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Microcrystal Arthritis:
From Gout To Osteoarthritis
Vilnius, Lithuania, 22.9.2017
Prof Alexander So
Service of Rheumatology
CHUV and UNIL, Lausanne, Switzerland
2
Happy anniversary
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Disclosures
• Consultant: Grunenthal, Menarini, SOBI
• Advisory boards: Grunenthal, SOBI, Pfizer
• Speaker: Grunenthal, Pfizer
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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
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Microcrystals identified in
synovial fluid
Acute gouty arthritis
Tophus
Renal stone
Chondrocalcinosis Osteoarthritis
Calcific periarthritis
Soft tissue calcification
Inflammation Cellular activation Apoptosis & cell death
What diseases present to a rheumatologist in Switzerland?
Dumusc A, unpublished data
Crystals form on the cartilage surface
10 Baker JF, Arthritis Rheum. 2010 Mar;62(3):895. doi: 10.1002/art.27301.
Do not forget the synovium
Fondation RMR et Service de Rhumatologie, Lausanne
BCP crystals in synovium
Crystal identification is vital to make the correct diagnosis
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)
OA Milwaukee shoulder syndrome Periarthritis/tendonitis
Hydroxyapatite (HA) Hexagonal-shaped 5 nm thickness; 40-200 nm length; 25 nm largeur
1.67:1
Octa-Calcium phosphate (OCP) 15 nm 1.33:1
Tri-calcium phosphate (TCP) 1.50:1
Calcium pyrophosphate dihydrate (CPPD)
Rod-or rhomboidal-shaped Weakly positively birefringent Triclinic & monoclinic 3:1
1-20 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
15-20 µm Ca oxalate-associated arthritis
Conventional Radiology
Richette P et al. Rheumatology (Oxford). 2009 Jul;48(7):711-5.
Imaging by Ultrasound (US) and DECT
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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, 499-504 Ottaviani S et al. Joint, Bone Spine 2012, 79, 441-445 McQueen F et al, Arthritis Res Ther. 2011;13(6):246
US characteristics of gout and CPPD
Zufferey P. Arthritis Res Ther. 2015 Jul 22;17:188. doi: 10.1186/s13075-015-0701-7.
ACR/EULAR criteria 2015
Neogi T, et al. Ann Rheum Dis 2015;74:1789–1798. doi:10.1136/annrheumdis-2015-208237
SCORE OF > 8 CLASSIFIES INDIVIDUAL AS HAVING GOUT
Pathophysiology of Crystal Deposition Diseases
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ASYMPTOMATIC ACUTE ARTHRITIS CHRONIC ARTHRITIS
Serum concentration > Solubility threshold
IL 1 is a key cytokine in crystal-induced 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
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A trigger (signal 2) is needed for acute inflammation
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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; 65:1381-1384. Ottaviani, , Arthritis Res Ther. 2013; 15:R123 Chen et al Semin Arthritis Rheum 2010; 40: 210-214
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, 2010. Schumacher R, Arthritis Care Res, 2012. 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, 2011
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IL-1 inhibition by anakinra in calcific periarthritis
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Zufferey P. A pilot study of IL-1 inhibition in acute calcific periarthritis of the shoulder. Ann Rheum Dis. 2013; 72:465-467
Chronic deposits
• Erosions
• Cartilage destruction
• Chronic inflammation
• Systemic effects of chronic low grade inflammation?
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Epidemiology of Gout
24 Kuo CF. Nat Rev Rheumatol. 2015 Nov;11(11):649-62. doi: 10.1038/nrrheum.2015.91.
Prevalence of gout and hyperuricemia on the increase
25 Kuo CF. Nat Rev Rheumatol. 2015 Nov;11(11):649-62. doi: 10.1038/nrrheum.2015.91.
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Production and export of uric acid
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What drives hyperuricemia?
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Manhattan Plot of Serum Urate
18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 19 21 20 22
Chromosome
replicated among 32,813 independent individuals
known novel network
Courtesy of Prof Anna Kottgen, University of Freiburg
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
Is hyperuricemia harmful?
• Metabolic syndrome
• Hypertension
• CV disease
• Worsening renal function
• Allopurinol treatment reduces BP1
• Excess risk of CHD mortality in gout (HR 1.5)2
• Allopurinol increases eGFR (3.2ml/min)3
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1 Agarwal V. J Clin Hypertens (Greenwich). 2013 Jun;15(6):435-42. 2 Clarson L. Eur J Prev Cardiol. 2013 Nov 26 3. Kanji T. BMC Nephrol. 2015 Apr 19;16:58.
Crystals and OA
• CPPD associated with OA and aging
• HA crystals found in rapid destructive OA (Milwaukee shoulder)
• UA levels associated with knee OA
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Cartilage mineralization correlates with OA severity
Fuerst, M. & Bertrand J., Arthritis Rheum. 2009
Is OA linked to crystal deposition?
