treatment of ra 2014
DESCRIPTION
The 1rst Kuwait-North American Update in Internal Medicine Conference 8-9 February 2014. TREATMENT OF RA 2014. Henri A. Ménard, MD, FRCP (C) Professor of Medicine McGill University McGill University Health Center. Anti-Sa. Anti-CCP RF. Amyloidosis Vasculitis. Destruction. Break of - PowerPoint PPT PresentationTRANSCRIPT
TREATMENT OF RA 2014
The 1rst Kuwait-North American Update in Internal Medicine Conference
8-9 February 2014
Henri A. Ménard, MD, FRCP (C)
Professor of Medicine
McGill University
McGill University Health Center
Sequence of Events in RA
Immune response Pathologic inflammatory response
T100
LymphomaCVD
Destruction AmyloidosisVasculitis
T0
Pre- Early- Established- RA
GenesEnvironment
Anti-CCPRF
Break of tolerance RA Onset
Anti-Sa
Smoking Habit
Ulnar Drift
Rheumatoid Hand
Oral health: Parodontitis
• Chronic Inflammatory condition.
• Erosive disease
• Associated with RF, HLA DR4 and Coronary Artery Disease.
• Intriguing because associated with Porphyromonas gingivalis. The
bacterial PADI and its products are very different from that of the
mammalian PADIs’. Break of tolerance???
• Circumstantial evidence only. No hard data available.
(Ménard HA Dresden Symposium on Autoimmunity 2007)
Principles of Patient Centered RA Treatment in 2014
• DO MORE THAN LESS clinical observation and biological documentation of the disease to pinpoint the particular context of your patient where N=1.
• EXPLAIN AND REASSURE the patient and the family;• INSIST ON LIFESTYLE ISSUES: smoking, oral hygiene (flossing)
and beware of the associated obesity and metabolic syndrome: PREHABILITATION is better than REHABILITATION;
• TREAT EARLY AND AGGRESSIVELY with full DMARDs combos and use biologicals when needed;
• USE TOOLS BORROWED FROM THE BUSINESS WORLD to contract with the patient short term and long term objectives with periodic timely deliverables (Treat-to-Target approach);
• ADAPT AND ADJUST as the disease evolves and changes.
To treat moving targets in vivo we need to develop HUMAN BIOMARKER(S)
Clinical : intra vs extra-articular featuresSerologic : anti-Sa For Prognosis and Monitoring Genomic
immune response genes (SE and non-SE),pharmacogenomics (drug metabolism),innate immunity genes (cytokine SNPs)
Immunopathologic : Cell mediated vs humoralEvolutive disease = Δ physiopathical pattern
Personalizing Is Challenging
To chose the best drug for the right patient at the right time, we need to STOP EMPIRICISM i.e.
Stop making real world medical decisions and using guidelines based on trial data;
Start dissecting each individual patient as a N=1 trial, not as a member of poorly characterized cohorts of N=1000.
Know why & when one starts & stops a drug Know why & when one needs to change/switch Know why & when to reassess.
Personalizing Is Challenging
Contribution of Cytokines to RA Clinical Manifestations
IL-6LiverAPR, anemia
TNF, IL-17, IL-6, IL-1Bone Erosion
Joint
IL-1, IL-17Cartilage Degradation MMP
TNF, IL-17, IL-6, IL-1Leukocyte Chemotaxis
TNF, IL-6Angiogenesis
Colmegna et al. Clin Pharmacol Ther 2012;91:607-20
Do Our Treatments Regulate Citrullinated Ags – ACPAs?
Anti-CP Abs
Effect Of MTX On CitrullinationIn UMR 106 Cells
Dose-response curve of in vitro MTX treatment of UMR 106 cells at 10 µg of total proteins/lane at in vivo therapeutic concentrations.
0
10
20
30
40
50
60
70
80
90
100
0 1 10 50 100
MTX (nM)
% In
hibi
tion
PAD
2CM
C
0 1 10 50 100
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11392
MTX (nM)
Lora M et al (Ménard HA) ACR 2005
Henri-André Ménard MD & Maximilien Lora PhDMSK Research Axis 0f The McGill University Health Center At The Royal Victoria Hospital, Montreal (QC), CANADA H3A 1A1
A Scientific Basis For A Century Of Empiricism In Treating RA: All DMARDs Downregulate The Production
Of Citrullinated Proteins/Antigens In Vitro.
