Microcrystal Arthritis:

From Gout To Osteoarthritis

Vilnius, Lithuania, 22.9.2017

Prof Alexander So

Service of Rheumatology

CHUV and UNIL, Lausanne, Switzerland

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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Dumusc A, unpublished data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

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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