Microcrystal Arthritis: From Gout To Osteoarthritis Vilnius, Lithuania,

Transcription

1 Microcrystal Arthritis: From Gout To Osteoarthritis Vilnius, Lithuania, Prof Alexander So Service of Rheumatology CHUV and UNIL, Lausanne, Switzerland

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3 Happy anniversary 3

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5 Disclosures Consultant: Grunenthal, Menarini, SOBI Advisory boards: Grunenthal, SOBI, Pfizer Speaker: Grunenthal, Pfizer 5

6 Outline Spectrum of microcrystal induced joint diseases Pathophysiology of crystal-induced disease Epidemiology of gout New observations on crystals and OA How can we treat gout better 6

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8 Microcrystals identified in synovial fluid Acute gouty arthritis Tophus Renal stone Chondrocalcinosis Osteoarthritis Calcific periarthritis Soft tissue calcification Inflammation Cellular activation Apoptosis & cell death

9 What diseases present to a rheumatologist in Switzerland? Dumusc A, unpublished data

10 Crystals form on the cartilage surface Baker JF, Arthritis Rheum Mar;62(3):895. doi: /art

11 Do not forget the synovium BCP crystals in synovium Fondation RMR et Service de Rhumatologie, Lausanne

12 Crystal identification is vital to make the correct diagnosis

13 Crystals Appearance Size Molar ratio Ca:P Conditions Basic calcium phosphate (BCP) Clumps & globules Amorphous-looking Appear as «shiny coins» when clumped Non-birefringent 1 nm (individual) 5-20 µm (clumps) Hydroxyapatite (HA) Hexagonal-shaped 5 nm thickness; nm length; 25 nm largeur 1.67:1 Octa-Calcium phosphate (OCP) 15 nm 1.33:1 OA Milwaukee shoulder syndrome Periarthritis/tendonitis Tri-calcium phosphate (TCP) 1.50:1 Calcium pyrophosphate dihydrate (CPPD) Rod-or rhomboidal-shaped Weakly positively birefringent Triclinic & monoclinic 3: µm 1:1 Pseudogout CPPD deposition disease OA Monosodium urate (MSU) Needle-shaped Frequently intracellular Strongly negatively birefringent 2-30 µm Acute/chronic gout OA?? Calcium oxalate (CO) Tetragonal, bypyramidal, octahedral or envelope shape µm Ca oxalate-associated arthritis

14 Richette P et al. Rheumatology (Oxford) Jul;48(7): Conventional Radiology

15 Imaging by Ultrasound (US) and DECT 15 US signs need to be used in combination US is a highly specific but not very sensitive tool US requires operator training DECT is not as sensitive as hoped for, but is highly specific Ottaviani S et al, Clin Exp Rheumatol 2012, 30, Ottaviani S et al. Joint, Bone Spine 2012, 79, McQueen F et al, Arthritis Res Ther. 2011;13(6):246

16 US characteristics of gout and CPPD Zufferey P. Arthritis Res Ther Jul 22;17:188. doi: /s

17 ACR/EULAR criteria 2015 SCORE OF > 8 CLASSIFIES INDIVIDUAL AS HAVING GOUT Neogi T, et al. Ann Rheum Dis 2015;74: doi: /annrheumdis

18 Pathophysiology of Crystal Deposition Diseases Serum concentration > Solubility threshold ASYMPTOMATIC ACUTE ARTHRITIS CHRONIC ARTHRITIS 18

19 IL 1 is a key cytokine in crystalinduced joint inflammation IL1 and IL1 are produced Inhibition of IL1 suppresses signs and symptoms of inflammation Crystals differ in their capacity to elicit IL1 release 19

