Rheumatoid arthritis: A heterogeneous disease with a heterogeneous response to treatment

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1 Rheumatoid arthritis: A heterogeneous disease with a heterogeneous response to treatment Pr Pierre Miossec MD PhD Clinical Immunology Unit Hôpital Edouard Herriot Lyon miossec@univ-lyon1.fr

cells in migration to joints Mesenchymal cells in residence inside joints Chronic

2 Pathogenesis of Rheumatoid Arthritis Exogenous factors Bacteria? Virus? Smoking Endogenous factors Sex Hormones Genetic factors Blood-derived mononuclear cells in migration to joints Mesenchymal cells in residence inside joints Chronic inflammatory reaction Production of proinflammatory factors Bone and cartilage destruction

3 Rheumatoid arthritis: more than one picture Early Late Benign Responder Severe Non-responder

4 Rheumatoid arthritis: markers and heterogeneity in treatment response Environmental factors: smoking, food, parasites DNA markers: Shared epitope, other gene polymorphisms (SNP) RNA markers: from one gene to the whole genome Proteins: antibodies (rheumatoid factors, anti-ccp) cytokines, markers of formation/degradation of bone, cartilage, synovium; biopsies

5 Where to look for markers of heterogeneity and treatment response Environmental factors: population studies DNA markers: blood is fine RNA markers: blood or synovium? Proteins: reflection of local and systemic situation Structure of the synovium, cartilage, bone : synovial fluid, urine or blood markers synovium biopsy

6 Heterogeneity of rheumatoid arthritis Typical RA: HLA DR shared epitope, anti-ccp, smoking Atypical RA: lack of common markers less severe pathegenesis less understood

7 Markers of heterogeneity: 3 exemples DNA: Genetic markers and heterogeneity in disease expression and treatment response RNA: Synoviolin out of a large list of genes Protein: Levels of TNF and anti-tnf response: systemic vs. joint levels; bone, synovium, cartilage biomarkers; proteomic studies

8 SNP analysis in RA: success or expensive failure? HLA-DR Shared Epitope 41, 44, 11 PTPN22 TRAF1-C5 region STAT4 PADI4 (Asia) R Plenge 29

9 Shared epitope association with increased risk of destruction and treatment with infliximab 6 5 Odd ratio /- +/- +/+ Increased risk related to SE Destruction Infliximab treatment Risk for destruction was calculated in a population of 637 RA patients Risk to be treated with infliximab was calculated in a population of 165 treated patients

10 Association between the SE status and the risk for RA joint destruction in Syria and France 1 8 Odds Ratio N/N S/N S/S France Syria

11 Markers of heterogeneity: 3 exemples DNA: Genetic markers and heterogeneity in disease expression and treatment response RNA: Synoviolin out of a list of genes Protein: Levels of TNF and anti-tnf response: systemic vs. joint levels; bone, synovium, cartilage biomarkers; proteomic studies

12 Non-hypothesis-driven single gene selection: responders vs. non-responders Affymetrix U133A micro-array expression profile in whole blood ACR 5-7 vs. ACR response to infliximab Hetergeneity of published signatures: Paxgene, Whole blood, PBMC Array technology Kinetics t, 6m ACR ACR 7-5

13 Synoviolin contribution to RA Synovial hyperplasia imbalance between synoviocyte proliferation and defective apoptosis contributes to RA chronicity Synoviolin is a novel E3 ubiquitin ligase with anti-apoptotic effects and identified in RA synoviocytes and synovial lining tissue Mice transgenic for synoviolin develop spontaneous arthritis and KO mice are resistant Synoviolin mrna levels are increased in RA blood using extensive micro-arrays

14 Expression of synoviolin in RA synovium Control Ab Anti-synoviolin Ab A B SL C D L F F SL = sublining L = lining F = follicle

15 Synoviolin is expressed in RA synovium and blood immune cells Synovium CD3 + synoviolin + CD14 + synoviolin + CD2 + synoviolin + Blood Synoviolin/PPIB mrna * * CD3 CD14 CD19

16 Synoviolin is over-expressed in RA blood Synoviolin/PPIP P mrna HC * RA

17 Synoviolin is over-expressed in infliximab non-responders Synoviolin/PPIB mrna HC ACR 7 ACR 2-5 RA * ACR mrna Synoviolin/PPIB wks 22 ACR * 22 ACR2

18 Induction of synoviolin in RA synoviocytes by proinflammatory cytokines

19 Endogenous synoviolin regulates cytokine, chemokine and MMP expression in RA synoviocytes synoviolin IL-6 IL-8 MMP1 MMP3 gene express sion (%) * * * gene expressio on (%) * * sirna control sirna synoviolin

