Rheumatoid Arthritis dr. C. Verweij Clinical aspects / Pathology / Risk factors / Epidemiology VUmc, Pathologie Biomarkers

34 important questions on Rheumatoid Arthritis dr. C. Verweij Clinical aspects / Pathology / Risk factors / Epidemiology VUmc, Pathologie Biomarkers

What is Rheumatoid arthritis?

Chronic inflammatory joint disease, 1% population affected, Incidence higher in female than men, Unknown etiology, Multifactorial disease.

What characterizes the pathopathophysiology of  the joint in RA?

Immune cells and processes
Dendritic cells/Antigen presenting cells
Macrophages
T-­‐lymphocytes
B-­‐lymphocytes
Angiogenesis
Hyperplasia synovial lining

Inflammatory mediators
TNF-­‐α
IL-­‐1
IL-­‐6
IL-­‐17
GM-­‐CSF

What are the auto-antibodies in RA?

• Rheumatoid Factor (RF)
– Antibody against the Fc portion of IgG

• Anti-Citrullinated Protein Autoantibodies (ACPA)
– Enzymatic conversion of protein arginine -> citrulline
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What is the flowchart measurements biomarker discovery?

From (complex) disease through system biology to systematic solutions, to discover biomarkers - pathways for diagnosis, prognosis, therapy and prevention.

How does the flowchart measurements biomarker discovery go?

Complex disease 
1) patient cohorts/ biobanks
2) sequencing - genotyping -biostatistcs

Systems biology
3) transcriptopmics: DNA chips and arrays
4) proteomics/flow cytometry
5) metabonomics
6) bioinformatics

systemetic solutions
7) bioimaging
8) pharmaco/ toxico- genomics / genetics
9) clinical parameters

What is an advantage of transcriptomics?

Hypothesis free approach of studying complex diseases

What is the procedure of cluster  analysis of mircoarray? 

Unsupervised/supervised subclassification based on differentially expressed genes and/or predetermined sample classification

What is the procedure of SAM of mircoarray? 

List of significantly different expressed genes between the eg. disease subclasses

Background-colorWhat is the procedure of PAM of mircoarray? 

List of genes which predicts to what subclass a sample/patient corresponds

What is the procedure of SOURCE of mircoarray? 

Online information on the function of these genes

What is the procedure of Pathway analyses/Gene-set level analyses of mircoarray? 

Online algorithms “GSEA” (Sabramanian et al, PNAS. 2005, 102(43):
15545), “PLAGE” (Tomfor et al, BMC Bioinformatics. 2005 6:225)
and “Panther” (Applied Biosystems)

What is the whole procedure of microarray?

Cluster analysis, SAM, PAM, SOURCE, Pathway analyses/Gene-set level analyses

What is know about the etiology of RA?

Etiology unknown
• Genetic
• Environmental: -smoking -infection?
• Autoimmunity
-autoreactive T cells (SE, CD4 Tm cells, IFNy)
-autoreactive B-cells/ autoantibodies (RF, ACPA)
-pro-inflammatory cytokines (TNFa, IL-1, IL-6)

What is a multifactorial disease, and why is RA one?

Polygenic (multiple genes involved);  Environmental


Name biomarkers in preclinical RA

- Autoantibodies IgM-­‐RF and/or ACPA are present years before diagnosis of arthritis 
Rheumatoid Factor (RF) and/or anti-citrullinated protein antibodies (ACPA)


Gene signatures in peripheral blood cells implicated with risk to develop arthritis involve:

I. IFN-­‐mediated immunity 
II.  Chemokine/cytokine activity
III. Lymphocyte abundance

What is the Logistic regression of Transcriptome biomarker to predict risk for development of arthritis?

• Subgroups I and II (IFN and chemokine/cytokine) are associated with arthritis development (OR 21.0; 95% C.I. 2.8-­‐156.1; P=0.003) 
• Subgroup III (B lymphocyte abundancy) is associated with protection (OR 0.38; 95% C.I. 0.21-­‐ .70; P=0.002) 

What is the Type I IFN signature of RA?

