RA Patklin H.Sukma.pdf
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Transcript of RA Patklin H.Sukma.pdf
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INTRODUCTION
Total Concept Diagnosis of Rheumatoid Arthritis
PT SALI POLAPA BERSAMA
By : Herlangi Sukma
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RHEUMATOID ARTHRITIS
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Manifestation• Joint swelling
(symmetrical)• Pain• Loss of mobility• Fatigue
Consequences• Destruction of cartilage• Erosion of bones• Deformation• Disability• Death
RHEUMATOID ARTHRITIS
DESTRUCTIVE DISEASE
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Rheumatic Diseases
Rheumatism• „Rheuma“ is derived from the Greek
and describes a flowing pain
• A non-specific term for medical problems affecting the heart, bones, joints, kidney, skin and lung no injury or tumor
• Rheumatism, about 400 diseases, that often differ significantly in cause, symptoms, disease progression, therapy and health consequences
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Rheumatoid Arthritis
PT. SALI POLAPA BERSAMA
• Morning stiffness lasting for at least 1 hr.
• Arthritis of 3 or more joint areas
• Arthritis of hand joints
• Symmetric arthritis
• Rheumatoid nodules
• Serum Rheumatoid Factor (RF)
• Typical radiographic changes
Arnett FC et al, Arthritis Rheum 31:315-324,1988
Classification criteria of RA (ACR-1987, rev.)
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What happens ?• Swelling of the synovial lining, causing
pain, stiffness, redness and swelling around the joint
• Rapid division and growth of cells (pannus), which causes the synovium to thicken
• Inflamed cells release enzymes that damage, bone & cartilage. The involved joint looses its shape and alignment
• Pain and loss of movement
Rheumatoid Arthritis
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Rheumatoid Arthritis
RA/RIS/09-07PT. SALI POLAPA BERSAMA
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Stages of Rheumatoid Arthritis
RA/RIS/09-07
Early Intermediate Late
RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
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Clinician Treatment :1. Symptoms
2. Causative
RA/RIS/09-07
RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
Anamnesis and Clinical picture
Morning stiffness of jointsSymmetrical joint inflammationRheumatoid nodulesFeverMyalgia
Laboratory Tests :ESRCRPRheumatoid FactorsAnti-CCP
Imaging Technologies
X-RayUltrasoundMRT
- Medication- Fisiotherapy
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Rheumatoid Arthritis
Key facts• Rheumatoid arthritis (RA) is a chronic,
progressive and disabling autoimmune disease• RA causes stiffness, pain, loss of mobility,
inflammation, and erosion in the joints• RA affects 1 % of the population• over 40 % of RA patients are disabled within 3 years * RA is an autoimmune disease
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What is an Autoimmune Disease ?
• When your body is attacked ...
• .... by bacteria, viruses or parasites ....
• .... your immune system defends you
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The Loss of Immunological Tolerance
• Normal• Immune system attacks foreign antigens
but tolerizes the own cells
• Pathological• Immune system attacks foreign and self
• antigens and destroys the tissues and organs -
+
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Autoimmune Disease ?
PT SALI POLAPA BERSAMA
This is Autoimmunity
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Prevalence of Autoimmune Diseases?
According toRose et al., 1998, The Autoimmune diseases, 3rd Ed.US Census Bureau, Int. Data Base, 2004
Total Prevalence of Autoimmune diseases
• Canada - 1.0 Mio.• Brazil - 5.8 Mio.• Mexico - 3.3 Mio.• Germany - 2.6 Mio.• France - 1.9 Mio.• Russia - 4.5 Mio.
• Iran - 2.1 Mio.• Egypt - 2.4 Mio.• Ethiopia - 2.3 Mio.• India - 33.3 Mio• China - 41.0 Mio.• Thailand - 2 Mio.
PT SALI POLAPA BERSAMA
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Prevalence of Autoimmune Diseases?
