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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

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slide1

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

slide2

Anti-Sa

Anti-CCP

RF

Amyloidosis

Vasculitis

Destruction

Break of

tolerance

RA Onset

CVD

Lymphoma

Environment

Genes

Sequence of Events in RA

Pre-

Early-

Established- RA

Immune response

Pathologic inflammatory response

T0

T100

slide3

Rheumatoid Hand

Smoking Habit

Ulnar Drift

oral health parodontitis
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
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.
slide6

Personalizing Is Challenging

  • To treat moving targets in vivo we need to develop HUMAN BIOMARKER(S)
      • Clinical : intra vs extra-articular features
      • Serologic : 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 vshumoral
      • Evolutive disease = Δphysiopathical pattern
slide7

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.
slide8

Contribution of Cytokines to RA Clinical Manifestations

APR, anemia

Liver

IL-6

Leukocyte Chemotaxis

TNF, IL-17, IL-6, IL-1

Angiogenesis

TNF, IL-6

Cartilage Degradation

MMP

IL-1, IL-17

Bone Erosion

TNF, IL-17, IL-6, IL-1

Joint

Colmegna et al.ClinPharmacolTher 2012;91:607-20

effect of mtx on citrullination in umr 106 cells

MTX (nM)

MTX (nM)

10

100

50

0

1

113

92

CMC

% Inhibition

53

113

PAD2

92

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.

Lora M et al (Ménard HA) ACR 2005

slide11

CTRL

10

50

100

200

µM

MTX

Folinic

UMR106

ECV304

CTRL

MTX

Folinic

H

O

H

µM

O

µM

CTRL

0.1

1.0

10

CTRL

0.1

1.0

10

193

N

N

193

193

115

PADs

97

+ NH3

+ H+

115

+ H2O

115

97

Ca++

97

NH

NH

53

O

NH2

H2N+

NH2

53

PeptidylArginine

PeptidylCitrulline

CTRL

10

50

100

200

µM

NS

53

115

193

37

97

115

PAD2

97

53

CTRL

10

50

100

200

µM

193

CTRL

25

125

250

µM

115

97

115

96

53

51

CTRL

500

1000

µM

Sub-confluent

Confluent

CTRL

10

50

100

CTRL

10

50

100

µM

193

115

115

96

97

53

51

µM

CTRL

250

500

1000

115

96

Anti-Sa

CTRL

100 µM

Anti-CMC

-

-

+

+

Ca2+

51

113

CTRL

10

50

100

µM

92

37

193

Sa

53

CTRL

750 µM

115

PAD2

113

92

Sa

53

A Scientific Basis For A Century Of Empiricism In Treating RA: All DMARDs Downregulate The Production Of Citrullinated Proteins/Antigens In Vitro.

  • CRA Kanaskis 2009 and ACR Philadelphia 2009
  • MTX, blocks PADI-2 activity in proliferating cellswithout 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.
  • HCQ, AZT and, SSZ decrease the quantity of PADIs in resting and proliferating cells in vitro.
  • Corticosteroids have no direct effect on citrullination .
  • DMARDs decrease the afferent antigenic input while Prednisone and the Biologicals suppress the efferent mechanisms of the immune synapse involving citrullinated epitopes.

Henri-André Ménard MD & Maximilien Lora PhD

MSK Research Axis 0f The McGill University Health Center At The Royal Victoria Hospital, Montreal (QC), CANADA H3A 1A1

RESULTS

INTRODUCTION

RESULTS

RESULTS

Azathioprine (AZA)

Clinical concentration 0.5 to 10µM

Prednisone (Pred)

Clinical concentration 0.1 µM

Methotrexate (MTX)

Clinical concentration: 25 nM

CITRULLINATION

is the conversion of an arginine within a peptidic link to a citrulline in an enzymatic process carried out by PeptidylArginine Deiminases.

WB with anti-CMC

AZA treated subconfluent UMR106 cells.

