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Lupus Allan D. Corpuz, MD, FPCP, DPRA
Section of Rheumatology Department of Medicine
Philippine GENERAL HOSPITAL
Objectives • Recognize the clinical manifestations of SLE • Order the important diagnostic tests • Enumerate the treatment modalities • Know when and where to refer • Counsel patients with the disease
What is SLE: Systemic
What is SLE: Autoimmune
pDCs
Res(ng epithelium Dysregulated (ssue
Chemokine
BAFF/BlyS ANA
Type I IFNs
virus
AutoAb
IC 1. Voulgarelis M, et al. Nat Rev Rheumatol.2010;101:529-‐537. 2. Jonsson R, et al. Immunol LeQ. 2011;141:1-‐9. 3. Nocturne G,et al. Nat Rev Rheumatol. 2013 Jul 16. doi: 10.1038
IL-‐1β, IFN-‐γ,T
NF-‐α
What is SLE: Autoimmune
What is SLE: Autoimmune
What is SLE: Chronic, Relapsing, Inflammatory
What is SLE: Primarily Female
9 1
The Impaired Immune System in SLE
Pathogenesis
T cells
B cells
Complement
Pathogenesis: Panoramic View
APOPTOSIS: Programmed
Cell Death
But some things don’t go as programmed…
Complement in the Pathogenesis of SLE
What it is NOT
In Summary • What it Is – Systemic – Autoimmune – Chronic – Relapsing – Inflammatory – Often febrile – Female – Impaired Immune System – Can be controlled
• What It is Not – Uniformly fatal – Hopeless – Curable
DIAGNOSIS
1997 update of the 1982 ACR Classification Criteria
Malar rash
Discoid Rash
Discoid Rash
Oral Ulcer
Photosensitive Rash
Serositis
Non-erosive arthritis
Nephritis
Seizures Psychosis
WBC < 4000/mm3 Platelet <100,000/mm3
Hemolytic Anemia
Positive Antinuclear Antibody
Immunologic Disorder • Anti-dsDNA • Anti-Smith • Positive finding of aPL Abs – Abnormal serum concentration of IgG/IgM
Anticardiolipin Abs – (+) test result for lupus anticoagulant – False (+) serologic test for syphilis known to be (+) for
6mos and confirmed by T.pallidum immobilization or FTA-Abs test
Frequency of Manifestations of SLE
2012 SLICC Criteria
In Summary: SOAP BRAIN MD • Serositis • Oral Ulcer • Arthritis • Photosensitivity • Blood disorder • Renal Disorder • ANA • Immunologic Disorder • Neurologic Disroder • Malar rash • Discoid Rash
At least
4 of the11
Fulfillment of these criteria is NOT an
absolute requirement for Dx
DIAGNOSTIC TESTING
• No clinical manifestation or lab test can serve as a definitive diagnostic test
• SLE is diagnosed based on a constellation of characteristic signs and symptoms and lab findings in the appropriate clinical context
Serologic Tests 790 PART 7 | DIAGNOSTIC TESTS AND PROCEDURES IN RHEUMATIC DISEASES
Because of the characteristic presence of these autoantibod-ies among the ANA diseases, ANAs have long been specu-lated to play a role in disease pathogenesis. Anti-DNA antibodies, for instance, have been suspected to promote inflammation in SLE nephritis via immune complex deposi-tion, direct binding to cross-reactive glomerular antigens, and/or intracellular penetration and induction of cellular toxicity.6 Similarly, ribonucleoprotein antibodies such as anti-Ro/SSA, anti-La/SSB, and anti-Sm have been impli-cated in the pathogenesis of cutaneous or cardiac manifesta-tions by penetrating live cells and/or binding to exposed antigens in the skin and/or the heart.7,8 Sera containing anti-Scl-70 (topoisomerase I) activity can induce high levels of interferon (IFN)-α, correlating with diffuse cutane-ous scleroderma and lung fibrosis9; also, anti-Jo-1- or anti-Ro/SSA-positive sera from myositis patients have been demonstrated to induce type I IFN and/or intercellular adhesion molecule (ICAM)-1 on endothelial cells.10,11
However, autoantibodies alone appear insufficient to account for disease pathogenesis. Induction of type I IFN activity by anti-Ro/SSA–containing sera, for instance, appears restricted to patients with SLE or SS, not asymp-tomatic individuals,12 and surface binding of topoisomerase I may be required for a pathogenic effect of anti-Scl-70 antibodies.13 This may reflect additional biologic issues among or effects of the autoantigens themselves, such as novel conformations or epitopes: for instance, a proteolyti-cally sensitive conformation of histidyl-transfer RNA syn-thetase (HisRS), the target of the pulmonary fibrosis–related Jo-1–specific antibody, has been described in the lung,14 and an apoptope (epitope expressed on apoptotic cells) of Ro/SSA may be specific to SLE, suggesting a unique role of apoptosis in disease pathogenesis.15 The autoantigens them-selves may have unique biologic functions: 60-kD Ro/SSA, for instance, may serve as a receptor for the antiphospholipid-related β2-glycoprotein I, and this dynamic may account for differences in Ro antibody pathogenicity.16 However, many autoantigens likely have intrinsic proinflammatory proper-ties, such as stimulation of innate inflammation by DNA and RNA via Toll-like receptors (TLRs) 3, 7, and 9,17,18 or induc-tion of smooth muscle responses by the centromere protein CENP-B via CCR3.19 Apparent remission of SLE in a patient has been correlated with loss of TLR responsiveness, anti-body deficiency, and disappearance of anti-DNA, supporting such concepts.20 Thus the pathogenesis of the connective tissue diseases appears to reflect a complex interplay between direct inflammatory or other biologic effects of the autoan-tigens and consequences of autoantibody responses.