20 A trigger (signal 2) is needed for acute inflammation 20

21 Summary of studies with IL1 inhibitors in gout Agent Study References Anakinra Open-label study in acute gout 10 patients Open-label study in 26 patients Open study 40 patients Open study in 10 patients So A et al,, Arthritis Res Ther, 2007 Ghosh P et al, Arthritis Care Res (Hoboken) 2013; 65: Ottaviani,, Arthritis Res Ther. 2013; 15:R123 Chen et al Semin Arthritis Rheum 2010; 40: Rilonacept RCT in 10 patients with chronic gouty arthritis RCT in prevention of gout flares on initiating allopurinol 241 patients RCT in acute gout, 225 patients Terkeltaub R et al, A&R, Schumacher R, Arthritis Care Res, Terkeltaub R, Arthritis Res Ther, 2013; 15:R25. Canakinumab RCT phase II dose finding study vs. triamcinolone acetate, 200 patients RCT of canakinumab vs. triamcinolone acetate in acute gout, 456 patients RCT of canakinumab vs. colchicine in prevention of acute flares on initiating allopurinol, 200 patients So A et al A&R, 2010 Schlesinger N et al A&R, 2012 Schlesinger N et al ARD,

22 IL-1 inhibition by anakinra in calcific periarthritis Zufferey P. A pilot study of IL-1 inhibition in acute calcific periarthritis of the shoulder. Ann Rheum Dis. 2013; 72:

23 Erosions Cartilage destruction Chronic inflammation Systemic effects of chronic low grade inflammation? Chronic deposits 23

24 Epidemiology of Gout Kuo CF. Nat Rev Rheumatol Nov;11(11): doi: /nrrheum

25 Prevalence of gout and hyperuricemia on the increase Kuo CF. Nat Rev Rheumatol Nov;11(11): doi: /nrrheum

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27 27 Production and export of uric acid

28 28 What drives hyperuricemia?

29 Manhattan Plot of Serum Urate known novel network Chromosome Courtesy of Prof Anna Kottgen, University of Freiburg replicated among 32,813 independent individuals

30 Genetics of gout Seven genome-wide significant loci ABCG2 is major locus in gout (1.14x SLC2A9) SLC2A9 is major locus in serum urate PDZK1 GCKR SLC17A1 SLC22A11/A12 PIK3R6 (phosphoinositide-3-kinase, regulatory subunit 6), implicated in camp-dependent tubule formation Courtesy of Prof Tony Merriman, Otago University, New Zealand

31 Is hyperuricemia harmful? Metabolic syndrome Hypertension CV disease Worsening renal function Allopurinol treatment reduces BP 1 Excess risk of CHD mortality in gout (HR 1.5) 2 Allopurinol increases egfr (3.2ml/min) 3 1 Agarwal V. J Clin Hypertens (Greenwich) Jun;15(6): Clarson L. Eur J Prev Cardiol Nov Kanji T. BMC Nephrol Apr 19;16:58. 31

32 CPPD associated with OA and aging HA crystals found in rapid destructive OA (Milwaukee shoulder) UA levels associated with knee OA Crystals and OA 32

33 Cartilage mineralization correlates with OA severity Fuerst, M. & Bertrand J., Arthritis Rheum. 2009

34 Is OA linked to crystal deposition? CPPD and HA crystals activate NLRP3 inflammasome to produce IL-1b 1 Animal model of OA linked to inflammasome 2 Anti-IL1 therapy tested in OA 1. Pazar B. J Immunol. 2011; 186: Jin C. PNAS 2011; 108:

35 BCP crystals induce mild synovial inflammation Ea HK. PLoS One. 2013;8(2):e doi: /journal.pone

36 BCP crystals induce OA like changes in cartilage with little inflammation 36

37 Safranin-O Micro CTscan a SHAM Just after 1 month MNX 2 months 4 months 400X Crystal deposits were found in 100% of operated mice (n=80) Mineralization preceeds cartilage degradation b Time after MNX Carbonate apatite (%) Proteins (%) Polysaccharides (%) TRG (%) 2 months months

38 Safranin-O loss score (A.U) Safranin-O loss and IL-6 staining colocalize and are positively correlated Safranin-O loss IL-6 NF T NF T IL-6 (A.U)

39 IL-6 induces BCP crystal formation in chondrocytes Chondrocytes ± IL-6 Alizarin red, FTIR Nt IL-6 Alizarin FTIR 39

40 HA crystals induce proteoglycan loss and IL-6 expression which can be prevented by Tocilizumab Safranin-O loss IL-6 expression Safranin-O loss (A.U) tcz: anti IL-6R ckm: anti IL-1

