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Home , Gout, Osteoarthritis, Pegloticase

and : What Works and What Doesn’t?

Ahmad M Salah, DO , Franciscan Health Alliance, Midwestern University ACOI 2019 Annual Convention Disclosures None Osteoarthritis and Gout – Epidemiology Highlights, Clinical Relevance

Brief Overview of Osteoarthritis and Gout Pathophysiology

Review of Current Treatment Modalities and Evidence-Based Recommendations

What is on the Horizon?

Emphasis on Patient-centered Care and Education for Osteoarthritis and Gout

Objectives Osteoarthritis OA affects ~30 million Americans (~35% of Americans ≥65yo)1

A leading cause of among older adults in the US, top 10 causes of disability worldwide1

5th most expensive condition treated in US hospitals @ $40 billion1

Annual direct per-patient cost $1500 - $20,0002

~25% of OA patients have limitations in activities of daily living1

Increased CVD risk, depression, suicidal ideation2

Osteoarthritis Highlights Worse with activity Morning stiffness < 30 minutes “Gelling” Bony hypertrophy Limited mobility

Clinical Features Osteoarthritis Distribution

Heberden’s and Bouchard’s nodes signify primary nodal OA

Google Image Search Pathophysiology Osteoarthritis

Nat Rev Rheumatol. 2015 Apr;11(4):206-12. Trauma/Microfracture

Chondrocyte transformation to inflammatory catabolic phenotype

Articular Degradation of ECM (metalloproteinases) Activity/Cytokine Release

Subchondral exposure

Journal of Pharmacy Research 7 (2013) 132-138 Exposed to Suboptimal Rapid attempt Hypomineralized + shock to refortify bone growth factors absorption

Subchondral Bone Ther Adv Musculoskel Dis (2013) 5(2) 77–94 Osteoarthritis not arthrosis

Ther Adv Musculoskel Dis (2013) 5(2) 77–94 Kapoor, Mohit et al. “Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.” Nature Reviews Rheumatology 7 (2011): 33-42 Nature Medicine Volume 19, pages 667–669 (2013) What Works for Osteoarthritis?

Google Image Search • Nonpharmacologic • Patient Education, Low-impact , PT, Aqua PT, Treatment for • Drugs (Tylenol, NSAIDs, , ) • Supplements (+/- + chondroitin OA sulfate, ) • Injections (CSI, HAI) • Clinical Trials (DMOADs) Education on , treatment and recommendations → improved and function long term

Major obstacle is quality of education given by healthcare providers

Multidisciplinary approach is generally beneficial for patient outcomes (physician, nurse, pharmacist, physical therapist)

Patient Education American Academy of Family Physicians

Am Fam Physician. 2012 Jan 1;85(1):49-56 American College of Rheumatology

Arthritis Care & Research Vol. 64, No. 4, April 2012, pp 465–474 Journal of the American Society 49:808-823, 2001 American College of Rheumatology Glucosamine/

• Theory: Glucosamine is component of • In vitro studies: glucosamine increases synthesis of by chondrocytes • Conflicting evidence • Relief should be noted in 2-3 months, otherwise discontinue

Vogelgesang, Scott. “Osteoarthritis.” Rheumatology Secrets, Elsevier Health Sciences, 2014, pp. 389–390. Intra-Articular Tx

Corticosteroids:

• Q3-4 months • Short-term efficacy demonstrated

Viscosupplementation

• Q6-12 months • Shows some superior benefit for long-term efficacy

ACR 2012 Guidelines for OA Treatment Action Plan

It’s important to Patients oftentimes establish an action just want to know plan with your their options and patient how to use them Google Image Search : anti-NGF monoclonal Ab – SC/IV

Tissue Gene-C: TGF-Beta 1 Transduced Chondrocytes – IA

SM04690: WNT pathway inhibitor – IA

DMOADs – Phase III Trials Tanezumab • Anti-Nerve Growth Factor monoclonal antibody – IV/SC Q8 weeks • Improved pain, stiffness, and limitations of physical function • SE: abnormal peripheral sensation, rapid progression of OA with NSAID use

J Anaesthesiol Clin Pharmacol. 2018 Jan-Mar; 34(1): 111–116 J Pain Res. 2018; 11: 151–164. J Pain Res. 2018; 11: 151–164. J Pain Res. 2018; 11: 151–164. IL-1β elevates NGF TGF-β1 induces Mechanical expression in the NGF expression in loading stimulates synovium and the synovium and NGF expression by chondrocytes chondrocytes chondrocytes

Role of Nerve Growth Factor (NGF) Tissue Gene-C (Invossa)

Osteoarthritis Cartilage. 2015 Dec;23(12):2109-2118 https://www.tissuegene.com/en_US/technology/invossa • High quantities of TGF-β1 in articular cartilage TGF-β1 • Overexpression of TGF-β1 → chondrogenesis and growth of articular chondrocytes SM04690

• WNT pathway inhibitor – IA • Dual MOA: anti-inflammatory and reduces cartilage degradation • Clinically significant improvement in joint space width by x-ray Gout ~2% in men > 30yo, Prevalence increasing women > 50yo worldwide ~9% in men > 80yo

Most prevalent inflammatory in men > 40yo Gout Positive Family History in 25% Highlights

Risk Factors: diet, , , HTN, , CKD, ARBs, β-blockers

Protective: low-fat dairy, , , CCB,

Rheum Dis Clin North Am. 2014 May ; 40(2): 155–175. G. Ragab et al. / Journal of Advanced Research 8 (2017) 495–511 Clinical Features Gout

