Prediction of Future Onset of Rheumatoid Arthritis in Individuals Without Current Inflammatory Arthritis

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1 Prediction of Future Onset of Rheumatoid Arthritis in Individuals Without Current Inflammatory Arthritis ACR Clinical Research Conference: Preclinical Rheumatic Disease Session V: Predicting Future Clinically-apparent Rheumatic Disease October 26, 2013 Dirkjan van Schaardenburg Jan van Breemen Research Institute Reade, Amsterdam

2 Disclosure statement Co-patent holder of a gene signature that confers increased risk of RA

3 Key references van de Stadt LA, Witte BI, BosWH, van Schaardenburg D. A prediction rule for the development of arthritis in seropositive arthralgia patients. Ann RheumDis Nov28 Karlson EW, Ding B, KeenanBT, LiaoK, Costenbader KH, Klareskog L, AlfredssonL, Chibnik LB. Association of Environmental and Genetic Factors and Gene Environment Interactions With Risk of Developing Rheumatoid Arthritis. Arthritis Care & Research 2013; 65: Arend WP, FiresteinGS. Pre-rheumatoidarthritis: predispositionand transitionto clinical synovitis. Nat Rev Rheumatol 2012:

4 Individuals Without Current Inflammatory Arthritis = you

5 Screening the general populationin The Netherlands Tuberculosis Lung cancer Breast cancer Cervix cancer Colon cancer Metabolic disease

6 Requirements for screening the population Test asymptomatic persons for a disease Test (sens/spec, adverse effects, cost ) Asymptomatic phase Cost-effective intervention available

7 Screening the general population in The Netherlands Tuberculosis Lung cancer Breast cancer Cervix cancer Colon cancer??? Metabolic disease

8 Screening the populationforra Thereis nosingle test forra RA prevalence1%, howmanyare at risk? RA does have anasymptomaticphase Cost-effective intervention not yet available

9 Arthritis prevention in seropositive arthralgia patients by dexamethasone 2x100mg? 100 % 90 % 80 % % months Numbers at risk Bos WH, Ann Rheum Dis 2010

10 Conclusion: screening is now only for research. Two questions: Whoshallwe test (and howto getthem)? Whatshallwe test??

11 Epigenetic modifications Hormonal factors Environmental factors - Smoking, dust - Alcohol non-use -Obesity - Hyperlipidemia - High birth weight Infections -Lung -Gingiva -Gut? Tissue damage Loss of mobility Genetic susceptibility Autoimmunity Arthralgia Arthritis Premature death HLA-DRB1 (ACPA, RF, anti-carp) PTPN22 + Conception Subclinical inflammation - acute phase reaction - cytokines - interferon activity

12 ACR/EULAR 2010 classification criteria for RA Joint Involvement(range 0-5) 1 medium-large joint 2-10 medium-large joints 1-3 small joints 4-10 small joints >10 joints(at least 1 small joint) Score >=6 indicates RA Serology(range 0-3) Neither RF or ACPA positive At least one test low positive titre At least one test high positive titre Duration of synovitis (range 0-1) <6 weeks >=6 weeks 0 1 Acute Phase Reactants (range 0-1) Neither CRP or ESR abnormal Abnormal CRP or abnormal ESR 0 1

13 ACR/EULAR 2010 classification criteria for RA Joint Involvement(range 0-5) 1 medium-large joint 2-10 medium-large joints 1-3 small joints 4-10 small joints >10 joints(at least 1 small joint) Score >=6 indicates RA Serology(range 0-3) Neither RF or ACPA positive At least one test low positive titre At least one test high positive titre Duration of synovitis (range 0-1) <6 weeks >=6 weeks 0 1 Acute Phase Reactants (range 0-1) Neither CRP or ESR abnormal Abnormal CRP or abnormal ESR 0 1

14 Auto-antibodies precede RA onset Cumulative % positive before symptoms % positive IgM-RF or anti-ccp anti-ccp IgM-RF 49% 41% 28% Years before start of symptoms Nielen et al, Arthritis Rheum 2004

