[PDF] - 4/3/18 Disclosures None Resolving Controversies in Gout PDF Document

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Resolving Controversies in Gout Management

Andrew J. Gross, MD Rheumatology Clinic Chief Clinical Professor University of California, San Francisco

Disclosures

None

Teaching Objectives

Understand management of acute gout
Understand the management of chronic gout and the

approaches to uric acid lowering therapy.

Acute Gout Management

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Acute Gout - Case 1

A 75 year old man with a history of diabetes, CKD, and gout is admitted with 1 day of acute swelling and pain in the right ankle. His temp is 99.4. The ankle is warm and swollen. The other joints seem unremarkable. Arthrocentesis in the ED demonstrates negatively birefringent crystals. Cell count 85,000 WBC – 91% PMNs. What do you do next:

A. Hold allopurinol & wait for cultures
B. Inject corticosteroids into the joint
C. Prescribe a prednisone taper
D. Prescribe naproxen 500 mg BID
E. Prescribe IV antibiotics & wait for

the results of the gram stain & Cx

75 y.o. man with DM, CKD with 1 day acutely swollen & warm ankle with low-grade fever. Synovial fluid shows negatively birefringent crystals & WBC 85,000. What do you do next:

A. Hold allopurinol & wait

for GS & Cx

B. Inject corticosteroid
C. Prednisone taper
D. Naproxen 500 mg BID
E. IV antibiotics and wait

for GS & Cx

5

Acute Gout - Case 1

A 75 year old man with a history of diabetes, CKD, and gout is admitted with 1 day of acute swelling and pain in the right ankle. His temp is 99.4. The ankle is warm and swollen. The other joints seem unremarkable. Arthrocentesis in the ED demonstrates negatively birefringent crystals. Cell count 85,000 WBC – 91% PMNs. What do you do next:

A. Hold allopurinol & wait for cultures
B. Inject corticosteroids into the joint
C. Prescribe a prednisone taper
D. Prescribe naproxen 500 mg BID
E. Prescribe IV antibiotics and wait for

the results of the gram stain & Cx

Differential Diagnosis of monoarticular arthritis

Septic Arthritis

– Gram Positive cocci – Gram Negative Rods – Lyme disease – Tb/Fungal

Crystal Arthritis

– Gout – Pseudogout

Spondyloarthritis (e.g.

Reactive Arthritis)

Vasculitis
Palindromic Rheumatism
Trauma
Exacerbation of

Osteoarthritis

1-5% of patients with crystal arthritis will also have septic arthritis of the same joint

Papanicolas et al, J Rheumatol 2012; Shah K, et al, J Emerg Med 2007

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What can help us feel more confident this is a gout attack and not infection without waiting for the cultures?

Acute Gouty Arthritis

Provocation: trauma, ethanol,

exercise, new medication

First Attack:

– fourth to sixth decade of life – 90% Monoarticular – 50% Podagra

Sites:

– 1st MTP – Instep, mid-foot, ankle, knee – wrist, fingers, elbow

http://images.rheumatology.org/image_dir/album75676/md_99-14-0009.tif.jpg

Septic Arthritis most commonly affects large joints

The Value of a Careful Joint Exam

http://www.eorthopod.com/public/patient_education/6588/gout.html

Tip: In a patient with a history of many attacks of gout, attacks tend to be

ligoarticular or polyarticular. This

can be appreciated by doing a very careful joint examination.

Acute Gout - Case 2

A 53 year old man with HTN, nephrolithiasis, and a history of “crystal proven gout” comes to see you for acute foot pain. His first attack of gout came in his 1st toe about 2 years ago with a sudden onset of intense pain that gradually improved over 2 weeks. Since then he has had 2 more attacks in both feet. Negatively birefringent crystals were seen in joint fluid aspirated from his ankle. The most recent attack started 3 days ago in his 1st toe and instep. On examination there is marked swelling, erythema and tenderness

ver the 1st MTP bursa as well as the 1st

metatarsal-tarsal joint.