Autoimmune Disease (AID) Prevalence• Autoimmune thyroid disease 2.0 % • Rheumatoid arthritis 1.0 %• Systemic Lupus erythematodes 0.5 %• Celiac disease 0.4 %• Pernicious anemia 0.1 %
PT SALI POLAPA BERSAMA
J. DARMAWAN*,, K. D. MUIRDEN , H. A. VALKENBURG* and R. D. WIGLEY , 1993
0,2 % in 4683 rural and 0,3 % in 1071 urban in Semarang - Indonesia
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What is an Autoimmune Disease ?
Organ specific• Hashimoto‘s
Thyroiditis• Celiac disease• Pernicious anemia• Goodpasture‘s
syndrome• AI Liver Diseases
Systemic• Rheumatoid arthritis• Systemic Lupus
Erythematodes (SLE)• Antiphospholipid
syndrome (APS)• Wegeners‘s
granulomatosis
PT SALI POLAPA BERSAMA
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Laboratory investigations• ESR / CRP level
• Rheumatoid Factor (RF)
• Complete Blood Count (CBC)
• Electrolytes
• Creatinin level
• Hepatic panel (AST, ALT and albumin)
• Urinalysis
• Synovial fluid analysis
• Auto-antibodies
(ACR Subcommitee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002)
RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
PT. SALI POLAPA BERSAMA
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Laboratory investigations
• ESR / CRP level
• Rheumatoid Factor (RF)
• Complete Blood Count (CBC)
• Electrolytes
• Creatinin level
• Hepatic panel (AST, ALT and albumin)
• Urinalysis
• Synovial fluid analysis
• Auto-antibodies
(ACR Subcommitee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002)
RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
HUMASED 40
IMTEC Hs CRP ELISAHs CRP (Fotometri)CRP (turbidimetri)Humatex CRP
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Laboratory investigations
• ESR / CRP level
• Rheumatoid Factor (RF)
• Complete Blood Count (CBC)
• Electrolytes
• Creatinin level
• Hepatic panel (AST, ALT and albumin)
• Urinalysis
• Synovial fluid analysis
• Auto-antibodies
(ACR Subcommitee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002)
RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
Humatex RF Latex (Rapid Test)RF latex reagent (turbidimetry)IMTEC IgM-RF ELISAIMTEC IgA-RF ELISAIMTEC IgG-RF ELISAIMTEC RF-Sreen IgGAM ELISA
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Humatex RF Cat.No. 40052, 40050, 40053 • Latex agglutination qualitative, cut-off 20 IU/ml• Semi quantitative, diluted with Glycine-NaCl Buffer
sensitivity 12 IU/ml standard “International Reference Preparation of Rhematoid Arthritis Serum” (WHO).
1 : 2 24 IU/ml
1 : 4 48 IU/ml1 : 8 96 IU/ml1 : 16 192 IU/ml1 : 32 384 IU/ml
• Sensitivity : ≥ 12 IU/ml
Rheumatoid Arthritis
PT SALI POLAPA BERSAMA
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RF HUMAN• Cat.No. 11261P • Photometric-Turbidimetry, with standard concentration
on the label. • Sensitivity : 20 – 100 IU/ml, no prozone up to 1,000 IU/
ml• Diluent, Latex, • Std. (conc. on label), calib. Curve 1 - 5
PT SALI POLAPA BERSAMA
Rheumatoid Arthritis
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IMTEC RF IgG, IgA, IgM• ELISA Quantitative determination of Rheumatoid
Factors
• RF Ig G, Cat.no. ITC60007
• RF Ig A, Cat.no. ITC60010
• RF Ig M, Cat.no. ITC60003
Rheumatology
PT SALI POLAPA BERSAMA
Consisting of :
- CAL 1 – 5 = 12,5 – 25 – 50 – 100 - 200 U/ml
- CTRL +, CTRL - , BUFF WASH, BUFF DIL, CONJ., SUBS, STOP.Sol.