INTRODUCTION
MATERIALS AND METHODS
RATIONALE AND HYPOTHESIS
CONCLUSIONS
ACKNOWLEDGEMENT
RESULTS
RA patients have IgG auto-antibodies against citrullinated (cit-)epitopes.
RESULTS RESULTS
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Anti-CMC Anti-Sa
Sa
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- + Ca2+ - +
Sa
UMR106 and ECV304 cell lines were treated for 4 days with increasing doses of methotrexate (MTX), sulphasalazine (SSZ), azathioprine (AZT), hydroxychloroquine (HCQ) or Prednisone (Pred) at doses corresponding to those obtained in vivo during RA treatment. We estimated semi-quantitatively by western blot (WB) on cell extracts, their effect on the production of all cit-proteins (detected by a rabbit anti-CMC serum) and cit-antigens (detected by anti-Sa RA sera).
Factual commonality 1: pharmacologically unrelated drugs, the DMARDs have survived empirically as good treatment for RA;Factual commonality 2: cit-proteins (non-specific products of inflammation), have a central role in RA as they induce a specific autoimmune response that drives the disease;Factual commonality 3: biologicals target effector mechanisms, downstream from the immunological synapse with little effect on auto-Abs and they all work most efficiently when combined with DMARDs ;Hypothetical commonality 4: DMARDs have a common mode of action complementary to biologicals via inhibition of citrullination, an event upstream from the immunological synapse.
All DMARDs downregulate the productionof cit-proteins/antigens in vitro.
- MTX blocks PAD-activity in proliferating cells via a folate dependent pathway. The effect is independent of adenosine receptors (not shown) and the quantity of PAD-protein is unchanged. - AZT, SSZ and HCQ decrease the quantity of PADs in various conditions either in resting or dividing cells. - Prednisone has no effect on citrullination in dividing cells but has an unexpected upregulating effect at high dose in resting cells.
Those data support our hypothesis that DMARDs all work by decreasing the cit-Ag load in vivo. In patients with autoAbs to a cit-protein Ag like cit-vimentin/Sa, DMARDs may influence the putative ongoing auto-Ab response to cit-vimentin (anti-Sa), thus acting on the two major elements of the autoimmune amplification loop responsible for chronicity.
UMR106 cells have PAD activity at
confluence only.
ECV304 cells have PAD activity at both subconfluence and
confluence.
WB with anti-SaMTX (100 nM) treatment of UMR106 at subconfluence showed a decrease in
PAD activity. This MTX effect was prevented by folinic acid (20 µM).
At the same dosage, MTX had no effect on PAD activity of confluent UMR106 or subconfluent and confluent ECV304
Methotrexate (MTX)Clinical concentration: 25 nM
Sulphasalazine (SSZ)Clinical concentration 50 µM
Azathioprine (AZA)Clinical concentration 0.5 to 10µM
Hydroxychloroquine (HCQ)Clinical concentration 1 µM
Prednisone (Pred)Clinical concentration 0.1 µM
WB with anti-PAD2MTX treatment showed no decrease in
PAD-2 protein
H
NOH
NH
H2N+ NH2
+ H2O
NO
NH
O NH2
+ NH3 + H+
PeptidylArginine PeptidylCitrulline
PADsCa++
CITRULLINATION
is the conversion of an arginine within a peptidic link to a citrulline in an enzymatic process carried out by
PeptidylArginine Deiminases.
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CTRL 25 125 250 µM
WB with anti-CMCSSZ treated subconfluent UMR 106 cells.
SSZ at 250 µM significantly decreased PAD activity.
WB with anti-CMCSSZ treated confluent UMR 106 cells.SSZ at 500 and 1000 µM significantly
decreased PAD activity.
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CTRL 500 1000 µM
WB with anti-CMC SSZ treated subconfluent ECV304 cells.
SSZ at 1000 µM significantly decreased PAD activity.
At the same dosage, SSZ had no effect on ECV304 confluent assays.
The Abs are present before or at disease onset at40-80% sensitivity with >95% specificity.
WB with anti-PAD2 SSZ treated subconfluent ECV304 cells.
SSZ at 750 µM significantly decreased PAD2 protein.
CTRL 10 50 200 µM100
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WB with anti-CMCAZA treated confluent UMR106
cells.AZA at 200 µM decreased PAD
activity.