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4/3/18 4 Test Your Knowledge…

All of the following are reasonable treatments for acute gout EXCEPT:

a) NSAIDS (naproxen 500mg 2x/d, indomethacin 50mg 3x/d) b) Prednisone 20-60 mg/d, tapered over 6-18 days c) Intra-muscular corticosteroid injection. (Triamcinolone 60- 80 mg IM; may need to repeat in a couple of days) d) Intra-articular steroid injection (Triamcinolone 20-40 mg) e) Colchicine 0.6 mg every hour for 6 doses

All of the following are reasonable treatments for acute gout EXCEPT:

A. NSAIDS
B. Prednisone Taper
C. IM Triamcinolone
D. Intra-Articular

Triamcinolone

E. Colchicine every hour

5

Test Your Knowledge…

All of the following are reasonable treatments for acute gout EXCEPT:

a) NSAIDS (naproxen 500mg 2x/d, indomethacin 50mg 3x/d) b) Prednisone 20-60 mg/d, tapered over 6-18 days c) Intra-muscular corticosteroid injection. (Triamcinolone 60- 80 mg IM; may need to repeat in a couple of days) d) Intra-articular steroid injection (Triamcinolone 20-40 mg) e) Colchicine 0.6 mg every hour 1.2 mg then 0.6 mg 1 hour

later. (Do not repeat for 2 weeks if patient has CKD.)

Update: Low dose Colchicine is effective for acute gout

Terkeltaub RA, et al, Arthritis Rheum 2010, PMID 20131255 “high-dose” colchicine (1.2 mg followed by 0.6 mg every hour for 6 hours [4.8 mg total]) “low-dose” colchicine (1.2 mg followed by 0.6 mg in 1 hour [1.8 mg total])

Diarrhea

26%, 0% 77%, 19%

% of patients improved % improvement any, severe

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Efficacy of NSAIDs & Corticosteroids for Acute Gout

NSAIDS (naproxen 500mg BID, indocin 50mg TID, diclofenac 50 mg BID)
Prednisone: 60mg qd, taper over 6-18 days

Janssens H, et al, Lancet 2008, PMID 18514729 also see Rainer TH, et al, Ann Intern Med 2016, PMID 26903390

Prednisone Naproxen

Treatment of Acute Gout

NSAIDs are problematic in patients with CKD

Withdrawal of NSAIDs for 1 year (along with control of hyperuricemia) resulted in improved renal function in patients.

Perez-Ruiz F, et al, Nephron 2000, PMID 11096285

Henry D, et al, Br J Pharmacol 1997,

NSAIDs use was associated with increased risk of CKD in patients with hyperuricemia or gout (matched case-control study)

[Risk of CKD]

Update: Targeting Inflammatory Pathways to treat acute gout

Burns CM, Wortmann RL, Lancet, 2011, PMID 20719377

Mechanisms

f

Inflammation in Gout

Update: Targeting Inflammatory Pathways to treat acute gout

All patients received anakinra (IL-1 receptor antagonist)
Treated with 100 mg SQ injection daily for 3 days ($50-100/injection)
All 10 patients with acute gout responded rapidly to anakinra.
9/10 had complete resolution of gout symptoms in 3 days
No adverse effects were observed.
Similar Results reported by Chen K et al, Semin Arthritis Rheum 2010
ASGARD Study in process comparing anakinra vs. solumedrol in CKD

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Chronic Gout Management Chronic Gout - Case 3

The same 53 year old man with HTN, nephrolithiasis and gout returns 9 months later complaining of another flare of joint pain in his feet (now 4 total in 3 years). His medications include ASA, HCTZ, lisinopril, and ibuprofen for the joint

pain. He asks what can be done to prevent future attacks.

Choose the most correct answer: A. Modify his diet to avoid foods with moderate-high purine content B. Stop the thiazide C. Stop the ACE inhibitor D. Treat with probenecid E. Treat with colchicine

53 y.o. man with HTN and nephrolithiasis with 4 gout attacks over 3 years asks what can be done to prevent future attacks. Choose most correct answer:

A. Avoid moderate-high

purine foods

B. Stop thiazide
C. Stop ACE inhibitor
D. Treat with probenecid
E. Treat with colchicine

5

Case 3 (continued)

The same 53 year old man with HTN and nephrolithiasis returns 9 months later complaining of another flare of joint pain in his feet (now 4 total in 3 years). His medications include ASA, HCTZ, lisinopril, and ibuprofen for the joint

pain. He asks what can be done to prevent future attacks.