15 % positive IgM-RF or anti-ccp anti-ccp IgM-RF 49% 41% 28% Years before start of symptoms Risk of RA within 5 years General population High-risk population RF 1,5% 38% Anti-CCP 5% 70% RF or accp 2% 44% RF and accp 100% 100% Nielen A&R 2004

16 Strategy: find seropositive persons(1) Sounds inflammatory... let s do a test It hurts here, in the morning

17 Strategy: find seropositive persons (2) Should I test? My mother has RA...

18 Prospectivestudysince2003 of seropositive arthralgia patients: Inclusion criteria accp2 and/or IgM-RF positive (History of) arthralgia and/or relative with RA 374 patients (76% female, mean age 49) 131 (35%) patients developed arthritis (92% RA)

19 Present position: prediction of RA in seropositive persons van de Stadt ARD 2012

20 Percent arthritis free survival 100% 80% 60% 40% 20% Survival per risk group low intermediate high 0% Time (months) (41%) patients 102 (27%) patients HR (95% CI): 4.3 ( ) (31%) patients HR (95% CI): 14 (7.7-25)

21 ROC curves Risk model Risk rule (whole points) AUC 0.82 ( ) AUC 0.82 ( )

22 ROC curves Risk model Risk rule (whole points) AUC 0.82 ( ) AUC 0.82 ( )

23 Smoking and overweightpredictra in 55 seropositive arthralgia patients De Hair MJ, ARD 2012

24 Disability before treatment Neovius ARD 2011

25 Improveprediction: symptoms Qualitative study: Birmingham (UK) & Amsterdam (NL) Quantitative questionnaire: under construction Poster 2257 Tuesday, by RJ Stack

26 Whatis the newsonbiomarkers? Genetics Antibodies Cytokines Other biomarkers

27 Strategy: find persons at a genetic risk

28 Genetic risk score ROC curve for genetic risk score using 31 markers as predictor for RA phenotypes. Chibnik et al, PLoS One 2011

29 Addenvironmentalto geneticfactors in seropositive RA (Karlson et al AC&R 2013)

30 Whatis the newsonbiomarkers? Genetics Antibodies Cytokines Other biomarkers

31 ACPA epitope spreading, as well as increase in concentration, avidity and hypoglycosylation precedes RA Median number of peptides Number of ACPA n = Years before RA diagnosis LA van de Stadt, Arthritis Rheum 2011 M edian titre (AU/ml) CCP1 ceno1 cfib1 cfib3 cvim1 Antibody Titers n = Years before RA diagnosis

32 Protein modification: citrullination

33 Carbamylation

34 Shi PNAS 2011 Anti-CarPpredicts radiographic progression

35 Anti-CarP in arthralgia patients Shi A&R 2012

36 Anti-CarPpredicts arthritis independent of ACPA and RF HR 1.56 ( ) Shi A&R 2012

37 Role of autoantibodies in RA Some trigger ACPA Anti-CarP AHA

38 Whatis the newsonbiomarkers? Genetics Antibodies Cytokines Other biomarkers

39 Soluble levels of cytokines and chemokines in controls, pre-patients and RA patients Kokkonen et al Arthritis Rheum 2010

40 Cytokine score Sokolove PlosOne 2012

41 Whatis the newsonbiomarkers? Genetics Antibodies Cytokines Otherbiomarkers...

42 Gene Signatures associated with arthritis development Type I IFN gene activity OR: 21.0; P=0.003 Arthritis β IFNα/ IFNAR Type I IFN gene set (signature) Increased expression of IFN response genes (IRGs) IRG s B-cell abundance OR 0.38; P=0.002 No Arthritis B-cell receptor B-cell gene set (signature) Increased expression of B-cell related genes B-cell L.G. Van Baarsen et al., Arthritis Rheum. 62: (2010)

