E-mail: Dr.Schoessler@arcor.de
Prof. Dr. Falk Hiepe
Charite University Hospital
Department of Rheumatology & Clinical Immunology
Schumannstrae 20/21
10117 Berlin, GERMANY
Phone: +49 (0) 30-450-513012
Fax: +49 (0) 30-450-51392
E-mail: Falk.Hiepe@charite.de
Marvin J. Fritzler, MD, PhD
Professor of Medicine
Arthritis Society Chair
Faculty of Medicine
University of Calgary
Calgary, Alberta, CANADA
Phone: +01 403-220-3533
Fax: +01 403-283-5666
E-mail: Fritzler@ucalgary.ca

Contents
Preface, 2nd edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XV
Preface, 1st edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XVI
Notes for the Use of this Book . . . . . . . . . . . . . . . . . . . . . . . . . .

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

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

Part 1
Autoantibodies in Systemic Autoimmune Diseases
Alanyl-tRNA (tRNAAla ) Synthetase Antibodies . . .
Alpha-Actinin Antibodies . . . . . . . . . . . . . . .
Alpha-Enolase Antibodies . . . . . . . . . . . . . . .
Alpha-Fodrin Antibodies . . . . . . . . . . . . . . .
Aminoacyl-tRNA Synthetase Antibodies . . . . . .
Annexin V Antibodies . . . . . . . . . . . . . . . . .
Antineutrophil Cytoplasmic Antibodies (ANCA) . .
Antinuclear Antibodies (ANA) . . . . . . . . . . . .
ASE-1 Antibodies . . . . . . . . . . . . . . . . . . . .
Asparaginyl-tRNA (tRNAAsp ) Synthetase Antibodies
Assemblyosome Antibodies . . . . . . . . . . . . . .
Azurocidin Antibodies . . . . . . . . . . . . . . . . .
Beta-Fodrin Antibodies . . . . . . . . . . . . . . . . .
Beta-2 Glycoprotein I (2-GPI) Antibodies . . . . .
BPI Antibodies . . . . . . . . . . . . . . . . . . . . .
C1D Antibodies . . . . . . . . . . . . . . . . . . . . .
C1q Antibodies . . . . . . . . . . . . . . . . . . . . .
CADM-140 Antibodies . . . . . . . . . . . . . . . . .
Calpastatin Antibodies . . . . . . . . . . . . . . . . .
Calreticulin Antibodies . . . . . . . . . . . . . . . . .
cANCA (C-ANCA) . . . . . . . . . . . . . . . . . . .

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10
10
10
12
13
15
16
19
21
21
22
22
24
24
27
28
28
30
31
32
33

VI

C
Cardiolipin Antibodies . . . . . . . . . . . . . . . . . . .
Cathepsin G Antibodies . . . . . . . . . . . . . . . . . .
CCP Antibodies . . . . . . . . . . . . . . . . . . . . . . .
CD16 Antibodies . . . . . . . . . . . . . . . . . . . . . .
CENP-B Antibodies . . . . . . . . . . . . . . . . . . . . .
CENP-C Antibodies . . . . . . . . . . . . . . . . . . . . .
CENP-E Antibodies . . . . . . . . . . . . . . . . . . . .
CENP-F Antibodies . . . . . . . . . . . . . . . . . . . . .
Centriole Antibodies . . . . . . . . . . . . . . . . . . . .
Centromere Antibodies . . . . . . . . . . . . . . . . . . .
Centrophilin Antibodies . . . . . . . . . . . . . . . . . .
Centrosome Antibodies . . . . . . . . . . . . . . . . . .
Chromatin Antibodies . . . . . . . . . . . . . . . . . . .
Chromo Antibodies . . . . . . . . . . . . . . . . . . . . .
Citrullinated Protein/Peptide Antibodies . . . . . . . . .
Coilin Antibodies . . . . . . . . . . . . . . . . . . . . . .
Collagen Antibodies . . . . . . . . . . . . . . . . . . . .
CRP Antibodies . . . . . . . . . . . . . . . . . . . . . . .
Cryoglobulins . . . . . . . . . . . . . . . . . . . . . . . .
Cytoplasmic Linker Protein 170 (CLIP-170) Antibodies
DEK Antibodies . . . . . . . . . . . . . . . . . . . . . . .
Double-Stranded DNA (dsDNA) Antibodies . . . . . .
EEA-1 Antibodies . . . . . . . . . . . . . . . . . . . . . .
EF1A Antibodies . . . . . . . . . . . . . . . . . . . . . . .
EJ Antibodies . . . . . . . . . . . . . . . . . . . . . . . .
Elastase Antibodies . . . . . . . . . . . . . . . . . . . . .
ENA Antibodies . . . . . . . . . . . . . . . . . . . . . . .
Endothelial Cell Antibodies . . . . . . . . . . . . . . . .
EPCR Antibodies . . . . . . . . . . . . . . . . . . . . . .
Exosome Antibodies . . . . . . . . . . . . . . . . . . . .
Fer Antibodies . . . . . . . . . . . . . . . . . . . . . . . .
Ferritin Antibodies . . . . . . . . . . . . . . . . . . . . .
Fibrillarin Antibodies . . . . . . . . . . . . . . . . . . . .
Fibrillin 1 Antibodies . . . . . . . . . . . . . . . . . . . .
Fibroblast Antibodies . . . . . . . . . . . . . . . . . . . .
Filaggrin Antibodies . . . . . . . . . . . . . . . . . . . .
Glutaminyl-tRNA (tRNAGlu ) Synthetase Antibodies . .
Glycyl-tRNA (tRNAGly ) Synthetase Antibodies . . . . .
GM1 Antibodies . . . . . . . . . . . . . . . . . . . . . .
Golgi Apparatus Antibodies . . . . . . . . . . . . . . . .
Gu Antibodies . . . . . . . . . . . . . . . . . . . . . . . .
GWB Antibodies . . . . . . . . . . . . . . . . . . . . . .