Choose the most correct answer: A. Modify diet to avoid foods with mod-high purine content B. Stop the thiazide C. Stop the ACE inhibitor D. Treat with probenecid E. Treat with colchicine

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4/3/18 7 Uric Acid homeostasis

Treatment Approaches:

Reduce Intake
Reduce Production
(Increase Metabolism)
Increase Excretion

Neogi T, N Engl J Med, 2011, PMID 21288096

Non-Pharmacologic Uric Acid Lowering Therapy

Treatment Approaches:

Reduce Intake
Reduce Production
(Increase Metabolism)
Increase Excretion

Update: Not all high purine foods contribute to development of gout

Adapted from Choi HK, et al, New Engl J Med 2004, PMID 15014182

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 Total Meat Seafood Purine-rich Vegetables Total Dairy

Relative Risk of Developing Gout

Men in the top quintile of intake compared with those in the lowest quintile (multivariate analysis) Higher risk Lower risk

Diet and Risk of Gout in Men

Treating Gout: Diet & Meds

Foods Moderately to Very High in Purines

Hearts, sweetbreads, liver,

Kidney, Herring, smelt, sardines, mussels, anchovies, Yeast

Grouse, Turkey, Partridge,

Goose, Pheasant, Mutton, Veal, Bacon

Salmon, Trout, Haddock,

Scallops

Medications that inhibit uric acid secretion

Thiazide diuretics
Aspirin (< 1 gm/d)

Johns Hopkins: Diet and Gout

http://www.johnshopkinshealthalerts.com/reports/arthritis/460-1.html

Beverages associated with hyperuricemia

Beer
High fructose drinks

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Reasons to Start Uric Acid Lowering Therapy (ULT):

All of the following are indications for starting Uric Acid Lowering Therapy in patients with an established diagnosis of gouty arthritis EXCEPT:

a. Tophaceous Gout
b. Recurrent attacks of gout (≥2 attacks/year)
c. History of erosions on x-rays characteristic of gout
d. Serum urate ≥8.0
e. Presence of CKD class II or greater

All of the following are indications for starting Uric Acid Lowering Therapy in patients with an established diagnosis of gouty arthritis EXCEPT:

a. Tophaceous gout
b. ≥2 gout attacks/yr
c. Erosions on x-rays
d. Serum urate ≥8.0
e. CKD class ≥ II

5

Reasons to Start Uric Acid Lowering Therapy (ULT):

All of the following are indications for starting Uric Acid Lowering Therapy in patients with an established diagnosis of gouty arthritis EXCEPT:

a. Tophaceous Gout
b. Recurrent attacks of gout (≥2 attacks/year)
c. History of erosions on x-rays characteristic of gout
d. Serum urate ≥8.0
e. Presence of CKD class II or greater

Improved Outcomes in Gout Patients who achieve Uric Acid Reductions to Levels ≤6.0 mg/dl

Reduced frequency of attacks

(Li-Yu J et al. J Rheumatol 28:577-580,2001; Shoji A et al. Arthritis Rheum 51: 321-325, 2004; Becker MA et al. N Engl J Med 353: 2540-2461, 2005)

Reduced tophus size

(Perez-Ruiz F et al. J Clin Rheumatol 5:49-55, 1999; Becker MA et al N Engl J Med 353: 2540-2461, 2005)

Deplete crystal stores in synovial fluid

(Li-Yu J et al. J Rheumatol 28:577-580,2001)

Improved renal function in gout patients from less NSAID use

(Perez-Ruiz F et al. Nephron 856: 287-291, 2000)

Slows progression of existing renal disease

(Siu Y-P et al. Am J Kidney Dis 47:51-59, 2006) Perez-Ruiz F and Liote F. Lowering serum uric acid levels: what is the optimal target for improving clinical outcomes in gout? Arthritis Rheum 57:1324-1328, 2007

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High serum urate level increases the risk of recurrent gout flares

Observational study of 267 patients with 1st episode of gout Shoji A, et al, Arthritis Rheum 2004, PMID 15188314

Average serum urate during the whole investigation period (mg/dL) Incidence of recurrent gouty attack >1 year after each patient’s first visit (%)