METHODS OF DETECTION
Table 55-1 Antinuclear Antibody (ANA)-Associated Diseases and Related Conditions
ConditionPatients with ANAs (%)
Diseases for Which ANA Testing Is Helpful for Diagnosis
Systemic lupus erythematosus 99-100Systemic sclerosis 97Polymyositis/Dermatomyositis 40-80Sjögren’s syndrome 48-96
Diseases in Which ANA Is Required for Diagnosis
Drug-induced lupus 100Mixed connective tissue disease 100Autoimmune hepatitis 100
Diseases in Which ANA May Be Useful for Prognosis
Juvenile idiopathic arthritis 20-50Antiphospholipid antibody syndrome 40-50Raynaud’s phenomenon 20-60
Some Diseases for Which ANA Typically Is Not Useful
Discoid lupus erythematosus 5-25Fibromyalgia 15-25Rheumatoid arthritis 30-50Relatives of patients with autoimmune disease 5-25Multiple sclerosis 25Idiopathic thrombocytopenic purpura 10-30Thyroid disease 30-50Patients with silicone breast implants 15-25Infectious disease Varies widelyMalignancies Varies widely
Healthy (“Normal”) Individuals
≥1 : 40 20-30≥1 : 80 10-12≥1 : 160 5≥1 : 320 3
Adapted from Kavanaugh A, Tomar R, Reveille J, et al, American College of Pathologists: Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens, Arch Pathol Lab Med 124:71–81, 2000.
detected by FANA testing led to the description of Smith (Sm), nuclear ribonucleoprotein (nRNP), Ro/Sjögren’s syn-drome (SSA), and La/SSB specificities, which later gained further biologic prominence with the demonstration that their autoantigens play prominent roles in cellular homeo-stasis (e.g., snRNPs, targets of anti-Sm and anti-nRNP) and in regulation of premessenger RNA splicing.5 Subsequent investigations have revealed an ever growing array of auto-antigens (Table 55-2), many of which remain largely uncharacterized. Thus, ANAs not only serve as diagnostic markers in autoimmunity but to this day have greatly aided studies on cellular biochemistry.
RELEVANCE OF ANTINUCLEAR ANTIBODIES TO DISEASE PATHOGENESIS
KEY POINT
ANAs and their respective autoantigens have been implicated in disease pathogenesis as producing directly toxic or other proinflammatory effects.
KEY POINTS
The gold standard screening test for ANAs is the fluorescent ANA test.
Many antibody tests, including ANA screening in some laboratories, are performed via enzyme-linked immunosorbent assay (ELISA) because this method affords higher throughput testing, but this technique often results in lower specificity.
Optimal clinical interpretation of ANA tests requires knowledge of the technique(s) used in each specific case.
Antinuclear Antibodies • Anti-nuclear (or anticytoplasmic) Abs bind to cells fixed on a
slide • Addition of a secondary Ab (with an attached fluorescent
dye) • Dilution at 1:40 and 1:160 buffered solution • The titer is a measure of the amount of ANA in the blood
(higher titer – more autoABs) • Standardization: 30% of normal individuals will have a
positive test at 1:40 (sensitive) • At 1:160, only 5% of normal individuals will have a positive
test (specific)
False Positives • 32% in normal individuals (>1:40) • 13% (>1:80) • 3% (>1:320) • Relatively constant over time
Tan EM, Feltkamp TE, Smolen JS, et al. Range of an(nuclear an(bodies in "healthy" individuals. Arthri(s Rheum 1997; 40:1601.