41 IL6 and calcium crystal deposition are linked in exp OA Calcification inhibitors or IL-6 inhibitors

42 How to improve gout patient care Patient and physician education Using old drugs correctly and safely New drugs are needed Targeting treatment to specific objectives and disease groups 42

43 Traitement de goutte Putting out the fire Eliminate risks and causes 43

44 Basis of Gout therapy Managing the acute attack of gout Effective treatment of inflammation Reduction of pain Avoiding iatrogenic complications 44 Managing hyperuricemia Dietary modification ULT Use of prophylaxis therapy to prevent gout flare during ULT Adherence to treatment

45 Cas 1 Crise de goutte avec tophus Insuffisance cardiaque sévère Péricardite chronique Diabète Insuffisance rénale chronique stade 4 Acide urique 800umol CRP 87

46 ULT: Les recommendations 46

47 Barriers to effective treatment Treat to target Improving patient adherence Maintaining patient adherence Co-morbidities and drug interactions 47

48 Nurse-led care versus general practitioner care of people with gout: a UK community-based randomised controlled trial Michael Doherty University of Nottingham, UK

49 baseline nurse group Results GP group p value number age (yrs), mean (SD) 62.0 (10.8) 63.7 (11.9) men 89.8% 88.5% white race 96.5% 97.3% BMI (SD) 29.8 (5.4) 29.8 (4.8) GFR, mean (SD) 71.5 (15.9) 70.2 (15.9) age 1 st attack, mean (SD) 50.4 (12.8) 51.0 (14.7) disease duration, 11.6 (9.8) 12.7 (10.6) attacks in last yr, mean (SD) 4.2 (5.1) 3.8 (4.6) tophi (n) 13.7% (35) 8.8% (23) ULT 40% 39% allopurinol mean dose (SD) 225 (94) 227 (106) SUA (µmol/l), mean (SD) (100.5) (98.2) SUA<360 µmol/l 22.3% 21.5% 0.805

50 year 2 outcomes µmol/l nurse group results GP group p value mean SUA (SD) µmol/l (85.4) (108.5) <0.001 SUA<360 µmol/l 91.4% 26.3% <0.001 SUA<300 µmol/l SUA 2Y 84.3% 14.5% <0.001 attacks in Y2, mean (SD) 0.77 (2.40) 2.04 (4.53) <0.001 >2 attacks in Y2, (n) 14.5% (37) 35.1% (92) <0.001 >4 attacks in Y2, % (n) 4.7% (12) 17.6% (46) <0.001 tophi (n) 3.5% (9) 9.5% (25) <0.01 SF-36 physical component (16.61) (14.77) <0.01 (physical functioning, role-physical, bodily pain, vitality all <0.05) GIS gout concern overall (26.49) (26.91) <0.001 GIS unmet gout Rx need (17.64) (20.61) <0.001 (gout meds side-effects, well-being during attack, concern during attack NS) GAQ overall last 4w (NRS) 2.53 (2.55) 3.09 (2.63) <0.05 GAQ pain severity 2.25 (2.38) 3.16 (2.87) <0.001 GP nurse µmol/l SUA

51 References 1. Oumoumi P. Imaging in Gout and Other Crystal-Related Arthropathies. Rheum Dis Clin North Am Nov;42(4): doi: /j.rdc So A and F Martinon. Inflammation in gout: mechanisms and therapeutic targets. Nature Rev Rheumatology 2017 (in press). 3. Abishek A. Long-term persistence and adherence on urate-lowering treatment can be maintained in primary care-5-year follow-up of a proof-of-concept study. Rheumatology (Oxford). 2017; 56: Dumusc A, So A. Interleukin-1 as a therapeutic target in gout. Current opinion in rheumatology. 2015; 27: Wüthrich H. Guidelines for the treatment of gout: a Swiss perspective. Swiss Med Wkly. 2016; 146:w

52 Ačiū Thank you 52