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34
37
38
39
40
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71
72
72
74
74

C
Heat Shock Protein (Hsp) Antibodies . . . . . . . . . . . . .
Histidyl-tRNA (tRNAHis ) Synthetase (HRS) Antibodies . . .
Histone Antibodies . . . . . . . . . . . . . . . . . . . . . . . .
HMG Antibodies . . . . . . . . . . . . . . . . . . . . . . . . .
HsEg5 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . .
5-HT4 Receptor Antibodies . . . . . . . . . . . . . . . . . . .
Human Neutrophil Elastase (HNE) Antibodies . . . . . . . .
IFI 16 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . .
IgA Autoantibodies . . . . . . . . . . . . . . . . . . . . . . . .
Isoleucyl-tRNA (tRNAIle ) Synthetase Antibodies . . . . . . .
Ja Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Jo-1 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . .
Keratin Antibodies (AKA) . . . . . . . . . . . . . . . . . . . .
Ki Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . .
Kinectin Antibodies . . . . . . . . . . . . . . . . . . . . . . . .
KJ Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . .
KS Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ku Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . .
L5/5S Antibodies . . . . . . . . . . . . . . . . . . . . . . . . .
L7 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . .
L12 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . .
Lactoferrin Antibodies . . . . . . . . . . . . . . . . . . . . . .
Lamin Antibodies . . . . . . . . . . . . . . . . . . . . . . . . .
La/SS-B Antibodies . . . . . . . . . . . . . . . . . . . . . . . .
LE Cell Factor . . . . . . . . . . . . . . . . . . . . . . . . . . .
LEDGF (Lens Epithelial Derived Growth Factor) Antibodies
Leucyl-tRNA (tRNALeu ) Synthetase Antibodies . . . . . . . .
Lipoprotein Lipase (LPL) Antibodies . . . . . . . . . . . . . .
Lupus Anticoagulant (LA) . . . . . . . . . . . . . . . . . . . .
Lysosome Antibodies . . . . . . . . . . . . . . . . . . . . . . .
Lysozyme Antibodies . . . . . . . . . . . . . . . . . . . . . . .
Lysyl-tRNA (tRNALys ) Synthetase Antibodies . . . . . . . . .
M3mAchR (M3R) Antibodies . . . . . . . . . . . . . . . . . .
Mas Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . .
MBL Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . .
MCV Antibodies . . . . . . . . . . . . . . . . . . . . . . . . .
Mi-2 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . .
Midbody Antibodies . . . . . . . . . . . . . . . . . . . . . . .
MMP Antibodies . . . . . . . . . . . . . . . . . . . . . . . . .
Mpp1 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . .
Mpp10 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . .
MSA Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . .

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VII

VIII

C
Myeloperoxidase Antibodies . . . . . . . . . . . . . . .
Myosin Antibodies . . . . . . . . . . . . . . . . . . . .
Nedd5 Antibodies . . . . . . . . . . . . . . . . . . . . .
NMDA Receptor Antibodies . . . . . . . . . . . . . . .
NOR-90 Antibodies . . . . . . . . . . . . . . . . . . . .
Nucleolar Antibodies . . . . . . . . . . . . . . . . . . .
Nucleolin Antibodies . . . . . . . . . . . . . . . . . . .
Nucleophosmin Antibodies . . . . . . . . . . . . . . .
Nucleosome Antibodies . . . . . . . . . . . . . . . . .
NuMA Antibodies . . . . . . . . . . . . . . . . . . . . .
OJ Antibodies . . . . . . . . . . . . . . . . . . . . . . .
oxLDL Antibodies . . . . . . . . . . . . . . . . . . . . .
pANCA (P-ANCA) . . . . . . . . . . . . . . . . . . . .
PCNA Antibodies . . . . . . . . . . . . . . . . . . . . .
PDGF Receptor (PDGFR) Antibodies . . . . . . . . .
Perinuclear Factors (PNF) . . . . . . . . . . . . . . . .
Phosphatidic Acid (PA) Antibodies . . . . . . . . . . .
Phosphatidylcholine (PC) Antibodies . . . . . . . . . .
Phosphatidylethanolamine (PE) Antibodies . . . . . .
Phosphatidylinositol (PI) Antibodies . . . . . . . . . .
Phosphatidylserine (PS) Antibodies . . . . . . . . . . .
Phospholipid (PL) Antibodies . . . . . . . . . . . . . .
PL-7 Antibodies . . . . . . . . . . . . . . . . . . . . . .
PL-12 Antibodies . . . . . . . . . . . . . . . . . . . . .
PM-1 Antibodies . . . . . . . . . . . . . . . . . . . . . .
PMS1 Antibodies . . . . . . . . . . . . . . . . . . . . .
PM/Scl Antibodies . . . . . . . . . . . . . . . . . . . .
PM/Scl-75 Antibodies . . . . . . . . . . . . . . . . . .
PM/Scl-100 Antibodies . . . . . . . . . . . . . . . . . .
Poly (ADP-Ribose) Polymerase (PARP) Antibodies . .
Proteasome Antibodies . . . . . . . . . . . . . . . . . .
Proteinase 3 Antibodies . . . . . . . . . . . . . . . . . .
Protein C Antibodies . . . . . . . . . . . . . . . . . . .
Protein S Antibodies . . . . . . . . . . . . . . . . . . .
Prothrombin Antibodies . . . . . . . . . . . . . . . . .
RA33 Antibodies . . . . . . . . . . . . . . . . . . . . .
Replication Protein A (RPA) Antibodies . . . . . . . .
Rheumatoid Factors (RF) . . . . . . . . . . . . . . . .
Ribosomal Antibodies . . . . . . . . . . . . . . . . . .
Ribosomal P Protein (RPP) Antibodies . . . . . . . . .
Ribosomal RNA Processing (Rrp) Protein Antibodies
RNA Antibodies . . . . . . . . . . . . . . . . . . . . . .

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C
RNA Helicase II Antibodies . . . . . . . . . . . . .
RNA Helicase A (RHA) Antibodies . . . . . . . . .
RNAP-I Antibodies . . . . . . . . . . . . . . . . . .
RNAP-II Antibodies . . . . . . . . . . . . . . . . .
RNAP-III Antibodies . . . . . . . . . . . . . . . . .
RNA Polymerase (RNAP) Antibodies . . . . . . . .
Ro52 Antibodies . . . . . . . . . . . . . . . . . . . .
Ro60 Antibodies . . . . . . . . . . . . . . . . . . . .
Ro/SS-A Antibodies . . . . . . . . . . . . . . . . . .
28S rRNA Antibodies . . . . . . . . . . . . . . . . .
S10 Antibodies . . . . . . . . . . . . . . . . . . . . .
Sa Antibodies . . . . . . . . . . . . . . . . . . . . .
SAP Antibodies . . . . . . . . . . . . . . . . . . . .
SC Antibodies . . . . . . . . . . . . . . . . . . . . .
Scl-70 Antibodies . . . . . . . . . . . . . . . . . . .
Single-Stranded DNA (ssDNA) Antibodies . . . .
Sip1 Antibodies . . . . . . . . . . . . . . . . . . . .
Sm Antibodies . . . . . . . . . . . . . . . . . . . . .
snoRNP Antibodies . . . . . . . . . . . . . . . . . .
snRNP Antibodies . . . . . . . . . . . . . . . . . .
SR Protein Antibodies . . . . . . . . . . . . . . . .
SRP Antibodies . . . . . . . . . . . . . . . . . . . .
SS-56 Antibodies . . . . . . . . . . . . . . . . . . .
SS-A Antibodies . . . . . . . . . . . . . . . . . . . .
SS-B Antibodies . . . . . . . . . . . . . . . . . . . .
ssDNA Antibodies . . . . . . . . . . . . . . . . . . .
Threonyl-tRNA (tRNAThr ) Synthetase Antibodies
Th/To Antibodies . . . . . . . . . . . . . . . . . . .
Thrombomodulin Antibodies . . . . . . . . . . . .
Topoisomerase I Antibodies . . . . . . . . . . . . .
Topoisomerase II Antibodies . . . . . . . . . . . . .
Trimethylguanosine Antibodies . . . . . . . . . . .
U1-RNP Antibodies . . . . . . . . . . . . . . . . . .
U2-RNP Antibodies . . . . . . . . . . . . . . . . . .
U4/U6-RNP Antibodies . . . . . . . . . . . . . . .
U5-RNP Antibodies . . . . . . . . . . . . . . . . . .
U7-RNP Antibodies . . . . . . . . . . . . . . . . . .
U11-RNP Antibodies . . . . . . . . . . . . . . . . .

