laboratory testing for lupus systemic erythematosus · anti-nuclear antibody (ana) ... predictive...

Laboratory Diagnosis of Lupus Systemic Erythematosus Dr Liz Yuen

Chemical Pathology

PWH

Allied Health Committee of Pathology Commissioned Training Programme 2012/13

Outline

1. Clinical features of SLE

2. Local epidemiology of SLE

3. Anti-nuclear antibodies (ANA)

4. Anti-dsDNA antibodies

5. Anti-extractable nuclear antigen antibodies (ENA)

6. Anti-phospholipid antibodies

7. Other autoantibodies useful in SLE

8. Summary

SLE

1. A non-organ-specific autoimmune disease.

2. A multi-system disease that affects all persons of all ages and both sexes, although it is most prevalent in women during childbearing years.

3. Multiple abnormalities of the immune system – autoantibodies to nuclear antigens.

SLE

• Worldwide prevalence 1.4 – 17.2 per 10,000

• Prevalence in mainland Chinese

• 3 – 8 per 10,000

• Hong Kong Chinese

• Prevalence 10 per 10,000 (0.1%) (0.19% for female, 0.02% for male)

• Annual incidence 6.7 per 100,000

• Female to male ratio

• < 5% pre-pubertal

Predisposing genetic factors

Environmental factors - Estrogens - Ultraviolet light

Drugs Infectious agents

Abnormal immune response

Inflammation Tissue damage

SLE Etiology Still poorly known

Diagnostic Criteria for SLE

• 1971 The American Rheumatism Association

• 1982 Revised Criteria - The American College of Rheumatology

• 1997 Update of the 1982 Revised Criteria - The American College of Rheumatology

Criteria

1. Malar Rash 2. Discoid rash 3. Photosensitivity

4. Oral ulcers 5. Nonerosive arthritis 6. Pleuritis or pericarditis

7. Renal disorder Persistent proteinuria > 0.5 grams per day or > than 3+ OR Cellular casts (may be red cell, hemoglobin, granular, tubular, or mixed)

8. Neurological disorder

Seizures and psychosis

9. Hematologic disorder

Hemolytic anemia with reticulocytosis OR Leukopenia OR Lymphopenia OR Thrombocytopenia

10. Immunologic disorder

Anti-dsDNA Ab , Anti-Sm Ab, or antiphospholipid Ab

11. Positive anti-nuclear antibody

An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs .

1997 Update of the 1982 American College of Rheumatology Revised Criteria for Classification of Systemic Lupus Erythematosus

4 or more criteria are present, serially or simultaneously

Clinical features – Local data

Mok CC. 2010

Disease duration 10.3±7.2 years; women:men = 8.6:1; mean age of onset 30.5±13 years

Clinical features – ethnic differences

Mok et al. 2005

SLE Assessment

Chemical Pathology

Haematology

Clinical Immunology

Anatomical Pathology

Clinical and radiological assessment

Anti-nuclear Antibody (ANA)

Anti-nuclear Antibody (ANA)

• One of the ACR 1997 diagnostic criteria

• Sensitive

• Positive in 96% of SLE

• Non-specific

• Other autoimmune and non-autoimmune diseases

• Healthy populations

• Higher ANA titre autoimmune disease more likely

• If positive, need follow-up tests to determine the Ab specificities (the fluorescence pattern helps)

• Little clinical value to monitor ANA level

Qualitative – immunofluorescence pattern

Semi-quantitative – titres

ANA – laboratory methods

Indirect immunofluorescence assay (IFA)

Indirect Immunofluorescent Assay

Slide

Cell

Patient serum with auto-Abs

Anti-serum with fluorescent conjugated capturing Abs

ANA

Kumar et al. Diag Path 2009

ANA titre

Satoh et al. Expert Rev Clin Immunol 2007

Positive% in healthy controls vs. negative% in SLE or systemic sclerosis at different serum dilutions in IFA ANA assay.

False positive

False negative

ANA titre - local

• IFA using HEp2 cells as substrate

• N = 95 (female = 76, male = 19)

• Age range 19 – 60 yrs

0

5

10

15

20

25

30

35

40

19 - 20 21 - 30 31 - 40 41 - 50 51 - 60

Age (yr)

ANA result Frequency %

<1:40 60 63.2%

1:40 18 18.9%

1:80 8 8.4%

1:160 2 2.1%

>1:160 7 7.4%

How to discriminate ANA-positive healthy individuals?