Uric Acid Reduction: The Controversy

Indications for Uric Acid Lowering Therapy (ULT):

Presence of Tophus or Tophi
Frequent attacks of acute gout (≥2 per year)
CKD stage 2 or worse C

A A

Continue to regularly monitor serum urate

Uric Acid Reduction: The Controversy

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Uric Acid Reduction: The Controversy

“Evidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (“treat to target”) outweigh the harms associated with repeated monitoring and medication escalation.” ACP’s “5th recommendation”: “An alternative strategy [to “treat to target”] bases the intensity of urate–lowering treatment on the goal of avoiding recurrent gout attacks (“treat to avoid symptoms”), with no monitoring of urate levels.

Chronic Management in patients with recurrent attacks of gout

Uric Acid Lowering Therapy to Prevent & Treat Tophi!

Higher urate levels are associated with gout flares

229 gout patients treated for > 5-yrs with ULT (with sUA < 6 mg/dL repeatedly)

Perez-Ruiz F, at al, Arthritis Rheum, 2011 Gout flare rate by serum urate level after discontinuation

f ULT

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Personal Practice

Shared Decision-Making Model
Long term ULT decisions

– years, but not necessarily lifelong – Prophylaxis (or abortive Rx) during titration (3-6 months)

Serum Urate Target (monitor sUA and adherence)

< 5 mg/dL for gout patients with aggressive disease < 6 mg/dL for gout patients with active disease (flares or tophi) < 7 mg/dL for gout patients that are in remission (on or off Rx)

Pharmacologic Uric Acid Lowering Therapy

Treatment Approaches:

Reduce Intake
Reduce Production
(Increase Metabolism)
Increase Excretion

Uric Acid Lowering Therapy: Uricosurics

Modified from Burns CM, Wortmann RL, Lancet, 2011, PMID 20719377

Lesinurad

Urine Blood

Uric Acid Lowering Therapy: Uricosurics

Uricosurics

Probenecid, 500-1000 mg 2x/d ($45/mo)
Lesinurad, 200 mg 1x/d ($371/mo)

(Approved in combination with a xanthine oxidase inhibitor)

Indication:

– Normal kidney function – Relatively low uric acid secretion (“underexcretors”) 24 hr urine collection: <700 mg/d of uric acid

Contraindications

– Chronic Kidney Disease – Nephrolithiasis

The Medical Letter on Drugs and Therapeutics, 2017 2012 American College of Rheumatology guidelines for management of gout, Khanna D, et al, Arthritis Rheum 2012, PMID 23024028

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Pharmacologic Uric Acid Lowering Therapy

Treatment Approaches:

Reduce Intake
Reduce Production
(Increase Metabolism)
Increase Excretion

Xanthine Oxidase Inhibitors: Allopurinol - starting dose 100 mg/d (or less). Gradually titrate up the dose every 2-5 weeks to chosen target. Dose can be raised above 300 mg/d

Allopurinol warnings

2% develop a maculopapular eruption
0.1% develop hypersensitivity reaction (DRESS or SJS)
Cutaneous Rash 92%
Fever 87%
Renal Dysfunction 85%
Eosinophilia 73%
Hepatitis 68%
Leukocytosis 39%
Death 21%

Stamp LK, et al, Nat Rev Rheumatol 2016 Hande et al, Am J Med 76:47,1984, Kim SC, et al, Arthritis Care Res, 2013

Rash onset:

median 30 days after starting allopurinol
90% with 180 days

Update: Mitigating the Risk of Allopurinol Hypersensitivity

HLA-B*5801 increases the risk of SJS/TEN up to 580 fold
HLA-B*5801 has been found to vary by race/ethnicity

and geographic region. In the US: – Caucasians & Hispanics <1% – African Americans 3.8% – Asians 7.4%

Testing for HLA-B*5801 prior to allopurinol initiation in

the US is cost-effective among African Americans and Asians, but not among Caucasians or Hispanics.

Jutkowitz E, et al, Sem Arth Rheum 2017

So what is the concern about allopurinol in patients with CKD ?