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IX

Part 2
Systemic Autoimmune Diseases Syndromes, Diagnostic Criteria,
Symptoms
Abortion, spontaneous . . . . . . . .
Acidosis, renal-tubular . . . . . . . .
Acro-Osteolysis . . . . . . . . . . . .
Addisons disease . . . . . . . . . . .
Adrenocortical failure . . . . . . . .
Aldolase, elevated in plasma . . . . .
Alopecia . . . . . . . . . . . . . . . .
Alveolitis . . . . . . . . . . . . . . . .
Amaurosis fugax . . . . . . . . . . .
ANCA-associated vasculitis . . . . .
Anemia . . . . . . . . . . . . . . . .
Anti-Jo-1 syndrome . . . . . . . . .
Antiphospholipid syndrome (APS) .
Anti-SRP syndrome . . . . . . . . .
Anti-Synthetase syndrome . . . . . .
Arthralgia . . . . . . . . . . . . . . .
Arthritis . . . . . . . . . . . . . . . .
Behcet disease . . . . . . . . . . . . .
Bronchial asthma . . . . . . . . . . .
Budd-Chiari syndrome . . . . . . .
Buttery rash . . . . . . . . . . . . .
Calcinosis cutis . . . . . . . . . . . .
Cardiomyopathy . . . . . . . . . . .
Catastrophic APS . . . . . . . . . .
Cavernous sinus thrombosis . . . .
Cerebral infarction . . . . . . . . . .
Cerebral ischemia . . . . . . . . . . .
Chorea . . . . . . . . . . . . . . . . .
Churg-Strauss syndrome (CSS) . . .
Claudication of extremities . . . . .
Claudication of masticatory muscles
Cogans syndrome . . . . . . . . . .
Congenital heart block . . . . . . . .
Conjunctivitis . . . . . . . . . . . . .
Connective tissue diseases . . . . . .
Creatine kinase, elevated in plasma .
CREST syndrome . . . . . . . . . .
Cryoglobulinemia . . . . . . . . . .
Cryoglobulinemic nephropathy . . .

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

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XI

XII

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

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235

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

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253

XIII

XIV

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

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264

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

Preface, 2nd edition

The determination of autoantibodies has become an integral part of the diagnosis
and dierential diagnosis, as well as the estimation of the prognosis and development of autoimmune diseases. Furthermore, because many disease-associated
autoantibodies are detectable in preclinical stages, they have assumed a potential
role in the very early diagnosis or risk assessment of disease development. The
growing knowledge about the pathogenic and diagnostic value of autoantibodies
in systemic diseases, and the discovery of novel autoantibodies and changes in
classication criteria necessitated the publishing of a revised and supplemented
2nd edition. Besides the clinically relevant autoantibodies also antibodies that may
serve as tools in molecular, cell and tumor biological studies have been included.
However due to the rapid development, the alphabetical catalogue of relevant or
potential relevant autoantibodies is incomplete. Therefore, the authors appreciate
helpful comments for future editions.
Karsten Conrad
Marvin J. Fritzler
Falk Hiepe
Werner Schler

Preface, 1st edition

Among the challenges facing the new millennium physician are tremendous
changes in biomedical and information technologies that are rapidly changing the
nature and complexity of clinical practice. Since the discovery of the LE cell over
50 years ago, there has been a logarithmic increase in the description and clinical
application of autoantibodies in an ever-widening spectrum of diseases. Systemic
rheumatic diseases are among the most complex of these diseases because the
clinical presentation and constellation of ndings are in part reected by the
spectrum of autoantibodies found in these conditions. The litany of autoantibody
acronyms, 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 antibody
alphabet soup has threatened to move clinical diagnostics into a literal Tower of
Babel.