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IMTEC RF Screen IgGAM• ELISA Quantitative determination of Rheumatoid
Factors
• Cat.no. ITC60000
Rheumatology
PT SALI POLAPA BERSAMA
Consisting of :
- CAL 1 – 5 = 12,5 – 25 – 50 – 100 - 200 U/ml IgGAM
- CTRL +, CTRL - , BUFF WASH, BUFF DIL, CONJ., SUBS, STOP.Sol.
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Laboratory investigations
• ESR / CRP level
• Rheumatoid Factor (RF)
• Complete Blood Count (CBC)
• Electrolytes
• Creatinin level
• Hepatic panel (AST, ALT and albumin)
• Urinalysis
• Synovial fluid analysis
• Auto-antibodies
(ACR Subcommitee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002)
RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS. HUMACOUNT INSTRUMENT
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Laboratory investigations
• ESR / CRP level
• Rheumatoid Factor (RF)
• Complete Blood Count (CBC)
• Electrolytes
• Creatinin level
• Hepatic panel (AST, ALT and albumin)
• Urinalysis
• Synovial fluid analysis
• Auto-antibodies
(ACR Subcommitee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002)
RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
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Laboratory investigations
• ESR / CRP level
• Rheumatoid Factor (RF)
• Complete Blood Count (CBC)
• Electrolytes
• Creatinin level
• Hepatic panel (AST, ALT and albumin)
• Urinalysis
• Synovial fluid analysis
• Auto-antibodies
(ACR Subcommitee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002)
RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
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Laboratory investigations
• ESR / CRP level
• Rheumatoid Factor (RF)
• Complete Blood Count (CBC)
• Electrolytes
• Creatinin level
• Hepatic panel (AST, ALT and albumin)
• Urinalysis
• Synovial fluid analysis
• Auto-antibodies
(ACR Subcommitee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002)
RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
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Laboratory investigations
• ESR / CRP level
• Rheumatoid Factor (RF)
• Complete Blood Count (CBC)
• Electrolytes
• Creatinin level
• Hepatic panel (AST, ALT and albumin)
• Urinalysis
• Synovial fluid analysis
• Auto-antibodies : Anti CCP, Anti RA33
(ACR Subcommitee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002)
RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
Bezugslinie / Reference Line /Linea di rifertimento
Nukleosom / Nucleosomes
Histon / HistonesSmD1
U1-snRNPSS-A / Ro 60 kD
SS-B / LaScl 70Zentromer / CentromereJo-1
SS-A / Ro 52 kD
cut-off-Kontrolle / ControlFunktionskontrolle / Functional Control
ELISA
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HUMAN-IMTEC - Key Notes
HUMAN-IMTEC - Quality
• Certified under DIN EN ISO 13485:2001 and DIN EN ISO 9001
• First manufacturer of IVD in Germany to meet the requirements of the European IVD directive
• Proven quality for over 15 years
PT SALI POLAPA BERSAMA
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Human - IMTEC - Key Notes
Inovation – IMTEC
IMTEC products has protected and patented in 20 countries Germany and International.
It shows inovation and profesional competency
PT SALI POLAPA BERSAMA
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Human - IMTEC-Product Line
The IMTEC product
range includes ...