– Relatively high expression of IFN related genes (IRGs) 
– Type I IFN: IFNα, IFNβ (IFN-­‐κ/δ/ε/τ /ω/ζ)

What can type I IFNs do?

type I IFNs may break tolerance 

Which cells are present in follicular subtype RA

CD22, CD3, CD21L
*Adaptive inflammatory response 
>T/B cells, APC,
>IFN type I/IL-7/Stat-1
*Proteases
>MMP-1, MMP-3

Which cells are present in diffuse and aggregate subtype RA?

CD22, CD3, CD22, CD21L
Tissue remodeling
*Proteases
 >MMP-11 and >MMP-13


Molecular and histochemical tissue subtypes in RA: Name the characteristics of immune-mediated RA

CD22, CD3, CD21L
Synovial Tissue: immune activation, MMP-1/3 
Synoviocytes: proliferation/TGFβ-induced

Molecular and histochemical tissue subtypes in RA: Name the characteristics of immune-independent, stromal RA

CD22, CD3, CD21L
Synovial Tissue: remodeling, MMP-11/13
Synoviocytes:  IGF2/IGFBP5 growth regulators


IFN comprises three major groups: 

 IFN type I
• IFN-­‐a, IFN-­‐b, IFN-­‐d, IFN-­‐k, IFN-­‐t, and IFN-­‐v
• All on chromosome 9, receptor subunits IFNAR1/IFNAR2

IFN type II 
• IFNɣ, chromosome 12, specific receptor IFNGR

IFN type III
• IFN-­‐λ1 (IL-­‐29), IFN-­‐λ2 (IL-­‐28A) and IFN-­‐λ3 (IL-­‐28B)
• Chromosome 19, receptor subunits IFNLR1/IL10R2

Which type IFN is associated with a number of autoimmune diseases? Name 4 diseases.

Type I IFNs. 
SLE, 
SS,Sjögren's syndrome
MS, 
SSc, Scleroderma and Systemic Sclerosis

Which genes are overexpressed in (RA)?

Type I interferon (IFN)-­‐induced genes 

Name 7 IFN type I pro-­inflammatory activities

• Stimulation of Th1-­‐type T cells and B cell responses
• Stimulation of CTL responses 
• Proliferation of memory CD8+ T cells
• Promote the survival and differentiation of B cells
• DC activation (APC function)
• Chemokine induction
• Anti-­‐apoptotic

Name 4 IFN type I anti-­inflammatory activities

• Anti­‐proliferative effects 
• Reduces TNF and Il-­‐6 production 
• Increases IL10 and IL1RA production 
• downregulates MMP3


IFN type I pro‐ or anti­‐inflammatory effect in RA?

• IFNβ is effective in inhibiting disease activity MS
• IFNβ is effective in experimental arthritis models 
• IFN response activity associated with low disease activity
• IFN response activity associated with Virus response signature
• No effect IFNβ therapy in RA 

Name 5 Targeted Therapies in RA

1) Anti­‐TNF (APC produces TNF)
2) Anakinra (APC produces IL-1)
3) Tociluzimab (APC produces IL-6)
4) Abatacept (Binding of APC or Bcell to Tcell)
5) Rituximab (Bcell)

What are the 8 effects mediated by TNF-α?

1) cytokine release, cytotoxicity
2) cytokine release, NO production, cognate interactions
3) cytokine release, ROI/ RNI, granule release
4) suppresion, cytokine release
5) MMP expression, GAG release, NO production
6) MMP expression, adhesion molecules, HLA class II
7) angiogenesis, adhesion molecules
8) bone and cartilage resorption

Which gene signatures characterize preclinical RA?

IFN- and Bcell genes

What predicts non-­response to rituximab in RA=

IFN signature


What does rituximab regulates in RA, which is associated with responder status?

IFN activity

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