It is important to appreciate how the antibody alphabet soup can be useful in

the diagnosis and management of systemic rheumatic diseases. The applications
are as varied and rich as are the multiplicity of the autoantibody specicities. Certainly, autoantibody testing is not required to make a diagnosis in a woman who
presents with a photosensitive skin rash, pericarditis, glomerulonephritis, anemia
and psychosis. This patient clearly has SLE and the detection of autoantibodies
conrms the obvious.What may not be as clear is that the presence of anti-dsDNA
could correlate with nephritis and the presence of anti-ribo P may indicate manifestations of central nervous system lupus in the presence of confounding factors
such as infections and drug use. In addition, not all patients present with classical
textbook features of systemic rheumatic diseases. Unfortunately, in many cases
the time interval from the onset of symptoms to a conrmed diagnosis and meeting 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 the
suspicion of evolving disease and forecasting prognosis. A good example is the
use of autoantibodies in the initial evaluation of Raynauds phenomenon. If the
ANA and other autoantibody tests are negative, the likelihood that his patient has
primary Raynauds disease is likely and the concern that the clinical course will
transform into systemic rheumatic disease is lessened. On the other hand, ample

P, 1
clinical studies have shown that the presence of anti-topo-I (Scl-70) is a harbinger
of diuse scleroderma, antibodies to CENP are more predictive of the limited
form of the disease, and the presence of anti-PM/Scl, indicates a sclerodermapolymyositis overlap syndrome. There many other examples of the clinical utility
of autoantibody testing in isolated clinical scenarios such as polyarthritis, myositis, neuropathies, cytopenias, and vasculopathies that are characteristic, but not
specic for, any single systemic
rheumatic disease. In many of these instances the

presence of one or more alphabet soup antibodies can be a prologue to diseases

that are likely to evolve during patient follow-up.
While the diagnosis of forme fruste disease is an important use of autoantibody
testing, another valuable use is that they provide an understanding of the pathogenesis. This has been clearly illustrated with the subsets of disease such as neonatal
lupus syndrome, subacute cutaneous lupus, homozygous C2 deciency, interstitial
lung disease, granulocytopenia, and Sjgrens syndrome that are strongly associated with anti-SS-A/Ro. Compelling evidence shows that anti-SS-A/Ro binds with
the cognate antigen in the fetal heart and in keratinocytes exposed to ultraviolet
light. On the other hand, it is not clear how or if the same antibody participates
in the development of keratoconjunctivitis sicca. The demonstration that ribosomal P proteins and other autoantigens are found on the surface of some normal
and apoptotic cells may provide an important clue to their potential pathogenic
role. The notion that some autoantibodies may be ngerprints incriminating a
cause or etiology of the disease are also being claried. For example, antibodies
to brillarin (U3-RNP) are induced in certain strains of mice by heavy metal exposure and systemic sclerosis patients with these autoantibodies have high levels
of 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 and
nanotechnology) will change the complexion of the autoantibody testing by providing a wealth of serological information that will almost certainly challenge
current paradigms and clinical associations. It is now possible to use a drop of
blood to analyze serum for the presence of over 100 dierent autoantibodies in a
single test that can be completed and reported within minutes. Second, it is anticipated that autoantibody testing will be a critical part of monitoring and evaluating
patients placed on a variety of the newer biological therapeutics. For example, it is
increasingly clear that interferon and tumor necrosis factor blockade therapies are
associated with the induction of autoantibodies and, in some cases, full blown disease. Interestingly, these observations fall on the historical evidence that drugs such
as procainamide and hydralazine can induce autoantibodies and lupus syndromes.
Third, it is likely that autoantibody testing will replace more invasive and costly
diagnostic techniques such as the salivary gland biopsy for Sjgrens syndrome,
the small bowel biopsy for coeliac disease, the nerve and skin biopsy for vasculitis, the muscle biopsy for myositis, and many others. Fourth, carefully designed