Bezugslinie / Reference Line /Linea di rifertimento
Nukleosom / Nucleosomes
Histon / HistonesSmD1
U1-snRNPSS-A / Ro 60 kD
SS-B / LaScl 70Zentromer / CentromereJo-1
SS-A / Ro 52 kD
cut-off-Kontrolle / ControlFunktionskontrolle / Functional Control
ELISA LIALine Immuno Assay
IFAImmunofluorescence
PT SALI POLAPA BERSAMA
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12.07.09
Human - IMTEC-Productline
ELISA - Principle•Antigens immobilized on a polystyrene microplate
•Sample incubation / Wash
•Secondary Ab / Wash
•Conjugate catalyzed color change of Substrate
•Stop solution will stop the reaction
•Optical density read-out with Microplate Reader (450/620 nm)
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Human - IMTEC-Product Line
LIA - Principle• Antigens immobilized in a line on
a synthetic membrane
• Sample incubation / Wash
• Secondary Ab / Wash
• Precipitating Substrate - Visualization
• Visual comparison to Cut-Off Control line
Bezugslinie / Reference Line /Linea di rifertimento
Nukleosom / Nucleosomes
Histon / HistonesSmD1
U1-snRNPSS-A / Ro 60 kD
SS-B / LaScl 70Zentromer / CentromereJo-1
SS-A / Ro 52 kD
cut-off-Kontrolle / ControlFunktionskontrolle / Functional Control
PT SALI POLAPA BERSAMA
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Human - IMTEC-Product Line
Immunofluorescence - Principle
• Cells or tissues immobilized on a glass slide
• Incubations of serial sample dilutions
• Secondary Ab - Marked with fluorescent-dye
• Microscopy
PT SALI POLAPA BERSAMA
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Rheumatoid ArthritisELISA
• IMTEC-ANA SCREEN
- IMTEC ds DNA Ab
- IMTEC NUCLEOSOME
- -IMTEC ENA SCREEN
- -IMTEC ENA PROFILE
- -IMTEC ANTI CCP
- -IMTEC ANTI RA33
- -IMTEC RF Screen
- -IMTEC RF IG G
- -IMTEC RF IG M
- -IMTEC RF IG A- -IMTEC PR3 AB
- -IMTEC MPO-ANCA
LINE IMMUNOASSAY (LIA)
• -IMTEC ANA (LIA)
• -IMTEC ANA / dsDNA-LIA
IMTEC TESTSFor RA
Bezugslinie / Reference Line /Linea di rifertimento
Nukleosom / NucleosomesHiston / HistonesSmD1
U1-snRNPSS-A / Ro 60 kD
SS-B / LaScl 70Zentromer / CentromereJo-1
SS-A / Ro 52 kD
cut-off-Kontrolle / ControlFunktionskontrolle / Functional Control
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RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
UpdatedDiagnosis of
RA
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Sensitivity and specificity of auto antibodies in RA
Marker Sensitivity (%) Specificity (%)
RF 50-90 Low*
APF 33 73-99
AKA 26-33 88-99
Anti Sa 22-40 98
Anti-CCP 50-76 95-98
* CCP = Cyclic Citrunillated Peptides
Anti-RA 33 36 98
RA-33 = hnRNP-A2
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• Antibodies directed against human γ-globulin Fc (mainly IgM, less often IgG or IgA)
• IgM RF calibrated against WHO reference preparation
• Sensitivity 80% in patients with RA• Specificity ranges from 80-90%• High titer predicts adverse outcome
erosive arthritis, vasculitis
• ELISA detects all isotypes
RHEUMATOID ARTHRITIS
RHEUMATOID FACTORS
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Why testing RF on ELISA ?
• Fully automatable • Detection of all relevant Ig-classes
The simultaneous detection of IgA and IgM class RF is nearly 100 % specific for RA *
• High sensitivity• Standardized method• Information on therapy outcome
Domer et al., Curr Opin Rheumatol 2004;16:246–253.
Bobbio-Pallavicini, F. et al. Ann Rheum Dis 2007;66:302
*
RHEUMATOID ARTHRITIS
RHEUMATOID FACTORS
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High IgA rheumatoid factor levels are associated with poor clinical response to TNFa inhibitors in RABobbio-Pallavicini, F. et al. Ann Rheum Dis 2007;66:302-307
DETECTION OF RF ISOTYPES
INCREASED RELEVANCE
High IgA rheumatoid factor levels are associated with greater risk of developing RAJonsson & Valdimarsson. Ann Rheum Dis 1993;52:161-164
Strong association between IgA RF and bone erosions – More radical treatment is neededBobbio-Pallavicini, F. et al. Ann Rheum Dis 2007;66:302-307
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Rheumatic DiseasesRheumatoid Arthritis (~70%)Sjögren’s Syndrome (~90%)Lupus (~20%)Kryoglobuline Syndrome (90%)
Lung DiseaseInterstitial Fibrosis
InfektionsHepatitis C VirusAcute viral InfectionEndokarditisTuberkulosis
OtherSarcoidosisInflammationAging
RHEUMATOID FACTORS
NEED FOR SPECIFICITY
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• Autoantibodies directed against cyclic citrullinated peptide (derived from filaggrin)
• Sensitivity 60 - 80 %; Specificity > 95 %
• Prognostic marker positive up to 9 years before clinical manifestations
• approx. 30 % of CCP+ are RF IgM-
A Specific Marker for Rheumatoid Arthritis
DIAGNOSTIC ALGORITHM
ANTI-CCP
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Citrullination
• Deimination (Citrullination) of proteins by the enzyme peptidyl-arginin-deiminase (PAD).