43 Validation study design PAXgene tube (Inclusion) Follow up Arthritis (n=44) Median time to conversion 8 months (IQR 5-13) Isolate RNA Arthralgia (n=115) 23 months (IQR12-30) Multiplex qpcr (Fluidigm) IFN score B-cell score No Arthritis (n=71)

44 Gene expression analysis: IFN high and B-cell low score HR 0.16 P=0.003 Independent of ACPA and RF HR 6.22 P=0.003 Independent of ACPA and RF Unpublished data

45 Intracellular signal protein η 20 arthralgia arthralgia 20 arthralgia arthritis 11/40 were14-3-3ηpositive(28%) 9/11 positivesdevelopedarthritis(sens. 82%) 18/29 negatives did not develop arthritis(spec. 62%) Poster 1389 Monday

46 A roleas biomarkerforimaging? WaitforLisa Mandl Gent Y, Arthritis Rheum 2012

47 Predictionrule2nd generation... Clinical characteristics ACPA/RF Antibodies: anti-carp IFN and B-cellscore Hyperlipidemia (14-3-3η)

48 More potentialfuturebiomarkers Symptom measurement Periodontitis assessment Microbiome analysis(mouth, gut, lung) Imaging(PET, MRI...) T/B-cell clonal assessment Epigenetics

49 Conclusions The at-riskphaseof RA is veryexciting Catching at-risk persons is quite difficult Progress is relatively slow Preventionof RA is stillfaraway

50 Wanneer is het RA? Polyartritis, voldoet aan ACR criteria Oligoartritis Artralgie Alleen RF of anti-ccp

51 Strategy for prediction/prevention of RA Population with risk factor (family history, symptoms, )

52 Strategy for prediction/prevention of RA Population with risk factor (family history, symptoms, ) Internet questionnaire?

53 Strategy for prediction/prevention of RA Population with risk factor (family history, symptoms, ) Test ACPA

54 Strategy for prediction/prevention of RA Population with risk factor (family history, symptoms, ) Test ACPA Finger prick postal test?

55 Strategy for prediction/prevention of RA Population with risk factor (family history, symptoms, ) Test ACPA Θ = low risk No action (or test other biomarkers)

56 Strategy for prediction/prevention of RA Population with risk factor (family history, symptoms, ) Test ACPA Θ = low risk No action (or test other biomarkers) = at risk Determine risk score (symptoms, biomarkers)

57 Strategy for prediction/prevention of RA Population with risk factor (family history, symptoms, ) Test ACPA Θ = low risk No action (or test other biomarkers) = at risk Determine risk score (symptoms, biomarkers) Low risk lifestyle

58 Strategy for prediction/prevention of RA Population with risk factor (family history, symptoms, ) Test ACPA Θ = low risk No action (or test other biomarkers) = at risk Determine risk score (symptoms, biomarkers) Low risk lifestyle High risk lifestyle + trial of preventive treatment

59 Epigenetic modifications Hormonal factors Environmental factors Smoking, dust Alcohol non-use Obesity Hyperlipidemia High birth weight Infections Lung Gingiva Gut? Genetic susceptibility HLA-DRB1 PTPN22 Conception Autoimmunity Arthralgia (ACPA, RF, anti-carp) + Subclinical inflammation acute phase reaction cytokines interferon activity Arthritis Tissue damage Loss of mobility Premature death Increase chance of success of immune suppression / tolerization Increase chance of finding persons at risk

60 Acknowledgements Mark Nielen Wouter Bos Lottevan de Stadt Margret de Koning Rob van de Stadt Gertjan Wolbink Dörte Hamann Theo Rispens Karim Raza Rebecca Stack Christian Mallen Ben Dijkmans Cor Verweij Connie Jimenez Conny van derlaken Lilian van Tuyl Jing Shi Leendert Trouw Rene Toes Paul Peter Tak Danielle Gerlag

61 Acute phase response increases subclinically prior to RA 3 CRP CRP (mg/l) 2 1 Patients Controls Years Onset RA Nielen et al, Arthritis Rheum 2004