XVII

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P, 1

studies that assess the cost eectiveness of autoantibody testing are required. On
one hand, there is the notion that in many patients, including the woman with
unequivocal features of SLE described above, that even the relatively inexpensive
autoantibody test is superuous and not cost eective. However, the implications
of longer term health care costs of missing an early diagnosis in a patient with
forme fruste disease must also be carefully considered. A cost-eective and rational approach to autoantibody testing algorithms and clinical practice guidelines
are overdue. Clinical studies to address these issues will prove worthwhile and save
patients from needless, expensive and invasive tests, and missed diagnosis that can
lead to signicant morbidity and mortality.
This book and reference guide is intended to assist the physician understand
and interpret the variety of autoantibodies that are being used as diagnostic and
prognostic tools for patients with systemic rheumatic diseases. Although the landscape of autoantibody testing continues to change, this information will be a useful
and 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 diseases
is divided into two main sections. The autoantibodies observed in autoimmune
diseases are described in alphabetical order in Part 1, and autoimmune disorders
as well as symptoms that indicate the possible presence of an autoimmune disease
are listed in Part 2. Guide marks (the symbol
) were inserted to ensure fast
and easy cross-reference between symptoms, a given autoimmune disease and
associated autoantibodies. Bibliographic references were omitted due to the broad
scope of the subject matter. Only the rst authors of historical or some important
recent publications have been named.

With some exceptions (e. g., antinuclear antibodies) the prex anti- was omitted 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 terminology is indicated as such, and the names preferred by the authors are used in
the alphabetical index.
The autoantibody description section begins, in some cases, with a brief introduction or historical account. This is followed by information on the target
structures (autoantigens), detection methods, clinical relevance, and indications
for testing of the autoantibody.
The authors rating of the clinical relevance of each autoantibody listed in the
book is indicated using variable coloring and lettering.
White Letters on
Green Background
These are autoantibodies of high diagnostic relevance (markers for diagnosis,
prognosis or monitoring) that can usually be determined in all laboratories.

Black Letters on
Medium Green Background
These are diagnostically relevant autoantibodies that are not measurable in all
laboratories and therefore are determined in specialized laboratories only.
Black Letters on
Light Green Background
The clinical relevance of these antibodies is (still) unclear due to their very
low frequency of detection, discrepancies between the ndings of dierent studies
(lack of comparability due to dierences in study design, methodology, ethnic differences, etc.), methodological problems, or preliminary nature of study ndings.
Black Letters on
White Background
These autoantibodies are currently not clinically relevant, are no longer clinically relevant, or are clinically relevant only in isolated cases. This can also include
disease-specic autoantibodies if their testing does not provide any added diagnostic advantages over other parameters.

Part 1

Autoantibodies in Systemic
Autoimmune Diseases

GWB A

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, GW2
and GW3 as well as other components such as Ago2, Ge-1/Hedls and RAP55. They
are localized to discrete cytoplasmic structures that are involved in mRNA processing. 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 interference silencing complex (RISC) (reviewed in Jakymiw et al., 2007). The most
common 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).

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

75

A S A D

76

N: The frequency of detection of anti-GWB depends on the cell line and

tissue that is used for the assay because GWB are most highly expressed in
rapidly 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 as
anti-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 screening using HEp-2 cells (Stinton et al., 2004). They are primarily associated with

Sjgrens syndrome, ataxia and other neuropathies,
systemic lupus erythematosus (SLE), primary biliary cirrhosis (Bloch et al., 2005) and also found in
other systemic autoimmune rheumatic diseases.
A systematic study of cohorts of various autoimmune diseases is needed now
that 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 other
autoantibodies (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 during
screening with HEp-2 cells, serological follow-up to rule out reactivity with other
cytoplasmic antigens that give a similar pattern (i. e. EEA-1, lysosome) is required.
This can be partly accomplished by co-localization studies. However, it should
be noted that GWB are quite heterogeneous with respect to content of any one
of the components. Thus, analyses of autoantibodies with multiplexed array technologies are preferred once the distinctive staining pattern is identied. At the
clinical interface, examinations should be performed, e. g., to detect the potential
development of connective tissue disease (Sjgrens syndrome) and neurological
conditions such as ataxia and sensory/motor neuropathies. Cooperation with a
research laboratory can be useful, e. g., for determination of the specicity and
further evaluation of the potential clinical relevance of these antibodies.

H-RNA (RNAH ) S (HRS) A

Heat Shock Protein (Hsp) Antibodies

Collective term for all autoantibodies directed against heat shock proteins/heat
stress proteins (Hsp).
Autoantigens
Various heat shock proteins (heat-stress-induced proteins) like Hsp60, Hsp70 and
Hsp90.
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 for
diagnosis of arteriosclerosis and autoimmune diseases of the inner ear is being
evaluated.
Histidyl-tRNA (tRNAHis )
Synthetase (HRS) Antibodies
See
Jo-1 antibodies,
Aminoacyl-tRNA synthetase antibodies.
Histone Antibodies
Synonym: Anti-histone antibodies (AHA).