Monoarticular Abrupt, Rapid Night or Early (85%) (hours) morning

+/- Low-grade Articular and Acral Extra-articular distribution Google Image Search • Urate underexcretion (90%) • Impaired renal urate transport Gout • Hyperparathyroidism, hypothyroidism • Metabolic and respiratory Pathophysiology • Drugs (Cyclosporine – – Nicotinic acid – – Lasix – Ethambutol – (<325mg) – Pyrazinamide Gout – Pathophysiology Basics

Uric acid is the end product of degradation

The human species lacks uricase – which oxidizes to more soluble

Interestingly, we have the gene for uricase but it is inactive

Hypothesized to be an evolutionary development as uric acid has potent and free scavenger functionality

Janson, Robert W. “Gout.” Rheumatology Secrets, by Sterling G. West, Elsevier, 2015, pp. 337–345. Underexcretion Pathway OAT1 OAT3

The genetics of and gout - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/The-uric-acid-transportasomeUrate-transporters-in- renal-proximal-tubules-are-involved-in_fig2_230791101 What Works for Gout?

https://www.arthritis.org/about- arthritis/types/gout/articles/best-and-worst-gout-foods-12.php Adherence to gout Studies show 50-80% of management is very low patients stop taking ULT at compared to other chronic about 12 months

Gout education increases Knowledge about gout and its compliance dramatically treatment is lacking, both in (adherence at 1 year ↑ 40-70%, patients and HCPs 85% adherence at 5 years)

Patient Education Systematic review of RCTs evaluated interventions that improve adherence

Education on pathogenesis, co-morbidities and management of gout → increased adherence

Patient Education cont… Hyperuricemia is primarily genetically driven – patient should not be ashamed or blame themselves

Gout requires long-term treatment → goal is to reduce sUA → eliminate substrate for gout attacks

Lowering sUA initially may to gout flares → goal is to eliminate crystal burden → no more attacks!

NSAIDs, , treat acute but do not treat gout/sUA

Treatment is important → increased frequency of flares, affected → permanent/deforming joint damage

Patient Education Talking Points Rheumatology 2018;57:i51-i58 Rheumatology 2018;57:i51-i58 Rheumatology 2018;57:i51-i58 Current Rheumatology Reports (2018) 20:12 Ther Clin Risk Manag. 2018; 14: 793–802. Ther Clin Risk Manag. 2018; 14: 793–802. Rheumatol Ther. 2019 Jun; 6(2): 179–193. Rheumatol Ther. 2019 Jun; 6(2): 179–193. Gout – Management

Dietary Do not generally treat asymptomatic • Avoid purine-rich foods hyperuricemia • Meats (esp organ meats – liver, , etc.) • only ~1/10 have gout • (esp shellfish, sardines/anchovies) • Uric acid >10mg/dL → 50% have gout • Avoid excess (sodas, fruit juices) • Some suggest treating hyperuricemia to reduce • Vitamin C, reduced-fat dairy, tart cherries – reduce risk of nephrolithiasis but no consensus gout risk • Purine-rich vegetables (rich green leafy i.e. spinach) not associated with gout risk

Rheum Dis Clin North Am. 2014 May ; 40(2): 155–175. G. Ragab et al. / Journal of Advanced Research 8 (2017) 495–511 Acute – 1.2mg → 1 hr → 0.6mg

Prophylactic – 0.6mg daily

Colchicine

Probenecid • Inhibits proximal tubule urate reabsorption • Avoid in CKD, nephrolithiasis, elderly • Not commonly used as it is generally less effective and more limitations

Arthritis Research & Therapy December 2016, 18:214, Patient Related Outcome Measures 2018:9 231–238

Arthritis Rheumatol. 2016 Aug; 68(8): 1793–1796 Inhibits function of (URAT1, OAT4) ≠ reabsorption of uric acid in the kidney Lesinurad Approved for combination therapy with an XOI, not monotherapy

Patient Related Outcome Measures 2018:9 231–238 Arthritis Rheumatol. 2016 Aug; 68(8): 1793–1796

• Allopurinol Hypersensitivity Syndrome (0.1%- • 40mg – 80mg (can use higher doses) 0.4%) • More expensive than allopurinol • More common in patients who had • Safe in patients who had AHS maculopapular rash 2/2 allopurinol (5-10%) • Hepatic clearance • Caution in patients with CKD and/or on diuretics • Clinical: rash, fever, eosinophilia, hepatic necrosis, leukocytosis, worsening renal function • Tx: high dose steroids and dialysis • Start at 50mg with slow up titration in higher risk patients

Xanthine Oxidase Inhibitors

Pegloticase

Pegylated Recombinant Uricase

• Uric Acid → Allantoin • Pegylated: reduces immunogenicity (compared to ) • 8mg Q2weeks • Check uric acid before each infusion to ensure appropriate uric acid lowering – if levels >6.0 → concern for Ab and loss of efficacy, increased risk of anaphylaxis • Don’t use ULT concurrently as can mask uric acid increase when Ab formation occurs

Rheumatol Ther (2019) 6:179–193

Dual MOA without affecting XO

• Inhibits IL-1β expression (anti-inflammatory) • Blocks URAT1, OAT4, OAT10 transporters () No established superiority to XOI or anti-inflammatories, but single-drug regimen could improve adherence

Combination therapy with XOI is safe and effective

Arhalofenate Dual Mechanism Thank You