• ANA in healthy individuals and patients with limited symptoms

• Most will not develop systemic rheumatic diseases

• Autoantibodies are typically present many years before the diagnosis of SLE

ANA-positive apparently healthy subjects

How to discriminate ANA-positive healthy individuals?

918 healthy individuals and 153 patients with autoimmune rheumatic diseases ANA-positive individual were reevaluated after 3.6 – 5.0yr ANA by IFA cut-off at 1:80

Mariz et al. Arthritis & Rheumatism 2011

118/918 (12.8%) 138/153 (90.2%)

Follow-up of 40 healthy ANA-positive subjects at 3.6 – 5 years • None developed autoimmune rheumatic diseases • 29 remained ANA positive • 11 returned normal (initial ANA at 1:80)

Conclusion The findings suggest that the ANA titre and especially the pattern on Hep-2 cells strongly enhances our ability to discriminate ANA-positive healthy individuals and patients with autoimmune rheumatic diseases.


IFA ANA - criticisms

• Labor-intensive

• Subjective

• Variability in fluorescent microscopes

• Variability in human interpretation

Other methods OR

Automation of IFA


ELISA (enzyme-linked immunosorbent assay) / EIA (enzyme immunoassay)

• Selected ANAs ± HEp2 cell extracts • Objective results • Ability to automate

• No ANA pattern / titre


Fluorescent microsphere-based immunoassays

ANA IFA and ELISA / bead-based immunoassays – same?

Comparison study: IFA vs. ELISA

Copple et al. Am J Clin Pathol 2011

Copple et al. Am J Clin Pathol 2011

Specificity in healthy controls (n = 100) BioRad: 36% Phadia: 94% Aesku: 96% INOVA: 80% IFA: 100%

Sensitivity in SLE patients (n = 30) BioRad: 96.6% Phadia: 96.6% Aesku: 90.0% INOVA: 96.6% IFA: 80%

ANA – IFA automation?

• Automated digital imaging

• Fluorescence intensity quantification (titre)

• Modern pattern recognition algorithms for automated interpretation of immunofluorescence pattern

Components - a fluorescence microscope - a LED light source - a motorized scanning stage - a CCD camera - Software

http://www.labodia.com/eng/aklides/aklides_eng.htm

ANA - summary

1. First line test for symptomatic patients, NOT A SCREENING TEST FOR HEALTHY SUBJECTS

2. Various methods available, IFA is the gold standard

3. Cut-off at 1:160 high negative predictive value

4. Once positive, no need to monitor ANA level

5. Additional tests required for define Ab specificities

6. Negative ANA dose not exclude SLE

Specific ANA (1) Anti-dsDNA Antibody (DNA)

Anti-dsDNA Ab

• Present in 40% - 80% of SLE patients


• A specific marker

• Present in < 2% of patients with other autoimmune diseases

• Negative in drug-induced lupus

• Level reflects disease activity, lupus nephritis in particular – useful for disease monitoring

• May become negative in patients in remission / after treatment

Anti-dsDNA Ab methods

ELISA / Fluorescent microsphere-based

immunoassays

- Automation

- Quantitative

- Specificity?

RIA (Farr assay)

- Detect high avidity Abs

- Correlate best with disease activity

- Radioactive

-Manual

IFA using Crithidia lucilae

- Simple

- Not quantitative

- Sensitivity?

Anti-dsDNA Antibody by immunofluorescence

Crithidia luciliae • kinetoplast containing pure circular

dsDNA

Anti-dsDNA Ab method comparison

Antico et al. Lupus 2010

A. LIAISON dsDNA (DiaSorin) – chemiluminescent immunoassay (IgG) B. EliA dsDNA (Phaida) – fluorometric enzyme immunoassay (IgG) C. Orgentec anti-dsDNA (IgG) D. DIASTAT anti-dsDNA (Axis-Shield Diagnostics) (IgG) E. IFA using Crithidia lucilae (IgG) F. RIA (all isotypes)

SLE 54 Control 28 (patients with other CTD such as Sjögren syndrome, systemic sclerosis and polymyositis)

Limitations of first-generation EIA tests using DNA purified from tissue • presence of contaminating proteins such as histones • alteration of DNA molecules during the coating procedures

Antico et al. Lupus 2010

Sensitivity Specificity

Positive predictive

value

Negative predictive

value

The results suggest that newer commercial EIA methods seem to have overcome the problems of first-generation assays.