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A S A D
History: Histone antibodies appear to be involved in the LE cell phenomenon that
was rst described in 1948. H2A-H2B antibodies and, more recently, H1 antibodies
have been implicated in this phenomenon, which was an important milestone in
the discovery of autoantibodies associated with SLE (
LE cell factor).
Autoantigens
Histones can be found in almost all eukaryotic cell nuclei. The histone family
contains 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 with
double-stranded DNA, called nucleosomes. The DNA thereby wraps around
dimeric H2A-H2B and H3-H4, while H1 binds to DNA on the surface of the
nucleosome. The bead-like nucleosomes help bundle the DNA into a more
compact chromatin structure. All histones and histone complexes can be targeted
by autoantibodies.
Detection Methods
IIF using HEp-2 cells: Chromatin can be visualized like the pattern produced
by
dsDNA antibodies (homogeneous staining of interphase nuclei and of the
chromatin 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 solid
phase 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 rheumatic
disorders:
Systemic lupus erythematosus (SLE; 5080 %),
drug-induced
lupus (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 undierentiated connective tissue diseases (up to 90 %), primary biliary cirrhosis (up to
55 %), autoimmune hepatitis (up to 35 %). Furthermore, AHA are detectable in
patients with neoplastic diseases, subacute sensoric neuropathies and infections.

HMG A
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 is
characteristic of drug-induced lupus.
AHA can be of the IgG, IgM or IgA isotype. IgG AHA appear to be related to
the disease activity of lupus.
In patients with SSc, AHA are associated with lung, heart and kidney involvement (Hesselstrand et al., 2003). A strong correlation of AHA with the number
of morphea lesions and the number of involved areas of the body have been
described 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, sulfasalazine or captopril use).
N: To establish the diagnosis of drug-induced lupus, the potential presence
of SLE marker antibodies (i. e.,
dsDNA and
Sm antibodies) must be ruled
out using the appropriate tests. Antihistone antibodies tend to disappear within
one year of discontinuing the causative drug.
2. Dierential recognition of antinuclear antibodies in sera presenting a typical
chromatin uorescence pattern.

HMG Antibodies

Autoantigens
Chromosomal high mobility group (HMG) proteins. The proteins HMG-1, -2, -14
and -17 have been described as target proteins of autoantibodies involved in systemic autoimmune diseases. Furthermore, antigens with HMG motifs (HMG-box
proteins such as Sp100, SOX13) can be targeted by antibodies from autoimmune
patients (Fida etal., 2002).
Detection Methods
WB using cell extracts or HMG preparations.
EIA using biochemically puried HMG.

79

Part 2

Systemic Autoimmune Diseases

Syndromes, Diagnostic Criteria,
Symptoms

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S A D S, D, S

Abortion, spontaneous
Recurrent spontaneous abortions that generally occur after the 10th week of gestation (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 severe
acral microcirculatory disorder.
Addisons disease

May be due to thrombosis of the blood vessels of the adrenal glands as a rare
complication (<1%) of
antiphospholipid syndrome.
Adrenocortical failure

Addisons disease
Aldolase, elevated in plasma

Polymyositis/dermatomyositis

Mixed connective tissue disease (MCTD)

193

Alopecia

Diuse (alopecia diusa) or localized alopecia (alopecia areata) may occur in cutaneous 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. Rare

ophthalmologic manifestation of
antiphospholipid syndrome (in 5 %). Also
symptom of
giant cell arteritis (temporal arteritis).
ANCA-associated vasculitis

Group of primary systemic vasculitides associated with ANCA (
cANCA/proteinase

3 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 degree
of inammatory activity. Coombs-positive autoimmune hemolytic anemia may
occur in
systemic lupus erythematosus and rarely in other
connective tissue
diseases. 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 antibody
syndrome, cardiolipin antibody syndrome
APS is one of the most common autoimmune diseases. Its clinical picture is extremely variable, and the complications arising from the disease may be minimal
to life-threatening. The features of APS include venous and arterial thrombosis,
recurrent spontaneous abortions, neurological complications and phospholipid
antibody expression. APS may occur as an isolated disease entity (formerly primary antiphospholipid syndrome) or in combination with another autoimmune
disease, especially systemic lupus erythematosus (formerly secondary antiphospholipid syndrome).