False Negatives • From technical and physical nuances • Method of substrate fixation, the solubility of the
antigen (eg, Ro, La, PCNA, and Ku), and the localization of the antigen outside the nucleus (ie, Jo-1 and single stranded DNA)
• There is rarely any need to request testing for antibodies to DNA, Sm, RNP, Ro/SSa, or La/SSb unless the ANA is known to be positive
• Elderly (<1:80 titer) Tan EM, Feltkamp TE, Smolen JS, et al. Range of an(nuclear an(bodies in "healthy" individuals. Arthri(s Rheum 1997; 40:1601.
IF (1:160) vs ELIA • ELIA: recombinant technology (using kits); faster,
no training needed • Agreement: 87-95% • Sensitivity: 69-98% • Specificity: 81-98%
• Still with high # of false +
Jaskowski TD, Schroder C, Mar(ns TB, Mouritsen CL, Litwin CM, Hill HR: Screening for an(nuclear an(bodies by enzyme immu-‐ noassay. Am J Clin
Pathol 1996, 105:468-‐473.
Bizzaro N, Tozzoli R, Tonu^ E, Piazza A, Manoni F, Ghirardello A, Basse^ D, Villalta D, Pradella M, Rizzo^ P: Variability between methods to determine ANA, an;-‐dsDNA and an;-‐ENA
auto an;bodies: a collabora;ve study with the biomedical industry. J Immunol Methods 1998, 219:99-‐107.
Interpretation
A negative or low titer ANA-IF in the
setting of low clinical suspicion of rheumatic disease usually indicates the
absence of significant ANAs and
argues against the diagnosis of one of the ANA diseases
When to treat Although the ANA-IF pattern and titer may provide
insight into the specific auto-Ag(s) targeted, as well as the potential likelihood of CTD,
such correlations should ONLY guide, NOT absolutely determine, clinical
decisions
Some specific ANAs possess diagnostic significance and would need follow-up with specialized assays BUT ONLY IN THE SETTING OF STRONG
CLINICAL SUSPICION because: 1. the PPV of an ANA in the absence of other clinical signs of CTD is low, in part because it may precede clinical disease by many years 2. because of the relatively high incidence of ANA in normal individuals
If specific testing is negative in the setting of high clinical suspicion, repeat testing at a later
date may be warranted, because titers of such autoantibodies can fluctuate over time, irrespective of disease course.
General Guidelines • -ANA testing is not helpful in confirming a
diagnosis of rheumatoid arthritis or osteoarthritis therefore should not be used in such conditions.
• - ANA testing is not recommended to evaluate fatigue, back pain or other musculoskeletal pain unless accompanied by one or more of the clinical features in favor of a CTD.
• - ANA testing should usually be ordered only once. • - Positive ANA tests do not need to be repeated.
• - Negative tests need to be repeated only if there is a strong suspicion of an evolving CTD or a change in the patient's illness suggesting the diagnosis should be revised.
• - A positive ANA test is important only in conjunction with clinical evaluation and in the absence of symptoms and signs of a CTD; a positive ANA test only confounds the diagnosis. A positive ANA test can also be seen in healthy individuals, particularly the elderly or in a wide range of diseases other than CTD, where it has no diagnostic or prognostic value.
Kavanaugh A, Tomar R, Reveille J, Solomon DH, Homburger HA: Guidelines for Clinical Use of the An;nuclear An;body Test and Tests for Specific Auto an;bodies to Nuclear An;gens.
Arch Pathol Lab Med 2000, 124:71-‐81.
Guidelines and Protocols Advisory CommiOee. BCGuide-‐ lines.ca 2007.
Other Serologic Tests
Other Tests • CBC with platelet count • U/A, 24 hour urine studies (TV, TP, Crea) • BUN, Creatinine • Electrolytes • LFTs • CXR • 2D Echo • Kidney Biopsy • Complement (C3, C4, CH50)
IMPACT on LIFE • Chronically fatigued: vicious cycle • Inability to finish school and find jobs • Inability to sustain jobs • Depression and Anxiety • Family Support
SUMMARY • Systemic autoimmune chronic relapsing
inflammatory disease • Protean Manifestations (SOAP BRAIN MD) • No definitive diagnostic test • Use and Interpret S/Sx and tests based on a
clinical context • Poor HRQoL