Specific ANA (2) Anti-Extractable Nuclear Antigens Antibodies (ENA)

Anti-ENA Antibodies

ENA Antigens Frequency in SLE

nRNP Anti-nuclear ribonucleoprotein (RNP) 25 – 47 %

Sm Anti-Sm 5 – 30 %

SS-A (Ro) Proteins 60 and 52 kDa, complexed with Y1 – Y5 snRNAs

24 – 60 %

SS-B (La) Phosphoproteins 48 kDa, complexed with Y1 nascent RNA

9 – 35 %

Scl-70 DNA topoisomerase I Scleroderma

Jo-1 Histidyl tRNA synthetase protein Polymyositis / dermatomyositis

Anti-Sm Ab

• Direct against 7 proteins that constitute the common core of U1, U2, U4 and U5 small nuclear ribonucleoprotein (snRNP).


• Detectable in 5 – 30% SLE patients

• More common African-Americans than Europeans

• Highly specific

• Almost always associated with anti-RNP

• Useful for diagnosis of SLE

Anti-ENA Ab methods

ELISA / EIA

Immunoblot / Western blot

Fluorescent microsphere-based immunoassay

Counter-immunoelectrophoresis (CIEP)

Anti-ENA Ab – Western blot

Anti-Phospholipid Antibodies

Anti-phospholipid syndrome Primary disorder or associated with other systemic autoimmune diseases.

International Criteria for the Classification of Antiphospholipid Syndrome

Clinical criteria • Vascular thrombosis: one or more episodes of arterial, venous, or small vessel thrombosis,

involving any organ and confirmed by appropriate imaging and/or histopathologic analyses. • Pregnancy morbidity: one or more unexplained deaths of a morphologically normal fetus after 10 weeks of gestation OR before 34 weeks of gestation due to preelampsia, eclampsia, or placental insufficiency OR 3 or more unexplained spontaneous abortions before 10 weeks of gestation.

Laboratory criteria • IgG or IgM isotype anti-cardiolipin antibody at medium or high titre on ≥ 2 occasions at least 12 weeks apart measured by a standardized ELISA. • Lupus anticoagulant on ≥ 2 occasions at least 12 weeks apart according to guidelines of the ISTH. • Anti-b2 glycoprotein I antibody (IgG or IgM isotypes) on ≥ 2 occasions at least 12 weeks apart

measured by a standardized ELISA according to recommended procedures.

One clinical criterion plus one laboratory criterion must be present

Anti-phospholipid Ab

• Can be detected in 1 – 5% of healthy women

• One of the ACR 1997 diagnostic criteria for SLE

• Abnormal IgM or IgG anti-cardiolipin Ab

• Lupus anticoagulant

• False-positive syphilis serology

• The Venereal Disease Research Laboratory (VDRL) test

• Detect antibodies produced by patients with syphilis which reacts with extract from ox hearts (e.g. cardiolipin).

• 1/3 SLE patients have antiphospholipid Abs

• 1/3 of these (~11% of SLE patients) sustain thromboembolic event or recurrent miscarriages as a consequence

• All women with SLE who want to become pregnant should be tested


Anti-cardiolipin Ab (ELISA)

Lupus anticoagulant

Anti-2GPI (ELISA)

Cardiolipin & 2-glycoprotein I

Prothrombin & 2-glycoprotein I (only a subpopulation of these autoantibodies can induce a prolongation of a clotting assay).

2-glycoprotein I alone but there are multiple epitopes


• 3 assays for anti-phospholipid Ab

• Lupus anticoagulant correlates best with thrombotic complications / recurrent fetal losses

• Highest risk in “triple-positive”

• Transient presence of anti-phospholipid Ab in SLE patients / fluctuations with disease activity or treatment with corticosteroids.

• A positive result should be confirmed

Newer Auto-antibodies in SLE Anti-nucleosome Ab (AnuA) Anti-RNA Helicase A Ab (RHA)

Anti-nucleosome Ab • Nucleosome – the fundamental package unit of

dsDNA

• ~200bp of DNA wrapped twice around the (H2A-H2B-H3-H4)2 histone octamer with histone H1 bound on the outside

• A metanalysis in 2012

• Data shown that anti-nucleosome Ab are highly accurate diagnostic marker for SLE.