Sneddons syndrome and
Budd-Chiari syndrome are partially attributable
to APS. The
catastrophic antiphospholipid syndrome is a rare form of APS
characterized by extensive vascular occlusions in multiple organ systems, leading
to renal failure and malignant arterial hypertension, severe CNS manifestations,
acrocyanosis and gangrene.
A workshop, preceding the Eleventh International Congress on antiphospholipid
antibodies (aPL) in Sydney, Australia, considered revisions to the international
classication criteria for APS.

A (APS)

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 thrombosis. Thrombosis must be conrmed by objective validated criteria
(i. e. unequivocal ndings of appropriate imaging studies or histopathology). For histopathologic conrmation, thrombosis should be present
without signicant evidence of inammation in the vessel wall.
2. Pregnancy morbidity
a) One or more unexplained deaths of a morphologically normal
fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the
fetus, or
b) One or more premature births of a morphologically normal neonate
before the 34th week of gestation because of (i) eclampsia or severe
preeclampsia dened according to standard denitions, or (ii) recognized features of placental insuciency, or
c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal
abnormalities and paternal and maternal chromosomal causes excluded. In studies of populations of patients who have more than one
type of pregnancy morbidity, investigators are strongly encouraged
to stratify groups of subjects according to a, b, or c above.
Laboratory criteria**
1. Lupus anticoagulant (LA) present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of
the International Society on Thrombosis and Haemostasis (Scientic
Subcommittee on LAs/phospholipid-dependent antibodies) (Brandt et
al., 1995, Wislo et al., 2002). See
Lupus anticoagulant.
2. Anticardiolipin (aCL) antibody of IgG and/or IgM isotype in serum or
plasma, 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.

195

S A D S, D, S

196

3. Anti- 2 glycoprotein I antibody of IgG and/or IgM isotype in serum

or plasma (in titer > the 99th percentile), present on two or more
occasions, at least 12 weeks apart, measured by a standardized EIA,
according to recommended procedures (Reber et al., 2004). See
2
glycoprotein I antibodies.
Denite APS is considered to be present if at least one of the clinical
criteria and one of the laboratory criteria are met.
It must be pointed out that the classication of APS should be avoided
if less than 12 weeks or more than 5 years separate the positive aPL test
and the clinical manifestation.

Coexisting inherited or acquired factors for thrombosis are not reasons for excluding patients from APS trials. However, two subgroups of APS patients should
be recognized, according to: (a) the presence, and (b) the absence of additional
risk 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 established
risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated
LDL or low HDL cholesterol, cigarette smoking, family history of premature cardiovascular disease, body mass index 30 kg m2, microalbuminuria, estimated
CFR < 60 m
min1 ), inherited thrombophilias, oral contraceptives, nephrotic
syndrome, malignancy, immobilization, and surgery. Thus, patients who full
criteria should be stratied according to contributing causes of thrombosis.

Investigators are strongly advised to classify APS patients in studies into one
of the following categories: I, more than one laboratory criteria present (any
combination); 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 endocarditis 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
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 presence
of necrotizing myopathy (Dimitri et al., 2007).
Autoantibodies:
SRP antibodies serve as diagnostic marker.
Ro52 antibodies
can 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 additional occurrence of arthralgia/arthritis and interstitial lung involvement (alveolitis, pulmonary brosis) and the detection of autoantibodies that react with tRNA
synthetases (especially Jo-1).

Major criteria of the anti-synthetase syndrome

1. Polymyositis
2. Polysynovitis (arthralgia, arthritis, tenosynovitis)

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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 markers. Among these,
Jo-1 antibody is the most common detectable biomarker.

Ro52 antibodies are found at high frequencies but without aid in diagnosing
this type of autoimmune myositis.
Arthralgia

Common feature of all degenerative and inammatory rheumatic diseases; frequently occurs as a manifestation of systemic and organ-specic autoimmune
diseases.
Autoantibodies: Patients suspicious for inammatory rheumatic disease should
be screened for
antinuclear antibodies (ANA),
antineutrophil cytoplasmic antibodies (ANCA),
CCP/citrullinated protein/peptide antibodies and
rheumatoid factor (RF).
Arthritis

Characteristic feature of inammatory joint diseases: HLA-B27 associated

spondylarthropathia,
juvenile chronic arthritis (JIA),
rheumatoid arthritis
(RA).
Common symptom of systemic autoimmune diseases:
Connective tissue
diseases,
systemic vasculitides,
relapsing polychondritis,
hypocomplementemic urticarial vasculitis syndrome.
Autoantibodies: Patients suspicious for inammatory rheumatic diseases should
be screened for
antinuclear antibodies (ANA),
antineutrophil cytoplasmic