• Posttranslational protein modification, leading to modified biochemical characteristics
• Citrullination mainly occurs for proteins of the cytoskeleton (i.e.. cytokeratin, vimentin, filaggrin)
• Citrullination is involved the regulatory process of apoptosis
DIAGNOSTIC ALGORITHM
ANTI-CCP
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Anti-CCP Prognosis of Disease Outcome
• Presence of CCP antibodies is associated with development of erosive arthritis.
• The presence of anti-CCP in high titer has important prognostic implications
• Anti-CCP helps in predicting which RA patients will have persistent disease, and erosive disease
DIAGNOSTIC IMPORTANCE
ANTI-CCP
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• Increasing sensitivity• Detecting RF / CCP seronegative patients• Specific for anti-nuclear antigen• Anti-RA33 associated with mild disease
heterogeneous nuclear ribonucleoprotein A2
• Single Early RA-Marker in 13 % of RA Patients• Specificity of 90 %
increasing to 96 % if negative for Anti-U1-snRNP
MOST SENSITIVE DIAGNOSIS OF RA
ANTI-RA33 ANTIBODIES
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RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS
RF < 50 U/ml
Anti CCP -
Anti RA33 * ( + )
One of third RA patients is detectable of Anti RA33 and it shows similar specifity like RF
UPDATED DIAGNOSIS OF RA
* Anti RA33 is patented product HUMAN - IMTEC
Anti CCP +
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Human – IMTEC ELISA SYSTEM
InfrastructureValidated Automation
PT SALI POLAPA BERSAMA
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An attractive alternativeHumatemp
Automated Washer
Pipette
Humareader Plus
ELISYS UNOOr
Humareader Single
Humareader HS
Humawash Manual
IMTEC ELISA SYSTEM
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Human - IMTEC Productline
The high diversity in diseases and tests requires flexible solutions for laboratories....
…HUMAN IS ONE OF THE CHOICESFOR FLEXIBLE SOLUTION….
PT SALI POLAPA BERSAMA
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The complexities of Rheumatoid Arthritis
J Clin Invest, 116, 4, 2006
RA/RIS/09-07
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Autoimmune market worldwide
Help out of the Jungle
Autoimmune Diagnostics is a complex and continuously changing field
Human is the guide to help and provide
up to date autoimmune diagnostics
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Autoimmune market worldwide
Customized DiagnosticsEach laboratory requires customized solutions that fit best to their daily routine based on ...
• Turn-over• Test frequency• Test diversity• Official requirements
HUMAN is the right partner…..
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Human - IMTEC Product Line
Our ToolsFlyers, Workshops,Seminars,Congress participation
PT SALI POLAPA BERSAMA
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Laboratory investigations
• ESR / CRP level• Rheumatoid Factor (RF)• Complete Blood Count (CBC)• Electrolytes• Creatinin level• Hepatic panel (AST, ALT and albumin)• Urinalysis• Synovial fluid analysis
• Auto-antibodies
(ACR Subcommitee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002)
SUMMARY : Total Concept Diagnosis Of RASUMMARY : Total Concept Diagnosis Of RA
PT. SALI POLAPA BERSAMA
UPDATED DIAGNOSIS Of RA
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