Assay Methods / Antigens Sensitivity Specificity

ANuA H1-stripped nucleosomes 61% 95.7%

Whole nucleosomes 59% 87.5%

Anti-dsDNA

ELISA 55.8% 92.5%

Crithidia 33.6% 97.2%

RIA 60.2% 96.7% Bizzaro et al. Autoimmunity 2012

Anti-RNA helicase A Ab

• RNA helicase A – a multifunctional nuclear protein that binds to dsDNA, RNA, mRNA, and highly structured viral RNA.

• Detectable in ~6% of SLE patients

• Not detectable in other systemic autoimmune diseases

• Less frequent in African-Americans (2.9%)

• More frequently found in young patients

• More frequently found in the early stage of disease

• The level dropped dramatically within a few years and often become undetectable.

Summary

1. Systemic Lupus Erythematosus

• Prevalence 0.1% (0.19% for female, 0.02% for male)

• Annual incidence 6.7 per 100,000

2. Laboratory play an important role in diagnosis and monitoring

3. Wide range of methodologies

4. Appropriate request and interpretation for anti-nuclear antibodies

5. Disease marker antibodies

• Anti-dsDNA antibodies – frequent monitoring

• ENA: Sm (Ro, La, RNP)

6. Three methods for detection of anti-phospholipid antibodies

Acknowledgement

Dr Danny Leung, SO

Ms Janet Tang, AMT

Clinical Immunology Unit

Department of Chemical Pathology

Prince of Wales Hospital

References

1. Mok CC. Epidemiology and survival of systemic lupus erythematosus in Hong Kong Chinese. Lupus 2010;0:1-5.

2. Mok CC, Tang SSK, To CH, Petri M. Incidence and risk factors of thromboembolism in systemic lupus erythematosus. Arthritis & Rheumatism 2005;52(9):2274-2782.

3. Kumar Y, Bhatia A, Minz RW. Antinuclear antibodies and their detection methods in diagnosis of connective tissue diseases: a journey revisited. Diagnostic Path 2009;4:1-10.

4. Satoh M, Chan EKL, Sobel ES, Kimpel DL, et al. Clinical implication of autoantibodies in patients with systemic rheumatic diseases. Expert Rev Clin Immunol 2007;3(5):721-738.

5. Antico A, Platzgummer S, Bassetti D, et al. Diagnosing systemic lupus erythematosus: new-generation immunoassays for measurement of anti-dsDNA antibodies are an effective alternative to the Farr technique and the Crithidia lucilae immunofluorescence test. Lupus 2010;19:906-912.

References

6. Migliorini P, Baldini C, Rocchi V, Bombardieri S. Anti-Sm and anti-RNP antibodies. Autoimmunity 2005;38(1):47-54.

7. Bizzaro N, Villalta D, Giavarina D, Tozzoli R. Are anti-nucleosome antibodies a better marker than anti-dsDNA antibodies for systemic lupus erythematosus? A systematic review and a study of metanalysis. Autoimmunty 2012 (in press).

8. Ortel TL. Antiphospholipid syndrome: laboratory testing and diagnostic strategies. Am J Hematol 2012;87:S75-S81.

9. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306.

10. De Groot P, Urbanus RT. The significance of autoantibodies against 2-glycoprotein I. Blood 2012;120(2):266-274.

11. Danza A, Ruiz-Irastorza G, Khamashta M. Antiphospholipid syndrome in obstetrics. Best Pract Res Clin Obstet Gyn 2012;26:65-76.

References

12. Villalta D, Tozzoli R, Tonutti E, Bizzaro N. The laboratory approach to the diagnosis of autoimmune disease: is it time to change? Autoimmun Rev 2007;6:359-365.

13. Melegari A, Bonaguri C, Russo A, Luisita B, et al. A comparative study on the reliability of an automated system for the evaluation of cell-based indirect immunofluorescence. Autoimmun Rev 2012;11:713-716.

14. Yamasaki Y, Narain S, Yoshida H, et al. Autoantibodies to RNA helicase A. Arthritis & Rheumatism 2007;56(2):596-604.

15. Egner W. The use of laboratory tests in the diagnosis of SLE.J Clin Pathol 2000;53:424-432.

16. Mariz HA, Sato EI, Barbosa SH, et al. Pattern on the antinuclear antibody-Hep-2 test is a critical parameter for discriminating antinuclear antibody positive healthy individuals and patients with autoimmune rheumatic diseases. Arthritis & Rheumatism 2011;63(1):191-200.

17. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. NEJM 2003;349:1526-33.

Types of lupus erythematosus • Systemic lupus erythematosus (SLE), 70%

• Cutaneous lupus, 15%

• Drug-induced lupus erythematosus, 5% • ~ 15,000 cases reported annually in the United States • > 80 offending drugs • 99% disappear within 3 months of withdrawing the

offending drug

• Overlap syndrome / mixed connective tissue disease, 10% • Systemic sclerosis, polymyositis/dermatomyositis

Clinical features (1) 1. Skin

• Malar (butterfly) rash, discoid rash, alopecia

2. Constitutional symptoms e.g. fatigue, fever, lymphadenopathy, anorexia and nausea

3. Neurological

• CNS: aseptic meningitis, cerebrovascular disease, demyelinating syndrome, headache / migraine, movement disorder, transverse myelitis, seizure, acute confusion, cognitive dysfunction, psychosis

• PNS: acute inflammatory demyelinating syndrome, myasthenia gravis, polyneuropathy

4. Musculoskeletal

• Arthralgia, myalgia, arthritis, myositis

Clinical features (2)

5. Cardiovascular-respiratory

• Pleuritis, pleural effusion, pneumonitis, fibrosing aveolitis

• Pericarditis, pericardial effusion, valvular disease, atherosclerosis (lupus patients between the ages of 35 and 45 are 50 times more likely to have a heart attack)

6. Kidneys

7. Blood (cytopenias)

8. Eye

• Cataract, retinal vasculitis, Sjögren syndrome

9. Gastrointestinal tract

• Mouth ulcers, Sjögren syndrome

SLE – standard treatment 1. Antimalarials e.g. hydroxychloroquine

• Unclear mechanism of actions • Not used as primary treatment for major organ involvement

2. Corticosteroids e.g. prednisolone • Broad immunosuppressive effects • Long term side effects: decreased bone mineral density, weight

gain, hypertension, diabetes mellitus, glaucoma, and cataract

3. Cyclophosphamide • Reserved for severe manifestations • Highly toxic - premature ovarian failure, infertility, and

increased risk for malignancies 4. Azathioprine

• Maintenance treatment for lupus nephritis

5. Mycophenolate mofetil (MMF) • Induction and maintenance treatment for lupus nephritis

6. Methotrexate

SLE – novel treatment

Lo & Tsokos. Ann NY Acad Sci 2012

http://en.wikipedia.org/wiki/File:Biological_cell.svg

Luminex xMAP technology

1. Bio-Rad: Bio-Plex® suspension array system

2. BMD (Biomedical Diagnostics): FIDIS™ system

3. INOVA Diagnostics, Inc: QUANTA Plex®.

4. ZEUS Scientific: AtheNA Multi-Lyte® Test System

http://www.luminexcorp.com/Applications/ClinicalDiagnostics/AutoimmuneDisease/index.htm

Hong Kong Lupus Association

• http://www.hklupus.org.hk/www/index.php?option=com_content&task=category&sectionid=3&id=68&Itemid=42

C3 and C4

• Complement system

• Innate immune system

• Clears pathogens

• > 30 plasma and membrane-bound proteins (inactive precursors)

• SLE patients

• Activation of the complement systems

• Decrease in complement proteins concentrations

C3 and C4

1. ↑SLE disease activity significantly decreased levels of C3 and C4.

2. Impending flare of SLE may be heralded by progressive fall of C3 and C4 levels.

3. SLE patients with renal involvement have markedly reduced C3 and C4 levels more frequently than patients with only extra-renal involvement.

SLICC

• The Systemic Lupus International Collaborating Clinics / American College of Rheumatology (SLICC/ACR) Damage Index for SLE

• Damage index: permanent damage that has developed since the diagnosis of the disease was made.

SLEDAI

• Systemic Lupus Erythematosus Disease Activity Index

• Activity index: clinical features due to ongoing inflammation

Weight Descriptor Definition

8 Seizure Recent onset (last 10 days). Exclude metabolic, infectious, drug cause, or seizure due to past irreversible CNS damage.