WB with anti-CMCAZA treated subconfluent
UMR106 cells.AZA at 50 µM to 200 µM
significantly decreased PAD activity.
193
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53
CTRL 10 50 200 µM100
WB with anti-CMCAZA treated subconfluent ECV304
cells.AZA decreased PAD activity at all
concentrations tested.At the same dosage, AZA had little
effect on ECV304 confluent assays.
CTRL 50 200 µM100
193
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53
10
WB with anti-CMCHCQ treated subconfluent &
confluent UMR106 cells.HCQ at 50 µM to 100 µM
significantly decreased PAD activity.
193
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53
CTRL 50 µM100Sub-confluent Confluent
10 CTRL 50 10010
µMCTRL 50 10010
WB with anti-CMCHCQ treated subconfluent
ECV304 cells.HCQ at 50 and 100 µM decreased PAD activity.
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97
53
115
193
µMCTRL 50 10010
WB with anti-CMCHCQ treated confluent
ECV304 cells.HCQ at 50 and 100 µM decreased PAD activity.
CTRL 100 µMWB with anti-PAD2
HCQ treated subconfluent
ECV304 cells.
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193
37
CTRL 1.0 µM10UMR106 ECV3040.1 CTRL 1.0 100.1 µM
WB with anti-CMCPred. treated
subconfluent UMR106 & ECV304 cells.
Pred. had no effect on PAD activity.
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193
CTRL 1.0 100.1 µM
WB with anti-CMCPred. treated confluent UMR106 cells.
Pred. at 10µM might be increasing PAD activity.
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53
193
37
WB with anti-CMCPred. treated confluent ECV304 cells.
Pred. at 10 µM may actually increase PAD activity.
CTRL 1.0 100.1 µM
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37
CTRL 250 500 1000 µM
CTRL 750 µM
PAD2
CTRL MTXMTX
Folinic Folinic
NS
19311597
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11597
PAD2
CRA Kanaskis 2009 and ACR Philadelphia 2009
1. MTX, blocks PADI-2 activity in proliferating cells without affecting the quantity of enzyme. It does so via folate-dependent and adenosine receptor-independent pathways. The induction of a PAD Inhibitor is a possibility.
2. HCQ, AZT and, SSZ decrease the quantity of PADIs in resting and proliferating cells in vitro.
3. Corticosteroids have no direct effect on citrullination .
4. DMARDs decrease the afferent antigenic input while Prednisone and the Biologicals suppress the efferent mechanisms of the immune synapse involving citrullinated epitopes.
Conclusions on Citrullination in RAThose in vitro data provide an explanation for why the pharmacologically diverse DMARDs are successful in RA : they are PADIBs
1. Individually, with MTX being the best at it;
2. In combination with each other, providing a variety of not mutually exclusive inhibition modalities;
3. Essential to use with biologicals as they are unique in decreasing the afferent arm of the immune process;
4. Especially relevant when ACPAs (anti-Sa) drive the disease.
Take Home Message On Anti-CCP• They relate to immune response genes specifically
predisposing to RA but are not always associated with severe or even actual disease. In the context of N = 1,
• most useful when negative to rule out RA;• low titers may lead to circular clinical reasoning;• high titres most useful to rule in RA.
• Their prognostic value is based on longitudinal and transversal testing of RA COHORTS. They are less reliable at disease onset in personalized N=1 medicine.
• Normalization is unusual and, as currently tested for, unchanging titers do not allow immune monitoring.
Ménard HA, Editorial. J Rheumatology 2009
Take Home Message On Anti-Sa
• strictly linked to RA disease: DIAGNOSIS• closely linked with the more severe erosive long term
phenotype: PROGNOSIS
• titers vary with activity as pathogenic antibodies do:
MONITORING• normalization is achievable and may turn out to be a
robust marker of remission maintenance at T0/S0:
REMISSION
Ménard HA, Editorial J Rheumatology 2009
TREATMENT IMPLICATIONS
MTX, HCQ, SSZ,AZT= PADIBs ABATACEPT
RITUXIMAB
ACPAs
ANTI-CYTOKINES
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STE
ROID
S
PKIs ?
PKIs ?
PKIs ?
PKIs ?
PKIs ?
HA MÉNARD, Jan 2013
FORGET THIS OSLER’S QUOTATION
"When a patient with arthritis comes through the front door,
I want to leave by the back door".
Times are changing
SHUKRANALA ALDAWAH
QUESTIONS?COMMENTS?