• CPPD and HA crystals activate NLRP3 inflammasome to produce IL-1b1
• Animal model of OA linked to inflammasome2
• Anti-IL1 therapy tested in OA
34 1. Pazar B. J Immunol. 2011; 186:2495-2502 2. Jin C. PNAS 2011; 108:14867-14872.
BCP crystals induce mild synovial inflammation
35 Ea HK. PLoS One. 2013;8(2):e57352. doi: 10.1371/journal.pone.0057352.
BCP crystals induce OA like changes in cartilage with little inflammation
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SHAM Just after 2 months 1 month
Mic
ro C
T-
scan
4 months
Time after MNX Carbonate apatite (%)
Proteins (%) Polysaccharides (%) TRG (%)
2 months 50 37 11 2
4 months 32 30 35 3
b
400X
MNX a
Sa
fran
in-O
• Crystal deposits were found in 100% of operated mice (n=80)
• Mineralization preceeds cartilage degradation
Safranin-O loss IL-6
Sa
fra
nin
-O lo
ss
sc
ore
(A
.U)
IL-6 (A.U)
Safranin-O loss and IL-6 staining
colocalize and are positively correlated
NF NF
T T
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IL-6 induces BCP crystal formation in chondrocytes
• Alizarin
• FTIR
Chondrocytes ± IL-6 Alizarin red, FTIR
Nt IL-6
HA crystals induce proteoglycan loss and IL-6 expression which can be prevented by Tocilizumab
Safranin-O loss (A.U)
Safranin-O loss IL-6 expression
tcz: anti IL-6R
ckm: anti IL-1
IL6 and calcium crystal deposition are linked in exp OA
Calcification
inhibitors
or
IL-6
inhibitors
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
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Traitement de goutte
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Putting out the fire Eliminate risks and causes
Basis of Gout therapy
• Managing hyperuricemia – Dietary modification
– ULT
– Use of “prophylaxis therapy” to prevent gout flare during ULT
– Adherence to treatment
• Managing the acute attack of gout – Effective treatment of
inflammation
– Reduction of pain
– Avoiding iatrogenic complications
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Cas 1
• Crise de goutte avec tophus • Insuffisance cardiaque
sévère • Péricardite chronique • Diabète • Insuffisance rénale
chronique stade 4 • Acide urique 800umol • CRP 87
ULT: Les recommendations
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Barriers to effective treatment
• Treat to target
• Improving patient adherence
• Maintaining patient adherence
• Co-morbidities and drug interactions
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Michael Doherty
University of Nottingham, UK
Nurse-led care versus general practitioner care of people with gout: a UK
community-based randomised controlled trial
number 255 262
age (yrs), mean (SD) 62.0 (10.8) 63.7 (11.9) 0.086
men 89.8% 88.5% 0.636
white race 96.5% 97.3% 0.406
BMI (SD) 29.8 (5.4) 29.8 (4.8) 0.979
GFR, mean (SD) 71.5 (15.9) 70.2 (15.9) 0.359
age 1st attack, mean (SD) 50.4 (12.8) 51.0 (14.7) 0.599
disease duration, 11.6 (9.8) 12.7 (10.6) 0.249
attacks in last yr, mean (SD) 4.2 (5.1) 3.8 (4.6) 0.357
tophi (n) 13.7% (35) 8.8% (23) 0.077
ULT 40% 39% 0.875
allopurinol mean dose (SD) 225 (94) 227 (106) 0.889
SUA (µmol/l), mean (SD) 443.1 (100.5) 438.9 (98.2) 0.630
SUA<360 µmol/l 22.3% 21.5% 0.805
Results p value GP group nurse group baseline
results p value GP group nurse group year 2 outcomes
GP nurse
µmol/l
µmol/l
SUA 2Y
SUA baseline
mean SUA (SD) µmol/l 261.6 (85.4) 427.9 (108.5) <0.001
SUA<360 µmol/l 91.4% 26.3% <0.001
SUA<300 µmol/l 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 40.61 (16.61) 36.96 (14.77) <0.01
(physical functioning, role-physical, bodily pain, vitality all <0.05)
GIS gout concern overall 39.97 (26.49) 55.73 (26.91) <0.001
GIS unmet gout Rx need 22.75 (17.64) 36.10 (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
References
1. Oumoumi P. Imaging in Gout and Other Crystal-Related Arthropathies. Rheum Dis Clin North Am. 2016 Nov;42(4):621-644. doi: 10.1016/j.rdc.2016.07.005.
2. 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; 56:529-533.
4. Dumusc A, So A. Interleukin-1 as a therapeutic target in gout. Current opinion in rheumatology. 2015; 27:156-163.
5. Wüthrich H. Guidelines for the treatment of gout: a Swiss perspective. Swiss Med Wkly. 2016; 146:w14341.
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Ačiū
Thank you
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