8 Psychosis Altered ability to function in normal activity due to severe disturbance in the perception of reality. Include hallucinations, incoherence, marked loose associations, impoverished thought content, marked illogical thinking, bizarre, disorganized or catatonic behavior. Exclude uremia and drug causes.


8 Organic brain syndrome

Altered mental function with impaired orientation, memory or other intellectual function with rapid onset and fluctuating clinical features. Include clouding of consciousness with reduced capacity to focus and inability to sustain attention to environment, plus at least 2 of the following: perceptual disturbance, incoherent speech, insomnia or daytime drowsiness, or increased or decreased psychomotor activity. Exclude metabolic, infectious or drug causes.

8 Visual disturbance

Retinal and eye change of SLE. Include cytoid bodies, retinal hemorrhages, serious exudate of hemorrhage in the choroid, optic neuritis, seleritis or episcleritis. Exclude hypertension, infection or drug causes.

8 Cranial nerve disorder

New onset sensory or motor neuropathy involving cranial nerves. Include vertigo due to lupus.

8 Lupus headache Severe persistent headache: may be migrainous but must be non-responsive to narcotic analgesia.

8 Cerebrovascular accident

New onset of CVA. Exclude arteriosclerosis or hypertensive causes.


8 Vasculitis Ulceration, gangrene, tender finger nodules, periungual infarction, splinter hemorrhages, or biopsy or angiogram proof of vasculitis.

4 Arthritis More than 2 joints with pain and signs of inflammation.

4 Myositis Proximal muscle aching/weakness associated with elevated CK or EMG changes or a biopsy showing myositis.

4 Urinary casts Heme-granular or red blood cell casts

4 Hematuria > 5 red blood cells / high power field. Exclude stone, infection, and other causes.

4 Proteinuria New onset or recent increase of more than 0.5g/24 hrs

4 Pyuria > 5 WBC / high power field. Exclude infection.

2 Rash New of ongoing inflammatory lupus rash.

2 Alopecia New of ongoing abnormal patchy or diffuse loss of hair due to active lupus.

2 Mucosal ulcers New of ongoing oral or nasal ulcerations due to active lupus.

2 Pleurisy Classic and severe pleuritic chest pain or pleural rub or effusion or new pleural thickening due to lupus.


2 Pericarditis Classic and severe pericardial pain or pleural rub or effusion or ECG confirmation.

2 Low complement Decrease in CH50, C3, C4 below the lower limit of normal for testing laboratory.

2 Increased DNA binding

>25% binding by Farr assay or above normal range for testing laboratory.

1 Fever > 38C. Exclude infectious causes.

1 Thrombocytopenia < 100,000 platelets / mm3

1 Leukopenia < 3000 WBC / mm3. Exclude infectious cause.

Total score Sum of weights

Score if descriptor is present at time of visit or in the preceding 10 days.

Antigen Molecular Structure Autoantibody frequency

Native DNA Double-stranded DNA 40 – 90

Denatured DNA Single-stranded DNA 70

Chromatin (nucleosome) H1, H2A, H2B, H3, H4 50 – 70

Sm Proteins 29 (B’), 28 (B), 16 (D), and 13 (E) kDa, complexed with U1, U2 and U4 – U6 snRNAs; spliceosome component

15 – 30

Nuclear RNP (U1nRNP) Proteins 70, 33 (A), and 22 (C) kDa; spliceosome component

30 - 40

SS-A/Ro Proteins 60 and 52 kDa, complexed with Y1-Y5 RNAs

24 – 60

SS-B/La Phosphoproteins 48 kDa, complexed with Y1 nascent RNA Pol transcripts

9 – 35

Ku Proteins 86 and 66 kDa, DNA-binding proteins

1 – 19

hnRNP protein A1 Nuclear protein 34 kDa 31 – 37

Antigen Molecular Structure Autoantibody frequency

Proliferating cell nuclear antigen (PCNA)

Protein 36 kDa; auxiliary protein of DNA polymerase

3

Ribosomal RNP Phosphoproteins 38, 16 and 15 kDa associated with ribosomes

10 – 20

Hsp-90 Heat-shock protein 90 kDa 5 – 50

Golgi complex Golgins, giantin Unknown

HMG-17 DNA associated proteins, 9 to 17 kDa 34 – 70

2-glycoprotein I Anionic phospholipids, cardiolipin 25

laboratory testing for lupus systemic erythematosus · anti-nuclear antibody (ana) ... predictive...

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