AZA at 50 µM to 200 µM significantly decreased PAD activity.

WB with anti-Sa

MTX (100 nM) treatment of UMR106 at subconfluence showed a decrease in PAD activity. This MTX effect was prevented by folinic acid (20 µM).

WB with anti-CMC

Pred. treated subconfluent UMR106 & ECV304 cells.

Pred. had no effect on PAD activity.

WB with anti-PAD2

MTX treatment showed no decrease in PAD-2 protein

WB with anti-CMC

AZA treated confluent UMR106 cells.

AZA at 200 µM decreased PAD activity.

RA patients have IgG auto-antibodies

against citrullinated (cit-)epitopes.

CTRL

0.1

1.0

10

µM

At the same dosage, MTX had no effect on PAD activity of confluent UMR106 or subconfluent and confluent ECV304

193

WB with anti-CMC

Pred. treated confluent UMR106 cells.

Pred. at 10µM might be increasing PAD activity.

115

The Abs are present before or at disease onset at

40-80% sensitivity with >95% specificity.

97

Sulphasalazine (SSZ)

Clinical concentration 50 µM

WB with anti-CMC

AZA treated subconfluent ECV304 cells.

AZA decreased PAD activity at all concentrations tested.

At the same dosage, AZA had little effect on ECV304 confluent assays.

53

RATIONALE AND HYPOTHESIS

CTRL

0.1

1.0

10

µM

193

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.

WB with anti-CMC

SSZ treated subconfluent UMR 106 cells.

SSZ at 250 µM significantly decreased PAD activity.

115

WB with anti-CMC

Pred. treated confluent ECV304 cells.

Pred. at 10 µM may actually increase PAD activity.

97

Hydroxychloroquine (HCQ)

Clinical concentration 1 µM

53

37

CONCLUSIONS

WB with anti-CMC

HCQ treated subconfluent & confluent UMR106 cells.

HCQ at 50 µM to 100 µM significantly decreased PAD activity.

WB with anti-CMC

SSZ treated confluent UMR 106 cells.

SSZ at 500 and 1000 µM significantly decreased PAD activity.

All DMARDs downregulate the production

of 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.

MATERIALS AND METHODS

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).

CTRL

10

50

100

µM

WB with anti-CMC

HCQ treated subconfluent ECV304 cells.

HCQ at 50 and 100 µM decreased PAD activity.

115

97

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.

53

WB with anti-PAD2

HCQ treated subconfluent

ECV304 cells.

UMR106 cells have PAD activity at confluence only.

WB with anti-CMC

HCQ treated confluent ECV304 cells.

HCQ at 50 and 100 µM decreased PAD activity.

97

ECV304 cells have PAD activity at both subconfluence and confluence.

WB with anti-PAD2

SSZ treated subconfluent ECV304 cells.

SSZ at 750 µM significantly decreased PAD2 protein.

ACKNOWLEDGEMENT

53

conclusions on citrullination in ra
Conclusions on Citrullination in RA
  • Those in vitro data provide an explanation for why the pharmacologically diverse DMARDs are successful in RA : they are PADIBs
    • Individually, with MTX being the best at it;
    • In combination with each other, providing a variety of not mutually exclusive inhibition modalities;
    • Essential to use with biologicals as they are unique in decreasing the afferent arm of the immune process;
    • Especially relevant when ACPAs (anti-Sa) drive the disease.
take home message on anti ccp
Take Home MessageOnAnti-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
Take Home MessageOn 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

ABATACEPT

ANTI-CYTOKINES

RITUXIMAB

TREATMENT IMPLICATIONS

PKIs ?

MTX, HCQ, SSZ,AZT= PADIBs

PKIs ?

PKIs ?

STEROIDS

ACPAs

PKIs ?

PKIs ?

forget this osler s quotation
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

HA MÉNARD, Jan 2013

shukran ala aldawah

SHUKRANALA ALDAWAH

QUESTIONS?

COMMENTS?