20 Markers of heterogeneity: 3 exemples DNA: Genetic markers and heterogeneity in disease expression and treatment response RNA: Synoviolin out of a list of genes Protein: Levels of TNF and anti-tnf response: systemic vs. joint levels; bone, synovium, cartilage biomarkers; proteomic studies

21 TNF as a marker of response Contribution of TNF has been shown at the site of inflammation Blood TNF could reflect joint-derived TNF Detection is complex because of endogenous inhibitors ELISA: protein levels (pg/ml), free or complexed with sr Bioassay: functional activity reflecting free levels (U/ml); addition of exogenous TNF to measure circulating inhibitors (sr, Ab) Differences reflect ligand receptor interactions

22 TNF mrna levels in RA blood and response to TNF inhibition Changes at 22 weeks Link to treatment response TNF-α mrna / PPIB mrna,6,5,4,3,2,1 * Controls Week Week 22 * TNF-α mrna / PPIB mrna,6,5,4,3,2,1 * * * * Controls A NR B RC NR D ER Week Week 22

23 Effect of addition of RA plasma on IL-6 production by TNF-stimulated synoviocytes 12 IL-6 produc ction (ng/ml) Plasma Plasma +TNF % 1% 5% 1% 2% Plasma concentration

24 TNF bioactivity in plasma and response to infliximab Plasma 25 A 9 B Before After Before After Plasma Before After Before After First infusion Ninth infusion Clinical response ACR 5 A: 6/6 B: 5/6 C: 1/6 9 % correct prediction Plasma First infusion Ninth infusion C Before After Before After First infusion Ninth infusion

25 Response to infliximab and IL-6 and OPG production by TNF-stimulated synoviocytes A 8 p =.1 B 25 p <.5 Delta IL-6 production (ng/ml) Good clinical responders Poor clinical responders Delta OPG production (ng/ml) Good clinical responders Poor clinical responders IL-6 OPG

26 Levels of biactive TNF are higher in patients with the A/A or A/G -38 TNF SNP genotypes Bioactive TNF TNF protein by ELISA

27 TNF levels in rheumatoid arthritis and response to treatment Bioactive circulating TNF may reflect production in the joint Local TNF expression in synovium biopsies is associated with response (PP Tak) Other sites such as lymph nodes are probably involved Thus to respond to a TNF inhibitor, disease has to be higly TNF-driven Increase of TNF inhibitor dosage has only a modest effect

28 Increased levels of urinary Glucosyl-Galactosyl- Pyrridinoline Glc-Gal-PYR (synovium) and CTX-II (cartilage) in RA patients Glc-Gal-PYD nmol l/mmol creat * creat CTX-II ng/mmol * RA HC RA HC

29 Increased levels of Glc-Gal-PYR and CTX-II in destructive RA Glc-Gal-PYD nmol/ /mmol creat Limited destruction Extensive destruction CTX-II ng/mmo ol creat Limited destruction Extensive destruction

30 Reduction of urinary Glucosyl-Galactosyl-Pyrridinoline levels during infliximab treatment 25 U-Glc-Gal-PYD (nmo ol/mmol Cr) Baseline P <.1 One year

31 Only RA with progressive joint damage show changes in levels of Glc-Gal-PYR and CTX-II after infliximab Delta Glc-Gal-PYD nmol/mmol creat No progressive joint damage Progressive joint damage CTX-II ng/mm mol creat No progressive joint damage * Progressive joint damage

32 Proteomic analysis of plasma from RA patients High MW NR R Low MW NR R

33 Apolipoprotein A1 as a marker of response to infliximab The 28 kda peak of apolipoprotein A1 at baseline was increased in the responders

34 Platelet factor 4 as a marker of response to infliximab The 7.77 peak of platelet factor 4 at baseline was decreased in the responders

35 Rheumatoid arthritis: a heterogeneous disease Different levels of RA heterogeneity have been defined and better markers are needed Because destruction is irreversible, sooner remains better Early definition of prognosis will improve management Prediction of treatment response and tolerance will improve early choice and schedule of administration A marker of disease severity cannot be at the same time a marker of treatment response Relative importance of markers: safety; non response; response Such markers have to be tested during clinical trials

MAF Shalaby Prof. Rheumatology Al Azhar University, Cairo, Egypt.

MAF Shalaby Prof. Rheumatology Al Azhar University, Cairo, Egypt. AUTOIMMUNE DISEASE RA SLE VASCULITIS RELAPSING POLYCHONDRITIS SS DM/PM SJOGREN S SYNDROME RHEUMATOID ARTHRITIS Classically immune mediated