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Recommended maintenance dose of allopurinol based on the GFR

GFR (ml/min) Dose (mg/d) 100 300 80 250 60 200 40 150 20 100 10 50

Adapted from Kelley, Textbook of Rheumatology, 1997

Renally-Dosed Allopurinol : Safety and Efficacy

Adherence to published allopurinol dosing guidelines led to suboptimal control of hyperuricemia and did not prevent hypersensitivity reactions. Dalbeth N et al. J Rheumatol, 2006 Severe hypersensitivity reactions are not dose dependent. Puig JG

et al. J. Rheumatol, 1989

No increase in adverse reactions to allopurinol in patients receiving higher than recommended creatinine clearance- adjusted doses. Vazquez-Mellado J et al. Ann Rheum Dis, 2001 Starting allopurinol at a dose of 1.5 mg per unit of estimated GFR is associated with a reduced risk of allopurinol hypersensitivity.

Stamp LK, et al, Arthritis Rheum 2012

What about febuxustat?

Update: Why not just prescribe febuxostat?

19 230 59 706 162 1944 500 1000 1500 2000 1-month 12-month

US Dollars Allopurinol Probenecid Febuxostat

Courtesy of Gabriela Schmajuk UCSF

Costs of urate-lowering therapies

Use of febuxostat as 2nd line therapy after allopurinol is cost effective

Beard SM, et al, Eur J Health Econ 2014

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Tip: Treat with Colchicine when initiating uric acid reducing agent

>60% of patients will have a gout flare after starting

treatment with febuxostat or allopurinol. (Becker MA ,et al,

NEJM 2005)

Colchicine 0.6mg/d prophylactic therapy helps prevent

attacks

Avoid continuing colchicine for more than 6 months
Colchicine toxicity: (especially in renal insufficiency)

– Myopathy – Neuropathy – Bone marrow suppression – GI upset

2012 American College of Rheumatology guidelines for management of gout Khanna D, et al, Arthritis Rheum 2012, PMID 23024028

“Treatment Failure Gout”

In the majority of patients with gout, there is inadequate

control of hyperuricemia or gout symptoms

Usually this is due to:

– Inadequate management by the physician – Poor compliance by the patient with medical therapy

UK community-based RCT : Nurse-led care vs. general practitioner care of gout

Methods: 517 participants with acute gout randomized to

67

Nurse-led (n=255) GP (n = 262) Age (years)

62 64

Male (%)

90% 89%

Mean disease duration (yrs)

11.6 12.7

Attacks per year (prior year)

4.2 3.8

Tophi

13.7% 8.8%

Mean sUA umol/L

443 439

GFR

71.5 70.2

ULT use

40% 39%

Withdrew during study

8.6% 20.6% nurse-led, trained about gout and its management according to recommended best practice [EULAR and BSR guidelines] continuing GP care

UK-RN study: ULT use

39% 54% 40% 97% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% On ULT GP0 GP2 | RN0 RN2 439 240 443 470 100 200 300 400 500 Mean Allopurinol dose (mg/dy) GP0 GP2 | RN0 RN2

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UK-RN study: Serum urate outcomes

29% 95% 0% 20% 40% 60% 80% 100% sUA < 6 mg/dL GP0 GP2 | RN0 RN2 7.4 7.0 7.4 4.2 2 4 6 8 10 Mean sUA mg/dL GP0 GP2 | RN0 RN2 16% 88% 0% 20% 40% 60% 80% 100% sUA < 5 mg/dL GP0 GP2 | RN0 RN2

UK-RN study: Clinical Outcomes

8.8% 9.6% 13.7% 2.6% 0% 5% 10% 15% 20% Tophi GP0 GP2 | RN0 RN2 3.8 2.0 4.2 0.8 1 2 3 4 5 Number of Gout attacks/year GP0 GP2 | RN0 RN2

Summary

In patients presenting with monoarticular

arthritis, infection is the primary concern

Recognize signs of acute gout
Gout can cause severe arthritis but can easily be

managed (although often it is not).

Chronic Gout can be managed with diet,

uricosurics and/or xanthine oxidase inhibitors

Shared decision making with patients can help

address the controversy of “treat to target” versus “treat to symptoms”

Thanks!

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Additional Reading

2012 American College of Rheumatology guidelines

for management of gout. Part 1 & 2, Arthritis Care & Res 2012, PMID 23024028 & 23024029

Does this adult patient have septic arthritis?